KIT (CD117) Expression in Benign and Malignant Sweat Gland Tumors.

KIT (CD117, c-kit) is a receptor tyrosine kinase involved in the tumorigenesis of several neoplasms. KIT is expressed by the secretory cells of normal sweat glands. We studied the KIT expression and KIT mutational status in various benign and malignant tumors of eccrine and apocrine glands. We included a total of 108 cases comprising 10 benign and 6 malignant sweat gland tumors, and KIT expression was immunohistochemically detected (positive rate): 10 syringomas (0%), 8 poromas (25%), 20 mixed tumors (40%), 21 spiradenomas (43%), 1 cylindroma (0%), 5 hidradenomas (40%), 7 syringocystadenoma papilliferum cases (0%), 1 papillary hidradenoma (100%), 2 tubulopapillary hidradenomas (50%), 8 hidrocystomas (29%), 2 adenoid cystic carcinomas (100%), 5 porocarcinomas (20%), 6 apocrine carcinomas (33%), 10 extramammary Paget diseases (30%), 1 spiradenocarcinoma (100%), and 1 syringocystadenocarcinoma papilliferum (0%). Most KIT-positive cells were luminal cells, arising from glandular structures. We performed polymerase chain reaction-single-strand conformation polymorphism for detecting KIT mutational status. All cases showed no mutations at hot spots for KIT (exons 9, 11, 13, and 17). KIT mutation does not seem to be mechanism for KIT expression, but the expression may be from native sweat glands.

Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours.

AIMS: We aimed to elucidate the clinicopathological and immunohistochemical features of leiomyosarcoma (LMS) of the gastrointestinal (GI) tract. METHODS AND RESULTS: We encountered seven cases of GI-LMS in the colon (n = 4), rectum (n = 1), jejunum (n = 1) and stomach (n = 1). They ranged from 1 to 25 cm (median, 8.5 cm) in size and had high mitotic counts (median 38 per 50 high-power fields). Morphologically, the tumours were composed mainly of spindle cells with eosinophilic cytoplasm and various degrees of nuclear atypia and pleomorphism. Immunohistochemically, the tumours were positive for α-smooth muscle actin (86%), muscle-specific actin (71%), desmin (86%), calponin (71%), h-caldesmon (57%) and smoothelin (71%). All were negative for KIT, CD34, protein kinase C theta and DOG1. Local recurrence and distant metastasis occurred in one and three patients, respectively. We then reviewed 55 cases of GI-LMS from the era following the recognition of gastrointestinal stromal tumours. Among 29 of 55 cases for whom follow-up information was available, the estimated 5-year overall survival rate was 51.6%; tumour size ≥5 cm was correlated significantly with shorter overall survival time (P = 0.0016), while mitotic count (≥50 or ≥100 per 50 high-power fields) proved to be no prognostic factor. CONCLUSIONS: GI-LMSs have distinctive clinicopathological and immunohistochemical features and exhibit aggressive biological behaviour.

Sarcomatoid carcinoma of the remnant stomach: report of a case.

We herein report a case of sarcomatoid carcinoma that developed in a remnant stomach. A 76-year-old male with a history of distal gastrectomy for a duodenal ulcer 28 years earlier underwent investigation for a tumor in the remnant stomach. An endoscopic survey showed a round elevated tumor measuring 6 cm in diameter, and a biopsy specimen suggested carcinosarcoma. A total gastrectomy of the remnant stomach was performed, and the excised tumor was identified to be a malignant neoplasm consisting of both carcinomatous and sarcomatous components. A diagnosis of sarcomatoid carcinoma was made since the epithelial markers were positive even in the mesenchymal elements of the tumor. To our knowledge, only 4 cases of sarcomatoid carcinoma of the stomach have been reported in the English literature so far.

Granulomatosis with Polyangiitis Presenting with Thrombovasculitic and Necrotizing Pachy- and Leptomeningitis Accompanied by a Brain Tumor-like Lesion.

