Endoscopic Submucosal Dissection for Early Esophageal Adenocarcinoma: Low Rates of Metastases in Mucosal Cancers with Poor Differentiation.

BACKGROUND AND AIMS: Endoscopic resection (ER) is accepted as standard treatment for intramucosal esophageal adenocarcinoma (EAC) with well or moderate differentiation. Poor differentiation (PD) is judged as a risk factor for lymph node metastasis (LNM) and surgery is recommended. However, the evidence for this recommendation is weak. Study aim was to analyze the clinical course of patients after ER of EAC with PD. PATIENTS AND METHODS: Patients undergoing endoscopic submucosal dissection for EAC were included from 16 German centers. Inclusion criteria were PD in the resection specimen, R0 resection and endoscopic follow-up. Primary outcome was the metastasis rate during follow-up. Analysis was performed retrospectively in a prospectively collected database. RESULTS: 25 patients with PD as single risk factor (group A) and 15 patients with PD and additional risk factors (submucosal invasion and/or lymphovascular invasion) were included. The metastasis rate was was 1/25 (4.0%; 95%CI 0.4-17.2) in group A and 3/15 (20.0%; 95%CI 6.0-44.4%) in group B, respectively (p=0.293). The rate of EAC-associated deaths was 1/25 (4%; 95%CI 0.4-17.2%) versus 3/15 (20%; 95%CI 6.0-44.4%) in group B (p=0.293) while the overall death rate was 7/25 (28.0%; 95%CI 13.5-47.3%) versus 3/15 (20%; 95%CI 6.0-44.4%) (p=0.715). Median follow-up was 30 months (IQR 15-53). CONCLUSIONS: During long-term follow-up the risk of metastasis is low after ER of mucosal EAC with PD as single risk factor. A conservative approach seems justified in this small patient group. However, the treatment strategy has to be determined on an individualized basis until further prospective data are available.

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.

High viral loads: what drives fatal cases of COVID-19 in vaccinees? - an autopsy study.

The rate of SARS-CoV-2 infections in vaccinees has become a relevant serious issue. This study aimed to determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types for deceased individuals with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Twenty-nine consecutively collected cases were analyzed and compared to 141 nonvaccinated control cases. Autopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within organ systems in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively; P = 0.008) mainly with Ct-values of higher than 25 in non-respiratory samples. However, vaccinated cases also showed high viral loads, reaching Ct-values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors, such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. The virus dissemination observed in our case study may indicate that patients with an impaired immune system have a decreased ability to eliminate the virus. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies. Fatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions.

[18F]fluorodeoxyglucose-positron emission tomography and glucose-transporter type 1 expression in untreated primary small bowel adenocarcinoma.

BACKGROUND: Literature reporting [18F]fluorodexoyglucose positron emission tomography (FDG-PET) of small bowel adenocarcinoma, a rare tumor, is sparse. To assess FDG uptake in small bowel adenocarcinoma, we retrospectively analyzed a large, single-center database and determined the expression of glucose-transporter type 1 (GLUT-1). METHODS: Screening of PET datasets in the database (N.=28,961 scans) for untreated histologically-confirmed primary small bowel adenocarcinoma revealed evaluable PET datasets for eight patients. Maximum and peak standardized uptake values (SUVmax and SUVpeak, respectively) were calculated via volume-of-interest (VOI) analysis. Additionally, GLUT-1 expression on tumor specimens was prospectively immunohistochemically assessed. RESULTS: All primary tumors showed high FDG uptake: mean SUVmax was 9.5±2.6 (range: 5.0-13.0) and SUVpeak, 8.1±2.3 (range: 3.9-10.7). Corresponding biopsy specimens (N.=7) demonstrated high GLUT-1 expression. CONCLUSIONS: Primary small bowel adenocarcinomas have a high GLUT-1 expression. Tumor lesions consistently demonstrated high FDG uptake pre-treatment, suggesting FDG-PET utility in staging and follow-up of these tumors.

