Detection of human papillomavirus in small cell carcinomas of the anus and rectum

Small cell carcinomas represent <1% of colorectal/anal carcinomas and have a poor prognosis. Anorectal squamous cell carcinomas are often associated with high-risk human papillomavirus (HPV) infection, similar to squamous and small cell carcinomas of the uterine cervix. In HPV infection, the oncoprotein E7 inactivates the tumor suppressor Rb, leading to p16 upregulation; however, in small cell carcinomas, the Rb pathway is often blocked by other mechanisms; thus, increased p16 may not indicate HPV infection. P16 immunohistochemistry (IHC) may have a limited role in evaluating small cell carcinomas for HPV infection. Formalin-fixed, paraffin-embedded tissue sections of previously diagnosed small cell carcinomas of the anus (n=5) and rectum (n=11) were subjected to IHC for p16, CDX2, and p63, followed by in situ hybridization for high-risk HPV. All (100%) cases of anal and rectal small cell carcinomas were positive for p16, and 100% of anal and 82% of rectal small cell carcinomas were positive for high-risk HPV. The majority of cases showed low or very low HPV copy numbers. In 6 cases, HPV was detected only by using the HPV-16 genotype-specific assay detecting very low copy numbers (1 to 2 viral copies). The majority of tumors expressed p63, which was more pronounced in the anal tumors. CDX2 expression was observed predominantly in rectal tumors. High-risk HPV can be detected using in situ hybridization in the majority of anorectal small cell carcinomas, which are uniformly p16 positive by IHC. HPV-targeted therapy could result in better control of these aggressive neoplasms.     

Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.     

Detection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix

Human papillomavirus (HPV) has been implicated as an etiologic agent for the development of primary small cell carcinoma of the uterine cervix, a rare but highly aggressive malignancy. It has been shown that the HPV E6 and E7 oncoproteins are able to inactivate the tumor suppressor functions of p53 and Rb. In squamous cell carcinoma and adenocarcinoma of the cervix, HPV infection is also associated with overexpression of p16, a cyclin-dependent kinase inhibitor. In this study, 22 cases of primary small cell carcinoma of the uterine cervix were subjected to broad-spectrum HPV DNA amplification and typing, and immunohistochemically examined for the expression of p16, Rb, and p53 proteins. The results show that HPV DNA was detected in every case (100%), with 18 cases (82%) harboring type 18. The tumor cells exhibited strong nuclear staining for p16 in 20 cases (91%). This was associated with a complete loss of Rb nuclear staining in tumor cells in 16 cases (73%). The p53 protein was essentially undetectable in all cases. In contrast, HPV DNA was not detected in 9 colorectal and 8 urinary bladder small cell carcinomas included in this study for comparison. While similar p16 and Rb expression patterns were observed in these HPV-negative tumors, a different expression pattern for p53 was noted where strong nuclear staining was seen in 8 cases (47%; P = 0.0004 compared with cervical tumors). These observations indicate that different mechanisms are involved in the pathogenesis of small cell carcinomas of the uterine cervix and support the notion that nuclear p16 overexpression serves as an indication of Rb defunctioning in tumor cells, which may or may not result from high-risk HPV infection.     

Distribution of hsp-27 and HER-2/neu in in situ and invasive ductal breast carcinomas

Background: The overexpression of heat shock protein 27 (hsp-27) in early-stage breast cancer is associated with histopathologic features of poor prognosis and clinically with an increased probability of disease recurrence. Hsp-27 is overexpressed in 25% of invasive ductal carcinomas (IDC); however, its distribution in ductal carcinoma in situ (DCIS) and DCIS associated with IDC has not been investigated. We postulated that hsp-27 might be detected and variably expressed in DCIS and, like HER-2/neu oncoprotein expression, might be a tumor-specific marker worthy of future clinical investigation. Methods: To test these hypotheses, the distribution of hsp-27 in noncomedo and comedo DCIS, and DCIS associated with IDC, was evaluated by immunohistochemistry and compared with HER-2/neu expression within the same cancers. Results: Hsp-27 was overexpressed in 28 of 47 (60%) cases of DCIS; expression in pure DCIS was 16 of 24 (67%), and 12 of 23 (50%) in DCIS associated with IDC. Hsp-27 expression by in situ and invasive components of the same neoplasm were concordant in 22 of 23 (95%) cases tested. Comedo variants appeared to have somewhat higher hsp-27 expression than noncomedo DCIS, whether or not there was an associated IDC. These results are reminiscent of HER-2/neu oncoprotein expression in DCIS and DCIS associated with IDC observed by others. However, although 4 of 22 (18%) cancers containing DCIS + IDC expressed HER-2/neu, no relationship with hsp-27 expression in the same cancers was observed. Conclusions: We found a high incidence of hsp-27 overexpression in DCIS and in DCIS associated with IDC. This rate is twice that previously observed in IDC alone. Hsp-27 expression is independent of HER-2/neu expression.     

