Expression of cyclin Ds in relation to p53 status in human breast carcinomas

 Cyclin D1 has been reported to be overexpressed in many tumours, including breast carcinomas. Cyclin D1 was first identified as a protooncogene (BCL1/PRAD1), and its overexpression was related to tumour proliferation. The product has also recently been identified as important in mediating cell cycle growth arrest via the p53 pathway in murin fibroblast cell lines. Ninety breast carcinomas previously analysed for p53 status were analysed for amplification of cyclin D1, D2 and D3 genes by Southern blot analysis and for protein expression by immunhistochemistry. In 10 samples gene amplification was detected at the cyclin D1 locus. No gene amplification was detected at the cyclin D2 and D3 loci. Immunoreactivity for cyclin D1 was detected in 38 (42.2%) tumour tissue samples. Fifty samples were immunostained for cyclin D2 and D3. Only 2 samples (4%) showed immunoreactivty for cyclin D2, and 9 samples (18%) for cyclin D3. Cyclin D1 protein overexpression was significantly more often found in tumours with wild type p53 and in tumours with higher grades of differentiation expressing ER. No association was seen between gene amplification of the cyclin D1 gene and p53 status. We conclude there is a relationship between wild type p53 and cyclin D1 protein overexpression in clinical material, indicating that cyclin D1 may be another downstream effector of p53. Received: 25 November 1997 / Accepted: 30 March 1998     

Mammographically detected in situ lobular carcinomas of the breast

We present ten cases of mammographically detected lobular carcinoma in situ (LCIS), involving a single area of variable size (up to a quadrant) in seven cases and the entire gland in three cases. Histologically, calcifications were associated with necrotic central areas within the in situ carcinomatous foci. Multiple foci of LCIS were observed in all five cases in which mastectomy had been performed. Cytologically, the lesions were characterized by a solid proliferation of round noncohesive cells with nuclei of intermediate size. Immunocytochemically, all cases were E-cadherin and p53 negative, and c-ErbB-2, GCDFP-15 and estrogen receptor positive. The proliferation index, evaluated with Ki67, was in the low range. Four cases were associated with foci of infiltrating lobular carcinoma (ILC). These findings contradict the commonly held opinion that LCIS is not mammographically detectable because of its lack of necrosis and calcification. This study documents the existence of a variant of LCIS exhibiting the mammographic features and central necrosis classically associated with ductal carcinoma in situ (DCIS), while retaining the spatial distribution, cytological composition and immunocytochemical features of lobular carcinoma. Received: 23 July 1999 / Accepted: 22 October 1999     

Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients

The search for better prognostic indicators and new treatment modalities in node-negative breast carcinoma patients is important. The aim of this study was to determine the immunohistochemical expression of central cell regulator proteins in relation to hormone receptor status, tumour-cell differentiation and prognosis. We investigated the immunoreactivity of p27, p21, cdk4, cyclin D1 and p53 in 77 node-negative breast carcinomas, with long-term follow-up (mean 163 months; range 20−227). Nuclear staining for p27 was seen in 87% of the carcinomas, for cdk4 in 92%, for p21 in 68%, for cyclin D1 in 58% and for p53 in 18%. Oestrogen receptor (ER) and progesterone receptor (PgR) nuclear staining was seen in 69% and 65% of the tumours, respectively. No correlation between the levels of p21 and p53 was observed. P21 overexpression was, however, associated with positive ER status. Elevated levels of p27 and cyclin D1 correlated with positive hormone status (both ER and PgR). We did find a significant correlation between p27 and cyclin D1 and histological grade of the tumours, with extensive positive immunostaining of p27 and cyclin D1 in well-differentiated carcinomas. The only significant prognostic factor in our series was histological grading. Ten-year relapse-free survival was significantly prolonged in patients with histological grade I tumours versus histological grade II and III tumours. Our results suggest that the expression of p27 and cyclin D1 is closely linked to hormone receptor status in breast carcinomas and to tumour differentiation, a finding that may be of importance in the treatment of hormone-dependent tumours. Received: 26 March 1998 / Accepted: 29 April 1999     

Adenoid cystic carcinoma arising in an adenomyoepithelioma of the breast

 Adenomyoepithelioma is a mixed epithelial and myoepithelial tumour. In rare cases adenomyoepitheliomas give rise to carcinomas with epithelial, myoepithelial, or mixed epithelial and myoepithelial differentiation. Carcinomas arising in adenomyoepithelioma range from low grade to high grade, and 15 cases have been reported in the literature. We describe a 36-year-old woman with a very rare adenoid cystic carcinoma arising in a tubular adenomyoepithelioma. The histogenesis of carcinoma arising in an adenomyoepithelioma is discussed. Received: 15 September 1997 / Accepted: 10 October 1997     

