Coverage Policy Manual
Policy #: 2011002
Category: Radiology
Initiated: January 2011
Last Review: July 2018
  Positron Emission Mammography (PEM)

Description:
Positron emission mammography (PEM) is a form of positron emission tomography (PET) that uses a high-resolution, mini-camera detection technology for imaging the breast. As with PET, PEM provides functional rather than anatomic information about the breast. PEM has been studied primarily for use in presurgical planning and staging; it also has been used to monitor therapy response and breast cancer recurrence.
  
Positron emission mammography (PEM) is a form of positron emission tomography (PET) that uses a high-resolution, mini-camera detection technology for imaging the breast. As with PET, a radiotracer, usually 18F-fluorodeoxyglucose (FDG), is administered and the camera is used to provide a higher resolution image of a limited section of the body than would be achievable with FDG-PET. Gentle compression is used, and the detector(s) are mounted directly on the compression paddle(s) (Birdwell, 2009; Eo, 2012; Tafreshi, 2010). PEM was developed to overcome the limitations of PET for detecting breast cancer tumors. Patients usually are supine for PET procedures, and the breast tissue may spread above the chest wall, making it potentially difficult to differentiate breast lesions from other organs that take up the radiopharmaceutical. PET’s resolution is generally limited to about 5 mm, which may not detect early breast cancer tumors (Prekeges, 2012). PEM allows for the detection of lesions smaller than 2 cm and creates images that are more easily compared to mammography, since they are acquired in the same position. Three-dimensional reconstruction of the PEM images is also possible. As with PET, PEM provides functional rather than anatomic information on the breast (Birdwell, 2009; Eo, 2012; Tafreshi, 2010). In studies of PEM, exclusion criteria included some patients with diabetes (e.g., references (Berg, 2011; Berg, 2012). PET may be used for other indications for breast cancer patients, namely, detecting loco-regional or distant recurrence or metastasis (except axillary lymph nodes) when suspicion of disease is high and other imaging is inconclusive.
 
In August 2003, the U.S. Food and Drug Administration (FDA) cleared the PEM 2400 PET Scanner (PEM Technologies, Ridgefield, NJ) for marketing through the 510(k) process. FDA determined that this device was substantially equivalent to existing devices for “medical purposes to image and measure the distribution of injected positron emitting radiopharmaceuticals in human beings for the purpose of determining various metabolic and physiologic functions within the human body.” (FDA, 2013)
 
In March 2009, FDA cleared the Naviscan PEM Flex™ Solo II High Resolution PET Scanner (Naviscan, San Diego, CA) for marketing through the 510(k) process for the same indication. The PEM 2400 PET Scanner was the predicate device. The newer device is described by the manufacturer as “a high spatial resolution, small field-of-view PET imaging system specifically developed for close-range, spot, ie, limited field, imaging.”
 
On September 11, 2008, there was a class 2 recall of the Naviscan PET Systems PEM Flex™ Solo II PET Scanner due to “a report from a user indicating that the motorized compression exceeded 25 pounds of compression force during the pre-scan positioning of the patient.” The recall was terminated on March 13, 2009 (FDA, 2008). Software for the PEM Flex™ Solo I and PEM Flex™ Solo II PET scanners was recalled in August 2007; the recall was terminated on May 14, 2008.14 In December 2013, Naviscan was acquired by Compañía Mexicana de Radiología SA (CMR; Queretaro, Mexico),15 which currently markets the PEM Flex™ Solo II PET Scanner in the United States (private communication). FDA Product Code: KPS
  
There are no specific CPT codes for PEM. The most appropriate code would probably be the unlisted diagnostic nuclear medicine code (78999) or the PET imaging limited area code might be used (78811): Positron emission tomography (PET) imaging; limited area (e.g., chest, head/neck).
 

Policy/
Coverage:
The use of positron emission mammography does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the use of positron emission mammography is considered investigational.  Investigational services are contract exclusions in most member benefit certificates of coverage.
 

Rationale:
A literature search using MEDLINE was performed through December 9, 2010 using the term “positron emission mammography.” The most recent, highest quality evidence is summarized in this section. No randomized, controlled trials beginning with use of PEM and following up through clinical outcomes were found, nor were any meta-analyses. One single-arm, prospective study and two comparative, prospective studies are summarized.
 
In an early 4-site clinical study (NCT00484614), 94 women with suspected or proven breast cancer were given a median dose of 13 mCi FDG and imaged with PEM (Birdwell, 2009). Median time from injection to imaging was 99 minutes; imaging took 10 minutes per image, and median slice thickness was 5.2 mm. “Unevaluable” cases were excluded (n not reported). Eight readers had mammography and clinical breast examination (CBE) results, as well as clinical information, but not information on surgical planning or outcomes. At least 2 readers evaluated each case in random order. Median patient age was 57 years with median tumor size of 22 mm on pathology. Seventy-seven percent of the primary lesions were nonpalpable. The performance of PEM in this study is as follows:
    • BIRADS 4b, c or 5 (probably malignant) assigned to 39 of 44 (89%) pathologically confirmed breast cancers. Missed lesions ranged in size from 1 to 10 mm; all were malignant, and 4 of 5 were low grade.
    • Extensive ductal carcinoma in situ (DCIS) predicted in 3 cases and confirmed to be malignant; they were not detected by other imaging modalities used.
    • Among the 44 patients with proven breast cancer, 5 incidental benign lesions were correctly classified and 4 of 5 incidental malignant tumors were detected, 3 of which were not detected with other imaging modalities (not evident whether MRI was performed on these specific patients).
    • Correctly detected multifocality in 64% of the 31 patients evaluated for it, and correctly predicted its absence in 17 patients.
    • Correctly predicted 6 of 8 patients undergoing partial mastectomy who had positive margins and 11 of 11 who had negative margins.
 
