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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 63  |  Issue : 4  |  Page : 559-563
Neuroendocrine carcinomas of the breast: Case series with review of literature


Department of Pathology and Pediatric Surgery, Maulana Azad Medical College and Associated Hospitals, New Delhi - 110 002, India

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Date of Submission21-Nov-2019
Date of Decision12-Apr-2020
Date of Acceptance29-Apr-2020
Date of Web Publication28-Oct-2020
 

   Abstract 


Background: The breast tumors with neuroendocrine differentiation show features similar to their counterparts in other organs. Neuroendorine carcinomas account for less than 0.1% of all breast carcinomas. Aims: To study the demographics and clinicopathological prameters ten cases showing neuroendocrine carcinoma breast. Material and Methods: Ten cases showing neuroendocrine carcinoma were studied. The data was analysed for demographics and clinicopathological prameters. The Immunohistochemistry for ER, PR, Her2neu, Synaptophysin, Chromogranin, NSE, Ki67 index and EMA were done in these cases. Results: Nine Trucut biopsies were reported as infiltrating duct carcinoma and one case as IDC with neuroendocrine differentiation with focal mucinous areas.The histopathological slides of breast excision specimens revealed clusters of cells arranged in sheets and small nests separated by thin fibrous septae in eight of the cases. Trabeculae were noted in two case and in another rosettes were noted. DCIS component was noted in two cases. Infiltration into fat in five of the cases. One case showed pools of mucin. The tumour cells were positive for synaptophysin in 5/10 cases, chromogranin in 8/10 cases and NSE in 9/10 cases. Estrogen receptor positivity was noted 6 cases (6/10), progesterone receptor positivity in 8 cases (8/10) and Her2neu positivity in 5 cases (5/10). Conclusion: NECB cases are more likely to ER/PR positive with variability of expression of neuroendocrine markers. These tumors are more aggressive with propensity for distant metastasis. Endocrine therapy may be more beneficial than standard chemotherapy. Anti-angiogenic markers are an exciting new approach for these case, which is yet to be explored.

Keywords: Infiltrating duct carcinoma, neuroendocrine carcinoma, neuroendocrine diferentiation

How to cite this article:
Singh V, Kaur N, Mandal S, Mallya V, Tomar R, Khurana N, Bains L. Neuroendocrine carcinomas of the breast: Case series with review of literature. Indian J Pathol Microbiol 2020;63:559-63

How to cite this URL:
Singh V, Kaur N, Mandal S, Mallya V, Tomar R, Khurana N, Bains L. Neuroendocrine carcinomas of the breast: Case series with review of literature. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Nov 25];63:559-63. Available from: https://www.ijpmonline.org/text.asp?2020/63/4/559/299335





   Introduction Top


The breast tumors with neuroendocrine differentiation show features similar to their counterparts in other organs. Carcinomas with neuroendocrine differentiation constitute around 1% of breast carcinomas. Neuroendorine carcinomas account for less than 0.1% of all breast carcinomas. These tumors can be divided into neuroendocrine differentiation well differentiated, neuroendocrine differentiation poorly differentiated, and invasive ductal carcinoma not otherwise specified with neuroendocrine differentiation (IDC NOS) according to WHO 2018.[1] Feyrter F, Hartmann G first described the neuroendocrine tumor of breast in 1963.[2] However, classification of neuroendocrine breast carcinoma (NEBC), together with a clinical and prognostic analysis, was done by two American pathologists: Antonio Cubilla and James Woodruff in 1977.[3] About 50% of low- or intermediate-grade neuroendocrine tumors express chromogranin and only 16% express synaptophysin.[1],[4] Present study reviews 10 cases of neuroendocrine carcinoma breast.


   Materials and Methods Top


Seven hundred and twenty case of breast carcinoma were retrospectively examined over the past 5 years out of which 10 cases showing neuroendocrine carcinoma were studied. The data was analyzed for demographics, clinicopathological parameters, and treatment history. The immunohistochemistry (IHC) for ER, PR, Her2neu, Synaptophysin, Chromogranin, NSE, Ki67 index, and EMA were done in these cases.

