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Tumor Scintigraphy Page 1 of 51
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Aetna Better Health® 2000 Market Street, Suite 850 Philadelphia, PA 19103
AETNA BETTER HEALTH®
Clinical Policy Bulletin: Tumor Scintigraphy
Revised February 2015
Number: 0168
(Replaces CPBs 239, 309, 320)
Policy
ProstaScint
Aetna considers ProstaScint scans medically necessary for either of the following
indications:
1. Pre-operative staging of newly diagnosed persons 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 persons or persons treated with radiation therapy in
whom there is a high suspicion of undetected residual prostate cancer or cancer
recurrence.
Aetna considers ProstaScint scans experimental and investigational for all other
indications because its effectiveness for indications other than the ones lsited above has
not been established.
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 persons 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 persons 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
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3. Detection of occult recurrent ovarian cancer in persons with suspected recurrence
suggested by rising tumor markers, when no other imaging or physical examination
technique can locate the suspected disease.
Aetna considers Oncoscint immunoscintigraphy experimental and investigational for all
other indications such as any of the following because it has not been established to have
a clearly defined role 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 persons with these conditions; or
3. In other colorectal cancer persons not meeting criteria #1 or #2 above (for instance,
post-operative colorectal cancer persons with rising serum CEA levels and
negative standard imaging and other studies.
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. Aetna considers the CEA-scan experimental
and investigational for all other indications because its effectiveness for indications other
than the ones listed above has not been established.
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 evaluation of metastatic thyroid cancer; or
3. 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)
Aetna considers technetium-99m-sestamibi scintigraphy experimental and investigational
for all other indications such as the following because its role for these indications has not
been established:
1. For detection of malignant axillary adenopathy secondary to breast cancer; or
2. For evaluation of central nervous system (CNS) neoplasms; or
3. For imaging of breast cancer (known as Miraluma scan).
OctreoScan
Aetna considers an OctreoScan, using octreotide (Sandostatin) tagged with radiolabeled
111Indium-pentetreotide, medically necessary for the diagnosis and staging of persons
with primary and metastatic neuroendocrine tumors bearing somatostatin receptors. Such
tumors include any of the following:
Carcinoid tumors/carcinoid syndrome
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Gastrinomas
Glucagonomas
Insulinomas
Islet cell tumors of the pancreas
Medullary thyroid carcinoma (MTC)
Neuroendocrine carcinoma of the rectum
Paragangliomas
Pheochromocytomas
Pituitary adenomas
Tumor-induced osteomalacia (oncogenic osteomalacia) (for diagnosis only)
VIPoma (vasoactive intestinal peptide) -- persons present with Verner-Morrison
syndrome: watery diarrhea, hypokalemia and achlorhydria
Aetna considers 111
In-pentetreotide (OctreoScan) experimental and investigational for all
other indications such as any of the following because the sensitivity and specificity of this
test for the following indications has been demonstrated to be inadequate:
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
Radiolabeled Octreotide for Therapeutic Use
Aetna considers radiolabeled octreotide medically necessary for the treatment of
gastroenteropancreatic neuroendocrine tumors. The gamma emitting imaging
radionuclide (111
In-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.
Aetna considers radiolabeled octreotide experimental and investigational for the treatment
of incompletely resected meningioma because its effectiveness for this indication has not
been established.
Lymphoscintigraphy and Sentinel Lymph Node Biopsy
Aetna considers lymphoscintigraphy and sentinel lymph node biopsy (SLNB) medically
necessary for persons with malignant melanoma. In addition, Aetna considers radioactive
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colloid and/or blue dye identification of the sentinel node in the axilla followed by SLNB
medically necessary for persons with breast cancer. Lymphoscintigraphy and SLNB is
considered experimental and investigational for all other indications (e.g., as a screening
test in persons with a BRCA mutation, with or without prophylactic mastectomy) because
its effectiveness for indications other than the ones listed above has not been established.
Meta-Iodobenzylguanidine (MIBG) Imaging
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:
Adrenal medulla hyperplasia
Carcinoid tumors
Neuroblastoma
Paraganglioma
Pheochromocytoma
Thyroid carcinoma.
Aetna considers I-123 labeled MIBG imaging experimental and investigational in the
management of all conditions, such as any of the following, because its value for these
indications has not been established:
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
Tracking response to medications for members with CHF
Aetna considers I-131 labeled MIBG radiotherapy experimental and investigational as
a treatment for neuroblastoma, pheochromocytoma and all other indications because its
effectiveness for these indications has not been established.
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. Aetna considers iobenguane I-123 injection
experimental and investigational for all other indications because its effectiveness for
indications other than the ones listed above has not been established.
Scintimammography and Breast Specific Gamma Imaging (BSGI)
Aetna considers scintimammography, including breast-specific gamma imaging (BSGI;
also known as molecular breast imaging), experimental and investigational as an adjunct
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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
because its effectiveness has not been established.
Technetium-Tc 99m Tilmanocept (Lymphoseek)
Aetna considers technetium Tc 99m tilmanocept (Lymphoseek) injection medically
necessary for location of lymph nodes in persons with breast cancer or melanoma who
are undergoing surgery to remove tumor-draining lymph nodes.
Aetna considers technetium Tc 99m tilmanocept injection experimental and
investigational for all other indications (e.g., oral cavity squamous cell carcinoma)
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 (CT, 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] greaetr 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.
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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.
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All articles regarding Tc-MIBI in the evaluation of breast masses suffer from 2 major
drawbacks: (i) 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 (ii) 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
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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
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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 asociates (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
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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 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
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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”.
Hruska and colleagues (2014) compared diagnostic performance of MBI performed with
standard 10-min-per-view acquisitions and half-time 5-min-per-view acquisitions, with and
without wide beam reconstruction (WBR) processing. A total of 82 bilateral, 2-view MBI
studies were reviewed. Studies were performed with 300 MBq Tc-99 m sestamibi and a
direct conversion MBI (DC-MBI) system. Acquisitions were 10 min-per-view; the first half
of each was extracted to create 5-min-per-view datasets, and WBR processing was
applied. The 10-min-, 5-min-, and 5-min-per-view WBR studies were independently
interpreted in a randomized, blinded fashion by 2 radiologists. Assessments of 1 to 5
were assigned; 4 and 5 were considered test positive. Background parenchymal uptake,
lesion type, distribution of non-mass lesions, lesion intensity, and image quality were
described. Considering detection of all malignant and benign lesions, 5 min-per-view MBI
had lower sensitivity (mean of 70 % versus 85 % (p ≤ 0.04) for 2 readers) and lower area
under curve (AUC) (mean of 92.7 versus 99.6, p ≤ 0.01) but had similar specificity (p =
1.0). WBR processing did not alter sensitivity, specificity, or AUC obtained at 5 min-per-
view. Overall agreement in final assessment between 5-min-per-view and 10-min-per-
view acquisition types was near perfect (κ = 0.82 to 0.89); however, fair-to-moderate
agreement was observed for assessment category 3 (probably benign) (κ = 0.24 to 0.48).
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Of 33 malignant lesions, 6 (18 %) were changed from assessment of 4 or 5 with 10-min-
per-view MBI to assessment of 3 with 5-min-per-view MBI. Image quality of 5-min-per-
view studies was reduced compared to 10-min-per-view studies for both readers (3.24
versus 3.98, p < 0.0001 and 3.60 versus 3.91, p < 0.0001). WBR processing improved
image quality for 1 reader (3.85 versus 3.24, p < 0.0001). The authors concluded that
although similar radiologic interpretations were obtained with 10-min- and 5-min-per-view
DC-MBI, resulting in substantial agreement in final assessment, notable exceptions were
found: (i) perceived image quality at 5 min-per-view was lower than that for 10-min-per-
view studies and (ii) 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
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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
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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.”
