Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma

The clinical and pathologic features of 26 examples of a histopathologically distinct form of metaplastic carcinoma of the breast are reported. All neoplasms had overt carcinoma with direct transition to a cartilaginous and/or osseous stromal matrix without an intervening spindle cell zone or osteoclastic giant cells. Therefore, we designate this distinctive form of metaplastic carcinoma as "matrix-producing carcinoma" (MPC). All patients were women, the average age was 58 years, and all patients were eligible for a minimum of 5 years follow-up (mean follow-up period, 8.6 years). Twenty-three patients were treated by a form of mastectomy and three were treated by local excision. The 5-year survival rate for patients following mastectomy or partial mastectomy was 70%, contrasted with 50% for patients treated by local excision. The cumulative 5-year survival rate for MPC was 68%. All of the nine lesions that recurred did so within 2.5 years of initial therapy. Eight of these patients (89%) died from tumor within 4 years of initial therapy. The ninth was alive at last contract. Radiation and chemotherapy were of limited effectiveness. Significant features of the neoplasm associated with progression were large size, diffuse cellularity of the stromal matrix, and atypical cartilaginous metaplasia. Ultrastructural examination of one case and immunohistochemical evaluation of 12 cases revealed MPC to have myoepithelial characteristics.     

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.     

Myoepithelial cells in the differential diagnosis of complex benign and malignant breast lesions: an immunohistochemical study.

The distinction between sclerosing adenosis, radial scars, noninvasive carcinomas occurring in sclerosing adenosis, and invasive carcinoma can be difficult. The identification of a myoepithelial (ME) cell layer is helpful in establishing a diagnosis of complex benign breast proliferation as well as intraepithelial neoplasia in sclerosing adenosis. We reviewed pathologic material from patients with tubular carcinoma (23) and complex breast proliferations (28), including sclerosing adenosis (12), radial scars (9), sclerosing adenosis with intraepithelial neoplasia (5), and sclerosing adenosis with atypical apocrine metaplasia (2). Immunoperoxidase stains on formalin-fixed, paraffin-embedded tissue using a muscle actin-specific antibody of clone HHF35 and high molecular weight cytokeratin of clone 34 beta E12 (HMW keratin) were performed to identify myoepithelial cells. Muscle actin was uniformly reliable in staining ME cells, as well as other actin-containing cells such as myofibroblasts and vascular smooth muscle. HMW keratin was less reliable, being poorly sensitive and less specific than muscle actin for labeling of ME cells. ME cells were readily identified at the periphery of ductules in all complex benign breast lesions. The presence of ME cells distinguished intraepithelial neoplasia involving sclerosing adenosis from invasive carcinomas. Well differentiated invasive carcinoma forming tubular structures lacked a ME cell layer.     

Nodular sclerosing adenosis (adenosis tumor) of the breast. An immunohistologic study particularly in reference to the relationship with radial cicatrix and to the differential diagnosis with tubular carcinoma

The clinical and pathologic findings of four cases of palpable sclerosing adenosis of the breast, called "adenosis tumor", are reported. Adenosis tumor is a rare lesion that clinically and sometimes histologically is misinterpreted as mammary carcinoma. In our study, adenosis tumor was detected in four women of 35-39 years (average 37 years). All cases were treated by local excision. None of the lesions had recurred at follow-up, 1-3 years later. Microscopically the most frequent growth pattern was classical sclerosing adenosis. Other findings were epitheliosis, collagenous spherulosis, microcysts, apocrine metaplasia and radial scars. Only in one case were detected foci of lobular carcinoma in situ. With immunoperoxidase staining, the proliferating cells stained positively for cytokeratin (AE1/AE3) and actin, revealing epithelial and myoepithelial differentiation. Coexpression of actin, S-100 protein and GFAP was detected in numerous stromal myofibroblast-like cells. In sclerosing adenosis and in radial scar the tubules were surrounded by a continuous intact basement membrane composed of type IV collagen, whereas in tubular carcinoma basement membranes are almost entirely absent.     

