Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms.

BACKGROUND: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically. METHODS: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case. RESULTS: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions. CONCLUSIONS: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.

Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer.

OBJECTIVES: This study describes the outcomes of patients with colorectal peritoneal carcinomatosis (PC) with or without liver metastases (LMs) after curative surgery combined with hyperthermic intraperitoneal chemotherapy, in order to assess prognostic factors. BACKGROUND: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) increases overall survival (OS) in patients with PC. The optimal treatment both for PC and for LMs within one surgical operation remains controversial. METHODS: Patients with PC who underwent CRS followed by HIPEC were evaluated from a prospective database. Overall survival and disease free survival (DFS) rates in patients with PC and with or without LMs were compared. Univariate and multivariate analyses were performed to evaluate predictive variables for survival. RESULTS: From 1999 to 2011, 22 patients with PC and synchronous LMs (PCLM group), were compared to 36 patients with PC alone (PC group). No significant difference was found between the two groups. The median OS were 36 months [range, 20-113] for the PCLM group and 25 months [14-82] for the PC group (p > 0.05) with 5-year OS rates of 38% and 40% respectively (p > 0.05). The median DFS were 9 months [9-20] and 11.8 months [6.5-23] respectively (p = 0.04). The grade III-IV morbidity and cytoreduction score (CCS) >0 (p < 0.05) were identified as independent factors for poor OS. Resections of LMs and CCS >0 impair significantly DFS. CONCLUSIONS: Synchronous complete CRS of PC and LMs from a colorectal origin plus HIPEC is a feasible therapeutic option. The improvement in OS is similar to that provided for patients with PC alone.

Pure mucinous carcinomas of the breast: prognostic study including DNA flow cytometry.

BACKGROUND: Prognostic factors for pure mucinous carcinomas of the breast are controversial; data on DNA ploidy and S-phase fraction (SPF) are lacking. We examined the relation of these parameters with histological features and patient survival. METHODS: DNA flow cytometry was performed on 69 fresh or frozen pure mucinous carcinomas samples. Results were interpreted according to patient survival. RESULTS: Tumor size exceeded 2 cm in 40.5% of cases. Lymph nodes were involved in 11.5% of cases and never when tumor size was less than 2 cm. Aneuploidy was only observed in one-quarter of the tumors. Very few tumors had a high-SPF or a high histological grade (7.2% of all cases). These two parameters were of prognostic value respectively for disease-free (P=0.035) and overall survival (0.050). Patients with tumors>2 cm had shorter overall survival than patients with tumors≤2 cm (P=0.028). Disease-free and overall survivals were not influenced by nodal status and hormone receptors (HRs) status. Patients with aneuploid tumors had shorter disease-free survival than patients with diploid tumors (P=0.031). The combination of tumor size and DNA ploidy was strongly predictive of survival (P<10(-3)): six patients with large aneuploid tumors had a poor outcome (1-year overall survival 16.7%). CONCLUSION: We identified a subset of patients with a poor prognosis, namely those with large aneuploid tumors. This study confirms the good prognosis of pure mucinous carcinomas, particularly when tumor is less than 2 cm (corresponding to cases without lymph nodes involvement), thus challenging the need for axillary nodal examination.

[Low-grade endometrial stromal sarcoma: contribution of hormone therapy and etoposide]. / Sarcome du chorion cytogène de bas grade. Mise au point sur l'intérêt de l'hormonothérapie et de l'étoposide à partir de 4 cas.

Endometrial stromal sarcoma is a rare malignant uterine tumor. We report 4 cases of low-grade endometrial stromal sarcoma, corresponding to the form with a mitotic index at less than 10 mitoses per 10 high power fields (HPF), from which we carried out a review of the literature and defined the potential interest of hormone therapy and chemotherapy by etoposide. Generally diagnosed in pre-menopause, the main clinical signs, which are not very specific, are metrorrhagia and pelvic pain. The etiologic diagnosis is established from the pathology analysis. Intravascular extension, which is observed in nearly 50% of patients, should evoke the disease. The initial treatment is mainly based open surgery, generally total hysterectomy with annexectomy. There is no effective adjuvant treatment. The potential of reccurences remains around 50% with a 34-month median. Several therapeutic options are possible after recurrence but no standard treatment has been established. We are mainly interested in three medical options but the surgery remains an alternative of choice. Chemotherapy by oral etoposide offers easy administration, good compliance and acceptable toxicity with median 20-month remission in 3 patients before progression. Hormone therapy with progestogens (hormone receptor expression of the tumor is 71% for estrogens and 95% for progesterone) is widely studied in the literature with a 46% response rate and 46% rate of disease stabilization. Hormone therapy with an anti-aromatase appears to be a promising treatment according to the bibliographic references on this subject. Overall, prognosis of low-grade endometrial sarcoma is relatively good with 100% survival at 5 years. The progression pattern is slow, requiring regular and prolonged surveillance.

