Abstract
Neuroendocrine features are detectable in carcinomas of the breast either as scattered cells, that are recognized by their expression of neuroendocrine cell markers. Instead, pure breast carcinomas with neuroendocrine features (NEBC) are very rare and represent <1% of all breast cancer. Usually NEBC may be well or poorly differentiated and more frequent in older woman. These tumors showed variable histological pattern but a common feature is represented by expression of neuroendocrine markers. Here we report a case of a primary multicentric low-grade neuroendocrine carcinoma of the breast presented because of its rarity and for the unusual tubular and cribriform pattern resembling a well-differentiated conventional breast carcinoma. The tumor was treated with left quadrantectomy with concomitant wide excisional biopsy of other two nodules and lymph node sentinel biopsy. No recurrence was observed during 1-year follow-up. Because of its rarity and variability of morphologic features, there exist diagnostic challenges for pathologists to differentiate primary NEBC to some conventional breast carcinomas and to the breast metastasis from neuroendocrine tumor of the lung or gastrointestinal tract. It is important to be able recognize this tumor in order to avoid potential misdiagnosis and improper management of afflicted patients.
Introduction
Neuroendocrine carcinomas of breast (NECB) occurring as “primary” breast lesions are extremely rare and often will represent a metastasis from another area of the body [1–4]. In 2003 WHO classification system have established that the immunohistochemical expression of NE markers in more than 50% of the tumor cells is a necessary requisite for the diagnosis of primary pure carcinoma NECB [5]. Following the above criteria, NECB constitute approximately 1% of all breast carcinomas [5]. The biological outcome of NECB is controversial when compared with conventional breast cancers. Because their rarity the diagnosis and management of these tumors is difficult [6]. The present report describes a case of multicentric low-grade NECB with an unusual tubular and cribriform pattern treated with breast conservation.
Clinical presentation
A 50-year-old woman visited our Institution for the multiple nodules of left breast. The woman reported having noticed many months before the presence of these nodules small while taking a shower. Ultrasonography and magnetic resonance imaging (MRI) confirmed the presence of five nodules in a background of entirely fatty breast parenchyma (Fig. 1). The largest lesion measured 1.5 cm in maximum diameter, the lower 1.0 cm. No enlarged axillary lymph nodes were noted. Tru-cut biopsy of two nodules largest showed an epithelial neoplasia composed of cribrifom and tubular-type glands. In addition to routinely breast markers (ER, PgR, Ki67 and HER2) an immunohistochemical panel with neuroendocrine markers was required. Immunohistochemical staining for NSE, chromogranin and synaptophysin were positive and Ki67 was low (<5% ). A first diagnosis of well differentiated neuroendocrine breast carcinoma was made. The frozen sections of the greater nodule and lymph node sentinel confirmed a diagnosis of well-differentiated carcinoma with negative axillary lymph node. The patient underwent left upper outer quadrantectomy with a wide excision of two nodules of lower inner quadrant and axillary lymph node resection. Histologically all nodules showed same features with a prevalent tubular, cribriform and papillary pattern (Fig. 2a,b). Tubular-type and cribriform glands were lined by cuboidal or columnar cells with faintly eosinophilic or clear cytoplasm in a fibrovascular stroma (Fig. 3). A low-grade ductal carcinoma in situ was also present (Figure 4). Immunohistochemical staining for NSE, chromogranin and synaptophysin were positive (Fig. 5a–b). All tumors were positive for estrogen receptors (>90% ) but negative for progesterone and HER2. Ki67 was low (<5% ). Lymph nodes examination revealed the absence of micro-metastasis. A final diagnosis of multicentric low-grade neuroendocrine carcinoma was made. After surgery a total body CT scan and octreoscan were negative and showed no other lesions. No recurrence was observed during 1-year follow-up.
