Pathologic variables predictive of breast events in patients with ductal carcinoma in situ

Central pathology review of ductal carcinoma in situ from 1,456 patients enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-24 was performed to determine predictors for ipsilateral breast tumor recurrences and contralateral breast cancers. Findings after a median follow-up time of 10.5 years revealed ductal comedo necrosis, micropapillary histologic tumor type, and multifocality to be independent high risk factors for ipsilateral breast tumor recurrence. Risk increased for slight comedo necrosis vs absent and for moderate to marked comedo necrosis vs slight. The presence of a micropapillary tumor type and gross tumor size (> or = 1.0 cm) were independently found as risk factors for contralateral breast cancers. Although 47% of ipsilateral and 66% of contralateral events were invasive carcinomas, overall mortality was only 2.3%, a conundrum possibly related to the small size of the latter. The similar predictive role of comedo necrosis in this study and that reported previously from NSABP B-17 (total of 2,079 patients) strongly supports its role as a simple high-risk predictor for ipsilateral breast tumor recurrences.     

Microsatellite analysis of breast carcinoma and corresponding local recurrences

Local recurrence is a serious complication of breast carcinoma that reduces quality of life and influences prognosis. The aim of this study was to determine whether local recurrences of breast carcinoma are genetically related to the primary tumours. Forty cases of locally recurrent breast carcinomas (median onset: 3.6 years after primary surgery) were analysed: 22 patients had undergone breast-conserving therapy and 18 mastectomy. Eighteen microsatellites on chromosomes 2p, 3p, 5q, 10q, 11p, 11q, 13q, 17q, 17p, 18p were amplified by PCR using fluorescent-labelled primers, automatically detected after polyacrylamide gel electrophoresis and analysed for loss of heterozygosity (LOH) or microsatellite instability (MSI). Follow-up data were available for 39 cases with a median value of 89 months. All LOH and MSI found in the primary tumours were also present in the corresponding recurrences, indicating that they are genetically related to the primary tumours and not secondary malignancies in the same breast. MSI was found in three cases, of which one harboured MSI at more than two loci. The median value of LOH per case was significantly higher in the recurrent (four per case) compared to the primary tumours (two per case; p < 0.001, Mann-Whitney test), reflecting the genotype of tumour progression. Early local recurrence was associated with specific LOH for TP53.15 (p = 0.018, log-rank test) in the primary tumours. LOH on D13S1699 or D17S855 was associated with lymph node metastases (p = 0.024 and p = 0.019, respectively; chi-square test). In addition, tumour grade, lack of oestrogen or progesterone receptor expression, young patient age and early appearance of local recurrence significantly correlated with poor survival. The development of local recurrence despite clear resection margins may result from residual DCIS distant from the invasive carcinoma, homing of circulating tumour cells, or genetically altered, histologically normal breast tissue not immediately adjacent to the invasive carcinoma.     

Molecular cytogenetic investigations of synchronous bilateral breast cancer

BACKGROUND: Bilaterality in breast cancer is a rare event and together with an early onset of disease points towards inheritance of the disease. However, most cases seem to occur sporadically, either in a synchronous or metachronous manner. METHODS: Thirty two invasive carcinomas and one in situ carcinoma from 16 patients with synchronous, bilateral breast cancer were investigated by means of comparative genomic hybridisation (CGH) and polymerase chain reaction based multiplex microsatellite analysis. The results were analysed conventionally and were also subjected to a biomathematical cluster analysis. RESULTS: On average, bilateral breast cancer cases showed a low number of genetic alterations, a low frequency of genetic amplifications, and a high rate of chromosomal 16q losses. A distinct, characteristic genetic alteration associated with bilateral breast disease could not be found. Although two tumour pairs appeared to be related using biomathematical processing for microsatellite analysis, this result was reproduced by CGH data processing in one patient only. CONCLUSIONS: Most synchronous, bilateral breast cancer cases seem to represent independent tumours rather than metastatic events. Nevertheless, the possibility of a specific susceptibility remains.     

