Objectives: We conducted a retrospective review of patients with extrapulmonary small cell carcinomas (EPSCCs) to explore the distribution, treatments, patterns of relapse and outcomes by primary site. Setting: We have reviewed the outcomes of one of the largest data sets of consecutive patients with EPSCC identified from two major cancer centres. Participants: Consecutive patients with a histopathological diagnosis of EPSCC from the two institutions were retrospectively identified. Primary and secondary outcome measures: Outcomes were evaluated including stage at presentation, treatments given, sites of relapse, time to distant relapse, progression-free survival and overall survival (OS). Results: From a total 159 patients, 114 received first-line chemotherapy, 80.5% being platinum-based. Response rate was 48%. Commonest primary sites were genitourinary and gynaecological. 44% of patients presented with metastatic disease. 55.9% relapsed with liver the commonest site, whereas only 2.5% developed brain metastases. Median OS was 13.4 months for all patients, 7.6 months and 19.5 months for those with metastatic and non-metastatic disease, respectively. Gynaecological and head and neck patients had significantly better OS compared to gastrointestinal patients. Conclusions: EPSCCs demonstrate high response rates to chemotherapy and high rates of distant metastases. Primary sites may influence prognosis, and survival is optimal with a radical strategy. Brain metastases are rare and we therefore do not recommend prophylactic cranial irradiation.

IntroductionEpendymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion.MethodsPatient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing.ResultsBoth patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo.DiscussionOthers who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.

ABSTRACT A case of disseminated oral melanoma in a two year old female dog with unilateral protuberance of the eye bulb and progressive seizure is described. Imaging exams revealed increase of the submandibular, maxillary and cerebral regions, nodular pattern in lungs and increased ovarian dimensions. The cytology of the submandibular mass indicated a malignant epithelial proliferation, whereas the excisional biopsy indicated an amelanotic melanoma. At necropsy, a locally infiltrating gingival mass and white nodules in the lymph nodes, kidneys, lung, brain and ovaries were observed, indicative of metastases. Histopathological diagnosis consisted of an undifferentiated malignant metastatic neoplasm. Nucleus with coarse chromatin, prominent nucleoli, bizarre mitotic figures and multinucleated cells were the major malignant features. There was a poor melanocytic pigment differentiation in the peritrabecular space of facial bones, confirmed by Fontana-Masson and Giemsa histochemical techniques. Only a few cells were immunohistochemically positive for PNL-2 and Melan-A and the diagnosis of a disseminated amelanotic melanoma was performed. The diagnostic challenge was based on marked neoplastic undifferentiation, with multisystemic metastasis and mutual involvement of uncommon anatomic sites, associated with a large variability of cellular patterns, highlighting the decisive role of immunohistochemistry for diagnostic confirmation. Therefore, the clinical importance of this study is to warn the clinical and scientific community about the diagnostic challenge, considering the amelanotic melanoma as a differential even in cases of poorly apparent and/or nonpigmented oral lesions.