对乳腺浸润性导管癌和浸润性小叶癌鉴别诊断的探讨

目的 探讨组织形态上易混淆的浸润性导管癌(IDC)与浸润性小叶癌(ILC)的鉴别诊断方法 .方法 收集北京大学第一医院1998年1月至2001年12月4年间普通外科诊治并有完整随访资料的IDC Ⅰ级24例、ILC 12例和具有混合性导管-小叶特征的浸润性癌(简称混合癌)14例共50例原发性乳腺癌患者资料和标本.采用EnVision法免疫组织化学染色检测E-钙黏蛋白(E-cad)、p120连环蛋白(p120ctn)、上皮膜蛋白(EMP)1和DVL1.结果 E-cad在IDC Ⅰ级和ILC中的阳性率分别为83.3%(20/24)和0,其差异有统计学意义(P<0.01);p120ctn在IDC Ⅰ级中阳性率为100.0%,且均为胞膜着色,在ILC中亦为12例均阳性,但均为细胞质着色;EMP1和DVL1在IDC Ⅰ级和ILC中的阳性分别为95.8%(23/24)和12例,54.2%(13/24)和5例,其差异无统计学意义(P>0.05).E-cad和p120ctn联合使用将14例混合痛确诊为IDC 12例和ILC 2例.结论 E-cad和p120ctn联合使用可以鉴别易混淆的IDC和ILC,使组织分型更准确.EMP1、DVL1不能作为鉴别IDC和ILC的指标.     

Clinicopathlogic and immunohistochemical characteristics of triple negative invasive lobular carcinoma

Purpose

Our study is performed to find out clinicopathlogic and immunohistochemical (IHC) characteristics of triple negative invasive lobular carcinoma (ILC), as has been demonstrated in their invasive ductal counterparts.

Materials and Methods

Retrospective analysis of variable clinicopathlogic parameters and IHC stains for androgen receptor, estrogen receptor, progesterone receptor, p53, c-kit, galectin-3, cytokeratin 5 (CK5), CK5/6, vimentin, E-cadherin, epidermal growth factor receptor, and HER2 were performed in 117 cases of ILC.

Results

Eight cases (6.8%) were triple negative carcinoma (TNC), which showed higher incidence of high histologic grade than non-TNC (p = 0.019). Galectin-3 was expressed with higher incidence in tumor cells of TNC (62.5%) than those of non-TNC (7.3%) (p = 0.000). In contrast, galectin-3 was expressed with higher incidence in stromal cells of non-TNC (53.2%) than those of TNC (12.5%) (p = 0.029). CK5 and CK5/6 were not expressed in all ILCs.

Conclusion

TNC in ILC showed distinct clinicopathologic and IHC characteristics such as higher histologic grade and increased expression of galectin-3, compared to non-TNC in ILC. TNC in ILC was less frequent and did not show CK5 and CK5/6 expression when compared to TNC in invasive ductal carcinoma.     

Infiltrating lobular carcinoma of the breast

On review of the histology of 1050 primary breast carcinomas, 103 cases of infiltrating lobular carcinoma were identified and clinical and survival data collected in each case. The tumours were then separated into four groups on the basis of histological pattern and these groups shown to have significantly different survival times. Assessment of the presence of in situ carcinoma, elastosis and intracyto-plasmic lumina was performed in each case and the effect of these features on survival investigated. In addition to stage of disease at presentation, the major significant factor in predicting survival of patients with this type of invasive carcinoma is histological type.     

Array-based comparative genomic hybridization of ductal carcinoma in situ and synchronous invasive lobular cancer

It has been increasingly recognized that ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and invasive cancer of the breast are often closely associated with one another. However, the genomic relationship between these histologically distinct entities has not been well characterized. Refinements in high-resolution comparative genomic hybridization (CGH) techniques allow for a detailed comparison of genomic alterations in synchronously occurring tumors. The following case illustrates how array CGH may be used to better understand whether synchronous neoplasms share a common origin.     

Paucity of fibronectin in invasive lobular carcinoma of breast

Fifty-four cases of invasive carcinoma of breast were immunostained for fibronectin and laminin. They included 36 cases of invasive ductal carcinoma and 18 cases of invasive lobular carcinoma. Although there was some heterogeneity within tumours, it was found that whilst the majority of ductal carcinomas (31/36) had abundant fibronectin at cell/stroma boundaries or diffusely throughout stroma, a substantial proportion of lobular carcinomas (12/18) had very little (P less than 0.001). This difference could not be related to differences in laminin immunoreactivity, which was most commonly scanty or absent in both tumour types. It is postulated that the characteristic infiltration pattern of lobular carcinoma may be attributed in part to paucity of stromal fibronectin.     

Mixed ductal‐lobular carcinomas: evidence for progression from ductal to lobular morphology

Mixed ductal–lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent ‘collision’ of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E‐cadherin–catenin complex was normal in the ductal component in 77.6% of tumours; and (3) in the lobular component, E‐cadherin was almost always aberrantly located in the cytoplasm, in contrast to invasive lobular carcinoma (ILC), where E‐cadherin is typically absent. Comparative genomic hybridization and multiregion whole exome sequencing of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. The mutations identified varied between cases; those associated with a common clonal ancestry included BRCA2, TBX3, and TP53, whereas those associated with clonal divergence included CDH1 and ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and lobular morphology can arise via a ductal pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence probably occurs early, and is frequently associated with complete loss of E‐cadherin expression, as in ILC, whereas, in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from the ductal to the lobular phenotype occurs late in tumour evolution, and is associated with aberrant expression of E‐cadherin. The mechanisms driving the phenotypic change may involve E‐cadherin–catenin complex deregulation, but are yet to be fully elucidated, as there is significant intertumoural heterogeneity, and each case may have a unique molecular mechanism. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

上皮钙依赖粘附素相关分子在乳腺浸润性小叶癌和导管癌中的表达及意义

目的 探讨上皮钙依赖粘附素相关分子α-、β-、γ-catenin在乳腺浸润性小叶癌（ILC）和浸润性导管癌（IDC）中的表达及其意义。方法 采用免疫组织化学LSAB法检测了19例ILC和32例IDC组织中α-、β-、γ-catenin的表达,并根据阳性癌细胞占肿瘤细胞的比例进行半定量化分析和统计学x^2检验。结果 α-、β-、γ-catenin在19例ILC中表达缺失和明显减少的分别为15例（78.9%),10例（52.6%)和16例（84.2%),而在32例IDC癌组织中的表达缺失和明显减少为24例（75.0%),14例（43.8%)和26例(81.3%)例。另外,这3种蛋白在浸润性癌组织中表达强度弱于原位癌灶的表达强度。α-catenin和β-catenin在乳腺浸润性癌中的表达具有明显的正相关性,未发现α-、β-、γ-catenin在乳腺浸润性癌中的表达与有无伴有淋巴结转移病例之间的关系有统计学意义。结论 α-、β-、γ-catenin在乳腺ILC和IDC中表达均为明显缺失和减少,说明这些粘附分子在乳腺浸润性癌发生中确实丧失了其正常的细胞粘附功能。     

Cytologic diagnosis of invasive lobular carcinoma: factors associated with negative and equivocal diagnoses

Fine-needle aspiration biopsy (FNAB) of invasive lobular carcinoma (ILC) is associated with notoriously high rates of false negative and equivocal diagnoses. To identify causative factors, we reviewed the cytologic features of presurgical FNAB smears of ILC and correlated the cytologic findings with the number of passes, tumor size, mammographic findings, and the histologic characteristics of the tumor. Smear cellularity, presence of single intact epithelial cells, nuclear size, nuclear atypia, palpability of the tumor, and histologic type of ILC (classic versus nonclassic) were statistically significant in establishing an unequivocally positive diagnosis. We also found that the cytologic cellularity of the lesion does not reflect the actual cellularity of the tumor but instead is an indicator of the architectural arrangement of the neoplastic cells; tumors that form epithelial cell groups, such as in nonclassic ILC, tend to yield more cellular aspirates that are diagnostic for carcinoma. In contrast, classic ILC, in which single neoplastic cells are embedded in fibrous stroma, is more likely to yield a paucicellular smear with subtle atypia and rare single intact epithelial cells. As such, an inconclusive diagnosis in a certain percentage of classic ILC cases may be unavoidable.     

Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ

Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, α-, β- and γ-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and α- and β-catenin expression was found; in 50 per cent of these cases, additional loss of γ-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied—remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and α-, β- and γ-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma. © 1997 John Wiley & Sons, Ltd.     

