Tumor Scintigraphy

Number: 0168

(Replaces CPBs 239, 309, 320)

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses tumor scintigraphy.

1. Medical Necessity

   1. ProstaScint

      Aetna considers ProstaScint scans medically necessary for either of the following indications:

      1. Pre-operative staging of newly diagnosed members with biopsy-proven prostate cancer that is thought to be clinically localized after standard diagnostic evaluation, but who have a moderate to high probability of occult extra-prostatic metastasis; or
      2. Staging of post-prostatectomy members or members treated with radiation therapy in whom there is a high suspicion of undetected residual prostate cancer or cancer recurrence.

   2. Oncoscint

      Aetna considers monoclonal antibody (MAb) imaging (also known as radioimmunoscintigraphy and Oncoscint immunoscintigraphy) using satumomab pendetide medically necessary for any of the following indications:

      1. As an alternative to second-look laparotomy to detect occult colorectal carcinoma in members with suspected recurrence suggested by an elevated carcino-embryonic antigen (CEA) level, but who have no evidence of disease on conventional imaging modalities (including CT scan); or
      2. Detection of occult colorectal carcinoma in members about to undergo a potentially curative resection of an apparently isolated recurrence located at a single site (e.g., lung or liver) which has been identified on conventional imaging modalities (including CT scan) and for whom the detection of occult lesions elsewhere would alter the surgical management; or
      3. Detection of occult recurrent ovarian cancer in members with suspected recurrence suggested by rising tumor markers, when no other imaging or physical examination technique can locate the suspected disease.

   3. CEA-Scan

      Aetna considers CEA-Scan^® using Tc-99m-arcitumomab, a radiodiagnostic agent produced by Immunomedics, for use in conjunction with computerized tomography (CT) scans medically necessary for detection of recurrent or metastatic colorectal cancer in the liver and extra-hepatic abdomen and pelvis. 

   4. Technetium-99m-Sestamibi Scintigraphy

      Aetna considers technetium-99m-sestamibi (Tc-MIBI) scintigraphy medically necessary for any of the following indications:

      1. For assessment malignant bone and soft tissue tumor response to therapy; or
      2. For detection of malignant axillary adenopathy secondary to breast cancer; or
      3. For evaluation of metastatic thyroid cancer; or
      4. For evaluation of parathyroid adenoma. Note: Technetium tc-99m pertechnetate (thallium) subtraction scan with technetium tc-99m sestamibi scan for parathyroid adenomais is considered medically necessary.

   5. OctreoScan

      Aetna considers an OctreoScan, using octreotide (Sandostatin) tagged with radiolabeled ¹¹¹Indium-pentetreotide, medically necessary for the diagnosis and staging of members with primary and metastatic neuroendocrine tumors bearing somatostatin receptors.  Such tumors include any of the following:

      1. Carcinoid tumors/carcinoid syndrome
      2. Carotid body tumors
      3. Gastrinomas
      4. Glucagonomas
      5. Insulinomas
      6. Islet cell tumors of the pancreas
      7. Medullary thyroid carcinoma (MTC)
      8. Neuroendocrine carcinoma of the rectum
      9. Paragangliomas
      10. Pheochromocytomas
      11. Pituitary adenomas
      12. Tumor-induced osteomalacia (oncogenic osteomalacia) (for diagnosis only)
      13. VIPoma (vasoactive intestinal peptide) - persons present with Verner-Morrison syndrome: watery diarrhea, hypokalemia and achlorhydria.

   6. Radiolabeled Octreotide for Therapeutic Use

      Aetna considers radiolabeled octreotide medically necessary for the treatment of gastroenteropancreatic neuroendocrine tumors. The gamma emitting imaging radionuclide (¹¹¹In-octreotate) is replaced by a beta imaging therapy radionuclide (90Y-octreotide).  Guidelines from the UKNETwork for Neuroendocrine Tumours (Ramage et al, 2005) state that targeted radionuclide therapy, including 90Y-octreotide (also known as 90Y-DOTATOC), is a useful palliative option for symptomatic individuals with inoperable or metastatic gastroenteropancreatic neuroendocrine tumors where there is corresponding abnormally increased uptake of the corresponding radionuclide imaging agent.

   7. Lymphoscintigraphy and Sentinel Lymph Node Biopsy

      Aetna considers lymphoscintigraphy and sentinal lymph node biopsy (SLNB) medically necessary for the following indications:

      1. For cervical cancer, Merkel cell carcinoma, occult cervical (head and neck) metastases, penile cancer, uterine neoplasms (endometrial cancer and uterine sarcoma), and vulvar cancer;
      2. For members with ductal carcinoma in-situ (DCIS) when one of the following criteria is met:
         
         
         1. Member is undergoing mastectomy; or
         2. DCIS is larger than 3 cm; or
         3. DCIS is associated with a palpable mass; or
         4. DCIS with suspected or proven microinvasion; or
         5. DCIS with high grade histology; or
         6. DCIS with comedo necrosis on pathology;
      3. For members with malignant melanoma (excluding in situ (Stage 0) melanoma);
      4. Radioactive colloid and/or blue dye identification of the sentinel node in the axilla followed by SLNB for persons with breast cancer.

   8. Meta-Iodobenzylguanidine (MIBG) Imaging

      1. Aetna considers I-131 labeled meta-iodobenzylguanidine (MIBG, also known as iobenguane I-131) imaging medically necessary for localizing or confirming any of the following conditions:
         
         
         1. Adrenal medulla hyperplasia
         2. Carcinoid tumors
         3. Neuroblastoma
         4. Paraganglioma
         5. Pheochromocytoma
         6. Thyroid carcinoma.
      2. Aetna considers I-131 labeled MIBG radiotherapy medically necessary for treatment recurrent high-risk neuroblastoma.  Aetna considers I-131 MIBG experimental, investigational, or unproven as a treatment for all other indications because its effectiveness for these indications has not been established.

   9. Azerda

      Aetna considers iobenguane I-131 injection (Azedra) medically necessary for the treatment of adults and adolescents aged 12 years and older with pheochromocytoma or paraganglioma that is unresectable, have spread beyond the original tumor site and require systemic anti-cancer therapy.

   10. AndreView

       Aetna considers iobenguane I-123 injection (AdreView, GE Healthcare) medically necessary for the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests. 

   11. Technetium-Tc 99m Tilmanocept (Lymphoseek)

       Aetna considers technetium Tc 99m tilmanocept (Lymphoseek) injection medically necessary for location of lymph nodes in members with breast cancer or melanoma who are undergoing surgery to remove tumor-draining lymph nodes.

2. Experimental, Investigational, or Unproven

   The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. CEA-scan for all other indications
   2. Iobenguane I-123 injection (AdreView) for all other indications 
   3. Lymphoscintigraphy and SLNB for all other indications (e.g., as a screening test in persons with a BRCA mutation, with or without prophylactic mastectomy, and diagnosis of atypical Spitz nevus, extremity and truncal soft tissue sarcomas, and oral cavity cancers
   4. Meta-iodobenzylguanidine (MIBG, I-123 labeled, also known as iobenguane I-131) imaging in the management of all conditions, such as any of the following:
      
      
      • Arrhythmia
      • Arrhythmogenic right ventricular cardiomyopathy
      • Cardiomyopathy
      • Congestive heart failure (CHF)
      • Diabetes mellitus
      • Differentiating Parkinson's disease from multiple system atrophy or progressive supranuclear palsy
      • Drug-induced cardiotoxicity
      • Heart transplantation
      • Hypertension
      • Idiopathic ventricular fibrillation
      • Ischemic heart disease
      • Selection of therapeutic strategy (e.g., pharmacologic versus non-pharmacologic treatment) for heart failure
      • Tracking response to medications for members with CHF.

   5. Oncoscint immunoscintigraphy for all other indications such as any of the following in the management of individuals with these indications:

      1. As a screening tool for cancers; or
      2. Detection of occult disease in persons who have melanoma, breast cancer, thrombosis, inflammatory disease, lymphoma, or prostate cancer because there are insufficient scientific data to document the clinical utility of Oncoscint immunoscintigraphy in the management of members with these conditions; or 
      3. In other colorectal cancer persons not meeting criteria #1 or #2 above (for instance, post-operative colorectal cancer members with rising serum CEA levels and negative standard imaging and other studies

   6. OctreoScan (¹¹¹In-pentetreotide) for all other indications such as any of the following:

      • Astrocytomas
      • Chemodectomas
      • Hodgkin lymphoma
      • Meningiomas
      • Neuroblastoma (olfactory, mediastinal)
      • Merkel cell tumors
      • Non-Hodgkin's lymphoma
      • Ocular melanoma
      • Sarcoidosis
      • Small-cell lung cancer, primary or metastatic
      • Thymoma
   7. ProstaScint scans for all other indications 
   8. Radiolabeled octreotide for the treatment of incompletely resected meningioma
   9. Scintimammography, including breast-specific gamma imaging (BSGI; also known as molecular breast imaging) as an adjunct to mammography for imaging of breast tissue, for the detection of axillary metastases, staging the axillary lymph nodes in members with breast cancer, and to assess response to adjuvant chemotherapy in members with breast cancer, and for all other indications 
   10. Sentinel lymph node mapping in ovarian tumors
   11. Technetium-99m-sestamibi scintigraphy experimental, investigational, or unproven for all other indications such as the following because its role for these indications has not been established:
       
       
       1. For evaluation of central nervous system (CNS) neoplasms; or
       2. For evaluation of indeterminate renal masses; or
       3. For imaging of breast cancer (known as Miraluma scan); or
       4. For prediction of pathologic non-response to neoadjuvant chemotherapy in breast cancer

   12. Technetium Tc 99m tilmanocept injection experimental, investigational, or unproven for all other indications (e.g., brain tumors, ductal carcinoma in situ, endometrial cancer, head and neck squamous cell carcinoma, Merkel cell carcinoma, and oral cavity squamous cell carcinoma).

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Tumor Scintigraphy:
CPT codes covered if selection criteria are met for ProstaScint, Oncoscint, CEA-Scan, Technetium-99m-Sestamibi Scintigraphy, OctreoScan, Radiolabeled Octreotide, Meta-Iodobenzylguanidine (MIBG), and Breast Specific Gamma imaging:
78800	Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); limited area
78801	multiple areas
78802	whole body, single day imaging
78803	tomographic (SPECT)
78804	whole body, requiring 2 or more days imaging
Other CPT codes related to the CPB:
78830	Radiopharmaceutical localization of tumor, inflammatory process or distribution of radiopharmaceutical agent(s) (includes vascular flow and blood pool imaging, when performed); tomographic (SPECT) with concurrently acquired computed tomography (CT) transmission scan for anatomical review, localization and determination/detection of pathology, single area (eg, head, neck, chest, pelvis), single day imaging
78831	tomographic (SPECT), minimum 2 areas (eg, pelvis and knees, abdomen and pelvis), single day imaging, or single area imaging over 2 or more days
78832	tomographic (SPECT) with concurrently acquired computed tomography (CT) transmission scan for anatomical review, localization and determination/detection of pathology, minimum 2 areas (eg, pelvis and knees, abdomen and pelvis), single day imaging, or single area imaging over 2 or more days
ProstaScint:
HCPCS codes covered if selection criteria are met:
A9507	Indium In-111 capromab pendetide, diagnostic, per study dose, up to 10 millicuries
ICD-10 codes covered if selection criteria are met:
C61	Malignant neoplasm of prostate
Z85.46	Personal history of malignant neoplasm of prostate
Oncoscint:
HCPCS codes covered if selection criteria are met:
A4642	Indium In-111 satumomab pendetide, diagnostic, per study dose, up to 6 millicuries
ICD-10 codes covered if selection criteria are met:
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid junction, and anus
C56.1 - C56.9	Malignant neoplasm of ovary
Z85.038	Personal history of other malignant neoplasm of large intestine
Z85.048	Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus
Z85.43	Personal history of malignant neoplasm of ovary
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C43.0 - C43.9	Malignant melanoma of skin
C50.001 - C50.929	Malignant neoplasm of breast
C61	Malignant neoplasm of prostate
C81.00 - C86.6	Lymphosarcoma and reticulosarcoma
G35	Multiple sclerosis
I25.10	Atherosclerotic heart disease of native coronary artery without angina pectoris
I82.0 - I82.91	Other venous embolism and thrombosis
J41.0 - J47.9	Chronic lower respiratory diseases
K50.00 - K51.919	Regional enteritis and ulcerative colitis
M05.00 - M06.9	Rheumatoid arthritis and other inflammatory polyarthropathies
Z12.0 - Z12.9	Encounter for screening for malignant neoplasms
CEA-Scan:
HCPCS codes covered if selection criteria are met:
A9568	Technetium Tc-99m arcitumomab, diagnostic, per study dose, up to 45 millicuries
ICD-10 codes covered if selection criteria are met:
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid junction, and anus
Z85.038	Personal history of other malignant neoplasm of large intestine
Z85.048	Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus
Technetium-99m-Sestamibi Scintigraphy:
HCPCS codes covered if selection criteria are met:
A9500	Technetium Tc-99m sestamibi, diagnostic, per study dose, up to 40 millicuries
A9512	Technetium tc-99m pertechnetate (thallium) subtraction scan
HCPCS codes not covered for indications listed in the CPB:
S8080	Scintimammography (radioimmunoscintigraphy of the breast), unilateral, including supply of radiopharmaceutical
ICD-10 codes covered if selection criteria are met:
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage
C47.0 - C47.9 C49.0 - C49.9	Malignant neoplasm of connective and other soft tissue
C73	Malignant neoplasm of thyroid gland
C77.3	Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes [only with primary breast cancer]
D34	Benign neoplasm of thyroid glands
D35.1	Benign neoplasm of parathyroid gland
Z85.850	Personal history of malignant neoplasm of thyroid
ICD-10 codes not covered for indications listed in the CPB:
C50.011 - C50.929	Malignant neoplasm of breast
C64.0 – C64.9	Malignant neoplasm of kidney, except renal pelvis
C71.0 - C72.9	Malignant neoplasm of brain and other and unspecified parts of nervous system
C79.00 – C79.02	Secondary malignant neoplasm of kidney and renal pelvis
C79.31 - C79.32	Secondary malignant neoplasm of brain and spinal cord
C79.81	Secondary malignant neoplasm of breast
C79.89	Secondary malignant neoplasm of other specified sites
D05.00 - D05.92	Carcinoma in-situ of breast
D30.10 – D30.12	Benign neoplasm of renal pelvis
D33.0 - D33.9	Benign neoplasm of brain and other parts of nervous system
D41.10 – D41.12	Neoplasm of uncertain behavior of kidney
D42.0 - D44.9	Neoplasm of uncertain behavior of endocrine glands and nervous system
D49.6	Neoplasm of unspecified behavior of brain
N28.89	Other specified disorders of kidney and ureter
OctreoScan:
HCPCS codes covered if selection criteria are met:
A9572	Indium In-111 pentetrotide, diagnostic, per study dose, up to 6 millicuries
ICD-10 codes covered if selection criteria are met:
C25.0 - C25.9	Malignant neoplasm of pancreas [VIPoma, Islet cell tumors]
C73	Malignant neoplasm of thyroid gland
C74.00 - C74.92	Malignant neoplasm of adrenal gland [paragangliomas, pheochromocytomas]
C75.1	Malignant neoplasm of pituitary gland
C75.2	Malignant neoplasm of craniopharyngeal duct
C75.5	Malignant neoplasm of aortic body and other paraganglia
C7A.00, C7A.090 - C7A.8	Malignant carcinoid tumors of other and unspecified sites
C7A.010 - C7A.019	Malignant carcinoid tumors of the same intestine
C7A.026	Malignant carcinoid tumor of the rectum [neuroendocrine carcinoma of the rectum]
D13.1	Benign neoplasm of stomach
D13.6	Benign neoplasm of pancreas
D13.7	Benign neoplasm of Islets of Langerhans [gastrinomas, glucagonomas, Islet cell tumors, insulinoma]
D32.1	Benign neoplasm of spinal meninges
D35.00 - D35.02	Benign neoplasm of adrenal gland [paragangliomas, pheochromocytomas]
D35.2	Benign neoplasm of pituitary gland
D35.3	Benign neoplasm of craniopharyngeal duct
D35.5	Benign neoplasm of carotid body
D35.6	Benign neoplasm of aortic body and other paraganglia
D3a.00 - D3a.8	Benign carcinoid tumor
D37.1 - D37.5	Neoplasm of uncertain behavior of stomach, intestines, and rectum
D37.8 - D37.9	Neoplasm of uncertain behavior of other and unspecified digestive organs
D38.1	Neoplasm of uncertain behavior of trachea, bronchus, and lung
D42.0 - D42.9	Neoplasm of uncertain behavior of meninges
D44.10 - D44.12	Neoplasm of uncertain behavior of adrenal gland
D44.3	Neoplasm of uncertain behavior of pituitary gland
D44.4	Neoplasm of uncertain behavior of craniopharyngeal duct
D44.6	Neoplasm of uncertain behavior of carotid body
D44.7	Neoplasm of uncertain behavior of paraganglia
D44.9	Neoplasm of uncertain behavior of unspecified endocrine glands
E34.0	Carcinoid syndrome
E83.89	Other disorders of mineral metabolism [tumor-induced osteomalacia TIO (oncogenic osteomalacia)]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C30.0	Malignant neoplasm of nasal cavity [neuroblastoma]
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [small-cell lung cancer]
C37	Malignant neoplasm of thymus [thymoma]
C38.1 - C38.8	Malignant neoplasm of mediastinum [neuroblastoma]
C4a.10 - C4a.9	Merkel cell carcinoma
C69.00 - C69.92	Malignant neoplasm of eye and adnexa[ocular melanoma]
C70.0	Malignant neoplasm of cerebral meninges [meningioma]
C71.0 - C71.9	Malignant neoplasm of brain [astrocytoma]
C72.20 - C72.59	Malignant neoplasm of cranial nerves [neuroblastoma, olfactory]
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma]
C75.5	Malignant neoplasm of aortic body and other paraganglia [chemodectomas]
C78.00 - C78.02	Secondary malignant neoplasm of lung
C78.1	Secondary malignant neoplasm of mediastinum
C78.30 - C78.39	Secondary malignant neoplasm of other and unspecified respiratory organs
C78.80 - C78.89	Secondary malignant neoplasm of other and unspecified digestive organs and spleen
C79.2	Secondary malignant neoplasm of skin
C79.31	Secondary malignant neoplasm of brain
C79.32 - C79.49	Secondary malignant neoplasm of other parts of nervous system
C79.70 - C79.72	Secondary malignant neoplasm of adrenal gland
C81.00 - C81.99	Hodgkin lymphoma
C82.00 - C96.9	Malignant neoplasm of lymphatic and hematopoietic tissue
D13.7	Benign neoplasm of endocrine pancreas [insulinomas]
D15.0	Benign neoplasm of thymus [thymoma]
D32.0	Benign neoplasm of cerebral meninges [meningioma]
D35.6	Benign neoplasm of aortic body and other paraganglia [chemodectomas]
D86.0 - D86.9	Sarcoidosis
Radiolabeled Ocreotide:
No specific code
ICD-10 codes covered if selection criteria are met :
C7a.00 - C7a.8	Malignant carcinoid tumors
D3a.00 - D3a.8	Benign carcinoid tumor
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C70.0	Malignant neoplasm of cerebral meninges [meningioma]
D32.0	Benign neoplasm of cerebral meninges [meningioma]
Lymphoscintigraphy and Sentinel Lymph Node Biopsy:
CPT codes covered if selection criteria are met:
38500 - 38530	Biopsy or excision of lymph node(s)
38792	Injection procedure; radioactive tracer for identification of sentinel node
+38900	Intraoperative identification (eg, mapping) of sentinel lymph node(s), includes injection of non-radioactive dye, when performed
78195	Lymphatics and lymph nodes imaging
HCPCS codes covered if selection criteria are met:
C7503	Open biopsy or excision of deep cervical node(s) with intraoperative identification (eg, mapping) of sentinel lymph node(s) including injection of non-radioactive dye when performed
ICD-10 codes covered if selection criteria are met:
C43.0 - C43.9	Malignant melanoma of skin
C4A.0 – C4A.9	Merkel cell carcinoma
C50.001 - C50.929	Malignant neoplasm of breast
C51.0 - C51.9	Malignant neoplasm of vulva
C53.0 - C55	Malignant neoplasm of uterus
C60.0 - C60.9	Malignant neoplasm of penis
C76.0	Malignant neoplasm of head, face and neck
C79.81	Secondary malignant neoplasm of breast
D05.00 - D05.02, D05.80 - D05.92	Carcinoma in situ of breast
D05.10 – D05.12	Intraductal carcinoma in situ of breast
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C01 - C06.9	Malignant neoplasm of oral cavity
C49.10 – C49.6	Malignant neoplasm of other connective and soft tissue [extremity and truncal soft tissue sarcomas]
C56.1 – C56.9	Malignant neoplasm of ovary
D03.0 - D03.9	Melanoma in situ [stage 0]
D22.0 – D22.9	Melanocytic nevi [Atypical spitz nevus]
Z15.01	Genetic susceptibility to malignant neoplasm of breast [BRCA1 or BRCA2 mutations confirmed by molecular susceptibility testing for breast cancer]
I-123 labeled Meta-Iodobenzylguanidine (MIBG) Imaging:
HCPCS codes not covered for indications listed in the CPB:
A9509	Iodine I-123 sodium iodide, diagnostic, per millicurie
A9516	Iodine I-123 sodium iodide, diagnostic, per 100 microcuries, up to 999 microcuries
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
I50.1 - I50.9	Heart failure
Azedra (iobenguane I-131) :
HCPCS codes covered if selection criteria are met:
A9590	Iodine I-131, iobenguane, 1 mCi
ICD-10 codes covered if selection criteria are met:
C74.00 - C74.92	Malignant neoplasm of adrenal gland [paragangliomas, pheochromocytomas]
D35.00 - D35.02	Benign neoplasm of adrenal gland [paragangliomas, pheochromocytomas]
I-131 labeled Meta-Iodobenzylguanidine (MIBG) Imaging:
HCPCS codes covered if selection criteria are met:
A9508	Iodine I-131 iobenguane sulfate, diagnostic, per 0.5 millicurie
A9590	Iodine I-131, iobenguane, 1 mCi
ICD-10 codes covered if selection criteria are met:
C72.20 - C72.59	Malignant neoplasm of cranial nerves [neuroblastoma]
C73	Malignant neoplasm of thyroid gland
C74.00 - C74.92	Malignant neoplasm of adrenal gland [localizing or confirming neuroblastoma or pheochromocytoma] [paraganglioma]
C75.4	Malignant neoplasm of carotid body [paragangliomas]
C75.5	Malignant neoplasm of aortic body and other paraganglia [paragangliomas]
C7a.00 - C7a.8	Malignant carcinoid tumors
D35.00 - D35.02	Benign neoplasm of adrenal gland [pheochromocytomas] [paraganglioma]
D35.5	Benign neoplasm of carotid body [paragangliomas]
D35.6	Benign neoplasm of aortic body and other paraganglia [paragangliomas]
D3a.00 - D3a.8	Benign carcinoid tumors
D37.1 - D37.5	Neoplasm of uncertain behavior of stomach, intestines, and rectum
D37.8 - D37.9	Neoplasm of uncertain behavior of other and unspecified digestive organs
D44.0, D44.2 - D44.6 D44.9	Neoplasm of uncertain behavior of other and unspecified endocrine glands
D44.10 - D44.12	Neoplasm of uncertain behavior of adrenal gland
D44.7	Neoplasm of uncertain behavior of aortic body and other paraganglia
E27.8	Other specified disorders of adrenal glands [adrenal medulla hyperplasia]
E34.0	Carcinoid syndrome
I-131 labeled Meta-lodobenzylquanidine (MIBG) Radiotherapy:
CPT codes not covered for indications listed in the CPB:
79005	Radiopharmaceutical therapy, by oral administration
79101	Radiopharmaceutical therapy, by intravenous administration
79300	Radiopharmaceutical therapy, by interstitial radioactive colloid administration
79403	Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous infusion
79445	Radiopharmaceutical therapy, by intra=arterial particulate administration
ICD-10 codes covered if selection criteria are met:
C72.20 - C72.59	Malignant neoplasm of cranial nerves [neuroblastoma]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma, pheochtomocytoma]
D35.00 - D35.02	Benign neoplasm of adrenal gland [pheochromocytoma]
I-123 Injection for Imaging:
HCPCS codes covered if selection criteria are met:
A9582	Iodine I-123 iobenguane, diagnostic, per study dose, up to 15 millicuries
ICD-10 codes covered if selection criteria are met (not all-inclusive):
C74.00 - C74.92	Malignant neoplasm of adrenal gland [for the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
E08.00 - E09.9	Secondary diabetes mellitus
E10.10 - E13.9	Diabetes mellitus
G20.A1 - G20.C	Parkinson's disease
G23.0 - G23.9	Other degenerative diseases of the basal ganglia [progressive supranuclear palsy]
I10 - I16.2	Hypertensive disease
I21.01 - I25.9	Ischemic heart disease
I21.A1	Myocardial infarction type 2
I21.A9	Other myocardial infarction type
I42.0 - I42.9	Cardiomyopathy
I47.0 - I49.9	Cardiac dysrhythmias
I50.20 - I50.9	Congestive heart failure
Z48.21, Z94.1	Heart replaced by transplant
Z79.3 Z79.890 - Z79.899	Long-term (current) use of other medications
Scintimammography and Breast Specific Gamma Imaging (BSGI):
CPT codes not covered for indications listed in the CPB:
78195	Lymphatics and lymph nodes imaging
78800	Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); limited area
78801	multiple areas
78803	tomographic (SPECT)
78804	whole body, requiring 2 or more days imaging
HCPCS codes not covered for indications listed in the CPB:
A9500	Technetium Tc-99m sestamibi, diagnostic, per study dose, up to 40 millicuries
S8080	Scintimammography (radioimmunoscintigraphy of the breast), unilateral, including supply of radiopharmaceutical
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C50.011 - C50.929	Malignant neoplasm of the breast
C76.1	Malignant neoplasm of thorax [axilla]
C79.81	Secondary malignant neoplasm of the breast
C79.89	Secondary malignant neoplasm of other specific sites [axillary metastases]
D05.00 - D05.92	Carcinoma in situ of breast
D09.8	Carcinoma in situ of other specified sites [axilla]
Z12.39	Encounter for screening for malignant neoplasms of breast
Technetium-Tc 99m Tilmanocept (Lymphoseek):
HCPCS codes covered if selection criteria are met :
A9520	Technetium Tc-99m tilmanocept, diagnostic, up to 0.5 millicuries
ICD-10 codes covered if selection criteria are met:
C43.0 - C43.9	Malignant melanoma of skin
C50.011 - C50.929	Malignant neoplasm of breast
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C01 - C06.9	Malignant neoplasm of oral cavity
C4A.0 – C4A.9	Merkel cell carcinoma
C44.42	Squamous cell carcinoma of skin of scalp and neck
C54.0 – C54.9	Malignant neoplasm of corpus uteri
C71.0 – C71.9	Malignant neoplasm of brain
D05.10 – D05.12	Intraductal carcinoma in situ of breast

