Significant association of MCP1 rs1024611 and CCR2 rs1799864 polymorphisms with colorectal cancer and liver metastases susceptibility and aggressiveness: A case-control study.

BACKGROUND: The MCP-1/CCR2 axis is one of the major chemokine signaling pathways that play a crucial role in the tumor microenvironment and has been involved in triggering various tumor progression mechanisms, such as increasing the immunosuppressive cells recruitment and promoting tumor cell proliferation and invasiveness. AIM: The current study investigated the association of MCP1 (rs1024611) and CCR2 (rs1799864) genes variants with the risk as well as prognosis of colorectal cancer (CRC) and colorectal liver metastases (CRLM). SUBJECTS AND METHODS: A retrospective cohort study involved 408 patients (284 CRC and 124 CRLM), and 284 healthy control was conducted. Genotyping of selected polymorphisms was performed by PCR-RFLP assays and confirmed by microchip and capillary electrophoresis. RESULTS: The results highlighted a positive association between MCP1 rs1024611 (non-AA) and CCR2 rs1799864 (GA) genotypes with increased CRC and CRLM risk. Correlation between SNPs and clinicopathological characteristics revealed a positive association between MCP1 rs1024611 and CCR2 rs1799864 (dominant model) and CRC poor prognosis features. Kaplan-Meier survival analysis revealed a significant association between MCP1 rs1024611 non-AA carriers and decreased survival rate. Neoadjuvant treatment showed an improvement in CRC and CRLM survival rates among carriers of MCP1 and CCR2 wild-type genotype. FOLFIRI chemotherapy exhibits reduced survival rates for patients who carried mutated genotypes of MCP1 and CCR2 polymorphisms. CONCLUSION: Considering our results, we suggest That both MCP1 and CCR2 polymorphisms may constitute independent factors for CRC and CRLM occurrence and can be helpful targets for an efficient therapeutic approach.

Clinicopathological characteristics and mutational profile of KRAS and NRAS in Tunisian patients with sporadic colorectal cancer

Background/aim: Colorectal cancer (CRC) is a major public health problem worldwide and in Tunisia due to its increasing rate of incidence. KRAS and NRAS mutations have become a pivotal part of CRC diagnosis, given their association to treatment resistance with antiepidermal growth factor receptor (EGFR) monoclonal antibodies. In this study, we aimed to screen for mutations in KRAS and NRAS genes in Tunisian patients with CRC and explore their correlations with clinicopathological features. Materials and methods: AmoyDx KRAS and NRAS mutation real-time PCR kits were used to screen for mutations in KRAS (exon 2) and NRAS (exons 2, 3, and 4) in 96 CRC tumors. Results: KRAS exon 2 mutations were found in 41.7% (40/96) of the patients. Codon 12's most abundant mutations were G12D and G12V, followed by G12A, while G13D is the predominant mutation in codon 13. KRAS exon 2 mutations were associated with older patients (P = 0.029), left-sided tumors (P = 0.037), and greater differentiation (P = 0.044). The prevalence rate of NRAS mutations was 7.3%, mostly in exon 2. These mutations were associated with early stages of the disease (P = 0.039) and the absence of lymph node metastasis (P = 0.045). Conclusion: It can be inferred from this study that Tunisian CRC patients have a similar frequency of KRAS and NRAS mutations compared to those observed in other populations. Consequently, screening for KRAS and NRAS mutations is crucial for the orientation of therapies and the selection of appropriate candidates, while also helping to avoid unnecessary toxicity and increased costs for patients.

MUC1 and MUC5AC implication in Tunisian colorectal cancer patients

Background/aim: Mucins, such as MUC1 and MUC5AC, are known for their protective and moisturizing role in intestinal epithelium. Their expression is tightly controlled given their essential role in normal tissue homeostasis, whereas their deregulation leads to chronic inflammation, and even cancer. This study aimed to assess the expression profiles of MUC1 and MUC5AC and their implications in colorectal carcinogenesis. Materials and methods: A retrospective study of 202 patients who underwent colorectal cancer (CRC) surgery was conducted. The expression of MUC1 and MUC5AC was investigated by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). Statistical analysis of mucin expression pattern, as well as the clinicopathological criteria of the patients, was performed using the chi-square test, survival curves were plotted using the Kaplan­Meier product-limit method, and differences between the survival curves were tested using the log-rank test. Results: The expression of both mucins was abnormally high in the tumor tissues for both mRNA and protein. MUC1 expression was correlated with advanced cancer stages and lymph node metastases for both the mRNA (P < 0.016 and P < 0.002, respectively) and protein level (P < 0.006 and P < 0.001, respectively). However, MUC5AC expression did not pinpoint any significant association between the clinicopathological criteria, but patients who expressed MUC5AC showed an increase in overall survival (P < 0.009). Conclusion: The expression of MUC1 might be a poor prognostic biomarker in CRC and could play a role in tumor transformation and metastasis. However, MUC5AC expression might be a good prognostic in the Tunisian cohort.

Follicular carcinoma arising from struma ovarii. A case report.

Struma ovarii is a monodermal variant of ovarian teratoma. Thyroid-type carcinoma arising in struma ovarii is rare. The most common type is papillary carcinoma, followed by typical follicular carcinoma. A 75-year-old hypertensive patient consulted for the sensation of a painless pelvic mass that has been progressing for six months. The abdominopelvic ultrasound showed a right lateralized abdominopelvic mass measuring 14x13x8 cm with a solid and cystic double component. The patient underwent a unilateral right adnexectomy. Grossly, the tumor was encapsulated and lobulated. On cut sections, it was solid brown whitish in color and gelatinous. On histological examination, it was formed of follicular structures of variable size filled with a dense colloid. From this goiter a malignant tumor proliferation arose, arranged in sheets, trabeculae and follicular structures, and the tumor cells were cubic or polyhedral moderately atypical with few mitotic figures. There were no papillary-like nuclear features. There was focal capsular and vascular invasion. Immunohistochemical study showed positive immunostaining of tumor cells with TTF1. Postoperative course was uneventful. The exact prognosis of thyroid-type carcinoma arising in struma ovarii is still unclear because of its rarity, inadequate follow-up, and the absence of consensus in diagnosis and treatment.

Chronic gastritis classifications.

Chronic gastritis are inflammatory diseases of the gastric mucosa whose diagnosis depends on  pathological examination. They are frequent and cover a significant part of the daily activity of pathologists. Their origin is often infectious, particularly by Helicobacter Pylori. Several classifications of chronic gastritis were proposed but in order to achieve standardization in the drafting of pathological reports of gastric biopsies, pathologists currently following the recommendations of the revisted Sydney System. OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link for Gastritis Intestinal metaplasia Assessment) stages are increasingly used since they allow the clinicians to select patients with « high risk ¼ chronic gastritis, which require special monitoring. The aim of this paper was to perform a review of the different classifications of chronic gastritis currently available to pathologists.

Extracapsular involvement in nodal metastasis as a prognostic factor in colorectal cancer.

BACKGROUND: Extracapsular extension of nodal metastasis has recently emerged as an important prognostic factor in different malignancies. In colorectal cancer (CRC), only a limited number of studies have been published and its prognostic value has not yet been completely established. AIMS: To assess the incidence of extracapsular invasion (ECI) in lymph node (LN) metastasis in colorectal adenocarcinoma and to investigate the correlation between this parameter and other clinico-pathological factors.  Furthermore, its effect on overall and disease free survival were evaluated. METHODS: Seventy-five patients who underwent colorectal resection for adenocarcinoma with node metastasis were included in this study. Extracapsular invasion was evaluated by two pathologists. Associations between clinicopathologic factors, survival, and the nodal findings were evaluated. The 2009 pTNM staging of CRC was used. RESULTS: Extracapsular invasion was identified in 45 patients (60 %). Average follow-up time was 25 months. Extracapsular invasion was correlated with pT stage> pT2 (p=0,015), pN stage > pN1 (p= 0,014), distant metastasis at diagnosis (p=0,005) and later (p=0,01) and with local recurrences (p=0,0001). Univariate analysis indicated that ECI tends to decrease overall survival but not significantly.  Multivariate analysis showed that age and synchronic metastasis were independent prognostic factors (HR = 2,03 and 2,24; p= 0,039 and 0,012 respectively). Patients with ECI had a significantly worse five-year disease-free survival than ECI-negative groups. CONCLUSION: In patients with CRC, ECI in regional LNs would reflect an aggressive behavior. It would therefore be useful to include this parameter in standardized pathologic reports and future staging systems.

Fetoplacental malformations and abnormalities. A retrospective analysis of 398 cases.

BACKGROUND: The fetoplacental examination is actually very important and sometimes necessary to confirm or correct prenatal diagnosis. AIM: to deduce a list of indications of fetoplacental examination and to determine the type and frequency of malformations found. METHODS: a retrospective study including 398 consecutive fetoplacental examinations, including abortions, stillbirths and children died perinatally. The cases were referred in the department of pathology of the M. Slim Hospital (North Tunis) from 1992 and 2012. RESULTS: The mean maternal age was 32,58 years. The average gravidity was 2,65 and the average rate was 1,48. Maternal conditions were dominated by preeclampsia. The main indication motivating the request for fetoplacental examination was a spontaneous abortion in 45,73% of cases. The rate of stillbirths was 15,61% and that of children who died in the perinatal period was 13,28%. The sex ratio was 1,4 and the medium term was 19,38 SA. 170 fetuses had abnormalities (43,14%). The most frequent abnormalities were chromosomal aberrations (27,64%), followed by facial abnormalities (25,88%) and central nervous system abnormalities (18,82%). We examined 283 placentas, 49% of them contained abnormalities. Ischemic lesions were the main placental abnormalities (41%). CONCLUSIONS:   An efficient fetopathological examination should be as complete as possible, including examination of placenta. Everything must be integrated into a data collection and complete clinical information.

Pathological response of colorectal liver metastases treated after induction treatment.

BACKGROUND: Mortality for colorectal cancer is mainly due to liver metastases, surgical resection remains the curative treatment and use of neoadjuvant therapy improves resectability of metastases. Pathological response is an important prognostic factor. AIM: To evaluate tumor response by Tumor regression grade (TRG) according Rubbia-Brandt et al and correlation with survival. To establish chemotherapy-related liver injury. METHODS: Thrity-eight patients resected for colorectal cancer liver metastases after neoadjuvant chemotherapy were enrolled in this study. Tumor regression grade (TRG) according to Gradding Rubbia-Brandt et al. was evaluated. RESULTS: Sex ratio was 1.5 with an average age of was 55 years. Twenty-five patients were in stage IV (65.7% of patients with synchronous liver metastases). Overall survival was 62% at 12 months, 42% at 24 months and 21% at 36 months. Thirty-four patients (89.5%) received Oxaliplatin and nine (23.7%) irinotecan. Twenty patients (52.6%) had no histologic response (TRG 4 and 5), nine (23.7%) had a major response (TRG 1 and 2) and nine had a partial response (TRG3). Survival was more important with major pathologic response than with partial response or no response. No statistically significant relation was found between survival and the different types of response. Chemotherapy-related liver injury were present in 21 patients (55.2%).  Conclusions: Scoring system with three grades are currently recommanded to evaluate pathological response and new histopathological data are proposed. Larger studies are required to validate these items and their utility for therapeutic decisions.

Resected colorectal cancer liver metastases : Prognostic study about 110 patients.

INTRODUCTION: The prognosis of hepatic metastases in colorectal cancers is constantly being improved at the cost of multidisciplinary care, allowing each patient to have an adapted strategy. The prognostic factors make it possible to recognize patients needing further treatment after resection and closer monitoring. OBJECTIVE: The aim of our study was to conduct a prognostic study to identify factors influencing survival at 5 years for patients operated of colorectal liver metastases. METHODS: This is a retrospective study conducted over a period of 10 years (2005-2015). All patients operated for liver metastasis of colorectal cancers were included. The primary endpoint was overall survival. Secondary endpoints were recurrence-free survival and operative morbidity and mortality. The proportions were compared by the Chi 2 test. The survival curves were established according to the Kaplan-Meier method and the comparison of the curves according to the Logrank test. A univariate and then multivariate Cox model was used to determine prognostic factors. The significance level was set at 0.05. RESULTS: Overall survival of our patients at 3 and 5 years was 49% and 32% respectively. Recurrence-free survival was 21% at 3 years and 15% at 5 years. In multivariate analysis, the hepatic resection margin <1 mm and the number of hepatic metastases ≥3 were independent factors correlated with survival. CONCLUSIONS: colorectal liver metastases surgery improves patient survival. Some factors need to be sought to adapt care strategies.

Incidental gallbladder cancer diagnosed on cholecystectomy specimens: a study of 30 cases.

Background - The gallbladder cancer is a rare cancer with poor prognosis. The association with gallstone disease is the main risk factor of this cancer. Aim - Describe the demographics, clinic-pathologic and therapeutic management of incidentally gallbladder cancer diagnosed on cholecystectomy specimens. Methods - retrospective study including 30 cases of gallbladder cancer incidentally detected on cholecystectomy specimens. Results - The incidence of gallbladder cancer incidentally discovered was 0.83%. The sex ratio M/F was 0.5 and the average age was 68 years. The main risk factor was cholelithiasis (38%). Adenocarcinoma was the most frequent histological type found in 86.6% of cases and it was biliary-type in 56.6% of cases. 76,7% of the tumors were classified in early stages (stages 0, I and II) and 23,3% were in advanced stages (III and IV). A simple cholecystectomy was curative in 66.7% of cases. Overall survival rate was 56.7% at one year. The best survival rate was for the early stages: 100% stages 0-I and 45.4% stage II. Conclusions - The gallbladder cancer has poor prognosis because of its late diagnosis. Thorough sampling and careful attention on histological examination of all parts of cholecystectomy specimens allows detection of early cancer with better prognosis.

Relationship between SDF-1G801A polymorphism and its expression in Tunisian patients with colorectal cancer.

The aim was to evaluate the relationship between SDF-1G801A polymorphism and its immunohistochemical expression in colorectal cancer tissues in the Tunisian cohort. The molecular and immunohistochemical analysis showed that SDF-1G801A polymorphic variant was higher in CRC patients with TNM stage II and III, the SDF-1 expression was significantly increased from normal mucosa to primary tumor (p < 0.05). CRC patients have higher frequency of A allele (52.01%) than controls (26.8%) (P = 0.0001). Thus, SDF-1 polymorphism is a risk factor of colorectal cancer susceptibility in our population, the polymorph genotype of SDF-1 maybe associated with clinical manifestations in CRC patients in Tunisia.

Chondroid syringoma: report of four cases.

Chondroid syringomas or mixed tumors of the skin are relatively rare adnexal tumors constituting 0.01% to 0.1% of all primary skin tumors. The majority of chondroid syringomas occur at the head and neck region (80%). Their clinical presentation is not specific and the final diagnosis is based on histopathologic examination. The authors report four cases of benign chondroid syringoma in three women and one man aged 26, 45, 50, and 38 years, respectively. They presented with a slow-growing, painless and firm subcutaneous nodule measuring between 1 and 3 cm involving the lower eyelid, the nasogenien groove, the nose, and the chin, respectively. All patients underwent uneventful surgical excision of the nodules. Histologic examination of the surgical specimen was compatible with benign chondroid syringoma in all cases. Chondroid syringomas must be considered in the differential diagnosis of any small subcutaneous nodule in the head and neck region in middle-aged patients. The treatment of choice is total excision, with wide disease-free margins, to rule out malignancy and reduce the risk of recurrence and malignancy in the future.

Biological significance of promoter hypermethylation of p14/ARF gene: relationships to p53 mutational status in Tunisian population with colorectal carcinoma.

One of the most important pathways which are frequently affected in colorectal cancer is p53/ (MDM2)/p14ARF pathway. We aim to determine the methylation pattern of p14/ARF in relation to mutation of p53. This correlation was studied to investigate whether their alterations could be considered as a predictor factor of prognosis in colorectal cancer and whether it can be useful in early-stage diagnosis. Statistical analyses show that p14/ARF hypermethylation was correlated with rectum location (p = 0.004), primary TNM stage (p = 0.016), and advanced Astler-Coller stage (p = 0.024). The RT-PCR that revel 31 % of patients did not express p14/ARF mRNA or at very low level. A high concordance between CpG hypermethylation and the low levels (p < 0.005) was shown. In addition, our analyses demonstrate that patients with mutation in the p53 gene have a lack of the protein expression (p < 0.005). This category with negative expression of p53 had a shorter survival rate (p < 0.005). On the one hand, MSP pattern of p14/ARF were correlated with a lack of p53 expression (p = 0.007). We found that p53/p14ARF pathway was frequently deregulated among our patients. In our study, we demonstrate that hypermethylation of p14/ARF occurs early during CRC tumorogenesis. However, we did not find correlation between p14/ARF and survival. These results suggest that p14/ARF methylation pattern may constitute a predictor factor of CRC in early stage but it could not be considered as a prognostic factor. On the other hand and because of the reversibility of the methylation mechanism, it may be appropriate to target the demethylation of p14/ARF to develop new drogues for CRC.

Celiac disease in Tunisian children: a second screening study using a "new generation" rapid test.

This work aims to estimate celiac disease prevalence in school-children in the island of Djerba and assess rapid method feasibility for screening. We screened 2064 schoolchildren by a rapid method to detect IgA anti-tissue transglutaminase and IgA deficiency. Children with positive results were tested for IgA anti-transglutaminase and anti-endomysium by conventional tests. In positive children, intestinal biopsy was performed. IgA deficiency suspected by rapid method was confirmed by nephelometry. In these cases IgG anti-endomysium was performed. Rapid test was positive in 7 children; conventional serology was positive in all and 6 of them accepted the biopsy. Total villous atrophy was observed in 5 while intestinal mucosa was normal in one. Among children with positive serology, 3 had silent form, 1 chronic diarrhea, one growth failure and 2 had borderline growth. IgA deficiency was suspected in 13 cases and was confirmed in 11 children tested. Prevalence of celiac disease was 0.24-0.34% and that of IgA deficiency 0.5-0.6%. This screening study confirms that celiac disease is relatively common in schoolchildren in Tunisia. It confirms also that even those with symptoms typical for celiac disease escape diagnosis. Rapid test is better accepted by parents and children than test requiring a venous blood sample.

Is galectin-3 antibody a useful marker in the diagnosis of malignant pleural mesothelioma?

Malignant pleural mesothelioma (MPM) is a challenging diagnosis characterized by the absence of real specific diagnostic markers. Positivity with the galectin-3 antibody was assessed by a cytoplasmic expression in 17 MPM. Fourteen cases expressed the galectin-3 antibody. The three negative cases consisted of epithelioid, biphasic, and sarcomatoid MPM. The 14 positive cases consisted of epithelioid MPM in 12 cases, sarcomatoid MPM in one case, and biphasic MPM in one case. In spite of our inability to prove the real diagnostic value of the galectin-3 antibody, our findings make us wonder about the implication of this antibody in the carcinogenesis of MPM.

Evaluation of microsatellite instability, MLH1 expression and hMLH1 promoter hypermethylation in colorectal carcinomas among Tunisians patients.

BACKGROUND: About 10% to 15% of sporadic colorectal cancers demonstrate high level of microsatellite instability that is generally associated with aberrant methylation of hMLH1 promoter. AIM: To investigate the association between MSI status, hMLH1 protein expression and methylation status of the hMLH1 promoter in a cohort of Tunisian sporadic colorectal cancer. METHODS: Expression of MLH1 and MSH2 was determined by immunohistochemistry and the MSI status was analysed by microfluid-based on-chip electrophoresis. Methylation of the hMLH1 gene promoter was determined by methylation-specific PCR. RESULTS: Of the 150 colorectal cancers 57% were MSS, 28% were MSI-L and 15%were MSI-H. MSI-H tumors were more frequently right-sided, exhibited a stage III of TNM and tended more to be mucinous. The MSI status had no effect on overall patient survival. Most of the MSS/MSI-L 79% cancers were unmethylated at the hMLH1 promoter, while 26% MSI-H cancers were unmethylated. 84% of MSS and MSI-L expressed MLH1 and 52% of MSI-H expressed MLH1. Of the methylated MSI-H cases, 35% expressed MLH1 protein while 100% of the unmethylated MSI-H were positive for MLH1 staining. Of 11 MSI-H cancers with loss of MLH1 expression, all cases were also methylated while 50% MSI-H cancers with positive immunostaining for MLH1 were methylated at the hMLH1 promoter. CONCLUSION: Our study showed that MSI-H phenotype was mucinous, right-side and exhibit stade III of TNM. The relative correlation of MLH1 expression and promotor hypermethylation of hMLH1 for the MSI status is similar to that reported for several study.

Mucinous breast carcinoma with neuroendocrine differentiation: Case report.

Mucinous carcinoma of the breast is rare representing 2% of all breast carcinomas. It can be classified as either a pure or a mixed type. Pure mucinous breast carcinoma has a less aggressive behavior compared with mixed breast mucinous carcinoma. The latter shows frequent neuroendocrine differentiation.

Puzzling hepatic tumor: Epithelioid angiomyolipoma.

Hepatic epithelioid angiomyolipomas are uncommon mesenchymal neoplasms. They are difficult to diagnose by imaging, especially when the fatty component is scant or absent. The gold standard for the diagnosis is histologic examination coupled with an immunohistochemical study. Positive HMB45 immunostaining of the myoid cells is a major diagnostic feature.

A rare and distinct hepatic tumor: Hepatocholangiocarcinoma.

The rare histological features of hepatocholangiocarcinoma require a thorough sampling of the surgical specimen and the application of immunohistochemical techniques to confirm the diagnosis.

Mixed fibrolamellar hepatocellular carcinoma.

Pure and mixed fibrolamellar hepatocellular carcinomas display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.