CAUSES OF FALSE NEGATIVE-FINDINGS:

Background parenchymal enhancement (BPE)

BPE refers to the normal enhancement of glandular tissue after contrast administration. First described for MRI, it has also been described for CEM and is classified according to BIRADS in: minimal, mild, moderate, and marked. No clear pattern in the variation of BPE during the menstrual cycle has yet been demonstrated at CEM, so there is no current recommendation to time the imaging process around the menstrual cycle.

BPE makes lesion detection difficult by obscuring the mass and non-mass enhancement, similar to that seen at breast MRI. Pathologic enhancement and normal BPE must be distinguished. Keys to a differential diagnosis are symmetry of the enhancement on the recombined image and morphology on the LE image.

Fig 2: Breastfeeding patient referred to our department for a self-palpation lump in UEQ/RB since two months ago. A) Low energy images with extremely dense breasts. No nodular images are observed. B) Recombined images with heterogeneous enhancements are observed in both breasts, highlighting mass-like enhancement in IIQ/LB. C) Sonographically, this enhancements correlate with areas of ductal ectasias and accumulation of breast tissue. These findings are expected in breastfeeding patients. If there is any doubt or a suspicious lesion is observed, the biopsy should not be delayed. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.

Fig 16: Patient with a history of breast cancer in the right breast, treated with conservative treatment (tumorectomy + hormone-radiotherapy). First CEM control is performed. A) Low energy images. Global glandular asymmetry, in relation to post-treatment changes in RB. B) Recombined images. Intense non-mass enhancement of diffuse distribution, with area of ​​increased enhancement in UOQ/RB (circle), without clear correlation in low energy image. C) Post-contrast MRI. Correlation with CEM findings are observed, showing a non-mass enhancement more evident in UOQ/RB (arrows). Given the patient's oncological history and the unavailability of previous comparative studies, it was decided to perform a CEM-guided biopsy, with a negative histological result for malignancy. The findings are interpreted as asymmetric BPE given the post-treatment changes in RB. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.

Incomplete or inadequate lesion visualization (blind areas on mammograms)

This happens when a lesion is not included in the mammographic field of view. The most common blind areas include the axillary tail and areas of the breast that are high on the posterior chest wall, inferior medial, or in the intermammary or inframammary fold. In some cases this is solved with additional projections, however, there are regions that are not included in the CEM (thoracic wall or intermammary region, for example) that must be studied by targeted US and/or MRI.

Fig 3: Patient undergoing their first screening mammogram. A) Mammogram. Partially included left axillary lymphadenopathy is visualized (white circle), so the patient is recalled. B) Left breast CEM in three projections (CC, MLO, ML). At the union of the inner quadrants, it can be observed a spiculated nodule in the posterior third with mass enhancement in recombined images, partially included (yellow circle). C) Sonographically, it is observed as an isoechogenic nodule with poorly defined borders with posterior shadow. D) Due to the partial inclusion of the lesion, complementary MRI is performed showing the entire nodule and its margins (white arrow). This case exemplifies one of the locations known as blind areas, since being in the posterior third it is not always included in the mammography. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.

Lack of enhancement in some tumors

Some malignant tumors may present with lack of enhancement. This find can be included in low grade small tumors, invasive lobular carcinomas, mucinous and encapsulated papillary carcinomas, and areas of ductal carcinoma in situ (DCIS):

• Invasive lobular carcinomas can be difficult to diagnose, given their diffuse infiltrative behavior, they often show weak enhancement and architectural distortions or asymmetries on LE images.
  

  Fig 4: 45-year woman with a new palpable lump. A) Low energy images show a nodule with partially erased/spiculated edges in the middle third of UOQ/LB (circle). B) In recombined images, faint ring-enhancement is associated (arrow) resembling a complicated cyst with thick walls. C) Sonographically it correlates with a poorly defined nodule that presents a posterior shadow that has to be biopsied. Histological result was triple negative IDC with central necrosis. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
  

  Fig 5: 27-year old woman presents with a palpable new-appearing nodule in the right breast. A) Low-energy images show increased glandular density with pseudonodular morphology in the middle third of UQU/RB (circle). B) Recombined images depict avid ring uptake with thick and irregular walls and unenhancing void area inside (arrow). C) Sonographically, it correlates with a thick-walled cystic lesion and a solid component with increased Doppler signal. D) MRI showing multiseptated solid-cystic lesion with marked enhancement after contrast administration (arrowhead). Histological result was triple negative IDC, Ki67:90%. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
• Both mucinous carcinomas which contain large amounts of fluid and scarce viable cells and encapsulated papillary carcinomas that are composed of solid and cystic components results in lesions with little or no enhancement or as rim enhancement at CEM.
  