[HER2 gene amplification assay: is CISH an alternative to FISH?]. / Recherche de l'amplification du gène HER2: la CISH est-elle une alternative à la technique FISH?

The HER2 proto-oncogene encodes a transmembrane protein, which is considered to function as a growth factor receptor. Overexpression of this protein found by immunohistochemistry in about 20% of infiltrating breast carcinomas, has a predictive value of response to treatment by trastuzumab, an anti-HER2 humanized monoclonal antibody. Search for HER2 gene amplification is necessary to adapt the immunohistochemical technique quality and also in the cases of delicate analysis or weak overexpression. It is usually carried out by Fluorescence In Situ Hybridization (FISH). A more recent hybridization technique, named CISH because of its chromogenic revelation is an alternative method, which gives highly correlated results with FISH. We present details of this technique, which may be more familiar for the pathologists than FISH, because reading analysis is similar to that of immunohistochemical staining.

Comparison of the Bard Trak test with voided urine cytology in the diagnosis and follow-up of bladder tumors.

OBJECTIVES: To compare the results of the BTA Trak test with voided urine cytology (VUC) in the diagnosis and follow-up of bladder tumors. PATIENTS AND METHODS: Urine samples were obtained from 53 patients with bladder tumor (77 samples) and 53 patients treated for bladder tumor with no evidence of disease on the basis of cystoscopic evaluation (88 samples). Urine samples were collected prior to cystoscopy. The BTA assay was performed by the BTA Trak test according to the manufacturer's recommendations. A value >14 U/ml was considered abnormal. RESULTS: There was a statistically significant increase in median BTA value with increasing stage of tumor: 11.9, 57.9 and 391.0 U/ml respectively for stages pTa, pT1 and pT2/3 (p<0.0001, Kruskal-Wallis test). There was also a correlation between increasing grade and median BTA values measured at 6.9, 13.1 and 235.0 U/ml in grades 1, 2 and 3 tumors respectively (p<0.0001, Kruskall-Wallis test). The overall sensitivity of the BTA Trak test was 58.4% compared to 46.7% for VUC, a difference of 11.7%, which was statistically significant (McNemar test, p<0.005). The sensitivity of both tests combined was 63.6%. The specificity of the VUC (94.3%) was significantly higher than that of the BTA Traktrade mark (75.0%) (p<0.005, McNemar test). The accuracy of the Bard Trak test (67.3%) was similar to that of VUC (66.9%). CONCLUSION: The BTA Trak test is more sensitive than urinary cytology in the detection of bladder tumors but the improvement involved is insufficient to consider decreasing the frequency of endoscopic examinations in the follow-up of superficial bladder tumor.

[Ovarian serous tumors of limited malignancy and invasive peritoneal implants. Review of the literature]. / Tumeurs séreuses de l'ovaire à malignité limitée et implants péritonéaux invasifs. Revue de la littérature.

The prognosis for patients with ovarian serous borderline tumors is generally considered to be excellent. It is worse for women with an advanced stage, especially when invasive peritoneal implants are present. There is no general agreement regarding standard treatment in such cases. To clarify the significance of this invasive peritoneal proliferation and to devise a rational treatment approach, we review the available series. From this review of literature, it appears necessary to emphasize the importance of an initial adequate peritoneal staging of all ovarian tumors. After a complete removal of the lesions, the question of adjuvant therapy must be discussed.

Inflammatory breast metastasis from primary ovarian cancer: case report.

A case of an inflammatory breast metastasis from ovarian carcinoma is reported. Recognition of this inflammatory lesion as being metastatic is useful in avoiding inadequate treatment.

Metastatic gastric cancer arising from breast carcinoma: endoscopic ultrasonographic aspects.