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Background

Nuclear imaging is assuming an increasing role in the management of patients with cancer. Tumor scintigraphy involves the intravenous administration of a radio-pharmaceutical, defined as an isotope attached to a carrier molecule, which localizes in certain tumor tissues and the subsequent imaging and computer acquisition of data. The goal of tumor scintigraphy is to enable the interpreting physician to detect and evaluate primary, metastatic, or recurrent tumor tissue by producing images of diagnostic quality. In general, tumor scintigraphy may be used for, but is not limited to, detection of certain primary, metastatic, and recurrent tumors, evaluation of abnormal imaging and non-imaging findings in patients with a history of certain tumors, and reassessment of patients for residual tumor burden after therapy. Specific clinical applications differ depending upon the specific radiopharmaceutical that is used.

Traditional imaging modalities (computed tomography [CT], and magnetic resonance imaging [MRI]) for prostate cancer perform very poorly and bone scanning, although having a high positive predictive value, is insensitive for metastasis and is used only in those patients with a reasonable probability of metastatic disease (e.g., prostate-specific antigen [PSA] greater than 10). The ProstaScint scan uses a monoclonal antibody-based imaging agent (In111-Capromab Pendetide) and was approved by the U.S. Food and Drug Administration (FDA) for use in patients with biopsy proven prostate cancer in whom there is a high clinical suspicion of occult metastatic disease and who have had a negative or equivocal standard staging evaluation.

Patients with primary colorectal carcinoma undergo an extensive pre-operative staging work-up. Unfortunately, the accuracy of non-surgical staging techniques (CT or MRI) has been shown to be poor. Recurrent disease is seen in up to 40% of patients with Dukes stage B or C colorectal carcinoma, generally within the first 18 months post-operatively. Carcinoembryonic antigen (CEA) levels are used to monitor patients for recurrent disease; however, almost 1/3 of patients with recurrence do not have elevated CEA levels. Both CT and MRI have been shown to be inadequate in the detection of local or lymph node recurrence. In regards to ovarian cancer, serum CA-125 levels have been shown to be useful in predicting the presence of ovarian cancer, but negative titers do not preclude malignancy.  In clinical trials, OncoScint has a sensitivity of 70% versus 44% for CT, and a specificity of 55% (79% for CT) in patients with ovarian cancer. Carcinomatosis was detectable by antibody imaging in 71% of patients, but in only 45% by CT.

Oncoscint is an IgG murine monoclonal antibody that specifically targets the cell surface mucin-like glycoprotein antigen TAG-72, which is commonly found on colorectal and ovarian carcinomas. It is reported to be reactive with 83% of colorectal carcinomas and 97% of ovarian carcinomas. According to the available literature, a major advantage of Oncoscint is that it allows one to survey the entire body, thus permitting the detection of occult metastases that can have a major impact on tumor staging. Clinical studies have documented only minimal cross reactivity with other tumors or normal tissues (i.e., the false-positive rate is very low). Additionally, the results of the Oncoscint exam have been reported to result in a change in patient management in 25% of cases, and the examination also detected sites of occult disease in 10% of patients. Oncoscint can also be used to confirm the absence of other sites of disease prior to surgery. This is important for the patient about to undergo a potentially curative resection of an isolated recurrence of colorectal carcinoma located in a single site, i.e., lung or liver.

CEA-Scan is a nuclear imaging test which uses a monoclonal antibody fragment (arcitumomab) labeled with technetium 99 that reacts with CEA, a tumor marker for cancer of the colon and rectum. CEA-Scan can be used to detect recurrent or metastatic colorectal carcinoma in conjunction with standard imaging modalities. The agent is not indicated as a screening tool for colorectal cancer. The sensitivity of CEA-Scan has been shown to be superior to conventional imaging modalities in evaluation of the extra-hepatic abdomen (55% versus 32%) and pelvis (69% versus 48%). The scan findings are not superior to conventional exams in evaluation of the liver (63% versus 64%); however, the findings are often complementary. Lesion detection is in part related to lesion size, with a sensitivity of 80% for lesions over 2 cm. Detection of lesions smaller than 1 cm is 60%. CEA-Scan has been shown to have potential clinical benefit in 1/3 of colorectal cancer patients.

Since its introduction, technetium-99m-sestamibi (also known as technetium-99m-MIBI) has been shown to be of value in assessing malignant bone and soft tissue tumor response to therapy. Technetium-99m-sestamibi (Miraluma) has also been proposed as the radio-pharmaceutical agent for use during scintimammography in the evaluation of women with dense breast tissue and possibly for women who have had partial mastectomy, previous biopsies, radiation therapy or silicone implants. Although Miraluma may be more sensitive than thallium in the evaluation of breast lesions greater than 1.5 cm in size and was approved in May, 1997 by the FDA for use as a nuclear medicine test to be used in breast imaging, the reported sensitivities and specificities of Miraluma imaging vary based on size and the palpable nature of the finding. There is a lack of evidence in the medical literature demonstrating an acceptable level of sensitivity and specificity in detecting small, non-palpable breast lesions less than 1.2 cm, with or without microcalcification. Overall, Miraluma has a sensitivity of 83 to 96% (average 85%) and a specificity of 72 to 100% (average 81%) for malignancy. The negative predictive value has been reported to be between 88 to 97%. False-positive examinations have been described with fibroadenomas, papillomas, epithelial hyperplasia, and fibrocystic breast disease. Patients with fibrocystic disease are more likely to have false-positive examinations even though the Miraluma exam has been reported to be unaffected by the density of the breast. Most false-negative examinations occur with lesions smaller than 1 cm in size or in lesions not palpable. Studies now indicate that the examinations sensitivity drops to 51% to 72% for non-palpable lesions. And lastly, the available literature shows that Miraluma is not competitive with mammography on either a cost-effective or sensitivity basis in the screening of patients for breast cancer.

1. the reported results for these studies focuses on a pre-selected patient population resulting in a very high incidence of cancer in the patients sent for the examination. This suggests a selection bias and sensitivity of the examination is likely over-estimated; and
2. the mean lesion size is generally over 1.0 to 1.5 cm where mammographic findings can aid in differentiating a benign from a malignant lesion. 

Other drawbacks include the lack of an adequately high negative predictive value, which means malignant lesions may be missed, and false positive exams occur in benign lesions such as fibroadenomas. Since the implications of a missed diagnosis of breast cancer can be disastrous to patient outcome, the available literature states that Miraluma has no role in breast cancer screening to confirm the presence or absence of malignancy (particularly clinically occult abnormalities), and it is not an alternative to biopsy. Stereotactic and ultrasound guided biopsies of breast lesions are minimally invasive and can provide a definitive diagnosis. Despite optimism in the nuclear medicine literature, the literature on balance states that this examination probably has no role in the evaluation of patients with suspected breast malignancy. Determining a subset of women that would benefit from this procedure will be difficult until larger prospective studies have been performed. Mammography remains the generally accepted standard for screening. Continued evaluation with diagnostic mammography, ultrasound and surgical biopsy remains the diagnostic work-up that is most frequently recommended. The Institute of Medicine of the National Academy of Science recently concluded that “scintimammography has shown diagnostic potential as an adjunct to mammography, but the technical limitations such as resolution have precluded it from becoming more widely used. Although it has FDA approval, the current data do not justify its implementation on a standard basis. Technological improvements and novel radioactive compounds could potentially improve its utility, but at the moment its future is uncertain. The method also has potential for use in functional imaging applications, but further study and development are needed.”

An assessment prepared for the Agency for Healthcare Research and Quality (Bruening et al, 2006) concluded that scintimammography is not sufficiently accurate to rule out breast cancer in women with abnormal mammograms or physical findings suggestive of breast cancer. The report found that, for every 1,000 women with negative scintimammogram results, about 907 women would avoid an unnecessary biopsy but 93 women would have missed cancers.

Scintimammography utilizing high-resolution gamma cameras (e.g., Dilon Scan/Dilon 6800 camera, Dilon Technologies, LLC, Newport News, VA), also known as breast-specific gamma imaging (BSGI), has a spatial resolution of less than 4 mm and is being marketed to help identify cancerous breast tissue that is undetected by mammography. Proponents believe this technology is useful as a complementary tool in the detection of breast cancer in women with difficult to read mammograms, such as those with dense breast tissue, breast implants or scar tissue from previous breast surgery. According to the advocates of this technology, by operating on a cellular or molecular level, BSGI is not affected by tissue density and can help detect cancers at very early stages and allow for optimal intervention and treatment. Its ability to accurately detect breast cancer has the potential to significantly reduce the number of unnecessary, invasive biopsies.

Brem and colleagues have published several comparative studies on the use of BSGI for the diagnosis of breast cancer. In one comparative study, Brem et al (2007) compared the sensitivity of BSGI for the detection of ductal carcinoma in situ (DCIS) with the results obtained with mammography and magnetic resonance imaging (MRI) based on the histopathology of biopsy-proven DCIS. After injection of technetium 99m-sestamibi, patients had BSGI in craniocaudal and mediolateral oblique projections. Imaging findings were compared to findings at biopsy or surgical excision. Breast MRI was performed on 7 patients with 8 biopsy-proven foci. Pathologic tumor size of the DCIS ranged from 2 to 21 mm (mean of 9.9 mm). Of 22 cases of biopsy-proven DCIS in 20 women, 91% were detected with BSGI, 82% were detected with mammography, and 88% were detected with MRI. The authors reported that BSGI had the highest sensitivity for the detection of DCIS, although the small sample size did not demonstrate a statistically significant difference. Two cases of DCIS (9%) were diagnosed only after BSGI demonstrated an occult focus of radiotracer uptake in the contralateral breast, previously undetected by mammography and there were 2 false-negative BSGI studies. In another study, Brem and colleagues (2008) reported the sensitivity and specificity of BSGI for the detection of breast cancer using pathologic results as a reference standard as 96.4% and 59.5%, respectively, a positive predictive value of 68%, and a negative predictive value of 94% for non-malignant lesions. The smallest invasive cancer and DCIS detected by BSGI was reported to be 1 mm.

In a retrospective review, Zhou et al (2008) reported the results of BSGI on 176 patients who underwent BSGI evaluation. A total of 128 patients underwent BSGI because of suspicious imaging, abnormal physical examination, or were considered high risk for breast cancer with dense breasts. BSGI was positive in 12 of 107 patients with breast imaging reporting and data system (BI-RADS) 1, 2, or 3. Two of these were cancer. Of the 21 patients with BI-RADS 4, 18 were BSGI-negative (11 with benign biopsy, 7 observed), and 3 were BSGI-positive with 2 being cancerous. Forty-eight patients with a new diagnosis of cancer obtained BSGI for further work-up. It was positive at a new location in 6 cases: 2 cases were new cancers in the contralateral breast, 1 was in the ipsilateral breast, and the remaining 3 had benign pathology. The authors reported that clinical management was changed significantly in 14.2% of the 176 patients, with another 6.3% in whom a negative BSGI could have prevented a biopsy. The authors concluded,  "Potential roles for BSGI in the current paradigm of breast imaging include screening and diagnosis. BSGI has the ability to pick up mammography occult breast cancers and can be especially useful in high-risk patients with dense breasts in whom the sensitivity and specificity of mammography suffers significantly. Another promising use of BSGI could be further evaluation of BI-RADS 4 patients to see if invasive biopsy can be avoided. A larger series of patients is needed to confirm this hypothesis."

Recent studies of scintimammography utilizing BSIG are promising; however, patient populations were small and focused on a pre-selected patient population resulting in a very high incidence of cancer in the patients sent for examination. This suggests a selection bias and sensitivity of the examination is likely over-estimated. In addition, there are no studies that evaluate change in clinical practice if the breast-specific gamma camera was used in stead of, or in addition to, MRI or ultrasound, and its impact on clinical outcomes. The effectiveness of scintimammography in screening or diagnostic strategies needs to be evaluated in large-scale clinical trials.

The American College of Radiology (ACR) and Society for Pediatric Radiology (SPR)'s practice guideline for the performance of tumor scintigraphy (with gamma cameras) (2010) stated that "[m]ore recently, breast-specific gamma imaging (BSGI) which uses a high-resolution, small-field-of-view gamma camera optimized to image breast tumors has been developed. Areas of active investigation concerning potential indications include determination of extent of disease in women with newly diagnosed breast cancer, and evaluation of patients with dense breasts. Additional clinical evidence is needed to assess where BSGI will fit in the imaging algorithm of breast cancer. When BSGI is performed, the ability to correlate BSGI findings with other breast imaging techniques and a defined protocol for evaluation of abnormalities seen only on BSGI should be in place".

O'Connor and associates (2010) noted that recent studies have raised concerns about exposure to low-dose ionizing radiation from medical imaging procedures. Little has been published regarding the relative exposure and risks associated with breast imaging techniques such as BSGI, molecular breast imaging (MBI), or positron emission mammography (PEM). The purpose of this article was to estimate and compare the risks of radiation-induced cancer from mammography and techniques such as PEM, BSGI, and MBI in a screening environment. The authors used a common scheme for all estimates of cancer incidence and mortality based on the excess absolute risk model from the BEIR VII report. The lifetime attributable risk model was used to estimate the lifetime risk of radiation-induced breast cancer incidence and mortality. All estimates of cancer incidence and mortality were based on a population of 100,000 females followed from birth to age 80 and adjusted for the fraction that survives to various ages between 0 and 80. Assuming annual screening from ages 40 to 80 and from ages 50 to 80, the cumulative cancer incidence and mortality attributed to digital mammography, screen-film mammography, MBI, BSGI, and PEM was calculated. The corresponding cancer incidence and mortality from natural background radiation was calculated as a useful reference. Assuming a 15% to 32% reduction in mortality from screening, the benefit/risk ratio for the different imaging modalities was evaluated. Using conventional doses of 925 MBq Tc-99m sestamibi for MBI and BSGI and 370 MBq F-18 FDG for PEM, the cumulative cancer incidence and mortality were found to be 15 to 30 times higher than digital mammography.  The benefit/risk ratio for annual digital mammography was greater than 50:1 for both the 40 to 80 and 50 to 80 screening groups, but dropped to 3:1 for the 40 to 49 age group. If the primary use of MBI, BSGI, and PEM is in women with dense breast tissue, then the administered doses need to be in the range 75 to 150 MBq for Tc-99m sestamibi and 35 MBq to 70 MBq for F-18 FDG in order to obtain benefit/risk ratios comparable to those of mammography in these age groups. These dose ranges should be achievable with enhancements to current technology while maintaining a reasonable examination time. The authors concluded that the results of the dose estimates in this study clearly indicate that if molecular imaging techniques are to be of value in screening for breast cancer, then the administered doses need to be substantially reduced to better match the effective doses of mammography.