  Fig 6: Recall Screening contrasnt-enhanced mammography. A) In the middle third of LOQ/RB, a small nodule with partially obscured margins is identified (circle). B) Recombined images show an heterogenous mass enhancement (arrow). C) Sonographically, it correlates with a discrete, ill-defined hypoechogenic area. A biopsy was performed, with the result of mucinous carcinoma. This type of lesion generally presents mild enhancement, with low conspicuity if there is BPE marking. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
• Areas of DCIS usually have microcalcifications and show subtle or no enhancement on recombined images. 

Recombined images should be evaluated as an additional tool for the study of breast lesions and not a replacement. The diagnostic key to avoid false negatives is the joint evaluation of the recombined images and LE images, in addition to the rest of the diagnostic techniques that we have available. It is important to emphasize that the lack of enhancement in suspicious lesions in LE images should not rule out tissue sampling. In the presence of suspicious calcifications, the lack of enhancement is a sign that does not allow the biopsy to be skipped. In those suspicious calcifications where enhancement is observed, it is useful for us to perform a more targeted biopsy. 

Errors of Characterization

It consists of an interpretive error in breast images in which a finding is identified but erroneously characterized as benign. For example, round or oval masses with circumscribed margins are frequently associated with benignity, however these characteristics are not exclusive to benign lesions, and may occur in malignant lesions, especially in patients carrying BRCA mutations and in triple-negative invasive ductal carcinoma.

Fig 7: 66-year old woman with a slow-growing palpable nodule in her left breast. A) Low energy images. Nodular lesion with well-defined edges in LIQ/LB, suggestive of a cyst (circle). B) Recombined images. Faint ring enhancement, with hyperenhancing focal mural thickening (arrow). C) Ultrasound. Cystic lesion with solid component (asterisk) that presented increased Doppler signal (not included) and that correlates with mural thickening seen in CEM. A biopsy was performed resulting in IDC. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.

Contrast material extravasation

If the extravasation was not recognized before imaging, this may result in lack of enhancement on CEM images. In CEM, it could be difficult to confirm if contrast has reached the breast. At the time of contrast injection, the patient may feel local discomfort. In cases where it is suspected, the study should be repeated one or two days later.

Fig 8: CEM of a patient with a recent diagnosis of a left IDC. A) CEM performed where hardly any BPE is identified in recombined images. Contrast extravasation was suspected since the patient reported local discomfort at the venipuncture site. B) CEM performed two days later, where an increase in BPE is observed in the recombined images. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.

CAUSES OF FALSE-POSITIVE FINDINGS:

False-positive findings consist of enhancement of benign lesions or lesions with increased vascularity due to inflammation or artifacts: 

• BENIGN LESIONS:
  • Within the breast:
    • Fibroadenoma and phyllodes tumor are benign fibroepithelial lesions with variable enhancement patterns and may appear as enhancing lesions on CEM images, depending on their histologic composition. Equally to MRI, fibroadenomas can present with progressive mass-like enhancement, with hypoenhancement septa, being characteristic of this entity.
      

      Fig 14: 42-year old patient patient with a new self-palpation nodule in her right breast. A) Low energy images. Two nodules, one irregular in UQU/RB and the other one with circumscirte margins in UOQ/RB. Besides, there is another incidental nodule with well-defined edges in UOQ/LB (circle). B) Recombined images. Right breast with a multifocal cancer an ipsilateral lymph node metastasis. Left nodule associates intense enhancement with a lobulated-appearing mass, where hypouptake of septa is sensed (arrows), which correlates on MRI (C) where hypouptake septa are identified (arrowhead), pathognomonic findings of fibroadenoma. D) US. Solid nodule with a lobulated appearance with some hyperechoic septa. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
    • Papilomas are composed of epithelial cells with a fibrovascular core causing variable enhancement.
    • Pseudoangiomatous stromal hyperplasia, is a benign entity of the breast. Two presentations are mainly identified, diffuse non-mass PASH and nodular PASH (less common and which radiologically can be indistinguishable from a fibroadenoma). In the diffuse form, they can present in CEM as non-mass type enhancement, being difficult to rule out malignant lesion (IDC or ILC).
    • Intramammary lymph nodes: are typically enhancing masses due to the vascular supply of the cortex. LE images with a fatty hilum and circumscribed margins are the clues.
      

      Fig 11: A-B) Low energy images. UOQ/RB nodule, with well-defined edges, close to a blood vessel, small, highly suggestive of an intramammary lymph node (circle). C-D) Associates faint mass enhancement (arrow). Many times the nodes can present mild-moderate mass enhancement. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
    • Radial scar usually appears as an architectural distortion with or without enhancement on recombined images and may mimic breast cancer. The key is to correlate surgical and radiotherapy history, as well as the comparison with previous studies.
    • Sclerosing adenosis is a benign proliferative lesion that could manifest as multiple small nodules, fibrous tissue and variable microcysts. Does not seem to present distinctive features on CEM, and can mimic ductal enhancement or faint mass/non-mass enhancement, being difficult to differentiate from the background parenchyma, making biopsy very difficult.
      

      Fig 13: Patient with known breast cancer in the UOQ/LB (asterisk). A) Low energy images. Irregular focal asymmetry in middle third of OQT/RB, with partially obscured edges (circle). B) Recombined images. It correlates with irregular mass enhancement (arrow). Given the patient's context, it was decided to performa a stereotactic vacuum-assisted biopsy, which resulted in sclerosing adenosis. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
  • Outside the breast:
    • Dermal lesions (including verrucous lesions, neurofibromas, hemangiomas or other hypervascularized lesions). LE images will show the superficial location of the lesion.
      

      Fig 9: Patient with known mucinous carcinoma in UOQ/RB. A) Low energy images. Nodular lesion in the right axilla (arrow). B) In combined images, it shows intense homogenous mass enhancement (arrowhead). It can be seen that in both low-energy and combined images, a radiolucent halo is observed around the lesion that raises the suspicion that the lesion is cutaneous, which is confirmed by clinical inspection (C). Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
       
    • The nipple is a hypervascular area that can present enhancement, usually symmetrical. If it is asymmetrical and there is suspicion of malignancy after clinical inspection, a skin biopsy can be performed.
• Infectious/inflammatory conditions:
  • Mastitis or abscess: Given the increase in local vascularization due to an inflammatory or infectious process, it may be reflected in an enhancement in the recombined images. It is important to correlate the findings with clinical history, laboratory tests, as well as the evolution and response to medical treatment.
  • Complicated/complex cysts: In the case of a complicated cyst, we could find an absence of enhancement (or negative enhancement) in the combined images, surrounded by a ring enhancement (eclipse sign). In the case of a complex cyst, this could be accompanied by solid mural lesions or thick wall/septa. It is important to emphasize that cystic-looking lesions can sometimes mimic malignant lesions, so if suspected, a biopsy/FNE should be performed.
    

    Fig 10: 35 year-old woman with 4 days palpable lump, associated with pain and erythema. A) Low energy images. Retroareolar nodule with partially darkened edges, cystic in appearance (circle). B) Recombined images. Ring enhancement, with internal void signal (eclipse-sign), compatible with a cystic lesion (arrow). C) US. Cystic lesion, which presents fine and mobile echoes inside, with no associated color Doppler signal. Fine needle aspiration was performed, releasing purulent-looking fluid. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
  • After undergoing Neoadjuvant chemotherapy (NAC), the inflammatory changes that occur can sometimes be mistakenly identified as a false partial response, when in reality there is still residual fibrosis that is showing enhancement. Besides, later changes after radiation therapy seen at contrast-enhanced imaging include asymmetric decreased parenchymal enhancement in the treated breast.
    

    Fig 17: 46-year old patient with triple negative IDC (cT2N0M0) left breast cancer that has indication for neoadjuvant treatment. A) Pre-neoadjuvant CEM. Intense mass enhancement in UOQ/LB (circle). B) Post-neoadjuvant CEM. Decrease both in diametrer and conspicuity of the mass enhancement, but with persistence of a low heterogenous non-mass enhancement (arrows), concluded as a partial response to neoadjuvant therapy. Tumorectomy was performed, showing complete histological response with abundant fibrotic changes in the surgical specimen. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
  • Fat necrosis with heterogeneous forms of presentation, may present peripheral enhancement and typically presents calcifications and fatty content on LE images. Correlate with patient history (biopsies, trauma, surgeries).
    

    Fig 15: Patient recalled from the screenning program due to focal asymmetry in the anterior third of LIQ/LB. A) Low energy images. Small focal asymmetry is observed in the anterior third of LIQ/LB (circle). B) Recombined images. Focal asymmetry is associated with faint peripheral enhancement (more evident in CC projection (arrows). C) Ultrasonographically, it is observed as a hypoechoic nodular lesion, associated with edematous thickening of the subcutaneous tissue, without increased Doppler signal and increased surrounding echogenicity of the fat; findings compatible with little hematoma and fat necrosis. The patient referred previous traumatic blow the preciding weeks. D) Ultrasound at 6 months show practical resolution of the findings, with persistence of a small nodular formation with a residual cystic appearance. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.
     
• Artifact of contamination of contrast material: Spillage of contrast material onto the patient's skin, detector, or paddle from the technologist's hands or from the intravenous line is rare but can mimic non-mass-enhancement (NME) on recombined images. Features that may suggest contamination of the contrast material are the presence of NME in only one breast, and if it were present in both breasts in a mirrored pattern, it suggests contamination in the paddle, the detector, or both. To avoid these artifacts, it is important to take care of cleaning the mammogram. It is recommended to change gloves between contrast administration and patient positioning.
  

  Fig 12: A) Low energy image. There are not any suspicious findings. B) Recombined image. Non-mass enhancement, mottled appearance, is identified. Given the morphology and no correlation with low energy images, contrast contamination is suspected. C) The patient and equipment were cleaned, and the acquisition was repeated, where contrast splatter has desapeared. Department of Breast Radiology, Hospital del Mar; Barcelona, Spain.