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前情提要 乳腺神经内分泌癌约占所有乳腺癌的0.3%～0.5%【1,2】。 由于乳腺神经内分泌癌罕见，目前在中国对该病的了解仅限于个例报告和小样本病例，仍然缺乏大样本数据分析。 2017年5月11日，英国生物医学中心（BMC）出版、中山大学肿瘤防治中心旗下《癌症》在线发表中国医学科学院北京协和医学院肿瘤医院和国家癌症中心李轶群（音）、杜丰、朱闻捷、徐兵河的研究报告，进行了迄今为止最全面的文献检索，分析了126例中国人群乳腺神经内分泌癌的临床病理特征、治疗和转归。 本研究报道了1990～2015年中国医学科学院北京协和医学院肿瘤医院和国家癌症中心诊断的7例乳腺神经内分泌癌病例。此外，还对万方和维普数据库进行文献检索，收集并审阅了2003～2015年发表的文献。非中国期刊发表的乳腺神经内分泌癌病例报告未被收入。若超过50%的组织标本显示神经内分泌标志物，而且确定为导管原位癌和/或影像学检查排除乳房外转移，则确认诊断。计算流行病学、临床和病理学特征、治疗和随访的描述性统计学指标。 该院诊断的7例患者（女性6例，男性1例）中位年龄49岁（范围33～78岁）。所有患者均表现为乳房肿块，1例患者出现皮肤溃疡。其中，5例患者为分化良好的疾病亚型，2例患者分化不良。5例患者为管腔亚型早期病变。6例患者接受化疗和手术，1例患者仅接受化疗。雌激素受体阳性患者接受内分泌疗法。随访时间范围为31～59个月。末次随访5例患者无肿瘤，1例死于其他原因，1例失访。 文献检索得到乳腺神经内分泌癌126例，包括该院病例。本研究分析了中国126例乳腺神经内分泌癌病例的临床病理特征。患者平均年龄53.2岁，其中男性7例（5.6%）、女性119例（94.4%）。几乎所有患者（124例，98.4%）表现为乳房肿块，6例（4.8%）有血性乳头溢液。85例经过超声检查和66例经过乳腺钼靶检查的患者未发现乳腺神经内分泌癌特有影像。大多数患者（100例，79.4%）接受乳房切除手术，小部分患者（18例，14.3%）接受保乳手术，7例（5.5%）患者接受乳房手术但是相应报告未说明手术确切类型，1例患者（0.8%）仅接受化疗。共有55例患者接受辅助化疗，其中53例最初接受乳腺导管浸润癌治疗，其中51例接受蒽环类和紫杉类治疗方案，2例接受依托泊苷和顺铂治疗方案，2例接受小细胞癌常用治疗方案。 根据2012年世界卫生组织（WHO）分类，52例分化良好，26例分化不良，其余48例无病理学分类。I、II、III、IV期乳腺癌患者比例分别为：23.8%（30例）、47.6%（60例）、11.1%（14例）、3.2%（4例）；其余18例无病理学分期。雌激素受体、孕激素受体表达患者分别为102例（81.0%）、91例（72.2%），人表皮生长因子受体2（HER2）蛋白过表达患者19例（15.1%）。 所有病例超过50%的肿瘤细胞至少有一种神经内分泌标志（嗜铬粒蛋白A[CgA]、突触小泡蛋白[Syn]、神经元特异性烯醇化酶[NSE]）。 随访时间范围为4～144个月。发现疾病复发13例，其中小细胞型（分化不良）4例和非小细胞型（分化良好）9例。7例患者死于乳腺神经内分泌癌，其中4例为小细胞型、3例为非小细胞型。 对于中国的乳腺神经内分泌癌患者，确定平均年龄为53.2岁，这似乎早于导管浸润癌的发病年龄【3】。本研究6例患者出现了血性乳头溢液。Kawasaki等【4】检查了89例有血性乳头溢液症状而入院彻底检查患者的病理学，发现其中24例（27.0%）有神经内分泌癌。乳腺神经内分泌癌可能占有乳头溢液相关乳房病变重要份额。根据既往研究报告的影像学资料进行比较，乳腺神经内分泌癌与导管浸润癌无差异【5,6】，这在本研究中得到证实。此外，在本研究中，大多数乳腺神经内分泌癌病例显示雌激素受体表达阳性，支持最近对基因表达谱的研究结果【7】，表明乳腺神经内分泌癌主要属于管腔型。 目前，乳腺神经内分泌癌尚无标准疗法，文献报道的大多数治疗方法与本研究的治疗方法与导管癌治疗相似，一线疗法为手术，其次为蒽环类、紫杉类化疗和内分泌疗法【1,8】。然而，乳腺神经内分泌癌患者能否获益于化疗尚不明确。目前的数据提供很少证据支持使用小细胞或非小细胞癌方案。 已经发表的乳腺神经内分泌癌患者预后结果互相矛盾【8-10】。本研究126例乳腺神经内分泌癌患者有小细胞癌18例、非小细胞癌60例，其中分别有9例（50.0%）、51例（85.0%）健在且无肿瘤复发。总体而言，死于乳腺神经内分泌癌患者7例，其中小细胞乳腺癌4例（57.1%）。 因此，由于2003年世界卫生组织首次将乳腺神经内分泌癌列为独立疾病分类，许多乳腺神经内分泌癌病例仍有待阐明其病因和治疗。本研究发现中国乳腺神经内分泌癌患者的发病年龄似乎大于导管浸润癌患者。血性乳头溢液可能提示存在乳腺神经内分泌癌。大多数乳腺神经内分泌癌患者为管腔亚型疾病。手术用于一线疗法，化疗的作用尚不清楚。小细胞亚型与非小细胞亚型相比，可能与较高的复发率和死亡率有相关性。 Chin J Cancer. 2017 May 11;36(1):45. Neuroendocrine carcinoma of the breast: a review of 126 cases in China. Li Y, Du F, Zhu W, Xu B. Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China. Neuroendocrine carcinoma of the breast (NECB) accounts for approximately 0.3%-0.5% of all breast cancers [1,2]. Due to the rarity of NECB, current understanding of this disease in China is limited to case reports and small case series, and large data analysis is still lacking. Therefore, we conducted the most comprehensive literature search to date, aiming to analyze the clinicopathologic characteristics as well as treatment and outcome of NECB in the Chinese population. In the present study, we reported seven NECB cases diagnosed between 1990 and 2015 at the National Cancer Center & Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Additionally, we performed a literature search of the Wanfang and Weipu databases (using the following key words: breast, neuroendocrine, tumor/carcinoma/neoplasm/cancer, primary tumor/carcinoma/neoplasm/cancer, and