Kim (2012) evaluated the adjunctive benefits of BSGI versus MRI in breast cancer patients with dense breasts. This study included a total of 66 patients (44.1 +/- 8.2 years) with dense breasts (breast density greater than 50%) and already biopsy-confirmed breast cancer. All of the patients underwent BSGI and MRI as part of an adjunct modality before the initial therapy. Of 66 patients, the 97 undetermined breast lesions were newly detected and correlated with the biopsy results. Twenty-six of the 97 breast lesions proved to be malignant tumors (invasive ductal cancer, n = 16; DCIS, n = 6; mixed or other malignancies, n = 4); the remaining 71 lesions were diagnosed as benign tumors. The sensitivity and specificity of BSGI were 88.8% (confidence interval (CI): 69.8 to 97.6%) and 90.1% (CI: 80.7 to 95.9%), respectively, while the sensitivity and specificity of MRI were 92.3% (CI: 74.9 to 99.1%) and 39.4% (CI: 28.0 to 51.7%), respectively (p < 0.0001). MRI detected 43 false-positive breast lesions, 37 (86.0%) of which were correctly diagnosed as benign lesions using BSGI. In 12 malignant lesions less than 1 cm, the sensitivities of BSGI and MR imaging were 83.3% (CI: 51.6 to 97.9%) and 91.7% (CI: 61.5 to 99.8%), respectively. The author concluded that BSGI showed an equivocal sensitivity and a high specificity compared to MRI in the diagnosis of breast lesions. In addition, BSGI had a good sensitivity in discriminating breast cancers less than or equal to 1 cm. The results of this study suggested that BSGI could play a crucial role as an adjunctive imaging modality which can be used to evaluate breast cancer patients with dense breasts.

Keto et al (2012) prospectively compared the sensitivity of BSGI to MRI in newly diagnosed ductal carcinoma-in-situ (DCIS) patients. Patients with newly diagnosed DCIS from June 1, 2009, through May 31, 2010, underwent a protocol with both breast MRI and BSGI. Each imaging study was read by a separate dedicated breast radiologist. Patients were excluded if excisional biopsy was performed for diagnosis, if their MRI was performed at an outside facility, or if final pathology revealed invasive carcinoma. There were 18 patients enrolled onto the study that had both MRI and BSGI for newly diagnosed DCIS. The sensitivity for MRI was 94% and for BSGI was 89% (p > 0.5, NS). There was 1 index tumor not seen on either MRI or BSGI, and 1 index tumor seen on MRI but not visualized on BSGI. The authors concluded that although BSGI has previously been shown to be as sensitive as MRI for detecting known invasive breast carcinoma, this study shows that BSGI is equally as sensitive as MRI at detecting newly diagnosed DCIS. They stated that as a result of the limited number of patients enrolled onto the study, larger prospective studies are needed to determine the true sensitivity and specificity of BSGI.

Spanu et al (2012) investigated the clinical impact of breast scintigraphy acquired with a breast specific γ-camera (BSGC) in the diagnosis of breast cancer (BC) and assessed its incremental value over mammography (Mx). A consecutive series of 467 patients underwent BSGC scintigraphy for different indications: suspicious lesions on physical examination and/or on ultrasonography (US)/MRI negative at Mx (BI-RADS 1 or 3), characterization of lesions suspicious at Mx (BI-RADS 4), pre-operative staging in lesions highly suggestive of malignancy at Mx (BI-RADS 5). Definitive histopathological findings were obtained in all cases after scintigraphy: 420/467 patients had BC, while 47/467 patients had benign lesions. The scintigraphic data were correlated to Mx BI-RADS category findings and to histology. The incremental value of scintigraphy over Mx was calculated. Scintigraphy was true-positive in 97.1% BC patients, detecting 96.2% of overall tumor foci, including 91.5% of carcinomas less than or equal to 10 mm, and it was true-negative in 85.1% of patients with benign lesions. Scintigraphy gave an additional value over Mx in 141/467 cases (30.2%). In particular, scintigraphy ascertained BC missed at Mx in 31 patients with BI-RADS 1 or 3, including 26 patients with heterogeneously/high dense breast (19/26 with tumors less than or equal to 10 mm) and detected additional clinically occult ipsilateral or contralateral tumor foci (all less than 10 mm) or the in-situ component sited around invasive tumors in 77 BC patients with BI-RADS 4 or 5, changing surgical management in 18.2% of these cases; moreover, scintigraphy ruled out malignancy in 33 patients with BI-RADS 4. BSGC scintigraphy proved a highly sensitive diagnostic tool, even in small size carcinoma detection, while maintaining a high specificity. The procedure increased the sensitivity of Mx, especially in dense breast and in multi-focal/multi-centric disease, as well as the specificity. It better defined local tumor extension, thus guiding the surgeon to a more appropriate surgical treatment. Moreover, these researchers stated that “However, also this scintigraphic procedure presents some limitations, such as radiation exposure that could limit its routine use, especially in screening programs. Tumor size seemed to represent the most important factor affecting the performance of scintigraphy, since the majority of false-negative findings were related to sub-centimetric carcinomas. Moreover, lesion site may also affect sensitivity, since a high percentage of small tumors negative at breast scintigraphy in our series were located in internal quadrants or were excluded from the field of view of the device as happened in two cases …. A larger clinical application of BSGC scintigraphy is thus suggested although many prospective trials are needed, particularly with the aim of identifying those subgroups of patients who would more benefit from scintigraphy employment …. However, cost-benefit analysis is needed to justify the use of BSGC scintigraphy in combination with conventional diagnostic imaging methods as an adjunctive tool”.

Mitchell et al (2013) determined the ability of breast imaging with 99mTc-sestamibi and a direct conversion- MBI system to predict early response to neoadjuvant chemotherapy (NAC). Patients undergoing NAC for breast cancer were imaged with a direct conversion-MBI system before (baseline), at 3 to 5 weeks after onset, and after completion of NAC. Tumor size and tumor-to-background (T/B) uptake ratio measured from MBI images were compared with extent of residual disease at surgery using the residual cancer burden. A total of 19 patients completed imaging and proceeded to surgical resection after NAC. Mean reduction in T/B ratio from baseline to 3 to 5 weeks for patients classified as RCB-0 (no residual disease), RCB-1 and RCB-2 combined, and RCB-3 (extensive residual disease) was 56% (SD, 0.20), 28% (SD, 0.20), and 4% (SD, 0.15), respectively. The reduction in the RCB-0 group was significantly greater than in RCB-1/2 (p = 0.036) and RCB-3 (p = 0.001) groups. The area under the receiver operator characteristic curve for determining the presence or absence of residual disease was 0.88. Using a threshold of 50% reduction in T/B ratio at 3 to 5 weeks, MBI predicted presence of residual disease at surgery with a diagnostic accuracy of 89.5% (95% confidence interval [CI]: 0.64% to 0.99%), sensitivity of 92.3% (95% CI: 0.74% to 0.99%), and specificity of 83.3% (95% CI: 0.44% to 0.99%). The reduction in tumor size at 3 to 5 weeks was not statistically different between RCB groups. The authors concluded that changes in T/B ratio on MBI images performed at 3 to 5 weeks following initiation of NAC were accurate at predicting the presence or absence of residual disease at NAC completion. They stated that “A limitation of MBI is its inability to depict axillary node involvement and potentially to visualize tumors close to the chest wall ….  Our results are promising, but larger studies evaluating the use of 99mTc-sestamibi and dedicated gamma cameras are needed to support these findings”.

1. perceived image quality at 5 min-per-view was lower than that for 10-min-per-view studies and
2. in a number of cases, assessment was down-graded from a recommendation of biopsy to that of short interval follow-up. 

These investigators stated that “A limitation of this study was that most patients had either photopenic or mild background uptake; only 4 patients (8 breasts) were assigned moderate or marked background uptake. All lesions downgraded at 5 min-per-view were in patients with photopenic or mild background uptake. Hence, the effect of moderate or marked background parenchymal uptake on lesion detection at 5 min-view could not be assessed in this study. An additional limitation was that the detection task was a combined detection and characterization process. Lesions, when identified, were done so using the BI-RADSlike assessment scale at the breast level. A subtlety of this analysis is that breasts characterized as 3 were treated as screen failures (MBI negative as a test result with a binary decision)”.

Neuroendocrine tumors generally are small and slow-growing in nature, which makes them difficult to detect and localize using conventional imaging techniques such as CT and MRI. Octreotide (Pentetreotide In-111) is a synthetic octapeptide analog of somatostatin that binds to somatostatin receptors on cell surfaces throughout the body. The OctreoScan, which uses this radiopharmaceutical, can assist in staging the patient's disease more accurately by offering highly sensitive, whole-body detection and localization of primary and metastatic receptor-bearing neuroendocrine tumors, especially if they are small. Octreotide has been shown to have an overall sensitivity of about 96% in the detection of carcinoid tumors. The literature indicates that, before consideration of aggressive cytoreductive hepatic surgery, an OctreoScan can be used for ruling out extrahepatic metastases. As a consequence of the ability of OctreoScan to demonstrate somatostatin receptor-positive tumors, it can be used to select those patients who are likely to respond favorably to octreotide treatment. Finally, the literature states that a negative OctreoScan implies that the tumors are not expressing somatostatin receptors; this is often associated with a more anaplastic histology.

There is currently insufficient evidence to support the use of Octreoscan for patients with granulomatous diseases (e.g., sarcoidosis). In particular, guidelines from the Society for Nuclear Medicine (2004) stated that gallium scintigraphy is used to localize inflammation in sarcoidosis. 

Carbone and colleagues (2003) examined Octreoscan scintigraphy as a tool for classifying and assessing disease activity in sarcoidosis and idiopathic interstitial pneumonia (IIP), in comparison of the radiological imaging and dyspnea symptom scores. A total of 33 patients of which 16 with sarcoidosis (mean age of 43.6 years, range of 30 to 58 years) and 17 with histologically diagnosed IIP (mean age of 62.2 years, range of 35 to 79 years) were enrolled in the study. Clinical history was taken as well as physical examination, chest X-ray, and pulmonary function tests were assessed. A high-resolution computed tomography scan (HRCT) was carried out in patients affected by sarcoidosis, who had a normal chest X-ray, and in IIP patients. Both groups were evaluated with the Octreoscan uptake index (UI; normal value: less than or equal to 10). In patients affected with sarcoidosis, the Octreoscan UI was significantly higher than in patients with IIP (16.35 +/- 3.1 and 10.06 +/- 0.8, respectively; p < 0.01) and was correlated with the radiographical staging (p < 0.01) and with the degree of dyspnea (p < 0.01). In patients with IIP, the Octreoscan UI was slightly above the normal limit (range of 10.3 to 11.7) in non-specific interstitial pneumonia (NSIP) and desquamative interstitial pneumonia (DIP), whereas in usual interstitial pneumonia (UIP) Octreoscan UI was always within normal limit (less than or equal to 10 UI). A negative correlation was observed with histological findings (p < 0.01) and with HRCT appearance (p < 0.01). The authors concluded that Octreoscan UI is correlated with the degree of dyspnea in patients affected by sarcoidosis and can quantify more accurately the degree of pulmonary involvement, as compared to radiological assessment. Moreover, they stated that further studies are needed to evaluate Octreoscan as an early test for predicting disease progression.

Kroot et al (2006) reported on a case in which sarcoidosis in a clinically unaffected joint was demonstrated by somatostatin receptor scintigraphy. The patient presented with decreased hearing, secondary amenorrhea, vertigo, dry eyes, and progressive loss of vision. Because the differential diagnosis consisted of sarcoidosis and lymphoma, somatostatin receptor scintigraphy with indium-111-DTPA octreotide was performed. Increased uptake was observed in the parotid gland, bilateral orbits, nose, and the right knee. Remarkably, on clinical examination, no signs of arthritis of the right knee were observed. Additional tissue analysis of the right knee revealed the diagnosis of sarcoidosis leading to successful treatment with prednisolone, anti-malarials, and azathioprine. This case underlines the diagnostic potential of somatostatin receptor scintigraphy in patients with sarcoidosis, even in clinically unaffected tissue.

Radiolabeled octreotide is also being studied for the treatment of radio-resistant solid tumors especially small tumors (a few millimeters in diameter) whose uptake is maximal, allowing more homogeneous distribution than that achieved with large tumors. The gamma emitting imaging radionuclide (¹¹¹In-octreotate) is replaced by a beta emitting therapeutic radionuclide (90Y-ostreotide) (OctreoTher). Guidelines from the UKNETwork for Neuroendocrine Tumours (Ramage et al, 2005) state that targeted radionuclide therapy is a useful palliative option for symptomatic patients with inoperable or metastatic neuroendocrine tumors where there is corresponding abnormally increased uptake of the corresponding radionuclide imaging agent.

There are no randomized controlled clinical trials of targeted radionuclide therapy of neuroendocrine tumors. In a retrospective study (n = 21), Bodei and colleagues (2004) assessed the effectiveness of Yttrium-90 [90Y]-DOTA-Phe1-Tyr3-octreotide (90Y-DOTATOC) therapy in metastatic medullary thyroid cancer (MTC) patients with positive OctreoScan, progressing after conventional treatments. Two patients (10%) obtained a complete response (CR), as evaluated by CT, MRI and/or ultrasound, while a stabilization of disease (SD) was observed in 12 patients (57%); 7 patients (33%) did not respond to therapy. The duration of the response ranged between 3 to 40 months. Using biochemical parameters (calcitonin and CEA), CR was observed in 1 patient (5%), while partial response was observed in 5 patients (24%) and stabilization in 3 patients (14%). Twelve patients had progression (57%); and CR was observed in patients with lower tumor burden and calcitonin values at the time of the enrollment. These investigators concluded that this retrospective analysis is consistent with the literature, regarding a low response rate in MTC treated with 90Y-DOTATOC. Patients with smaller tumors and higher uptake of the radiopeptide tended to respond better. Studies with 90Y-DOTATOC administered in earlier phases of the disease will help to evaluate the ability of this treatment to enhance survival.

Waldherr et al (2002) reported on a prospective phase II study to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 90Y-DOTATOC. A total of 39 patients with progressive neuroendocrine gastroentero-pancreatic and bronchial tumors were treated with 4 intravenous injections of  90Y-DOTATOC, administered at intervals of 6 weeks, and were followed for a median duration of 6 months (range of 2 to12 months). T he investigators reported an objective response rate of 23%. For endocrine pancreatic tumors (13 patients), the objective response rate was 38%. Complete remissions were found in 5% (2/39), partial remissions in 18% (7/39), stable disease in 69% (27/39), and progressive disease in 8% (3/39). The investigators reported that a significant reduction of clinical symptoms could be found in 83% of patients with diarrhea, in 46% of patients with flushing, in 63% of patients with wheezing, and in 75% of patients with pellagra. Side effects were grade 3 or 4 lymphocytopenia in 23%, grade 3 anemia in 3%, and grade 2 renal insufficiency in 3%.

Paganelli et al (2002) reported on a study fo 90Y-DOTATOC in 87 patients with neuroendocrine tumors. The investigators stated that most patients responded with stabilization of disease (48%); however, objective responses were observed in 28% of patients, including 5% of patients showing a complete response. The median duration of response was 24 months. The investigators reported that gastrointestinal side effects were mild and included nausea and vomiting, which occurred in approximately 50% of patients.

Weiner and Thakur (2005) noted that radiolabeled peptide therapy is usually indicated for patients with widespread disease that is not amenable to focused radiation therapy or is refractory to chemotherapy. Phase I and phase II studies using various radiolabeled peptides (including (111)In-pentetreotide, 90Y-DOTATOC, 90Y-DOTA-lanreotide, and Lutetium-177 [177Lu]-DOTA-octreotate) for the treatment of patients with neuroendocrine malignancy are in progress. This is in agreement with the observations of Oberg and Eriksson (2005) as well as Kwekkeboom and colleagues (2005). Oberg and Eriksson stated that tumor-targeted treatment for malignant carcinoid tumor is still investigational, but has become of significant interest with the use of radiolabeled somatostatin analogs. (111)Indium-DTPA-octreotide has been used as the first tumor-targeted treatment, with rather low response rates (in the order of 10 to 20%) and no significant tumor shrinkage. The second radioactive analog which has been applied in the clinic is 90Y-DOTATOC (OctreoTher), which has given partial and complete remissions in 20 to 30% of patients. The most significant side effects have been kidney dysfunction, thrombocytopenia and liver toxicity. Kwekkeboom et al noted that treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. In a review of the literature on somatostatin analogues in the treatment of gastroentero-pancreatic neuroendocrine tumors, Delaunoit et al (2005) stated that overall, radiolabeled somatostatin analogues have shown some activities in controlling tumor growth and clinical symptoms have been reduced significantly. Toxic effects encountered have been manageable with adequate supportive care. Delaunoit et al (2005) concluded that radiolabeled somatostatin analogues “constitute a promising alternative for treating patients with progressive and symptomatic disease” and that “[t]he results of larger ongoing studies are eagerly awaited.”

In a phase II study, Johnson and colleagues (2011) evaluated the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 μg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992 to 1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and greater than or equal to 18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.

Schulz et al (2011) stated that the standard surgical treatment for meningiomas is total resection, but the complete removal of skull base meningiomas can be difficult for several reasons. Thus, the management of certain meningiomas of the skull base -- for example, those involving basal vessels and cranial nerves -- remains a challenge. In recent reports it has been suggested that somatostatin (SST) administration can cause growth inhibition of unresectable and recurrent meningiomas. The application of SST and its analogs is not routinely integrated into standard treatment strategies for meningiomas, and clinical studies proving growth-inhibiting effects do not exist. The authors reported on their experience using octreotide in patients with recurrent or unresectable meningiomas of the skull base. Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Post-operative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months. Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range of 48 to 180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption. The authors concluded that although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful.

In patients with primary cutaneous malignant melanoma, accurate staging of the primary tumor and detection of any occult micro-metastases in the regional lymph node basin is most important in determining survival and successful outcome of treatment. According to accepted guidelines, preoperative cutaneous lymphoscintigraphy can be used to visualize the lymphatic drainage patterns from primary tumors and intraoperative lymphatic mapping can be used to identify the first sentinel lymph node in direct communication with the primary tumor. Only individuals with histologically confirmed sentinel node metastases are selected to undergo radical node dissection and eventually receive adjuvant treatments, sparing those with tumor-free sentinel node the morbidity of these therapies.

In the past, it was routine practice to carry out axillary lymph node dissection at the time of surgical removal of a primary, malignant breast tumor. As breast cancer is being diagnosed at an earlier stage in a growing percentage of cases, this procedure has proven to be unnecessary in a demonstrable proportion of patients. As an alternative management strategy, several authorities have recommended identification of the sentinel node to predict the disease status of the axilla and consequently determine whether axillary lymph node dissection is indicated. This can be accomplished using lymphoscintigraphy or injection of isosulfan blue, or both, followed by biopsy. The sentinel node can be identified in 80 % of patients and accurately predicts the status of the remainder of the axillary nodes in 95 % to 98 % of patients. If the node is negative by frozen section nothing more is done.  If it is positive, a standard axillary dissection is done. By limiting the number of lymph nodes removed, the injury to the circulatory system is minimized, and the risk of arm swelling (lymphedema) following treatment for breast cancer may be reduced.

