Positron Emission Tomography (PET)

Number: 0071

Policy

Cardiac Indications

Aetna considers positron emission tomography (PET) medically necessary for the following cardiac indications:
1. Evaluation of Coronary Artery Disease
  
  PET scans using rubidium-82 (Rb-82) or N-13 ammonia done at rest or with pharmacological stress are considered medically necessary for non-invasive imaging of the perfusion of the heart for the diagnosis and management of members with known or suspected coronary artery disease, provided such scans meet either one of the two following criteria:
  1. The PET scan is used in place of, but not in addition to, a single photon emission computed tomography (SPECT), in persons with conditions that may cause attenuation problems with SPECT (obesity (BMI greater than 40), large breasts, breast implants, mastectomy, chest wall deformity, pleural or pericardial effusion); or
  2. The PET scan is used following an inconclusive SPECT scan (i.e., the results of the SPECT are equivocal, technically uninterpretable, or discordant with a member's other clinical data); or
  3. For use in assessment of coronary artery disease after cardiac transplant.
  In these cases, the PET scan must have been considered necessary in order to determine what medical or surgical intervention is required to treat the member.
2. Assessment of Myocardial Viability
  
  Fluorodeoxy-D-glucose (FDG)-PET scans are considered medically necessary for the determination of myocardial viability prior to re-vascularization, either as a primary or initial diagnostic study or following an inconclusive SPECT. The greater specificity of PET makes a SPECT following an inconclusive PET not medically necessary.
  
  The identification of members with partial loss of heart muscle movement or hibernating myocardium is important in selecting candidates with compromised ventricular function to determine appropriateness for re-vascularization. Diagnostic tests such as FDG-PET distinguish between dysfunctional but viable myocardial tissue and scar tissue in order to affect the management decisions in members with ischemic cardiomyopathy and left ventricular dysfunction.
  
  Aetna considers PET for absolute quantitation of myocardial blood flow (AQMBF) experimental and investigational because the value of this test in guiding management has not been established.
3. Cardiac Sarcoid
  
  FDG-PET is considered medically necessary to identify and monitor response to therapy for established or strongly suspected cardiac sarcoid.
Oncologic indications

Aetna considers FDG-PET medically necessary for the following oncologic indications, when the following general and disease-specific criteria for diagnosis, staging, restaging and monitoring are met, and the FDG-PET scan is necessary to guide management:
- Acute myeloid leukemia
- Ampullary cancer
- Anal cancer
- Appendiceal cancer
- Brain tumors
- Breast cancer
- Burkitt's lymphoma
- Castleman's disease
- Cervical cancer
- Chordoma
- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with suspected Richter's transformation
- Colorectal cancer
- Diffuse large B-cell lymphoma (DLBCL)
- Esophageal cancer
- Ewing sarcoma and osteosarcoma
- Fallopian tube cancer
- Follicular lymphoma
- Gastric cancer
- Gastrointestinal stromal tumors
- Head and neck cancers (excluding cancers of the central nervous system)
- Hodgkin lymphoma
- Mantle cell lymphoma
- Marginal Zone and MALT lymphoma
- Melanoma
- Merkel cell carcinoma
- Mesothelioma
- Multiple myeloma and plasmacytomas
- Neuroendocrine tumors
- Non-Hodgkin's lymphoma (for select subtypes, see section II.B.8.)
- Non-small cell lung carcinoma
- Occult primary cancers
- Ovarian cancer
- Pancreatic cancer
- Paraneoplastic syndrome
- Penile cancer
- Post-transplant lymphoproliferative disorder
- Primary cutaneous B-cell lymphoma
- Primary peritoneal cancer
- Small cell lung carcinoma
- Small bowel adenocarcinoma
- Soft tissue sarcoma
- Solitary pulmonary nodules
- T-cell lymphoma (includes peripheral T-cell lymphoma, Mycosis Fungoides/Sézary Syndrome, primary cutaneous CD30+ T-cell lymphoproliferative disorders)
- Testicular cancer
- Thymic malignancies
- Thyroid cancer
- Vaginal cancer.
PET-CT Fusion: The fusion of PET and CT imaging into a single system (PET/CT fusion) is considered medically necessary for any oncologic indication where PET scanning is considered medically necessary. PET-CT fusion is considered experimental and investigational for cardiac and neurologic indications; a PET scan without CT is adequate to evaluate the brain and myocardium (NIA, 2005).
1. General Criteria
  1. Diagnosis
    
    The PET results may assist in avoiding an invasive diagnostic procedure, or the PET results may assist in determining the optimal anatomic location to perform an invasive diagnostic procedure. In general, for most solid tumors, a tissue diagnosis is made prior to the performance of PET scanning. PET scans following a tissue diagnosis are performed for the purpose of staging, not diagnosis. Therefore, the use of PET in the diagnosis of lymphoma, esophageal carcinoma, colorectal cancers, and melanoma is rarely considered medically necessary.
  2. Staging
    
    PET is considered medically necessary in situations in which clinical management of the member would differ depending on the stage of the cancer identified and either:
    1. The stage of the cancer remains in doubt after completion of a standard diagnostic work-up, including conventional imaging (computed tomography, magnetic resonance imaging, or ultrasound); or
    2. The use of PET would potentially replace one or more conventional imaging studies when it is expected that conventional study information is insufficient for the clinical management of the member.
  3. Re-staging
    
    PET is considered medically necessary for re-staging after completion of treatment for the purpose of detecting residual disease, for detecting suspected recurrence in persons with signs or symptoms of recurrence, or to determine the extent of recurrence. Use of PET is also considered medically necessary if it could potentially replace one or more conventional imaging studies when it is expected that conventional study information is insufficient for the clinical management of the member. PET for post-treatment surveillance is considered experimental and investigational, where surveillance is defined as use of PET beyond the completion of treatment, in the absence of signs or symptoms of cancer recurrence or progression, for the purpose of detecting recurrence or progression or predicting outcome.
  4. Monitoring
    
    PET for monitoring tumor response during the planned course of therapy is not considered medically necessary except for breast cancer. Re-staging occurs only after a course of treatment is completed.
2. Disease-Specific Criteria
  1. Characterization of Solitary Pulmonary Nodules (SPNs)
    
    FDG-PET is considered medically necessary for the characterization of newly discovered SPNs in persons without known malignancy when the general medical necessity criteria for oncologic indications (above) are met and the following conditions are met:
    - A concurrent thoracic CT has been performed, which is necessary to ensure that the PET scan is properly coordinated with other diagnostic modalities; and
    - A single indeterminate or possibly malignant lesion, more than 0.8 cm and not exceeding 4 cm in diameter, has been detected (usually by CT).
    The primary purpose of the PET scan of SPN should be to determine the likelihood of malignancy in order to plan the management of the member.
    
    Note: A biopsy is not considered medically necessary in the case of a negative PET scan for SPNs, because the member is presumed not to have a malignant lesion, based upon the PET scan results.
    
    Note: In cases of serial evaluation of SPNs using both CT and regional PET chest scanning, such PET scans are not considered medically necessary if repeated within 90 days following a previous negative PET scan.
  2. Non-Small Cell Lung Carcinoma (NSCLC)
    
    FDG-PET scans are considered medically necessary for the diagnosis, staging and re-staging of non-small cell lung carcinoma (NSLC) when the general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  3. Small Cell Lung Carcinoma (SCLC)
    
    FDG-PET scans are considered medically necessary for staging of persons with SCLC that has been determined to be of limited-stage after standard staging evaluation (including CT of the chest and upper abdomen, bone scan, and brain imaging).
  4. Mesothelioma
    
    FDG-PET scans are considered medically necessary for diagnosis and staging of malignant pleural mesothelioma when the general medical necessity criteria for oncologic indications (II. A. listed above) are met. According to National Comprehensive Cancer Network (NCCN) guidelines (version 2.2018), FDG-PET-CT scans may be useful in the pre-treatment evaluation of mesothelioma for those being considered for surgery.
  5. Colorectal Cancer and Small Bowel Adenocarcinoma
    
    FDG-PET scans are considered medically necessary for diagnosis Footnotes1*, staging, and re-staging of colorectal cancer and small bowel adenocarcinoma when the general medical necessity criteria for oncologic indications (II. A. listed above) are met. According to the Centers for Medicare & Medicaid Services (CMS), medical evidence supports the use of FDG-PET as a useful tool in determining the presence of hepatic/extra-hepatic metastases in the primary staging of colorectal carcinoma, prior to selecting the treatment regimen. Use of FDG-PET is also supported in evaluating recurrent colorectal cancer or small bowel adenocarcinoma where the member presents with clinical signs or symptoms of recurrence.
    
    Footnotes1*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of colorectal cancer is rarely considered medically necessary.
  6. Anal Cancer
    
    FDG-PET scans are considered medically necessary for the diagnosis of anal canal carcinomas when medical necessity criteria for oncologic indications (II.A. listed above) are met. According to NCCN guidelines on "Anal carcinoma" (v 2.2018), PET/CT may be considered in the workup and treatment planning for anal cancer; however, PET/CT scan does not replace a diagnostic CT.
  7. Hodgkinslymphoma
    
    FDG-PET scans are considered medically necessary for the diagnosis Footnotes2*, staging and re-staging of Hodgkin lymphoma when the general medical necessity criteria for oncologic indications (II. A. listed above) are met.
    
    Footnotes2*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of Hodgkin lymphoma is rarely considered medically necessary.
  8. Non-Hodgkin's Lymphoma subtypes including post-transplant lymphoproliferative disorder and Castleman's disease
    
    FDG-PET scans are considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met for the following indications:
  9. Melanoma
    
    FDG-PET scans are considered medically necessary for the diagnosis Footnotes3*, staging, and re-staging of melanoma when the general medical necessity criteria for oncologic indications (II. A. listed above) are met. FDG-PET is considered experimental and investigational and not medically necessary for use in evaluating regional nodes in persons with melanoma.
    
    Footnotes for Diagnosis*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of melanoma is rarely considered medically necessary.
  10. Esophageal Cancer
    
    FDG-PET is considered medically necessary for the diagnosis Footnotes4*, staging and re-staging of esophageal carcinoma when general medical necessity criteria for oncologic indications (II. A. listed above) are met. Medical evidence is present to support the use of FDG-PET in pre-surgical staging of esophageal cancer.
    
    Footnotes4*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of esophageal cancer is rarely considered medically necessary.
  11. Gastric Cancer
    
    FDG-PET is considered medically necessary for diagnosis, Footnotes5* staging and re-staging of gastric carcinoma when general medical necessity criteria for oncologic indications (II. A. listed above) are met. Consensus guidelines support the use of FDG-PET in the pre-surgical staging of gastric cancer.
    
    Footnotes5*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of gastric cancer is rarely considered medically necessary.
  12. Gastrointestinal Stromal Tumors
    
    FDG-PET is considered medically necessary for diagnosis Footnotes6*, staging and re-staging of gastrointestinal stromal tumors (GIST) when general medical necessity criteria for oncologic indications (II. A. listed above) are met. Consensus guidelines support the use of FDG-PET in the pre-surgical staging of GIST.
    
    Footnotes6*Note: A diagnostic tissue sample is usually obtainable without PET localization. Therefore, PET for diagnosis of GIST is rarely considered medically necessary.
  13. Head and Neck Cancers
    
    FDG-PET scans are considered medically necessary for the diagnosis, staging, and re-staging of head and neck cancers when general medical necessity criteria for oncologic indications (II.A. listed above) are met. The head and neck cancers encompass a diverse set of malignancies of which the majority is squamous cell carcinomas. Persons with head and neck cancers may present with metastases to cervical lymph nodes but conventional forms of diagnostic imaging fail to identify the primary tumor. Persons with cancer of the head and neck are left with 2 options, either to have a neck dissection or to have radiation of both sides of the neck with random biopsies. PET scanning attempts to reveal the site of primary tumor to prevent adverse effects of random biopsies or unneeded radiation.
  14. Thyroid Cancer
    FDG-PET scans are considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met, for
    1. staging or restaging of thyroid cancers where there are inconclusive findings on conventional imaging;
    2. staging or restaging of thyroid cancer of follicular, papillary or Hurthle cell origin previously treated by thyroidectomy and radioiodine ablation with an elevated or rising serum thyroglobulin (Tg) greater than 10 ng/ml and negative I-131 whole body scintigraphy.
    FDG-PET is considered not medically necessary for determining which members with metastatic thyroid cancer are at highest risk for death, because this information is for informational purposes only and has not been demonstrated to alter member management.
    
    FDG-PET scans are considered experimental and investigational for other thyroid cancer indications.
  15. Thymic Malignancies
    
    FDG-PET scans are considered medically necessary for the diagnosis, staging, and re-staging of thymic malignancies (thymomas and thymic carcinomas) when the general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  16. Breast Cancer
    
    FDG-PET scans are considered medically necessary for members with breast cancer for the following indications, where general medical necessity criteria for oncologic indications (II. A. listed above) are met:
    - Initial staging of members with stage III or higher when conventional imaging is equivocal; or
    - Monitoring tumor response to treatment for persons with locally advanced and metastatic breast cancer when a change in therapy is contemplated; or
    - Restaging of members with known metastases; or
    - Evaluating suspected recurrence (new palpable lesions in axilla or adjacent area, rising tumor markers, changes in other imaging which are equivocal or suspicious).
    FDG-PET is considered experimental and investigational for the initial diagnosis of breast cancer and for the staging of axillary lymph nodes.
  17. Cervical Cancer
    
    FDG-PET scans are considered medically necessary for the diagnostic workup of cervical cancer, for detection of pre-treatment metastases (staging) in women who are newly diagnosed with cervical cancer and have negative conventional imaging (CT or MRI), and for restaging of cervical cancer when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  18. Vaginal Cancer
    
    FDG-PET scans are considered medically necessary for the diagnostic workup of vaginal cancer for evaluating the primary vaginal tumor and abnormal lymph nodes when general medical necessity criteria for oncologic indications (II. A. listed above) are met. FDG-PET scans are considered medically necessary for evaluating tumor recurrence. FDG-PET scans are considered experimental and investigational for staging and restaging and for surveillance.
  19. Vulvar Cancer
    
    FDG-PET scans are considered medically necessary for the diagnostic workup of vulvar cancer for evaluating regional lymph node metastases in some patients and hematogenous spread in rare patients with distant dissemination at the time of diagnosis when general medical necessity criteria for oncologic indications (II. A. listed above) are met. FDG-PET scans are considered experimental and investigational for staging and restaging of vulvar cancer.
  20. Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancer
    
    FDG-PET scans are considered medically necessary for re-staging (detecting recurrence) of previously treated women with a rising CA-125 level who have negative or equivocal conventional imaging (CT or MRI) when general medical necessity criteria for oncologic indications (II.A listed above) are met.
    
    FDG-PET scans are considered experimental and investigational for diagnosis, staging, and monitoring of ovarian cancer, fallopian tube cancer and primary peritoneal cancer.
  21. Testicular Cancer
    
    FDG-PET scans are considered medically necessary for re-staging (detecting recurrence) of testicular cancer in men with previously treated disease who have a residual mass with normal or persistently elevated serum markers (e.g., alpha fetoprotein or serum chorionic gonadotropin) when general medical necessity criteria for oncologic indications (II.A. listed above) are met.
    
    FDG-PET scans are considered experimental and investigational for diagnosis, staging and monitoring of testicular cancer.
  22. Multiple Myeloma and Plasmacytomas
    
    FDG-PET scans are considered medically necessary for evaluating suspected plasmacytomas (staging) in persons with multiple myeloma and for re-staging of persons with solitary plasmacytomas when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  23. Ewing Sarcoma, Chordoma and Osteosarcoma
    
    FDG-PET scans are considered medically necessary for the diagnosis, staging and re-staging of osteosarcoma, chordoma, and Ewing sarcoma family of tumors when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  24. Soft Tissue Sarcoma
    
    FDG-PET scans are rarely medically necessary for soft tissue sarcomas. FDG-PET scans are considered medically necessary for staging prior to resection of an apparently solitary metastasis, or for grading unresectable lesions when the grade of the histopathological specimen is in doubt, when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
    
    FDG-PET scans are considered experimental and investigational for re-staging of soft tissue sarcomas.
  25. Neuroendocrine Tumors
    
    FDG-PET scans are considered medically necessary for the diagnosis, staging and re-staging of persons with pheochromocytoma/paragangliomas and other neuroendocrine tumors when general medical necessity criteria for oncologic indications (II.A. listed above) are met.
  26. Pancreatic Tumors
    
    FDG-PET scans are considered medically necessary for diagnosis and staging of pancreatic tumors where imaging tests (CT or MRI) are equivocal, when general medical necessity criteria for oncologic indications (II. A. listed above) are met. FDG-PET scans are considered experimental and investigational for restaging of pancreatic cancer.
  27. Brain Cancer
    
    FDG-PET scans are considered medically necessary for diagnosis and staging, where lesions metastatic from the brain are identified but no primary is found, and for restaging, to distinguish recurrent tumor from radiation necrosis, when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  28. Occult Primary
    
    FDG-PET is considered medically necessary for staging in carcinomas of unknown primary site in tumors of indeterminate histology where the primary site can not be identified by endoscopy or other imaging studies (CT, MRI) and where loco-regional therapy for a single site of disease is being considered, when general medical necessity criteria for oncologic indications (II. A. listed above) are met. FDG-PET scans are considered experimental and investigational for diagnosis or re-staging of carcinomas of unknown primary.
  29. Paraneoplastic Syndromes
    
    FDG-PET is considered medically necessary for diagnosis and staging of persons suspected of having a paraneoplastic syndrome when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  30. Merkel Cell Carcinoma
    FDG-PET is considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met for evaluating
    1. The possibility of a skin metastasis from a non-cutaneous carcinoma (e.g., small cell carcinoma of the lung), especially in cases where CK20 is negative,
    2. Regional and distant metastases, or
    3. The extent of lymph node and/or visceral organ involvement.
  31. Penile Cancer
    
    FDG-PET is considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met for evaluation of persons with penile cancer who have positive lymph nodes (PLNs) and an abnormal CT or MRI.
  32. Uterine Sarcoma
    
    FDG-PET is considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met for diagnosis, staging and restaging of persons with uterine sarcoma in persons with known or suspected extrauterine disease.
  33. Cancer of Ampulla
    
    PET scanning is considered medically necessary when general medical necessity criteria for oncologic indications (II. A. listed above) are met for staging and re-staging of cancer of ampulla where conventional imaging is equivocal or where it appears that disease is localized and potentially curative resection is being considered.
  34. PET Scan for Acute Myeloid Leukemia:
    
    Aetna considers PET scan for acute myeloid leukemia (AML) medically necessary if extramedullary disease is suspected, and when general medical necessity criteria for oncologic indications (II. A. listed above) are met.
  35. FDG-PET in Place of ^99mTc Skeletal Scintigraphy
    
    There is no longer a temporary shortage of technetium 99-m (^99mTc), which is used in nuclear medicine for skeletal scintigraphy (bone scans). Therefore, Aetna will no longer consider FDG-PET an acceptable alternative to bone scans for detecting skeletal abnormalities for medically necessary indications.
  36. NaF-18 PET
    
    Aetna considers NaF-18 PET experimental and investigational for identifying bone metastasis of cancer and all other indications because of insufficient evidence.
  37. Carbon-11 labeled 5-HTP PET
    
    Aetna considers carbon-11 labeled 5-HTP PET experimental and investigational for carcinoid and all other indications because of insufficient evidence.
  38. Fluciclovine f-18 PET and Choline C-11 PET
    
    Aetna considers fluciclovine f-18 PET or choline c-11 PET medically necessary for restaging of men with a suspected recurrence of prostate cancer who meet all of the following criteria:
    1. Member has previously been treated with prostatectomy and/or radiation therapy; and
    2. Member has a consecutive rise in PSA; and
    3. PSA ≥ 1 ng/mL; and
    4. CT scan and bone scan are negative for metastatic disease.
  39. Gallium-68 PSMA PET:
    
    Aetna considers gallium-68 PSMA PET/CT scan experimental and investigational for re-staging of prostate cancer because the effectiveness of this approach has not been established.
  40. Gallium Ga 68 dotatate PET and Copper Cu 64 dotatate PET
    Aetna considers gallium Ga 68 dotatate PET (Netspot) medically necessary for the diagnosis, staging and re-staging of persons with pheochromocytoma/paragangliomas and other neuroendocrine tumors when general medical necessity criteria for oncologic indications (II.A. listed above) are met.
    
    Aetna considers copper Cu 64 dotatate PET (DetectNet) experimental and investigational for neuroendocrine tumors and for all other indications.
  41. 18F-FDOPA-PET Scan for Prognosis of Brain Cancer:
    
    Aetna considers 18F-FDOPA-PET/CT scan experimental and investigational for prognosis of brain cancer because the effectiveness of this approach has not been established.
  42. Cerianna (Fluoroestradiol F-18) PET for Breast Cancer:
    
    Aetna considers Cerianna (fluoroestradiol F-18) PET imaging experimental and investigational for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in recurrent or metastatic breast cancer because the effectiveness of this approach has not been established.
  43. Additional Experimental and Investigational Oncological Indications
    
    Aetna considers FDG-PET scans experimental and investigational for the evaluation of adrenal carcinoma, bladder cancer, chondrosarcoma, clear cell carcinoma of the uterus, desmoid tumors/fibromatosis, endometrial cancer, extra-gonadal seminoma including mediastinal seminoma, intraductal papillary mucinous neoplasm of the pancreas, and neuroganglioma of the psoas muscle; follow-up of amyloidosis in bone marrow transplant recipients, gallbladder cancer, gestational trophoblastic neoplasia, giant cell tumor of the bone, hemangioendothelioma, hepatic sarcoma, hepatobiliary cancer, hepatocellular carcinoma, hypercalcemia of malignancy, kidney cancer, leukemia (e.g., ALL, hairy cell; excluding AML and CLL/SLL with suspected Richter's transformation), lymphangiomatosis, malignant degeneration of neurofibromas, neuroblastoma, neurofibromatosis, Paget's disease (including extra-mammary Paget's disease), peri-ampullary cancer, pilar tumor, pituitary adenoma, placental cancer, plasmacytoid dendritic cell neoplasm, pleomorphic adenoma, prostate cancer, schwannoma, serous papillary endometrial carcinoma, skin cancer (excluding melanoma and Merkel cell carcinoma), spindle cell sarcoma, staging of biopsy-proven solitary fibrous tumor of pleura, ureteral cancer, uterine papillary mesothelioma, Wilms tumor, or for other oncologic indications (e.g., re-staging of Waldenstrom macroglobulinemia; and treatment planning for atypical teratoid/rhabdoid tumor) not listed as medically necessary in this policy because of insufficient evidence of effectiveness.
    
    Aetna considers PET-probe guided surgical resection experimental and investigational for recurrent ovarian cancer and other indications because its effectiveness has not been established.
Neurologic Indications

Aetna considers FDG-PET medically necessary only for pre-surgical evaluation for the purpose of localization of a focus of refractory seizure activity.

Aetna considers PET scans experimental and investigational for Alzheimer's disease (including the use of florbetapir-PET and flutemetamol F18-PET for imaging beta-amyloid), dementia, Huntington disease, Parkinson's disease, or for other neurologic indications not listed as medically necessary in this policy because of insufficient evidence of its effectiveness.
Other Indications

Aetna considers FDG-PET medically necessary for diagnosis, staging and re-staging of Langerhans cell histiocytosis.

Aetna considers FDG-PET experimental and investigational for adrenoleukodystrophy, aortic/large-vessel vasculitis, chronic osteomyelitis, coccidioidomycosis (also known as valley fever, San Joaquin Valley fever, California valley fever, and desert fever), eosinophilia, Erdheim-Chester disease, fever of unknown origin, hepatic encephalopathy, infection of knee replacement prostheses, infection of hip arthroplasty, Moyamoya disease, opsoclonus (opsillopsia) myoclonus syndrome, pigmented villonodular synovitis, pleural effusion, rheumatoid arthritis, Rosai-Dorfman disease, sarcoid/sarcoidosis, screening in Li-Fraumeni syndrome, splenomegaly, Takayasu's arteritis, xanthogranuloma, and other indications not listed as medically necessary in this policy because of a lack of sufficient evidence of the effectiveness of FDG-PET for these indications.

Aetna considers whole body PET experimental and investigational for evaluation of unspecified periodic fever syndrome because of insuffcient evidence of its effectiveness.
Gamma Camera PET Scan

Aetna considers PET scanning with a gamma camera experimental and investigational for all indications because of insuffcient evidence of its effectiveness.
PET/MRI

Aetna considers PET/MRI experimental and investigational for all indications because of insufficient evidence of its effectiveness.
Positron Emission Mammography (PEM)

Aetna considers positron emission mammography (PEM) experimental and investigational because of insufficient evidence of its effectiveness.
PET Scan for Screening

Aetna considers PET scans for screening of asymptomatic members for breast cancer, lung cancer and other indications experimental and investigational, regardless of the number and severity of risk factors applicable to the member.
Amyloid-PET for Diagnosis of Sporadic Cerebral Amyloid Angiopathy

Aetna considers amyloid-PET for the diagnosis of sporadic cerebral amyloid angiopathy experimental and investigational because of insufficient evidence of its effectiveness.
Florbetapi-PET for Diagnosis of Cerebral Amyloid Angiopathy-Related Hemorrhages

Aetna considers florbetapi-PET imaging for the diagnosis of cerebral amyloid angiopathy-related hemorrhages experimental and investigational because of insufficient evidence of its effectiveness.

Background

Policy above is adapted from eviCore imaging guidelines.

Positron emission tomography (PET) also known as positron emission transverse tomography (PETT), or positron emission coincident imaging (PECI), is a non-invasive diagnostic imaging procedure that assesses the level of metabolic activity and perfusion in various organ systems of the human body. A positron camera (tomograph) is used to produce cross-sectional tomographic images, which are obtained from positron emitting radioactive tracer substances (radiopharmaceuticals) such as 2-[F-18] fluoro-d-glucose (FDG) that are administered intravenously to the member.

