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.     

Histiocytoid breast carcinoma: Histological, immunohistochemical, ultrastructural, cytological and clinicopathological studies

Histiocytoid breast carcinoma (HBC) is a rare variant of breast carcinoma and often causes a diagnostic dilemma because of its histological similarities to some types of breast cancer and benign lesions. To elucidate the incidence of HBC and its biological properties, histological specimens from 1010 breast cancer patients treated at Yokohama Minami Kyosai Hospital between 1972 and 1996 were reviewed. Three cases of pure HBC and three cases of combined HBC (two with pleomorphlc lobular carcinoma and one with apocrine ductal carcinoma) were found, yielding an Incidence of 0.3% for each. Two of the three pure HBC cases contained foci of in situ lobular carcinoma. Targetoid and Indian file invasive patterns, the features characteristic of lobular carcinoma, were present in all three pure HBC cases and in two of the three combined HBC with pleomorphic lobular carcinoma. These results, together with those of previous studies, suggested that the majority of HBC are of lobular origin, although the apocrine ductai origin is also possible in a small number of HBC. Diastase-resistant periodic add-Schiff-positive granules and granular immunoreactivities for gross cystic disease fluid protein-15 (GCDFP-15) were characteristic of the histiocytoid tumor cells in both the pure and combined HBC, suggesting the apocrine differentiation of tumor cells. All three pure HBC cases were in stage 1 and were free of the disease for up to 5 years and 1 month after the lumpectomy. Thus, the prognosis of HBC appears to be dependent on the stage of the disease and may not always be poor, as indicated by the original report mentioning a preferential eyelid metastasis.     

Pleomorphic lobular carcinoma in pleural fluid: diagnostic pitfall for atypical mesothelial cells

Pleomorphic lobular carcinoma (PLC) is a subtype of infiltrating lobular carcinoma because of its dyscohesiveness, linear infiltration pattern, and lack of membranous E-cadherin staining. However, it differs from classic lobular carcinoma because of its high-grade cytology and more aggressive clinical behavior. In breast fine-needle aspiration biopsies, PLC can be confused with invasive ductal carcinoma, particularly the apocrine variant. In this report, we illustrate how metastatic PLC in body fluid specimens shows many of the same cytomorphologic changes that occur in reactive/atypical mesothelial cells. Fortunately, the immunohistochemical staining pattern of PLC can help to distinguish it from other possible diagnoses in the differential, such as reactive/atypical mesothelial cells and other metastatic neoplasms. However, the frequent apocrine features seen in this variant of breast carcinoma can cause nonspecific immunohistochemical positivity that may make the interpretation difficult. This is the first report illustrating the cytopathology and immunohistochemical findings of pleomorphic lobular carcinoma in body cavity fluid cytology. Our case highlights the important issues and pitfalls to be aware of when making this diagnosis.     

Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation.

Pleomorphic lobular carcinoma of the breast is a recently recognized subtype of invasive lobular carcinoma (ILC). Cytologic features are pleomorphic to a degree that contrasts with the cytologic uniformity of classic ILC. It is this feature that simultaneously gives its name to the tumor and highlights the difficulty of identifying it correctly and distinguishing it from ductal carcinoma. In our series of 10 cases, six tumors also contained lobular carcinoma in situ. Nodal metastases were typically sinusoidal. All tumors showed the dissociated, linear, and single file pattern of classic ILC, together with a targetoid distribution. Intracytoplasmic lumina were present in 50% of the tumors. An eosinophilic, slightly granular cytoplasm suggests the possibility of apocrine differentiation, a suggestion derived also from the frequent presence of foamy cells, a cell type previously identified in histiocytoid lobular carcinoma and shown to have apocrine features. The GCDFP-15 apocrine marker was positive in all 10 tumors, while all control ILCs were negative, confirming the presence of apocrine differentiation in pleomorphic lobular carcinoma. Six of 10 patients died within 42 months of diagnosis. Three other patients developed recurrence or distant metastases at short intervals. Pleomorphic lobular carcinoma is a very aggressive tumor. This behavior is perhaps predictable on the basis of tumor size at presentation and the frequency of nodal metastases. Since grading of lobular carcinoma is difficult, recognition of the pleomorphic subtype is useful in identifying a lethal variant.     

