Efficacy and Safety of Topical Corticosteroid Treatment under Occlusion for Severe Alopecia Areata in Children. A single-center retrospective analysis.

BACKGROUND: Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). AIM: We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in pediatric patients with severe AA. METHODS: We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 hours under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a Severity of Alopecia Tool (SALT) score of 20 or less at six months. We analyzed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus-pituitary-adrenal axis. RESULTS: Nineteen patients reached SALT 20 or less at the 6-month treatment. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of adrenal insufficiency. However, the cortisol level of the patients recovered to normal at least 1-month after lowering TCS potency or changing to non-steroidal treatments. LIMITATIONS: Retrospective design and small sample size. CONCLUSION: This study shows that a potent TCS occlusion may be a safe treatment option in pediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for pediatric AA.

Carbon footprint and cost reduction by endoscopic grading of gastric intestinal metaplasia using narrow-band imaging.

BACKGROUND AND AIM: Gastric intestinal metaplasia (GIM) is a high-risk factor for the development of gastric cancer. Narrow-band imaging (NBI) enables endoscopic grading of GIM (EGGIM). In the era of climate change, gastrointestinal endoscopists are expected to reduce greenhouse gas emissions and medical waste. Based on the diagnostic performance of NBI endoscopy, this study measured the environmental impact and reduced cost of implementing EGGIM during gastroscopy. METHODS: Using NBI endoscopy in 242 patients, EGGIM classification and operative link on GIM (OLGIM) staging were prospectively performed in five different areas (lesser and greater curvatures of the corpus and antrum, and the incisura angularis). We estimated the environmental impact and cost reduction of the biopsy procedures and pathological processing if EGGIM were used instead of OLGIM. RESULTS: The diagnostic accuracy of NBI endoscopy for GIM was 93.0-97.1% depending on the gastric area. When a high EGGIM score ≥ 5 was the cut-off value for predicting OLGIM stages III-IV, the area under the curve was 0.862, sensitivity was 81.9%, and specificity was 90.4%. The reduction in the carbon footprint by EGGIM was -0.4059 kg carbon dioxide equivalents per patient, equivalent to 1 mile driven by a gasoline-powered car. The cost savings were calculated to be $47.36 per patient. CONCLUSIONS: EGGIM is a reliable method for identifying high-risk gastric cancer patients, thereby reducing the carbon footprint and medical costs in endoscopy practice.

A Standardized Pathology Report for Gastric Cancer: 2nd Edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

Extrapleural Malignant Solitary Fibrous Tumor Presenting as Invasive Bilateral Paravertebral Tumors: A Case Report.

Solitary fibrous tumors (SFTs) commonly arise from the pleura and are mostly benign. However, they may develop anywhere in the body, and 10%-30% are malignant. Classically, SFTs appear as solitary enhancing masses, and bilateral presentation is extremely rare. In this case, an 88-year-old male presented with back pain and a history of chronic tuberculous empyema. Imaging studies revealed bilateral paravertebral masses with aggressive radiologic features, which were speculatively presumed as thoracic malignancies in association with chronic empyema. Herein, we report a unique case of bilateral paravertebral malignant SFTs that were accurately diagnosed with a CT-guided coaxial needle biopsy.

A standardized pathology report for gastric cancer: 2nd edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

Resection speed of endoscopic submucosal dissection according to the location of gastric neoplasia: a learning curve using cumulative sum analysis.

BACKGROUND: There is few study evaluating the relationship between endoscopic submucosal dissection (ESD) resection speed and the lesion characteristics of gastric neoplasia. We investigated the learning curve of consecutive ESDs using cumulative sum (CUSUM) analysis. METHODS: A total of 356 ESDs performed by a single endoscopist were grouped chronologically into three learning periods. The ESD procedure was defined to be fast when resection speed was > 9.0 cm2/hour. The CUSUM method was used to assess the number of ESDs required for achieving proficiency and mastery. RESULTS: Mean resection speed was significantly faster in Phase III (15.1 cm2/hour) compared to those in Phase I (9.3 cm2/hour) and II (11.4 cm2/hour) (p < 0.001). Tumors in the stomach's upper and middle third location were significantly associated with difficulty in attaining the fast resection speed (odds ratios, 0.05 and 0.36) compared to the lower third location. The number of ESDs required to achieve a competency for fast resection was 15 for tumors in the lower third of the stomach and 98 for those in the upper/middle third location, respectively. In the lower third location of the tumor, the CUSUM curve revealed that 75 cases were needed to achieve proficiency and 174 cases to achieve mastery. However, mastery was not achieved in ESD for the upper/middle third tumor during the study period. CONCLUSION: The time required to achieve relevant competency in gastric ESD depends on the tumor location.