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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
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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.
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.
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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.
Tamaki et al (2009) compared the predictive value of cardiac I-123 MIBG imaging for
sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG),
heart rate variability (HRV), and QT dispersion in patients with chronic heart failure
(CHF). Cardiac MIBG imaging, SAECG, 24-hr Holter monitoring, and standard 12-lead
electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients
with a radionuclide left ventricular ejection fraction (LVEF) less than 40 %. The cardiac
MIBG washout rate (WR) was obtained from MIBG imaging. Furthermore, the time and
frequency domain HRV parameters were calculated from 24-hr Holter recordings, and QT
dispersion was measured from the 12-lead ECG. During a follow-up period of 65 ± 31
months, 18 of 106 patients died suddenly. A multi-variate Cox analysis revealed that WR
and LVEF were significantly and independently associated with SCD, whereas the
SAECG, HRV parameters, or QT dispersion were not. Patients with an abnormal WR
(greater than 27 %) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95
% confidence interval: 1.55 to 14.76). Even when confined to the patients with LVEF
greater than 35 %, SCD was significantly more frequently observed in the patients with
than without an abnormal WR (p = 0.02). The authors concluded that cardiac MIBG WR,
but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with
mild-to-moderate CHF, independently of LVEF. This study has several drawbacks: (i)
small and empirically chosen study population sample size and empirically chosen follow-
up period length, (ii) single-center study, (iii) patients NYHA functional class IV were not
included in the study, and (iv) 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
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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
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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
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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
ultrasonography (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,
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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
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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
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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.
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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
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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)
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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.
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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.
CPT Codes / HCPCS Codes / ICD-9 Codes
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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
ProstaScint:
HCPCS codes covered if selection criteria are met:
A9507 Indium In-111 capromab pendetide, diagnostic, per study dose, up to
10 millicuries
ICD-9 codes covered if selection criteria are met:
185 Malignant neoplasm of prostate
V10.46 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-9 codes covered if selection criteria are met:
153.0 - 153.9 Malignant neoplasm of colon
154.0 - 154.8 Malignant neoplasm of rectum, rectosigmoid junction, and anus
183.0 Malignant neoplasm of ovary
V10.05 Personal history of malignant neoplasm of large intestine
V10.06 Personal history of malignant neoplasm of rectum, rectosigmoid
junction, and anus
V10.43 Personal history of malignant neoplasm of ovary
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
