Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients.

BACKGROUND: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. METHODS: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). RESULTS: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. CONCLUSIONS: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.

Clear cell neuroendocrine tumor in the gallbladder diagnosed as a benign polyp preoperatively: a case report.

BACKGROUND: Gallbladder neuroendocrine neoplasm is a rare disease that is divided into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Clear cell NETs of the gallbladder are extremely rare. We report the case of a patient with polypoid clear cell NET G1 of the gallbladder who underwent laparoscopic cholecystectomy. CASE PRESENTATION: A 10-mm pedunculated polyp in the gallbladder neck was detected on a follow-up abdominal ultrasound in a 60-year-old man with chronic hepatitis and hepatitis B without medication. Six months later, an abdominal ultrasound revealed that the tumor had enlarged to 12 mm in size. He was asymptomatic and had no abnormalities in other laboratory examinations, including the tumor markers, carcinoembryonic antigen and CA19-9. Abdominal ultrasound showed a 12-mm polyp in the neck of the gallbladder with perfusion and focal thickening of the gallbladder wall. A gallbladder stone was also seen in the fundus. An enhanced computed tomography scan and magnetic resonance imaging revealed a polypoid lesion and gallbladder stone located at the neck of the gallbladder and the fundus, respectively. Malignancy could not be excluded, and hence, a laparoscopic cholecystectomy was performed. Pathologically, a pedunculated polyp (14 × 11 × 15 mm) was observed in the neck of the gallbladder, and the polypoid lesion comprised nests or trabecular growths of clear NET cells in the lamina propria (ENETS: T1N0M0; AJCC: T1aN0M0). Immunohistochemical staining with synaptophysin, chromogranin A, and CD56 was confined to the tumor. The pathological diagnosis was clear cell NET G1 of the gallbladder. Although clear cell NET is often described as a distinct manifestation of von Hippel-Lindau disease (VHL), the patient had no past medical or family history of VHL. Until his one-and-a-half-year follow-up, the patient was doing well and without any signs of recurrence. CONCLUSION: We report an extremely rare case of gallbladder clear cell NET G1. When NET G1 is incidentally identified in a gallbladder surgical specimen, clinical information and pathological findings should be considered as references.

Drill needle aspiration biopsy for submucosal tumors in an experimental study.

BACKGROUND AND AIMS: EUS-guided FNA biopsy has been widely performed to aid in the diagnosis of submucosal tumors (SMTs). However, in cases of small tumors, the diagnostic yield of EUS-FNA is poor. Therefore, it is necessary to develop a new needle for the diagnosis. We developed a device with a new mechanism that we refer to as a drill needle aspiration biopsy (DNAB). The aim of this study was to evaluate the use of DNAB in resected gastric SMT specimens. METHODS: A drill needle with a sharp tip and wide ditch was inserted into a catheter for angiography. Continuous suction is enabled through the catheter at the tip. DNAB was performed with one pass and one stroke in 13 gastric SMTs resected by operation. Similarly, FNA was performed by one pass and ten strokes. These gastric tumors included nine diagnosed gastrointestinal stromal tumors and four undiagnosed SMTs by preoperative examinations. The tissue quantity between DNAB and FNA was macroscopically and microscopically examined. RESULTS: All 13 drill biopsy specimens were obtained. Additionally, all 13 gastric SMTs, including 4 undiagnosed tumors, could be diagnosed by DNAB. The quantity of each specimen obtained by DNAB was macroscopically and microscopically much greater than that by FNA. In particular, for tumors <25 mm in the longer axis, the ratio of microscopic diagnosable cases was 100 % (7/7) for DNAB and 42.9 % (3/7) for FNA. CONCLUSIONS: DNAB is a novel method that can obtain more tissue than FNA for small gastric SMT.

A case of non-esophageal eosinophilic gastrointestinal disease diagnosed by mucosal incision-assisted biopsy.

