Rare Mullerian adenosarcoma of the uterine cervix arising on a background of endometriosis: A diagnostic challenge with risk of malignant transformation-A case report and review of the current literature.

Endometriosis may contribute to Mullerian adenosarcoma development but makes diagnosis challenging given similar symptoms. Survival benefit has not been definitively shown for chemotherapy, hormonal therapy, or radiotherapy, consolidating surgery as the mainstay treatment. Local excision may be a treatment option for patients with confined tumors wishing to preserve their fertility.

Mixed Endometrial Epithelial Carcinoma: Epidemiology, Treatment and Survival Rates-A 10-Year Retrospective Cohort Study from a Single Institution.

Mixed endometrial carcinoma (MEEC) refers to rare endometrial tumours that are composed of two or more distinct histotypes, at least one of which is serous or clear cell. The aim of this study was to evaluate the epidemiology, treatment outcomes and survival rates of patients with mixed endometrial carcinoma. The medical records of 34 patients diagnosed with MEEC between March 2010 and January 2020 were reviewed retrospectively. Clinicopathological variables and treatment strategies were assessed, and overall survival and disease-free survival rates were evaluated. The histology of endometrioid and serous component was found in 26 (76.5%) patients, followed by serous and clear-cell components (5/34, 14.5%) and mixed endometrioid serous and clear-cell components (3/34, 8.8%). The median age at diagnosis was 70 years (range 52-84), and the median follow-up time was 55 months. The 5-year disease-free survival and the 5-year overall survival were 50.4% and 52.4%, respectively. Advanced disease stage was identified as an independent predictor of inferior disease-free (<0.003) and overall survival (p < 0.001). Except for stage, none of the traditional prognostic factors was associated with disease recurrence or death from disease. MEECs represent rare high-risk endometrial carcinomas with significant diagnostic and treatment challenges. Undoubtedly, the implementation of a molecular analysis can offer further diagnostic and management insights.

The Prognostic Characteristics and Recurrence Patterns of High Grade Endometrioid Endometrial Cancer: A Large Retrospective Analysis of a Tertiary Center.

High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95-223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29-183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement.

Challenges in management of Bartholin gland leiomyoma: A case report.

Leiomyomas are uncommon vulvar neoplasms often misdiagnosed as other Bartholin gland pathology. This case report describes a case of accelerating growth of a vulvar mass, initially diagnosed as Bartholin cyst. Surgical excision led to a histopathologic diagnosis of vulvar leiomyoma. The postoperative recovery was complicated by secondary hematoma and dehiscence of the surgical site. There was no recurrence at 2 years follow-up.

Bartholin's gland carcinoma-the diagnostic and management challenges of a rare malignancy-a case report and review of current literature.

Background: Bartholin's gland carcinoma (BGC) accounts for approximately 5% of all vulval malignancies-making it an extremely rare malignancy of the female genital tract. It commonly manifests as a painless unilateral mass, near the introitus. BGC more commonly occurs in post-menopausal women. Unfortunately, over half of cases are associated with a missed or delayed diagnosis as it is often mistaken for a Bartholin's gland cyst or abscess. These tumours have a predilection for local and perineural invasion. Magnetic resonance imaging (MRI) is the imaging modality of choice for suspected Bartholin's tumour. Although no current guidance dedicated to the management of BGC exists, the majority of cases are treated by primary excision and bilateral groin node dissection (GND). Chemoradiotherapy has a role in both the adjuvant and palliative setting. BGC are typically associated with more advanced disease at presentation, higher rates of recurrence and poorer prognosis than other vulval cancer sub-types. Case Description: We share a case report of primary BGC-supported by high-quality radiological and surgical images; and further supplemented by a detailed review of current literature. Conclusions: We aim to generate improved clinician awareness of this rare pathology, highlighting the need for vigilance to avoid misdiagnosis and subsequent treatment delay; as well as contribute towards generating consensus on the approach to management of this gynaecological malignancy.

Perivascular epithelioid cell tumour and investigation of genetic susceptibility.

A patient in her 60s was referred to be investigated for an incidental large uterus with a history of renal cell carcinoma and melanoma. Uterine biopsy revealed features of perivascular epithelioid cell tumours (PEComas) and she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Final histology confirmed PEComa with malignant features. Genomic studies did not reveal any deleterious germline variants; however, in view of her history, she is now under a 6-month follow-up with gynaecology-oncology. PEComas are rare tumours associated with tuberous sclerosis and melanoma, sharing genetic abnormalities. Gynaecological PEComas usually present with no or non-specific symptoms. Preoperative investigations are often misleading. Final histology and immunohistochemistry have overlapping features with smooth muscle tumours. Although rare, PEComas need to be treated aggressively to minimise the potential risk of spread. There is currently little evidence about further adjuvant treatment and no clear follow-up protocol. However, the literature suggests that the prognosis is generally good.

Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells.

Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.

The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers.

PURPOSE: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. EXPERIMENTAL DESIGN: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. RESULTS: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition-high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. CONCLUSIONS: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

Histomolecular features of high-grade endometrial cancers.

High-grade endometrial cancers (ECs) are an aggressive subset of ECs accounting for 70-80% of EC-related deaths. Currently, staging surgery, together with chemotherapy or radiotherapy, is the primary treatment strategy for these cancers. The widespread use of next-generation sequencing has led to a refined understanding of EC's genomics with important information for diagnosis and therapy for individual patients (precision medicine). However, advances in the genomics assessment of high-grade tumors have been slower due to their lower incidence than low-grade EC. This article will briefly introduce the current state of knowledge of the genomics of G3 endometrioid EC, serous uterine cancer, clear cell uterine carcinoma and uterine carcinosarcoma and discuss its implications for diagnosis and targeted therapy.

