Primary neuroendocrine tumors (NETs) of the breast are a. Neuroendocrine Tumors of the Breast. Resident Short Review

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1 Resident Short Review Neuroendocrine Tumors of the Breast Primary neuroendocrine tumors of the breast are a rare and underrecognized subtype of mammary carcinoma. Neuroendocrine tumors of the breast occur predominately in postmenopausal women. The tumors are subclassified into well-differentiated and poorly differentiated neuroendocrine tumors, and invasive breast carcinoma with neuroendocrine features. Well-differentiated tumors show architectural similarity to carcinoids of other sites but lack characteristic neuroendocrine nuclei. Poorly differentiated neuroendocrine tumors are morphologically identical to small cell carcinoma of the lung. Neuroendocrine differentiation, seen in up to 30% of invasive breast carcinomas, is most commonly associated with mucinous and solid papillary carcinomas. The diagnosis of neuroendocrine differentiation requires expression of the neuroendocrine markers synaptophysin or chromogranin. The main differential diagnosis is a metastatic neuroendocrine tumor from an extramammary site. Neuroendocrine tumors of the breast are treated similarly to other invasive breast carcinomas. Although no consensus has been reached on the prognosis, most studies suggest a poor outcome. (Arch Pathol Lab Med. 2017;141: ; doi: /arpa RS) Primary neuroendocrine tumors (NETs) of the breast are a unique but rare subtype of breast cancer. 1 Neuroendocrine differentiation in breast carcinomas was first described by Feyrter and Hartmann 2 in 1963, based on positive silver staining in mucinous carcinomas of the breast. In 1977 Cubilla and Woodruff 3 published the first case series and coined the term primary carcinoid of the breast. Azzopardi et al 4 in 1982, based on positive modified silver staining and demonstration of neuroendocrine secretory granules on electron microscopy, referred to these tumors as argyrophilic carcinomas. It was not until 1985 that Bussolati et al 5 demonstrated positive chromogranin A staining in these tumors, providing conclusive evidence of hormone production. Sapino et al 6 in 2001 proposed the first diagnostic criteria for NETs of the breast, suggesting that tumors with greater than 50% expression of neuroendocrine markers Accepted for publication November 10, From the Department of Pathology, The University of Chicago Medicine, Chicago, Illinois (Dr Rosen); and the Department of Pathology, Rush Presbyterian St. Luke s Medical Center, Chicago, Illinois (Dr Gattuso). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Lauren Elizabeth Rosen, MD, Department of Pathology, The University of Chicago Medicine, 5841 S Maryland Ave, Chicago, IL ( Lauren.Rosen@uchospitals.edu). Lauren Elizabeth Rosen, MD; Paolo Gattuso, MD (specifically chromogranin and synaptophysin) be classified as primary neuroendocrine breast carcinomas. Neuroendocrine carcinoma of the breast was endorsed as a distinct entity in the 2003 World Health Organization (WHO) Pathology and Genetics of Tumours of the Breast and Female Genital Organs, 7 and the proposed criteria from Sapino et al 6 was adopted. The 2003 WHO divided neuroendocrine carcinomas into solid neuroendocrine carcinoma, small cell/oat cell carcinoma, and large cell neuroendocrine carcinoma. 7 The term neuroendocrine carcinoma of the breast was revised to carcinomas with neuroendocrine features in the 2012 WHO Classification of Tumours of the Breast. 1 In addition, it was acknowledged that the 50% threshold for neuroendocrine marker positivity was arbitrary and this criterion was removed. 1 Carcinomas with neuroendocrine features are subclassified into 3 groups: well-differentiated neuroendocrine tumor (WD-NET), which are low-grade tumors that architecturally resemble carcinoid tumors of other sites; poorly differentiated neuroendocrine carcinoma (PD-NEC) or small cell carcinoma, which is identical to its pulmonary counterpart; and invasive breast carcinoma with neuroendocrine differentiation (IBC-NED), which is a breast carcinoma of special or no special type that demonstrates neuroendocrine differentiation by immunohistochemistry. 