Abstract
Neuroendocrine neoplasms of the breast (Br-NENs) are rare tumors of the mammary gland. Their definition and classification have been a matter of discussion for more than half a century, as they present some degree of overlap with other malignancies in the mammary gland. The recent evolutions in the understanding of the pathogenesis of neuroendocrine neoplasms (NENs) as well as the novel tools in the diagnostic arsenal of the pathologists, and a better correlation with clinical data, have led to improved classification schemes for these entities, beginning from those arising in digestive and thoracic organs. These new classification concepts have been recently expanded to NENs arising in every anatomical site, with the proposal of a common classification framework that has been applied in the 5th edition of the WHO classification of tumors. These concepts include the recognition of two distinct families of NENs (neuroendocrine tumors, NETs, and neuroendocrine carcinomas, NECs), the identification of mixed neuroendocrine/non-neuroendocrine neoplasms, and the application of definite morphological and immunohistochemical criteria for the diagnosis of NENs. The last WHO classification of Br-NENs, however, still seems to leave several unanswered questions and unmet needs in the understanding of diagnostic and clinical features of these entities. This review will critically revise the current classification of Br-NENs, underlining its lights and shadows and focusing on the identification of diagnostic histopathological criteria that can help the univocal recognition of Br-NET, Br-NEC, and Br-MiNEN.
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References
Feyrter F, Hartmann G (1963) Uber die carcinoide Wuchsform der carcinoma mammae, insbesondere das carcinoma solidum (gelatinosum) mammae. Frankf Z Pathol 73:24–39
Uccella S, Finzi G, Sessa F, La Rosa S (2020) On the endless dilemma of neuroendocrine neoplasms of the breast: a journey through concepts and entities. Endocr Pathol 31(4):321–329. https://doi.org/10.1007/s12022-020-09637-y
Gallo M, Campione S, Di Vito V, Fortunati N, Lo Calzo F, Messina E, Ruggeri RM, Faggiano A, Colao AAL (2021) Primary neuroendocrine neoplasms of the breast: still open issues. Front Endocrinol (Lausanne). 26(11):610230. https://doi.org/10.3389/fendo.2020.610230.PMID:33584543;PMCID:PMC7874233
Ellis P, Schnitt SJ, Sastre-Garau X et al (2003) Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) Tumours of the breast and female genital organs: pathology and genetics. IARC Press, Lyon, pp 13–59
Bussolati G, Badve S (2012) Carcinomas with neuroendocrine features. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (eds) WHO classification of tumours of the breast. IARC Press, Lyon, pp 62–63
Klöppel G (2017) Neuroendocrine neoplasms: dichotomy, origin and classifications. Visc Med. 33(5):324–330. https://doi.org/10.1159/000481390
Uccella S, La Rosa S, Metovic J, Marchiori D, Scoazec JY, Volante M, Mete O, Papotti M (2021) Genomics of high-grade neuroendocrine neoplasms: well-differentiated neuroendocrine tumor with high-grade features (G3 NET) and neuroendocrine carcinomas (NEC) of various anatomic sites. Endocr Pathol 32(1):192–210. https://doi.org/10.1007/s12022-020-09660-z
Rindi G, Klimstra DS, Abedi-Ardekani B et al (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 31:1770–1786
La Rosa S, Sessa F, Uccella S (2016) mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 27(4):284–311. https://doi.org/10.1007/s12022-016-9432-9
Rakha EA, Reis-Filho JS, Sasano H, Wu Y (2019) Neuroendocrine neoplasms: introduction. In: WHO classification of tumours editorial board. Breast tumours. WHO classification of tumours series, 5th ed. IARC, Lyon, p 155
WHO Classification of Tumors Editorial Board (2020) Female genital tumours. 5th Edition. Lyon: International Agency for Research on Cancer World Health Organisation
WHO Classification of Tumors Editorial Board (2021) Thoracic tumours. 5th Edition. Lyon: International Agency for Research on Cancer World Health Organisation
Inno A, Bogina G, Turazza M, Bortesi L, Duranti S, Massocco A, Zamboni G, Carbognin G, Alongi F, Salgarello M, Gori S (2016) Neuroendocrine carcinoma of the breast: current evidence and future perspectives. Oncologist. 21(1):28–32. https://doi.org/10.1634/theoncologist.2015-0309
Rakha EA, Reis-Filho JS, Sasano H, Wu Y (2019) Neuroendocrine tumor. In: WHO classification of tumours editorial board. Breast tumours. WHO classification of tumours series, 5th ed. IARC: Lyon, pp 156-158
Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY et al (2017) Risk Factors and preventions of breast cancer. Int J Biol Sci 13(11):1387–1397. https://doi.org/10.7150/ijbs.21635
Marchiò C, Geyer FC, Ng CK, Piscuoglio S, De Filippo MR, Cupo M, Schultheis AM, Lim RS, Burke KA, Guerini-Rocco E, Papotti M, Norton L, Sapino A, Weigelt B, Reis-Filho JS (2017) The genetic landscape of breast carcinomas with neuroendocrine differentiation. J Pathol. 241(3):405–419. https://doi.org/10.1002/path.4837