PET assesses the function of tissues and organs by monitoring the metabolic or biochemical activity while tracking the movement and concentration of a radioactive contrast agent. The technique uses special computerized imaging equipment and rings of detectors surrounding the individual to record gamma radiation produced when positrons (positively charged particles) emitted by the radioactive agent collide with electrons. Integrated PET/CT imaging is a technique in which both PET and CT are performed sequentially during a single visit on a hybrid PET/CT scanner. The CT and PET images are then co-registered using fusion software, enabling the physiologic data obtained on PET to be localized according to the anatomic CT images. When PET/CT is performed, a low radiation dose CT without contrast is typically used to keep the radiation dose as low as possible and to limit adverse events. A higher resolution CT requires a higher dose of radiation and intravenous (IV) contrast. The Biograph mCT-X and mCT-S (Biograph HD) are examples of PET/CT devices.

A BlueCross BlueSheild Association's special report on PET for post-treatment surveillance of cancer (2009) found that there is simply inadequate direct and indirect evidence supporting the effectiveness of PET scanning for the purpose of surveillance. Reflecting this lack of evidence, current practice guidelines appear unanimously to recommend against the use of PET for surveillance. No strong support of the use of PET for surveillance was found in editorials, case reports, or other studies. The report concluded that given such problems such as lead time bias, length bias, and the uncertain diagnostic characteristics of PET in the surveillance setting, it would be difficult to determine if the effectiveness of PET for surveillance could be determined with observational data. Clinical trials may be necessary to determine whether PET surveillance is effective in improving health outcomes. (Note: surveillance is defined as use of PET beyond the completion of treatment, in the absence of signs or symptoms of cancer recurrence or progression, for the purpose of detecting recurrence or progression or predicting outcome).

Guidelines on screening for tumors in paraneoplastic syndromes from the European Federation of Neurological Societies (Titulaer, et al., 2011) state that, for screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). The guidelines recommend mammography for breast cancer screening, followed by MRI. Ultrasound is the investigation of first choice for the pelvic region, followed by CT. The guidelines state that dermatomyositis patients should have CT of the thorax and abdomen, ultrasound of the pelvic region and mammography in women, ultrasound of testes in men under 50 years and colonoscopy in men and women over 50 years. The guidelines recommend, if primary screening is negative, repeat screening after 3 to 6 months and screening every 6 months up until four years. In Lambert-Eaton myasthenic syndrome, screening for 2 years is sufficient.

PET/MRI is a hybrid imaging technology that incorporates MRI soft tissue morphological imaging and PET functional imaging. PET/MRI systems use software to fuse image data from two separately performed imaging examinations. Performing the PET and MRI scans simultaneously in the same imaging session purportedly prevents issues associated with image data mismatching that may occur with image fusion software. A combined PET/MRI approach is suggested for imaging anatomical, biochemical and functional characteristics of disease. The Biograph mMR is an example of a PET/MRI device. There are few studies that have focused on PET/MRI technology and its advantages over PET/CT fusion, which is the current standard of care. An assessment by the Australian Health Policy Advisory Committee on Technology (Mundy, 2012) concluded that there are few clinical studies in the literature reporting on the use of hybrid PET‐MRI systems. The report noted that initial, small scale studies indicate that PET‐MRI hybrid scanning systems are as effective at imaging regions of interest in certain brain cancers and head and neck cancer as PET‐CT hybrid scanners; however these imaging studies do not indicate the effect on clinical outcomes for these patients or a change in patient management. The review stated that, based on the small number of published studies it appears that hybrid PET‐MRI may be a promising imaging modality, especially for pediatric patients, with the added benefit of reduced exposure to radiation compared to a PET‐CT scan. The report noted, however, that recent developments in CT design have resulted in scanners that deliver a reduced radiation dose. In addition, combined PET‐MRI systems are not capable of producing as high‐quality images as stand-alone imaging systems. The report concluded that "combined PET‐MRI systems are currently of benefit in the research, rather than clinical setting." The report stated that larger studies with clinical outcomes are required to demonstrate the effectiveness of the modality. The report noted concerns regarding the paucity of evidence in respect to the clinical effectiveness of hybrid PET‐MRI scanners and the potential for increased costs due to workforce issues including training requirements, time taken for interpretation of images, increasing capacity for image storage and the impact on patient flow.

Absolute quantitation of myocardial blood flow (AQMBF) imaging is an additional physiological assessment during a pharmacologic stress/rest PET or PET/CT myocardial perfusion imaging. Following stress/rest PET or PET/CT myocardial perfusion imaging, images for PET myocardial perfusion imaging are acquired to allow quantitation of AQMBF. The report quantifies in ml/g/min for rest, stress, and indexed/reserve flow for each coronary bed and for the global left ventricular. Performance of quantitation of myocardial blood flow by cardiac PET is currently non-standardized between different vendor products.

Anal Cancer

The National Comprehensive Cancer Network (NCCN) on "Anal carcinoma" (v 2.2018) states that PET/CT scanning can be considered to verify staging before treatment, and that it has been reported to be useful in the evaluation of pelvic nodes, even for those who have "normal-sized" lymph nodes on CT imaging and have anal canal cancer. However, the NCCN panel does not consider PET/CT to be a replacement for a diagnostic CT.

PET for Orthopedic Prostheses

Manthey and co-workers (2002) described 18F-FDG-PET findings in patients referred for evaluation of painful hip or knee prostheses. These investigators studied 23 patients with 28 prostheses, 14 hip and 14 knee prostheses, who had a complete operative or clinical follow-up. 18F-FDG-PET scans were obtained with an ECAT EXACT HR+ PET scanner. High glucose uptake in the bone prostheses interface was considered as positive for infection, an intermediate uptake as suspect for loosening, and uptake only in the synovia was considered as synovitis. The imaging results were compared with operative findings or clinical outcome. FDG-PET correctly identified 3 hip and 1 knee prostheses as infected, 2 hip and 2 knee prostheses as loosening, 4 hip and 9 knee prostheses as synovitis, and 2 hip and 1 knee prostheses as unsuspected for loosening or infection. In 3 patients covered with an expander after explantation of an infected prosthesis, FDG-PET revealed no further evidence of infection in concordance with the clinical follow-up. FDG-PET was false-negative for loosening in 1 case. The authors concluded that these preliminary findings suggested that FDG-PET could be a useful tool for differentiating between infected and loose orthopedic prostheses as well as for detecting only inflammatory tissue such as synovitis.

Germ Cell Tumors (CGT)

Karapetis and colleagues (2003) stated that FDG-PET may detect residual or recurrent malignancy in patients with germ cell tumors (GCT) following chemotherapy. The objective of the present study was to evaluate the use of FDG-PET in the setting of advanced GCT, and to determine the influence of FDG-PET on subsequent patient management. A computerized search of the patient database of the Department of Medical Oncology, Guy's Hospital, London, United Kingdom, and a manual search of medical records, were conducted. All male patients with metastatic or extra-gonadal GCT treated with chemotherapy between July 1996 and June 1999 inclusive were identified. Data from patients that had a PET scan following chemotherapy were analyzed. Reported PET scan findings were compared with subsequent clinical management and patient outcome. A total of 30 patients with metastatic testicular GCT and 3 patients with extra-gonadal GCT were treated with chemotherapy. Of these, 15 patients (12 testicular; 3 extra-gonadal; 10 non-seminoma; and 5 seminoma) were investigated following chemo-therapy with at least 1 FDG-PET scan. Seven patients had 2 or more PET scans, and a total of 26 FDG-PET scans was performed. The most frequent indication for PET scan was evaluation of a residual mass (11 patients). Three patients had an FDG-PET to evaluate thymic prominence. Minimum follow-up from first PET scan was 18 months. Three of 26 PET scans had false-positive findings. Four PET scans yielded findings of equivocal significance with repeat PET scan recommended. Relapse of disease occurred in 3 patients; 2 of whom had normal previous PET scans and 1 had a previous equivocal result. Moreover, PET had an impact on patient management in only 1 case where it "prompted" surgical excision of a residual mass. Normal PET scans provided reassurance in patients with residual small masses but did not alter their subsequent management. The authors concluded that a residual mass was the most common indication for PET. For the majority of patients PET did not have a discernible influence on clinical management. They stated that

oncologists should exercise caution in their interpretation of PET scan findings and guidelines for the appropriate use of PET in testicular cancer management need to be developed, and
prospective trials are required to define the clinical role of PET in this setting.

Hepatocellular Carcinoma

Wolfort et al (2010) the effectiveness of FDG-PET for the detection and staging of hepatocellular carcinoma (HCC). In addition, these researchers also assessed the correlation between FDG-PET positivity, tumor size, AFP, and histological grade. All patients on the hepatobiliary and liver transplant service with biopsy proven HCC that underwent FDG-PET between January 2000 and December 2004 were selected for a retrospective review. Results of the FDG-PET scans were compared with other imaging studies (CT, MRI, ultrasonography), intra-operative findings, tumor size, AFP levels, and histological grade. Of the 20 patients who underwent 18F-FDG PET, increased FDG uptake was noted in 14 scans (70 %). These 20 patients fell into 2 groups:

for detecting HCC (group A) and
for staging HCC (group B).

There were 7 patients in group A; only 2 scans (28.6 %) showed increased uptake. There were 13 patients in group B; 12 scans (92.3 %) showed increased uptake. In group B, 11 of the 13 scans (84.6 %) provided an accurate representation of the disease process. Two scans failed to accurately portray the disease; 1 scan failed to show any increase in uptake, and the other scan failed to detect positive nodes that were found during surgery. FDG-PET detected only 2 of 8 tumors (25 %) less than or equal to 5 cm in size. All 12 PET scans (100 %) in tumors greater than or equal to 5 cm and/or multiple in number were detected by FDG-PET. FDG-PET scans with AFP levels less than 100 ng/ml were positive in 5 of 9 patients (55.6 %). In patients with levels greater than 100 ng/ml, 6 of 7 patients (85.7 %) had positive scans. Histologically, there were 6 well-differentiated, 6 moderately differentiated, and 2 poorly differentiated HCCs. FDG-PET detected 4 of 6 for both well- and moderately-differentiated HCCs. Both poorly- differentiated HCCs were detected. The intensity was evenly distributed between the different histological grades. There was a strong correlation of FDG uptake with tumor size. There were 5 HCCs with primary tumors greater than 10 cm in size; 4 showed intense uptake on the scan. In contrast, of the 8 tumors less than or equal to 5 cm in size, 6 were negative for uptake. The sensitivity of FDG-PET in detecting HCC less than or equal to 5 cm in size is low and therefore may not be helpful in detecting all of these tumors. For larger tumors, there is a strong correlation of sensitivity and uptake intensity with tumor size and elevated AFP levels. FDG-PET sensitivity and uptake intensity did not correlate with histological grade. In the setting of extra-hepatic disease, FDG-PET seems to be an effective accurate method for HCC staging; however, whether PET offers any benefit over traditional imaging has yet to be determined.

An UpToDate review on "Staging and prognostic factors in hepatocellular carcinoma" (Curley et al, 2013) states that "Positron emission tomography with fluorodeoxyglucose (FDG-PET) is being investigated as a complementary staging tool that may help to define prognosis in some patients …. Positron-emitting radionuclides other than FDG (such as 11C-acetate) are under investigation as potentially more useful agents for imaging and staging HCC". Furthermore, National Comprehensive Cancer Network (NCCN)’s clinical guideline on "Hepatobiliary cancers" (Version 4.2018) notes that PET/CT is not adequate for screening and diagnosis of hepatocellular carcinoma. In addition, PET/CT is not recommended for detection of HCC because of limited sensitivity. There is no mentioning of its use for staging.

Pediatric Abdominal Tumors

Murphy et al (2008) stated that PET/CT scan provides both functional and anatomical information in a single diagnostic test. It has the potential to be a valuable tool in the evaluation of pediatric abdominal tumors. The goal of this study was to report the authors' early experience with this technology. Children who underwent PET/CT scan in the work-up for abdominal neoplasms between July 2005 and January 2008 were identified. Retrospective reviews of all radiological studies, operative notes, and pathological reports were undertaken. A total of 36 patients were collected. These included Burkitt's lymphoma (n = 8), neuroblastoma (n = 7), rhabdomyosarcoma (n = 6), ovarian tumor (n = 3), Wilms tumor (n = 2), HCC (n = 2), paraganglioma (n = 1), germ cell tumor (n = 1), undifferentiated sarcoma (n = 1), renal primitive neuroectodermal tumor (n = 1), gastro-intestinal stromal tumor (n = 1), adrenocortical carcinoma (n = 1), inflammatory pseudotumor (n = 1), and adrenal adenoma (n = 1). All neoplasms were FDG were avid. These investigators identified several potential uses for PET/CT scan in this group of patients. These included

pre-operative staging,
selection of appropriate site for biopsy,
identification of occult metastatic disease,
follow-up for residual or recurrent disease, and
assessment of response to chemotherapy.

It can also be valuable when the standard diagnostic studies are equivocal or conflicting. The authors concluded that these preliminary data indicated that PET/CT is a promising tool in the evaluation of pediatric abdominal malignancies. The delineation of the exact role of this diagnostic modality will require additional experience. It should also be noted that the National Comprehensive Cancer Network's clinical practice guideline on "Kidney cancer" (Version 2.2019) states "PET alone is not a tool that is standardly used to diagnose kideny cancer or follow for evidence of relapse after nephrectomy"

Mody and colleagues (2006) described the use of FDG-PET in a series of 7 children (11 scans) with primary hepatic malignancies (5 patients with hepatoblastoma, 2 patients with hepatic embryonal rhabdomyosarcoma), together with other imaging (CT and MRI), serum tumor markers, and tumor pathology. These patients with pathologically proven hepatic malignancies underwent 11 FDG-PET scans for staging (1 patient) or restaging (6 patients). Tumor uptake of FDG was assessed qualitatively and compared with biochemical and radiological findings. Abnormal uptake was demonstrated in 6 of 7 patients (10 of 11 scans). Three patients subsequently underwent partial hepatic resection, and 1 underwent brain biopsy, confirming in each that the abnormal uptake of FDG indicated viable tumor. In 1 patient, intense uptake was due to necrotizing granulomas. In 1 patient, images were suboptimal due to non-compliance with fasting. The authors concluded that primary hepatic tumors of childhood usually demonstrate increased glycolytic activity, which allows them to be imaged using PET and the tracer 18F-FDG. The technique is probably most useful for assessing response to therapy, in following alfa-fetoprotein (AFP)-negative cases and for detecting metastatic disease although a large series of patients will need to be studied to confirm these initial findings. Non-neoplastic inflammation may also accumulate FDG and could be confused with malignancy. As these tumors are rare, prospective multi-center studies are needed to determine the true clinical utility of FDG-PET imaging in the management of children with primary hepatic malignancies.

Langerhans Cell Histiocytosis (LCH)

Phillips and colleagues (2009) assessed the effectiveness of FDG-PET scans in identifying sites of active disease and assessing response to therapy in patients with Langerhans cell histiocytosis (LCH). Changes in standardized uptake value (SUV) indicated increased or decreased disease activity before changes are evident by plain films or bone scans. A total fo 102 PET scans for 44 patients (3 adults and 41 children) with biopsy-proven LCH were compared with 83 corollary imaging modalities and were rated for overall clinical utility: false positive or negative ("inferior"), confirming lesions identified by another imaging modality ("confirmatory"), or showing additional lesions, response to therapy or recurrence of disease activity ("superior"), in comparison to bone scans, MRI, CT or plain films. FDG-PET was rated superior in that 90/256 (35 %) new, recurrent, or lesions responding to therapy were identified via change in SUV before other radiographical changes. Positron emission tomography scans confirmed active LCH in 146/256 (57 %). FDG-PET was superior to bone scans in that 8/23 (34 %) lesions, 11/53 (21 %) comparisons to lesions found by MRI, 13/64 (20 %) CT, and 58/116 (50 %) plain films. Positron emission tomography scans confirmed lesions found by: 14/23 (61 %) bone scans, 33/53 (62 %) MRI, 45/64 (65 %) CT, and 54/116 (46 %) of plain films. The authors concluded that whole body FDG-PET scans can detect LCH activity and early response to therapy with greater accuracy than other imaging modalities in patients with LCH lesions in the bones and soft tissues. Whole-body FDG-PET scanning is an important and informative study at diagnosis and for following disease course in patients with LCH.

Krajicek et al (2009) stated that pulmonary Langerhans cell histiocytosis (PLCH) is an inflammatory lung disease strongly associated with cigarette smoking and an increased risk of malignant neoplasms. Although the chest CT scan characteristics of PLCH are well-recognized, the PET scan characteristics of adults with PLCH are unknown. These researchers identified 11 patients with PLCH who underwent PET scanning over a 6-year period from July 2001 to June 2007. The presenting clinic-radiologic features including PET scan and chest CT scan findings were analyzed. Five of 11 patients had positive PET scan findings. Of the 5 PET scan-positive patients, 4 (80 %) were women, 4 (80 %) were current smokers, and the median age was 45 years (age range of 31 to 52 years). PET scan-positive findings were more likely to be present if the scan was performed early in the clinical course. Three PET scan-positive patients (60 %) had multi-organ involvement. PET scan-positive patients had predominantly nodular inflammatory lung disease (greater than 100 nodules) with most nodules measuring less than 8 mm, whereas all PET scan-negative patients had predominantly cystic lung disease with fewer nodules (less than 25 nodules). Notable abnormal PET scan findings included foci of increased uptake in nodular lung lesions, thick-walled cysts, bone, and liver lesions. The mean maximum standardized uptake value of the PET scan-positive lesions ranged from 2.0 to 18.2. The authors concluded that PLCH may be associated with abnormal thoracic and extra-thoracic PET scan results. Patients with nodular disease seen on chest CT scans appear more likely to have abnormal PET scan findings. They stated that these findings suggested that PET scan imaging cannot reliably distinguish between the benign inflammatory nodular lesions of PLCH and malignant lesions.

Adam et al (2010) noted that PLCH manifests with dyspnea and a cough with no significant expectoration, with spontaneous pneumothorax being the first symptom in some patients. The disease is caused by multiple granulomas in terminal bronchioles, visible on high resolution CT (HRCT) as nodules. During the further course of the disease, these nodules progress through cavitating nodules into thick-walled and, subsequently, thin-walled cysts. LCH may affect the lungs only or multiple organs simultaneously. Pulmonary LCH may continually progress or remit spontaneously. Treatment is indicated in patients in whom pulmonary involvement is associated with multi-system involvement or when a progression of the pulmonary lesions has been confirmed. To document the disease progression, examination of the lungs using HRCT is routinely applied. Increasing number of nodules suggests disease progression. However, determining the number of nodules is extremely difficult. Measuring radioactivity of the individual small pulmonary loci (nodules) using PET is not possible due to the high number and small size of the nodules. The authors’ center has a register of 23 patients with LCH; the pulmonary form had been diagnosed in 7 patients. A total of 19 PET and PET-CT examinations were performed in 6 of these patients. PET-CT was performed using the technique of maximum fluorodeoxyglucose accumulation in a defined volume of the right lung - -SUV(max) Pulmo. In order to compare the results of examinations performed using the same and different machines over time as well as in order to evaluate pulmonary activity, the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung (SUV(max) Pulmo) to maximum fluorodeoxyglucose accumulation in a defined volume of the liver tissue (SUV(max) Hepar) ratio (index) was used. The disease progression was evaluated using the SUV(max) Pulmo/SUV(max) Hepar index in the six patients with pulmonary LCH. The index value was compared to other parameters characterizing the disease activity (HRCT of the lungs, examination of pulmonary function and clinical picture). The SUV(max) Pulmo/SUV(max) Hepar index correlated closely with other disease activity parameters. The traditional PET-CT examination is useful in detecting the LCH loci in the bone, nodes and other tissue but not in the presence of diffuse involvement of pulmonary parenchyma. Measuring the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung and expressing this activity as the SUV(max) Pulmo/SUV(max) Hepar index appears to be a promising approach. The authors concluded that their initial experience suggested that the results obtained using this method correlate well with other parameters that characterize activity of P LCH. However, they noted that this was a pilot study and further verification is required.

An UpToDate review on "Pulmonary Langerhans cell histiocytosis" (King, 2012) states that "Fluorodeoxyglucose-PET (FDG-PET) scans may show increased uptake in patients with PLCH, particularly when obtained early in the course of disease. This was evaluated in a series of 11 patients with PLCH, five of whom had abnormal FDG uptake in the lungs. The patients with FDG-PET positivity were more likely to have nodular radiographic pattern, suggesting earlier disease; those with negative FDG-PET scans were more likely to have a cystic pattern and fewer nodules, suggesting later disease". The study cited was that by Krajicek et al (2009).

Large-Vessel Vasculitis

Blockmans et al (2009) stated that ultrasonography, MRI, and PET are increasingly studied in large-vessel vasculitis. These imaging modalities have broadened the knowledge on these disorders and have a place in the diagnostic approach of these patients. Temporal artery ultrasonography can be used to guide the surgeon to that artery segment with the clearest "halo" sign to perform a biopsy, or in experienced hands can even replace biopsy. The distal subclavian, axillary, and brachial arteries can also be examined. High-resolution MRI depicts superficial cranial and extra-cranial involvement patterns in giant cell arteritis (GCA). Contrast enhancement is prominent in active inflammation and decreases under successful steroid therapy. Presence of aortic complications such as aneurysm or dissection can be ruled out within the same investigation. Large thoracic vessel FDG-uptake is seen in the majority of patients with GCA, especially at the subclavian arteries and the aorta. However, FDG-PET can not predict which patients are bound to relapse, and once steroids are started, interpretation is hazardous, which makes its role in follow-up uncertain. Increased thoracic aortic FDG-uptake at diagnosis of GCA may be a bad prognostic factor for later aortic dilatation. In patients with isolated polymyalgia rheumatica – who have less intense vascular FDG uptake – symptoms are caused by inflammation around the shoulders, hips, and spine. The authors concluded that ultrasonography, MRI, and PET remain promising techniques in the scientific and clinical approach of large-vessel vasculitis.

Neuroblastoma

In a phase I trial, Taggart et al (2009) compared 2 functional imaging modalities for neuroblastoma:

metaiodobenzylguanidine (MIBG) scan for uptake by the norepinephrine transporter and
(18)F(FDG-PET) uptake for glucose metabolic activity.

Patients were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. (131)I-MIBG therapy was administered on days 0 and 14. For each patient, these researchers compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semi-quantitative score. The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6 % when examining the 139 unique anatomical lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (p < 0.001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semi-quantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment. The authors concluded that MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.

Cardiac Sarcoidosis and Cardiomyopathies

Sharma (2009) reviewed the role of various imaging modalities in the evaluation of cardiac sarcoidosis and other cardiomyopathies. No study prospectively established the accuracy of each of the various techniques for diagnosing myocardial involvement in patients with suspected cardiac sarcoidosis. Cardiac magnetic resonance imaging (CMR) is demonstrated to have a sensitivity of 100 % and specificity of approximately 80 %, and positive predictive value of approximately 55 % in diagnosing cardiac sarcoidosis. Recent studies have shown that FDG-PET has 100 % sensitivity of detecting earlier stages of sarcoidosis. Both FDG-PET and CMR may provide complementary information for the diagnosis and assessment of efficacy of therapy in patients with cardiac involvement from sarcoidosis. The author concluded that clinical and sub-clinical cardiac involvement is common among patients with sarcoidosis. A structured clinical assessment incorporating advanced cardiac imaging with CMR and FDG-PET scanning is more sensitive than the established clinical criteria. Cardiac MRI is an established imaging modality in the diagnosis of various other cardiomyopathies. The author stated that well designed prospective clinical trials are awaited to define the exact role of these imaging studies in the diagnosis and guidance of therapy.

Kawano et al (2012) stated that sarcoidosis is a multi-systemic granulomatous disease of unknown etiology. These researchers reported an unusual case of sarcoidosis in a woman presenting with cardiac sarcoidosis and massive splenomegaly with a familial history of cardiac sarcoidosis. Cardiac sarcoidosis was diagnosed based on electrocardiogram, echocardiogram, 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) and skin histological findings. They performed splenectomy to rule out malignant lymphoma, and histological findings confirmed sarcoidosis. After splenectomy, these investigators initiated prednisolone therapy. At 20 months following diagnosis, she was symptom free. The authors concluded that echocardiography and 18F-FDG-PET may be a key diagnostic tool and prednisolone therapy may be safe, effective, and feasible for cardiac sarcoidosis.

A review in UpToDate on "Clinical manifestations and diagnosis of cardiac sarcoidosis" (Blankstein and Stewart, 2018) states that FDG-PET can detect active myocardial inflammation, which can be used to determine the likelihood of cardiac sarcoidosis (CS) when used in the appropriate clinical context. The authors further state that FDG-PET is more sensitive than gallium-67 scintigraphy, thallium-201, or technicium-99m single-photon emission computed tomography (SPECT). The authors state that in patients who have known extracardiac sarcoidosis, characteristic cardiac magnetic resonance imaging (CMR) or 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) findings can be used to confirm the diagnosis of CS. Endomyocardial biopsy is often not required; and in the absence of biopsy-proven extracardiac sarcoidosis, or when data are inconclusive, integrating data from CMR imaging and FDG-PET may be useful for establishing the likelihood of CS.

An UpToDate review on "Management and prognosis of cardiac sarcoidosis" (Blankstein and Cooper, 2018) states that several studies have demonstrated that advanced cardiac imaging with cardiac magnetic resonance (CMR) or 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has predictive value for adverse cardiovascular events including death. Furthermore, retrospective studies in patients with known or suspected CS have found that abnormal cardiac PET findings are associated with adverse cardiac events including sustained VT and death. "A retrospective study of 118 patients referred for cardiac PET with known or suspected CS with a mean follow-up of 1.5 years found that 31 patients (26 percent) developed death or VT requiring therapy. Patients who had both abnormal uptake of FDG by the myocardium (eg, focal inflammation) and a resting perfusion defect (eg, scar or compression of the microvasculature) had a fourfold increase in the annual rate of VT or death compared with patients with normal imaging. These findings remained significant even after accounting for the Japanese Ministry of Health and Welfare (JMHW) criteria and LVEF. Individuals who had evidence of focal FDG uptake involving the right ventricle had the highest rate of death or VT. The presence of evidence of extracardiac inflammation was not associated with adverse events, suggesting that such features should not be used in deciding on the role of ICD therapy."