172.0 - 172.9 Malignant melanoma of skin
174.0 - 175.9 Malignant neoplasm of breast
185 Malignant neoplasm of prostate
200.00 - 202.88 Lymphosarcoma and reticulosarcoma
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340 Multiple sclerosis
429.2 Cardiovascular disease, unspecified
453.0 - 453.9 Other venous embolism and thrombosis
490 - 496 Chronic obstructive pulmonary disease and allied conditions
555.0 - 556.9 Regional enteritis and ulcerative colitis
714.0 - 714.9 Rheumatoid arthritis and other inflammatory polyarthropathies
V76.0 - V76.9 Special screening for malignant neoplasms
Other ICD-9 codes related to the CPB:
795.79 Other and unspecified nonspecific immunological findings
CEA-Scan:
HCPCS codes covered if selection criteria are met:
A9568 Technetium Tc-99m arcitumomab, diagnostic, per study dose, up to
45 millicuries
ICD-9 codes covered if selection criteria are met:
153.0 - 153.9 Malignant neoplasm of colon
154.0 - 154.8 Malignant neoplasm of rectum, rectosigmoid junction, and anus
V10.05 Personal history of malignant neoplasm of large intestine
V10.06 Personal history of 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-9 codes covered if selection criteria are met:
170.0 - 170.9 Malignant neoplasm of bone and articular cartilage
171.0 - 171.9 Malignant neoplasm of connective and other soft tissue
193 Malignant neoplasm of thyroid gland
226 Benign neoplasm of thyroid glands
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227.1 Benign neoplasm of other endocrine glands and related structures,
parathyroid gland
V10.87 Personal history of malignant neoplasm of thyroid
ICD-9 codes not covered for indications listed in the CPB:
174.0 - 175.9 Malignant neoplasm of breast
191.0 - 192.9 Malignant neoplasm of brain and other and unspecified parts of
nervous system
196.3 Secondary and unspecified malignant neoplasm of lymph nodes of
axilla and upper limb
198.3 Secondary malignant neoplasm of brain and spinal cord
198.4 Secondary malignant neoplasm of other parts of nervous system
198.81 Secondary malignant neoplasm of breast
225.0 - 225.9 Benign neoplasm of brain and other parts of nervous system
233.0 Carcinoma in-situ of breast
237.0 - 237.6 Neoplasm of uncertain behavior of endocrine glands and nervous
system
OctreoScan:
HCPCS codes covered if selection criteria are met:
A9572 Indium In-111 pentetrotide, diagnostic, per study dose, up to 6
millicuries
ICD-9 codes covered if selection criteria are met:
157.0 - 157.9 Malignant neoplasm of pancreas [VIPoma, Islet cell tumors]
192.1 Malignant neoplasm of cerebral meninges [meningioma]
193 Malignant neoplasm of thyroid gland
194.0 Malignant neoplasm of adrenal gland [paragangliomas,
pheochromocytomas]
194.3 Malignant neoplasm of pituitary gland and craniopharyngeal duct
194.6 Malignant neoplasm of aortic body and other paraganglia
201.00 - 201.98 Hodgkin's disease
209.00 - 209.16 Malignant carcinoid tumor of small intestine
209.20 - 209.29 Malignant carcinoid tumor of other and unspecified sites
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209.30 Malignant poorly differentiated neuroendocrine tumors
209.40 - 209.69 Benign carcinoid tumor
211.1 Benign neoplasm of stomach
211.6 Benign neoplasm of pancreas, except islets of Langerhans
211.7 Benign neoplasm of Islets of Langerhans [gastrinomas,
glucagonomas, Islet cell tumors]
225.2 Benign neoplasm of cerebral meninges [meningioma]
225.4 Benign neoplasm of spinal meninges
227.0 Benign neoplasm of adrenal gland [paragangliomas,
pheochromocytomas]
227.3 Benign neoplasm of pituitary gland and craniopharyngeal duct
(pouch)
227.6 Benign neoplasm of aortic body and other paraganglia
235.2 Neoplasm of uncertain behavior of stomach, intestines, and rectum
235.5 Neoplasm of uncertain behavior of other and unspecified digestive
organs
235.7 Neoplasm of uncertain behavior of trachea, bronchus, and lung
237.0 Neoplasm of uncertain behavior of pituitary gland and
craniopharyngeal duct
237.2 Neoplasm of uncertain behavior of adrenal gland
237.3 Neoplasm of uncertain behavior of paraganglia
237.4 Neoplasm of uncertain behavior of other and unspecified endocrine
