Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.

OBJECTIVE: Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer. METHODS: Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score

Whole-exome Sequence Analysis of Gastric-type Adenocarcinoma of the Uterine Cervix and Adjacent Lobular Endocervical Glandular Hyperplasia in the Same Case.

Lobular endocervical glandular hyperplasia (LEGH) may be a precursor lesion of gastric-type adenocarcinoma of the uterine cervix (GAS). However, the genetic mechanisms underlying its carcinogenesis remain unclear. To elucidate the oncogenic process from LEGH to GAS, we compared gene mutations in early-stage GAS and adjacent LEGH in the same case. Fresh-frozen tissue sections were obtained from a patient with Stage IB3 GAS and adjacent LEGH who had undergone hysterectomy. Using laser microdissection, we harvested the LEGH and GAS portions separately from these sections and extracted the genomic DNA. Somatic variant analysis using whole-exome sequencing used DNA from the normal myometrium as a reference sequence. Somatic variants involving amino acid substitutions were detected in 61 and 125 locations in LEGH and GAS, respectively. Seven variants were common in both lesions, of which the pathogenic variant was GNAS only (c.2531G>A, p.R844H), a mutation frequently reported in pancreatic and colorectal cancers. LEGH had no other pathogenic variants; another pathogenic variant in GAS was found only at the same amino acid site as GNAS (c.2530C>T, p.R844C). In the present case, LEGH and GAS shared the same pathogenic variant of GNAS, indicating that both lesions had a common origin. Furthermore, the current results showed that the second GNAS variant is associated with the progression of LEGH to GAS. Further studies are required to elucidate GAS's pathogenesis and biological characteristics.

Exploring LGR5 as a prognostic marker of extrahepatic cholangiocarcinoma: insights from expression analysis and clinical correlations.

BACKGROUND: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker of colorectal cancer and may be a CSC marker of other cancer types. Few studies have been conducted on LGR5 expression in extrahepatic cholangiocarcinoma (ECC). METHODS: We analyzed LGR5 expression using RNAscope, a highly sensitive RNA in situ hybridization technique. Fifty-three ECCs were selected from the medical archives at Shinshu University Hospital and analyzed using a tissue microarray. LGR5 expression levels were divided into expression and no expression groups. LGR5 expression and clinicopathological characteristics were analyzed. RESULTS: Among 25 cases, no LGR5-positive dots were identified. Among 28 cases, some LGR5-positive dots were observed in carcinoma cells, together with a wide range of LGR5-positive cells. LGR5 expression was conspicuous in glandular duct formations. Well- to moderately differentiated types showed significantly higher LGR5 expression than the poorly differentiated type (p = 0.0268). LGR5 expression was associated with good overall survival (p = 0.0219) and good disease-free survival (DFS) (p = 0.0228). High LGR5 expression was associated with well- to moderately-differentiated types, indicating a favorable prognosis. In terms of DFS, multivariate analysis showed that high LGR5 expression was an independent favorable prognostic factor (p = 0.0397). CONCLUSIONS: These findings suggest that LGR5 is a promising, novel prognostic marker.

Leucine-rich repeat-containing G protein-coupled receptor 5 expression in lymph node metastases of colorectal cancer: Clinicopathological insights and prognostic implications.

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a significant cancer stem cell marker in colorectal cancer (CRC), lacks lymph node (LN) expression studies. In this study, we identified LGR5 expression by RNAscope, a highly sensitive RNA in situ method, and analyzed its association with clinicopathological characteristics. Tissue microarrays were generated from primary tumors (PTs) and LN metastases in paraffin-embedded blocks of 38 CRC surgical resection materials. LGR5 expression by RNAscope was evaluated by dividing the expression levels into negative and positive expression. In all but two cases of LN metastasis, LGR5-positive dots were detected in tumor cells, and there was a wide range of LGR5-positive cells. More LGR5-positive dots were identified in the gland-forming region. Twenty-three cases were classified into a high LGR5-expression group, and 15 cases were classified into a low LGR5-expression group. In the high LGR5-expression group, the histological grade was lower than in the low LGR5-expression group (p = 0.0159), while necrosis was significantly more prevalent (p = 0.0326), and the tumor, node, metastasis stage was significantly lower (p = 0.0302). There was no association between LGR5 expression levels in LN metastases and LGR5 expression levels in PT tissue. LGR5 expression in LN metastases may influence prognosis. Further analysis may lead to new therapeutic strategies.