A 46-year-old woman presented at our hospital with anorexia, vomiting, and diarrhea. Blood tests indicated markedly increased eosinophil counts, and esophagogastroduodenoscopy revealed slight erythema in the gastric body. Computed tomography showed edematous thickening of the stomach and small intestinal walls and peritonitis. Thus, eosinophilic gastrointestinal disease was suspected. Endoscopic biopsies from the esophagus, stomach, and duodenum were collected, but no significant increases in eosinophil counts were observed. Little ascites effusion was detected and puncture cytology was difficult to perform. Thus, a sample of the muscularis propria layer was obtained by mucosal incision-assisted biopsy. Histopathological examination of the biopsy revealed significant eosinophilic infiltration within the muscularis propria layer of the stomach, confirming the diagnosis of non-eosinophilic esophagitis eosinophilic gastrointestinal disease. The patient was treated with a leukotriene receptor antagonist and prednisolone, and her clinical symptoms and gastrointestinal wall thickening rapidly improved. The Japanese diagnostic guideline for non-eosinophilic esophagitis eosinophilic gastrointestinal disease requires endoscopic biopsy or eosinophilic infiltration of ascites fluid. When diagnosis is difficult using conventional methods, as in this case, mucosal incision-assisted biopsy is useful as a next step.

Diffusely infiltrative squamous cell carcinoma of the esophagus presenting as a case with diagnostic difficulty.

We report a rare case of diffusely infiltrative squamous cell carcinoma of the esophagus. The patient, a 68-year-old man, was admitted to our hospital for investigation of dysphagia. Esophagography and upper gastrointestinal endoscopy revealed esophageal stenosis and gastric cancer. As a biopsy from the esophagus revealed no sign of malignancy, he underwent only distal gastrectomy. After 3 months, the stenosis became worse. Again, biopsy from a gastrointestinal endoscopy showed no malignancy, but endobronchial ultrasound-guided transbronchial needle aspiration revealed squamous cell carcinoma of the esophagus. Despite various treatments, the patient died of disease progression 20 months after its onset. Autopsy revealed diffusely infiltrative squamous cell carcinoma of the esophagus, which is a rare malignancy with few case reports documented.

[Leptomeningeal carcinomatosis following 27 years remission from breast cancer with epidermoid: a case report].

We herein report a patient with leptomeningeal carcinomatosis (LC) in long-term remission from breast cancer, co-existing with a posterior fossa epidermoid and an increase in the serum CA19-9 level which complicated the diagnosis. A 59-year-old woman underwent a left mastectomy due to breast cancer 27 years ago. She was admitted to our hospital suffering from a headache and diplopia. Her serum CA19-9 level on admission was elevated, and diffusion weighted images showed a high-intensity tumor in the prepontine and left cerebello-pontine cistern. A left lateral suboccipital craniotomy with endoscopic assistance was performed for tissue sampling. The pathological diagnosis was an epidermoid and LC from breast cancer. She died of progression of leptomeningeal carcinomatosis 31 days after surgery. LC alone following long-term remission from breast cancer is extremely rare. Meningeal irritation co-existing with an epidermoid mimicking chemical meningitis is even rarer. Pathological confirmation is required for such rare cases.

Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy.

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.

Possible relationship between fibrosis of IgG4-related thymitis and the profibrotic cytokines, transforming growth factor beta 1, interleukin 1 beta and interferon gamma: a case report.

BACKGROUND: IgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4-positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry. CASE PRESENTATION: A 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery). CONCLUSIONS: Our results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4-related thymitis as well as in the other affected lesions of IgG4-related disease.

Autopsy case of opsoclonus-myoclonus-ataxia and cerebellar cognitive affective syndrome associated with small cell carcinoma of the lung.

We report an autopsy case of paraneoplastic opsoclonus-myoclonus-ataxia syndrome associated with small cell carcinoma of the lung. Chemotherapy and lung lobectomy resulted in complete tumor remission and disappearance of myoclonus. However, emotional and behavioral disturbances relapsed and remitted associated with exacerbation of truncal ataxia and ocular flutter, which responded favorably to prednisolone. At autopsy, after 2 years and 11 months of illness, there was no recurrence of cancer. Neuropathologically, only the cerebellum was affected, with diffuse loss of Purkinje cells and dentate neurons, suggesting that the paraneoplastic cerebellar involvement may be responsible for the cognitive affective symptoms in our patient.

Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma.

