Micropapillary carcinoma is an entity defined histologically in many organs. It is associated with lymph node metastasis and poor prognosis. The main mechanism for its histopathologic appearance is reverse polarization. Although the studies on this subject are limited, carcinomas with micropapillary morphology observed in different organs are examined by immunohistochemical and molecular methods. Differences are shown in these tumors compared with conventional carcinomas regarding the rate of somatic mutations, mRNA and miRNA expressions, and protein expression levels. TP53, PIK3CA, TERT, KRAS, EGFR, MYC, FGFR1, BRAF, AKT1, HER2/ERBB2, CCND1, and APC mutations, which genes frequently detected in solid tumors, have also been detected in invasive micropapillary carcinoma (IMPC) in various organs. 6q chromosome loss, DNAH9, FOXO3, SEC. 63, and FMN2 gene mutations associated with cell polarity or cell structure and skeleton have also been detected in IMPCs. Among the proteins that affect cell polarity, RAC1, placoglobin, as well as CLDNs, LIN7A, ZEB1, CLDN1, DLG1, CDH1 (E-cadherin), OCLN, AFDN/AF6, ZEB1, SNAI2, ITGA1 (integrin alpha 1), ITGB1 (integrin beta 1), RHOA, Jagged-1 (JAG1) mRNAs differentially express between IMPC and conventional carcinomas. Prediction of prognosis and targeted therapy may benefit from the understanding of molecular mechanisms of micropapillary morphology. This review describes the molecular pathologic mechanisms underlying the micropapillary changes of cancers in various organs in a cell polarity–related dimension.

Objective: Malignant lymphoma is one of the most common cancer type around the world. In this study, the distribution and demographic characteristics of the histologic subgroups of mature lymphoid neoplasms in Northeast Turkey were investigated. Methods: The study consists of 1136 patients diagnosed as mature lymphoid neoplasm between 2008 and 2014. The demographic data of the patients were analysed and histological subgrouping was performed according to the World Health Organization classification. Results: Mature B-cell neoplasms accounted for 79.2% (n=900) of all lymphoid neoplasms, Hodgkin lymphoma (HL) for 10.9% (n=124), mature T/natural killer-cell neoplasms for 9% (n=102), and histiocytic and dendritic cell neoplasms for 0.9% (n=10). In our study, the most common subtypes of lymphoid neoplasms were as follows: diffuse large B-cell lymphoma (n=261; 23%), plasma cell myeloma (n=252; 22.2%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=230; 20.2%), mycosis fungoides (MF) (n=66; 5.8%) and nodular sclerosing type classical HL (n=63; 5.5%). Only 2.9% of the cases of non-Hodgkin lymphoma (NHL) were follicular lymphoma. All patients with HL were diagnosed by a lymph node biopsy. However, 48.1% of the patients with NHL arose from extranodal sites. Conclusion: This is the first study investigating the distribution of lymphoid neoplasms in Northeast Anatolia region with the review of the literature. The present study showed that the epidemiologic features similar to those reported in Western and Asian countries, whereas some subtypes showed distinct features. The high frequency of MF and the low frequency of follicular lymphoma are interesting findings of this study.

Advances in molecular techniques have revealed that different molecular mechanisms are responsible for the behavior of cancer cells. Molecular alterations play a critical role in both the differential diagnosis of cancer and in the development of targeted therapies. Studies have identified the same potentially targetable mutations across various tumor types, supporting the emergence of tumor-agnostic therapies. To date, five biomarkers have been approved for tumor-agnostic therapy: microsatellite instability (MSI), neurotrophic tyrosine receptor kinase (NTRK) fusion, tumor mutation burden (TMB), BRAF V600E mutation, and rearranged during transfection (RET) fusions. The United States Food and Drug Administration (FDA) has approved pembrolizumab for MSI-high tumors or tumors with a high TMB. Larotrectinib and entrectinib have been approved for the treatment of NTRK gene fusion-positive tumors. Additionally, the combination of dabrafenib and trametinib has been approved for BRAF V600E mutations, and selpercatinib has been approved for RET fusion-positive cancers as of 2022. Positive responses to agnostic therapy, a significant milestone in cancer treatment, depend on the identification of new agnostic biomarkers. Ongoing research is focused on defining additional molecular changes, such as programmed death-ligand 1 (PD-L1), Kirsten rat sarcoma virus (KRAS), neuregulin 1 (NRG1), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK), AKT serine/threonine kinase (AKT), human epidermal growth factor receptor 2 (HER2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and breast cancer gene (BRCA), as potential agnostic biomarkers in various cancer types.

Micropapillary carcinoma (MPC) is a type of tumor that is histopathologically characterized by the presence of small papillary structures. Literature data on somatic mutations in MPCs are very limited. One hundred fifty-nine colon resection cases diagnosed with adenocarcinoma whose DNA mutations were analyzed by next-generation sequencing (NGS) were retrospectively reviewed. In 10 cases, the MPC area exceeded 5%. Chi-square test was used to evaluate histopathologic characteristics and somatic mutations in MPCs and non-MPCs. The relationship between mutations and clinicopathological parameters in all cases was investigated. The presence of MPC areas in carcinomas was associated with higher histologic grades (MPC: n = 6; 60% vs. non-MPC: n = 22; 14.8%), more advanced pathologic T (pT4 MPC: n = 5; 50% vs. non-MPC: n = 46; 34.6%) and N stages (pN2b MPC: n = 5; 50% vs. non-MPC: n = 26; 19.5%) and more frequent tumor deposits (MPC: n = 7; 87.5% vs. non-MPC: n = 44; 46.8%), lymphovascular invasion (MPC: n = 8; 80% vs. non-MPC: n = 83; 55.7%), and perineural invasion (MPC: n = 7; 70% vs. non-MPC: n = 42; 28.2%). A significant difference was found between MPCs and non-MPCs in terms of histological grade (p = 0.002) and perineural invasion (p = 0.01). TP53, KRAS, and PIK3CA genes were the most frequently mutated genes in both MPCs and non-MPCs (TP53 MPC: n = 6; 100% vs. non-MPC: n = 72; 64.9% – KRAS MPC: n = 4; 40% vs. non-MPC: n = 66; 44.3% – PIK3CA MPC: n = 2; 20% vs. non-MPC: n = 32; 21.5%). There was no statistically significant difference in somatic mutations between the groups (TP53: p = 0.177, KRAS: p = 1.000, PIK3CA: p = 1.000, BRCA2: p = 0.181, ERBB2: p = 0.327, BRAF: p = 1.000, MAP2K1: p = 0.062). A significant difference was found between the TP53 mutant and TP53 wild-type groups in terms of tumor deposits (p = 0.033) and perineural invasion (p = 0.046). The male rate was significantly higher in KRAS wild-type cases (n = 69; 77.5%) compared to KRAS mutant cases (n = 38; 54.3%) (p = 0.002). The mean age, T and N staging were significantly different between PIK3CA mutant and PIK3CA wild-type cases (p = 0.01; p = 0.033; p = 0.019, respectively). We found that MPCs had more advanced clinical stages and histological features associated with poor prognosis, such as advanced T and N stages, higher histological grade, presence of tumor deposits, lymphovascular and perineural invasion.

Background and Objectives: Serrated adenocarcinoma (SAC) is a distinctive neoplasm that is histopathologically characterized by the presence of epithelial serration, an eosinophilic cytoplasm, and a vesicular nucleus. However, the literature data concerning somatic mutations in SACs remain extremely limited. Materials and Methods: A total of 159 colon resection cases diagnosed with adenocarcinoma whose DNA mutations were analyzed by next-generation sequencing (NGS) were retrospectively reviewed. In 23 cases, the SAC area exceeded 50%. A chi-square test was used to evaluate histopathologic characteristics and somatic mutations in SACs and non-serrated adenocarcinomas (non-SACs). Results: A significant difference was found in histological grade (p = 0.019) between SACs and non-SACs. TP53, KRAS, and PIK3CA genes have been identified as the most frequently mutated genes in both SACs and non-SACs. No statistically significant difference in somatic mutations was observed between the two groups (p > 0.05). Conclusions: In the present study, a higher prevalence of KRAS mutations was observed in SACs compared to BRAF mutations (KRAS: 39.1%, BRAF: 4.3%). This finding is consistent with the recent literature reporting a higher prevalence of KRAS mutations in colorectal SACs, in contrast to previous studies. The somatic mutation results of our study and the previous literature data suggest the potential importance of epigenetic alterations documented in the literature in the development of SACs.

Background/Objectives: Although Ki-67 is not formally incorporated into the grading system of pulmonary neuroendocrine neoplasms (PNENs), it is widely used as an adjunct marker to reflect proliferative activity and support diagnostic stratification. Manual Ki-67 assessment is subject to interobserver variability and methodological limitations. This study aimed to evaluate the reliability and performance of two artificial intelligence (AI)-based image analysis systems in Ki-67 index assessment and to compare their results with expert pathologist evaluation in pulmonary neuroendocrine tumors. Methods: A total of 63 pulmonary neuroendocrine neoplasm cases, including typical carcinoid (n = 29), atypical carcinoid (n = 13), and large cell neuroendocrine carcinoma (n = 21), were retrospectively analyzed. Ki-67 proliferation indices were independently assessed by four pathologists within predefined hotspot regions, counting approximately 2000 tumor cells per case. The same regions were analyzed using two AI-based image analysis systems (Roche uPath Ki-67 and Virasoft Virasight Ki-67). Interobserver agreement among pathologists was evaluated using the intraclass correlation coefficient (ICC), and concordance between manual and AI-based assessments was assessed using Spearman’s correlation and linear regression analyses. To account for potential scanner/platform effects, slides were digitized using two different whole-slide scanners (VENTANA DP^® 600 and Leica Aperio AT2), and color normalization and quality control procedures were applied prior to AI-based analysis. For clinical interpretability, Ki-67 indices were stratified into categorical groups based on tumor subtype-specific thresholds (0–25%: high), and agreement between manual and AI-based categorical scoring was evaluated using Cohen’s kappa coefficient. Results: Among the 63 pulmonary neuroendocrine neoplasm cases, Ki-67 proliferation indices varied across tumor subtypes, with typical carcinoids showing low, atypical carcinoids intermediate, and large cell neuroendocrine carcinomas high proliferative activity. Interobserver agreement among four pathologists was excellent (ICC = 0.998, 95% CI: 0.996–0.998). Strong correlations were observed between manual Ki-67 assessments and AI-derived indices, with Spearman correlation coefficients of 0.961 (95% CI: 0.918–0.982) for Roche AI and 0.904 (95% CI: 0.821–0.949) for Virasoft AI, and 0.926 (95% CI: 0.842–0.968) between the two AI systems. Bland–Altman analyses demonstrated minimal mean differences and most cases within the 95% limits of agreement, indicating high concordance without systematic bias. Categorical agreement analysis, using subtype-specific Ki-67 thresholds (0–25%: high), showed excellent concordance between manual and AI-based scoring (Cohen’s kappa 0.877 for Roche AI and 0.827 for Virasoft AI; p < 0.001), confirming the clinical interpretability and reproducibility of AI-based Ki-67 assessment. Conclusions: AI-based Ki-67 index assessment shows strong concordance with expert pathologist evaluation and reflects biologically relevant differences among pulmonary neuroendocrine neoplasm subtypes. These results suggest that AI-assisted Ki-67 analysis may serve as a reproducible and objective adjunct to routine diagnostic practice in pulmonary neuroendocrine tumors.