The expression of MDM2 in gastrointestinal stromal tumors: immunohistochemical analysis of 35 cases.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the digestive system. The assessment of their biological behavior still remains a scientific challenge. To date, there are no well-established biological prognostic markers of GIST. Our aim is to study the expression of the MDM2 oncoprotein in GIST through an immunohistochemical analysis. METHODS: It was a retrospective study of 35 cases of GIST diagnosed from 2009 to 2012 in the department of pathology of Hassan II university hospital, Fès, Morocco. MDM2 immunohistochemical staining was performed on archival paraffin-embedded and formalin-fixed specimens (with a threshold of nuclear positivity > 10%). Analysis of correlations between MDM2 immunoexpression and clinicopathological features of GIST has been performed. RESULTS: The mean age was 55.23 years (range 25-84 years) with a male predominance (sex ratio = 1.5). The stomach was the main site of GIST, with 17 cases (48.57%) followed by the small bowel (9 cases, 25.71%). The spindle cell type GIST was the most frequent morphological variant (29 cases, 82.85%). Tumor necrosis was present in 8 cases (22.85%). Two patients (5.71%) had very low risk GIST, 5 (14.28%) had low risk GIST, 7 patients (20%) had intermediate risk tumors. The remaining 21 cases (60%) had high risk GIST. At the time of diagnosis, 9 patients (25.71%) had metastatic tumors. At immunohistochemical analysis, 40% of cases (14 patients) stained positive for MDM2. Of these MDMD2-positive tumors, 11/14 (78.57%) had high risk tumors and 8/14 cases (57.14%) presented with metastatic GIST. MDM2 positivity was significantly associated with the metastatic status (p = 0.001). CONCLUSION: The current study suggests that MDM2 immunohistochemical expression is a negative histoprognostic factor in GIST with a statistically significant correlation with metastasis.

Microsatellite Instability Analysis in Gastric Carcinomas of Moroccan Patients.

Aim: To investigate correlations between microsatellite instability (MSI) and the phenotype, clinicopathological features, and overall survival (OS) in Moroccan gastric cancer (GC) patients. We evaluated the mutation frequency of 22 MSI-target genes in MSI-positive tumors. Materials and Methods: MSI evaluation were performed for 97 gastric tumors by multiplex polymerase chain reaction (PCR) using a panel of five quasimonomorphic mononucleotide repeat markers (NR27, NR21, NR24, BAT25, and BAT26). The mutation profiles of 22 MSI-target genes were assessed by multiplex PCR and genotyping. Kaplan-Meier curves, the log-rank test, and the Cox proportional hazard regression model were used to conduct survival analyses. Results: Microsatellite stable (MSS) status was observed in 77/97 (79.4%) gastric cancer samples, MSI-Low in 7 (7.2%) samples, and MSI-High (MSI-H) in 13 (13.4%) cases. The MSI-H phenotype was significantly associated with older age (p = 0.004), tumor location (p < 0.001), and intestinal-type of Lauren classification (p < 0.001). Among the 22 MSI target genes analyzed, the most frequently altered genes were HSP110 (84.6%), EGFR (30.8%), BRCA2 (23.1%), MRE11 (23.1%), and MSH3 (23.1%). Multivariate analysis revealed the MSS phenotype (Hazard ratio, 0.23; 95% confidence interval, 0.7-7.4; p = 0.014) as an independent indicator of poor prognosis in our population. Conclusions: This study is the first analysis of MSI in Moroccan GC patients. MSI-H GCs have distinct clinicopathological features and an improved OS. We have identified candidate target genes altered in MSI-positive tumors with potential clinical implications. These findings can guide immunotherapy designed for Moroccan GC patients.

Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients.

INTRODUCTION: The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis. METHODS: Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI). RESULTS: Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). Discussion/Conclusion. We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.

[Cheilitis granulomatosa revealing Crohn's disease]. / Macro-chéilite granulomatose révélant une maladie de Crohn.

Many disorders of the digestive tract cause cutaneous manifestations that may be an indication of an underlying condition; hence dermatologist plays a key role in recommending that the patient see a gastroenterologist. Conversely, gastroenterologist often sees patients with mucocutaneous lesions suggesting possible association with well-known digestive disorders. Chronic inflammatory bowel diseases are the typical example of this essential collaboration between the two specialities. We report a case of Crohn's disease revealed by cheilitis granulomatosa. This study involved a 30-year old female patient followed up for cheilitis granulomatosa in the Department of Dermatology. Somatic examination was unremarkable apart from dermatologic lesions (indurated white faciolabial edema and diffuse gingivitis). Biopsy of the labial lesion revealed perivascular epithelioid and giant-cell granulomas without caseous necrosis. Ileocolonoscopy was performed due to suspected inflammatory colitis. It showed gaping and ulcerated Bauhin valve with slightly erythematous ileal mucosa. Anatomo-pathologic study objectified chronic inflammatory bowel disease (CIBD) such as ileocolic Crohn's disease. Patient's evolution was marked by some episodes of rectal bleeding with anoperineal lesions 6 months later: a wide anterior anal fissure with aphthous ulceration 5 cm from the anal margin, complicated, a few weeks later, by the onset of perianal fistulized abscess requiring surgical drainage and seton installation. Hence the indication for thorough treatment of Crohn's disease after complete drying up of the abscess. Dermatologic lesions vary in patients with CIBD. In some cases, they occur in patients with IBD whereas, in other cases, they precede or accompany digestive manifestations, allowing diagnosis of sometimes clinically latent bowel disease.

[Tumors of the small bowel: about 27 cases]. / Les tumeurs du grêle: à propos de 27 cas.

Tumors of the small bowel account for 5% of all tumors of the gastrointestinal tract. Although important progress has been made from a radiological and endoscopic point of view, they have a poor prognosis due to delayed diagnosis. This occurs because of the absence of clinical manifestations and of the difficulties of exploration. This study aimed to highlight the endoscopic and histologic features of tumors of the small bowel. We conducted a retrospective descriptive study in the Department of Hepato-Gastroenterology at the University hospital Hassan II, Fez, over a period of 11 years (2002-2012). We analyzed the epidemiological, clinical, endoscopic and histologic features of tumors of the small bowel. Data were collected from the medical records of 27 patients. The average age was 48 years [21-80 years] with a male predominance (H/F:2.4). Melenas led to the discovery of tumor in 55% of cases, abdominal mass in 15% of cases and Koenig syndrome or occlusive syndrome in 11% of cases. One patient had a history of celiac disease. CT enteroclysis showed the seat of the tumor in 18 cases. Push enteroscopy for detection of proximal tumors and double-balloon enteroscopy for detection of distal tumor were performed in 8 patients (30%). Endoscopy showed ulcerated lesion in 37.5% of cases, ulcerated stenotic lesion in 50% of cases and ulcerobudding stenotic lesion in 25% of cases. Surgery with anatomopathological examination of the surgical specimen allowed the diagnosis in 18 cases. The histologic type was dominated by stromal tumors in 14 cases (51%), followed by adenocarcinomas in 5 cases (18.5%), B-cell non-Hodgkin lymphoma in 4 cases (15%), neuroendocrine carcinoma of the jejunum in 1 case. Tumors of the small bowel are rare but they are characterized by a poor prognosis. Current imaging techniques (CT enteroclysis and MR enterography) coupled with endoscopic examinations, in particular double-balloon enteroscopy, allow earlier diagnosis and mortality reduction.