Histopathology and Cytology of Pulmonary Myoepithelial Neoplasms: 2 Cases.

Myoepithelial neoplasms (MNs) of the lung are extremely rare tumors. Approximately 40 cases of pulmonary MNs have been reported to date. Herein, we report extremely rare cases of different types of pulmonary MN, including cytological features. Case 1 is an 18-year-old female, and case 2 is a 73-year-old female patient. They presented to our hospital with nodules of the lung. Histological examination revealed tumor cells with round to oval nuclei and acidophilic cytoplasm that formed nests or fascicles with mild hyalinized stroma in case 1 and tumors containing the bi-phasic components of a nest-like and fascicle pattern with pleomorphism in case 2. Immunohistochemically, these tumors were positive for cytokeratin (CK) AE1/AE3, CK5/6, vimentin, calponin, and EMA, and focal positive for S-100a protein and alpha smooth muscle actin. The pathological diagnoses in cases 1 and 2 were myoepithelioma and myoepithelial carcinoma, respectively. In conclusion, we encountered two cases of extremely rare MNs that occurred in the lung. This disease can be diagnosed by collecting appropriate cytological and histological findings and should be listed as a differential diagnosis.

Advanced gallbladder cancer accompanied with cancer-associated dermatomyositis: A case report and literature review.

RATIONALE: Muscle weakness due to cancer-associated dermatomyositis (CADM) can be misdiagnosed as cancer cachexia and disuse atrophy. PATIENT CONCERNS: A 75-year-old female was admitted to our institute with muscle weakness, dysphagia, and suspected gallbladder cancer. Computed tomography and cytopathological examinations of the liver biopsy and fine-needle aspiration from swollen lymph nodes using endoscopic ultrasonography revealed cancer in the gallbladder body and metastasis to the lymph nodes around the abdominal aorta. We avoided the administration of anticancer drugs due to her poor general condition. DIAGNOSIS: Subsequently, we diagnosed her with muscle weakness and dysphagia as a result of CADM using species from muscle and skin biopsy. INTERVENTIONS AND OUTCOMES: Prednisolone therapy and anticancer agents partially improved the patient symptoms. LESSONS: CADM is reported to be associated with a high incidence of dysphagia, which may aid in the diagnosis of this disease.

Transcriptomic Analysis of Annexin A10 and Chemosensitivity in Gastric Adenocarcinoma Cells.

BACKGROUND/AIM: Gastric cancer (GC) is the third-leading cause of cancer-related deaths worldwide; thus, novel diagnostic and therapeutic biomarkers are needed. Annexin A10 (ANXA10) is a calcium- and phospholipid-binding protein. As far as we are aware, there are no reports describing the detailed functions of ANXA10 in GC. Therefore, we investigated the downstream mRNA variation and the effects of ANXA10 on chemoresistance in GC cell lines. MATERIALS AND METHODS: ANXA10 knockout GC cell lines were generated, and we performed functional analyses, chemosensitivity drug testing, and microarray analyses. Additionally, immunohistochemistry for ANXA10 was performed on 40 patients with GC who had received 5-fluorouracil (5-FU)-based chemotherapy to compare their prognosis and clinicopathological factors. RESULTS: ANXA10 knockout GC cells showed significantly increased proliferation, invasion, and sensitivity to 5-FU. The overall survival of ANXA10-positive cases was considerably lower than that of ANXA10-negative cases in GC patients who received 5-FU-based chemotherapy. Microarray analysis revealed candidate pathways regulated by ANXA10 and claudin 1 (CLDN1), keratin 80 (KRT80), RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), and solute carrier family 7 member 5 (SLC7A5) genes. CONCLUSION: ANXA10 knockout increased the susceptibility of GC cell lines to 5-FU; ANXA10 may be a predictive indicator for response to 5-FU treatment in GC cases. ANXA10 may be involved in the pathogenesis of GC, in collaboration with CLDN1, KRT80, RBCK1, and SLC7A5.