We report a case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic pachymeningitis with a huge brain tumor-like lesion. A 57-year-old man acutely developed consciousness disturbance. Magnetic resonance imaging revealed a right frontal lobe mass with thickened, contrast-enhanced dura. Computed tomography revealed sinusitis and multiple lung nodules. The presence of proteinase 3-anti-neutrophil cytoplasmic antibody indicated GPA. Histopathology of the excised brain tissues revealed thrombovasculitis with heavy neutrophilic infiltration in the pachy- and leptomeninges covering an ischemic cerebral cortex. The patient improved with corticosteroids and rituximab. Our case warrants considering GPA as a cause of hypertrophic pachymeningitis with brain-tumor like lesions.

[Recurrent advanced gastric cancer diagnosed 20 years after partial gastrectomy].

A 67-year-old woman underwent partial gastrectomy (por2+sig, stage IIIA) for gastric cancer. She was admitted to our hospital because of swelling of her left neck lymph nodes 20 years after surgery. A biopsy specimen revealed poorly differentiated adenocarcinoma with signet-ring cell carcinoma. We diagnosed recurrence of gastric cancer and gave chemotherapy, but she died of myelosuppression and disseminated intravascular coagulation 2 years later. On autopsy, we examined all organs except the brain, but the primary lesion was not recognized. We concluded that this case was late recurrence after partial gastrectomy for advanced gastric cancer.

Myasthenic crisis appearing after resection of intracardiac ectopic thymoma with superior vena cava syndrome.

BACKGROUND: We describe herein an extremely rare case of intracardiac ectopic thymoma-only two pure cases have been reported to date-associated with myasthenia gravis, an infrequent complication of ectopic thymoma. CASE PRESENTATION: A 71-year-old woman with superior vena cava syndrome was found to have a large mass mainly located in the right atrium. Tumor resection under cardiopulmonary bypass was performed. The pathological diagnosis was type AB ectopic thymoma. The postoperative course was complicated by progressive respiratory failure, and she was diagnosed with myasthenic crisis based on clinical signs and the edrophonium test. The patient recovered and was weaned from prolonged mechanical ventilation after receiving intravenous immunoglobulin, and was subsequently discharged uneventfully. CONCLUSIONS: This is the first report of myasthenic crisis due to intracardiac ectopic thymoma. Residual thymoma is a risk factor for the development of post-thymectomy myasthenia gravis, and long-term follow-up is required.

[Neoadjuvant chemotherapy with intraperitoneal paclitaxel for advanced gynecologic cancer].

OBJECTIVES: We evaluated safety and activity of intraperitoneal paclitaxel [=PTX (ip)] for neoadjuvant chemotherapy (NAC) of patients with advanced gynecologic cancer. METHODS: 13 patients with gynecologic cancer who had diffuse peritoneal dissemination received PTX (ip) with systemic chemotherapy (TC regimen) for NAC. After 3-6 courses of NAC, interval debulking surgery (IDS) was done. At IDS, we explored intraperitoneal cavity and debulked as much as possible, and examined pathological effects of NAC. RESULTS: PTX (ip) was well tolerated with apparent anti-cancer activity. Eleven patients were done with IDS after 3-6 NAC courses. Ten of 11 patients were completed an optimal surgery without extended resections. Eight of 11 patients with IDS had grade 2 (5 cases) or grade 3 (3 cases) effects of pathological examination. CONCLUSION: According to this exploratory research, we considered PTX (ip)=80 mg/m2 with PTX (iv)=115 mg/m2 and CBDCA (iv) AUC=4 as an optimum drug dose. Although evaluated in a small number of patients, PTX (ip) appeared to have safety and anti-cancer activity, and should be evaluated further.

Pediatric plexiform fibromyxoma: A PRISMA-compliant systematic literature review.

BACKGROUND: Plexiform fibromyxoma (PF) is a rare gastric mesenchymal tumor, with approximately 80 cases reported to date. Gastrointestinal stromal tumor, the most common primary mesenchymal tumor of the stomach, shows different biological and clinical characteristics between adult and pediatric patients. OBJECTIVES: This systematic literature review was conducted to elucidate the pathological and clinical features of pediatric PF compared to adult PF. METHODS: MEDLINE (1948 to March 2018) and EMBASE (1947 to March 2018) were searched, and all English articles that reported clinical data on PF patients were identified. Two authors independently reviewed the articles and extracted data to assess immunohistochemistry, sex, chief complaint, tumor size, tumor-related mortality, and tumor recurrence and metastasis. RESULTS: A total of 41 reports with 80 PF patients (of whom 70 were adult PF and 10 were pediatric PF patients) confirmed by histological and immunohistochemical findings were included. Of a total of 80 tumors, 62 (78%) were located in the gastric antrum, 42 (65%) presented with ulceration, and 48 (74%) were resected by partial gastrectomy. Median tumor size of the resected specimen was larger in pediatric PF than in adult PF cases (5.3 cm vs 4.0 cm, P = .036). However, there was no difference between pediatric and adult PFs in immunohistochemical expression, sex predominance, chief complaint, tumor-related mortality, and tumor recurrence and metastasis during the follow-up periods. CONCLUSION: Other than increased tumor growth in pediatric PFs, PF is a single disease entity with similar pathological features and benign clinical behavior regardless of onset age.

PDGF-BB is a novel prognostic factor in colorectal cancer.

PURPOSE: Human platelet-derived growth factor BB (PDGF-BB) is thought to be involved in human malignancies. Its overexpression has been reported in some human tumors. However, its expression in colorectal cancer has not been studied. We thus investigated the clinicopathological and biological significance of PDGF-BB gene expression in human colorectal cancer. EXPERIMENTAL DESIGN: Using real-time reverse transcription-PCR, we evaluated PDGF-BB expression status and correlated data with clinicopathological parameters in 60 patients with colorectal cancer. Additionally, we established a colorectal cancer cell line expressing PDGF-BB and investigated its effects on cell invasion and proliferation. RESULTS: The incidence of vascular invasion was significantly greater in patients expressing PDGF-BB at a high level than in those at a low level (P < .05). Patients with high PDGF-BB expression had a significantly poorer survival rate than those with low PDGF-BB expression (P < .05). A multivariate analysis demonstrated that PDGF-BB expression was an independent prognostic factor. We demonstrated in vitro that cells transduced with PDGF-BB showed greater invasiveness (P < .05) and migration (P < .001) than did mock transduced cells. In a xenograft study, cells transduced with PDGF-BB had higher proliferation rates than mock transfected cells. CONCLUSION: PDGF-BB expression may be a new prognostic indicator for patients with colorectal cancer.

A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease.

AIM: To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease. METHODS: Using a cDNA microarray containing over 22000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azan-stained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis. RESULTS: We identified 39 genes that collectively showed a good correlation (r > 0.50) between gene-expression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis, we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r = 0.76, 2.2% vs 2.8%, P < 0.0001) and 12 independent additional test samples (r = 0.75, 9.8% vs 8.6%, P < 0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r = -0.53), type IV collagen 7s (r = 0.48), hyaluronic acid (r = 0.41), and aspartate aminotransferase to platelets ratio index (APRI) (r = 0.38). CONCLUSION: Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

Activation of STAT3/5 signal pathways in complete mole and repression in choriocarcinoma cell lines.