Infiltrating lobular carcinoma of the breast with histiocytoid features: three cases

Histiocytoid carcinoma of the breast, a cellular variant of invasive breast cancer, is mainly found among infiltrating lobular carcinomas (ILC). It can be easily confused with benign conditions or other mammary tumors also composed of cells with a pink granular to foamy cytoplasm and an eccentric nucleus. We report 3 cases of histiocytoid ILC. Our aim is to discuss recent immunocytochemical data that could suggest a special type of apocrine differentiation of tumor cells, including a diffuse immunoreactivity for GCDFP-15 (Gross Cystic Disease Fluid Protein 15) and a predominant expression of androgen receptor, and to describe the features useful for the differential diagnosis.     

Flache epitheliale Atypie

According to the WHO, flat epithelial atypia (FEA) is defined as a neoplastic epithelial proliferation of ductal type in either a single or in multiple terminal duct lobular unit(s) limited to the periphery of the ductules in a clinging growth pattern. The atypical cells may form between one and several layers of epithelial cells that show low grade cytologic atypia. FEA most often presents as mammographic microcalcifications, which are typically round (secretory type and psammomatous calcification in an eosinophilic matrix, so-called ossifying calcifications). Clinical relevance is dependent on whether the lesion appears in isolation or whether it is an excision biopsy or a minimally invasive biopsy. Currently available data suggest that the risk of subsequent breast carcinoma in the ipsilateral breast is very low following the diagnosis of FEA. The differential diagnosis should include atypical ductal hyperplasia, low-grade clinging ductal carcinoma in situ, blunt duct adenosis and apocrine metaplasia.     

Cytological characteristics of invasive lobular carcinoma of the human breast

In contrast to invasive ductal carcinoma, invasive lobular carcinoma (ILC) of the breast is characterized by multiple ipsilateral occurrences and a higher incidence in the contralateral breast. It is therefore necessary to examine thoroughly whether there is any other carcinoma present before any breast-conserving surgery is carried out. We cytologically, histologically, and ultrastructurally investigated ILC and pure scirrhous carcinoma (PSC), a subtype of invasive ductal carcinoma, to establish cytological diagnostic criteria for the differential diagnosis of these two types of carcinoma that have high histological similarity. Cytologically, ILC cells showed linear or isolated cell arrangements and had small nuclei with round homogeneously distributed fine granular chromatin. The cytoplasm was light, and individual cells lacked cohesion. The carcinoma showed a rosary-like configuration. PSC cells, however, showed linear or cordlike arrangements. Individual cells showed a vertical arrangement. PSC cells had a linear cytoplasmic edge and were characterized by nuclear molding with coarse granular chromatin. These cytological findings were supported by histological and ultrastructural findings. These findings may contribute to histological estimation of ILC in preoperative cytological diagnosis.     

乳腺放射状硬化性病变的病理形态学观察

目的 探讨乳腺放射状硬化性病变的组织病理特点和鉴别诊断.方法 收集44例乳腺放射状硬化性病变,进行组织形态学和免疫组织化学SP法或EnVision二步法染色观察.结果 44例均发生在女性,年龄17～54岁(平均40.3岁).31例会诊者中13例误诊为癌.镜下病变呈放射状,中央为纤维瘢痕区,其内常有受压变形的腺管,周围有放射状分布的扩张腺管及不同程度增生的导管和小叶,可伴大汗腺、柱状细胞化生增生,其中14例见坏死,8例伴不典型导管增生.免疫组织化学染色显示纤维瘢痕组织内假浸润的变形腺管周围有肌上皮,旺炽性增生的上皮呈CK5/6阳性.结论 乳腺放射状硬化性病变有特殊的形态特点,易误诊为癌,需与导管内癌、小叶性肿瘤、小管癌、浸润性导管癌鉴别.     