Primary Colonic Epithelioid Angiosarcoma with Hepatic Metastasis: A Case Report.

Colonic angiosarcoma is an extremely rare and aggressive malignant tumor with poor prognosis. We report a case of colonic epithelioid angiosarcoma with colonic obstruction and rapidly progressive hepatic metastasis in a 44-year-old female. Abdominal CT revealed a heterogeneously enhancing irregular mass in the ascending colon, causing proximal bowel distension. The patient underwent surgery, and histopathological examination revealed a poorly differentiated carcinoma. A follow-up liver dynamic MRI after 4 months revealed newly developed diffusely scattered numerous small nodules in both hepatic lobes with peripheral and nodular marked arterial hyperenhancement, raising the suspicion of hepatic angiosarcoma. A pathologic second opinion was obtained, and additional immunohistochemistry revealed colonic epithelioid angiosarcoma. The patient showed progressive hepatic metastasis on follow-up abdominal CT after 6 months and died 8 months after initial diagnosis. We describe an educational case of colonic angiosarcoma, a rare malignant tumor, with rapidly progressive hepatic metastasis that showed radiologic findings suggestive of angiosarcoma and enabled a re-diagnosis for proper treatment and prognosis prediction.

Current guidelines for Helicobacter pylori treatment in East Asia 2022: Differences among China, Japan, and South Korea.

Helicobacter pylori (H. pylori) infection is highly prevalent in East Asia. The overall seroprevalence rate of H. pylori infection is 44.2% in China, 37.6%-43.2% in Japan, and 51.0% in South Korea. H. pylori can cause peptic ulcer disease and gastric cancer. East Asian countries have high rates of gastric cancer (age-standardized incidence rate: 20-30 per 100000). The Kyoto global consensus report emphasized that H. pylori gastritis should be considered the main cause for the development of gastric cancer. H. pylori treatment guidelines in China, Japan, and South Korea have recently been revised according to data from each of those countries. However, emerging antibiotic resistance is an important barrier to H. pylori eradication. The recommended H. pylori treatment regimens differ among those three East Asian countries. In this review, recent guidelines and up-to-date research on H. pylori treatment regimens from China, Japan, and South Korea are discussed.

Clinical Feasibility of Shear Wave Dispersion Slope for Noninvasive Diagnosis of Nonalcoholic Steatohepatitis in Patients With Morbid Obesity: Preliminary Results Using US Shear Wave Elastography.

ABSTRACT: We aimed to investigate the clinical feasibility of shear wave dispersion slope for assessing nonalcoholic steatohepatitis (NASH) in patients with morbid obesity before bariatric surgery.This prospective study collected data from 25 participants who received liver biopsy during bariatric surgery between February 2019 and December 2020. All participants underwent ultrasonography shear wave elastography before surgery and shear wave speed and shear wave dispersion slope were measured. Liver specimens were evaluated by 1 pathologist scored histologically for nonalcoholic fatty liver disease (NAFLD). Ultrasonography measurements were compared according to histopathologic findings. Diagnostic performance in differentiating NASH from NAFLD was evaluated using the area under the receiver operating characteristic curve (AUC). Median shear wave speed (1.48 vs 1.62 m/s, P = 0.014) and dispersion slope (8.40 vs 11.80 [m/s]/kHz, P = 0.004) were higher in NASH group than in NAFLD group. Shear wave dispersion slope tended to increase step by step as the severity of activity grade (P = 0.032) and hepatic fibrosis (P = 0.015) increased. The AUC of shear wave dispersion slope for differentiating NASH from NAFLD (AUC, 0.83; 95% confidence intervals, 0.66-1.00) was higher than that of shear wave speed (AUC, 0.78; 95% CI, 0.60-0.97), although it did not reach statistical significance (P = 0.729). Shear wave dispersion slope could be a feasible tool for assessing NASH in patients with morbid obesity.

Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients.

BACKGROUND AND AIM: Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. METHODS: This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. RESULTS: A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P < 0.001) without intergroup differences (P = 0.349). CONCLUSIONS: The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.

Standardization of the pathologic diagnosis of appendiceal mucinous neoplasms.

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the "Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm" to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

Scoring model for discriminating gastric cancer risk in patients with negative serum pepsinogen and anti-Helicobacter pylori antibody results.

BACKGROUND: The ABC test measures serum pepsinogen and anti-Helicobacter pylori IgG antibody levels to predict precancerous conditions in the stomach and gastric cancer. However, a limitation of this test is that the gastric cancer risk is not negligible in patients with a negative result. METHODS: Based on their ABC results, 1157 patients were classified into Groups A (n = 392), B (n = 479), C (n = 247), and D (n = 39). In Group A, 24.2% of patients had atrophic gastritis and/or intestinal metaplasia and had thus been incorrectly assigned to Group A. Patients in Group A were then assigned to derivation (n = 236) and validation (n = 156) cohorts by 3:2 random sampling. Logistic regression analyses were performed to identify the factors discriminating between a correct (true) and incorrect (false) Group A classification. RESULTS: A 4-point discriminative model was constructed based on a high-negative H. pylori IgG antibody titer and the patient's age (50-64 and ≥65 years). The areas under the receiver operating characteristic curve for the derivation and validation cohorts were 0.868 and 0.894, respectively. In the validation cohort, the addition of a discriminative model score ≥2 to the ABC method showed a similar accuracy for predicting gastric cancer risk compared with the ABC method alone (93.8% vs. 92.4%). CONCLUSION: The 4-point discriminative model may help identify patients with a normal serological test who are nonetheless at risk of developing gastric cancer.

Standard vs magnifying narrow-band imaging endoscopy for diagnosis of Helicobacter pylori infection and gastric precancerous conditions.

BACKGROUND: Advances in endoscopic imaging enable the identification of patients at high risk of gastric cancer. However, there are no comparative data on the utility of standard and magnifying narrow-band imaging (M-NBI) endoscopy for diagnosing Helicobacter pylori (H. pylori) infection, gastric atrophy, and intestinal metaplasia. AIM: To compare the diagnostic performance of standard and M-NBI endoscopy for H. pylori gastritis and precancerous conditions. METHODS: In 254 patients, standard endoscopy findings were classified into mosaic-like appearance (type A), diffuse homogenous redness (type B), and irregular redness with groove (type C). Gastric mucosal patterns visualized by M-NBI were classified as regular round pits with polygonal sulci (type Z-1), more dilated and linear pits without sulci (type Z-2), and loss of gastric pits with coiled vessels (type Z-3). RESULTS: The diagnostic accuracy of standard and M-NBI endoscopy for H. pylori gastritis was 93.3% and 96.1%, respectively. Regarding gastric precancerous conditions, the accuracy of standard and M-NBI endoscopy was 72.0% vs 72.6% for moderate to severe atrophy, and 61.7% vs. 61.1% for intestinal metaplasia in the corpus, respectively. Compared to type A and Z-1, types B+C and Z-2+Z-3 were significantly associated with moderate to severe atrophy [odds ratio (OR) = 5.56 and 8.67] and serum pepsinogen I/II ratio of ≤ 3 (OR = 4.48 and 5.69). CONCLUSION: Close observation of the gastric mucosa by standard and M-NBI endoscopy is useful for the diagnosis of H. pylori gastritis and precancerous conditions.

A practical individualized radiation precaution based on the dose rate at release time after inpatient 131I ablation therapy.

INTRODUCTION: Retained radioactivity of 131I after ablation therapy largely differs in each patient according to factors including the amount of remnant thyroid tissue, renal function, and use of recombinant human thyroid-stimulating hormone. To reduce unnecessary restriction of patient's daily life after inpatient 131I ablation therapy, we propose a practical individualized method for radiation precaution based on dose rate at release time. METHODS: We evaluated 215 patients with differentiated thyroid cancer who underwent inpatient 131I ablation therapy following total thyroidectomy. Effective dose equivalent rates at 1-m distance were measured upon release (EDRR) on day 2 and during delayed whole-body scan (EDRD) visits on day 6‒8 after 131I administration. The biexponential model was designed to estimate total effective dose equivalent to others. To assess conservativeness of our model, EDRD estimated by our model was compared with measured EDRD. EDRR-based periods of precaution not to receiving 1 mSv of radiation exposure were estimated and compared with those based on administered radioactivities on American Thyroid Association (ATA) recommendations. RESULTS: The EDRR ranged from 1.0-48.9 µSv/hr. The measured EDRD were equal to or lower than estimated EDRD in all patients, except for one, indicating that our model is sufficiently conservative. According to our model, no subjects needed additional daytime restriction after release. The maximum permissible times for public transportation use were longer in all patients compared with those based on administered radioactivities. Nighttime restriction periods were significantly shorter than those based on administered radioactivity; median periods requiring sleeping apart were 0 (range, 0‒5), 4 (range, 1‒14), and 3 (range, 2‒13) days after release in patients treated with radioactivity doses of 2.96, 5.50, and 7.40 GBq, respectively, needing 8, 16, and 19 additional days, respectively, based on administered radioactivity. CONCLUSIONS: Radiation safety instructions using proposed method based on EDRR of individual patient could safely reduce the burden of radiation precaution.

Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents.

P-glycoprotein (P-gp) inhibition has been studied to overcome multidrug resistance in cancer chemotherapy but failed in clinical trials due to low/toxic effects. Recently, a dual modulation of transporters and natural derivatives have been examined to surmount this limitation. We examined breast cancer resistance protein (BCRP) inhibition in vitro and in vivo by P-gp inhibitors derived from natural compounds in previous studies. P-gp inhibitors increased the accumulation of the anticancer drug, topotecan (TPT)-a substrate of P-gp and BCRP, albeit with higher affinity for BCRP-in BCRP-overexpressing cells, resulting in cell death. These dual inhibitors, when orally co-administered with TPT, enhanced TPT bioavailability with slightly reduced total oral clearance (Clt/F) in rats. In xenograft mice, they strengthened oral TPT-induced tumor reduction with no alterations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cremophor® EL, Tween® 80, and polyethylene glycol 400) on the transporters function. The excipients increased TPT accumulation in P-gp- or BCRP-overexpressing cells. Oral TPT bioavailability was higher with the formulation than with a control, as shown by the increases in the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from zero to infinity (AUCINF) (p< 0.01). Therefore, oral TPT bioavailability was enhanced by P-gp/BCRP dual inhibition, which resulted in a formulation-mediated increase in absorption and decrease in elimination, and a dual inhibitor-mediated decrease in elimination. These results suggest that the combination of dual inhibition by a natural derivative and the drug formulation can be a useful clinical approach.

Clinical applicability of gastroscopy with narrow-band imaging for the diagnosis of Helicobacter pylori gastritis, precancerous gastric lesion, and neoplasia.

Premalignant gastric lesions such as atrophic gastritis and intestinal metaplasia frequently occur in subjects with long-term Helicobacter pylori (H. pylori) infection. The regular arrangement of collecting venules (RAC) is seen in the normal gastric corpus, whereas mucosal swelling and redness without RAC are observed in H. pylori-infected mucosa. Despite successful H. pylori eradication, the presence of atrophic gastritis and/or gastric intestinal metaplasia (GIM) is a risk factor for gastric cancer. With the development of advanced imaging technologies, recent studies have reported the usefulness of narrow-band imaging (NBI) for endoscopic diagnosis of atrophic gastritis and GIM. Using NBI endoscopy with magnification (M-NBI), atrophic gastritis is presented as irregular coiled microvessels and loss of gastric pits. Typical M-NBI endoscopic findings of GIM are a light blue crest and a white opaque substance. Based on the microvascular patterns, fine network, core vascular, and unclear patterns are useful for predicting gastric dysplasia in polypoid lesions. For diagnosis of early gastric cancer (EGC), a systematic classification using M-NBI endoscopy has been proposed on the basis of the presence of a demarcation line and an irregular microvascular/microsurface pattern. Furthermore, M-NBI endoscopy has been found to be more accurate for determining the horizontal margin of EGC compared to conventional endoscopy. In this review, we present up-to-date results on the clinical usefulness of gastroscopy with NBI for the diagnosis of H. pylori gastritis, precancerous gastric lesion, and neoplasia.

Optimized diagnosis of Helicobacter pylori and tailored eradication therapy for preventing gastric cancer: a proposal for SHAKE strategy.

INTRODUCTION: To decrease gastric cancer-related mortality, the Korean National Cancer Screening Program provides biennial screening gastroscopy to all individuals aged >40 years. However, a test-and-treat strategy of Helicobacter pylori for preventing gastric cancer has not been established. AREAS COVERED: In this review, we present up-to-date results of endoscopic findings of H. pylori gastritis, optimal sites for H. pylori detection, gastric cancer risk assessment using serum pepsinogen, tailored eradication based on the antimicrobial resistance against H. pylori, and post-eradication surveillance. EXPERT OPINION: Here we propose approaches to H. pylori diagnosis and treatment for preventing gastric cancer, termed 'Screening for H. pylori in Korea and Eradication (SHAKE)' strategy. This strategy consists of the following: (1) optimized H. pylori diagnosis, (2) individualized management based on the H. pylori infection status, and (3) tailored eradication therapy. H. pylori gastritis can be diagnosed by endoscopic observation of the gastric mucosal pattern at the greater curvature of the corpus. Measurement of the serum pepsinogen I/II ratio is useful for assessing the risk of gastric cancer. As a first-line treatment, tailored eradication based on the results of molecular testing is effective in a country with a high rate of clarithromycin-resistant H. pylori.

A scoring system for the diagnosis of non-alcoholic steatohepatitis from liver biopsy.

BACKGROUND: Liver biopsy is the essential method to diagnose non-alcoholic steatohepatitis (NASH), but histological features of NASH are too subjective to achieve reproducible diagnoses in early stages of disease. We aimed to identify the key histological features of NASH and devise a scoring model for diagnosis. METHODS: Thirteen pathologists blindly assessed 12 histological factors and final histological diagnoses ('not-NASH,' 'borderline,' and 'NASH') of 31 liver biopsies that were diagnosed as non-alcoholic fatty liver disease (NAFLD) or NASH before and after consensus. The main histological parameters to diagnose NASH were selected based on histological diagnoses and the diagnostic accuracy and agreement of 12 scoring models were compared for final diagnosis and the NAFLD Activity Score (NAS) system. RESULTS: Inter-observer agreement of final diagnosis was fair (κ = 0.25) before consensus and slightly improved after consensus (κ = 0.33). Steatosis at more than 5% was the essential parameter for diagnosis. Major diagnostic factors for diagnosis were fibrosis except 1C grade and presence of ballooned cells. Minor diagnostic factors were lobular inflammation ( ≥ 2 foci/ × 200 field), microgranuloma, and glycogenated nuclei. All 12 models showed higher inter-observer agreement rates than NAS and post-consensus diagnosis (κ = 0.52-0.69 vs. 0.33). Considering the reproducibility of factors and practicability of the model, summation of the scores of major (× 2) and minor factors may be used for the practical diagnosis of NASH. CONCLUSIONS: A scoring system for the diagnosis of NAFLD would be helpful as guidelines for pathologists and clinicians by improving the reproducibility of histological diagnosis of NAFLD.

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study.

PURPOSE: The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice. MATERIALS AND METHODS: Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs. RESULTS: Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity. CONCLUSION: Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.