MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Salivary epithelial-myoepithelial carcinoma: clinical, morphological and molecular features.

Epithelial-myoepithelial carcinoma (EMC) is a rare biphasic tumor accounting for less than 2% of all salivary gland malignancies. It presents as a slowly growing, asymptomatic small size mass, with ulceration of overlying mucosa in some cases. Microscopically, it is characterized by glands lined by the simultaneous presence of two different cell components, inner epithelial cells and outer myoepithelial cells. Immunohistochemical staining of myoepithelial cells is variably positive for vimentin, Smooth Muscle Actin (SMA), Muscle Specific Actin (MSA), S100, Smooth Muscle Myosin Heavy Chain I(SM-MHC), calponin and p63. Several molecular alterations, mainly point mutations, have been described. Mutations of HRAS, AKT1, CTNNB1 and PIK3CA were highlighted in variable percentage of EMC samples. EMC is considered a low-grade malignant tumor with a 5-year survival rate of 94% that may commonly recur locally after resection in 30-50% of cases. At the moment, adequate resection with negative margins is the minimum recommended and necessary treatment.

Synchronous bilateral multifocal canalicular adenoma: a case report of an unusual finding.

Canalicular adenoma is a benign neoplasm of the minor salivary glands. The most common site is the upper lip, and the adenoma usually appears as a single lesion. Few cases of multiple foci of canalicular adenoma (CA) have been reported in literature. We report a case of a 78-year-old woman with CA of the nasolabial wrinkle on both sides of the nose, which occurred at the same time. The lesions recurred after about 1 year. This report adds to the literature another case of multiple, bilateral CA with synchronous occurrence.

Squamous metaplasia of the breast simulating a malignant neoplasm: a case.

Squamous metaplasia of the breast ductal epithelium is a well-documented lesion; however, it represents a very uncommon histopathologic finding. We present a case of primary florid squamous metaplasia of the mammary ducts closely simulating a breast carcinoma in a 67-year-old woman. Patient after ultrasound examination and mammography, was submitted to a fine-needle aspiration biopsy (FNAB) that was considered inconclusive, and, in order to suspicious clinic and mammographic findings, a frozen evaluation during the surgical excision was performed. Primary squamous cell metaplasia is rarely observed in the breast. This condition closely mimics a malignant lesion at US-scan, X-ray evaluation and even at FNAB. Frozen examination, in this case, is considered decisive, preserving the patient from an unnecessary aggressive surgical approach.

Extraskeletal chondroma of the masseter muscle: a case report with review of the literature.

The authors report a case of soft tissue chondroma of the masseter muscle in a 49-year-old man. The tumour was entirely composed of lobules of hyaline cartilage. The literature on head and neck soft tissue chondroma is also reviewed. To the authors' knowledge, this is the first case of muscular soft tissue chondroma in the head and neck region.

Huge primary retroperitoneal mucinous cystadenoma of borderline malignancy mimicking an ovarian mass: case report and review.

BACKGROUND: Primary retroperitoneal mucinous cystadenoma is a rare tumor only 48 cases have been reported in international literature. Patients affected by primary retroperitoneal mucinous cystadenoma/cystadenocarcinoma ranged in age from 17 to 86 years (median, 42.3 years) and the size of the cystis ranged from 5 to 35 cm (median, 16.1 cm). There is no unanimous opinion on the genesis of these tumors and, due to their extreme rarity, its histogenesis, biological behavior and the optimal management strategy remain at a speculative level. CASE REPORT: We report the case of a huge borderline primary retroperitoneal mucinous cystadenoma (24 x 25 cm) in a 35-year-old woman and the strategies adopted for the diagnosis and surgical management. CONCLUSION: Primary mucinous cystic tumor of the retroperitoneum was correctly diagnosed only at the time of surgery. As well as in the majority of cases reported in the literature, preoperative investigations were not able to give information about the tumor site. In spite of the short follow-up (two years), the patient's favorable course supports the hypothesis that primary retroperitoneal mucinous cystadenoma may be treated in the same manner as a primary ovarian tumor of the same grade and comparable stage.

A case of mesonephric adenocarcinoma of the vagina with a 1-year follow-up.

Mesonephric adenocarcinoma deriving from remnants of vaginal mesonephric ducts is one of the rarest tumors of the female genital tract with only three cases reported till date in international literature. Differential diagnosis from other aggressive tumors is complex and controversies exist in the literature regarding the biological behavior, prognosis, and optimal management strategies of these tumors. A 58-year-old woman presented with a large mass extending from the right adnexal region to the perineum and labia majora. CA125 was increased. A radical excision of the lesion with pelvic and para-aortic lymphadenectomy was performed. A well-capsulated mesonephric adenocarcinoma in a background of vaginal mesonephric remnants was diagnosed. Tumor cells showed immunoreactivity for pancytokeratin, cytokeratin (CK), CD 10, epithelial membrane antigen, vimentin, and calretinin; indeed they were negative for carcinoembryonic antigen, CK 20, estrogen receptor, and progesterone receptor. No evidence of lymph node involvement or metastatic disease was observed. The patient did not receive any adjuvant therapy and is alive and clinically free of disease at 1-year follow-up. In spite of the aggressive biological behavior attributed in literature to mesonephric carcinomas, which is probably due to the complex differential diagnosis with other müllerian tumors, the favorable course of our patient further supports the hypothesis that malignant mesonephric carcinomas may not behave aggressively and that radical surgery alone may be curative.

Primary signet-ring cell carcinoma of the uterine cervix with long term follow-up: case report.

BACKGROUND: The uterine cervix represents an exceptional localization of signet-ring cell adenocarcinoma (SRCA). Most commonly, endocervical tumors with such morphology are metastatic from the breast or gastrointestinal tract while primary pure or almost pure tumors are extremely rare. No previous case of primary pure endocervical SRCA with follow-up longer than three years has been found in the literature. CASE REPORT: The present report describes such a case of a 46-year-old woman without evidence of recurrence eight years after the diagnosis. The patient was referred to the Gynecology Department for persistent abnormal vaginal bleeding of three months duration. Specular examination and colposcopy revealed a cervical polypoid lesion occupying the posterior lip of the cervix and protruding from the external uterine orifice. A biopsy of the lesion was interpreted by the pathologist as SRCA. An extensive search for an extrapelvic primary cancer was undertaken but revealed no evidence of malignancy. The patient underwent radical hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraaortic lymph node sampling for FIGO Stage 1B1 cervical cancer without any adjuvant chemo- or radiotherapy. The histological diagnosis showed neoplastic signet-ring cells confined in the head of the cervical polyps with minimal stromal infiltration. After surgery the patient underwent close followup including periodic cervicovaginal smears, bimanual vaginal examination, complete laboratory tests, ultrasound and abdominopelvic computed tomography. CONCLUSIONS: The prognostic relevance of primitive pure SRCA in the uterine cervix is unclear because of the relatively small number of cases. However the two early deaths out of six reported cases and the absence of follow-up longer than three years for the other affected patients, seem to suggest an aggressive behavior. The present case represents an exceptional long-term survival, probably related to an early diagnosis and a prominent polypoid growth of the neoplasia outside the uterus.