Jiri Bouda

Weak expression of focal adhesion kinase (pp125FAK) in patients with cervical cancer is associated with poor disease outcome.

Purpose: The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. FAK expression has been linked to tumor cell invasion and metastasis, but data on cervical cancer are inconclusive. Our goal was to investigate FAK expression in cervical cancer and to assess whether its expression correlates with prognosis. Experimental Design: FAK expression was examined using immunohistochemistry with sections from 162 resected cervical cancer specimens. Kaplan-Meier survival curves were used to determine the significance of FAK expression in the prognosis of cervical cancer patients. Results: Specific FAK expression was found in the tumor cells, whereas normal cervical epithelium showed barely any FAK expression. Of 162 invasive cervical cancer specimens, 55 (34%) revealed weak expression of FAK, whereas moderate and strong expression was found in 63 (39%) and 44 (27%) tumors, respectively. Patients with tumors expressing weak amounts of FAK were characterized by a significantly poorer overall survival compared with those with moderate and high intratumoral FAK expression (P = 0.002). Weak expression of FAK correlated with pelvic lymph node metastasis (P = 0.026) and recurrent disease (P = 0.013). Multivariate Cox regression analysis revealed decreased FAK expression and pelvic lymph node metastasis to be significant independent factors predictive of poor disease outcome (hazard ratio, 0.36; P = 0.005; hazard ratio, 2.38; P = 0.018, respectively). Conclusions: Weak expression of FAK in invasive cervical cancer is a strong independent predictor of poor patient outcome. Further studies are warranted to elucidate whether FAK expression analysis is a suitable tool identifying patients at high risk even at an early clinical stage.

Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients.

This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola. Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells. Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as “Indian files”), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor γ gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal. We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.

Hidradenoma papilliferum with oxyphilic metaplasia: a clinicopathological study of 18 cases, including detection of human papillomavirus.

Reported here are 18 cases of hidradenoma papilliferum with oxyphilic metaplasia. All patients were women ranging in age from 29 to 74 years. Each presented clinically with a small, solitary tumor in the anogenital region. Microscopically, in addition to classic histopathological features, in every case there was oxyphilic metaplasia of the constituent epithelial cells. This finding could be likened to apocrine metaplasia, a term used in breast pathology. Other histopathological findings observed in this series, analogous to benign breast disease, included sclerosing adenosis-like changes, atypical apocrine adenosis-like changes, changes corresponding to usual ductal epithelial hyperplasia, epitheliomatosis with a streaming growth pattern, lamprocyte-like changes, clear cell change of the myoepithelium, foamy histiocyte reaction, and stromal fibrosis. Immunohistochemistry inferred that in the majority of cases oxyphilic metaplasia resulted from more lysosomes, whereas numerous mitochondria were detected in only 3 cases. Using 2 different PCR methods we identified HPV in 4 of 15 cases of hidradenoma with oxyphilic metaplasia. In addition, HPV was detected in 3 of 16 conventional papillary hidradenomas used as a control group. The following HPV types were identified: 16, 31, 33, 53, and 56. The last type was found in 5 cases. More than one HPV type from a single lesion was seen in 5 cases. Our observations are consistent with previous publications noting similarities between tumors of the breast and sweat glands. Oxyphilic metaplasia, areas with solid growth, and changes simulating atypical apocrine adenosis are rare and poorly recognized in hidradenoma papilliferum and may cause diagnostic difficulties; in our cases several submitting pathologists suspected malignancy. A causal role for HPV in hidradenoma papilliferum cannot be confirmed from our results, as the detection rate is too low. The exact role of the HPV in etiology and pathogenesis of this neoplasm has yet to be determined.

Primary cutaneous histiocyte and neutrophil-rich CD30+ and CD56+ anaplastic large-cell lymphoma with prominent angioinvasion and nerve involvement in the forehead and scalp of an immunocompetent woman

Background:  Cutaneous lymphomas co‐expressing CD56 and CD30 are very rare. They share a clinicopathological overlap with natural killer‐ (NK)/T‐cell lymphomas and anaplastic large‐cell lymphomas (ALCLs), two entities with widely disparate clinical behavior.

Significance of nuclear hTra2-beta1 expression in cervical cancer

Objective. Human Tra2‐beta1, a member of the serine/arginine‐rich splicing factors, is involved in C/A‐dependent mRNA processing and regulation of gene expression. Since several genes involved in cervical carcinogenesis are alternatively spliced and contain C/A rich elements, we aimed to analyze hTra2‐beta1 expression and subcellular localization in tumor tissue of women with cervical cancer and to determine its clinical significance. Design. Retrospective study. Setting. Tertiary‐care academic medical center. Sample. One hundred and five patients with cervical cancer and a mean follow up time of 73.1 months. Methods. Immunohistochemistry of paraffin‐embedded tissues was performed and hTra2‐beta1 expression was correlated with clinico‐pathological variables including patient outcome. Results. Cytoplasmic hTra2‐beta1 protein expression was found in 20% of cases, while all tumors revealed nuclear immunoreactivity with strong expression in 54.3% of cases. There was a significant inverse correlation between nuclear and cytoplasmic protein expression, suggesting a potentially relevant shuttle process of hTra2‐beta1 between both cellular compartments. Patients with weak expressing hTra2‐beta1 tumors showed an improved survival with a tumor‐related death rate of 8.3% compared to 23.7% in patients with moderate and high intranuclear hTra2‐beta1 expression, respectively. Conclusions. Our data support the hypothesis of a biological relevance for hTra2‐beta1 expression in cervical cancer. The observed shuttle process of this splicing factor with higher concentrations in the nucleus should have pronounced effects on the cellular function and tumor biology of the affected tumors, leading to the worse patient outcome.

