Concurrent NRAS-BRAF variants in metastatic colorectal cancer: a Tunisian case report.

Target therapy for metastatic colorectal cancer needs the determination of KRAS, NRAS, and BRAF mutation status to identify patients resistant to anti-EGFR treatment. RAS genes (KRAS/NRAS) are mutated in 40-60% of metastatic colorectal cancer and BRAF in 5-10%. The presence of a double mutation in RAS and BRAF is rare. Therefore, RAS and BRAF mutations were considered exclusive. Herein, we describe a novel concomitant NRAS/BRAF mutation identified in a series of 865 colorectal cancer patients.

[Sex cord tumors with annular tubules: About 4 cases and literature review]. / Les tumeurs des cordons sexuels à tubules annelés : à propos de 4 cas et revue de la littérature.

Sex cord tumor with annular tubules (SCTAT) is a rare ovarian tumor. It belongs to sex cord and stromal tumor of the ovary and represents less than 1% of cases. It includes two forms: the first one associated with Peuz-Jeghers syndrome and the second sporadic. We report 4 cases of SCTAT collected at the department of pathology of Salah Azaiez Institute of Tunis over the 12 last years. The age ranged from 10 to 32 years. Symptoms were non specific except for one case revealed by precocious puberty. One patient had Peutz-Jeghers syndrome associated. Tumors were unilateral. Gross findings showed often a solid tumor with yellow cut surface. Their size ranged from 0.5cm to 28cm. Their morphological features were characteristic. Immunohistochemistry showed that tumor cells expressed inhibin and claretinin. The treatment was surgical, often conservative. The diagnosis of malignancy wasn't focused on histological features, but on tumor extension, clinical course, and presence of metastases. Evolution was often favorable. We also performed a systematic review of the literature that identified 166 cases. Features of these cases were studied. We also compared these features between sporadic and syndromic forms and between benign and malignant forms. In conclusion, SCTAT is a rare tumor, usually benign. Its diagnosis is based on histological examination. There is a malignant potential especially in sporadic forms, estimated at 20%. Treatment is most often conservative, based on oophorectomy.

Cyclin D1: potential utility as marker for Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disorder of unknown etiopathogenesis. Diagnosis is based on the identification of CD1a positive histiocytic infiltrate. Activation of the mitogen-activated-protein-kinase (MAPK) is constantly observed in LCH and therefore downstream markers such as cyclin D1 may be a useful marker for LCH. The aim of this study was to investigate the expression of cyclin D1 in LCH. We assessed the immunohistochemical expression of cyclin D1 (clone SP4-R) in series of 16 cases of confirmed LCH. Expression of Cyclin D1 was scored as weak, moderate, and strong nuclear staining and results were interpreted by two pathologists. The percentage of positivity was assessed. The mean age of patients was 13.7 years old with a male to female ratio of 1:3. The most common involved site was bone (n = 9; 56,3%), followed by lymph node (n = 5; 31,2%) and skin (n = 2; 12,5%). All cases showed nuclear staining for cyclin D1 with variable intensity. It was assessed moderate in 43,8% (n = 7) and strong in 56,2% (n = 9). The percentage of positive cells was >50% in 13 cases and <50% in 3 cases. Our results have shown that all cases of Langerhans cell histiocytosis from various sites express cyclin D1. This finding may be attributed to MAPK pathway activation that has been described in LCH. Otherwise, cyclin D1 is not significantly expressed in reactive Langerhans cell proliferations. Therefore, cyclin D1 immunohistochemistry may be useful as a diagnostic marker and in excluding non-neoplastic mimics of LCH.

[Sclerosing rhabdomyosarcoma of the parotid gland: Unusual location of a rare mesenchymal tumor]. / Rhabdomyosarcome sclérosant de la parotide : localisation inhabituelle d'une tumeur mésenchymateuse rare.