Guidelines on penile cancer from the National Comprehensive Cancer Network (NCCN, 2016) recommend dynamic sentinel lymph node biopsy using lymphoscintigraphy for penile cancer with nonpalpable lymph nodes. NCCN guidelines on vulvar cancer (2016) recommend sentinel lymph node biopsy or unilateral inguinofemoral lymphadenectomy for primary vulvar tumors that are less than 2 cm, located 2 cm or more from the vulvar midline and in the setting of clinically negative femoral lymph nodes. A pre-operative lymphoscintigraphy may be performed to aid in anatomically locating the sentinel node.

Guidelines on uterine cancer from the National Comprehensive Cancer Network (NCCN, 2019) state that prospective and retrospective studies demonstrate that compared to systemic lymphadenectomy, sentinal lymph node mapping with ultrastaging may increase the detection of lymph node metastases with low false negative rates in women with apparent uterine-confined disease.

Pheochromocytoma is a rare tumor of catecholamine-secreting chromaffin cells. Several conventional and nuclear imaging modalities are currently available to localize pheochromocytoma. Computed tomography (CT) and magnetic resonance imaging (MRI) have good sensitivity but poor specificity for detecting pheochromocytoma. 

I-131 meta-Iodobenzylguanidine (MIBG) is a compound that is actively accumulated in neuroendocrine tumors and thyroid tumors, which express the noradrenaline transporter. While nuclear imaging approaches such as I-131 MIBG imaging have limited sensitivity, the specificity of I-131 MIBG scintigraphy is very good. According to the NCI PDQ Database, CT and MRI scans are about equally sensitive (98 to 100%) for pheochromocytoma, while MIBG scanning has a sensitivity of only 80%. However, MIBG scanning has a specificity of 100%, compared to specificity of 70% for CT and MRI. Thus, I-131 MIBG imaging provides a method for confirming that a tumor is a pheochromocytoma and rules out metastatic disease. Currently, I-131 MIBG is approved as an adjunctive diagnostic agent in the localization of primary or metastatic pheochromocytoma and neuroblastoma. According to the National Cancer Institute’s PDQ Database, for staging of neuroblastoma, bone should be assessed by MIBG scan (applicable to all sites of disease) and by technetium-99 scan if the results of the MIBG imaging are negative or unavailable. MIBG has also been used for detection of other neural crest tumors. 

Adrenomedullary imaging can also be performed with I-123 MIBG. Furthermore, I-123 MIBG scintigraphy is also used for characterization of the cardiac nervous system. Cardiac I-123 MIBG imaging, which reflects cardiac adrenergic nerve activity, may provide prognostic information on patients with congestive heart failure. It is also used in the diagnosis of other cardiac diseases such as cardiomyopathy and idiopathic ventricular fibrillation. Prospective randomized controlled studies are needed to ascertain the prognostic value of I-123 MIBG imaging in patients with heart failure and patients at risk for arrhythmia, and how I-123 MIBG imaging may affect management strategy. Furthermore, the FDA has not approved the use of I-123 MIBG for these purposes.

1. small and empirically chosen study population sample size and empirically chosen follow-up period length,
2. single-center study,
3. patients NYHA functional class IV were not included in the study, and
4. failure to include data from T-wave alternans testing, which has recently been shown to be useful for the risk stratification of SCD in CHF patients.

On September 19, 2008, the FDA approved iobenguane I-123 injection (AdreView) for the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests. Iobenguane accumulates in adrenergically innervated tissues as well as tumors derived from the neural crest. The uptake of iobenguane I-123 by metabolically active neuroblastoma or pheochromocytoma allows scintigraphic visualization of these tumors. The safety and effectiveness of iobenguane I-123 were assessed in a single-arm clinical study of patients with known or suspected neuroblastoma or pheochromocytoma. Diagnostic effectiveness was determined for 211 patients by comparison of focal increased radionuclide uptake on planar scintigraphy at 24 ± 6 hours post-administration of iobenguane I-123 injection against the definitive diagnosis (standard of truth). The standard of truth was a diagnosis of presence or absence of pheochromocytoma in 127 patients and neuroblastoma in 84 patients. The diagnosis was determined by histopathology or, when histopathology was unavailable, a composite of imaging, plasma/urine catecholamine and/or catecholamine metabolite measurements and clinical follow-up. In the detection of either neuroblastoma or pheochromocytoma, the iobenguane I-123's sensitivity and specificity were determined independently based upon results of 3 image-readers who were fully masked to clinical information. The sensitivity ranged from 77% to 80% and the specificity ranged from 69% to 77%. Performance characteristics were similar between the groups of patients who had either a pheochromocytoma or neuroblastoma truth standard.

The American Academy of Neurology's practice parameter on the diagnosis and prognosis of new onset Parkinson disease (Suchowersky et al, 2006) stated that there is insufficient evidence to determine if I-123 labeled MIBG cardiac imaging is useful in differentiating Parkinson's disease from multiple system atrophy or progressive supranuclear palsy.

According to available guidelines, surgical ablation is the treatment of choice for pheochromocytoma (Sweeney and Blake, 2002). Radiopharmaceutical ablation with MIBG has met with only "limited success" (NCI, 2003). The National Cancer Institute PDQ on pheochromocytoma stated that “treatment with targeted radiation therapy using I131meta-iodobenzylguanidine (I131 MIBG) has met with limited success. In approximately 35% of patients screened, the tumor has sufficient uptake of the radioisotope to allow for a therapeutic dose. In a group of 28 patients shown to have sufficient uptake of I131 MIBG, objective partial responses were observed in 29% and biochemical improvement was noted in 43%”. According to guidelines from the National Comprehensive Cancer Network (2003) on pheochromocytoma, MIBG may be used as an alternative to surgical debulking and medical therapy for persons with distant metastases who are enrolled in a clinical trial (NCCN, 2003).

Quach and colleagues (2011) analyzed the effects of (131) I-MIBG therapy on thyroid and liver function in patients with neuroblastoma. Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg of body weight, number of treatments, time from treatment to follow-up, sex, and patient age was examined. In patients who presented with grade 0 or 1 thyroid toxicity at baseline, 12 +/- 4% experienced onset of or worsening to grade 2 hypo-thyroidism and 1 patient developed grade 2 hyper-thyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76 +/- 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 +/- 5% experienced onset of or worsening to grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies. The authors concluded that prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypo-thyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. They stated that (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.

Lin et al (1999) discussed the potential diagnostic and therapeutic utility of somatostatin receptor scintigraphy and therapy with somatostatin. In-111 pentetreotide (In-111 octreotide), a somatostatin analog, was used to define the receptor status and the extent of disease in a case of malignant thymoma. Subsequent treatment with non-radioactive somatostatin inhibited tumor growth. The authors concluded that In-111 octreotide may be useful to define tumor receptor status and may provide prognostic information useful in determining subsequent therapy.

In a phase II study, Loehrer et al (2004) examined the objective response rate, duration of remission and toxicity of octreotide alone or with the later addition of prednisone in patients with unresectable, advanced thymic malignancies in whom the pre-treatment octreotide scan was positive. A total of 42 patients with advanced thymoma or thymic carcinoma were entered onto the trial, of whom 38 were fully assessable (1 patient had inconclusive histology; 3 patients had negative octreotide scan). Patients received octreotide 0.5 mg subcutaneously 3 times a day. At 2 months, patients were evaluated. Responding patients continued to receive octreotide alone; patients with progressive disease were removed from the study. All others received prednisone 0.6 mg/kg orally 4 times a day for a maximum of 1 year. Two complete responses ([CR]; 5.3%) and 10 partial responses ([PR]; 25%) were observed (4 PR with octreotide alone; the remainder with octreotide plus prednisone). None of the 6 patients without pure thymoma responded. The 1- and 2-year survival rates were 86.6% and 75.7%, respectively. Patients with an Eastern Cooperative Oncology Group performance status of 0 lived significantly longer than did those with a performance status of 1 (p = 0.031). The authors concluded that octreotide alone has modest activity in patients with octreotide scan-positive thymoma. Prednisone improves the overall response rate but is associated with increased toxicity. They stated that additional studies with the agent are warranted.

Ozkan et al (2011) evaluated the outcome of high-dose In-111 octreotide treatment and efficacy of long-acting release (LAR) sandostatin in patients with disseminated neuroendocrine tumors. A total of 14 patients (mean age of 51.8 +/- 13.2 years; 4 males and 10 females) receiving high-dose In-111 octreotide for the treatment of neuroendocrine tumors were included in the study. Monthly treatment with long-acting somatostatin analog (sandostatin LAR) was continued in 9 cases. During a 3-year period, a total of 45 courses of high-dose In-111 octreotide treatment were delivered to 14 patients. In 7 patients receiving an average of 4 treatment courses (6 carcinoid tumors, 1 thymoma, patients: 2, 4, 5, 11 to 14) stable disease was achieved (50%). In 2 patients with carcinoid tumors (patients 1 and 3) who received 4 treatment courses, PR was observed (14%). Five patients (36%; 4 NET, 1 gastrinoma; patients 6 to 10) died due to progressive disease following on average 2 treatment courses. On average, deaths occurred 2 months after the last treatment dose. No CR was seen; PR was achieved in 2 of the 9 patients receiving sandostatin LAR, while 4 had stable disease. Both treatments were associated with acceptable tolerability. The authors concluded that high-dose In-111 octreotide can be safely administered in conjunction with somatostatin analog in patients with disseminated NET and this treatment may help to stabilize the disease.

Gubens (2012) noted that thymomas and thymic carcinomas are rare diseases of the anterior mediastinum. Although some thymomas are quite indolent and able to be resected in a curative fashion, the treatment of metastatic disease remains a challenge, especially for the more aggressive thymic carcinoma histology. Based on the results of single-arm trials, combination chemotherapy is the standard of care in the first-line, and anthracycline-based treatments should be used if patients are reasonably fit. Several single-agent cytotoxic chemotherapy agents have some effectiveness in subsequent lines of therapy, especially pemetrexed and, in octreotide scan-positive patients, octreotide. The author stated that prospective trials of new agents are difficult to conduct given the rarity of thymoma, but various targeted therapies do show promise. Greater international research collaboration, as well as modern techniques in molecular and genomic characterization, should help to advance the treatment of thymic malignancies in the near future.

The NCCN clinical practice guideline on “Thymomas and thymic carcinomas” (Version 2.2013) lists etoposide, ifosfamide, pemetrexed, octreotide (LAR; with or without prednisone), 5-fluorouracil, gemcitabine, and paclitaxel as a second line chemotherapy. It also states that “None of these agents have been assessed in randomized trials. Octreotide may be useful in patients with thymoma who have a positive octreotide scan or symptoms of carcinoid syndrome …. Patients with thymoma also have an increased risk for second malignancies, although no particular screening studies are recommended”.

In a prospective study, Berczi and associates (2002) evaluated the effectiveness of technetium-99m-sestamibi and technetium-99m-pertechnetate subtraction scanning and US for imaging parathyroid glands in primary hyper-parathyroidism (pHPT). A total of 63 patients were surgically treated for pHPT. Pre-operative scintigraphy and US were performed in all cases. Bilateral neck exploration was carried out on each patient. Results of radionuclide studies and US were compared with surgical and histological findings. In 57 patients with pHPT the radionuclide scanning gave true-positive results. Four false-negative and 2 false-positive scintigrams were obtained. The sensitivity and the positive-predictive value (PPV) of scintigraphy were 93% and 97%, respectively. Forty-one cases were correctly localized by the US. A total of 17 US results were false-negative and 5 were false-positive. The sensitivity and the PPV for US were 71 and 89%, respectively. There was a statistically significant difference between the sensitivity of the scintigraphy compared with the US (p = 0.001). Sensitivities of radionuclide scans and US were higher for adenomas (100 and 83%) than for hyperplastic glands (75 and 40%). The sensitivity of technetium-99m-sestamibi and technetium-99m-pertechnetate subtraction scintigraphy (SS) was significantly higher compared with US. This sensitive method could help surgeons in performing a rapid and directed parathyroidectomy.

Barczynski and colleagues (2006) determined the sensitivity and PPV of SS versus US of the neck combined with rapid intact parathyroid hormone (iPTH) assay in US-guided fine-needle parathyroid aspirates in pre-operative localization of parathyroid adenomas and in directing surgical approach. The results of SS for localization of parathyroid adenoma were determined in 121 patients with pHPT and compared with findings at surgery and with the results of US alone (in patients without nodular goiter) and US in combination with the iPTH assay in US-guided fine-needle aspirates (FNAs) of suspicious parathyroid lesions (in patients with concomitant nodular goiter). All 121 patients had biochemically documented pHPT; all were referred for first-time surgery. Subtraction scintigraphy was performed with 99mTc-sestamibi and 99mTc-pertechnetate. High-resolution US of the neck was performed by a single endocrine surgeon and combined with US-guided FNAs of suspicious parathyroid lesions in all patients with nodular goiter (n = 43). The sensitivity and PPV of SS were significantly higher in patients without versus with goiter (89.3% and 95.7% versus 74.3% and 76.5%, respectively; p < 0.001). The sensitivity and PPV of US were significantly higher in patients without versus with goiter (96% and 97.3% versus 67.7% and 71.9%, respectively; p < 0.001). The iPTH assay of US-guided FNAs of suspicious parathyroid lesions in patients with nodular goiter significantly improved both the sensitivity and PPV of US imaging (90.7% and 100%, respectively), allowing for an accurate choice of surgical approach in 118 (97.5%) of 121 patients. Subtraction scintigraphy was more accurate than US alone in detection of ectopic parathyroid adenomas. However, US alone was characterized by a higher sensitivity in detection of small parathyroid adenomas (less than 500 mg) at typical sites (p < 0.01). The authors concluded that both the sensitivity and PPV of SS and US alone are comparable, with significantly less accurate results obtained in patients with goiter. In cases of equivocal results of US and/or in patients with concomitant goiter, an iPTH assay in US-guided FNAs of suspicious parathyroid lesions may be used to establish the nature of the mass, distinguish between parathyroid and non-parathyroid tissue (goiter, lymph nodes) and improve the accuracy of US parathyroid imaging, allowing for successful directing of surgical approach in a majority of patients.

Powell et al (2013) evaluated the benefit of adding a pertechnetate parathyroid scan (dual-isotope imaging) in the interpretation of sestamibi dual-phase parathyroid scintigraphy. A total of 116 dual Tc-99m sestamibi (MIBI) and Tc-99m pertechnetate subtraction parathyroid studies, performed between January 2000 and February 2006, were retrospectively reviewed. Dual-phase technetium sestamibi examinations were initially interpreted, with blinding to the technetium pertechnetate findings. Subsequently, technetium pertechnetate scan findings were added, and changes in interpretation were recorded. By adding Tc-99m pertechnetate imaging, the interpretation of 17 scans (17/116 = 14.6%) was substantially altered. This included 5 scans (4%) that changed from negative to positive and 9 scans (8%) that changed from equivocal to positive, excluding ectopic tissue and directing minimally invasive surgery, without the need for further imaging, such as ultrasound, in 12% of cases. One examination changed from positive to negative. In addition, 2 scans changed from equivocal to negative, necessitating further pre-operative imaging for the evaluation of additional pathology such as thyroid nodules and lymph nodes and the consideration of hyperplasia. Among the remaining 99 patients, Tc-99m pertechnetate scans may also have contributed to the diagnosis in the 66 positive Tc-99m MIBI scans by increasing confidence in the interpretation and obviating additional imaging; 10 cases remained equivocal. The authors concluded that by adding Tc-99m pertechnetate imaging, scan interpretation was changed in 14.6% of cases, and interpretation confidence was enhanced in all but 10 remaining equivocal cases. The addition of a dual-isotope subtraction also eliminated the need for additional testing, such as ultrasound, in 12% of our cases. Increased confidence in interpretation that comes with dual-isotope subtraction may come at the cost of slight lengthening of imaging time but likely simplifies pre-operative localization and decreases intraoperative time for many patients with primary hyperparathyroidism.

Also, an UpToDate review on “Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism” (Yip et al, 2013) states that “Subtraction thyroid scan -- Even with the addition of SPECT, distinguishing abnormal parathyroid glands from thyroid pathology can be difficult. If necessary, a subtraction thyroid scan can be obtained by using two radiotracers (dual isotope scintigraphy). The use of technetium plus a second radiotracer such as 123I or 99mTc pertechnetate (thallium) permits selective imaging of the thyroid gland”.

Moran and Paul (2002) noted that oncogenic hypophosphatemic osteomalacia is a rare condition. The causative tumor is often difficult to locate. Primary tumors have been reported in the head and neck, skeleton, and soft tissue. Octreotide scanning was used in this case and detected a mesenchymal tumor in the pubic symphysis.

Takahashi et al (2008) reported the case of a 31-year old woman with tumor-induced osteomalacia suffering from slowly progressive bilateral muscle weakness predominantly in the proximal muscles and multiple bone pains for the past 2 years. She was unable to walk or raise her arms above the shoulder. These investigators suspected tumor-induced osteomalacia due to decreased serum phosphate and 1alpha, 25 (OH),-vitamin D3 levels, low percentage of tubular reabsorption of phosphate (%TRP), adult onset, and no family history of osteomalacia. Regular imaging examinations could not detect the location of the primary tumor: however, indium-111 octreotide scintigraphy detected the causative primary mesenchymal tumor in the right sole. Pain and muscle weakness improved promptly after tumor resection, and she was able to walk 6 days post-operatively. This was the first case report in Japan describing the detection of the primary tumor site by indium-111 octreotide scintigraphy.

Seijas et al (2009) noted that oncogenic osteomalacia is a rare paraneoplastic syndrome of acquired hypophosphatemic osteomalacia, resulting from a deficit in renal tubular phosphate reabsorption, in which fibroblast growth factor 23 (FGF23) seems to be implicated. This condition is usually associated with a phosphaturic mesenchymal tumor of mixed connective tissue located in the bone or soft tissue. The clinical and the radiologic findings are the same as those seen in osteomalacia, and the biochemical features include renal phosphate loss, low serum phosphate and 1,25-(OH)(2) vitD(3) levels, increased alkaline phosphatase, and normal calcium, PTH, calcitonin, 25-OH-vitD(3) and 25,25-(OH)(2) vitD(3). These investigators presented 2 cases of oncogenic osteomalacia associated with phosphaturic mesenchymal tumors, which were histologically similar, but presented a completely different evolution. In the first patient, the tumor developed on the sole of the foot. Following removal of the mass, the symptoms resolved and biochemical and radiological parameters returned to normal. However, in the second patient, a liver tumor developed and resection did not resolve the disease. Multiple lesions appeared in several locations during follow-up. This disease usually remits with complete tumor resection. Nevertheless, if this is not possible, oral treatment with phosphate, calcium and calcitriol can improve the symptoms. If scintigraphy of the tumor shows octreotide receptors, patients may respond partially to therapy with somatostatin analogs, with stabilization of the lesion.

Hu et al (2011) stated that tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-over-expressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. These researchers reported a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than 3 years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the pre-operative level 1 hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in 4 days. Accordingly, her clinical symptoms were greatly improved within 1 month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "lomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation 1 year after surgery. The authors concluded that  although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

Jiang et al (2012) noted that TIO is an acquired form of hypophosphatemia. Tumor resection leads to cure. These researchers investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ((99) Tc(m)-OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in (99) Tc(m) -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by (99) Tc(m) -OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. The authors concluded that TIO is an important cause of adult-onset hypophosphatemia in China; (99) Tc(m)-OCT imaging successfully localized the tumor in the over-whelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up.

Sanchez et al (2013) reported the case of an oncogenic osteomalacia in a 50-yearold male. He suffered severe bone pain and marked muscular weakness of 4 years' duration. There were several vertebral deformities in the thoracic spine, bilateral fractures of the ilio-pubic branches, another fracture in the left ischio-pubic branch, and a Looser's zone in the right proximal tibia. An octreotide-Tc scan allowed to identify a small tumor in the posterior aspect of the right knee. It was surgically removed. Microscopically, it was a phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT). Expression of FGF-23 was documented by immune-peroxidase staining. There was rapid improvement, with consolidation of the pelvic fractures and the tibial pseudo-fracture. The laboratory values returned to normal.