OBJECTIVE: Because our previous study of microarray suggested that STAT5 and its downstream target, survivin, were up-regulated in complete mole (CM), we clarified the status of STAT-mediated signal transduction in CM and choriocarcinoma (CC). STUDY DESIGN: Proteins from 4 CM and normal villi and from 3 CC cell lines were subjected to Western blot (WB) analysis to evaluate STAT3 and 5 activation. After STAT and MEK inhibitor were added to these cells, the change in survivin expression was analyzed. Immunohistochemical staining was also done on CM and normal villi. RESULTS: WB showed that phosphorylated STAT3 and 5, which are active forms of STAT protein, as well as survivin, were significantly up-regulated in CM. Immunohistochemistry showed positive signals of pSTATs in the cytotrophoblast and syncytiotrophoblast layer in CM but not in normal villi. In contrast, the pSTAT signal was hardly detected by WB in CC cells. However, a high level of survivin expression was maintained in CC by activation of the MEK signal pathway. CONCLUSION: An activated STAT signal may contribute to hyperplastic cell growth of trophoblasts in CM. CC cells might be obtained independently of cytokine signals for tumor cell growth during the carcinogenic process.

Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis.

Reduced expression level of p27, a cyclin-dependent kinase inhibitor, is associated with high aggressiveness and poor prognosis of various malignant tumors, including gastric carcinoma. S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of substrate-recognition subunits of Skp1-Cullin-F-box ubiquitin-protein ligase complexes, is necessary for p27 ubiquitination and degradation. In the present study, we examined the clinical and biological significance of Skp2 expression in human gastric carcinoma and the relationship between the expression of Skp2 and p27. Northern blot analysis showed that Skp2 mRNA was overexpressed in carcinoma tissues (P < 0.05), and the high Skp2 expression group showed significantly poorer prognosis in 98 patients with gastric carcinoma (P < 0.05). Immunohistochemical analysis showed that Skp2 protein was expressed predominantly in carcinoma cells. We also found an inverse correlation between the expression of Skp2 mRNA and p27 protein in vivo (P < 0.01). To analyze the biological behavior of Skp2, we established stably Skp2-transfected gastric carcinoma cell lines. Western blot analysis showed that Skp2-transfected cells expressed lower levels of p27 protein than the control cells. Skp2-transfected cells showed significantly higher levels of growth rate (P < 0.05), percentage of bromodeoxyuridine-positive cells after serum starvation (P < 0.01), resistance to apoptosis induction by actinomycin D treatment (P < 0.05), and invasion potential (P < 0.01) than the control cells. These findings indicate that Skp2 expression can modulate the malignant phenotype of gastric carcinoma, possibly via p27 proteolysis. Skp2 can play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinoma as well as a strong prognostic marker.

Identification of molecular markers for metastasis-related genes in primary breast cancer cells.

Comparing differential gene expression profiles established by cDNA microarray between normal cells (N), primary carcinoma cells (T), and metastatic carcinoma cells (M) may determine those critical genes directly associated with progression and metastasis of breast cancer. Total RNA was extracted by laser microdissection (LMD) from 20 slices of T, N and M from 6 cases. After amplification by a T7-based system, differentially expressed genes between T, N and M were identified by cDNA microarray. In addition, to clarify the mechanism for altered gene expression, we determined the methylation status by sequencing after bisulfite treatment for intriguing genes. As a result, the expression of motility related protein-1 (MRP-1/CD9), peripheral myelin protein-22 (PMP-22), and caspase 3 (CASP-3) were down-regulated in M compared to T. We focused especially on MRP-1 and found that the expression status of MRP-1 was significantly inversely associated with stage of disease in 56 cases of breast cancer (P<0.05), and the relapse free survival in 5 years was significantly higher in MRP-1 positive cases than those negative cases (P<0.05). Conversely, overexpression, by 11-fold, of signal transduction and translation factors were observed in T compared to N. The cancer specific methylation was observed only in CASP-3 in a case. In conclusion, the establishment of the present assay allows us to detect genes directly associated with each cell population within tumor tissue and gives us clues to identify metastasis-related genes comprehensively in clinical breast cancer cases.

Differential roles of E-type cyclins during transformation of murine E2F-1-deficient cells.

Deregulation of retinoblastoma gene product (pRB) is a hallmark of cancer, which acts as a transcriptional repressor by targeting E2F transcription factors. A transcription factor E2F-1 is not only important for S phase entry of cell cycle, but also stimulates gene expression of pro-apoptotic molecules. To investigate roles of E2F-1 and its target genes in cellular transformation, we studied murine E2F-1-deficient embryonic fibroblasts. Compared with control wild-type cells, E2F-1-deficient cells at early passages were less sensitive to exposure to gamma-radiation and showed an increase of colony formation, while their growth was slow. After sequential passages, the growth of E2F-1-deficient cells reached closely to that of wild-type cells. Immunoblot study of E2F target genes showed that multiple passages of E2F-1-deficient cells resulted in preferential increase of cyclin E2 expression. Furthermore, carcinogenicity study using N-nitrosomethylbenzylamine demonstrated that, compared to wild-type mice, fore-stomach tumors in E2F-1-deficient mice expressed an increased amount of cyclin E2, but not cyclin E1. Taken together, the present study shows that differential roles of E-type cyclins are involved at least partially in the process of cellular transformation, supporting the concept of important roles of the E2F regulatory pathway in carcinogenesis.

Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma.

PURPOSE: A low expression level of cyclin-dependent kinase (Cdk) inhibitor p27 is associated with high aggressiveness and poor prognosis of various carcinomas. Human Cdk subunit 1 (Cks1), as well as S-phase kinase-associated protein 2 (Skp2), is an essential and specific factor in the p27 proteolysis by SCF(Skp2) ubiquitin ligase. The purpose of this study is to clarify the clinical significance of Cks1 expression and the relationship between Cks1 and p27 expression in gastric carcinomas. EXPERIMENTAL DESIGN: We measured Cks1 expression using quantitative reverse transcription-PCR in 76 human gastric carcinomas and p27 expression using immunohistochemistry in 28 cases. Moreover, we established Cks1- and/or Skp2-transfected gastric carcinoma cell lines and assessed the relationship between Cks1, Skp2, and p27 expression using quantitative reverse transcription-PCR and Western blot analysis. RESULTS: Cks1 high expression was correlated with poor prognosis (P < 0.05) and Cks1 expression was inversely correlated with the expression level of p27 protein in gastric carcinomas (P < 0.05). Using combined Skp2 data [T-a. Masuda, Cancer Res., 62: 3819-3825, 2002], 88.9% of the Cks1/Skp2 double-high cases expressed a low level of p27 protein and showed the poorest prognosis (P < 0.05). Western blot analysis showed that Cks1/Skp2-cotransfected cells expressed a much lower level of p27 protein than the controls. CONCLUSIONS: These findings indicate that Cks1, as well as Skp2, regulates the expression level of p27 protein in gastric carcinomas. Cks1 could play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinomas as well as a strong prognostic marker.

A new case of zoonotic onchocercosis in northern Kyushu, Japan.

A case of zoonotic onchocercosis has been found in a resident who lived in Iizuka City, Fukuoka Prefecture, Japan for some time. A 24-year-old male developed a painful nodule on the middle finger of his right hand. The nodule was surgically removed from the vagina fibrosa tendinis of the finger at Beppu Medical Center, Beppu City, Oita Prefecture in 2012. The causative agent was identified as a female Onchocerca dewittei japonica based on its histopathological characteristics. The identity of the filarioid has been confirmed by sequencing the cox1 gene. The present study indicates that the zoonotic onchocercosis caused by O. dewittei japonica has been concentrated in northeast Kyushu.

Successful treatment of pure red cell aplasia with cyclosporin A and erythropoietin after thymectomy in a 88-year old woman.

An 88-year old Japanese female with pure red cell aplasia was treated safely and effectively by a combination of thymectomy, cyclosporin A, and erythropoietin. The thymoma was histologically classified as lymphocytic type or cortical type, which are uncommon in cases of a thymoma accompanied by pure red cell aplasia. Immunohistochemical analysis of the thymoma and bone marrow revealed a predominance of CD8(+) cells. Thymectomy alone was ineffective, but cyclosporin A treatment subsequent to thymectomy was safe and effective and resulted in the disappearance of a Vbeta12 bearing T-cell clone in the bone marrow. Additional treatment with erythropoietin enhanced the effects of cyclosporin A and restored the patient's hemoglobin to normal levels. The beneficial effect of cyclosporin A may be attributed not to a broad immunomodulatory effect, but to a local effect on a limited T-cell subset.