The diffuse type of invasive lobular carcinoma of the breast: morphology and prognosis

Invasive lobular carcinoma (ILC) of the breast represents a heterogeneous group of tumors, which can be classified according to the histological growth pattern into classic ILC and its variants and according to the cytomorphological characteristics into pleomorphic and non-pleomorphic subgroups. The most established morphological prognostic factors in ILC are the lymph-node status, the tumor size and the presence or absence of pleomorphic cytological features. In the present study, we analyzed the distribution of the lesions in 130 consecutive cases of ILC documented on large histological sections and followed up to, on average, 78 months (range 4–131 months). We found that 39% of the cases were unifocal, 12% multifocal, 28% diffuse and 19% combined (where the term combined represents those cases containing minor areas of diffuse growth of the tumor cells). In three cases, the distribution of the lesions could not be assessed. The diffuse cases were associated with a higher cancer-related death rate (25%) than the average (12%), the unifocal, the multifocal and the combined tumors (6–8%). The diffuse growth pattern represented a significant negative prognostic factor in relation to overall survival, but not in relation to disease-free survival. The only further negative prognostic factors found in this study were: more than three positive lymph nodes, tumor size larger than or equal to 40 mm and presence of pleomorphic cytological features. We propose to delineate the diffuse group of the ILCs as a separate diagnostic category with distinct morphological and radiological features and with unfavorable prognosis.     

PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma

Mutations in the PIK3CA gene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis of PIK3CA mutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1-20 of the PIK3CA gene were subjected to SSCP analysis followed by direct sequencing. PIK3CA mutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p = 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p = 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation between PIK3CA mutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status, p53 gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas, PIK3CA alterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence of PIK3CA mutations.     

Histopathological and clonal study of combined lobular and ductal carcinoma of the breast

Lobular carcinoma in situ (LCIS) clinically constitutes a risk factor for the subsequent development of either invasive lobular carcinoma (ILC) or invasive ductal carcinoma (IDC). In order to approach the possibility of this common precursor of both ILC and IDC, we investigated combined lobular and ductal carcinomas. Thirty‐two cases of lobular carcinoma were picked up out of 773 cases of operated breast carcinomas. The histopathological detailed re‐examination using immunostain of E‐cadherin and β‐catenin revealed a rather high frequency of combined lobular carcinomas than previous reports. Clinicopathologically, combined lobular carcinomas were younger and smaller than pure lobular carcinomas, and the cytological atypia was relatively low. These results suggested that combined lobular carcinomas could be detected in the earlier stage of breast cancer. Furthermore, the lobular and ductal components of combined carcinomas coexisted in the neighborhood and were distributed contiguously. The immunohistochemical phenotypes of both components were accorded in most combined cases. A genetic analysis using methylation‐specific PCR on the HUMARA gene demonstrated that the same allele was inactivated in both lobular and ductal components in all detectable cases of combined carcinoma. Therefore, it is reasonable to assume that both lobular and ductal components of combined carcinomas are clonal and derived from the LCIS as the common precursor lesion, which may contradict the conventional concept that the lobular and ductal carcinomas arise from distinct differentiation pathways.     

Clonal profiling of mixed lobular and ductal carcinoma revealed by multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization

A needle biopsy of a mass in the right breast of a 36‐year‐old woman revealed invasive ductal carcinoma (IDC), and approximately 20% of cancer cells showed unequivocal membranous staining with the HercepTest. After systemic therapy with trastuzumab and paclitaxel followed by FEC (fluorouracil + epirubicin + cyclophosphamide), a right mastectomy was performed. By histological and immunohistochemical examinations, the resected tumor consisted mainly of E‐cadherin‐negative invasive lobular carcinoma (ILC), and the rest was ERBB2‐positive IDC; thus, the diagnosis was mixed ductal and lobular carcinoma. Multiplex ligation‐dependent probe amplification and fluorescence in situ hybridization (FISH) analyses revealed that ILC and IDC shared high‐level amplification of CCND1 in homogeneously staining regions (HSR) and that IDC had an additional HSR‐type amplicon of ERBB2. These findings strongly indicate that IDC and ILC had a common precursor cell with CCND1 amplification. Review of the biopsy specimen with FISH showed IDC with gene amplifications of CCND1 and ERBB2 as a minor component, IDC without amplification of CCND1 or ERBB2 as a major component, and a minute portion of ILC with CCND1 amplification. We speculate that chemotherapy and trastuzumab caused a marked reduction in IDC; however, ILC with CCND1 amplification was resistant to chemotherapy and grew.     