Lymphangitis carcinomatosa from gallbladder cancer.

A 61-year-old woman was admitted to our hospital with productive cough and fever. Computed tomography images revealed ground glass opacities in both lung fields, and a space-occupying lesion in the gallbladder. Transbronchial lung biopsy revealed a poorly differentiated adenocarcinoma with invasion of the lymph ducts; accordingly, a diagnosis of lymphangitis carcinomatosa was made. We could not administer chemotherapy due to poor performance status, and the patient died of respiratory failure 30 days after admission. Owing to pathological autopsy findings of poorly differentiated adenocarcinoma in the gallbladder, we diagnosed this as a rare case of gallbladder cancer presenting with lymphangitis carcinomatosa.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

Utility of TMPRSS4 as a Prognostic Biomarker and Potential Therapeutic Target in Patients with Gastric Cancer.

BACKGROUND: Transmembrane serine protease 4 (TMPRSS4) belongs to the family of type II transmembrane serine proteases that are known to be upregulated in many malignant tumors. However, there is a paucity of studies documenting the clinical impact and biological effects of TMPRSS4 on gastric cancer (GC) patients who underwent surgery. METHODS: Tissues samples were obtained from 105 patients with GC who underwent gastrectomy followed by adjuvant chemotherapy, excluding those at stage I. The expression of TMPRSS4 was examined through immunohistochemical analysis. The association between TMPRSS4 expression and clinico-pathological features as well as prognosis was assessed. Moreover, the effects of TMPRSS4 expression on cell migration and sensitivity to 5-FU were investigated. RESULTS: The expression rate of TMPRSS4 was 56.3% (59/105) in GC cases. The expression of TMPRSS4 was positively correlated with the depth of tumor (T) and venous (V) invasion. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the TMPRSS4-positive group was significantly lower than that of the TMPRSS4-negative group (p=0.0001 and p=0.005, respectively). Especially, there was significant differences in OS and RFS of patients with stage III cancer between the two groups (p=0.0064 and 0.012, respectively). Multivariate analysis demonstrated that TMPRSS4 expression and the stage of cancer were crucial prognostic factors for RFS. TMPRSS4-silenced GC cells exhibited increased sensitivity to 5-FU when compared with the non-specific control siRNA-transfected cells. CONCLUSION: TMPRSS4 can be considered as a potential prognostic biomarker, especially for stage III, and a promising therapeutic target for GC.

High Annexin A10 expression is correlated with poor prognosis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death. Owing to its poor prognosis, new molecular biomarkers for PDAC are needed. Annexin A10 (ANXA10) is a calcium-/phospholipid-binding protein belonging to the annexin family of proteins. ANXA10 is not only associated with gastric phenotypes, but also acts an independent prognostic factor in several cancers. However, the role of ANXA10 in PDAC remains unknown. Therefore, we examined the relationship between ANXA10 and the prognosis of PDAC. We analyzed the expression of ANXA10 using data from public databases, and performed immunohistochemistry analysis for 81 PDAC cases. We then investigated the relationship between ANXA10 expression and clinicopathological features. ANXA10 was detected in 47 of 81 PDAC cases (58%). High expression of ANXA10 was significantly related to poor overall survival (OS; p=0.011). Univariate analysis of OS revealed three prognostic parameters: tumor grade (p=0.046), perineural invasion (p=0.017), and ANXA10 expression (p=0.012). Multivariate analysis indicated that ANXA10 expression (p<0.01) alone was a prognostic factor in PDAC cases. Our findings suggest that ANXA10 expression is an independent prognostic factor in PDAC cases and shows promise as a new biomarker in PDAC.

Systemic Inflammatory Score Predicts Response and Prognosis in Patients With Lung Cancer Treated With Immunotherapy.

AIM: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. PATIENTS AND METHODS: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. CONCLUSION: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.

Anterior Mediastinal Leiomyosarcoma: A Case Report and Literature Review.