A preliminary study of IgG4 expression and its prognostic significance in oral squamous cell carcinoma.

BACKGROUND: IgG4, which plays a pivotal role in the progression of phenotypically diverse tumors, serves as a prognostic marker because of its influence on cancer immunity. Nevertheless, the functions of IgG4 in tongue squamous cell carcinoma (TSCC) remained to be identified. METHODS: To evaluate the significance of IgG4 expression in TSCC, we performed immunohistochemical analysis of patients with TSCC (n = 50) to evaluate the correlation of IgG4 expression with patients' clinicopathological features and prognoses. RESULTS: Higher IgG4 expression detected in TSCC tissues was associated with the less advanced mode of invasion (Yamamoto-Kohama [YK] 1-3) (P = 0.031) and with well-differentiated TSCC (P = 0.077). Kaplan-Meier analyses revealed that the higher IgG4 expression group exhibited better prognosis indicated by overall survival (OS) (P = 0.04) and recurrence-free survival (RFS) (P = 0.016). Univariate analysis of OS indicated that IgG4 expression was associated with longer OS (P = 0.061), and multivariate analysis of RFS revealed that IgG4 expression served as an independent prognostic factor for longer RFS (P = 0.005). CONCLUSION: These results indicate that relatively higher IgG4 levels serve as a favorable prognostic factor for TSCC.

Interleukin-6 Stromal Expression is Correlated with Epithelial-Mesenchymal Transition at Tumor Budding in Colorectal Cancer.

Background. Tumor budding is a poor prognostic factor in colorectal adenocarcinoma, but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding and its association with tumor budding in colorectal adenocarcinoma. Methods. The clinicopathological and prognostic significance of IL6 in tumor budding was examined using a tissue microarray consisting of 36 patient samples of tumor budding in colorectal adenocarcinoma. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results. IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. Tumor budding grade was higher in the IL6-positive group in cancer stroma than in the IL6-negative group (P = .0161), while the IL6-positive group significantly exhibited the epithelial-mesenchymal transition phenotype compared with the IL6-negative group in cancer stroma (P = .0301). There was no significant difference in overall survival between colorectal adenocarcinoma patients in the IL6-positive and -negative groups in cancer stroma. Conclusion. Tumor budding may be affected by IL6 expression, and IL6 expression in cancer stroma at tumor budding may be an important prognostic marker.

Mucosal damage in pancreaticobiliary maljunction is stronger in the gallbladder than in the bile duct.

BACKGROUND: The frequency of gallbladder carcinoma is high in pancreaticobiliary maljunction (PBM), and the mechanism of carcinogenesis is not well understood. METHODS: The expression of γH2AX, the most sensitive marker for detecting DNA damage, was analyzed using immunohistochemistry in patients with PBM, in which the gallbladder and bile duct were simultaneously resected. Gallbladder and bile ducts were evaluated in non-neoplastic regions in 13 cases of PBM without cancer in the gallbladder and bile ducts. RESULTS: The median frequencies of γH2AX expression in the bile duct and gallbladder within the same case were 5.9% (range 1.7-12.05%) and 9.9% (range 2.8-25%), respectively, and were significantly higher in the gallbladder mucosa (P < 0.0004). γH2AX expression strongly correlated in the bile duct and gallbladder (r = 0.9436, P < 0.0001). PBM caused marked mucosal damage to the gallbladder. CONCLUSIONS: Mucosal damage may be involved in carcinogenesis, which may be useful for predicting malignant transformation.

ARL4C is associated with epithelial-to-mesenchymal transition in colorectal cancer.