Lavigne M, Menet E, Tille JC, Lae M, Fuhrmann L, Bonneau C, Deniziaut G, Melaabi S, Ng CCK, Marchiò C, Rouzier R, Bièche I, Vincent-Salomon A (2018) Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. Mod Pathol 31(1):68–82. https://doi.org/10.1038/modpathol.2017.107
Bussolati G, Gugliotta P, Sapino A, Eusebi V, Lloyd RV (1985) Chromogranin-reactive endocrine cells in argyrophilic carcinomas (“carcinoids”) and normal tissue of the breast. Am J Pathol. 120(2):186–92
Miremadi A, Pinder SE, Lee AH, Bell JA, Paish EC, Wencyk P, Elston CW, Nicholson RI, Blamey RW, Robertson JF, Ellis IO (2002) Neuroendocrine differentiation and prognosis in breast adenocarcinoma. Histopathology 40(3):215–222. https://doi.org/10.1046/j.1365-2559.2002.01336.x
Tang F, Wei B, Tian Z, Gilcrease MZ, Huo L, Albarracin CT, Resetkova E, Zhang H, Sahin A, Chen J, Bu H, Abraham S, Wu Y (2011) Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges. Histopathology 59(1):106–115. https://doi.org/10.1111/j.1365-2559.2011.03880.x
Metovic J, Castellano I, Marinelli E, Osella-Abate S, Sapino A, Cassoni P, Papotti M (2021) INSM1 Expression in breast neoplasms with neuroedocrine features. Endocr Pathol. https://doi.org/10.1007/s12022-021-09682-1
Terlević R, Perić Balja M, Tomas D, Skkenderi F, Kruslin B, Vranic S, Demirovic A (2019) Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer. Ann Diagn Pathol 38:62–66
Kelten Talu C, Savli TC, Huq GE, Leblebici C (2019) Histopathological and clinical differences between primary breast carcinomas with neuroendocrine features and primary breast carcinomas mimicking neuroendocrine features. Int J Surg Pathol 27(7):744–752. https://doi.org/10.1177/1066896919851873
Lai BS, Tsang JY, Poon IK, Shao Y, Chan SK, Tam FK, Cheung SY, Shea KH, Tse GM (2020) The clinical significance of neuroendocrine features in invasive breast carcinomas. Oncologist. 25(9):e1318–e1329. https://doi.org/10.1634/theoncologist.2020-0081
Sapino A, Righi L, Cassoni P, Papotti M, Gugliotta P, Bussolati G (2001) Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women. Mod Pathol 14:768–776
Uccella S, Asa SL, Mete O. Metastatic neuroendocrine neoplasms of unknown primary Site. In: Asa SL, La Rosa S, Mete O (eds) The Spectrum of Neuroendocrine Neoplasia. Springer: Cham. https://doi.org/10.1007/978-3-030-54391-4_16
Irelli A, Sirufo MM, Morelli L, D’Ugo C, Ginaldi L, De Martinis M (2020) Neuroendocrine cancer of the breast: a rare entity. J Clin Med 9(5):1452. https://doi.org/10.3390/jcm9051452
Rakha EA, Reis-Filho JS, Wu Y (2019) Neuroendocrine carcinoma. In: WHO classification of tumours editorial board. Breast tumours. WHO classification of tumours series, 5th ed. IARC, Lyon, pp 159-161
McCullar B, Pandey M, Yaghmour G, Hare F, Patel K, Stein K, Feldman R, Chandler JC, Martin MG (2016) Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung. Breast Cancer Res Treat 158:195–202
Shin SJ, DeLellis RA, Ying L, Rosen PP (2000) Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 24:1231–1238
Uccella S, La Rosa S, Volante M, Papotti M (2018) Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol 29(2):150–168. https://doi.org/10.1007/s12022-018-9522-y
Yang L, Roy M, Lin H, Shen Y, Albarracin C, Huo L, Chen H, Wei B, Bedrosian I, Bu H, Wu Y (2021) Validation of prognostic significance of the proposed uniform classification framework in neuroendocrine neoplasms of the breast. Breast Cancer Res Treat 186(2):403–415. https://doi.org/10.1007/s10549-021-06099-6
Özdirik B, Kayser A, Ullrich A, Savic LJ, Reiss M, Tacke F, Wiedenmann B, Jann H, Roderburg C (2020) Primary neuroendocrine neoplasms of the breast: case series and literature review. Cancers (Basel). 12(3):733. https://doi.org/10.3390/cancers12030733
Pini GM, Uccella S, Corinti M, Colecchia M, Pelosi G, Patriarca C (2021) Primary MiNEN of the urinary bladder: an hitherto undescribed entity composed of large cell neuroendocrine carcinoma and adenocarcinoma with a distinct clinical behavior: description of a case and review of the pertinent literature. Virchows Arch. 479(1):69–78. https://doi.org/10.1007/s00428-021-03023-7
Maragliano R, Libera L, Carnevali I, Pensotti V, De Vecchi G, Testa M, Amaglio C, Leoni E, Formenti G, Sessa F, Furlan D, Uccella S (2013) mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN) of the ovary arising from endometriosis: molecular pathology analysis in support of a pathogenetic paradigm. Endocr Pathol 3. https://doi.org/10.1007/s12022-021-09689-8
Uccella S, La Rosa S (2020) Looking into digestive mixed neuroendocrine - nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors. Histopathology 77(5):700–717. https://doi.org/10.1111/his.14178
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Uccella, S. The classification of neuroendocrine neoplasms of the breast and its clinical relevance. Virchows Arch 481, 3–12 (2022). https://doi.org/10.1007/s00428-021-03223-1
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DOI: https://doi.org/10.1007/s00428-021-03223-1