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Purpose@#Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer.Currently, no effective treatment options for this condition exist. Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by nuclear factor erythroid-derived 2-like 2 (NFE2L2) gene and its endogenous inhibitor, Kelch-like ECH-associated protein 1 (KEAP1), both participate in cellular defense mechanisms against oxidative stress and contribute to chemoresistance and tumor progression in numerous types of cancers. This study aimed to evaluate the expression patterns of NRF2 and KEAP1 and their prognostic value in operable TNBC. @*Methods@#Tissue microarrays were prepared using tumor tissues collected from 203 patients with TNBC who underwent surgery. Immunohistochemical staining analyses of NRF2 and KEAP1 were performed. The expression of each immunomarker was categorized into two groups (low or high) based on the median H-score. We analyzed the association between the expression of each immunomarker and clinicopathological information to predict survival.A total of 225 TNBC samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate our results. @*Results@#NRF2 immunoreactivity was detected in the nucleus and was associated with histologic grade and Ki-67 index, whereas KEAP1 immunoreactivity was detected in the cytoplasm and was associated with the Ki-67 index. Survival analyses showed that NRF2 and KEAP1 expressions were independent prognostic factors for overall survival (OS) (hazard ratio [HR], 2.45 and 0.30; p = 0.015 and 0.016, respectively) and disease-free survival (HR, 2.27 and 0.42; p = 0.019 and 0.022, respectively). NFE2L2 mRNA expression was an independent prognostic factor for OS (HR, 0.59; p = 0.009) in the METABRIC dataset. @*Conclusion@#High NRF2 and low KEAP1 expressions independently predicted poor survival in patients with operable TNBC. Further investigations are warranted to examine the possible therapeutic benefits of targeting the KEAP1-NRF2 pathway for TNBC treatment.
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Breast metastases from extramammary malignancies are rare. Here, we report a case of breast metastasis from hepatocellular carcinoma (HCC) after breast mass excision in a 63-year-old woman. A new breast nodule was noticed after transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiation therapy for HCC. Breast ultrasound and core needle biopsy were performed to differentiate between the breast tumors. The biopsy result was invasive breast carcinoma, and wide excision of the breast was performed. The final pathological diagnosis was HCC breast metastasis based on histological findings and immunohistochemical staining results. After 9 months of follow-up, HCC and breast metastasis recurred. Despite palliative treatment, the patient died due to complications and general health deterioration. Although breast metastasis due to HCC is very rare, HCC breast metastasis should be considered when a new breast mass is discovered in a patient with a history of HCC for effective treatment and management.
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Receptor-interacting serine/threonine-protein kinase (RIPK) 3 is a member of the TNF receptor-I signaling complex and mediates necroptosis, an inflammatory cell death. Ulcerative colitis (UC) is an excessive inflammatory disease caused by uncontrolled T cell activation. The current study is aimed to determine whether RIPK3 inhibitor attenuates UC development inhibiting inflammation and necroptosis using experimental colitis mice model. Dextran sulfate sodium-induced colitis mice were administered RIPK3 inhibitor (3 mg/ml) 3 times and their tissues were analyzed by immunohistochemistry. RIPK3, mixed lineage kinase domain-like (MLKL), phosphorylated MLKL, IL-17, and CD4 in colitis patient colon tissues were detected using confocal microscopy. Protein levels were measured using immunohistochemistry and ELISA. The differentiation of Th17 cells was evaluated using flow cytometry. The expression of proinflammatory cytokines and necroptosis in peripheral blood mononuclear cells from UC patients was decreased markedly by RIPK3 inhibitor treatment. We also observed that the injection of RIPK3 inhibitor improves colitis severity and protects intestinal destruction. RIPK3 inhibitor reduced necroptosis factors and proinflammatory cytokines in the colon and consequently protected colon devastation. The expression of inflammatory mediators in experimental colitis mice splenocytes was decreased significantly by RIPK3 inhibitor treatment. These results suggest that RIPK3 inhibitor ameliorates severity of experimental colitis and reduces inflammation through the inhibition of inflammatory response and necroptosis and support RIPK3-targeting substances for treatment of UC.
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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.
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The first edition of the ‘Standardized Pathology Report for Colorectal Cancer,’ which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of “standard data elements” and “conditional data elements.” Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as “standard data elements,” while other prognostic factors and factors related to adjuvant therapy are classified as “conditional data elements” so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.
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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.
