[A Case of GIST That Recurred More Than 30 Years after Surgery and Could Be Resected].

The patient was a 77-year-old woman. She underwent a partial gastrectomy at the age of 40, and a partial colectomy at the age of 75 following a diagnosis of a carcinoid. In November 2019, a 1.5 cm mass with a clear boundary was found in the pancreatic tail, which was strongly stained uniformly. And furthermore, multiple masses between 2 cm and 3 cm with a clear boundary was found inside liver segment S1 and S6 and S7 and S8 on CT, which was strongly stained at the edge in the early phase and was seen as a low density area in the late phase. At a result of image examination, it was diagnosed as a pancreatic tail neuroendocrine tumor and its multiple liver metastases. The distal pancreatectomy, posterior segmentectomy, and partial S1 lt and S8 liver resection were performed. With postoperative pathological diagnosis, the pancreatic tumor was accessory spleen, and liver tumor were epithelioid type GIST which were positive for CD34 and PDGFRA and negative for c- kit. The pathology specimen of colectomy was re-examined, and the diagnosis from the previous surgery was changed to GIST from a carcinoid. Epithelioid type GIST was associated with a PDGFRA gene mutation and was known to have many gastric origins. Based on the clinical course, it was diagnosed as recurrence of gastric GIST at 40 years after 30 years or more.

Biliary tumors with pancreatic counterparts.

Some biliary diseases mimic pancreatic diseases pathologically as well as pathogenetically. Such diseases can be called "biliary diseases with pancreatic counterparts". Biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of bile ducts (IPNB), hepatobiliary mucinous cystic neoplasm (hMCN), and IgG4-inflammatory pseudotumor represent the biliary counterparts of pancreatic intraepithelial neoplasm (PanIN), intraductal papillary mucinous neoplasm of pancreas (IPMN), pancreatic MCN, and mass forming type 1 autoimmune pancreatitis (AIP), respectively. BilIN and PanIN represent pre-invasive intraepithelial stages of nodular sclerosing cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. IPNB and IPMN are grossly visible, predominant papillary, intraductal neoplasms that may progress to invasive carcinoma. Morphologically similar MCNs with subepithelial ovarian-like stroma occur in both the hepatobiliary system as well as the pancreas. IgG4-inflammatory pseudotumor, usually of the lymphoplasmacytic type, and mass forming type 1 AIP represent IgG4-related disease in the biliary tree and pancreas respectively. The biliary tract, which is associated with the peribiliary glands, including the pancreatic acini, can be regarded as an incomplete pancreas, so several diseases mimicking pancreatic diseases may be expected to occur in the biliary tract (biliary diseases with pancreatic counterparts).

Neoplastic Ruptured Cerebral Aneurysm Caused by Intimal Sarcoma: A Case Report.

Intimal sarcomas (ISAs) are extremely rare malignant tumors that histologically occur in the tunica intima of large blood vessels of the systemic and pulmonary circulation. Herein, we describe a case of an ISA-based neoplastic aneurysm in the middle cerebral artery (MCA) that resulted in a subarachnoid hemorrhage (SAH). The patient presented to our hospital with severe consciousness disturbance (Glasgow Coma Scale E1V1M2) and anisocoria. On admission, computed tomography (CT) showed a diffuse SAH. At 8 months prior, he presented to a previous hospital with hoarseness. Thoracic CT revealed a threatened rupture of the aorta of the arch. After total arch replacement, he had been diagnosed with ISA from the pathological findings of the resected aorta. Thereafter, he had been treated with adjuvant chemotherapy and radiotherapy without any cerebral vascular imaging studies, before admission at our hospital. Angiogram revealed a multilobar fusiform aneurysm on the right MCA. We performed a superficial temporal artery-MCA anastomosis, trapping, and resection of the affected MCA (including the aneurysm), followed by external decompression. Microscopic hematoxylin-eosin staining showed proliferation of atypical spindle-shaped cells with enlarged nuclei in the lumen of the affected MCA. Immunostaining showed CD31 (±), ERG (+), MDM2 (+), CDK4 (+, slightly), SMA (±), MIB-1 index 13.9%, factor VIII (±), and desmin (-). These pathological findings indicated metastasis of the ISA, which formed the neoplastic aneurysm. An ISA can cause a neoplastic cerebral aneurysm. Therefore, once a patient is diagnosed with an ISA, it is necessary to check periodically the cerebral arteries.

Aggressive recurrence of gastric cancer as a granulocyte-colony-stimulating factor-producing tumor.

A 62-year-old Japanese man presented with a 1-month history of inter-digestive epigastralgia. His family history included a sister with gastric cancer. Gastroendoscopy and gastrography demonstrated a type-2 tumor in the upper region of the stomach. CT scan and fluorodeoxyglucose-positron emission tomography (FDG-PET) scan demonstrated gastric cancer and its metastatic lymph nodes. The patient underwent total gastrectomy with splenectomy and extended lymph node dissection. Although postoperative adjuvant chemotherapy by S-1 was started, the deteriorating condition of the patient prevented drug administration and even eating meals. On the 19th postoperative day (POD), FDG-PET scan of the body demonstrated new uptake in the liver and lymph node around the aorta. Without any sign of infection, leukocytosis developed around the 30th POD. On the 49th POD, remarkable uptake in the whole upper abdomen was detected on FDG-PET scan. Finally, leukocyte count increased to 125,200 and granulocyte colony stimulating factor (G-CSF) was elevated to 28 pg/ml on the 54th POD. The patient died of multiple liver metastases and carcinomatous peritonitis only 56 days after surgery. G-CSF-producing tumor is a rare but aggressive disease, particularly as recurrent tumor. If leukocytosis is detected in relation to a non-lympho hematopoietic malignant tumor, G-CSF-producing tumor should be considered and FDG-PET scan is recommended for early detection. Chemotherapy for G-CSF-producing tumor must be conducted as soon as possible.

Histopathological findings after ultraselective transcatheter arterial chemoembolization for hepatocellular carcinoma.

AIM: To evaluate the histopathologic findings in the surgical specimen of hepatocelluar carcinoma after transcatheter arterial chemoembolization (TACE) at the most distal portion of the sub-subsegmental artery of the liver (ultraselective TACE). METHODS: Histolopathologic findings from nine tumors with a mean diameter of 3.1 cm +/- 1.7 from patients who underwent hepatectomy after ultraselective TACE were evaluated, especially with regard to the relationship between peritumoral liver parenchymal necrosis and portal vein visualization during TACE. Portal vein visualization was classified into three grades by a spot digital radiograph obtained just after TACE: 0, no obvious portal vein visualization; 1, visualization of the portal vein adjacent to the tumor; and 2, visualization in the whole embolized area or extending into the surrounding non-embolized areas. Unenhanced computed tomography (CT) was obtained 1 week later and surgical resection was performed 37 +/- 6.3 days after ultraselective TACE. RESULTS: Portal vein visualization during TACE was classed as grade 1 in 5 tumors and grade 2 in 4. Histopathologically, complete tumor necrosis was observed in 7 tumors (77.8%). In 2 tumors (1 of grade 1, the other grade 2), a small viable portion or viable daughter nodule was seen. Macroscopic parenchymal necrosis adjacent to the tumor was observed in all 4 grade 2 tumors including gas-containing areas on CT obtained 1 week after TACE. CONCLUSIONS: Ultraselective TACE induces not only complete tumor necrosis but also peritumoral parenchymal necrosis, similar to that after radiofrequency ablation, when the portal veins are markedly visualized during the TACE procedure.

Clinicopathological significance of antinuclear antibodies in non-alcoholic steatohepatitis.

AIM: Serum antinuclear antibodies (ANA) are occasionally noted in patients with non-alcoholic steatohepatitis (NASH). We examined the significance of ANA in NASH. METHODS: We compared clinicopathological features in patients with ANA-positive NASH (n = 35) and ANA-negative NASH (n = 36). Inflammatory cell profiles and the distribution of oxidative stress markers were also examined immunohistochemically. RESULTS: ANA-positive NASH was significantly associated with female gender (P = 0.005), high degree of portal inflammation (P = 0.039), interface activity (P = 0.036) and hepatocellular ballooning (P = 0.0008). In addition, ANA of high titer (320-fold or more) was significantly associated with the histological grade and stage of NASH (P = 0.02). The degree of steatosis wais rather mild in the high-titer ANA group(P = 0.01). The analysis of inflammatory cell profiles revealed that CD3-positive T cells were predominant and plasma cells were rather few in the portal area and hepatic lobules in both ANA-positive and ANA-negative groups. There was no difference in the distribution of oxidative stress markers between ANA-positive and ANA-negative groups. CONCLUSION: These findings suggest that the presence of ANA may be related to the progression of NASH and that a different type of autoimmune mechanism may be involved in the pathogenesis of NASH with ANA, compared to the pathogenesis of autoimmune hepatitis.

Pulmonary Neoplasms in Patients with Birt-Hogg-Dubé Syndrome: Histopathological Features and Genetic and Somatic Events.

Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.

Nodular fasciitis of the ulnar nerve at the palm.

A 42-year-old woman complained of progressive induration in the right palm. As the mass was impossible to separate from the ulnar nerve, we excised the mass together with the digital nerve and grafted 4cm of the sural nerve. The final diagnosis was nodular fasciitis.

Differences in emotional distress among inpatients with type 1, obese type 2, and non-obese type 2 diabetes mellitus.

Objective The purpose of this study was to determine the differences in emotional distress among three groups of inpatients with type 1, obese type 2, and non-obese type 2 diabetes during hospitalization. Methods The 42 participating inpatients were divided into three groups: type 1 diabetes (n=11), obese type 2 diabetes [body mass index (BMI) ≥25 kg/m(2); n=24], and non-obese type 2 diabetes (BMI <25 kg/m(2); n=7). The Problem Areas in Diabetes (PAID) scale, which is a self-administered questionnaire to assess emotional distress in the patients with diabetes, was performed at admission and discharge. Results The total PAID score was similar and tended to improve during hospitalization in all three groups, although there were differences among the groups in the scores of particular questions. At admission, the score of the question "worrying about low blood sugar reactions?" was significantly different among the three groups and highest in the patients with type 1 diabetes. At discharge, the score of "not accepting diabetes?" was significantly different among the three groups and highest in the patients with non-obese type 2 diabetes, while that of "feeling unsatisfied with your diabetes physician?" was significantly different among the three groups and highest in the patients with obese type 2 diabetes. The score of "feelings of deprivation regarding food and meals?" significantly worsened in the patients with obese type 2 diabetes during hospitalization compared with the patients in with non-obese type 2 diabetes. Conclusion The characteristics of emotional distress during hospitalization varied among the patients with the three types of diabetes, thus emphasizing the importance of tailoring support according to the type of diabetes.

Clinicopathologic significance of combined hepatocellular-cholangiocarcinoma with stem cell subtype components with reference to the expression of putative stem cell markers.

OBJECTIVES: To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-like 1 homolog (DLK1), as well as putative stem cell markers, such as NCAM/CD56 and CD133. METHODS: In this study we examined the expression of stem cell markers using immunohistochemistry. RESULTS: Thirty-six cases of combined HC-CC were subclassified into 24 cases, with more than 5% stem cell features (group B) and 12 cases with less than 5% stem cell areas (group A). The postoperative overall survival rate was worse for group B than for group A. DLK1 was frequently expressed in group B cases compared with group A, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cases. CONCLUSIONS: The 2010 WHO classification seems important for elucidating the pathogenesis of stem cell-related liver cancers.

α-Fetoprotein-producing gastric carcinoma and combined hepatocellular and cholangiocarcinoma show similar morphology but different histogenesis with respect to SALL4 expression.

α-Fetoprotein is expressed in hepatocellular carcinoma, yolk sac tumor, and some gastric carcinomas. The α-fetoprotein-producing gastric carcinoma composed of hepatoid and common adenocarcinoma shows morphological similarities to combined hepatocellular and cholangiocarcinoma. In this study, the expression of putative hepatic stem/progenitor markers (EpCAM, OV-6, DLK-1, and NCAM/CD56), hepatocyte markers (HepParI, α-fetoprotein, glypican 3), and the germ cell marker SALL4 was examined in α-fetoprotein-producing gastric carcinoma (20 cases) and combined hepatocellular and cholangiocarcinoma (20 cases) for evaluation of pathologic differentiation and also the histogenesis of both tumors. The SALL4 protein was expressed in 95% of α-fetoprotein-producing gastric carcinoma, including the hepatoid component (hepatoid gastric carcinoma), but was absent in combined hepatocellular and cholangiocarcinoma. Glypican 3 and α-fetoprotein were detected in all hepatoid-type α-fetoprotein-producing gastric carcinoma but variably in combined hepatocellular and cholangiocarcinoma. NCAM/CD56 was expressed focally in combined hepatocellular and cholangiocarcinoma but was rare in hepatoid gastric carcinoma. EpCAM, DLK-1, and OV6 were variably expressed in hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma. SALL4 was a useful differential marker for combined hepatocellular and cholangiocarcinoma and hepatoid gastric carcinoma. The histogenesis of hepatoid gastric carcinoma expressing SALL4 seems to reflect fetal gut differentiation or involve the germ cell lineage and may be different from that of combined hepatocellular and cholangiocarcinoma involving the hepatic stem cell or progenitor cell lineages. In conclusion, hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma shared morphologies, whereas the distinction of hepatoid gastric carcinoma from combined hepatocellular and cholangiocarcinoma is possible by immunostaining for SALL4. These 2 tumors seem to differ in their histogenesis with respect to SALL4 expression.1.

Portal blood supply to locally progressed hepatocellular carcinoma after transcatheter arterial chemoembolization: Observation on CT during arterial portography.

AIM: To analyze the clinical features of locally progressed hepatocellular carcinoma (HCC) supplied by portal blood (PB) after transcatheter arterial chemoembolization (TACE). METHODS: This cohort included 12 tumors (mean diameter ± SD, 1.8 ± 0.8 cm) in 10 patients. PB supply to tumors was judged by CT during arterial portography (CTAP). Imaging data and the clinical course were retrospectively evaluated. RESULTS: Six tumors initially had a small tumor portion supplied by PB. In four tumors, TACE was incomplete because of technical problems. PB supply to recurrent tumors was demonstrated 7.3 ± 3.7 months after TACE. On follow-up arteriography, all embolized branches were occluded or severely attenuated. Four tumors showing a partial stain were treated by additional TACE (n = 3) or TACE plus radiofrequency (RF) ablation (n = 1), one without staining was treated by RF ablation, and seven were followed-up. All tumors progressed except for one treated by RF ablation. On serial CTAP images, relatively large-diameter portal veins directly entered 11 tumors (91.7%) and connected with intratumoral vessels in nine (75%). During follow-up, partial arterial supply was demonstrated in two tumors and additional TACE was performed. Nine patients died after 31.4 ± 16.2 months due to tumor progression (n = 8), or hepatic failure (n = 1). One patient has survived for 53 months despite multiple tumors. CONCLUSIONS: PB supply to locally progressed tumor after TACE became apparent on CTAP. Arterial damage by TACE, incomplete TACE, and preexisting tumor tissues supplied by PB may be the main causes.

A case of primary small cell carcinoma of the breast.