The results from this pilot study are reported in detail to illustrate the potential uses of PEM that were being considered.
 
A follow-up article on the same trial (NCT00484614) reported on 77 patients (Berg, 2006). This article also indicated that patients with type I or II diabetes were excluded (apparently because FDG is glucose based so diabetic patients must have well controlled glucose for the test to work). Readers had access to the mammographic and clinical findings, as it was assumed they would in clinical practice. The median dose of FDG was 12 mCi (range: 8.2-21.5 mCi). Of the 77 patients, 33 had suspicious findings on core biopsy prior to PEM, 38 had abnormalities on x-ray mammograms, and 6 had suspicious findings on CBE. Five women had personal histories of breast cancer, one of whom had had reconstructive surgery. The median age was 53 years. Forty-two of 77 cases were malignant and 2 had atypical ductal hyperplasia. The sensitivity and specificity of PEM was 93% and 85%, respectively, for index lesions and 90% and 86%, respectively, for index and incidental lesions. These values were similar or higher if lesions clearly benign on conventional imaging and diabetic patients were excluded. Adding PEM to x-ray mammography and ultrasound (when available) yielded sensitivity and specificity of 98% and 41%, respectively.
 
At a single site, a prospective study comparing PEM and MRI (1.5 T) was conducted to assist in pre-surgical planning (Schilling, 2011). The performance of PEM, MRI, and whole-body positron emission tomography (WBPET) were compared with final surgical histopathology among 208 women with newly diagnosed, biopsy-proven breast cancer. For PEM and WBPET (performed consecutively), the median FDG dose was 432.9 MBq (equivalent to 11.7 mCi). Patients’ 4-6 hour fasting glucose had to be less than 7.8 mmol/L. One of 6 readers evaluated the PEM, x-ray mammography, and MRI images with access to conventional imaging (mammography or ultrasound) results “but without influence of the alternative (PEM or MRI) imaging modality”; WBPET images were interpreted by a nuclear physician. For evaluating PEM images, readers used a proposed PEM lexicon based on MRI BI-RADS. Patients underwent surgery about three weeks after PEM and WBPET imaging. There were 182 malignant index lesions (45.6% clinically palpable), and 67 additional ipsilateral lesions. Of 250 patients approached to participate in this study, 239 enrolled, 31 were disqualified, and 26 were ineligible because they underwent PEM or MRI before study entry; the analysis therefore includes 182 patients. On pathology, 77.5% of patients had invasive disease; 20.9% DCIS; and 1.6% Paget’s disease. For index lesions, both PEM and MRI have a sensitivity of 92.8% (95% confidence interval [CI]: 88%, 96%; p=not significant [NS] between tests), which was greater than the WBPET sensitivity of 67.9% (95% CI: 60%, 70%; p<0.001). The specificity was not reported since only malignant index lesions were analyzed. The sensitivity of PEM and MRI were not affected by breast density, menopausal status, or use of hormone replacement therapy. PEM tended to overestimate the size of the largest lesion, compared to surgical pathology and MRI (120 mm for PEM vs. 95 mm for pathology and MRI); however, the Spearman’s correlation coefficient between size on surgery versus size on either PEM or MRI was the same at 0.61. Twelve lesions were missed on both PEM and MRI; three of them were not in the PEM field of view. For the 67 additional ipsilateral lesions, the sensitivity of PEM and MRI were 85% (95% CI: 70%, 94%) and 98% (95% CI: 89%, 100%; p=0.074) respectively; and the specificity of PEM and MRI, were 74% (95% CI: 54%, 89%) and 48% (95% CI: 29%, 68%; p=0.096), respectively. Although the differences in sensitivity and specificity between PEM and MRI are not statistically significant, the difference in numerical values is quite large (i.e., 85% vs. 98% and 74% vs. 48%), further investigation is needed to determine whether these are two points along the same operating curve (i.e., whether PEM is being read to emphasize specificity compared to MRI). Additional, larger studies are also warranted.
 
The results of a trial comparing PEM and MRI were reported at the 2010 Annual Meeting of the Radiological Society of North American (RSNA) and simultaneously published in the journal Radiology (Berg, 2011). The study was funded in part by Naviscan, which manufacturers the FDA-cleared PEM device, and by the National Institutes of Health. The first author is a consultant to Naviscan; other authors include a former employee and a current employee.
 
