Yersu Kapran

Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries

Purpose: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. Experimental Design: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. Results: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings in Turkish colorectal carcinoma were most similar to those reported for Western cases. Conclusions: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.

Cystic lymphangioma of the right adrenal gland.

Lymphangiomas are benign malformations of the vessels. They are commonly located in the neck, axillary region and mediastinum. Lymphangioma of the adrenal gland is very rare. These lesions were first discovered as incidental autopsy findings. As the imaging techniques have improved, they now appear as incidental findings at abdominal ultrasonography and computed tomography scan examinations. They are usually asymptomatic. We present a 26-year-old woman admitted to the hospital, complaining of weakness, putting on weight, and lumbago. Her laboratory findings were within normal limits. Radiological examination revealed a 7 cm cystic lesion located in the right adrenal gland. Right adrenalectomy was performed. Histopathological examination and immunohistochemical analysis of the cystic lesion was consistent with a lymphangioma.

Case Report: Adrenal LH/hCG Receptor Overexpression and Gene Amplification Causing Pregnancy-Induced Cushing’s Syndrome

Transient pregnancy-induced Cushing’s syndrome (CS) is extremely rare, with only several cases reported in the literature. Ectopic LH/hCG-receptors (LHCGR) in the adrenal gland have been suggested to be involved in the pathogenesis of this condition. We report the clinical, molecular, and genetic features of a patient with pregnancy-induced CS. A 29-year-old female patient developed CS during multiple pregnancies, leading to repeated miscarriage. Signs and symptoms of hypercortisolism resolved soon after delivery or abortion, only to recur in subsequent pregnancies. In the non-pregnant state, hCG stimulation testing resulted in elevated cortisol levels. Serum cortisol was not suppressible with dexamethasone. The adrenals exhibited bilateral adrenal cortical nodular hyperplasia. Quantitative RT-PCR revealed a 2-fold increase in LHCGR and progesterone receptor mRNA expression and decreased estrogen receptor-beta expression in the patient’s adrenal tissue relative to normal adrenals. Higher intensity of immunostaining for LHCGR was observed, particularly within the nodular lesions, compared to controls. Quantitative PCR revealed a LHCGR-to-β-actin ratio of 1.5 in genomic DNA from adrenal and peripheral leukocytes, suggesting the presence of a germline duplication of the LHCGR gene. LHCGR overexpression resulting from germline gene duplication may be a potential pathogenic mechanism underlying this case of pregnancy-induced CS.

Fourth versus eighth week surgery after neoadjuvant radiochemotherapy in T3-4/N0+ rectal cancer: Istanbul R-01 study

BACKGROUND AND PURPOSE The optimum duration between neoadjuvant radiochemotherapy and transmesorectal excision in locally advanced rectal cancer has not been defined yet. This randomized study was designed to compare the efficacy of four-week versus eight-week delay before surgery. METHODS One-hundred and fifty-three patients with locally advanced low- or mid-rectum rectal adenocarcinoma were included in this single center prospective randomized trial. Patients were assigned to receive surgical treatment after either four weeks or eight weeks of delay after chemoradiotherapy. Patients were followed for local recurrence and survival, and surgical specimens were examined for pathological staging and circumferential margin positivity. RESULTS 4-week and 8-week groups did not differ with regard to lateral surgical margin positivity (9.2% vs. 5.1%, P=0.33, respectively), pathological tumor regression rate (P=0.90), overall survival (5-year, 76.5% vs. 74.2%, P=0.60) and local recurrence rate (11.8% vs. 10.3%, 0.77). Overall survival was better in patients with negative surgical margins (78.8% vs. 53.0%, P=0.04). Local recurrence rate was significantly higher among patients with positive surgical margin (28.5% vs. 9.3%, P=0.02). CONCLUSIONS Intentional prolongation of the chemoradiotherapy-surgery interval does not seem to improve clinical outcomes of patients with locally advanced rectal cancer. Surgical margin positivity seems to be more important with this regard.

The Use of the Bethesda Terminology in Thyroid Fine-Needle Aspiration Results in a Lower Rate of Surgery for Nonmalignant Nodules A Report From a Reference Center in Turkey

The Bethesda system (BS) for reporting thyroid fine-needle aspiration (FNA), which classifies nodules as nondiagnostic (ND), benign (B), atypia/follicular lesion of undetermined significance (AUS/FLUS), suspicious for follicular neoplasm (SFN/FN), suspicious for malignancy (SFM), or malignant (M), uses clinically valuable management guidelines. The authors employed a similar in-house classification system (IS) for thyroid FNAs, using the categories of ND, B, suspicious follicular cells (SFC), follicular lesion/neoplasm (FL/FN), SFM, and M. The authors compared IS and BS, and assessed the utility of BS in clinical practice. A total of 581 nodules with cytological/histological follow-up were examined and indeterminate lesions by BS were reclassified. The sensitivity and specificity for malignancy using IS were similar to that of BS (77% vs 99%). However, when SFN/FN and SFM were both considered positive, the results for IS and BS were as follows: sensitivity, 85% versus 85%; specificity, 87% versus 94%; and diagnostic accuracy, 86% versus 90%, respectively. Discrepancies between cytological and histological data were evident in 35 cases among all categories of BS except AUS/FLUS. The rate of surgery for nonmalignant nodules was lesser (20% vs 9%) by BS. Among 34 AUS/FLUS cases with follow-up data, hypocellularity was the case in 11 (46%) nonneoplastic and 10 (100%) neoplastic nodules. The use of BS results in a lower rate of surgery for nonmalignant nodules even though patients with borderline cytopathologic features are still encountered. AUS/FLUS category can be separated into subgroups according to the factors causing difficulties in the interpretation. There is a need of accumulation of AUS/FLUS cases to do further evaluations and studies.