BACKGROUND: ADP-ribosylation factor-like protein 4 C (ARL4C) is a member of the ARF small GTP-binding protein subfamily. The ARL4C gene is highly expressed in colorectal cancer (CRC). ARL4C protein promotes cell motility, invasion, and proliferation. METHODS: We investigated the characteristics of ARL4C by comparing its expression at the invasion front and relationships with clinicopathological data using RNAscope, a highly sensitive RNA in situ method. RESULTS: In all cases, ARL4C expression was observed in cancer stromal cells and cancer cells. ARL4C expression in cancer cells was localized at the invasion front. In cancer stromal cells, ARL4C expression was significantly stronger in cases with high-grade tumor budding than in cases with low-grade tumor budding (P = 0.0002). Additionally, ARL4C expression was significantly increased in patients with high histological grade compared with those with low histological grade (P = 0.0227). Furthermore, ARL4C expression was significantly stronger in lesions with the epithelial-to-mesenchymal transition (EMT) phenotype compared with the non-EMT phenotype (P = 0.0289). In CRC cells, ARL4C expression was significantly stronger in cells that had the EMT phenotype compared with those with a non-EMT phenotype (P = 0.0366). ARL4C expression was significantly higher in cancer stromal cells than in CRC cells (P < 0.0001). CONCLUSION: Our analysis reinforces the possibility that ARL4C expression worsens the prognosis of patients with CRC. Further elucidation of the function of ARL4C is desired.

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice.

Although endometriosis is primarily benign, it has been identified as a risk factor for endometriosis-associated ovarian cancer (EAOC). Genetic alterations in ARID1A, PTEN, and PIK3CA have been reported in EAOC; however, an appropriate EAOC animal model has yet to be established. Therefore, the present study aimed to create an EAOC mouse model by transplanting uterine pieces from donor mice, in which Arid1a and/or Pten was conditionally knocked out (KO) in Pax8-expressing endometrial cells by the administration of doxycycline (DOX), onto the ovarian surface or peritoneum of recipient mice. Two weeks after transplantation, gene KO was induced by DOX and endometriotic lesions were thereafter removed. The induction of only Arid1a KO did not cause any histological changes in the endometriotic cysts of recipients. In contrast, the induction of only Pten KO evoked a stratified architecture and nuclear atypia in the epithelial lining of all endometriotic cysts, histologically corresponding to atypical endometriosis. The induction of Arid1a; Pten double-KO evoked papillary and cribriform structures with nuclear atypia in the lining of 42 and 50% of peritoneal and ovarian endometriotic cysts, respectively, which were histologically similar to EAOC. These results indicate that this mouse model is useful for investigating the mechanisms underlying the development of EAOC and the related microenvironment.

ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis.

Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A-/- and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A-/- cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P = .0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten-/-;Arid1a-/- mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P = .003) and atypical hyperplasia (P < .0001) compared with that in the same tissues from Pten-/-;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.

IgG4 expression and IgG4/IgG ratio in the tumour invasion front predict long-term outcomes for patients with intrahepatic cholangiocarcinoma.

IgG4-positive plasma cells are reportedly increased in the tumour microenvironment, and a high number of these cells in tumours is a poor prognostic factor in several cancers. However, there are no reported analyses of IgG4 expression in intrahepatic cholangiocarcinoma (ICC). This study aimed to analyse the correlations between prognosis-related clinicopathological features of patients with ICC and IgG4 expression. We identified 37 ICC patients who underwent surgical resection between January 2010 and December 2020. The number of IgG-positive and IgG4-positive plasma cells in the tumour, invasion front, and stroma near the tumour was analysed by immunostaining. Furthermore, we examined the association of prognosis-related clinicopathological data with the number of IgG4-positive plasma cells and IgG4/IgG ratio in ICC patients. The IgG4-positive plasma cell percentages for the intra-tumour area, invasion front, and non-cancerous area (NCA) near the tumour were 91.9%, 56.8%, and 81.1%, respectively. IgG-positive plasma cells were observed in each region for all cases, except for NCA tissue in one case. A high IgG4 expression level and IgG4/IgG ratio in the invasion front were significantly associated with poor overall survival (OS) (log-rank test p=0.0438 and p=0.0338, respectively). Multivariate analysis for OS revealed that high IgG4 expression (p=0.0140), lymph node metastasis (p=0.0205), and positive surgical margin (p=0.0009) or a high IgG4/IgG ratio (p=0.0051), lymph node metastasis (p=0.0280), and positive surgical margin (p=0.0009) were independent poor prognostic factors. In conclusion, a high IgG4 expression level and IgG4/IgG ratio in the invasion front are independent poor prognostic factors for ICC. Targeted therapy for IgG4 may improve the prognosis for patients with ICC.