glands
237.6 Neoplasm of uncertain behavior of meninges
259.2 Carcinoid syndrome
275.8 Disorders of calcium metabolism, other specified disorders of mineral
metabolism [tumor-induced osteomalacia TIO (oncogenic
osteomalacia)]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
135 Sarcoidosis
160.0 Malignant neoplasm of nasal cavities [neuroblastoma]
162.2 - 162.9 Malignant neoplasm of bronchus and lung [small-cell lung cancer]
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164.0 Malignant neoplasm of thymus [thymoma]
164.2 - 164.9 Malignant neoplasm of mediastinum [neuroblastoma]
173.0 - 173.9 Malignant neoplasm of skin [Merkel cell tumors]
190.0 - 190.9 Malignant neoplasm of eye [ocular melanoma]
191.0 - 191.9 Malignant neoplasm of brain [astrocytoma]
192.0 Malignant neoplasm of cranial nerves [neuroblastoma, olfactory]
194.0 Malignant neoplasm of adrenal gland [neuroblastoma]
194.6 Malignant neoplasm of aortic body and other paraganglia
[chemodectomas]
197.0 Secondary malignant neoplasm of lung
197.1 Secondary malignant neoplasm of mediastinum
197.3 Secondary malignant neoplasm of other respiratory organs
197.8 Secondary malignant neoplasm of other digestive organs and spleen
198.2 Secondary malignant neoplasm of skin
198.3 Secondary malignant neoplasm of brain and spinal cord
198.4 Secondary malignant neoplasm of other parts of nervous system
198.7 Secondary malignant neoplasm of adrenal gland
200.00 -
200.88, 202.00
- 208.92
Malignant neoplasm of lymphatic and hematopoietic tissue [except
Hodgkin's]
209.17 Malignant carcinoid tumor of the rectum [neuroendocrine carcinoma
of the rectum]
211.7 Benign neoplasm of Islets of Langerhans [insulinomas]
212.6 Benign neoplasm of thymus [thymoma]
227.6 Benign neoplasm of aortic body and other paraganglia
[chemodectomas]
Radiolabeled Ocreotide:
There is no specific code for radiolabeled octreotide:
ICD-9 codes covered if selection criteria are met :
209.00 - 209.30 Malignant carcinoid tumor
209.40 - 209.69 Benign carcinoid tumor
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ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
192.1 Malignant neoplasm of cerebral meninges [meningioma]
225.2 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
ICD-9 codes covered if selection criteria are met:
172.0 - 172.9 Malignant melanoma of skin
174.0 - 175.9 Malignant neoplasm of breast
198.81 Secondary malignant neoplasm of breast
233.0 Carcinoma in-situ of breast
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
V84.01 Genetic susceptibility to malignant neoplasm of breast [BRCA1 or
BRCA2 mutations confirmed by molecular susceptibility testing for
breast cancer]
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
ICD-9 codes covered if selection criteria are met:
192.0 Malignant neoplasm of cranial nerves [neuroblastoma]
193 Malignant neoplasm of thyroid gland
194.0 Malignant neoplasm of adrenal gland [localizing or confirming
neuroblastoma or pheochromocytoma] [paraganglioma]
194.5 Malignant neoplasm of carotid body [paragangliomas]
194.6 Malignant neoplasm of aortic body and other paraganglia
[paragangliomas]
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209.00 - 209.30 Malignant carcinoid tumor
209.40 - 209.69 Benign carcinoid tumor
227.0 Benign neoplasm of adrenal gland [pheochromocytomas]
[paraganglioma]
227.5 Benign neoplasm of carotid body [paragangliomas]
227.6 Benign neoplasm of aortic body and other paraganglia
[paragangliomas]
235.2 Neoplasm of uncertain behavior of stomach, intestines, and rectum
235.5 Neoplasm of uncertain behavior of other and unspecified digestive
organs
237.2 Neoplasm of uncertain behavior of adrenal gland
237.3 Neoplasm of uncertain behavior of paraganglia
237.4 Neoplasm of uncertain behavior of other and unspecified endocrine
glands
255.8 Other specified disorders of adrenal glands [adrenal medulla
hyperplasia]
259.2 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-9 codes not covered for indications listed in the CPB (not all-inclusive):
194.0 Malignant neoplasm of adrenal gland [neuroblastoma,
pheochtomocytoma]
