RAD51 Expression as a Biomarker to Predict Efficacy of Preoperative Therapy and Survival for Esophageal Squamous Cell Carcinoma: A Large-cohort Observational Study (KSCC1307).

OBJECTIVE: The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND: It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS: A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS: In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS: In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

Solid-type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex.

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.

Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease.

BACKGROUND AND AIM: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment.

Intestinal Behçet's Disease with Primary Myelofibrosis Involving Trisomy 8.

Behçet's disease (BD) is a disorder characterized by systemic inflammation of multiple organs, including the intestines. Several studies have reported a relationship between myelodysplastic syndrome and BD, and trisomy 8 was frequently seen, especially in intestinal BD. However, the association of BD with primary myelofibrosis (PMF) has not been well documented. A 58-year-old Japanese female was diagnosed with PMF in 2014. The symptoms of PMF resolved with ruxolitinib. However, she developed fever and intestinal perforation due to multiple ulcers in the terminal ileum in 2017. Intestinal perforation recurred 1 month later, and the dose of ruxolitinib was tapered. After discontinuation of ruxolitinib, she presented with recurrent oral aphthous ulcers and uveitis. Subsequently, intestinal perforation recurred, and she was diagnosed with intestinal BD. Trisomy 8 was identified in her peripheral blood. She underwent steroid therapy, azathioprine, and infliximab. This case suggests relationships between PMF, trisomy 8, and BD.

Amide proton transfer imaging to predict tumor response to neoadjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND AND AIM: The amount of proteins and peptides can be estimated with amide proton transfer (APT) imaging. Previous studies demonstrated the usefulness of APT imaging to predict tumor malignancy. We determined whether APT imaging can predict the tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced rectal cancer (LARC). METHODS: Seventeen patients with LARC who underwent a pretherapeutic magnetic resonance examination including APT imaging and NAC (at least two courses) were enrolled. The APT-weighted imaging (WI) signal intensity (SI) (%) was defined as magnetization transfer ratio asymmetry (MTRasym ) at the offset of 3.5 ppm. Each tumor was histologically evaluated for the degree of degeneration and necrosis and then classified as one of five histological Grades (0, none; 1a, less than 1/3; 1b, 1/3 to 2/3; 2, more than 2/3; 3, all). We compared the mean APTWI SIs of the tumors between the Grade 0/1a/1b (low-response group) and Grade 2/3 (high-response group) by Student's t-test. We used receiver operating characteristics curves to determine the diagnostic performance of the APTWI SI for predicting the tumor response. RESULTS: The mean APTWI SI of the low-response group (n = 12; 3.05 ± 1.61%) was significantly higher than that of the high-response group (n = 5; 1.14 ± 1.13%) (P = 0.029). The area under the curve for predicting the tumor response using the APTWI SI was 0.87. When ≥2.75% was used as an indicator of low-response status, 75% sensitivity and 100% specificity of the APTWI SI were obtained. CONCLUSION: Pretherapeutic APT imaging can predict the tumor response to NAC in patients with LARC.

The Altered Mucosal Barrier Function in the Duodenum Plays a Role in the Pathogenesis of Functional Dyspepsia.

BACKGROUND: An altered gastrointestinal barrier function is reportedly associated with the pathogenesis of functional dyspepsia (FD); however, the pathogenesis of FD has not yet been fully elucidated. AIMS: The objective of the present study was to determine whether the mucosal barrier function is impaired in patients with FD and to investigate the mechanisms underlying FD. METHODS: The present study included patients with FD (FD group, n = 24), non-FD patients with abdominal symptoms (symptomatic control group, n = 14), and patients with no abdominal symptoms (asymptomatic control group, n = 20). The groups were compared regarding the mucosal electrical impedance (MI) values of the stomach and duodenum, which were measured using a tissue conductance meter during esophagogastroduodenoscopy. RESULTS: There were no significant differences between the three groups in the MI of the stomach. In contrast, the duodenal MI of the FD group (17.8 ± 4.3 Ω) was significantly lower than those of the symptomatic control group (27.2 ± 6.4 Ω, p < 0.0001) and asymptomatic control group (23.0 ± 7.4 Ω, p = 0.016). The expression of zonula occludens-1 (ZO-1) was significantly lower in the FD group than in the symptomatic control group (p = 0.011), where ZO-1 was positively correlated with the duodenal MI (ß = 0.513, p = 0.017). The interleukin (IL)-1ß expression was significantly higher in the FD group than in the symptomatic control group (p = 0.041), where IL-1ß was inversely correlated with the duodenal MI (ß = - 0.600, p = 0.004). CONCLUSIONS: The mucosal barrier function of the duodenum was altered in patients with FD. Both a decreased ZO-1 and increased IL-1ß may play a role in the pathogenesis of FD.