Discussion
A focal neuroendocrine differentiation is not uncommon and may be present in conventional or special type of breast carcinoma (BC), particularly mucinous and solid papillary carcinomas. Moreover, primary neuroendocrine carcinoma of the breast (NECB) are rare and represents <1% of all breast tumors [5–11]. Criteria for diagnosis of NECB have been recently established recently by the WHO classification system, who has clarified the confusing interpretation of the phenomenon of neuroendocrine differentiation in breast cancer disease [5,6]. WHO’s classification clearly establish that the presence of morphological features common to neuroendocrine tumors of gastrointestinal tract and of the lung and immunohistochemical expression of NE markers in more than 50% of the tumor cell population are essential requisite for the diagnosis of primary NECB [5,6]. These tumors can show different histological patterns and degree of differentiation [5,6]. A first pattern usually matches with well differentiated tumors and is composed of solid nests and trabeculae or showed carcinoid-like features [5,8,10]. Another group of NEBC is an high-grade tumor composed of small, dark cells with scant cytoplasm, high mitotic count and necrosis resembling to oat cell carcinoma of the lung (small cell carcinoma) [5,9]. In this spectrum of neuroendocrine features from low-grade malignant to high-grade malignant NEBC, it is possible to identify a third group of invasive breast carcinoma with conventional patterns (ductal, mucinous, papillary) that exhibit a neuroendocrine differentiation recognized by expression of neuroendocrine cell markers [5,6,12]. Chromogranin A and synaptophysin have been considered the most sensitive and specific neuroendocrine markers for this type of tumor [5,6,12,13]. At the molecular level, recent gene expression profiling studies have shown that NEBC pertain to the luminal molecular type, being positive for hormone receptors and negative for HER2 and have confirmed that is an entity distinct from invasive ductal carcinomas of no special type [6,12]. However a differential diagnosis between NEBC and DCI can be difficult. In fact, clinical presentation and macroscopic appearance of NEBC are similar to conventional breast cancer [5,6,12,13]. A diagnosis of NECB may be suspected on cytologic smears but should be confirmed at histological level with neuroendocrine markers. NECB with predominant solid, alveolar or papillary pattern may be confused with lobular and solid papillary carcinoma on FNAB or core biopsy [10]. In our case, a differential diagnosis with the tubular and cribriform carcinoma should be made. Tubular carcinoma is composed of open tubules with angulated shaped arranged haphazardly in a desmoplastic stroma. Cribriform carcinoma showed a sieve-like pattern in a prominent fibroblastic stroma and tumor cells are small to moderate in size. Clear cells are not uncommon in BC and are observed also in papillary carcinoma as NEBC [13]. The surgical excision of nodule with histopathologic examination is necessary for the final diagnosis. In all cases a metastasis from the neuroendocrine tumor originated in the lung or gastrointestinal (GI) tract should be always excluded because this distinction is crucial for determination of appropriate clinical management [1–4]. There were histological similarities between the metastatic neuroendocrine neoplasm and NEBC: the presence of a ductal carcinoma in situ as it was in our patient and the positivity for estrogen receptors in the majority of primary NEBC support the diagnosis of primary NECB. Furthermore well-differentiated neuroendocrine tumors often showed immunoreactivity for site-specific markers. Finally, all the pathologic findings should be interpreted in the context of the clinical history and imaging findings in order to exclude the presence of lesions in other sites. The clinical effect of neuroendocrine breast cancer is still a matter of debate; as the conventional BC, the histological grade and steroid receptor expression highly influenced the clinical evolution of NEBC [6]. When compared with conventional BC, NE differentiation does not affect the prognosis in terms of clinical behavior. Nevertheless, due to the rarity of this entity, there are few data and no consensus regarding the optimal management of this breast tumor [6–10]. To time, primary NECB are treated as invasive conventional carcinoma, including mastectomy or wide surgical excision of nodule with negative margins, and sentinel lymph node biopsy, but none of reports analyzed NECB based on its distinct subtypes [6,12,14]. A breast-conserving surgery can be proposed for low-grade NECB. Surgery with platinum- or anthracycline-based chemotherapy regimens are used in small cell NECB [9,14]. The optimal treatment of poorly differentiated tumors and NECB in advanced stage should be established in multi-disciplinary oncological group for treating neuroendocrine tumor disease, as NET of gastro-entero-pancreatic district.
In conclusion this report describes a well-differentiated, multicentric, neuroendocrine tumor of the breast with a tubular and cribriform pattern. It is necessary to differentiated this tumor from other invasive mammary carcinomas, as cribriform or solid papillary carcinoma by routinely using an immunohistochemical panel with neuroendocrine markers. Furthermore a breast metastasis from neuroendocrine carcinoma of the lung or the GI tract it must always be excluded after a careful clinical examination for determination of appropriate therapeutic management. Finally in case of well-differentiated NEBC, a conservative approach with surgical excision of nodule with negative margins, and sentinel lymph node biopsy followed by a follow-up, should be the therapy of choice.