Pathologie (Heidelberg, Germany)最新文献

Background: Muscle-invasive and metastatic urothelial carcinoma (UC) represents a heterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes.

Aims: This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC.

Results and discussion: Muscle-invasive and metastatic UC exhibits a wide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

Bronchopulmonary neuroendocrine neoplasms (BP-NENs) account for approximately 30% of all NENs. Although BP-NENs and NENs of the gastroenteropancreatic organs (GEP-NENs) share morphological and molecular features, they differ in terms of their terminology and classification. Bronchopulmonary neuroendocrine tumors (BP-NETs) have classically been termed as carcinoid and grouped into typical (TC) and atypical carcinoid (AC) based on the presence or absence of necrosis and mitotic count. In the most recent World Health Organization (WHO) classification for NENs of endocrine organs (WHO 2022), BP-NETs-NET G1 and G2-are introduced as synonyms of TC and AC, respectively. However, the Ki-67 index, which defines the grade of NETs in digestive organs, is only discussed in the descriptive text and not included into the criteria for classification of BP-NENs. In addition, well-differentiated NENs with high mitotic counts which correspond to NET G3 in the GEP organ system are not defined. This review discusses the role of Ki-67 for a proper classification of BP-NETs/carcinoids.

Neuroendocrine carcinomas (NEC) are poorly differentiated neuroendocrine neoplasms that can occur ubiquitously in the mucosa-bearing organs of the gastrointestinal tract. Based on their morphology, they are classified into large cell (LCNEC) and small cell NEC (SCNEC). The most common form of mixed differentiation is the combination with an adenocarcinoma, referred to as mixed adenoneuroendocrine carcinoma (MANEC). NEC/MANEC exhibit a significantly poorer prognosis than the adenocarcinomas of their respective primary sites, which is inextricably linked to their typical histomorphology. Adenocarcinomas with aberrant expression of neuroendocrine markers do not show a worse clinical course. Molecularly, NEC/MANEC have a profile comparable to the adenocarcinomas of their site of origin and a profile divergent from neuroendocrine tumors. Analyses of gastric NEC/MANEC have shown frequent MYC amplifications, which are reflected in MYC signatures in various transcriptome analyses.The cellular origin of NEC remains a subject of controversial discussion. New insights are provided by a MYC-driven, genetically modified mouse model that led to the development of large gastric tumors. These tumors were histologically identified as LCNEC and were accompanied by both neuroendocrine and non-neuroendocrine precursor lesions. Using immunofluorescence, a derivation from resident neuroendocrine cells in the gastric corpus was demonstrated, suggesting that at least a portion of LCNEC may originate directly from neuroendocrine cells.

With the widespread use of diverse modern molecular testing tools, the last two decades have seen significant advances in the classification of soft tissue neoplasms. Specifically, numerous molecularly defined new entities have been introduced and many established older entities have received more insightful molecular studies that have developed their classification further. The discrepant therapeutic and prognostic implications of this evolving complexity of the nosology of neoplastic diseases make the precise subtyping of soft tissue neoplasms unavoidable. However, these rapid developments of the modern diagnostic molecular pathology did not only offer efficient solutions to many complex classification issues, but they were accompanied by similarly complex and diverse emerging problems. Most importantly, these advances have not only challenged the historical dogma of some phenotypes that were once considered specific, but they also have questioned the value of diagnostic immunohistochemistry compared to emerging modern diagnostic molecular tools. Moreover, the central question of when to test, what to test, and how to test became more confusing. This review addresses the major molecular categories in soft tissue neoplasms, their characteristics, and the criteria to be used for selecting the most appropriate molecular diagnostic tool to be used in individual cases with a special focus on the value of next generation immunohistochemistry as a substitute for molecular testing.

Urothelial carcinoma (UC) is by far the most common malignant neoplasm of the urinary bladder; however, there are both benign and malignant changes of the urothelium which morphologically resemble urothelial carcinomas or other carcinomas of the urinary bladder. Thus, these mimickers can cause problems in the histomorphological diagnosis. This article provides an overview of possible mimickers and pitfalls of bladder cancer as well as practical notes on the diagnostic procedure, partly using case studies.

Background: Mismatch repair deficiency (dMMR) with microsatellite instability (MSI) is frequent in cancer, particularly in gastrointestinal and endometrial malignancies. The increased tumor mutational burden renders dMMR/MSI tumors suitable targets for immune checkpoint inhibitors-provided the regulatory genetic defect can be detected. dMMR and MSI are considered equally effective predictors of the efficacy of ICIs; however, while dMMR testing is based on detection of missing MMR proteins in immunohistochemistry (IHC), MSI polymerase chain reaction (PCR) testing focuses on the consequences of dMMR at the genomic level.

Materials and methods: A retrospective analysis was carried out in a large cancer cohort (n = 1306). dMMR was tested by four IHC reactions (MLH1, PMS2, MSH2, MSH6), and MSI was assessed by pentaplex PCR (BAT-25, BAT-26, MONO-27, NR-21, NR-24) in 703 cases. In 64 cases (5%), technical failures (mostly poor preanalytical fixation) prevented dMMR/MSI testing. Tumors were colorectal (CRC; n: 978), cancer of unknown primary (n: 126), endometrial (n: 39), pancreatic (n: 36), and gastric (n: 33). dMMR was diagnosed as classical, nonclassical, or unusual, depending on IHC.

Results: The MSI-high incidence was 12.1% overall and similar in the CRC subcohort. Interestingly, the dMMR incidence was higher in the total cohort (20.3%) and similar in the CRC subcohort. The incidences of proficient MMR (pMMR) and microsatellite stability (MSS) were similar in the total cohort and in the CRC subcohort. A 19.3% discrepancy was found between MMR IHC and MSI PCR for the entire cohort, independent of tumor types. In the case of pMMR, the discrepancy rate for MSS/MSI-low was low (2.0%; entire cohort and the CRC subcohort). However, the discrepancy between dMMR and MSI-high was high within the entire cohort (60.9%) and in the CRC (58.6%) and non-CRC subcohorts (68%). This high discrepancy was not due to tumors with a low T/N ratio. Regarding dMMR phenotypes, classical dMMR had a ~ 60% correlation with MSI-high status, while non-classical dMMR had a much lower and unusual dMMR a very low (< 10%) correlation with MSI-high in the entire cohort and in the CRC subcohort. Overall, the MSI PCR sensitivity for MMR IHC status was very low.

Conclusion: dMMR and MSI-high likely result in an increased rate of structurally altered proteins, i.e., neoantigens, and the efficacy of cancer immunotherapies is thus expected to be higher. We compared MMR IHC to MSI PCR in a large cohort of cancer patients to study how PCR test results correlate to MMR IHC. Our data imply that preanalytical factors strongly influence the results of MMR IHC and MSI PCR and may question the current dogma that dMMR phenotype and genetic MSI status are equivalent predictive markers for immunotherapies.