Histopathological study of invasive ductal carcinoma (IDC) of the pancreas without associated cancerous occlusion of the main pancreatic duct

BACKGROUND/PURPOSE: [corrected] Invasive ductal carcinoma (IDC) of the pancreas may be associated with cancerous occlusion of the main pancreatic duct (MPD) in its growth process, but at quite low a frequency; there are patients who do not develop this occlusion. METHODS: This study examined the histological features of surgical specimens from 8 patients with IDC without MPD occlusion, in comparison to 32 patients with IDC with this occlusion (controls). The pancreatic duct was identified by confirming the presence of mural elastic fibers on the wall of the pancreatic duct. Immunohistochemical staining was done with Ki-67 antibody. RESULTS: The frequency of IDC without MPD occlusion was very low (5.0% [2/40] patients at Kurume University and 3.1% [4/126] patients at Juntendo University). The number of intraductal carcinoma components was 1.5 +/- 1.1 per specimen in the IDCs without occlusion and 5.9 +/- 2.4 in the controls (P < 0.001). The Ki-67 labeling index was 18.0 +/- 11.7% in the IDCs without occlusion and 30.0 +/- 12.1% in the controls (P < 0.05). The number of intraductal carcinoma components and the Ki-67 labeling index were significantly lower in the IDCs without occlusion than in the controls. CONCLUSIONS: Our findings suggested that these two types of IDC could have different biological features.     

Estrogen receptor-positive breast carcinomas in younger women are different from those of older women: A pathological and immunohistochemical study

The higher frequency of triple-negative and HER-2-positive tumors detected in younger patients has been suggested as an explanation for the more aggressive tumor types observed in this age group. However, estrogen receptor (ER)-positive tumors are the most frequent subtype of breast carcinomas identified, even in younger patients. In this retrospective study, the morphological and immunohistochemical profiles of ER-positive breast carcinomas from women 35 yrs and younger that were diagnosed between 1997 and 2007 were evaluated. From these cases, 213 were selected based on the availability of pathology reports and paraffin blocks. For comparison, 117 consecutive cases of breast carcinomas diagnosed in patients >60 yrs from 2006 were included. Paraffin-embedded tumors were stained for expression of ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), Ki-67 antigen, epidermal growth factor receptor (EGFR), cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays. ER-positive carcinomas were diagnosed in 120 (56.1%) samples of the younger patient group and in 92 (78.6%) samples of the older patient group. Of these ER-positive carcinomas, 48 (40%) from the younger patient group presented the subtype luminal A, compared with 53 (57.6%) from the older patient group (p = 0.01). Tumors from the younger patient group were also associated with increased vascular involvement, co-expression of HER-2, and decreased expression of CD117. These results highlight differences in expression markers and the pathology of ER-positive tumors detected in younger women, with a notable characteristic being co-expression of HER-2.     

Ki-ras point mutation in codon 12 and expression ofp53 in mucin-producing tumor of the pancreas

