Invasive breast carcinoma with neuroendocrine differentiation

A 52-year-old female was referred to our institution for assessment of BI-RADS 4b abnormality seen in her screening mammogram.

The patient does not have a personal or familiar relevant clinical history. Physical examination revealed two small painless palpable masses in the inner quadrants of the left breast and no palpable adenopathy. The palpable masses were clinically indeterminant.

Mammogram revealed two small opacities with irregular contours in the lower-inner quadrant of the left breast, adjacent to the retro-areolar area, without associated microcalcifications (figure 1), corresponding to the palpable abnormalities.

The palpable nodules were also visible on ultrasonography, showing as hypoechoic solid lesions, with irregular microlobulated contours with associated posterior shadowing, measuring 12 mm and 11 mm (figure 2).

The lesions were classified as BI-RADS 5 on mammogram and ultrasound, and an ultrasound-guided biopsy was performed for tissue sampling.

Breast magnetic resonance imaging (MRI) was also performed for local staging.

Both lesions showed a low signal intensity on T2-weighted images (WI), and after administration of contrast, the T1-FS WI showed an early and avid enhancement with late washout (figure 3).

The lesions also revealed a high signal intensity in the diffusion – WI. There was no invasion of the skin, nipple-areolar complex, or extension to the pectoralis major muscle.

Staging computed tomography (CT) was performed and revealed suspicious hepatic lesions, which were then better characterized by an abdominal MRI (figures 4 and 5). The hepatic suspicious metastatic lesions presented rim enhancement and target sign. 

Neuroendocrine neoplasm presents different features compared to other solid malignancy subtypes [1]. Neuroendocrine cells appear in nearly all organ systems, being more frequent in the gastroenteropancreatic and bronchopulmonary systems [1]. However, primary neuroendocrine carcinoma of the breast (NECB) is a rare subtype of breast malignancy, and its prevalence is estimated less than 0.1% of breast carcinomas  [2,3]. It is reported to account for 2-5% of all-invasive breast carcinomas as well  [4]. NECB was first included in 2003 World Health Organization (WHO) when the expressing neuroendocrine markers were present in more than 50% of tumour cells [1]. However, the latest version of WHO Classification of breast tumours, published in 2019, defined NECB in three subgroups: 1. Well-differentiated neuroendocrine tumours (NETs); 2. Highly aggressive neuroendocrine carcinomas (NECs); 3. Invasive breast carcinoma of no special type (IBCs-NST) with neuroendocrine differentiation [5].

Like other breast carcinomas, NEBC is more common in female patients (6^th-7^th decade of age) [1,6].

It is reported that the main clinical features of NECB are like other carcinomas of no special type, including breast lump, possible bloody nipple discharge, and eventual skin retraction [1,7].

Radiological characteristics are nonspecific, due to the tumour rarity. On mammography, some studies report a circumscribed, round/oval high-density mass, with obscured, indistinct or microlobulated margins [7, 8]. On ultrasound, it is described as a hypoechoic irregular solid mass, sometimes with high vascularity and normal sound transmission  [7, 8]. Calcifications were uncommon compared to invasive carcinoma [7]. On MRI the NECBs are suggested as a mass with ill-defined and irregular margins, with washout kinetics, and usually with a heterogeneous internal enhancement pattern [7].

NECBs are more likely to present metastasis at diagnosis, compared to invasive ductal carcinomas of no special type (IDCs-NST) [1]. The most common sites for metastasis include the liver, bone, brain, bone marrow, lungs, pleura, and skin [9-11]. In our case, the patient presented liver metastases at diagnosis, characterized by CT and MRI imaging, and proved by histological findings (figures 4, 5). The biopsy is necessary for a definite diagnosis.

The diagnosis of NEBC is made based on the similarity with lung and gastrointestinal NETs as well as neuroendocrine markers  [4]. Usually, NEBCs are hormone receptor-positive (HR+) and HER2-negative, and it is believed that may have a worse prognosis compared to invasive breast cancer without neuroendocrine differentiation [4].

Due to the morphological similarity of neuroendocrine tumours, NEBC may be easily misdiagnosed as metastases of neuroendocrine tumours to the breast. However, it is crucial to distinguish these two entities to avoid unnecessary treatments and surgical procedures [11,12]. 

The histopathologic and immuno-histochemical distinction between these two entities can be challenging, particularly in the absence of a clinical history of a prior extramammary neuroendocrine neoplasm. Nevertheless, there are some tips that can guide us to the final diagnosis. The characteristics that are suggestive of NEBC (and less likely of secondary lesions) include: a greater degree of nuclear atypia, irregular nuclear membranes, and frequent mitotic activity; the presence of an in situ component; absence of typical features of small-cell carcinoma or large-cell neuroendocrine carcinoma; expression of GATA3 and mammaglobin; positive expression of hormone receptors (PR and ER) [11,12].

In our case, breast histopathological analysis revealed the diagnosis of invasive carcinoma with neuroendocrine differentiation, luminal B, Ki67 70%, HER2-, CK19 + (figure 6). The biopsy of the liver lesion confirmed hepatic metastases from breast carcinoma with neuroendocrine differentiation (figure 7). Since the patient presented stage IV at the diagnosis, it was decided to proceed with medical treatment.

Due to its rarity, the clinical, imaging features, treatment, and prognosis, remain controversial and nonspecific in the literature.

The diagnosis of NECB is based on biopsy, morphological features, and neuroendocrine biomarkers [1]. Most of the studies, like Yang et al. and Wang et al., report a worse clinical outcome concerning NECB, when compared to other tumours like IDC-NST [13,6]. Most NECB treatments include surgery as first-line therapy followed by taxane-based or anthracycline-chemotherapy, endocrine therapy, and targeted therapy given to the receptor status [1].

Written informed patient consent for publication has been obtained.