Experpt consensus is that immunosuppressive therapy is recommended for selected patients with CS, thus Blankstein and Stewart (2018) recommend FDG-PET in patients who are candidates for immunosuppressive therapy for CS. In this setting, FDG-PET would be useful for the following reasons: the presence of myocardial as well as extracardiac inflammation would indicate a greater role for systemic immunosuppressive therapy, and the FDG-PET scan could serve as a baseline upon which to compare future FDG-PET studies to determine response to therapy.

Bone Marrow Involvement

In a meta-analysis, Chen et al (2011) evaluated the ability of FDG PET or PET/CT scan to ascertain the presence of bone marrow (BM) involvement in aggressive and indolent non-Hodgkin's lymphoma (NHL). These researchers conducted a systematic Medline search of articles published (last update, May 2010). Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed. A total of 8 studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of non-Hodgkin aggressive lymphoma were 0.74 (95 % CI: 0.65 to 0.83) and 0.84 (95 % CI: 0.80 to 0.89), respectively. Pooled sensitivity and specificity for the detection of non-Hodgkin indolent lymphoma were 0.46 (95 % CI: 0.33 to 0.59) and 0.93 (95 % CI: 0.88 to 0.98), respectively. The authors concluded that diagnostic accuracy of FDG PET or PET/CT scans was slightly higher but without significant statistical difference (p = 0.1507) in patients with non-Hodgkin aggressive lymphoma as compared with those with non-Hodgkin indolent lymphoma. The sensitivity to detect indolent lymphoma BM infiltration was low for FDG PET or PET/CT.

Sentinel Lymph Node Biopsy for Melanoma

Dengel et al (2011) stated that the false-negative rate for sentinel lymph node biopsy (SLNB) for melanoma is approximately 17 %, for which failure to identify the sentinel lymph node (SLN) is a major cause. Intra-operative imaging may aid in detection of SLN near the primary site, in ambiguous locations, and after excision of each SLN. In a pilot study, these researchers (2011) evaluated the sensitivity and clinical utility of intra-operative mobile gamma camera (MGC) imaging in SLNB in melanoma. From April to September 2008, 20 patients underwent Tc99 sulfur colloid lymphoscintigraphy, and SLNB was performed with use of a conventional fixed gamma camera (FGC), and gamma probe followed by intra-operative MGC imaging. Sensitivity was calculated for each detection method. Intra-operative logistical challenges were scored. Cases in which MGC provided clinical benefit were recorded. Sensitivity for detecting SLN basins was 97 % for the FGC and 90 % for the MGC. A total of 46 SLN were identified: 32 (70 %) were identified as distinct hot spots by pre-operative FGC imaging, 31 (67 %) by pre-operative MGC imaging, and 43 (93 %) by MGC imaging pre- or intra-operatively. The gamma probe identified 44 (96 %) independent of MGC imaging. The MGC provided defined clinical benefit as an addition to standard practice in 5 (25 %) of 20 patients. Mean score for MGC logistic feasibility was 2 on a scale of 1 to 9 (1 = best). The authors concluded that intra-operative MGC imaging provides additional information when standard techniques fail or are ambiguous. Sensitivity is 90 % and can be increased. This pilot study has identified ways to improve the usefulness of an MGC for intra-operative imaging, which holds promise for reducing false negatives of SLNB for melanoma.

Schwannoma (Acoustic Neuroma)

Schwannoma (also known as an acoustic neuromas) are benign nerve sheath tumors composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves. They are mostly benign and less than 1 % become malignant, degenerating into a form of cancer known as neurofibrosarcoma. Schwannomas can arise from a genetic disorder called neurofibromatosis. Schwannomas can be removed surgically, but can then recur. The imaging procedure of choice for schwannomas is magnetic resonance imaging, with or without gadolinium contrast, which can detect tumors as small as 1 to 2 mm in diameter. There are studies reporting FDG uptake in schwannomas, but no studies demonstrating better accuracy or improvements in clinical outcomes with PET over MRI.

Focal Eosinophilic Liver Disease (FELD)

Kim et al (2010) reviewed the FDG PET findings of focal eosinophilic liver disease (FELD) and correlated them with radiologic and pathologic findings. A total of 14 patients, who were clinically or pathologically diagnosed as FELD and underwent CT and/or MR and PET, were enrolled. Two radiologists analyzed CT and MRI regarding size, shape, margin, attenuation, signal intensity (SI), and enhancement patterns of the lesion, both qualitatively and quantitatively. One pathologist determined whether the lesion is eosinophilic abscess (EA) or infiltration. One nuclear medicine physician reviewed the PET images and calculated the peak SUV of the lesion. PET findings were then correlated with CT or MRI, and pathologic findings. Eighty-five lesions were detected on CT (n = 85) and MRI (n = 10). Only 4 of the lesions showed FDG uptake and their mean SUV was 4.0. The size of the lesions with FDG uptake (26.5 mm) was significantly larger than those without uptake (11.8 mm). Mean attenuation and SI differences between the lesion and adjacent liver on CT and T2-weighted MRI tended to be larger in the uptake group (64.3 and 124.5) than the group without uptake (28.5 and 43.5). Among the 4 histologically confirmed lesions, 2 EAs and 1 of the 2 EIs showed FDG uptake. The authors concluded that most FELD do not show FDG uptake on PET. However, larger nodules with greater attenuation or SI differences from the background liver on CT or T2-weighted MRI or those with EA on pathology tend to show FDG uptake on PET.

Also, an UpToDate review on "Clinical manifestations, pathophysiology, and diagnosis of the hypereosinophilic syndromes" (Roufosse et al, 2012) does not mention the use of PET/positron emission tomography.

Erdheim-Chester Disease

An UpToDate review on "Erdheim-Chester disease" (Jacobsen, 2012) states that "imaging studies include magnetic resonance imaging (MRI) of the brain, a computed tomography (CT) scan or an MRI of the entire aorta, a cardiac MRI, a CT scan of the chest, abdomen, and pelvis (which can also be used to image the entire aorta), and a transthoracic echocardiography. An MRI of the spinal cord is only necessary if the patient has signs or symptoms of spinal cord involvement. The utility of positron emission tomography (FDG-PET) scanning is unclear and not routinely recommended at present".

Myoclonus

UpToDate reviews on "Opsoclonus myoclonus ataxia" (Dalmau and Rosenfeld, 2012) and "Symptomatic (secondary) myoclonus" (Caviness, 2012) do not mention the use of PET and/or CT.

Penile Cancer

Available evidence on the use of PET for penile cancer is limited to use of PET in evaluation of inguinal lymph nodes, with most of the evidence limited to case reports. A recent review article in UpToDate (Lynch, 2012) on "Carcinoma of the penis: Diagnosis, treatment, and prognosis" states describes PET scans as a "evolving imaging technique" that is "promising". Furthermore, the NCCN’s clinical practice guideline on penile cancer (NCCN, version 2.2018) states that (for evaluation and risk stratification) "while studies have looked at the use of nanoparticle-enhanced MRI, positron emission tomography-CT (PET/CT), and 18F-fluorodeoxyglucose (FDG) PET/CT, their small sample requires validation in larger prospective studies".

Endometrial Cancer and Uterine Sarcoma

The Society for Gynecologic Oncology guidelines on serous papillary endometrial cancer made no recommendation for PET (Boruta et al, 2009).

Kakhki et al (2013) systematically searched the available literature on the accuracy of 18F-FDG PET imaging for staging of endometrial cancer. PubMed, SCOPUS, ISI Web of Knowledge, Science Direct, and Springer were searched using "endometr^* and PET" as the search terms. All studies evaluating the accuracy of 18F-FDG PET in the staging of endometrial carcinoma were included. Statistical pooling of diagnostic accuracy indices was done using random-effects model. Cochrane Q test and I index were used for heterogeneity evaluation. A total of 16 studies (807 patients in total) were included in the meta-analysis. Sensitivity and specificity for detection of the primary lesions were 81.8 % (77.9 % to 85.3 %) and 89.8 % (79.2 % to 96.2 %); for lymph node staging were 72.3 % (63.8 % to 79.8 %) and 92.9 % (90.6 % to 94.8 %); and for distant metastasis detection were 95.7 % (85.5 % to 99.5 %) and 95.4 % (92.7 % to 97.3 %). The authors concluded that because of low sensitivity, diagnostic utility of 18F-FDG PET imaging is limited in primary tumor detection and lymph node staging of endometrial cancer patients. However, high specificities ensure high positive-predictive values in these 2 indications. Diagnostic performance of 18F-FDG PET imaging is much better in detection of distant metastases. Moreover, they stated that larger studies with better design are needed to draw any more definite conclusion.

Sadeghi et al (2013) reviewed the medical literature on the application of 18F-FDG PET imaging in the management of uterine sarcomas and presented the results in systematic review and meta-analysis format. Medline, SCOPUS, and ISI Web of Knowledge were searched electronically with "PET and (uterine or uterus)" as key words. All studies evaluating the accuracy of 18F-FDG imaging in the staging or restaging of uterine sarcomas were included if enough data could be extracted for calculation of sensitivity and/or specificity. A total of 8 studies were included in the systematic review. Only 2 studies reported the accuracy of 18F-FDG PET imaging in the primary staging of uterine sarcoma with low sensitivity for lymph node staging. For re-staging (detection of recurrence), all 8 included studies had quantitative data, and the patient-based pooled sensitivity and specificity were 92.1 % (95 % CI: 82.4 to 97.4) and 96.2 % (95 % CI: 87 to 99.5), respectively. On a lesion-based analysis, sensitivity was 86.3 % (95 % CI: 76.7 to 92.9), and specificity was 94.4 % (95 % CI: 72.7 to 99.9). Device used (PET versus PET/CT), spectrum of studied patients, and histology of the sarcoma seem to be factors influencing the overall accuracy of 18F-FDG PET imaging. The authors concluded that 18F-FDG PET and PET/CT seem to be accurate methods for detection and localization of recurrence in patients with uterine sarcoma. Moreover, they stated that further large multi-center studies are needed to validate these findings and to correlate both sarcoma type and spectrum of patients to the diagnostic performance of 18F-FDG PET imaging in recurrence detection. The studies evaluating the accuracy of 18F-FDG PET imaging for the primary staging of uterine sarcoma are very limited, and no definite conclusion can be made in this regard.

The National Comprehensive Cancer Network (NCCN) on "Uterine neoplasms" (Version, 1.2019) states to consider whole body PET/CT for initial workup of endometrial carcinoma if metastasis is suspected in select patients, and for select patients who may be candidates for surgery/locoregional therapy. For uterine sarcoma, NCCN recommends consideration of whole body PET/CT for inital workup or post-treatment surveillance of uterine sarcoma to clarify ambiguous findings, or if metastasis is suspected in select patients.

Spindle Cell Sarcoma and Soft Tissue Sarcoma

Spindle cell sarcoma is a type of connective tissue cancer in which the cells are spindle-shaped when examined under a microscope. It is considered a type of soft tissue sarcoma. An UpToDate review on "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma" (Ryan and Meyer, 2012) states that "A number of studies report that PET and integrated PET/CT using fluorodeoxyglucose (FDG) can distinguish benign soft tissue tumors from sarcomas, with the greatest sensitivity for high grade sarcomas. However, the ability to differentiate benign soft tissue tumors from low or intermediate grade sarcomas is limited, and PET and PET/CT are not routinely recommended for the initial work-up of a soft tissue mass. One exception may be in the characterization of a suspected peripheral nerve sheath tumor in a patient with neurofibromatosis; in this scenario, PET imaging can be helpful in distinguishing an MPNST from a neurofibroma. Consensus guidelines for workup of a soft tissue sarcoma of the extremity and trunk issued by the National Comprehensive Care Network (NCCN) suggest that PET scan may be useful in the prognostication, grading, and determining response to neoadjuvant chemotherapy in patients with soft tissue sarcoma. However, this recommendation is based upon a single study from the University of Washington that found that FDG-PET was useful to predict the outcomes of patients with high-grade extremity soft tissue sarcomas who were treated initially with chemotherapy. Patients with a baseline tumor SUV max ≥ 6 who had a < 40 percent decrease in FDG uptake after neoadjuvant chemotherapy were found to be at high risk of systemic disease recurrence. The clinical utility of having this information prior to surgical treatment is unclear. At present, the use of PET for prognostication or assessment of treatment response is not considered routine at most institutions .... PET scanning can achieve whole body imaging, and it is widely considered to be more sensitive than CT for the detection of occult distant metastases in a variety of solid tumors. However, the utility of PET alone or with integrated CT for staging of distant disease extent in STS (soft tissue sarcomas) is unclear as evidenced by the following reports".

Wilms Tumor

The National Wilms Tumor Study Group and the International Society for Paediatric Oncology protocols recommend chest x-ray and CT imaging for lung metastases (Bhatnager, et al., 2009). There is no recommendation for use of PET in these protocols.

A review on renal neoplasms in childhood in Radiology Clinics of North America (Geller & Kochan, 2011) states that current Central Oncology Group (COG) protocols call for the use of chest CT for documentation and follow-up of pulmonary metastases. The review makes no recommendation for use of PET in Wilm’s tumor.

A GeneReviews review of Wilms tumor (Dome & Huff, 2011) states that: "Positron emission tomography (PET) is not a routine component of the initial evaluation of Wilms tumor, though most Wilms tumors take up the radiotracer fluoro-deoxyglucose. PET may play a role in the detection of occult metastatic sites at recurrence." This GeneReviews article provides one reference in support of the use of PET for detection of occult metastases (Moinul Hossain, et al., 2010) of 27 patients with Wilm’s tumor, reporting that there were 34 positive scans, of which 8 were in lungs. The Moinus Hossain article noted, however, that lung lesions less than 10 mm were not consistently visualized on PET scans. The study was done in persons with known Wilms tumor, and did not report whether the PET scans were more accurate than other imaging modalities.

Current NCCN guidelines on "Kidney cancer" (Version 2.2019) make no recommendation for use of PET. The guidelines state that the value of PET in kidney cancer "remains to be determined" and that "PET alone is not a tool that is standardly used to diagnose kidney cancer or follow for evidence of relapse after nephrectomy." Although NCCN guidelines address kidney cancer, they do not have specific recommendations on Wilms tumors.

PET-Probe Guided Surgery

PET-probe guided (assisted) surgery is used for intraoperative localization of PET-positive recurrent/metastatic lesions. The surgery utilizes a hand-held PET probe, essentially is a high energy gamma probe designed to process the 511 keV photons of PET tracers, to localize areas of uptake and guide excision. There is no clinical evidence to support the use of PET-probe guided surgical resection for recurrent ovarian cancer.

Pilar Tumor

Siddha et al (2007) stated that pilar tumor is a rare neoplasm arising from the external root sheath of the hair follicle and is most commonly observed on the scalp. These tumors are largely benign, often cystic, and are characterized by trichilemmal keratinization. Wide local excision has been the standard treatment. Recent reports have described a rare malignant variant with an aggressive clinical course and a propensity for nodal and distant metastases which, therefore, merits aggressive treatment.

Khachemoune et al (2011) stated that a proliferating pilar tumor is a rare neoplasm arising from the isthmus region of the outer root sheath of the hair follicle. It is also commonly called a proliferating trichilemmal cyst. It was first described by Wilson-Jones as a proliferating epidermoid cyst in 1966. Proliferating pilar tumor was then distinguished from proliferating epidermoid cysts in 1995. It occurs most commonly on the scalp in women older than 50 years. Most tumors arise within a pre-existing pilar cyst. Even though they usually are benign in nature, malignant transformation with local invasion and metastasis has been described. A tentative stratification of proliferating pilar tumors into groups as benign, low-grade malignancy, and high-grade malignancy has been introduced. They may be inherited in an autosomal-dominant mode, linked to chromosome 3. Imaging studies are not usually indicated, but they may show a lobulated cystic mass, coarse calcification, or ring-like mineralization. Because some subcutaneous tumors located in the midline of the body may have connections to the central nervous system (e.g., scalp cavernous angioma, which may be part of the symptom complex known as sinus pericranii), imaging tumors in this location with CT or MRI prior to removal should be considered. The best modality to determine bony invasion or erosion is CT scanning, and proliferating pilar tumors are frequently found as incidental subcutaneous nodules on brain CT scans. They most frequently display iso-intensity on T1-weighted images and heterogeneous signal on T2-weighted images. However, for deeper tissue invasion, MRI is best.

Pancreatic Cancer

Currently, there is insufficient evidence to support PET scan for restaging of pancreatic cancer.

Topkan et al (2013) examined the impact of [(18)F]fluorodeoxyglucose-positron emission tomography (PET)/computed tomography (CT) restaging on management decisions and outcomes in patients with locally advanced pancreatic carcinoma (LAPC) scheduled for concurrent chemoradiotherapy (CRT). A total of 71 consecutive patients with conventionally staged LAPC were restaged with PET/CT before CRT, and were categorized into non-metastatic (M0) and metastatic (M1) groups. M0 patients received 50.4 Gy CRT with 5-fluorouracil followed by maintenance gemcitabine, whereas M1 patients received chemotherapy immediately or after palliative radiotherapy. In 19 patients (26.8 %), PET/CT restaging showed distant metastases not detected by conventional staging. PET/CT restaging of M0 patients showed additional regional lymph nodes in 3 patients and tumors larger than CT-defined borders in 4. PET/CT therefore altered or revised initial management decisions in 26 (36.6 %) patients. At median follow-up times of 11.3, 14.5, and 6.2 months for the entire cohort and the M0 and M1 cohorts, respectively, median overall survival was 16.1, 11.4, and 6.2 months, respectively; median loco-regional progression-free survival was 9.9, 7.8, and 3.4 months, respectively; and median progression-free survival was 7.4, 5.1, and 2.5 months, respectively (p < 0.05 each). The authors concluded that these findings suggested that PET/CT-based restaging may help select patients suitable for CRT, sparing those with metastases from futile radical protocols, and increasing the accuracy of estimated survival. (This was a small study examining the use of PET/CT for restaging in loco-regional pancreatic cancer; and the findings were preliminary)

Javery et al (2013) evaluated the impact of FDG-PET or PET/CT (PI) on pancreatic cancer management when added to CT or MRI (CDI). A total of 49 patients underwent 79 PI examinations. Discordant findings on PI and CDI were assessed for clinical impact. Overall, 15 of 79 PI-CDI pairs were discordant; 10 of 79 PI favorably; and 5 of 79 unfavorably altered management. PI favorably altered management more often when ordered for therapy monitoring compared to staging [risk ratio 13.00 (95 % confidence interval [CI]: 1.77 to 95.30)] or restaging [risk ratio 18.5 (95 % CI: 2.50 to 137.22)]. The authors concluded that PI favorably alters management more often when used for therapy monitoring compared to staging or restaging.

Furthermore, a UpToDate review on "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer" (Fernandez-del Castillo, 2013) states that "The utility of PET scans in the diagnostic and staging evaluation of suspected pancreatic cancer, particularly whether PET provides information beyond that obtained by contrast-enhanced MDCT, remains uncertain …. Taken together, the data are insufficient to conclude that PET or integrated PET/CT provides useful information above that provided by contrast-enhanced CT. Consensus-based guidelines for staging of pancreatic cancer from the NCCN state that the role of PET/CT remains unclear. Definitive assessment of the role of PET as a component of the diagnostic and/or staging evaluation awaits a large prospective study designed to assess the benefit of PET (preferably integrated PET with a contrast-enhanced CT) in patients with a negative or indeterminate CT scan, with a prospectively designed cost effectiveness analysis".

The American Society of Clinical Oncology (ASCO)’s clinical practice guideline on "Locally advanced, unresectable pancreatic cancer" (Balaban et al, 2016) stated that "The routine use of positron emission tomography imaging for the management of locally advanced, unresectable pancreatic cancer is not recommended".

The National Comprehensive Cancer Network (NCCN) on "Pancreatic adenocarcinoma" (Version 2.2018) states that "PET/CT may be considered after formal pancreatic CT protocol in high-risk patients to detect extra pancreatic metastasis. It is not a substitute for high-quality, contrast-enhanced CT". Furthermore, the "role of PET/CT (without iodinated intravenous contrast) remains unclear".

Adult Onset Still's Disease

Funauchi et al (2008) reported the case of a 35-year old woman was admitted to the authors’ hospital because of high fever and skin rash, and subsequently diagnosed as having adult onset Still's disease (AOSD). Because of resistance to the steroid hormones, high levels of the serum-soluble form of the interleukin-2 receptor and splenomegaly, these researchers suspected a possible diagnosis of malignant lymphoma and performed PET, which disclosed an intense accumulation of 2-deoxy-2 [F18] fluoro-D-glucose (FDG) in the liver and spleen. However, bone marrow aspiration and liver biopsy did not reveal any malignant cells. After the treatment of high-dose adrenocorticosteroids and plasma exchange, her symptoms and laboratory data, including PET findings, gradually improved. The authors concluded that this was a rare case of severe AOSD in which an intense accumulation of FDG was detected by PET, and a differential diagnosis from malignant lymphoma may be difficult by FDG-PET alone, so that careful evaluation by techniques including histopathological examination may be necessary.

Assessment of Splenic Lesions

An UpToDate review on "Approach to the adult patient with splenomegaly and other splenic disorders" (Landaw and Schrier, 2014) states that "A variety of imaging techniques are available for assessment of splenic lesions (e.g., splenic cysts, other space-occupying lesions), including CT scanning, magnetic resonance imaging, ultrasound, Tc-99m sulfur colloid scintigraphy, and 18F-FDG PET. Although the age of the patient, clinical symptomatology, and imaging characteristics might help the radiologist arrive at the correct diagnosis, one study has concluded that PET scanning offered no additional information over that obtained using CT scanning alone, and that a history of prior malignancy was the only independent predictor for a splenic lesion being malignant (odds ratio 6.3; 95 % CI 2.3-17)".

X-Linked Adrenoleukodystrophy (X-ALD)

Salsano et al (2014) investigated the cerebral glucose metabolism in subjects with X-linked adrenoleukodystrophy (X-ALD) by using brain [(18)F]-fluorodeoxyglucose PET (FDG-PET). This was a cross-sectional study in which 12 adults with various forms of X-ALD underwent clinical evaluation and brain MRI, followed by brain FDG-PET, neuropsychological assessment, and personality and psychopathology evaluation using the Symptom Checkist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III). When compared to healthy control subjects (n = 27) by using Statistical Parametric Mapping 8 software, the patients with X-ALD-with or without brain MRI changes-showed a pattern of increased glucose metabolism in frontal lobes and reduced glucose metabolism in cerebellum and temporal lobe areas. On single case analysis by Scenium software, these researchers found a similar pattern, with significant (p < 0.02) correlation between the degree of hyper-metabolism in the frontal lobes of each patient and the corresponding X-ALD clinical scores. With respect to personality, these investigators found that patients with X-ALD usually present with an obsessive-compulsive personality disorder on the MCMI-III, with significant (p < 0.05) correlation between glucose uptake in ventral striatum and severity of score on the obsessive-compulsive subscale. The authors concluded that they examined cerebral glucose metabolism using FDG-PET in a cohort of patients with X-ALD and provided definite evidence that in X-ALD the analysis of brain glucose metabolism reveals abnormalities independent from morphologic and signal changes detected by MRI and related to clinical severity. They stated that brain FDG-PET may be a useful neuroimaging technique for the characterization of X-ALD and possibly other leukodystrophies.

The drawbacks of this study were:

the number of patients was limited because of the rarity of X-ALD,
patients were not randomized, and
the use of some drugs (e.g., corticosteroids, baclofen and valproic acid) by some symptomatic patients; these drugs might influence FDG-PET data.

Furthermore, these investigators stated that the findings of this study lay the foundations of larger studies that might assess whether the abnormal brain glucose metabolism detected in X-ALD can be used as a surrogate marker.

Melanoma

The National Comprehensive Cancer Network (NCCN) on "Cutaneous melanoma" (Version 1.2019) states that "routine cross-sectional imaging (CT, PET/CT, or MRI) is not recommended for patients with stage 0, I, and II disease." However, "in patients with stage III disease, PET/CT scan may be more useful. In particular, PET/CT scans can help to further characterize lesions found to be indeterminate on CT scan, and can image areas of the body not studied by the routine body CT scan." Thus, the NCCN panel provides a category 2B recommendation for cross-sectional imaging at baseline for staging of stage III sentinel node positive disease, or a category 2A recommendation to assess specific signs or symtpoms. The NCCN panel "encourage baseline chest/abdominal/pelvic CT with or without PET/CT in patiens with stage IV melanoma".

Castleman Disease

A review of PET in HIV-associated multi-centric Castleman disease (Rossotti et al, 2012) concluded "So far, FDG-PET/CT use for diagnosing Castleman disease has been reported in only a small number of patients. Data defining sensitivity and specificity of FDG-PET/CT for Castleman disease diagnosis are lacking". Guidelines from the European Association of Nuclear Medicine and the Society for Nuclear Medicine and Molecular Imaging on PET in inflammation and infection (Jamar et al, 2013) stated that Castleman disease is one of several "well-described applications, but without sufficient evidence-based indication" for PET. Furthermore, current British guidelines for HIV-associated malignancies (Bower et al, 2014) states that regarding Castleman disease, "The role of functional imaging such as fluorodeoxyglucose positron emission tomography (FDG-PET) scans is uncertain; although a small study indicated that in individuals with active MCD, FDG-PET scans more frequently detected abnormal uptake than CT". Guidelines from the National Comprehensive Cancer Network "B-cell lymphomas" (NCCN, 2018) recommend FDG-PET in the workup of patients with Castleman disease.

Gallium Ga 68 Dotatate PET (NetSpot) for Neuroendocrine Tumors

The FDA labeling that states that NETSPOT "is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients." The labeling describes the three open label single center studies of NETSPOT that were submitted to the FDA. One study of subjects with neuroendocrine tumors (n = 97) reported on the correlations between the NETSPOT to CT, MRI, and SPECT images obtained within the previous three years. A second study of subjects with suspected neuroendocrine tumors (n = 104) compared NETSPOT to histopathology or clinical follow-up. A third study evaluated subjects (n = 63) for neuroendocrine tumor recurrence using histopathology or clinical follow-up as a reference standard.

