A rare case of cerebral phaeohyphomycosis caused by Fonsecaea species in a renal transplant patient.

Cerebral phaeohyphomycosis (CP) is a serious form of phaeohyphomycosis. We report a case of CP caused by Fonsecaea species in a 66-year-old immunocompromised renal transplant recipient female. Craniotomy was performed on an irregularly enhancing right cerebellar hemisphere lesion and abscess and tissue samples collected for microbiological and histological evaluation, showing fungal elements and Fonsecaea species was isolated. Antifungal treatment with voriconazole & liposomal amphotericin B was initiated with a temporary improvement in the patient's condition. Deep vein thrombosis jeopardized patient's prognosis. Despite aggressive surgical and medical intervention, our patient succumbed to the disease. Historically, CP has been linked with fatality rates as high as 65 %, despite surgical intervention and systemic antifungal medication.

Imaging features of the renal lymphoma: case report and literature review.

Renal affection is common in disseminated non-Hodgkin's lymphoma (NHL) which is known as secondary renal lymphoma (SRL). Primary renal lymphoma (PRL) is an exceedingly uncommon disease, which accounts for less than 1% of all renal masses. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in both primary as well as secondary renal lymphomas. PRL is of paramount importance clinically as it is usually managed with neo-adjuvant chemotherapy followed by nephrectomy in contrast to the more frequently seen renal cell carcinoma, which is treated surgically. This outstanding difference in management challenges the longstanding approach that preoperative biopsies are not mandatory prior to nephrectomy for renal masses. Because of its relative rarity, the imaging features of PRL have been described in a few studies, and having an understanding of these typical imaging patterns is crucial for making an accurate diagnosis and differentiation from other renal malignancies. Here, we present a case of a secondary renal lymphoma and discuss its differential imaging features.

Leiomyoadenomatoid tumors: A type of rare benign epididymal tumor.

Primary tumors of the epididymis are mostly benign in nature, and the most common type is adenomatoid tumors followed by leiomyomas. Leiomyoadenomatoid tumors are very rare benign epididymal neoplasms composed of two components: gland-like structures lined by cuboidal cells and bundles of smooth muscle components. The goal of treatment is testicular-preserving surgery. A preoperative and intraoperative evaluation plays an important role in proper management. To the best of our knowledge, few cases have been reported in the literature. We report a case of a right epididymal tail leiomyoadenomatoid tumor in a 49-year-old male who underwent trans-scrotal exploration and tumor excision.

Prognostic significance of MGMT methylation and expression of MGMT, P53, EGFR, MDM2 and PTEN in glioblastoma multiforme.

The study investigated the pattern of MGMT promoter methylation and the expression of MGMT, P53, EGFR, MDM2 and PTEN proteins in glioblastomas multiforme (GBM) and evaluated their prognostic significance. We carried out a retrospective study of 80 GBM. Expression of MGMT as well as of P53, EGFR, MDM2 and PTEN was investigated by immunohistochemistry. MGMT promoter methylation was investigated by methylation specific-PCR of bisulfite-treated DNA. Twenty-five GBM exhibited MGMT expression. Methylation of MGMT promoter was detected in 35.1% of cases. No significant concordance was reported between MGMT promoter methylation and protein expression (κ=-0.047, p=0.11). MGMT promoter methylation was significantly associated only with PTEN expression (p=0.001): no other significant association was identified with clinical parameters as well as with expression of P53, EGFR and MDM2 (p >0.05). Tumor recurrence was significantly associated with unmethylated MGMT promoter (p=0.01) but not with MGMT expression (p=0.51). Recurrence-free survival (RFS) was significantly better among patients with methylated MGMT promoter (log rank, p <0.0001) and PTEN expression (log rank, p=0.025) but not with MGMT expression (log rank, p=0.308). As well, using univariate analysis, MGMT promoter methylation (p=0.001) and PTEN expression (p=0.044) were significantly associated with RFS. In multivariate analysis, only MGMT promoter methylation was significantly associated with RFS (p=0.003). Together, our findings support that MGMT protein expression doesn't reflect the MGMT promoter methylation status. Furthermore, MGMT promoter methylation remains a useful prognostic marker in Tunisian patients with GBM. PTEN expression could be a potential prognostic marker of this tumor.

Immunohistochemical analysis of c-erbB-2, Bcl-2, p53, p21WAF1/Cip1, p63 and Ki-67 expression in hydatidiform moles.

