CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2022; 82(01): 68-84
DOI: 10.1055/a-1557-1280
GebFra Science
Original Article

Invasive Breast Carcinoma with Neuroendocrine Differentiation: A Single-Center Analysis of Clinical Features and Prognosis

Invasives Mammakarzinom mit neuroendokriner Differenzierung: eine monozentrische Analyse der klinischen Merkmale und Prognose
Natalia Krawczyk
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Rowena Röwer
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Martin Anlauf
2   Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
3   Institute of Pathology, Cytology and Molecular Pathology, St. Vincenz Hospital, Limburg, Germany
,
Caja Muntanjohl
3   Institute of Pathology, Cytology and Molecular Pathology, St. Vincenz Hospital, Limburg, Germany
,
Stephan Ernst Baldus
2   Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
4   Institute of Pathology, Cytology and Molecular Pathology, Bergisch Gladbach, Germany
,
Monika Neumann
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Maggie Banys-Paluchowski
5   Department of Obstetrics and Gynaecology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
6   Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
,
Sabine Otten
2   Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
,
Katharina Luczak
2   Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
,
Eugen Ruckhäberle
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Svjetlana Mohrmann
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Jürgen Hoffmann
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Thomas Kaleta
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Bernadette Jaeger
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
,
Irene Esposito
2   Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
,
Tanja Fehm
1   Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany
› Author Affiliations

Abstract

Introduction Invasive breast cancer with neuroendocrine differentiation is a rare subtype of breast malignancy. Due to frequent changes in the definition of these lesions, the correct diagnosis, estimation of exact prevalence, and clinical behaviour of this entity may be challenging. The aim of this study was to evaluate the prevalence, clinical features, and outcomes in a large cohort of patients with breast cancer with neuroendocrine differentiation.

Patients Twenty-seven cases of breast cancer with neuroendocrine differentiation have been included in this analysis. Twenty-one cases were identified by systematic immunohistochemical re-evaluation of 465 breast cancer specimens using the neuroendocrine markers chromogranin A and synaptophysin, resulting in a prevalence of 4.5%. A further six cases were identified by a review of clinical records.

Results Median age at the time of diagnosis was 61 years. 70% of patients had T2 – 4 tumors and 37% were node-positive. The most common immunohistochemical subtype was HR-positive/HER2-negative (85%). 93% were positive for synaptophysin and 48% for chromogranin A. Somatostatin receptor type 2A status was positive in 12 of 24 analyzed tumors (50%). Neuroendocrine-specific treatment with somatostatin analogues was administered in two patients. The 5-year survival rate was 70%.

Conclusions Breast cancer with neuroendocrine differentiation is mostly HR-positive/HER2-negative and the diagnosis is made at a higher TNM stage than in patients with conventional invasive breast carcinoma. Moreover, breast cancer with neuroendocrine differentiation was found to be associated with impaired prognosis in several retrospective trials. Due to somatostatin receptor 2A expression, somatostatin receptor-based imaging can be used and somatostatin receptor-targeted therapy can be offered in selected cases.

Zusammenfassung

Einleitung Invasives Mammakarzinom mit neuroendokriner Differenzierung ist eine seltene Unterart von Brustkrebs. Da die Definition dieser Läsionen häufig geändert wurde, kann eine korrekte Diagnose sowie eine richtige Einschätzung der genauen Prävalenz und des klinischen Verhaltens dieser Entität Schwierigkeiten bereiten. Ziel dieser Studie war es, die Prävalenz, die klinischen Merkmale und das Outcome in einem großen Patientenkollektiv von Frauen mit Mammakarzinom und neuroendokriner Differenzierung zu evaluieren.

Patientinnen Die Daten von 27 Patientinnen mit Brustkrebs mit neuroendokriner Differenzierung wurden in diese Analyse aufgenommen. 21 Fälle wurden durch eine systematische immunohistochemische Reevaluierung von 465 Brustkrebsproben mit Verwendung der neuroendokrinen Basismarker Chromogranin A und Synaptophysin identifiziert, was einer Prävalenz von 4,5% entspricht. Sechs weitere Fälle wurden durch eine Überprüfung der klinischen Krankenakten indentifiziert.

Ergebnisse Das durchschnittliche Alter zum Zeitpunkt der Diagnose betrug 61 Jahre. 70% der Patientinnen hatten T2 – 4 Tumoren, und 37% hatten positive Lymphknotenbefunde. Die häufigste immunohistochemische Unterart war HR-positiv/HER2-negativ (85%). 93% waren für Synaptophysin und 48% für Chromogranin A positiv. Der Somatostatin-Rezeptor-2A-Status war in 12 von 24 analysierten Tumoren positiv (50%). Zwei Patientinnen erhielten eine neuroendokrin-spezifische Therapie mit Somatostatin-Analoga. Die 5-Jahres-Überlebensrate betrug 70%.