227.0 Benign neoplasm of adrenal gland [pheochromocytoma]
I-123 Injection for Imaging:
HCPCS codes covered if selection criteria are met:
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A9582 Iodine I-123 iobenguane, diagnostic, per study dose, up to 15
millicuries
ICD-9 codes covered if selection criteria are met (not all-inclusive):
194.0 Malignant neoplasm of adrenal gland [for the detection of primary or
metastatic pheochromocytoma or neuroblastoma as an adjunct to
other diagnostic tests]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
249.00 - 249.91 Secondary diabetes mellitus
250.00 - 250.93 Diabetes mellitus
332.0 - 332.1 Parkinson's disease
333.0 Other degenerative diseases of the basal ganglia [progressive
supranuclear palsy]
357.2 Polyneuropathy in diabetes
362.01 - 362.07 Anterior and posterior subcapsular polar cataract
366.41 Diabetic cataract
401.0 - 405.99 Hypertensive disease
410.00 - 414.9 Ischemic heart disease
425.4 Other primary cardiomyopathies
427.0 - 427.9 Cardiac dysrhythmias
428.0 Congestive heart failure
V42.1 Heart replaced by transplant
V58.69 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)
HCPCS codes not covered for indications listed in the CPB:
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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-9 codes not covered for indications listed in the CPB (not all-inclusive):
174.0 - 175.9 Malignant neoplasm of the breast
195.1 Malignant neoplasm of thorax [axilla]
198.81 Secondary malignant neoplasm of the breast
198.89 Secondary malignant neoplasm of other specific sites [axillary
metastases]
233.0 Carcinoma in situ of breast
234.8 Carcinoma in situ of other specified sites [axilla]
V76.10 -
V76.19
Special screening examination 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-9 codes covered if selection criteria are met:
172.0 - 172.9 Malignant melanoma of skin
174.0 - 174.9 Malignant neoplasm of female breast
175.0 - 175.9 Malignant neoplasm of male breast
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
141.0 - 145.9 Malignant neoplasm of oral cavity
The above policy is based on the following references:
ProstaScint
1. Howell T, Hailey D. Use of In-111 Capromab Pendetide in detecting metastatic
prostate cancer. HTB-5. Edmonton, AB: Alberta Heritage Foundation for Medical
Research (AHFMR); 1999.
2. Texter JH Jr, Neal CE. The role of monoclonal antibody in the management of
prostate adenocarcinoma. J Urol. 1998;160(6 Pt 2):2393-2395.
3. Sodee DB, Ellis RJ, Samuels MA, et al. Prostate cancer and prostate bed SPECT
imaging with ProstaScint: Semiquantitative correlation with prostatic biopsy results.
Prostate. 1998;37(3):140-148.
Tumor Scintigraphy Page 37 of 51
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4.
5.
6.
7.
8.
9.
10.
11.
12.
Petronis JD, Regan F, Lin K. Indium-111 capromab pendetide (ProstaScint)
imaging to detect recurrent and metastatic prostate cancer. Clin Nucl Med. 1998;23
(10):672-677.
Kahn D, Williams RD, Manyak MJ, et al. 111Indium-capromab pendetide in the
evaluation of patients with residual or recurrent prostate cancer after radical
prostatectomy. The ProstaScint Study Group. J Urol. 1998;159(6):2041-2047.
Murphy GP, Maguire RT, Rogers B, et al. Comparison of serum PSMA, PSA levels
with results of Cytogen-356 ProstaScint scanning in prostatic cancer patients.
Prostate. 1997;33(4):281-285.
Sodee DB, Conant R, Chalfant M, et al. Preliminary imaging results using In-111
labeled CYT-356 (Prostascint) in the detection of recurrent prostate cancer. Clin
Nucl Med. 1996;21(10):759-767.
Haseman MK, Reed NL, Rosenthal SA. Monoclonal antibody imaging of occult
prostate cancer in patients with elevated prostate-specific antigen. Positron
emission tomography and biopsy correlation. Clin Nucl Med. 1996;21(9):704-713.
Neal CE, Meis LC. Correlative imaging with monoclonal antibodies in colorectal,
ovarian, and prostate cancer. Semin Nucl Med. 1994;24(4):272-285.
Howell T, Hailey D. Use of In-111 capromab pendetide in detecting metastatic
prostate cancer. HTB-5. Edmonton, AB: Alberta Heritage Foundation for Medical
Research (AHFMR); 1999.