Analysis of the gene-expression profile regarding the progression of human gastric carcinoma.

BACKGROUND: Tumor tissue consists of a variable mixture of tumor and host-cell populations. Recent developments in laser microdissection (LMD) and cDNA microarray analysis have encouraged us to study the differential gene expression profiles among normal cells, primary carcinoma cells, and metastatic carcinoma cells in cases of gastric carcinoma. METHODS: Total RNA was extracted from the cells obtained by means of LMD from the primary carcinoma, the corresponding gastric epithelium, and the lymph node metastasis in 5 cases of primary gastric carcinoma. RNA was amplified by the T7-based amplification system to be applied to a cDNA microarray. Thereafter, the differentially expressed genes among the 3 populations were evaluated. RESULTS: cDNA samples for microarray studies were successfully obtained from each cell population of 5 cases. The cDNA microarray demonstrated that several interesting genes, such as cell-cycle regulators and growth factors, were overexpressed in the metastatic cells compared with in the primary carcinoma cells. Oncogenes and cell-adhesion molecules were more overexpressed in the primary carcinoma cells than in the normal cells. On the other hand, caspase 8 and cadherin were more suppressed in the primary carcinoma cells than in the normal cells. Interestingly, among the matrix metalloproteinase family, only MMP7 was identified as a differentially overexpressed gene in both the primary carcinoma and the metastatic cells in comparison with the normal cells. CONCLUSIONS: This study demonstrated that the combined use of LMD, T7-based amplification, and a cDNA microarray enabled us to identify genes directly associated with each population of tumor tissue. The method will open up new possibilities for the precise gene analysis of tumor progression and metastasis.

Extranodal multiple involvement of enteropathy-type T-cell lymphoma without expression of CC chemokine receptor 7.

Enteropathy-type T-cell lymphoma (ETCL) is a rare extranodal lymphoma that tends to disseminate into the intestines and other extranodal organs. We present a case of ETCL with involvement of the lungs and kidneys and report CC chemokine receptor 7 (CCR7) expression of lymphoma cells. A 73-year-old man was admitted to the hospital with a complaint of abdominal pain. Multiple ulcers and perforations were observed in the small intestine, and partial resection of the ileum was performed. Histological examination of the resected specimen revealed diffuse proliferation of atypical large lymphoid cells. The diagnosis was ETCL with dissemination into the lungs and kidney. Lymphoma cells of the small intestine and in pleural effusion were CD3+, CD4+, CD7+, CD8-, CD25-, CD56-, CD103 +/-, and TIA-1+. Rearrangement of the T-cell receptor beta gene was detected, and human T-lymphotropic virus was not integrated. Combination chemotherapy did not result in a sustained response. The results for CCR7 expression of lymphoma cells in the lung and pleural effusion were negative. Therefore we concluded that lymphoma cells did not migrate into the lymph nodes but instead spread into the extranodal organs.

A case of synchronous metastasis of breast cancer to stomach and colon.

A case of synchronous metastasis of breast cancer to the stomach and colon is reported. A 38-year-old woman with a history of bilateral breast cancer was admitted for endoscopic examination because of occult blood. Endoscopic examination showed elevated lesions on the mucosal surface of the stomach and cecum. Histopathological examination of the biopsy specimens obtained from both sites showed adenocarcinoma, comprised of tumor cells with structural and nuclear atypia, which were similar to those of the primary breast cancer cells. In immunohistochemical analysis, these tumor cells stained positive for ER. Therefore, we diagnosed a synchronous metastasis of breast cancer to the stomach and colon. Synchronous metastasis of breast cancer to the stomach and colon without liver metastasis or peritoneal dissemination is extremely rare, with only 4 reported cases existing in literature.