Extensive intraductal component (EIC) and estrogen receptor (ER) status in breast cancer

The extensive intraductal component (EIC) of primary breast carcinoma is a special spread pattern observed In the breast. Extensive intradwtal component may extend diffusely over the entim breast. Therefore, EIC Is considered to be an important risk factor for local recurrence in breast-conserving therapy. However, the pathogenesis of EIC remains uncertain. Whether or not the estrogen receptor (ER) has an influence on its biologic behavior has not been fully studied. A consecutive series of 142 breast carcinomas submitted to the pathology department were examined on step gross dons of 5.0 mm thick. Extensive intraductal component was determined and divided into three types. Estrogen receptor was examined using both immunohistochemistry (ER-IHC) and enzyme immunoassay (ER-EIA). Extensive intraductal component was found In 78 of 138 (56.52%) invaslve carcinomas including invasive ductal carcinoma with a predominant intraductal component. Estrogen receptor-IHC positivity was 42.96% (61/142) in the Invasive breast carcinoma. Estrogen receptor positivity showed no significant difference between ElC-positive and -negative cases, as well as between EIC and Invasive main tumor in the ElC-positive cases. But within the ElC-positive group, ER positivity was found to be higher in the peripheral type of ElC-II and ElC-III than in the central type of ElC-I ( P <0.05). Although ER may not play an essential role in the pathogenesis of EIC, it has shown some significance in the development of peripheral type EIC because of its higher presence in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I.     

Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas

 The biological significance of the differential expression of cytokeratin (CK) polypeptides in breast carcinomas is unclear. We examined the CK profiles of 101 primary infiltrating ductal breast carcinomas using monoclonal antibodies directed against 11 different CKs and against vimentin. Two major CK phenotypes were distinguished: first, a phenotype expressing only the simple-epithelial CKs 7 (variably), 8, 18 and 19, and secondly, a bimodal phenotype co-expressing significant amounts of one or more of the stratified-epithelial CKs 4, 14 and 17. The vast majority of G1 and G2 carcinomas had the simple-epithelium phenotype, as did a subgroup of G3 carcinomas. Interestingly, the majority (62%) of G3 carcinomas exhibited the bimodal phenotype, with the expression of CKs 4, 14 and 17 being statistically correlated with poor histological differentiation and absence of steroid hormone receptors. The distribution of vimentin only partially overlapped with that of these stratified-epithelial CKs. Prognostic analyses suggested that the presence of CKs 4, 14 and/or 17 was associated with short overall and disease-free survival in subgroups comprising G3, oestrogen-receptor-negative and vimentin-negative tumours. In node-positive tumours the correlation between these CKs and a shorter disease-free interval attained statistical significance (log rank, 0.0096). Thus, abnormal CK profiles in ductal breast carcinomas appear to reflect disturbed regulation of differentiation-related gene expression programmes and may prove to be of clinical value. Received: 26 August 1997 / Accepted: 11 February 1998     

Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas

 A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa (κ) statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low κ for this category), DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; κ for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in κ. Size measurement of DCIS was less consistent than that of invasive carcinoma.The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (κ, 0.92) and least consistent for medullary carcinomas (κ, 0.56). Consistency of grading using the Nottingham method was moderate (κ=0.53) and consistency of diagnosing vascular invasion, fair (κ=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.     

Molecular pathology of ovarian carcinomas

 There is evidence that ovarian cancer may be derived from the progressive transformation of benign and/or borderline tumours. Mutations involving different oncogenes and tumour suppressor genes accumulate during the process of malignant transformation, and the alterations of genes involved in the pathogenesis of familial ovarian cancer are probably early events in ovarian tumorigenesis. BRCA-1 and BRCA-2 act as classical tumour suppressor genes in hereditary tumours, but their role in sporadic tumours remains controversial; however, a high frequency of allele losses in BRCA-1 (17q) and BRCA-2 (13q) loci has been observed in both familial and sporadic tumours. The possible role of mismatch repair genes and microsatellite instability is also controversial, but a role for them has been proposed in borderline tumours. Mutations in K-ras are specific for mucinous tumours and may be related to mucinous differentiation. Finally, a role in tumour progression has been proposed for both c-erb B-2 and p53, but their practical value in prognosis remains questionable. Received: 29 May 1997 / Accepted: 2 April 1998     

Carcinoma in a solitary intraductal papilloma of the breast

Herein is reported a rare case of carcinoma arising from papilloma of the breast. A 63-year-old postmenopausal woman noticed a nodule approximately 1 cm in diameter in her left breast. Ultrasonography indicated a mass with a solid pattern within an intracystic tumor measuring 1.5 × 1.5 × 1.4 cm in diameter located near the left nipple. On total image analysis malignancy could not be denied, therefore lumpectomy with resection of the surrounding tissue was performed. Histologically the tumor consisted of cancerous and papilloma components. The cancer cells had high-grade nuclear atypia, were irregular, and contained abundant eosinophilic cytoplasm with a thin vascular stalk. In contrast, the tumor cells had no atypia, and had a thick stroma in the papilloma components. Both lesions could be distinguished clearly from each other. In addition, a transition from papillary to cancerous elements in some areas was seen. An additional partial mastectomy was performed after the lumpectomy but no carcinoma foci were noted in the excised tissue. Possible occurrence of cancerous change in solitary intraductal papilloma of the breast was suspected.     