Immunoglobulin G4 (IgG4)-related disease of the stomach - a challenging differential diagnosis in suspected gastric cancer.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) can involve different organs and is diagnosed by a combination of clinicopathological features, including storiform fibrosclerosis infiltrated by numerous IgG4-positive plasma cells that frequently forms tumor-like lesions with or without associated obliterative phlebitis. Involvement of the stomach is rare and can occur as part of a multiorgan involvement of IgG4-RD or as isolated gastric involvement. CASE REPORT: We report 2 female patients with therapy-refractory gastric ulcers associated with gastric wall thickening and lymphadenopathy that were highly suggestive of gastric cancer or lymphoma. Biopsies failed to confirm a diagnosis, and IgG4-RD was diagnosed only after surgical resection in both patients. The previous literature on gastric IgG4-RD is summarized and shows different characteristics in patients with multiorgan IgG4-RD and isolated gastric IgG4-RD. As reported for autoimmune pancreatitis type 1, patients with multiorgan IgG4-RD are mainly elderly men with frequently elevated serum IgG4 concentrations. In contrast, isolated gastric IgG4-RD predominantly affects female patients with normal serum IgG4 levels. Surgical resection is commonly performed due to the clinical suspicion of malignancy and the absence of findings indicative of IgG4-RD on biopsy. Today, diagnosis is confirmed histopathologically only after resection. CONCLUSION: IgG4-RD should be taken into account when gastric malignancy is suspected endoscopically or radiologically and biopsies fail to confirm the presence of a malignancy (especially subepithelial tumors or refractory gastric ulcers). Serum IgG4 concentrations are insufficient to confirm localized gastric IgG4-RD. Diagnostic workups need to be improved to avoid unnecessary surgical resections with the attendant potential morbidity and mortality.

Level of interobserver variability estimation as a valuable tool: assessment of tumour budding in colon cancer.

AIMS: Tumour budding is considered to be a good marker for progression and prognosis in colorectal carcinomas. A uniform classification system has been established recently. The natural element of uncertainty in the practice of human medicine is also exhibited in the assessment of tumour budding. We tested the hypothesis that interobserver variability can be estimated during the assessment process and investigated its potential clinical implication. METHODS AND RESULTS: Six investigators with different levels of experience could perceive different levels of difficulty (LOD) and estimated different levels of interobserver variability (LOIV) (Li1, lower than average; Li2, average; Li3, higher than average) during the assessment of tumour budding in 244 cases of colon cancer (pT3/4). In total, the LOIV showed following distribution: Li1: 36.1%, Li2: 43.9% and Li3: 20.0%. The LOIV was correlated significantly with the LOD given by the investigator. In total, the agreement rates with the final consensus classification were: Li1: 93.4%, Li2: 78.5% and Li3: 58.4%. The relative risk of disagreement with the final consensus classification was more than six times higher when a case was estimated to have a high rather than a low interobserver variability. CONCLUSION: Our data show that the investigator can estimate the interobserver variability during the ongoing rating process in pT3/4 colon cancer. The LOIV/LOD seems to be a valuable parameter of the assessment quality. For Li3 cases further measures seem mandatory.

Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?

Background and study aims Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric cancer (EGC) fulfilling guideline resection criteria or the expanded resection criteria in Asia. It is unclear whether the expanded criteria can be transferred to European patients, and long-term follow-up data are lacking. The aim of this study was to evaluate long-term follow-up data after ESD of EGCs in Europe. Patients and methods Patients with EGC who underwent ESD were included in this single-center study at a German referral center. Patient and lesion characteristics, procedure characteristics, and follow-up data were recorded prospectively. Results A total of 179 patients with 191 EGCs were included over a period of 141 months, with 29.6 % of lesions meeting guideline criteria and 48.6 % meeting expanded criteria. The en bloc resection rate was 98.4 % for guideline criteria and 89.0 % for expanded criteria lesions (P = 0.09), and the R0 resection rate was 90.2 % and 73.6 %, respectively (P = 0.02). The main reason for the expanded criteria was a lesion diameter > 20 mm (81.6 %). COMPLICATIONS: perforation 1 %, delayed bleeding 6.3 %, stricture 2.1 %, procedure-related mortality 1.1 %. Local recurrence rate was 0 % for guideline criteria and 4.8 % for expanded criteria lesions (P = 0.06), and the rate of metachronous neoplasia was 15.1 % and 7.1 %, respectively (median follow-up 51 and 56 months, respectively); 92.9 % of metachronous neoplasia were treated curatively with repeat ESD. One patient developed lymph node metastasis after ESD of a submucosal invasive expanded criteria lesion. Long-term-survival was comparable between the two criteria (P = 0.58). No gastric cancer-related death was observed in either group. Conclusions ESD can achieve high rates of long-term curative treatment using the expanded criteria in EGCs in Western countries. We recommend ESD as treatment of choice not only for guideline criteria EGCs but also for intramucosal nonulcerated EGCs regardless of their diameter.

