[Clinical Analysis of Pulmonary Pleomorphic Carcinoma:Report of Four Cases].

Of 243 resected cases of primary non-small cell lung cancer for ten years in our hospital, we experienced 4 patients (1.6%) of pulmonary pleomorphic carcinoma. All patients were males and heavy smokers. Histologically, the vascular invasion was showed in 3 of 4 patients. In only one patient, recurrence was recognized, and he died 18 months after surgery. The other 3 patients were alive without recurrence for 86, 92, and 60 months after surgery. In general, prognosis of pulmonary pleomorphic carcinoma is very poor. But in my study, 3 of 4 patients of pulmonary pleomorphic carcinoma survive from this disease. As the planning of an appropriate treatment strategy of pulmonary pleomorphic carcinoma,further detailed assessment of adjuvant chemotherapy, such as immune check point inhibitors, will be considered to be necessary.

[Clinicopathological features of hemorrhagic gastrointestinal stromal tumor].

In order to demonstrate the bleeding risk factors of GIST (gastrointestinal stromal tumor), we retrospectively investigated clinicopathological features between hemorrhagic (H group, 24 cases) and nonhemorrhagic GIST (NH group, 30 cases). In addition, we investigated features between the E group (6 cases) necessitating TAE (trans-catheter arterial embolization) and NE group (other 48 cases). Whereas H group partly includes high-risk grade GIST with chronic bleeding, meanwhile the E group (reflecting acute bleeding) is characterized by a highly enhanced mass with ulceration, comprising of smaller low-risk grade GIST. Amongst the 29 cases for forceps biopsy, which were 6 cases (21%) including one of E group, needed be hospitalized for postbiopsy bleeding. Acute bleeding in GIST may not be associated with malignant transformation. Postbiopsy bleeding or massive hemorrhage can also be encountered particularly in highly enhanced GIST with ulceration, even with a small and low-risk grade.

Gastric Hyperplastic Polyp with Xanthoma Observed by Magnification Narrow-Band Imaging Endoscopy and Endoscopic Ultrasonography : Report of a Case.

We experienced an extremely rare case of gastric hyperplastic polyp with xanthoma. A 73-year-old Japanese man was transferred to our hospital from a referral hospital for further evaluation of a pedunculated gastric polyp and early gastric cancer. Esophagogastroduodenoscopy (EGD) revealed a yellow-whitish pedunculated polyp arising from the anterior wall of the fornix. Magnification narrow-band imaging (NBI) endoscopy revealed extended and tortuous microcapillaries and a swollen interfoveolar pattern on the polyp's surface, but there was no sign of malignancy. Endoscopic ultrasonography (EUS) revealed an irregularity of the first layer and a thickened second layer. The third layer was intact. A hyperechoic area was seen in the thickened second layer. Endoscopic submucosal dissection (ESD) for early carcinoma of the antrum and endoscopic mucosal resection (EMR) for a polyp in the fornix were performed in one session. Histological examination of the specimen of the fornix polyp revealed lengthened, branched and dilatated gastric foveolae and a tight sheet of foamy histiocytes in the stroma. The background mucosa of the polyp was atrophic. The pathologic evidence was gastric hyperplastic polyp with proliferation of xanthoma. The early cancer of the antrum was intramucosal tubular adenocarcinoma and was resected curatively.

Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors.

BACKGROUND: Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS: The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRß, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-ß [p-IGF-1Rß]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS: The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRß, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rß, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRß and p-IGF-1Rß were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS: The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs.

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma.

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit α (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

Successful conversion surgery following chemotherapy with an immune checkpoint inhibitor in an older adult patient with stage IVB esophageal squamous cell carcinoma: a case report.