Hydatidiform moles (HM) are characterized by an abnormal proliferating trophoblast with a potential for a malignant transformation. Similar to other human tumors, trophoblastic pathogenesis is likely a multistep process involving several molecular and genetic alterations. The study was performed to investigate the expression patterns of c-erbB-2 and Bcl-2 oncoproteins, p53, p21WAF1/CIP1 and p63 tumor suppressor proteins and Ki-67 cell proliferation marker in HM. We conducted a retrospective study of 220 gestational products, including 39 hydropic abortions (HA), 41 partial HM (PHM) and 140 complete HM (CHM). The expression of c-erbB-2, Bcl-2, p53, p21WAF1/CIP1, p63 and Ki-67 was investigated by immunohistochemistry on archival tissues. c-erbB-2 expression was observed in three PHM and 10 CHM. Bcl-2 immunostaining was significantly higher in PHM (61%) and CHM (70.7%) compared with HA (7.7%, p = 0.001 and p < 0.0001, respectively). p53 expression was stronger in CHM (73.6%) compared with PHM (24.4%, p < 0.0001) and HA (12.8%, p < 0.0001). p21WAF1/CIP1 staining was observed as well in molar and non-molar gestations (p > 0.05). p63 immunoexpression was significantly described in CHM (85.7%) and PHM (78%) compared with HA (10.2%, p < 0.0001 and p = 0.0001, respectively). Ki-67 was significantly expressed in CHM (72.1%) compared with HA (46.2%, p = 0.005). Altered expression of Bcl-2, p53, p63 and Ki-67 reflects the HM pathological development. Immunohistochemical analysis is beneficial to recognize the HM molecular and pathogenic mechanisms. Furthermore, it could serve as a useful adjunct to conventional methods for refining HM diagnosis.

Immunohistochemical Characterization Improves the Reproducibility of the Histological Diagnosis of Ovarian Carcinoma

Background: Ovarian cancer is the leading cause of gynecologic cancer-related death. Histological assessment remains the standard clue for the diagnosis of ovarian carcinoma. Misinterpretation and inconsistent application of histological criteria may lead to significant interobserver variability and poor reproducibility of the diagnosis. In this study, we investigated the discrepancy in histological diagnosis and the significance of a designed panel of immunohistochemical markers for the improvement of the diagnostic reproducibility of ovarian carcinomas. Methods: We performed a retrospective study on 74 ovarian carcinomas. All tumor slides were independently reviewed by two pathologists. The results for seven available immunomarkers as p53, WT-1, p16INK4A, CK7, CK20, and estrogen and progesterone receptors were determined for all cases by immunohistochemistry. Results: The histological diagnosis review performed using standard histology showed a concordance of diagnoses in 86% of cases with Cohen's kappa of 0.80. Immunohistochemical results increased significantly the diagnosis reproducibility with a concordance of 91% and a Cohen's kappa of 0.86 (P = 0.001). Conclusion: Although the histological diagnosis remains reliable, the use of a designed panel of immunohistochemical markers improves significantly the interobserver concordance and the classification accuracy of ovarian carcinomas.

Hepatotoxicity of vanadyl sulfate in nondiabetic and streptozotocin-induced diabetic rats.

This study examined the effects of vanadyl sulfate (VOSO4) on the livers of nondiabetic and streptozotocin-induced diabetic rats. Rats were divided into 6 groups. Groups 1, 2, and 3 consisted of nondiabetic rats that were, respectively, control animals or those receiving an intraperitoneal (i.p.) injection of either 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Groups 4, 5, and 6 consisted of diabetic animals that were, respectively, control animals or those treated with 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Results showed that VOSO4 reduced body mass in nondiabetic rats, whereas it increased body mass in diabetic groups. Plasma transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, and alkaline phosphatase activities and malondialdehyde levels were increased, while liver catalase and superoxide dismutase activities were profoundly decreased in diabetic animals in comparison with enzyme activities in the nondiabetic group. Rats in the diabetic group also showed notable oxidative damage to the liver. Treatment of diabetic rats with VOSO4 decreased the hepatotoxic markers, significantly restored the activities of antioxidant enzymes, and attenuated histopathological changes in liver tissue. In nondiabetic rats, VOSO4 treatment increased most of the hepatotoxic markers, reduced antioxidant enzyme activities, and induced pronounced oxidative damage in liver tissue. These data suggest that treatment with VOSO4 exerts toxic effects in healthy animals and significantly prevents liver oxidative damage in streptozotocin-induced diabetic rats, but without total safety. Further studies are needed to clarify its mechanism of action.

Mechanisms of chromium hexavalent-induced apoptosis in rat testes.