Jing et al (2013) stated that TIO is an endocrine disorder caused by tumors producing excessive fibroblast growth factor-23 (FGF-23). The causative tumors are generally small, slow-growing benign mesenchymal tumors. The only cure of the disease depends on resection of the tumors, which are extremely difficult to localize due to their small sizes and rare locations. Since these tumors are known to express somatostatin receptors, this research was undertaken to evaluate efficacy of [Tc-99m]-HYNIC-octreotide (99mTc-HYNIC-TOC) whole body imaging in this clinical setting. Images of 99mTc-HYNIC-TOC scans and clinical chart from 183 patients with hypophosphatemia and clinically suspected TIO were retrospectively reviewed. The scan findings were compared to the results of histopathologic examinations and clinical follow-ups. Among 183 patients, 72 were confirmed to have TIO while 103 patients were found to have other causes of hypophosphatemia. The possibility of TIO could not be either diagnosed or excluded in the remaining 8 patients. For analytical purposes, these 8 patients who could neither be diagnosed nor excluded as having TIO were regarded as having the disease, bringing the total of TIO patients to 80. The 99mTc-HYNIC-TOC scan identified 69 tumors in 80 patients with TIO, which rendered a sensitivity of 86.3% (69/80). 99mTc-HYNIC-TOC scintigraphy excluded 102 patients without TIO with a specificity of 99.1% (102/103). The overall accuracy of 99mTc-HYNIC-TOC whole body scan in the localization of tumors responsible for osteomalacia is 93.4% (171/183). The authors concluded that whole body 99mTc-HYNIC-TOC imaging is effective in the localization of occult tumors causing TIO.

Furthermore, an UpToDate review on “Hereditary hypophosphatemic rickets and tumor-induced osteomalacia” (Scheinman and Drezner, 2013) states that “The diagnosis of tumor-induced osteomalacia should be suspected from the clinical constellation of acquired hypophosphatemia and osteomalacia or rickets in association with renal phosphate wasting (but no other proximal tubular defects) and an inappropriately low plasma calcitriol concentration.  The phenotype is similar to X-linked and autosomal dominant hypophosphatemic rickets but the family history is negative and the disorder is acquired. Finding the tumors can be a major diagnostic challenge, and may involve total body magnetic resonance imaging (MRI), scintigraphy using octreotide labeled with indium-111 (because the tumors typically express somatostatin receptors), or scintigraphy combined with positron emission tomography/computerized tomography (PET/CT)”.

Leong et al (2011) noted that a new low-molecular-weight mannose receptor-based, reticuloendothelial cell-directed, (99m)Tc-labeled lymphatic imaging agent, (99m)Tc-tilmanocept, was used for lymphatic mapping of sentinel lymph nodes (SLNs) from patients with primary breast cancer or melanoma malignancies.  This novel molecular species provided the basis for potentially enhanced SLN mapping reliability. In a prospectively planned, open-label phase II clinical trial, (99m)Tc-tilmanocept was injected into breast cancer and cutaneous melanoma patients before intra-operative lymphatic mapping. Injection technique, pre-operative lympho-scintigraphy (LS), and intra-operative lymphatic mapping with a hand-held gamma detection probe were performed by investigators per standard practice. A total of 78 patients underwent (99m)Tc-tilmanocept injection and were evaluated (47 melanoma, 31 breast cancer). For those whom LS was performed (55 patients, 70.5%), a (99m)Tc-tilmanocept hot spot was identified in 94.5% of LS patients before surgery. Intra-operatively, (99m)Tc-tilmanocept identified at least 1 regional SLN in 75 (96.2%) of 78 patients: 46 (97.9%) of 47 in melanoma and 29 (93.5%) of 31 in breast cancer cases.  Tissue specificity of (99m)Tc-tilmanocept for lymph nodes was 100%, displaying 95.1% mapping sensitivity by localizing in 173 of 182 nodes removed during surgery.  The overall proportion of (99m)Tc-tilmanocept-identified nodes that contained metastatic disease was 13.7%.  Five procedure-related serious adverse events occurred, none related to (99m)Tc-tilmanocept. The authors concluded that these findings demonstrated the safety and effectiveness of (99m)Tc-tilmanocept for use in intra-operative lymphatic mapping.  The high intra-operative localization and lymph node specificity of (99m)Tc-tilmanocept and the identification of metastatic disease within the nodes suggested SLNs are effectively identified by this novel mannose receptor-targeted molecule.

Tokin et al (2012) stated that SLN mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs.  (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC).  It is used in conjunction with vital blue dyes (VBDs) that relies on simple lymphatic drainage for localization.  Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids.  [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies.  These researchers compared [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer.  Data from the phase III clinical trials of [(99m)Tc]tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC.  The primary end-points were SLN localization rate and degree of localization.  A total of 6 studies were used for a meta-analysis to identify the colloid-based SOC; 5 studies (6,134 patients) were used to calculate the SOC localization rate of 95.91% (CI: 0.9428 to 0.9754) and 3 studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI: 1.5136 to 1.8230).  The lower bound of the confidence interval was used for comparison to Tilmanocept.  Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99% (CI: 0.9977 to 1.0000) localization rate and degree of localization of 2.16 (CI: 1.964 to 2.3600).  The authors concluded that Tilmanocept was superior to the Nanocoll SOC for both end-points (p < 0.0001).

Sondak et al (2013) stated that [(99m)Tc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for SLN identification.  Two nearly identical non-randomized phase III trials compared [(99m)Tc]tilmanocept to VBD. Patients received [(99m)Tc]tilmanocept and blue dye.  Sentinel lymph nodes identified intra-operatively as radioactive and/or blue were excised and histologically examined.  The primary end-point, concordance, was the proportion of blue nodes detected by [(99m)Tc]tilmanocept; 90% concordance was the pre-specified minimum concordance level.  Reverse concordance, the proportion of radioactive nodes detected by blue dye, was also calculated.  The prospective statistical plan combined the data from both trials. A total of 15 centers contributed 154 melanoma patients who were injected with both agents and were intra-operatively evaluated.  Intra-operatively, 232 of 235 blue nodes were detected by [(99m)Tc]tilmanocept, for 98.7% concordance (p < 0.001).  [(99m)Tc]Tilmanocept detected 364 nodes, for 63.7% reverse concordance (232 of 364 nodes).  [(99m)Tc]Tilmanocept detected at least 1 node in more patients (n = 150) than blue dye (n = 138, p = 0.002).  In 135 of 138 patients with at least 1 blue node, all blue nodes were radioactive.  Melanoma was identified in the SLNs of 22.1% of patients; all 45 melanoma-positive SLNs were detected by [(99m)Tc]tilmanocept, whereas blue dye detected only 36 (80%) of 45 (p = 0.004).  No positive SLNs were detected exclusively by blue dye.  Four of 34 node-positive patients were identified only by [(99m)Tc]tilmanocept, so 4 (2.6%) of 154 patients were correctly staged only by [(99m)Tc]tilmanocept.  No serious adverse events were attributed to [(99m)Tc]tilmanocept. The authors concluded that [(99m)Tc]Tilmanocept met the pre-specified concordance primary end-point, identifying 98.7% of blue nodes.  It identified more SLNs in more patients, and identified more melanoma-containing nodes than blue dye.

Wallace et al (2013) stated that SLN surgery is used world-wide for staging breast cancer patients and helps limit axillary lymph node dissection.  In 2 open-label, non-randomized, within-patient, phase III clinical trials, [(99m)Tc]Tilmanocept was evaluated to assess the lymphatic mapping performance. A total of 13 centers contributed 148 patients with breast cancer.  Each patient received [(99m)Tc]tilmanocept and VBD.  Lymph nodes identified intra-operatively as radioactive and/or blue stained were excised and histologically examined.  The primary end-point, concordance (lower boundary set point at 90%), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept. A total of 13 centers contributed 148 patients who were injected with both agents.  Intra-operatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04% (p < 0.0001).  [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7%) were detected by VBD.  [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001).  In 129 of 131 patients with greater than or equal to 1 blue node, all blue nodes were radioactive.  Of 33 pathology-positive nodes (18.2% patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312).  No pathology-positive SLNs were detected exclusively by VBD.  No serious adverse events were attributed to [(99m)Tc]tilmanocept. The authors concluded that [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary end-point.  Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients.  This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

On March 13, 2013, The FDA approved Lymphoseek (technetium Tc 99m tilmanocept) Injection for location of lymph nodes in patients with breast cancer or melanoma who are undergoing surgery to remove tumor-draining lymph nodes. The most common side effects identified in clinical trials was pain or irritation at the injection site.

In a prospective, non-randomized, single-arm, part of an ongoing phase III clinical trial, Marcinow et al (2013) evaluated the preliminary utility of technetium Tc 99m (99mTc)-tilmanocept in patients with oral cavity squamous cell carcinoma (OSCC). Patients had previously untreated, clinically and radiographically node-negative OSCC (T1-4aN0M0) at an academic tertiary referral center. Patients received a single dose of 50 µg 99mTc-tilmanocept injected peri-tumorally followed by dynamic planar LS and fused single-photon emission computed tomography/computed tomography (SPECT/CT) prior to surgery. Surgical intervention consisted of excision of the primary tumor and radio-guided SLN dissection followed by planned elective neck dissection (END).  The excised lymph nodes (SLNs and non-SLNs) underwent histopathologic evaluation for presence of metastatic disease. Main outcome measures were false-negative rate and negative-predictive value of SLNB using 99mTc-tilmanocept and comparison of planar LS with SPECT/CT in SLN localization. Twelve of 20 patients (60%) had metastatic neck disease on pathologic examination.  All 12 had at least 1 SLN positive for metastases.  No patients had a positive END node who did not have at least 1 positive SLN.  These data yielded a false-negative rate of 0% and negative-predictive value of 100% using 99mTc-tilmanocept in this setting.  Dynamic planar LS and SPECT/CT revealed a mean (range) number of hot spots per patient of 2.9 (1-7) and 3.7 (1-12), respectively.  Compared with planar LS, SPECT/CT identified additional putative SLNs in 11 of 20 cases (55%). The authors concluded that the high negative-predictive value and low false-negative rate in identification of occult metastases shows 99mTc-tilmanocept to be a promising agent in SLN identification in patients with OSCC.  Use of SPECT/CT improved pre-operative SLN localization including delineation of SLN locations near the primary tumor when compared with planar LS imaging.

Ma and colleagues (2014) compared the potential application of (99m)Tc-3P-Arg-Gly-Asp ((99m)Tc-3P4-RGD2) scintimammography (SMM) and (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SMM for the differentiation of malignant from benign breast lesions. A total of 36 patients with breast masses on physical examination and/or suspicious mammography results that required fine needle aspiration cytology biopsy (FNAB) were included in the study. (99m)Tc-3P4-RGD2 and (99m)Tc-MIBI SMM were performed with SPECT at 60 mins and 20 mins, respectively, after intravenous injection of 738 ± 86 MBq radiotracers on a separate day. Images were evaluated by the tumor to non-tumor localization ratios (T/NT). Receiver operating characteristic (ROC) curve analysis was performed on each radiotracer to calculate the cut-off values of quantitative indices and to compare the diagnostic performance for the ability to differentiate malignant from benign diseases. The mean T/NT ratio of (99m)Tc-3P4-RGD2 in malignant lesions was significantly higher than that in benign lesions (3.54 ± 1.51 versus 1.83 ± 0.98, p < 0.001). The sensitivity, specificity, and accuracy of (99m)Tc-3P4-RGD2 SMM were 89.3%, 90.9% and 89.7%, respectively, with a T/NT cut-off value of 2.40. The mean T/NT ratio of (99m)Tc-MIBI in malignant lesions was also significantly higher than that in benign lesions (2.86 ± 0.99 versus 1.51 ± 0.61, p < 0.001). The sensitivity, specificity and accuracy of (99m)Tc-MIBI SMM were 87.5%, 72.7% and 82.1%, respectively, with a T/NT cut-off value of 1.45. According to the ROC analysis, the area under the curve for (99m)Tc-3P4-RGD2 SMM (area = 0.851) was higher than that for (99m)Tc-MIBI SMM (area = 0.781), but the statistical difference was not significant. The authors concluded that (99m)Tc-3P4-RGD2 SMM does not provide any significant advantage over the established (99m)Tc-MIBI SMM for the detection of primary breast cancer. The T/NT ratio of (99m)Tc-3P4-RGD2 SMM was significantly higher than that of (99m)Tc-MIBI SMM. Both tracers could offer an alternative method for elucidating non-diagnostic mammograms.

Sharma et al (2014) evaluated the diagnostic utility of a single vial ready to label with [99m]Tc kit preparation of DTPA-bis-methionine (DTPA-bis-MET) for the detection of primary breast cancer. The conjugate (DTPA-bis-MET) was synthesized by covalently conjugating 2 molecules of methionine to DTPA and formulated as a single vial ready to label with [99m]Tc lyophilized kit preparations. A total of 30 female patients (mean age of 47.5 ± 11.8 years; range of 21 to 69 years) with radiological/clinical evidence of having primary breast carcinoma were subjected to [99m]Tc-methionine scintigraphy. The whole body (anterior and posterior) imaging was performed on all the patients at 5 mins, 10 mins, 1 hr, 2 hrs, and 4 hrs following an intravenous administration of 555 to 740 MBq radioactivity of [99m]Tc-methionine. In addition, scintimammography (static images; 256 × 256 matrix) at 1, 2, and 4 hrs was also performed on all the patients. The resultant radiolabel, that is, [99m]Tc-DTPA-bis-MET, yielded high radiolabeling efficiency (greater than 97.0%), radiochemical purity (166 to 296 MBq/μmol), and shelf-life (greater than 3 months). The radiotracer primarily was excreted through the kidneys and localized in the breast cancer lesions with high target-to-nontarget ratios. The mean ± SD ratios on the scan-positive lesions acquired at 1, 2, and 4 hrs post-injection were 3.6 ± 0.48, 3.10 ± 0.24, and 2.5 ± 0.4, respectively. [99m]Tc-methionine scintimammography demonstrated an excellent sensitivity and positive predictive value of 96.0% each for the detection of primary breast cancer. The authors concluded that ready to label single vial kit formulations of DTPA-bis-MET can be easily synthesized as in-house production and conveniently used for the scintigraphic detection of breast cancer and other methionine-dependent tumors expressing the L-type amino acid transporter-1 receptor. The imaging technique thus could be a potential substitute for the conventional SPECT-based tumor imaging agents, especially for tracers with non-specific mitochondrial uptake. However, they stated that the diagnostic efficacy of [99m]Tc-methionine needs to be evaluated in a large cohort of patients through further multi-centric trials.

Liu et al (2014) explored the diagnostic performance of 99mTc-3(poly-(ethylene glycol),PEG)4-RGD2 (99mTc-3PRGD2) SMM in patients with either palpable or non-palpable breast lesions and compared SMM to mammography to assess the possible incremental value of SMM in breast cancer detection. These researchers also investigated the αvβ3 expression in malignant and benign breast lesions. A total of 94 patients with 110 lesions were included in this study. Mammograms were evaluated according to the Breast Imaging Reporting and Data System (BI-RADS) by a specialized imaging radiologist. Prone SMM was performed 1 hour after injection of 99mTc-3PRGD2. Scintigraphic images were interpreted independently by 2 experienced nuclear medicine physicians using a 3-point system, and the kappa value was calculated to determine the inter-reader agreement. The McNemar test was used to compare SMM and mammography with respect to sensitivity, specificity, and accuracy. Diagnostic values for breast cancer detection were evaluated for each lesion. Immunohistochemistry was performed to evaluate integrin αvβ3 expression. Histopathology revealed 46 malignant lesions and 64 benign lesions. The overall sensitivity, specificity, accuracy, PPV, and negative-predictive value (NPV) of SMM were 83%, 73%, 77%, 69%, and 85%, respectively. The kappa value between the 2 reviewers was 0.63. The diagnostic values of SMM were higher than those of mammography in evaluating overall breast lesions. A sensitivity of 91% was achieved when SMM and mammography results were combined with 60% of all false-negative mammography findings classified as true-positive results by SMM. Integrin αvβ3 expression was positively identified using SMM imaging. The authors concluded that SMM is a promising tool to avoid unnecessary biopsies when used in addition to mammography and can be used to image αvβ3 expression in breast cancer with good image quality.

I-123 Labeled MIBG Imaging

Nakajima et al (2015) noted that cardiac neuroimaging with (123)I-MIBG has been officially used in clinical practice in Japan since 1992.  The nuclear cardiology guidelines of the Japanese Circulation Society, revised in 2010, recommended cardiac (123)I-MIBG imaging for the management of HF patients, particularly for the assessment of HF severity and prognosis of HF patients. Consensus in North American and European countries regarding incorporation into clinical practice, however, has not been established yet. These investigators summarized 22-year of clinical applications in Japan of (123)I-MIBG imaging in the field of cardiology; these applications are reflected in cardiology guidelines, including recent methodological advances.  A standardized cardiac (123)I-MIBG parameter, the heart-to-mediastinum ratio (HMR), is the basis for clinical decision-making and enables common use of parameters beyond differences in institutions and studies. Several clinical studies unanimously demonstrated its potent independent roles in prognosis evaluation and risk-stratification irrespective of HF etiologies.  An HMR of less than 1.6 to 1.8 and an accelerated washout rate are recognized as high-risk indicators of pump failure death, SCD, and fatal arrhythmias and have independent and incremental prognostic values together with known clinical variables, such as LVEF and brain natriuretic peptide.  These researchers stated that another possible use of this imaging technique is the selection of therapeutic strategy (e.g., pharmacologic treatment and non-pharmacologic treatment with an implantable cardioverter-defibrillator or cardiac resynchronization device); however, this possibility remains to be investigated. Recent multiple-cohort database analyses definitively demonstrated that patients who were at low risk for lethal events and who were defined by an HMR of greater than 2.0 on (123)I-MIBG studies had a good long-term prognosis.

Tc 99m Tilmanocept for Head and Neck Squamous Cell Carcinoma

In a multi-center, non-randomized, open-label, single-arm, phase III clinical  trial, Agrawal et al (2015) determined the false negative rate (FNR) of SLNB relative to the pathologic nodal status in patients with intra-oral or cutaneous head and neck squamous cell carcinoma (HNSCC) undergoing tumor resection, SLNB, and planned END.  Negative predictive value, overall accuracy of SLNB, and the impact of radiopharmaceutical injection timing relative to surgery were assessed. This trial enrolled 101 patients with T1-T4, N0, and M0 HNSCC.  Patients received 50 µg [(99m)Tc]tilmanocept radiolabeled with either 0.5 mCi (same day) or 2.0 mCi (next day), followed by lymphoscintigraphy, SLNB, and END.  All excised tissues were evaluated for tissue type and tumor presence.  [(99m)Tc]Tilmanocept identified 1 or more SLNs in 81 of 83 patients (97.6%).  Of 39 patients identified with any tumor-positive nodes (SLN or non-SLN), 1 patient had a single tumor-positive non-SLN in whom all SLNs were tumor-negative, yielding an FNR of 2.56%; NPV was 97.8% and overall accuracy was 98.8%.  No significant differences were observed between same-day and next-day procedures. The authors concluded that use of receptor-targeted [(99m)Tc]tilmanocept for lymphatic mapping allowed for a high rate of SLN identification in patients with intra-oral and cutaneous HNSCC; SLNB employing [(99m)Tc]tilmanocept accurately predicted the pathologic nodal status of intra-oral HNSCC patients with low FNR, high NPV, and high overall accuracy.  The authors concluded that the use of [(99m)Tc]tilmanocept for SLNB in select patients may be appropriate and may obviate the need to perform more extensive procedures such as END.

An UpToDate review on “Overview of the diagnosis and staging of head and neck cancer” (Poon and Stenson, 2015) does not mention the use of Tc 99m tilmanocept injection as a management tool.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Head and neck cancers” (Version 1.2015) does not mention the use of Tc 99m tilmanocept injection as a management tool.

I-131 MIBG for Treatment of Neuroblastoma

George et al (2016) stated that iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria.  These researchers evaluated response and toxicity following a dosimetry-based, individualized approach. A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed.  Patients received I-mIBG therapy following relapse (n = 9), in refractory disease (n = 12), or with surgically unresectable disease despite conventional treatment (n = 4).  Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations; 3-D tumor dosimetry was also performed for 8 patients. The mean administered activity was 11,089 ± 7,222 MBq and the mean whole-body dose for a single administration was 1.79 ± 0.57 Gy.  Tumor-absorbed doses varied considerably (3.70 ± 3.37 mGy/MBq).  CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments.  Further acute toxicity was found in 49% of patients.  All acute toxicities resolved with appropriate therapy.  The overall response rate (ORR) was 58% (complete response [CR] or partial response [PR]), with a further 29% of patients having stable disease (SD). The authors concluded that a highly personalized approach combining patient-specific dosimetry and clinical judgement enabled delivery of high activities that can be tolerated by patients, particularly with stem cell support.  They reported excellent response rates and acceptable toxicity following individualized I-mIBG therapy. 