Adenomyoepithelioma of the breast with malignant features

 The clinico-pathological features of 7 cases of adenomyoepithelioma of the breast with features suggestive of malignancy are presented. There was a high incidence of local tumour recurrence, in 2 cases as high-grade infiltrating carcinoma of the breast of no special type (”ductal”, grade III). One patient died as the result of a clinically diagnosed cerebral metastasis. Histological examination of the primary breast tumours reveals two main patterns: (1) tumours consisting in part of typical adenomyoepitheliomas but which merge with areas of obviously invasive malignant cells and (2) neoplasms that have the overall architecture of an adenomyoepithelioma but which, on close examination, are found to contain foci of cellular atypia and increased mitotic activity. The two patterns of tumour exhibit the same clinical behaviour and should be distinguished from adenomyoepitheliomas, which are cytologically bland throughout. Received: 3 April 1997 / Accepted: 27 May 1997     

20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

The 20q13 region harboring recently described putative oncogenes is frequently amplified in invasive ductal carcinoma (IDC). The aim of this study was to examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5 patients, comparative genomic hybridization (CGH) after laser microdissection revealed 20q13 amplification in four of five cases of IH, in all of three cases of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two specimens analyzed. The amplification rate, however, was higher in DCIS and IDC. In phenotypically normal ductal epithelium normal values were found for 20q13 copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented here is small, our results suggest that mutations in the 20q13.2 region in IH may be associated with accelerated proliferation and hyperplasia of the ductal epithelium. Progression to DCIS and ICD is accompanied by a further increase in the 20q13.2 copy number. Received: 17 March 1999 / Accepted: 22 June 1999     

Invasive ductal carcinoma with a predominant intraductal component arising in a fibroadenoma of the breast

A rare case of invasive ductal carcinoma with a predominant intraductal component arising within a fibroadenoma of the breast in a 42 year old Japanese female was investigated by light microscopy. The patient, who had a well-defined, rubbery breast tumor measuring 2.0 X 3.0 cm, had undergone a tumorectomy 21 months after she noticed the tumor. Histologically, the fundamental architecture of the tumor showed an intracanalicular-type of fibroadenoma, but extensive proliferation of atypical cells was noticed in the lumen of the ducts. Tumor cells in the canaliculi had characteristics of ductal carcinoma, such as solid, comedo and cribriform patterns. As most of the ducts were occupied by carcinoma cells with several foci of microinvasion in the stroma of the fibroadenoma, it was diagnosed as invasive ductal carcinoma with a predominant intraductal component arising within a fibroadenoma. This coexistence of in situ proliferation and invasive lesions of carcinoma within a fibroadenoma suggest the origin of the carcinoma to have been in the epithelial component of the fibroadenoma. In addition, this study clarifies the fact that carcinoma cells may proliferate and spread along the lumen of pre-existing ducts of the fibroadenoma and speculates that the duct system of the fibroadenoma has complete continuity.     

乳腺导管内乳头状瘤凝集素受体的定量研究

运用凝集素亲合组化并结合图像分析技术，对１０例乳腺导和乳头状瘤（ＩＤＰＢ）、８例正常乳腺、１０例单纯性乳腺小叶增生、１２例乳腺癌进行了定量研究。结果显示：大豆素（ＳＢＡ）受体的含量随着细胞的恶变而增高。ＩＤＰＢ中该受体的含量明显高于正常乳腺组和不叶增生组，但低于乳腺癌组，提示该病可能为乳腺的一种癌前病变。花生素（ＰＮＡ）受体的含量在ＩＤＰＢＫ 明显的高于其它各组，而ＰＮＡ受体含量与免疫反应有关因此     

Expression of E-cadherin and its relation to the p53 protein status in human breast carcinomas