breast tumor/carcinoma/neoplasm/cancer). Articles published between 2003 and 2015 were collected and reviewed (Table 1). NECB case reports published in non-Chinese journals were not included in this study. The diagnosis was confirmed if (a) more than 50% of the tissue specimens exhibited neuroendocrine markers, and (b) ductal carcinoma in situ was identified and/or imaging examinations and extramammary sites were excluded. Descriptive statistics were calculated for epidemiologic, clinical, and pathologic features, for treatment, and for follow-up. The main clinicopathologic features of the seven cases diagnosed at our hospital are summarized in Table 2. There were six female patients and one male patient. The median age was 49 years (range, 33-78 years). All patients presented with breast lump, and one patient developed skin ulceration. Five of seven patients had the well-differentiated subtype of disease, and two patients had poorly-differentiated disease. Five patients had early-stage disease of luminal subtype. Six patients received chemotherapy and surgery, whereas one patient received chemotherapy alone. Patients with positive estrogen receptors (ERs) received endocrine therapy. The follow-up time ranged from 31 to 59 months. Five patients were alive without tumor at the last follow-up, one died of other causes, and one was lost to follow-up. Our literature search yielded 126 cases of NECB, including our own. We analyzed the clinicopathologic features of 126 NECB cases in China (Table 3). The patients' average age was 53.2 years; there were seven male patients (5.6%) and 119 female patients (94.4%). Almost all patients (124/126, 98.4%) presented with a breast lump; six patients (4.8%) had bloody nipple discharge. No unique appearance of NECB was identified on 85 patients who underwent ultrasound examination or 66 patients who underwent mammography examination. Most patients (100/126, 79.4%) underwent mastectomy. A small percentage of patients (18/126, 14.3%) underwent breast-conserving surgery. Seven patients (5.5%) underwent breast surgery; however, the exact type of surgical procedures was not provided in the corresponding reports. One patient (0.8%) received chemotherapy alone. Overall, 55 patients received adjuvant chemotherapy; of these, 53 were initially treated with regimens for infiltrative ductal carcinoma (IDC) of the breast, including 51 receiving anthracycline- and taxane-based regimens and two receiving etoposide- and cisplatin-based regimens, and two were initially treated with the commonly used regimens for small cell carcinoma (Table 4). According to the 2012 World Health Organization (WHO) classification, 52 cases were well-differentiated, and 26 were poorly-differentiated, the remaining 48 had no information of pathology. The percentages of patients with different stage breast cancer were as follows: stage I, 23.8% (30 of 126); stage II, 47.6% (60 of 126); stage III, 11.1% (14 of 126); and stage IV, 3.2% (4 of 126); the remaining 18 had no information about pathology. ER and progesterone receptor were present in 102 (81.0%) and 91 (72.2%) patients, respectively; and human epidermal growth