Consensus guidelines from the National Comprehensive Cancer Network (NCCN, 2018) states: "Several studies have also shown diagnostic utility, as well as high sensitivity, of PET/CT imaging using the radiolabeled somatostatin analog gallium-68 (68Ga) dotatate. Unless otherwise indicated, somatostatin receptor-based imaging in this discussion includes imaging with either somatostatin receptor scintigraphy or 68-Ga dotatate PET/CT."

A systematic evidence review of somatostatin imaging for neuroendocrine tumors (Chou, et al., 2017) found somatostatin-receptor PET was associated with greater sensitivity than OctreoScan and FDG-PET, and also higher sensitivity for identification of primary neuroendocrine tumors than CT/MRI. The review found, however, that, for metastatic lesions, three studies reported inconsistent findings, with some studies finding no clear differences between somatostatin-receptor PET and MRI, or MRI associated with slightly higher sensitivity. The review also concluded that most studies reported no clear differences in specificity between somatostatin-receptor PET and alternative imaging modalities.

The review found that "[e]vidence on how comparative diagnostic accuracy varies according to tumor characteristics is limited" (Chou, et al., 2017). Most studies appeared to evaluate accuracy for diagnosis of more well-differentiated/indolent neuroendocrine tumors, though details about tumor grade and type were relatively limited.

The review noted that, although studies found that somatostatin receptor PET was associated with changes in management in a substantial proportion of patients, the studies had important methodological limitations. In particular, the studies did not pre-define "changes in management" or report use of standardized protocols to guide management decisions in response to somatostatin-receptor PET imaging findings, and no study included a comparison group of patients who underwent somatostatin-receptor PET without alternative imaging. The review also found that no study was designed to assess clinical outcomes associated with use of somatostatin-receptor PET.

The investigators noted that limitations of this review include the relatively small number of studies available for specific imaging comparisons and types of neuroendocrine tumors, the lack of evidence on how patient and tumor characteristics impact diagnostic accuracy, and methodological limitations in the studies, including suboptimal and heterogeneous reference standards and use of a case-control design in a number of studies (Chou, et al., 2017). Most studies reported results based on per-lesion analyses, which may not be as clinically relevant as per-patient analyses. Per-lesion analyses may also result in higher precision of estimates than warranted, since one patient may have many lesions. Some studies were not designed to or failed to report specificity, providing incomplete information regarding diagnostic accuracy.

Copper Cu-64 Dotatate PET (DetectNet) for Neuroendocrine Tumors

The use of a PET-emitter with a longer half-life such as copper-64 (T1/2 = 12.7 hours), such as Cu-64 dotatate (DetectNet) is being investigated as an alternative to Ga-68 DOTATE for neuroendocrine tumors, as the latter requires a generator because of its very short half life. A review (Eychenne, et al., 2020) concluded that despite a higher dosimetric impact for copper-64 (only 17.6% of radioactive decay lead to positron emission), copper-64 somatostatin analogs appear to be an advantageous alternative to gallium-68 radiopharmaceuticals. Compared to gallium-68, in addition to economic advantages, copper-64 has a lower positron range which leads to a better PET intrinsic resolution and a higher half-life which allows for a more flexible scanning window. The authors concluded, however, that "[t]he better patient care management and outcomes remain to be proven and the work is in progress to establish these points" [citing Carlsen, et al., 2020; Delpassand, et al., 2020].

Giant Cell Tumor of the Bone

Muheremu and Niu (2015) examined PET/CT and its applications for the diagnosis and treatment of bone tumors. The advantages and disadvantages of PET/CT were also evaluated and compared with other imaging methods and the prospects of PET/CT were discussed. The PubMed, Medline, Elsevier, Wanfang and China International Knowledge Infrastructure databases were searched for studies published between 1995 and 2013, using the terms "PET/CT", "positron emission tomography", "bone tumor", "osteosarcoma", "giant cell bone tumor" and "Ewing sarcoma". All the relevant information was extracted and analyzed. A total of 73 studies were selected for the final analysis. The extracted information indicated that at present, PET/CT is the imaging method that exhibits the highest sensitivity, specificity and accuracy. The authors concluded that although difficulties and problems remain to be solved, PET/CT is a promising non-invasive method for the diagnostic evaluation of and clinical guidance for bone tumors.

An UpToDate review on "Giant cell tumor of bone" (Thomas and Desai, 2015) states that "There are limited data regarding the utility of fluorine-18 fluorodeoxyglucose (18F-FDG)-PET for newly diagnosed GCTB. Unlike many benign bone tumors, GCTB accumulate the FDG tracer, presumably because the osteoclast-like giant cells are intensely metabolically active. However, whether there are any advantages to evaluation with FDG PET as compared to conventional imaging with CT, MRI, and bone scan is unclear".

Furthermore, NCCN’s clinical practice guideline on "Bone cancer" (Version 1.2019) does not mention PET imaging as a management tool for giant cell tumor of the bone.

NaF-18 PET for Bone Metastasis

According to CMS (2010), there is insufficient evience to determine that the results of NaF-18 PET imaging to identify bone metastases improve health outcomes of beneficiaries with cancer. Thus, the CMS decided that this use is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act.

Plasmacytoid Dendritic Cell Neoplasm

Kharfan-Dabaja et al (2013) stated that blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an exceedingly rare disorder categorized under acute myeloid leukemia by the World Health Organization (WHO). Phenotypically, malignant cells co-express CD4(+) and CD56(+) without co-expressing common lymphoid or myeloid lineage markers. BPDCN frequently expresses CD123, TCL1, BDCA-2, and CD2AP. Restriction of CD2AP expression to plasmacytoid dendritic cells makes it a useful tool to help confirm diagnosis. Clonal complex chromosome aberrations are described in 2/3 of cases; 80 % of BPDCN cases present with non-specific dermatological manifestations, prompting inclusion in the differential diagnosis of atypical skin rashes refractory to standard treatment. Prognosis is poor, with a median survival of less than 18 months. No prospective randomized data exist to define the most optimal frontline chemotherapy. Current practice considers acute myeloid leukemia-like or acute lymphoblastic leukemia-like regimens acceptable for induction treatment. Unfortunately, responses are short-lived, with second remissions difficult to achieve, underscoring the need to consider hematopoietic cell transplantation early in the disease course. Allografting, especially if offered in first remission, can result in long-term remissions. The authors concluded that pre-clinical data suggested a potential role for immunomodulatory agents in BPCDN. However, further research efforts are needed to better understand BPDCN biology and to establish evidence-based treatment algorithms that might ultimately improve overall prognosis of this disease.

Also, an UpToDate review on "Blastic plasmacytoid dendritic cell neoplasm" (Gurbuxani, 2015) does not mention PET scan as a management tool.

Squamous Cell Carcinoma (e.g., Cutaneous (SCC) and Vaginal Cancer)

An UpToDate review on "Clinical features and diagnosis of cutaneous squamous cell carcinoma (SCC)" (Lim and Asgari, 2012) does not mention the use of PET.

Bentivegna et al (2011) stated that [(18)F]fluoro-deoxy-glucose positron-emission tomography combined with integrated computed tomography (FDG-PET/CT) is commonly used for advanced stage cervical cancer but its efficiency is discussed in early stage. These researchers evaluated false negative rate of FDG-PET/CT in early-stage cervical and vaginal cancer. Patients treated between 2005 and 2008 for stage IB1 cervical cancer and stage I vaginal cancer and who underwent a FDG-PET/CT followed by a pelvic lymphadenectomy were studied. A total of 18 patients were included with bilateral pelvic lymphadenectomy (16 cervical cancers, 2 vaginal cancers). The median age of patients was 41 years. Radical hysterectomy was performed for 16 patients, by a laparoscopic approach in 15 cases and by a laparotomic approach in 1 case. One patient had a simple hysterectomy and 1 had exclusive radiotherapy. No patient had pelvic or para-aortic fixation on FDG-PET/CT; 3 patients have proven pelvic involvement and 1 had para-aortic metastases. The false-negative rate and negative predictive value of FDG-PET/CT were 17 % and 83 %, respectively. The authors concluded that the accuracy of FDG-PET/CT imaging in predicting the pelvic nodal status is very low in patients with early-stage cervical and vaginal cancer and is not able to replace surgical exploration.

An UpToDate review on "Vaginal cancer" (Karam et al, 2015) states that "Imaging studies – The only imaging studies that are part of the International Federation of Gynecology and Obstetrics (FIGO) staging for vaginal cancer are chest and skeletal radiography . However, advanced imaging, such as computed tomography (CT), magnetic resonance imaging (MRI) and 18-fluoro-2-deoxyglucose-positron emission tomography and CT (FDG-PET/CT) can be helpful for treatment planning. MRI can assist in determining the primary vaginal tumor size and local extent. Vaginal tumors generally are best seen on T2 imaging, and instilling gel into the vaginal canal, which distends the vaginal walls, often aids in visualizing and assessing the thickness of the vaginal tumor. FDG-PET can also be helpful for evaluating the primary vaginal tumor and abnormal lymph nodes …. Routine use of imaging studies was not recommended. Computed tomography (CT) and/or positron emission tomography (PET) should be performed ONLY if recurrence is suspected".

The National Comprehensive Cancer Network (NCCN) Imaging Appropriate Use Criteria (2018) for "Squamous cell skin cancer" includes a category 2A recommendation for the option of PET/CT for staging. PET/CT option for palpable regional lymph nodes or abnormal lymph nodes identified by imaging studies; FNA or core biopsy positive indications. For imaging to determine size, number, and location of nodes and to rule out distant disease. PET/CT of the nodal basin can be useful for RT planning.

Alzheimer’s Disease

The Centers for Medicare & Medicaid Services (CMS) released a decision memorandum on PET for suspected dementia. Although CMS announced limited coverage of PET to distinguish Alzheimer's disease from fronto-temporal dementia when the distinction is uncertain and other criteria are met, the decision memorandum recognized that there is no available literature that directly evaluated the impact on patient outcomes of adding PET in patients with early dementia who have undergone standard evaluation who do not meet the criteria for Alzheimer disease due to variations in the onset, presentation, or clinical course (suggesting other neurodegenerative causes for the disorder such as fronto-temporal dementia). In addition, CMS found no trials that examined the impact of PET in changing the management as a surrogate for evaluating PET impact on health outcomes in patients with this sort of difficult differential diagnosis. The assessment also recognized that there are no established cures for either Alzheimer disease or fronto-temporal dementia. A paucity of medications are available for Alzheimer's disease, which have a limited ability to decrease the rate of cognitive decline when administered early in the course of the disease. CMS coverage determination was primarily based on the value of PET in providing information useful in "non-medical decision-making." Aetna, however, does not consider non-medical decision-making a medically necessary indication for testing. Because of a lack of adequate evidence that PET scanning alters clinical management of such persons such that clinical outcomes are improved, Aetna considers PET scanning for differentiating Alzheimer disease from fronto-temporal dementia experimental and investigational.

An assessment prepared for the California Technology Assessment Forum (CTAF) concluded that PET for Alzheimer's disease does not meet CTAF's criteria (Feldman, 2004). The assessment stated: "The critical question that remains unanswered by this and the other studies of PET in the evaluation of AD/dementia is: To what extent does PET improve diagnostic accuracy beyond what can be obtained with a thorough clinical evaluation? Given that the sensitivity of clinical criteria are reported to be about 80 % to 90 %, it is difficult for any diagnostic test to significantly improve diagnostic accuracy. And given the fact that treatment of the most common non-AD dementias (e.g., Dementia of Lewy Bodies or vascular dementias) with cholinesterase inhibitor drugs is not likely to be harmful and in fact may be beneficial to these patients, it may be that an empirical approach of ruling out reversible causes of dementia and treating all others with cholinesterase inhibitor drugs is appropriate and cost effective."

The assessment noted that the greatest promise of PET in Alzheimer disease is likely to be in improving a clinician's ability to identify at-risk patients and to offer them treatment before they are significantly affected by Alzheimer disease. Few studies, however, have enrolled patients with mild symptoms or mild cognitive impairment so it is unclear what role PET is destined to play in identifying this subgroup of patients most likely to benefit from current and emerging therapies for Alzheimer's disease.

Clark et al (2011) examined if florbetapir F 18 PET imaging performed during life accurately predicts the presence of β-amyloid in the brain at autopsy. Prospective clinical evaluation conducted February 2009 through March 2010 of florbetapir-PET imaging performed on 35 patients from hospice, long-term care, and community health care facilities near the end of their lives (6 patients to establish the protocol and 29 to validate) compared with immunohistochemistry and silver stain measures of brain β-amyloid after their death used as the reference standard. PET images were also obtained in 74 young individuals (18 to 50 years) presumed free of brain amyloid to better understand the frequency of a false-positive interpretation of a florbetapir-PET image. Major outcome measures were correlation of florbetapir-PET image interpretation (based on the median of 3 nuclear medicine physicians' ratings) and semi-automated quantification of cortical retention with post-mortem β-amyloid burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study). Florbetapir-PET imaging was performed a mean of 99 days (range of 1 to 377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7 %) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of β-amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni ρ, 0.78 [95 % confidence interval, 0.58 to 0.89]; p < 0.001]) and silver stain neuritic plaque score (Bonferroni ρ, 0.71 [95 % confidence interval [CI]: 0.47 to 0.86]; p < 0.001). Florbetapir-PET images and postmortem results rated as positive or negative for β-amyloid agreed in 96 % of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the non-autopsy cohort. The authors concluded that florbetapir-PET imaging was correlated with the presence and density of β-amyloid. These data provided evidence that a molecular imaging procedure can identify β-amyloid pathology in the brains of individuals during life. Moreover, they stated that additional studies are needed to understand the appropriate use of florbetapir-PET imaging in the clinical diagnosis of Alzheimer disease and for the prediction of progression to dementia.

In an editorial that accompanied the afore-mentioned study, Breteler (2011) stated that "[o]nly through future studies using rigorous study design can the role of either florbetapir-PET imaging or plasma β-amyloid 42/40 in diagnosis or prediction of AD be determined".

Yeo et al (2015) noted that amyloid imaging using fluorine 18-labeled tracers florbetapir, florbetaben, and flutemetamol has recently been reported in Alzheimer's disease (AD). These researchers systematically searched Medline and Embase for relevant studies published from January 1980 to March 2014. Studies comparing imaging findings in AD and normal controls (NCs) were pooled in a meta-analysis, calculating pooled weighted sensitivity, specificity, and diagnostic odds ratio (OR) using the DerSimonian-Laird random-effects model. A total of 19 studies, investigating 682 patients with AD, met inclusion criteria. Meta-analysis demonstrated a sensitivity of 89.6 %, a specificity of 87.2 %, and an OR of 91.7 for florbetapir in differentiating AD patients from NCs, and a sensitivity of 89.3 %, a specificity of 87.6 %, and a diagnostic OR of 69.9 for florbetaben. There were insufficient data to complete analyses for flutemetamol. The authors concluded that these findings suggested favorable sensitivity and specificity of amyloid imaging with fluorine 18-labeled tracers in AD. They stated that prospective studies are needed to determine optimal imaging analysis methods and resolve outstanding clinical uncertainties.

In a Cochrane review, Smailagic and colleagues (2015) determined the diagnostic accuracy of the ^¹⁸F-FDG PET index test for detecting people with mild cognitive impairment (MCI) at baseline who would clinically convert to AD dementia or other forms of dementia at follow-up. These investigators searched the Cochrane Register of Diagnostic Test Accuracy Studies, Medline, Embase, Science Citation Index, PsycINFO, BIOSIS previews, LILACS, MEDION, (Meta-analyses van Diagnostisch Onderzoek), DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment Database), ARIF (Aggressive Research Intelligence Facility) and C-EBLM (International Federation of Clinical Chemistry and Laboratory Medicine Committee for Evidence-based Laboratory Medicine) databases to January 2013. They checked the reference lists of any relevant studies and systematic reviews for additional studies. The authors included studies that evaluated the diagnostic accuracy of ^¹⁸F-FDG PET to determine the conversion from MCI to AD dementia or to other forms of dementia, i.e., any or all of vascular dementia, dementia with Lewy bodies, and fronto-temporal dementia. These studies necessarily employ delayed verification of conversion to dementia and are sometimes labelled as 'delayed verification cross-sectional studies'. Two blinded review authors independently extracted data, resolving disagreement by discussion, with the option to involve a third review author as arbiter if necessary. They extracted and summarized graphically the data for 2-by-2 tables. They conducted exploratory analyses by plotting estimates of sensitivity and specificity from each study on forest plots and in receiver operating characteristic (ROC) space. When studies had mixed thresholds, they derived estimates of sensitivity and likelihood ratios at fixed values (lower quartile, median and upper quartile) of specificity from the hierarchical summary ROC (HSROC) models. These researches included 14 studies (421 participants) in the analysis. The sensitivities for conversion from MCI to AD dementia were between 25 % and 100 % while the specificities were between 15 % and 100 %. From the summary ROC curve we fitted we estimated that the sensitivity was 76 % (95 % confidence interval (CI): 53.8 to 89.7) at the included study median specificity of 82 %. This equated to a positive likelihood ratio of 4.03 (95 % CI: 2.97 to 5.47), and a negative likelihood ratio of 0.34 (95 % CI: 0.15 to 0.75). Three studies recruited participants from the same Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort but only the largest ADNI study (Herholz 2011) was included in the meta-analysis. In order to demonstrate whether the choice of ADNI study or discriminating brain region (Chetelat 2003) or reader assessment (Pardo 2010) made a difference to the pooled estimate, the authors performed 5 additional analyses. At the median specificity of 82 %, the estimated sensitivity was between 74 % and 76 %. There was no impact on their findings. In addition to evaluating AD dementia, 5 studies evaluated the accuracy of ^¹⁸F-FDG PET for all types of dementia. The sensitivities were between 46 % and 95 % while the specificities were between 29 % and 100 %; however, they did not conduct a meta-analysis because of too few studies, and those studies which we had found recruited small numbers of subjects. These findings were based on studies with poor reporting, and the majority of included studies had an unclear risk of bias, mainly for the reference standard and participant selection domains. According to the assessment of Index test domain, more than 50 % of studies were of poor methodological quality. The authors concluded that it was difficult to determine to what extent the findings from the meta-analysis can be applied to clinical practice. Given the considerable variability of specificity values and lack of defined thresholds for determination of test positivity in the included studies, the current evidence does not support the routine use of ^¹⁸F-FDG PET scans in clinical practice in people with MCI. The ^¹⁸F-FDG PET scan is a high-cost investigation, and it is therefore important to clearly demonstrate its accuracy and to standardize the process of ^¹⁸F-FDG PET diagnostic modality prior to its being widely used. They stated that future studies with more uniform approaches to thresholds, analysis and study conduct may provide a more homogeneous estimate than the one available from the included studies we have identified.

Morris et al (2016) stated that imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for AD; and PET using (18)F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, these researchers performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analyzed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified 9 studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the 3 beta-amyloid radiotracers. All tracers performed better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis were comparable to those of other imaging or biomarker techniques used to diagnose AD. The authors concluded that further research is needed to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway.

Tiepolt et al (2016) investigated the value of early PET images using the novel Aβ tracer [(18)F]FBB in the diagnosis of AD. This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [(11)C]PiB (11 patients) or [(18)F]FBB (11 patients) in routine clinical practice. Images were acquired 1 to 9 mins after administration of both tracers and 40 to 70 mins and 90 to 110 mins after administration of [(11)C]PiB and [(18)F]FBB, respectively. The patients also underwent [(18)F]FDG brain PET imaging; PET data were analyzed visually and semi-quantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated. Regional visual scores of early Aβ tracer and [(18)F]FDG PET images were significantly correlated (Spearman's ρ = 0.780, p < 0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [(18)F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [(18)F]FDG data (r = 0.779, p < 0.001), but there were no differences between [(18)F]FBB and [(11)C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [(18)F]FDG PET images were correlated with MMSE scores (ρ = 0.458, p = 0.032, and ρ = 0.456, p = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [(18)F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. The authors concluded that early [(18)F]FBB and [(11)C]PiB PET brain images were similar to [(18)F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [(18)F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. They stated that the potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts.

Stefaniak and O'Brien (2016) stated that management strategies for dementia are still very limited, and establishing effective disease modifying therapies based on amyloid or tau remains elusive. Neuroinflammation has been increasingly implicated as a pathological mechanism in dementia and demonstration that it is a key event accelerating cognitive or functional decline would inform novel therapeutic approaches, and may aid diagnosis. Much research has therefore been done to develop technology capable of imaging neuroinflammation in-vivo. The authors performed a systematic search of the literature and found 28 studies that used in- vivo neuroimaging of 1 or more markers of neuroinflammation on human patients with dementia. The majority of the studies used PET imaging of the 18kDa translocator protein (TSPO) microglial marker and found increased neuroinflammation in at least 1 neuroanatomical region in dementia patients, most usually AD, relative to controls, but the published evidence to date does not indicate whether the regional distribution of neuroinflammation differs between dementia types or even whether it is reproducible within a single dementia type between individuals. It is less clear that neuroinflammation is increased relative to controls in MCI than it is for dementia, and therefore it is unclear whether neuroinflammation is part of the pathogenesis in early stages of dementia. The authors concluded that despite its great potential, this review demonstrated that imaging of neuroinflammation has not thus far clearly established brain inflammation as an early pathological event. They stated that further studies are needed, including those of different dementia subtypes at early stages, and newer, more sensitive, PET imaging probes need to be developed.

Rodriguez-Vieitez et al (2017) stated that for amyloid PET tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal AD and 9 AD dementia patients underwent [18F]THK5317, carbon-11 Pittsburgh Compound-B ([11C]PIB), and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET to assess the possible use of early-phase [18F]THK5317 and R1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal versus AD dementia) of [18F]THK5317 (early-phase SUVr and R1) was compared with that of [11C]PIB (early-phase standard uptake value ratio [SUVr] and R1) and [18F]FDG. Strong positive correlations were found between [18F]THK5317 (early-phase, R1) and [18F]FDG, particularly in frontal and temporo-parietal regions. Differences in correlations between early-phase and R1 ([18F]THK5317 and [11C]PIB) and [18F]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. The authors concluded that these findings suggested that early-phase [18F]THK5317 and R1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single PET study with [18F]THK5317 may provide information about both tau pathology and brain perfusion in AD, with potential clinical applications.

Breast Cancer

An assessment by the Blue Cross and Blue Shield Association Technology Evaluation Center on PET for breast cancer (2003) stated that FDG-PET for evaluating breast cancer does not meet its criteria for initial staging of axillary lymph nodes, for detection of loco-regional recurrence or distant metastasis/recurrence, or for evaluating response to treatment.

Pritchard et al (2012) studied the use of 2-[(18)F] FDG PET in assessing lymph nodes and detecting distant metastases in women with primary breast cancer. Women diagnosed with operable breast cancer within 3 months underwent FDG-PET at 1 of 5 Ontario study centers followed by axillary lymph node assessment (ALNA) consisting of sentinel lymph node biopsy (SLNB) alone if sentinel lymph nodes (SLNs) were negative, SLNB with axillary lymph node dissection (ALND) if SLNB or PET was positive, or ALND alone if SLNs were not identified. Between January 2005 and March 2007, a total of 325 analyzable women entered this study. Sentinel nodes were found for 312 (96 %) of 325 women and were positive for tumor in 90 (29 %) of 312. ALND was positive in 7 additional women. Using ALNA as the gold standard, sensitivity for PET was 23.7 % (95 % CI: 15.9 % to 33.6 %), specificity was 99.6 % (95 % CI: 97.2 % to 99.9 %), positive-predictive value was 95.8 % (95 % CI: 76.9 % to 99.8 %), negative-predictive value was 75.4 % (95 % CI: 70.1 % to 80.1 %), and prevalence was 29.8 % (95 % CI: 25.0 % to 35.2 %). Using logistic regression, tumor size was predictive for prevalence of tumor in the axilla and for PET sensitivity. PET scan was suspicious for distant metastases in 13 patients; 3 (0.9 %) were confirmed as metastatic disease and 10 (3.0 %) were false-positive. The authors concluded that FDG-PET is not sufficiently sensitive to detect positive axillary lymph nodes, nor is it sufficiently specific to appropriately identify distant metastases. However, the very high positive-predictive value (96 %) suggests that PET when positive is indicative of disease in axillary nodes, which may influence surgical care.

Infectious Endocarditis

Yan and colleagues (2016) systematically conducted a meta-analysis of the available evidence for PET/CT using 18F-fluorodeoxyglucose as tracers in the imaging of infectious endocarditis (IE). Databases, including PubMed, Embase, and Web of Science, were searched for studies that examined the diagnostic value of 18F-FDG PET/CT for patients with IE. The reference lists following review articles and those of the included articles were checked to complement the electronic searches. The data extraction and methodological quality assessment were completed by 2 independent reviewers, and the meta-analysis was then conducted using Meta-Disc software, version 1.4. A total of 6 studies involving 246 patients was included. The results of the meta-analysis indicated that the pooled sensitivity was 61 % (95 % CI: 52 to 88 %), and the pooled specificity was 88 % (95 % CI: 80 to 93 %). The positive likelihood ratio was 3.24 (95 % CI: 1.67 to 6.28, p = 0.224), and the negative likelihood ratio was 0.50 (95 % CI: 0.32 to 0.77, p = 0.015). The diagnostic odds ratio (OR) was 6.98 (95 % CI: 2.55 to 19.10, p = 0.145), the overall area under the curve (AUC) was 0.8230 (SE = 0.1085), and the Q^* value was 0.7563 (SE = 0.0979). The authors concluded that 18F-FDG PET/CT is currently not sufficient for the diagnosis of IE because of its low sensitivity.

Diagnosis of Gallbladder Cancer

National Comprehensive Cancer Network’s clinical practice guideline on "Hepatobiliary cancers"(Version 4.2018) states that PET/CT has limited sensitivity but high specificity in the detection of regional lymph node metastases in gallbladder cancer. PET/CT may be considered when there is an equivocol finding on CT/MRI. "The routine use of PET/CT in preoperative setting has not been established in prospective trials."

