neuroendocrine breast cancer NEBC non-palpable breast lesion NPBL NEBC

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1 TUMOR Vol. 33, February Clinical Research DOI: /j.issn Copyright 2013 by TUMOR 10 1* 1* neuroendocrine breast cancer NEBC NEBC NEBC non-palpable breast lesion NPBL NEBC X NEBC estrogen receptor ER progesterone receptor PR 2 human epidermal growth factor receptor 2 HER2 A chromgranin A CgA synapsin Syn 2 1 NEBC breast cancer with neuroendocrine differentiation BC-NE NEBC R737.9 A (2013) Diagnosis and treatment of neuroendocrine breast cancer: A retrospective analysis of ten cases and review of the literature MAO Feng 1*, PAN Bo 1*, SUN Qiang 1, WANG Chang-jun 1, WANG Xue-fei 1, ZHOU Yi-dong 1, GUAN Jinghong 1, ZHAO Da-chun 2, LI Wen-bo 3, ZHU Qing-li 3, LIANG Zhi-yong 2 1. Department of Breast Surgery; 2. Department of Pathology; 3. Department of Diagnostic Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing , China To investigate the characteristics of clinical manifestations, diagnosis and treatment of NEBC (neuroendocrine breast cancer). This was a retrospective study. Ten consecutive female patients with NEBC were admitted in Department of Breast Surgery, Peking Union Medical College Hospital between January 2004 and December The average age of the ten patients was 52 years, and the follow-up period was months (median 84 months). Clinically, most of the NEBC manifested as breast lump, sometimes as NPBL (non-palpable breast lesion) or nipple discharge. An ultrasound examination usually revealed heterogeneous echoic mass with irregular shape and clear boundary. Mammography showed no significantly different changes from other kinds of breast cancer. Nine patients received curative resection for NEBC, among whom, seven underwent modified radical mastectomy, one underwent nipple and areola-sparing modified radical mastectomy, one with nipple discharge underwent excision of duct and relevant lobule and hook-wire-guided biopsy of breast lump, and later right mastectomy with sentinel lymph node biopsy. The expressions of hormone receptors like ER (estrogen receptor) /PR (progesterone receptor) were usually positive in NEBC, while the Correspondence to: SUN Qiang sunqiangpumc@sina.com The authors declare no conflicts of interest. *2 Received Accepted

2 expression of HER2 (human epidermal growth factor receptor 2) was usually negative ( ) to positive (+). At least one neuroendocrine marker like Syn (synapsin) or CgA (chromgranin A) was positive. During the follow-up period, metastasis was found in two patients and one of them had passed away. NEBC is a clinical entity different from breast cancer with BC-NE (breast cancer with neuroendocrine differentiation). NEBC may affect younger patients in China, ultrasound examination is valuable for diagnosis, and surgical and comprehensive therapy may achieve satisfactory outcome with relatively good prognosis, although there might be cases of metastasis. Breast neoplasms; Carcinoma, neuroendocrine; Diagnosis; Therapy [TUMOR, 2013, 33 (02): ] neuroendocrine breast cancer NEBC 1% 3% [1, 2] World Health Organization WHO NEBC 50% NEBC [1, 3] NEBC NEBC NEBC NEBC NEBC NEBC % 10/ B non-palpable breast lesion NPBL CT CT 2 NEBC 50% invasive ductal carcinoma with neuroendocrine differentiation IDC-NE carcinoma in situ with neuroendocrine differentiation CIS-NE A chromgranin A CgA synapsin Syn disease-free survival DFS 2 DFS overall survival OS 1.6 Kaplan-Meier DFS OS NEBC 1 color Doppler flow index CDFI cm cm

3 NPBL 2 core-needle biopsy CNB NEBC CT NEBC T ptis pt 2 N pn 0 pn 1 M estrogen receptor ER 100% 10/10 progesterone receptor PR 70% 7/10 2 human epidermal growth factor receptor 2 HER2 CgA Syn 1 Syn 100% 10/10 CgA 50% 5/ % 2 20% A 4 40% 2 20% cm 2 PA 5 TA PA 2 GA VP PA cm Fig. 1 Ultrasonography showed that NEBC often manifests as hypoechoic mass with irregular contour, clear boundary (see Fig. 1A and 1C), and abundant arterial blood supply (see Fig. 1B and 1D). NEBC: Neuroendocrine breast cancer. 1 Fig. 2 Histology and immunohistochemistry of NEBC. Fig. 2A and 2B showed the tumor cells in NEBC which were arranged in a palisade manner or in an islet style separated by fibrous septa (hematoxylin and eosin staining, 100). Fig. 2C and 2D showed the positive expressions of CgA and Syn in NEBC (immunohistochemistry, 150). NEBC: Neuroendocrine breast cancer; CgA: Chromgranin A; Syn: Synapsin. 2