Clinical usefulness of magnifying colonoscopy for the diagnosis of ulcerative colitis-associated neoplasia.

BACKGROUND AND AIM: The aim of this investigation was to evaluate the efficacy of Japanese magnifying colonoscopic classifications for ulcerative colitis-associated neoplasia (UCAN). METHODS: We reviewed the colonoscopy records from 2011 to 2018 at our institutions and identified cases of endoscopically or surgically resected UCAN observed by magnifying narrow-band imaging (NBI) endoscopy and magnifying chromoendoscopy. Association between magnifying endoscopic classification and histopathological findings was investigated retrospectively. Japan NBI expert team (JNET) classification and pit pattern classification were applied. RESULTS: There were 17 patients who had a diagnosis of UCAN. Tumors of types 2A, 2B and 3 by JNET classification correlated with the histopathological findings of low-grade dysplasia (LGD)/high-grade dysplasia (HGD), HGD, and massively submucosal invasive (mSM) carcinoma, respectively. Tumors of types III/IV, VI low irregularity, and VI high irregularity/VN by pit pattern classification were correlated with the histopathological findings of LGD/HGD, HGD, and mSM carcinoma, respectively. CONCLUSIONS: Japan NBI expert team classification and pit pattern classification may be predictive of the histological diagnosis and invasion depth of UCAN. This needs to be investigated prospectively in a large cohort or in a randomized clinical trial.

An invasive presentation of parotid lymphadenoma: A first reported case.

Lymphadenoma, a rare benign tumor recognized in the WHO salivary gland tumor classification of 2005, poses diagnostic and treatment challenges due to its rarity and distinct histopathological characteristics. We report a unique case of lymphadenoma in a 45-year-old male patient who presented with a hard, painless tumor in the right parotid gland that had been present since he was 15 years old. Distinctively, MRI and CT imaging revealed signs of infiltration into the surrounding muscle tissues, challenging the traditional notion of lymphadenomas as tumors with clear boundaries. The histopathological examination identified the characteristic epithelial and lymphoid cell proliferation, suggestive of a lymphadenoma. However, the possibility of sebaceous differentiation due to faintly pale cells within the epithelial component was inconclusive. The tumor's invasive nature and the high risk of facial nerve paralysis associated with surgical resection led to the patient's decision against treatment. Findings from this case underline the need for caution in diagnosing lymphadenoma, given its potential to show invasive images and the risks associated with a malignant diagnosis based solely on these images. Furthermore, the observations from this case present new insights into the FDG-PET findings of lymphadenoma, contributing to the overall understanding of this rare tumor's clinical implications. Future studies are warranted to provide more clarity on this condition.

Metabolic remodeling of pyrimidine synthesis pathway and serine synthesis pathway in human glioblastoma.

Glioblastoma is the most common brain tumor with dismal outcomes in adults. Metabolic remodeling is now widely acknowledged as a hallmark of cancer cells, but glioblastoma-specific metabolic pathways remain unclear. Here we show, using a large-scale targeted proteomics platform and integrated molecular pathway-level analysis tool, that the de novo pyrimidine synthesis pathway and serine synthesis pathway (SSP) are the major enriched pathways in vivo for patients with glioblastoma. Among the enzymes associated with nucleotide synthesis, RRM1 and NME1 are significantly upregulated in glioblastoma. In the SSP, SHMT2 and PSPH are upregulated but the upstream enzyme PSAT1 is downregulated in glioblastoma. Kaplan-Meier curves of overall survival for the GSE16011 and The Cancer Genome Atlas datasets revealed that high SSP activity correlated with poor outcome. Enzymes relating to the pyrimidine synthesis pathway and SSP might offer therapeutic targets for new glioblastoma treatments.

Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma.

Salivary secretory carcinoma (SASC) is frequently associated with ETV6-neurotrophic tyrosine receptor kinase (NTRK) 3 fusion and more rarely with RET, MET, or ALK rearrangement. We aimed to elucidate the potential diagnostic utility of pan-tropomyosin receptor kinase (Trk) immunohistochemistry and its relationship with the fusion gene subtype in SASC. We examined 33 cases of SASC for immunoexpression of pan-Trk, ALK and ROS1, and gene rearrangement of the ETV6, NTRK3, and RET genes using fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Thirty (90.9%) of 33 SASCs harbored ETV6-NTRK3 fusion gene transcripts by RT-PCR and/or both ETV6 and NTRK3 gene rearrangements by FISH, and 3 cases (9.1%) had RET gene rearrangement. Most NTRK3-rearranged SASCs (27/33 cases; 81.8%) had conventional ETV6 exon 5-NTRK3 exon 15 fusion, whereas 2 cases (6.1%) had both the conventional fusion and a novel ETV6 exon 4-NTRK3 exon 15 fusion variant. In the remaining one case (3%), only FISH revealed both ETV6 and NTRK3 rearrangements, suggesting an ETV6-NTRK3 fusion with an as yet undetermined break point. All 30 SASCs with ETV6-NTRK3 fusion and/or NTRK3 rearrangement showed nuclear and cytoplasmic immunoreactivity for pan-Trk. In contrast, 3 SASCs with RET rearrangement showed negative or only weak cytoplasmic staining for pan-Trk. There was no case harboring ALK and ROS1 rearrangements. All 17 non-SASC tumors were negative for pan-Trk. The results suggest that nuclear and cytoplasmic immunoreactivity for pan-TRK may be helpful to identify ETV6-NTRK3-fused SASCs and to distinguish them from RET-rearranged SASCs and morphological mimics.

Role of barium enema examination for the diagnosis of submucosal invasion depth in T1 colorectal cancers.

BACKGROUND: The indication for endoscopic resection for submucosally invasive colorectal cancer (T1-CRC) depends on the preoperative diagnosis of invasion depth. The aim of this investigation was to evaluate the association between barium enema examination (BE) profile views and depth of submucosal (SM) invasion in CRCs. METHODS: We reviewed the radiographic and endoscopic findings of 145 T1-CRCs diagnosed from 2008 to 2019. We measured the widths of horizontal and vertical rigidity under a BE profile view corresponding to CRC and compared the values with SM invasion depth. Horizontal rigidity was defined as the horizontal length and vertical rigidity as the vertical width of the barium defect corresponding to each target lesion. The most appropriate cut-off values for predicting SM invasion ≥1.8 mm were calculated by receiver operating characteristic curve analysis. RESULTS: Values of horizontal rigidity (r = 0.626, P < 0.05) and vertical rigidity (r = 0.482, P < 0.05) correlated significantly with SM invasion depth. The most appropriate cut-off values for the prediction of SM invasion depth ≥ 1.8 mm were 4.5 mm for horizontal rigidity, with an accuracy of 80.7%; and 0.7 mm for vertical rigidity, with an accuracy of 77.9%. The prevalence of lympho-vascular invasion was significantly different when those cut-off values were applied (43.2% vs. 17.5% for horizontal rigidity, P < 0.005). CONCLUSIONS: In T1-CRC, values of horizontal and vertical rigidities under a BE profile view were correlated with SM invasion depth. While the accuracy of the rigidities for the prediction of SM invasion depth ≥ 1.8 mm was not high, horizontal rigidity may be predictive of lympho-vascular invasion, thus aiding in therapeutic decision-making.

Glomus tumor of the duodenum: a rare case report.