The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.

Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project.

PURPOSE: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. METHODS: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. RESULTS: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). CONCLUSION: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.

Yolk sac tumours of the female genital tract in older adults derive commonly from somatic epithelial neoplasms: somatically derived yolk sac tumours.

AIMS: To report 18 yolk sac tumours (YSTs) of the female genital tract (17 ovary, one uterus) in patients aged 40 years or over, most arising from a somatic epithelial neoplasm. METHODS AND RESULTS: Six patients had pure YST, two were associated with immature teratoma (one with an endometrioid adenocarcinoma) and in 11 there was an epithelial neoplasm comprising high-grade serous carcinoma (HGSC) (n = 5), clear cell carcinoma (n = 1), borderline clear cell adenofibroma (n = 1), endometrioid adenocarcinoma (n = 2), serous tubal intra-epithelial carcinoma (n = 1) and large-cell neuroendocrine carcinoma (n = 1). In one case of pure YST, there was an ipsilateral endometriotic cyst but no other neoplastic component. In two cases, the YST was a hepatoid variant and in most of the others it exhibited predominantly glandular morphology, closely mimicking an epithelial neoplasm. CONCLUSIONS: Pathologists should be aware of the association between YST and an epithelial neoplasm, the former probably arising from the latter through a process of neometaplasia/retrodifferentiation. Those rare gynaecological pure glandular YSTs in adults may arise secondary to total overgrowth of an epithelial neoplasm. Pathologists need a high index of suspicion to diagnose the YST component, as the morphology is characteristically of a glandular variant with marked morphological overlap with adenocarcinomas. There is also often significant immunophenotypical overlap with epithelial neoplasms, as the YST component may be positive with epithelial membrane antigen (EMA), BerEP4 and cytokeratin 7 (CK7), as well as YST markers. We propose the term 'somatically derived YSTs' for these neoplasms and suggest unification of the terminology between different sites where such neoplasms occur.

Primary Endometrial Yolk Sac Tumor With Endodermal-Intestinal Differentiation Masquerading as Metastatic Colorectal Adenocarcinoma.

Yolk sac tumors (YSTs) with a somatic glandular pattern can be difficult to recognize histologically because they reproduce developing intestinal, hepatic, or lung tissue and can express markers such as CDX2 and TTF1. We report an unusual case of a primary endometrial YST showing florid endodermal-intestinal differentiation in a 63-yr-old woman with a history of colorectal adenocarcinoma. Histologically, the tumor exhibited a glandular and papillary architecture and showed widespread immunoreactivity for CDX2 and focal staining for CK20 and CEA, mimicking metastatic colorectal carcinoma on biopsy. The presence of subnuclear cytoplasmic clearing and positive staining for germ cell markers, however, pointed toward a diagnosis of primary endometrial YST, and this was supported by the radiologic and the subsequent pathologic finding of a primary endometrial-based lesion. YSTs in this age group usually arise in association with somatic tumors and in this case a small focus of coexistent endometrioid adenocarcinoma was identified within the uterus. Despite surgery and adjuvant chemotherapy, the patient showed disease progression with liver and lung metastases 6 mo postoperatively.

Isocitrate dehydrogenase 1 mutations (IDH1) and p16/CDKN2A copy number change in conventional chondrosarcomas.

To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75% of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours.

Concurrent necrotising otitis externa and adenocarcinoma of the temporal bone: a diagnostic challenge.

We present a case of an 81-year-old man who was diagnosed with a necrotising (malignant) otitis externa (NOE). Initial biopsies from the external auditory canal showed scanty squamous epithelium but no evidence of malignancy. Despite an initial improvement on intravenous antibiotics and subsequent discharge from hospital, the patient returned with worsening otalgia. Following readmission to the hospital, intravenous antibiotics were restarted. Despite this, the patient developed a lower motor neurone palsy of cranial nerve VII on the ipsilateral side of the pain. He was taken to the theatre for an exploration of the left mastoid with further biopsies. Adenocarcinoma was diagnosed histologically and the patient was started on palliative radiotherapy. This case adds to the known literature on metastatic disease in the temporal bone and highlights the need to exclude malignancy in cases of NOE.

Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.

Ollier disease and Maffucci syndrome are characterized by multiple central cartilaginous tumors that are accompanied by soft tissue hemangiomas in Maffucci syndrome. We show that in 37 of 40 individuals with these syndromes, at least one tumor has a mutation in isocitrate dehydrogenase 1 (IDH1) or in IDH2, 65% of which result in a R132C substitution in the protein. In 18 of 19 individuals with more than one tumor analyzed, all tumors from a given individual shared the same IDH1 mutation affecting Arg132. In 2 of 12 subjects, a low level of mutated DNA was identified in non-neoplastic tissue. The levels of the metabolite 2HG were measured in a series of central cartilaginous and vascular tumors, including samples from syndromic and nonsyndromic subjects, and these levels correlated strongly with the presence of IDH1 mutations. The findings are compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in individuals with these syndromes.

Epithelioid hemangioma of the penis: case report and review of literature.

INTRODUCTION: Epithelioid hemangioma is a rare vascular tumor found in the penis. It is essential to avoid misdiagnosis with Peyronie's disease and penile cancer, as management differs significantly. CASE PRESENTATION: We present a case of epithelioid hemangioma of the penis in a 50-year-old Caucasian man. We also review the literature to evaluate the incidence of benign vascular anomalies of the penis and their management. CONCLUSIONS: Epithelioid hemangioma of the penis should be considered in the differential diagnosis of patients presenting with painful penile lumps. A thorough histological and immunohistochemical examination is required to make the diagnosis. Optimal management is complete local excision and periodic physical examination for local recurrence.