Endoscopic submucosal dissection for early rectal neoplasia: experience from a European center.

Background and study aims Endoscopic resection is a curative treatment option for large nonpedunculated colorectal polyps (LNPCPs). Endoscopic submucosal dissection (ESD) allows en bloc resection but ESD experience is still limited outside Asia. The aim of our study was to evaluate the role of ESD in the treatment of early rectal neoplasia in a European center. Patients and methods 330 patients referred for endoscopic resection of rectal LNPCPs were included prospectively. Results ESD was performed for 302 LNPCPs (median diameter 40 mm). Submucosal invasive cancer (SMIC) was present in 17.2 % (n = 52). SMIC was associated with Paris type (54.5 % among type 0-Is lesions, 100 % of 0-Is-IIc type, 0 % of 0-IIa, 14.9 % of 0-IIa-Is, and 59.3 % of 0-IIa-IIc type; P < 0.001) and with surface pattern (71.4 % among nongranular plus mixed surface lesions, 17.9 % of lesions with granular surface and nodule ≥ 10 mm). For SMICs, resection rates were en bloc 81.4 %, R0 65.1 %, and curative 30.2 %. Curative resection rate improved from 13.6 % to 47.6 % over the study period (P = 0.036). The reason for 83.3 % (25/30) of noncurative resections was submucosal invasion exceeding 1000 µm. For benign lesions (n = 250, 82.8 %), the R0 resection increased from 55.2 % to 84.8 % over the study period (P < 0.001). Recurrence rate was 4.8 %, bleeding rate 5.2 %, and perforation rate 0.8 % (all complications managed conservatively). Median follow-up was 35 months. Conclusions The majority of rectal LNPCPs are benign lesions. ESD offers high R0 resection and low recurrence rates but EMR may be appropriate. In lesions with a risk for SMIC, ESD should be offered to achieve R0 resection. Despite high rates of R0 resection the curative resection rate of ESD for rectal SMIC is < 50 %. Pretherapeutic lesion selection needs improvement.

Lymph node hypoplasia is associated with adverse outcomes in node-negative colon cancer using advanced lymph node dissection methods.

PURPOSE: Lymph node size as a prognostic parameter has not been investigated well in the past. Recent data, however, have indicated that this parameter could be even more important than the lymph node count. METHODS: Based on the results of earlier studies, we analyzed the lymph node size and number of node-negative colon cancer patients with regard to survival. Data from 115 node-negative cases of colon cancer were analyzed. Lymph nodes with diameters ≤5 mm were defined as small, and all other lymph nodes were classified as intermediate/large in size and labeled LN5. All of the cases were categorized according to the number of LN5s. The LN5 very low (LN5vl) group included cases with less than two LN5s. All of the other cases were assigned to the LN5 low/high (LN5l/h) group. RESULTS: The overall survival analysis revealed significantly worse outcomes for the LN5vl group, with a mean survival of 34 months compared to the LN5l/h group, with a mean survival of 40 months (P = 0.022). After adjusting for the pT1/2 and pT3/4 stages, we still found a significant outcome difference (P = 0.012). Multivariate analysis identified LN5vl and T-stage as being independently correlated with the outcome. The vast majority of LN5vl cases (91 %) were located in the left colon. The location itself, however, was not prognostic (P = 0.478). CONCLUSION: LN5 count, as a marker of immune response, could be shown as being prognostic in node-negative colon cancer. Patients with low LN5 counts showed poor outcomes. These patients could perhaps profit from adjuvant chemotherapy.

'Neuroendocrine' middle ear adenomas: consistent expression of the transcription factor ISL1 further supports their neuroendocrine derivation.

AIMS: Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours. METHODS AND RESULTS: We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases. CONCLUSIONS: Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site.