We report a case of angiosarcoma arising in the breast following breast-conserving surgery with radiation therapy for breast carcinoma. The patient, a 49-year-old postmenopausal woman, had undergone breast-conserving surgery for invasive ductal carcinoma of the left breast (pT2 pN0 M0 Stage IIA). Adjuvant radiotherapy (50 Gy with a booster dose to the tumor bed of 10 Gy) was then performed for the residual breast tissue and the patient was treated with hormone therapy (tamoxifen, 20 mg daily) for 5 years. She presented with skin erosion with bleeding 10 years after the initial operation. Incisional biopsy revealed angiosarcoma of the breast, and total mastectomy was subsequently performed. The patient was the treated with chemotherapy (weekly paclitaxel, 80 mg/m2 x cycles) and has remained well without evidence of local or distant recurrence.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma with squamous differentiation: a novel histological finding.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm originating from the nasopharyngeal surface epithelium. Histopathologically, TL-LGNPPA is characterized by cuboidal/columnar tumor cells forming papillary fronds and thyroid transcription factor-1 (TTF-1) expression resembling papillary thyroid carcinoma. To date, the recorded histological features of TL-LGNPPA have been almost uniform, and the range of histological variations in this tumor type has not been sufficiently understood. Here, we report on a 68-year-old man with TL-LGNPPA. Microscopic examination of the resected tumor revealed findings typical of papillary adenocarcinoma of this type, and moreover, this case showed scattered squamous cell foci as a hitherto unreported finding. The squamous cells showed no obvious nuclear atypia or proliferating activity, and their presence was similar to the "squamous metaplasia" of papillary thyroid carcinoma. Immunohistochemically, p40 and TTF-1 coexpression was observed in the squamous cell nuclei, indicating their origin from the glandular tumor cells of TL-LGNPPA.

Mucoepidermoid carcinoma with extensive spindled morphology and melanocytic marker expression.

Mucoepidermoid carcinoma (MEC) is the most common malignant neoplasm of the salivary gland. Albeit common, histologic variants have rarely been noted in MEC. Here, we report a 49-year-old man with a sublingual gland tumor. Histologically, the tumor was composed of spindle cells arranged in interlacing fascicules or globular nests. A few bland small glands containing mucous cells were also scattered. The spindle tumor cells completely lacked immunoreactivity for cytokeratin, and exhibited immunoreactivity for vimentin, S-100, HMB-45, Melan A, and SOX10. The tumor was initially suspected to be clear cell sarcoma, malignant melanoma, or perivascular epithelioid cell tumor with a few entrapped nonneoplastic duct epitheliums. However, reverse-transcription polymerase chain reaction revealed the CRTC3-MAML2 fusion gene product diagnostic of MEC. In fact, a very minor component of the epithelial cells was reminiscent of conventional MEC, whereas major spindled tumor cells possessed markedly altered differentiation. This is the first case report of MEC with extensive spindled morphology and melanocytic marker expression.

Primary pulmonary glomus tumor of uncertain malignant potential: A case report with literature review focusing on current concepts of malignancy grade estimation.

We report a 38-year-old woman with a left lung tumor presenting as obstructive pneumonia. Bronchoscopic examination revealed a polypoid tumor filling the left main bronchus. The tumor was partially resected by a snaring procedure for diagnostic purposes. Microscopic examination revealed a submucosal tumor located underneath normal bronchial epithelium. The tumor was composed of sheets of uniform oval to cuboidal cells encompassing numerous blood vessels. Immunohistochemically, the tumor cells exhibited smooth muscle markers, but were negative for neuroendocrine markers. The diagnosis of primary pulmonary glomus tumor was therefore made. Subsequent bronchoscopic intervention allowed us to pin-point the origin of the tumor: superior segmental B6a/b. She underwent a left lower lobe superior segmental resection successfully. Glomus tumors are relatively rare soft tissue tumors, and those of bronchopulmonary origin are exceedingly rare clinical condition. Among primary lung tumors, the carcinoid tumor is a mimic of the glomus tumor, and differentiating these tumors is known to be difficult, especially using small biopsy samples. In the present case, a large tissue sample obtained by bronchoscopic snaring was quite useful for the correct preoperative diagnosis. Because of the disease rarity, malignancy grade estimation of visceral glomus tumors has not been clearly addressed. Recently, the histopathological diagnostic criteria for malignant glomus tumors was defined in the WHO classification of soft tissue and bone tumors 4th edition. Here we also reviewed the literature on primary bronchopulmonary glomus tumors with special attention to the current concept of malignancy grade estimation.

