Gyula Pekar

Breast cancer multifocality, disease extent, and survival

The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma.

The distribution of lesions in 1–14-mm invasive breast carcinomas and its relation to metastatic potential

We analyzed 301 consecutive cases of 1–14-mm invasive breast carcinomas documented in large-format histological sections to determine the distribution of invasive and in situ foci. We also aimed to determine whether this distribution was related to the frequency of demonstrable vascular invasion and lymph node metastases. One third of the carcinomas (31.9%, 96 cases) had a multifocal invasive component and a more than doubled relative risk of vascular invasion (RR = 2.3642, 95% confidence interval (CI) = 1.5077–3.7073) and lymph node metastasis (RR = 2.7760, 95% CI = 1.6337–4.7171) compared to unifocal invasive carcinomas. Invasive carcinomas with diffuse in situ component had an elevated relative risk for vascular invasion (RR = 2.2201, 95% CI = 1.4049–3.5083) and lymph node metastasis (RR = 1.9201, 95% CI = 1.1278–3.2691) compared to those with unifocal or multifocal in situ lesions. However, multifocality of the invasive component was associated with a substantially elevated risk of vascular invasion and lymph node metastasis, even in cases with diffuse in situ component. Similar observations were made in the 1–9- and 10–14-mm invasive carcinoma subgroups. These findings indicate that lesion distribution has prognostic relevance for 1–14-mm invasive breast carcinomas and underline the importance of using special techniques in breast pathology for proper assessment of this parameter.

Multifocal breast cancer documented in large-format histology sections: Long-term follow-up results by molecular phenotypes

The prognostic significance of molecular phenotype in breast cancer is well established in the literature. Recent studies have demonstrated that subgross lesion distribution (unifocal, multifocal, and diffuse) and disease extent also carry prognostic significance in this disease. However, the correlation of molecular phenotypes with subgross parameters has not yet been investigated in detail.

High-risk HPV infection and CIN grade correlates to the expression of c-myc, CD4+, FHIT, E-cadherin, Ki-67, and p16INK4a.

Objective: This study aimed to investigate correlations between a panel of biomarkers/tumor markers and high-risk (HR) human papillomavirus (HPV)-positive versus HR-HPV-negative cervical lesions. Materials and Methods: The study included 188 women who consecutively attended a colposcopy clinic because of PAP smears suggesting cervical intraepithelial neoplasia (CIN), and 40 women with normal vaginal cytology. Tissue microarray blocks were prepared from representative cervical cone or punch biopsies. Sections were stained for 12 biological markers, previously shown to be relevant in cervical neoplasms, and expression was correlated to the presence or absence of HR-HPV in cervical lesions. Results: No correlations between expression of biomarkers and HPV status were found in normal epithelium. Expression of c-myc, CD4+, Ki-67, and p16INK4a correlated significantly to HR-HPV-infected epithelium compared with HR-HPV-negative epithelium. When adjustment was made for CIN grade, only the expression of Ki-67 correlated significantly with HPV status and CIN grade. Human papillomavirus status was stratified to normal epithelium, low-grade CIN, and high-grade CIN. Fragile histidine triad (FHIT), E-cadherin, Rb, Ki-67, and p16INK4a expression was significantly increased in HPV-positive tissue by increasing CIN grade. No correlation to tumor marker expression was observed in the HPV-negative tissue. Conclusions: This study described correlations, previously not investigated, between HPV status and tumor marker expression, that is, E-cadherin, Rb, and fragile histidine triad. Surprisingly, p16INK4a was not, although Ki-67 expression was, independently correlated to HPV positivity. The results of this study suggest that p16INK4a instead correlates independently with increasing CIN grade.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

Molecular phenotype of the foci in multifocal invasive breast carcinomas: Intertumoral heterogeneity is related to shorter survival and may influence the choice of therapy

Multiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent and are associated with a poorer prognosis. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci.

Molecular phenotypes of unifocal, multifocal, and diffuse invasive breast carcinomas.

We analyzed the subgross distribution of the invasive component in 875 consecutive cases of breast carcinomas using large-format histology sections and compared the immunophenotype (estrogen and progesterone receptor expression, HER2 overexpression and expression of basal-like markers, CK5/6, CK14, and epidermal growth factor receptor) in unifocal, multifocal, and diffuse tumors. Histology grade and lymph node status were also analyzed. Unifocal invasive carcinomas comprised 58.6% (513/875), multifocal invasive carcinomas 36.5% (319/875), and diffuse invasive carcinomas 4.9% (43/875) of the cases. The proportion of lymph node-positive cases was significantly higher in multifocal and diffuse carcinomas compared to unifocal cancers, but no other statistically significant differences could be verified between these tumor categories. Histological multifocality and diffuse distribution of the invasive tumor component seem to be negative morphologic prognostic parameters in breast carcinomas, independent of the molecular phenotype.

Tissue tumor marker expression in smokers, including serum cotinine concentrations, in women with cervical intraepithelial neoplasia or normal squamous cervical epithelium

OBJECTIVE The purpose of this study was to investigate correlations between smoking and serum cotinine, respectively, and tumor marker expression in cervical intraepithelial neoplasia (CIN) and normal epithelium. STUDY DESIGN Women (n = 228) with cervical biopsy specimens that ranged histologically from normal to carcinoma in situ (CIN III) were included. Expression of 11 tumor markers with possible relevance in cervical neoplasms was studied. Smoking habits were recorded, and serum was assessed for cotinine concentrations. RESULTS No differences were found in tumor marker expression in normal epithelium between smokers and nonsmokers. The tumor suppressors p53 and fragile histidine triad and the immunologic marker interleukin-10 were underexpressed, and the tumor markers cyclooxygenase-2 and Ki-67 were overexpressed in smoking, compared with nonsmoking, women with CIN and particularly in all fertile women. CONCLUSION The molecular pattern indicates that smoking exerts unfavorable effects in cervical neoplasia. This provides biologic evidence of smoking being a true cofactor in cervical neoplasia.

Comparison of the Subgross Distribution of the Lesions in Invasive Ductal and Lobular Carcinomas of the Breast: A Large-Format Histology Study

To compare the lesion distribution and the extent of the disease in ductal and lobular carcinomas of the breast, we studied 586 ductal and 133 lobular consecutive cancers. All cases were documented on large-format histology slides. The invasive component of ductal carcinomas was unifocal in 63.3% (371/586), multifocal in 35.5% (208/586), and diffuse in 1.2% (7/586) of the cases. The corresponding figures in the lobular group were 27.8% (37/133), 45.9% (61/586), and 26.3% (35/133), respectively. When the distribution of the in situ and invasive component in the same tumors was combined to give an aggregate pattern, the ductal carcinomas were unifocal in 41.6% (244/586), multifocal in 31.6% (185/586), and diffuse in 26.8% (157/586) of the cases. The corresponding figures in the lobular category were 15.0% (20/133), 54.2% (72/133), and 30.8% (41/133), respectively. Ductal cancers were extensive in 45.7% (268/586), lobular in 65.4% (87/133) of the cases. All these differences were statistically highly significant (P < 0.0001). While the histological tumor type itself (ductal versus lobular) did not influence the lymph node status, multifocal and diffuse distribution of the lesions were associated with significantly increased risk of lymph node metastases in both ductal and lobular cancers.

Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content

To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.