Publications by authors named "Ryo Sugimoto"

52 Publications

Coexistence of salivary duct, myoepithelial and epithelial-myoepithelial carcinomas in the parotid gland: a case report and literature review.

J Surg Case Rep 2021 Jun 4;2021(6):rjab230. Epub 2021 Jun 4.

Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate Japan.

Few reports have described two or more histologically-distinct carcinoma types within the same salivary gland. A 62-year-old man presented to our hospital after detecting a mass in the right parotid gland. Computed tomography revealed a tumor (5.1 × 5.0 cm) within the right parotid gland. Tumor resection with lymph node dissection was performed. The proliferation of three morphologically-different tumor cells was demonstrated on histopathologic examination (salivary duct carcinoma [SDC], myoepithelial carcinoma and epithelial-myoepithelial carcinoma [EMC]). The shape of the inner layer of cells in the EMC was similar to the SDC. Specifically, it appeared that the cells were a mixture of the two tumors with reciprocal transfer in the same area. Immunohistochemical staining showed that the SDC cells and the EMC inner cells were positive for AR, HER2 and p53. Thus, we suggest that our case represented a high-grade transformation.
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http://dx.doi.org/10.1093/jscr/rjab230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177961PMC
June 2021

SMARCB1-deficient sinonasal carcinoma: a case report and literature review.

J Surg Case Rep 2021 Apr 30;2021(4):rjab161. Epub 2021 Apr 30.

Departments of Molecular Diagnostic Pathology, Yahaba-cho, Shiwa-gun, Iwate, Japan.

SWItch/Sucrose Non-Fermentable (SWI/SNF) -related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) deficient sinonasal carcinoma (SdSNC) is a rare variant of sinonasal undifferentiated carcinoma (SNUC). A 72-year-old man was referred to our hospital with complaints of left facial pain and nasal obstruction. Computed tomography (CI) revealed a tumor 5.5 cm in size in the left nasal cavity. Atypical cells with eosinophilic cytoplasm proliferating as solid nests and exhibiting necrosis were observed and diagnosed as poorly differentiated carcinoma. Carbon ion radiotherapy was performed. Follow-up CI revealed multiple masses in both lungs. Partial resection of the right lung was performed. Proliferating atypical cells with clear-to-eosinophilic cytoplasm were observed and resembled those in the paranasal sinus tumor. Immunohistochemical analysis indicated a metastatic lung tumor derived from the SNUC revealed completely negative SMARCB1 expression in the nuclei of the tumor cells. SdSNC is difficult to diagnose. However, molecular targeted therapy may be useful. Thus, it is necessary and important to recognize this rare cancer accurately.
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http://dx.doi.org/10.1093/jscr/rjab161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088288PMC
April 2021

Microenvironmental markers are correlated with lymph node metastasis in invasive submucosal colorectal cancer.

Histopathology 2021 Apr 21. Epub 2021 Apr 21.

Division of Gastroenterology, Department of Internal Medicine, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan.

Aims: Recent studies have shown that the microenvironment can include cancer cells and cancer-associated fibroblasts (CAFs) and that both play important roles in the progression and metastasis of CRC. Here, we aimed to analyze the expression patterns of cancer cell- and CAF-related proteins in submucosal invasive colorectal cancer (SiCRC) and whether such markers are correlated with lymph node metastasis (LNM).

Methods And Results: Quantitative analysis was conducted for Ki-67, p53, β-catenin, and MMP7 to assess cancer cell markers. In addition, we examined CAF markers, including α-SMA, CD10, podoplanin, FSP-1, PDGF-α, PDGF-β, AEBP1, FAP-1, ZEB1 and TWIST1. In both cases, we conducted digital pathology with Aperio software. We also examined the expression patterns of biomarkers using hierarchical cluster analysis. Two subgroups were established based on the expression patterns of cancer cell- and CAF- related markers, and the associations of these subgroups with clinicopathological variables. In multivariate analysis, subgroup 2, which was characterized by high expression of Ki-67, p53, FAP-1, PDGF α, PDGF β, and TWIST1, was correlated with LNM (p < 0.01). Next, we examined the associations of individual biomarkers with LNM. Multivariate analysis showed that high expression levels of Ki-67 and FA1 were significantly associated with LNM (p < 0.05).

Conclusions: Our findings showed that expression patterns of cancer cell- and CAF related proteins may allow for stratification of patients into risk categories for LNM in SiCRC. In addition, Ki-67- and FAP-1-expressing microenvironmental cells might be helpful for identification of correlations with LNM in SiCRC.
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http://dx.doi.org/10.1111/his.14388DOI Listing
April 2021

Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling.

Br J Cancer 2021 Apr 3;124(9):1556-1565. Epub 2021 Mar 3.

Division of Biomedical Research and Development, Iwate Medical University Institute for Biomedical Sciences, Iwate, Japan.

Background: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge.

Methods: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples.

Results: "Founder" mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, "truncal" mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than "non-founder" and "branch" mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring.

Conclusions: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.
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http://dx.doi.org/10.1038/s41416-021-01266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076308PMC
April 2021

Undifferentiated carcinoma arising from intracranial epidermoid cyst.

Pathol Int 2021 Apr 9;71(4):281-283. Epub 2021 Feb 9.

Departments of Molecular Diagnostic Pathology, Iwate Medical University, Iwate, Japan.

