RAS Mutations Predict Recurrence-Free Survival and Recurrence Patterns in Colon Cancer: A Unicenter Study in Morocco.

PURPOSE: To date, only a few studies have investigated the role of molecular alterations in cancer recurrence. This exploratory study aimed to evaluate the impact of molecular alterations on the time and site of recurrence in patients with stage I-IV CRC and to identify the risk factors predicting recurrence-free survival in colon cancer. METHODS: A total of 270 patients were retrospectively included. We assessed the full RAS status using Sanger and pyrosequencing. MSI status was determined by immunohistochemical analysis. Molecular alterations were correlated with recurrence timing (early or late), recurrence patterns, and recurrence-free survival. Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. RESULTS: Of the 270 patients, 85 (31%) experienced recurrence, among whom 53% had mutant full RAS status, 48% had KRAS mutations, and 31.4% had KRAS p. G12V mutation subtype. Compared with those with late recurrence, patients with early recurrence were significantly older (P = 0.02) and more likely to have poorly differentiated tumors, a higher rate of positive lymph nodes, KRAS mutations, and especially KRAS p. G12V mutation variant. RAS mutation status, KRAS mutations, and rare mutations are more common in patients with lung cancer recurrence. Multivariate logistic regression analysis revealed that differentiation, perineural invasion, full RAS mutation status, and KRAS codon 13 mutations were independent factors for recurrence-free survival in colon cancer. CONCLUSION: In this cohort, the timing and patterns of recurrence appeared to be associated with the patient's molecular profile. KRAS codon 12 mutations were the worst predictors of recurrence-free survival at all stages in our population.

An inflammatory myofibroblastic tumor of the ampulla of Vater, an exceptional location: a case report.

Introduction and importance: Inflammatory myofibroblastic tumors constitute a group of mesenchymal tumors associated with inflammatory infiltration. They occur mainly in young patients. It is classified by the World Health Organization as a borderline neoplasm. They are observed in many organs, particularly the lungs. Digestive localization is rare, and localization into the ampulla of Vater has been reported once. Case presentation: We report the case of a 39-year-old patient who was admitted for cholestatic jaundice with right hypochondrium pain. Computed tomography and magnetic resonance imaging revealed a tumor at the biliopancreatic junction. A cephalic duodenopancreatectomy was performed, and a histological examination of the surgical specimen revealed an inflammatory myofibroblastic tumor of the ampulla of Vater. The postoperative evolution was without any complications. Clinical discussion: This is the second case of localization of an inflammatory myofibroblastic tumor in Vater's ampulla. The therapeutic approach is the complete excision of these inflammatory tumors, thus reducing the risk of local recurrence. In the literature, all cases of incomplete excision have resulted in recurrences. Conclusion: Inflammatory myofibroblastic tumors are rare. The diagnosis was based on histopathological findings and confirmed using immunohistochemical techniques.

Lymph Nodes With Germinal Centers Are Not Associated With Tumor Response After Neoadjuvant Treatment in Locally Advanced Rectal Cancer.

In patients with locally advanced rectal cancer, neoadjuvant radiotherapy or chemoradiotherapy followed by total mesorectal excision as a standard of care. We aimed to explore the number, size, germinal centers, extracapsular invasion of lymph nodes (LN), and their impact on overall survival and disease free survival. Furthermore we also investigated the characteristics of lymph nodes in patients who received neoadjuvant therapy and those who underwent surgery between 2011 and 2018. The count and measurement of lymph nodes was assessed by careful visual inspection and manual palpation. The predictive cut-off value of the lymph node ratio (LNR) was determined based on the receiver operating characteristic (ROC), method and the survival outcomes based on Kaplan-Meier curves. We found that the size and the number of lymph nodes decreased significantly after neoadjuvant treatment. The mean LN for patients who received neoadjuvant therapy was 12.68 ± 6.69 and for patients who did not receive neoadjuvant therapy was 16.29 ± 5.61 (P = .012). The average size for patients who received neoadjuvant therapy followed by surgery was 3.30 ± 1.10 versus 4.22 ± 1.18 mm for control group (surgery only) (P < .001), an LNR of 0.13 (sensitivity: 86%, specificity: 47%, AUC: 60%, 95% CI, 0.41%-0.76%) predicted recurrence and metastasis. Presence of lymph nodes with germinal centers was significantly associated with absence of vascular invasion, nodal tumor deposits, distant metastasis, and lower age group (<50 years). However there was no association seen between overall survival and relapse free, total number of lymph nodes enlarged and extracapsular invasion in positive nodes. Finally there is no association between lymph nodes with germinal centers and tumor response after neoadjuvant treatment in locally advanced rectal cancer.

Dermatofibrosarcoma protuberans of the anterior abdominal wall: case report and literature review.

Dermatofibrosarcoma protuberans (DFSP) is a rare and slowly growing cutaneous tumor with high risk of local invasion and recurrence. Here, we report a case of a DFSP of the anterior abdominal wall diagnosed in a 45-year-old woman. The clinical examination showed an indurated well-limited oval mass localized in the supra-umbilical level and measuring 5 cm by 3 cm. The histological finding of skin biopsy was consistent with the diagnosis of DFSP. A wide local excision was performed while respecting minimum safety margins of 3 cm. The primary closure was possible after advancing the subcutaneous adjacent tissue. The histological examination of the surgical specimen confirmed the DFSP diagnosis and determined safe microscopic margins. After 4 years of regular follow-up, no locoregional or distant recurrence was observed. We discuss through this case the diagnosis difficulties and the particularities of the abdominal wall localization.

Prognostic Impact of Tumor Budding on Moroccan Colon Cancer Patients.

BACKGROUND: Tumor budding is now emerging as one of the robust and promising histological factors that play an important role in colon cancer. In this study, we aimed to investigate the association between tumor budding and tumor clinicopathological factors, tumor molecular signature, and patient survival for the first time in a Moroccan population. METHODS: We collected data of 100 patients operated from colon adenocarcinoma. Tumor budding was assessed on HES slides, according to the International Tumor Budding Consensus Conference 2016 recommendations. The expression of MMR proteins was performed by immunohistochemistry. KRAS and NRAS mutations testing was performed by Sanger sequencing and pyrosequencing. RESULTS: High tumor budding grade (BUD 3) was found to be significantly associated with adverse clinicopathological features including older age (P=0.03), presence of perineural invasion (P=0.02), presence of vascular invasion (P=0.05), distant metastases (P < 0.001), advanced TNM stage (P=0.001), the occurrence of relapse (P=0.04), and the high number of deceased cases (P=0.02). Interestingly, we found that tumors with high-grade tumor budding were more likely to be microsatellite stable (MSS) (P=0.005) and harbor more KRAS mutations (P=0.02). Tumors with high-grade tumor budding were strongly associated with KRAS G12D mutation (P=0.007). In all stages, high tumor budding was correlated with poorer overall survival (P=0.04) and decreased relapse-free survival with a difference close to significance ((P=0.09). We concluded that high tumor budding was strongly associated with unfavorable clinicopathological features and special molecular biomarkers and effectively affects the overall survival of CC patients. CONCLUSIONS: Based on these findings and the ITBCC group recommendations, tumor budding should be taken into account along with other clinicopathologic factors in the risk assessment of colorectal cancer.

Impact of mental imagery on enhancing surgical skills learning in novice's surgeons: a pilot study.

OBJECTIVE: Mental imagery (MI) has long been used in learning in both fields of sports and arts. However, it is restrictively applied in surgical training according to the medical literature. Few studies have evaluated its' feasibility and usefulness. The aim of this study is to assess the impact of mental imagery on surgical skills learning among novice's surgeons. MATERIAL AND METHODS: In this pilot prospective randomized comparative study; we recruited 17 residents and interns of surgery education curriculum. They were all included in their first semester of the curricula. Two groups were randomly designed. Group (a) including "Mental Imagery" volunteers (n = 9) which benefited from a mental imagery rehearsal exercise prior to physical practice, while the control group (b) (n = 8) didn't underwent any MI process prior to surgery practice. Each participant of both groups was invited to perform an intestinal hand-sewn anastomosis on bovine intestine. Each procedure was evaluated and analyzed according to 14 qualitative criteria while each criterion was scored 0, 1 or 2 respectively assigned to the gesture was not acquired, gesture was performed with effort, or mastered gesture. The final score is 28 for those who master all 14 gestures. A non-parametric statistical comparison between the both studied groups was performed. RESULTS: Both groups of surgery students demonstrated equivalent age, sex ratio, laterality, and surgical experience. The mean overall score is significantly higher in the MI group (a) (17.78; SD = 2.42) compared to the control group (b) (10.63, SD = 2.85). However, advanced analysis of individual assessment items showed significant statistical difference between both groups only in 6 out of 14 assessed items. CONCLUSION: Indeed, mental imagery will not be able to substitute the traditional learning of surgery for novice surgeons; it is an important approach for improving the technical skills acquisition and shortening the physical learning.

Comparative analysis of clinicopathologic features between adenoma and hyperplasia in surgically treated patients for hyperparathyroidism: A retrospective study.

BACKGROUND: Hyperparathyroidism (HPT) is a common endocrine disorder resulting from overproduction of parathyroid hormone (PTH). Usually HPT is caused by parathyroid adenoma (PA) or parathyroid hyperplasia (PH). Our aim is to assess clinicopathologic features associated with PA and PH in patients with HPT. METHODS: We retrospectively collected 29 cases of HPT recorded at the Department of Pathology of Hassan II University Hospital of Fes, Morocco, from 2013 to 2016. RESULTS: The mean age was 52.14 ± 15.7 years (range of 22-76 years), 13 patients (44.8%) had primary HPT, 16 (55.2%) had secondary HPT. The largest size of the resected parathyroid specimens ranged from 1 to 3.6 cm (mean of 2.26 ± 0.66 cm). Seventeen patients (58.6%) had PA, the remaining cases were diagnosed as PH. There were no significant statistical differences between PA and PH in age, sex, clinical presentation, preoperative serum PTH, or in parathyroid gland size (P > 0.05). However compared to PH, PA is more often a single-gland disease, found in primary HPT with higher preoperative calcium level (P ˂ 0.05). CONCLUSIONS: In patients surgically treated for HPT, PA is associated with some distinctive clinicopathologic features. These findings could be helpful to pathologists and clinicians for appropriate clinicopathologic management.

Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report.

This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.

The Effect of Lymph Nodes' Histologic Response on Survival Outcomes in Moroccan Patients with Rectal Cancer.

Prognosis for patients with locally advanced rectal cancer remains controversial. The purpose of this study was to elucidate possible association between therapeutic effect on lymph nodes (LNs) and patient prognosis. Overall, 149 patients with rectal cancer received preoperative radiotherapy in concomitance with chemotherapy or exclusive radiotherapy before rectal excision. Microscopic examination of formalin-fixed lymph nodes was assessed for therapeutic effect. The establishment of groups combined reaction tissue types of fibrosis, colloid, and necrosis after neoadjuvant treatment was assigned. The average age was 56.38 years, ranged between 22 and 88 years, 53% were female, and 47% were men, with a sex ratio of 1 : 12. In the present study, we noticed that after a median follow-up time of 40.67 months (0-83; SD: 21.1), overall survival was statistically significant depending on age groups. Kaplan-Meier analysis showed significant differences in the rate of patients with an age under 65 years (70.64%) versus those with an age over 85 years (36.5%) (p < 0.001). Also, the OS was statistically significant depending on therapeutic effect groups composed of 0TE (No Therapeutic effect), C+ (presence of only colloidal effect), F+ (presence of only fibrosis tissue), and ME+ (mixture of 2 or 3 types of therapeutic effect) group. Indeed, we observed a significantly higher OS rate in the ME + group (86%) compared with the OS rate of LNs group with no therapeutic effect (57%) (p=0.028). Additionally, there was a significant association between the presence of fibrosis on LNs and an extended delay of more than 8 weeks to neoadjuvant treatment completion and surgery. Our study indicates that the best patient prognosis could be predicted based on tumor presenting a best pathologic effect on lymph nodes, and that delaying surgery for more than 8 weeks to neoadjuvant treatment completion improves therapeutic response on LNs.

Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population.

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p = 0.016, r = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.

Acute cecal volvulus: A diagnostic and therapeutic challenge in emergency: A case report.

INTRODUCTION: Cecal volvulus is an uncommon cause of intestinal obstruction due to an axial twist of the caecum, ascending colon and terminal ileum around the mesenteric pedicle. It is responsible for 1%-1.5 of all intestinal obstructions in adult. The clinical signs may be highly variables and can be responsible of delays in diagnostic and treatment. The delay in diagnosis leads to intestinal necrosis or perforation. The mortality ranges from 10 to 40% depending on the presence of a viable or gangrenous intestine. PRESENTATION OF CASE: A 64 year old woman admitted the emergency department for acute bowel obstruction. Clinical examination found typically acute bowel obstruction signs. Plain radiography showed dilated gas-filled segment of the colon in the left side of abdomen and volvulus of cecum was suspected. Enhanced abdominal CT scan confirmed the diagnosis. Emergency exploratory laparotomy was performed and confirmed the cecal volvulus. A manual untwisting of volvulus and a Caecopexy were performed. The patient subsequently recovered uneventfully and was discharged on postoperative day 3. DISCUSSION: The management of cecal volvulus requires prompt (emergency) diagnosis and prompt surgical intervention. Any delay in diagnosis may lead to intestinal necrosis or perforation and worsening the prognosis in patients who are generally elderly. Several authors reported a high mortality rate of cecal volvulus due to delay to diagnosis and surgical intervention. CONCLUSION: The low incidence of this condition needs a high index of suspicion and emergency surgical management. Despite significant progress in medical imaging, the preoperative diagnosis of cecal volvulus is very difficult. As a result, the treatment is often delayed.

[Total small bowel volvulus complicating common incomplete mesentery, an exceptional complication in adults: about a case]. / Volvulus total du grêle sur mésentère commun incomplet, une complication exceptionnelle chez l'adulte: à propos d'un cas.

Total small bowel volvulus complicating common incomplete mesentery is an arrest of rotation of the primary intestinal loop at 180°. The root of the mesentery is very short and the whole small intestine is located on the superior mesenteric artery axis. Patients are at very high risk of small bowel volvulus and enteromesenteric infarction. Acute volvulus requires emergency surgery; imaging must not delay surgery. Surgery is based on the untwisting of the volvulus (counterclockwise) after the assessment of intestinal viability. The intestine placed in the complete common mesentery position: the cœcum is situated in the right iliac region. We report the case of a 60-year old patient admitted with total small bowel volvulus on an incomplete common mesentery who underwent emergency surgery with favorable postoperative outcome.

Predictive factors of disease-free survival after complete pathological response to neoadjuvant radiotherapy for rectal adenocarcinoma: retrospective case series.

BACKGROUND: Many data suggest that patients with low rectal adenocarcinoma who achieved ypT0N0 status have improved survival and disease-free survival (DFS) compared to all other stages however only few data are available regarding the specific prognosis factors of this subgroup. This study aimed to evaluate predictive factors for disease free survival after complete pathological response (CPR) in cases of low rectal adenocarcinoma. MATERIALS AND METHODS: From January 2005 to December 2013, all patients with low rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy followed by total mesorectal excision and achieved CPR were included at 7 Moroccan and 1 Algerian centres. Predictive factors for disease-free survival were analysed by uni and multivariate analysis. RESULTS: Eigthy-four (12.1%) patients achieved a CPR (ypT0N0). Multivariate analysis revealed that both poorly differentiated tumors (OR, 9.23; 95 CI 1.35-62.82; P = 0.023) and the occurrence of perineal sepsis (OR, 13.51; 95 CI 1.96-93.12; P = 0.008) were independently associated with impaired DFS. CONCLUSIONS: Patients with low rectal cancer who exhibited a CPR after neoadjuvant therapy have good prognoses; however, the occurrence of perineal sepsis and/or poor initial differentiation may be associated with impaired DFS in these patients. TRIAL REGISTRATION: The study was retrospectively registered the 28th July 2018 in ClinicalTrials.gov register with the reference NCT03601689.

Isolated splenic lymphangioma presenting as a huge mass causing anemia and abdominal distension in an adult patient: a case report.

BACKGROUND: Lymphangiomas are uncommon benign lesions of lymphatic vessels very rarely affecting the spleen. Isolated involvement of the spleen in adult patients is rarely reported. CASE PRESENTATION: We report a case of a 40-year-old Arabic woman who presented with a 25-cm abdominal mass, fatigue, and anemia evolving for 6 months. Her physical examination revealed anemic syndrome and an enormous splenomegaly extending beyond the umbilical area. An abdominal computed tomographic scan showed a 25-cm splenic mass with multiple hypodense nodules without enhancement after contrast injection. A surgical total splenectomy was performed. Histopathological analysis led to the diagnosis of cystic splenic lymphangioma. The patient's postoperative course was uneventful, and she was discharged from the hospital. CONCLUSIONS: Isolated splenic lymphangioma in adult patients is very rare. The preoperative diagnosis is challenging because imaging techniques are not specific. Pathological analysis of the resected specimen is the only effective way to render the definitive diagnosis. Splenic lymphangiomas have a benign course after complete surgical resection.

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.

Bilateral pheochromocytoma with ganglioneuroma component associated with multiple neuroendocrine neoplasia type 2A: a case report.

BACKGROUND: Composite pheochromocytoma/paragangliomas are very rare tumors composed of ordinary pheochromocytoma paragangliomas associated with neurogenic tumors. Several hereditary susceptibility disorders are known to be associated with pheochromocytoma/paragangliomas such as multiple endocrine neoplasia type 2 (2A or B). To the best of our knowledge, only four cases of composite pheochromocytoma/paragangliomas associated with multiple endocrine neoplasia type 2 have been reported. CASE PRESENTATION: A 40-year-old Arabic woman presented with headache, palpitations, paroxysmal hypertension, and weight loss, which she had had for the last 3 years. She had a familial history of diabetes and multiple endocrine neoplasia type 2. A radiological examination revealed thyroid lesions and bilateral adrenal medulla tumors. Our patient had undergone bilateral adrenalectomy, total thyroidectomy with cervical lymphadenectomy, and parathyroidectomy. A pathological examination confirmed the multiple endocrine neoplasia type 2A consisting of left medullary pheochromocytoma, right medullary composite pheochromocytoma-ganglioneuroma, medullary carcinoma of the thyroid with lymph node metastasis and parathyroid hyperplasia. A genetic analysis also revealed that our patient had a RET germline mutation. CONCLUSION: Composite pheochromocytoma/paraganglioma associated with multiple endocrine neoplasia type 2 is a very rare occurrence, as the current literature provides only a few cases. Further reported cases are needed in order to understand the behavior and the pathogenesis of this uncommon entity.