1 HISTOGENESIS There are 2 main theories on the histogenesis of primary NETs of the breast. The first, more controversial theory, is that these tumors evolve from neoplastic transformation of native neuroendocrine cells. 8,9 Although some authors have reported neuroendocrine cells in benign breast tissue, these findings have been largely disputed and unconfirmed. 9 The more accepted theory is that neuroendocrine differentiation arises from divergent differentiation of neoplastic stem cells into epithelial and endocrine cell lines during early carcinogenesis. 8,9 This theory is supported by the lack of benign NETs of the breast and evidence that the neuroendocrine cells are clonally related to malignant epithelial cells. 9,10 CLINICAL FEATURES The true incidence and clinical features of NETs of the breast are difficult to define, since neuroendocrine markers are not routinely used in breast cancer diagnosis and studies use varying marker positivity to define neuroendocrine differentiation. Neuroendocrine tumors of the breast account for less than 1% of breast cancers. 1 According to the current WHO classification, there are no remarkable differences in clinical presentation from other types of breast cancer. 1 Very rare cases present with hormonal hypersecretion syndromes secondary to ectopic hormone Arch Pathol Lab Med Vol 141, November 2017 Neuroendocrine Tumor of Breast Rosen & Gattuso 1577

2 production. 1 Neuroendocrine tumors of the breast occur predominately in white postmenopausal women in the sixth to seventh decade of life; however, rare cases have been reported in males Patients commonly present with stage 2 disease and have an increased propensity for regional lymph node metastases compared to those with invasive ductal carcinoma, not otherwise specified (IDC- NOS). 14 Neuroendocrine tumors of the breast have imaging characteristics that differ from IDC-NOS. By mammography, NETs are frequently heterogenously dense oval or lobulated masses with indistinct margins. 15 Neuroendocrine tumors are more likely to present as mass lesions on mammography and less likely to demonstrate calcifications than IDC-NOS. 15 The mammographic findings of NET closely mimic those of triple-negative breast cancers. 15 By ultrasonography, NETs often appear as irregular masses with indistinct borders and lack posterior enhancement. 15 PATHOLOGIC FINDINGS Tumors ranged in size from 0.8 to 13.5 cm with a mean size of 2.7 cm in one study and were significantly larger than control IDC-NOS (2.13 cm). 14,16 Grossly, tumors may be infiltrative or expansile and those with mucin production are soft and gelatinous. 16 In a retrospective review, most NETs were classified as WD-NET (155 of 284 cases, 55%), followed by PD-NEC and IBC-NED. 11 The latter entity is likely underdiagnosed, as it commonly lacks histologic features of neuroendocrine differentiation and neuroendocrine markers are not routinely performed in diagnosis. While WD-NETs tend to be of low to intermediate grade, overall NETs tend to be grade 3 lesions. 13 Well-differentiated NETs of the breast are defined by the WHO as tumors consisting of cellular solid expansile nests and trabeculae (Figure 1, A and B). 1 Other architectural patterns such as ribbons, cords, and rosettes are uncommonly present. 1 The tumor cells can be spindled, plasmacytoid, or polygonal and are separated by thin fibrovascular septae (Figure 1, C and D). 1,16 The cells may have abundant granular or clear vacuolated cytoplasm. 16 Evidence of mucin production may be present in the form of extracellular deposits or signet ring cells. 16 The nuclear features of NETs of the breast vary from the classic smooth nuclear borders and salt and pepper chromatin seen in carcinoids of other sites. Nuclei are often pleomorphic with irregular nuclear membranes, and chromatin ranges from evenly distributed with inconspicuous nucleoli to hyperchromatic or vesicular with prominent nucleoli. 16 Primary small cell carcinoma of the breast is histologically similar to its lung counterpart, characterized by densely packed hyperchromatic cells with scant cytoplasm, streaming, and crush artifact (Figure 2, A). 1,17 Nuclear molding is not a prominent feature. 17 Neuroendocrine differentiation has been demonstrated in up to 30% of invasive ductal carcinomas, and is most frequently found in mucinous carcinomas, particularly the hypercellular variant, and solid papillary carcinomas. 1 Invasive breast carcinoma with neuroendocrine differentiation is a diagnostic challenge owing to the variably present and often subtle cytologic features of neuroendocrine differentiation. Most commonly, neuroendocrine differentiation is suspected on the basis of mucinous histology or a solid papillary growth pattern. It is important to note that invasive lobular carcinoma, and in particular the alveolar variant, can also demonstrate neuroendocrine differentiation. 16 Mucinous carcinoma is histologically characterized by nests of tumor cells floating in mucin lakes with fine fibrovascular septae. 18 At least 90% of the tumor must have mucinous histology to be classified as a pure mucinous carcinoma. 18 Neuroendocrine differentiation is more frequently seen with the hypercellular variant of mucinous carcinoma, characterized by large clusters of tumor cells (Figure 2, B). 18 Solid papillary carcinoma is a rare form of breast carcinoma composed of large circumscribed nests of small monotonous polygonal to spindled cells and fine fibrovascular septae (Figure 2, C). 19 Tumor cells may form pseudorosettes around the fibrovascular cores, which can contain hyaline cartilage. 19 Neuroendocrine differentiation is present in up to 50% of cases. 19 While circumscribed, the periphery of these tumors often lacks myoepithelial cells and in the absence of definite invasive growth, solid papillary carcinoma is regarded as in situ carcinoma. 19 While WD-NETs tend to be of low to intermediate grade, overall NETs tend to be grade 3 lesions. 13 Ductal carcinoma in situ can also display neuroendocrine differentiation. Endocrine ductal carcinoma in situ (E-DCIS) is a distinct subtype of in situ carcinoma, characterized most frequently by a solid expansion of ducts with prominent fibrovascular septae and frequently, spindled cells with nuclear palisading (Figure 2, D). 20 Cytologic features are similar to those of WD-NETs. 20 Endocrine DCIS is often of low nuclear grade, with eccentric nuclei and open chromatin. Mucin production, either intracellular or extracellular, is seen in up to two-thirds of cases, and occasionally microglandular spaces or rosettes can be present. 20 ANCILLARY STUDIES Although morphologic features may suggest neuroendocrine differentiation, the diagnosis of NET requires expression of neuroendocrine markers. The most sensitive and specific immunohistochemical markers are synaptophysin and chromogranin A. 21 Neuron-specific enolase (NSE) and CD56 may show positivity but are less sensitive and specific. 21 Well-differentiated NETs and PD-NECs are more likely to show diffuse neuroendocrine marker positivity than IBC-NEDs. 22 Both chromogranin and synaptophysin expression are seen in up to 50% of PD- NECs, and NSE in 100%. 1 Neuroendocrine differentiation can also be demonstrated ultrastructurally with electron microscopy. By electron microscopy, NETs show dense core granules corresponding to chromogranin expression and clear presynaptic vesicles corresponding to synaptophysin expression. 1 Hormone markers show positivity in most WD-NETs and in greater than 50% of PD-NECs. Most NETs fall into the luminal B molecular subtype and are estrogen receptor (ER) and progesterone receptor (PR) positive, and Her2 negative. 21 Studies have shown that NETs are more likely to be ER and PR positive than IDC-NOS. Wei et al 14 demonstrated that 92% (68 of 72) of NETs were ER positive and 69% (51 of 72) were PR positive as compared to 72% (3696 of 5165) and 57% (2950 of 5165), respectively, of IDC-NOS. Poorly differentiated NECs of the breast, similar to small cell carcinomas of other sites, often show expression of thyroid transcription factor 1 (TTF1). 14 Up to 45% of poorly differentiated NETs also show expression of androgen receptor, which is often coexpressed with gross cystic disease fluid protein 15 (GCDFP15) Arch Pathol Lab Med Vol 141, November 2017 Neuroendocrine Tumor of Breast Rosen & Gattuso