Concomitant Association of Thyroid Sarcoidosis and Graves’ Disease

Objective: Graves’ disease (GD) with sarcoid involvement of the thyroid gland has rarely been reported. Method: We report a case of GD with thyroid sarcoidosis in a 28-year-old woman. Thyroid function was assessed by triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH) and TSH receptor antibodies (TSH-R Ab). Thyroid scintigraphy, ultrasound and fine-needle aspiration biopsy were performed. The patient underwent surgery. Result: The patient had a nodular goiter. Serum T3, T4 and TSH-R Ab levels were elevated with suppressed TSH level. Scintigraphy showed diffuse activity as seen in GD, and ultrasound revealed that parenchyma was heterogenous. Sarcoidosis was discovered on routine chest X-ray. Although no sarcoid involvement was found on specimen, the thyroid gland showed non-caseating granulomas on histology. Conclusion: Since sarcoid involvement of the thyroid gland can cause hypofunction, we report the uncommon infiltration of sarcoidosis with hyperthyroidism.

Immunohistochemical detection of E-cadherin, α- and β-catenins in papillary thyroid carcinoma

E-cadherin and catenins play a major role in neoplastic cell behavior as a suppressor of invasion and/or metastasis. The aim of this study was to determine E-cadherin, α-catenin and β-catenin expressions in papillary thyroid carcinoma (PTC) and to correlate the results of expression to initial clinicopathological parameters and clinical outcome. Forty-one cases (mean age 37.3±11.2 yr) with PTC were studied. Patients were followed-up with a mean period of 47.6±27.0 months. A retrospective immunohistochemical analysis of E-cadherin, α-catenin and β-catenin was performed on paraffin-embedded tissue sections. Tissues from ten patients with benign goiter were used as controls. E-cadherin, α- and β-catenin immunoreactivities were found in 80% (33/41), 76% (31/41) and 97% (40/41) of patients respectively. No correlation was found between E-cadherin, α- and β-catenin immunoreactivities and sex, local invasion or lymphatic spread at the time of initial examination. Distant metastases and/or local recurrences developed in 6 patients during follow-up. Recurrences/metastases developed both E-cadherin, α- and β-catenin positive and negative primary tumors. Disease-free survival curves according to Kaplan-Meier analysis and log-rank test did not show any significant differences between E-cadherin, α- and β-catenin positive and negative patients. According to our findings, E-cadherin, α- and β-catenin expressions may not add any valuable information to the follow-up in a subgroup of PTC patients with a relatively benign course.

Siegfried Oberndorfer: a tribute to his work and life between Munich, Kiel, Geneva, and Istanbul

In 1907 Siegfried Oberndorfer published his observations and interpretations on tumorlets (“Geschwulstchen”) in the small intestine, which he called carcinoids (“karzinoide Tumoren”). This article pursues the questions why this discovery was so unique and what role it played in the later life of Siegfried Oberndorfer.

Co-Secretion of Aldosterone and Cortisol by an Adrenocortical Carcinoma

We report a rare case of adrenocortical carcinoma. A 26-year-old woman presented with hypokalemia and hypertension due to hyperaldosteronism. She had no signs of Cushing’s syndrome. Endocrinological data showed excess of aldosterone production and nonsupressible cortisol production on 2 mg of dexamethasone. Magnetic resonance imaging showed left adrenal tumor. Transabdominal left adrenalectomy was performed and histopathological diagnosis was adrenocortical carcinoma. Her blood pressure and hypokalemia returned to normal after adrenalectomy. There is no recurrence after 36 months. We want to emphasis the importance of adrenal tests before the operation even if there are no signs of excess cortisol production.

Multihormonality and entrapment of islets in pancreatic endocrine tumors

We analyzed pancreatic endocrine tumors (PETs) from 200 patients for the incidence of multihormonality and entrapped islets and correlated the results with clinicopathological features. Our series included 86 cases (43%) of functioning PET and 114 cases (57%) of nonfunctioning PET. Classified according to the WHO classification, there were 32 well-differentiated benign PETs, 85 well-differentiated PETs with uncertain behavior, and 83 well-differentiated malignant PETs. All tumors were immunostained for pancreatic hormones (insulin, glucagon, somatostatin, and pancreatic polypeptide) and for additional hormones such as gastrin, vasoactive intestinal polypeptide, calcitonin, seratonin, and adrenocorticotropic hormone. Multihormonality was found in 34% of all PETs and it was a frequent finding in the tumors of the uncertain behavior (38.8%) group. Islet entrapment was found in 57 tumors (28.5%) and was significantly more frequent in PETs with uncertain and malignant behavior than benign ones (p=0.01). In 57 cases, we also investigated whether ductule entrapment accompanied islet entrapment. Of these 57 tumors, 45 (79%) tumors had accompanying ductule entrapment. Ductule entrapment did not show significant correlation with malignancy and was a more frequent finding in nonfunctioning tumors. We conclude that the incidence of multihormonality in PETs is not as high as suggested previously and islet entrapping may reflect aggressive tumor growth and may be a complementary criterion for predicting the biological behavior of PETs.