Linitis plastica of the stomach was diagnosed in four patients. Endoscopic ultrasonography (EUS) was performed in four cases; they were monitored by EUS and had their treatment adapted accordingly. According to the present study, the typical criteria of gastric linitis at EUS are: (a) rigidity of the gastric wall; (b) a wall thickness exceeding 6 mm; (c) a second enlarged layer marginally more echogenic than the fourth hypoechogenic layer (muscularis propria); (d) a third hyperechogenic enlarged layer; and (e) a poor demarcation between layers. Gastric linitis appears more likely to be specific metastasis from lobular breast carcinoma. In most of the follow-up cases, EUS showed correlation with a subsequent decrease of the CA15.3 level. At present, EUS seems to be the most effective and least invasive examination for clinical diagnosis and treatment surveillance of secondary gastric linitis arising from infiltrating lobular carcinoma (ILC) of the breast.

[Granulocytic sarcoma of the testis without hematological manifestations]. / Sarcome granulocytaire du testicule sans manifestation hématologique.

A 30-year-old man with a testicular tumor ressembling a "round cell sarcoma" was treated for rhabdomyosarcoma. Complete remission was achieved but the patient relapsed and died of the disease. A retrospective diagnosis of granulocytic sarcoma was established using an anti-myeloperoxidase antibody, unfortunately not available at the time of the initial diagnosis. No hematological disorders were observed during the course of the disease. Four cases of granulocytic sarcoma of the testis have been reported in the literature. All these cases where accompanied or followed by leukemia. The present case seems to be the first case of granulocytic sarcoma of the testis not accompanied by hematological disorders.

[Intra-nodal palisading leiomyoblastoma expression HMB 45]. / Léiomyoblastome palissadique intra-ganglionnaire exprimant HMB 45.

With a follow up of 14 years, a benign intra nodal palissading smooth muscle tumor is reported as an original lesion because of the expression of HMB 45. This antibody is now well known to be expressed by non melanocytic smooth muscle lesions, like angiomyolipoma, "sugar tumors" of the lung, pulmonary lymphangiomyomatosis and some others, often linked to tuberous sclerosis. The case reported seems to be a new member of the merging concept of "Perivascular Epithelioid Cells (PEC)".

Histological features of large bone allografts.

We performed biopsies during reoperation for minor complications in two active young patients 9 and 19 months after massive bone allograft implantation for bone tumour. The grafts were dead and resorption-apposition activity, when present, was predominantly in subperiosteal areas. Inflammatory infiltration was very seldom found. Features considered as 'microfractures' or 'microcracks' were noted in the cortical ring together with the formation of woven bone, in areas with remodelling. Such cracks are likely to be of mechanical origin and do not inevitably lead to complications.

[Granulomatous mastitis and corynebacteria infection. Two case reports]. / Mastites granulomateuses et corynébactéries. A propos de deux observations.

Diagnosis of granulomatous mastitis must be based on a multidisciplinary approach. First, it's necessary to eliminate carcinomatous mastitis. Usually, the diagnosis is unknown except for tuberculous and sarcoidosis granulomatous mastitis. On observations in two cases of Corynebacterium granulomatous mastitis, we discussed the diagnosis and therapeutic approach. When there is a clinical suspicion of granulomatous mastitis, surgical biopsy with immediate histological analysis and bacteriological culture of mammary tissue should be performed. This multidisiplinary approach should reduce the number of idiopathic granulomatous mastitis observed. Antibiotic treatment is required after biopsy or surgical excision of granuloma.

[Recommendations for the immunohistochemical evaluation of hormone receptors on paraffin sections of breast cancer. Study Group on Hormone Receptors using Immunohistochemistry FNCLCC/AFAQAP. National Federation of Centres to Combat Cancer/French Association for Quality Assurance in Pathology]. / Recommandations pour l'évaluation immunohistochimique des récepteurs hormonaux sur coupes en paraffine dans les carcinomes mammaires. Groupe d'Etude des Récepteurs Hormonaux par Immunohistochimie FNCLCC/AFAQAP. Fédération Nationale des Centres de Lutte Contre le Cancer Association Française d'Assuransce de Qualité en Pathologie.

These recommendations regard the immunohistochemical evaluation of estrogen and progesterone receptors in paraffin sections of breast cancers. All the components of the procedure are dealt with: fixation, antigen retrieval, antibodies, controls, analysis and interpretation of immunostaining, report and quality assurance parameters. The purpose of these guidelines is to serve as a basis for standardization of techniques and results and to improve quality control.