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Purpose@#Expanded indications for endoscopic submucosal dissection (ESD) in early gastric cancer (EGC) remain controversial due to the potential risk of undertreatment after adequate lymph node dissection (LND). Regional LND (RLND) is a novel technique used for limited lymphadenectomy to avoid gastrectomy. This study established the safety and effectiveness of RNLD as an additional treatment option after ESD for expanded indications. @*Materials and Methods@#A total of 69 patients who met the expanded indications for ESD were prospectively enrolled from 2014 to 2017. The tumors were localized using intraoperative esophagogastroduodenoscopy (EGD) before RLND. All patients underwent RLND first, followed by conventional radical gastrectomy with LND. The locations of the preoperative and intraoperative EGD were compared. Pathologic findings of the primary lesion and the RLND status were analyzed. @*Results@#The concordance rates of tumor location between the preoperative and intraoperative EGD were 79.7%, 76.8%, and 63.8% according to the longitudinal, circumferential, and regional locations, respectively. Of the 4 patients (5.7%) with metastatic LNs, 3 were pathologically classified as beyond the expanded indication for ESD and 1 had a single LN metastasis in the regional lymph node. @*Conclusions@#RLND is a safe additional option for the treatment of EGC in patients meeting expanded indications after ESD.
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Purpose@#Expanded indications for endoscopic submucosal dissection (ESD) in early gastric cancer (EGC) remain controversial due to the potential risk of undertreatment after adequate lymph node dissection (LND). Regional LND (RLND) is a novel technique used for limited lymphadenectomy to avoid gastrectomy. This study established the safety and effectiveness of RNLD as an additional treatment option after ESD for expanded indications. @*Materials and Methods@#A total of 69 patients who met the expanded indications for ESD were prospectively enrolled from 2014 to 2017. The tumors were localized using intraoperative esophagogastroduodenoscopy (EGD) before RLND. All patients underwent RLND first, followed by conventional radical gastrectomy with LND. The locations of the preoperative and intraoperative EGD were compared. Pathologic findings of the primary lesion and the RLND status were analyzed. @*Results@#The concordance rates of tumor location between the preoperative and intraoperative EGD were 79.7%, 76.8%, and 63.8% according to the longitudinal, circumferential, and regional locations, respectively. Of the 4 patients (5.7%) with metastatic LNs, 3 were pathologically classified as beyond the expanded indication for ESD and 1 had a single LN metastasis in the regional lymph node. @*Conclusions@#RLND is a safe additional option for the treatment of EGC in patients meeting expanded indications after ESD.
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PURPOSE: The diagnostic criteria of gastric intraepithelial neoplasia (IEN) are controversial across the world. We investigated how many discrepancies occur in the pathologic diagnosis of IEN and early gastric carcinoma in endoscopic submucosal dissection (ESD) specimens, and evaluated the reasons of the discordance. MATERIALS AND METHODS: We retrospectively reviewed 1,202 ESD specimens that were originally diagnosed as gastric IEN and early carcinoma at 12 institutions. RESULTS: The final consensus diagnosis of carcinoma were 756 cases, which were originally 692 carcinomas (91.5%), 43 high-grade dysplasias (5.7%), 20 low-grade dysplasias (2.6%), and 1 others (0.1%), respectively. High- and low-grade dysplasia were finally made in 63 and 342 cases, respectively. The diagnostic concordance with the consensus diagnosis was the highest for carcinoma (91.5%), followed by low-grade dysplasia (86.3%), others (63.4%) and high-grade dysplasia (50.8%). The general kappa value was 0.83, indicating excellent concordance. The kappa values of individual institutions ranged from 0.74 to 1 and correlated with the proportion of carcinoma cases. The cases revised to a final diagnosis of carcinoma exhibited both architectural abnormalities and cytologic atypia. The main differential points between low- and high-grade dysplasias were the glandular distribution and glandular shape. Additional features such as the glandular axis, surface maturation, nuclear stratification and nuclear polarity were also important. CONCLUSION: The overall concordance of the diagnosis of gastric IEN and early carcinoma in ESD specimens was excellent. It correlated with the proportion of carcinoma cases, demonstrating that the diagnostic criteria for carcinoma are more reproducible than those for dysplasia.
Subject(s)
Consensus , Diagnosis , Retrospective Studies , Stomach NeoplasmsABSTRACT
Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory disorder characterized by specific pathological findings and elevated serum IgG4 level. IgG4-RD in the stomach is rare, and occasionally diagnosed as gastric subepithelial tumor (SET) by endoscopy or computed tomography scan. Two female patients in the age group of 40–50 years were diagnosed with 4 cm sized gastric SET. One underwent laparoscopic gastric wedge resection. Another one had a history of subtotal gastrectomy for early gastric cancer and idiopathic thrombocytopenic purpura with oral steroids administration. She underwent a completion total gastrectomy with splenectomy for the gastric SET and ITP. The pathology showed storiform fibrosis, and IgG4 was positive in immunohistochemistry (IHC) stain. IgG4-RD is known as a medical disease that could be treated with oral steroids. The difficulty in preoperative diagnosis of the disease occasionally causes unnecessary gastric resection. Thus, preoperative diagnostic methods for IgG4-RD such as deep biopsy with IHC stain or magnetic resonance imaging are needed.