Primary mediastinal sarcomas are extremely rare. Additionally, mediastinal leiomyosarcomas account for approximately 9% of mediastinal sarcoma cases. Until date, only few cases of anterior mediastinal leiomyosarcomas have been reported. Herein, we report a case of an 85-year-old female with an anterior mediastinal mass of 15 mm. Histological examination revealed spindle tumor cells showing a fascicular growth pattern. Immunohistochemically, the tumor cells were focal positive for desmin, calponin, and α-smooth muscle actin. The pathological diagnosis was leiomyosarcoma. In conclusion, we encountered a case of a very rare leiomyosarcoma that occurred in the anterior mediastinum, and our report may contribute to the understanding of this disease.

Annexin A10 Expression Is Associated With Poor Prognosis in Small Bowel Adenocarcinoma.

BACKGROUND/AIM: Small bowel adenocarcinoma (SBA) is a relatively rare malignant epithelial neoplasm. Thus, little is known about prognostic biomarkers of SBA. Annexin A10 (ANXA10) is a member of the annexin family. The significance of ANXA10 expression in SBA is unclear. This is the first study to examine the expression of ANXA10 in SBA. MATERIALS AND METHODS: We immunohistochemically evaluated ANXA10 expression of SBA and studied the relationship between ANXA10 expression and clinicopathological factors. RESULTS: ANXA10 expression was detected in 17 (56.7%) of 30 SBA cases and was significantly associated with poor overall survival. Univariate predictors for poor prognosis were tumour size (p=0.017) and ANXA10 expression (p=0.026). In multivariate analysis, ANXA10 expression (p=0.038) and tumour size (p=0.024) were found to be independent predictors of poor prognosis. CONCLUSION: ANXA10 could be a new prognostic biomarker for SBA.

Laparoscopic resection for a large gastrointestinal stromal tumor (GIST) with diaphragm invasion following preoperative imatinib treatment: A case report.

INTRODUCTION: Neoadjuvant imatinib for large GISTs may prevent tumor rupture and the need for extended surgery by reducing tumor size. In this study, we present a case of large gastric GIST with diaphragm invasion, due to the patient receiving laparoscopic resection following preoperative imatinib treatment. PRESENTATION OF CASE: A 72-year-old woman was hospitalized with left hypochondriac pain for a month. Examinations revealed a large heterogeneous gastric mass measuring 80 mm in size, arising from the greater curvature of the corpus. The mass invaded the left thoracic diaphragm. Treatment with imatinib at an initial dosage of 400 mg/day was initiated. After a further two months of follow-up, the lesion had sustained reduction to 50 mm in size, however, the invasion to the diaphragm remained. The patient eventually underwent laparoscopic partial gastrectomy and partial resection of the diaphragm with curative intent. Adjuvant chemotherapy was initiated at one month after the surgery, however, was discontinued due to nausea. After one-year follow-up, no recurrence was noted. DISCUSSION: Neoadjuvant imatinib may shrink tumor size remarkably and prevent tumor rupture during surgery, and thus lead to increased rates of complete resection. To date, several publications have directly compared the oncologic results between laparoscopic and open resection for GISTs. In the present case, the tumor was movable, and moderately fixed on diaphragm. It was favorable condition for laparoscopic surgery. CONCLUSIONS: This is the first report of a large gastric GIST invading the diaphragm that was successfully treated by laparoscopic resection after tumor reduction by neoadjuvant imatinib.

Nuclear grade and comedo necrosis of ductal carcinoma in situ as histopathological eligible criteria for the Japan Clinical Oncology Group 1505 trial: an interobserver agreement study.

OBJECTIVE: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. METHODS: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. RESULTS: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). CONCLUSION: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.

Loss of Annexin A10 Expression Is Associated with Poor Prognosis in Early Gastric Cancer.