4 Table 1 The clinicopathological characteristics, surgical procedures and pre- and post-operative therapies for ten patients with NEBC Case No. Gender Age/year Clinical Manifestations Surgical procedure Pathology Comprehensive therapy Disease-free survival t/month Follow-up results 1 Female 30 Discharge from the right breast nipple Resection of the duct and relevant lobule plus Hookwire-guided open biopsy of right breast lump; mastectomy of right breast plus sentinel lymph node biopsy 2 Female 42 Breast lump Excisional biopsy followed by modified radical mastectomy 3 Female 43 Breast lump Excisional biopsy modified radical mastectomy 4 Female 45 NPBL Hookwire-guided excisional biopsy modified radical mastectomy Right NEBC (histological grade 1, tumor 0.4 cm in diameter), mostly intra-ductal growth, with focal invasion; IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 20%, p53 ( ); SLN (0/1) Left invasive NEBC (histological grade 2, tumor size 2.0 cm 1.5 cm 1.0 cm); IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 50%, p53 ( ); LN (1/23) Right solid NEBC (histological grades 2-3, tumor size 1.1 cm 1.2 cm 0.6 cm); IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 75%, p53 ( ); LN (0/18) Right NEBC (histological grade 1, tumor less than 6 mm in diameter); IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ); LN (0/13) 5 Female 51 Breast lump Nipple sparing mastectomy Breast NEBC (histological grade and tumor size were unclear); IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ); LN (0/13) 6 Female 52 Pulmonary nodule post breast cancer surgery Bronchoscopic biopsy of lung tumors 7 Female 54 Breast lump Excisional biopsy modified radical mastectomy 8 Female 56 Breast lump CNB followed by modified radical mastectomy 9 Female 70 Breast lump CNB followed by modified radical mastectomy 10 Female 77 Status post excisional biopsy of breast lump Ectopic cells infiltrating the submucosa of right brochus; IHC: ER ( ), PR ( ), HER2 ( ), CgA (focal ), Syn ( ), Ki-67 and p53 (unclear). Impression: Histological grades 1-2 neuroendocrine carcinoma originated from the breast. Right NEBC (histological grades 2-3, tumor size 1.1 cm 1.2 cm 0.6 cm); IHC: ER ( ), PR ( ), HER2 ( ), CgA (focal ), Syn ( ), Ki-67 80%, p53 ( ), CD56 ( ), E-cadherin ( ); LN (1/19) Right NEBC (histological grade 2, tumor size 3.0 cm 2.9 cm 2.2 cm) with subcutaneous infiltration; IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 5%, p53 ( ); LN (0/24) Right NEBC (histological grades 1-2, tumor size 2.5 cm 2.2 cm 1.7 cm); IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 10%, p53 ( ); LN (0/17) Modified radical mastectomy Malignant nodule was found in axillary fatty tissues (histological grade 2, tumor 1.1 cm in diameter) and NEBC was considered; IHC: ER ( ), PR ( ), HER2 ( ), CgA ( ), Syn ( ), Ki-67 15%, p53 ( ); LN (0/25) Endocrine therapy 12 Alive, good general Adjuvant chemotherapy with TA regimen and endocrine therapy Adjuvant chemotherapy and endocrine therapy 11 Alive, good general 78 Alive, good general Endocrine therapy 43 Alive, good general Adjuvant radiotherapy endocrine therapy; rescue chemotherapy with GA and VP regimens after metastasis Endocrine therapy; rescue chemotherapy with two cycles of VP regimen and six cycles of PA regimen after metastasis Adjuvant chemotherapy with PA regimen and endocrine therapy Neoadjuvant chemotherapy with PA regimen; adjuvant chemo- and radio-therapy 70 Metastases in bone, lungs and pleura with malignant pleuritis; alive and independent 144 Lung metastasis in 2007 and died in Alive, good general 71 Alive, good general Endocrine therapy 71 Alive, good general Endocrine therapy 49 Alive, good general NEBC: Neuroendocrine breast cancer; NPBL: Non-palpable breast lesion; CNB: Core-needle biopsy; IHC: Immunohistochemistry; ER: Estrogen receptor; PR: Progesterone receptor; HER2: Human epidermal growth factor receptor 2; CgA: Chromgranin A; Syn: Synapsin; SLN: Sentinel lymph node; LN: Lymph node; TA: Docetaxel plus epirubicin; GA: Gemcitabine plus epirubicin; VP: Etoposide plus cisplatin; PA: Paclitaxel plus epirubicin.

