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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 15  |  Issue : 2  |  Page : 176-179

Primary neuroendocrine breast carcinoma: A rare case report


1 Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission20-Dec-2021
Date of Acceptance01-Feb-2022
Date of Web Publication24-May-2022

Correspondence Address:
Dr. Madhu Kumar
Department of Pathology, King George's Medical University, Shahmina Road, Chowk, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_389_21

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  Abstract 


Primary neuroendocrine carcinoma of the breast is a very rare occurrence accounting for <0.1% of all breast cancers. For the diagnosis, it requires the diffuse expression of neuroendocrine markers (chromogranin, synaptophysin, neuron-specific enolase) and the lack of simultaneous neuroendocrine carcinoma in extramammary sites. The breast carcinomas with focal neuroendocrine differentiation are defined as scattered tumor cells that stain positive with neuroendocrine markers. These tumors are usually seen in elderly women around sixth or seventh decade of life, as reported in literatures. The high nuclear grade and regional lymph node metastasis was also significant negative prognostic factors for overall survival. We study a case of primary neuroendocrine carcinoma of breast in a 46-year-old lady, on the basis of histopathology and immunohistochemistry.

Keywords: Breast, lymph node metastases, neuroendocrine carcinoma, neuroendocrine markers


How to cite this article:
Kumar M, Singh A, Vimal JK, Kumar V. Primary neuroendocrine breast carcinoma: A rare case report. Indian J Health Sci Biomed Res 2022;15:176-9

How to cite this URL:
Kumar M, Singh A, Vimal JK, Kumar V. Primary neuroendocrine breast carcinoma: A rare case report. Indian J Health Sci Biomed Res [serial online] 2022 [cited 2022 Jul 2];15:176-9. Available from: https://www.ijournalhs.org/text.asp?2022/15/2/176/345830




  Introduction Top


The World Health Organization (WHO) Classification of tumors in 2003 defined neuroendocrine carcinoma of the breast as having more than 50% neoplastic tumor cells expressing neuroendocrine markers.[1] These tumors are usually seen in elderly women around sixth or seventh decade of life, as reported in literatures.[2],[3] Primary breast neuroendocrine tumors (NET) are a rare histological type representing <0.1% of all breast cancers.[4],[5] We report a case of primary neuroendocrine carcinoma of breast in a 46-year-old lady.

Objective

The objective was to study the rare case of primary neuroendocrine breast carcinoma on the basis of histopathology and immunohistochemistry.


  Case Report Top


A 46-years-lady presented with breast lump that was gradually increasing in size during last 1 year. On physical examination, a hard nontender lump 4 cm × 3 cm in size was noted in the left lower quadrant of breast and her axillary lymph nodes were palpable. No previous medical or surgical history was available. Her X-ray of the chest and ultrasonography of the abdomen were normal. Clinically, she was diagnosed with intraductal breast carcinoma. Fine-needle aspiration cytology (FNAC) of the breast was advised. Mammography showed ill-defined, irregular outline, space-occupying lesion in the left lower quadrant of the breast and few lymph nodes were also seen in the left axilla. The patient underwent a modified radical mastectomy with axillary resection and the specimen was submitted for a histopathological examination.


  Results Top


FNAC was done and cytology smear showed atypical cells arranged in small sheets and clusters as well as predominantly singly lying cells in the background of hemorrhage. Individual atypical cells are mildly pleomorphic, polygonal, round-to-oval nucleus with fine-to-coarse chromatin and mild-to-moderate amount of cytoplasm. FNAC smear reported as intraductal carcinoma breast [Figure 1]. On gross examination of left modified radical mastectomy with axillary resection, entire breast tissue measuring 12 cm × 11 cm × 7 cm was received along with axillary tail and axillary lymph nodes, level 2 and interpectoral lymph nodes were also received. On cut section, an ill-defined tumor measuring 3.5 cm × 3.0 cm × 2.5 cm was present in the lower quadrant of the breast, firm in consistency with very small areas of hemorrhage [Figure 2]. Representative sections were taken, processed, sections were cut, and stained with hematoxylin and eosin. On microscopic examination, the breast parenchyma in the region of tumor showed that the tumor cells arranged in sheets, solid nests, and separated by thick and thin fibrous stroma. Individual tumor cells were mildly pleomorphic, relatively small to large, uniform in size and shape with granular salt paper nuclear chromatin, and moderate amount of eosinophilic cytoplasm [Figure 3]. Mitosis >2-3/HPF,lymphovascular invasion and ductal carcinoma in situ components were seen. Out of 14 axillary lymph nodes, two lymph nodes were positive for tumor deposits [Figure 4]. Differential diagnosis was high-grade neuroendocrine tumor or carcinoma, metastatic neuroendocrine carcinoma, intraductal carcinoma with solid papillary type, and intraductal carcinoma with neuroendocrine differentiation. An immunohistochemical examination revealed synaptophysin, chromogranin, neuron-specific enolase (NSE), gross cystic disease fluid protein-15 positivity, ER, PR, HER2 neu, and p63 negative in tumor cells, and Ki67% was more than 20% in hotspot areas (>20%/10 HPF) [Figure 5] and [Figure 6]. Primary neuroendocrine breast carcinoma with metastatic to the axillary lymph nodes was the final diagnosis.
Figure 1: Fine-needle aspiration cytology smear showed atypical cells arranged in small sheets, nests, and clusters as well as predominantly singly lying cells in the background of hemorrhage. Individual atypical cells are mildly pleomorphic, polygonal, round-to-oval nucleus with fine-to-coarse chromatin and mild-to-moderate amount of cytoplasm ([a-c], H and E stain, ×4, ×20, ×40)

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Figure 2: Gross examination: Solid, firm in consistency, measuring 3.5 cm × 3.0 cm × 2.5 cm was present in the lower quadrant of the breast

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Figure 3: Microscopic examination: Tumor cells arranged in small sheets and solid nests and separated by fibrous stroma. Individual tumor cells were mildly pleomorphic, relatively small to large, uniform in size and shape with granular salt paper nuclear chromatin, and moderate amount of eosinophilic cytoplasm ([a-d], H and E stain, ×4, ×10, ×20, ×40)

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Figure 4: Ductal carcinoma in situ component, mitoses (>2–3/high-power field), and lymph nodes were positive for tumor deposits and lymphovascular invasion was also seen ([a-c], H and E stain, ×20, ×20, ×20)

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Figure 5: Immunohistochemical examination: Synaptophysin, chromogranin, neuron-specific enolase, and gross cystic disease fluid protein-15 diffuse positivity in tumor cells (Immunohistochemical stain, ×40)

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Figure 6: Immunohistochemical examination: ER, PR, HER2 neu negative in tumor cells, and Ki67% were elevated (Immunohistochemical stain, ×40)

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  Discussion Top


Primary neuroendocrine carcinomas of the breast are currently included in the latest WHO classification of breast tumors. Primary neuroendocrine carcinoma of breast are rare subtype of breast cancer first recognized in by Feyrter and Hartmann 1963.[6] Frequency increases with age, no carcinoid syndrome present, and clinical presentation and prognosis same as ductal carcinoma not otherwise specified (NOS). The breast tumors with neuroendocrine differentiation show features similar to their counterparts in other organs. In this study, the age of patient was 46 years; usually, these tumors are seen in elderly women around sixth or seventh decade of life, as reported in literatures.[2] In this study, the age of patient was 46 years; usually, these tumors are seen in elderly women around sixth or seventh decade of life, as reported in literatures.[2] Mostly, cases presented with breast lumps, predominantly in retroareolar or upper outer quadrants. This patient was presented with lower quadrants of the breast. The size of tumor varied from 1 to 14 cm. The tumor size in this case was 3.5 cm.

Neuroendocrine differentiation arises from divergent differentiation of neoplastic stem cells into epithelial and endocrine cell lines during early carcinogenesis.[7] Neuroendocrine differentiation has been demonstrated in up to 30% of invasive ductal carcinomas, and is most frequently found in mucinous carcinomas.[7] In primary neuroendocrine carcinoma of the breast, more than 50% of the cell population shows neuroendocrine differentiation.[8] In the present case study, NSE, synaptophysin, and chromogranin, all three markers, were diffuse positive in tumor cells. Breast carcinoma, NOS, with focal endocrine differentiation revealed by immunohistochemical expression in scattered cells is not included in this group.[8] Breast neuroendocrine carcinomas used to be known as argyrophilic breast carcinoma, breast carcinoid tumor, or endocrine carcinoma but now are classified as breast carcinoma with neuroendocrine differentiation or primary neuroendocrine breast carcinoma.[9],[10] The 2003 WHO Classification of Breast Tumors recognizes neuroendocrine carcinoma as a distinct histological entity, with the same morphological characteristics as NET of the gastrointestinal tract (GIT), pancreas, and lung, with more than 50% positive immunostaining of tumor cells by a neuroendocrine marker such as chromogranin or synaptophysin.[9] Four groups are described: solid neuroendocrine carcinomas, atypical carcinoids, small-cell carcinomas, and large-cell neuroendocrine carcinomas.[9] Among the neuroendocrine markers, NSE was positive in all cases with variable expression of either synaptophysin or chromogranin.[7],[11],[12] NSE was positive in 100% cases, synaptophysin was positive in 60% cases, while chromogranin was positive in 78% cases. Zekioglu et al. found synaptophysin positivity in 91.7% of cases and chromogranin in 41.7% of cases.[12]

Primary neuroendocrine carcinoma 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 ductal carcinoma in situ. Nuclear atypia or pleomorphism in also favors a primary NET of the breast.[13] The patient received chemotherapy and doing well after 6 months of follow-up.