BACKGROUND: Glomus tumors (GTs) are mesenchymal neoplastic lesions arising from the glomus bodies and generally occur in the fingers and toes. Gastrointestinal GTs are rare, and most of them originate from the stomach; however, GT arising from the duodenum is exceedingly rare. CASE PRESENTATION: A 68-year-old man was admitted due to abdominal pain. Endoscopy showed a round, smooth, elevated mass in the second portion of the duodenum with central ulceration. Abdominal contrast computed tomography showed a hypervascular tumor measuring 26 mm in diameter in the second portion of the duodenum, and pancreatic invasion was suspected. Endoscopic ultrasonography of the lesion confirmed a hypoechoic mass arising from the fourth layer of the duodenal wall. A biopsy was performed for central ulceration, and immunochemical studies showed positive results for smooth muscle actin (SMA) and negative results for S100, C-Kit, and CD34. Leiomyoma or gastrointestinal stromal tumor was suspected and pancreatoduodenectomy was performed. The specimen exhibited a vascular-rich tumor, 24 × 24 × 19 mm in size, with deep ulceration in the duodenum. Histological examination showed uniform small round cells with central nuclei and a pale cytoplasm (glomus cell) with perivascular proliferation. Immunochemical studies showed that the tumor was positive for SMA and collagen type IV, and negative for C-Kit, CD34, desmin, and S100. We diagnosed the tumor as a GT of the duodenum. CONCLUSION: GTs of the duodenum are exceedingly rare, but should be considered in the differential diagnoses of duodenal submucosal lesions.

Numerous lymph node metastases in early gastric cancer without preoperatively enlarged lymph nodes: a case report.

BACKGROUND: According to the 2018 Japanese gastric cancer treatment guidelines (ver. 5), a reduced extent of lymphadenectomy (D1 or D1+) is indicated for cT1 N0 tumors that do not meet the criteria for endoscopic resection. However, early gastric cancer with multiple lymph node metastases is not unknown, and cases have been reported. We report a case of a patient with early gastric cancer and numerous nodal metastases who underwent laparoscopic proximal gastrectomy based on a preoperative diagnosis of T1 N0. CASE PRESENTATION: A 69-year-old woman underwent emergent endoscopic hemostasis for massive hematemesis of the stomach, and endoscopic examination showed ulceration with a visible vessel. Pathological biopsy examination of the ulcer identified poorly differentiated adenocarcinoma with signet ring cells. The patient was diagnosed with early gastric cancer that was not indicated for endoscopic resection because of the ulceration and histological type. Endoscopic ultrasound showed that the third layer was poorly demarcated at the ulcer scar, indicating invasion to the submucosal layer. Computed tomography did not reveal enlarged lymph nodes or distant metastasis. The preoperative diagnosis was early gastric cancer of the fundus without nodal metastasis, and laparoscopic proximal gastrectomy with D1+ lymphadenectomy was performed. The initial postoperative pathological diagnosis was intramucosal carcinoma without lymphovascular invasion; however, the presence of 26 lymph node metastases was revealed unexpectedly. Additional pathological examination of more resected specimens transected every 2-3 mm revealed that only one lesion contained a small number of cancer cells in the lymphatic duct below the muscularis mucosa. CONCLUSIONS: We report a case of early gastric cancer with 26 nodal metastases in which lymph node involvement was not identified prior to surgery. These findings indicate that the extent of lymphadenectomy and the surgical procedure should be carefully decided even in cT1 N0 early gastric cancer when several risk factors for lymph node metastasis are present.

Colorectal diffuse large B-cell lymphoma: molecular subclassification and prognostic significance of immunoglobulin gene translocation.