 In breast carcinomas the TP53 gene is altered in 10–30% of cases. Alteration of the gene may lead to a general genomic instability, detected as deletions and/or amplifications at the gene level, and as altered expression at the mRNA and protein level. We have demonstrated a strong association between down-regulation of E-cadherin protein expression and alterations of the p53 protein, detected as TP53 gene mutation and/or protein accumulation in tumour samples from 210 patients with breast carcinomas (P <0.001). Investigation of allelic imbalance using microsatellite markers located near the E-cadherin locus was also performed. A higher frequency of loss of heterozygosity in the microsatellite marker closest to the E-cadherin locus was observed in samples with down-regulation of E-cadherin protein expression. A higher frequency of down-regulation of the E-cadherin protein expression was found in invasive lobular carcinomas than in invasive ductal carcinomas, although this difference was of borderline significant (P=0.084). Cases in the present series were also immunostained for c-erbB-2 protein overexpression. A significant association between p53 protein accumulation and cerbB-2 protein overexpression was seen (P=0.036). The results of the present study indicate that p53 protein may play a role in regulation of E-cadherin protein expression. Received: 29 May 1997)Accepted: 10 June 1997     

Acinic cell carcinoma of the breast: an immunohistochemical and ultrastructural study

The clinicopathological features of six cases of breast carcinomas showing features of acinic cell differentiation, which are similar to those seen in homologous tumors of salivary glands, are presented. The patients, all women, were 35–80 years of age. One case recurred after 4 years, and in two cases axillary lymph-node metastases were found at the time of surgery. Histologically the tumors showed a microglandular pattern merging with solid areas. Cytologically, immunohistochemically, and ultrastructurally the tumors were very similar to cases of acinic cell carcinoma of the parotid gland.The differential diagnostic criteria with microglandular adenosis and carcinomas showing granular cytoplasm are discussed. It seems that acinic cell carcinomas of the breast have to be added to the long list of tumors that affect the salivary glands and can also arise in the breast. Received: 19 November 1999 / Accepted: 7 February 2000     

The role of the Epstein-Barr virus in the oncogenesis of EBV(+) gastric carcinomas

 Five hundred and thirteen cases of gastric carcinoma were investigated for the presence of viral RNA, and the clinico-pathological data, geno-type, BamHIF restriction fragment polymorphism (RFLP) and specific LMP-1 30 bp gene deletion were also examined. EBVs detected in lymphocytes in 20 normal gastric mucosa, 7 lymphoma cell lines (LCLs) maintained in severe combined immunodeficiency (SCID) mice and 18 non-Hodgkin’s lymphomas were compared with those in the gastric carcinoma cases. Thirty-three cases (6.4%) were demonstrated to be positive for EBV by means of EBER-1 RNA in situ hybridization. Clinico-pathological data showed no statistically significant difference in histological grading, location of cancer and status of vessel and lymphatic invasion between the EBV-positive and -negative groups, although the former significantly predominated in the submucosal invasion group (submucosal vs mucosal P=0.021; submucosal vs advanced cancer P=0.033). Some of these data were different from corresponding data in earlier reports. In cases that were evaluated by molecular biology, type A, wild-type F and LMP-1 gene deletion predominated except one in 21 informative cases, one in 24 and two in 16, respectively. EBVs detected in lymphocytes in normal gastric mucosa, LCLs in SCID mice and non-Hodgkin’s lymphoma were also predominantly affected by type A, wild-type F and LMP-1 gene deletion with few exceptions. The results indicate a lack of genetic differences among EBVs in gastric carcinoma, normal population, LCLs of SCID mice and non-Hodgkin lymphomas. Some EBV infections in gastric carcinomas may be transient, especially in the submucosal invasion group. Received: 7 July 1998 / Accepted: 24 September 1998     

Diagnostic cytological features of neuroendocrine differentiated carcinoma of the breast

 Neuroendocrine (NE) features characterize a minority of carcinomas of the breast corresponding to definite subtypes, which cover a wide spectrum of differentiation. Breast metastases from NE tumours of gastrointestinal origin are not rare, and to determine whether NE carcinomas in the breast could be differentiated from other tumours on fine needle aspiration (FNA) we analysed the cytological features of 13 primary NE breast carcinomas of different types (7 carcinoid-like, 5 mucinous and 1 solid spindle cell). Smears of carcinoid-like carcinomas showed specific features that made it possible to differentiate them from other primary tumours, but not from breast metastases of NE carcinomas. These features were: cell clusters with rigid borders, single cells with a plasmacytoid appearance and peripheral cytoplasmic granules evident on Giemsa staining and immunoreactive for chromogranin A. In mucinous NE carcinomas such granules were less apparent, and the cytological features could have been mistaken for those of fibroadenomas, as in the case of non-NE mucinous carcinomas. The solid spindle cell type showed noncohesive fusiform cells and moderate nuclear pleomorphism, a pattern similar to that of atypical carcinoids of the lung. Received: 8 December 1997 / Accepted: 7 May 1998