5 DFS 78 2 DFS 70% 2 OS 90% 2 20% [4, 5] 30% 50% breast cancer with neuroendocrine differentiation BC-NE NEBC WHO NEBC 50% Syn CgA B chromgranin B CgB neuron-specific enolase NSE BC-NE 2.0% 5.6% [2, 6] NEBC 0.13% 0.27% [7, 8] NEBC 0.39% 10/2 558 NEBC [3] [8] [4] 5 NEBC 70 NEBC 52 NEBC NPBL [9] 7 NEBC NEBC NEBC X Wu [10] NEBC [8, 10] 8 NEBC NEBC NEBC CDFI NEBC NEBC cm [8] Wu [10] Ogawa [11] NEBC NEBC / A B apocrine amphicrine 26% NEBC WHO NEBC NEBC luminal [1] 1 NEBC basal-type cytokeratins [12] NEBC [1, 13] ER PR NEBC ER NEBC [13] NEBC HER2 NEBC [14, 15] NEBC Zhang [16] 107 NEBC NEBC

6 PR NEBC 1 12 DFS NEBC 2 DFS 70% 2 OS 90% 2 DFS 2 OS [ % DFS 94% OS 98% 5 DFS 86% 5 OS 96%] NEBC NEBC NEBC 30 NEBC NEBC Meta NEBC [ ] [1] RIGHI L, SAPINO A, MARCHIÒ C, et al. Neuroendocrine differentiation in breast cancer: established facts and unresolved problems[j]. Semin Diagn Pathol, 2010, 27(1): [2] ROVERA F, MASCIOCCHI P, COGLITORE A, et al. Neuroendocrine carcinomas of the breast[j]. Int J Surg, 2008, Suppl 1:S113-S115. [3] ZEKIOGLU O, ERHAN Y, CIRIS M, et al. Neuroendocrine differentiated carcinomas of the breast: a distinct entity[j]. Breast, 2003, 12(4): [4]. [J]., 1996, 3(3): [5] CUBILLA A L, WOODRUFF J M. Primary carcinoid tumor of the breast. A report of eight patients[j]. Am J Surg Pathol, 1977, 1: [6] SCOPSI L, ANDREOLA S, PILOTTI S, et al. Argyrophilia and granin (chromogranin/ secretogranin) expression in female breast carcinomas. Their relationship to survival and other disease parameters[j]. Am J Surg Pathol, 1992, 16(6): [7] GÜNHAN-BILGEN I, ZEKIOGLU O, USTÜN E E, et al. Neuroendocrine differentiated breast carcinoma: imaging features correlated with clinical and histopathological findings[j]. Eur Radiol, 2003, 13(4): [8],,. [J]., 2009, 25(4): [9],,,. [J]., 2007, 17(5): [10] WU J, YANG Q X, WU Y P, et al. Solid neuroendocrine breast carcinoma: mammographic and sonographic features in thirteen cases[j]. Chin J Cancer, 2012, 31(11): [11] OGAWA H, NISHIO A, SATAKE H, et al. Neuroendocrine tumor in the breast[j]. Radiat Med, 2008, 26(1): [12] ERSAHIN C, BANDYOPADHYAY S, BHARGAVA R. Thyroid transcription factor-1 and basal marker --expressing small cell carcinoma of the breast[j]. Int J Surg Pathol, 2009, 17(5): [13] BERRUTI A, SAINI A, LEONARDO E, et al. Management of neuroendocrine differentiated breast carcinoma[j]. Breast, 2004, 13(6): [14] WATROWSKI R, JÄGER C, MATTERN D, et al. Neuroendocrine carcinoma of the breast-- diagnostic and clinical implications[j]. Anticancer Res, 2012, 32(11): [15] YAVAS G, KARABAGLI P, ARAZ M, et al. HER-2 positive primary solid neuroendocrine carcinoma of the breast: a case report and review of the literature[j]. Breast Cancer, 2012, 19, [Epub ahead of print]. [16] ZHANG Y, CHEN Z, BAO Y, et al. Invasive neuroendocrine carcinoma of the breast: a prognostic research of 107 Chinese patients[j]. Neoplasma, 2013, 60(2): [ ]