Gastric cancer (GC) is the third most common cause of cancer-related mortality. The diagnosis and treatment of early GC is a crucial strategy for prognostic improvement of GC. Annexin A10 (ANXA10), a calcium-/phospholipid-binding protein, is a member of the annexin family. The significance of ANXA10 expression in early GC remains unclear. This is the first report to investigate ANXA10 expression in early GC. We performed immunohistochemistry to evaluate ANXA10 expression in early GC, and the correlation between ANXA10 and clinicopathological factors. The loss of ANXA10 expression was detected in 63 (61.2%) of 103 early GC cases and significantly correlated with poor overall survival in patients. Sex, pT stage, pN stage, histology, and ANXA10 expression were associated with poor survival. Sex, histology, and ANXA10 expression were determined as independent predictors of survival in early GC patients. ANXA10 immunostaining could be a new decision-making biomarker in GC.

Intramucosal Poorly Differentiated Adenocarcinomas Detected in a Patient with Long-Standing Ulcerative Colitis.

We report a case of long-standing ulcerative colitis with intramucosal well- and poorly differentiated adenocarcinomas detected over a 6-month duration. A Japanese man in his sixties with a 31-year history of ulcerative colitis had a 1.1-cm-sized intramucosal well-differentiated tubular adenocarcinoma in the rectum resected by endoscopic submucosal dissection. At the follow-up colonoscopy, a biopsy near the endoscopic submucosal dissection scar revealed poorly differentiated adenocarcinoma, and a total proctocolectomy was performed 6 months after the endoscopic submucosal dissection. The whole colorectal pathological exam showed 2 flat foci of intramucosal poorly differentiated adenocarcinoma, 4 and 2 mm in size each, near the endoscopic submucosal dissection scar in the rectum, and an increased number of Paneth cells, thickened muscularis mucosa, and widening of the distance between the gland base and muscularis mucosa in the transverse colon to the rectum. Adenocarcinomas were not found in areas where architecturally severe changes of the mucosa or the highest number of Paneth cells proliferation were detected. Multiple biopsies using magnifying narrow band imaging or crystal violet staining around the initial high-grade dysplasia or intramucosal adenocarcinoma were effective to find other lesions, such as poorly differentiated adenocarcinoma foci in the mucosa in a long-standing ulcerative colitis patient.

CD204-Positive Tumor-associated Macrophages Relate to Malignant Transformation of Colorectal Adenoma.

BACKGROUND/AIM: Colorectal adenoma is well known as a precursor lesion of colorectal adenocarcinoma (ADC). We recently reported the significance of CD204 (+) tumor-associated macrophages (TAMs), a vital component of the tumor microenvironment, in the carcinoma development of gastric adenoma. The aim of the present study was to clarify the roles of TAM in the malignant transformation of colorectal adenoma. MATERIALS AND METHODS: We immunohistochemically assessed the TAM number in 88 tubular or tubulovillous adenomas that were classified into L (low-grade adenomas) or H (high-grade adenomas). RESULTS: Larger adenoma size, higher frequency of villous structure, loss of proliferation polarity, p53 expression, larger TAM numbers and larger microvessel density (MVD) were detected in Group H than in Group L adenomas. Positive relations were observed between TAM and MVD, proliferation polarity and the expression of p53. CONCLUSION: CD204 (+) TAM is a novel component in the malignant transformation of colorectal adenoma.

Long-term follow-up study of gastric adenoma; tumor-associated macrophages are associated to carcinoma development in gastric adenoma.

