Beyond germline genetic testing - heterozygous pathogenic variants in PMS2 in two children with osteosarcoma and ependymoma

Background Lynch syndrome (LS) is not considered part of childhood cancer predisposition syndromes. Case presentation Analysis of a pediatric osteosarcoma (OS) displayed hypermutation (16.8), alternative lengthening of telomeres (ALT), loss of PMS2 expression in tumor tissue (retained in non-neoplastic cells), PMS2 loss of heterozygosity (LOH), and high-degree of microsatellite instability (MSI) tested by PCR. A heterozygous duplication c.1076dup p.(Leu359Phefs*6) in exon 10 of NM_000535.6:PMS2 was detected by SNV analysis in peripheral blood, confirming diagnosis of LS in the patient. The tumor molecular features suggest LS-associated development of OS. In a second case, whole-genome sequencing identified a heterozygous SNV c.1 A > T p.? in exon 1 of PMS2 in tumor and germline material of a girl with ependymoma. Tumor analysis displayed evidence for ALT and low mutational burden (0.6), PMS2 expression was retained, MSI was low. Multiplex ligation-dependent probe amplification identified no additional PMS2 variant and germline MSI testing did not reveal increased gMSI ratios in the patient´s lymphocytes. Thus, CMMRD was most closely excluded and our data do not suggest that ependymoma was related to LS in the child. Conclusions Our data suggest that the LS cancer spectrum may include childhood cancer. The importance of LS in pediatric cancers necessitates prospective data collection. Comprehensive molecular workup of tumor samples is necessary to explore the causal role of germline genetic variants

Endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: long-term follow-up in a Western center

Background/Aims Endoscopic submucosal dissection (ESD) has been established as a treatment modality for superficial esophageal squamous cell carcinoma (ESCC). Long-term follow-up data are lacking in Western countries. The aim of this study was to analyze long-term survival in a Western center. Methods Patients undergoing ESD for ESCC were included. The analysis was performed retrospectively using a prospectively collected database. Results R0 resection rate was 96.7% (59/61 lesions in 58 patients). Twenty-seven patients (46.6%) fulfilled the curative resection criteria (M1/M2) (group A), 11 patients (19.0%) had M3 lesions without lymphovascular invasion (LVI) (group B), and 20 patients (34.5%) had lesions with submucosal invasion or LVI (group C). Additional treatment was recommended after non-curative resection. It was not performed in 20/31 patients (64.5%), mainly because of comorbidities (75%). Twenty-nine out of 58 (50.0%) patients died during a mean follow-up of 3.7 years. Death was related to ESCC in 17.2% (5/29) of patients. The disease-specific survival rate after curative resection was 100%. Overall survival rates after 5 years were 61.5%, 63.6% and 28.1% for groups A, B, and C, respectively. The overall survival was significantly worse after non-curative resection (p=0.038). Conclusions Non-curative resection is frequent after ESD for ESCC in Western patients. The long-term prognosis is limited and mainly determined by comorbidity. Early diagnosis and pre-interventional assessments need to be improved

All-Body-Cavity (ABC)-scopy: an approach for a feasible method of minimally invasive autopsy to allow for postmortem tissue sampling in cases where a conventional autopsy is denied

Objectives The decreasing autopsy numbers in many western countries have been partially attributed to the invasiveness of the autopsy, which causes relatives to decline postmortem examination. This issue has been addressed by developing methods of minimally or non-invasive autopsy, which could be shown to increase acceptance for autopsies. The aim of this study is to compare the All-Body-Cavity-scopy (ABC-scopy) to conventional autopsies for diagnostic accuracy. Methods The ABC-scopy is an endoscopic approach for minimally invasive autopsy involving laparoscopic and thoracoscopic evaluation of the accessible organs, followed by excision biopsies of relevant organs and conspicuous findings. The method was performed in 10 cases on deceased patients scheduled for autopsy, each followed by a conventional autopsy. Results The results gathered from ABC-scopy through observation and histopathological evaluation provided an acceptable diagnostic accuracy in 9 out of 10 autopsies when compared to those of the conventional autopsy for diagnostic findings. Conclusions The ABC-scopy is a feasible approach for minimally invasive autopsy that provides acceptable diagnostic value. Despite its minimally invasive nature, the procedure enables representative histology through providing large size excision biopsies from intraabdominal and thoracic organs, which is especially useful for examining disseminated diseases such as metastasized tumors

Granulomatous dermatitis: a rare pitfall in lymphoma staging with [18F]FDG-PET/CT

A 36-year-old male with anaplastic large T cell lymphoma (A; nodal manifestations in the left iliac and left inguinal region, arrow) who had received six cycles of chemotherapy (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) presented for restaging prior to autologous stem cell transplantation. A few days earlier, the patient had noticed multiple new tender subcutaneous nodules, and erythemato-squamous, polymorphous, partially atrophic plaques all over his body (B1). [18F]FDG-positron emission tomography/computed tomography (PET/CT) showed complete metabolic response of primary lymphoma manifestations but revealed intense tracer accumulation in the disseminated subcutaneous nodules (B, axial image B2). Besides cutaneous involvement by T cell lymphoma, differential diagnoses included cutaneous sarcoidosis and pityriasis rosea. Biopsy of a subcutaneous nodule revealed no evidence of malignancy but granulomatous inflammation (B3) most consistent with reactive granulomatous dermatitis. After initiation of prednisone therapy, all (sub-)cutaneous lesions quickly resolved, and the patient was eligible for stem cell transplantation. Follow-up [18F]FDG-PET/CT demonstrated only residual tracer uptake of some lesions and a sustained complete lymphoma response (C). Reactive granulomatous dermatitis is a very rare skin disease with only several hundred cases reported worldwide so far [1], most commonly associated with autoimmune disorders such as rheumatoid arthritis. Furthermore, it has been associated with hematologic malignancies, including — in approximately 3% of cases — (B cell) lymphoma [1,2,3]. To our knowledge, this is one of the very first cases of granulomatous dermatitis in anaplastic large T cell lymphoma [4], and the first visualization of granulomatous dermatitis by [18F]FDG-PET/CT mimicking cutaneous lymphoma manifestations

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT)

Background Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. Case Presentation A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. Conclusion This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable