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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.

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.

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 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. Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.

SummaryThe 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 can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ∼ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ∼1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.HighlightsThe projection of FTE subtypes refines the molecular classification of serous OCComprehensive single-cell profiling of FTE cells identifies 6 molecular subtypesSubstantial non-genetic heterogeneity of HGSOC identified in 1700 tumorsA mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis

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.

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.

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.

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.

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.

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.

This summer's orgy of sporting events has been eagerly awaited by youngsters and adults alike. Unlike the masses, however, I care for neither England nor any other team in Euro 2004. Watching men running around in shorts has always seemed like a waste of time to me. And for the patriots out there: aren't there more relevant reasons to be proud of your country? People are quick to blame trashy soaps for the rise of the couch potato, whereas watching football is seen to be the virtue of a true man. However, at 90 minutes a go (plus 30 minutes of halftime and postmatch arguing), a football match is three time as long …