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Aims: Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs., Methods and Results: We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs., Conclusions: These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy., (© 2021 John Wiley & Sons Ltd.)

Background: Persistent Helicobacter pylori ( H. pylori ) infection causes chronic inflammation, atrophy of the gastric mucosa, and a high risk of developing gastric cancer. In recent years, awareness of eradication therapy has increased in Japan. As H. pylori infections decrease, the proportion of gastric cancers arising from H. pylori uninfected gastric mucosa will increase. The emergence of gastric cancer arising in H. pylori uninfected patients though rarely reported, is a concern to be addressed and needs elucidation of its clinicopathological features., Aim: To evaluate the clinicopathological features of early gastric cancer in H. pylori -uninfected patients., Methods: A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019. Of these, 30 lesions in 30 patients were diagnosed as H. pylori -uninfected gastric cancer (HpUIGC). We defined a patient as H. pylori -uninfected using the following three criteria: (1) The patient did not receive treatment for H. pylori , which was determined by investigating medical records and conducting patient interviews; (2) Lack of endoscopic atrophy; and (3) The patient was negative for H. pylori after being tested at least twice using various diagnostic methods, including serum anti- H. pylori -IgG antibody, urease breath test, rapid urease test, and microscopic examination., Results: The frequency of HpUIGC was 1.2% (30/2462) for the patients in our study. The study included 19 males and 11 females with a mean age of 59 years. The location of the stomach lesions was divided into three sections; upper third (U), middle third (M), lower third (L). Of the 30 lesions, 15 were U, 1 was M, and 14 were L. Morphologically, 17 lesions were protruded and flat elevated type (0-I, 0-IIa, 0-IIa + IIc), and 13 lesions were flat and depressed type (0-IIb, 0-IIc). The median tumor diameter was 8 mm (range 2-98 mm). Histological analysis revealed that 22 lesions (73.3%) were differentiated type.The HpUIGC lesions were classified into fundic gland type adenocarcinoma (7 cases), foveolar type well-differentiated adenocarcinoma (8 cases), intestinal phenotype adenocarcinoma (7 cases), and pure signet-ring cell carcinoma (8 cases). Among 30 HpUIGCs, 24 lesions (80%) were limited to the mucosa; wherein, the remaining 6 lesions showed submucosal invasion. One of the submucosal invasive lesions showed more than 500 μm invasion. The mucin phenotype analysis identified 7 HpUIGC with intestinal phenotype and 23 with gastric phenotype., Conclusion: We elucidated the clinicopathological characteristics of HpUIGC, revealing recognition not only undifferentiated-type but also differentiated-type. In addition, intestinal phenotype tumors were also observed and could be an important tip., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to the manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The special AT-rich sequence binding protein 2 (SATB2) is a sensitive and specific diagnostic marker for colorectal adenocarcinoma and reduced expression of SATB2 is associated with a poor prognosis. Colitis-associated colorectal adenocarcinoma often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the SATB2 expression profile in colitis-associated carcinoma has not been defined. We performed immunohistochemistry for SATB2 as well as CDX2, MUC5AC, MUC6 and mismatch repair proteins on 60 consecutive colitis-associated carcinomas from 58 inflammatory bowel disease patients and compared the expression profile to a control group of 32 sporadic colorectal carcinomas. Only 26 (43%) colitis-associated carcinomas expressed SATB2, compared to 29 (91%) sporadic colorectal carcinomas (p < 0.0001). MUC5AC expression was more frequently observed in colitis-associated carcinomas than sporadic colorectal caracinomas (52% and 25% respectively; p = 0.013). Eight (13%) cases of colitis-associated carcinoma showed loss of CDX2 expression, which was retained in all of the sporadic controls (p = 0.047). In colitis-associated carcinoma, 50% of SATB2 negative cases had lymph node metastasis compared to only 15% of SATB2 positive cases (p = 0.007). Loss of SATB2 was particularly frequent in mucinous-type tumors, occurring in 83% of these cases. There was no significant association between SATB2 expression and mismatch repair protein status. These data show that the immunoprofile of colitis-associated carcinoma is different than that seen in sporadic cases. In particular, SATB2 is significantly less sensitive in colitis-associated carcinoma and it should be interpreted cautiously as a marker of colorectal origin in colitis patients. The association between loss of SATB2 and lymph node metastasis suggests that it may have similar prognostic value in the setting of inflammatory bowel disease as in sporadic cases.

Lung adenocarcinomas (ADCs) have been roughly divided into two groups: the terminal respiratory unit (TRU) type and non-TRU type. These ADCs appear to develop through exclusive carcinogenetic pathways because of differences in their cellular morphologies and the profiles of protein expression and genetic alterations. The TRU type develops from atypical adenomatous hyperplasia as a precursor. On the other hand, the histogenesis of the non-TRU type has not yet been defined in detail. We herein investigated histopathological changes in the non-tumor lung tissues of patients with non-TRU-type ADCs in order to define their potential histogenesis. The non-TRU type preferentially occurs in patients with interstitial pneumonia, in whom tumors are located in honeycomb lesions and are associated with bronchiolar metaplasia (BM). Among patients without interstitial pneumonia, non-tumor lung tissues from non-TRU-type ADCs were often affected by multiple BM. In these cases, tumors often were associated with BM. Metaplastic cells adjacent to non-TRU-type ADCs ectopically expressed HNF-4α, a marker for non-TRU-type ADCs. These results suggest that the non-TRU type develops through distinct histogenesis, in which BM is implicated.

Background: Although magnifying endoscopy with narrow-band imaging (ME-NBI) can help identify the horizontal margin (HM) of early gastric cancer (EGC), little is known about the factors that can clarify the HM by using ME-NBI. We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI., Methods: The HMs of 639 differentiated-type EGCs treated with endoscopic submucosal dissection or surgery were analyzed using conventional endoscopy and ME-NBI. The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured., Results: In 13 lesions (2.0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas., Conclusions: Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM.

Aims: To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma., Methods and Results: Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups., Conclusions: Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features., (© 2016 John Wiley & Sons Ltd.)

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression., Competing Interests: The authors have declared that no competing interests exist.

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P < 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearman's rank-order correlation, P = 0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas., (© 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Small non-protein coding RNA, microRNA (miR), which regulate messenger RNA levels, have recently been identified, and may play important roles in the pathogenesis of various diseases. The present study focused on miR-31 and investigated its potential involvement in lung carcinogenesis. The expression of miR-31 was altered in lung cancer cells through either the amplification or loss of the host gene locus. The strong expression of miR-31 in large cell carcinomas was attributed to the gene amplification. Meanwhile, the loss of miR-31 expression was more frequently observed in aggressive adenocarcinomas. Thus, miR-31 may play a pleiotropic role in the development of lung cancers among different histological types. To the best of our knowledge, this is the first study to show the potential causative mechanism of the altered expression of miR-31 and suggest its potentially diverse significance in the different histological types of lung cancers.

The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.

Aims: This study aimed to characterize the clinicopathological features of invasive micropapillary carcinoma (IMPC) of the stomach., Methods and Results: Seventeen cases of gastric IMPC were identified from histological reviews of 1178 consecutive cases. IMPC components occupied 10-90% of the entire tumours. Fifteen tumours showed invasion into the muscularis propria or deeper, whereas two tumours were limited to the submucosa. All 17 cases were associated with tubular or papillary adenocarcinoma. Lymphatic and venous invasion were identified more frequently in cases with IMPC components than in those without (P = 0.0023 and P = 0.0009, respectively). Nodal metastases were identified in 14 of 17 (82%) cases with IMPC components, whereas they were detected in 540 of 1161 (47%) cases with no IMPC components (P = 0.0053). Multivariate analysis demonstrated that the presence of IMPC was an independent predictor of nodal metastasis., Conclusions: Conservative treatments, such as endoscopic resection, should not be used for gastric carcinoma with IMPC components, as these cases are associated with a high propensity for lymphovascular invasion and nodal metastasis., (© 2011 Blackwell Publishing Limited.)