Modak et al (2016) stated that arsenic trioxide has in-vitro and in-vivo radio-sensitizing properties.  These researchershypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent (131)I-metaiodobenzylguanidine ((131)I-MIBG) and tested the combination in a phase II clinical trial. Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289).  The planned treatment was (131)I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m(2)) intravenously on days 6 to 10 and 13 to 17.  Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0.  Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in (123)I-MIBG or PET scans. A total of 21 patients were treated: 19 with neuroblastoma and 2 with MP; 14 patients received (131)I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide.  One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia; 19 patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue; 12 of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease.  Objective improvements in semi-quantitative (131)I-MIBG scores were observed in 6 patients.  No response was seen in MP; 17 of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy.  Mean 5-year overall survival (± SD) for neuroblastoma was 37% ± 11%.  Mean absorbed dose of (131)I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. The authors concluded that (131)I-MIBG plus arsenic trioxide was well-tolerated, with an adverse event profile similar to that of (131)I-MIBG therapy alone.  The addition of arsenic trioxide to (131)I-MIBG did not significantly improve response rates when compared with historical data with (131)I-MIBG alone. 

In a Cochrane review, Kraal et al (2017) evaluated the effectiveness as well as adverse effects of 131I-MIBG therapy in patients with newly diagnosed high-risk (HR) neuroblastoma (NBL). These investigators searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 3), Medline (PubMed) (1945 to April 25, 2016) and Embase (Ovid) (1980 to April 25, 2016).  In addition, they hand-searched reference lists of relevant articles and reviews.  These researchers also assessed the conference proceedings of the International Society for Pediatric Oncology, Advances in Neuroblastoma Research and the American Society of Clinical Oncology; all from 2010 up to and including 2015. The authors scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institutes of Health Register for ongoing trials (www.clinicaltrials.gov) on April 13, 2016. Randomized controlled trials (RCTs), controlled clinical trials (CCTs), non-randomized single-arm trials with historical controls and cohort studies examining the effectiveness of 131I-MIBG therapy in 10 or more patients with newly diagnosed HR NBL were selected for analysis. Two review authors independently performed the study selection, risk of bias assessment and data extraction. They identified 2 eligible cohort studies including 60 children with newly diagnosed HR NBL.  All studies had methodological limitations, with regard to both internal (risk of bias) and external validity.  As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible.  In 1 study, the objective response rate (ORR) was 73% after surgery; the median overall survival (OS) was 15 months (95% confidence interval (CI): 7 to 23); 5-year OS was 14.6%; median event-free survival (EFS) was 10 months (95% CI: 7 to 13); and 5-year EFS was 12.2%.  In the other study, the ORR was 56% after myeloablative therapy and autologous stem cell transplantation; 10-year OS was 6.25%; and EFS was not reported.  With regard to short-term adverse effects, 1 study showed a prevalence of 2% (95% CI: 0% to 13%; best-case scenario) for death due to myelosuppression.  After the 1st cycle of 131I-MIBG therapy in 1 study, platelet toxicity occurred in 38% (95% CI: 18% to 61%), neutrophil toxicity in 50% (95% CI: 28% to 72%) and hemoglobin toxicity in 69% (95% CI: 44% to 86%); after the 2nd cycle this was 60% (95% CI: 36% to 80%) for platelets and neutrophils and 53% (95% CI: 30% to 75%) for hemoglobin.  In 1 study, the prevalence of hepatic toxicity during or within 4 weeks after last the MIBG treatment was 0% (95% CI: 0% to 9%; best-case scenario).  Neither study reported cardiovascular toxicity and sialoadenitis.  One study assessed long-term adverse events in some of the children: there was elevated plasma thyroid-stimulating hormone in 45% (95% CI: 27% to 65%) of children; in all children, free T4 was within the age-related normal range (0%, 95% CI: 0% to 15%).  There were no secondary malignancies observed (0%, 95% CI: 0% to 9%), but only 5 children survived more than 4 years. The authors identified no RCTs or CCTs comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in patients with newly diagnosed HR NBL.  They found 2 small observational studies including children.  They had high risk of bias, and not all relevant outcome results were available.  Based on the currently available evidence, the authors could not make recommendations for the use of 131I-MIBG therapy in patients with newly diagnosed HR NBL in clinical practice; they stated that more high-quality research is needed.

OctreoScan for Carotid Body Tumors

Wienekec and Smit (2009) stated that extra-adrenal paragangliomas are neoplasms of the paraganglia located within the paravertebral sympathetic and parasympathetic chains. Thus, paragangliomas may arise anywhere along these tracts and common sites of occurrence include abdomen, retroperitoneum, chest and mediastinum and various head and neck locations such as jugulo-tympanic membrane, orbit, nasopharynx, larynx, vagal body and carotid body.

Martinelli et al (2009) stated that CBTs are very rare lesions which should be treated as soon as possible even when benign since small tumor size permits easier removal and lower incidence of peri-operative complications and recurrence. Malignant forms are rare and they can be identified by lymph node invasion and metastases in distant locations. The need of reliable and effective diagnostic modalities for both primary CBTs and its metastases or recurrence is evident. These investigators reviewed their experience and attempt to define the role of color coded ultrasound (CCU) and somatostatin receptor scintigraphy (SRS) with Indium-111-DTPA-pentetretide (OctreoScan) using both planar and single photon emission tomography (SPECT) technique in the diagnosis and follow-up of these uncommon lesions within a multi-disciplinary approach.

Gad et al (2014) noted that carotid body tumors (CBTs)were first described by von Haller in 1743. The incidence of CBTs is less than 1 in 30000; CBTs represent more than 50% of neck paragangliomas (PGLs), yet still a very rare cause of neck lumps. Like other paragangliomas, CBTs originate from the neural crest. The most common site is the carotid body. These lesions are rare before the age of 20. Recent studies have reported that CBTs are more common in females rather than males (1.9:1) but, there are some Asian centers reporting their data vice versa.

Medscape review on “Carotid Body Tumors” (Chaaban, 2017a) stated that “Carotid body tumors (CBTs) are rare neoplasms, although they represent about 65% of head and neck paragangliomas. These tumors develop within the adventitia of the medial aspect of the carotid bifurcation”.

Furthermore, Medscape review on “Carotid Body Tumors Workup” (Chaaban, 2017b) stated that “In patients who are suspected to have multiple small tumors, such as those with familial carotid body tumors (CBTs), performing a physical examination and supplementing it with imaging studies (including a CT, MRI, or metaiodobenzylguanidine [MIBG] scintigraphy) is essential. MIBG scans are quicker to perform than MRI and are also used in patients who are claustrophobic. The only issue with this scan is that it can only be used in patients who have functional tumors. In cases in which the tumor is nonfunctional, a better test is a pentetreotide scan, which uses a radiolabeled somatostatin analogue”. 

OctreoScan for the Diagnosis of Carcinoid Syndrome / Lung Carcinoids

Kadikoylu and colleagues (2006) noted that type I gastric carcinoid tumors result from hypergastrinemia in 1% to 7% of patients with pernicious anemia. These researchers diagnosed pernicious anemia in a 48-year old woman with complaint of fatigue for 3 months. She had no gastro-intestinal (GI) symptoms. Endoscopic examination of the upper GI revealed atrophic gastritis and a polypoid lesion in the corpus of 3 to 4 mm in size; endoscopic polypectomy was carried out. Histopathological examination of the specimen revealed positive chromogranin A and synaptophysin staining compatible with the diagnosis of a carcinoid tumor. Serum gastrin level was increased, urinary 5-hydroxyindoleacetic acid was within the normal range. There was no other symptom, sign, or laboratory finding of a carcinoid syndrome in the patient. No metastasis was found with indium-111 octreotide scan, CT of abdomen and thorax. The authors concluded that type I gastric carcinoid tumors were only rarely solitary and patients with tumors of less than 1 cm in size may benefit from endoscopic polypectomy.

Bhatia and associates (2006) stated that bronchopulmonary carcinoids are neuroendocrine tumors. They can present with Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion. Curative resection is possible only after adequate localization of the ectopic source. These investigators described a case that illustrated the role of octreotide scanning in the management of a broncho-pulmonary carcinoid. The use of pre-operative and post-operative octreotide scanning aided in performing a limited resection, thus preserving the lung parenchyma. The authors proposed that octreotide scanning could be a very important and informative test in the management of carcinoid tumors. In situations when conventional imaging was inconclusive, octreotide scanning may be of help in determining the source of ectopic ACTH syndrome.

Furthermore, an UpToDate review on “Diagnosis of carcinoid syndrome and tumor localization” (Strosberg, 2020) does not mention octreotide scan as a diagnostic tool.

Danti and colleagues (2020) examined the capability of contrast-enhanced multi-detector computed tomography (CE-MDCT) and spectrum of molecular imaging to characterize typical carcinoids (TCs) of lung and their relationship with Ki-67 index. These researchers analyzed 68 patients with histological diagnosis of pulmonary TC, which underwent both MDCT and nuclear molecular imaging (somatostatin receptor scintigraphy/SPECT with 111In-pentetreotide and 18F-FDG-PET/CT) at staging evaluation before surgery. The MDCT scan was reviewed for the following features: size, margins, contrast enhancement, presence of calcifications, bronchial obstruction, lymph nodes and metastases. In 111In-pentetreotide SPECT, tumor/non-tumor ratio was measured at 4- and 24-hour post-injection and the percent difference was calculated (T/NT%). FDG uptake was measured as the ratio between lesion SUVmax and liver SUVmean (SUV ratio). All imaging features were correlated between them and with Ki-67 index. A total of 44 of the 68 lesions (65%) were in the right lung. In MDCT, scan lesions appeared as a well-defined nodule in 44 patients (65%) and irregular mass in 24 patients (35%). Contrast intense enhancement was present in 53 patients (78%), calcifications in 20 patients (29%) and bronchial obstruction in 24 patients (35%). Lymph nodes and metastasis were present in 13 (19%) and 15 (22%) patients. Ki-67 index was negatively correlated with T/NT% and positively with SUV ratio; T/NT% and SUV ratio were inversely correlated. The presence of irregular margins and metastases was negatively related to T/NT%. The presence of a mass, irregular margins, bronchial obstruction, lymph nodes and metastasis was positively related to higher SUV ratio. The presence of irregular margins, bronchial obstruction, lymph nodes and metastases was significantly correlated with a higher grade of Ki-67 index. The authors concluded that MDCT and nuclear molecular imaging were important to characterize lung TCs. The majority of TCs appeared as a well-defined nodule generally not associated with extra-thorax signs. These investigators found a significant correlation between some MDCT aspects, nuclear medicine features and Ki-67 index; they stated that the association of MDCT and nuclear medicine imaging may be useful in predicting proliferative activity and prognosis of lung TCs.

Technetium-99m-Sestamibi Scintigraphy for Prediction of Pathologic Non-Response to Neoadjuvant Chemotherapy in Breast Cancer

Collarino and colleagues (2018) noted that interest in technetium-99m (99mTc)-sestamibi imaging for NAC response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. In a meta-analysis, these investigators evaluated the diagnostic performance of 99mTc-sestamibi to predict pathologic non-response to NAC for primary LABC. Studies with a minimum of 10 LABC patients that had evaluated 99mTc-sestamibi imaging for NAC non-response using conventional planar scintimammography, breast-specific γ-imaging, and/or SPECT/CT were included.  The histopathologic findings were the reference standard.  The meta-analysis was performed using a mixed logistic regression model. The search revealed 14 eligible studies with 529 patients.  Of the 14 studies, 11 had evaluated scintimammography and 3 breast-specific γ-imaging.  No studies examining SPECT or SPECT/CT were found.  The overall estimated pooled sensitivity, specificity, and positive and negative likelihood ratios of 99mTc-sestamibi imaging to predict non-responsiveness to NAC were 70.3% (95% CI: 56.5% to 81.3%), 90.1% (95% CI: 77.5% to 96.0%), 7.13 (95% CI: 3.08 to 16.53), and 0.33 (95% CI: 0.22 to 0.49), respectively.  Only 3 studies (107 patients) evaluated 99mTc-sestamibi imaging during NAC, reported an estimated pooled sensitivity of 87% (95% CI: 72% to 100%) and specificity of 93% (95% CI: 85% to 100%). The authors concluded that only planar 99mTc-sestamibi imaging had been investigated for NAC non-response in LABC; but showed low sensitivity to predict pathologic non-response.  However, most studies focused on the prediction of pathologic complete response after NAC.  Although experience was limited, 99mTc-sestamibi uptake during NAC appeared highly sensitivity for the prediction of non-responsiveness.  Moreover, they stated that features such as SPECT/CT imaging, standardized quantification, relation to tumor subtypes, and proper timing have been insufficiently evaluated and require further investigation.

Technetium-99m Tilmanocept Lymphoscintigraphy for Detection / Staging of Oral Squamous Cell Carcinoma (OSCC)

den Toom and associates (2021) noted that SLNB has proven to reliably stage the clinically negative neck in early-stage OSCC.  These researchers stated that [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.  In a prospective, within-patient evaluation study, these investigators compared [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection.  A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2 to 4 hours post-injection.  The injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9 %), compared with [99mTc]Tc-nanocolloid (60.9 %; p < 0.001).  Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95 %) compared with [99mTc]Tc-nanocolloid (3.16 %; p = 0.010).  No significant difference was observed in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232).  A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297).  Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57 %) and [99mTc]Tc-nanocolloid (0.86 %) (p = 0.052).  A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).  The authors concluded that these findings suggested that [99mTc]Tc-tilmanocept had a higher injection site clearance, but a lower uptake in the SLN, resulting in an SLN-to-injection site ratio that was not significantly different from [99mTc]Tc-nanocolloid.  The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intra-operative detection of SLNs; however, this might be overcome by a higher injection dose.

The authors stated that one of this trial’s drawbacks was the difference in amount of radioactivity between both tracers in the first 10 patients: 74 MBq [99mTc]Tc-tilmanocept versus 120 MBq [99mTc]Tc-nanocolloid, respectively.  [99mTc]Tc-tilmanocept was approved by the FDA and EMA (European Medicines Agency) for identification of SLNs using 74 MBq in a 2-day protocol.  In the authors’ institution, SLNB is routinely performed with 120 MBq [99mTc]Tc-nanocolloid.  Because the first 10 patients were surgically treated based on [99mTc]Tc-nanocolloid, they received this routinely used amount of radioactivity to safely perform SLNB.  This difference was corrected during quantitative analysis by correlating measured radioactivity in the Volumes of interest (VOIs) to the radioactive-dose injected.  In the second 10 patients, [99mTc]Tc-tilmanocept was leading for SLNB procedure; thus, the amount of radioactivity could be equalized for both tracers (74 MBq).  Another drawback was the impossibility of comparing hotspots at different time-points post-injection.  Due to the impossibility of performing attenuation correction on planar lymphoscintigraphy, these researchers unfortunately could not reliably compare SLN visualization at different time-points due to different imaging modalities.  Intensity of hotspots could easily be under- or over-estimated based on physiological structures in near surroundings (e.g., mandible).  On planar lymphoscintigraphy, only anterior-posterior or oblique images could be used.  This impeded these investigators from differentiating and analyzing hotspots located in the same plane.  Therefore, they opted to perform only quantitative analysis based on SPECT-CT.

Doll and colleagues (2021) stated that neck management in patients with early-stage, clinically node-negative OSCC remains a matter of discussion; SLNB represents a treatment alternative to avoid elective neck dissection (END) in this cohort and different protocols and tracers exist.  In a single-center study, these researchers presented the clinical outcome of SLNB using 99mTc-tilmanocept in a 2-day protocol in patients suffering from early-stage OSCC.  A total of 13 patients 6 men and 7 women; mean age of 65.7 years, range of 47 to 89 years) were included in this study.  Most of the patients suffered from an OSCC of the floor of mouth (n = 6), followed by tongue (n = 5) and upper alveolar crest/hard palate (n = 2); SLNs were successfully identified in all cases (range of 1 to 7).  The average hospital length of stay (LOS) was 4.7 days (range of 3 to 8 days) and mean duration of surgical intervention was 121 mins (range of 74 to 233 mins); 1 patient who suffered from an OSCC of the tongue was SLN-positive (SLN+).  The mean follow-up for all SLN-negative (SLN-) patients (n = 12) was 20.3 months (range of 10 to 28 months).  No local or nodal recurrences were observed within the observation period.  In this patient cohort, SLNB using 99mTc-tilmanocept in a 2-day protocol proved to be a safe and reliable staging method for patients suffering from early-stage, clinically SLN- OSCC.  The authors concluded that these findings and their possible superiority to colloid tracers have to be confirmed in prospective, large, multi-center RCTs.

Iobenguane I-131 Injection (Azedra) for the Treatment of Pheochromocytoma or Paraganglioma

van Hulsteijn and colleagues (2014) stated that (131)I-MIBG therapy can be used for palliative treatment of malignant paraganglioma and pheochromocytoma (PPGLs).  These researchers performed a systematic review and meta-analysis assessing the effect of (131)I-MIBG therapy on tumor volume in patients with malignant PPGLs. A literature search was performed in December 2012 to identify potentially relevant studies.  Main outcomes were the pooled proportions of CR, PR and SD after radionuclide therapy.  A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level.  Pooled proportions with 95% (CI were reported. A total of 17 studies concerning a total of 243 patients with malignant PPGLs were treated with (131)I-MIBG therapy.  The mean follow-up ranged from 24 to 62 months.  A meta-analysis of the effect of (131)I-MIBG therapy on tumor volume showed pooled proportions of CR, PR and SD of 0.03 (95% CI: 0.06 to 0·15), 0.27 (95% CI: 0.19 to 0.37) and 0.52 (95% CI: 0.41 to 0.62), respectively, and for hormonal response 0.11 (95% CI: 0.05 to 0.22), 0.40 (95% CI: 0.28 to 0.53) and 0.21 (95% CI: 0.10 to 0.40), respectively.  Separate analyses resulted in better results in hormonal response for patients with paraganglioma than for patients with pheochromocytoma. The authors concluded that data on the effects of (131)I-MIBG therapy on malignant PPGLs suggested that SD concerning tumor volume and a partial hormonal response could be achieved in over 50% and 40% of patients, respectively, treated with (131)I-MIBG therapy.  However, it could not be ruled out that SD reflected not only the effect of MIBG therapy, but also (partly) the natural course of the disease.

Carrasquillo and associates (2016) noted that PPGLs are rare tumors arising from chromaffin cells.  Available therapeutic modalities consist of chemotherapy, tyrosine kinase inhibitors, and MIBG.  I-131 MIBG is taken up via specific receptors and localizes into many but not all PPGLs.  Because these tumors are rare, most therapy studies are retrospective presentations of clinical experience.  Numerous retrospective studies and a few prospective studies have shown favorable responses in this disease, including symptomatic, biochemical, and objective responses.

Inaki and co-workers (2017) PPGLs are rare neuroendocrine tumors derived from the adrenal medulla or extra-adrenal paraganglioma from extra-adrenal chromaffin tissue.  Although malignant PPGLs has miserable prognosis, the treatment strategy remains to be established.  An internal radiation therapy using 131I-MIBG called MIBG therapy has been attempted as one of the systemic treatment of malignant PPGLs.  In a phase-I clinical trial, these researchers evaluated the safety and the efficacy of MIBG therapy for refractory PPGLs.  Patients with refractory PPGLs will be enrolled in this study.  The total number of patients for registration is 20.  The patients receive a fixed dose of 7,400 MBq of 131I-MIBG.  Adverse events (AEs) are surveyed during 20 weeks after 131I-MIBG injection and all severe AEs will be documented and reported in detail in accordance with the Common Terminology Criteria for Adverse Events (CTCAE).  Examination and imaging diagnosis are performed in 12 weeks after 131I-MIBG injection for the evaluation of therapeutic effect in accordance with the Response Evaluation in Solid Tumors (RECIST).  The authors concluded that the current study is the first multi-institutional prospective study of MIBG therapy and thereby will play a significant role in improving the patients' prognosis of refractory PPGLs.