We report a rare case of primary small cell carcinoma of the breast. A 44-year-old woman was admitted to our hospital with a mass in her left breast. Fine-needle biopsy revealed small cell carcinoma with neuroendocrine differentiation resembling small cell carcinoma of the lung. Systemic computed tomography (CT) and magnetic resonance imaging (MRI) revealed no primary site in the lung or any other organ. A modified radical mastectomy with removal of the axillary lymph node (Bt + Ax, R2) was performed. Histological examination revealed that the tumor was composed of small round to oval cells with a large nuclear-cytoplasmic ratio. The tumor cells were positive for neuroendocrine differentiation markers such as synaptophysin, CD56, and neuron-specific enolase (NSE), but negative for thyroid transcription factor-1 (TTF-1), leukocyte common antigen (LCA), estrogen receptor (ER), and progesterone receptor (PR). Interestingly, the tumor cells lacked immunoreactivity for epithelial markers, including cytokeratin AE1/3, CAM5.2, and epithelial membrane antigen (EMA). The patient was given adjuvant chemotherapy for axillary lymph node metastasis. There were no signs of recurrence 22 months after surgery.

Osteopontin is involved in the formation of epithelioid granuloma and bile duct injury in primary biliary cirrhosis.

Recently, it was shown that osteopontin (OPN) is involved as a chemoattractant cytokine in the recruitment of macrophages and T lymphocytes in the granulomas of diverse etiologies and also plays an important role in the production of autoantibodies and development of autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by immune-mediated bile duct damage with frequent epithelioid granulomas. In this study, the expression of OPN was immunohistochemically examined in 25 PBC and 52 control livers. Epithelioid cells within granuloma in PBC expressed OPN variably. These cells were also positive for CD68, suggesting their histiocyte/macrophage lineage. In addition, strong expression of OPN was seen in the cytoplasm of mononuclear cells infiltrating around granulomas and also damaged bile ducts in PBC. The number of such positive mononuclear cells and the ratio of OPN-positive cells/total infiltrating cells in portal tracts were higher in PBC than in controls. The majority of these OPN-positive cells were found to be IgG- or IgM-producing plasma cells. These suggest that in PBC, OPN is an important immune molecule in portal tracts, and contributes to the recruitment of mononuclear cells into epithelioid granuloma and also participates in bile duct injury via B-cell differentiation and plasma cell expansion.

Autoimmune hepatitis associated with bile duct injury resembling chronic non-suppurative destructive cholangitis.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are representative autoimmune liver diseases in which hepatocytes and intrahepatic bile ducts, respectively, are selectively damaged by autoimmune mechanisms. Bile duct injury and loss is characteristic of PBC and chronic non-suppurative destructive cholangitis (CNSDC), in particular, is a histological hallmark of PBC. In this report, we present an unusual case of AIH accompanied by CNSDC-like bile duct injury in a 46-year-old woman. The patient's serum aminotransferase level was abnormally high. The serum levels of alkaline phosphatase, gamma-GTP and IgG were also elevated, but the IgM level was within normal limits. The titer of antismooth muscle antibody (SMA) was 1:80, while antinuclear autoantibody (ANA) and the M2 fraction of antimitochondrial antibody (AMA) were both negative. Liver biopsy disclosed CNSDC-like bile duct injuries and severe interface hepatitis and lobular hepatitis with perivenular zonal necrosis were observed. The aggregate score of the International Autoimmune Hepatitis Group corresponded to the category of probable AIH. Immunohistochemically, histocompatibility leukocyte antigen-DR, which is aberrantly expressed in the damaged bile ducts of PBC, was not found in the injured bile ducts of this case. Laboratory data were much improved by treatment with prednisone, but ursodeoxycholic acid was not effective. Although the possibility of an overlapping syndrome of AIH- and AMA-negative PBC could not be excluded, this case was diagnosed as AIH with CNSDC-like bile duct lesions.