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Downregulation of human leukocyte antigen (HLA) class I has been postulated to be a mechanism of adaptive immune escape in various tumors, especially microsatellite instability–high (MSI‐H) colorectal cancer (CRC). In this study, we aimed to investigate HLA class I and β2‐microglobulin (β2M) expression in MSI‐H and microsatellite‐stable (MSS) CRCs and determine its prognostic impact. The representative areas from the tumor center (TC) and tumor periphery (TP) from 300 CRCs, including 161 MSI‐H and 139 MSS cases, were selected to construct a tissue microarray. Immunohistochemistry (IHC) for HLA A/B/C, β2M, CD3, and CD8 was performed. Reduced HLA A/B/C expression was detected in 113 (70.2%) MSI‐H and 54 (38.8%) MSS cases, while reduced β2M expression was observed in 69 (42.9%) MSI‐H and 17 (12.2%) MSS cases. Although reduced β2M expression was associated with higher pathological tumor (pT) stage in MSI‐H CRC with borderline significance, no association was found between HLA A/B/C and β2M expression and survival. Interestingly, reduced HLA A/B/C expression in MSS was associated with higher stage, and reduced HLA A/B/C and β2M expression was an independent prognostic factor in multivariate analysis. In conclusion, reduced HLA A/B/C and β2M expression was frequently observed in immunotherapy‐naive MSI‐H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitor. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor prognosis in MSS cancers. Overall, IHC for HLA A/B/C and β2M might be a feasible predictive or prognostic tool in CRC. Reduced HLA A/B/C and β2M expression is frequently observed in immunotherapy‐naive MSI‐H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitors. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor survival in MSS cancers, but not in MSI‐H tumors, indicating that cell‐mediated antitumoral immune response may also play an important role in MSS CRC. Together, IHC for HLA A/B/C and β2M can be a predictive or prognostic tool in CRC.

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia [BilIN]), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4 , ROBO1 , and DICER1 . In mutational signature analysis, six mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

CT plays a central role in determining the resectability of pancreatic cancer, which directs the use of neoadjuvant therapy. This study aimed to assess the diagnostic accuracy of CT in predicting circumferential resection margin (CRM) involvement in patients with resectable or borderline resectable pancreatic head cancer. Seventy-seven patients who were scheduled for upfront surgery for resectable or borderline resectable pancreatic head cancer were prospectively enrolled, and 75 patients (38 male and 37 female; mean age ± standard deviation, 68 ± 11 years) were finally analyzed. The CRM status was evaluated separately for the superior mesenteric artery (SMA) and posterior and superior mesenteric vein/portal vein (SMV/PV) margins. Three independent radiologists reviewed the preoperative CT images and evaluated the resection margin status. The reference standard for CRM status was pathologic examination of pancreaticoduodenectomy specimens in an axial plane perpendicular to the axis of the second portion of the duodenum. The diagnostic accuracy of CT was assessed for overall CRM involvement, defined as involvement of the SMA or posterior margins (per-patient analysis), and involvement of each of the three resection margins (per-margin analysis). The data were pooled using a crossed random effects model. Forty patients had pathologically confirmed overall CRM involvement in pancreatic cancer, while CRM involvement was not seen in 35 patients. For overall CRM involvement, the pooled sensitivity and specificity were 15% (95% confidence interval: 7%-49%) and 99% (96%-100%), respectively. For each of the resection margins, the pooled sensitivity and specificity were 14% (9%-54%) and 99% (38%-100%) for the SMA margin, 12% (8%-46%) and 99% (97%-100%) for the posterior margin; and 37% (29%-53%) and 96% (31%-100%) for the SMV/PV margin, respectively. CT showed very high specificity but low sensitivity in predicting pathological CRM involvement in pancreatic cancer.

The incidence and mortality rates of colorectal cancer (CRC) has been reported to be strongly associated to sex/gender difference. CRC shows sexual dimorphism, and sex hormones have been shown to affect the tumor immune microenvironment. This study aimed to investigate location-dependent sex differences in tumorigenic molecular characteristics in patients with colorectal tumors, including adenoma and CRC. A total of 231 participants, including 138 patients with CRC, 55 patients with colorectal adenoma, and 38 healthy controls, were recruited between 2015 and 2021 at Seoul National University Bundang Hospital. All patients underwent colonoscopy and acquired tumor lesion samples were further analyzed for programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) expression, deficient mismatch repair (dMMR), and microsatellite instability (MSI) status. This study was registered with ClinicalTrial.gov, number NCT05638542. The average of combined positive score (CPS) was higher in serrated lesions and polyps (lesions/polyps) compared to conventional adenomas (5.73 and 1.41, respectively, P < 0.001). No significant correlation was found between sex and PD-L1 expression within the groups, regardless of histopathological diagnosis. In multivariate analysis where each sex was further stratified by tumor location due to their interaction in CRC, PD-L1 expression was inversely correlated with males having proximal CRC with a CPS cutoff of 1 (Odds ratio (OR) 0.28, P = 0.034). Females with proximal CRC showed a significant association with dMMR/MSI-high (OR 14.93, P = 0.032) and high EGFR expression (OR 4.17, P = 0.017). Sex and tumor location influenced molecular features such as PD-L1, MMR/MSI status and EGFR expression in CRC, suggesting a possible underlying mechanism of sex-specific colorectal carcinogenesis.

Aberrant expression of CD5 has been reported in 5-10% of diffuse large B-cell lymphomas (DLBCLs). CD5+ DLBCL had been recognized as an aggressive immunophenotypic subgroup of DLBCL in the 2008 WHO classification of haematolymphoid neoplasm; however, it was eliminated from the list of subgroups of DLBCLs in the revised 2016 classification. Nevertheless, there is much controversy regarding the clinical significance of CD5 expression, and many researchers still assert that this subgroup exhibits an extremely unfavorable prognosis with frequent treatment failure. We retrospectively investigated 405 DLBCLs recruited from three university hospitals in Korea from 1997 to 2013. The clinical profile, immunophenotype, and chromosomal structural alterations of the BCL2 and MYC genes were compared according to CD5 expression. A total of 29 cases of de novo CD5+ DLBCL were identified out of 405 in our series (7.4%). Clinicopathologic correlation was performed in all 29 CD5+ DLBCLs and 166 CD5- DLBCLs which were eligible for full clinical review and further pathologic examination. Compared with CD5- counterparts, CD5+ DLBCLs showed female preponderance, frequent bone marrow involvement, higher lactate dehydrogenase level, advanced Ann Arbor stages and poorer prognosis (all p<0.05). Pathologically, the expression of CD5 positively correlated with that of BCL2, MYC and Ki-67 (all p<0.05). Coexpression of BCL2 and MYC, which is referred to as a double-expressor, was relatively more common in CD5+ DLBCL, whereas translocation or amplification of these genes was very rare. in conclusion, the expression of CD5 is an independent poor prognostic factor of DLBCLs, and this subgroup displays unique clinicopathologic features. Although the exact mechanism remains uncertain, consistent activation of BCL2 and MYC by alternative pathways other than chromosomal translocation may contribute to the pathogenesis.

Abstract Background This study prospectively evaluated the risk of relapse according to the status of histologic activity in patients with ulcerative colitis (UC) who achieved deep remission. Methods Patients with UC in clinical remission (partial Mayo score ≤1) and endoscopic remission (ulcerative colitis endoscopic index of severity ≤1) were enrolled. Rectal biopsies were performed in patients, and histologic remission was defined as a Robarts histopathology index of ≤3. Receiver-operating characteristic curve analysis was conducted to determine fecal calprotectin cutoff values for histologic remission. The cumulative risk of relapse was evaluated using the Cox proportional hazards model. Results Among the 187 patients enrolled, 82 (43.9%) achieved histologic remission. The best cutoff value of fecal calprotectin for predicting histologic remission was 80 mg/kg (area under the curve of 0.646, sensitivity of 74%, and specificity of 61%). Among 142 patients who were followed up for >3 months, 56 (39.4%) showed clinical relapse during a median of 42 weeks. The risk of relapse was lower in patients with histologic remission than in those with histologic activity (P = .026). In multivariable analysis, histologic remission (hazard ratio [HR], 0.551; 95% confidence interval [CI], 0.316-0.958; P = .035), elevated C-reactive protein levels (HR, 3.652; 95% CI, 1.400-9.526; P = .008), and history of steroid use (HR, 2.398; 95% CI, 1.196-4.808; P = .014) were significantly associated with clinical relapse. Conclusions In patients with UC who achieved clinical and endoscopic remission, histologic remission was independently associated with a lower risk of clinical relapse. Lay Summary In patients with ulcerative colitis who achieved clinical and endoscopic remission, histologic remission was independently associated with a lower risk of clinical relapse. This benefit of reaching histologic remission was maintained regardless of treatment de-escalation.

Due to the extremely indolent behavior, a subset of noninvasive encapsulated follicular variant papillary thyroid carcinomas has been classified as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)” since 2016 and is no longer considered carcinoma. Since the introduction of this new terminology, changes and refinements have been made in diagnostic criteria. Initially, the incidence of NIFTP was estimated substantial. However, the reported incidence of NIFTP varies greatly among studies and regions, with higher incidence in North American and European countries than in Asian countries. Thus, the changes in the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) differ inevitably among regions. Because more conservative surgery is recommended for NIFTPs, distinguishing NIFTPs from papillary thyroid carcinomas in preoperative fine-needle aspiration cytology became one of the major concerns. This review will provide comprehensive overview of updates on diagnostic criteria, actual incidence and preoperative cytologic diagnoses of NIFTP, and its impact on the ROM in TBSRTC.

Cytologic diagnosis of thyroid follicular adenoma and carcinoma, and Hurthle cell adenoma and carcinoma (FACHAC) is challenging due to cytomorphologic features that overlap with other follicular-patterned lesions. This study was designed to analyze diagnostic categories (DCs) of preoperative fine needle aspiration cytology (FNAC) of histologically proven thyroid FACHACs to evaluate under- or misdiagnoses in FNAC and elucidate potential causes for such phenomena. A total of 104 thyroid nodules with preoperative FNAC which were diagnosed as FACHAC in resection specimens were included in this study. Of these, 66 cases had also undergone thyroid core needle biopsy (CNB); FNAC and CNB DCs were compared in these cases. Various cytologic and histologic parameters were compared between the nodules with different FNAC DCs. After a review of FNAC slides, DCs were re-assigned in 20 (19.2%) out of the 104 cases. Of the 66 cases with CNB diagnoses which were mostly classified as lower DCs in FNAC, 31 (47.0%) were diagnosed as suspicious for a follicular neoplasm in CNB. Cases which were underdiagnosed in FNACs were associated with lower cellularity, predominant macrofollicular pattern, absence of microfollicles arranged in trabecular pattern, and absence of transgressing vessels in cytology smears. High cellularity, microfollicles arranged in trabecular pattern, nucleolar prominence, and large cell dysplasia were more frequently found in malignancy than in benign neoplasm. In conclusion, thyroid FACHACs seem to be under- and misdiagnosed in preoperative FNAC. Innate characteristics of the nodules were associated with under-diagnosis as well as the quality of the FNAC specimens. Certain cytomorphologic features can be helpful in differentiating malignancy among FACHACs.

According to molecular profiling studies, a considerable number of patients with pancreatic cancer harbor potentially actionable mutations. However, there are limited relevant data from the Korean population. We assessed the molecular profiles of patients with pancreatic cancer in Korea. This study collected molecular profiling data from patients with pancreatic cancer who visited Seoul National University Bundang Hospital between March 2018 and August 2020. Formalin-fixed, paraffin-embedded tumor specimens were sequenced using a targeted next-generation sequencing (NGS) platform. Cancer-associated mutations were analyzed, and potentially actionable mutations were identified. Potentially actionable mutations were classified into “highly actionable” and “modifies options” based on the Know Your Tumor registry study. In total, 87 patients with NGS tumor panel data were identified. Sixty-one patients (70.1%) had metastatic disease at the time of tissue acquisition. Tissues were obtained from the primary tumors and metastatic sites in 41 (47.1%) and 46 (52.9%) patients, respectively. At least one pathogenic mutation was reported in 86 patients (98.9%). The frequencies of four common mutations in our cohort were similar to those in The Cancer Genome Atlas data. Potentially actionable mutations were identified in 27 patients (31.0%). Of these, mutations categorized as highly actionable and modifies options were identified in 12 (13.8%) and 18 patients (20.7%), respectively. The most frequent highly actionable mutations were located in DNA damage response genes, such as BRCA1 , BRCA2 , or ATM ( n  = 6, 6.9%). Two patients with germline BRCA1 mutations received maintenance poly(adenosine diphosphate-ribose) polymerase inhibitor therapy. One patient has been receiving maintenance treatment for 18 months while remaining in radiologically complete remission. Mutational profiles using targeted NGS in Korean patients with pancreatic cancer were similar to those in Western patients. The present study supports the clinical potential and possible expanded clinical use of genetic profiling.

Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.