Interim FDG-PET for Prognosis in Follicular Lymphoma

Adams and colleagues (2016) systematically reviewed the prognostic value of interim and end-of-treatment FDG-PET in follicular lymphoma during and after first-line therapy. The PubMed/Medline database was searched for relevant original studies. Included studies were methodologically assessed, and their results were extracted and descriptively analyzed. A total of 3 studies on the prognostic value of interim FDG-PET and 8 studies on the prognostic value of end-of-treatment FDG-PET were included. Overall, studies were of poor methodological quality. In addition, there was incomplete reporting of PFS and OS data by several studies, and none of the studies incorporated the Follicular Lymphoma International Prognostic Index (FLIPI) in the OS analyses. Two studies reported no significant difference in PFS between interim FDG-PET positive and negative patients, whereas 1 study reported a significant difference in PFS between the 2 groups. Two studies reported no significant difference in OS between interim FDG-PET positive and negative patients; 5 studies reported end-of-treatment FDG-PET positive patients to have a significantly worse PFS than end-of-treatment FDG-PET negative patients, and 1 study reported a non-significant trend towards a worse PFS for end-of-treatment FDG-PET positive patients. Three studies reported end-of-treatment FDG-PET positive patients to have a significantly worse OS than end-of-treatment FDG-PET negative patients. The authors concluded that the available evidence does not support the use of interim FDG-PET in follicular lymphoma. Although published studies suggested end-of-treatment FDG-PET to be predictive of PFS and OS, they suffered from numerous biases and failure to correct OS prediction for the FLIPI.

Mesothelioma

Positron emission tomography has limited sensitivity for mesothelioma. Furthermore, current guidelines have not incorporated PET scanning into the management of persons with mesothelioma. The available literature on the effect of PET on clinical outcomes of malignant mesothelioma are limited. In a small feasibility study, Francis and colleagues (2007) evaluated the role of serial (18)F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma. Patients were prospectively recruited and underwent both (18)F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based (18)F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured. A total of 23 patients were suitable for both radiological and (18)F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30 % of baseline (range of 11 % to 71 %). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (p = 0.015). Neither a reduction in the maximum standardized uptake value (p = 0.097) nor CT (p = 0.131) demonstrated a statistically significant association with patient survival. The authors concluded that semi-quantitative (18)F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma.

Ceresoli et al (2007) noted that most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of their disease. Assessment of the response with conventional criteria based on computed tomography (CT) measurements is challenging, due to the circumferential and axial pattern of growth of MPM. Such difficulties hinder an accurate evaluation of clinical study results and make the clinical management of patients critical. Several radiological response systems have been proposed, but neither WHO criteria nor the more recent RECIST uni-dimensional criteria nor hybrid uni- and bi-dimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria for MPM have been published. Although they are already being used in current clinical trials, they have been criticized based on the high grade of inter-observer variability and on theoretical studies of mesothelioma growth according to non-spherical models. Computer-assisted techniques for CT measurement are being developed. The use of FDG-PET for prediction of response and, more importantly, of survival outcomes of MPM patients is promising and warrants validation in large prospective series. New serum markers such as osteopontin and mesothelin-related proteins are under evaluation and in the future might play a role in assessing the response of MPM to treatment.

Sorensen et al (2008) stated that extra-pleural pneumonectomy (EPP) in MPM may be confined with both morbidity and mortality, and careful pre-operative staging identifying resectable patients is important. Staging is difficult and the accuracy of pre-operative CT scan, 18F-FDG PET/CT scan (PET/CT), and mediastinoscopy is unclear. These investigators compared these staging techniques to each other and to surgical-pathological findings. Subjects were patients with epithelial subtype MPM, aged less than or equal to 70 years, and had lung function test allowing pneumonectomy. Pre-operative staging after 3 to 6 courses of induction chemotherapy included conventional CT scan, PET/CT, and mediastinoscopy. Surgical-pathological findings were compared to pre-operative findings. A total of 42 consecutive patients were without T4 or M on CT scan. PET/CT showed inoperability in 12 patients (29 %) due to T4 (7 patients) and M1 (7 patients). Among 30 patients with subsequent mediastinoscopy, including 10 with N2/N3 on PET/CT, N2 were histologically verified in 6 (20 %). Among 24 resected patients, T4 occurred in 2 patients (8 %), and N2 in 4 (17 %), all being PET/CT negative. The PET/CT accuracy of T4 and N2/N3 compared to combined histological results of mediastinoscopy and EPP showed sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios of 78 % and 50 %, 100 % and 75 %, 100 % and 50 %, 94 % and 75 %, not applicable and 5.0, and 0.22 and 0.67, respectively. The authors concluded that non-curative surgery is avoided in 29 % out of 42 MPM patients by pre-operative PET/CT and in further 14 % by mediastinoscopy. Even though both procedures are valuable, there are false negative findings with both, urging for even more accurate staging procedures.

A recent review on malignant peritoneal mesothelioma (Turner et al, 2012) stated the role of PET in the diagnosis of malignant peritoneal mesothelioma is "unclear". The British Thoracic Society pleural disease guideline on "Investigation of a unilateral pleural effusion in adults" (Hooper et al, 2010) mentioned the use of CT, but not the use of PET.

Zahid et al (2011) addressed the question – which diagnostic modality [computed tomography (CT), positron emission tomography (PET), combination PET/CT and magnetic resonance imaging (MRI)] provides the best diagnostic and staging information in patients with malignant pleural mesothelioma (MPM). Overall, 61 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. These investigators concluded that fluorodeoxyglucose (FDG)-PET is superior to MRI and CT but inferior to PET-CT, in terms of diagnostic specificity, sensitivity and staging of MPM. Four studies reported outcomes using FDG-PET to diagnose MPM. PET diagnosed MPM with high sensitivity (92 %) and specificity (87.9 %). Mean standardized uptake value (SUV) was higher in malignant than benign disease (4.91 versus 1.41, p < 0.0001). Lymph node metastases were detected with higher accuracy (80 % versus 66.7 %) compared to extra-thoracic disease. Three studies assessed the utility of PET-CT to diagnose MPM. Mean SUV was higher in malignant than benign disease (6.5 versus 0.8, p < 0.001). MPM was diagnosed with high sensitivity (88.2 %), specificity (92.9 %) and accuracy (88.9 %). PET-CT had low sensitivity for stage N2 (38 %) and T4 (67 %) disease. CT-guided needle biopsy definitively diagnosed MPM after just 1 biopsy (100 % versus 9 %) much more often than a 'blind' approach. CT had a lower success rate (92 % versus 100 %) than thoracoscopic pleural biopsy but was equivalent to MRI in terms of detection of lymph node metastases (p = 0.85) and visceral pleural tumor (p = 0.64). CT had a lower specificity for stage II (77 % versus 100 %, p < 0.01) and stage III (75 % versus 100 %, p < 0.01) disease compared to PET-CT. Overall, the high specificity and sensitivity rates seen with open pleural biopsy make it a superior diagnostic modality to CT, MRI or PET for diagnosing patients with MPM.

An UpToDate review on "Diagnostic evaluation of pleural effusion in adults: Additional tests for undetermined etiology" (Lee, 2012) states that "Positron emission tomography (PET)/CT has an emerging role: 18-fluorodeoxyglucose (FDG)-avidity confirms, but cannot differentiate between inflammatory and malignant disease. Focal increased uptake of FDG in the pleura and the presence of solid pleural abnormalities on CT are suggestive of malignant pleural disease. A PET-CT pattern composed of pleural uptake and increased effusion activity had an accuracy of 90 percent in predicting malignant pleural effusions in 31 patients with known extrapulmonary malignancy and a pleural effusion [24]. A negative PET/CT would favor a benign etiology [25]. PET/CT may also highlight extrapleural abnormalities that may be the cause of the effusion …. CT scan of the thorax with contrast should be performed in virtually all patients with an undiagnosed pleural effusion. Additional imaging modalities that may be helpful are CT pulmonary angiogram and positron emission tomography (PET)/CT scans".

Furthermore, the NCCN clinical practice guideline on "Malignant Pleural Mesothelioma" (Version 2.2018) states that pretreatment evaluation for patients diagnosed with MPM is performed to stage and assess whether patients are candidates for surgery. Evaluation may include FDG-PET/CT but only for patients being considered for surgery. PET/CT "should be obtained before pleurodesis, if practical, because talc produces pleural inflammation, which can affect the FDG avidity."

Non-Small Cell Lung Cancer

Spiro et al (2008) stated that guidelines issued by the National Institute for Clinical Excellence (NICE) in the England and Wales recommend that rapid access to (18)F-deoxyglucose positron emission tomography (FDG-PET) is made available to all appropriate patients with non-small-cell lung cancer (NSCLC). The clinical evidence for the benefits of PET scanning in NSCLC is substantial, showing that PET has high accuracy, sensitivity and specificity for disease staging, as well as pre-therapeutic assessment in candidates for surgery and radical radiotherapy. Moreover, PET scanning can provide important information to assist in radiotherapy treatment planning, and has also been shown to correlate with responses to treatment and overall outcomes. If the government cancer waiting time targets are to be met, rapid referral from primary to secondary healthcare is essential, as is early diagnostic referral within secondary and tertiary care for techniques such as PET. Studies are also required to explore new areas in which PET may be of benefit, such as surveillance studies in high-risk patients to allow early diagnosis and optimal treatment, while PET scanning to identify treatment non-responders may help optimize therapy, with benefits both for patients and healthcare resource use. Further studies are needed into other forms of lung cancer, including small-cell lung cancer and mesothelioma. The authors concluded that PET scanning has the potential to improve the diagnosis and management of lung cancer for many patients. Further studies and refinement of guidelines and procedures will maximize the benefit of this important technique.

The NCCN Imaging Appropriate Use Criteria (2018) provides category 2A recommendations for FDG PET/CT (if not previously done) for IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV, or IVA (M1b) as diagnostic workup in non-small cell lung cancer (NSCLC). PET/CT if not previously performed, PET/CT performed skull base to knees or whole body. Positive PET/CT findings for distant disease need pathologic or other radiologic confirmation. If PET/CT is positive in the mediastinum, lymph node status needs pathologic confirmation. CT and PET used for staging should be within 60 days before proceeding with surgical evaluation. For stage IA, consider EBUS or EUS. In addition, NCCN provides a 2A recommendation for FDG PET/CT for treatment response assessment for locoregional recurrence or symptomatic local disease, post therapy.

Moyamoya Disease

An UpToDate review on "Moyamoya disease: Etiology, clinical features, and diagnosis" (Suwanwela, 2016) states that "Although supporting evidence is limited, additional methods that may be useful to determine the extent of inadequate resting brain perfusion and blood flow reserve in patients with Moyamoya disease prior to and after treatment include perfusion CT, Xenon-enhanced CT, perfusion-weighted MRI, PET, and SPECT with acetazolamide challenge".

Osteomyelitis

A proposed decision memo for FDG-PET for infection and inflammation from the CMS (Phurrough et al, 2007) stated that there is insufficient evidence to conclude that FDG- PET for chronic osteomyelitis, infection of hip arthroplasty and fever of unknown origin are reasonable and necessary. Thus, CMS proposed to continue national non-coverage for these indications.

Pre-Transplant PET Scans for Prognosis in Refractory/Relapsed Hodgkin Lymphoma Treated with Autologous Stem Cell Transplantation

Adams and Kwee (2016) systematically reviewed the prognostic value of pre-transplant FDG-PET in refractory/relapsed Hodgkin lymphoma treated with ASCT. Medline was searched for appropriate studies; included studies were methodologically appraised. Results of individual studies were meta-analyzed, if possible. A total of 11 studies, comprising 745 refractory/relapsed Hodgkin lymphoma patients who underwent FDG-PET before autologous SCT, were included. The overall methodological quality of these studies was moderate. The proportion of pre-transplant FDG-PET positive patients ranged between 25 and 65.2 %; PFS ranged between 0 and 52 % in pre-transplant FDG-PET positive patients, and between 55 and 85 % in pre-transplant FDG-PET negative patients; OS ranged between 17 and 77 % in pre-transplant FDG-PET positive patients, and between 78 and 100 % in FDG-PET negative patients. Based on 5 studies that provided sufficient data for meta-analysis, pooled sensitivity and specificity of pre-transplant FDG-PET in predicting treatment failure (i.e., either progressive, residual, or relapsed disease) were 67.2 % (95 % CI: 58.2 to 75.3 %) and 70.7 % (95 % CI: 64.2 to 76.5 %), respectively. Based on 2 studies that provided sufficient data for meta-analysis, pooled sensitivity and specificity of pre-transplant FDG-PET in predicting death during follow-up were 74.4 % (95 % CI: 58.8 to 86.5 %) and 58.0 % (95 % CI: 49.3 to 66.3 %), respectively. The authors concluded that the moderate quality evidence suggested pre-transplant FDG-PET to have value in predicting outcome in refractory/relapsed Hodgkin lymphoma patients treated with ASCT.

Post-Autologous Stem Cell Transplantation (ASCT)

Dickinson et al (2010) noted that the utility of (18)F-FDG-PET for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain – existing studies include a range of histological subtypes or have a limited duration of follow-up. A total of 39 patients with primary-refractory or relapsed DLBCL with pre-ASCT PET scans were analyzed. The median follow-up was 3 years. The 3-year progression-free survival (PFS) for patients with positive PET scans pre-ASCT was 35 % versus 81 % for those who had negative PET scans (p = 0.003). The overall survival (OS) in these groups was 39 % and 81 % (p = 0.01), respectively. In a multi-variate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS; PET negativity (p = 0.04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post-ASCT. Although those with positive scans can still be salvaged with current treatments, PET may be useful for selecting patients eligible for novel consolidation strategies after salvage therapies. The findings of this small study need to be validated by well-designed studies.

Rheumatoid Arthritis

Beckers et al (2006) evaluated rheumatoid arthritis (RA) synovitis with FDG-PET in comparison with dynamic MRI and ultrasonography (US). A total of 16 knees in 16 patients with active RA were assessed with FDG-PET, MRI and US at baseline and 4 weeks after initiation of anti-TNF-alpha treatment. All studies were performed within 4 days. Visual and semi-quantitative (standardized uptake value, SUV) analyses of the synovial uptake of FDG were performed. The dynamic enhancement rate and the static enhancement were measured after intravenous gadolinium injection and the synovial thickness was measured in the medial, lateral patellar and suprapatellar recesses by US. Serum levels of C-reactive protein (CRP) and metalloproteinase-3 (MMP-3) were also measured. FDG-PET was positive in 69 % of knees, while MRI and US were positive in 69 % and 75 %, respectively. Positivity on one imaging technique was strongly associated with positivity on the other two. FDG-PET-positive knees exhibited significantly higher SUVs, higher MRI parameters and greater synovial thickness compared with PET-negative knees, whereas serum CRP and MMP-3 levels were not significantly different. SUVs were significantly correlated with all MRI parameters, with synovial thickness and with serum CRP and MMP-3 levels at baseline. Changes in SUVs after 4 weeks were also correlated with changes in MRI parameters and in serum CRP and MMP-3 levels, but not with changes in synovial thickness. The authors concluded that FDG-PET is a unique imaging technique for assessing the metabolic activity of synovitis. The FDG-PET findings are correlated with MRI and US assessments of the pannus in RA, as well as with the classical serum parameter of inflammation, CRP, and the synovium-derived parameter, serum MMP-3. They stated that further studies are needed to establish the place of metabolic imaging of synovitis in RA.

Solitary Fibrous Tumor

A Medscape review on "Solitary fibrous tumor workup" (Ng, 2015), an UpToDate review on "Solitary fibrous tumor" (Demicco and Meyer, 2016).

Soft Tissue Sarcoma

The National Comprehensive Cancer Network (NCCN) guidelines on "Soft tissue sarcoma" (version 2.2018) state that PET/CT scan may be useful in staging, prognostication, and grading as part of additional imaging studies for soft tissue sarcoma of the extremity/superficial truck and head/neck. PET/CT may be useful in determining response to neoadjuvant chemotherapy for lesions that are larger than 3 cm, firm, and depp (not superficial) in stage II/III disease. The NCCN Imaging Appropriate Use Criteria (2018) provides a category 2A recommendation for use of PET/CT under certain circumstances for diagnostic purpose for the indication of lesion that has a reasonable chance of being malignant., or for treatment response assessment in IIA, IIB, III disease with lesions larger than 3 cm, firm and deep, post preoperative chemotherapy.

NCCN Imaging Appropriate Use Criteria (2018) provides the following category 2A recommendations for PET/CT in soft tissue sarcoma -gastrointestinal stromal tumors (GIST):

Diagnostic:
- GIST is resectable with negative margins but with risk of significant morbidity; Planned treatment with imatinib: Obtain baseline PET/CT if using PET/CT during follow-up. PET is not a substitute for CT.
- GIST is definitively unresectable, recurrent, or metastatic: Obtain baseline PET/CT if using PET/CT during follow-up. PET is not a substitute for CT.
Treatment Response Assessment:
- GIST is resectable with negative margins but with risk of significant morbidity; Post imatinib: Imaging to assess preoperative imatinib response. PET may give indication of imatinib activity after 2-4 weeks of therapy when rapid readout of activity is necessary. Progression may be determined by abdominal/pelvic CT or MRI with clinical interpretation. PET/CT scan may be used to clarify if CT or MRI are ambiguous. Routine long-term PET follow-up is rarely indicated.
- GIST is definitively unresectable, recurrent, or metastatic; Post imatinib: Imaging to assess preoperative imatinib response. PET may give indication of imatinib activity after 2-4 weeks of therapy when rapid readout of activity is necessary. Progression may be determined by abdominal/pelvic CT or MRI with clinical interpretation. PET/CT scan may be used to clarify if CT or MRI are ambiguous. Routine long-term PET follow-up is rarely indicated. In some patients it may be appropriate to image before 3 months.
- Post resection; Persistent gross residual disease with or without prior preoperative imatinib; Post continuation of imatinib: Imaging to assess preoperative imatinib response and evaluate patient compliance. PET may give indication of imatinib activity after 2-4 weeks of therapy when rapid readout of activity is necessary. Progression may be determined by abdominal/pelvic CT or MRI with clinical interpretation. PET/CT scan may be used to clarify if CT or MRI are ambiguous. Routine long-term PET follow-up is rarely indicated.
- Disease progression; Dose escalation of imatinib as tolerated or treatment changed to sunitinib: Reassess therapeutic response with CT or MRI. Consider PET only if CT or MRI results are ambiguous.
Follow-up:
Post resection; Discovery of metastatic disease or persistent gross residual disease with or without prior preoperative imatinib; Post continuation of imatinib: PET/CT may be used to clarify if CT or MRI are ambiguous.

NCCN Imaging Appropriate Use Criteria (2018) does not make a recommendation for PET/CT for soft tissue sarcoma - retroperitoneal/intra-abdominal tumors; however, they do provide a category 2A recommendation for PET or PET/CT for staging of rhabdomyosarcoma. PET or PET/CT may be useful for initial staging because of the possibility of nodal metastases and the appearance of unusual sites of initial metastatic disease in adult patients.

PET Scan for Acute Myeloid Leukemia

National Comprehensive Cancer Network’s clinical practice guideline on "Acute myeloid leukemia" (Version 3.2017) states that "If extramedullary disease is suspected, a PET/CT is recommended".

Amyloid-PET for the Diagnosis of Sporadic Cerebral Amyloid Angiopathy

Charidimou and colleagues (2017) performed a meta-analysis synthesizing evidence of the value and accuracy of amyloid-PET in diagnosing patients with sporadic cerebral amyloid angiopathy (CAA). In a PubMed systematic literature search, these researchers identified all case-control studies with extractable data relevant for the sensitivity and specificity of amyloid-PET positivity in symptomatic patients with CAA (cases) versus healthy participants or patients with spontaneous deep intra-cerebral hemorrhage (ICH) (control groups). Using a hierarchical (multi-level) logistic regression model, these investigators calculated pooled diagnostic test accuracy. A total of 7 studies, including 106 patients with CAA (greater than 90% with probable CAA) and 151 controls, were eligible and included in the meta-analysis. The studies were of moderate-to-high quality and varied in several methodological aspects, including definition of PET-positive and PET-negative cases and relevant cutoffs. The sensitivity of amyloid-PET for CAA diagnosis ranged from 60 % to 91 % and the specificity from 56 % to 90 %. The overall pooled sensitivity was 79 % (95 % CI: 62 to 89) and specificity was 78 % (95 % CI: 67 to 86) for CAA diagnosis. A pre-defined subgroup analysis of studies restricted to symptomatic patients presenting with lobar ICH CAA (n = 58 versus 86 controls) resulted in 79 % sensitivity (95 % CI: 61 % to 90 %) and 84 % specificity (95 % CI: 65 % to 93 %). In pre-specified bivariate diagnostic accuracy meta-analysis of 2 studies using 18F-florbetapir-PET, the sensitivity for CAA-ICH diagnosis was 90 % (95 % CI: 76 % to 100 %) and specificity was 88 % (95 % CI: 74 % to 100 %). The authors concluded that amyloid-PET appeared to have moderate-to-good diagnostic accuracy in differentiating patients with probable CAA from cognitively normal healthy controls or patients with deep ICH. They stated that given that amyloid-PET labels both cerebrovascular and parenchymal amyloid, a negative scan might be useful to rule out CAA in the appropriate clinical setting.

These investigators noted that not all studies reviewed in this meta-analysis were prospective; they had a relatively small sample size, with different demographics, disease duration, and severity and were in general restricted to survivors of lobar ICH who were able to undergo research imaging. This is a well-appreciated bias source in diagnostic test accuracy studies. A main drawback pertains to how to classify cases as amyloid-PET positive or negative. The methods and threshold used to define PET positive versus negative cases varied across the 7 studies of this analysis, something incorporated into data synthesis by the use of a hierarchical model. Nevertheless, the pooled estimates might still naturally depend on the exact method and cut-offs used to discriminate PET positive cases. For 3 studies, these researchers used data from visual assessment, which was practical for wide clinical application but required a good inter-observer reproducibility and validation against quantitative assessment. One study that used both visual assessment and quantitative Pittsburgh compound B (PiB)-PET methods reported slightly worse performance of the former. One 18F-florbetapir-PET study reported perfect agreement (κ = 1) between 2 trained neurologists from a tertiary CAA center. For 4 studies, these investigators used commonly applied quantitative cutoffs toward theoretically more objective categorization. They stated that further systematic studies are needed to directly compare the reliability and diagnostic value of amyloid-PET according to the methods used to define positivity, i.e., visual versus quantitative analysis. The authors stated that despite the drawbacks, their findings were hypothesis-generating and provided preliminary diagnostic accuracy data based on the totality of current evidence about amyloid-PET use in patients with CAA. They stated that further larger prospective studies, including longitudinal PET cohorts, are needed to provide external validation and to examine if amyloid-PET can be useful for detecting CAA pathology in patients in whom diagnostic certainty would have substantial clinical relevance and for patient selection for trials.

In an editorial that accompanied the afore-mentioned study by Charidimou et al (2017), Raposo and Sonnen (2017) stated that "Increasing evidence suggests that amyloid-PET can label vascular amyloid deposits. This meta-analysis promotes the hypothesis that amyloid-PET can accurately discriminate patients without dementia with probable CAA from cognitively normal healthy controls or patients with deep ICH. Further well-powered studies with pathologically proven CAA are warranted to assess the diagnostic value of amyloid-PET in challenging cases (single lobar ICH, mixed hemorrhage, patients with suspected CAA with cognitive impairment) and to determine a standardized method to define PET positivity".

Florbetapir Imaging

Yang and colleagues (2012) noted that important florbetapir scan limitations are

positive scan does not establish a diagnosis of AD or other cognitive disorder, and
the scan has not been shown to be useful in predicting the development of dementia or any other neurologic condition, nor has usefulness been shown for monitoring responses to therapies.

The authors stated that "the ultimate clinical value of florbetapir imaging awaits further studies to assess the role, if any, that it plays in providing prognostic and predictive information. For example, the prognostic usefulness of florbetapir imaging in identifying persons with mild cognitive impairment or cognitive symptoms who may be at risk for progression to dementia has not been determined. Nor are data available to determine whether florbetapir imaging could prove useful for predicting responses to medication. These concerns prompted the FDA to require a specific "Limitations of Use" section in the florbetapir label".

Florbetapir-PET Imaging for the Diagnosis of Cerebral Amyloid Angiopathy-Related Hemorrhages

Raposo and colleagues (2017) examined if 18F-florbetapir, a PET amyloid tracer, could bind vascular amyloid in CAA by comparing cortical florbetapir retention during the acute phase between patients with CAA-related lobar ICH and patients with hypertension-related deep ICH. Patients with acute CAA-related lobar ICH were prospectively enrolled and compared with patients with deep ICH. 18F-florbetapir PET, brain MRI, and APOE genotype were obtained for all participants. Cortical florbetapir SUVr was calculated with the whole cerebellum used as a reference. Patients with CAA and those with deep ICH were compared for mean cortical florbetapir SUVr values. A total of 15 patients with acute lobar ICH fulfilling the modified Boston criteria for probable CAA (mean age of 67 ± 12 years) and 18 patients with acute deep ICH (mean age of 63 ± 11 years) were enrolled. Mean global cortical florbetapir SUVr was significantly higher among patients with CAA-related ICH than among patients with deep ICH (1.27 ± 0.12 versus 1.12 ± 0.12, p = 0.001). Cortical florbetapir SUVr differentiated patients with CAA-ICH from those with deep ICH (AUC = 0.811; 95 % CI: 0.642 to 0.980) with a sensitivity of 0.733 (95 % CI: 0.475 to 0.893) and a specificity of 0.833 (95 % CI: 0.598 to 0.948). The authors concluded that these findings suggested that cortical florbetapir binding was increased in patients with CAA with lobar ICH relative to patients with deep ICH. In-vivo detection of vascular Aβ deposits might promote early diagnosis of CAA. However, they noted that 18F-florbetapir PET used as a diagnostic tool for acute CAA-related ICH appeared limited by its sensitivity. They stated that larger studies with pathologically proven CAA and age-matched healthy controls are needed to establish its relevance in clinical practice.