Cytological grading of breast neoplasia and its correlation with histological grading

Cytological grading of breast cancer is not well established despite histological grading having gained a strong foothold. In our study we have analyzed 50 cases of breast carcinoma which included invasive ductal carcinoma, invasive lobular carcinoma, mucinous carcinoma, stromal sarcoma, apocrine carcinoma, papillary carcinoma. Papanicolaou smears were graded according to established Hunt's, Simplified Black and Modified Black grading systems. They were then compared with the Scarff Bloom Richardson grading system. Simplified Black grading system has been recommended for cytological grading of breast neoplasia because of its lucidity and its reproducibility. Cytological grading of breast neoplasia is important for neo adjuvant chemotherapy and also for predicting the prognosis of the patient on FNAC alone. Incorporation of other parameters like apoptosis and bcl-2 is also recommended.     

Lobular carcinoma in situ diagnosed by core needle biopsy: when should it be excised?

Core needle biopsy is the preferred technique for evaluating breast masses and abnormal mammographic findings. The frequency of detection of noninvasive lobular lesions by core needle biopsy is increasing. Historically, the diagnosis of lobular carcinoma in situ has been considered a risk factor for the development of invasive carcinoma, and treatment has consisted of careful clinical follow-up with or without chemopreventive therapeutic agents such as tamoxifen citrate. We retrospectively reviewed core needle biopsy material with the primary diagnoses of lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia in conjunction with clinical and radiographic findings to make recommendations as to when excision may be merited. We searched our database for core needle biopsy cases with lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia as the primary diagnosis. Microcalcifications had been sampled with a stereotactically guided, 11 G Mammotome biopsy device, and masses had been sampled with an ultrasound guided, 18 G core needle. Glass slides were reviewed and histological parameters assessed. Mammographic findings were reviewed, and clinical information was obtained from the medical record. When available, excisional biopsy material was reviewed. The 2337 breast core needle biopsies performed from January 1995 to December 2001 included 35 (1.5%) with classic lobular carcinoma in situ (14), lobular neoplasia (4), and atypical lobular hyperplasia (17) as the primary diagnosis. Twelve of these 35 cases (34%) had histological evidence of microcalcifications directly associated with the lobular carcinoma in situ, lobular neoplasia, atypical lobular hyperplasia. Radiologic review revealed 21 calcifications, 6 ultrasonographic masses, and 8 mammographic masses and/or architectural distortions. Excisional biopsy had been performed in 17 cases (49%). In six cases diagnosed as in situ on core needle biopsy, excisional biopsy revealed invasive carcinoma. All of these patients had radiographically detectable masses. Eleven cases had excisional biopsies that showed histology similar to that of the core needle biopsies. The most important predictor of invasive carcinoma on excision was a synchronous mass lesion. Lobular carcinoma in situ involving adenosis and lobular carcinoma in situ with pagetoid spread on core needle biopsies did not show a histologically more aggressive lesion on excision and, therefore, may not require additional surgery. Histologically identified calcifications were associated with lobular lesions 34% of the time; however, their presence inside an in situ lobular lesion did not portend worse pathology on re-excision and should not be a criterion for excision. Based on these findings, we recommend excisional biopsy of lobular carcinoma in situ, atypical lobular hyperplasia or lobular neoplasia only when it is associated with a synchronous mass lesion.     

Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours

Gap junctional intercellular communication (GJIC) has been proposed as a cellular mechanism for tumour suppression and there is experimental evidence in support of this. If aberrant GJIC contributes to the formation of human breast tumours, one might expect that the connexins (gap junction proteins) expressed by epithelial cells in normal human breast would be down-regulated in tumour epithelial cells, or that tumour cells might show aberrant expression of other connexin family members. This study examines the immunocytochemical expression of connexins 26 (Cx26) and 43 (Cx43) in normal human breast, 11 benign breast lesions, two special-type carcinomas, and 27 invasive carcinomas of no special histological type (NST). Cx26 generally was not expressed at detectable levels in normal human breast, but punctate Cx43 immunostaining of the myoepithelial cells was found. Cx43 staining of the myoepithelium was also a feature of the benign lesions and ductal carcinoma in situ (DCIS). In general, the epithelial cells of benign lesions failed to stain for either connexin. Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma. Cx26 was up-regulated in the carcinoma cells of 15 of the 27 invasive NST carcinomas, although the staining was usually cytoplasmic and heterogeneous. Cx43 was expressed by stromal cells, possibly myofibroblasts, in all NST carcinomas. Furthermore, there was heterogeneous Cx43 expression in the carcinoma cells of 14 of the 27 NST carcinomas and the staining was often intercellular and punctate, characteristic of functional connexins. Up-regulation of Cx26 and/or Cx43 in the carcinoma cells of over two-thirds of invasive lesions of NST is not necessarily inconsistent with a tumour suppressor role for GJIC. However, the role of gap junctions in the formation and progression of solid human tumours is likely to be more complex than indicated from experimental systems. © 1998 John Wiley & Sons, Ltd.     

Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up

The histological tumour type determined by current criteria has been investigated in a consecutive series of 1621 women with primary operable breast carcinoma, presenting between 1973 and 1987. All women underwent definitive surgery with node biopsy and none received adjuvant systemic therapy. Special types, tubular, invasive cribriform and mucinous, with a very favourable prognosis can be identified. A common type of tumour recognized by our group and designated tubular mixed carcinoma is shown to be prognostically distinct from carcinomas of no special type; it has a characteristic histological appearance and is the third most common type in this series. Analysis of subtypes of lobular carcinoma confirms differing prognoses. The classical, tubulo-lobular and lobular mixed types are associated with a better prognosis than carcinomas of no special type; this is not so for the solid variant. Tubulo-lobular carcinoma in particular has an extremely good prognosis similar to tumours included in the 'special type' category above. Neither medullary carcinoma nor atypical medullary carcinoma are found to carry a survival advantage over carcinomas of no special type. The results confirm that histological typing of human breast carcinoma can provide useful prognostic information.     

Apocrine carcinoma of the breast containing foam cells. An electron microscopic and immunohistological study

The detailed light and electron microscopic and immunohistological features of an invasive apocrine carcinoma of the breast developing in a 78-year-old woman are presented. The stroma of the tumour contained non-neoplastic lipid-filled (foam) cells. To our knowledge, these cells have not been described before in invasive breast carcinoma. Their electron microscopic and immunohistological features confirm their histiocytic nature.     

c-erbB-2 expression in different histological types of invasive breast carcinoma.

Sections of 149 breast carcinomas were examined for the over-expression of c-erbB-2 oncoprotein using the avidin-biotin immunoperoxidase technique and two different specific antibodies. These included the polyclonal antibody 21N and the monoclonal antibody 4D5. The tumours were divided into two main groups. The first included 75 cases of invasive ductal and classic invasive lobular carcinomas. The second group consisted of 74 cases with histological types known to have a good prognosis, including mucinous, alveolar variant of invasive lobular, medullary, tubular, cribriform and papillary carcinomas. Fifteen (20%) tumours of the first group were positive with the two antibodies. Fourteen of these were of the ductal type and one was a mixed invasive ductal and lobular carcinoma. Ten of the pure ductal cases had areas of comedo carcinoma. The intraductal elements in a further tumour were positively stained with 21N antibody only. None of the second group of tumours, which included histological types known to have good prognosis, stained with 4D5, although one mucinous carcinoma was positively stained with 21N. These findings suggest that in invasive breast carcinoma immunostaining for c-erbB-2 is mainly seen in a subgroup of ductal tumours, and that almost all other histological types, especially those associated with good prognosis, lack this expression.     