Rosenthal SA, Haseman MK, Polascik TJ. Utility of capromab pendetide
(ProstaScint) imaging in the management of prostate cancer. Tech Urol. 2001;7
(1):27-37.
Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide
immunoscintigraphy in the detection of early, recurrent prostate carcinoma after
radical prostatectomy. Cancer. 2002;94(4):987-996.
OncoScint
1. Pinkas L, Robins PD, Forstrom LA, et al. Clinical experience with radiolabelled
monoclonal antibodies in the detection of colorectal and ovarian carcinoma
recurrence and review of the literature. Nucl Med Commun. 1999;20(8):689-696.
2. Goldenberg DM. Perspectives on oncologic imaging with radiolabeled antibodies.
Cancer. 1997;80(12 Suppl):2431-2435.
3. Raderer M, Becherer A, Kurtaran A, et al. Comparison of iodine-123-vasoactive
intestinal peptide receptor scintigraphy and indium-111-CYT-103
immunoscintigraphy. J Nucl Med. 1996;37(9):1480-1487.
4. Neal CE, Johnson DL, Cornwell VL, et al. Quantitative analysis of In-111
satumomab pendetide immunoscintigraphy. An aid to visual interpretation of
images in patients with suspected carcinomatosis. Clin Nucl Med. 1996;21(8):638-
642.
5. Divgi CR. Status of radiolabeled monoclonal antibodies for diagnosis and therapy
of cancer. Oncology (Huntingt). 1996;10(6):939-954, 957-958.
6. Sharkey RM, Juweid M, Shevitz J, et al. Evaluation of a complementarity-
determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal
antibody in preclinical and clinical studies. Cancer Res. 1995;55(23 Suppl):5935s-
5945s.
7. Bohdiewicz PJ, Scott GC, Juni JE, et al. Indium-111 OncoScint CR/OV and F-18
FDG in colorectal and ovarian carcinoma recurrences. Early observations. Clin
Nucl Med. 1995;20(3):230-236.
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8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Volpe CM, Abdel-Nabi HH, Kulaylat MN, et al. Results of immunoscintigraphy using
a cocktail of radiolabeled monoclonal antibodies in the detection of colorectal
cancer. Ann Surg Oncol. 1998;5(6):489-494.
Larson SM. Improving the balance between treatment and diagnosis: A role for
radioimmunodetection. Cancer Res. 1995;55(23 Suppl):5756s-5758s.
Harrison KA, Tempero MA. Diagnostic use of radiolabeled antibodies for cancer.
Oncology (Huntingt). 1995;9(7):625-631, 634, 636, 641.
Edlin JP, Kahn D. Detection of recurrent colorectal carcinoma with In-111 CYT-103
scintigraphy in a patient with nondiagnostic MRI and CT. Clin Nucl Med. 1994;19
(11):1004-1007.
Kim SL, Goldschmid S. Monoclonal antibody imaging in colon cancer: A transition
from basic science to clinical application. Am J Gastroenterol. 1994;89(10):1910-
1912.
Corman ML, Galandiuk S, Block GE, et al. Immunoscintigraphy with 111In-
satumomab pendetide in patients with colorectal adenocarcinoma: Performance
and impact on clinical management. Dis Colon Rectum. 1994;37(2):129-137.
Markowitz A, Saleemi K, Freeman LM. Role of In-111 labeled CYT-103 immuno-
scintigraphy in the evaluation of patients with recurrent colorectal carcinoma. Clin
Nucl Med. 1993;18(8):685-700.
No authors listed. Oncoscint for detection of disseminated colorectal and ovarian
cancer. Med Lett Drugs Ther. 1993;35(898):52-53.
Galandiuk S. Immunoscintigraphy in the surgical management of colorectal cancer.
J Nucl Med. 1993;34:541-544.
Caretta RF. The role of immunoscintigraphy in cancer diagnosis. New Perspect
Cancer Diagn Manage. 1993;1:24-26.
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of (99m)Tc-tilmanocept injection. Onco Targets Ther. 2014;7:1151-1158. Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
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