BACKGROUND: Chemotherapy and chemoradiotherapy are common treatments for esophageal squamous cell carcinoma with distant metastasis; however, the prognosis remains poor, and complete remission is difficult to achieve. Here, we report a case of an older adult patient with esophageal squamous cell carcinoma who underwent surgery following combined treatment of immunotherapy and chemotherapy and achieved pathological complete response. CASE PRESENTATION: An 80-year-old woman presenting with difficulty swallowing was referred to our hospital. She was diagnosed with esophageal squamous cell carcinoma with distant metastasis of the lymph node at the dorsal side of the IVC and the left supraclavicular lymph node. She was treated with pembrolizumab, cisplatin, and 5-fluorouracil. After four pharmacotherapy courses, primary tumor and metastatic lymph node shrinkage was observed. The patient underwent thoracoscopic subtotal esophagectomy and regional lymph node dissection. The lymph node at the dorsal side of the IVC was not resected, and the left supraclavicular lymph node was removed. Histological examination revealed complete response with no residual tumor or lymph node metastasis. The patient had no recurrence 10 months postoperatively without adjuvant chemotherapy. CONCLUSIONS: Conversion surgery following preoperative therapy, including immunotherapy, may be an effective treatment strategy for improving survival in patients with esophageal squamous cell carcinoma even among older adult patients.

Refractory splenic bleeding from splenic angiosarcoma: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Atraumatic splenic rupture (ASR) is a rare state that accounts for only <1 % of splenic ruptures. One of the causes of ASR is splenic neoplasm such as angiosarcoma. The treatment strategy for ASR is still unclear given the small number of cases reported in detail. CASE PRESENTATION: A 75-year-old woman presenting with abdominal pain with shock was referred to our hospital. Emergency computed tomography revealed splenic rupture, and hemodynamic stabilization was obtained by emergent vascular embolization. Rebleeding occurred 27 days after the initial treatment, and splenectomy was performed. Pathologically, ASR was diagnosed as caused by splenic angiosarcoma. CLINICAL DISCUSSION: ASR is a very rare disease. The etiology of ASR has been reported as neoplastic, infectious, and so on. The treatment for ASR should be decided considering the etiology of ASR, hemodynamic stability, volume of blood transfusion, patient status, severity of the splenic injury, and volume of intraperitoneal bleeding. CONCLUSIONS: We experienced a very rare case of ASR, in which diagnosis was challenging and the timing of surgery was difficult to determine. When splenic rupture has an atraumatic cause, splenectomy should be considered because of the possibility of malignancy.

Histological background of dedifferentiated solitary fibrous tumour.

AIMS: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs. METHODS: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed. RESULTS: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of ß-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%). CONCLUSIONS: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

Schwannoma mimicking pancreatic carcinoma: A case report.

BACKGROUND: Schwannoma of the pancreas is extremely rare. We report a case of pancreatic schwannoma that was difficult to distinguish from pancreatic carcinoma before surgery. CASE SUMMARY: A 66-year-old male underwent a right-lobe hepatectomy for hepatocellular carcinoma. Post-surgical computed tomography showed a 10 mm long solid mass with ischemia, with no expansion into the main pancreatic duct. Upon magnetic resonance cholangiopancreatography, the tumor had high signal intensity in diffusion weighted images, consistent with pancreatic carcinoma. Endoscopic ultrasound (EUS) was performed to obtain more information about the tumor, and showed a 14 mm solid and hypoechoic mass in the pancreatic body. Contrast enhanced EUS revealed that the tumor showed a hyperechoic mass in the early phase, and the contrasting effect continuation was very short; findings also consistent with pancreatic carcinoma. Thus, we preoperatively diagnosed his condition as a pancreatic carcinoma and performed distal pancreatectomy with splenectomy. Microscopic examination showed that the tumor was in fact a benign schwannoma. Histology showed a proliferation of spindle-shaped cell in a vague fascicular and haphazard pattern, with palisading arrangement. CONCLUSION: Schwannoma of the pancreas is very rare, however, clinicians should consider schwannoma as the differential diagnosis for pancreatic tumors.

Clinicopathological review of solitary fibrous tumors: dedifferentiation is a major cause of patient death.