Gene expression of membrane transporters: Importance for prognosis and progression of ovarian carcinoma

Membrane transporters (such as ABCs, SLCs and ATPases) act in carcinogenesis and chemoresistance development, but their relevance for prognosis of epithelial ovarian cancer (EOC) remains poorly understood. We evaluated the gene expression profile of 39 ABC and 12 SLC transporters and three ATPases in EOC tissues and addressed their putative role in prognosis and clinical course of EOC patients. Relative gene expression in a set of primary EOC (n=57) and in control ovarian tissues (n=14) was estimated and compared with clinical data and survival of patients. Obtained data were validated in an independent set of patients (n=60). Six ABCs and SLC22A18 gene were significantly overexpressed in carcinomas when compared with controls, while expression of 12 ABCs, five SLCs, ATP7A and ATP11B was decreased. Expression of ABCA12, ABCC3, ABCC6, ABCD3, ABCG1 and SLC22A5 was higher in high grade serous carcinoma compared with other subtypes. ABCA2 gene expression significantly associated with EOC grade in both sets of patients. Notably, expression level of ABCA9, ABCA10, ABCC9 and SLC16A14 significantly associated with progression-free survival (PFS) of the disease in either pilot or validation sets. ABCG2 level associated with PFS in the pooled set of patients. In conclusion, ABCA2, ABCA9, ABCA10, ABCC9, ABCG2 and SLC16A14 present novel putative markers of EOC progression and together with the revealed relationship between ABCA12, ABCC3, ABCC6, ABCD3, ABCG1 and SLC22A5 expression, and high grade serous type of EOC should be further examined by larger follow-up study.

Vulvar Syringomas With Deep Extension: A Potential Histopathologic Mimic of Microcystic Adnexal Carcinoma

We present a case of multiple vulvar syringomas, some of which extended unusually deep into the dermis occasioning histopathologic resemblance to microcystic adnexal carcinoma. The pertinent literature is discussed.

Depth and patterns of adnexal involvement in primary extramammary (Anogenital) paget disease: A study of 178 lesions from 146 patients

Abstract:Extramammary Paget disease (EMPD) is a rare neoplasm usually presenting in the anogenital area, most commonly in the vulva. Adnexal involvement in primary EMPD is a very common feature and serves as a pathway for carcinoma to spread into deeper tissue. The depth of carcinomatous spread along the appendages and the patterns of adnexal involvement were studied in 178 lesions from 146 patients with primary EMPD. Hair follicles and eccrine ducts were the adnexa most commonly affected by carcinoma cells. The maximal depth of involvement was 3.6 mm in this series. When planning topical therapy or developing novel local treatment modalities for EMPD, this potential for significant deep spread along adnexa should be taken into account.

P27 as a prognostic factor of early cervical carcinoma.

Objective The aim of this study was to clarify whether the evaluation of cell-cycle regulatory protein p27 can serve as a prognostic factor in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical carcinoma. Patients and Methods A retrospective study was performed on 130 surgically treated patients with FIGO stage IB cervical carcinoma with at least a 5-year follow-up. The expression of p27 was investigated independently by 2 experienced pathologists using immunohistochemistry. The prognostic significance of established prognostic factors and p27 expression were analyzed using univariate and multivariate analyses. Results In a univariate analysis, lymph node status, tumor diameter, Gynecologic Oncology Group (GOG) score, lymph vascular space invasion, and p27 expression were significant prognostic factors for overall survival (OS). We found a correlation between p27 expression and lymph node status, tumor diameter, invasion, and GOG score. The p27 expression was a statistically significant prognostic factor for OS in a univariate analysis (log-rank test, P = 0.03). In a multivariate analysis, only lymph node status and tumor diameter were statistically significant prognostic factors for OS. Conclusions This study demonstrated that a low p27 expression is associated with lymph node metastasis, deep stromal invasion, tumor diameter more than 20 mm, and high GOG score and had a prognostic influence on OS in a univariate analysis in a series of 130 women with FIGO stage IB cervical carcinoma. Lymph node status and the diameter of the tumor were the only statistically significant prognostic factors in multivariate analysis.

CD44 as a cancer stem cell marker and its prognostic value in patients with ovarian carcinoma

Abstract The aim of our study was to clarify whether the CD44 adhesion molecule as a cancer stem cell marker could also serve as a prognostic factor in patients with epithelial ovarian cancer (EOC). A retrospective study was performed on 87 patients with histologically verified EOC. Specimens of both primary tumour and implantation metastases were tested from 48 of them. CD44 expression was detected by immunohistochemistry. We looked for the cut-off levels of CD44 expression using the Cox regression model. We confirmed statistically significant prognostic factors for overall survival (OS) and disease-free interval (DFI) to be: stage of the disease, postoperative residual tumour and papillary serous histological type. We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%. CD44 was neither a prognostic factor of OS nor of DFI. IMPACT STATEMENT What is already known about this subject: Epithelial ovarian cancer is the second most common gynaecological cancer in developed countries. Despite great efforts devoted to ovarian cancer research during past decades, levels of patient mortality have changed very little. Cancer stem cells (CSCs) are subpopulations of cells with typical characteristics of stem cells – i.e. the ability to self-renew and differentiate in a variety of cell types. The main surface marker typical for CSCs is CD44. The aim of our study was to clarify whether the CD44 as a CSCs marker could serve as a prognostic factor in patients with epithelial ovarian cancer. Previous studies published on this topic revealed controversial results. The novelty of our study lies in looking for the cut-off using the Cox regression model. What this study adds: We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%, however, CD44 was neither a prognostic factor of overall survival nor of disease-free interval. We propose to investigate other markers including other CSCs as a prognostic factors or potential aims for targeted therapy in ovarian cancer.