Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

A Nationwide Study on HER2-low Breast Cancer in South Korea: Its Incidence of 2022 Real World Data and the Importance of Immunohistochemical Staining Protocols.

Purpose: Notable effectiveness of trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced breast cancer (BC) has focused pathologists' attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results. Materials and Methods: The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected. Results: Total 11,416 patients from twenty-five institutions included in this study. Of these patients, 40.7% (range: 6.0%-76.3%) were classified as HER2-zero, 41.7% (range: 10.5%-69.1%) as HER2-low, and 17.5% (range: 6.7%-34.0%) as HER2-positive. HER2-low tumors were associated with positive ER and PR statuses (p<0.001 and p<0.001, respectively). Antigen retrieval times (≥ 36 min vs. < 36 min) and antibody incubation times (≥ 12 min vs. < 12 min) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy (CNB) and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3259) of the patients. Conclusion: The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.

Prognostic Significance of Intratumoral and Peritumoral Budding in Distal Extrahepatic Bile Duct Carcinoma.

INTRODUCTION: Although tumor budding (TB) has been recognized as a representative adverse prognosticator in gastrointestinal malignancies, it is not well-elucidated in distal extrahepatic bile duct carcinoma (DBDC). Herein, we investigated the prognostic significance of peritumoral (PTB) and intratumoral (ITB) budding according to the modified DBDC staging of the 8th edition of the American Joint Committee on Cancer. METHODS: PTB and ITB were independently evaluated in a cohort of DBDC patients (n = 410) based on the 2016 International Tumor Budding Consensus Conference (ITBCC). RESULTS: High levels of PTB (PTBHigh, ≥ grade-2) and ITB (ITBHigh, ≥ grade-3) were identified in 316 (77%) and 238 (58%) cases, respectively. In univariate analysis, PTBHigh and ITBHigh, larger size and sclerosing tumor growth pattern, higher histologic grade, extrapancreatic location, adenocarcinomas unrelated to intraductal papillary neoplasm of the bile duct (IPNB), pancreatic, duodenal, and lymphovascular invasion, perineural invasion, cancer involvement of the bile duct resection margin, nodal metastasis, and higher T and N categories and disease stages were associated with shorter patient overall survival (OS) times. In multivariate analysis, PTBHigh and ITBHigh remained poor independent prognostic indicators of OS in DBDC patients. Specifically, ITBHigh could predict poor prognosis in patients with stage I (T1N0) DBDC. CONCLUSIONS: Both PTBHigh and ITBHigh were strong prognostic indicators in patients with DBDC. Thus, ITB could be used to predict worse prognoses in patients with DBDC, in which PTB is difficult to assess, especially for patients with stage I (T1N0) DBDC.

Prognostic Significance of Cyclin D1 Expression in Small Intestinal Adenocarcinoma.

Cyclin D1, a critical cyclin-dependent kinase (CDK) 4/6-dependent regulator of G1/S transition, has attracted much interest as a therapeutic target. The cyclin D1 expression in small intestinal adenocarcinomas (SIACs) has not yet been comprehensively studied, owing to the rarity of this tumor. We investigated the clinicopathological and prognostic significance of the cyclin D1 expression in 232 surgically resected primary SIACs through a multi-institutional study. A high expression of cyclin D1 (cyclin D1High) was detected in 145 SIAC cases (63%), which was significantly higher than that in normal small intestinal mucosa (11%). Cyclin D1High was more commonly found in SIACs with a lower T-category and disease stage and KRAS mutation and predicted better patient survival. Multivariate analysis revealed that cyclin D1High, the absence of retroperitoneal seeding and lymphovascular invasion, and the lower N-category were identified as independent prognostic indicators for patients with SIACs. Specifically, cyclin D1High affected patient survival in the lower stage group (stages I and II). In conclusion, cyclin D1 was commonly overexpressed in SIACs, and cyclin D1High acted as a favorable prognostic indicator in patients with SIACs. These findings in SIACs may, thus, be important to further comprehend the mechanism of cyclin D1 in carcinogenesis and to strategize appropriate patient therapies.

Prognostic Potential of Cyclin D1 Expression in Colorectal Cancer.