11q13 Amplification in local recurrence of human primary breast cancer

Breast cancer can relapse both locally and at distant metastatic sites. The mechanism of Iocal recurrence is unknown, but seems to be due not only to the number of residual cancer cells (inadequate irradiation or surgery), but also to their genetically determined malignant potential. To identify genetic alterations associated with local recurrence risk in breast carcinoma, we analyzed 28 local recurrences and 173 primary breast tumors for the ten most frequently altered genetic regions in breast carcinomas, i.e., loss of heterozygosity on chromosomal arms 1p, 3p, 7q, 11p, 17p, 17q, and 18q, and amplification of the MYC and ERBB2 protooncogenes and of genes in 11q13. Only INT2/FGF3 and CCND1, located in 11q13, were more frequently amplified in local recurrences than in primary tumors (39% vs. 17%; P < 0.01). Moreover, recurrence-free survival was shorter when the 11q13 region was amplified. These results suggest that one or more genes located in 11q13 play an important role in local relapses of breast cancer.     

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer

Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.     

Genetic heterogeneity in ductal carcinoma of the breast

Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones.     

Allelotype analysis of flow-sorted breast cancer cells demonstrates genetically related diploid and aneuploid subpopulations in primary tumors and lymph node metastases

Flow cytometric DNA content measurements have demonstrated extensive DNA ploidy heterogeneity in primary breast carcinomas. However, little is known at the molecular level about the clonal relationship between these tumor cell subpopulations, or about the molecular genetic changes associated with aneuploidization. We have used flow cytometric cell sorting to dissect some of this complexity by isolating clonal subpopulations in breast carcinomas for comparative molecular genetic analysis. Clonal subpopulations were isolated from 12 primary breast carcinomas and 5 lymph node metastases from 4 cases based on DNA content and cytokeratin 8/18 labeling. DNA from these clones was screened for allelic imbalances with 92 polymorphic microsatellite markers mapped to 39 different chromosome arms. Diploid and aneuploid populations were concurrently present in 11 out of 12 primary tumors. The DNA ploidy status of primary tumors was identical to that of the related lymph node metastases. Allelic imbalance was present in 10 out of 11 diploid clones (mean, 3.4 +/- 4.2). All allelic imbalances observed in the diploid clones recurred in the cognate aneuploid clones, but were, in the latter, accompanied by additional allelic imbalances at other loci and/or chromosome arms (mean, 10.9 +/- 5.8). In only two of the four metastatic cases did the allelotypes of metastatic clones show small differences relative to their cognate primary tumors. The primary diploid tumor clone recurred in all lymph node metastases. This study indicates that the majority of allelic imbalances in breast carcinomas are established during generation of DNA ploidy diversity. Recurrence of the allelic imbalances in diploid clones in the aneuploid clones suggests linear tumor progression, whereas the simultaneous presence of early diploid and advanced aneuploid clones in both primary and metastatic tumor sites suggests that acquisition of metastatic propensity can be an early event in the genetic progression of breast cancer.     

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with high-level microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotype-positive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.     

Genetic alterations in gastric cancers from British patients

Twenty-six gastric carcinoma and matching normal tissue DNAs, which had previously been analyzed for alterations of the APC (adenomatous polyposis coli) and MCC (mutated in colorectal cancer) genes were further investigated for the following genetic alterations: mutation and loss of heterozygosity (LOH) of the p53 gene, replication error (RER) and LOH at 12 microsatellite repeat loci, and mutation of the hMSH2 gene. In addition, 9 of the 26 gastric carcinomas were analyzed for genetic alterations using comparative genomic hybridization (CGH). Somatic mutations of the p53 gene were found to be frequent being detected in 31% of gastric carcinomas while LOH at the p53 locus was observed in 37.5% of informative cases. Loss of wild type p53 allele was detected in the majority (7 of 8) tumors found to be harboring a mutation. In the hMSH2 gene, an intronic 4 base pair insertion at 31 base pairs upstream of the beginning of exon 13 was detected in both tumor and normal tissue from one gastric carcinoma case. RER was detected in 11.5% of gastric carcinomas, at one or more microsatellite repeat loci. Of the 12 microsatellite repeat loci analyzed LOH was most frequently observed at D22S351 (30% informative cases) suggesting that a tumor suppressor gene on 22q may be important in gastric carcinogenesis. In support of this, CGH analysis carried out on 9 of the gastric carcinomas identified loss of chromosome 22 in 5 of these tumors.     