Mucin-producing tumors (MPTs) of the pancreas show a variety of clinical characteristics, including massive production of mucin in the pancreatic duct, dilatation of the main pancreatic duct, and a better prognosis than common invasive ductal carcinoma (IDC). These characteristics suggest that MPTs and IDCs have different cytomolecular backgrounds. The present study was designed to assess the differences in cytomolecular background between MPTs and IDCs, especially the differences in Ki-ras point mutation (PM) and wild and mutant typep53 expression. Cytomolecular backgrounds were compared in a 13 MPTs [8 carcinomas (MPCas) and 5 benign tumors (MPBTs)] and 36 IDCs. Cytomolecular studies included the evaluation of Ki-ras PM and the expression of Ki-ras p21, wild-typep53 (w-p53), and mutant-typep53 (m-p53). Ki-ras PM was assessed by the allele-specific oligonucleotide dot blot hybridization method, and the expression of p21 andp53 was assessed by an immunohistochemical staining method with monoclonal antibodies. Ki-ras PM was seen in 97% of IDCs and in 77% of MPTs (100% of MPCas and 40% of MPBTs), and MPBTs showed a significantly lower incidence of Ki-ras PM (versus IDC,P < 0.01). Guanine-Guanine-Thymine (GGT) to Guanine-Adenine-Thymine (GAT) mutation was seen in 55% of IDCs and 62% MPTs (87% of MPCas and 20% of MPBTs), and MPCas showed a significantly higher incidence of percent GAT mutation (versus IDC,P < 0.05). Ki-ras p21 was expressed in 43% of IDCs and in 31 % of MPTs (50% of MPCas and 20% of MPBTs). w-p53 and m-p53 were expressed in 51 % and 78% of IDCs and in 54% and 62% of MPTs (38% and 63% of MPCas and 20% and 60% of MPBTs), respectively. In MPBTs, hyperplasias showed higher rates of p21, w-p53, and m-p53 expression than cystadenomas. The study suggested that GAT mutation may be involved in the tumorigenesis of MPTs. It is suggested that MPBTs, especially hyperplasias, may be classified as low-grade malignancies like MPCas.     

Heat shock protein 27 overexpression in breast cancer lymph node metastasis

Background: Heat shock protein 27 (hsp-27) is overexpressed in 67% pure ductal carcinoma in situ (DCIS), in 50% DCIS associated with invasive ductal carcinoma (IDC), and in 25% IDC alone. If this decrease in hsp-27 expression has a role in the progression of malignancy in IDC, we postulate a further reduction in expression in nodal metastasis. Methods: To test this hypothesis, we evaluated the distribution of hsp-27 in primary IDC and in synchronous regional lymph node metastasis within the same patient by immunohistochemistry. Results: Nine of 30 primary IDCs (30%) and 22 of 30 lymph node metastases (73%) overexpressed hsp-27. Contrary to our hypothesis, of 21 IDCs with no or low hsp-27 expression, 13 (62%) had overexpression of this protein within nodal metastasis. Conclusions: hsp-27 appears to confer cytoprotection for metastatic cells, which may help explain why hsp-27 overexpression is associated with reduced disease-free survival in breast carcinomas.     

孕激素受体a、b在乳腺浸润性导管癌中的表达及意义

目的探讨孕激素受体a（PR-a）、孕激素受体b（PR-b）在乳腺浸润性导管癌（IDC）中的表达及其与各临床病理指标的相关性,探讨PR亚型与预后的关系。方法采用免疫组化法检测100例IDC组织中PR-a、PR-b的表达,分析其与雌激素受体仅（ER-a）、雌激素受体B（ER-β）、人类表皮生长因子受体2（HER-2）、核增殖抗原Ki-67、淋巴结转移、细胞学分级、TNM分期及脉管癌栓的相关性,研究PR-a／PR-b比值与各指标的关系。结果PR-a阳性55例（55％）,PR-b阳性58例（58％）。PR-a与HER-2、Ki-67的表达呈正相关（P〈0．05）,与淋巴结转移负相关（P〈0．05）,与ER-β及脉管癌栓负相关（P〈0．01）,与ER-a、细胞学分级、TNM分期无相关;PR-b与淋巴结转移、细胞学分级、TNM分期负相关（P〈0．05）,与HER-2、Ki-67及脉管癌栓亦呈负相关（P〈0．01）,与ER-a、ER-B无相关。PR-a／PR-b〉1者32例（48．5％）,=1者18例（27．3％）,〈1者16例（24．2％）。PR-a／PR-b〉1组的HER-2、Ki-67、高细胞学分级、高TNM分期、淋巴结阳性率高于PR-a／PR-b≤1组（P〈0．05）。结论PR-b的表达与HER-2、Ki-67、淋巴结转移、细胞学分级、TNM分期及脉管癌栓均呈负相关,而PR-a与各指标的相关性各不相同,PR-b阳性及PR-a／PR-b≤1可作为IDC预后良好的指标。     

Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases

High-grade invasive ductal carcinomas (IDCs) of the breast with large, central acellular zones on their cut surfaces are usually associated with the myoepithelial immunophenotype of carcinoma cells, which includes the expression of S-100 protein, alpha-smooth muscle actin, and keratin 14. To clarify the clinical significance of these features of IDCs, the authors compared the incidence of the myoepithelial immunophenotype immunohistochemically, patient prognosis, and metastatic sites of the tumor between 20 high-grade IDCs with large, central acellular zones and 40 control high-grade IDCs without these zones. The myoepithelial immunophenotype was detected in 16 IDCs (80%) with large, central acellular zones but in only seven IDCs (18%) without. The risk ratio of metastasis, especially in the brain and lung, and death from cancer were significantly higher (p = 0.0096 and p = 0.030) for the 20 IDCs with large, central acellular zones than for those without by Cox's univariate analysis. Using Cox's multivariate analysis, large, central acellular zones in IDCs were an indicator of high risk of brain and lung metastases and of death by cancer independent of nodal status and tumor size. Examination of large, central acellular zones and myoepithelial immunophenotype in high-grade IDCs appears helpful in predicting patient prognosis and preferential metastatic sites of the tumors.     

Resection of four synchronous invasive ductal carcinomas in the pancreas head and body associated with pancreatic intraepithelial neoplasia: Report of a case

This report describes a very rare case of four synchronous invasive ductal carcinomas (IDCs) in the pancreas head and body with possible multicentricity. The patient was a 75-year-old woman. Abdominal dynamic computed tomography showed four low-density masses (25 mm, 20 mm, 10 mm, and 10 mm in diameter) in the pancreas head and body. The patient underwent a pylorus-preserving subtotal pancreatoduodenectomy. Histologically, the discontinuity between the four tumors was confirmed; one tumor (20 mm) was moderately differentiated tubular adenocarcinoma, and the others (25 mm, 10 mm, and 10 mm) were papillary adenocarcinomas. Two smaller papillary adenocarcinomas were composed of abundant fibrosis, pancreatic intraepithelial neoplasia (PanIN) 2–3, and IDC with stromal invasion. PanIN-1-2 lesions proximal to the four IDCs were evident. The immunohistochemical staining by CK20, MUC1, and Ki-67 revealed apparently different features for 2 IDCs (25 mm and 20 mm) and somewhat differential features for three papillary adenocarcinomas. Therefore, the progression of PanIN to IDC and multicentric occurrences of these four IDCs were possible. In this report, we show that immunohistochemistry and the confirmation of the presence of PanINs in IDC were useful to some extent for the study of multiple pancreatic cancers.     

p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas

Two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are considered non-HPV-associated. Recently, immunohistochemical detection of p16 and p53 has been proposed to differentiate these 2 types of VSCCs. We conducted a histologic study with immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerase chain reaction using 2 different sets of primers in 92 cases of VSCCs to evaluate the usefulness of immunohistochemistry in the classification of VSCCs and to describe the clinico-pathologic characteristics of both types of VSCCs. HPV was detected in 16/92 (17.4%) specimens, HPV16 being identified in 75% of positive cases. A significant number of discrepancies between histology and HPV detection were observed, with 37.5% of HPV-positive tumors being keratinizing and 9.2% of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100% and 6.2% of HPV-positive tumors and in 2.3% and 64.5% of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and of p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8% HPV-positive tumors, including 3 keratinizing tumors. All these cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6% of HPV-negative cases; 90.8% of them were positive for p53 but all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and negative tumors. In summary, the current morphologic criteria to discriminate HPV-positive and negative VSCCs have a significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSSCs, which improves the results of histologic classification.     

Human papillomavirus-related small cell carcinoma of the oropharynx

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSqCC) represents an important subgroup of head and neck cancer that is characterized by a distinct risk factor profile, a relatively consistent microscopic appearance, and a favorable prognosis. A growing experience with HPV testing of OPSqCCs has uncovered variants that deviate from prototypic HPV-related cancer with respect to morphology but not clinical behavior. In effect, HPV positivity confers a favorable prognosis independent of morphologic subtype. We report 5 cases of HPV-related oropharyngeal carcinomas with well-developed features of small cell carcinoma (SCC) to define the prognostic impact of HPV positivity in a tumor type universally regarded as highly aggressive. Four of the SCCs arose in association with a conventional HPV-related OPSqCC. All 5 SCCs were HPV positive by in situ hybridization. By immunohistochemistry, all 5 cases were p16 positive, synaptophysin positive, and cytokeratin 5/6 negative. Four of the patients were men. The mean age was 61 years (range, 49 to 67 y). The SCCs were associated with metastatic spread to distant sites (60%) and poor survival outcomes: 3 patients (60%) died as a result of their disease (mean survival time, 10 mo; range, 6 to 15 mo). HPV testing has disclosed a previously unrecognized variant of HPV-related oropharyngeal carcinoma that is microscopically characterized by the small cell phenotype. Recognition of this component, even in association with conventional HPV-related OPSqCC, is important as it may indicate an aggressive phenotype that supersedes HPV positivity as a prognostic indicator.     

BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.     

Expression of p16(INK4A), p53, and Rb proteins are independent from the presence of human papillomavirus genes in oral squamous cell carcinoma.

BACKGROUND: The overexpression of p16(INK4A) and suppression of p53 and Rb proteins are key features of oncogenic transformation by human papillomaviruses (HPV) in anogenital cancers. HPV genomes are often detected in cancers of the oral cavity, but it is unclear whether HPV has a specific oncogenic role there. OBJECTIVES: The objectives of the study were to investigate the expression of p53, Rb, and p16(INK4A) proteins and identify HPV infection and viral integration into the host genome. METHODS: Seventy-nine cases of oral squamous cell carcinoma (OSCC) were studied by immunohistochemistry. Polymerase chain reaction (PCR) was performed to identify HPV DNA from the samples. The results were correlated with clinical data. RESULTS: Thirty-three cases were HPV positive for high-risk HPV (HR-HPV) types, of which 27 harbored HPV16. In 25 of 27 HPV16-positive tumors, the HPV16 genome was fully integrated into the host genome, as evidenced by the lack of PCR-amplifiable E2 gene sequences. Forty-five patients were p53 overexpressing, 20 with HR-HPV-positive and 25 with HR-HPV-negative tumors. p16(INK4A) protein was overexpressed in 4 of 31 HR-HPV-positive and 9of 45 HR-HPV-negative cases. Twenty-six of 32 HR-HPV-positive and 37 of 44 HR-HPV-negative samples exhibited pRb nuclear staining. These differences between HR-HPV-positive and -negative tumors were not statistically significant. No correlation was found between these biological factors and tumor location, stage, differentiation grade, or alcohol or tobacco abuse. CONCLUSIONS: A tumor immunophenotype, similar to HPV-related anogenital cancers, is not present in OSCC and highly oncogenic HPV types are therefore unlikely to be specific or independent risk factors for oral cancer.     

UbcH10在乳腺浸润性导管癌中的表达及预后分析

目的:探讨UbcH10在乳腺浸润性导管癌中的表达及其与预后的关系。方法:采用免疫组化检测100例乳腺浸润性导管癌组织中UbcH10、ER、PR、Ki-67、p53和HER-2的表达差异,分析UbcH10表达与年龄、TNM分期、分化程度、ER、PR、Ki-67、p53表达及HER-2等特征及预后的相关性。结果:UbcH10在乳腺浸润性导管癌中高表达,在乳腺癌组织与癌旁组织及乳腺良性肿瘤中的表达存在显著差异;UbcH10的表达在不同分化程度之间和乳腺癌各分子分型之间有统计学差异;UbcH10的表达与Ki-67、HER-2表达有相关性;UbcH10的表达与病人年龄、肿块大小、区域淋巴结转移、肿瘤TNM分期、ER、PR、p53表达状态无相关性;UbcH10高表达组预后差,阳性表达的生存时间低于阴性表达。结论:UbcH10在乳腺浸润性导管癌中高表达,预后较差。     

Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study

It is not clear whether invasive breast carcinomas with medullary features (IBCMFs, atypical medullary carcinomas) constitute a specific phenotype of breast cancer that is of biologic significance. Because medullary features are common in BRCA1-associated carcinomas and these tumors frequently show a basal-like phenotype, we examined whether IBCMFs expressed basal/myoepithelial markers and had a basal-like phenotype. We studied the immunohistochemical expression of 15 markers in tissue microarrays containing samples from 35 IBCMFs and 39 grade 3 invasive ductal carcinomas (IDCG3s) of no special type. In addition, we analyzed EGFR, C-MYC, and CCNE gene amplification by fluorescence in situ hybridization, because the expression of these genes is known to be associated with the basal-like phenotype. We defined the basal-like phenotype according to the criteria of Nielsen et al as being those tumors that were ER/HER2-negative and cytokeratin (CK) 5/6- and/or epidermal growth factor receptor-positive. IBCMFs were more frequently hormone receptor- and HER2-negative, but had greater expression of proliferation markers and p53. In addition, IBCMFs more frequently expressed basal/myoepithelial markers, such as CK5/6 and P-cadherin. A basal-like phenotype was found in 62.9% of IBCMFs but in only 18.9% of IDCG3s. No differences in gene amplification were found between IBCMFs and IDCG3s, although C-MYC amplification was more common in tumors without a basal-like phenotype. The identification of IBCMF as an independent group of tumors could be of clinical significance, given the high incidence of cases with a basal-like phenotype, which is a group of tumors with different prognosis and chemotherapy response from those of IDCG3s of no special type.     

p53 overexpression is a predictor of local recurrence after treatment for both in situ and invasive ductal carcinoma of the breast

BACKGROUND: Several biological markers have been related to prognosis in mammary ductal carcinoma. The aim of the study was to determine biological markers that could predict local recurrence following treatment for all stages of primary operable ductal carcinoma of the breast. MATERIALS AND METHODS: A consecutive series of patients treated for pure ductal carcinoma in situ (DCIS, n = 110) and invasive ductal carcinoma (IDC, n = 243) was studied. Twenty-three patients with DCIS were excluded because of lack of original paraffin embedded tissue. All patients had been treated between July 1996 and December 2001. Median follow-up was 49.8 mo. From the original paraffin embedded tumors, tissue microarrays (TMAs) were constructed. On these TMAs, immunohistochemistry was performed for estrogen-receptor (ER), progesterone-receptor (PR), Her2/neu, p53, and cyclin D1. Main outcome was the event of LR. All analyses were stratified for diagnosis (DCIS or IDC) and pathological grade. RESULTS: In univariate analyses, Her2/neu overexpression (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.1-8.7, P = 0.032) and p53 overexpression (HR 3.5, 95% CI 1.3-9.3, P = 0.014) were associated with LR in patients treated for both DCIS and IDC. In multivariate analysis, p53 overexpression (HR 3.0, 95% CI 1.1-8.2, P = 0.036 and HR 4.4, 95% CI 1.5-12.9, P = 0.008) and adjuvant radiotherapy (HR 0.2, 95% CI 0.1-0.8, P = 0.026) were independent common predictors of LR in patients who had received treatment for both DCIS and IDC. CONCLUSIONS: p53 overexpression is a common predictor of LR following treatment for all stages of primary operable ductal carcinoma of the breast. This marker may help in planning optimal treatment and follow-up.     

Histopathologic characteristics predicting HER-2/neu amplification in breast cancer

The HER-2/neu gene is a proto-oncogene that is amplified in 10-30% of breast cancers. New drugs for targeted therapy, such as Herceptin, are effective for patients with HER-2/neu-positive tumors, making it necessary to have a noncostly and accurate method to assess HER-2/neu status. We studied the correlation of findings made by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) staining and the possibility of combining IHC and other clinicopathologic characteristics of breast tumors to predict FISH-determined HER-2/neu status. The clinicopathologic characteristics analyzed were the size of the tumor, p53, lymph-vascular invasion, estrogen/progesterone receptors (ER/PR), tumor grade, axillary lymph node status, and patient age. A total of 199 cases of invasive breast cancer studied at the UCLA Pathology Laboratory during 2003 were included in this study. Tumors with IHC 0, 1+, 2+, and 3+ scores were found to be FISH positive in 3.5%, 6.4%, 25.7%, and 81.5% of the respective groups. Our study showed a strong association between the FISH-negative and IHC scored 0 and 1+ tumors, suggesting that the FISH test may not be necessary in these cases (p<0.0001). Although the concordance between IHC 3+ and FISH positive is high, 18% of the patients with overexpression of HER-2/neu fail to show gene amplification by FISH. HER-2/neu positivity was found to be proportionally associated with increasing grade in infiltrating ductal carcinoma (p<0.0001). p53-positive tumors are more likely to be HER-2/neu amplified (p=0.0003). Tumors that are negative for ER/PR are also associated with HER-2/neu positivity by FISH (31.15%, p=0.0016). FISH-determined HER-2/neu status is not associated with histologic type, tumor size, nodal status, lymph-vascular invasion, or patient age.