3 Figure 1. A, Well-differentiated neuroendocrine tumor of the breast with a trabecular growth pattern. B, The tumor demonstrates strong expression of chromogranin A. C, Another well-differentiated neuroendocrine tumor composed of plasmacytoid cells with eccentric nuclei and a moderate amount of eosinophilic granular cytoplasm. D, The tumor cells show strong expression of synaptophysin (hematoxylin-eosin, original magnification 3200 [A and C]; original magnification 3200 [B and D]). DIFFERENTIAL DIAGNOSIS The differential diagnosis of NETs of the breast is broad and includes both benign and malignant entities. The most important differential diagnosis that must be excluded is a metastatic neuroendocrine tumor from an extramammary site. Metastases to the breast account for less than 1% of breast tumors and are most commonly hematologic or metastases from the contralateral breast. 24 Metastatic neuroendocrine tumors account for 1% to 2% of metastases to the breast. 24 Primary NETs and metastatic neuroendocrine carcinomas to the breast can show considerable morphologic overlap, and differentiation is challenging in the absence of clinical history of a prior or concurrent extramammary tumor. 24 In one review, 25 up to 44% (8 of 18) of metastatic neuroendocrine tumors to the breast were misdiagnosed as primary breast tumors. The distinction of primary from metastatic neuroendocrine tumor is critical to avoid misdiagnosis and unnecessary surgical and medical therapy in the latter. Approximately 68% (15 of 22) of primary NETs are associated with DCIS, and this is the most convincing evidence of a primary breast tumor. 24 The presence of nuclear atypia or pleomorphism in a well-differentiated tumor favors a primary NET of the breast. 24 A panel of immunohistochemical stains can prove useful in distinguishing these 2 entities. As both primary and metastatic tumors show neuroendocrine differentiation, neuroendocrine markers are not useful, nor are ER and PR, which can also show positivity in metastases. 24 The most specific markers for a breast primary are GATA3, mammaglobin, and GCDFP15, for which secondary tumors are consistently negative. 24 TTF1 shows positivity in approximately 70% (7 of 10) of metastases from the lung, and CDX2 shows positivity in 100% (5 of 5) of metastases from the gastrointestinal tract. 24 While CDX2 consistently shows negativity in primary NETs of the breast, strong TTF1 positivity can be observed in poorly differentiated breast NETs. 24 Neuroendocrine differentiation in breast carcinomas is often overlooked in routine practice. Tang et al 16 reported that neuroendocrine differentiation was missed in up to 69% (51 of 74) of breast carcinomas. Given the inconsistent neuroendocrine features in primary NETs of the breast and lack of routine testing for neuroendocrine markers, this rate of misdiagnosis is not surprising. The morphologic findings of a nested or trabecular architecture, nuclear or cytoplasmic Arch Pathol Lab Med Vol 141, November 2017 Neuroendocrine Tumor of Breast Rosen & Gattuso 1579

4 Figure 2. A, Poorly differentiated neuroendocrine carcinoma of the breast composed of densely packed cells with a high nuclear to cytoplasmic ratio and cellular streaming. B, Hypercellular variant of mucinous carcinoma of the breast composed of large clusters of tumor cells floating in mucin. C, Solid papillary carcinoma composed of solid nests of cells with delicate and hyalinized fibrovascular septae. D, Endocrine ductal carcinoma in situ consisting of a duct expanded by a solid proliferation of monotonous cells with thin fibrovascular septae and nuclear palisading (hematoxylin-eosin, original magnifications 3100 [A through C] and 3200 [D]). features of neuroendocrine differentiation, mucin production, or a solid papillary growth pattern should prompt a pathologist to order neuroendocrine markers. The misdiagnosis of NET as IDC-NOS is likely of little consequence at this time, as no consensus has been reached as to the clinical and prognostic significance of neuroendocrine differentiation. The differential diagnoses of E-DCIS and solid papillary carcinoma include usual ductal hyperplasia (UDH). 