The neuroendocrine tumor of the breast was first described in 1963 by Feyrter and Hartmann . In 1977, Cubilla and Woodruff presented the first case series and identified breast cancers with neuroendocrine differentiation as primary carcinomas of breast . The histogenesis of the tumor has not been fully clarified yet and is often thought to result from the differentiation of multipotent stem cells into the neuroendocrine carcinoma phenotype . The diagnosis of neuroendocrine tumor of the breast is generally established by microscopic detection of the neuroendocrine structure in the cancer cell and the positive neuroendocrine markers such as chromogranin A and synaptophysin. Neuron-specific enolase and CD56 can also be checked, but they are not as sensitive and specific as the former two . In the 2003 classification, the prevalence of these tumors was estimated to be between 2% and 5%. However, in the Surveillance Epidemiology and End Results (SEER) database, only 142 NEBC cases were identified between 2003 and 2009, which corresponds to a prevalence of <0.1% . In sum, a full literature review shows that the incidence of neuroendocrine breast tumors has been reported in rates ranging between 0.3% and 20%. In our case series, this rate was 3%, and the lack of uniform morphological and immunohistochemical diagnostic criteria could account for the different prevalence results reported in the literature. In most cases, NECB appears as a painless palpable retroareolar mass with secondary symptoms such as skin ulcers, bloody nipple discharge, lymphadenopathy, or retraction of the nipple [8,17]. All of our patients had presented to our clinic for palpable mass. Most NECB patients are postmenopausal women of advanced age, and the incidence of the disease is lower in men and younger women . In the literature, the age of onset has been reported as most frequent in the 6th and 7th decades. Hence, the mean age 61.1 in the present study is consistent with literature. In NEBC patients, 7 were premenopausal and 29 postmenopausal, and in the comparison group, 485 patients were premenopausal and 440 postmenopausal. The difference between the groups was statistically significant (p<0.001). Radiological features of NECB are nonspecific in most cases. Some investigators have stated that NEBCs are observed as hypoechoic masses with irregular morphology in mammography and ultrasound, as well as small-sized lesions not associated with microcalcifications [18-20]. In the present study, high-density masses were detected in the MMG with irregular (77%), microlobulated (80%) and spiculated margins (63%), unaccompanied by asymmetry and structural distortion, along with microcalcification in 4 patients (18%). It may also appear in USG as hypervascular, hypoechoic solid masses, with irregular form and enhanced posterior echogenicity . In our study, hypoechoic (68%), borderless (63%), no posterior acoustic characteristics (59%) were common findings in the Ultrasound. The most frequent findings in MR are irregular masses with irregular margins and wash-out time-intensity kinetics, which are features highly suspicious for malignancy . Some studies also noted that irregular lesions are often detected by hypointense on NECB-T1 weighted sequences with early and intense enhancement [18-20]. In our study, the MRI showed masses with irregular (100%), microlobulated (54%) and spiculated (27%) margins, and isointensity to parenchyma on T1 (100%). Fine needle aspiration cytology is not recommended due to the similarity of NECB’s cytological features to invasive ductal carcinoma and intraductal papilloma [1,22]. The use of detailed immunohistochemical staining and various imaging techniques is essential for an accurate diagnosis. Chromogranin A (CgA) and synaptophysin (SYN) are the most sensitive neuroendocrine markers [23,24], whereas neuron-specific enolase (NSE) and CD56 are less sensitive and less specific [9,25]. While NECB is usually positive for hormone receptors (ER, PR), HER2 is almost always negative, although there have been reports of HER2(+) NECB [21,26]. In 2008, Weigelt et al. described a limited cohort of 5 luminal A and 1 luminal B tumor cases, and 6 NEBCs . In a larger series, Bogine et al. subdivided 112 NEBCs with luminal phenotype into 42% luminal A and 58% luminal B (28]. However, HER2 is only amplified in sporadic cases [21,29,30]. In the present study, regarding the molecular subtypes of the 36 NEBC patients, 16 were Luminal A, 13 Luminal B HER2(-), and 7 Luminal B HER2(+). 7 patients (19.4%) were HER-2(+) in the NECB group.When NEBC were compared to ductal carcinomas (n = 925), NEBC were more often HER2 negative (p = 0.039), ER positive (p = 0.05) ,PR positive (0.03) .
Due to the similarity to neuroendocrine tumors, the NECB can easily be confused with metastases of neuroendocrine tumors to the breast. The presence of a ductal in situ component is a histological evidence that the breast is the primary organ of origin . Besides, an expression of transcription factors such as GATA3, a more sensitive and specific marker than mammaglobin, also indicates breast origin. Although GATA3 is also expressed in urothelial, renal, germ cell tumors and paragangliomas [32-34], a positive expression has not been defined in the extramamary NEN. In addition, positive expression of hormone receptors (PR, ER) in well/moderately differentiated NECB are instrumental in differentiating primary and secondary lesions [35,36]. In the present study, the expression neuroendocrine markers were investigated with immunohistochemical staining, including chromogranin A (CGA), synaptophysin (SYN), neuron-specific enolase (NSE), and CD56. In immunohistochemical staining, the presence of at least 1 non-uniform expression of Chromogranin A (CGA) or synaptophysin (SYN) was considered neuroendocrine marker-positive. The prognostic implications of neuroendocrine differentiation in breast carcinoma are still debated. Historically, based on small-scale studies, NEBC was thought to have a prognosis that is similar [37,39], or even better [40, 41], compared to invasive ductal carcinoma. However, recent studies have suggested that NEBC could be associated with worse long-term outcomes [8, 42-46]. Among these, the population-based study from SEER database has demonstrated that overall survival (OS) and disease-specific survival (DSS) were significantly shorter in NEBC compared with non-NEBC at the same stage . In addition, a large retrospective study by Zhang et al. reported a higher probability of local recurrence and poorer OS for NEBCs . Some studies have claimed that the most important factor is tumor grade (G) and there is no difference in prognosis of NECB and other mammary carcinomas [46,47]. In the available literature, the prognostic factors affecting survival are indicated as disease stage, number of lymph-node metastases, and ER and PR status [46-49]. In the present study, age, grade, metastatic status, number of lymph nodes and molecular type were identified as prognostic factors that significantly affect survival in both groups. The limited number of studies in the literature and lack of standardization in definition and classification may account for these conflicting results concerning the clinical outcome of NEBC. Similarly, some authors have investigated the possible effect of histological subtyping of NEBC according to the 2012 WHO classification on prognosis, providing different evidence. Cloyd et al. have shown that small cell carcinoma subtype is associated with worse DSS and OS compared to well-differentiated NECB and invasive carcinoma with neuroendocrine characteristics . Four (11.2%) the patients with NECB follow up, and 252 (26.4%) the IDC/NOS patients died. The difference was statistically significant (p=0.034). However, the difference in terms of survival was not significant between the groups. The absence of a significant sign or symptom and the lack of standards in diagnosis brings about challenges in diagnosing NECB. Very rarely, NEBC can demonstrate particular clinical features associated with hormonal hypersecretion . In fact, anecdotal cases with symptoms secondary to ectopic secretion of calcitonin, norepinephrine or ACTH have been reported in the literature [51-53]. Similar to typical luminal subtypes of breast cancer, NEBC can metastasize to multiple sites, the most frequent being bone and liver [50,54]. In terms of stage IV disease, there was metastasis in 5 patients (13.9%) in the NECB group and 38 (4.1%) in the comparison group. The difference was statistically significant (p=0.005). However, there was no significant difference with regard to location of metastasis. There is no established standard treatment protocol because there are no large clinical studies in the literature . Treatment is similar to that for other conventional types of invasive breast carcinomas and depend on tumor size, location, and clinical stage [55-57]. There is a general consensus on treating small cell NECB with chemotherapy regiments similar to these for small cell lung carcinoma [58,59]. While most NECB treatments reported in the literature (regarding well/moderately differentiated NECB) are similar to ductal type treatment, Anlauf et al. emphasize the importance of treatment according to NET guidelines . According to both guidelines, surgery is the first-line treatment for early NECB. The surgical procedure (breast conserving partial mastectomy, total mastectomy) depends on the location of the tumor and the clinical stage . In well/moderately differentiated NECB, surgery usually follows radiotherapy depending on tumor size and lymph node status [1,62]. Chemotherapy is used as adjuvant therapy in cases with high risk of relapse, or as neoadjuvant therapy in cases of locally advanced or inoperable NECB . Up to date, there is not sufficient data to determine the most effective chemotherapy regimen. In general, poorly differentiated or small cell NEBCs are treated with regimens containing platinum/etoposide, whereas anthracyclines and/or taxanes-based chemotherapy are used for other types of NEBCs . The effectiveness of antihormonal treatment has been demonstrated in patients with hormone receptor-positive breast carcinoma. Richter-Ehrenstein et al. suggested using adjuvant antihormonal therapy as the standard treatment approach in the hormone receptor-positive NECB . On the other hand, in a study by Lopez et al., all patients with NECB (n=7) received antihormonal therapy . The prognostic role of HER-2 in NECB is not clear, but it can be assumed that it is analogous to other invasive breast carcinomas, meaning that anti-HER2 therapy is recommended for HER2-positive NECB. Somatostatin receptors (SSTRs) are G-protein-coupled receptors expressed by NET cells at lung, prostate and gastrointestinal level, as well as by ductal breast cancer cells. There are 5 known subtypes of SSTRs (named SSTR1 to SSTR5), with SSTR2A being the subtype most commonly expressed in breast cancer and most closely associated with luminal tumors . In SSR-positive tumors, peptide receptor radionuclide treatment (PRRT), a tumor-targeted systemic radiotherapy, has been recommended as a treatment alternative in unresponsive cases . In the present study, no somatostatin analogues or PRRT were administered in the treatment of patients, and they have been treated like invasive breast carcinoma. In recent years, studies have been conducted to determine new therapeutic approaches and potential targets in NEBC. In 2014, the first molecular target was identified by Ang et al., who detected a PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutation in 20% of the NEBCs . In metastatic NECB, targeting PIK3CA by alpelisib has become a prominent therapeutic approach , and Vranic et al. found a TROP-2 (Trophoblast cell-surface antigen 2) protein expression in 21% of NEBC cases, which is a novel molecular target. This suggests that that a small proportion of NEBCs may be sensitive to therapy with Sacituzumab govitecan [68,69]. However, since all currently approved biomarkers of response to immune checkpoint inhibitors (PD-L1 expression, high tumor mutational burden and microsatellite instability status) have proven negative, NEBC patients are not considered ideal candidates for immunotherapy . As a result, many studies have shown that these adjuvant systemic treatments, such as chemotherapy, radiotherapy and endocrine therapy, can play an important role and should be administered according to the individual characteristics of NEBC patients [55,63].