POEMS syndrome and calciphylaxis: an unrecognized cause of abnormal small vessel calcification.

BACKGROUND: Calciphylaxis is a syndrome consisting of vascular calcification, thrombosis, and skin necrosis. The syndrome develops often in chronic hemodialysis patients. However, there have been several case reports on calciphylaxis in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, a systemic disease associated with plasma cell dyscrasia and upregulation of vascular endothelial growth factor (VEGF). METHODS: In 76 POEMS patients and 86 age- and gender-matched disease controls, we studied abnormal small vessel calcification by computed tomography (CT) of the soft tissues. Clinical and laboratory profiles were compared between POEMS patients with and without calciphylaxis. Histological examination was performed in six autopsy cases. RESULTS: Small vessel calcification on CT was found in 17 % of POEMS patients and in none of the controls (P < 0.001). Autopsy confirmed calciphylaxis in 2 (33 %) patients. Among POEMS patients, higher disease activity, including more severe neuropathy and ascites, higher serum levels of interleukin-6, and lower serum albumin levels, was associated with the development of calciphylaxis. Serum levels of creatinine, calcium, and phosphate were not related to the presence of calciphylaxis. CONCLUSIONS: Calciphylaxis is often present in patients with POEMS syndrome. Upregulation of multiple inflammatory cytokines such as VEGF and interleukin-6 may contribute to the development of calciphylaxis, by entirely different mechanism from that in chronic dialysis. POEMS syndrome should be recognized as a potential cause of calciphylaxis.

Composite pheochromocytoma with a malignant peripheral nerve sheath tumor: Case report and review of the literature.

Adrenal tumors with more than one cellular component are uncommon. Furthermore, an adrenal tumor composed of a pheochromocytoma and a malignant peripheral nerve sheath tumor is extremely rare. A composite pheochromocytoma with malignant peripheral nerve sheath tumor in a 42-year-old man is reported here. After adequate preoperative control, left adrenalectomy was performed simultaneously with resection of the ipsilateral kidney for spontaneous rupture of the left adrenal tumor. Pathological findings demonstrated pheochromocytoma and malignant peripheral nerve sheath tumor in a ruptured adrenal tumor. To date, there have been only four reported cases of composite pheochromocytoma with malignant peripheral nerve sheath tumor, so the present case is only the fifth case in the world. Despite the very poor prognosis of patients with pheochromocytoma and malignant peripheral nerve sheath tumors reported in the literature, the patient remains well without evidence of recurrence or new metastatic lesions at 36 months postoperatively.

Coexistence of familial transthyretin amyloidosis ATTR Val30Met and spinocerebellar ataxia type 1 in a Japanese family--a follow-up autopsy report.

Three brothers in a family with Val30Met transthyretin (TTR) amyloid polyneuropathy (FAP) in Iiyama, Japan were studied pathologically. In this family, affected members have been reported to show typical clinical features of FAP, and some have been documented to exhibit symptoms and signs of central nervous system (CNS) involvement consisting of cerebellar ataxia and pyramidal tract signs. After the original description, this family was regarded as a unique phenotype of this form of FAP; however, subsequent molecular genetic studies revealed that some patients and asymptomatic members in the family had Val30Met TTR and/or spinocerebellar ataxia type 1 (SCA1) gene mutations. In this study, pathological examination of two patients with both FAP and CNS symptoms showed (1) TTR-immunoreactive leptomeningeal and cerebrovascular amyloid deposition compatible with Val30Met TTR FAP, and (2) neuronal loss and gliosis mainly in the Purkinje cell layer, spinocerebellar system, olivo-ponto-cerebellar system, dentato-rubral system, gracile nuclei, cuneate nuclei, and various nuclei of cranial nerves, accompanied by anti-expanded polyglutamine tract antibody positive neuronal intranuclear inclusions, all of which were compatible with the pathological findings of SCA1. On the other hand, the remaining patient with FAP symptoms only showed the former pathological finding alone. The present study demonstrates, at the pathological level, that Val30Met TTR FAP and SCA1 coexist in the same family members, and that the CNS dysfunction seen in the patients in this family is ascribable to SCA1 pathology but not to CNS amyloidosis.