Association of maspin expression with the high histological grade and lymphocyte-rich stroma in early-stage breast cancer

AIMS: Maspin is a recently described member of the serpin family or protease inhibitors that is known to be a tumour suppressor gene product. Loss of maspin expression has been found in most breast cancer cases and is correlated with cell motility and tumour invasiveness. However, its precise role in human breast cancer remains to be discovered. We aimed to evaluate the role of maspin in early-stage breast cancer. METHODS AND RESULTS: We analysed the expression of maspin in 192 stage I and II primary breast cancers by immunohistochemistry. Of these cases, 34.4% showed maspin expression. Maspin expression was more frequently found in invasive ductal carcinoma (36.4%) than in invasive lobular carcinoma (7.1%). High maspin expression was demonstrated in breast cancers showing high histological grade or lymphocyte-rich stroma (P < 0.05). Maspin expression was not associated with overall and disease-free survival rate of breast cancer. CONCLUSIONS: The results indicate that different biological mechanisms may be responsible for maspin expression in histologically distinct types of breast cancer. Our survey suggests that maspin expression in breast cancer might have a compensatory role rather than prognostic one.     

E-cadherin immunohistochemical analysis of histiocytoid carcinoma of the breast

Histiocytoid carcinoma is a rare type of invasive breast carcinoma. It has been considered to be a variant of lobular carcinoma, a variant of apocrine ductal carcinoma, and an apocrine variant of lobular carcinoma and to resemble lipid-rich carcinoma. In attempts to elucidate its histogenesis, investigators have used mucin and oil red O histochemical analysis and GCDFP-15 immunostaining. E-cadherin is a relatively recent addition to the armamentarium of immunohistochemical markers used for cell differentiation and is a member of a family of transmembrane glycoproteins that has been shown to have a strong correlation with the histologic phenotypes of breast carcinoma. Most ductal carcinomas show diffuse membrane expression of E-cadherin, and lobular carcinomas are characterized by complete lack of membrane staining of E-cadherin. The object of this study was to use E-cadherin immunohistochemical analysis to help clarify the histogenesis of histiocytoid carcinoma. Fourteen cases containing the diagnosis of histiocytoid carcinoma of the breast were identified at M. D. Anderson Cancer Center (Houston, TX) from 1988 to 2001. All cases were rereviewed, histologic features were evaluated, and immunohistochemical staining with E-cadherin and GCDFP-15 was performed. Clinical information was extracted from the patients' medical records. Eleven cases met published histologic criteria for histiocytoid carcinoma. The remaining three cases were apocrine carcinoma. The pattern of tumor infiltration was solid, without secondary lumen formation in all cases of histiocytoid carcinoma. Lobular carcinoma in situ was identified in eight cases, but was absent in three. There was no E-cadherin immunohistochemical staining in eight of the 11 cases of histiocytoid carcinoma (72.7%). GCDFP-15 was immunoreactive in all 10 cases of histiocytoid carcinoma where it was performed. Follow-up data was available for nine of the 11 cases of histiocytoid carcinoma: six patients were alive with disease at 1.5 to 48 months, one patient had died of disease at 60 months, and two patients had no evidence of disease at 32 and 45 months. We conclude that histiocytoid carcinoma has an immunophenotypical profile consistent with both ductal and lobular differentiation. Moreover, the lack of consistent morphologic features, a specific clinical profile, and a distinct immunohistochemical pattern lead us to hypothesize that histiocytoid carcinoma is not a special type of breast cancer.     

Antibodies targeting p63 react specifically in the cytoplasm of breast epithelial cells exhibiting secretory differentiation

AIMS: The nuclear detection of p63 in myoepithelial cells of the breast has been useful in identifying possibly invasive carcinomas. While examining myoepithelial cells for p63 a very strong cytoplasmic reaction product was noted in secretory cells. The aim was to determine whether this reaction is specific for p63 and indicative of all breast secretory cells. METHODS: Thirty breast specimens were tested immunohistochemically for p63 protein. These included seven with benign secretory changes, 10 secretory carcinomas (nine invasive), one microglandular adenosis, three lobular neoplasias, four invasive ductal carcinomas, three clear cell carcinomas, one squamous cell carcinoma and one mucinous carcinoma. RESULTS: Only cells exhibiting secretory changes or secretory carcinoma were cytoplasmically reactive for p63. The positive reaction was also present as an intraluminal secretory product. This reaction was not seen in cells undergoing apocrine differentiation or in other cells containing secretory vacuoles. CONCLUSIONS: Cells with secretory changes contain p63 protein or an antigenic equivalent. The detection of p63 protein continues to have considerable value for the identification of myoepithelial cells and thus the determination of invasion, but will also have value in the determination of secretory carcinomas of the breast and in understanding their development.     