The study was conducted at 6 sites among 388 women with newly diagnosed breast cancer detected at core-needle or vacuum-assisted biopsy and who were eligible for breast-conserving surgery. The median age was 58 years. Among 427 women originally enrolled, 18 were ineligible and 66 were excluded. The latter 66 patients were statistically significantly more likely than the women included in the analysis to have larger invasive tumor components, to be less likely to have one ipsilateral malignancy at study entry, and to be more likely to have known axillary node metastases (and more missing data). Among study participants included in the trial, tumor size was limited to 4 cm or less, or to 5 cm for women with large breasts. PEM and MRI were performed in random order without regard to timing in the menstrual cycle. The mean FDG dose used with PEM was 10.9 mCi, and the mean blood glucose level was 91 g/dL. PEM and MRI were read by different investigators; some but not all readers were blinded to results of the other test. PEM results with a BIRADS score of 4a or higher or a score of 3 with a recommendation for biopsy were considered a positive results. Negative cases included those with negative pathology or follow-up of at least 6 months with no suspicious change.
 
Prior to surgery, 404 malignancies were detected in 388 breasts. After surgery, 386 lesion sites in 371 breasts were confirmed. This difference is presumably due to biopsies that removed all malignant tissue. Among the 386 lesion sites confirmed during surgery, there was no statistically significant difference in the sensitivity of PEM (92.5%) and MRI (89.1%) when only tumor sites were included, although the authors state that “PEM tended to better depict cancer when it was present…(p=0.79, nonsignificant difference).” When both tumor and biopsy sites were included, MRI had a higher sensitivity than PEM (98.2% vs. 94.5%, respectively; p=0.004). There were no visible tumor or biopsy site changes in 7 breasts on MRI and in 19 cases on PEM; however, there was residual tumor on surgery in all of these breasts.
 
Twenty-one percent (82) of the 388 women had additional foci of tumor after study entry. The sensitivity in identifying breasts with these lesions was 60% for MRI and 51% for PEM. Of the 82 additional lesions, 21 (26%) were detected only with MRI, 14 (17%) only with PEM (p=0.31), and 7 (8.5%) only with conventional imaging. Adding PEM to MRI increased the sensitivity from 60% to 72% (p < 0.01). Twelve women with additional foci in the breast with the primary tumor were not identified by any of the imaging techniques. Among the women with an index tumor and no additional lesions in the ipsilateral breast, PEM was more specific than MRI (91.2% vs. 86.3%, respectively, p=0.032). There was no statistically significant different between PEM and MRI in accuracy or area under the receiver operating characteristic (ROC) curve. Again, the question arises whether the differences in specificity and sensitivity between the two tests are due to selecting different operating points along the ROC curve.
 
Of the 116 unknown malignant lesions at study entry, 53% were reported as suspicious on MRI versus 41% on PEM (p=0.04). PEM is more sensitive than MRI in detecting DCIS in this study. Adding PEM to DCIS would increase the sensitivity from 39% with MRI alone to 57% combined (p=0.001; another 7 DCIS foci were seen only on conventional imaging). MRI is more sensitive than PEM in detecting invasive cancer, but the two combined would still have a higher sensitivity than MRI alone (73% vs. 64%, p=0.025). MRI is more sensitive than PEM in dense breasts (57% vs. 37%, respectively, p=0.031.
 
Another factor that should be taken into account is the radiation dose associated with PEM. The label recommended dose of FDG for PEM is 370 MBq (10 mCi). An article published online in August 2010 calculated mean glandular doses, and from those, lifetime attributable risk of cancer (LAR) for film mammography, digital mammography, breast-specific gamma imaging (BSGI), and PEM (Hendrick, 2010). The author, who is a consultant to GE Healthcare and a member of the medical advisory boards of Koning (which are working on dedicated breast CT) and Bracco (MR contrast agents), used BEIR VII Group risk estimates to gauge the risks of radiation-induced cancer incidence and mortality from breast imaging studies. The estimated lifetime attributable risk of cancer for a patient with the average-sized compressed breast during mammography of 5.3 cm (it would be higher for larger breasts) for a single breast procedure at age 40 is:
    • 5 per 100,000 for digital mammography (breast cancer only),
    • 7 per 100,000 for screen film mammography (breast cancer only),
    • 55-82 per 100,000 for BSGI (depending on the dose of Technetium Tc 99m Sestamibi), and
    • 75 per 100,000 for PEM.
 
The corresponding lifetime attributable risk of cancer mortality at age 40 is:
    • 1.3 per 100,000 for digital mammography (breast cancer only),
    • 1.7 per 100,000 for screen film mammography (breast cancer only),
    • 26-39 per 100,000 for BSGI, and
    • 31 per 100,000 for PEM.
 
A major difference in the impact of radiation between mammography, on the one hand, and BSGI or PEM, on the other, is that for mammography the substantial radiation dose is limited to the breast. With BSGI and PEM, all organs are irradiated. Furthermore, as one ages, the risk of cancer induction from radiation exposure decreases more rapidly for the breast than for other radiosensitive organs. The organs at highest risk for cancer are the bladder with PEM and the colon with BSGI; these cancers, along with lung cancer, are also less curable than breast cancer. Thus, the distribution of radiation throughout the body adds to the risks associated with BSGI and PEM. Hendrick concludes that “The results reported herein indicate the BSGI and PEM are not good candidate procedures for breast cancer screening because of the associated higher risks for cancer induction per study compared with the risks associated with existing modalities such as mammography, breast US, and breast MR imaging. The benefit-to-risk ratio for BSCI and PEM may be different in women known to have breast cancer, in whom additional information about the extent of disease may better guide treatment.”
 
