False positive CEM findings
In addition to aforementioned benign entities, a couple specific scenarios may also lead to false positive CEM enhancement.
Enhancement of skin lesion
Some skin lesions, such as moles or seborrheic keratosis can enhance (Fig. 8). On a CEM LE images, dermal location of the finding may not be immediately evident. It may require physical examination and/or correlation with tomosynthesis.
Inflammation or infection
In the post-procedure/postoperative setting, due to an underlying seroma, hematoma, infection or fat necrosis, there may be associated, predominantly peripheral enhancement on CEM (Fig. 9). However, relatively thin rim of enhancement on RI due to inflammation should be distinguished from irregular, nodular or mass-like enhancement which may represent true positive enhancement of residual or recurrent disease.
False negative CEM findings
Potential reasons CEM can lead to false negative diagnoses are categorized into three main scenarios: (1) lack of enhancement due to small size and/or low grade histology of ductal carcinoma in situ or invasive breast cancer (true false negative), (2) missed abnormal enhancement due to marked BPE or misinterpretation of true enhancement as BPE and (3) limitations of the technique (e.g. the abnormal finding is not included in the image due to its location).
CEM relies on the principle of tumor angiogenesis, vessel immaturity and increased permeability, resulting in diffusion of contrast into the tumor, subsequently manifesting as contrast enhancement [3, 35, 36]. To ensure technical adequacy, similar to evaluation of breast MRI, assessment of the CEM images must be made for adequacy of contrast administration. Visualization of contrast in breast vessels is a good indicator of an adequate contrast bolus (Fig. 10).
Lack of contrast enhancement on CEM RI might be caused by inadequate contrast bolus due to many factors including small caliber of the injection catheter, inadequate rate of contrast administration, contrast extravasation, peripheral/central vessel occlusion or impaired cardiovascular function. In addition, motion may further limit lesion detection and characterization, especially if the cancer is small.
While MRI is overall a very sensitive test for breast cancer detection, false negative cases have also been reported [37,38,39,40]. In a non-randomized prospective multicenter study [38], false negative rates for MRI with respect to breast cancer detection were reported as 22% (22/97 breast cancers in 2157 women). In six patients (27% of the false negative cases), breast cancer was missed or misinterpreted due to small lesion size (13% of false negative cases), extensive diffuse contrast enhancement of breast parenchyma (9%), and technically inadequate examination (4.5%). 43% of such false negative cases (9/21) were pure DCIS or DCIS with invasive foci. 90% of false negative DCIS (8/9) had no enhancement on MRI.
Lack of enhancement due to small size
Similar to these observations with MRI, small cancer size possibly coupled with low grade histology and ductal carcinoma in situ (DCIS) with no associated mass are two reasons for the possible lack of enhancement of breast cancer on CEM. Regarding small size, tumor angiogenesis is incited as cancer grows typically beyond 0.3 cm and thus, like MRI [40], it can be extrapolated that false negatives may be seen with very small invasive carcinomas on CEM (Fig. 11).
Lack of enhancement in ductal carcinoma in situ
Lack of enhancement is more common in DCIS because the degree of angiogenesis is lower in DCIS than in invasive carcinomas [40]. Unlike MRI, CEM maintains sensitivity and specificity of diagnostic mammography for detecting a non-enhancing small invasive cancer or DCIS by detecting morphologic abnormalities such as focal asymmetry, distortion or microcalcifications [41, 42]. DCIS, presenting as microcalcifications as the only manifestation, can be identified on the LE image of CEM alone (Fig. 12), with additional evaluation by magnification views, as needed. This accounts for approximately 10% of cancers presenting with microcalcifications. CEM, therefore has the added value to identify DCIS with or without lesion enhancement. Stereotactic-guided needle core biopsy is usually subsequently used for a tissue diagnosis in such cases.
Missed abnormal enhancement due to marked background parenchymal enhancement (BPE)
An enhancing cancer may be missed if there is significant BPE or when there is asymmetric BPE. Just as in breast MRI, the level of BPE is reported on all CEM studies in order to convey to the reader the level of sensitivity. In contrast to breast MRI, marked BPE appears to be less prevalent on CEM studies based on our experience as well as Berg et al. 2021 [13].
Misinterpretation of true enhancement as background enhancement
Misinterpreted enhancement relates to misinterpreting cancer enhancement as benign, which has been described on MRI [40] and may be encountered on CEM. Misinterpretation may be due to the pattern of enhancement on RI (e.g. non-mass enhancement mimics asymmetric BPE). This could be a particular challenge when cancer enhancement presents as non-mass enhancement with a relatively lower degree of enhancement intensity, potentially coupled with similar enhancement to that of BPE.
Inappropriate technique
Not unique to CEM, imaging with inappropriate technique, can lead to “missing” the cancer. Enhancement may be missed if it is in a portion of the breast that is not in the imaging field (e.g., posterior breast mass on a study where there is not enough posterior breast tissue included on the image) [41]. Additionally, there are artifacts inherent to CEM [43] which may obscure findings, further highlighting importance of proper technique.
Modifications to diagnostic protocol to protect sensitivity of CEM
Several factors can lead to a false-negative CEM study as discussed above. Thoroughly assessing abnormal findings on LE is an important first step to protect the sensitivity of CEM in detecting high risk lesions, DCIS and/or small low-grade IDC. Adding breast ultrasound with CEM as an adjunctive diagnostic test will also increase sensitivity for lesion detection and characterization [5, 18] helping avoid unnecessary biopsies and additional short-term follow up studies. If there is a palpable abnormality without correlate on CEM/US, abnormal findings on LE images or clinical suspicion warrants, MRI should follow to look for an occult cancer.
Lastly, enhancing CEM findings may be challenging to biopsy without ultrasound correlate, necessitating the need for MRI for visualization and subsequent sampling. New CEM equipment allows biopsy capabilities, some in combination with tomosynthesis.