BACKGROUND: Some gastric adenomas may progress to adenocarcinoma in a short time, but others remain as adenoma for a long time. METHODS: Among 1138 cases diagnosed as adenoma by biopsy at Kure Medical Association Hospital between 1990 and 2010, 51 adenomas were enrolled. Of these, 28 adenomas (group A) were followed for 60 months or longer with no progression to adenocarcinoma within 60 months, and the other 23 adenomas (group B) were upgraded to carcinoma by consecutive biopsies performed within 1 year after the first biopsy. These adenomas were compared clinicopathologically and immunohistochemically. RESULTS: Macroscopically, the mean size of group B adenomas was significantly larger than that of group A adenomas (18.6 vs. 9.9 mm) at the first biopsy. The frequency of a depressed area in the adenoma was significantly higher in group B than group A. Microscopically none of group A but 7 (30.4%) of 23 group B adenomas showed severe atypia. Each of a highly proliferative gland measured by Ki-67 labeling, cellular atypical grade, gastric phenotype defined by MUC5AC and MUC6 and CD204-positive tumor-associated macrophage (TAM) was a significant risk factor for adenocarcinoma development in gastric adenoma by univariate analysis. Only moderate or severe atypia of adenoma cells and the TAM number in the stroma of adenomas were independent risk factors by multivariate analysis. CONCLUSIONS: As independent risk factors, cellular atypia may reconfirm the importance of morphological analysis, and the TAM number may indicate the significance of TAM function in gastric adenoma.

Aberrant DNA methylation of DLX4 and SIM1 is a predictive marker for disease progression of uterine cervical low-grade squamous intraepithelial lesion.

BACKGROUND: A few uterine cervical low-grade squamous intraepithelial lesions (LSILs) are known to progress with high-risk human papillomavirus (hrHPV). METHODS: One hundred and thirteen patients were classified into four groups according to their cervical cytology, hrHPV infection, and follow up. Cytology samples were examined for aberrant DNA methylation of DLX4 and SIM1 genes and protein expressions. CaSki cells were treated with 5-Aza-2'-deoxycytidine (5-aza-dC). RESULTS: Group 1 was negative for intraepithelial lesions or malignancies. LSIL in group 2 showed a continuance of LSIL for longer than 365 days and LSIL in group 3 showed an upgrading to high-grade (H) SIL or higher (HSIL+) within 365 days of LSIL diagnosis. Group 4 was squamous cell carcinoma. All but group 1 were infected with hrHPV. Significant differences existed in the frequency of DNA methylation between groups 2 and 3 (p = 0.044), between groups 3 and 4 (p = 0.020) for DLX4, and between groups 1 and 3 (p = 0.0003), and groups 2 and 3 (p = 0.005) for the SIM1 gene. DLX4 protein expression was significantly reduced in the DLX4 methylation positive tissues (p = 0.008). The 5-aza-dC treatment restored DLX4 mRNA expressions of CaSki cells (p < 0.005). The LSIL cases with DNA methylation of the SIM1 gene, or both genes, progressed faster to HSIL+ than did the others (p = 0.033 and p = 0.045, respectively). CONCLUSION: Aberrant DNA methylation of the DLX4 and SIM1 genes should be a novel progression marker for uterine cervical LSIL with hrHPV infection.

A case of adenoid cystic carcinoma of the esophagus.

Esophageal adenoid cystic carcinoma (EACC) is a very rare form of malignant tumor in the esophagus. Here, we report the case of a 78-year-old man who was diagnosed with EACC by preoperative endoscopic biopsy. Thoracoscopy-assisted subtotal esophagectomy with lymph node dissection was carried out. Microscopic examination of the resected specimen suggested that the tumor invaded to submucosal layer and showed no lymph node metastasis. Histologically, tumor primarily exhibited an alveolar solid pattern with partial cribriform and tubular patterns. Alcian blue staining showed many mucoid materials within the glandular cavity formed by tumor cells. Immunohistochemical studies revealed that the tumor cells reacted with pan-cytokeratin immunostains and expressed vimentin and S-100 protein. Collectively, the tumor was diagnosed as primary EACC, T1bN0M0 according to "Japanese Classification of Esophageal Cancer 10th edition." The patient showed no recurrence sign 12 months after the surgery.The current study also reviewed 35 EACC cases reported in Japanese literatures from 1990 to 2014. Combined with our case, we found that EACC is less frequently accompanied by lymph node metastasis as compared to esophageal squamous cell carcinoma, especially at the early stage. The prognosis of EACC is relatively better when tumors have no lymph node metastasis.