Since the use of BSGI or molecular breast imaging (MBI) has been proposed for women at high risk of breast cancer, it should be mentioned that there is controversy and speculation over whether some women, such as those with BRCA mutations, have a heightened radiosensitivity. (Berrington, 2009) (Ernestos, 2010) Of course, if women with BRCA mutations are more radiosensitive than the population as a whole, the above estimates may underestimate the risks they face from breast imaging with ionizing radiation (i.e., mammography, BSGI, MBI, PEM, SPECT/CT, breast-specific CT, and tomosynthesis; ultrasound and MRI do not involve the use of radiation). More research will be needed to resolve this issue. Also, the risk associated with radiation exposure will be greater for women at high risk of breast cancer, whether or not they are more radiosensitive, because they start screening at a younger age when the risks associated with radiation exposure are larger.
 
Summary
Three principal studies on PEM were reviewed. The first single arm study (Tafra,2005 (Berg, 2005) provided preliminary data on sensitivity. Given that there are one or more imaging tests for each potential use in breast cancer, any new or newly disseminating technology must be compared to the existing modalities. The two studies (Schilling, 2011) (Berg, 2011) comparing the use of PEM and MRI in presurgical planning are therefore important. However, each has its limitations, e.g., single site, lack of full blinding to results of alternate test, lack of adjustment for multiple comparisons. It is also possible that the apparent differences between PEM and MRI, e.g., possibly higher sensitivity for MRI and potentially higher specificity for PEM, are due in part to selection of different operating points on the ROC curve. Furthermore, ignoring the timing of testing in the newer Berg et al. study (Berg, 2011) might bias the results against MRI. One study reports that PEM provides some new information in the form of higher sensitivity for detecting DCIS. But this finding needs to be confirmed in additional studies. The Berg et al. study (Berg, 2011) includes a number of comparisons on subsets of the population (for example, women with no sign of multicentric or multifocal disease). This could be avoided by comparing MRI and PEM in women prior to biopsy and following them through to treatment, and ideally afterward as well to gauge patient outcomes. Finally, even if the addition of PEM to MRI improves accuracy, this finding must be weighed against the potential risk from radiation exposure associated with PEM and the lack of a full chain of evidence for some of these findings—e.g., that improved accuracy for some uses results in better patient outcomes. Thus, the impact on net health outcome is uncertain.
 
Ongoing Research
A search of “positron emission mammography” clinicaltrials.gov yielded eight trials:
    • one trial using fluorothymidine (FLT) as an alternative radiotracer to FDG was terminated due to poor accrual (NCT00934401);
    • one trial is ongoing but not recruiting patients (NCT00484614) and has two published reports discussed above (Tafra 2005, Berg 2006); and
    • Six ongoing trials. Two have a sample size (n) greater than 100.
        • PEM versus standard mammography for screening women with dense breast tissue or at high risk of breast cancer (NCT00896649), n=260
        • Presurgery PEM for newly diagnosed breast cancer (testing reduced dose of radiotracer; NCT01241721), n=130
        • PEM for evaluating response to neoadjuvant chemotherapy (NCT01012440); n=50
        • Histologic assessment of PEM versus MRI (NCT01249157); n=50
        • Staging of axillary lymph nodes using PEM (NCT01011946), n=50
        • PEM and biopsy accessory for diagnosis of breast cancer (NCT00981812), n=25
 
2012 Update
A literature search was conducted using the MEDLINE database through June 2012.  There was no new literature identified that would prompt a change in the coverage status.
 
Berg and colleagues published a second article (Berg, 2012) based on the same study that was discussed in the rationale of this policy (Berg, 2011). In this article (Berg, 2012), the performance of PEM and MRI was compared in detecting lesions in the contralateral breast among the same study population. In this case, readers were blinded to the results of the other test but knew the conventional imaging and pathology results from prestudy biopsies. After recording results for a single modality, the reader than assessed the results across all modalities. The readers had 1 to 15 years of experience in interpreting contrast-enhanced breast MRI and underwent training in interpreting PEM results; 5 of the 30 readers had prior experience in interpreting PEM images. The final sample size was 367. Nine patients were excluded because the highest scored lesion was a BIRADS 3 (probably benign) based on all imaging, and no follow-up or histopathology was performed. The contralateral breast could not be assessed in 12 women, e.g., due to prior mastectomy or lumpectomy and radiotherapy.
 
Fifteen (4.1%) of the 367 participants had contralateral cancer. PEM detected cancer in 3 of these women and MRI, in 14. The sensitivity of PEM and MRI was 20% (95% CI: 5.3%, 45.8%) and 93% (95% CI: 66%, 94%), both respectively (p<0.001), while the specificity was 95.2% (95% CI: 92.2%, 97.0%) and 89.5% (95% CI: 85.7%, 92.4%), both respectively (p=0.002). The area under the receiver operating characteristic curve was 68% (95% CI: 54%, 82%) for PEM and 96% (95% CI: 94%, 99%) for MRI (p<0.0001). There was no statistically significant differences across modalities in the accuracy or positive prediction value for women undergoing biopsies (21% for PEM vs. 28% for MRI; p=0.58). There were more benign biopsies based on MRI results (39 in 34 of 367 women) than for PEM results (11 in 11 of 367 women) (p<0.001). The authors discussed possible improvements in interpreting PEM, based in part on results of having the lead investigators reread the PEM images. They determined that 7 of 12 false-negative PEM results were due to investigator error. This could only be confirmed through further study. They also noted that a substantial proportion of contralateral lesions may be effectively treated by chemotherapy. They also noted that PEM cannot optimally evaluate the extreme posterior breast. Two additional articles (Narayanan, 2011) (Narayanan, 2011) on the same study were identified that focus on identifying malignant characteristics on PEM and on training and evaluating readers of PEM.
 