Schlussfolgerungen Brustkrebs mit neuroendokriner Differenzierung ist meist HR-positiv/HER2-negativ, und die Diagnose wird meist in einem höheren TNM-Stadium gestellt als bei Patientinnen mit herkömmlichem invasiven Mammakarzinom. Darüber hinaus war der Brustkrebs mit neuroendokriner Differenzierung in mehreren retrospektiven Studien mit einer schlechten Prognose assoziiert. Im Falle eines positiven SSTR2A-Status kann eine Somatostatin-Rezeptor-basierte Bildgebung eingesetzt werden, und in ausgewählten Fällen eine zielgerichtete Therapie mit Somatostatinanaloga angeboten werden.



Publication History

Received: 03 May 2021

Accepted after revision: 22 July 2021

Article published online:
18 November 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Oronsky B, Ma PC, Morgensztern D. et al. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017; 19: 991-1002
  • 2 Menendez P, Garcia E, Rabadan L. et al. Primary neuroendocrine breast carcinoma. Clin Breast Cancer 2012; 12: 300-303
  • 3 Rindi G, Klimstra DS, Abedi-Ardekani B. et al. 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 2018; 31: 1770-1786
  • 4 Anlauf M, Neumann M, Bomberg S. et al. [Neuroendocrine neoplasms of the breast]. Pathologe 2015; 36: 261-270
  • 5 Cubilla AL, Woodruff JM. Primary carcinoid tumor of the breast: A report of eight patients. Am J Surg Pathol 1977; 1: 283-292
  • 6 Feyrter F, Hartmann G. [On the Carcinoid Growth Form of the Carcinoma Mammae, Especially the Carcinoma Solidum (Gelatinosum) Mammae]. Frankf Z Pathol 1963; 73: 24-39
  • 7 Sapino A, Righi L, Cassoni P. et al. Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol 2000; 17: 127-137
  • 8 Ellis IO, Schnitt SJ, Sastre-Garau X, Bussolati G, Tavassoli FA, Eusebi V, Peterse JL, Mukai K, Tabár L, Jacquemier J, Cornelisse CJ, Sasco AJ, Kaaks R, Pisani P, Goldgar DE, Devilee P, Cleton-Jansen MJ, Børresen-Dale AL, vanʼt Veer L, Sapino A. Invasive breast carcinoma. In: Tavassoli FA, Devilee P. eds. World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003: 13-59
  • 9 Bussolati GBS. 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. World Health Organization Classification of Tumours; Vol. 4. Lyon, France: IARC Press; 2012: 62-63
  • 10 Tan PH, Ellis I, Allison K. et al. The 2019 World Health Organization classification of tumours of the breast. Histopathology 2020; 77: 181-185
  • 11 Schneeweiss A, Hartkopf AD, Müller V. et al. Update Breast Cancer 2020 Part 1 – Early Breast Cancer: Consolidation of Knowledge About Known Therapies. Geburtshilfe Frauenheilkd 2020; 80: 277-287
  • 12 Lüftner D, Schneeweiss A, Hartkopf AD. et al. Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics. Geburtshilfe Frauenheilkd 2020; 80: 391-398
  • 13 Huober J, Schneeweiss A, Hartkopf AD. et al. Update Breast Cancer 2020 Part 3 – Early Breast Cancer. Geburtshilfe Frauenheilkd 2020; 80: 1105-1114
  • 14 Tesch H, Müller V, Wöckel A. et al. Update Breast Cancer 2020 Part 4 – Advanced Breast Cancer. Geburtshilfe Frauenheilkd 2020; 80: 1115-1122
  • 15 Lux MP, Schneeweiss A, Hartkopf AD. et al. Update Breast Cancer 2020 Part 5 – Moving Therapies From Advanced to Early Breast Cancer Patients. Geburtshilfe Frauenheilkd 2021; 81: 469-480
  • 16 Tavassoli FA, Devilee P. World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: WHO; 2003: 9-112
  • 17 Wang J, Wei B, Albarracin CT. et al. Invasive neuroendocrine carcinoma of the breast: a population-based study from the surveillance, epidemiology and end results (SEER) database. BMC Cancer 2014; 14: 147
  • 18 Sawaki M, Yokoi K, Nagasaka T. et al. Prognostic importance of neuroendocrine differentiation in Japanese breast cancer patients. Surg Today 2010; 40: 831-835
  • 19 Bogina G, Munari E, Brunelli M. et al. Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome. Histopathology 2016; 68: 422-432
  • 20 van Krimpen C, Elferink A, Broodman CA. et al. The prognostic influence of neuroendocrine differentiation in breast cancer: results of a long-term follow-up study. Breast 2004; 13: 329-333
  • 21 Makretsov N, Gilks CB, Coldman AJ. et al. Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer. Hum Pathol 2003; 34: 1001-1008
  • 22 Park YM, Wu Y, Wei W. et al. Primary neuroendocrine carcinoma of the breast: clinical, imaging, and histologic features. AJR Am J Roentgenol 2014; 203: W221-W230
  • 23 Zhu Y, Li Q, Gao J. et al. Clinical features and treatment response of solid neuroendocrine breast carcinoma to adjuvant chemotherapy and endocrine therapy. Breast J 2013; 19: 382-387
  • 24 Marton I, Knezevic F, Ramic S. et al. Immunohistochemical expression and prognostic significance of HIF-1alpha and VEGF-C in neuroendocrine breast cancer. Anticancer Res 2012; 32: 5227-5232
  • 25 Howlader NNA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. eds. http://
  • 26 Kwon SY, Bae YK, Gu MJ. et al. Neuroendocrine differentiation correlates with hormone receptor expression and decreased survival in patients with invasive breast carcinoma. Histopathology 2014; 64: 647-659
  • 27 Lavigne M, Menet E, Tille JC. et al. Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. Mod Pathol 2018; 31: 68-82
  • 28 Wei B, Ding T, Xing Y. et al. Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer 2010; 116: 4463-4473
  • 29 Zhang Y, Chen Z, Bao Y. et al. Invasive neuroendocrine carcinoma of the breast: a prognostic research of 107 Chinese patients. Neoplasma 2013; 60: 215-222
  • 30 Roininen N, Takala S, Haapasaari KM. et al. Primary neuroendocrine breast carcinomas are associated with poor local control despite favourable biological profile: a retrospective clinical study. BMC Cancer 2017; 17: 72
  • 31 Cloyd JM, Yang RL, Allison KH. et al. Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast. Breast Cancer Res Treat 2014; 148: 637-644
  • 32 Rovera F, Lavazza M, La Rosa S. et al. Neuroendocrine breast cancer: retrospective analysis of 96 patients and review of literature. Int J Surg 2013; 11 (Suppl. 01) 79-83
  • 33 Righi L, Sapino A, Marchio C. et al. Neuroendocrine differentiation in breast cancer: established facts and unresolved problems. Semin Diagn Pathol 2010; 27: 69-76
  • 34 Tse GM, Ma TK, Chu WC. et al. Neuroendocrine differentiation in pure type mammary mucinous carcinoma is associated with favorable histologic and immunohistochemical parameters. Mod Pathol 2004; 17: 568-572
  • 35 Charfi S, Ayed CB, Mnif H. et al. Mammary neuroendocrine carcinoma with mucinous differentiation: a clinicopathological study of 15 cases. Breast Dis 2013; 34: 87-93
  • 36 Miremadi A, Pinder SE, Lee AH. et al. Neuroendocrine differentiation and prognosis in breast adenocarcinoma. Histopathology 2002; 40: 215-222
  • 37 Zekioglu O, Erhan Y, Ciris M. et al. Neuroendocrine differentiated carcinomas of the breast: a distinct entity. Breast 2003; 12: 251-257
  • 38 Lopez-Bonet E, Alonso-Ruano M, Barraza G. et al. Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 2008; 20: 1369-1374
  • 39 Papotti M, Macri L, Bussolati G. et al. Correlative study on neuro-endocrine differentiation and presence of somatostatin receptors in breast carcinomas. Int J Cancer 1989; 43: 365-369
  • 40 Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 2003; 24: 389-427
  • 41 Kumar U, Grigorakis SI, Watt HL. et al. Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1–5 and correlation with receptor protein expression and tumor pathology. Breast Cancer Res Treat 2005; 92: 175-186
  • 42 Buscail L, Esteve JP, Saint-Laurent N. et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci U S A 1995; 92: 1580-1584
  • 43 Terlevic R, Peric Balja M, Tomas D. et al. Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer. Ann Diagn Pathol 2019; 38: 62-66
  • 44 Phan AT, Dasari A, Liyanage N. et al. Tumor response in the CLARINET study of lanreotide depot vs. placebo in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). J Clin Oncol 2016; 34(4_suppl): 434
  • 45 Pavel M, Öberg K, Falconi M. et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31: 844-860
  • 46 Özdirik B, Kayser A, Ullrich A. et al. Primary Neuroendocrine Neoplasms of the Breast: Case Series and Literature Review. Cancers (Basel) 2020; 12: 733
  • 47 Latif N, Rosa M, Samian L. et al. An unusual case of primary small cell neuroendocrine carcinoma of the breast. Breast J 2010; 16: 647-651
  • 48 Dolan JT, Miltenburg DM, Granchi TS. et al. Treatment of metastatic breast cancer with somatostatin analogues–a meta-analysis. Ann Surg Oncol 2001; 8: 227-233
  • 49 Chapman JA, Costantino JP, Dong B. et al. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat 2015; 153: 353-360