Carcinoma arising within fibroadenomas of the breast. A clinicopathologic study of 105 patients.

The authors report the clinicopathologic features of 105 carcinomas arising within fibroadenomas (FAs) of the breast. The mean age of the patients was 44 years. The presentation and gross characteristics of these tumors rarely differed from those of uncomplicated FAs. Carcinoma in situ (CIS) was the predominant type of malignancy (95%) found to arise in FAs, and lobular and ductal types occurred with equal frequency. Nine of ten FAs harboring an invasive carcinoma also contained CIS supporting the origin of the infiltrative component in the FAs. CIS within FAs was associated with in situ malignancy in surrounding breast tissue in 21% of cases. Age, fibroadenoma size, and type and extent of CIS were similar in patients with disease limited to the FA and in those with associated malignant disease in the remainder of the breast. Axillary nodal metastases were not detected. Sixty-three patients were observed for a mean period of 8.4 years. Only one of 26 patients with CIS within an FA who was treated conservatively developed an ipsilateral carcinoma. None of the 26 developed contralateral carcinoma; however, 3 of 23 with similar lesions, who were treated by mastectomy, did so. The contralateral carcinomas were invasive in two patients, one of whom died with distant metastases. Seven patients with FAs harboring lobular CIS underwent bilateral mastectomy. Their postoperative course was uneventful. None of seven patients with invasive carcinoma arising in an FA, two of whom were treated conservatively, succumbed to disease. However, one developed contralateral carcinoma. The authors recommend breast-conserving therapy for CIS arising in an FA.     

Loss of heterozygosity in dysplasia and carcinoma of the gallbladder.

The loss or inactivation of genes at specific chromosomal loci is one of the important mechanisms during the tumor development in humans. To investigate the role of genetic alterations in the carcinogenesis of gallbladder carcinoma, 32 carcinoma cases and 11 dysplasia cases of gallbladder were analyzed for loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosomal regions 3p, 5q, 8p, 9p, 13q, 17p, and 18q with 17 microsatellite markers. Loss of one allele was identified on chromosomes 5q (55%) and 17p (40%) in dysplasias and on chromosomes 3p (52%), 5q (66%), 9p (52%), and 17p (58%) in carcinomas. LOH on chromosomes 13q and 18q was frequent only in advanced stage (III and IV) carcinomas (40% and 31%, respectively). LOH on chromosome 17p was correlated with intranuclear p53 accumulation. LOH on multiple chromosomes was more frequent in advanced carcinomas with metastasis than in cases without metastasis (P < .05). A widespread MI was observed in only one case of carcinoma. We conclude that LOH on 5q is an early change of carcinogenesis in gallbladder and that LOH on 3p and 9p is related to the progression of gallbladder carcinoma LOH on 13q and 18q is likely to be a late event. LOH on 17p occurs not only in dysplasia but also increases during the subsequent stages. Accumulation of LOH may be associated with carcinogenesis of the gallbladder, but the role of MI may not be significant.     

Clonal analysis of bilateral mammary carcinomas by clinical evaluation and partial allelotyping

Bilateral breast carcinomas may represent contralateral metastases or new primary tumors. The presence of carcinoma in situ, a lower grade, or a different histotype in the second tumor is considered a clinical criterion for a second primary tumor. In this study, 26 bilateral breast carcinomas from 13 patients were analyzed based on clinical criteria, and the results were compared with those obtained by partial allelotyping using 47 markers at 7 chromosomal arms. Of the 8 synchronous tumors, 5 were concluded to be distinct primary tumors using clinical criteria; some were confirmed by partial allelotyping. In the remaining 3 cases, partial allelotyping showed distinct primary tumors. Five patients had metachronous carcinomas with 3 distinct primary tumors, 1 metastasis, and 1 that was uncertain by clinical criteria. Three cases were confirmed by partial allelotyping, and the uncertain case was shown to be distinct primary tumors. No discrepant results were noted. Stringent application of clinical criteria is accurate for differentiating second primary tumors from metastases.     

Morphologically similar epithelial and stromal cells in primary bilateral breast tumors display different genetic profiles: implications for treatment.

The morphologic features of primary bilateral breast carcinoma have been well elucidated, but it is not known whether tumors at two sides share a common genetic profile and undergo the same clinical course. To address this issue, morphologically comparable epithelial and stromal cells in 18 paired primary bilateral breast tumors were microdissected and subjected to comparisons for the frequency and pattern of loss of heterozygosity (LOH) and microsatellite instability (MI), as well as the profiles of comparative genomic hybridization. Of 18 paired bilateral epithelial samples assessed with 10 DNA markers at five chromosomes, 78 altered loci were found; of these, 23 (29.5%) displayed concurrent and 55 (70.5%) showed independent LOH, MI, or both. Of 18 paired bilateral stromal samples assessed with the same markers, 70 altered loci were seen; of these, 9 (12.9%) displayed concurrent and 61 (87.1%) showed independent LOH, MI, or both. Collectively, all the markers and 30 (83.3%) of 36 paired bilateral epithelial and stromal cells displayed significantly more (P < 0.01) independent than concurrent LOH, MI, or both. In contrast, the epithelial cells of a pulmonary small cell carcinoma metastasized to both breasts displayed concurrent LOH at each of the four altered loci. Of seven selected cases for comparative genomic hybridization, six (86%) displayed chromosomal changes, but none showed an identical pattern and frequency of changes in both breasts. The significantly higher rate of independent genetic alterations in morphologically comparable cells of paired bilateral primary breast tumors supports the notion that the development and clinical course of tumors in two sides differ substantially; consequently, different interventions might be needed for the optimal management of bilateral breast tumors.     

Lobular carcinoma of the breast: Cytological features supporting the diagnosis of lobular cancer

Lobular carcinomas have a distinct natural history with a better response to endocrine therapy and a higher incidence of local recurrence and are more often bilateral. The cytological diagnosis of lobulur carcinoma permits a discriminating therapeutic approach with pre-operative Tamoxifen, more generous resection margins, and assessment of the contralateral breast. The cytological features of lobular cancer however are not well defined and the low cell yield from such neoplasms can result in a high false negative rate. To determine whether we could improve the pre-operative diagnosis, we reviewed the cytological features of 112 lobular carcinomas. They had small uniform sized nuclei with irregular outlines and inconspicuous nucleoli. The degree of dissociation was similar to duct carcinomas and the incidence of inadequate aspirates was no higher. We found no features that confidently diagnosed lobular cancer or its sub-types. However, using a combination of features, typing of lobular cancer on aspirated material is possible and should be attempted. © 1995 Wiley-Liss, Inc.     

Genetic evidence for the multi-step progression of mixed glandular–neuroendocrine gastric carcinomas

A mixed glandular-neuroendocrine gastric carcinoma shows discrete, juxtaposed areas of adenocarcinoma and neuroendocrine carcinoma. In order to gain insight into the genetic events and clonality associated with the dual differentiation of a mixed gastric carcinoma, eight cases (two true composite and six neuroendocrine-dominant carcinomas) were examined by analyzing the genome-wide loss of heterozygosity (LOH). Of the eight mixed gastric carcinomas, one true composite and five neuroendocrine-dominant carcinomas showed a primary LOH that was shared by both the glandular and neuroendocrine components and a secondary LOH or mutations that were restricted to the neuroendocrine components. The glandular components contained mixed cell populations with or without primary LOH events, suggesting that a primary LOH arose during adenocarcinoma progression and that the LOH-positive cell served as a precursor for a neuroendocrine carcinoma. The neuroendocrine components were of a homogeneous population with various genetic alterations such as a LOH, p53 mutations, and microsatellite instability-associated transforming growth factor (TGF)-beta RII mutation. Therefore, most (six of eight cases) mixed glandular-neuroendocrine gastric carcinomas were likely to have sequentially evolved from a glandular precursor to a genetically heterogeneous adenocarcinoma and then to neuroendocrine differentiation. Two components of the other true composite carcinomas were shown to have reciprocally lost different alleles of identical loci on multiple chromosomes, suggesting that, occasionally (one of eight cases), dual differentiation concurrently arises from a single precursor, possibly as a result of non-disjunctional cell division.     

Adenoid Cystic Carcinoma of the Breast

Twelve cases of pure adenoid cystic carcinoma of the breast were reviewed. Patients ranged in age from 34 to 69 years. Seven carcinomas were in the right breast, and five in the left; five of the 12 were located in the central region of the breast, five in the upper outer quadrant, and the two in the upper inner and lower inner quadrants, respectively. Average diameter of the primary tumors was 2.5 cm (range, 0.7 to 6.0). We graded the tumors according to a system used for adenoid cystic carcinoma of the salivary gland: five tumors were grade I, six were grade II, and one was grade III. An average of 5 years after diagnosis, all patients with grade I tumors were either alive without evidence of disease or had died of unrelated causes. Among the six patients with grade II tumors, one developed a local recurrence 5 years after diagnosis and subsequent pulmonary metastasis, and one died of metastatic adenoid cystic carcinoma 13 years after diagnosis. The one patient with grade III tumor had shown metastases in axillary lymph nodes at mastectomy, and she died of disease 2 years later. These findings suggest that the grading of adenoid cystic carcinoma of the breast may be important in prognosis and treatment selection.     

Pleomorphic lobular carcinoma in a male breast: a case report with review of the literature

Invasive lobular carcinoma (ILC) is a distinct type of breast carcinoma and represents 5-15% of invasive breast carcinomas in female. However, the occurrence of ILC is exceptional in male breast, and the incidence is 1.5-1.9% of male breast carcinomas. Herein, we report a case of pleomorphic lobular carcinoma in a male breast. A 76-year-old Japanese male with a history of treatment with a progestational agent for prostate cancer presented with a right breast tumor. Magnetic resonance imaging showed gynecomastia of bilateral breasts and an irregular-shaped nodule in his right breast. Histopathological study revealed infiltrative neoplastic growth of discohesive tumor cells arranged in single-filed linear cords or trabeculae. These neoplastic cells had variable-sized large nuclei containing occasional nucleoli. Immunohistochemically, these tumor cells lacked E-cadherin expression. Accordingly, an ultimate diagnosis of pleomorphic lobular carcinoma was made. This is the third documented case of pleomorphic lobular carcinoma of male breast. Our analyses of the clinicopathological features of this type of tumor revealed that patients were middle-aged or elderly men, and all cases were free from lymph node metastases or recurrence. Gynecomastia and a history of hormonal agent intake were present only in the current case. The most commonly proposed risk factor for the development of male breast cancer is elevated level of estrogen, and a possible link between the development of male breast cancer and estrogen therapy for prostate cancer has been suggested. The clinicopathological features of ILC of male breast remains unclear; therefore, additional studies are needed to clarify them.     

Primary signet ring cell carcinoma of the breast: A rare entity with unique biological behavior—A clinical study based on pure signet ring cell carcinoma cohort