Another study estimated the lifetime attributable risk of cancer and cancer mortality from use of digital mammography, screen film mammography, PEM, and MBI (O’Connor, 2010). Only the results for digital mammography and PEM are reported here. The study concludes that in a group of 100,000 women at age 80 years, a single digital mammogram at age 40 would induce 4.7 cancers with 1.0 cancer deaths, 2.2 cancers with 0.5 cancer deaths for a mammogram at age 50, 0.9 cancers with 0.2 cancer deaths for a mammogram at age 60, and 0.2 cancers with 0.0 cancer deaths for a mammogram at age 70. Comparable numbers of PEM would be 36 cancers and 17 cancer deaths for PEM at age 40; 30 and 15 for PEM at age 50, 22 and 12 for PEM at age 60, and 9.5 and 5.2 for PEM at age 70. The authors also analyze the cumulative effect of annual screening between ages 40 and 80, as well as between ages 50 and 80. For women at age 80 who were screened annually from ages 40 to 80, digital mammography would induce 56 cancers with 15 cancer deaths; for PEM, the analogous numbers are 800 cancers and 408 cancer deaths. For women at age 80 who were screened annually from ages 50 to 80, digital mammography would induce 21 cancers with 6 cancer deaths; for PEM, the analogous numbers are 442 cancers and 248 cancer deaths. However, background radiation from age 0 to 80 is estimated to induce 2,174 cancers and 1,011 cancer deaths. These calculations, as all estimates of the health effects of radiation exposure, are based on a number of assumptions. Comparing digital mammography and PEM, two conclusions are clear: Many more cancers are induced by PEM than by digital mammography; and for both modalities, adding annual screening from 40 to 49 roughly doubles the number of induced cancers. In a benefit/risk calculation performed for digital mammography but not for PEM, the authors nevertheless report that the benefit/risk ratio of annual screening is still about 3 to 1 for women in their 40s, although it is much higher for women 50 and older. The authors conclude “…that if molecular imaging techniques [including PEM] 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” (O’Connor, 2010).
  
2013 Update
A literature search conducted through June 2013 did not reveal any new information that would prompt a change in the coverage statement.
 
The American College of Radiology includes PEM in two sets of Appropriateness Criteria: one on breast screening (ACR, 2012; Mainiero, 2013) and the other on the initial diagnostic work-up of breast microcalcifications. In the first, PEM is given a rating of 2 (1, 2, 3=usually not appropriate) for its use in screening women at high or intermediate risk of breast cancer and a 1 for screening women at average risk of breast cancer (ACR, 2009). It also assigns a relative radiation level of 10 to 30 mSv. It also notes that “Radiation dose from BSGI and PEM are 15-30 times higher than the dose of a digital mammogram, and they are not indicated for screening in their present form.” In the second set of appropriateness criteria, PEM was assigned a rating of 1 (usually not appropriate) for the initial work-up of all 18 variants of microcalcifications. The authors note “The use of magnetic resonance imaging (MRI), breast specific gamma imaging (BSGI), positron emission mammography (PEM), and ductal lavage in evaluating clustered microcalcifications has not been established…. In general, they should not be used to avoid biopsy of mammographically suspicious calcifications” (ACR, 2009).
 
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In a substudy that compared the diagnostic performance of PEM with that of whole-body PET (WBPET) and PET/CT in 2 small cohorts of women with newly diagnosed breast cancer who were eligible for breast-conserving surgery participation, three of 6 sites were included in the Berg et al (2011) study. (Berg, 2011). Fasting blood glucose less than 148 mg/dL was required for study entry. Of 388 women in the original study, 178 (46%) participated in the substudy. Use of WBPET or PET/CT was determined by protocols at each participating site. Most patients (113 [63%]) underwent PEM followed by WBPET or PET/CT on the same day with the same radiotracer dose; the remaining 65 patients (37%) had PET/CT a median of 3 days before PEM (range, 20 days before to 7 days after) with a whole-body-specific dose of FDG. Sensitivity, specificity, and PPV for cancer detection were similar for PET/CT performed on the same day as PEM (mean FDG dose 411 MBq) or on a different day (mean FDG dose 566 MBq). These subgroups were therefore combined for analysis. Readers interpreting PEM images were blinded to WBPET and PET/CT results but had access to x-ray mammography, ultrasound, and prestudy biopsy results. For any identified lesion, a true positive was defined as diagnosis of malignancy within 1 year; true negative was defined as diagnosis of benign or high-risk pathology as the most severe finding, a probably benign lesion that decreased in size or resolved at any follow-up, or maximum BIRADS score of 2 after all imaging (PEM, MRI, x-ray mammography, and ultrasound). No statistical adjustment for multiple comparisons was made.
 