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http://dx.doi.org/10.1111/pin.13071DOI Listing
April 2021

Immunohistochemical Examination is Highly Sensitive and Specific for Detection of the V600E BRAF Mutation in Colorectal Serrated Lesions.

Appl Immunohistochem Mol Morphol 2020 Dec 9. Epub 2020 Dec 9.

Department of Molecular Diagnostic Pathology, School of Medicine.

Mutations in BRAF are important events in colorectal serrated lesions and specific genetic markers for the serrated pathway. However, examination of BRAF mutations is not easy in routine histopathologic analyses. Here, the authors examined 73 colorectal serrated lesions, including 21 hyperplastic polyps, 32 traditional serrated adenomas, and 30 sessile serrated lesions, for comparison of BRAF mutation status with immunopositive expression of the anti-BRAF V600E mutation-specific antibody VE1. Thirty-two tubular adenomas (TAs) were examined as controls. In addition, 5 examples of sessile serrated lesion with dysplasia were included. Mutations in BRAF (exon 15; V600E) and KRAS (exon 2) were analyzed in serrated lesions and TAs using pyrosequencing. Finally, the authors compared BRAF mutations with immunohistochemical expression of VE1 antibodies against the BRAF V600E mutation, which was examined based on quantitative analyses and correlations between semiquantitative (0, 1+, or 2+) and quantitative results in colorectal serrated lesions. The cut-off value of VE1 expression (32%) was set based on receiver operating characteristic curve analysis. In the current study, mutations in BRAF were well correlated with VE1 expression in serrated lesions, although no TAs without BRAF mutations were immunopositive. In contrast, serrated lesions and TAs with mutations in KRAS were not stained for VE1 expression. In serrated lesions, although the sensitivity was 96.2% to 100%, the specificity was 90.0% to 100%. In addition, there was also good correlation between semiquantitative and quantitative results. Analysis of BRAF V600E expression may be pathologically useful, particularly in routine histopathologic diagnosis.
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http://dx.doi.org/10.1097/PAI.0000000000000890DOI Listing
December 2020

A genome-wide study of the relationship between chromosomal abnormalities and gene expression in colorectal tumors.

Genes Chromosomes Cancer 2021 Apr 24;60(4):250-262. Epub 2020 Dec 24.

Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.

The role of somatic copy number alterations (SCNAs) that occur in colorectal tumors is poorly understood. SCNAs are correlated with corresponding gene expression changes that may contribute to neoplastic progression. Thus, we examined SCNAs and the expression of messenger RNAs (mRNAs) located at corresponding loci in colorectal neoplasia, a progression model of human neoplasm. We used 42 colorectal neoplastic samples, including adenomas, intramucosal cancers (IMC) and invasive colorectal cancers (CRC) that were microsatellite stable (MSS) using a genome-wide SNP array and gene expression array (first cohort). In addition, validation analyses were examined (37 colorectal neoplasias). None of the mRNAs with a corresponding SCNA was found in the adenomas. However, three mRNAs, including ARFGEF2 at 20q13.13, N4BP2L2 at 13q13.1 and OLFM4 at 13q14.3 with a copy number (CN) gain at the corresponding locus were upregulated in IMCs of the first cohort. Moreover, upregulated expression of ARFGEF2 and OLFM4 was upregulated in the validation analysis. Finally, 28 mRNAs with gains of corresponding loci were pooled in invasive CRC of the first cohort. The mRNAs, including ACSS2 (20q11.22), DDX27 (20q13.13), MAPRE1 (20q11.21), OSBPL2 (20q11.22) and PHF20 (20q11.22-q11.23) with CN gains of the corresponding loci were identified in 28 mRNAs. Four of these mRNAs (DDX27, MAPRE1, OSBPL2 and PHF20) were upregulated in the invasive CRC in the validation analysis. We conclude that specific 13q and 22q CN gains with gene expression changes in the corresponding loci may play an important role in IMC cells' progression into invasive CRC.
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http://dx.doi.org/10.1002/gcc.22924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898915PMC
April 2021

Programmed death ligand 1 protein expression is positively correlated with the solid predominant subtype, high MIB-1 labeling index, and p53 expression and negatively correlated with epidermal growth factor receptor mutations in lung adenocarcinoma.

Hum Pathol 2021 Feb 5;108:12-21. Epub 2020 Nov 5.

Department of Molecular Diagnostic Pathology, Iwate Medical University, Shiwa-gun, Iwate, 0283695, Japan.