Cyclin D1 is mainly known as an oncogenic driver in cancers, and the dysregulated cyclin D1/cyclin-dependent kinase (CDK) 4/6 axis is considered an attractive target for cancer therapy. Recent studies have reported that tumors respond to therapeutic interventions targeting altered cyclin D1 expression via application of the CDK4/6 inhibitor. However, the prognostic and therapeutic contributions of cyclin D1 to colorectal cancer (CRC) remain controversial. Herein, we assessed the associations between cyclin D1 expression and clinicopathological factors, including patients' overall survival (OS) and recurrence-free survival (RFS), in 495 surgically resected primary CRCs. We also examined previous studies for cyclin D1 in CRCs. High expressions of cyclin D1 (cyclin D1High) was observed in 389 CRC cases (78.6%). Cyclin D1High consistently predicted better patient OS and RFS in CRCs. Based on multivariate analysis, cyclin D1High and young age of patients remained as independent prognosticators of higher OS rate, whereas cyclin D1High, females, chemotherapy, absence of nodal metastasis, and lower T-category remained as independent prognosticators of better RFS. Cyclin D1 is commonly overexpressed in CRCs, and its expression can be used as a favorable prognostic indicator in patients with CRCs; this may be important for predicting responses to subsequent CDK4/6 inhibitors.

Tumor Microenvironment Prognostic Risk and Its Association With MUC5AC in Ampullary Carcinoma.

CONTEXT.­: The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. OBJECTIVE.­: To assess TME-based prognostic risk in AC. DESIGN.­: We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. RESULTS.­: TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). CONCLUSIONS.­: TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.

Computer-Aided Diagnosis Parameters of Invasive Carcinoma of No Special Type on 3T MRI: Correlation with Pathologic Immunohistochemical Markers.

Purpose: To investigate the correlation between computer-aided diagnosis (CAD) parameters in 3-tesla (T) MRI and pathologic immunohistochemical (IHC) markers in invasive carcinoma of no special type (NST). Materials and Methods: A total of 94 female who were diagnosed with NST carcinoma and underwent 3T MRI using CAD, from January 2018 to April 2019, were included. The relationship between angiovolume, curve peak, and early and late profiles of dynamic enhancement from CAD with pathologic IHC markers and molecular subtypes were retrospectively investigated using Dwass, Steel, Critchlow-Fligner multiple comparison analysis, and univariate binary logistic regression analysis. Results: In NST carcinoma, a higher angiovolume was observed in tumors of higher nuclear and histologic grades and in lymph node (LN) (+), estrogen receptor (ER) (-), progesterone receptor (PR) (-), human epidermal growth factor 2 (HER2) (+), and Ki-67 (+) tumors. A high rate of delayed washout and a low rate of delayed persistence were observed in Ki-67 (+) tumors. In the binary logistic regression analysis of NST carcinoma, a high angiovolume was significantly associated with a high nuclear and histologic grade, LN (+), ER (-), PR (-), HER2 (+) status, and non-luminal subtypes. A high rate of washout and a low rate of persistence were also significantly correlated with the Ki-67 (+) status. Conclusion: Angiovolume and delayed washout/persistent rate from CAD parameters in contrast enhanced breast MRI correlated with predictive IHC markers. These results suggest that CAD parameters could be used as clinical prognostic, predictive factors.

The T Category of Distal Extrahepatic Bile Duct Carcinoma: A Comparative Analysis With Invasive Tumor Thickness.

The T category of distal extrahepatic bile duct carcinoma (DBDC) is based on invasion depth from the basal lamina to the deepest infiltrating tumor cells. Recently, invasive tumor thickness (ITT) was proposed, defined as maximal vertical distance of invasive tumor components regardless of the basal lamina. We compared the predictive value of T category, and ITT grading in 424 surgically resected DBDCs. DBDCs were categorized as 6 Tis (1.4%), 134 T1 (<5 mm; 31.6%), 204 T2 (5 to 12 mm; 48.1%), and 80 T3 (>12 mm; 18.9%). With ITT, there were 6 G0 (no invasion; 1.4%), 3 G1 (<1 mm; 0.7%), 90 G2 (≥1 and <5 mm; 21.2%), 188 G3 (≥5 and <10 mm; 44.4%), and 137 G4 (≥10 mm; 32.3%). The 5-year survival rates of T1, T2, and T3 were 58.9%, 44.2%, and 18.2%, and those of ITT G1, G2, G3, and G4 were 33.3%, 54.1%, 51.6%, and 26.7%, respectively. The T category discriminated patient survival by overall (P<0.001) and pairwise (T1 vs. T2, P=0.007; T2 vs. T3, P<0.001) comparisons. ITT grading distinguished survival by overall and between G3-G4 (both P<0.001), with no survival differences observed between G1-G2 and G2-G3 comparisons. The T category more accurately discriminated patient survival than ITT grading. To determine the T category for DBDCs, (1) longitudinal sectioning on gross examination, especially for DBDCs with large papillary or nodular growth patterns; (2) evaluation of serial sections or alternative hematoxylin and eosin slides; (3) use of a straight or curved baseline depending on the shape of the peritumoral normal bile duct wall and/or the basal lamina of the peritumoral normal biliary epithelia/biliary intraepithelial neoplasias are recommended.

Granulocytic epithelial lesion (GEL) in heterotopic pancreas.

BACKGROUND: The diagnosis of type 2 autoimmune pancreatitis (AIP) is dependent on typical radiologic imaging and the presence of the granulocytic epithelial lesion (GEL), which is characterized by ductal neutrophilic infiltration with or without neutrophilic acinar infiltration. METHODS: We evaluated GEL and related clinicopathologic factors in 165 resected heterotopic pancreata (HPs) [57 gastric (35%), 56 duodenal (34%), 30 omental (18%), and 22 jejunal (13%)] and 29 matched orthotopic pancreata routinely examined during surgery. RESULTS: GEL was noted in 8% (13/165) of HPs, including ductal epithelial (6/13, 46%) and intraluminal (8/13, 62%) neutrophilic infiltrations. However, there was no GEL in orthotopic pancreata. Abdominal pain was observed in 6 (46%) patients with GEL-positive HPs. GEL was more commonly observed in HPs having symptoms (p = 0.029), a larger size (p = 0.028), and an infiltrative growth pattern (p = 0.006). In addition, periductal lymphoplasmacytic infiltration and fibrosis (both p < 0.001), interstitial fibrosis (p = 0.017), acinar neutrophilic infiltration (p = 0.032), venulitis (p = 0.050), acinar ductal metaplasia (ADM; p = 0.040), and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; p < 0.001) were more commonly seen in HPs with GEL than in those without GEL. Inflammatory bowel disease was present only in one patient with GEL-negative HP. CONCLUSIONS: GELs are detected in a subset of HPs without clinical evidence of AIP. Therefore, for the diagnosis of AIP, GEL should be carefully interpreted with the context of other histologic, clinical, and radiologic findings.

Clinicopathologic and Molecular Characteristics of and Diagnostic Dilemmas in Invasive Breast Carcinoma with Choriocarcinomatous Pattern apropos a New Case: A Literature Review with New Findings.

BACKGROUND: Invasive breast carcinoma with a choriocarcinomatous pattern (IBC-CP) is extremely rare, and its molecular basis is yet unclear. The choriocarcinomatous pattern is characterized by the biphasic arrangement of multinucleated syncytiotrophoblast-like cells around clusters of monotypic tumor cells in a hemorrhagic background, along with ß-human chorionic gonadotropin (ß-hCG) expression. The differentiation of IBC-CP from metastatic choriocarcinoma of the breast (MC-B) is difficult due to the histologic similarity. METHODS: Based on a literature review and our own case, the clinicopathologic differences between IBC-CP patients (n = 17) and MC-B patients (n = 8) were analyzed. Moreover, in our case of IBC-CP, next-generation sequencing (NGS) comparative analysis was conducted for both choriocarcinomatous and invasive breast carcinoma (IBC) components. RESULTS: Compared to the MC-B patients, the IBC-CP patients were older (p < 0.001) and less frequently had past histories of gestational trophoblastic disease/pregnancy/abortion (p = 0.001) and distant metastases (p = 0.005). Our case, a 49-year-old female patient, presented with masses in the right breast and axilla. Following neoadjuvant chemotherapy, a radical mastectomy found an 8.5-cm-sized tumor. Microscopically, multinucleated syncytiotrophoblast-like cells were observed around mononuclear tumor cells with hemorrhage and necrosis. Some tumor cells showed ß-hCG immunopositivity, which was compatible with IBC-CP. NGS results showed a missense mutation in exon 5 of the TP53 gene in both the choriocarcinomatous and IBC components. Meanwhile, copy number loss in the PTEN gene was only identified in the choriocarcinomatous components. CONCLUSION: The present IBC-CP case is triple-negative breast cancer with TP53 mutation. The PTEN gene may be associated with choriocarcinomatous differentiation. Obtaining a medical history is mandatory to exclude metastatic lesions.

Pancreatic Cysts after Endoscopic Ultrasonography-Guided Ethanol and/or Paclitaxel Ablation Therapy: Another Mimic of Pancreatic Pseudocysts.

BACKGROUND: Endoscopic ultrasound-guided ablation (EUS-A) therapy is a minimally invasive procedure for pancreatic-cystic tumors in patients with preoperative comorbidities or in patients who are not indicated for surgical resection. However, histopathologic characteristics of pancreatic cysts after ablation have not been well-elucidated. METHODS: Here, we analyzed pathological findings of 12 surgically resected pancreatic cysts after EUS-A with ethanol and/or paclitaxel injection. RESULTS: Mean patient age was 49.8 ± 13.6 years with a 0.3 male/female ratio. Clinical impression before EUS-A was predominantly mucinous cystic neoplasms. Mean cyst size before and after ablation therapy was similar (3.7 ± 1.0 cm vs. 3.4 ± 1.6 cm; p = 0.139). Median duration from EUS-A to surgical resection was 18 (range, 1-59) months. Mean percentage of the residual neoplastic lining epithelial cells were 23.1 ± 37.0%. Of the resected cysts, 8 cases (67%) showed no/minimal (<5%) residual lining epithelia, while the remaining 4 cases (33%) showed a wide range of residual mucinous epithelia (20-90%). Ovarian-type stroma was noted in 5 cases (42%). Other histologic features included histiocytic aggregation (67%), stromal hyalinization (67%), diffuse egg shell-like calcification along the cystic wall (58%), and fat necrosis (8%). CONCLUSION: Above all, diffuse egg shell-like calcification along the pancreatic cystic walls with residual lining epithelia and/or ovarian-type stroma were characteristics of pancreatic cysts after EUS-A. Therefore, understanding these histologic features will be helpful for precise pathological diagnosis of pancreatic cystic tumor after EUS-A, even without knowing the patient's history of EUS-A.

Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

A multicenter study of interobserver variability in pathologic diagnosis of papillary breast lesions on core needle biopsy with WHO classification.

BACKGROUND: Papillary breast lesions (PBLs) comprise diverse entities from benign and atypical lesions to malignant tumors. Although PBLs are characterized by a papillary growth pattern, it is challenging to achieve high diagnostic accuracy and reproducibility. Thus, we investigated the diagnostic reproducibility of PBLs in core needle biopsy (CNB) specimens with World Health Organization (WHO) classification. METHODS: Diagnostic reproducibility was assessed using interobserver variability (kappa value, κ) and agreement rate in the pathologic diagnosis of 60 PBL cases on CNB among 20 breast pathologists affiliated with 20 medical institutions in Korea. This analysis was performed using hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin 5 (CK5) and p63. The pathologic diagnosis of PBLs was based on WHO classification, which was used to establish simple classifications (4-tier, 3-tier, and 2-tier). RESULTS: On WHO classification, H&E staining exhibited 'fair agreement' (κ = 0.21) with a 47.0% agreement rate. Simple classifications presented improvement in interobserver variability and agreement rate. IHC staining increased the kappa value and agreement rate in all the classifications. Despite IHC staining, the encapsulated/solid papillary carcinoma (EPC/SPC) subgroup (κ = 0.16) exhibited lower agreement compared to the non-EPC/SPC subgroup (κ = 0.35) with WHO classification, which was similar to the results of any other classification systems. CONCLUSIONS: Although the use of IHC staining for CK5 and p63 increased the diagnostic agreement of PBLs in CNB specimens, WHO classification exhibited a higher discordance rate compared to any other classifications. Therefore, this result warrants further intensive consensus studies to improve the diagnostic reproducibility of PBLs with WHO classification.

Expression of HER2 and Mismatch Repair Proteins in Surgically Resected Gallbladder Adenocarcinoma.

BACKGROUND: Gallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs. MATERIALS AND METHODS: To determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively. RESULTS: Three of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status. CONCLUSION: MMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

Tumor Microenvironmental Prognostic Risk in Primary Operable Small Intestinal Adenocarcinoma.

The tumor microenvironment (TME) has become an important area of investigation with respect to improving prognosis in malignancies. Here we evaluated TME prognostic risk in small intestinal adenocarcinomas based on histologic assessment of tumor budding at the peritumoral-invasive front (pTB) and stromal tumor-infiltrating lymphocytes (sTILs). pTB and sTILs were analyzed in 230 surgically resected small intestinal adenocarcinomas, as recommended by the International Tumor Budding Consensus Conference (ITBCC) and the International TILs Working Group (ITWG). On the basis of high levels of pTB count (≥10) and sTIL density (≥20%), we combined pTB and sTIL to produce a collective TME-based prognostic risk index: low-risk (pTBLow/sTILHigh; n=39, 17.0%), intermediate-risk (pTBLow/sTILLow or pTBHigh/sTILHigh; n=99, 43.0%), and high-risk groups (pTBHigh/sTILLow; n=92, 40.0%). TME risk index provided better prognostic stratification than the individual pTB and sTIL (14.9 vs. 6.7 vs. 10.3). Tumors with higher TME prognostic risk were associated with an infiltrative growth pattern and nonintestinal immunophenotype (both P=0.001), pancreatic invasion (P=0.010), lymphovascular (P<0.001) or perineural invasion (P=0.006), higher T-category (P<0.001), N-category (P=0.004), and stage grouping (P=0.002), and KRAS mutation (P=0.008). In multivariate analysis, higher TME prognostic risk index (P<0.001), distal tumor location and nonintestinal immunophenotype (both P=0.001), higher N-category (P<0.001), and microsatellite stable (P=0.015) were worse-independent prognosticators. TME prognostic risk index consistently stratified patient survival regardless of tumor location (P<0.001 in proximal; P=0.002 in distal), stages (P<0.001 in lower stages I to II; P=0.028 in stage III), and DNA mismatch repair gene status (P<0.001 in microsatellite stable; P=0.001 in microsatellite instability). TME risk index is a powerful prognostic predictor for risk stratification of patients with small intestinal adenocarcinoma.

Hot snare polypectomy versus endoscopic mucosal resection for small colorectal polyps: a randomized controlled trial.

BACKGROUND AND AIMS: This study was performed to compare endoscopic mucosal resection (EMR) with hot snare polypectomy (HSP) in terms of the complete resection rate and the incidence of adverse events for resecting small (5-10 mm) colorectal polyps. METHODS: Small colorectal polyps (5-10 mm) with neoplastic features were randomly allocated to either the HSP or EMR group. A submucosal injection was performed prior to hot snaring in the EMR group only. Complete resection was defined as the absence of neoplastic tissue from two additional biopsies of the polypectomy site. R0 resection was defined as the absence of neoplastic tissue at the margin of the resected specimen. RESULTS: A total of 362 colon polyps from 272 patients were included, and 167 polyps in the HSP group and 155 polyps in the EMR group were analyzed. Between the polypectomy techniques, there was no significant difference in the complete resection rates, which were 96.4% (161/167) in the HSP group and 95.5% (148/155) in the EMR group (P = 0.67). The R0 resection rate in the HSP and EMR groups was significantly different, with 49.7% (83/167) and 74.8% (116/155), respectively (P < 0.001). There was no significant difference in the incidence of adverse events between the two groups. CONCLUSIONS: The complete resection rates for small (5-10 mm) polyps were not different between HSP and EMR. TRIAL REGISTRY: ClincialTrials.gov number NCT02239536.

Prognostic implication of SOX2 expression in small intestinal adenocarcinoma.

The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2-) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRASMT) (11.1 months) had significantly shorter overall survival than those with SOX2-/KRASWT (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.

Reply to Comment on "Jun, S.Y.; et al. Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma" Cancers 2020, 12, 2199.

We thank Giuffrida et al [...].

Loss of HES-1 Expression Predicts a Poor Prognosis for Small Intestinal Adenocarcinoma Patients.

Objective: Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to KRAS mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well-understood. Materials and Methods: To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and KRAS genotype, in 185 small intestinal adenocarcinomas. Results: The loss of HES-1 expression (HES-1Loss) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (P = 0.018), pancreatic invasion (P = 0.005), high grade (P = 0.043), and non-tubular histology (P = 0.004). Specifically, in tumors with mutant KRAS (KRAS MT), HES-1Loss was related to proximal location (P = 0.024), high T and N categories (P = 0.005 and 0.047, respectively), and pancreatic invasion (P = 0.004). Patients with HES-1Loss showed worse overall survival compared to those with intact HES-1 (HES-1Intact) (P = 0.013). Patients with HES-1Loss/KRAS MT (median, 17.3 months) had significantly worse outcomes than those with HES-1Intact/KRAS WT (39.9 months), HES-1Intact/KRAS MT (47.6 month), and HES-1Loss/KRAS WT (36.2 months; P = 0.010). By multivariate analysis, HES-1Loss (hazard ratio = 1.55, 95% confidence interval (CI), 1.07-2.26; P = 0.022) remained an independent prognostic factor. Conclusion: HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.

Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5-9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I-II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.