High expression of LGR6 is a poor prognostic factor in esophageal carcinoma.

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) promotes carcinogenesis and progression in some cancer types. However, there are few reports of LGR6 expression in esophageal squamous cell carcinoma (ESCC). LGR6 expression and clinicopathological features in ESCC were investigated by RNAscope, a highly sensitive RNA in situ hybridization method. METHODS: Appropriate tumors were selected from 41 cases of ESCC from which tissue microarrays were generated, and LGR6 expression was identified by RNAscope. RESULTS: Thirty-seven patients had LGR6 expression. High LGR6 expression was observed in 17 cases and low LGR6 expression in 24 cases. LGR6 expression was significantly higher in high histological grade ESCC than in low histological grade ESCC (P = 0.0023). ESCC patients who received neoadjuvant chemotherapy had significantly higher LGR6 expression than those without neoadjuvant chemotherapy (P = 0.0109). Furthermore, high LGR6 expression showed a poorer prognosis than low LGR6 expression (log-rank test, P = 0.0365). CONCLUSIONS: LGR6 may be a prognostic factor and a potential new therapeutic target in ESCC.

PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium.

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.

Syndrome of Inappropriate Antidiuretic Hormone Secretion as the Initial Presentation in a Patient with Stage I Small-cell Lung Cancer.

A 67-year-old man with a history of esophageal cancer resection was referred to our hospital because of nausea and appetite loss. Laboratory findings showed severe hyponatremia and were compatible with syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Chest computed tomography (CT) revealed a nodule measuring 13 mm in the lower lobe of the right lung. Right thoracotomy was performed, and the histopathological diagnosis was small-cell lung cancer (T1bN0M0; Stage 1b). Although SIADH is frequently associated with small-cell lung cancer, it is extremely rare as the initial clinical feature in stage I small-cell lung cancer.

Correlation of LGR5 expression and clinicopathological features in intrahepatic cholangiocarcinoma.

Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a known cancer stem cell marker. However, there are no reported analyses of LGR5 mRNA expression in normal liver and liver cancer tissues. Here, we evaluated LGR5 expression by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 25 samples of intrahepatic cholangiocarcinoma (ICC) selected from the medical archives at our hospital. LGR5 expression levels were divided into high and low expression groups by the five-grade scoring system, and clinicopathological features were analyzed. Low LGR5 expression was identified in some normal hepatocytes and bile duct cells. In addition, LGR5 expression was identified in all bile duct cancer samples except one case. Well-differentiated to moderately-differentiated adenocarcinoma tended to show higher LGR5 expression than poorly-differentiated adenocarcinoma (P = 0.0561), and the large duct type showed significantly higher LGR5 expression levels than the small duct type (P = 0.0225). Patients in the high LGR5 expression group tended to have good overall survival (OS) (P = 0.0623). The Cox proportional hazard regression model revealed that the high LGR5 expression group showed independently better OS for ICC (P = 0.0285). High LGR5 expression is possibly a good prognosis factor in ICC. However, the detailed mechanism of LGR5 in this disease remains unclear, and further analysis is warranted.

LGR5 expression and clinicopathological features of the invasive front in the fat infiltration area of pancreatic cancer.