Programmed death ligand 1 (PD-L1) protein expression is a proposed predictive biomarker of immunotherapy; thus, identification of the clinicopathological and molecular characteristics associated with PD-L1 expression is important and necessary. We examined PD-L1 immunohistochemical expression and its relationships with the clinicopathological and molecular characteristics of patients with surgically resected nonsmall cell lung carcinoma. PD-L1 expression differed according to the histological subtype. Among 633 patients with adenocarcinoma, 523 (82.6%) had no PD-L1 expression, 78 (12.3%) low expression, and 32 (5.1%) high expression. PD-L1 expression was more common in men (p < 0.001), in smokers (p = 0.002), and in patients with a more advanced stage (p = 0.002), the solid predominant subtype (p < 0.001), no epidermal growth factor receptor(EGFR) mutations (p < 0.001), a high MIB-1 labeling index (p < 0.001), and positive p53 immunohistochemical expression (p < 0.001). In a multivariate logistic regression analysis, the solid predominant subtype (odds ratio [OR] = 4.92, 95% confidence interval [CI]: 2.72-8.89, p < 0.001), no EGFR mutations (OR = 2.27, 95% CI: 1.35-2.7, p = 0.002), a high MIB-1 labeling index (OR = 2.78, 95% CI: 1.72-4.55, p < 0.001), and p53 positivity (OR = 2.13, 95% CI: 1.34-4.36, p = 0.042) were significantly and independently associated with PD-L1 expression. The combination of the solid predominant subtype with a high MIB-1 labeling index was strongly associated with positive expression of PD-L1. In the 193 patients with squamous cell carcinoma, 92 (47.7%) had no PD-L1 expression, 57 (29.5%) low expression, and 44 (22.8%) high expression. There were no significant correlations between PD-L1 expression and the evaluated clinicopathological or molecular characteristics of these patients. These results, indicating associations of PD-L1 with various clinicopathological or molecular characteristics in adenocarcinoma but not squamous cell carcinoma, may be useful for selecting patients with a good response to immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.humpath.2020.10.014DOI Listing
February 2021

Molecular alterations in gastric cancer and the surrounding intestinal metaplastic mucosa: an analysis of isolated glands.

Gastric Cancer 2021 Mar 3;24(2):382-391. Epub 2020 Nov 3.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwa, Yahaba, Morioka, 028-3695, Japan.

Background: Intestinal metaplasias (IMs) are generally regarded as pre-neoplastic gastric lesions. However, molecular alterations including genetic and epigenetic changes occurring in individual IM glands are not well defined.

Aims: We sought to identify DNA methylation status, microsatellite instability (MSI) and allelic imbalance (AI) occurring in individual IM glands and non-IM glands within the same mucosa.

Methods: We divided examined isolated gland obtained from GC into 4 components: isolated cancer, antral isolated intestinal metaplastic tissue, antral isolated non-metaplastic gland and isolated non-metaplastic gland derived from the greater curvature of the most distant gastric body without mucosal atrophy. We examined AI and microsatellite instability statuses using PCR-based microsatellite analysis. Next, the DNA methylation status (high methylation epigenome [HME], intermediate methylation epigenome [IME], and low methylation epigenome [LME]) was investigated. DNA methylation analysis of CDKN2A, mir34-b/c and MLHI genes was also performed.

Results: Although antral isolated IM glands were characterized by IME, isolated non-IM glands showed LME. In isolated cancer glands, HME was frequently found, compared with isolated non-IM glands. DNA methylation of mir34-b/c was common in isolated cancer and IM glands, whereas DNA methylation of CDKN2A was a rare event in isolated samples. The MLH1 gene was not methylated in isolated non-IM glands. Although multiple AIs were frequently found in isolated cancer glands, a few AIs were detected in isolated IM glands.

Conclusions: We suggest that the DNA methylation status and the status of the mir34-b/c gene among isolated samples of IMs and isolated non-IM glands have an impact on IM development.
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http://dx.doi.org/10.1007/s10120-020-01130-zDOI Listing
March 2021

Immunohistochemical Analysis of Mismatch Repair Gene Proteins in Early Gastric Cancer Based on Microsatellite Status.

Digestion 2020 Oct 14:1-10. Epub 2020 Oct 14.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa, Japan,

Background: Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis and is observed in 10-20% of early gastric cancers (EGCs). Early detection of EGCs with an MSI-high phenotype would be useful for elucidating the mechanisms of gastric carcinogenesis and improving outcomes in patients with GC.

Objective: We explored the usefulness of immunohistochemical expression of mismatch repair (MMR) proteins, including MLH1, PMS2, MSH2, and MSH6 in EGC.

Methods: We examined the expression of 4 MMR proteins using immunohistochemistry in 119 patients with EGC based on MS status, as determined by polymerase chain reaction-microsatellite analysis. In addition, methylation of the MLH1 gene was quantified by pyrosequencing.

Results: EGCs were classified into 46 MSI-high phenotypes and 73 microsatellite stable (MSS) phenotypes. Although loss of MLH1 expression was associated with loss of PMS2 expression in the MSI-high phenotype, discordant cases of loss of expression between MLH1 and PMS2 were found (MLH1 [-]/PMS2 [+], 3 cases). Loss of MLH1/PMS2 expression was observed in 2 of 73 MSS phenotypes. Loss of MSH2/MSH6 expression was found in 4 of 46 MSI-high phenotypes, whereas loss of MSH2/MSH6 expression was not detected in the MSS phenotype. In addition, loss of MLH1 expression was correlated with methylation of MLH1. However, there were discordant cases in which loss of MLH1 expression was not accompanied by methylation of MLH1.

Conclusion: Although immunostaining of MMR proteins could help predict MSI in EGCs, immunostaining did not have the same value as genetic testing for determination of MSI.
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http://dx.doi.org/10.1159/000510679DOI Listing
October 2020

Analysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA.

PLoS One 2020 7;15(10):e0239966. Epub 2020 Oct 7.

Division of Biomedical Research and Development, Iwate Medical University Institute of Biomedical Sciences, Yahaba, Japan.