Subject(s)
Female , Humans , Biopsy , Diagnosis , Endoscopy , Fibrosis , Gastrectomy , Gastrointestinal Stromal Tumors , Immunoglobulin G , Immunoglobulins , Immunohistochemistry , Magnetic Resonance Imaging , Pathology , Purpura, Thrombocytopenic, Idiopathic , Splenectomy , Steroids , Stomach Neoplasms , StomachABSTRACT
No abstract available.
Subject(s)
Humans , Adenoids , Carcinoma, Adenoid Cystic , Palate, HardABSTRACT
BACKGROUND: Mutations in the KRAS gene have been identified in approximately 50% of colorectal cancers (CRCs). KRAS mutations are well established biomarkers in anti–epidermal growth factor receptor therapy. Therefore, assessment of KRAS mutations is needed in CRC patients to ensure appropriate treatment. METHODS: We compared the analytical performance of the cobas test to Sanger sequencing in 264 CRC cases. In addition, discordant specimens were evaluated by 454 pyrosequencing. RESULTS: KRAS mutations for codons 12/13 were detected in 43.2% of cases (114/264) by Sanger sequencing. Of 257 evaluable specimens for comparison, KRAS mutations were detected in 112 cases (43.6%) by Sanger sequencing and 118 cases (45.9%) by the cobas test. Concordance between the cobas test and Sanger sequencing for each lot was 93.8% positive percent agreement (PPA) and 91.0% negative percent agreement (NPA) for codons 12/13. Results from the cobas test and Sanger sequencing were discordant for 20 cases (7.8%). Twenty discrepant cases were subsequently subjected to 454 pyrosequencing. After comprehensive analysis of the results from combined Sanger sequencing–454 pyrosequencing and the cobas test, PPA was 97.5% and NPA was 100%. CONCLUSIONS: The cobas test is an accurate and sensitive test for detecting KRAS-activating mutations and has analytical power equivalent to Sanger sequencing. Prescreening using the cobas test with subsequent application of Sanger sequencing is the best strategy for routine detection of KRAS mutations in CRC.
Subject(s)
Humans , Biomarkers , Codon , Colorectal NeoplasmsABSTRACT
BACKGROUND: The histomorphologic criteria for the pathological features of liver tissue from patients with non-alcoholic fatty liver disease (NAFLD) remain subjective, causing confusion among pathologists and clinicians. In this report, we studied interobserver agreement of NAFLD pathologic features and analyzed causes of disagreement. METHODS: Thirty-one cases of clinicopathologically diagnosed NAFLD from 10 hospitals were selected. One hematoxylin and eosin and one Masson's trichrome-stained virtual slide from each case were blindly reviewed with regard to 12 histological parameters by 13 pathologists in a gastrointestinal study group of the Korean Society of Pathologists. After the first review, we analyzed the causes of disagreement and defined detailed morphological criteria. The glass slides from each case were reviewed a second time after a consensus meeting. The degree of interobserver agreement was determined by multi-rater kappa statistics. RESULTS: Kappa values of the first review ranged from 0.0091-0.7618. Acidophilic bodies (k = 0.7618) and portal inflammation (k = 0.5914) showed high levels of agreement, whereas microgranuloma (k = 0.0984) and microvesicular fatty change (k = 0.0091) showed low levels of agreement. After the second review, the kappa values of the four major pathological features increased from 0.3830 to 0.5638 for steatosis grade, from 0.1398 to 0.2815 for lobular inflammation, from 0.1923 to 0.3362 for ballooning degeneration, and from 0.3303 to 0.4664 for fibrosis. CONCLUSIONS: More detailed histomorphological criteria must be defined for correct diagnosis and high interobserver agreement of NAFLD.
Subject(s)
Humans , Biopsy , Consensus , Diagnosis , Eosine Yellowish-(YS) , Fibrosis , Glass , Hematoxylin , Inflammation , Liver , Non-alcoholic Fatty Liver DiseaseABSTRACT
BACKGROUND: To identify the optimum culture conditions by investigating isolated rat hepatocytes cultured in medium containing different growth factors. METHODS: Hepatocytes were isolated from rats using a two-step perfusion technique and divided into the following four groups cultured in medium containing different growth factors: control, epidermal growth factor (EGF), insulin, and EGF+insulin. The viability of the cultured rat hepatocytes and liver function parameters, including albumin, ammonia, and urea in the culture medium, were measured. Hepatocyte morphology was examined by staining with hematoxylin and eosin, and albumin receptor expression was confirmed by immunofluorescence. RESULTS: Slightly higher viability was observed in the growth factor groups than in the control group, although without significance (P=0.073). The levels of albumin (P=0.001), ammonia (P<0.001), and urea (P=0.041) differed significantly among the four groups. The functional parameters in the growth factor groups, particularly the EGF+insulin group, were significantly superior to those in the control group. The morphology of the hepatocytes in all growth factor groups was well maintained at 10 days. However, the control group showed deterioration in cell morphology by day 7. CONCLUSIONS: Morphological and functional assessment indicated that the presence of growth factors, particularly EGF+insulin, provided culture conditions superior to those of non-supplemented medium.
Subject(s)
Animals , Rats , Ammonia , Eosine Yellowish-(YS) , Epidermal Growth Factor , Fluorescent Antibody Technique , Hematoxylin , Hepatocytes , Insulin , Intercellular Signaling Peptides and Proteins , Liver , Perfusion , Receptors, Albumin , UreaABSTRACT
PURPOSE: In 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype. MATERIALS AND METHODS: A total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped. RESULTS: In univariate survival analysis, tumor grade (p 10, is useful in defining L-Cell type. In this study, an L-cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa. CONCLUSION: From these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters.
Subject(s)
Diagnosis , Glucagon , Immunohistochemistry , Immunophenotyping , International Classification of Diseases , Lymph Nodes , Multivariate Analysis , Neoplasm Metastasis , Neuroendocrine Tumors , Phenotype , Prognosis , Rectal Neoplasms , World Health OrganizationABSTRACT
The occurrence of hepatocellular carcinoma (HCC) is closely associated with viral hepatitis or alcoholic hepatitis. Although active surveillance is ongoing in Korea, advanced or metastatic HCC is found at initial presentation in many patients. Metastatic HCC presents with a hypervascular intrahepatic tumor and extrahepatic lesions such as lung or lymph node metastases. Cases of HCC presenting as carcinoma of unknown primary have been rarely reported. The authors experienced a case of metastatic HCC in a patient who presented with a metastatic bone lesion but no primary intrahepatic tumor. This case suggests that HCC should be considered as a differential diagnosis when evaluating the primary origin of metastatic carcinoma.
Subject(s)
Humans , Male , Middle Aged , Antineoplastic Agents/therapeutic use , Bone Neoplasms/diagnosis , Carcinoma, Hepatocellular/diagnosis , Cervical Cord/pathology , Chemoembolization, Therapeutic , Gamma Rays , Liver Neoplasms/diagnosis , Magnetic Resonance Imaging , Neoplasms, Unknown Primary/pathology , Niacinamide/analogs & derivatives , Pelvic Bones/pathology , Phenylurea Compounds/therapeutic use , Tomography, X-Ray ComputedABSTRACT
Gastric metastasis from ovarian cancer is rarely reported worldwide. In Korea, only 2 such cases have been reported. Here we report a case of a 58-year-old woman with metastatic gastric cancer from an ovarian adenocarcinoma. Endoscopic examination showed that the cancer presented as a submucosal tumor without ulceration. A subsequent gastrectomy confirmed the diagnosis of metastatic ovarian serous adenocarcinoma.
Subject(s)
Female , Humans , Middle Aged , Adenocarcinoma , Diagnosis , Gastrectomy , Korea , Neoplasm Metastasis , Ovarian Neoplasms , Ovary , Stomach , Stomach Neoplasms , UlcerABSTRACT
Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (alpha-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, alpha-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.
Subject(s)
Animals , Mice , Actins/genetics , Antihypertensive Agents/therapeutic use , Collagen Type I/genetics , Diet, High-Fat/adverse effects , Fatty Liver/drug therapy , Fibrosis/etiology , Iridoids/therapeutic use , Leptin/genetics , Liver/metabolism , Mice, Inbred C57BLABSTRACT
Although, gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to that of Western countries. However, there is no Korean multidisciplinary guideline for gastric cancer and thus, a guideline adequate for domestic circumstances is required. Experts from related societies developed 22 recommendation statements for the diagnosis (n=9) and treatment (n=13) based on relevant key questions. Evidence levels based on systematic review of literatures were classified as five levels from A to E, and recommendation grades were classified as either strong or weak. The topics of this guideline cover diagnostic modalities (endoscopy, endoscopic ultrasound, radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, radiotherapy) and pathologic evaluation. External review of the guideline was conducted at the finalization phase.