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.

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.

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.

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.

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.

[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.

A rare case report of a myxoid liposarcoma arising from the broad ligament.

Myxoid liposarcoma (MLPS) is the second most prevalent subtype of liposarcoma. It is usually found in the deep tissues of the lower limbs and rarely in gynecologic tract. Herein we present the second case in the English literature of a primary MLPS arising from the broad ligament which was thought to be a borderline ovarian tumor. The aim is to discuss its clinical and pathological characteristics. A 42-year-old woman presented with pelvic pain for the last 6 months. Magnetic resonance imaging was not specific. She underwent a surgical resection of the tumor mass, and pathological examination confirmed the diagnosis of MLPS deriving from the broad ligament. She received radiotherapy and the patient is doing well at 3 months follow-up. The clinical aspects, pathological diagnosis, prognosis, and therapy approach of broad ligament MLPS are all poorly understood. Complete surgical resection with or without radiotherapy is the mainstay of treatment in located MLPS.

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.

Mucinous borderline ovarian tumors: pathological and prognostic study at Salah Azaiez Institute.

Introduction: ovarian Mucinous Borderline Tumors (MBT) are characterized by an epithelial proliferation similar to those of well differentiated adenocarcinomas but are distinguished by the absence of stromal invasion. They are often difficult to diagnose histologically. The aim of the work was to specify the pathological and clinical features and to highlight the prognostic of these tumors. Methods: study was retrospective including 49 cases of primary ovarian MBT, diagnosed at the Patholgy Department of Salah Azaiez Institute from 1992 to 2019. Results: median age was 48 years old. Histologically, the cases were divided into 34 cases of pure MBT, 13 cases with intraepithelial carcinoma and 2 cases associating an intraepithelial carcinoma with microinvasion. The majority of our cases were classified FIGO I and only one case FIGO III. Sixteen patients received conservative treatment and 30 received radical treatment. The treatment wasn't specified in three patients. The prognosis was good in the majority of cases. Only one patient had a contralateral recurrence after a follow-up period of three years. There were no significant differences regarding the risk of recurrence and risk factors such as age, gestation, hormonal status, FIGO stage and conservative treatment. We raised this part. Conclusion: the prognosis of the ovarian MBT is good. However, it is necessary to multiply the samples to avoid missing a carcinomatous focus with an anarchic invasion of the stroma which constitutes a poor prognosis factor. It was changed by these sentences below: the diagnosis of MBT is not easy. Indeed, the distinction of MBT from carcinomas remains the greatest challenge for pathologists. Once this diagnosis is made with certainty, the tumor can be considered to have a good prognosis, especially stage I tumors which are the most common.

Kefir milk alleviates benzene-induced immunotoxicity and hematotoxicity in rats.

The adverse health effects of benzene occupational and circumstance pollution exposure are an increasing concern. It leads to damage to various human tissues including bone marrow and ovarian tissues and many vital physiological processes. Previous studies showed that kefir is a rich probiotic, having protective effect, thanks to its antioxidant, anti-inflammatory, and immunomodulatory capacity. The purpose of this study was to evaluate the potential efficacy of kefir to remediate benzene toxicity in rat. Thirty-two female rats were randomly allocated and administered orally with benzene and/or kefir during a period of 21 consecutive days. At the end of the experiment, hematological and bone marrow cell changes were estimated. The animals exposed to benzene exhibited anemia and a significant decrease in the levels of white blood cell. Moreover, benzene led to the activation of gene expression of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), a myelotoxicity in bone marrow cells. Our data showed that kefir treatment alleviated benzene-associated weight loss and increased the number of whole blood cells in peripheral blood and nucleated cells in the bone marrow. Furthermore, these physiological results were observed with animals showing high concentrations of lactic acid bacteria (LAB) determined from fecal samples, which are considered an indicator of kefir-associated microorganisms. Our study suggests that kefir is a potential nutritional supplement target to attenuate hematotoxicity induced by benzene.

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.

The Management of Desmoid Tumors: A Retrospective Study of 30 Cases.

OBJECTIVES: Desmoid tumor also called aggressive fibromatosis is a rare type of benign tumor. It is a mesenchymal malignancy without metastatic potential. The standard management is resection, but other options including observation may be discussed. Desmoid-type fibromatosis may occur throughout the body, but the abdominal wall is the most common site. The aim of our study was to assess the clinicoepidemiological profile, prognostic factors, and treatment outcome of desmoid tumors. METHODS: A monocentric retrospective study was conducted over a period of 19 years between February 2000 and November 2019 at the oncology department of Salah Azaïz Institute. Our study concerns 30 patients with desmoid tumor. All data regarding patients were obtained from the medical record. RESULTS: Thirty patients were included. The median age was 35 years with a female predominance (sex ratio = 0.07). A palpable mass was the most common complaint (n = 27). Median tumor size was 5 cm. The principal site of involvement was the abdominal wall (n = 14). Surgery was performed in 27 patients. The histopathology reports listed 14 (52%) cases with negative margins and 13 (48%) cases with positive margins. Radiation therapy was performed in 2 patients. One patient received tamoxifen. Local recurrence occurred in 11 patients. Two patients died of their desmoid tumor. Abdominal wall tumors have less risk of recurrence compared with other sites (p=0.047). Macroscopic margin involvement (R2) was the only prognostic factor influencing disease-free-survival (p=0.034). CONCLUSION: Desmoid tumors are aggressive tumors with a tendency for local recurrence. Abdominal wall tumors have less risk of recurrence. Macroscopic margin involvement was the only prognostic factor that affects disease-free-survival.

Expression analysis of immune-regulatory molecules HLA-G, HLA-E and IDO in endometrial cancer.

HLA-G has been widely implicated in advanced cancers through different pathways of immunosuppression allowing tumor escape. Contrarily, HLA-E has a controversial role in the tumor escape from the immune system. IDO catabolic enzyme is known to be up-regulated in many tumors types allowing their immune escape. Based on these considerations, we investigated the expression of HLA-G, HLA-E and IDO molecules in endometrial cancer (EC) and their association with prognostic clinicopathologic parameters. Their expression were checked in tumoral and adjacent endometrial tissues. Both HLA-G and IDO immunostaining were significantly increased in EC tissues compared to normal residual endometrial glands (Mann Whitney U-test, p = 0.0001 and p = 0,020 respectively). However, HLA-E was highly expressed in tumoral tissues as well as in normal residual endometrial glands (respectively, 100% and 81.8%). Increased HLA-G expression levels were observed in high histological grade (grade 3), and in the non-endometrioid type 2 EC. Unexpectedly, patients with IDO Low expression had significantly impaired overall survival compared to patients with IDO High (log-rank p = 0.021). Conversely, HLA-E low expression was associated to an improved overall survival EC (log-rank p = 0.004). We concluded that, HLA-G and IDO are highly expressed in EC compared to adjacent normal endometrial tissues, that might be interesting for the EC outcome.