Alp Usubutun

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

BACKGROUND Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer. METHODS Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions. FINDINGS 22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively). INTERPRETATION To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva

BACKGROUND Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions. METHODS Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI). RESULTS Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold). CONCLUSION Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.

Activation of the Canonical Wnt Pathway during Genital Keratinocyte Transformation: A Model for Cervical Cancer Progression

Cervical carcinoma, the second leading cause of cancer deaths in women worldwide, is associated with human papillomavirus (HPV). HPV-infected individuals are at high risk for developing cervical carcinoma; however, the molecular mechanisms that lead to the progression of cervical cancer have not been established. We hypothesized that in a multistep carcinogenesis model, HPV provides the initial hit and activation of canonical Wnt pathway may serve as the second hit. To test this hypothesis, we evaluated the canonical Wnt pathway as a promoting factor of HPV-induced human keratinocyte transformation. In this in vitro experimental cervical carcinoma model, primary human keratinocytes immortalized by HPV were transformed by SV40 small-t (smt) antigen. We show that smt-transformed cells have high cytoplasmic beta-catenin levels, a hallmark of activated canonical Wnt pathway, and that activation of this pathway by smt is mediated through its interaction with protein phosphatase-2A. Furthermore, inhibition of downstream signaling from beta-catenin inhibited the smt-induced transformed phenotype. Wnt pathway activation transformed HPV-immortalized primary human keratinocytes even in the absence of smt. However, activation of the Wnt pathway in the absence of HPV was not sufficient to induce transformation. We also detected increased cytoplasmic and nuclear staining of beta-catenin in invasive cervical carcinoma samples from 48 patients. We detected weak cytoplasmic and no nuclear staining of beta-catenin in 18 cases of cervical dysplasia. Our results suggest that the transformation of HPV expressing human keratinocytes requires activation of the Wnt pathway and that this activation may serve as a screening tool in HPV-positive populations to detect malignant progression.

Vaginal high dose rate brachytherapy alone in patients with intermediate- to high-risk stage I endometrial carcinoma after radical surgery.

The objective of this study was to analyze the efficacy and morbidity of vaginal cuff brachytherapy alone in intermediate- to high-risk stage I endometrial cancer patients after complete surgical staging. Between October 1994 and November 2005, 128 patients with intermediate- to high-risk stage I endometrial adenocarcinoma were treated with high dose rate (HDR) brachytherapy alone after complete surgical staging. The intermediate- to high-risk group was defined as any stage I with grade 3 histology or stage IB grade 2 or any stage IC disease. The comprehensive surgery was in the form of total abdominal hysterectomy, bilateral salpingo-oophorectomy in addition to infracolic omentectomy, and routine pelvic and para-aortic lymphadenectomy. The median number of the lymph nodes dissected was 33. The median age at the time of diagnosis was 60 years. Forty patients were staged as IB (grade 2: 25 and grade 3: 15), and 88 patients were staged as IC (grade 1: 31, grade 2: 41, and grade 3: 16). A total dose of 27.5 Gy with HDR brachytherapy, prescribed at 0.5 cm, was delivered in five fractions in 5 consecutive days. Median follow-up was 48 months. Six (4.7%) patients developed either local recurrence (n= 2) or distant metastases (n= 4). Five-year overall survival and disease-free survival (DFS) rates are 96% and 93%, respectively. Only age was found to be significant prognostic factor for DFS. Patients younger than 60 years have significantly higher DFS (P= 0.006). None of the patients experienced grade 3/4 complications due to the vaginal HDR brachytherapy. Vaginal cuff brachytherapy alone is an adequate treatment modality in stage I endometrial adenocarcinoma patients with intermediate- to high-risk features after complete surgical staging with low complication rates.

Kindler syndrome: absence of definite ultrastructural feature.

Kindler syndrome is characterized by congenital blister formation, photosensitivity, poikiloderma, and cutaneous atrophy in later life. There are few reports about the ultrastructural features of this syndrome, but still there is no consensus about the basic disease. Here we report a case of Kindler syndrome with ultrastructural findings.

Comparison of WHO and endometrial intraepithelial neoplasia classifications in predicting the presence of coexistent malignancy in endometrial hyperplasia

OBJECTIVE The most commonly used classification system for endometrial hyperplasia is the World Health Organization system which is based on subjective criteria. Another classification system is endometrial intraepithelial neoplasia (EIN) system which uses diagnostic criteria including cytological demarcation, crowded gland architecture, minimum size of 1 mm, and careful exclusion of mimics, and aims to identify a precancer or cancer. The objective of this study was to compare the two classification systems in terms of predicting the presence of a coexistent cancer in surgically treated patients. METHODS Biopsy and hysterectomy specimens of 49 women who were subjected to surgery with a preoperative diagnosis of endometrial hyperplasia (EH) according to the WHO system were re-evaluated retrospectively by using EIN system. RESULTS Among the 49 patients, 69.4% had complex atypical EH and 75.5% had EIN at biopsy specimens. EIN was detected in 94.1% of complex atypical EH, and 41.7% of non-atypical EH. Nine women (18.4%) had endometrial cancer. Among women with cancer, all had complex atypical EH or EIN. The rate of coexistent endometrial cancer was 26.5% in women with complex atypical EH and 24.3% in women with EIN. CONCLUSION Diagnoses of atypical or complex atypical EH and EIN had similar sensitivities and negative predictive values in predicting the coexistent endometrial cancer. Either of these two classification systems may be used safely when an experienced pathologist is available. However, use of the objective EIN system may be preferred whenever possible to prevent diagnostic errors in centers where an experienced pathologist is not available.