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a strong cancer stem cell marker in colorectal cancer; however, there are many unclear aspects of LGR5 expression in pancreatic cancer. It has been reported that the interaction between tumor cells and stroma at the fat infiltration site has a significant effect on pancreatic cancer prognosis. Therefore, we report a clinicopathological study of LGR5 expression at the fat invasion front in pancreatic cancer. METHODS: LGR5 expression was analyzed in 40 pancreatic ductal adenocarcinoma cases with RNAscope, which is a newly developed high-sensitivity in situ hybridization method. Epithelial-mesenchymal transition (EMT) was analyzed by the expression of E-cadherin and vimentin via immunohistochemistry. RESULTS: LGR5-positive dots were identified in all cases, especially with glandular formation. In the fat invasion front, a high histological grade showed significantly reduced LGR5 expression compared with a low histological grade (p=0.0126). LGR5 expression was significantly higher in the non-EMT phenotype group than in EMT phenotype group (p=0.0003). Additionally, LGR5 expression was significantly lower in cases with high vascular invasion than in those with low vascular invasion (p=0.0244). CONCLUSIONS: These findings suggest that decreased LGR5 expression in the fat invasion front is associated with more aggressive biological behavior in pancreatic ductal adenocarcinoma, with higher tumor grade, EMT phenotype, and higher vascular invasion.

Usual Interstitial Pneumonia Pattern Interstitial Lung Disease Developed in a Patient with IgG4-related Chronic Sclerosing Sialadenitis.

A 69-year-old man was diagnosed with immunoglobulin (Ig) G4-related disease (IgG4-RD) at 62 years old. At that time, he had high serum IgG4 levels and bilateral submandibular gland swelling on CT; thus, a gland biopsy was performed. Because a reticular shadow was found on chest CT, a lung surgical biopsy was also performed. The specimens revealed usual interstitial pneumonia (UIP) pattern interstitial pneumonia with some IgG4-positive cells. The patient was subsequently followed up without treatment. His forced vital capacity and radiological findings progressively deteriorated, consistent with UIP pattern interstitial lung disease but different from a lung lesion of IgG4-RD.

Clinicopathological and prognostic significance of immunophenotypic characterization of endocervical adenocarcinoma using CLDN18, CDH17, and PAX8 in association with HPV status.

In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage-specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.

Superiority of sucrase-isomaltase to CD10 for immunohistochemical detection of intestinal absorptive cell phenotype in differentiated-type gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) can be divided immunophenotypically into gastric, intestinal, or mixed gastric and intestinal phenotypes. Cadherin 17 (CDH17) and CD10 have been used as comprehensive markers for intestinal epithelial cells and for small intestinal absorptive cells in GACs, respectively. Sucrase-isomaltase (SI) and CD10 are expressed in small intestinal absorptive cells and SI is more frequently expressed than CD10 in gastric intestinal metaplasia (IM). The aim of this study was to evaluate the potential of SI as a marker for intestinal absorptive cells compared to CD10 in differentiated-type (DT) GACs. We compared the immunohistochemical expression of CDH17, SI, and CD10 in IMs and tissue microarrays of 40 samples of DTGACs. In IMs and DTGACs, CDH17 showed a diffuse lateral cytoplasmic membrane staining both in columnar and goblet cells. SI and CD10 were expressed on the luminal surfaces of the columnar cells. In IMs, SI was positive both in both complete-type IMs and in incomplete-type IMs. CD10 was positive only in complete-type IMs. In DTGACs, CDH17, SI, and CD 10 were positive in 37 (92.5%), 22 (55%), and 11 (27.5%) cases, respectively. In SI-positive cases, the degrees of expression of SI were equal to (7 cases) or less than (15 cases) those of CDH17; the degrees of expression of SI were equal to (5 cases), more than (16 cases), or less than (1 case) those of CD10. In conclusion, SI is a more sensitive immunohistochemical marker for intestinal absorptive cells than CD10 in DTGACs.

IL-6 expression helps distinguish Castleman's disease from IgG4-related disease in the lung.

BACKGROUND: It is difficult to distinguish between multicentric Castleman's disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung. METHODS: We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected. RESULTS: In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level. CONCLUSION: Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD.