KRAS, NRAS and BRAF Mutational Profile of Colorectal Cancer in a Series of Moroccan Patients.

OBJECTIVES: The present study aimed to evaluate the frequencies of KRAS, NRAS, and BRAF mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC). METHODS: A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for KRAS/NRAS/BRAF mutations using Idylla™ technology and pyrosequencing. RESULTS: KRAS, NRAS, and BRAF mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. KRAS exon 2 mutations were identified in 87.9% of patients (102/116). KRAS G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with KRAS exon 2 wild-type (wt), 27.6% (32/116) harbored additional KRAS mutations. Concurrent KRAS mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the NRAS exon 2 wt patients, 64.3% (9/14) harbored additional NRAS mutations. Concurrent NRAS mutations were identified in 28.6% (4/14) of NRAS-mutant patients. Since 3.2% wt KRAS were identified with NRAS mutations, concomitant KRAS and NRAS mutations were identified in 2.4% (6/249) of patients. KRAS mutations were higher in the >50-year-old age-group (P = .031), and the tumor location was revealed to be significantly associated with KRAS mutations (P = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. NRAS mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%). CONCLUSION: Detection of KRAS mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare KRAS concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. KRAS testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.

Advanced Non-small Cell Lung Cancer: EGFR Mutation Analysis Using Pyrosequencing and the Fully Automated qPCR-Based IdyllaTM System.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status is of a major clinical significance in non-small cell lung cancer (NSCLC) management, as it guides therapeutic decision making to target patients for a better response to therapy. This implicates the introduction of EGFR mutation analysis as the standard of care for Moroccan NSCLC patients, which in itself entails the implementation of targeted methods for routine EGFR mutation analysis in our laboratories. In this study, we aimed to present 2 targeted methods for EGFR mutation identification and to determine the prevalence and spectrum of EGFR mutations in NSCLC Moroccan patients. METHODS: A retrospective investigation of a cohort of 340 patients was undertaken to analyze somatic EGFR mutations in exons 18 to 21 using pyrosequencing and the IdyllaTM system. RESULTS: Of the enrolled patients, 70.9% were males and 29.1% were females. Predominately, 92% of cases had adenocarcinoma, and 53.7% of patients self-reported a history of smoking. Overall, 73 patients (21.7%) harbored an EGFR mutation, the most prevalent of which were the exon 19 deletions (53.4%) followed by exon 21 substitutions (31%). Exon 18 mutations and exon 20 alterations occurred in 8.1% and 6.7% of the positive EGFR mutation cases, respectively. Of the analyzed cases, all of the EGFR-mutated patients had adenocarcinoma. EGFR mutation prevalence was significantly higher in females (females vs males: 38.4% vs 14.5%, P < .001) and non-smokers (non-smokers vs non-smokers: 36% vs 10.3%, P < .001). The featured pyrosequencing and the IdyllaTM system are targeted methods endowed with high sensitivity and specificity as well as other compelling characteristics which make them great options for routine EGFR mutation testing for advanced NSCLC patients. CONCLUSION: These findings underline the imperious need for implementing quick and efficient targeted methods for routine EGFR mutation testing among NSCLC patients, which is particularly useful in determining patients who are more likely to benefit from targeted therapy.

Frequency of anaplastic lymphoma kinase rearrangements in Moroccan patients with non small cell lung cancer: a multi-institutional national retrospective study.

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement is a predictive factor of response to ALK inhibitors in non small cell lung cancer (NSCLC). The prevalence of ALK rearrangements is well known in Whites and Asians. However, data identifying the frequency of this rearrangement in Moroccan and North African population are lacking. The objective of this study is to report the frequency of ALK rearrangement in a group of Moroccan patients with NSCLC. METHODS: A retrospective study was performed enrolling 120 Moroccan patients with NSCLC whose biopsy samples were tested for ALK rearrangement in order to identify the frequency of ALK rearrangement and its potential association with selected variables. The ALK testing was established using fluorescent in situ hybridization (FISH) or immunohistochemistry (IHC). RESULTS: The frequency of ALK rearrangement was 4.2% (5/120). All positive cases were males with advanced adenocarcinoma. ALK rearrangements prevalence was significantly higher in older patients. CONCLUSIONS: The frequency of ALK rearrangements among the Moroccan population tends to correlate with the average frequency reported worldwide, with some specific features. Further prospective studies with larger patients' numbers are needed to verify these findings.