Solitary fibrous tumor (SFT) is a soft-tissue neoplasm of intermediate malignant potential, presenting a wide histopathological spectrum. Poorer prognosis of hemangiopericytoma of the central nervous system (CNS), hypoglycemic SFT, and dedifferentiation are well-known characters of SFT, but their clinical significance were not demonstrated enough by large-sized study. Here, the clinicopathological features of SFTs are reviewed and the relationship between genetics and clinicopathological features is examined using 145 SFT cases. All cases were STAT6 IHC-positive and/or NAB2-STAT6 fusion gene-positive. Tumor location was classified into three categories: 30 pleuropulmonary, 96 non-pleuropulmonary/non-central nervous system (CNS), and 18 CNS tumors. The tumor developed recurrence in 21 of 93 available cases (22.5%), metastasis in 11 of 93 (11.8%), and tumor death in 9 of 93 (9.6%). Hypoglycemia occurred in 2 primary tumors and 1 metastatic tumor among 63 reviewable cases, and dedifferentiation occurred in 10 cases (6.8%) including 6 primary tumors, 2 recurrent tumors, and 2 metastatic tumors. Recurrence was positively associated with CNS location (p = 0.0109) and hypoglycemia (p = 0.001); metastasis was positively associated with CNS location (p = 0.0231), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001), while metastasis was negatively correlated with pleural location (p = 0.0471). Tumor death was positively associated with male sex (p = 0.0154), larger size (p = 0.0455), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001). Multivariate analysis revealed independent statistical significance of dedifferentiation for overall survival (p = 0.0467). Exon variant of the fusion gene had no statistical correlation with clinical outcome. In conclusion, dedifferentiation is a major prognostic factor of SFT, and specific location such as cerebromeningeal and intra-abdominal site and hypoglycemia also had a high risk for unfavorable prognosis.

Ascending colon cancer coincident with mesenteric phlebosclerosis associated with the long-term oral intake of Chinese herb containing gardenia fruit: A case report and literature review.

Mesenteric phlebosclerosis is a recently discovered rare ischemic colon disease. The relationship between mesenteric phlebosclerosis and the use of herbal medicine containing gardenia fruit was recently reported. Although the relationship between colon cancer and mesenteric phlebosclerosis has not been described, some cases of colorectal cancer coincident with mesenteric phlebosclerosis have been reported. We treated a 63-year-old female who was diagnosed with ascending colon cancer coincident with mesenteric phlebosclerosis. She had been taking a Chinese herb containing gardenia fruit for over 18 years. The ascending colon cancer was clinically diagnosed as T2, N0, and M0 according to Japanese classification of colorectal carcinoma and the mesenteric phlebosclerosis had spread from the cecum to the descending colon. She underwent laparoscopic subtotal colectomy with en bloc removal of the regional lymph nodes, and both the ascending colon cancer and mesenteric phlebosclerosis were completely resected. The microscopic findings show that the tumor was well-differentiated tubular adenocarcinoma invading the muscular propria with no regional lymph node metastasis, and the mesenteric phlebosclerosis lesion was characterized by marked fibrous thickening of the venous walls with calcification, marked transmural fibrosis and deposition of the collagen in the mucosa, accompanied by macrophages within the vessel walls. In literature review, 10 cases with colorectal cancer coincident with mesenteric phlebosclerosis were reported. 9 of 10 cases (90%) had cancer in the right-side colon affected by mesenteric phlebosclerosis, and 5 of 10 cases (50%) were associated with the use of a Chinese herb containing gardenia fruit. It was recently demonstrated that genipin, which is a metabolite bio-transformed from gardenia fruit, possesses carcinogenesis. We speculate that genipin may be associated with not only the development of mesenteric phlebosclerosis but also carcinogenesis in the right-side colon. In conclusion, our findings suggest that the safety of gardenia fruit should be re-evaluated, and gastroenterologists should be aware that gardenia fruit may be risk factor for not only the development of mesenteric phlebosclerosis but also carcinogenesis in the proximal colon.

Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma.

