Adenoid Cystic Carcinoma of the Vulva and Vagina: A Clinicopathologic, Immunohistochemical, and Molecular Characterization of Five Cases.

Adenoid cystic carcinoma (ACC) is a rare neoplasm most frequently observed in the salivary glands, that can occur in other organs, including the vulva and vagina. Oncogenic mechanisms involving MYB, NFIB , and MYB-NFIB rearrangements have been described, but evidence in the vulva and vagina remains scarce. Our aim is to report the clinicopathologic features, immunohistochemical, and molecular findings in a series of vulvar and vaginal ACCs. Five cases were included. Medical records and slides were reviewed. Formalin-fixed paraffin-embedded material was available in 4 cases, where additional immunohistochemical and molecular studies were carried out. Fluorescence in situ hybridization using MYB, MYBL1 , and NFIB bacterial artificial chromosome-clones break-apart and MYB::NFIB BAC-clones fusion probes was performed. The patients' mean age at diagnosis was 52 years. Tumor size ranged from 0.5 to 5 cm. Microscopic examination revealed tubular, cribriform, and solid patterns. Perineural invasion was seen in 4 cases. Patients were treated with surgery, some with adjuvant radiation therapy. During follow-up (mean: 11 yr), 4 patients developed local recurrences. Recently, one of these patients developed pulmonary disease. Cam 5.2, CK5/6, CD117, and DOG-1 were positive in all 4 cases and S100 and calponin were positive in 3 cases. MYB rearrangement was present in 3 cases, including one with concurrent MYB amplification. There were no MYBL1 or NFIB rearrangements and no MYB :: NFIB fusions. Our findings corroborate that the histologic, immunohistochemical, and oncogenic background is similar between ACCs of the lower female genital tract and ACCs elsewhere, although the canonical MYB::NFIB fusion seems to be a less common finding in this location.

Molecular characteristics of low-grade serous carcinoma in effusions.

OBJECTIVE: The molecular characteristics of low-grade serous carcinoma (LGSC) in serous effusions have not been studied previously. The present study analysed the molecular profile of LGSC at this anatomical site. METHODS: Specimens consisted of a series of 17 serous effusions (15 peritoneal, 2 pleural) from 16 patients, of which 15 were LGSC and 2 serous borderline tumour (SBT) who later progressed to LGSC. For comparative purposes, 9 surgical specimens from 6 patients with LGSC were analysed. Fresh-frozen cell pellets and surgical specimens underwent targeted next-generation sequencing covering 50 unique genes. RESULTS: Mutations were found in tumours from 14 of the 22 patients, of whom 4 had 2 different mutations and 10 had a single mutation. Overall, the most common mutations were in KRAS (n = 3) and BRAF (n = 3), followed by NRAS (n = 2), CDK2NA (n = 2), TP53 (n = 2), ATM (n = 2). Mutations in MET, STK11, ERBB2 and FLT3 were found in one case each. Patient-matched specimens had the same molecular profile. Both effusions with TP53 mutation had concomitant ATM mutation, and both stained immunohistochemically with a wild-type pattern. The absence of mutations was associated with a trend for shorter overall survival in univariate analysis (p = 0.072). CONCLUSIONS: The molecular alterations in LGSCs in serous effusions are consistent with those found in solid tumours, with frequent alterations in the mitogen-activated protein kinase pathway. Mutations in LGSC may be a marker of better outcomes.

Parathyroid carcinoma: Single centre experience.

