Türkan Küçükali

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.

Synchronous primary malignancies of the female genital tract

This study includes 29 patients with synchronous primary malignancies of the female genital tract. These patients constituted 1.7% of all genital malignancies. The most frequently observed synchronous neoplasms were those of the ovary together with the endometrium (51.7%). Most patients had early-stage and low-grade disease. Stage I disease was observed in 68.1% of patients with ovarian cancer. Patients with synchronous ovarian and endometrial cancer had a 73.3% 5-year survival rate, suggesting a favorable prognosis.

An allelic variant of Griscelli disease: presentation with severe hypotonia, mental-motor retardation, and hypopigmentation consistent with Elejalde syndrome (neuroectodermal melanolysosomal disorder).

Sirs: Griscelli disease, first described in 1978, is a rare autosomal recessive disorder characterized by pigmentary dilution, variable cellular and humoral immunodeficiency, acute phases of lymphocyte and macrophage activation that can lead to pancytopenia, increased serum triglyceride levels, and hypofibrinogenemia [4, 8, 10, 11]. Although neurological involvement was not reported initially, later it was observed that various central nervous system manifestations including hyperreflexia, convulsions, lethargy, coma, regression of developmental milestones, hypertonia, nystagmus, strabismus, and ataxia due to cellular infiltration can develop during the accelerated phase [1, 5, 6, 8, 11]. In 1997 the locus for Griscelli disease was mapped to chromosome 15q21, and two homozygous mutations were found in the Myosin-Va gene that maps to the same region [9]. On the other hand, there is another rare group of patients with hypopigLETTER TO THE EDITORS

Correlation between clinical and histopathologic risk factors and lymph node metastases in early endometrial cancer (a multivariate analysis of 183 cases).

This study includes 183 patients with clinical stage I endometrial cancer subjected to peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymphadenectomy and omental biopsy during a 12-year period in a single institution. The factors analyzed were age, menopausal state, cell type, grade, mitotic activity, myometrial invasion, lymphovascular space invasion, cervical involvement, microscopic vaginal metastases, adnexal metastases, peritoneal cytology, presence of concomitant endometrial hyperplasia and lymph node status. The overall incidences of pelvic and para-aortic lymph node metastases were found to be 15.3% (28/183) and 9.3% (17/183), respectively. In five of 17 patients (29.4%) with para-aortic nodal metastases, pelvic nodes were free of tumor. The most significant prognostic factors for positive pelvic and/or para-aortic nodes were found to be the depth of myometrial invasion, grade of tumor and age.

Griscelli syndrome: Report of Three Cases

The clinical features of three children with Griscelli syndrome and autopsy findings of two are presented. The patients were 5 years, 9 months, and 3 months old, respectively. Clinical features included partial albinism, hepatosplenomegaly, and various neurological symptoms. Light and electron microscopic studies of the skin were compatible with Griscelli syndrome. Postmortem examination of the viscera and central nervous system revealed lymphohistiocytic infiltration with erythrophagocytosis. Bilateral diffuse involvement of the central nervous system, cranial nerve, and spinal cord was detected in both cases.

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

Tumor status of lymph nodes in early endometrial cancer in relation to lymph node size

A retrospective analysis of 36 patients with metastatic nodes out of 209 consecutively managed patients with a clinically stage I endometrial cancer was carried out. Of the 1023 lymph nodes removed, 154 nodes were found to be metastatic. The mean number of the involved nodes was 4.27 (range: 1-29). Of the 154 positive nodes, 3 had nodal diameters < or = 3 mm (1.9%), 84 had diameters of 4-10 mm (54.6%), 60 had diameters of 11-20 mm (39.0%) and 7 had diameters more than 20 mm (4.5%). With increasing lymph node size, the frequency of tumoral involvement varies from 1.0% in nodes < or = 3 mm to 63.6% in nodes bigger than 20 mm. In terms of patients, nine of them were found to have a single metastatic node ranging from 6 mm to 10 mm in diameter. In the remaining 27 patients with multiple metastatic nodes, the biggest nodes encountered were 6-10 mm in 4 (14.8%), 11-20 mm in 17 (62.9%) and more than 20 mm in 6 (22.2%) patients. Since mere sampling of the lymphatic tissue directed particularly to the enlarged nodes may not show the true incidence of positive nodes, a complete lymphadenectomy is advocated in order to obviate an understaging problem.

Is there a correlation between tumor marker panel and tumor size and histopathology in well staged patients with borderline ovarian tumors

Aims. To investigate whether there is a correlation between serum tumor markers panel (CA 125, CA 19‐9, CA 15‐3, and carcinoembryonic antigen (CEA)) and tumor size and histopathology in well staged patients with borderline ovarian tumors (BOTs). Methods. Four tumor markers (CA 125, CA 19‐9, CA 15‐3, and CEA) were analysed clinically in 60 well staged patients with borderline ovarian tumor, for this retrospective observational study. Results. Most patients had serous histology and early stage disease, and the mean age at the time of diagnosis was 40.70 years (range: 19–73). Twenty‐nine patients (48.3%) had high CA 125 levels (>35 U/l), 15 patients (25%) had high levels of CEA (>4 ng/ml), 12 patients (20%) had high levels of CA 19‐9 (>37 U/ml), and 9 patients (15%) had high levels of CA 15‐3 (>30 ng/ml) at the time of initial surgery. The positive rate of CA 125, CA 19‐9, CA 15‐3, and CEA in serous tumor were 57.9, 7.9, 7.9 and 15.8%, respectively. These figures were 31.8, 40.9, 27.3 and 40.9% in mucinous tumor. The positive rate of CA 125 in the serous group was statistically significantly higher than that in the mucinous group, while the positive rates for CA 19‐9 and CEA in mucinous histology was significantly higher than those in serous tumors. In case of grouping the tumor size as <4, 4.1‐10 and >10 cm, the mean serum levels of tumor markers had significantly increased by increasing tumor size (p<0.05 for CA 125, and CA 19‐9, p>0.05 for CA 15‐3, and CEA). Conclusion. The high levels of tumor markers, especially for CA 125 and CA 19‐9, may indicate the larger tumor size. The elevation of serum CA 125 may suggest serous tumors, while the high level of serum CA 19‐9 and CEA may indicate mucinous BOTs.

The prognostic value of nuclear grading and the revised FIGO grading of endometrial adenocarcinoma.

The purpose of this study was to determine a convenient method for the modification of architectural grade by nuclear features and to evaluate the prognostic significance of the new International Federation of Gynecology and Obstetrics (FIGO) grading system by studying 288 patients with endometrioid endometrial carcinoma. All patients were subjected to initial surgical exploration and staging by 1988 FIGO guidelines. Three different grading systems were evaluated for their prognostic value: architectural, nuclear, and FIGO combined systems. All three grading systems significantly predicted poor survival, but only the FIGO grade (p < 0.001), stage (p < 0.001), and cervical involvement (p = 0.04) remained significant in multivariate analysis. In the architectural grade 2 group, the 5-year survival rate for 39 patients with grade 1 or 2 nuclei was 87%, compared with 66% for 35 patients with grade 3 nuclei (p = 0.03). In the architectural grade 1 group, the 5-year survival rate for 84 patients with grade 2 nuclei was 93% without significant difference from the original group (96%). FIGO grade 3 tumor predicted 70% of deaths (29/41), whereas architectural grade 3 tumor detected 41% (17/41) of deaths (p = 0.001). In conclusion, in determining the FIGO grade, upgrading of architectural grade 1 or 2 tumors by grade 3 nuclei was the most reliable method. The new FIGO grading system was prognostically superior to the previously used architectural grading system.