The cases with <50% neuroendocrine differentiation were classified as IDC with neuroendocrine differentiation, and those with >50% neuroendocrine differentiation expressing two or more neuroendocrine markers were grouped as NEBC. Based on WHO criteria, cases expressing 2 or more neuroendocrine markers were included in the study. These cases were classified on the basis of ER, PR, Her2neu, and Ki67 status into Luminal A, Luminal B, Basal and Her2neu types.


   Observations and Results Top


The comprised of eight cases of pure neuroendocrine carcinoma breast. There were 9 female and 1 male patient. The male to female ratio was 1:9. All cases were above 30 years of age (range 33–70 years). The upper outer quadrant and retroareolar region were most commonly involved. The size of tumor ranged from 1 cm to 14 cm. The clinical features of all the cases are tabulated in [Table 1]. Trucut biopsies the 9 cases were reported as infiltrating duct carcinoma (IDC), in 1 case IDC with neuroendocrine differentiation with focal mucinous areas were reported [Figure 1]a. The histopathological slides of breast excision specimens revealed clusters of cells arranged in sheets and small nests separated by thin fibrous septae in eight of the cases. The cells were small to medium sized with minimal amount of cytoplasm, stippled chromatin, and few cells showing prominent nucleoli. Trabeculae were noted in two case and in another rosettes were noted [Figure 1]b. DCIS component was noted in two cases [Figure 1]c. There was focal infiltration into fat in five of the cases [Figure 1]d and four case had areas of necrosis [Figure 1]e. Lymphovascular invasion was present in two case [Figure 1]f. In addition one case showed pools of mucin [Figure 2]a and b]. IHC was also done for defining the neuroendocrine status. Any two neuroendocrine marker positivity in more than 50% of the cells were considered as neuroendocrine carcinoma. The tumor cells were positive for synaptophysin in 5/10 cases, chromogranin in 8/10 cases, and NSE in 9/10 cases [Figure 2]c and d]. According to WHO, all the cases were diagnosed well-differentiated neuroendocrine tumor (WD-NET) except one which was diagnosed as poorly differentiated neuroendocrine carcinoma (PD-NEC), which showed expression of NSE and chromogranin [Figure 3]a and [Figure 3]b.
Table 1: Showing the clinical and histomorphological features of the cases

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Figure 1: (a) Trucut biopsies showing infilrating duct carcinoma (IDC) [HE × 100]. (b) Shows cells in trabeculae and rosettes with scant cytoplasm, stippled chromatin and few cells showing prominent nucleoli [HE × 200]. (c) Shows focal DCIS [HE × 200]. (d) Shows focal infiltration into fat [HE × 200]. (e) Shows areas of necrosis [HE × 200]. (f) Shows lymphovascular emboli [HE × 200]

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Figure 2: (a and b) Shows tumor cells pools of mucin. [HE × 100]. (c) Immunohistochemistry showing positivity for chromogranin [IHC × 200]. (d) Immunohistochemistry showing positivity for synaptophysin [IHC × 200]

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Figure 3: (a) Immunohistochemistry showing positivity for chromogranin in PD-NEC [IHC × 200]. (b) Immunohistochemistry showing positivity for NSE in PD-NEC [IHC × 200]. (c) Immunohistochemistry showing positivity for Ki67 in PD-NEC [IHC x 200]. (d) Immunohistochemistry showing positivity for Her2neu [IHC x 200]

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Estrogen receptor (ER) positivity was noted 6 cases (6/10), progesterone receptor (PR) positivity in 8 cases (8/10) and Her2neu positivity in 5 cases (5/10). An attempt also has been made to subtype these cases in various luminal categories based on expression of ER, PR, HER2 Neu, and Ki67 indices [Figure 3]c and d]. There being 7 cases of luminal A type, 1 case of luminal B type, 1 case of basal type and 1 case of Her2neu type [Table 2]. Luminal A was the most common type associated with NECB.
Table 2: Showing the hormone receptor expression and neuroendocrine marker expression