Circulating tumor DNA (ctDNA) is released from tumor cells into blood in advanced cancer patients. Although gene mutations in individual tumors can be diverse and heterogenous, ctDNA has the potential to provide comprehensive biomarker information. Here, we performed multi-region sampling (three sites) per resected specimen from 10 gastric cancer patients followed by targeted sequencing and proteomic profiling using reverse-phase protein arrays. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were present in all three regions and were designated as founder mutations. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis also demonstrated a good concordance between founder and truncal mutations, defined as mutations shared by all simulated clones at the trunk of the tumor phylogenetic tree. These findings led us to prioritize founder mutations for quantitative ctDNA monitoring by digital PCR with individually-designed primer/probe sets. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Proteomic heterogeneity was present across the tumor regions both within and between patients independent of mutational status. Our results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be immediately useful for quantitative ctDNA monitoring but do not provide sufficient information to predict the proteomic composition of tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239966PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540850PMC
November 2020

Primary esophageal malignant melanoma successfully treated with anti-PD-1 antibody for retroperitoneal recurrence after esophagectomy: A case report.

Int J Surg Case Rep 2020 10;75:152-156. Epub 2020 Sep 10.

Department of Surgery, Iwate Medical University School of Medicine, Iwate, Japan. Electronic address:

Introduction: Primary malignant melanoma of the esophagus (PMME) is a rare disease with a poor prognosis. Here, we report a case of retroperitoneal recurrence of PMME successfully treated with the anti-programmed cell death 1 antibody, nivolumab.

Presentation Of Case: A 70-year-old male with dysphagia was referred to our hospital. Esophagogastroscopy showed an elevated tumor in the lower thoracic esophagus. A histopathological examination of the biopsy revealed poorly differentiated squamous cell carcinoma. The patient was diagnosed with clinical T3N1M0 stage III esophageal squamous cell carcinoma and was treated with neoadjuvant chemotherapy followed by radical esophagectomy. A postoperative histopathological examination revealed that atypical cells with a brown pigment were scattered in the tumor. Immunohistochemical staining demonstrated positive expression of human melanoma black 45, melan A, and S100. A pathological diagnosis of PMME was confirmed. Sixteen months after surgery, abdominal computed tomography revealed solitary retroperitoneal recurrence in the lateral portion of the ascending colon. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) showed hypermetabolic accumulation with a maximum standardized uptake value of 5.8. The patient was treated with nivolumab (240 mg) every two weeks. After eight courses of nivolumab, abnormal accumulation of the retroperitoneal mass disappeared on PET, and this therapeutic effect continued for 20 months.

Conclusions: Nivolumab was effective for recurrence of PMME in our case. There are few reports of treatment with nivolumab for PMME. Further studies are necessary to establish the usefulness of nivolumab for PMME in the future.
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http://dx.doi.org/10.1016/j.ijscr.2020.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508692PMC
September 2020

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma.

Diagn Pathol 2020 Sep 17;15(1):111. Epub 2020 Sep 17.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan.

Background: Crawling-type adenocarcinoma (CRA) is an important gastric cancer (GC) subtype that exhibits a specific histological pattern and has characteristic clinicopathological findings. Despite its characteristic histology, little is known about the molecular characteristics of CRA.

Methods: We examined 177 GC cases, including 51 cases of CRA and 126 cases having conventional differentiated adenocarcinomas (CDAs). Results for immunohistochemistry (mucin phenotype; Muc5AC, Muc6, Muc2 and CD10, CDX-2, MLH-1, p53 and β-catenin), mutation analysis (TP53, KRAS and BRAF), microsatellite instability (BAT25, BAT26, D2S123, D5S346 and D17S250), DNA methylation status by a two-panel method (RUNX3, MINT31, LOX, NEUROG1, ELMO1 and THBD), MLH-1 promoter methylation, and allelic imbalance (AI; 1p, 3p, 4p, 5q, 8p, 9p, 13q, TP53, 18q and 22q) were examined.

Results: CRAs were more likely to occur in the middle third of the stomach, in younger patients and to be macroscopically depressed. Nuclear accumulation of β-catenin and loss of MLH-1 expression were less frequent among CRA cases compared to CDA cases. At a molecular level, CRA is often characterized by the deletion mutation c.529_546 (18-base pair deletion at codon 177-182 in exon 5) in the TP53 gene (10 cases). Although the low methylation epigenotype was significantly more frequent for CRAs compared to CDAs, multiple AIs were more often seen in CRAs relative to CDAs.

Conclusions: The results demonstrated that TP53 mutations, particularly c.529_546del, and multiple AIs are closely associated with CRA carcinogenesis. Our results suggest that CRA is an independent entity of GC in terms of clinicopathologic and molecular findings.
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http://dx.doi.org/10.1186/s13000-020-01026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500034PMC
September 2020

Epiploic appendage infarction of the sigmoid colon.

Pathol Int 2020 Nov 14;70(11):918-919. Epub 2020 Sep 14.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Iwate, Japan.

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http://dx.doi.org/10.1111/pin.13019DOI Listing
November 2020

Pulmonary epithelial-myoepithelial carcinoma without AKT1, HRAS or PIK3CA mutations: a case report.

Diagn Pathol 2020 Aug 28;15(1):105. Epub 2020 Aug 28.

Department of Molecular Diagnostic Pathology, Iwate Medical University, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 0283695, Japan.

Background: Pulmonary epithelial-myoepithelial carcinoma is a rare subtype of lung cancer. Because of its rarity, the molecular information on this carcinoma is insufficient.