PET for Pituitary Tumor

Seok et al (2013) stated that although magnetic resonance imaging (MRI) is a good visual modality for the evaluation of pituitary lesions, it has limited value in the diagnosis of mixed nodules and some cystic lesions. These investigators evaluated the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) for patients with pituitary lesions. (18)F-FDG PET and MRI were performed simultaneously in 32 consecutive patients with pituitary lesions. The relationships between FDG uptake patterns in PET and MRI findings were analyzed. Of 24 patients with pituitary adenomas, 19 (79.2 %) showed increased uptake of (18)F-FDG in the pituitary gland on PET scans. All patients with pituitary macroadenomas showed increased (18)F-FDG uptake on PET scans. Meanwhile, only 5 (50 %) of the 10 patients with pituitary microadenomas showed positive PET scans. Interestingly, of 2 patients with no abnormal MRI findings, 1 showed increased (18)F-FDG uptake on PET. For positive (18)F-FDG uptake, maximum standardized uptake values (SUV(max)) greater than 2.4 had 94.7 % sensitivity and 100 % specificity. In addition, SUV(max) increased in proportion to the size of pituitary adenomas. Most cystic lesions did not show (18)F-FDG uptake on PET scans. The authors concluded that about 80 % of pituitary adenomas showed positivity on PET scans, and SUV(max) was related to the size of the adenomas. They stated that PET may be used as an ancillary tool for detection and differentiation of pituitary lesions. They stated that further PET studies determining the right threshold of SUVmax or conjugating various tracer molecules will be helpful.

Chittiboina et al (2015) noted that high-resolution PET (hrPET) performed using a high-resolution research tomograph is reported as having a resolution of 2 mm and could be used to detect corticotroph adenomas through uptake of(18)F-fluorodeoxyglucose ((18)F-FDG). To determine the sensitivity of this imaging modality, the authors compared(18)F-FDG hrPET and MRI detection of pituitary adenomas in Cushing disease (CD). Consecutive patients with CD who underwent preoperative(18)F-FDG hrPET and MRI (spin echo [SE] and spoiled gradient recalled [SPGR] sequences) were prospectively analyzed; SUVs were calculated from hrPET and were compared with MRI findings. Imaging findings were correlated to operative and histological findings. A total of 10 patients (7 females and 3 males) were included (mean age of 30.8 ± 19.3 years; range of 11 to 59 years). MRI revealed a pituitary adenoma in 4 patients (40 % of patients) on SE and 7 patients (70 %) on SPGR sequences. (18)F-FDG hrPET demonstrated increased(18)F-FDG uptake consistent with an adenoma in 4 patients (40 %; adenoma size range of 3 to 14 mm). Maximum SUV was significantly higher for(18)F-FDG hrPET-positive tumors (difference = 5.1, 95 % confidence interval [CI]: 2.1 to 8.1; p = 0.004) than for(18)F-FDG hrPET-negative tumors. (18)F-FDG hrPET positivity was not associated with tumor volume (p = 0.2) or dural invasion (p = 0.5). Midnight and morning ACTH levels were associated with(18)F-FDG hrPET positivity (p = 0.01 and 0.04, respectively) and correlated with the maximum SUV (R = 0.9; p = 0.001) and average SUV (R = 0.8; p = 0.01). All(18)F-FDG hrPET-positive adenomas had a less than a 180 % ACTH increase and(18)F-FDG hrPET-negative adenomas had a greater than 180 % ACTH increase after CRH stimulation (p = 0.03). Three adenomas were detected on SPGR MRI sequences that were not detected by(18)F-FDG hrPET imaging. Two adenomas not detected on SE (but no adenomas not detected on SPGR) were detected on(18)F-FDG hrPET. The authors concluded that while(18)F-FDG hrPET imaging can detect small functioning corticotroph adenomas and is more sensitive than SE MRI, SPGR MRI is more sensitive than(18)F-FDG hrPET and SE MRI in the detection of CD-associated pituitary adenomas. Response to CRH stimulation can predict(18)F-FDG hrPET-positive adenomas in CD. This was a small study (n = 10).

Yao et al (2017) noted that pituitary adenomas (PAs) are the most common intra-sellar mass. Functional PAs constitute most of pituitary tumors and can produce symptoms related to hormonal over-production. Timely and accurate detection is therefore of vital importance to prevent potentially irreversible sequelae. Magnetic resonance imaging is the gold standard for detecting PAs, but is limited by poor sensitivity for microadenomas and an inability to differentiate scar tissue from tumor residual or predict treatment response. Several new modalities that detect PAs have been proposed. These researchers performed a systematic review of the PubMed database for imaging studies of PAs since its inception. Data concerning study characteristics, clinical symptoms, imaging modalities, and diagnostic accuracy were collected. After applying exclusion criteria, 25 studies of imaging PAs using PET, magnetic resonance spectroscopy (MRS), and single photon emission computed tomography (SPECT) were reviewed. PET reliably detects PAs, particularly where MRI is equivocal, although its efficacy is limited by high cost and low availability; SPECT possesses good sensitivity for neuroendocrine tumors but its use with PAs is poorly documented. MRS consistently detects cellular proliferation and hormonal activity, but warrants further study at higher magnetic field strength. The authors concluded that PET and MRS appeared to have the strongest predictive value in detecting PAs. MRS has the advantage of low cost, but the literature is lacking in specific studies of the pituitary. Due to high recurrence rates of functional PAs and low sensitivity of existing diagnostic work-ups, further investigation of metabolic imaging is needed.

An UpToDate review on "Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas" (Synder, 2017) states that "Pituitary imaging – We suggest MRI for the initial imaging study for suspected adenomas, because of its superior resolution and its ability to demonstrate the optic chiasm. MRI with gadolinium is preferred to computed tomography (CT) because it provides superior resolution of the mass and its relation to surrounding structures. MRI is also able to detect blood, thereby permitting recognition of hemorrhage into the pituitary and distinction of an aneurysm from other intrasellar lesions". This review does not mention PET imaging.

The National Comprehensive Cancer Network (NCCN) on "Neuroendocrine and adrenal tumors" (Version 3.2018) does not mention PET scan for pituitary tumors.

PET for Prostate Cancer

Although PET scans using the radioactive glucose analog FDG have proven to be a highly accurate imaging test for diagnosing and staging a variety of non-urologic cancer types, its role in the management of prostate malignancies is still being defined. The use of PET scanning in the diagnosis and staging of prostate cancer is hampered by the generally low metabolic activity of most prostate tumors and their metastases. It has shown promise for staging and re-staging persons with advanced-stage disease and aggressive tumors suspected by a high tumor grade and high prostate-specific antigen velocity. Further investigations are needed to ascertain the eventual place of PET scans in prostate cancer.

Vees et al (2007) evaluated the value of PET/computed tomography (CT) with either (18)F-choline and/or (11)C-acetate, of residual or recurrent tumor after radical prostatectomy (RP) in patients with a prostate-specific antigen (PSA) level of less than 1 ng/ml and referred for adjuvant or salvage radiotherapy. In all, 22 PET/CT studies were performed, 11 with (18)F-choline (group A) and 11 with (11)C-acetate (group B), in 20 consecutive patients (2 undergoing PET/CT scans with both tracers). The median (range) PSA level before PET/CT was 0.33 (0.08 to 0.76) ng/ml. Endorectal-coil magnetic resonance imaging (MRI) was used in 18 patients. A total of 19 patients were eligible for evaluation of biochemical response after salvage radiotherapy. There was abnormal local tracer uptake in 5 and 6 patients in group A and B, respectively. Except for a single positive obturator lymph node, there was no other site of metastasis. In the 2 patients evaluated with both tracers there was no pathological uptake. Endorectal MRI was locally positive in 15 of 18 patients; 12 of 19 responded with a marked decrease in PSA level (half or more from baseline) 6 months after salvage radiotherapy. The authors concluded that although (18)F-choline and (11)C-acetate PET/CT studies succeeded in detecting local residual or recurrent disease in about 50 % of the patients with PSA levels of less than 1 ng/ml after RP, these studies can not yet be recommended as a standard diagnostic tool for early relapse or suspicion of subclinical minimally persistent disease after surgery. Endorectal MRI might be more helpful, especially in patients with a low likelihood of distant metastases. Nevertheless, further research with (18)F-choline and/or (11)C-acetate PET with optimal spatial resolution might be needed for patients with a high risk of distant relapse after RP even at low PSA values.

Takahashi et al (2007) noted that 2-(18)F-fluoro-2-deoxy-D-glucose (FDG)-PET imaging in prostate cancer is challenging because glucose utilization in well-differentiated prostate cancer is often lower than in other tumor types. Nonetheless, FDG-PET has a high positive predictive value for untreated metastases in viscera, but not lymph nodes. A positive FDG-PET can provide useful information to aid the clinician's decision on future management in selected patients who have low PSA levels and visceral changes as a result of metastases. On the other hand, FDG-PET is limited in the identification of prostate tumors, as normal urinary excretion of radioisotope can mask pathological uptake. Moreover, there is an overlap in the degree of uptake between prostate cancer, benign prostatic hyperplasia and inflammation. The tracer choice is also important. (11)C-choline has the advantage of reduced urinary excretion, and thus (11)C-choline PET may provide more accurate information on the localization of main primary prostate cancer lesions than MRI or MR spectroscopy. (11)C-choline PET is sensitive and accurate in the pre-operative staging of pelvic lymph nodes in prostate cancer. A few studies are available but there were no PET or PET/CT studies with a large number of patients for tissue confirmation of prostate cancer; further investigations are required.

Greco et al (2008) stated that the patient population with a rising PSA post-therapy with no evidence of disease on standard imaging studies currently represents the second largest group of prostate cancer patients. Little information is still available regarding the specificity and sensitivity of PET tracers in the assessment of early biochemical recurrence. Ideally, PET imaging would allow one to accurately discriminate between local versus nodal versus distant relapse, thus enabling appropriate selection of patients for salvage local therapy. The vast majority of studies show a relatively poor yield of positive scans with PSA values less than 4 ng/ml. So far, no tracer has been shown to be able to detect local recurrence within the clinically useful 1 ng/ml PSA threshold, clearly limiting the use of PET imaging in the post-surgical setting. Preliminary evidence, however, suggested that 11C-choline PET may be useful in selecting out patients with early biochemical relapse (PSA less than 2 ng/ml) who have pelvic nodal oligometastasis potentially amenable to local treatment. The authors concluded that the role of PET imaging in prostate cancer is gradually evolving but still remains within the experimental realm. Well-conducted studies comparing the merits of different tracers are needed.

In a systematic review and meta-analysis, Moshen and colleagues (2013) evaluated 23 studies of 11C-acetate PET in prostate cancer. For evaluation of primary tumor, pooled sensitivity was 75.1 (69.8 to 79.8) % and specificity was 75.8 (72.4 to 78.9) %. For detection of recurrence, sensitivity was 64 (59 to 69) % and specificity was 93 (83 to 98) %. Sensitivity for recurrence detection was higher in post-surgical versus post-radiotherapy patients and in patients with PSA at relapse of greater than 1 ng/ml. Studies using PET/computed tomography versus PET also showed higher sensitivity for detection of recurrence. Imaging with 11C-acetate PET can be useful in patients with prostate cancer. This is especially true for evaluation of patients at PSA relapse, although the sensitivity is overall low. For primary tumor evaluation (localization of tumor in the prostate and differentiation of malignant from benign lesions), 11C-acetate is of limited value due to low sensitivity and specificity. The authors concluded that due to the poor quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed. They stated that the quality of the conducted studies on the application of 11C-acetate in prostate cancer was usually poor. This is especially true for studies on re-staging at PSA relapse. The major drawback in the quality of the included studies in the present meta-analysis was poor and/or inconsistent gold standard. The researchers rarely provided histology results as the main gold standard method and usually relied on follow-up and conventional imaging (i.e., CT, bone scan, etc.). This is a major issue of the present study and these findings should be interpreted with the knowledge of this limitation. They noted that high quality prospective studies with consecutive patient recruitment and applying the best gold standard (histology confirmation preferably) are definitely needed.

Ceci et al (2014) investigated the clinical impact of (11)C-choline PET/CT on treatment management decisions in patients with recurrent prostate cancer (rPCa) after radical therapy. Enrolled in this retrospective study were 150 patients (95 from Bologna, 55 from Wurzburg) with rPCa and biochemical relapse (PSA mean ± SD 4.3 ± 5.5 ng/ml, range of 0.2 to 39.4 ng/ml) after radical therapy. The intended treatment before PET/CT was salvage radiotherapy of the prostatic bed in 95 patients and palliative androgen deprivation therapy (ADT) in 55 patients. The effective clinical impact of (11)C-choline PET/CT was rated as major (change in therapeutic approach), minor (same treatment, but modified therapeutic strategy) or none. Multi-variate binary logistic regression analysis included PSA level, PSA kinetics, ongoing ADT, Gleason score, tumor, node, metastasis (TNM), age and time to relapse. Changes in therapy after (11)C-choline PET/CT were implemented in 70 of the 150 patients (46.7 %). A major clinical impact was observed in 27 patients (18 %) and a minor clinical impact in 43 (28.7 %). (11)C-choline PET/CT was positive in 109 patients (72.7 %) detecting local relapse (prostate bed and/or iliac lymph nodes and/or para-rectal lymph nodes) in 64 patients (42.7 %). Distant relapse (para-aortic and/or retroperitoneal lymph nodes and/or bone lesions) was seen in 31 patients (20.7 %), and both local and distant relapse in 14 (9.3 %). A significant difference was observed in PSA level and PSA kinetics between PET-positive and PET-negative patients (p < 0.05). In multi-variate analysis, PSA level, PSA doubling time and ongoing ADT were significant predictors of a positive scan (p < 0.05). In statistical analysis no significant differences were observed between the Bologna and Wurzburg patients (p > 0.05). In both centers the same criteria to validate PET-positive findings were used: in 17.3 % of patients by histology and in 82.7 % of patients by correlative imaging and/or clinical follow-up (mean follow-up of 20.5 months, median of 18.3 months, range of 6.2 to 60 months). The authors concluded that (11)C-Choline PET/CT had a significant impact on therapeutic management in rPCa patients. It led to an overall change in 46.7 % of patients, with a major clinical change implemented in 18 % of patients. Moreover, they stated that further prospective studies are needed to evaluate the effect of such treatment changes on patient survival.

Giovacchini et al (2015) examined if [11C]choline PET/CT can predict survival in hormone-naive PCa patients with biochemical failure. This retrospective study included 302 hormone-naive PCa patients treated with radical prostatectomy who underwent [11C]choline PET/CT from December 1, 2004 to July 31, 2007 because of biochemical failure (prostate-specific antigen, PSA, greater than 0.2 ng/ml). Median PSA was 1.02 ng/ml. PCa-specific survival was estimated using Kaplan-Meier curves. Cox regression analysis was used to evaluate the association between clinicopathological variables and PCa-specific survival. The coefficients of the covariates included in the Cox regression analysis were used to develop a novel nomogram. Median follow-up was 7.2 years (1.4 to 18.9 years). [11C]Choline PET/CT was positive in 101 of 302 patients (33 %). Median PCa-specific survival after prostatectomy was 14.9 years (95 % CI: 9.7 to 20.1 years) in patients with positive [11C]choline PET/CT. Median survival was not achieved in patients with negative [11C]choline PET/CT. The 15-year PCa-specific survival probability was 42.4 % (95 % CI: 31.7 to 53.1 %) in patients with positive [11C]choline PET/CT and 95.5 % (95 % CI: 93.5 to 97.5 %) in patients with negative [11C]choline PET/CT. In multi-variate analysis, [11C]choline PET/CT (hazard ratio [HR] 6.36, 95 % CI: 2.14 to 18.94, p < 0.001) and Gleason score greater than 7 (HR 3.11, 95 % CI: 1.11 to 8.66, p = 0.030) predicted PCa-specific survival. An internally validated nomogram predicted 15-year PCa-specific survival probability with an accuracy of 80 %. The authors concluded that positive [11C]choline PET/CT after biochemical failure predicts PCa-specific survival in hormone-naive PCa patients. Moreover, they stated that prospective studies are needed to confirm our results before more extensive use of [11C]choline PET/CT for prognostic stratification of PCa patients.

An UpToDate review on "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" (Moul and Lee, 2015) states that "Newer imaging techniques using 18F-NaF positron emission tomography (PET)/computed tomography (CT) and 11-choline PET/CT are under development and appear to offer improved sensitivity and specificity compared with technetium 99 radionuclide bone scans. However, false-positive scans remain a significant concern and there is a steep learning curve associated with interpretation of this approach. The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Working Group recommends using 18F-NaF PET/CT for skeletal assessment in biochemical recurrence as an initial scan with PSA >5 ng/mL or for doubling of PSA after a prior negative scan …. Early studies suggest that 18-fluorine-labeled choline, 18-F sodium fluoride, and 11-carbon-labeled acetate may be better tracers for use in recurrent prostate cancer. PET and PET/CT with these tracers is still considered investigational in men with a PSA-only recurrence".

The National Comprehensive Cancer Network (NCCN) Imaging Appropriate Use Criteria (2018) for prostate cancer states that 18F sodium fluoride PET/CT can be considered for equivocal results on initial bone scan. Bone imaging should be performed for any patient with symptoms consistent with bone metastases. NCCN provides the following category 2A recommendations:

Treatment Response Assessment:
- Metastatic disesae; post ADT or localized on observation: 11C choline or 18F fluciclovine PET/CT for further soft tissue imaging may be considered. 18F sodium fluoride PET/CT can be considered for equivocal results on initial bone scan, or can be considered after bone scan for further evaluation when clinical suspicion of bone metastases is high.
- Post radical prostatectomy; PSA persistence or PSA recurrence; Post treatment; 11C choline or 18F fluciclovine PET/CT for further soft tissue imaging may be considered. 18F sodium fluoride PET/CT can be considered for equivocal results on initial bone scan or can be considered after bone scan for further evaluation when clinical suspicion of bone metastases is high.
- Radiation therapy recurrence; PSA persistence/recurrence or positive DRE; Candidate for local therapy: original clinical stage T1-T2, NX or N0, life expectancy > 10 yr, PSA now < 10ng/mL; Studies negative for distant metastases; Post treatment; May consider: 11C choline PET/CT or PET/MRI, or 18F fluciclovine PET/CT or PET/MRI, or 18F sodium fluoride PET/CT.
- Advanced disease; Post systemic therapy for castration-naïve disease; May consider: 11C choline PET/CT or PET/MRI, or 18F fluciclovine PET/CT or PET/MRI, or 18F sodium fluoride PET/CT.
Staging:
- Post radical prostatectomy; PSA persistence (Failure of PSA to fall to undetectable levels) or PSA recurrence (Undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or more determinations). PET/CT using 11C choline tracers may identify sites of metastatic disease in men with biochemical recurrence after primary treatment failure. If PET imaging is used, histologic confirmation is recommended whenever feasible due to significant rates of false positivity. 18F sodium fluoride PET/CT can be considered for equivocal results on initial bone scan, or can be considered after bone scan for further evaluation when clinical suspicion of bone metastases is high.
- Radiation therapy recurrence; PSA persistence/recurrence or positive DRE; Candidate for local therapy: original clinical stage T1-T2, NX or N0, life expectancy > 10 yr, PSA now < 10ng/mL; May consider: 11C choline PET/CT or PET/MRI, or18F fluciclovine PET/CT or PET/MRI.
- Advanced disease; Post systemic therapy for castration-naïve disease; Studies negative for distant metastases; Post systemic therapy for M0 CRPC; PSA increasing; May consider: 11C choline PET/CT or PET/MRI, or 18F fluciclovine PET/CT or PET/MRI, or 18F sodium fluoride PET/CT.
- Advanced disease; CRPC; Studies positive for metastases; No visceral metastases or visceral metastases with adenocarcinoma histology; Post systemic therapy for M1 CRPC; May consider: 11C choline PET/CT or PET/MRI, or18F fluciclovine PET/CT or PET/MRI, or 18F sodium fluoride PET/CT.

PET for Ureteral Cancer

An UpToDate review on "Malignancies of the renal pelvis and ureter" (Richie and Kantoff, 2017) states that "The diagnosis of a tumor of the renal pelvis or ureter is usually suspected based upon an abnormal computed tomography (CT) or retrograde pyelography". It does not mention PET as a diagnostic tool.

Cerianna (Fluoroestradiol F-18) PET Imaging for Breast Cancer

Evangelista et al (2016) determined the correlation between 16α-18F-fluoro- 17β-estradiol (18F-FES) uptake and the expression and functionality of estrogen receptors (ERs), and examined the ability of 18F-FES PET to predict the response to hormonal therapy (HT) in patients with locally advanced or metastatic breast cancer (BC). These researchers carried out literature searches in the major literature data-bases to select English-language articles dealing with 18F-FES PET and BC. Studies that included patients with BC undergoing 18F-FES PET alone or in combination with other imaging modalities and included the absolute numbers of true-positive, true-negative, false-positive and false-negative test results were selected. They found 23 studies, published between 1988 and December 2014, that critically examined the role of 18F-FES PET in BC patients. Two separate meta-analyses were performed: the 1st one evaluated the correlation between 18F-FES uptake and ER expression; and the 2nd one determined the predictive value of 18F-FES in response to HT. For the 1st meta-analysis, these investigators considered 9 selected studies with a total of 238 patients. A pooled sensitivity of 82 % (95 % CI: 74 to 88 %) and a pooled specificity of 95 % (95 % CI: 86 to 99 %) for the evaluation of ER functional status by 18F-FES PET were found; 7 studies, with a total of 226 patients, were considered eligible for the analysis of predict ion for response. The pooled sensitivities and specificities were 63.9 % (95 % CI: 46.2 to 79.2 %) versus 66.7 % (95 % CI: 52.1 to 79.2 %), and 28.6 % (95 % CI: 17.3 to 42.2 %) versus 62.1 % (95 % CI: 48.4 to 74.5%), for a SUV cut-off of 1.5 and 2.0, respectively. The authors concluded that a good correlation between 18F-FES uptake and ER expression by immunohistochemistry emerges, while the role of 18F-FES in predicting the response to endocrine therapy in advanced BC remains undetermined.

Jones et al (2019) noted that dedicated breast PET (dbPET) is an emerging technology with high sensitivity and spatial resolution that enables detection of sub-centimeter lesions and depiction of intra-tumoral heterogeneity. These investigators reported their initial experience with dbPET using [F-18]fluoroestradiol (FES) in assessing ER+ primary BCs. A total of 6 patients with greater than 90 % ER+ and HER2- BCs were imaged with dbPET and breast MRI. Two patients had invasive lobular carcinoma (ILC), 3 had invasive ductal carcinoma (IDC), and 1 had an unknown primary tumor. One ILC patient was treated with letrozole, and another patient with IDC was treated with neoadjuvant chemotherapy without endocrine treatment. In this small cohort, these researchers observed FES uptake in ER+ primary breast tumors with specificity to ER demonstrated in a case with tamoxifen blockade. FES uptake in ILC had a diffused pattern compared to the distinct circumscribed pattern in IDC. In evaluating treatment response, the reduction of SUVmax was observed with residual disease in an ILC patient treated with letrozole, and an IDC patient treated with chemotherapy. The authors concluded that future study is critical to understand the change in FES SUVmax after endocrine therapy and to consider other tracer uptake metrics with SUVmax to describe ER-rich BC. These researchers stated that limitations of this study included variations of FES uptake in different ER+ BC diseases and exclusion of posterior tissues and axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. These investigators stated that further studies involving larger numbers of ER+ BC patients are needed to validate these preliminary findings.

Katzenellenbogen (2020) stated that many BC and prostate cancer are driven by the action of steroid hormones on their cognate receptors in primary tumors and in metastases, and endocrine therapies that inhibit hormone production or block the action of these receptors provide clinical benefit to many but not all of these cancer patients. Because it is difficult to predict which individuals will be helped by endocrine therapies and which will not, PET imaging of estrogen receptor (ER) and progesterone receptor (PgR) in BC, and androgen receptor (AR) in prostate cancer can provide useful, often functional, information on the likelihood of endocrine therapy response in individual patients. The author discussed the development of 3 PET imaging agents, 16α-[18F]fluoroestradiol (FES) for ER, 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for PgR, and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) for AR, and the evolution of their clinical use. A number of active clinical trials (some multi-center) continue to examine the predictive value of FES-PET, often together with FDG-PET or other targeted imaging agents, or to examine its ability to identify metastases and intra-patient heterogeneity. Suggestions for best practices in the clinical use of FES-PET have been published, as has a simulation of the cost-effectiveness of FES-PET versus conventional work-up of patients with metastatic BC. The author concluded that the use of PET imaging of steroid receptors enables observation of the extent of cancer metastasis and predicts responsiveness to endocrine therapies. Its use in evaluating new aspects of tumor clinical status non-invasively suggests a robust future for PET imaging in providing meaningful benefit for patients with BC and prostate cancer.

Ulaner et al (2020) noted that invasive lobular carcinoma (ILC) demonstrates lower conspicuity on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET than the more common invasive ductal carcinoma (IDC). Other molecular imaging methods may be needed for evaluation of this malignancy. As ILC is nearly always (95 %) ER-positive, ER-targeting PET tracers such as 16α-[18F]-fluoroestradiol ([18F]FES) may have value. These investigators reviewed prospective trials at Memorial Sloan Kettering Cancer Center (MSK) utilizing [18F]FES PET/CT to evaluate metastatic ILC patients with synchronous [18F]FDG and [18F]FES PET/CT imaging, which allowed a head-to-head comparison of these 2 PET tracers. A total of 6 prospective clinical trials utilizing [18F]FES PET/CT in patients with metastatic BC were carried out at MSK from 2008 to 2019. These trials included 92 patients, of which 14 (15 %) were of ILC histology; 7 of 14 patients with ILC had an [18F]FDG PET/CT performed within 5 weeks of the research [18F]FES PET/CT and no intervening change in management. For these 7 patients, the [18F]FES and [18F]FDG PET/CT studies were analyzed to determine the total number of tracer avid lesions, organ systems of involvement, and SUVmax of each organ system for both tracers. In the 7 comparable pairs of scans, there were a total of 254 [18F]FES-avid lesions (SUVmax 2.6 to 17.9) and 111 [18F]FDG-avid lesions (SUVmax 3.3 to 9.9) suspicious for malignancy. For 5 of 7 (71 %) of ILC patients, [18F]FES PET/CT detected more metastatic lesions than [18F]FDG PET/CT. In the same 5 of 7 patients, the SUVmax of [18F]FES-avid lesions was greater than the SUVmax of [18F]FDG-avid lesions; 1 patient had [18F]FES avid metastases with no corresponding [18F]FDG avid metastases. There were no patients with [18F]FDG avid distant metastases without [18F]FES avid distant metastases, although in 1 patient liver metastases were evident on [18F]FDG but not [18F]FES PET. The authors concluded that [18F]FES PET/CT compared favorably with [18F]FDG PET/CT for detection of metastases in patients with metastatic ILC. Moreover, these researchers stated that larger, prospective trials of [18F]FES PET/CT in ILC should be considered to examine ER-targeted imaging for clinical value in patients with this histology of BC.

