Publications by authors named "Seung-Mo Hong"

296 Publications

Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma cannot be predicted by the 2019 World Health Organization classification.

Asian J Surg 2021 Mar 22. Epub 2021 Mar 22.

Department of Surgery and Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address:

Background: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification.

Methods: This retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019.

Results: During the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 WHO classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell features. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. 2019 WHO classification was not associated with post-resection prognosis.

Conclusions: 2019 WHO classification was not associated with post-resection prognosis, thus was considered as simplified histologic classification requiring prognostic validation. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.
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http://dx.doi.org/10.1016/j.asjsur.2021.03.002DOI Listing
March 2021

Post-resection prognosis of patients with hepatic epithelioid hemangioendothelioma.

Ann Surg Treat Res 2021 Mar 26;100(3):137-143. Epub 2021 Feb 26.

Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare borderline vascular tumor. This retrospective, single-center study evaluated the outcomes of hepatic resection (HR) in patients with hepatic EHE.

Methods: Over the 10-year period from 2009 to 2018, 11 patients with hepatic EHE underwent HR, accounting for 0.1% of the 11,979 adults who underwent HR at our center. Diagnosis of hepatic EHE was confirmed by immunohistochemical staining for CD34, CD31, and factor VIII-related antigen.

Results: The 11 patients included 9 females (81.8%) and 2 males (18.2%) with mean age of 43.5 ± 13.6 years. Preoperative imaging resulted in a preliminary diagnosis of suspected liver metastasis or EHE, with 9 patients (81.8%) undergoing liver biopsy. No patient presented with abnormally elevated concentrations of liver tumor markers. The extents of HR were determined by tumor size and location from trisectionectomy to partial hepatectomy. All patients recovered uneventfully from HR. Five patients showed tumor recurrence, with 4 receiving locoregional treatments for recurrent lesions. The 1-, 3- and 5-year disease-free survival rates were 90.9%, 54.5%, and 54.5%, respectively. Currently, all patients remain alive and are doing well. Univariate analysis on tumor recurrence showed that tumor size ≥ 4 cm was significantly associated with tumor recurrence (P = 0.032), but tumor number ≥ 4 was not related to (P = 0.24).

Conclusion: Hepatic EHE is a rare form of primary liver tumor often misdiagnosed as a metastatic tumor. Because of its malignant potential, HR is indicated if possible. HR plus, when necessary, treatment of recurrence yields favorable overall survival rates in patients with hepatic EHE.
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http://dx.doi.org/10.4174/astr.2021.100.3.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943284PMC
March 2021

A comparison between 25-gauge and 22-gauge Franseen needles for endoscopic ultrasound-guided sampling of pancreatic and peripancreatic masses: a randomized non-inferiority study.

Endoscopy 2021 Mar 2. Epub 2021 Mar 2.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background:  Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and fine-needle biopsy (FNB) are the current standard of care for sampling pancreatic and peripancreatic masses. Recently, a 22G EUS-FNB needle with Franseen geometry was developed, and this device was also introduced in a 25G platform. We compared the performance of the 25G and 22G Franseen needles for EUS-guided sampling of pancreatic and peripancreatic solid masses.

Methods:  We conducted a parallel-group randomized non-inferiority trial at a tertiary-care center from November 2018 to May 2019. The primary outcome was the quality of the histologic core assessed using the Gerke score. The optimal histologic core is indicated by a Gerke score of 4 or 5, which enables optimal histologic interpretation. The overall diagnostic accuracy and adverse event rate were also evaluated.

Results:  140 patients were enrolled and randomized (1:1) to the 25G and 22G groups. Tissue acquisition by EUS-FNB was successful in all patients. The optimal histologic core procurement rate was 87.1 % (61/70) for the 25G needle vs. 97.1 % (68/70) for the 22G; difference -10 % (95 % confidence interval -17.35 % to -2.65 %). High quality specimens were more frequently obtained in the 22G group than in the 25G group (70.0 % [49/70] vs. 28.6 % [20 /70], respectively;  < 0.001). The overall diagnostic accuracy did not differ between the groups (97.4 % for 25G vs. 100 % for 22G).

Conclusions: The 25G Franseen needle was inferior to the 22G needle in histologic core procurement. Therefore, for cases in which tissue architecture is pivotal for diagnosis, a 22G needle, which procures relatively higher quality specimens than the 25G needle, should be used.
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http://dx.doi.org/10.1055/a-1369-8610DOI Listing
March 2021

Clinicopathological features and post-resection outcomes of inflammatory pseudotumor of the liver.

Ann Hepatobiliary Pancreat Surg 2021 Feb;25(1):34-38

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Backgrounds/aims: Hepatic inflammatory pseudotumor (HIPT) is a rare disease characterized by chronic infiltration of inflammatory cells and area of fibrosis. The objective of this retrospective observational study was to investigate clinicopathological features and outcomes of patients who underwent hepatic resection (HR) for HIPT.

Methods: From 2009 to 2018, seven patients with HIPT underwent HR, accounting for 0.06% of 11,979 adults who underwent HR at our center.

Results: These seven patients included five men and two women. Their mean age was 62.3±11.6 years. In four patients with hepatitis B virus (HBV)-associated liver cirrhosis or chronic hepatitis, liver masses were suspected of hepatocellular carcinoma (HCC) or combined HCC-cholangiocarcinoma based on imaging studies. In three patients without HBV infection, two patients were suspected of HCC, for whom liver biopsy was not performed. One patient was suspected of liver abscess or HIPT, for whom percutaneous liver biopsy was performed and the mass was diagnosed with HIPT. However, this patient underwent HR owing to abdominal pain. No patient presented with abnormally elevated levels of alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, or CA19-9. During a mean follow-up period of 76.4±34.8 months, no patient experienced recurrence of HIPT.

Conclusions: HIPT, a rare form of liver disease, is often misdiagnosed as malignant liver tumor. Active histological diagnosis is warranted for patients with suspected HIPT to avoid unnecessary operation. HR can be indicated in case of diagnostic ambiguity of HIPT or under a clinical diagnosis of malignant liver tumor.
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http://dx.doi.org/10.14701/ahbps.2021.25.1.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952659PMC
February 2021

Clinicopathological features and post-resection outcomes of hepatocellular adenoma.

Ann Hepatobiliary Pancreat Surg 2021 Feb;25(1):25-33

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Backgrounds/aims: Hepatocellular adenomas (HCA) are rare benign liver tumors with the potential of malignant transformation and risk of bleeding. We investigated the clinicopathological features and outcomes of HCA in 19 patients who underwent surgical resection.

Methods: This retrospective observational study included 19 patients who underwent hepatic resection during a 9-year period from 2011 to 2019.

Results: The incidence of HCA was 0.18% of all hepatic resection cases during the study period. The mean age of the patients was 34.3±9.6 years, and 12 patients (63.2%) were female. Abdominal pain was present as initial clinical manifestation in 5 patients and the other 14 patients had no specific symptoms. HCA was diagnosed in 7 out of 8 patients who underwent liver biopsy. R0 resection was performed in 18 patients (94.7%) and laparoscopic liver resection was performed in 11 patients (57.9%). The mean tumor size was 5.6±3.6 cm and 17 patients had a single tumor. Immunohistochemical analysis of the resected tumor specimens revealed hepatocyte-nuclear-factor-1 mutated HCA in 2 (10.5%), -catenin-mutated HCA in 2 (10.5%), inflammatory HCA in 12 (63.2%) and unclassified HCA in 3 (15.8%). There were no pathognomonic findings in the preoperative liver imaging studies among these four groups. Currently, all patients are alive with a mean follow-up period of 40.1±26.3 months. One patient showed residual tumors after incomplete resection.

Conclusions: Surgical resection may be indicated if imaging studies show diagnostic ambiguity, growing tumor or symptomatic mass. Because of the risk of tumor recurrence and malignant transformation, long-term follow-up is necessary.
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http://dx.doi.org/10.14701/ahbps.2021.25.1.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952660PMC
February 2021

Profiling of conditionally reprogrammed cell lines for in vitro chemotherapy response prediction of pancreatic cancer.