Hexavalent chromium (CrVI)-containing compounds, present in industrial settings and in the environment, are known as carcinogens and mutagens. The present study is designed to test the hypothesis that oxidative stress mediates CrVI-induced apoptosis in testis. Male Wistar rats received an intraperitoneal injection of potassium dichromate at doses of 1 and 2 mg kg-1. Superoxide anion production was assessed by the determination of the reduction of cytochrome c and iodonitrotetrazolium, lipid peroxidation (LPO), metallothioneins (MTs), and catalase (CAT) activity. Apoptosis was evaluated by DNA fragmentation detected by agarose gel electrophoresis. Germinal cells apoptosis was detected by toluidine blue staining. The expression of Bax and Bcl-2 proteins (Pts) was also investigated. After 15 days of treatment, an increase of LPO and MT levels occurred, while CAT activity was decreased. Testicular tissues of treated rats showed pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern. Intense apoptosis was observed in germinal cells of Cr-exposed rats. Bax Pt expression was induced in spermatogonia and spermatocytes cells of CrVI-treated rats. In contrast, Bcl-2 Pt was occasionally observed in germ cells of CrVI-exposed rats. These results clearly suggest that CrVI subacute treatment causes oxidative stress in rat testis leading to apoptosis.

Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.

Effects of oral administration of 2,4-dichlorophenoxyacetic acid (2,4-D) on reproductive parameters in male Wistar rats.

The 2,4-dichlorophenoxyacetic acid (2,4-D) is used worldwide in agriculture as a selective herbicide. It has been shown to produce a wide range of adverse effects on the health of both animals and humans from embryotoxicity and teratogenicity to neurotoxicity. In the present study, we have examined the effect of 2,4-D on male reproductive function of rats. Male Wistar rats received daily by force-feeding 100 or 200 mg of 2,4-D/kg body weight for 30 consecutive days. Rats exposed to 100 and 200 mg of 2,4-D/kg showed a significant decrease in body weights only after 24 days of treatment and in relative weights of testis, seminal vesicles and prostate at killing day, when compared with controls. Moreover, a decrease in testosterone and an increase in FSH and LH serum levels were detected in treated rats. Besides, exposure to this herbicide induced pronounced testicular histological alterations with enlarged intracellular spaces, tissue loosening and dramatic loss of gametes in the lumen of the seminiferous tubules. In addition, a decreased motility and a number of epididymal spermatozoa with an increased sperm abnormality rate were found in treated rats in comparison with control. With the highest dose, histological observations of seminal vesicles indicated a considerable decrease of secretions in the lumen, a thinness of the muscle layer surrounding the epithelium with branched mucosal crypts and reduced luminal space. In prostate, the heights of the cells decreased while acinar lumen were enlarged and they lost the typical invaginations. Our results suggest that a subacute treatment of 2,4-D promotes reproductive system toxicity.

Meningeal Hemangiopericytomas and Meningomas: a Comparative Immunohistochemical and Genetic Study.

BACKGROUND: The meningeal hemangiopericytoma (MHPC) is a vascular tumor arising from pericytes. Most intracranial MHPCs resemble meningiomas (MNGs) in their clinical presentation and histological features and may therefore be misdiagnosed, despite important differences in prognosis. MATERIALS AND METHODS: We report 8 cases of MHPC and 5 cases of MNG collected from 2007 to 2011 from the Neuro-Surgery and Histopathology departments. All 13 samples were re reviewed by two independent pathologists and investigated by immunohistochemistry (IHC) using mesenchymal, epithelial and neuro-glial markers. Additionally, we screened all tumors for a large panel of chromosomal alterations using multiplex ligation probe amplification (MLPA). Presence of the NAB2-STAT6 fusion gene was inferred by immunohistochemical staining for STAT6. RESULTS: Compared with MNG, MHPCs showed strong VIM (100% of cases), CD99 (62%), bcl-2 (87%), and p16 (75%) staining but only focal positivity with EMA (33%) and NSE (37%). The p21 antibody was positive in 62% of MHPC and less than 1% in all MNGs. MLPA data did not distinguish HPC from MNG, with PTEN loss and ERBB2 gain found in both. By contrast, STAT6 nuclear staining was observed in 3 MHPC cases and was absent from MNG. CONCLUSIONS: MNG and MHPC comprise a spectrum of tumors that cannot be easily differentiated based on histopathology. The presence of STAT6 nuclear positivity may however be a useful diagnostic marker.

Hexavalent Chromium-Induced Apoptosis in Rat Uterus: Involvement of Oxidative Stress.