CXC chemokine receptor 4 (CXCR4) expression is reportedly correlated with both vascular endothelial growth factor (VEGF) expression and poor prognosis in a variety of cancers. Its relation to CXC chemokine receptor 7 (CXCR7) is also noted in several malignancies, including rhabdomyosarcoma (RMS) cell lines. However, the correlations between these chemokine receptors and angiogenic factors have not yet been adequately investigated in RMS clinical specimens. By immunohistochemistry, we assessed CXCR4, CXCR7, CC chemokine receptor 6, CC chemokine receptor 7, VEGF expression, microvessel density, and MIB-1 labeling index in 82 formalin-fixed RMS specimens, including 34 primary alveolar RMS and 44 primary embryonal RMS (ERMS). Twenty-six frozen samples were available for investigation by quantitative reverse transcription polymerase chain reaction to detect the messenger RNA expression levels of these molecules. We also evaluated their significance with respect to clinicopathological factors and patient survival rates. Primary RMS showed high expression of CXCR7 (83.1%) regardless of the histologic subtype. High cytoplasmic CXCR4 and high VEGF expression revealed significant correlations in both ERMS and alveolar RMS (P = .0051 and P = .0003, respectively). By univariate analysis of ERMS cases, the tumors with high VEGF expression showed significantly poor prognoses (P = .0017). High VEGF expression also was the independent adverse prognostic factor for ERMS. Because CXCR4, CXCR7, and VEGF are widely expressed in RMS, the combination of these antagonists may provide a potential target for molecular therapy.

Peroxiredoxins, thioredoxin, and Y-box-binding protein-1 are involved in the pathogenesis and progression of dialysis-associated renal cell carcinoma.

Patients with end-stage renal disease are exposed to increased oxidative stress and impairment of antioxidant mechanisms. We focused on dialysis renal cell carcinoma (RCC), including epithelial hyperplasia in acquired cystic disease of the kidney (ACDK). We attempted to obtain insight into the carcinogenesis and tumor progression in terms of cellular defense mechanisms associated with oxidative stress by investigating the expression of antioxidant proteins by immunohistochemistry. We evaluated retrospectively 43 cases of dialysis RCC and, as a control group, 49 cases of sporadic RCC. Peroxiredoxin (Prx) 1, 3, 4, 5, and 6 expression in dialysis RCC was positively correlated with the duration of dialysis. In epithelial hyperplasia, in 17 cases of acquired cystic disease of the kidney, Prxs and thioredoxin were highly expressed. Moreover, in dialysis RCC, Prx 3, 4, and 5 immunoreactivity and nuclear expression of Y-box-binding protein-1 were higher than in sporadic RCC. In dialysis RCC, Prx 3, 4, and 5 immunoreactivity positively correlated with the Fuhrman nuclear grade. These data suggest that oxidative stress during dialysis enhances antioxidant activity, with an inhibiting effect on carcinogenesis. Once cancer has developed, antioxidant activity might have a stimulating effect on the progression of dialysis RCC.

Microarray analysis of the genes induced by tetracycline-regulated expression of NDRF/NeuroD2 in P19 cells.

NeuroD-related factor (NDRF)/NeuroD2 is a basic helix-loop-helix (bHLH) protein that plays important roles in neuronal development. To elucidate the NDRF transcription network, we used mouse cDNA microarray analysis combined with a tetracycline-regulatable expression system in P19 embryonal carcinoma cells. Five genes were identified to be up-regulated in the presence of NDRF protein. RNA hybridization analysis confirmed that brain-lipid-binding protein (BLBP) and inhibitor of differentiation 1 (Id1) genes were among the five genes that were rapidly and significantly up-regulated after induction of NDRF. When a dominant negative form of NDRF protein was expressed during retinoic acid-induced neuronal differentiation of P19 cells, the BLBP gene, but not the Id1 gene, was potently repressed. Immunohistochemical analysis revealed that both NDRF and Id1 immunoreactivities were observed in some granule cells of the cerebellum in the postnatal period. These results suggest that NDRF or its related bHLH proteins may act upstream of these genes in a subset of developing neurons.