EBioMedicine 2021 Mar 25;65:103218. Epub 2021 Feb 25.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. Electronic address:

Background: The establishment of patient-derived models for pancreatic ductal adenocarcinoma (PDAC) using conventional methods has been fraught with low success rate, mainly because of the small number of tumour cells and dense fibrotic stroma. Here, we sought to establish patient-derived model of PDAC and perform genetic analysis with responses to anticancer drug by using the conditionally reprogrammed cell (CRC) methodology.

Methods: We performed in vitro and in vivo tumourigenicity assays and analysed histological characteristics by immunostaining. We investigated genetic profiles including mutation patterns and copy number variations using targeted deep sequencing and copy-number analyses. We assessed the responses of cultured CRCs to the available clinical anticancer drugs based on patient responsiveness.

Findings: We established a total of 28 CRCs from patients. Of the 28 samples, 27 showed KRAS mutations in codon 12/13 or codon 61. We found that somatic mutations were shared in the primary-CRC pairs and shared mutations included key oncogenic mutations such as KRAS (9 pairs), TP53 (8 pairs), and SMAD4 (3 pairs). Overall, CRCs preserved the genetic characteristics of primary tumours with high concordance, with additional confirmation of low-AF NPM1 mutation in CRC (35 shared mutations out of 36 total, concordance rate=97.2%). CRCs of the responder group were more sensitive to anticancer agents than those of the non-responder group (P < 0.001).

Interpretation: These results show that a pancreatic cancer cell line model can be efficiently established using the CRC methodology, to better support a personalized therapeutic approach for pancreatic cancer patients.

Funding: 2014R1A1A1006272, HI19C0642-060019, 2019R1A2C2008050, 2020R1A2C209958611, and 2020M3E5E204028211.
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http://dx.doi.org/10.1016/j.ebiom.2021.103218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921470PMC
March 2021

Long-term outcomes of endoscopic papillectomy for early-stage cancer in duodenal ampullary adenoma: Comparison to surgical treatment.

J Gastroenterol Hepatol 2021 Feb 18. Epub 2021 Feb 18.

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.

Background And Aim: While recent evidences support endoscopic resection as curative in ampullary tumors with high-grade intraepithelial neoplasia, only small case series have reported endoscopic management of early-stage ampullary cancer; thus, radical surgery remains the only accepted treatment modality. We evaluated the long-term outcomes of early ampullary adenocarcinoma administered endoscopic management.

Methods: We retrospectively reviewed electronic medical records of 715 patients undergoing endoscopic papillectomy (EP) in a single tertiary medical center in Korea in 2004-2016. We included patients incidentally diagnosed with early-stage adenocarcinoma (Tis and T1a, American Joint Committee on Cancer 8th edition) after EP and with >2 years of follow-up data and analyzed their demographics, histopathologic data, and clinical outcomes.

Results: Among 70 total patients in the EP-alone (n = 42) and subsequent surgery (n = 28) groups, we observed no significant differences in demographics or tumor size (2.0 ± 0.6 vs 1.9 ± 0.5 cm, P = 0.532), histologic grade (P = 0.077), tumor extent (P = 1.000), lymphovascular invasion (2.4% vs 10.7%, P = 0.344), or complete resection rates (57.1% vs 57.1%, P = 1.000) between groups. Adenocarcinoma lesions were larger in the subsequent surgery group (0.7 ± 0.5 vs 1.1 ± 0.7 cm, P = 0.002). The EP-alone group received more additional ablative treatment (42.9% vs 14.3%, P = 0.024). The 5-year disease-free and cancer-free survival rates were 79.1% vs 87.4% (P = 0.111) and 93.5% versus 87.4% (P = 0.726), respectively, and did not differ significantly between groups.

Conclusions: Endoscopic papillectomy followed by endoscopic surveillance showed long-term outcomes comparable with surgical resection for early ampullary cancer and maybe curable alternative to surgery for incidentally found early-stage ampullary cancer, especially in patients unfit for or refusing radical surgery.
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http://dx.doi.org/10.1111/jgh.15462DOI Listing
February 2021

A Clinically Applicable 24-Protein Model for Classifying Risk Subgroups in Pancreatic Ductal Adenocarcinomas using Multiple Reaction Monitoring-Mass Spectrometry.

Clin Cancer Res 2021 Feb 16. Epub 2021 Feb 16.

Department of Biomedical Engineering, Seoul National University College of Medicine

Purpose: Pancreatic ductal adenocarcinoma (PDAC) subtypes have been identified using various methodologies. However, it is a challenge to develop classification system applicable to routine clinical evaluation. We aimed to identify risk subgroups based on molecular features and develop a classification model that was more suited for clinical applications.

Experimental Design: We collected whole dissected specimens from 225 patients who underwent surgery at Seoul National University Hospital, between October 2009 and February 2018, in Korea. Target proteins with potential relevance to tumor progression or prognosis were quantified with robust quality controls. We used hierarchical clustering analysis to identify risk subgroups. A random forest classification model was developed to predict the identified risk subgroups, and the model was validated using transcriptomic datasets from external cohorts (N = 700), with survival analysis.

Results: We identified 24 protein features that could classify the four risk subgroups associated with patient outcomes: Stable; Exocrine-like; Activated; and Extracellular matrix (ECM)-Remodeling. The "Stable" risk subgroup was characterized by proteins that were associated with differentiation and tumor suppressors. "Exocrine-like" tumors highly expressed pancreatic enzymes. Two high-risk subgroups, "Activated" and "ECM-Remodeling," were enriched in such terms as cell cycle, angiogenesis, immuno-competence, tumor invasion-metastasis, and metabolic reprogramming. The classification model that included these features made prognoses with relative accuracy and precision in multiple cohorts.

Conclusions: We proposed PDAC risk subgroups and developed a classification model that may potentially be useful for routine clinical implementations, at the individual level. This clinical system may improve the accuracy of risk prediction and treatment guidelines.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3513DOI Listing
February 2021

Pancreatic cancer pathology viewed in the light of evolution.

Cancer Metastasis Rev 2021 Feb 8. Epub 2021 Feb 8.

Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA.

One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This "evolutionary view" creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.
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http://dx.doi.org/10.1007/s10555-020-09953-zDOI Listing
February 2021

Tumor Microenvironmental Prognostic Risk in Primary Operable Small Intestinal Adenocarcinoma.

Am J Surg Pathol 2021 Jan 13. Epub 2021 Jan 13.

Department of Pathology Clinical Research Center, Incheon St. Mary's Hospital Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

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.
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http://dx.doi.org/10.1097/PAS.0000000000001668DOI Listing
January 2021

Feasibility of HER2-Targeted Therapy in Advanced Biliary Tract Cancer: A Prospective Pilot Study of Trastuzumab Biosimilar in Combination with Gemcitabine Plus Cisplatin.

Cancers (Basel) 2021 Jan 6;13(2). Epub 2021 Jan 6.

Asan Medical Center, Department of Oncology, University of Ulsan College of Medicine, Seoul 05505, Korea.

The prognosis of advanced biliary tract cancer (BTC) is poor with the standard gemcitabine and cisplatin (GemCis) regimen. Given that the rates of human epidermal growth factor receptor 2 (HER2) positivity in BTC reaches around 15%, HER2-targeted therapy needs further investigation. This study aims to evaluate the preliminary efficacy/safety of first-line trastuzumab-pkrb plus GemCis in patients with advanced BTC. Patients with unresectable/metastatic HER2-positive BTC received trastuzumab-pkrb (on day 1 of each cycle, 8 mg/kg for the first cycle and 6 mg/kg for subsequent cycles), gemcitabine (1000 mg/m on day 1 and 8) and cisplatin (25 mg/m on day 1 and 8) every 3 weeks. Of the 41 patients screened, 7 had HER2-positive tumours and 4 were enrolled. The median age was 72.5 years (one male). Primary tumour locations included extrahepatic (N = 2) and intrahepatic (N = 1) bile ducts, and gallbladder (N = 1). Best overall response was a partial response in two patients and stable disease in two patients. Median progression-free survival (PFS) was 6.1 months and median overall survival (OS) was not reached. The most common grade 3 adverse event was neutropenia (75%), but febrile neutropenia did not occur. No patient discontinued treatment due to adverse events. Trastuzumab-pkrb with GemCis showed promising preliminary feasibility in patients with HER2-positive advanced BTC.
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http://dx.doi.org/10.3390/cancers13020161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825072PMC
January 2021

T2 gallbladder cancer shows substantial survival variation between continents and this is not due to histopathologic criteria or pathologic sampling differences.

Virchows Arch 2021 Jan 7. Epub 2021 Jan 7.

Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Davutpasa Cad No 4., Topkapi, Istanbul, Turkey.

Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.
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http://dx.doi.org/10.1007/s00428-020-02968-5DOI Listing
January 2021

Desmin and CD31 immunolabeling for detecting venous invasion of the pancreatobiliary tract cancers.

PLoS One 2020 30;15(11):e0242571. Epub 2020 Nov 30.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Although venous invasion (VI) is a poor prognostic factor for patients with pancreatobiliary tract cancers, its histopathologic characteristics have not been well described. We evaluated the patterns of VI and the added benefit provided by CD31, desmin, and dual CD31‒desmin immunolabeling for identification of VI. We included 120 surgically resected pancreatobiliary tract cancer cases-59 cases as a test set with known VI and 61 cases as a validation set without information of VI. VI was classified into three patterns: intraepithelial neoplasia-like (IN-like), conventional, and destructive. Hematoxylin and eosin (H&E) staining and CD31, desmin, and dual CD31‒desmin immunolabeling were performed. Foci number and patterns of VI were compared with the test and validation sets. More foci of VI were detected by single CD31 (P = 0.022) than H&E staining in the test set. CD31 immunolabeling detected more foci of the conventional pattern of VI, and desmin immunolabeling detected more foci of the destructive pattern (all, P < 0.001). Dual CD31‒desmin immunolabeling identified more foci of VI (P = 0.012) and specifically detected more foci of IN-like (P = 0.045) and destructive patterns (P < 0.001) than H&E staining in the validation set. However, dual CD31‒desmin immunolabeling was not helpful for detecting the conventional pattern of VI in the validation set. Patients with VI detected by dual CD31‒desmin immunolabeling had shorter disease-free survival (P <0.001) than those without VI. VI detected by dual CD31‒desmin immunolabeling was a worse prognostic indicator (P = 0.009). More foci of VI could be detected with additional single CD31 or dual CD31‒desmin immunolabeling. The precise evaluation of VI with dual CD31‒desmin immunolabeling can provide additional prognostic information for patients with surgically resected pancreatobiliary tract cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242571PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703967PMC
January 2021

Prognostic implication of SOX2 expression in small intestinal adenocarcinoma.

Virchows Arch 2020 Oct 25. Epub 2020 Oct 25.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

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 (KRAS) (11.1 months) had significantly shorter overall survival than those with SOX2-/KRAS (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.
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http://dx.doi.org/10.1007/s00428-020-02946-xDOI Listing
October 2020

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

Cancers (Basel) 2020 Oct 15;12(10). Epub 2020 Oct 15.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

We thank Giuffrida et al [...].
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http://dx.doi.org/10.3390/cancers12102987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602524PMC
October 2020

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic microcystic serous cystic neoplasms: a retrospective study.

Endoscopy 2020 Oct 15. Epub 2020 Oct 15.

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.