factor receptor 2 (HER2) protein was overexpressed in 19 (15.1%) patients. All cases were positive for at least one of the neuroendocrine markers (chromogranin A [CgA], synaptophysin [Syn], and neuron-specific enolase [NSE]) in more than 50% of tumor cells. Table 3 summarizes the clinicopathologic features of the 126 cases. The follow-up time ranged from 4 to 144 months. Disease recurrence was found in 13 cases, including 4 small cell type (poorly-differentiated) cases and 9 non-small cell type (well-differentiated) cases. Seven patients died of NECB, of which four had small cell type disease and three had non-small cell type disease. The treatment and follow-up of the 126 cases are shown in Table 4. For NECB patients in China, we determined an average age of 53.2 years, which seems to be older than the onset of IDC [3]. Six patients in our study presented with bloody nipple discharge. Kawasaki et al. [4] examined the pathology of 89 patients who came to the hospital for a thorough examination of symptomatic bloody nipple discharge and found that 24 (27.0%) of them had neuroendocrine carcinomas. NECB may account for an important share of breast conditions associated with bloody nipple discharge. In previous reports, NECB showed no difference when compared with IDC based on imaging [5,6], which was confirmed in the present study. In addition, in our study, most NECB cases showed positive ER expression, which supported the results of recent studies on gene expression profiling [7], suggesting that NECB belongs to the luminal type. Currently, there is no standard therapy for NECB. Most treatments of NECB reported in the literature and in the present study are similar to the treatment of ductal-type carcinoma, with surgery as the first-line therapy, followed by anthracycline- and taxane-based chemotherapy and endocrine therapy [1,8]. However, whether NECB patients can benefit from chemotherapy is unknown. Current data provide little evidence to support the use of regimens for either small cell or non-small cell carcinoma. Conflicting results of the prognosis of patients with NECB have been reported [8-10]. Among 126 Chinese cases included in the present study, nine of 18 patients (50.0%) with the small cell carcinoma were alive without tumor relapse, whereas the percentage was 85.0% (51/60) for those with non-small cell carcinoma. Overall, 57.1% (4/7) of patients who died of NECB had small cell breast cancer. In summary, since NECB was first listed by the WHO in 2003 as a separate unique category, many NECB cases remain to be elucidated about their etiology and treatment. In this study, we found that the onset age of NECB patients in China seems to be older than that of IDC patients. Bloody nipple discharge may indicate the existence of NECB. Most NECB patients have the luminal subtype disease. Surgery is used as the first-line therapy, and the role of chemotherapy is still unknown. The small cell subtype may be associated with more frequent relapse and a higher mortality compared with the non-small cell subtype. References
PMID: 28490384 DOI: 10.1186/s40880-017-0211-x |
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