BackgroundPrimary signet ring cell carcinoma (SRCC) of the breast is a rare entity, and only a few case reports of the pure SRCC cases could be found in English literatures. We summarized the clinicopathological characteristics of a relatively large cohort of pure breast SRCCs for the first time.MethodsWe reviewed the medical records of 23 cases of pure breast SRCC with a median follow-up time of 70 months.ResultsThree patients had bilateral primary breast cancer (BC) and two of them had bilateral pure SRCCs. 30 % of patients had the malignant tumor family history including two bilateral BC patients. Malignant calcification was observed in 35.3 % of mammography images. Multifocal lesions were microscopically found in 26.1 % of cases. 63.6 % of the cases had lymph node metastasis, 45.5 % were classified as Stage III, 69.6 % had high value of Ki-67 index, and 34.8 % were triple negative subtype. 19.0 % of patients had local recurrence, and 52.6 % had distant metastasis. Four in five patients with positive tumor family history and follow-up data had relapse of SRCC. The 5-year overall survival rate was 73.7 %, the 5-year relapse-free survival rate was 54.3 %, and the 5-year breast cancer specific survival rate was 78.3 %.ConclusionPure SRCC of the breast showed an aggressive behavior. Neoadjuvant chemotherapy could be considered, breast-conserving surgery should be prudently chosen, and axillary lymph node dissection may be necessary. The high rate of positive tumor family histories and high bilateral incidence, which showed an adverse effect on prognosis, indicate the unique genetic burden of SRCC.     

Molecular clonality determination of ipsilateral recurrence of invasive breast carcinomas after breast-conserving therapy: comparison with clinical and biologic factors

We established clonality relationships between invasive ipsilateral breast failures (IBFs; local recurrences) and initial invasive carcinomas using a molecular polymerase chain reaction loss of heterozygosity (LOH) assay for 26 patients treated with breast-conserving therapy for invasive carcinoma with no distant metastases (DMs) before the IBE LOH was +/- 50% allelic loss. Eighteen IBFs (69%) were related clonally to initial carcinomas; 8 (31%) were clonally distinct, second primary carcinomas. IBFs and initial invasive carcinomas were morphologically similar in 6 (75%) of 8 clonally different cases. Clinical IBF classification and molecular assay results differed in 11 cases (42%). The mean intervals to IBF were 4.7 years in related and 8.7 years in different cases (P = .013). In 6 patients, DMs developed; 5 had related IBFs. In related IBF cases, the mean increase in fractional allelic loss (FAL) of IBFs associated with DMs was 18.9% compared with 7.6% in cases unassociated with DMs (P = .004). Molecular assays can accurately establish the clonality of most IBFs. Morphologic comparison and clinical IBF classification are unreliable methods of determining clonality. Clonally related IBFs occurred sooner than clonally different IBFs. Patients with clonally related IBFs are the main pool in which DMs occur Not all clonally related IBFs have the same DM association; those with large FAL gains were associated with DMs. Molecular clonality assays may provide a reliable means of identifying patients who might benefit from systemic chemotherapy at the time of IBF.     

乳腺纤维瘤病样梭形细胞癌临床病理分析

目的 探讨乳腺纤维瘤病样梭形细胞癌（fibromatosis-like spindle cell carcinoma,FLSCC）临床病理特征。方法 对3例FLSCC病例进行光镜观察和免疫组化染色[CK、CK（34βE12）、vimentin、SMA、ER、PR、Ki-67、c-erbB-2]。结果 3例均为女性,年龄分别为47、53、56岁,均可触及乳腺肿块。肿瘤境界清楚,但镜下边缘呈浸润性。肿瘤主要是梭形细胞、多边形细胞、少量的管状腺体及鳞上皮巢混合,间质纤维明显增生伴胶原化,细胞成束状排列或散在分布,似纤维瘤病样改变。梭形细胞分化良好,异型性不明显,部分区域细胞较丰富,其间聚集的上皮簇或片状多边形细胞核有轻度异型,可见少数核分裂象。多边形细胞与梭形细胞有移行。病变中亦可见淋巴细胞、浆细胞聚集浸润。上皮细胞、多边形细胞及部分梭形细胞CK（34βE12）、CK（AE1／AE3）阳性,CK阴性的梭形细胞表达vimentin、SMA。3例均行肿块切除,其中1例,术后4个月复发,再行乳腺根治术。结论 乳腺（纤维瘤病样）梭形细胞癌是一种少见的、低度恶性肿瘤,诊断需依赖免疫组化标记并与乳腺其它梭形细胞肿瘤相鉴别。