BACKGROUND : Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been increasingly used for the management of various solid pancreatic tumors. This study aimed to evaluate the feasibility and safety of EUS-RFA for serous cystic neoplasms (SCNs). METHODS : 13 patients with microcystic SCNs with honeycomb appearance underwent EUS-RFA using a 19-gauge RFA needle. Before ablation, cystic fluid was aspirated until a thin layer of fluid remained. RESULTS : EUS-RFA was successful in all patients. Seven patients underwent a single session and the remaining six patients underwent a second session of EUS-RFA. One patient (7.7 %) experienced self-limited abdominal pain after EUS-RFA. During a median follow-up period of 9.21 months (interquartile range [IQR] 5.93 - 15.38), the median volume of the SCNs decreased from 37.82 mL (IQR 15.03 - 59.53) at baseline to 10.95 mL (IQR 4.79 - 32.39) at the end of follow-up. A radiologic partial response was achieved in eight patients (61.5 %). CONCLUSIONS : EUS-RFA is technically feasible and showed an acceptable rate of adverse events for patients with SCNs. A long-term follow-up study is required to evaluate the efficacy of EUS-RFA.
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http://dx.doi.org/10.1055/a-1250-7786DOI Listing
October 2020

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Mod Pathol 2021 01 12;34(1):4-12. Epub 2020 Oct 12.

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.
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http://dx.doi.org/10.1038/s41379-020-00683-9DOI Listing
January 2021

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

Front Oncol 2020 19;10:1427. Epub 2020 Aug 19.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to 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. 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 genotype, in 185 small intestinal adenocarcinomas. The loss of HES-1 expression (HES-1) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category ( = 0.018), pancreatic invasion ( = 0.005), high grade ( = 0.043), and non-tubular histology ( = 0.004). Specifically, in tumors with mutant (), HES-1 was related to proximal location ( = 0.024), high T and N categories ( = 0.005 and 0.047, respectively), and pancreatic invasion ( = 0.004). Patients with HES-1 showed worse overall survival compared to those with intact HES-1 (HES-1) ( = 0.013). Patients with HES-1/ (median, 17.3 months) had significantly worse outcomes than those with HES-1/ (39.9 months), HES-1/ (47.6 month), and HES-1/ (36.2 months; = 0.010). By multivariate analysis, HES-1 (hazard ratio = 1.55, 95% confidence interval (CI), 1.07-2.26; = 0.022) remained an independent prognostic factor. HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.
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http://dx.doi.org/10.3389/fonc.2020.01427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466551PMC
August 2020

Comprehensive histological evaluation with clinical analysis of venous invasion in pancreatic ductal adenocarcinoma: From histology to clinical implications.

Pancreatology 2020 Oct 25;20(7):1486-1494. Epub 2020 Aug 25.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs.

Methods: Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (H&E)-stained slides.

Results: Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps < .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps < .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (>4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps < .05).

Conclusion: Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.
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http://dx.doi.org/10.1016/j.pan.2020.08.015DOI Listing
October 2020

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer.

Cancer Res Treat 2021 Jan 31;53(1):162-171. Epub 2020 Aug 31.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated.

Materials And Methods: A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core.

Results: The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS.

Conclusion: The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.
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http://dx.doi.org/10.4143/crt.2020.704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812013PMC
January 2021

CT-determined resectability of borderline resectable and unresectable pancreatic adenocarcinoma following FOLFIRINOX therapy.

Eur Radiol 2021 Feb 26;31(2):813-823. Epub 2020 Aug 26.

Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Objectives: We aimed to assess the ability of CT-determined resectability, as defined by a recent version of NCCN criteria, and associated CT findings to predict margin-negative (R0) resection in patients with PDAC after neoadjuvant FOLFIRINOX chemotherapy.

Methods: Sixty-four patients (36 men and 28 women; mean age, 58.8 years) with borderline resectable or unresectable PDAC who received neoadjuvant FOLFIRINOX were evaluated retrospectively. CT findings were independently assessed by two abdominal radiologists according to NCCN criteria (version 3. 2019). Tumor resectability was classified as resectable, borderline resectable, or unresectable, and change in resectability was classified as regression, stability, or progression. The associations of R0 resection rate with CT-determined resectability and change in resectability categories were evaluated, as were the sensitivity and specificity of NCCN criteria for R0 resection. Factors associated with R0 resection were identified by logistic regression analysis.

Results: R0 resection rate did not differ significantly among the resectable, borderline resectable, or unresectable PDAC (67-73%, p = 0.95) or among PDAC with regression, stability, or progression (56-77%, p = 0.39). The sensitivity and specificity for R0 resection were 67% and 37%, respectively, for resectability (resectable/borderline vs. unresectable) and 80% and 21%, respectively, for changes in resectability (regression/stable vs. progression). Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with R0 resection (p = 0.01).