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   Discussion Top


Primary neuroendocrine carcinoma of breast are rare subtype of breast cancer first recognized in by Feyrter and Hartmann 1963.[2] Neuroendocrine tumors of the breast account for less than 1% of breast cancers.[4] In 2003, WHO defined mammary neuroendocrine carcinoma as tumor with >50% neoplastic cells expressing at least two neuroendocrine markers. In the present study most of the cases presented with breast lumps predominantly in retroareolar or upper outer quadrants. The size of tumor varied from 1 cm to 14 cm. Neuroendocrine tumors of the breast occur predominately in postmenopausal women in the sixth to seventh decade of life. However, rarely have been reported in males. In the present study three patients were above the age of 60 years and rest were below the age of 40–50 years with one patient of 30 years of age. In the present study one patient was male. Patients mostly 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 (IDCNOS).[1]

Tumors mostly range in size from 0.8 to 13.5 cm. In this study it ranged in size from 1 to 14 cm.[5] Neuroendocrine differentiation arises from divergent differentiation of neoplastic stem cells into epithelial and endocrine cell lines during early carcinogenesis.[4]

Well-differentiated NETs of the breast are defined by the WHO as tumors consisting of cellular solid expansile nests, trabeculae, ribbons, cords, and rosettes The tumor cells can be spindled, plasmacytoid, or polygonal. They may be separated by thin fibrovascular septae. The cells may have abundant granular or clear vacuolated cytoplasm. The nucleas has smooth nuclear borders with salt and pepper chromatin. Mucin extracellular may be present. Primary small cell carcinoma of the breast is histologically similar to its lung counterpart It is characterized by densely packed hyperchromatic cells with scant cytoplasm. Nuclear molding may not be a prominent feature.[4] Trucut sections from the cases were initially diagnosed as IDC-NOS. Resection specimens revealed tumor cells in clusters and/or sheets. These cases had solid nests of tumor cells separated by thin fibrous septae. One case showed pools of mucin within the tumor component. IHC revealed neuroendocrine marker positivity in >50% tumor cells.[6],[7],[8] According to WHO, all these cases were diagnosed as well-differentiated neuroendocrine tumor (WD-NET) except one which was diagnosed as poorly differentiated neuroendocrine carcinoma (PD-NEC) or small cell carcinoma. Neuroendocrine differentiation has been demonstrated in up to 30% of invasive ductal carcinomas, and is most frequently found in mucinous carcinomas.[4]

In the present study ER, PR, and Her2neu status was variable. Five cases showed positivity for both ER and PR, three cases were only PR positive, one case was ER positive and one case was triple negative. Most of NETs fall into the luminal B molecular subtype and are estrogen receptor (ER) and progesterone receptor (PR) positive, and Her2 negative. They are more likely to be ER and PR positive than IDC-NOS. Wei et al. demonstrated that 92% (68 of 72) of NETs were ER positive and 69% (51 of 72) were PR positive as compared to IDC-NOS.[5] In the present series PR positivity was 80% which was similar to the study by Rovera et al.[9] 50% cases were Her2neu positive. There are very few studies which have subclassified NECB cases into molecular subtype.[7] In the present study an attempt has been made to classify the cases according to the molecular subtype. Seven of the 10 cases belonged to luminal A type (70%). The NECB cases were more likely to be ER/PR positive and Her2neu negative. Weigelt et al. demonstrated that NECB of luminal A phenotype have amplification of genes for chromogranin, synaptophsin, CD56, bombesin, collagenases, and metalloproteases.[10]

Among the neuroendocrine markers NSE was positive in all cases with variable expression of either synaptophysin or chromogranin.[4],[8],[11] NSE was positive in 100% cases, synaptophysin was positive in 60% cases while chromogranin was positive in 78% cases. Zekioglu et al. found synaptophsin positivity in 91.7% cases and chromogranin in 41.7% cases.[11]

The differential diagnosis includes metastatic neuroendocrine tumors which account for 1—2% of metastases to the breast. Primary NETs and metastatic neuroendocrine carcinomas to the breast can show considerable morphologic overlap. The distinction of primary from metastatic neuroendocrine tumor is critical to avoid misdiagnosis. Primary NETs are associated with DCIS. Nuclear atypia or pleomorphism in also favors a primary NET of the breast.[12]

There are no specific guidelines for grading, staging, or treatment of primary NETs of the breast. They are staged and treated similarly to conventional breast cancer.[5] Surgical management, like conventional breast cancer, is based on tumor location and stage.[5] Patients with WD-NET and IBC-NED should be given cytotoxic therapy similar to that for conventional breast cancer. In Patients with PD-NEC protocols similar pulmonary small cell carcinoma is followed. Hormone therapy is used based on receptor status of the patient.[4]


   Conclusion Top


NECB cases are more likely to ER/PR positive with variability of expression of neuroendocrine markers. NSE was uniformly positive in all cases. These tumors are more aggressive with propensity for distant metastasis. Endocrine therapy to be more beneficial than standard chemotherapy. Anti-angiogenic markers are an exciting new approach for these case, which is yet to be explored.

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Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Bussolati G, Badve S. Carcinomas with neuroendocrine features. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van der Vijver MJ, editors. WHO Classification of Tumours of the Breast. World Health Organization Classification of Tumours. Vol. 4. Lyon, France: IARC Press; 2012. p. 62-3.   Back to cited text no. 1
    
2.
Feyrter F, Hartmann G. Über die carcinoide Wuchsform der Carcinoma mammae, insbesondere das Carcinoma Solidum (gelatinosum) mammae. Frankf Z Pathol 1963;73:24-39.  Back to cited text no. 2
    
3.
Cubilla AL, Woodruff JM. Primary carcinoid tumor of the breast: A case report of eight patients. Am J Surg Pathol 1997;1:283-92.  Back to cited text no. 3
    
4.
Rosen LE, Gattuso P. Neuroendocrine tumors of the breast. Arch Pathol Lab Med 2017;141:1577-81.  Back to cited text no. 4
    
5.
Wei B, Ding T, Xing Y, Wei W, Tian Z, Tang F, et al. Invasive neuroendocrine carcinoma of the breast: A distinct subtype of aggressive mammary carcinoma. Cancer 2010;116:4463-73.  Back to cited text no. 5
    
6.
Gupta RK, Holloway LY, Wakefield SJ. Needle aspiration cytology, immunocytochemistry, and electron microscopic study in a case of carcinoid of the male breast. Diagn Cytopathol 1993;9:461-4.  Back to cited text no. 6
    
7.
Papotti M, Tanda F, Bussolati G, Pugno F. Argyrophilic neuroendocrine carcinoma of the male breast. Ultrastruct Pathol 1993;17:115-21.  Back to cited text no. 7
    
8.
Scopsi L, Andreola S, Saccozzi R, Pilotti S, Boracchi P, Rosa P, et al. Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I). Am J Surg Pathol 1991;15:1063-71.  Back to cited text no. 8
    
9.
Rovera F, Masciocchi P, Coglitore A, Pilotti S, Boracchi P, Rosa P, et al. Neuroendocrine carcinomas of the breast. Int J Surg 2008;6:S113-5.  Back to cited text no. 9
    
10.
Bussolati G, Gugliotta P, Sapino A, Eusebi V, Lloyd RV. Chromogranin-reactive endocrine cells in argyrophilic carcinomas (”carcinoids”) and normal tissue of the breast. Am J Pathol 1985;120:186-92.  Back to cited text no. 10
    
11.
Zekioglu O, Erhan Y, Ciris M, Bayramoglu H. Neuroendocrine differentiated carcinomas of the breast: A distinct entity. Breast 2003;12:251-7.  Back to cited text no. 11
    
12.
Mohanty SK, Kim SA, DeLair DF. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. Mod Pathol 2016;29:788-98.  Back to cited text no. 12
    

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Correspondence Address:
Shramana Mandal
Department of Pathology, 642.Pocket E, Mayur Vihar Phase II, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_908_19

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