Lymph node metastasis occurs in as many as 16% of patients with submucosal invasive colorectal carcinoma. We investigated the association between histopathological factors and lymph node metastases in 322 consecutive patients with submucosal invasive colorectal carcinoma who had undergone radical colectomy with lymph node dissection to detect patients at high risk of lymph node metastasis without measuring the depth of submucosal invasion. Lymph node metastasis was found in 46 (14.3%) of 322 patients with submucosal invasive colorectal carcinoma. Univariate analysis showed that each of the following histopathological factors had a significant influence on lymph node metastasis: invasion depth, lymphatic invasion, venous invasion, tumor differentiation, growth pattern of the intramucosal tumor component, complete disruption of the muscularis mucosa due to tumor invasion, and tumor budding at the submucosal invasive front. Multivariate analysis showed that lymphatic invasion (P<0.01), tumor differentiation (P<0.01), and tumor budding (P<0.01) were significantly associated with lymph node metastasis. All 46 cases of lymph node metastasis showed at least one of the following findings: lymphatic invasion, moderately or poorly differentiated tumor grade, tumor budding, or complete disruption of the muscularis mucosa due to tumor invasion. Patients with submucosal invasive colorectal carcinoma that show at least one of three factors--lymphatic invasion, moderately or poorly differentiated tumor grade, or tumor budding--are at high risk for lymph node metastasis. All of the patients with lymph node metastasis, who did not have any of these factors, showed a completely disrupted muscularis mucosa.

Osteoclast-like giant cells (OGC) are rare in gastric carcinomas. Histopathological study of seven gastric carcinomas with OGC demonstrated three distinct types: lymphoepithelioma-like carcinoma (LELC), non-LELC, and giant cell tumor (GCT) types. LELC is a poorly differentiated adenocarcinoma with prominent lymphoid stroma. The LELC type (n = 4) showed similar histology to LELC of the stomach, except that they were accompanied by OGC and granulomatous reaction. Epstein-Barr virus (EBV) infection was demonstrated by EBV-encoded RNA (EBER) in situ hybridization (ISH) in all the neoplastic cells. The non-LELC type (n = 2) consisted of EBV-negative carcinoma cells with inflammatory infiltrates. OGC and granulomas were frequently observed in the glandular lumens with accumulated mucus. The GCT type (n = 1) was a neuroendocrine carcinoma, containing many OGC with metaplastic bone formation, which showed typical morphological features of OGC in GCT of the bone. In all three types, OGC expressed CD68, but not cytokeratin, indicating that OGC had a reactive histiocytic lineage. Both LELC and non-LELC types are included in the differential diagnosis of isolated granulomatous gastritis, and EBER-ISH was useful for the identification of LELC type. Both LELC and no-LELC types were also suggested to have better prognoses, but the behavior of the GCT type needs to be further characterized.

The novel stem cell marker SALL4 has been identified as a diagnostic marker of germ cell tumors, especially yolk sac tumors, in gonadal organs. To clarify the significance of SALL4 as an oncofetal protein, we investigated SALL4 expression by immunohistochemistry in non-neoplastic stomach and gastric carcinoma with particular emphasis on á-fetoprotein (AFP)-producing gastric carcinoma, as AFP-producing gastric carcinoma shares expression of AFP and glypican 3 (GPC3) with yolk sac tumors and hepatic neoplasms. A total of 338 gastric carcinomas, 60 hepatocellular carcinomas, and 48 cholangiocellular carcinomas were studied by immunohistochemistry on tissue microarrays. In addition, more detailed whole tissue section immunohistochemistry was performed on non-neoplastic gastric tissue from 5 adult and 8 fetal specimens, 6 hepatoblastomas, and 31 cases of AFP-producing gastric carcinomas. SALL4 expression was observed in the neofetal stomach in gestational week 9 and disappeared thereafter. It was also identified by tissue microarray study in a fraction of gastric carcinomas (51 of 338, 15%), associated with older age (P=0.0001), male sex (P=0.0033), intestinal-type histology (P=0.0001), and synchronous liver metastasis (P=0.0047). AFP and GPC3 were closely associated with SALL4 expression in gastric carcinoma (both, P<0.0001), and a full-section study indicated that SALL4 was positive in all 31 cases of AFP-producing gastric carcinoma with diffuse staining in 24 cases (78%). Diffuse SALL4 expression was observed in the histologic patterns of hepatoid (89%), glandular (57%), and clear cell (39%) AFP-producing gastric carcinoma. In addition, SALL4 expression was completely negative in hepatoblastoma (n=6) and hepatocellular carcinoma (n=60). SALL4 is an oncofetal protein similar to AFP and GPC3, but it represents fetal gut differentiation in gastric carcinoma. SALL4 is a sensitive marker for AFP-producing gastric carcinoma and is especially useful to distinguish hepatoid gastric carcinoma from hepatocellular carcinoma.