Nonrandomized Comparative Studies
Schilling et al (2011) conducted a single-site, prospective study comparing PEM and magnetic resonance imaging (MRI) (1.5 T) for presurgical planning (Schilling, 2011). Performance of PEM, MRI, and whole-body positron emission tomography (WBPET) were compared with final surgical histopathology in women with newly diagnosed, biopsy-proven breast cancer. For PEM and WBPET (performed consecutively), median FDG dose was 432.9 MBq (equivalent to 11.7 mCi); 4-to-6 hour fasting glucose less than 7.8 mmol/L was required for study entry. One of 6 readers evaluated PEM, x-ray mammography, and MRI images with access to conventional imaging (mammography or ultrasound) results “but without influence of the alternative (PEM or MRI) imaging modality”; WBPET images were interpreted by a nuclear medicine physician. For evaluating PEM images, readers used a proposed PEM lexicon based on MRI BI-RADS. Patients underwent surgery approximately 3 weeks after PEM and WBPET imaging. Of 250 patients approached to participate in this study, 31 were disqualified, and 26 were ineligible because they underwent PEM or MRI before study entry; the analysis therefore included 182 patients. Almost half (46%) of lesions were clinically palpable. On pathology, 78% of patients had invasive disease; 21% DCIS; and 2% Paget’s disease. For index lesions, both PEM and MRI had a sensitivity of 93% (95% CI, 88 to 96; p=not significant), which was greater than the sensitivity of WBPET (68% [95% CI, 60 to 70]; p<0.001). Specificity was not reported because only malignant index lesions were analyzed. Sensitivity of PEM and MRI was not affected by breast density, menopausal status, or use of hormone replacement therapy. PEM tended to overestimate the size of the largest lesion, compared with surgical pathology and MRI (120 mm for PEM vs 95 mm for pathology and MRI); however, correlation between tumor size on histopathology versus size on either PEM or MRI was the same (r=0.61). Twelve lesions were missed on both PEM and MRI; 3 of them were not in the PEM field of view due to patient positioning. For 67 additional ipsilateral lesions detected (40 malignancies), sensitivity of PEM and MRI was 85% (95% CI, 70 to 94) and 98% (95% CI, 89 to 100; p=0.074), respectively; and specificity of PEM and MRI were 74% (95% CI, 54 to 89) and 48% (95% CI, 29 to 68; p=0.096), respectively. Further investigation is needed to determine whether these are 2 points along the same operating curve (ie, whether PEM is being read to emphasize specificity compared with MRI). Additional larger studies also are warranted.
 
In the WBPET cohort (n=69), PEM detected 61 (92%) of 66 index tumors, and WBPET detected 37 (56%; McNemar’s test, p<0.001). In the PET/CT cohort (n=109), PEM detected 104 (95%) of 109 index tumors, and PET/CT detected 95 (87%, McNemar’s test, p=0.029). As shown in Table 1, PEM was statistically more sensitive than WBPET (McNemar’s test, p=0.014) and PET/CT (McNemar’s test, p=0.003) for detecting additional ipsilateral malignant tumors, but no statistically significant differences in specificity, PPV, or NPV between PEM and WBPET or PET/CT were found. Table 1 also shows sensitivities of imaging modalities by index tumor size. Trends for decreasing sensitivity with decreasing tumor size were statistically significant for both WBPET (Cochran-Armitage test, p<0.001) and PET/CT (Cochran-Armitage test, p=0.004) but not for PEM (Cochran-Armitage test, p=0.15). Samples were small for most of these comparisons. Other test performance characteristics (ie, specificity, PPV, and NPV) were not reported by tumor size.
 
The greatest weakness of this substudy was the choice of comparators. Current clinical practice guidelines do not include PET imaging in the diagnostic work-up of newly diagnosed breast lesions (14) nor for post-operative surveillance (Khatcheressian, 2013). Conventional imaging (x-ray mammography, ultrasound, and/or MRI) would have been a more informative comparator.
 
Performance of PEM, WBPET, and PET/CT for Ipsilateral Malignant Tumors in Kalinyak et al (2014) (Kalinyak, 2014)
In the comparison Sensitivity by size of index tumorc
Where n=69
>2 to ≤5 cm - PEM 1.0 (12/12); WBPET 0.92 (11/12)
>1 to ≤2 cm – PEM 0.93 (26/28)a; WBPET  0.61 (17/28)
>0.5 to ≤1 cm – PEM 0.91 (21/23)a; WBET 0.39 (9/23)
>0.1 to ≤0.5 cm – PEM 0.67 (2/3); WBET 0 (0/3)
Where n=109
>2 to ≤5 cm - PEM 0.96 (25/26); WBPET 0.96 (25/26)
>1 to ≤2 cm – PEM 0.96 (53/55); WBPET  0.89 (49/55)
>0.5 to ≤1 cm – PEM 0.96 (22/23); WBET 0.83 (19/23)
>0.1 to ≤0.5 cm – PEM 0.80 (4/5); WBET 0.40 (2/5)
 
PEM (n=69) sensitivity score 0.47a, specificity score of 0.91; PPV score of 0.58; NPV score of 0.86
WBPET (n=69) sensitivity score 0.07; specificity score of 0.96; PPV score of 0.33; NPV score of 0.79
PEM (n=109) sensitivity score of 0.57b; specificity score of 0.91, PPV score of 0.62; NPV score of 0.89
PET/CT (n=109) sensitivity score 0.13; specificity score 0.95; PPV score of 0.43; NPV score of 0.80
 
PPV, positive predictive value; NPV, negative predictive value; WBPET, whole-body positron emission tomography
Statistically significant comparisons are noted.
a Statistically significant difference vs WBPET (McNemar’s test)
b Statistically significant difference vs PET/CT (McNemar’s test)
c There were no index tumors >5 cm.
  
Single-Arm Studies
Caldarella et al (2014) conducted a systematic review with meta-analysis of PEM studies in women with newly discovered breast lesions suspicious for malignancy (Caldarella, 2013). Literature was searched through January 2013. Eight studies (total N=873) of 10 or more patients (range, 16-388) that used histological review as criterion standard, including the 3 studies described in detail below, were included. Pooled sensitivity and specificity were 85% (95% confidence interval [CI], 83 to 88; I2=74%) and 79% (95% CI, 74 to 83; I2=63%), respectively. Pooled positive and negative predictive values were 92% and 64%, respectively. Comparator arms were not pooled. Other limitations of the study included substantial statistical heterogeneity in meta-analyses and lack of blinding of both PEM and histopathology readers in individual studies.
 
(Specificity of PEM combined with conventional imaging was lower than PEM alone due to the large number of false positive lesions prompted by conventional imaging.)
Other Indications
No full-length, published studies were identified that addressed other indications for PEM, including management of breast cancer and evaluation for recurrence of breast cancer.
 
A substudy (Kalinyak, 2014) compared PEM with whole-body positron emission tomography (PET) and with PET/computed tomography (CT) in separate small cohorts. Although PEM was found to be more sensitive than both imaging modalities, specificity, PPV, and negative predictive value were not statistically different. Further, clinical relevance of the findings is uncertain because PET imaging is not currently used in the diagnostic work-up of newly diagnosed breast lesions.
 
National Comprehensive Cancer Network
Current (version 2.2013) NCCN guidelines for breast cancer screening and diagnosis do not include PEM (NCCN, 2013).
 
American Society of Clinical Oncology
Current (2013) ASCO guidelines for follow-up and management of breast cancer after primary treatment do not include PEM  (ASCO, 2013).
 
Ongoing Clinical Trials
A search of online clinical site, ClinicalTrials.gov, using the search term, “positron emission mammography,” yielded 4 active studies of PEM, 2 of which are comparative:
 
Fluorine-18 labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC) PET and PEM versus MRI as a staging tool and indicator of therapeutic response in breast cancer patients (NCT01864083), N=50
• Single-arm studies
o Diagnosis of breast carcinoma: characterization of breast lesions with ClearPEM-Sonic feasibility study (NCT01569321), N=20. A European collaborative group, Crystal Clear Collaboration, is developing ClearPEM-Sonic, which uses PEM plus ultrasound to collect metabolic, morphologic, and structural information about tissues imaged (Crystal, 2011).
 
  
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
In 2014, the Agency for Healthcare Research and Quality (AHRQ) published a technical brief on imaging techniques for treatment evaluation of metastatic breast cancer (Gold, 2014). PEM was not included.
 
Yamamoto and colleagues (2015) in Japan conducted a retrospective review of 54 women younger than 50 years (mean age: 43 years) who were suspected of or diagnosed with breast cancer (n=45) or presented for screening (n=9) (Yamamoto, 2015). The objective of the study was to evaluate performance characteristics of PEM compared with WBPET. All women underwent both tests. Imaging sensitivity overall was statistically greater with PEM (79% vs 48%), driven by increased sensitivity for tumors 1 cm or smaller (67% vs 13%). That is, sensitivity for larger tumors did not differ statistically between groups. Specificity of PEM and WBPET was comparable (91% vs 94%, respectively). Major limitations of this study include its small size, data-driven (and unreported) threshold for PEM positivity, and uninformative comparator.
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
PEM as a Screening Test for Breast Cancer
In 2016, Yamamoto and colleagues reported a retrospective review of the opportunistic use of PEM for breast cancer screening in 265 women with breast symptoms (Yamamoto, 2016). Images were evaluated by agreement of 2 experienced readers who had access to clinical information. The maximum PEM uptake value (PUVmax) was calculated by tissue concentration (mCI/g) × body weight (g)/injected FDG dose (mCI). Using a threshold of 1.97, 22 (8.3%) women had abnormal uptake and were recalled. Six (2.3%) cancers were found by PEM. Although higher than the usual detection rate with mammography and physical examination, this was not a general screening population. Sensitivity and specificity were calculated by clinical follow-up. The sensitivity of PEM in this population was 76% and specificity was 85%.
 
The evidence is insufficient to determine the effects of the technology on health outcomes.
 
PEM for Evaluation of Suspicious Breast Lesion on Conventional Breast Cancer Evaluation
Muller and colleagues evaluated the diagnostic accuracy of PEM using PUVmax as a threshold (instead of a ratio) in 108 patients with 151 suspected lesions (Muller, 2016). The dose of FDG was 3.5 MBq per kilogram of body weight, with a mean of 231.8 MBq. PUV in lesions, tumors, benign lesions, and healthy tissue on the contralateral side were assessed. Biopsy could be performed at the same time as the PEM using the same machine, and suspected carcinoma was compared with histopathology. The mean PUVmax for malignant tumors was 3.78 and the mean PUVmax for normal breast tissue was 1.17 (p<0.001). Using a PUV of greater than 1.9 as a threshold, 31 (20.5%) of 151 lesions were identified as malignant and underwent biopsy. Histopathologic evaluation showed 26 malignant (true positive) and 5 benign lesions (false positive). There were no false-negative lesions reported, although only lesions suspected of carcinoma by PEM underwent histopathologic analysis. Patients who were not biopsied had clinical follow-up for 3 years. The threshold of 1.9 was found via ROC analysis. At this threshold, PEM was reported to have 100% sensitivity and 96% specificity. Based on these positive results, the German health administration is funding a follow-up multicenter study.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
The American College of Radiology has included positron emission mammography (PEM) in 4 sets of appropriateness criteria: one on breast screening, one on breast pain, one on palpable breast masses, and one on monitoring response to neoadjuvant systemic therapy for breast cancer (ACR, 2017).

CPT/HCPCS:
78811Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78999Unlisted miscellaneous procedure, diagnostic nuclear medicine

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American College of Radiology (ACR).(2012) ACR Appropriateness Criteria® breast cancer screening. 2012. Available online at: http://www.acr.org/~/media/ACR/Documents/AppCriteria/Diagnostic/BreastCancerScreening.pdf. Last accessed May 2013.

Berg WA, Madsen KS, Schilling K et al.(2011) Breast cancer: Comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology 2011; 258(1):59-72.

Berg WA, Madsen KS, Schilling K et al.(2012) Comparative effectiveness of positron emission mammography and MRI in the contralateral bread of women with newly diagnosed breast cancer. AJR Am J Roentgenol 2012; 198(1):219-32.

Berg WA, Weinberg IN, Narayanan D et al.(2006) High-resolution fluorodeoxyglucose position emission tomography with compression (“position emission mammography”) is highly accurate in depicting primary breast cancer. Breast J 2006; 12(4):309-23.

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Berrington de Gonzalez A, Berg CD, Visvanathan K et al.(2009) Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst 2009; 101(3):205-9.

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Caldarella C, Treglia G, Giordano A.(2013) Diagnostic Performance of Dedicated Positron Emission Mammography Using Fluorine-18-Fluorodeoxyglucose in Women With Suspicious Breast Lesions: A Meta-analysis. Clin Breast Cancer 2013.

Crystal Clear Collaboration.(2011) Clear PEM sonic, 2011. Available online at:http://crystalclear.web.cern.ch/crystalclear/pemsonic.html. Last accessed May 2014.

Ernestos B, Nikolaos P, Koulis G et al.(2010) Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. Int J Radiat Oncol Biol Phys 2010; 78(4):1199-205.

Ernestos B, Nikolaos P, Koulis G et al.(2010) Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. Int J Radiat Oncol Biol Phys 2010; 78(4):1199-205.

Expert Panel on Breast Imaging, American College of Radiology, Slanetz PJ, et al.(2017) ACR Appropriateness Criteria®: Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. 2017; https://acsearch.acr.org/docs/3099208/Narrative/. Accessed August 25, 2017.

FDA. 510(k) summary:(2014) PEM 2400 PET scanner, 08/13/2003. Available online at: http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pmn&id=K032063. Last accessed May 2014.

Fikes BJ.(2013) Naviscan's assets sold to Mexican company. The San Diego Union-Tribune, 12/11/2013. Available online at: http://www.utsandiego.com/news/2013/Dec/11/naviscan-sold-mexican-cmr-positron/. Last accessed May 2014.

Gold LS, Lee CI, Devine B, et al.(2015) Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Oct. (Technical Briefs, No. 17.). http://www.ncbi.nlm.nih.gov/books/NBK253155/. Accessed May 21, 2015.

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Kalinyak JE, Berg WA, Schilling K et al.(2014) Breast cancer detection using high-resolution breast PET compared to whole-body PET or PET/CT. Eur J Nucl Med Mol Imaging 2014; 41(2):260-75.

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Moy L, Heller SL, Bailey L, et al.(2017) ACR Appropriateness Criteria(R) Palpable Breast Masses J Am Coll Radiol. May 2017;14(5s):S203-s224. PMID 28473077

Muller FH, Farahati J, Muller AG, et al.(2016) Positron emission mammography in the diagnosis of breast cancer. Is maximum PEM uptake value a valuable threshold for malignant breast cancer detection? Nuklearmedizin. 2016;55(1):15-20. PMID 26627876

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Narayanan D, Madsen KS, Kalinyak JE et al.(2011) Interpretation of positron emission mammography: feature analysis and rates of malignancy. AJR Am J Roentgenol 2011; 196(4):956-70.

O’Connor MK, Li H, Rhodes DJ et al.(2010) Comparison of radiation exposure and associated radiation-induced cancer risks from mammography and molecular imaging of the breast. Med Phys 2010; 37(12):6187-98.

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