Conclusion: CT-determined resectability after neoadjuvant FOLFIRINOX chemotherapy was relatively insensitive and non-specific for predicting R0 resection. Low-contrast enhancement of soft tissue contacting artery may increase the ability of CT to predict R0 resection.

Key Points: • Margin-negative resection rate of pancreatic cancer following FOLFIRINOX therapy did not differ among each resectability (67-73%, p = 0.95) based on NCCN criteria or changes in resectability categories (56-77%, p = 0.39). • The sensitivity and specificity for margin-negative resection were 67% and 37% for resectability (resectable/borderline vs. unresectable) and 80% and 21% for changes in resectability (regression/stable vs. progression). • Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with margin-negative resection (p = 0.01).
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http://dx.doi.org/10.1007/s00330-020-07188-8DOI Listing
February 2021

CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype.

Int J Mol Sci 2020 Aug 12;21(16). Epub 2020 Aug 12.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring / fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes ( < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs.
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http://dx.doi.org/10.3390/ijms21165794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461050PMC
August 2020

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma.

Cancers (Basel) 2020 Aug 6;12(8). Epub 2020 Aug 6.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

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; = 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.
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http://dx.doi.org/10.3390/cancers12082199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465895PMC
August 2020

Chromogranin A Expression in Rectal Neuroendocrine Tumors Is Associated With More Aggressive Clinical Behavior and a Poorer Prognosis.

Am J Surg Pathol 2020 11;44(11):1496-1505

Departments of Pathology.

Although rectal neuroendocrine tumors (NETs) with an L-cell phenotype and small size are generally less clinically serious, the new 2019 World Health Organization (WHO) classification system has categorized all of these lesions as malignant. Identifying biomarkers of rectal NETs is thus important for stratifying their clinical behavior. Chromogranin A protein expression was assessed in 538 endoscopically or surgically resected rectal NETs and compared with clinicopathologic factors to identify its clinical and prognostic significance. All of the rectal NETs analyzed (100%) were synaptophysin positive, but chromogranin A labeling was only detected in 111 cases (20.6%). Chromogranin A expression in the rectal NETs was more commonly associated with older age (50 y and older; P=0.013), male sex (P=0.002), radical resection (P=0.003), large tumor size (≥1 cm; P=0.038), muscularis propria invasion (P=0.002), lymphovascular (P=0.014) and perineural (P<0.001) invasion, an involved resection margin (P=0.028), and lymph node metastasis (P=0.003). Patients with chromogranin A expression had higher plasma chromogranin A levels (P=0.023) than those without chromogranin A expression during follow-up. The 10-year disease-free survival rate in rectal NET patients with chromogranin A expression (91.5%) was significantly shorter than the negative cases (99.7%) by both univariate (hazard ratio=14.438; 95% confidence interval: 2.911-71.598; P<0.001) and multivariate (hazard ratio=12.099; 95% confidence interval, 2.044-71.608; P=0.006) analyses. In summary, rectal NETs that are positive for chromogranin A are less common than those with synaptophysin expression and show more aggressive clinical behavior. Chromogranin A is therefore a prognostic indicator of higher recurrence risk in patients with endoscopically or surgically resected rectal NETs.
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http://dx.doi.org/10.1097/PAS.0000000000001526DOI Listing
November 2020

Distribution pattern of tumor infiltrating lymphocytes and tumor microenvironment composition as prognostic indicators in anorectal malignant melanoma.

Mod Pathol 2021 01 24;34(1):141-160. Epub 2020 Jul 24.

Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P < 0.001) compared to those in nonrecurrent and surviving patients. The high total TIL and tumor-associated macrophage (TAM) groups had significantly better overall survival outcomes compared to the low total TIL and TAM groups (P = 0.007 and P = 0.035, respectively). In addition, the presence of CD3 + TILs in the invasion front was an independent favorable prognostic indicator (P = 0.003, hazard ratio = 0.21, 95% confidential interval, 0.01-0.41). Patients with inflamed or brisk-infiltration type tumors also had a significantly better overall survival than that of patients with immune-desert/excluded and absent/non-brisk type tumors (P = 0.03 and P = 0.0023, respectively). In conclusion, TILs have a strong prognostic value in ARMM, and the quantification of TILs and an analysis of the TIL phenotype and infiltration pattern during pathological diagnosis are essential to guide treatment strategies and accurate prognosis in ARMM.
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http://dx.doi.org/10.1038/s41379-020-0633-xDOI Listing
January 2021

Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms.

J Pathol 2020 11 19;252(3):252-262. Epub 2020 Sep 19.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5515DOI Listing
November 2020

Lymph node size and its association with nodal metastasis in ductal adenocarcinoma of the pancreas.

J Pathol Transl Med 2020 Sep 21;54(5):387-395. Epub 2020 Jul 21.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Although lymph node metastasis is a poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC), our understanding of lymph node size in association with PDAC is limited. Increased nodal size in preoperative imaging has been used to detect node metastasis. We evaluated whether lymph node size can be used as a surrogate preoperative marker of lymph node metastasis.

Methods: We assessed nodal size and compared it to the nodal metastatic status of 200 patients with surgically resected PDAC. The size of all lymph nodes and metastatic nodal foci were measured along the long and short axis, and the relationships between nodal size and metastatic status were compared at six cutoff points.

Results: A total of 4,525 lymph nodes were examined, 9.1% of which were metastatic. The mean size of the metastatic nodes (long axis, 6.9±5.0 mm; short axis, 4.3±3.1 mm) was significantly larger than that of the non-metastatic nodes (long axis, 5.0±4.0 mm; short axis, 3.0±2.0 mm; all p<.001). Using a 10 mm cutoff, the sensitivity, specificity, positive predictive value, overall accuracy, and area under curve was 24.8%, 88.0%, 17.1%, 82.3%, and 0.60 for the long axis and 7.0%, 99.0%, 40.3%, 90.6%, and 0.61 for the short axis, respectively.

Conclusions: The metastatic nodes are larger than the non-metastatic nodes in PDAC patients. However, the difference in nodal size was too small to be identified with preoperative imaging. The performance of preoperative radiologic imaging to predict lymph nodal metastasis was not good. Therefore, nodal size cannot be used a surrogate preoperative marker of lymph node metastasis.
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http://dx.doi.org/10.4132/jptm.2020.06.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483027PMC
September 2020

Large tumor size, lymphovascular invasion, and synchronous metastasis are associated with the recurrence of solid pseudopapillary neoplasms of the pancreas.

HPB (Oxford) 2021 Feb 9;23(2):220-230. Epub 2020 Jul 9.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Solid pseudopapillary neoplasms (SPNs) of the pancreas have low malignant potential. However, malignant SPNs are not fully understood.

Methods: To evaluate risk factors affecting malignant potential, the clinicopathologic features of 375 surgically resected SPNs were compared.

Results: Fifty (13.3%) had malignant histologic features. Twenty-seven and 22 had perineural and lymphovascular invasions, respectively. Adjacent organ invasion was noted in 9 cases. Recurrence occurred in 8 cases. The median recurrence time after surgical resection was 67 months and was associated with a higher pT category (P = 0.001), lymphovascular invasion (P < 0.001), and synchronous metastasis (P < 0.001). SPN patients with malignant histologic features had worse recurrence-free survival (RFS; 10-year survival rate, 73.2%) than those without malignant histologic features (96.3%; P = 0.01). Patients with a higher pT category (P = 0.04), synchronous metastasis (P < 0.01), and lymphovascular invasion (P < 0.01) had worse RFS. Lymphovascular invasion (P = 0.042) and a higher T category (P = 0.002) were poor prognostic factors for recurrence.

Conclusion: Lymphovascular invasion and a higher T category were worse prognostic factors for recurrence in SPN patients with malignant histologic features. For SPN patients with malignant histologic features, a longer follow-up may be required.
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http://dx.doi.org/10.1016/j.hpb.2020.05.015DOI Listing
February 2021