The classification and histologic grading criteria for neuroendocrine neoplasm of the GIT and hepatobiliary organs, WHO 2019, classify well-differentiated NETs to Grade 1 (carcinoid-like low grade), Grade 2 (atypical carcinoid-like intermediate grade) tumors, and Grade 3, while poorly differentiated neuroendocrine carcinoma (NECs) are small- and large-cell carcinoma on the basis of mitotic rate (mitoses/2 mm2) and Ki-67 index (%).[14] Neuroendocrine neoplasia of the breast represents a less well-defined group of neoplasms than analogous entities in other organs, such as the lung and the gastroenteropancreatic tract. True primary neuroendocrine neoplasms of breast are classify as NET and carcinomas (small-cell neuroendocrine carcinoma, or large-cell neuroendocrine carcinoma) as well as neuroendocrine differentiation overridden by morphological tumor type such as NOS, mucinous, and solid papillary.[15] The breast carcinomas with focal neuroendocrine differentiation defined as scattered tumor cells that stain positive with neuroendocrine markers.[16]

Previous reports of literature mention that NEC breast shows aggressive behavior compared to ductal carcinomas with a higher propensity for local and distant recurrence. However, more recent data suggest that this tumor has more favorable prognosis.[2] Higher grade, increased tumor size, and regional lymph node metastasis are associated with poor prognosis and decreased disease-free survival.[3]


  Conclusion Top


Neuroendocrine carcinomas of the breast are rare tumors. One thing should always keep in mind to exclude metastatic neuroendocrine tumor and always search for primary in the lung, GIT, and pancreas. Histopathological and immunohistochemical examination is the only way to exclude all the differential diagnosis and achieve their correct diagnosis, as well as facilitating a prognostic information and treatment therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tavassoli FA, Devilee P. Pathology and Genetics Tumours of the Breast and Female Genital Organs. Lyon: World Health Organization (WHO) Classification of Tumours; 2003. p. 32-4.  Back to cited text no. 1
    
2.
Yaren A, Kelten C, Akbulut M, Teke Z, Duzcan E, Erdem E. Primary neuroendocrine carcinoma of the breast: A case report. Tumori 2007;93:496-8.  Back to cited text no. 2
    
3.
Wei B, Ding T, Xing Y, Wei W, Tian Z, Tang F, et al. Invasive neuroendocrine carcinoma of the breast: A distinctive subtype of aggressive mammary carcinoma. Cancer 2010;116:4463-73.  Back to cited text no. 3
    
4.
Singh S, Aggarwal G, Kataria SP, Kalra R, Duhan A, Sen R. Primary neuroendocrine carcinoma of breast. J Cytol 2011;28:91-2.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Fujimoto Y, Yagyu R, Murase K, Kawajiri H, Ohtani H, Arimoto Y, et al. A case of solid neuroendocrine carcinoma of the breast in a 40-year-old woman. Breast Cancer 2007;14:250-3.  Back to cited text no. 5
    
6.
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. 6
    
7.
Rosen LE, Gattuso P. Neuroendocrine tumors of the breast. Arch Pathol Lab Med 2017;141:1577-81.  Back to cited text no. 7
    
8.
Sapino A, Righi F, Cassoni P, Papotti M, Gugliotta P, Bussolati G. Expression of the neuroendocrine phenomenon in carcinoma of the breast. Semin Diagn Pathol 2000;17:127-37.  Back to cited text no. 8
    
9.
Ellis IO, Schnitt SJ, Sastre-Garau X. Invasive breast carcinoma. In: Tavassoli FA, Devilee P, editors. World Health Organization Classification of Tumours. Pathology and Genetics of the Tumours of Breast and Female Genital Organs. Lyon: IARC Press; 2003. p. 13-59.  Back to cited text no. 9
    
10.
Tavosoli FA. Pathology of the Breast. 1st ed. Norwalk: Connecticut. Appleton and Lange; 2000.  Back to cited text no. 10
    
11.
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. 11
    
12.
Zekioglu O, Erhan Y, Ciriş M, Bayramoglu H. Neuroendocrine differentiated carcinomas of the breast: A distinct entity. Breast 2003;12:251-7.  Back to cited text no. 12
    
13.
Mohanty SK, Kim SA, DeLair DF, Bose S, Laury AR, Chopra S, et al. 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. 13
    
14.
Klimstra DS, Klöppel G, La Rosa S, Rindi G. Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours Editorial Board editors. WHO classification of tumours, 5th ed. Digestive system tumours. Lyon: IARC; 2019. p. 16-9.  Back to cited text no. 14
    
15.
Tan PH, Ellis I, Allison K, Brogi E, Fox SB, Lakhani S, et al. The 2019 World Health Organization classification of tumours of the breast. Histopathology 2020;77:181-5.  Back to cited text no. 15
    
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Irshad A, Ackerman SJ, Pope TL, Moses CK, Rumboldt T, Panzegrau B. Rare breast lesions: Correlation of imaging and histologic features with WHO classification. Radiographics 2008;28:1399-414.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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