10 The solid growth pattern and streaming of cells seen in both solid papillary carcinoma and E-DCIS closely mimic UDH. Neuroendocrine marker positivity confirms a diagnosis of E- DCIS or solid papillary carcinoma, as neuroendocrine positivity is not seen in any benign breast lesion. Cytokeratin 5/6 negativity and diffuse ER positivity will also exclude UDH. Unlike UDH, solid papillary carcinomas often lack a myoepithelial cell layer and will be negative by myoepithelial (smooth muscle myosin and p63) markers. 26 TREATMENT AND PROGNOSIS There are no specific guidelines for grading, staging, or treatment of primary NETs of the breast. 1,14 The most recent WHO classification states that grading is unlikely to be clinically significant. 1 It is recommended that NETs of the breast be staged and treated similarly to conventional breast cancer. 10,14 Surgical management, like conventional breast cancer, is based on tumor location and stage. 10,14 It is recommended that patients with WD-NET and IBC-NED receive cytotoxic therapy similar to that for conventional breast cancer, and those with PD-NEC with similar protocols as for pulmonary small cell carcinoma. 10 The use of hormone therapy should be based on receptor status. 10 In 2 studies, 14,27 patients with NETs of the breast treated with endocrine therapy and radiotherapy had longer overall survival (OS) and disease-free survival than those who did not receive treatment, while patients who received chemotherapy had lower OS and disease-free survival than those who did not. The poor response to chemotherapy is hypothesized to be due to either chemoresistance commonly seen in neuroendocrine tumors of other sites, or the lack of an appropriately determined regimen. 14 No consensus has been reached on the prognosis for NETs of the breast. There are conflicting results in the literature, likely due to limited number of cases, and varying inclusion 1580 Arch Pathol Lab Med Vol 141, November 2017 Neuroendocrine Tumor of Breast Rosen & Gattuso

5 criteria. 21 Most of these studies support a poor prognosis for NETs of the breast. 10,12 14,27 Cloyd et al 11 were the first to examine prognosis for NETs by histologic subtype. Stage for stage, NETs of the breast had a worse 5-year OS than IDC- NOS. 11 Well-differentiated NETs and IBC-NED had a similar 5 year OS and disease-specific survival (DSS), while PD-NEC had a significantly poorer 5 year OS and DSS. 11 In another study, 12 neuroendocrine differentiation was found to be an independent adverse prognostic factor for OS and DSS. Neuroendocrine tumors of the breast have a significantly higher rate of local and distant recurrence than IDC- NOS. 14 CONCLUSIONS Breast carcinoma is a heterogeneous disease, composed of many different subtypes with varying clinical characteristics. Neuroendocrine tumors of the breast are a distinct subtype, first recognized by the WHO in Neuroendocrine tumors of the breast consist of 3 subtypes: WD-NET, IBC- NED, and PD-NET. As these tumors are rare, diagnosis requires exclusion of metastasis from an extramammary site. This entity is underrecognized owing to lack of consensus on the degree of neuroendocrine differentiation required for the diagnosis, and the often limited cytologic evidence of neuroendocrine differentiation. The identification of NETs depends primarily on architecture, and less so on nuclear features of neuroendocrine differentiation seen in neuroendocrine tumors of other sites. While no consensus has been reached on the clinical or prognostic significance of this entity, most large studies using updated criteria suggest a poor prognosis when compared to IDC-NOS. References 1. Bussolati G, Badve S. Carcinomas with neuroendocrine features. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van der Vijver MJ, eds. WHO Classification of Tumours of the Breast. Lyon, France: IARC Press; 2012: World Health Organization Classification of Tumours; vol Feyrter F, Hartmann G. 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