The present study is designed to test the hypothesis that oxidative stress mediates hexavalent chromium (VI)-induced apoptosis in uterus. Female Wistar rats received an intraperitoneal (i.p.) injection of potassium dichromate at doses of 1 and 2 mg/kg. Superoxide anion production was assessed by determination of the reduction of cytochrome c and iodonitrotetrazolium (INT), lipid peroxidation (LPO), metallothioneins (MTs), and catalase (CAT) activity. The expression of Bax and Bcl-2 proteins was investigated. After 15 days of treatment, an increase of LPO and MT levels occurred, whereas CAT activity decreased. Intense apoptosis was observed in endometriotic stromal cells of Cr-exposed rats. Bax protein expression was induced in endometriotic stromal cells with 1 mg of Cr(VI)/kg, and in stromal and epithelial cells at the higher dose. These results clearly suggest that Cr(VI) subacute treatment causes oxidative stress in rat uterus, leading to endometriotic stromal cells apoptosis.

Glioma epidemiology in the central Tunisian population: 1993-2012.

BACKGROUND: Glioma is a heterogeneous central nervous system (CNS) tumor group that encompasses different histological subtypes with high variability in prognosis. The lesions account for almost 80% of primary malignant brain tumors. The aim of this study is to extend our understanding of the glioma epidemiology in the central Tunisian region. MATERIALS AND METHODS: We analyzed 393 gliomas recorded in cancer registry of central Tunisia from 1993 to 2012. Crude incidence rates (CR) and world age-standardized rates (ASR) were estimated using annual population data size and age structure. Statistic correlations were established using Chi-square and Kaplan-Meier test. RESULTS: Tunisian glioma patients were identified with a mean age at diagnosis of 48 years and 1.5 sex ratio (male/female). During the 19 years period of study the highest incidence value was observed in male group between 1998 and 2002 (CR: 0.28, ASR: 0.3). Incidence results underline increasing high grade glioma occurring in the adulthood in the last period (2007-2012). Median survival was 27 months, with 1-, 2- and 5-year survival rates of 42%, 30% and 26%, respectively. Survival was greater in patients with younger age, lower tumor grade, infratentrial tumor location and undergoing a palliative treatment. CONCLUSIONS: This central Tunisia gliomas registry study provides important information that could improve glioma management and healthcare practice.

Unusual gestational choriocarcinoma arising in an interstitial pregnancy.

INTRODUCTION: Choriocarcinoma is a highly malignant trophoblastic neoplasm. Its association with ectopic pregnancy is very rare and usually with aggressive behavior. PRESENTATION OF CASE: We report a new case arising in an interstitial pregnancy occurring in a 46-year-old woman. The patient was admitted for severe pelvic pain and abundant metrorrhagia. One month ago, she had had a laparoscopic resection of an interstitial pregnancy subsequent to failure of chemotherapy by methotrexate. The raise of serum ßhCG level and the hyperechoic intrauterine mass were in favor of gestational trophoblastic disease. Urgent laparotomy was performed for circulatory collapse. Hysterectomy was done. Histological examination revealed a choriocarcinoma. The patient underwent chemotherapy. Two years later, neither metastasis nor recurrence was detected. DISCUSSION: Clinical diagnosis of primary interstitial choriocarcinoma is difficult, since it is rare and manifesting by non-specific abnormal vaginal bleeding. Imaging findings are also not helpful in ectopic location. The frequency of metastasis is related to the delayed diagnosis. Serial measurement of ßhCG level was the most useful marker of diagnosis and follow up. Histopathological examination remains the only tool of the precise diagnosis. Choriocarcinoma has a very good prognosis even in advanced stages, since it is very chemosensitive. CONCLUSION: The current trend of the treatment of ectopic pregnancy by conservative surgery requires adequate monitoring of ßhCG and careful examination of pathologic specimens to avoid misdiagnosis of ectopic gestational trophoblastic disease.

Ewing's Sarcoma: An Uncommon Breast Tumor.

Ewing's sarcoma/primitive neuroectodermal tumors (EWS/PNET) are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno-phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22) translocation.

Vanadyl sulfate treatment stimulates proliferation and regeneration of beta cells in pancreatic islets.

We examined the effects of vanadium sulfate (VOSO4) treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4 at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4 also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4 treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats.

PHACES syndrome associated with carcinoid endobronchial tumor.

PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphé, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells.

Mammary-like adenocarcinoma of the vulva associated to Paget's disease: a case report.

Mammary-like adenocarcinoma of the vulva associated to Paget's disease is exceedingly rare. So, it is very important to perform all the pathological and immunohistochemical investigations to achieve differential diagnosis from both a metastatic lesion from an orthotopic breast cancer and a vulvar adnexal tumor. This report describes a case of vulvar Paget's disease associated with underlying mammary-like adenocarcinoma diagnosed in the Department of Obstetrics and Gynecology of Farhat Hached university hospital of Sousse in Tunisia. We also review previously reported cases of primary breast-like carcinoma of the vulva with or without Paget's disease.

TCTN3 mutations cause Mohr-Majewski syndrome.

Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.