Intestinal intussusception in a young women: unusual cause and specific management.

BACKGROUND: Intussusception in adults is a rare cause of abdominal pain that is often associated with organic pathology. We describe a case of ileocolic intussusception revealing a cecal adenocarcinoma in a young woman successfully managed by laparoscopic-assisted surgery adhering to oncological principles. CASE PRESENTATION: A 30-year-old woman with a family history of colon adenocarcinoma in a young brother presented to our emergency department with a 2-month history of intermittent colicky abdominal pain accompanied by nausea and vomiting. Physical examination showed a palpable mass in the right lower quadrant of the abdomen. Computed tomography showed a 3-layered structure giving the characteristic target-shaped appearance in the ascending colon, highly suggestive for an ileocolic intussusception associated with right colic parietal thickening and an adjacent lymphadenopathy. Patient was planned for laparoscopic exploration and eventually definitive surgery. Intra-operatively, we found an ileocolic intussusception with thickening of the colic wall and slight proximal intestinal dilation. Multiple lymphadenopathies along the ileocecal artery were observed. Laparoscopic right hemicolectomy was performed following strict oncologic principles with "en bloc resection" and lymphadenectomy given the risk of an underlying malignancy. Considering this risk, previous reduction of the invaginated segments was not attempted and primary extracorporeal anastomosis was performed using manual sutures. Macroscopic examination of the resected specimen revealed a tumor mass of the caecal wall .The histological analysis identified a moderately differentiated tubular adenocarcinoma invading the serosa (T3) without permeation of the lymphatic or venous capillaries. No lymphatic metastasis of 28 nodes removed was seen. Postoperative course was uneventful and patient was discharged 5 days after surgery. Postoperative chest, abdomen, and pelvis CT scan were normal. Therefore, tumor is classified as stage II A (T3N0 M0).There was loss of MLH2 and MSH6 protein expression on immunohistochemistry findings reflecting a microsatellite instability phenotype, and the patient was followed up without adjuvant chemotherapy. CONCLUSION: Ileocolic intussusception rarely revealed a cancer in young adults. Laparoscopic surgery has a special interest in the diagnosis and treatment in this pathology. Oncogenetic consultation should be required in malignant lesion.

Frequency and types of EGFR mutations in Moroccan patients with non-small cell lung cancer.

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small cell lung cancer (NSCLC), particularly in adenocarcinoma histology. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion reported in Asian populations than Caucasian populations. There is a lack of data on these mutations in north Africa. METHODS: Tumor specimens from Moroccan patients with NSCLC were collected from five pathology laboratories between November 2010 and December 2017 to determine frequency and types of EGFR mutations. Tumors were tested in a reference center for EGFR by polymerase chain reaction and sequencing of exons 18, 19, 20, and 21. RESULTS: A total of 334 patients were enrolled: 242 (72.5%) males and 92 females (27.5%). A total of 56.9% had a history of smoking. EGFR testing of the 334 lung adenocarcinoma samples demonstrated a wild-type EGFR in 261 (78.1%) and mutated EGFR in 73 (21.9%). Mutations were mainly detected in the exon 19 deletion (65.8%), followed by exon 21 L858 (17.8%) and other exon 21 codon mutations (5.5%) and exon 18 (6.8%), whereas primary mutations of exon 20 were less frequent (4.1%). In patients with advanced NSCLC, the detection of EGFR mutation was independently associated with sex (41.3% female vs 14.5% male; p < 0.001) and smoking status (34.8% nonsmokers vs 12.9% active smokers; p < 0.001). The mean age was significantly different between the two groups (p = 0.041). CONCLUSION: Our findings confirm the genetic heterogeneity of NSCLC worldwide, reporting frequency of EGFR mutations in Moroccan patients with NSCLC between those of Asian and Caucasian populations.

Epidemiologic profile of pediatric brain tumors in Morocco.

INTRODUCTION: Brain tumors are the most common solid tumors diagnosed among children below 15 years worldwide. However, little is known about the profile of pediatric brain tumors in Africa. The purpose of this study was to further elaborate the epidemiological profile of pediatric brain tumors in Africa, specifically Morocco. METHODS: A retrospective review was conducted of all patients with primary brain tumors in the age group 0-19 years, from 2003 to 2007, from multiple centers in two cities of Rabat and Casablanca, Morocco. Only patients with histopathological confirmation were included (n = 542). Descriptive epidemiologic profiles were created for the patients by age, sex, and histological subtypes of brain tumors. RESULTS: Overall medulloblastoma was the most common brain tumor (34.5%), followed by pilocytic astrocytoma (17.3%) and diffuse astrocytoma grade 2 (12.5%). Brain tumors occurred most commonly in 5-9-year age group followed by 10-14-year age group with the former being more common among males and the latter being more common among females. We also found medulloblastoma to be the most common brain tumor in the 0-14-year-olds. CONCLUSIONS: In this rare study focused on pediatric brain tumors in Morocco, most of the findings were consistent with past studies from other parts of the world. However, we found medulloblastoma to be the most common pediatric brain tumor followed by astrocytoma.

A rare case of locally advanced fibrosarcoma of diaphysal humerus managed successfully with limb-sparing procedures after neoadjuvant chemotherapy.

Fibrosarcomas (FS) of bone are a rare malignancy accounting for less than 5% of all primary malignant bone neoplasms. Diagnosis and treatment approaches of this entity are complex and require a skilled and experienced multidisciplinary team.Authors report their experience with a case of FS of humerus showing a pathologic complete response to neo-adjuvant chemotherapy based on adriamycin, cisplatin and ifosfamid. This approach allowed limb-sparing surgery with an excellent functional and psychological result.

The Frequency and Specific Features of Rare Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma whose Tumors harbor positive EGFR mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are a heterogeneous group of genetic alterations mainly identified in lung adenocarcinoma (AC). They occur in exon 18 to 20 of the EGFR gene. Common EGFR mutations are deletions in exon 19 and substitutions in exon 21, while mutations in exon 18 and exon 20 are rare. Their response to tyrosine kinase inhibitors (TKI) is different, common EGFR mutations are more sensitive to TKI with better response rate and survival, whereas rare EGFR mutations are TKI resistant with poor prognosis and clinical outcomes. The objective of the present study was to report the frequency and characteristics of rare EGFR mutations in a group of Moroccan patients with lung AC harboring a positive EGFR mutation. PATIENTS AND METHODS: All cases of Moroccan patients with lung AC harboring mutated EGFR were collected from 334 EGFR test requested. Common EGFR mutations were defined as deletions in exon 19 and substitutions in exon 21 while mutation in exons 18 and 20 were qualified as rare EGFR mutations. Patients' characteristics were reported and compared between the two groups of common and rare EGFR mutations. RESULTS: EGFR mutations were positive in 73/334 of all requested tests. Common EGFR mutations accounted 89% (65/73). Rare EGFR mutations were present in 8 cases (11%). Rare EGFR mutations were composed of 62.5% exon 18 mutations (5/8) and 37.5% exon 20 mutation (3/8). The frequency of regular smokers in patients with tumors expressing rare EGFR mutations was significantly higher than that found in patients with tumors having common EGFR mutations (p=0.013). DISCUSSION: The frequency found in the present study was consistent with the literature data. However, we found that rare EGFR mutations occurred mostly in exon 18 rather than exon 20, findings that are discordant with the available literature. Thus, we could suggest that Moroccan patients with rare EGFR mutations would benefit more from TKI treatment. CONCLUSION: Rare EGFR mutations are a heterogeneous subset of genetic alterations in lung AC. Their study deserves a real relevant interest. Some one tenth of lung AC tumors in Moroccan patients harbor a rare EGFR mutation. Further prospective studies are needed, in larger numbers of patients, to assess their specific characteristics and outcomes.

Leiomyosarcoma of the thyroid gland.

The existence of primary thyroid sarcomas represents a contentious issue. Some authors believe that thyroid sarcomas are, in fact, anaplastic carcinomas with sarcomatous (spindle cell) features. From the standpoint of treatment and prognosis, the histogenesis of thyroid 'sarcomas' is academic, because these tumors, irrespective of the therapeutic intervention, are lethal 1. Primary thyroid leiomyosarcomas are extremely rare. Only nine isolated cases have been reported in the literature and such tumors carry a very poor prognosis [1-7] .

[Kikuchi-Fujimoto disease: about a case]. / Maladie de Kikuchi-Fujimoto: à propos d'un cas.

Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare cause of benign cervical adenopathies. It is an anatomoclinic entity of unknown cause. Diagnosis is based on histologic examination of the lymph nodes. Patient's evolution is generally favorable with spontaneous healing after a few weeks. We here report the case of a 9-year old girl presenting with cervical lymphadenopathy associated with fever. Cervical lymph node biopsy showed Kikuchi-Fujimoto disease. Patient's evolution was marked by regression of adenopathies without receiving any treatment.

Sebaceous carcinoma of the parotid gland: a case report and review of the literature.

BACKGROUND: Sebaceous carcinoma is a rare malignancy primarily with aggressive growth affecting the cutaneous tissues of the periocular region. Sebaceous carcinoma of the parotid gland is exceedingly rare, with only 32 cases reported in the literature. Our case brings this total to 33. CASE PRESENTATION: We present a case of a 57-year-old Moroccan woman with a firm, painless, slowly enlarging swelling at her left parotid area, with normal overlying skin and no palpable neck nodes. Parotidectomy with facial nerve preservation was performed, and microscopic examination showed sebaceous carcinoma. Then, she underwent adjuvant radiotherapy. With a follow up of 20 months, head and neck computed tomography revealed no recurrence. CONCLUSIONS: The optimal treatment is unclear. With more cases reported, clinicopathological characteristics and histogenesis are increasingly understood. Therefore the treatment for this rare tumor continues to evolve.

[Advances in the diagnosis and management of gastrointestinal tumours: 5 cases]. / Nouvelles acquisitions diagnostiques et thérapeutiques sur les tumeurs stromales digestives: à propos de cinq cas.

INTRODUCTION: Gastrointestinal stromal tumours (GIST) are the most frequent mesenchymatous tumours of the digestive tract. Options for diagnosis and treatment have developed rapidly in recent years. The authors report five cases of GIST. CASES: The study concerns 5 patients: 3 men and 2 women, with a mean age at diagnosis of 39.8 years. We describe the circumstances of discovery and the clinical and morphological characteristics of these tumours. They were located in the oesophagus (1 case), stomach (2 cases), small intestine (1 case) and mesentery (1 case). Tumour size ranged from 4-20 cm. Liver metastasis was identified at initial diagnosis for one patient. Immunohistochemical analysis identified expression of CD34, CD117 and S-100 proteins in all cases and smooth muscle actin in 2 cases. All the patients underwent surgical resection for GIST, and one received chemotherapy. No patient received imatinib treatment. After a mean follow-up of 40 months: one patient presented peritoneal carcinosis at one year, and 3 patients liver metastasis at 2 years; one of the latter died. DISCUSSION: The cases reported here are original by the rarity of their localization (especially the oesophagus and the mesentery). Diagnosis and treatment options for patients are described in a discussion of the recent advances in the field. CONCLUSION: GIST are the most frequently mesenchymatous tumours of the digestive tract. They must be recognized, especially in view of their frequency. Optimal management today involves complete tumour resection and imatinib.

Primary hepatoid carcinoma of the ovary: a case report.

Primary hepatoid carcinoma of the ovary (HCO) is a very rare type of high-grade invasive malignant ovarian tumor with hepatic differentiation and production of α-fetoprotein (AFP). We describe a 78-year-old Moroccan woman who presented to our hospital with abdominal distension and purplish nodules infiltrating the para umbilical skin with weight loss and impairment of her performance status. Excisional biopsy of the para umbilical nodule revealed a cutaneous localization of moderately differentiated adenocarcinoma and pelvic ultrasonography noted the presence of a tumoral right adnexal mass. The patient underwent an exploratory laparoscopy which found peritoneal carcinomatosis with pelvic adhesions allowing only a peritoneal biopsy. Diagnosis of primary hepatoid carcinoma of the ovary was established on the basis of classic histopathologic findings, immunohistochemical staining and marked elevation in serum of α-fetoprotein more than the carbohydrate antigen 125. The patient received 3 cycles of chemotherapy based on Carboplatin and Paclitaxel with disease progression. No second line chemotherapy was given because of the drop of patient's performance status to 3. The patient died one month later.

Rapidly fatal Askin's tumor: a case report and literature review.

An 18-year-old male presented with a mass in the right anterior chest wall. Chest Computed tomography revealed a heterogenous mass of 19X13 cm in the right hemithorax with areas of necrosis. There was associated pleural effusion and infiltration of the soft parts of the chest wall. Bronchoscopy showed a tumor in middle lobe bronchus. CT guided biopsy of the mass was performed. Histological examination showed small round tumor cells with scanty cytoplasm, the nuclei are large and hyperchromatic. The tumor cells were positive for CD99 and neuron specific enolase, negative for cytokeratin, leukocyte common antigen and myogenin. Based on these histologic and immunohistochemical findings, the diagnosis of askin's tumor was made. The extension assessment was negative and the patient was given chemotherapy. Two months later, our patient died. Askin's tumor is a rare, highly malignant tumor affecting children and young adults. It is classified as primitive neuroectodermal tumor of the thoracopulmonary region. Prognosis remains poor. In our case, several prognostic factors may explain the shirt 'term survival, despite no distant metastasis were found: important tumor size, impossibility of surgical treatment and pleural effusion.

Tracheobronchopathia osteochondroplastica associated with skin cancer: a case report and review of the literature.

BACKGROUND: Tracheobronchopathia osteochondroplastica (TO) is a rare disorder of unknown cause affecting the large airways. It is characterized by the accumulation of bony and cartilaginous nodules in the tracheal and bronchial mucosa. Approximately 300 cases of tracheobronchopathia osteochondroplastica have been reported since Wilks first identified it in 1857. Tomography and computed tomography scanning (CT) can be suggestive but final verification requires biopsy. Neoplastic disorders are, among others, blamed in etiology. We describe here, for the first time, a case of TO associated with skin cancer. CASE PRESENTATION: A 40-year-old man with a scalp cancer was admitted for further evaluation of an occasional dry cough. Her medical history was otherwise unremarkable, and physical examination showed no abnormalities.The chest CT scan demonstrated multiple nodular densities in the trachea and proximal bronchi. The fiberoptic bronchoscopy showed multiple nodules in the trachea suggesting a malignant infiltration.Microscopic examination of the biopsy material revealed fragments of normal cartilage and bone formation with normal mucosa which confirmed the diagnosis of TO.Patient underwent surgery for scalp cancer. For TO, case has followed up. At twelve-month follow up, scalp tumor did not recur and cough ceased. CONCLUSION: TO is a rare, benign disease that should be kept in mind especially in patients with tracheal irregularities in their chest imaging. Association with malignant tumors is reported.In patients with malignancy, TO can easily be misdiagnosed if it is not known as a diagnosis possibility of malignant invasion of the trachea. Therefore, it is important to be aware of this possibility, in order to prevent unnecessary treatments to patients.

Frequency and Spectrum of KRAS Mutations in Moroccan Patients with Lung Adenocarcinoma.

Background. In lung adenocarcinoma, the frequency of KRAS mutations is ethnicity dependent with a higher proportion in African Americans and white Caucasians than in Asians. The prevalence of these mutations among North Africans patients is unknown. The objective of this study was to report the frequency and spectrum of KRAS mutations in a group of Moroccan lung adenocarcinoma patients. Methods. Tumor specimens from 117 Moroccan patients with lung adenocarcinoma were selected to determine frequency and spectrum of KRAS mutations. KRAS mutations in codons 12 and 13 of exon 2 were analyzed using conventional DNA sequencing. Results. The overall frequency of the KRAS mutations was 9% (11/117). In the population with KRAS mutations, there was a trend towards more male (P = 0.06) and more smokers (P = 0.08) compared to patients with wild type KRAS. KRAS mutations were located at codon 12 in 10 out of 11 patients (91%). The G12C mutation was the most frequent KRAS mutation (73%). Conclusion. This is the first study to date examining the frequency and spectrum of KRAS mutations in lung adenocarcinomas in North African and Arab populations. KRAS mutation frequency in Moroccan patients was comparable with the frequency observed in East-Asian population. KRAS mutations are more likely observed in males and smokers and to be transversions. Further studies, in larger numbers of patients, are needed to confirm these findings.

Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict response to tyrosine kinase inhibitors. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites. The prevalence of these mutations among North African patients is unknown. The objective of this study was to report the frequency and spectrum of EGFR mutations in a group of Moroccan patients with lung adenocarcinoma (AC). METHODS: Tumor specimens from 137 Moroccan patients with lung AC were selected to determine frequency and spectrum of EGFR mutations. Mutation detection techniques were polymerase chain reaction amplification and sequencing of exons 18, 19, 20, and 21. RESULTS: The overall frequency of the EGFR mutation was 21%. Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). EGFR mutation rate was significantly higher in women and in never smokers. CONCLUSION: Some one fifth of lung AC tumors in Moroccan patients harbor EGFR mutations. This mutation frequency is higher than that found in whites but lower than in Asian population. Further studies, in larger numbers of patients, are needed to confirm these findings.

Coexistence of Hodgkin's Lymphoma and Castleman's Disease: A Case Report with Successful Response to Chemotherapy and Radiotherapy.

Background. Castleman's disease is a rare clinicopathological entity of unknown origin. Coexistence of Hodgkin's lymphoma and Castleman's disease is rare. We report a case of Hodgkin's disease of cervical lymph nodes in a patient previously diagnosed with Castleman's disease. Case Presentation. A 43-year-old man admitted in July 2009 for a right cervical pain with lymph node at the physician examination. He underwent a right adenectomy and histological studies showed typical features of Castleman's disease. Three years after, the patient consulted for increasing the volume of cervical lymph node. Clinical examination showed a right cervical lymph node of 3 cm. The computed tomography scan of chest, abdominal and pelvic was normal. Histological and immunohistochemical studies of cervical lymph node biopsy specimen were in favor of Castleman's disease associated with Hodgkin's disease. Reed-Sternberg cells were positive for CD15 and CD30. The patient received chemotherapy based on anthracyclines, bleomycin, vinblastine, and dacarbazine (ABVD) and radiotherapy with complete response. Conclusion. Prevalence of Hodgkin's lymphoma in Castleman's disease is more difficult to establish because of the low number of cases reported in the literature.