Boers et al (2020) noted that molecular imaging with PET is a powerful tool to visualize BC characteristics. Nonetheless, implementation of PET imaging into cancer care is challenging, and essential steps have been outlined in the international "imaging biomarker roadmap". These investigators identified hurdles and provide recommendations for implementation of PET biomarkers in BC care, focusing on the PET tracers 2-[18F]-fluoro-2-deoxyglucose ([18F]-FDG), sodium [18F]-fluoride ([18F]-NaF), 16α-[18F]-fluoroestradiol ([18F]-FES), and [89Zr]-trastuzumab. Technical validity of [18F]-FDG, [18F]-NaF, and [18F]-FES is established and supported by international guidelines. However, support for clinical validity and utility is still pending for these PET tracers in BC, due to variable end-points and procedures in clinical studies. The authors concluded that evaluation of clinical validity and utility is essential towards implementation; however, these steps are still lacking for PET biomarkers in BC. This could be solved by adding PET biomarkers to randomized trials, development of imaging data warehouses, and harmonization of end-points and procedures.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on "Breast cancer" (Version 6.2020) does not mention 18F-fluoroestradiol PET as a management tool.

DOPA-PET/CT Scan for Prognosis of Brain Cancer

Isal et al (2018) stated that in diffuse grade II to III gliomas, a high 3,4-dihydroxy-6-(18F)-fluoro-L-phenylalanine (18F-FDOPA) PET uptake, with a standardized uptake value (SUVmax) / contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. In a pilot study, these researchers determined the prognostic value of this high 18F-FDOPA uptake in diffuse grade II to III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm/year. A total of 20 patients (42 ± 10 years, 10 women) with newly-diagnosed diffuse grade II to III gliomas (17 with IDH mutation) were retrospectively included. All had a 18F-FDOPA PET, quantified with SUVmax ratio, along with a serial MRI enabling VDE determination. SUVmax ratio was above 1.8 in 5 patients (25 %) all of whom had a VDE less than 4 mm/year (100 %) and IDH mutation (100 %). Moreover, a SUVmax ratio above 1.8 was associated with higher rates of VDE less than 4 mm/year in the overall population (45 % versus 0 %, p = 0.04) and also in the subgroup of patients with IDH mutation (45 % versus 0 %, p = 0.10). The authors concluded that the findings of this pilot study showed that in diffuse grade II to III gliomas, a high 18F-FDOPA uptake would be predictive of low tumor growth, with a different prognostic significance than IDH mutation. These investigators noted that 18F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse grade II to III gliomas.

The authors stated that the most important limitations of the present study were its limited sample size and its retrospective and single-center nature. They stated that further larger-scale studies are needed, especially for the subgroups of patients with IDH-mutant 1p/19q co-deleted oligodendrogliomas or wild-type IDH astrocytoma, in order to confirm the low growth rate as well as the good prognosis of patients showing a SUVmax ratio of greater than 1.8. Secondly, the average time between MRI 1 and MRI 2 (82 days ± 29) could be sometimes short to define precisely tumor growth rate. However, a minimum delay of 40 days was observed between the 2 investigations. Finally, the growth rate of tumor was chosen as a surrogate for clinical course in this study since no OS could be obtained in this population owing to the long clinical course duration of diffuse low-grade gliomas.

Patel et al (2018) reported the potential value of pre-operative 18F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients. A total of 45 patients with a pathological diagnosis of glioma with pre-operative 18F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum 18F-FDOPA SUV in tumor to normal tissue (T/N SUVmax) were measured and used to predict tumor grade, molecular status, and OS. A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r = 0.67), volume of T2 hyperintensity (r = 0.42), and 18F-FDOPA uptake (r = 0.60) (p < 0.01 for each correlation). The volume of contrast enhancement and 18F-FDOPA T/N SUVmax were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I to III), as well as for high-grade gliomas (WHO III to IV) compared with low-grade gliomas (WHO I to II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and 18F-FDOPA T/N SUVmax could each differentiate patient groups. No significant differences in 18F-FDOPA uptake were observed by IDH or MGMT status. Multi-variable Cox regression suggested age (hazard ratio [HR] 1.16, p = 0.0001) and continuous measures of 18F-FDOPA PET T/N SUVmax (HR 4.43, p = 0.016) were significant prognostic factors for OS in WHO I to IV gliomas. The authors concluded that the findings of this study suggested a potential role for the use of pre-operative 18F-FDOPA PET in suspected glioma. Increased 18F-FDOPA uptake may not only predict higher glioma grade, but also worse OS. These researchers stated that prospective studies are needed to validate these observations and to determine the impact of routine pre-operative implementation of 18F-FDOPA PET scanning combined with MRI in clinical decision-making, cost of care, and patient outcomes.

The authors stated that the findings of this study should be interpreted in the context of its limitations. The retrospective nature of the study did not allow for the control of potential confounding variables in the analysis (e.g., physician biases regarding when to order the 18F-FDOPA scan). Additionally, the use of SUVmax within the tumor region instead of strictly examining the distribution in MR-defined regions (e.g., CE or T2/FLAIR hyperintense regions) was a potential limitation; but was chosen based on similar approaches and the ease of rapid evaluation in clinical contexts. The highest 18F-FDOPA extra-striatal uptake was noticed outside of the MRI-based tumor region in 11 cases (24.4 %) during the blinded analysis, and 9 of these instances occurred in the posterior fossa in normal brain tissue. This may represent a pattern of normal brain biodistribution of 18F-FDOPA uptake. The reasons for this finding of increased 18F-FDOPA uptake in the posterior fossa despite absence of glioma remain unclear. Previous studies in canine and rodent brain have identified expression of the L-type amino acid transporter 1 (LAT1, the primary transporter responsible for 18F-FDOPA uptake in the brain) in the cerebellum, which was found to correlate with 18F-FDOPA uptake. The fact that no recurrences occurred in the non-co-localizing regions (predominantly posterior fossa) suggested that high 18F-FDOPA uptake in the posterior fossa should not pose a clinical concern if the suspected glioma was outside of the posterior fossa based on MRI.

Humbert et al (2019) evaluated the therapeutic impact and diagnostic accuracy of 18F-DOPA PET/CT in patients with glioblastoma or brain metastases. Patients with histologically proven glioblastoma or brain metastases were prospectively included in this mono-centric clinical trial (IMOTEP). Patients were included either due to a clinical suspicion of relapse or to assess residual tumor infiltration after treatment. Multi-modality brain MRI and 18F-DOPA PET were performed. Patient data were discussed during a Multidisciplinary Neuro-oncology Tumor Board (MNTB) meeting. The discussion was first based on clinical and MRI data, and an initial diagnosis and treatment plan were proposed. Secondly, a new discussion was conducted based on the overall imaging results, including 18F-DOPA PET. A second diagnosis and therapeutic plan were proposed. A retrospective and definitive diagnosis was obtained after a 3-month follow-up and considered as the reference standard. A total of 106 cases were prospectively examined by the MNTB. All patients with brain metastases (n = 41) had a clinical suspicion of recurrence. The addition of 18F-DOPA PET data changed the diagnosis and treatment plan in 39.0 % and 17.1 % of patients' cases, respectively. Concerning patients with a suspicion of recurrent glioblastoma (n = 12), the implementation of 18F-DOPA PET changed the diagnosis and treatment plan in 33.3 % of cases. In patients evaluated to assess residual glioblastoma infiltration after treatment (n = 53), 18F-DOPA PET data had a lower impact with only 5.7 % (3/53) of diagnostic changes and 3.8 % (2/53) of therapeutic plan changes. The definitive reference diagnosis was available in 98/106 patients. For patients with tumor recurrence suspicion, the adjunction of 18F-DOPA PET increased the Younden's index from 0.44 to 0.53 in brain metastases and from 0.2 to 1.0 in glioblastoma, reflecting an increase in diagnostic accuracy. The authors concluded that 18F-DOPA PET had a significant impact on the management of patients with a suspicion of brain tumor recurrence, either glioblastoma or brain metastases, but a low impact when used to evaluate the residual glioblastoma infiltration after a 1st-line radio-chemotherapy or 2nd-line bevacizumab.

Chiaravalloti et al (2019) examined the PFS and the OS in a population affected by primary brain tumors (PBT) evaluated by 18F-DOPA PET/CT. A total of 133 subjects with PBT (65 women and 68 men, mean age of 45 ± 10 years) underwent 18F-FDOPA PET/CT after treatment. Of them, 68 (51.2 %) were grade II, 34 (25.5 %) were grade III and 31 (23.3%) were grade IV. PET/CT was scored as positive or negative and standardized uptake value ratio (SUVr) was calculated as the ratio between SUVmax of the lesion versus that of the background. Patients have been observed for a mean of 24 months. The outcome of 18F-FDOPA PET/CT scan was significantly related to the OS and PFS in grade II gliomas. In grade II PBT, the OS proportions at 24 months were 100 % in subjects with a negative PET/CT scan and 82 % in those with a positive scan. Gehan-Breslow-Wilcoxon test showed a significant difference in the OS curves (p = 0.03) and the HR was equal to 5.1 (95 % CI: 1.1 to 23.88). As for PFS, the proportion at 24 months was 90 % in subjects with a negative PET/CT scan and 58 % in those with a positive scan. Gehan-Breslow-Wilcoxon test showed a significant difference in the OS curves (p = 0.007) and the HR was equal to 4.1 (95 % CI: 1.3 to 8). These researchers did not find any significant relationship between PET outcome and OS and PFS in grade III and IV PBT. The authors concluded that a positive 18F-FDOPA PET/CT scan was related to a poor OS and PFS in subjects with low-grade PBT. This imaging modality could be considered as a prognostic factor in these subjects.

Cicone et al (2019) noted that the role of amino acid PET in glioma grading and outcome prognostication has not yet been well established. This is particularly true in the context of the new WHO 2016 classification, which introduced a definition of glioma subtypes primarily based on molecular fingerprints. These investigators correlated F-DOPA uptake parameters with IDH mutation, 1p/19q status, and survival outcomes in patients with glioma. The study population consisted of 33 patients (17 men/16 women, mean age of 46 ± 13 years) who underwent F-DOPA PET/CT for the evaluation of tumor extent before the start of chemo- or radiotherapy. The presence of IDH mutation and 1p/19q status was assessed in all the cases. Tumor volume and semi-quantitative uptake parameters, namely SUVmax, tumor-to-normal brain ratio and tumor-to-normal striatum ratio, were calculated for each tumor. Imaging-derived parameters were compared between patients stratified according to molecular fingerprints, using parametric or non-parametric tests, where appropriate. The Kaplan-Meier method was used to assess differences of OS and PFS between groups. PET parameters were also tested as prognostic factors in univariate Cox survival regression models. There were 12 IDH-wild-type and 21 IDH-mutant patients. Stratification according to 1p/19q co-deletion resulted in 20 non-co-deleted and 13 co-deleted patients. Median follow-up time from PET/CT examination was 30.5 months (range of 3.5 to 74 months). Semi-quantitative uptake parameters did correlate neither with IDH mutation nor with 1p/19q status. Uptake was similar in low-grade and high-grade tumors, respectively. In addition, F-DOPA uptake parameters, macroscopic tumor volume, or tumor grade did not stratify OS, while a correlation between SUVmax and PFS was shown in the subgroup of astrocytoma. On the other hand, IDH mutation status and presence of 1p/19q co-deletion had a significant impact on survival outcomes. The prognostic value of IDH mutation status was also confirmed in the subgroup of patients with astrocytic tumors. The authors concluded that F-DOPA uptake parameters did not correlate with tumor molecular and histological characteristics; the predictive value of PET-derived parameters on outcomes of survival was limited.

Furthermore, an UpToDate review on “Overview of the clinical features and diagnosis of brain tumors in adults” (Wong and Wu, 2020) does not mention DOPA PET/CT as a management option.

FDG-PET/CT Scan for Initial Staging of Kaposi's Sarcoma

Bertagna et al (2010) reported on the case of a 38-year old man who was affected by the human immunodeficiency virus (HIV) with a diagnosis of Castleman's disease, plasmablastic type human herpes virus 8 (HPV-8) infection, and Kaposi sarcoma (KS) based on a histological examination of 1 cervical lymph node biopsy. The patient underwent (18)F-FDG-PET/CT. The authors concluded that (18)F-FDG-PET/ CT appeared to be a valuable tool in patients with HIV-associated Castleman's disease and KS; it allowed accurate staging and identified more sites of disease than conventional CT.

Ozdemir et al (2014) stated that although mucocutaneous sites are the most frequently encountered sites of involvement, KS may also occasionally involve the breast and the skeletal, endocrine, urinary and nervous systems. Various imaging modalities may be used to delineate the extent of the disease by detecting unexpected sites of involvement. These investigators reported a case of classical type KS, in whom staging with (18)F-FDG PET/CT imaging disclosed widespread disease and unexpected findings of bone and salivary gland involvement.

Furthermore, an UpToDate review on “AIDS-related Kaposi sarcoma: Staging and treatment” (Groopman, 2020) does not mention PET/CT as a staging tool.

Gallium-68 PSMA PET/CT Scan for Re-Staging of Prostate Cancer

National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 2.2020) states that “Newer tracers under development, but they are neither FDA cleared nor readily available and are considered investigational at this time. For instance, gallium-68 prostate-specific membrane antigen (PSMA) may provide better detection of recurrences at lower PSA levels than reported for FDA-approved imaging agents; and has comparable sensitivity (76 % - 88 %) and specificity (86 % - 100 %)“.

PET Scan for Evaluation of Basaloid Squamous Cell Carcinoma

Soriano et al (2005) stated that the course and prognosis of basaloid squamous cell carcinoma (BSCC) are not well-known. These investigators examined the course and prognosis in a population of BSCC patients. They analyzed a retrospective cohort of 49 patients with BSCC in comparison with a cross-matched population of 49 patients treated for well-to-moderately differentiated SCC. The statistical analysis showed that survival in BSCC group was lower than in the SCC group. Local recurrence in the BSCC group was not higher than in the SCC group, but mortality by distant metastasis was 6 times higher than in the SCC population. The authors considered BSCC patients as a high-risk population and these investigators completed diagnosis explorations including a FDG-PET before curative treatment. They also recommended post-operative or exclusive radiotherapy (RT), which may be associated with concomitant chemotherapy.

Soriano et al (2008) described the natural history and evaluated the prognosis of BSCC of the upper aero-digestive tract as compared to the usual SCC. A total of 62 patients with BSCC and 62 patients with SCC were matched with regards to TNM classification, localization and therapeutic modalities. Histological criteria, follow-up and 5-year survival were compared between the 2 groups. Survival rates were significantly higher in patients with SCC as compared to patients with BSCC. The rate of distant metastasis was 6 times higher in cases of BSCC, which was the major cause of mortality. The authors concluded that the findings of this study showed that BSCC has distinct histopathologic features and an aggressive clinical course, justifying its consideration as a separate entity with poor prognosis. The authors proposed to systematically perform a chest CT-scan and FDG-PET to rule out early distant metastasis and to include adjuvant chemotherapy in treatment protocols.

Silverton et al (2016) noted that treatment with tumor necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is observed emerging between TNF antagonists and development of SCCs of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus [HPV] infection). These researchers presented the case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to the authors’ institution after several months of increasing left pelvis and buttock pain. Evaluation with a CT-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a FDG-PET, an additional area of uptake was identified in the left posterior rectum corresponding to a 1-cm nodule palpable on digital examination. Colonoscopic biopsy revealed a BSCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have resulted in this unrestrained neoplastic growth; thus, it underscored the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage.

National Comprehensive Cancer Network’s clinical practice guideline on “Squamous cell skin cancer” (Version 1.2020) does not mention FDG-PET as a management tool.

PET Scan for Evaluation of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

Yamashita et al (2019) stated that identifying malignancy in intraductal papillary mucinous neoplasm (IPMN) of the pancreas remains challenging. These researchers examined the usefulness of 18-FDG PET/CT in distinguishing malignant from benign IPMN of the pancreas. The cases of 79 patients with IPMN of the pancreas who underwent surgical resections between 1996 and 2016 at the authors’ institution were enrolled in the present retrospective analysis of predictors for malignancy in IPMN of the pancreas. 18-FDG PET/CT evaluations were performed in 38 patients, and the usefulness of 18-FDG PET/CT for detecting malignancy in IPMN of the pancreas was evaluated. Three factors were significantly related to malignancy in IPMN; the diameter of the main pancreatic duct, the serum value of carcinoembryonic antigen (CEA), and the neutrophil-to-lymphocyte ratio (NLR). 18-FDG PET accumulation was significantly related to malignancy in IPMN; sensitivity of 0.82 and specificity of 0.71. Independent predictors for malignancy in IPMN were as follows: 18-FDG PET accumulation, CEA greater than 1.0 ng/ml, and NLR greater than 2.63. The authors concluded that 18-FDG PET accumulation is a potent new marker for distinguishing malignant from benign IPMNs of the pancreas.

Regenet et al (2020) noted that malignant or high-risk IPMN require surgical resection but surgery should be avoided in patients with IPMN carrying a low risk of malignancy; and 18F-FDG PET has been studied mostly in small, single-center, retrospective series. In a prospective, non-comparative, multi-center study, these researchers examined the value of 18F-FDG PET/CT in differentiating between benign and malignant IPMN of the pancreas. The primary end-point was the specificity of PET/CT for identifying malignant IPMN (in-situ or invasive carcinoma). Final diagnosis was obtained from pathological examination of the resected specimen. Among 120 patients analyzed, 99 had confirmed IPMN, including 24 with malignant lesions, namely 9 with carcinoma in-situ and 15 with invasive carcinoma. The 18-F-FDG PET/CT was positive in 44 and 31 patients in the overall and IPMN populations, respectively. In the 99 IPMN patients, PET/CT showed 13 true-positive, 18 false-positive, 57 true-negative and 11 false-negative results. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for the diagnosis of malignancy were 54.2 %, 76.0 %, 83.8 % and 41.9 %, respectively, versus 64.9 %, 75.9 %, 82.9 % and 54.5 % in the overall population. These investigators could not identify a cut-off value for SUVmax to distinguish benign from malignant lesions. Conventional imaging included CT, magnetic resonance cholangiopancreatography (MRCP) and endoscopic US. In IPMN patients who underwent the 3 techniques, sensitivity, specificity, NPV and PPV were 66.7 %, 84.4 %, 84.4 % and 66.7 %, respectively. The authors concluded that in this study, 18-F-FDG PET/CT did not perform better than conventional imaging to differentiate malignant from benign IPMN.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Pancreatic adenocarcinoma” (Version 1.2020) does not mention FDG-PET as a management option.

PET Scan for Re-Staging of Malignant Peripheral Nerve Sheath Tumor

Kim et al (2017) stated that malignant peripheral nerve sheath tumor (MPNST) is a highly malignant tumor and rarely occurs in the head and neck. These researchers described the imaging features of MPNST of the head and neck. They retrospectively analyzed computed tomography (CT; n = 14), magnetic resonance imaging (MRI; n = 16), and 18-fludeoxyglucose (FDG) positron emission tomography/computed tomography (18F-FDG PET/CT; n = 5) imaging features of 18 MPNSTs of the head and neck in 17 patients. Special attention was paid to determine the nerve of origin from which the tumor might have arisen. All lesions were well-defined (n = 3) or ill-defined (n = 15) masses (mean of 6.1 cm). Lesions were at various locations but most commonly the neck (n = 8), followed by the intra-cranial cavity (n = 3), para-nasal sinus (n = 2), and orbit (n = 2). The nerve of origin was inferred for 11 lesions: 7 in the neck, 2 in the orbit, 1 in the cerebello-pontine angle (CPA), and 1 on the parietal scalp. Attenuation, signal intensity, and enhancement pattern of the lesions on CT and MRI were non-specific. Necrosis/hemorrhage/cystic change within the lesion was considered to be present on images in 13 and bone change in 9. On 18F-FDG PET/CT images, all 5 lesions demonstrated various hyper-metabolic foci with maximum standard uptake value (SUVmax) from 3.2 to 14.6 (mean of 7.16 ± 4.57). The authors concluded that MPNSTs could arise from various locations in the head and neck. Moreover, these investigators noted that although non-specific, a mass with an ill-defined margin along the presumed course of the cranial nerves may aid the diagnosis of MPSNT in the head and neck.

Tripathy et al (2019) stated that MPNSTs are a highly malignant group of soft tissue sarcomas and carry a very poor prognosis. Metastasis to bilateral adrenal glands is very rare in such group of neoplasms. These researchers discussed the case of a 85-year old man who was diagnosed with MPNST from pre-vertebral mass with metastases to bilateral adrenal glands and bone marrow from the beginning, and the role of serial 18F-FDG PET/CT scans in response assessment first to sunitinib (tyrosine kinase inhibitor) and then to liposomal doxorubicin.

Schwabe et al (2019) stated that distinguishing between benign peripheral nerve sheath tumors (BPNSTs) and MPNSTs in neurofibromatosis type 1 (NF1) patients before excision could be challenging. How could MPNST be most accurately diagnosed using clinical symptoms, MRI findings (tumor size, depth, and necrosis), PET measures (SUVpeak, SUVmax, SUVmax tumor/SUVmean liver, and qualitative scale), and combinations of the above? All NF1 patients who underwent PET imaging at the authors’ institution (January 1, 2007 to December 31, 2016) were included. Medical records were reviewed for clinical findings; MR images and PET images were interpreted by 2 fellowship-trained musculoskeletal and nuclear medicine radiologists, respectively. Receiver operating characteristic (ROC) curves were created for each PET measurement; the area under the curve (AUC) and thresholds for diagnosing malignancy were calculated. Logistic regression determined significant predictors of malignancy. The study population of 41 patients contained 34 benign and 36 malignant tumors. Clinical findings did not reliably predict MPNST. Tumor depth below fascia was highly sensitive; larger tumors were more likely to be malignant but without a useful cut-off for diagnosis. Necrosis on MRI was highly accurate and was the only significant variable in the regression model. PET measures were highly accurate, with AUCs comparable and cut-off points consistent with prior studies. A diagnostic algorithm was created using MRI and PET findings. The authors concluded that MRI and PET were more effective at diagnosing MPNST than clinical features. These researchers created an algorithm for pre-operative evaluation of PNSTs in NF1 patients, for which additional validation will be indicated.

There is a lack of evidence regarding the use of PET for re-staging of malignant peripheral nerve sheath tumor.

PET Scan for Re-Staging of Waldenstrom Macroglobulinemia

Muz and colleagues (2020) noted that Waldenstrom macroglobulinemia (WM) is a rare B-cell malignancy characterized by secretion of immunoglobulin M (IgM) and cancer infiltration in the bone marrow. Chemokine receptor such as CXCR4 and hypoxic condition in the bone marrow play crucial roles in cancer cell trafficking, homing, adhesion, proliferation, survival, and drug resistance. These investigators used CXCR4 as a potential biomarker to detect hypoxic-metastatic WM cells in the bone marrow and in the circulation by using CXCR4-detecting radio-pharmaceutical. They radio-labeled a CXCR4-inhibitor (AMD3100) with 64Cu and tested its binding to WM cells with different levels of CXCR4 expression using gamma counter in-vitro. The accumulation of this radio-pharmaceutical tracer was tested in-vivo in subcutaneous and intra-tibial models using PET/CT scan. In addition, peripheral blood mononuclear cells (PBMCs) spiked with different amounts of WM cells ex-vivo were detected using gamma counting. In-vitro, 64Cu-AMD3100 binding to WM cell lines demonstrated a direct correlation with the level of CXCR4 expression, which was increased in cells cultured in hypoxia with elevated levels of CXCR4; and decreased in cells with CXCR4 and HIF-1α knockout. Moreover, 64Cu-AMD3100 detected localized and circulating CXCR4high WM cells with high metastatic potential. The authors concluded that they developed a molecularly targeted system, 64Cu-AMD3100, which bound to CXCR4 and specifically detected WM cells with hypoxic phenotype and metastatic potential in the subcutaneous and intra-tibial models. The researchers stated that these preliminary findings using CXCR4-detecting PET radio-pharmaceutical tracer indicated a potential technology to predict high-risk patients for the progression to WM due to metastatic potential.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma” (Version 2.2020) does not mention PET as a management tool.