Immunohistochemical analysis of pleomorphic lobular carcinoma: higher expression of p53 and chromogranin and lower expression of ER and PgR

AIMS: Pleomorphic lobular carcinoma of the breast is a histological variant of infiltrating lobular carcinoma with a poor prognosis. The aim of this study is to investigate the immunohistochemical profile of this distinctive breast carcinoma in comparison with the classical type. The expression of cytokeratin, epithelial membrane antigen, gross cystic disease fluid protein-15, chromogranin, oestrogen and progesterone receptors and p53 oncoprotein was investigated to examine whether the expression of these markers correlates with the aggressiveness of this variant. METHODS AND RESULTS: Sections from 10 cases of pleomorphic lobular carcinomas were reviewed and examined for the expression of cytokeratin of high and low molecular weight, epithelial membrane antigen (EMA), gross cystic disease fluid protein-15 (GCDFP-15), chromogranin, oestrogen (ER) and progesterone receptors (PgR), and p53 oncoprotein. Immunohistochemical staining was performed on paraffin wax embedded sections. Ten cases of classical lobular carcinomas were used for comparison. A semiquantitative count of the percentage of positive tumour cells was recorded. Pleomorphic lobular carcinomas have most of the characteristic histological features of the classical type but have nuclear anaplasia and abundant granular cytoplasm. Clinically they exhibited poor prognosis and a high frequency of nodal metastases. All of the pleomorphic lobular carcinomas expressed low and high molecular weight keratin, EMA, and GCDFP-15, eight cases expressed nuclear p53 at a range between 10% and 45%. All cases expressed chromogranin (3-5%). ER and PgR were weakly positive in two cases and negative in eight cases. Classical infiltrating lobular carcinomas were all positive for cytokeratin, EMA, ER and PgR and negative for GCDFP-15. Only five cases of classical lobular carcinoma expressed p53 positivity with up to 5% nuclear staining while chromogranin showed less expression (1-2%). CONCLUSION: Pleomorphic lobular carcinoma exhibits distinct cellular features with apocrine differentiation, higher expression of chromogranin and p53 protein and lower ER and PgR in comparison with classical lobular carcinomas. Determination of p53 overexpression and reduced or absent expression of ER and PgR may help predict the behaviour of this variant of lobular carcinoma.     

Pathological prognostic factors in breast cancer. IV: Should you be a typer or a grader? A comparative study of two histological prognostic features in operable breast carcinoma

In a study of 1529 patients with primary operable breast carcinoma we have assessed the effect of applying both histological grade and tumour type to determine their comparative value as prognostic factors in human breast cancer. The prognostic group the patient was placed in, based on histological type alone, was less accurate than using grade and type together for many tumours. The importance of performing histological grading of ductal/no special type carcinoma (50% of the women in this series) is confirmed in this series. The 10-year-survival varied from 76% for women with grade 1 carcinoma to 39% for those with grade 3 tumours. Some of the 'special types' of breast carcinoma including tubular, tubulo-lobular, invasive cribriform and grade 1 mucinous carcinomas behaved as would be predicted, with a greater than 80% 10-year-survival in this series. Others, including grade 2 mucinous carcinomas, however, behaved less well with a 60% to 80% 10-year-survival. Indeed, many of the histological tumour types including tubular mixed, ductal/no special type, mixed ductal with special type and lobular carcinomas of classical, solid or mixed types showed a variation in behaviour that could not be predicted by typing alone. Histological grade and tumour type, when used together, more accurately predicted prognosis. In multivariate analysis of a larger group of 2658 cases of primary breast carcinomas (including the 1529 study cases) when histological grade, lymph node status and tumour size were entered, grade was the most important factor in predicting for survival. When histological type of carcinoma was included it was also found to be independently significant, although comparatively of less importance than grade. We conclude that tumours should be typed and graded in order to predict prognosis most accurately and to enable the choice of optimum treatment for women with primary breast carcinoma.