Cystic fibroadenoma of the breast: a case report

Fibroadenoma is the most common breast tumor in adolescent and young women. Fibroadenomas that consist of sclerosing adenosis, papillary apocrine metaplasia, epithelial calcifications, and/or cysts greater than 3 mm are considered as complex fibroadenoma. The relative risk of developing breast cancer in patients with complex fibroadenoma is increased, compared to women with noncomplex fibroadenoma. Extensive cystic degeneration in a fibroadenoma, so called "cystic fibroadenoma" is very rare. Herein, we present a case of such a lesion in a 43-year-old female who has been on follow-up for fibrocystic changes of the breast, and discuss both radiological and histopathologic differential diagnosis of this lesion with other cystic lesions of the breast, including cystic papilloma. The patient is free of disease after 17 months of clinical follow-up.     

The significance of atypical apocrine cells in fine-needle aspirates of the breast

Apocrine metaplastic cells are frequently present in fine-needle aspirates (FNAs) of breast lesions, especially fibrocystic disease. Occasionally, apocrine cells may be atypical and present diagnostic difficulties. The morphologic features of six breast FNAs that contained atypical apocrine cells in breast aspirates. In the six abnormal cases, the large, pleomorphic, atypical apocrine cells were the predominant cell type and occurred singly and in syncytial tissue fragments. The cells had large, eccentric, vesicular nuclei and usually multiple macronucleoli. The histologic diagnoses in the cases were apocrine carcinoma (five cases) and atypical apocrine metaplasia (one case). In comparison, benign apocrine cells are relatively small and uniform and arranged in cohesive, orderly sheets. It is concluded that, in breast FNAs, the predominance of atypical apocrine cells, occurring singly and in syncytia, should raise the suspicion of carcinoma.     

Non-operative breast pathology: apocrine lesions

Apocrine metaplasia is a very common finding in the female breast after the age of 25. It is so common that many people regard it as a normal component of the breast. This, however, is only really the case in apocrine sweat glands of the axilla and in the peri-areolar apocrine glands. The apocrine cell does, however, contribute to a number of different breast lesions, some of which are very taxing diagnostically; apocrine variants of both in-situ and invasive cancer are encountered. This review considers the common apocrine metaplastic lesions seen in fibrocystic change as well as apocrine adenoma, apocrine change within sclerosing adenosis, atypical apocrine lesions and apocrine malignancies.     

The spectrum of apocrine lesions of the breast

Apocrine change is seen in a wide spectrum of breast lesions, ranging from microscopic cysts to invasive carcinoma. This article reviews the range of apocrine lesions and discusses the clinical significance of these lesions. Although apocrine change in many cases does not present any diagnostic difficulty, apocrine proliferations demonstrating cytologic atypia can be particularly challenging. The histologic criteria that have been proposed to foster reproducibility in categorizing such lesions are reviewed. This review attempts to clarify the terminology that has been applied to a range of benign lesions, including sclerosing adenosis and complex sclerosing lesions, containing foci of apocrine change. Malignant apocrine lesions, including both in situ and invasive carcinoma, are also discussed.     

The challenge of apocrine proliferations of the breast: A morphologic approach

Apocrine phenotype in breast is common and can be seen in a broad spectrum of lesions ranging from simple cyst to infiltrating carcinoma. The majority of apocrine lesions of the breast are benign in nature and do not represent a diagnostic challenge; however, there are a few that can cause diagnostic problems, such as the case of apocrine proliferations with atypia and low-grade apocrine ductal carcinoma in situ. Furthermore, the role of atypical apocrine proliferations in the pathway to infiltrating carcinoma is still uncertain, and studies with long-term clinical follow-up are necessary to clarify and understand the significance of these apocrine lesions of the breast. The purpose of this article is to review the most recent literature concerning apocrine lesions, with emphasis on borderline apocrine proliferations.     

Apocrine adenosis: a precursor of aggressive breast cancer?

AIM--To investigate overexpression of c-erbB2, expression of the p53 protein product and proliferation rates in benign breast lesions with specific reference to apocrine adenosis. METHODS--Twenty one cases of apocrine adenosis were stained with monoclonal antibodies to p185, the protein product of the c-erbB2 oncogene, the protein product of the p53 tumour suppressor gene and to the cell cycle related protein Ki67. Three cases were associated with concomitant ductal carcinoma in situ of large cell type and two were associated with invasive tubular or cribriform carcinoma. RESULTS--Twelve (57.1%) cases showed membrane staining for c-erbB2 oncoprotein of apocrine cells within sclerosing adenosis and six (28.6%) had occasional p53 protein positive cells. One case not associated with carcinoma showed extensive staining of apocrine metaplasia outside the area of apocrine adenosis. The proliferation rate, as measured by Ki67 staining, was increased in some of the lesions and all lesions showed at least some of the cells to be in the cell cycle. CONCLUSIONS--The expression of abnormal oncogene products and increased proliferation in some of these apocrine lesions questions the supposed degenerative nature of the atypia seen in such cases and suggests that there may be an association between these lesions and large cell ductal carcinoma in situ and hence invasive carcinoma.     

Cytophotometric analysis of nuclear DNA-content in so-called obliterating mastopathy with epithelial hyperproliferation

INTRODUCTION: Histogenesis, microscopic appearance, and clinical significance of so-called "obliterating mastopathy with epithelial hyperproliferation" are described. This focal lesion, which was recently re-evaluated by Hamperl (1975), may simulate scirrhous carcinoma in X-ray mammography. In histologic specimens similarities to special types of tubular carcinomas may cause problems in differential diagnosis. In order to gain a better insight into their behavior, cytophotometric DNA-analysis was applied to 10 selected cases. MATERIALS AND METHODS: DNA-determination was performed on Feulgen stained sections by means of a Leitz microspectrophotometer MPV 1. The plug technique was used after careful focussing of cell nuclei. Intraductal and extraductal epithelial proliferations have been analyzed in separate series. RESULTS: In four series of extraductal pseudoinfiltration and in six series of intraductal hyperproliferation, normoploid DNA-patterns were found. One series of apocrine metaplasia and one of atypical intraductal proliferation were read as borderline cases, but one case of atypical apocrine metaplasia revealed an aneuploid DNA-pattern, thus indicating the malignant nature of the lesions. DISCUSSION: "Obliterating mastopathy with epithelial hyperproliferation" is regarded a high risk disease which may progress to invasive carcinoma. According to the gross morphologic appearance of the focal lesions, the term "pseudoscirrhus" is proposed. Therapeutic approach depends mainly on the degree of epithelial hyperproliferation and cellular atypia. Focal lesions should be removed by wide excision, whereas in cases of multicentric development, subcutaneous mastectomy and plastic augmentation is recommended.     

Hemangiopericytoma of the breast

Hemangiopericytoma, an uncommon neoplasm derived from pericytes, occurs in many locations throughout the body. The clinical course of this tumor is variable with the most malignant lesions capable of producing metastases. This report describes 5 patients who had hemangiopericytoma of the breast. All were women between 47 and 57 yr old. The tumors varied from 3.2 to 19 cm (average, 9 cm). Three were treated by mastectomy and two by local excision. All remained disease free for a median duration of 22 mo and for an average of 46 mo (3 to 144 mo). We have found eight additional already published examples of mammary hemangiopericytoma in adult women ranging in age from 33 to 67 yr (average, 51 yr). The tumors averaged 6 cm (1 to 29 cm) in diameter. Three were treated by mastectomy and 5 by excision. All 8 patients remained disease free at last follow-up, averaging 84 mo (16 to 276 mo). Thus, it appears that hemangiopericytoma arising in the breast is a clinically low-grade form of sarcoma regardless of tumor size. Whenever possible, initial treatment should be complete local excision with breast preservation. Total mastectomy may be necessary for exceptionally large lesions.     

Atypical squamous metaplasia of seromas in breast needle aspirates from irradiated lumpectomy sites: a potential pitfall for false-positive diagnoses of carcinoma

The presence of squamous metaplasic cells is an uncommon finding in fine-needle aspiration (FNA) biopsies of the breast. We report that FNA smears containing atypical squamous metaplastic cells derived from the lining of seroma-type cavities following lumpectomy and irradiation in patients with breast cancer can be a potential pitfall for a false-positive diagnosis of recurrent malignancy. Four fine-needle breast aspirates from two adult patients with previous histories of invasive breast carcinoma were retrieved. One specimen was from a 56-yr-old female, while the remaining three FNAs aspirates were from a 75-yr-old female. Both patients presented with indurated cystic lesions arising at irradiated lumpectomy sites. The cytospins from the 56-yr-old patient showed markedly atypical cells having enlarged, degenerating, hyperchromatic nuclei and surrounding dense cytoplasm with sharp borders that were suspicious for carcinoma. A mastectomy revealed irradiation changes and atypical squamous metaplastic cells lining a cystic cavity consistent with a seroma, but there was no evidence of residual cancer. After three aspirations yielded "atypical" diagnoses, the second patient underwent core needle biopsies that also revealed changes consistent with a seroma cavity lined by atypical squamous metaplastic cells. We believe this is the first report of squamous metaplasia occurring in a seroma cavity following lumpectomy and irradiation of the breast. The squamous metaplastic cells in aspirates of these cystic lesions may display significant cellular atypia that can potentially result in a false-positive diagnosis of malignancy.     

Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas

Loss of heterozygosity (LOH), a genetic change frequently detected in cancer, can also occur in benign epithelial foci in the breast. To characterize LOH in benign breast tissue, 32 cases containing the various components of fibrocystic change in the absence of malignancy were studied. Microdissected foci of ductal hyperplasia, apocrine metaplasia, sclerosing adenosis, and morphologically normal terminal duct lobular units (TDLUs) were analyzed for LOH at 14 polymorphic loci representing seven chromosomal arms. LOH was detected in 22% of normal TDLUs (6/27), 17% of adenosis (4/23), 19% of hyperplasia (4/21), and 53% of apocrine metaplasia (10/19) specimens. Because of the high percentage of LOH in apocrine metaplasia in nonneoplastic specimens, the genetic relationship between apocrine metaplasia and cancer was studied in a panel of breast cancer cases. Of 14 examples of apocrine metaplasia adjacent to a carcinoma, seven were found to have LOH with at least one marker. In all seven cases, the tumor and apocrine metaplasia shared LOH at one or more markers. The results demonstrate that LOH occurs frequently in the components of fibrocystic change as well as in normal TDLUs and suggest that foci of apocrine metaplasia can share a genetically altered precursor cell with an associated carcinoma.     

Noninvasive carcinoma of the breast presenting in adenosis.

Although sclerosing adenosis is a common abnormality in the female breast, malignant change presenting in this setting is exceedingly rare, as fewer than 20 cases have been reported. Since sclerosing adenosis is a lesion of the mammary lobule, it is not surprising that the majority of reported cases have been lobular carcinoma in situ (LCIS). Nine patients with noninvasive carcinoma, restricted in the initial biopsy specimen to foci of sclerosing adenosis, are reported. Seven of the patients had LCIS, one had intraductal carcinoma (DCIS), and one had both LCIS and DCIS. In six of the nine patients, the carcinoma was an incidental finding in a breast biopsy performed for fibrocystic changes or for a fibroadenoma, and in three patients, the abnormality presented as a grossly discrete lesion due to confluence of foci of adenosis (tumoral adenosis). It is important to recognize this microscopic pattern of neoplasia to prevent its misdiagnosis as invasive carcinoma. Two patients had no further treatment following initial excisional biopsy. No residual carcinoma was found in the breast or in lymph nodes in the four patients who had mastectomy. Eight of these patients have been followed for an average of 3 yr (range, 2 to 7 yr), and all are alive and well, without recurrence. Because of the possibility of multifocality, the rarity of the lesion, and the relatively brief follow-up interval, it seems prudent to treat these patients in a manner comparable to that of patients with more common presentations of noninvasive carcinoma.     

Fine needle aspiration cytology of benign breast lumps: a review of experience with 651 cases

A detailed cytomorphologic study was done on fine needle aspiration smears from 651 benign breast lumps. Cytological categorization enabled the distinction of proliferative from non-proliferative and infective lesions in the majority of the cases. Lumpectomy provided the histological diagnosis in 584 cases, most of which were proliferative lesions. Gross cystic disease and fibroadenoma were the most common lesions encountered. Microcysts with apocrine change, sclerosing adenosis, proliferative disease without atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ were associated with the dominant lesion in many of the cases. In all these cases, retrospective analysis of the cytological smears was done in an attempt to identify cytological features which may indicate these lesions.     

Metaplastic carcinoma of the breast arising within complex sclerosing lesion: a report of five cases

AIMS: This study presents a series of five cases in which metaplastic carcinoma, predominantly low-grade adenosquamous carcinoma, of the breast is seen arising within a background of a complex sclerosing lesion. This association has been recognized previously but has not been documented in detail. This study describes the characteristics of the components present in each case and discusses the existing literature. This observation adds further evidence to support an association between some types of invasive breast carcinoma and sclerosing lesions of the breast. METHODS AND RESULTS: Four of these cases were received as referral cases for opinion. The fifth was received as part of the routine surgical workload within our own institution. Two patients presented following mammographic screening and three symptomatically; their mean age was 62 years (range 49-68). The mean lesion size was 16 mm (range 7-24). All five lesions showed features of a complex sclerosing lesion/radial scar in the form of central sclerosis with elastosis and radiating benign entrapped tubules. One had associated benign papillary structures and two had focal benign squamous metaplasia. Four cases showed coexisting but distinct areas of low-grade adenosquamous carcinoma with glandular and squamous epithelial differentiation in a spindle cell background. One case had associated undifferentiated spindle cell carcinoma. Detailed immunophenotypic characteristics of two cases are presented. CONCLUSIONS: This series illustrates a postulated but previously unconfirmed association between an unusual form of metaplastic breast carcinoma (adenosquamous carcinoma) and complex sclerosing lesions. The mechanisms of induction of breast carcinoma are poorly understood but these observations further emphasize the potential for sclerosing lesion of the breast to be associated with, and possibly give rise to, invasive carcinoma of different types. The precise nature of the interaction between the pathological processes remains unclear.     

Expression of c-erbB2, p53, Bcl-2, Bax,c-myc and Ki-67 in apocrine metaplasia and apocrine change within sclerosing adenosis of the breast

Molecular evidence has recently suggested a number of different pathways leading to the development of ductal carcinoma of the breast. The links between atypical ductal hyperplasia and low-grade ductal carcinoma in situ and lobular neoplasia and lobular carcinoma are well known pathologically, but high-grade in situ and invasive carcinomas appear to have a different biological oncogenetic pathway. Morphologically there is a similarity between apocrine cells and some cases of high-grade ductal carcinoma. In order to investigate this possibility a number of different biological markers known to occur in high-grade breast carcinomas were assessed in both apocrine metaplasia (APM) and a putative premalignant lesion called apocrine change within sclerosing adenosis (AA). In 64 cases of APM and 18 cases of AA we examined for expression of c-erbB2, p53, Bcl-2, Bax, c-myc and Ki-67 proteins using immunocytochemistry. c-erbB2 expression was seen in 55.6% of AA cases and in 10.9% of APM cases. p53 expression was detected in 27.8% of AA cases but only 1.6% of APM cases. All cases of AA and APM were negative for the anti-apoptotic protein Bcl-2, but all the APM and 33.3% of AA cases showed cytoplasmic positivity for Bax, a pro-apoptotic protein. All the cases of AA and APM were positive for c-myc oncoprotein, however, the mean percentage of nuclear positivity was 50% in AA and 37% in cases of APM cases. The mean percentage positivity for Ki-67, a proliferation associated antigen, was 3.6% in AA and 1.3% in APM. The results indicate that a subset of breast lesions containing APM epithelium show abnormal oncoprotein and apoptosis-related protein expression and have a higher proliferation rate.     

Surgical excision outcome after radial scar without atypical proliferative lesion on breast core needle biopsy: a single institutional analysis

Radial scar (RS) has been recognized as a risk factor for developing breast cancer, and excision is recommended for patients with RS identified on core needle biopsy (CNB). However, recent literatures suggest that the increased risk may be caused by concurrent proliferative lesions on the biopsy, rather than radial scar itself. In this study, we investigated the follow-up excision (FUE) results for patients with RS on CNB with no history of a prior or a concurrent breast cancer or atypical proliferative lesions (APLs). A total of 113 RS cases including 32 cases with APLs or carcinoma and 81 cases without APLs on CNB were included in this study. Forty cases (49%) without APLs had FUE. No significant difference in radiologic and clinical findings was identified between cases with FUEs and cases without FUEs. Of the 40 cases with FUE, 9 cases (22.5%) were upgraded including 3 atypical ductal hyperplasias, 4 lobular neoplasias, 1 flat epithelial atypia, and 1 atypical apocrine adenosis. However, no case was upgraded to invasive carcinoma or ductal carcinoma in situ. All cases with mammotome CNBs were not upgraded. Our data suggest that conservative follow-up with imaging rather than surgical excisions may be more appropriate for patients with only RS on biopsy, especially for patients with mammotome CNBs.