Case Presentation: We report a case of pulmonary epithelial-myoepithelial carcinoma without AKT1, HRAS or PIK3CA mutations in a 76-year-old woman. Computed tomography revealed a tumor located in the left lower lung. Thoracoscopic left lower lobectomy was performed. Histopathologically, the tumor consisted of duct-like structures and polygonal and spindle cell features. The duct-like structures were composed of two distinct cell layers. The inner layer consisted of cuboidal cells that were positive for pan-cytokeratin and negative for p63, whereas the outer layer consisted of polygonal and spindle cells that were positive for p63 and weakly positive for pan-cytokeratin. We evaluated mutations in AKT1, BRAF, CTNNB1, HRAS, KRAS and PIK3CA but did not detect any mutations.

Conclusion: Pulmonary epithelial-myoepithelial carcinoma is a rare subtype of lung cancer, with only 56 previous cases reported in the English literature. The genetic alterations in pulmonary epithelial-myoepithelial carcinoma are still unknown. We examined the 6 genes mutation analysis, however no mutation was detected.
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http://dx.doi.org/10.1186/s13000-020-01020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456004PMC
August 2020

Submarine groundwater discharge: A previously undocumented source of contaminants of emerging concern to the coastal ocean (Sydney, Australia).

Mar Pollut Bull 2020 Nov 8;160:111519. Epub 2020 Aug 8.

National Marine Science Centre, School of Environment, Science, and Engineering, Southern Cross University, Coffs Harbour, New South Wales, Australia; Department of Marine Sciences, University of Gothenburg, Gothenburg, Sweden.

Submarine groundwater discharge (SGD) is rarely considered as a pathway for contaminants of emerging concern (CECs). Here, we investigated SGD as a source of CECs in Sydney Harbour, Australia. CEC detection frequencies based on presence/absence of a specific compound were >90% for caffeine, carbamazepine, and dioxins, and overall ranged from 25 to 100% in five studied embayments. SGD rates estimated from radium isotopes explained >80% of observed CEC inventories for one or more compounds (caffeine, carbamazepine, dioxins, sulfamethoxazole, fluoroquinolones and ibuprofen) in four out of the five embayments. Radium-derived residence times imply mixing is also an important process for driving coastal inventories of these persistent chemicals. Two compounds (ibuprofen and dioxins) were in concentrations deemed a high risk to the ecosystem. Overall, we demonstrate that SGD can act as a vector for CECs negatively impacting coastal water quality.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111519DOI Listing
November 2020

Esophageal carcinosarcoma in which the sarcomatous element has sloughed off: A case report.

Int J Surg Case Rep 2020 3;74:27-31. Epub 2020 Aug 3.

Department of Surgery, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba, Iwate 028-3695, Japan.

Introduction: Most esophageal carcinosarcoma (ECS) tumors present as a polypoid tumor that is continuous with the superficial lesion and suspended by a pedicle. Here, we report a case of ECS in which a polypoid lesion sloughed off before surgery.

Presentation Of Case: A 76-year-old man with dysphagia was admitted to our hospital. Esophagogastroscopy revealed a 20-mm polypoid tumor continuous with a superficial lesion and attached to the lesion by a thin pedicle in the mid-thoracic esophagus. Histopathological examination of the endoscopic biopsy showed that the superficial lesion was a moderately differentiated squamous cell carcinoma and that the polypoid tumor contained a sarcomatous element. He was diagnosed with ECS and underwent radical esophagectomy with three-field lymph node dissection. In the resected specimen, no polypoid tumor was found, and only a superficial lesion was observed. The histopathological findings revealed only squamous cell carcinoma, and the pathological diagnosis was esophageal squamous cell carcinoma, pT1bN0M0, pathological stage I. The patient was discharged from the hospital 22 days after surgery and did not experience any complications. He is currently alive and remained cancer-free for three years since surgery was performed.

Discussion: Due to the distinctive configuration in which the polypoid lesion was connected to the superficial cancerous lesion by a very thin pedicle, researchers suggested that the polypoid tumor, which consisted of a sarcomatous element, was sloughed off before surgery.

Conclusion: We encountered a rare case of ECS in which the sarcomatous element sloughed off prior to surgical resection.
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http://dx.doi.org/10.1016/j.ijscr.2020.07.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415637PMC
August 2020

Super-late pulmonary recurrence after radical esophagectomy for esophageal squamous cell carcinoma.

Int J Surg Case Rep 2020 6;72:166-171. Epub 2020 Jun 6.

Department of Surgery, Iwate Medical University, Yahaba 028-3695, Japan.

Introduction: Pulmonary metastases from esophageal squamous cell carcinoma (ESCC) are often detected bilateral and multiple lesions and are often accompanied by metastases to other sites. The concept of oligometastasis has been developed, and limited distant metastases have been considered as indications for surgical resection for the purpose of extending overall survival. We herein present a long-surviving case of super-late pulmonary recurrence of ESCC, seven years after radical esophagectomy.

Presentation Of Case: A 71-year-old woman who underwent radical subtotal esophagectomy with three-field lymph node dissection with a diagnosis of an advanced poorly differentiated ESCC with cT3N1M0 seven years ago visited our hospital. Chest X-ray and computed tomography at the 7-year follow-up revealed a solitary pulmonary tumor, 1.5 cm in diameter, at the right middle lobe without any extrapulmonary metastases; however, we could not diagnose whether primary lung cancer or pulmonary metastasis of ESCC was present. Therefore, we performed thoracoscopic partial resection of the right middle lobe. A histopathological examination including immunohistochemical staining revealed that the tumor was not derived from both alveolar epithelium and neuroendocrine cells and was diagnosed as pulmonary oligometastasis of ESCC. She has been followed for four years without re-recurrence.

Conclusion: Pulmonary oligometastases of ESCC should be considered as surgical indications if the tumor is detected after a long disease-free interval without any extrapulmonary recurrences.
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http://dx.doi.org/10.1016/j.ijscr.2020.05.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299901PMC
June 2020

The clinicopathological and molecular features of sporadic gastric foveolar type neoplasia.

Virchows Arch 2020 Dec 12;477(6):835-844. Epub 2020 Jun 12.

Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan.

Gastric intraepithelial foveolar type neoplasia (IEFN) is not well defined. In addition, atrophic mucosa (AM) is an important issue to consider when evaluating gastric tumorigenesis. Here, we assessed the clinicopathological characteristics and molecular alterations contributing to the development of IEFN compared with intestinal type neoplasia. We examined the clinicopathological and molecular features of 42 cases of IEFN with low-grade dysplasia (LGD) and those of 77 cases of intraepithelial intestinal type neoplasia (IEIN) with LGD. The clinicopathological and molecular features examined included the AM status, mucin phenotype expression, CDX2 expression, p53 overexpression, β-catenin intranuclear accumulation, microsatellite instability (MSI), DNA methylation status (low methylation epigenotype [LME], intermediate ME, or high ME), allelic imbalances (AIs), and APC promoter 1B mutations. There were no differences in the frequencies of AM and rates of CDX2 expression between IEFN and IEIN cases. Although no differences in the frequencies of p53 overexpression and MSI were observed between the two histological types, intranuclear expression of β-catenin was significantly higher in IEIN than in IEFN. In addition, although the rate of LME was significantly higher in IEFN cases than in IEIN cases, IEFN was characterized by AIs at multiple foci. Finally, mutation of the APC promoter 1B, which is a characteristic of gastric adenocarcinoma and proximal polyposis of the stomach (potentially resembling IEFN), was detected in only one IEFN case. These findings suggested that IEFN may be an independent entity in terms of molecular alterations including the presence of multiple AIs and LME.
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http://dx.doi.org/10.1007/s00428-020-02846-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683467PMC
December 2020

[Lung Cancer Accompanied by Sarcoidosis with Mediastinal and Bilateral Hilar Lymphadenopathy;Report of a Case].

Kyobu Geka 2020 Jan;73(1):72-75

Department of Thoracic Surgery, Iwate Prefectural Isawa Hospital, Oshu, Japan.

A 64-year-old woman with complete atrioventricular block caused by sarcoidosis was emergently placed a pacemaker. A 10 mm nodule in the left upper lobe of the lung and the mediastinal and bilateral hilar lymphadenopathy was detected through chest computed tomography. To establish the diagnosis, resection of the tumor and #4L was performed. By intraoperative pathology, the nodule was diagnosed as an adenocarcinoma and #4L was found to be a granuloma without metastasis of carcinoma. Subsequently, left upper lobectomy and lymph node dissection (ND2a-2) was conducted. Pathological stage was stageⅠA1 lung cancer. No recurrence has been noted for a year postoperatively and lymphadenopathy has improved by administering prednisolone medication.
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January 2020

Sarcomatoid change associated with epithelial-mesenchymal transition in mucinous tubular and spindle cell carcinoma of the kidney: a case report.

Int J Clin Exp Pathol 2019 1;12(7):2767-2771. Epub 2019 Jul 1.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University 19-1, Morioka 020-8505, Japan.

We report an unusual case of mucinous tubular and spindle cell carcinoma (MTSCC) with sarcomatoid change in an 80-year-old Japanese male. In a resected specimen, a grayish-white tumor was found in the left kidney, and several metastases were observed in the right cervical bone and liver. Histologically, most of the main tumor examined showed MTSCC with sarcomatoid change. The transitions between the MTSCC and sarcomatoid components suggested that sarcomatoid transformation had occurred in the MTSCC. Immunohistochemically, the epithelial-mesenchymal transition (EMT)-associated marker ZEB1 was expressed in the sarcomatoid and transitional components. In contrast, ZEB1 expression was negative in the MTSCC component. The present findings support the view that MTSCC with sarcomatoid change represents MTSCC that develops a sarcomatoid component via EMT of the MTSCC component. EMT plays an important role in sarcomatoid change; thus, we conclude that MTSCC with sarcomatoid change is an 'EMT associated tumor'.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949544PMC
July 2019

The expression of gastrointestinal differentiation markers in extrahepatic cholangiocarcinoma: clinicopathological significance based on tumor location.

Hum Pathol 2019 10 8;92:91-100. Epub 2019 Aug 8.

Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Iwate 020-8505, Japan. Electronic address:

The expression of gastrointestinal differentiation markers is associated with the tumorigenesis and prognosis of digestive cancers. However, little is known about the significance of gastrointestinal differentiation marker profiles in patients with extrahepatic cholangiocarcinoma (CCA), which is classified as perihilar and distal CCA. The purpose of this study was to clarify the role of gastrointestinal differentiation marker expression in extrahepatic CCA based on tumor location. We examined the expression of gastrointestinal differentiation markers in resected perihilar (n = 30) and distal (n = 54) CCAs based on the immunohistochemical expression of the following markers: MUC2, MUC5AC, MUC6, CD10, CDX-2, and cytokeratin 20. Expression scores were determined semiquantitatively based on the rate of positively stained cells. Furthermore, we performed hierarchical clustering of the CCAs based on the immunohistochemical expression scores to evaluate differences in the expression patterns of the 6 gastrointestinal differentiation markers. Consequently, perihilar and distal CCAs were stratified into 2 subgroups each. Among the perihilar CCAs, subgroup 1 was characterized by lower expression of MUC5AC and MUC6, a larger median tumor size, and a significantly worse prognosis compared with subgroup 2. Furthermore, the immunohistological subgroup (subgroup 1 versus 2) and TNM stage (stage III versus II) were independent predictors of patient survival. Among the distal CCAs, subgroup 1 was characterized by lower expression of MUC5AC compared with subgroup 2. We suggest that gastrointestinal differentiation marker profiles are useful for stratifying perihilar and distal CCAs. In addition, gastrointestinal differentiation markers play a crucial role in tumor development, particularly in perihilar CCA.
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http://dx.doi.org/10.1016/j.humpath.2019.08.002DOI Listing
October 2019

Melanocytic Nevus of the Colon.

Case Rep Gastroenterol 2019 May-Aug;13(2):271-274. Epub 2019 Jun 26.

Department of Diagnostic Molecular Pathology, School of Medicine, Iwate Medical University, Morioka, Japan.

Here, we report a very rare case of melanocytic nevus of the colon. A 54-year-old woman with an unremarkable medical history visited our hospital for screening colonoscopy. Colonoscopy revealed a pigmented flat lesion in the ascending colon. Histological evaluation of a biopsy specimen revealed proliferation of pigmented cells in the lamina muscularis propria. On immunohistochemical analysis, pigmented cells were positive for S-100 protein and Melan-A expression, and a diagnosis of colonic melanocytic nevus was made. Although the pathogenesis underlying colonic melanocytic nevi remains unclear, we speculate that colonic melanocytic nevi develop via abnormal migration or differentiation of neural crest cells during embryogenesis.
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http://dx.doi.org/10.1159/000501196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639573PMC
June 2019

Gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with pancreatic acinar differentiation: a case report.

Diagn Pathol 2019 May 10;14(1):38. Epub 2019 May 10.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, 020-8505, Japan.

Background: Gastric mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are infrequently encountered in routine practice. Some gastric neuroendocrine carcinomas (NECs) have a variety of differentiation patterns; however, pancreatic acinar differentiation in gastric NECs is rare. The molecular abnormalities of NECs with pancreatic acinar differentiation are not well understood.

Case Presentation: A 67-year-old male with a gastric MiNEN with pancreatic acinar differentiation without any symptoms. The tumor consisted of two components, including both glandular and solid histological features. Although the former component was a common type of adenocarcinoma, the latter showed endocrine differentiation and expressed pancreatic acinar enzymes immunohistochemically. A positive signal with the anti-BCL10 antibody, which detects one of the pancreatic acinar enzymes, was also present specifically in the latter component. We also examined TP53 genomic mutations, DNA methylation status, and allelic imbalance (AI), which is an indicator of tumor aggressiveness. Although both components of this tumor showed no genomic mutation and a low methylation epigenotype, the frequency of AI was higher in the acinar-endocrine component than in the adenocarcinomatous component. The finding of AI indicated the progression of the conventional adenocarcinoma to an acinar-endocrine component and identified the aggressive potential of the acinar-endocrine component.

Conclusions: We report a rare case of gastric MiNEN with pancreatic acinar differentiation. AI analysis revealed tumor progression and aggressiveness. In addition, the usefulness of the anti-BCL10 antibody for detecting the acinar-endocrine component was suggested.
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http://dx.doi.org/10.1186/s13000-019-0815-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511127PMC
May 2019

Clinicopathological and Molecular Findings of Differentiated-Type Minute Gastric Intramucosal Neoplasia.

Digestion 2020 3;101(3):287-297. Epub 2019 Apr 3.

Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan.

Background/aims: To evaluate gastric early differentiate-type carcinogenesis, we attempted to identify clinicopathological and biological differences in differentiated-type minute intramucosal neoplasia (MIMN), which was defined as a tumor with a diameter of < 5 mm.

Methods: We examined clinicopathological findings and biological factors, including TP53 overexpression, mucin phenotype, Ki-67-positive rate, MLH1, intranuclear accumulation of β-catenin, and DNA methylation status (low methylation epigenotype [LME], intermediate methylation epigenotype, and high methylation epigenotype [HME]) in MIMNs. In addition, non-MIMNs were also analyzed. In the present study, MIMN and non-MIMN were also examined based on low-grade dysplasia, high-grade dysplasia, and intramucosal cancer (IMC).

Results: In clinicopathological findings, there were significant differences in sex ratios and tumor locations between MIMNs and non-MIMNs. Among the examined biological factors, no significant differences in the frequencies of biological factors were observed between the 2 intramucosal neoplasia types. However, the frequency of intranuclear accumulation of β-catenin was higher in non-MIMNs than in MIMNs. Finally, although the frequency of HME was significantly lower in MIMNs than in non-MIMNs, the opposite was observed for LME.

Conclusions: The current finding suggested that DNA methylation and accumulation of β-catenin were closely associated with tumor development from MIMN to non-MIMN.
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http://dx.doi.org/10.1159/000499464DOI Listing
March 2021

Mesenteric extraovarian Sertoli-Leydig cell tumor without DICER1 hotspot mutation: a case report.

Diagn Pathol 2019 Apr 1;14(1):27. Epub 2019 Apr 1.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505, Japan.

Background: Ovarian Sertoli-Leydig cell tumors (SLCTs) with androgenic manifestations harbor DICER1 mutations in 30-60% of cases. Ovarian SLCTs without DICER1 hotspot mutations have been reported to exhibit elderly onset and no androgenic manifestations. We present the first case of a primary mesenteric SLCT without DICER1 hotspot mutation.

Case Presentation: An 84-year-old woman presented with a 75-mm mesenteric solid tumor. She presented no androgenic or estrogenic manifestations. She underwent ileocecal resection. Histologically, her mesenteric tumor showed histopathological features that resembled moderately differentiated SLCT. Moreover, DICER1 hotspot mutation was not detected.

Conclusions: We described the first case of heterotopic primary mesenteric SLCT without DICER1 hotspot mutation.
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http://dx.doi.org/10.1186/s13000-019-0805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444432PMC
April 2019

Immunohistochemical analysis of the epithelial to mesenchymal transition in uterine carcinosarcoma.

Int J Gynecol Cancer 2019 Feb 13;29(2):277-281. Epub 2019 Jan 13.

Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan

Objective: Uterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS.

Methods: UCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells.

Results: The expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected.

Conclusion: These results suggest that the EMT plays an essential role in the pathogenesis of UCS.
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http://dx.doi.org/10.1136/ijgc-2018-000038DOI Listing
February 2019

Didehydroisobenzofuran: A New Reactive Intermediate for Construction of Isoacenofuran.

Chemistry 2018 Dec 14;24(71):18886-18889. Epub 2018 Nov 14.

Department of Applied Chemistry for Environment, Kwansei Gakuin University, 2-1 Gakuen, Sanda, 669-1337, Japan.

An efficient generation method of didehydroisobenzofuran, a new heteroaryne species, was developed by bromine/lithium exchange of the dibromoisobenzofuran. The reactive intermediate, thus generated, was trapped by appropriate arynophile to give the [2+2], [2+3], and [2+4] cycloadducts, respectively. Moreover, the reaction could be applied to the syntheses of isoanthracenofurans (anthra[2,3-c]furans), a new class of heteroacenes, with isoelectoronic structure to the corresponding acenoheteroles (anthra[2,3-b]furans).
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http://dx.doi.org/10.1002/chem.201804655DOI Listing
December 2018

Mobile-phone-based Rheinberg microscope with a light-emitting diode array.

J Biomed Opt 2018 09;24(3):1-6

Ritsumeikan University, College of Science and Engineering, Department of Electrical and Electronic, Japan.

Mobile phone technology has led to implementation of portable and inexpensive microscopes. Light-emitting diode (LED) array microscopes support various multicontrast imaging by flexible illumination patterns of the LED array that can be achieved without changing the optical components of the microscope. Here, we demonstrate a mobile-phone-based LED array microscope to realize multimodal imaging with bright-field, dark-field, differential phase-contrast, and Rheinberg illuminations using as few as 37 LED bulbs. Using this microscope, we obtained high-contrast images of living cells. Furthermore, by changing the color combinations of Rheinberg illumination, we were able to obtain images of living chromatic structures with enhanced or diminished contrast. This technique is expected to be a foundation for high-contrast microscopy used in modern field studies.
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http://dx.doi.org/10.1117/1.JBO.24.3.031007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975239PMC
September 2018

Analysis of the expression of cancer-associated fibroblast- and EMT-related proteins in submucosal invasive colorectal cancer.

J Cancer 2018 23;9(15):2702-2712. Epub 2018 Jun 23.

Division of Gastroenterology, Department of Internal Medicine, 19-1, Morioka 020-8505, Japan.

Recent studies have shown that cancer-associated fibroblasts (CAFs) and the epithelial-mesenchymal transition (EMT) play important roles in the progression and metastasis of CRC. Although prediction of lymph node metastasis in submucosal invasive colorectal cancer (SiCRC) is important, the relationships of CAF and EMT with lymph node metastasis of SiCRC have not yet been examined. Here, we aimed to analyze the expression patterns of CAF- and EMT-related proteins in SiCRC. The expression of CAF-related markers, including α-smooth muscle actin, CD10, podoplanin, fibroblast specific protein 1, and adipocyte enhancer-binding protein 1, and EMT-related proteins [zinc finger protein SNAI2 (ZEB1) and twist-related protein 1 (TWIST1) in SiCRC with (n = 29) or without (n = 80) lymph node metastasis was examined by immunohistochemistry. We examined the expression patterns of biomarkers using hierarchical cluster analysis. Consequently, four subgroups were established based on the expression patterns of CAF- and EMT-related markers, and the associations of these subgroups with clinicopathological variables. : In multivariate analysis, subgroup 2, which was characterized by high expression of all markers, was correlated with lymph node metastasis ( < 0.01). Next, we examined the associations of individual biomarkers with lymph node metastasis. Multivariate analysis showed that moderately differentiated adenocarcinoma was significantly associated with lymph node metastasis ( < 0.05). : Our findings showed that expression patterns of CAF markers and EMT-related proteins may allow for stratification of patients into risk categories for lymph node metastasis in SiCRC.
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http://dx.doi.org/10.7150/jca.25646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072811PMC
June 2018