Rhabdomyosarcoma is a malignant mesenchymal tumour with skeletal muscle differentiation. Its sclerosing variant is a rare entity, which is described in the latest WHO edition of soft tissues in association with the spindle cell subtype, with which it shares clinical, morphological and cytogenetic features. Cytogenetic advances have allowed a prognostic approach to fusiform/sclerosing cell rhabdomyosarcoma by individualizing 3 different genomic prognostic groups. The parotid location of sclerosing rhabdomyosarcoma is exceptional with only two reported cases in the literature. It can pose a diagnostic challenge because of its rarity and histological similarities with other malignancies. We report the third case of sclerosing rhabdomyosarcoma of the parotid gland, which occurred in a 7-year old girl, who had consulted for a painless swelling of the parotid region of 4 months duration. Gross examination of the partial parotidectomy demonstrated an ill-circumscribed 35×30mm, firm and white glistening tumor. Histologically, it was composed of cords and trabeculae of small round cells, with ovoid and often irregular nuclei. Mitoses were numerous. The cytoplasm was scanty and cell margins were unclear. Tumor cells were set in a prominent hyalinized matrix. Scattered rhabdomyoblastic-like tumor cells were noted. The diagnosis of sclerosing rhabdomyosarcoma was performed after the positive immunostaining with desmin, myogenin and smooth muscle actin. No cytogenetic or molecular studies were performed. The patient underwent adjuvant chemo and radiotherapy, without recurrences or distant metastases during the 8-year follow-up.

[Endometrial carcinoma: An histopathological and histoprognotic study about 62 patients in a center in the Tunisian north]. / Les carcinomes de l'endomètre : étude anatomopathologique et histopronostique à propos de 62 cas dans un centre du Nord tunisien.

Endometrial cancer is the most prevalent genital tract cancer in occident and the third most common cancer among women in Tunisia. It is dominated by carcinoma. The identification of prognostic factors allows a better understanding of its outcome and guides its therapeutic approach. We propose to describe the clinicopathological features and identify the histoprognostic factors of this cancer. It is a retrospective analysis of a series of 62 total hysterectomy specimens with bilateral salpingo-oophorectomy from women with primary carcinoma of the endometrium, colligated in Anatomy Laboratory and Pathology Salah Azaiz Institute of Tunis over a period of 5 years, from January 2003 to December 2007. The median age was 60 years. At the time of diagnosis, 25% of patients were nulliparous and 86% were menopaused. The endometrioid adenocarcinoma was the most common, accounting for 84% of cases (5% of them were grade 3). A myometrial invasion superior or equal to 50% was observed in 40% of cases. 42% of cases were classified as stage IA, 14% in stage IB, 16% in stage II, 18% stage III and 10% in stage IV. 22% of patients had nodal involvement. Overall survival at 5 years was 81%. In multivariate analysis, stage IV, nodal involvement and brachytherapy have influenced this rate. Event-free survival at 5 years was 71%. It was directly related to stage and nodal involvement. Stage, histological type, tumor grade, invasion of more than half of the myometrium and lymph node involvement were the most important adverse prognostic factors, dictating an appropriate management of these tumors.

Analysis of prognostic factors of nephroblastoma in a Tunisian cohort.

BACKGROUND: Nephroblastoma is the most common childhood abdominal malignancy. Many studies allowed a better understanding of prognostic factors and they permitted to adapt treatment according to a risk stratification approach. AIM: To assess the most significant factors influencing the survival of patients presenting nephroblastoma. METHODS: We conducted a retrospective study over a 10-year period between 2001 and 2010 including 42 nephrectomy specimens, assessed in the pathology department of Salah Azaiz Institute, from all children diagnosed with nephroblastoma. The tumors were subdivided into histological subtypes and histological risk groups according to the SIOP-2001 classification. Statistical analyses were performed using the Kaplan-Meir and the Cox regression methods. RESULTS: The median age was 38 months. The mixed type was the most common (40% of cases). The tumors were subdivided into intermediate histological risk group (81%) and high risk group (14%). The tumors were classified as stage I (38%), stage II (24%), stage III (9%), stage IV (17%) and stage V (12%). The four-year survival rate was 83% and the event free survival rate was 85%. Age, laterality, histological risk group, tumor volume, blastema volume, stage, capsular rupture and incomplete resection had a significant impact on survival. Predictive factors of relapse were: laterality, tumor volume, blastema volume, histological risk group, stage, capsular rupture and incomplete resection. CONCLUSION: Histological type and stage were identified as the most important prognostic factors in nephroblastoma. Further large studies are needed to establish the impact of absolute blastemal volume.

VISTA/CTLA4/PD1 coexpression on tumor cells confers a favorable immune microenvironment and better prognosis in high-grade serous ovarian carcinoma.

Introduction: Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer. Methods: In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed. Results and discussion: CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA+/CTLA4+/PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+/CTLA4+/PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p<0.001; respectively). VISTA+/CTLA4+/PD1+ in TCs and CD4+/CD8+TILswere associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells.

Ovarian ALK+ diffuse large B-cell lymphoma: a case report and a review of the literature.

Through this case presentation and a review of the literature, we aim to describe clinical and pathologic features and to distinguish the outcome of these tumors. A 25-year-old woman presented with pelvic pain and an iliac mass. Workup revealed a 53-mm cystic partitioned mass of the left ovary infiltrating the left sacrum. She underwent a left adnexectomy. Gross examination revealed a ruptured ovarian mass. When dissected, it showed grayish cerebroid aspects. Histologic examination revealed a malignant tumor proliferation of the diffuse large cells. An immunohistochemical analysis showed negative results for PLAP, αFP, ßHCG, CD117, CK20, and CD30. It also showed lack of B markers and T marker (CD3) and an expression of CD138 and anaplastic lymphoma kinase. The patient was treated by 6 cycles of CHOP chemotherapy and a pelvic radiotherapy. She presented with a 15-cm splenomegaly 26 months later and died of febrile neutropenia. Most patients follow an aggressive disease and are unlikely to respond to the standard.

Unusual presentation of uterine tumors resembling ovarian sex cord tumor: A rare case report of cervical involvement.

INTRODUCTION AND IMPORTANCE: Cervical localization of uterine tumor resembling an ovarian sex cord tumor is very rare (UTROSCT) and this is the third case reported in the English literature. Given its rarity, the diagnosis is frequently challenging. Our aim was to discuss pathological characteristics and treatment choices of this rare disease happening in a rare location. CASE PRESENTATION: Our case interested a 19-year-old female patient who presented with a lower abdominal pain and irregular menstrual cycles for a duration of two months. Gynecological examination revealed a cervical firm mass. The patient underwent a cervical lumpectomy. Microscopically, the tumor had nested and trabecular/cord patterns. Tumor cells had abundant cytoplasm, ovoid and spindle-shaped nuclei with fine chromatin. Mitoses were < 1/10 HPFs. A delicate vascular network of small capillaries was noted. Immunohistochemical staining showed that tumor cells were positive for Calretinin, AE1/AE3, Desmin, progesteron receptors, SMA and h-caldesmon. Pathological examination concluded to an UTROSCT. CLINICAL DISCUSSION: UTROSC is a rare tumor with only two cases with cervical involvement reported so far. They have an indolent clinical history and thus require a more cautious and less invasive therapeutic decision. The diagnosis remains on the pathological examination. CONCLUSION: This case is original by its location and the age of presentation. Careful follow-up is necessary searching for local recurrence or metastasis.

An incidental discovery of a gastric follicular dendritic cell sarcoma: A rare case report and a literature review.

Introduction: Follicular dendritic cell sarcomas (FDCS) are rare tumours, typically seen in lymph nodes. However, in about one third of the reported cases, a FDCS presents as an extranodal mass. Involvement of the gastrointestinal tract is rare, and the stomach is even rarer with only four cases described to date. The aim of this study was to review clinical characteristics, pathologic features, emphasize on differential diagnosis and discuss therapeutic modalities and prognosis of this rare entity.Case presentation: We report on a 36-year-old female patient with no past medical history, an incidentally discovered FDCS located in the stomach with the presence of lymph node metastasis at the time of diagnosis. The diagnosis of a FDCS was made on morphological and immunohistochemical findings where tumor cells expressed CD21 and CD23. The tumor was resected by gastrectomy with extended para-aortic lymphadenectomy, with uneventful postoperative course.Conclusions: Due to its rarity, FDCS is rarely included in the differential diagnosis of gastrointestinal spindle cell tumors. Complete surgical resection is the current gold standard of treatment.

Unexpected finding: Papillary thyroid carcinoma arising in a mature ovarian teratoma - A case report and literature review.

INTRODUCTION AND IMPORTANCE: Malignant transformation within mature cystic teratomas is a rare occurrence, with an estimated risk ranging from 0.17 % to 2 %. Squamous cell carcinoma is the most common malignancy associated with this condition, while papillary thyroid carcinoma rarely presents within ovarian teratomas. This transformation predominantly affects postmenopausal women but can, albeit rarely, manifest in younger women. CASE PRESENTATION: We present a case of a 37-year-old woman who was incidentally found to have a right ovarian cyst measuring 20 × 20 × 10 mm during a cesarean section, displaying characteristic features of a teratoma. Histological examination confirmed the presence of papillary thyroid carcinoma originating within the ovarian mature cystic teratoma. Immunohistochemical analysis demonstrated positive staining for specific thyroid differentiation markers, including TTF1 and Thyroglobulin. The patient was in good health otherwise, with normal clinical and radiological evaluations of the thyroid, and no additional treatment was administered. Currently, seven years after surgery, the patient remains free of recurrence. DISCUSSION/CONCLUSION: Given the rarity of this condition, established treatment protocols are lacking, and its histogenesis remains uncertain. To advance our understanding of pathogenesis, prognosis, and therapeutic strategies for this malignant transformation, the publication of additional cases with similar presentations would be highly valuable.

The enigmatic ear: Unveiling a rare case of a primary cutaneous CD8+ acral T-cell lymphoproliferative disorder with a literature review.

Introduction: Primary cutaneous CD8+ acral T-cell lymphoproliferative disorder (CD8+ ATCLPD) is a rare form of cutaneous T-cell lymphoma that commonly presents on the acral regions of the body. We report a case of a 61-year-old man diagnosed with primary cutaneous CD8+ ATCLPD of the ear. Case presentation: A 61-year-old man presented with a non-healing, erythematous painful macule on the ear that had been evolving for the past 3 months. The lesion was resected, and histopathological examination revealed a primary cutaneous CD8+ ATCLPD with acral localization. Further investigations including CT scan of the thorax, abdomen and pelvis were done to stage the disease. The results showed no extracutaneous involvement. Conclusion: Accurate identification of primary cutaneous CD8+ ATCLPD is crucial due to its distinct prognostic and therapeutic implications compared to other CD8+ cytotoxic lymphoid proliferations. Primary cutaneous CD8+ ATCLPD can be treated conservatively and typically follows a slow clinical course, regardless of the treatment method. Understanding the clinical context, as well as the morphological and immunophenotypic characteristics, can assist in making a precise diagnosis.

VISTA+/CD8+ status correlates with favorable prognosis in Epithelial ovarian cancer.

Immunotherapy by blocking immune checkpoint regulators has emerged as a new targeted therapy for some cancers. Among them V-domain Ig suppressor of Tcell activation (VISTA) which is identified as a novel checkpoint regulator in ovarian cancer. This study aimed to investigate the VISTA role in Epithelial ovarian cancer (EOC), and its relationship with tumor-infiltrating lymphocytes (TILs) markers and its prognostic value. The expression of VISTA, CD3, CD8, CD4, FOXP3, and CD56 was assessed in 168 EOC tissue microarrays (TMA) by immunohistochemistry (IHC). In addition, associations between VISTA, TILs, clinicopathological variables, and overall survival (OS) were analyzed. VISTA expression in IGRov1 cells, as well as in PBMC of EOC patient, was evaluated by western blot. VISTA expression was detected in 64,28% of tissues, among which 42.3% were positive for tumor cells (TCs), and 47,9% were positive for immune cells (ICs). In univariate analysis, VISTA expression was significantly associated with a high density of TILs:CD3+ (p = 0,001), CD4+ (p = 0,002) and CD8+ (p≤0,001), in ICs but not in TCs. In terms of OS, multivariate analysis showed a significant association between the high density of CD8+ TILs and VISTA positive staining in ICs (p = 0,044), but not in TCs (p = 0,108). Kaplan-Meier curves demonstrated no correlation between VISTA expression and prolonged OS in both ICs (p = 0,841) and TCs (p = 0,090). Classification of EOC tumor microenvironment based on VISTA and CD8+TILs expression, demonstrated four immune subtypes: VISTA+/CD8+, VISTA+/CD8-, VISTA-/CD8+ and VISTA-/CD8-. The dual positive VISTA+/CD8+ subtype was significantly associated with prolonged OS in both TCs and ICs (p = 0,012 and p≤0,01, respectively), whereas patients with VISTA+/CD8- had the worst OS. Our results showed that VISTA is highly expressed in the IGRov1 cell line and LT-CD8 from a patient with EOC. Our results highlighted the association of VISTA expression and CD8+ TILs in EOC, with prolonged OS in patients with VISTA+/CD8+ and proposed VISTA as a potential immunotherapeutic target in EOC.

Low-grade fibromyxoid sarcoma of the vulva presenting as a cystic mass: A case report and review of literature.

INTRODUCTION: Low-grade fibromyxoid sarcoma (LGFMS) is a tumor with a propensity for late recurrence which is rarely described in the vulva. CASE PRESENTATION: A 22-year-old woman presented with a growing right vulvar cystic mass that had been present for 2 months. She underwent surgical wide excision. The final pathologic diagnosis revealed LGFMS of the vulva and a right radical hemivulvectomy with negative margins was performed. RESULTS: The patient has not experienced a local or metastatic recurrence after 2-years follow- up. CONCLUSIONS: Despite being rare, LGFMS of the vulva should be taken into account when making a diagnosis of vulvar lesions. Definite diagnosis is based on pathological examination. MUC4 positivity is characteristically expressed. To prevent future recurrences, radical excision is necessary.

Pseudomyogenic hemangioendothelioma: A misleading vascular tumor.

INTRODUCTION: Pseudomyogenic hemangioendothelioma (PHE) is a rare vascular soft tissue tumor of intermediate malignancy. The aim of this study was to present a rare case of PHE in the back and to review its clinicopathological features, therapeutic modalities, evolutionary aspects and prognosis. CASE PRESENTATION: We report the case of a 21-year-old man who consulted for a multinodular mass at the scapula level, that increased in size within 2 months. An excisional surgery was performed. Macroscopic examination showed ulcerated centimetric nodules with a crusty surface. Microscopic examination showed a multinodular proliferation arranged in clusters, made of spindle cells or epithelioid cells with variable atypia. Immunohistochemical study showed the expression ofAE1-AE3, ERG and INI-1. There was no staining for EMA, CD34, and CD-31. The diagnosis of PHE was retained. DISCUSSION: PHE affects young adult males and usually develops in the extremities. Clinically, more than half of the patients present with local recurrence. Distant metastases have also been reported. Microscopically, PHE resembles a myoid tumor or epithelioid sarcoma because of the abundant eosinophilic cytoplasm and cell shape. Tumor cells express cytokeratin and inconsistently CD34 and CD31. Hence the need to complete the study of ERG and INI1 expression in all soft tissue epithelioid tumors. The translocation t(7;19)(q22; q13) as well as the expression of FOSB in immunohistochemistry allow to differentiate with epithelioid sarcoma. Surgery is the treatment option. CONCLUSION: PHE is a confusing entity with several mesenchymal neoplasms that must be carefully differentiated. Data regarding age, sex, location, course, and recurrence are important for proper diagnosis.