In a phase-I clinical trial, Noto and colleagues (2018) determined the maximum tolerated dose (MTD) of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGLs. A total of 21 patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Main outcome measures included dose-limiting toxicities (DLTs), AEs, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and OS. The MTD was determined to be 296 MBq/kg on the basis of 2 observed DLTs at the next dose level.  The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq).  Response was evaluated by total administered activity: 4 patients (19%), all of whom received greater than 18.5 GBq of study drug, had radiographic tumor responses of PR  by RECIST.  Best biochemical responses (CR or PR) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively; OS was 85.7% at 1 year and 61.9% at 2 years after treatment.  The majority (84%) of AEs were considered mild or moderate in severity. The authors concluded that these findings supported further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

On July 30, 2018, the FDA approved Azedra (iobenguane I-131) injection for the treatment of adults and adolescents aged 12 and older with pheochromocytoma or paraganglioma that is unresectable, have spread beyond the original tumor site and require systemic anti-cancer therapy.  This is the first FDA-approved drug for this use. The efficacy of iobenguane I-131 was shown in a single-arm, open-label, clinical trial in 68 patients that measured the number of patients who experienced a 50%or greater reduction of all anti-hypertensive medications lasting for at least 6 months.  This end-point was supported by the secondary end-point, overall tumor response measured by traditional imaging criteria.  The study met the primary end-point, with 17 (25%) of the 68 evaluable patients experiencing a 50%or greater reduction of all anti-hypertensive medication for at least 6 months.  Overall tumor response was achieved in 15 (22%) of the patients studied. The most common severe side effects reported by patients receiving iobenguane I-131 in clinical trials included lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio (INR; a laboratory test which measures blood clotting), nausea, dizziness, hypertension and vomiting.

Scintimammography and Breast Specific Gamma Imaging (BSGI)

Guo et al (2016) evaluated the accuracy of Tc-99m sestamibi (MIBI) scintimammography in the prediction of neoadjuvant chemotherapy response in breast cancer. “PubMed” (Medline included) and Embase database were searched for relevant publications in English. Methodological quality of the included studies was assessed with Quality Assessment of Diagnosis Accuracy Studies (QUADAS), and “Meta-Disc” and “Stata” software were used to determine pooled sensitivity, specificity, and diagnostic odds ratio (DOR), and construct a summary receiver-operating characteristic curve. A total of 14 studies (503 subjects) met the inclusion criteria. The pooled sensitivity was 0.86 [95% CI: 0.78 to 0.92] and the pooled specificity was 0.69 (95% CI: 0.64 to 0.74). Pooled likelihood ratio (LRp), negative likelihood ratio (LR-), and DOR were 2.64 (95% CI: 1.81 to 3.85), 0.26 (95% CI: 0.15 to 0.46), and 12.06 (95% CI: 6.94 to 20.96), respectively. The area under the summary receiver-operating characteristic curve was 0.86. For the prediction of pathological complete response (10 studies included), the pooled sensitivity and specificity and DOR were 0.86 (95% CI: 0.77 to 0.93), 0.67 (95% CI: 0.62 to 0.72), and 11.43 (95% CI: 5.95 to 21.97). The authors concluded that these results indicated that Tc-99m MIBI scintimammography had acceptable sensitivity in the prediction of neoadjuvant chemotherapy response in breast cancer; however, its relatively low specificity showed that a combination of other imaging modalities would still be needed. Subgroup analysis indicated that performing early mid-treatment Tc-99m MIBI scintimammography (using the reduction rate of 1 or 2 cycles or within the first half-courses of chemotherapy compared with the baseline) was better than carrying out later (after 3 or more courses) or post-treatment scintimammography in the prediction of neoadjuvant chemotherapy response.

The American College of Radiology (ACR)’s Expert Panel on Breast Imaging (Moy et al, 2017) stated that breast cancer is the most common female malignancy and the 2nd leading cause of female cancer death in the United States. Although the majority of palpable breast lumps are benign, a new palpable breast mass is a common presenting sign of breast cancer. Any woman presenting with a palpable lesion should have a thorough clinical breast examination, but because many breast masses may not exhibit distinctive physical findings, imaging evaluation is necessary in almost all cases to characterize the palpable lesion. Recommended imaging options in the context of a palpable mass include diagnostic mammography and targeted-breast ultrasound (US) and are dependent on patient age and degree of radiologic suspicion as detailed in the document Variants. There is little role for advanced technologies such as MRI, positron emission mammography, or molecular breast imaging in the evaluation of a palpable mass. When a suspicious finding is identified, biopsy is indicated. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multi-disciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Ching and Brem (2018) evaluated correlations between MBI descriptor characteristics and PPV in detecting breast cancer. These investigators carried out a retrospective review on 193 suspicious findings from 153 women (31 to 81 years) with positive MBI examinations. They assessed associations between lesion pattern (mass versus non-mass) and PPV; lesion pattern and suspected likelihood of cancer (low versus moderate versus high); background parenchymal uptake (BPU) (homogeneous versus heterogeneous) and PPV; breast density (dense versus non-dense) and PPV; and BPU and density; 110 of 153 patients were diagnosed with malignancy or high-risk pathology (PPV1 = 71.9%), and 130/193 biopsies resulted in malignant or high-risk lesions (PPV3 = 67.4%). Biopsies of mass versus non-mass findings had comparable PPV3 (71.7% versus 61.3%; p = 0 .0717). Mass findings were correlated with higher suspicion for cancer than non-mass findings (p < 0.001). There was no significant difference in PPV3 when comparing biopsies from homogeneous versus heterogeneous BPU (72.5% versus 60.7%; p = 0.103). No association was found between patients' BPU and diagnosed cancer or high-risk lesions (p = 0.513). Biopsies from non-dense breasts demonstrated higher PPV3 than biopsies from dense breasts (85.4% versus 60.6%; p = 0.0025); patients with non-dense breasts were more likely to be diagnosed with cancer or high-risk pathology (PPV1 = 87.8% versus 66.0%; p = 0.00844). Dense breasts had a greater association with heterogeneous BPU (p = 0.0844). The authors concluded that neither variability in mass or non-mass positive MBI findings, nor variability in BPU on MBI were significant determinants for the probability of malignancy; dense breasts were associated with lower predictability and heterogeneous BPU on MBI.

Collarino and colleagues (2018) examined the clinical utility of MBI in patients with proven invasive breast cancer scheduled for breast-conserving surgery (BCS). Following approval by the institutional review board and written informed consent, records of patients with newly diagnosed breast cancer scheduled for BCS who had undergone MBI for local staging in the period from March 2012 till December 2014 were retrospectively reviewed. A total of 287 women (aged 30 to 88 years) were evaluated; MBI showed T stage migration in 26 patients (9%), with frequent detection of in-situ carcinoma around the tumor. Surgical management was adjusted in 14 of these patients (54%). In 17 of 287 patients (6%), MBI revealed 21 proven additional lesions in the ipsilateral, contralateral breast or both. In 18 of these additional foci (86%), detected in 15 patients, malignancy was found; 13 of these 15 patients had ipsilateral cancer and 2 patients bilateral malignancy. In total, MBI revealed a larger tumor extent, additional tumor foci or both in 40 patients (14%), leading to treatment adjustment in 25 patients (9%). The authors concluded that the findings of this study supported that MBI is a useful imaging modality, which revealed a high rate of multi-focal or multi-centric lesions and bilateral disease not visualized by mammography and US. Additionally, MBI may play an important role in accurate delineation of the tumor extent during pre-operative planning. Thus, the incorporation of this modality to the clinical work-up may lead to better selection of patients who might benefit of BCS. However, these researchers stated that larger and prospective studies, preferably using low-dose MBI protocols, are needed to confirm these findings.

The authors stated that this study had several drawbacks. First, it was a retrospective study based on data collected in a single institution. Second, these investigators retrospectively excluded a relative large amount of patients with positive MBI studies due to missing histopathological data. This represented a potential bias of the presented MBI results. However, the excluded cases represented either patients in whom the unexpected detection of additional lesions was not clinically relevant (in the sense that it would not have altered the treatment plan), or patients with a relatively low probability of having additional malignant foci (BI-RADS 4a abnormalities without correlate at targeted US). Third, an injection dose of 600 MBq was applied using a single-head detector. Since others have found comparable results using low-dose protocols (260 to 500 MBq for single-head MBI or 150 to 300 MBq for dual-head MBI) versus high-dose protocols, it would be worthwhile to examine the performance of the low-dose protocol in the studied patient population, since it could lead to a significantly lower radiation exposure.

An UpToDate review on “Breast density and screening for breast cancer” (Freer and Slanetz, 2018) lists molecular breast imaging as an emerging technology.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Breast cancer screening and diagnosis” (Version 3.2018) states that “Current evidence does not support the routine use of molecular imaging (e.g., breast specific gamma imaging, sestamibi scan, or positron emission mammography) as screening procedures, but there is emerging evidence that these tests may improve detection of early breast cancers among women with mammographically dense breasts”.

Lymphoscintigraphy and Sentinel Lymph Node Biopsy for Merkel Cell Carcinoma

Guidelines on Merkel cell carcinoma from the National Comprehensive Cancer Network (2019) recommends consideration of radiation therapy to "draining nodal basin identified by lymphoscintigraphy in cases of profound immunosuppression (i.e., solid organ transplant recipients)".

Lymphoscintigraphy and Sentinel Lymph Node Biopsy for Atypical Spitz Nevus

Lallas and colleagues (2014) noted that SLNB has been proposed as a diagnostic method for estimation of the malignant potential of atypical Spitz tumors; however, although cell deposits are commonly detected in the SNLs of patients with atypical Spitz tumors, their prognosis is substantially better than that of patients with melanoma and positive SLNBs.  In a systematic review of published reports, these researchers examined the role of SLNB as a prognostic method in the management of atypical Spitz tumors.  The results of this analysis did not show any prognostic benefit of SLNB; having a positive SLN did not appear to predict a poorer outcome for patients with atypical Spitz tumors.  The authors concluded that these findings indicated that, especially in the pediatric population, it might be prudent initially to use complete excision with clear margins and careful clinical follow-up in patients with atypical Spitz tumors.

Furthermore, an UpToDate review on “Spitz nevus and atypical Spitz tumors” (Barnhill and Kim, 2021) states that “Sentinel lymph node biopsy (SLNB) in patients with atypical Spitz tumors is controversial.  At one time, SLNB was suggested for patients with ambiguous melanocytic tumors of > 1 mm thickness and deep dermal involvement to help determine the benign or malignant nature of the lesions.  Given the difficulty in differentiating atypical Spitz tumors from melanoma, patients with a positive SLNB often are treated with completion lymphadenectomy and adjuvant therapy as if they have stage III melanoma.  However, the survival benefit of this approach has not been evaluated in randomized trials and remains undetermined.  Data from a systematic review of 24 observational studies including a total of 541 patients with atypical Spitz tumors indicate that SLNB followed by completion lymph node dissection does not improve the prognosis for these patients.  In this review, SLNB was performed in 303 (56 %) patients and was positive in 119 (39 %), 97 of whom underwent completion lymph node dissection.  After an average follow-up time of 59 months, the survival rates among 119 patients with positive SLNB and 238 patients who were treated with wide excision alone were 99 and 98 %, respectively.  Four of 119 (4 %) patients with positive SLNB and 11 (5 %) of 238 treated with wide excision alone had regional recurrence during follow-up”.

Lymphoscintigraphy and Sentinel Lymph Node Biopsy for Cervical Cancer

Lai et al (2018) stated that pelvic lymphadenectomy is included as part of the standard protocol of radical hysterectomy for women with early-stage cervical cancer (Stage IA to IB1).  However, an important sequela to lymphadenectomy is the possible occurrence of lymphedema in the lower abdomen and lower extremities.  Previous studies also reported that women with lymphedema experience many emotional consequences, including anxiety and depression, as well as adjustment problems.  Approximately 10 % of women with clinical stage IB cervical cancer were involved with metastatic disease.  If investigators could better define the relevant lymphatic nodes that must be removed, it is then possible to limit routinely performed lymphadenectomy for regional nodal metastasis in the pelvis; thus, reducing the need for extended surgical staging (para-aortic lymphadenectomy).  In a systematic review, these investigators examined the evidence and updated available information regarding the current progress on the use of SLNB in women with early-stage cervical cancer.  All detection methods (pre-operative injection of radiocolloid tracer, intra-operative injection of blue dye, or a combination of both techniques) showed reasonable sensitivity (with a few exceptions), high specificity, low false-negative rate and high NPV.  The authors concluded that the findings of this review should convince the readers that SLNB has the potential to improve the quality of life (QOL) and the possibility to maintain relapse-free survival (RFS) for women with cervical cancer.  The proper identification of negative SLN allowed individualized therapy and may preclude the need of lymphadenectomy procedure in most of these women.

Furthermore, an UpToDate review on “Invasive cervical cancer: Staging and evaluation of lymph nodes” (Frumovitz, 2022) provides the following information:

Sentinel lymph node biopsy -- SLNB for patients with cervical cancer appears promising and is a National Comprehensive Cancer Network-approved option for those surgeons experienced with the procedure.  The usual technique includes the use of blue dye with or without technetium 99, but indocyanine green may be used if a near-infrared camera is available for detection.

Four criteria are widely accepted as necessary for determining which patients should undergo SLNB and include:

• Tumors of less than 4 cm.
• No suspicious lymph nodes identified during pre-operative imaging.
• Bilateral SLN detection.
• Ultra-staging (i.e., enhanced pathologic review, including additional sectioning and staining of the SLN).

Sentinel Lymph Node Biopsy for Ductal Carcinoma In-Situ

The American Society of Breast Surgeons Performance and Practice Guideline (2014) state that sentinel lymph node biopsy (SLNB) is a standard of care for axillary lyph node staging in most patients with cN0 breast cancer. The guidelines include the indication for SLNB in ductal carcinoma in situ (DCIS) sufficient to require mastectomy, or DCIS with suspected/proved microinvasion.

Ramzi et al (2020) stated that ductal carcinoma in situ (DCIS) of the breast does not metastasize to axillary lymph nodes; however, high-grade DCIS (HgDCIS) is often subjected to SLNB concomitant with definitive surgery.  This is to avoid further axillary surgery in the event of up-staging to invasive carcinoma, which often entails axillary lymph node dissection (ALND).  In a retrospective study, these investigators examined the validity of this approach.  This study included an analysis of consecutive pre-operatively diagnosed HgDCIS patients from a single screening unit between December 2014 and August 2016.  The main outcomes were the overall incidence of up-staging and the independent predictors of up-staging on multi-variable analysis.  The rates of various complications of SLNB versus ALND in 4 RCTs were used to calculate the up-staging rate below which SLNB could be safely omitted.  There were 224 eligible patients of whom 26 (11.6 %) were up-staged.  Axillary metastasis (pN1) occurred in 2 patients (0.9 %).  On Univariable analysis, up-staged patients were significantly younger (median (IQR) = 56.0 (51.0 to 63.0) versus 60.0 (54.0 to 65.0); p = 0.019).  Radiological size, pathological size, type of biopsy, type of operation, and comedo-necrosis were not significant (p > 0.05).  On multi-variable analysis, age as a continuous variable (OR 0.93; p = 0.031) and core biopsy (OR 2.62; p = 0.036) were the only independent predictors of up-staging.  Chi-square test showed that patients less than 55 years whose pre-operative diagnosis was made on core biopsy were at significantly higher risk of up-staging than the others (31.8 % versus 9.4 %; p = 0.002).  The authors concluded that up-staging of HgDCIS was infrequent.  According to the known rates of complications of SLNB relative to ALND, routine SLNB concomitant with surgery appeared to be more harmful than its routine omission.  A selective approach based on age and type of biopsy could be considered.

Gonzalez-Vidal et al (2020) noted that DCIS of the breast is a heterogeneous pathology, where subgroups have different behavior patterns.  As an intraductal lesion, which does not cross the basement membrane, and thus does not infiltrate, regional staging should not be necessary.  In recent years, together with the increase in the number of diagnoses of DCIS, there has been an increase in the performance of the SLNB.  The recommendations by the Spanish Society of Senology and Breast Pathology (SESPM) included: large tumors, high histological grade, comedo-necrosis, palpable mass and mastectomy.  These findings are related to micro-invasion, and therefore to a higher risk for axillary involvement.  Between 2006 and 2013, a total of 109 DCIS patients were retrospectively analyzed to examine the degree of compliance with the recommendations of the SESPM.  SLNB was the staging procedure for 105 (96.3 %) women.  A positive SLN was identified in 3 patients (2.8 %), micro-metastases in 14 (13.3 %) and isolated tumor cells (ITC) in 7 cases (6.6 %).  Two aspects influenced the positive result: comedo-necrosis and mastectomy (p < 0.001); whereby tumor size of greater than 4 cm and high histological grade were at the limit of significance; 2 of the 3 patients with macro-metastases received adjuvant treatment (axillary clearance or radiation therapy).  The finding of isolated tumor cells and micro-metastases did not modify the axillary management.  The authors concluded that in this cohort, the application of the SESPM criteria for SLNB, taken individually, has not provided any clinical benefit to women.  The results were in most of cases positive for micro-metastases and isolated tumor cells without changes in axillary management.  Following these recommendations, these investigators had up-staged 24 women and over-treated 102.  These researchers stated that there is a need for evidence-based guidelines, predictive analysis models, clinical algorithm, like the USC/Van Nuys Prognostic Index or the association study of several of them, in order to make appropriate shared decisions.

Shin et al (2021) noted that SLNB is unnecessarily performed too often, owing to the high up-staging rates of DCIS.  In a retrospective, single-center study, these researchers examined the up-staging rates of DCIS to invasive cancer, determined the prevalence of axillary lymph node metastasis, and identified the clinicopathological factors associated with up-staging and lymph node metastasis.  They e also examined surgical patterns among DCIS patients and determined whether SLNB guidelines were followed.  These researchers analyzed 307 consecutive DCIS patients diagnosed by pre-operative biopsy between 2014 and 2018.  Data from clinical records, including imaging studies, axillary and breast surgery types, and pathology results from pre-operative and post-operative biopsies, were extracted.  Univariate analyses using Chi-square tests and multiple logistic regression analyses were used to analyze the data.  The rate of up-staging to invasive cancer was 19.2 % (59/307).  DCIS diagnosed by core-needle biopsy (odds ratio [OR]: 6.861, 95 % CI: 2.429 to 19.379), the presence of ultrasonic mass-forming lesions (OR: 2.782, 95 % CI: 1.224 to 6.320), and progesterone receptor-negative status (OR: 3.156, 95 % CI: 1.197 to 8.323) were found to be associated with up-staging.  The rate of sentinel lymph node metastasis was only 1.9 % (4/202), and all were total mastectomy (TM) patients diagnosed by core-needle biopsy.  SLNB was performed in 37.2 % of 145 breast-conserving surgery (BCS)  patients and 91.4 % of 162 total mastectomy patients.  Among the 202 patients who underwent SLNB, 145 (71.7 %) without invasive cancer on final pathology had redundant SLNB; 2 of 59 patients (3.4 %) with disease upstaged to invasive cancer had inadequate primary staging of the axilla, as the rate seemed sufficiently small.  The authors concluded that this study demonstrated that DCIS diagnosed with core-needle biopsy, PR-negative status, and ultrasonic mass-forming lesions were significantly associated with up-staging to invasive cancer.  While the risk of up-staging was 19.2 %, the rate of SLN metastasis was very low.  Furthermore, only a few DCIS patients undergoing TM were found to have SLN metastases.  Therefore, SLNB should not be carried out in BCS patients.  Rather, SLNB should be reserved only for patients undergoing TM.  In carefully selected DCIS patients diagnosed with excisional biopsy, SLNB may be omitted, even during TM.

The authors stated that this study had several drawbacks.  First, this was a retrospective study and may have included selection bias.  Second, this study included a small number of patients in a single center; therefore, it was difficult to generalize the findings of the study in all patient populations.  A prospective, multi-center study is needed.  Third, these investigators could not identify the clinical significance of up-staging and SLN metastasis in DCIS patients because of the short follow-up duration.