Whole Body PET for Unspecified Periodic Fever Syndrome

An UpToDate review on “Periodic fever syndromes and other autoinflammatory diseases: An overview” (Nigrovic, 2020) does not mention whole body PET as a management tool.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
*Cardiac indications*:
CPT codes covered if selection criteria are met:
78429	Myocardial imaging, positron emission tomography (PET), metabolic evaluation study (including ventricular wall motion[s] and/or ejection fraction[s], when performed), single study; with concurrently acquired computed tomography transmission scan
78430	Myocardial imaging, positron emission tomography (PET), perfusion study (including ventricular wall motion[s] and/or ejection fraction[s], when performed); single study, at rest or stress (exercise or pharmacologic), with concurrently acquired computed tomography transmission scan
78431	multiple studies at rest and stress (exercise or pharmacologic), with concurrently acquired computed tomography transmission scan
78432	Myocardial imaging, positron emission tomography (PET), combined perfusion with metabolic evaluation study (including ventricular wall motion[s] and/or ejection fraction[s], when performed), dual radiotracer (eg, myocardial viability);
78433	with concurrently acquired computed tomography transmission scan
+78434	Absolute quantitation of myocardial blood flow (AQMBF), positron emission tomography (PET), rest and pharmacologic stress (List separately in addition to code for primary procedure)
78459	Myocardial imaging, positron emission tomography (PET), metabolic evaluation
78491	Myocardial imaging, positron emission tomography (PET), perfusion; single study at rest or stress
78492	multiple studies at rest and/or stress
Other CPT codes related to the CPB:
78464	Myocardial perfusion imaging; tomographic (SPECT), single study (including attenuation correction when performed), at rest or stress (exercise and/or pharmacologic), with or without quantification
78465	tomographic (SPECT), multiple studies, (including attenuation correction when performed), at rest and/or stress (exercise and/or pharmacologic) and redistribution and/or rest injection, with or without quantification
HCPCS codes covered if selection criteria are met:
A9526	Nitrogen N-13 ammonia, diagnostic, per study dose, up to 40 millicuries
A9552	Fluorodeoxyglucose F-18 FDG, diagnostic, per study dose, up to 45 millicuries
A9555	Rubidium Rb-82, diagnostic, per study dose, up to 60 millicuries
ICD-10 codes covered if selection criteria are met (not all-inclusive):
D86.85	Sarcoid myocarditis
I20.0 - I20.9	Angina pectoris
I21.01 - I22.2	ST elevation (STEMI) myocardial infarction involoving left main or left anterior descending coronary artery
I21.A1	Myocardial infarction type 2
I21.A9	Other myocardial infarction type
I24.0 - I24.9	Other acute and subacute forms of ischemic heart disease
I25.2	Old myocardial infarction
I25.811	Atherosclerosis of native coronary artery of transplanted heart without angina pectoris
I25.812	Atherosclerosis of bypass graft of coronary artery of transplanted heart without angina pectoris
I44.4 - I45.5	Atrioventricular, bundle branch, and other heart block
I48.0, I48.2, I48.91	Atrial fibrillation
I50.1 - I50.9	Heart failure
*Oncologic indications and conditions other than cardiac and neurologic for PET and PET-CT Fusion*:
CPT codes covered if selection criteria are met:
78811	Positron emission tomography (PET) imaging; limited area (e.g., chest, head/neck)
78812	skull base to mid-thigh
78813	whole body
78814	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (e.g., chest, head/neck)
78815	skull base to mid-thigh
78816	whole body
Other CPT codes related to the CPB:
32095	Thoracotomy, limited, for biopsy of lung or pleura
32097	Thoracotomy, with diagnostic biopsy(ies) of lung nodule(s) or mass(es) (eg, wedge, incisional), unilateral
32100	Thoracotomy; with exploration
32408	Core needle biopsy, lung or mediastinum, percutaneous, including imaging guidance, when performed
38500 - 38530	Biopsy or excision of lymph node(s); open, superficial, by needle, superficial (e.g., cervical, inguinal, axillary), open, deep cervical node(s), with or without excision scalene fat pad, open deep axillary node(s) or open, internal mammary node(s)
61534	Craniotomy with elevation of bone flap; for excision of epileptogenic focus without electrocorticography during surgery
61536	for excision of cerebral epileptogenic focus, with electrocorticography during surgery (includes removal of electrode array)
82378	Carcinoembryonic antigen (CEA)
HCPCS codes covered if selection criteria are met:
A9515	Choline c-11, diagnostic, per study dose up to 20 millicuries
A9552	Fluorodeoxyglucose F-18 FDG, diagnostic, per study dose, up to 45 millicuries
A9587	Gallium ga-68, dotatate, diagnostic, 0.1 millicurie
A9588	Fluciclovine f-18, diagnostic, 1 millicurie
C9067	Gallium Ga-68, Dotatoc, diagnostic, 0.01 mci
G0235	PET imaging, any site, not otherwise specified
HCPCS codes not covered for indications listed in the CPB:
F18-FDOPA, Gallium-68 PSMA -no specific code:
A9586	Florbetapir f18, diagnostic, per study dose, up to 10 millicuries
A9591	Fluoroestradiol F 18, diagnostic, 1 millicurie
A9592	Copper Cu-64, dotatate, diagnostic, 1 millicurie
A9597	Positron emission tomography radiopharmaceutical, diagnostic, for tumor identification, not otherwise classified
A9598	Positron emission tomography radiopharmaceutical, diagnostic, for non-tumor identification, not otherwise classified
G0219	PET imaging whole body; melanoma for non-covered indications
G0252	PET imaging, full and partial-ring PET scanners only, for initial diagnosis of breast cancer and/ or surgical planning for breast cancer (e.g., initial staging of axillary lymph nodes)
S8085	Fluorine-18 fluorodeoxyglucose (F-18 FDG) imaging using dual-head coincidence detection system (non-dedicated PET scan) [when described as an FDG-SPECT scan]
Other HCPCS codes related to the CPB:
A4641	Radiopharmaceutical, diagnostic, not otherwise classified
A9580	Sodium fluoride F-18, diagnostic, per study dose, up to 30 millicuries [not covered when with NaF-18 PET for identifying bone metastasis of cancer]
Q9951	Low osmolar contrast material, 400 or greater mg/ml iodine concentration, per ml
Q9958 - Q9967	High osmolar contrast material
ICD-10 codes covered if selection criteria are met:
C00.0 - C21.8, C24.1, C25.0 - C25.9, C30.0 - C34.92, C38.0 - C43.9, C48.0 - C52, C53.0 - C53.9, C56.1 - C57.9, C60.0 - C60.9, C61, C62.00 - C62.92, C71.0 - C71.9, C73, C76.0	Malignant neoplasm of lip, oral cavity, and pharynx, esophagus, stomach, penis, prostate, testis, small intestine, colon, rectum, rectosigmoid junction, and anus [PET not covered for re-staging and surveillance], ampulla of vater, pancreas, peritoneum, nasal cavities, middle ear, and accessory sinuses, mediastinum, mesothelioma, respiratory system [PET not covered for screening of asymptomatic members for lung cancer and staging of biopsy for solitary fibrous tumor of pleura] and other intrathoracic organs, bones of skull and face, mandible, connective tissue and other soft tissue, [PET not covered for schwannoma], melanoma of skin, skin, breast, vulva, vagina [PET not covered for staging and restaging of vulvar or vaginal cancer], cervix uteri, ovary, fallopian tube, testis, eye, brain, [PET not covered for atypical teratoid/rhabdoid tumor], thyroid gland, thymus, head, face, and neck, other endocrine glands and related structures [including paragangliomas], other malignant neoplasm without specification of site [occult primary cancers]
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C45.0 - C45.9	Mesothelioma
C80.1	Malignant (primary) neoplasm, unspecified [unknown primary]
C81.00 - C90.02, C96.0 - C96.9	Malignant neoplasm of lymphatic and hematopoietic tissue [except xanthogranuloma]
C90.20 - C90.22	Extramedullary plasmacytoma
C90.30 - C90.32	Solitary plasmacytoma
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type
C92.00 - C92.02	Acute myeloblastic leukemia
C92.40 - C92.42	Acute promyelocytic leukemia
C92.50 - C92.52	Acute myelomonocytic leukemia
C92.60 - C92.62	Acute myeloid leukemia with 11q23-abnormality
C92.A0 - C92.A2	Acute myeloid leukemia with multilineage dysplasia
D00.00 - D01.3, D02.0 - D02.4, D05.0 - D05.92, D06.0 - D06.9, D09.0 - D09.19, D09.3 - D09.9	Carcinoma in situ lip, oral cavity, and pharynx, esophagus, stomach, colon, rectum, respiratory system, breast, and eye [major salivary glands not covered]
D37.01 - D37.09 D38.0 - D38.6	Neoplasm of uncertain behavior of major salivary glands, lip, oral cavity, and pharynx, larynx, trachea, bronchus, and lung, pleura, thymus, and mediastinum, and other and unspecified respiratory organs
D3a.00 - D3a.8	Neuroendocrine tumors
D43.0 - D43.9	Neoplasm of uncertain behavior of brain and central nervous system
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2	Castleman disease [not covered for re-staging of multi-centric Castleman's disease]
G40.00 - G40.919	Epilepsy and recurrent seizures [pre-surgical evaluation for localization of seizure focus]
R22.0 - R22.1, R90.0	Swelling, mass, or lump in head and neck
R56.1	Post traumatic seizures
R56.9	Unspecified convulsions [pre-surgical evaluation for localization of seizure focus only]
R91.1	Solitary pulmonary nodule
T66.xxx+	Radiation sickness, unspecified [radiation necrosis]
Z85.01, Z85.028, Z85.030 - Z85.038 Z85.040 - Z85.048, Z85.110 - Z85.12 Z85.21 - Z85.22, Z85.3 Z85.41, Z85.43, Z85.47 Z85.71 - Z85.79, Z85.820, Z85.830 Z85.840 - Z85.841, Z85.850 - Z85.858	Personal history of malignant neoplasm of esophagus, large intestine, rectum, rectosigmoid junction, and anus, trachea, bronchus and lung, larynx, nasal cavities, middle ear, and accessory sinuses, breast, stomach, cervix uteri, ovary, testis, lymphosarcoma and reticulosarcoma, Hodgkin's disease, bone, melanoma of skin, eye, brain, thyroid and neuroendocrine tumor
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B38.0 - B38.9	Coccidioidomycosis
C22.0 - C24.0, C24.8 - C24.9, C48.0	Malignant neoplasm of liver and intrahepatic bile ducts, gallbladder and other and unspecified parts of biliary tract and retro peritoneum
C44.00 - C44.99	Other and unspecified malignant neoplasm of skin
C46.0 - C46.9, C55	Malignant neoplasm of Kaposi's sarcoma and uterus, part unspecified
C49.8	Malignant neoplasm of overlapping sites of connective and soft tissue [not covered for spindle cell sarcoma]
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C58	Malignant neoplasm of placenta
C63.00 - C67.9	Malignant neoplasm of other male genital organs, bladder, and kidney and other and unspecified urinary organs [including Wilms' tumor]
C70.0 - C70.9, C72.0 - C72.1 C72.50 - C72.9	Malignant neoplasm of other and unspecified parts of nervous system
C77.9	Secondary and unspecified malignant neoplasm of lymph nodes, site unspecified
C78.2 - C78.39	Secondary malignant neoplasm of pleura and other respiratory organs
C78.6 - C78.7	Secondary malignant neoplasm of retroperitoneum and peritoneum, and liver, specified as secondary
C79.00 - C79.52	Secondary malignant neoplasm of kidney, other urinary organs, skin, brain and spinal cord, other parts of nervous system, and bone and bone marrow
C79.70 - C79.72	Secondary malignant neoplasm of adrenal gland
C79.82	Secondary malignant neoplasm of genital organs
C79.89	Secondary malignant neoplasm of other specified sites
C86.3	Blastic NK-cell lymphoma [plasmacytoid dendritic cell neoplasm]
C88.8	Other malignant immunoproliferative diseases
C90.10, C91, C91.40 - C91.42, C93.00 - C93.Z2, C94.00 - C94.82, C95.00 - C95.92	Plasma cell leukemia, lymphoid leukemia, monocytic leukemia, other leukemias of specified cell type, Leukemia of unspecified cell type, Hairy cell leukemia
D45 - D47.1, D47.3, D47.z1 - D47.9	Neoplasm of uncertain behavior of breast and other lymphatic and hematopoietic tissues
D01.40 - D01.9	Carcinoma in situ of anal canal, anus, unspecified, other and unspecified parts of intestine, liver and biliary system, and other and unspecified digestive organs
D04.0 - D04.9	Carcinoma in situ of skin
D07.1	Carcinoma in situ of vulva
D10.0 - D36.9	Benign neoplasms [including paraganglioma]
D37.6, D48.3 - D8.4	Neoplasm of uncertain behavior of liver and biliary passages, and retroperitoneum and peritoneum
D39.0 - D41.9, D44.0 - D44.9	Neoplasm of uncertain behavior of other and unspecified respiratory organs, genitourinary organs, and endocrine glands
D45, D46.0 - D46.9, D47.01 - D47.4, D47.Z9, D48.60 - D48.62	Neoplasm of uncertain behavior of breast and other lymphatic and hematopoietic tissues
D48.1	Neoplasm of uncertain behavior of connective and other soft tissue [includes giant cell tumor of the bone]
D49.3 - D49.7	Neoplasm of unspecified behavior of breast, bladder, other genitourinary organs, brain, and endocrine glands and other parts of nervous system
D49.9	Neoplasm of unspecified behavior, of unspecified site
D72.1	Eosinophilia
D73.2	Chronic congestive splenomegaly
D76.3	Other histiocytosis with massive lymphadenopathy [Roasi-Dorfman disease]
D86.0 - D86.9	Sarcoidosis
E71.520 - E71.529	X-linked adrenoleukodystrophy
E83.52	Hypercalcemia
E85.0 - E85.9	Amyloidosis
F01 - F99	Mental disorders
G00.0 - G37.9, G43.001 - G99.8 H00,011 - H59.89, H60.00 - H95.89	Diseases of the nervous system and sense organs [except pre-surgical evaluation for localization of seizure focus]
I00 - I52	Heart disease
I67.5	Moyamoya disease
J84.82	Adult pulmonary Langerhans cell histiocytosis
J90 - J91.8	Pleural effusion
K72.01, K72.11, K72.91	Hepatic encephalopathy
L72.11	Pilar cysts [Pilar tumor]
M01.x51 - M01.x59	Direct infection of hip in infectious and parasitic diseases classified elsewhere
M04.1	Periodic fever syndromes [evaluation of unspecified periodic fever syndrome]
M05.00 - M14.89	Inflammatory polyarthropathies
M12.20 - M12.29	Villonodular synovitis (pigmented)
M31.4	Aortic arch syndrome [Takayasu]
M86.30 - M86.9	Chronic multifocal osteomyelitis
M88.0 - M88.9	Osteitis deformans [Paget's disease of bone]
O01.0 - O01.9	Hydatidiform mole [gestational trophoblastic neoplasia]
Q89.09	Congenital malformations of spleen [congenital splenomegaly]
R16.1	Splenomegaly, not elsewhere classified
R25.0 - R29.91	Symptoms and signs involving nervous and musculoskeletal systems
R40.0 - R40.4	Somnolence, stupor and coma
R41.1 - R41.3	Amnesia
R41.9, R68.89	Other general symptoms
R42.0	Dizziness and giddiness
R44.0, R44.2 - R44.3 R55	Hallucinations and syncope and collapse
R50.9	Fever, unspecified [fever of unknown origin (FUO)]
R93.0	Abnormal findings on diagnostic imaging of skull and head, not elsewhere classified
R93.1 - R93.5	Abnormal findings on radiological and other examination of other intrathoracic organ
R94.01 - R94.138	Abnormal results of function studies of brain and central nervous system and peripheral nervous system and special senses
R94.30 - R94.39	Abnormal results of cardiovascular function studies,
T81.40xA - T81.49xS	Infection following a procedure [infection of hip arthroplasty]
T84.51x+ - T84.54x+	Infection and inflammatory reaction due to internal joint prosthesis [infection of hip arthroplasty or knee replacement prostheses]
Z00.00 - Z13.9	Persons encountering health services for examination
Z15.01	Genetic susceptibility to malignant neoplasm of breast [Li-Fraumeni syndrome]
Z85.00, Z85.810 - Z85.819	Personal history of malignant neoplasm of gastrointestinal tract, unspecified
Z85.05 - Z85.09	Personal history of malignant neoplasm of liver and of other gastrointestinal tract
Z85.20 - Z85.29	Personal history of malignant neoplasm of other respiratory and intrathoracic organs
Z85.42	Personal history of malignant neoplasm of other parts of uterus
Z85.46	Personal history of malignant neoplasm of prostate
Z85.48 - Z85.59	Personal history of malignant neoplasm of epididymis, other male genital organs, urinary organs, unspecified
Z85.6	Personal history of leukemia
Z85.71 - Z85.79	Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues
Z85.820 - Z85.828	Personal history of other malignant neoplasm of skin
Z85.848	Personal history of malignant neoplasm of other parts of nervous system
Z85.858 - Z85.859	Personal history of malignant neoplasm of other endocrine glands and related structures, other, and unspecified sites
Z96.641 - Z96.649	Presence of artificial hip
*Neurologic indications for PET*:
CPT codes covered for indications listed in the CPB:
78608	Brain imaging, positron emission tomography (PET); metabolic evaluation
78609	perfusion evaluation
HCPCS codes not covered for indications listed in the CPB:
A9586	Florbetapir F18, diagnostic, per study dose, up to 10 millicuries
A9587	Gallium ga-68, dotatate, diagnostic, 0.1 millicurie
A9599	Radiopharmaceutical, diagnostic, for beta-amyloid positron emission tomography (pet) imaging, per study dose
C9458	Florbetaben f18, diagnostic, per study dose, up to 8.1 millicuries
C9459	Flutemetamol f18, diagnostic, per study dose, up to 5 millicuries
Q9982	Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries
Q9983	Florbetaben f18, diagnostic, per study dose, up to 8.1 millicuries
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
F01.50 - F01.51 F03.90 - F03.91	Dementias
F02.80 - F02.81	Dementia in other diseases classified elsewhere with or without behavioral disturbance
F07.0	Personality change due to known physiological condition
F03.90 - F03.91	Unspecified dementia, without and with behavioral disturbance
G10	Huntington's disease
G20 - G21.9	Parkinson's disease
G30.0 - G30.9	Alzheimer's disease
I68.0	Cerebral amyloid angiopathy [sporadic]
R41.1 - R41.3	Amnesia
R43.0 - R43.9	Disturbances of smell and taste
Z13.858	Encounter for screening for other nervous system disorders
Z82.0	Family history of epilepsy and other diseases of the nervous system

The above policy is based on the following references:

Adam Z, Krejcí M, Pour L, et al. Different courses of recurrent or multisystem Langerhans cells histiocytosis in adults -- description of 22 cases from one centre. Vnitr Lek. 2010;56(6):542-556.
Adam Z, Rehák Z, Koukalová R, et al. Pulmonary Langerhans cell histiocytosis -- evaluation of the disease activity and treatment response using PET-CT (SUV(max) Pulmo/SUV(max) Hepar index). Description of own experience and literature review. Vnitr Lek. 2010;56(12):1228-1250.
Adams E, Asua J, Conde Olasagasti J, et al. Positron emission tomography: Experience with PET and synthesis of the evidence (INAHTA Joint Project). Boston, MA: U.S. Department of Veterans Affairs, Veterans Health Administration, Management Decision and Research Center, Technology Assessment Program (VATAP); 1999.
Adams E, Flynn K. Positron emission tomography: Descriptive analysis of experience with PET in VA. A systematic review update of FDG-PET as a diagnostic test in cancer and Alzheimer's disease. Technology Assessment Program Report No. 10. Boston, MA: U.S. Department of Veterans Affairs, Veterans Health Administration, Management Decision and Research Center, Technology Assessment Program (VATAP); 1998.
Adams HJ, Kwee TC. Prognostic value of pretransplant FDG-PET in refractory/relapsed Hodgkin lymphoma treated with autologous stem cell transplantation: Systematic review and meta-analysis. Ann Hematol. 2016;95(5):695-706.
Adams HJ, Nievelstein RA, Kwee TC. Prognostic value of interim and end-of-treatment FDG-PET in follicular lymphoma: A systematic review. Ann Hematol. 2016;95(1):11-18.
Advanced Accelerator Applications USA. Netspot (kit for the preparation of gallium Ga 68 dotatate injection), for intravenous use. Prescribing Information. Reference ID: 3939719. New York, NY: Advanced Accelerator Applications USA; revised June 2016.
Agency for Health Technology Assessment in Poland (AHTAPol). Cost-effectiveness analysis of PET-CT positron emission tomography and the diagnostic technologies financed from public sources in oncological diagnostics in Poland. Health Technology Assessment Report. Warsaw, Poland: AHTAPol; 2007.
Agency for Healthcare Research and Quality (AHRQ). Positron emission tomography for nine cancers (bladder, brain, cervical, kidney, ovarian, pancreatic, prostate, small cell lung, testicular). Prepared by the University of Alberta Evidence-Based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). Rockville, MD: AHRQ; 2008.
Albert M, DeCarli C, DeKosky S, et al. and the Alzheimer's Association Neuroimaging Workgroup. The use of MRI and PET for clinical diagnosis of dementia & investigation of cognitive impairment. A Consensus Report. Chicago, IL: Alzheimer's Association; April 2004.
American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 42, April 2003. Breast cancer screening. Obstet Gynecol. 2003;101(4):821-831.
American Society of Health-System Pharmacits (ASHP). Technetium Tc99m Albumin Aggregated Injection. Resolved Shortages Bulletin. Bethesda, MD: ASHP; April 20, 2014.
Aoyagi S, Sato-Matsumura KC, Shimizu H. Staging and assessment of lymph node involvement by 18F-fluorodeoxyglucose-positron emission tomography in invasive extra-mammary Paget's disease. Dermatol Surg. 2005;31(5):595-598.
Auguste P, Barton P, Hyde C, Roberts T. An economic evaluation of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. Health Technol Assess. 2011;15(18):1-54.
Balaban EP, Mangu PB, Khorana AA, et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(22):2654-2668.
Balk E, Lau J, and the New England Medical Center Evidence-Based Practice Center. Systemic review of positron emission tomography for the follow-up of treated thyroid cancer. Technology Assessment. Prepared for the Agency for Healthcare Research and Quality, Contract No. 270-97-0019. Baltimore, MD: Center for Medicare and Medicaid Services: April 10, 2002.
Bateman RJ, Eidelberg D. Testing a test for Alzheimer disease. Neurology. 2007;68(7):482-483.
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Last Review 04/15/2021

Effective: 10/23/1995

Next Review: 01/27/2022
Review History
Definitions

Positron Emission Tomography (PET)

Policy

Cardiac Indications

Evaluation of Coronary Artery Disease

Assessment of Myocardial Viability

Cardiac Sarcoid

Oncologic indications

General Criteria

Diagnosis:

Staging:

Re-staging:

Monitoring:

Disease-Specific Criteria

Characterization of Solitary Pulmonary Nodules (SPNs):

Non-Small Cell Lung Carcinoma (NSCLC):

Small Cell Lung Carcinoma (SCLC):

Mesothelioma:

Colorectal Cancer and Small Bowel Adenocarcinoma:

Anal Cancer:

Hodgkinslymphoma:

Non-Hodgkin's Lymphoma subtypes including post-transplant lymphoproliferative disorder and Castleman's disease:

Melanoma:

Esophageal Cancer:

Gastric Cancer:

Gastrointestinal Stromal Tumors:

Head and Neck Cancers:

Thyroid Cancer:

Thymic Malignancies:

Breast Cancer:

Cervical Cancer:

Vaginal Cancer:

Vulvar Cancer:

Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancer:

Testicular Cancer:

Multiple Myeloma and Plasmacytomas:

Ewing Sarcoma, Chordoma and Osteosarcoma:

Soft Tissue Sarcoma:

Neuroendocrine Tumors:

Pancreatic Tumors:

Brain Cancer:

Occult Primary:

Paraneoplastic Syndromes:

Merkel Cell Carcinoma:

Penile Cancer:

Uterine Sarcoma:

Cancer of Ampulla:

PET Scan for Acute Myeloid Leukemia:

FDG-PET in Place of 99mTc Skeletal Scintigraphy:

NaF-18 PET:

Carbon-11 labeled 5-HTP PET:

Fluciclovine f-18 PET and Choline C-11 PET:

Gallium-68 PSMA PET:

Gallium Ga 68 dotatate PET and Copper Cu 64 dotatate PET:

18F-FDOPA-PET Scan for Prognosis of Brain Cancer:

Cerianna (Fluoroestradiol F-18) PET for Breast Cancer:

Additional Experimental and Investigational Oncological Indications:

Neurologic Indications

Other Indications

Gamma Camera PET Scan

PET/MRI

Positron Emission Mammography (PEM)

PET Scan for Screening

Amyloid-PET for Diagnosis of Sporadic Cerebral Amyloid Angiopathy

Florbetapi-PET for Diagnosis of Cerebral Amyloid Angiopathy-Related Hemorrhages

Background

Anal Cancer

PET for Orthopedic Prostheses

Germ Cell Tumors (CGT)

Hepatocellular Carcinoma

Pediatric Abdominal Tumors

Langerhans Cell Histiocytosis (LCH)

Large-Vessel Vasculitis

Neuroblastoma

Cardiac Sarcoidosis and Cardiomyopathies

Bone Marrow Involvement

Sentinel Lymph Node Biopsy for Melanoma

Schwannoma (Acoustic Neuroma)

Focal Eosinophilic Liver Disease (FELD)

Erdheim-Chester Disease

Myoclonus

Diagnosis

Staging

Re-staging

Monitoring

Characterization of Solitary Pulmonary Nodules (SPNs)

Non-Small Cell Lung Carcinoma (NSCLC)

Small Cell Lung Carcinoma (SCLC)

Mesothelioma

Colorectal Cancer and Small Bowel Adenocarcinoma

Anal Cancer

Hodgkinslymphoma

Non-Hodgkin's Lymphoma subtypes including post-transplant lymphoproliferative disorder and Castleman's disease

Melanoma

Esophageal Cancer

Gastric Cancer

Gastrointestinal Stromal Tumors

Head and Neck Cancers

Thyroid Cancer

Thymic Malignancies

Breast Cancer

Cervical Cancer

Vaginal Cancer

Vulvar Cancer

Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancer

Testicular Cancer

Multiple Myeloma and Plasmacytomas

Ewing Sarcoma, Chordoma and Osteosarcoma

Soft Tissue Sarcoma

Neuroendocrine Tumors

Pancreatic Tumors

Brain Cancer

Occult Primary

Paraneoplastic Syndromes

Merkel Cell Carcinoma

Penile Cancer

Uterine Sarcoma

Cancer of Ampulla

FDG-PET in Place of ^99mTc Skeletal Scintigraphy

NaF-18 PET

Carbon-11 labeled 5-HTP PET

Fluciclovine f-18 PET and Choline C-11 PET

Gallium Ga 68 dotatate PET and Copper Cu 64 dotatate PET

Additional Experimental and Investigational Oncological Indications