Histiocytoid breast carcinoma: an apocrine variant of lobular carcinoma

Two cases of in situ and invasive histiocytoid breast carcinoma are described. The invasive components of both tumours showed architectural and cytological similarities to lobular carcinoma. The in situ components showed areas of classical lobular carcinoma in situ, areas of lobular carcinoma with apocrine features and areas with transitional features. It is concluded that histiocytoid carcinoma represents an apocrine variant of lobular carcinoma. Differentiation of this tumour from chronic sclerosing inflammation may be difficult in both primary and secondary lesions.     

乳腺浸润性小叶癌的临床病理特征

目的：探讨乳腺浸润性小叶癌( invasive lobular carcinoma, ILC)的临床病理特征及其预后因素。方法回顾性分析98例ILC和530例乳腺非特殊型浸润性癌患者的临床病理资料,观察ILC的临床病理特征及其预后因素。结果 ILC和非特殊型浸润性癌的中位随访时间分别为68．5、67个月。与非特殊型浸润性癌相比,ILC患者就诊时年龄较大,肿瘤较大,组织学分级多为2级,ER、PR阳性率高,HER-2多为阴性,Ki-67增殖指数较低,分子分型多为管腔A型(P<0．001)。 ILC中,经典型ILC肿瘤较小,组织学分级较低,Ki-67增殖指数较低,分子分型中管腔A型较多;非经典型ILC中管腔B型、三阴型和HER-2过表达型较多(P=0．035)。单因素分析显示经典型与非经典型ILC的无病生存率和总生存率差异均有统计学意义(P=0．043,P=0．048);ILC与非特殊型浸润性癌的无病生存率和总生存率差异无统计学意义(P=0．537,P=0．397);多因素分析显示,ILC中管腔A型患者的总生存率明显高于三阴型和HER-2过表达型(P=0．016,P=0．015)。结论 ILC的预后和组织学分型与分子分型有关,应为预后较差的患者探寻新的治疗策略。     

Malignant adenomyoepithelioma of the breast combined with invasive lobular carcinoma

Presented herein is the first case of malignant adenomyoepithelioma (malignant AME) of the breast combined with invasive lobular carcinoma (ILC) in a 53-year-old woman. Histologically, the tumor was composed of nodular proliferation of biphasic epithelial and myoepithelial carcinoma, partially surrounded by ILC. Interestingly, ILC metastasized to the axillary lymph nodes, while biphasic epithelial and myoepithelial carcinoma hematogenously metastasized to the lung and the kidney. On immunohistochemistry the biphasic carcinoma consisted of cytokeratin (CK) 8/18-positive/CK5/6-positive/smooth muscle actin (SMA)-negative inner carcinoma cells and CK8/18-positive/CK5/6-positive/SMA-positive outer carcinoma cells. The monophasic ILC cells had a CK8/18-positive/CK5/6-negative/SMA-negative staining pattern. Although it is unclear whether both ILC and biphasic epithelial and myoepithelial carcinoma originated from AME or whether ILC occurred independently of malignant AME, this is an exceptionally rare case, which might give rise to a special consideration of the histogenesis of breast cancer.     

Morpho-functional differentiation in lobular carcinoma of the breast

Lobular carcinoma of the breast has been studied using histochemical methods for mucosubstances; immunocytochemical methods for casein and actin; the ruthenium red electronycytochemical method for acid glycoproteins and an immunoelectroncytochemical method for casein. Mucosubstances and casein showed a similar cytoplasmic localization, but casein production was much more intense and also showed a more diffuse cytoplasmic localization. Occasionally casein assumed the form of target-like 'inclusions' as seen characteristically with the mucosubstances. The neoplastic cells were not stained by antisera against actin. Ultrastructurally, some cells showed an intracytoplasmic lumen with microvilli and/or an irregular outline at one extremity which was covered by microvilli. An electron-dense 'fuzz' and casein coated the microvilli of cells exposed respectively to ruthenium red and an anticasein serum followed by peroxidase--anti-peroxidase complexes. It is concluded that lobular carcinoma shows evidence of epithelial rather than myoepithelial differentiation with the emphasis on epithelial secretory cells engaged in intensive milk protein production. All 10 tumours tested for oestrogen receptors were positive in contradistinction to ductal carcinoma with a lower incidence of positivity. It appears that, in addition to distinctive histological and histochemical features, lobular carcinoma has an almost constant endocrine pattern in respect of its oestrogen receptor content.