Diaz Casas et al (2021) conducted a retrospective observational study to evaluate the benefit of SLNB in patients with DCIS. A total of 40 patients (all female) at the Breast and Soft Tissue Functional Unit of the National Cancer Institute met study inclusion criteria for their analysis. "Indications for performing a SLNB were: mastectomy performed due to poor breast-tumor relationship and multicentricity in 60% (n = 24); suspected infiltration in the initial biopsy 17.5% (n = 7); ductal carcinoma in comedo-type situ in 55% (n = 22); high histological grade in 60% (n = 24) of cases; and tumor size greater than 3 cm in one patient. Most of the patients had more than one indication 65% (n = 26) for SLNB." The authors found that 62.5% (n=25) of patients underwent mastectomy with SLNB, and the remaining 37.5% underwent conservative surgery with SLNB. Sentinel node identification was achieved in 100% of cases, using lymphoscintigraphy in 95% (n=38). Sentinel node was positive in four patients (10%), three of whom had infiltration in the surgical specimen reported. With a follow-up of 49 months, only one patient had a local relapse. None of the patients had axillary or distant recurrence. The authors concluded that "SLNB in DCIS should be limited to patients with risk factors for infiltration (tumor size greater than 3 cm, comedo-type histology, and high-grade DCIS), and patients with an indication for mastectomy. Its percentage of complications is low, and a high identification percentage in surgical groups with adequate training".

Davey et al (2022) stated that axillary lymph node status remains the most powerful prognostic indicator in invasive breast cancer; and DCIS is a non-invasive disease and does not spread to axillary lymph nodes.  The presence of an invasive component to DCIS mandates nodal evaluation via SLNB.  Quantification of the necessity of upfront SLNB for DCIS requires investigation.  The objective of this study was to establish the likelihood of having a positive SLNB (SLNB+) for DCIS and to establish parameters predictive of SLNB+.  These investigators carried out a systematic review according to the PRISMA guidelines; only prospective studies were included.  Characteristics predictive of SLNB+ were expressed as dichotomous variables and pooled as OR and associated 95 % CI using the Mantel-Haenszel method.  A total of 16 studies including 4,388 patients were included (mean patient age of 54.8 years (range of 24 to 92)).  Of these, 72.5 % of patients underwent SLNB (3,156 of 4,356 patients) and 4.9 % had SLNB+ (153 of 3,153 patients).  The likelihood of having SLNB+ for DCIS was less than 1 % (OR < 0.01, 95 % CI: 0.00 to 0.01; p < 0.001, I2 = 93 %).  Palpable DCIS (OR 2.01, 95 % CI:. 0.64 to 6.24; p = 0.230, I2 = 0 %), tumor necrosis (OR 3.84, 95 % CI: 0.85 to 17.44; p = 0.080, I2 = 83 %), and grade 3 DCIS (OR 1.34, 95 % CI: 0.80 to 2.23; p = 0.270, I2 = 0 %) all trended towards significance in predicting SLNB+.  The authors concluded that while aggressive clinicopathological parameters may guide SLNB for patients with DCIS, the absolute and relative risk of SLNB+ for DCIS was less than 5 % and 1 %, respectively.  Moreover, these researchers stated that well-designed RCTs are needed to establish fully the necessity of SLNB for patients diagnosed with DCIS.

The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for "Breast cancer" (NCCN, 2023) states “… a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure. Therefore, the performance of a sentinel lymph node (SLN) procedure should be considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future SLN procedure”.

Sentinel Lymph Node Biopsy for Extremity and Truncal Soft Tissue Sarcomas

Keung et al (2023) noted that regional lymph node metastasis (RLNM) occurs infrequently in patients with soft tissue sarcoma (STS), although certain STS subtypes have a higher propensity for RLNM.  The identification of RLNM has significant implications for staging and prognosis; however, the precise impact of node-positive disease on patient survival remains a topic of controversy.  Although the benefits of SLNB are well documented in patients with melanoma and breast cancer, whether this procedure offers a benefit in STS is controversial.  In a systematic review, these investigators carried out a literature search to determine if SLNB in patients with extremity/truncal STS impacts disease-free survival (DFS) or OS.  A total of 6 studies were included.  Rates of sentinel lymph node positivity were heterogeneous (range of 4.3 % to 50 %).  The impact of SLNB on patient outcomes remains unclear.  The overall quality of available evidence was low, as assessed by the GRADE system.  The authors concluded that the literature addressing the impact of nodal basin evaluation on the staging and management of patients with extremity/truncal STS was confounded by heterogeneous patient cohorts and clinical practices.  These researchers stated that prospective, multi-center studies are needed to determine the true incidence of RLNM and whether SLNB could benefit patients with clinically occult RLNM at diagnosis.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcoma” (Version 2.2022) does not mention SNLB as a management tool.

Sentinel Lymph Node Biopsy for Head and Neck Squamous Cell Carcinoma

Costantino et al (2022) defined the role of SLNB in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN).  These investigators carried out a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.  A total of 705 patients were included from 20 studies.  The pooled SLN identification rate was 98.8 % (95 %CI: 97.0 to 99.8).  The median number of SLN excised was 3.6 (n = 371, 95 % CI: 2.0 to 4.4).  The pooled SLNB positive rate and cumulative regional recurrence rate (RRR) in negative SLNB were 5.6 % (95 % CI: 2.6 to 9.6) and 2.9 % (95 % CI: 0.5 to 7.2), respectively.  The high SLN identification rate demonstrated SLNB feasibility in cSCCHN.  The low SLNB positive rate and the relatively high RRR raised some doubts concerning its clinical utility.  The authors concluded that further studies are mandatory to define predictors of lymph node metastases able to better select patients that may benefit from a SLNB.

Ilmonen et al (2022) stated that cutaneous SCC (cSCC) shows malignant behavior in 3 % to 4 % of patients with loco-regional metastases and a poor prognosis, metastases that are difficult to predict clinically.  Thus, SLNB has been employed, with contradictory findings.  In a retrospective study, these investigators clarified the prognostic value of SLNB in high-risk cSCC patients.  They completed a clinical study among 63 patients, pre-operatively classified as N0 with a high-risk primary cSCC of the HN who underwent SLNB between 2001 and 2014 at Helsinki University Hospital (Finland).  Considered high-risk, the inclusion criteria comprised at least 2 of the following characteristics: tumor diameter of 10 mm or greater and/or thickness of 4 mm or greater and a specific tumor location, such as the lips, ear, scalp and central face.  Patients were followed-up post-operatively for a median of 4.1 years (0.2 to 13.8 years).  Only 4 (6.3 %) patients had positive sentinel nodes; 1 of these patients died of cSCC, while the other 3 survived their disease; 5 (7.9 %) patients showed a negative SLNB ;but developed recurrence within 1 year post-operatively.  Recurrence appeared in the neck lymph nodes concurrently with loco-regional soft-tissue invasion in all patients.  Among these patients, 3 died for cSCC and the remaining 2 from other causes.  Comparing the SLNB-positive and SLNB-negative groups with recurrence, these researchers identified no significant differences in terms of patient or tumor characteristics.  The authors concluded that SLNB appeared to carry no prognostic value for identifying recurrent disease among high-risk cSCC in the HN area.

Pride et al (2022) noted that limited data exist on SLNB for cSCCHN.  In a retrospective study, these investigators reviewed the results of SLNB for patients with cSCCHN at the authors' institution.  They carried out a review for patients who underwent SLNB for cSCCHN over 19 years.  Patient demographics, immune status, tumor stage, total patients with positive SLNB, local recurrence, nodal recurrence, in-transit metastasis, and disease-specific death were recorded.  A total of 60 patients underwent lymphoscintigraphy, and an SLN was identified in 58 patients.  The mean follow-up was 3.2 years (range of 15 days to 16 years); 4 patients (6.9 %) had a positive SLNB.  All were Brigham and Women's Hospital (BWH) stage T2b tumors; 3 of these patients were immunosuppressed, 3 patients underwent neck dissection, and 2 patients received adjuvant radiation.  None developed local or regional recurrence.  Of the 53 patients with a negative SLNB, there were 4 local recurrences, 2 in-transit metastases, and no nodal recurrences.  The authors concluded that immunosuppressed patients with tumors BWH stage T2b or greater may be a reasonable cohort to focus future prospective studies on the use of SLNB in cSCCHN.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Head and neck cancers” (Version 2.2022) states that “Data are limited on the efficacy of SLN biopsy for oral cavity cancers … SLNB may be used to identify occult cervical metastases”. 

Technetium-99m Tilmanocept Lymphoscintigraphy for Detection of Brain Tumors / Endometrial Cancer / Head and Neck Cancer / Merkel Cell Carcinoma

Reddy et al (2022) stated that technetium Tc 99m tilmanocept is a synthetic radiotracer specifically designed for SLN mapping that has been FDA-approved in breast cancer, melanoma, and head and neck cancer.  No published studies exist for the use of this radiotracer in endometrial cancer.  In a prospective, open-label, single-cohort, feasibility study, these researchers determined the detection rate of bilateral SLNs in endometrial cancer with the concurrent use of technetium Tc 99m tilmanocept and ICG.  This trial was carried out with subjects receiving pre-operative cervical injections of technetium Tc 99m tilmanocept followed by subsequent imaging and SPECT/CT.  Intra-operative ICG injections were administered for all patients with near-infrared imaging used to visualize lymphatic vessels and nodes.  A laparoscopic gamma counter was used to detect radioactive SLN intra-operatively.  All 6 evaluated patients had FIGO grade 1 or 2 endometrioid histology.  Stage IA/IB were in 33 % and 66 % of patients, respectively.  Tilmanocept did not map any SLN in the first 6 patients but instead showed retention of the tracer in the cervical stroma, leading to study discontinuation for futility.  ICG mapped bilateral SLN in all patients with the most common location being the external iliac region, followed by the obturator and common iliac areas.  All patients had CD206 positive staining throughout the full wall thickness of ectocervix, transformation zone, endocervix, and lymphatic vessels.  No patients experienced AEs.  The authors concluded that technetium Tc 99m tilmanocept did not detect SLN in early-stage endometrial cancers and is unlikely to improve bilateral detection rate compared to ICG alone.  ICG remains a standard technique for SLN detection in low-stage, low-grade endometrial cancer.

National Comprehensive Cancer Network’s clinical practice guideline on “Merkel cell carcinoma” (Version 2.2022) does not mention Lymphoseek / technetium Tc 99m tilmanocept as a managemen tool.

Rovera et al (2023) stated that although many radiopharmaceuticals are currently available for SLNB, 99mTc-tilmanocept is of particular interest due to its low molecular weight and specific binding capability for the mannose receptors of lymphatic reticuloendothelial cells.  In a systematic review and meta-analysis, these investigators provided an update from a European expert panel on the performance of 99mTc-tilmanocept for SLNB.  They carried out a systematic literature search of the PubMed/Medline and Embase databases to identify studies on the use of 99mTc-tilmanocept for SN identification in oncological patients.  The articles' methodological quality was assessed before inclusion.  The pooled estimates of the pre-/intra-operative detection rates (DR; proportion of patients with 1 or more SN identified) and/or pN + sensitivity (SN + /pN + patients ratio), with 95 % CIs, were calculated for breast cancer, melanoma, and head and neck cancer.  A total of 24 studies were included in the systematic review, and 21 provided data for the meta-analysis.  According to data availability, the 99mTc-tilmanocept-estimated pooled pre-operative and intra-operative DRs were 0.94 (95 % CI: 0.88 to 1.01) and 0.99 (0.98 to 1.00) for breast cancer, 0.98 (0.96 to 0.99) and 1.00 (0.99 to 1.00) for melanoma, and 0.97 (0.93 to 1.02) and 0.99 (0.96 to 1.01) for head and neck carcinoma.  Finally, the pooled sensitivity for nodal metastasis in melanoma was 0.97 (95 % CI: 0.92 to 1.03).  The authors concluded that 99mTc-tilmanocept is a promising radiotracer for SN mapping in patients with breast cancer, melanoma, or head and neck cancer.  These researchers believed that multi-center studies are still needed to examine if 99mTc-tilmanocept is superior to other radiotracers used in clinical routine.

Ooms et al (2023) noted that SLNB is a staging procedure in the management of cutaneous malignancies of the head.  The ideal radiopharmaceutical is controversial.  In a retrospective, exploratory study, these investigators compared [99mTc]Tc-tilmanocept (TcTM) with [99mTc]Tc-sulphur colloid (TcSC) and [99mTc]Tc-albumin colloid (TcAC) for SLN detection in the head and neck region.  Data from 62 patients with cutaneous malignancies of the head who were injected with TcTM, TcSC, or TcAC before SLN imaging (SLN-I) and SLN excision (SLN-E) between 2012 and 2021 were analyzed.  SLN-I was carried out using planar lymphoscintigraphy and SPECT/CT, and a gamma probe was used for SLN-E.  The SLN-I localization rate (patients with SLNs) and degree (SLN number) and SLN-E re-localization rate (patients with SLNs) and ratio (SLN number in SLN-E/SLN number in SLN-I) were compared between TcTM, TcSC, and TcAC.  TcTM showed similar SLN-I localization rates for primaries in the anterior and posterior head region compared with TcSC (84.6 % versus 72.4 %, p = 0.680; both 100.0 %) and TcAC (84.6 % versus 75.0 %, p = 1.000; both 100.0 %).  The SLN-I localization degree for TcTM was higher for primaries in the anterior head region and similar for primaries in the posterior head region compared with TcSC (3.2 versus 2.3, p = 0.034; and 1.8 versus 2.2, p = 0.506) and TcAC (3.2 versus 2.0, p = 0.038; and 1.8 versus 2.7, p = 0.329).  The SLN-E re-localization rates and ratios were similar for all.  The authors concluded that based on the findings of this retrospective study, the use of TcTM should only be recommended for SLN detection in the head and neck region in patients with cutaneous malignancies in the anterior head region.  Moreover, these researchers stated that further studies are needed to confirm whether a higher SLN-I localization degree is associated with only a moderate increase in post-operative morbidity (thus preserving the benefits of SLN biopsy), whether a higher SLN-I localization degree is associated with a lower false-negative rate of SLNB in patients with cutaneous malignancies in the anterior head region, and whether these findings can be confirmed in a larger study population.

The authors stated that the drawbacks of this study included its retrospective design and the heterogeneity of the study population (e.g., in terms of the time interval between radiopharmaceutical injection and imaging and the small number of patients).  However, SLN localization rates and degrees should not have been affected by such heterogeneity, because additional images were obtained in cases in which SLN localization failed on early imaging; additionally, the exclusive focus of this study on cutaneous malignancies of the head may explain the small number of patients.  In addition, differences in experience between nuclear physicians in SLN-I and surgeons in SLN-E cannot be excluded; however, valid procedural standards likely mitigated the effects of such differences.  Furthermore, the 2 different imaging systems used during the study period were not applied equally in all patient groups; therefore, an influence of the imaging system on the results could not be excluded.  In general, it should be noted that comparing 3 different radiopharmaceuticals by comparing t3 groups of patients, each injected with 1 radiopharmaceutical, limited the generalizability and the level of evidence obtained from this study.  However, a study design in which all 3 radiopharmaceuticals are used consecutively in the same patient is not suitable due to the non-repeatability of the surgical procedure.

Coxon et al (2023) stated that many researchers have reported lymphatic and glymphatic structures in animal and human brains; however, tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described.  In a pilot study, these investigators enrolled patients undergoing SOC resection or stereotactic biopsy for the management of suspected intra-cranial tumors.  Patients received peri-tumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging.  A total of 14 patients with suspected brain tumors were included in this trial; and 1 was excluded from analysis because of tracer leakage during injection.  There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients.  On average, after correcting for radioactive decay, 70.7 % (95 % CI: 59.9 % to 81.6 %) of the tracer in the injection site, and 78.1 % (95 % CI: 71.1 % to 85.1 %) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the sub-arachnoid space.  The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites.  The authors concluded that in this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes.  The findings of this study showed an inefficiency of drainage from peri-tumoral brain parenchyma and highlighted a therapeutic opportunity to improve immune-surveillance of the brain.  Moreover, these researchers stated that the dynamics of how antigens and molecules may move from the brain parenchyma remains unclear in humans; therefore, this pilot study represented one approach to begin exploring these questions.  They stated that further investigation is needed to understand the basis of molecular transit in the brain and its implications for CNS immunity.

Sentinel Lymph Node Mapping in Ovarian Tumors

Nakhaei et al (2022) noted that since the presence of lymph node metastases upstages the disease and to reduce the morbidity of total lymphadenectomy, SLN mapping in ovarian mass has been the focus of extensive research.  In a systematic review and meta-analysis, these investigators examined the available evidence associated with ovarian SLN mapping and evaluated the feasibility of ovarian SLN mapping.  They searched PubMed and Scopus using the following keywords: (Sentinel lymph node) AND (Ovary OR Ovarian) AND (Tumor OR Neoplasm OR Cancer).  All studies with information regarding sentinel node biopsy in ovaries were included.  Different information including mapping material, injection sites, etc., was extracted from each study.  A total of 2 indices were calculated for included studies: detection rate and false-negative rate.  Meta-analysis was performed using Meta-MUMS software.  Pooled detection rate, sensitivity, heterogeneity, and publication bias were evaluated.  Quality of the studies was evaluated using the Oxford center for evidence-based medicine checklist.  Overall, the systematic review included 14 studies.  Ovarian SLN detection rate could vary depending on the type of tracer, site of injection, etc., which signified an overall pooled detection rate of 86 % (95 % CI: 75 to 93).  The forest plot of detection rate pooling was provided (Cochrane Q-value = 31.57, p = 0.003; I2 = 58.8 %).  Trim and fill method resulted in trimming of 7 studies, which decreased the pooled detection rate to 79.1 % (95 % CI: 67.1 to 87.5).  Overall, pooled sensitivity was 91 % (59 to 100) (Cochrane Q-value = 3.93; p = 0.41; I2 = 0 %).  The proportion of lymph node positive patients was 0 % to 25 % in these studies with overall 14.28 %.  The authors concluded that SLN mapping in ovarian tumors was feasible and appeared to have high sensitivity for detection of lymph node involvement in ovarian malignant tumors.  Mapping material, injection site, and previous ovarian surgery were associated with successful mapping.  Moreover, these researchers stated that larger studies are needed to better examine the sensitivity of this procedure in ovarian malignancies.  Lymphoscintigraphy was one of the key words associated with this study.

The authors stated that the main drawback of this study was that definitive diagnosis of benign or malignant ovarian mass before resection was not determined, which is a major limitation in the ovarian SLN mapping.  Thus, patients with malignant ovarian mass who were included in these studies were not enough for lymph node dissection and histopathological examination regarding false-negative rate and sensitivity assessment.

Technetium-99m-Sestamibi Single-photon Emission Computed Tomography/Computed Tomography for the Evaluation of Indeterminate Renal Masses

Basile et al (2024) stated that the diagnostic accuracy of current imaging techniques in differentiating benign from malignant neoplasms in the case of indeterminate renal masses is still sub-optimal.  In a systematic review and meta-analysis, these investigators examined the diagnostic accuracy of 99mTc-sestamibi (SestaMIBI) single-photon emission tomography computed tomography (SPECT)/CT in characterizing indeterminate renal masses by differentiating renal oncocytoma and hybrid oncocytic/chromophobe tumor (HOCT) from all other renal lesions; and from all malignant renal lesions.  Secondary outcomes were benign versus malignant; renal oncocytoma and HOCT versus clear cell (ccRCC) and papillary (pRCC) renal cell carcinoma; and renal oncocytoma and HOCT versus chromophobe renal cell carcinoma (chRCC).  They carried out a literature search up to November 2022 using the PubMed/Medline, Embase, and Web of Science databases; and PRISMA guidelines were followed to identify eligible studies.  Studies included were prospective and retrospective cross-sectional studies in which SestaMIBI SPECT/CT findings were compared to histology after renal mass biopsy or surgery.  A total of 8 studies entailing 489 patients with 501 renal masses met the inclusion criteria.  The sensitivity and specificity of SestaMIBI SPECT/CT for renal oncocytoma and HOCT versus all other renal lesions were 89 % (95 % CI: 70 % to 97 %) and 89 % (95 % CI: 86 % to 92 %), respectively.  Notably, for renal oncocytoma and HOCT versus ccRCC and pRCC, SestaMIBI SPECT/CT showed specificity of 98 % (95 % CI: 91 % to 100%) and similar sensitivity.  Owing to the relatively high risk of bias and the presence of heterogeneity among the studies included, the level of evidence was still low.  The authors concluded that sestaMIBI SPECT/CT exhibited good sensitivity and specificity in differentiating renal oncocytoma and HOCT from all other renal lesions, and in particular from those with more aggressive oncological behavior.  Moreover, these researchers stated that although these findings are promising, further studies are needed to support the use of SestaMIBI SPECT/CT outside research trials.

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References