OBJECTIVE: Parathyroid Carcinoma is a rare malignant neoplasm, accounting for less than 1% of primary hyperparathyroidism cases. Parathyroid carcinomas are characterized by markedly elevated levels of PTH, severe hypercalcemia and established target organ damage. The authors report the experience of a single centre regarding the management and outcome of patients with parathyroid carcinomas and revise relevant literature. DESIGN: Retrospective review of all patients with parathyroid carcinoma evaluated at a tertiary oncologic centre from 1991 until 2021. RESULTS: Seventeen patients were identified (10 males), with a mean age at diagnosis of 53 ± 16 years and a median follow-up of 16.5 years. Most patients presented with hypercalcemia (n = 15), with a mean serum calcium concentration of 13.5 mg/dl (9.6-16.5) and mean PTH of 1173 pg/ml (276-2500). Hyperparathyroidism-mediated organ damage was observed in most patients (n = 16), with predominant renal (n = 12) and skeletal (n = 9) complications. En bloc surgical resection was performed in nine patients. Three patients underwent adjuvant radiotherapy. Recurrence was observed in 8 cases (47.1%) after a median of 24 months following surgery and no independent predictors of recurrence were identified. The overall survival and disease specific survival at 5-year was 88% and 94%, respectively. CDC73 mutations were present in 38.5% of analysed patients and one patient was diagnosed with MEN1. CONCLUSION: Parathyroid carcinoma is associated with a significant rate of recurrence and limited effective treatment beyond initial complete surgical resection. Therefore, preoperatively high index of suspicion is paramount to optimize patient care. This is, to our knowledge, the largest Portuguese cohort published so far.

Claudin-10 is a new candidate prognostic marker in metastatic high-grade serous carcinoma.

The objective of this study was to analyze the expression and prognostic role of the tight junction protein claudin-10 in high-grade serous carcinoma (HGSC). Claudin-10 protein expression by immunohistochemistry was analyzed in 588 HGSC (414 effusions, 174 surgical specimens). Expression in mesotheliomas (n = 97; 47 effusions, 50 surgical specimens) was studied for comparative purposes. CLDN10 mRNA expression by quantitative RT-PCR (qRT-PCR) was analyzed in 40 HGSC effusions. Claudin-10 protein expression was found in 360/588 (61%) HGSC vs. 19/97 (20%) mesotheliomas (p < 0.001), and was higher in HGSC surgical specimens compared to effusions (p < 0.001). qRT-PCR confirmed the presence of CLDN10 mRNA in HGSC effusions. High (> 25%) claudin-10 expression in HGSC effusions was significantly associated with shorter overall survival (OS; p = 0.036) and progression-free survival (PFS; p = 0.045) in univariate analysis, and was an independent prognosticator of OS in multivariate analysis (p = 0.045). In conclusion, claudin-10 protein expression is higher in HGSC compared to mesothelioma, although the diagnostic power of this marker appear to be lesser than other claudin family members. Claudin-10 expression in HGSC effusions is marker of more aggressive disease.

UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease.

Background: Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Methods: Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Results: Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Conclusions: Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

Unusual Extensive Physiologic Pigmentation of the Tongue: A Case Report.

The deposition of colored endogenous or exogenous substances in the tissues of the tongue may result in pigmented lesions of the lingual mucosa. The accurate identification of the underlying condition can be difficult to achieve and relies mainly on patient history and clinical and histological evaluation. We present the case of a 30-year-old male referred to our hospital with a chief complaint of extensive pigmentation of the lingual dorsum. A diagnosis of physiologic pigmentation based on clinical and histological findings was made. Since some life-threatening diseases may present solely as pigmented lesions of the tongue, an early diagnosis is of utmost importance.

Osteosarcoma of the anterior maxilla mimicking a periapical pathology: A case report.

Osteosarcomas of the jaws (OSJ) are difficult to diagnose, rare malignant lesions, with uncharacteristic radiographic and clinical presentation. Early diagnosis and treatment are essential to improve long-term prognosis. The current report presents a rare case of a primary conventional osteoblastic osteosarcoma of the anterior maxilla in a 25-year-old female. She presented to a private dental clinic after developing pain, facial oedema and palpation tenderness of a mass associated with the upper right lateral incisor. The signs and symptoms mimicked very closely a regular radiolucent and symptomatic periapical pathology, and the definitive diagnosis was only possible through a combination of clinical, radiographic and histopathological findings. The patient was referred to an oncology facility, where she was submitted to radical excision surgery through a hemi-maxillectomy. Although other pathologies are uncommon, the differential diagnosis of lesions compatible with odontogenic periapical pathology should not be neglected.