The value of intraoperative consultation (frozen section) in the diagnosis of ovarian neoplasms

BACKGROUND Frozen Section is an important diagnostic tool to determine the nature of ovarian masses. However, like other diagnostic tools, frozen section also has some pitfalls. We aimed to discuss the source and the nature of inaccuracies associated with this procedure. METHODS In this retrospective study 360 cases of ovarian masses examined by frozen section were re-evaluated. The sensitivity, specificity and predictive values of frozen section diagnosis of ovarian tumors were calculated. The reasons for the erroneous frozen-section diagnoses were discussed. RESULTS Overall diagnostic agreement for ovarian lesions was 94.2%. Disagreements were found in nine cases (2.5%). Diagnosis was deferred to permanent sections in 12 cases (3.3%). The sensitivity for malignant tumors was 93.1% and specificity was 99.2%. The sensitivity for benign tumors was 99.2% and specificity was 92.1%. Most problematic cases were mucinous tumors, followed by tumors resembling fibrothecomas, in addition sections without viable tissue fragments or presence of extensive hemorrhage and necrosis also obscured the frozen diagnosis. Another factor was the lack of an effective communication between the surgeon and the pathologist. CONCLUSIONS For an effective usage of this method not only the pathologist but also the surgeons must know the pitfalls of this method and also there must be good communication between the pathologist and the surgeon. Especially deferred cases should be minimized by good communication. In fact its an intraoperative consultation method that enables the pathologist to gather all the preoperative, intraoperative findings and to be familiar with the further treatment plan of the patient.

Routine appendectomy in epithelial ovarian carcinoma : Is it necessary?

OBJECTIVE: To detect risk factors for the appendiceal metastasis and to define the role of routine appendectomy in patients with epithelial ovarian carcinoma. METHODS: A total of 285 patients with epithelial ovarian carcinoma who had undergone primary cytoreductive surgery including appendectomy were retrospectively evaluated. Appendiceal involvement was divided into 2 groups: gross and microscopic. Clinicopathologic variables were evaluated for possible significance in terms of appendiceal metastasis. A second analysis was performed using the same variables to detect a possible relation with microscopic metastasis. In a subgroup analysis, we also analyzed the role of routine appendectomy in patients with clinically early stage disease. RESULTS: One-hundred six patients were found to have appendiceal metastasis (37%). Univariate and multivariate analysis revealed stage of disease as the unique factor determining the appendiceal metastasis (P < .001). Five patients with apparently stage I-II disease were upstaged due to isolated appendiceal metastasis (4.9%). In the second analysis excluding the patients with gross involvement, ascites was an independent predictor of microscopic involvement (P < .01). CONCLUSION: Routine appendectomy is indicated in all epithelial ovarian carcinoma patients as part of the initial surgical staging procedure because of a considerable rate of upstaging in early stage disease and optimal cytoreduction in advanced stages. LEVEL OF EVIDENCE: II-3

Epithelioid sarcoma of vulva: a case report and review of the literature.

Epithelioid sarcoma of vulva is an extremely rare and aggressive tumor. In most patients it is asymptomatic, and the lesions are usually mistaken for benign processes, leading to diagnosis at later stages. We report a case of vulvar epithelioid sarcoma in a 51-yr-old woman presenting with a nodularity of vulva. Left hemivulvectomy with bilateral inguinal lymph node dissection was performed. There was no evidence of distant metastasis at the time of diagnosis. Following adjuvant chemoradiotherapy and three cycles of chemotherapy, the patient developed lung metastasis 4 mo after surgery and died of disseminated disease after 6 mo of diagnosis. Vulvar epithelioid sarcoma is rare; showing different behavior changing from an extremely aggressive tumor to behaviors like low-grade tumors. It is best treated by early diagnosis and initial eradication. Definitive surgery provides excellent local control and survival in low-grade tumors. The role of adjuvant treatment remains to be determined.

Human papillomavirus types in invasive cervical cancer specimens from Turkey.

The main aim of the study is to describe the human papillomavirus (HPV) type-specific distribution in invasive cervical cancer (ICC) specimens from Turkey. Paraffin-embedded ICC specimens were identified from the histopathologic archives of the Hacettepe University Medical School in Turkey. HPV detection was carried out through amplification of HPV DNA by a SPF-10 broad-spectrum primer polymerase chain reaction and subsequently followed by DNA enzyme immunoassay and genotyping by LiPA25 (version 1). Two hundred seventy-seven ICC cases diagnosed between 1993 and 2004 were retrieved. After histologic evaluation and human β-globin gene analysis for sample quality, 248 cases were considered suitable for HPV/DNA testing. HPV prevalence was 93.5% (232/248; 95% confidence interval: 90.5%–96.6%). The five most common HPV types identified as single types among HPV-positive cases were HPV16 (64.7%), HPV18 (9.9%), HPV45 (9.9%), HPV31 (3.0%), and HPV33 (2.2%). The study shows that in Turkey, HPV16/HPV18 accounted for 75.4% (95% confidence interval: 69.9%–81.0%) of HPV-positive ICC cases. This information is essential to evaluate the potential impact of the HPV vaccines in the country.