Primary colorectal diffuse large B-cell lymphoma (DLBCL) is rare, and its clinicopathological and genetic features are poorly understood. The aim of our study was to elucidate the frequency and prognostic significance of molecular subgroups in colorectal DLBCL. We examined 25 cases of colorectal lymphoma with DLBCL-like morphology and classified them into germinal center B-cell like (GCB)/non-GCB subgroups by immunohistochemistry (IHC) for CD10, bcl-6 and MUM1, or into double-expressor (DE)/non-DE subgroups by IHC for bcl-2 and c-myc. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were also investigated using break-apart fluorescence in situ hybridization (FISH). The 25 cases were classified into two entities-DLBCL, not otherwise specified (NOS) (n = 23; 92%) and high grade B-cell lymphoma, double hit (n = 2; 8%)-according to the recent WHO classification. None of them showed histological evidence of Epstein-Barr virus infection or high-grade transformation from low grade B-cell lymphoma. Ten cases were GCB-type and four cases were DE-type, but these subtypes did not contribute to clinicopathological differences. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were detected in 3 (12%), 3 (12%), 10 (40%), 14 (56%), 3 (12%), 3 (12%), and 0 (0%) of 25 cases, respectively. Of note, the presence of IGH translocation was significantly associated with better overall survival (P = .0053) and progression free survival (P = .0259). Similarly, the translocation involving at least one of the IGs (IGH, IGK, and/or IGL) was associated with more favorable prognosis in DLBCLs or even in DLBCL, NOS. This is the first report to reveal that a small subset of colorectal DLBCL corresponds to double-hit lymphoma. In addition, translocations involving at least one of the IGs may be a favorable prognostic factor in colorectal DLBCL. Testing the translocation involving rearrangement of IGs as well as MYC and BCL2/BCL6 may thus be useful for diagnosis and prognosis.

Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist.

The Cancer Genome Atlas Research Network classified gastric adenocarcinoma into four molecular subtypes: (1) Epstein-Barr virus-positive (EBV), (2) microsatellite-instable (MSI), (3) chromosomal instable (CIN), and (4) genomically stable (GS). The molecular subtypes of gastric hepatoid adenocarcinomas are still largely unknown. We analyzed 52 hepatoid adenocarcinomas for the expression of surrogate markers of molecular subtypes (MLH1, p53, and EBER in situ hybridization) and some biomarkers (p21, p16, Rb, cyclin D1, cyclin E, ß-catenin, Bcl-2, IMP3, ARID1A and HER2), and mutations of TP53, CTNNB1, KRAS, and BRAF. We analyzed 36 solid-type poorly differentiated adenocarcinomas as a control group. Hepatoid adenocarcinomas were categorized as follows: EBV group (EBER-positive), no cases (0%); MSI group (MLH1 loss), three cases (6%); "CIN or GS" (CIN/GS) group (EBER-negative, MLH1 retained), 49 cases (94%). In the CIN/GS group, most of the tumors (59%) had either p53 overexpression or TP53 mutation and a coexisting tubular intestinal-type adenocarcinoma component (90%), suggesting that most hepatoid adenocarcinomas should be categorized as a true CIN group. Hepatoid adenocarcinomas showed relatively frequent expressions of HER2 (score 3+/2+: 21%/19%). Hepatoid adenocarcinomas showed shorter survival, more frequent overexpressions of p16 (67%) and IMP3 (98%) than the control group. None of hepatoid adenocarcinomas had KRAS or CTNNB1 mutations except for one case each, and no hepatoid adenocarcinomas had BRAF mutation. In conclusion, gastric hepatoid adenocarcinomas are a genetically heterogenous group. Most hepatoid adenocarcinomas are "CIN," but a small number of hepatoid adenocarcinomas with MSI do exist. Hepatoid adenocarcinomas are characterized by overexpressions of p16 and IMP3.

Gastric Cancer of "Crawling Type" Detected by Additional Gastrectomy After Endoscopic Submucosal Resection.

"Crawling type" gastric cancer (GC) is known as a rare variant of early GCs, which is difficult to diagnose at an early stage because of low-grade nuclear atypia and a morphology mimicking intestinal metaplasia. This is a case report of a 69-year-old woman who was diagnosed with early-stage gastric cancer. She had endoscopic submucosal resection (ESD) and histologically, both horizontal and vertical margins were negative. Seven months after ESD, a new lesion of the stomach was detected by follow-up gastroscopy. Laparoscopic distal gastrectomy was performed and "crawling type" glands were observed throughout the whole area of the tumor. We should keep this variant in mind, especially when a tumor is superficial depressed or superficial flat type in the middle of the stomach. Careful observation with multiple biopsies of all mucosal layer and a re-biopsy is the key procedure for obtaining the right diagnosis. Endoscopic and histological characteristics should also be reviewed.

Clinicopathologic and Molecular Characteristics of Synchronous Colorectal Carcinoma With Mismatch Repair Deficiency.

Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient.