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The author reports an extremely rare case of atypical carcinoid of the pleura expressing KIT. An 81-year-old Japanese man with emphysema was found to have a mass (3×3×2 cm) in the left parietal pleura by various imaging modalities. Video-assisted tumorectomy was performed, but could not excise it completely. Histologically, the tumor was composed of atypical cells arranged in trabecular, ribbon-like, and rosette patterns. Mitotic figures and necrosis were present. The tumor cells were argyrophil. Immunohistochemically, the tumor cells were positive for pancytokeratins, cytokeratin (CK) 18, chromogranin (focal), p53, KIT, and Ki67 (labeling=17%). In contrast, the tumor cells were negative for CK5/6, CK7, CK19, CK20, CK34βE12, epithelial membrane antigen, vimentin, S100-protein, α-smooth muscle actin, desmin, CEA, TTF-1, CDX-2, AFP, HepPar-1, synaptophysin, CD56, CA19-9, CD15, neuron specific enolase, serotonin, CD34, platelet-derived growth factor-α, calretinin, thrombomodulin, WT-1, B72.3, and D2-40. The pathologic diagnosis was atypical carcinoid of the pleura. The patient was examined by whole body computed tomography, magnetic resonance imaging, and positron emission tomography, but there were no tumors other than the pleural tumor. Endoscopic examinations including upper and lower gastrointestinal tract revealed no tumors. Therefore, the pleural tumor was thought to be primary. Ten months later, the patient developed metastatic lesions in the vertebular and femoral bones, and died of respiratory failure. Autopsy was not performed. To the best of the author's knowledge, there are no cases of primary carcinoid in the pleura in the English literature. This case is also interesting in that the atypical carcinoid expressed KIT.

Clear cell adenocarcinoma of the urinary bladder is rare. A 73-year-old woman presented with chronic renal and cardiac failure. Blood tests showed elevated carcinoembryonic antigen and CA19-9 levels. Imaging techniques showed bilateral hydronephrosis and hydroureter. Cystoscopy showed a bladder tumor, and the biopsy showed malignant cells. The patient died 4 months later. Autopsy showed an elevated tumor of the bladder. Metastases to the liver, lungs, adrenal glands, spleen and bones were observed. The kidney showed chronic active pyelonephritis with hydronephrosis. The cause of death was chronic renal and cardiac failure and/or carcinomatosis. Histologically, the bladder tumor consisted of malignant clear cells arranged in solid nests and tubules. Histochemical stains for glycogen and mucins were negative. Metastases also showed similar histology. Immunohistochemically, the tumor cells were positive for carcinoembryonic antigen, CA19-9, CA125, CD10, pancytokeratins (AE1/3, CAM5.2), cytokeratin (CK) 34βE12, CK7, CK8, CK18, CK19, EMA, MUC1, p53, and Ki-67 (labeling=40%). They were negative for CK5/6, CK14, CK20, estrogen receptor, progesterone receptor, α-methylacyl-CoA-racemase, p63, CDX2, MUC2, MUC5AC, MUC6, CD45, CD34, vimentin, neuron-specific enolase, S100 protein, desmin, HMB45, AFP, α-smooth muscle actin, MDM2, HER2/neu, synaptophysin, and CD56. Metastases showed the same immunohistochemical findings.

Protein expression and gene mutational status of KIT and PDGFRA were investigated in formalin-fixed, paraffin-embedded specimens of 14 ipsilateral testicular seminomas. The analysis was performed by ordinary immunohistochemistry and polymerase chain reaction-direct sequencing methods. The genetic analysis was performed in exons 9, 11, 13, and 17 of KIT gene and in exons 12 and 18 of PDGFRA gene. Six point mutations of 5 types of KIT gene were recognized in 5 (36%) cases; exon 17 around codon 816 was a hotspot. The mutation sites of KIT gene were as follows: codon 557 in exon 11 (1 case), codon 816 in exon 17 (3 cases), codon 820 in exon 17 (1 case), and codon 822 in exon 17 (1 case). One patient showed multiple mutations of KIT gene. Immunoreactive KIT was recognized in 13 (93%) cases; the expression was strong in the 5 KIT mutation-positive cases, but variable or none in the 9 KIT mutation-negative cases. No PDGFRA gene mutations were observed in all the 14 cases. PDGFRA protein expression was weakly recognized in 12 cases but none in the remaining 2 cases. These data suggest, in testicular seminomas, that 36% of ipsilateral testicular seminomas have KIT mutations, KIT mutations are frequent around codon 816 of exon 17, multiple KIT mutations may be present, KIT expression is stronger in KIT mutation-positive cases than negative cases, PDGFRA gene mutations are absent, and PDGFRA protein is weakly expressed.

The author reports a very rare case of a gastrointestinal stromal tumor in the uterus. A 74-year-old woman was admitted to our hospital because of pelvic pain. Imaging modalities showed a large tumor of the posterior aspect of the uterus, and enucleation was performed. The tumor was attached to the posterior uterus, similar to subserosal leiomyoma. No attachment to the gastrointestinal organs was recognized. The tumor was soft, tan, and measured 13 x 15 x 12 cm. The tumor consisted of cellular spindle cells with focal necrotic areas. Mitotic figures were noted in 3 of 50 high-power fields. The tumor cells were positive for KIT, CD34, platelet-derived growth factor receptor alpha, and vimentin, but negative for alpha-smooth muscle actin, S100 protein, p53 protein, HMB45, and desmin. Ki-67 labeling was 3%. Five normal uteruses used as controls showed KIT-positive Cajal-like mesenchymal cell scattering in the myometrium. Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor alpha gene (exons 12 and 18) revealed a point mutation at codon 559 (GTT--GAT) of exon 11 of the c-kit gene. Other exons showed no abnormalities. This case shows that gastrointestinal stromal tumor may occur in the uterus.

Primary ovarian lymphoma is a rare disease, and its definition is still controversial. Many cases of primary ovarian lymphoma are diagnosed as diffuse large B-cell type, whereas the precursor lymphoblastic type is extremely rare. Herein, we describe a case of precursor B-cell lymphoblastic lymphoma of the ovary that was successfully treated with surgery and chemotherapy. A 19-year-old woman presented ovarian tumors and paraaortic lymphoadenopathy, which were suggestive of advanced ovarian cancer. Exploratory laparotomy and right salpingo-oophorectomy were performed, and the diagnosis of precursor B-cell lymphoblastic lymphoma was established. The patient was treated with a combination of chemotherapy and is currently disease-free 1 year after surgery. To our best knowledge, this is the fourth reported case of precursor lymphoblastic lymphoma of the ovary.

We investigated the expression of carbohydrate residues on the developing intrahepatic bile ducts of rats. At 17 days of gestation, immature biliary cells around the portal vein close to the hepatic hilum assumed one of the following forms: slitlike lumen, incomplete, or complete bile ductule-like structures. These immature biliary elements then rapidly spread throughout the liver along with development. At birth, a few mature interlobular bile ducts became visible in the portal tracts. The cytoplasm of immature biliary cells stained weakly for concanavalin A, Erythrina crista galli agglutinin, and Limax flavus agglutinin, whereas the luminal surface of immature biliary cells at 17 days of gestation was positive for lectins, similar to those that are expressed on the luminal surface of the mature bile ducts, including concanavalin A, succinyl wheat germ agglutinin, Vicia villosa agglutinin, soybean agglutinin, peanut agglutinin, Erythrina crista galli agglutinin, and Limax flavus agglutinin. As development progressed, the number of lectins binding to the cytoplasm of biliary cells gradually increased, and lectin bindings to the luminal surface of biliary cells gradually became intense. Immature biliary epithelial cells of three structures expressed similar carbohydrate residues in their cytoplasm and luminal surfaces. This study suggested that the profile of carbohydrate residues on the biliary epithelium changes with development. Therefore, this profile could be a useful tool with which to evaluate the development of the biliary tree as well as associated disorders.

Objective: We report the imaging features of hepatic peribiliary cysts (PC) and the course of their development on CT. Materials and Methods: Both CT and US findings were correlated with histopathologic findings in two patients with PC at autopsy. Five patients with cysts around the portal vein on CT but without histologic correlation were also included in this study. In six patients the course of PC development was observed. Results: In the two autopsy cases cystic dilatation of the peribiliary glands was confirmed. The cases showed continuous small cysts along the portal veins reflecting the periportal collar seen on CT and the abnormal MR signal intensity of the periportal area. Ultrasound (US) showed round or tubular anechoic lesions around the large portal tracts mimicking dilatation of the bile ducts. Clustered cysts and echogenic dots or bands around PC were also seen. In three of six cases the PCs gradually enlarged and increased in number. Conclusion: In patients with liver cirrhosis PCs can be demonstrated by CT, US, and MRI in the vicinity of the hepatic hilum. Peribiliary cysts enlarge gradually and must be differentiated from dilatation of bile ducts or edema of portal tracts

Partial nodular transformation (PNT) of the liver is a rare condition in which nonfibrous nodules composed of hyperplastic hepatocytes replace the hepatic parenchyma around the hepatic hilus. We report two autopsy cases involving PNT of the liver with portal vein thrombosis. Case 1 was a 27-year-old man with malignant lymphoma. Ascites gradually increased, and he died 4 years after the onset of his illness. Case 2 was a 73-year-old woman treated for cirrhosis for 4 years who died of renal failure. Postmortem examination of these two cases revealed numerous coalescent nodules in the hilus of the liver as well as portal vein thrombus in the hilus. Microscopically, these nodules in the perihilar area were composed of hyperplastic hepatocytes without fibrous rim, and the peripheral parenchyma showed atrophy to some extent. The portal vein thrombi in the hilus and large portal tracts were mainly fresh and partially organized. Portal vein branches in the peripheral small portal tracts were devoid of significant pathologic changes. We suggest that PNT of the liver in our cases occurred as the result of uneven blood supply to the perihilar parenchyma due to portal vein thrombosis in the hepatic hilus.

We investigated expression of carbohydrate chain structures during human intrahepatic bile duct development and maturation. Results of staining for ABH antigens were negative in the ductal plate and biliary cells migrating into the mesenchyma but were positive in newly formed bile ducts in the fetal liver and in maturing bile ducts in the postnatal liver. Staining for Lewisa, sialyl Lewisa and Lewisb antigens was negative in the ductal plate but positive in migrating biliary cells, newly formed ducts and maturing ducts. Staining for sialyl Lewisx antigen was positive in the ductal plate, migrating biliary cells and newly formed ducts but negative in the postnatal liver. Lewisy antigen staining was negative in the ductal plate and migrating biliary cells but positive in newly formed ducts and maturing ducts. Staining for T and Tn antigens was negative in the ductal plate, migrating biliary cells and newly formed ducts but positive in maturing ducts. Staining for Lewisx, sialyl Th and carcinoembryonic antigen was negative in all tissues. Receptors of Ulex europaeus agglutinin I and soybean agglutinin were absent in the ductal plate, migrating biliary cells and newly formed ducts but present in maturing large ducts. Staining for receptors of concanavalin A and Ricnus communis agglutinin I was negative in the ductal plate but positive in migrating biliary cells, newly formed ducts and maturing ducts. Staining for the receptor of succinylated wheat germ agglutinin was always positive. These findings suggest that carbohydrate chain structures change during intrahepatic bile duct development and maturation and that new carbohydrate chain structures gradually emerge as intrahepatic bile ducts develop and mature. (Hepatology 1994;20:388–397.)

Presence of pancreatic alpha-amylase, trypsinogen, and lipase in normal pancreatic ducts was evaluated immunohistochemically in 10 surgically resected normal pancreatic specimens, using monoclonal antibodies against human pancreatic alpha-amylase, trypsinogen, and lipase. Immunoreactivity to all enzymes occurred patchily in some epithelial cells not only of the common bile duct and its periductal glands but also of the main and interlobular pancreatic ducts and periductal glands in the main pancreatic duct, as well as in pancreatic acinar cells. Ductal staining was fine-granular, and generally present in the supranuclear cytoplasm. Immunoreactivity was abolished by preabsorption. Centroacinar cells and intercalated and intralobular pancreatic ducts did not stain for any enzyme. These findings suggest that some epithelial cells of the large-sized pancreatic duct and its periductal glands express pancreatic alpha-amylase-, trypsinogen-, and lipase-like peptides, as do some epithelial cells of common bile duct and its periductal glands.

We report a giant splenic epithelial cyst which produced carbohydrate antigen 19-9 (CA 19-9) in a 21-year-old woman with left abdominal pain. Imaging techniques revealed a huge cyst of the spleen, and laboratory data revealed elevated serum CA 19-9 (830 U/ml; normal, < 27 U/ml). After splenectomy, serum CA 19-9 level returned to normal. A unilocular splenic cyst measuring 16 x 14 x 13 cm contained brown fluid (900 ml) with a high level of CA 19-9 (10,150,000 U/ml). The wall of the splenic cyst was composed of inner stratified epithelium with mixed squamous and columnar differentiation; immunohistochemical analysis showed that the epithelial cells of the cyst showed strong immunoreactivity to CA 19-9. The inner connective tissue of the cyst wall devoid of epithelial cells was also strongly positive for CA 19-9. We suggest that epithelial cells of our splenic epithelial cyst produced a large amount of CA 19-9 which diffused into capillaries of the connective tissue of the cyst wall and entered into systemic circulation, resulting in the elevated serum CA 19-9.

Apolipoprotein A-1 is known to be one of inhibiting factors of cholesterol nucleation in bile, and decreased activity of apolipoprotein A-1 is considered to predispose cholesterol-supersaturated bile to formation of cholesterol crystals. To study the pathogenesis of the intrahepatic formation of cholesterol stones, we examined surgically resected liver specimens from six patients with intrahepatic cholesterol stones and compared the characteristic histopathological features with those of intrahepatic calcium bilirubinate stones, using morphological examination and immunohistochemical staining against apolipoprotein A-1. Morphologically, in all six patients with cholesterol stones the severity of chronic proliferative cholangitis with proliferation of the mucus-producing glandular elements in the walls of the large bile duct or periductal tissues was less extensive than that seen with calcium bilirubinate stones, and cholesterol crystals had formed in the septal and interlobular bile ducts. Immunohistochemically, unlike the normal liver and calcium bilirubinate stone-containing lobes, the hepatocytes and the epithelial lining of the bile ducts and peribiliary glands of the cholesterol stone-containing lobes did not react completely (some of the epithelial cells reacted only faintly) with apolipoprotein A-1 antibody. These findings suggest that an abundance of mucous substance and bacterial infection of the biliary tree may not be necessary for the formation of cholesterol stones, compared with findings in cases of calcium bilirubinate stones. We suggest that cholesterol crystals may be produced in the septal and interlobular bile ducts in the microenvironment of cholesterol-supersaturated bile and decreased activity of apolipoprotein A-1. (HEPATOLOGY 1993;17:531–537.)

Cystic dilatation of peribiliary glands of intrahepatic and extrahepatic bile ducts was investigated in autopsied livers with adult polycystic disease (n = 8), in autopsied livers with solitary nonparasitic cysts (n = 18) and in normal autopsied livers (n = 23). In normal livers, cystic dilatation of intrahepatic peribiliary glands was absent or slight, when present. In livers with solitary nonparasitic cysts, cystic dilatation of intrahepatic peribiliary glands was present in varying degrees. In livers with adult polycystic disease, intrahepatic peribiliary glands showed frequent and severe cystic dilatation so marked that it was grossly recognizable. In contrast, peribiliary glands of the extrahepatic bile ducts showed no cystic dilatation in most cases, regardless of the three conditions examined. Liver parenchymal cysts were numerous in livers with adult polycystic disease, few in livers with solitary nonparasitic cysts and nonexistent in normal livers. Von Meyenburg complexes were present in 87.5% of livers with adult polycystic disease, in 16.7% of livers with solitary nonparasitic cysts and in 4.3% of normal livers. These findings suggest that intrahepatic peribiliary glands undergo cystic dilatation in livers with adult polycystic disease-and, to a lesser degree and frequency in livers with solitary nonparasitic cysts, probably because of congenital or genetic factors-and that these cystic changes may comprise a part of numerous cysts of adult polycystic disease. (HEPATOLOGY 1992;16:334–340.)

Epithelia of intrahepatic bile ducts and peribiliary glands were immunohistochemically examined for pancreatic alpha-amylase and trypsin in 54 normal autopsied livers. alpha-Amylase was evaluated with a polyclonal antibody, and trypsin was assayed with both polyclonal and monoclonal antibodies. alpha-Amylase was observed in large ducts, septal ducts and peribiliary glands in most livers and was seen in interlobular ducts in seven (13%) livers. Trypsin immunoreactivity with the polyclonal antibody was observed in peribiliary glands in 21 (39%) livers; it was absent in intrahepatic bile ducts in all but one liver. Trypsin immunoreactivity with the monoclonal antibody was present in large ducts, septal ducts and peribiliary glands in about 70% of the livers and was seen in interlobular ducts in two (4%) livers. Bile ductules were always negative for the two antigens. Some epithelia of peribiliary glands positive for both alpha-amylase and trypsin histologically resembled pancreatic acinar cells. alpha-Amylase and trypsin immunoreactivities of intrahepatic biliary epithelia and pancreatic aninar cells were eliminated by absorption of primary antibodies by alpha-amylase or trypsin, suggesting the specificities of the immunoreactivities. These data suggest that epithelia of intrahepatic large ducts, septal ducts and peribiliary glands contain pancreatic alpha-amylase in most livers and that they contain trypsin in about 70% of livers. alpha-Amylase and trypsin may be secreted into intrahepatic bile duct lumens, thereby exerting important effects on the physiology of the intrahepatic biliary tree and hepatic bile.

Amyloid deposition in the hepatic parenchyma and portal tracts in the liver is well known in systemic amyloidosis. We recently experienced an autopsy case of systemic amyloidosis presenting the amyloid deposits in the intrahepatic biliary tree. This experience prompted us to survey 19 autopsy cases of systemic amyloidosis. Amyloid deposition was found just under the lining epithelium of the intrahepatic large bile duct in 10 of 19 cases and around the peribiliary glandular acini in 7 of the 19 cases, respectively. Amyloid deposition in the intrahepatic large bile duct and peribiliary glands was positively correlated with the degree of amyloid deposition in the liver but not with type of amyloid protein. Double-staining of amyloid and vascular endothelium disclosed that amyloid deposition was more closely related to the inner part of the peribiliary vascular plexus and to the vascular plexus encircling the peribiliary glands than the lining biliary epithelium and peribiliary glandular acinar cells themselves. The exact pathogenesis of amyloid deposition in these anatomical components, however, remains unclear. Although our cases failed to show any overt clinical symptomatologies related to amyloid deposition in these biliary components, it seems conceivable that more massive amyloid deposition in these anatomical components could give rise to some clinical symptoms. (HEPATOLOGY 1990;12:743–746).

A survey of Japanese autopsy cases of primary biliary cirrhosis disclosed that hepatocellular carcinoma is apparently becoming a better recognized complication of the advanced stage of primary biliary cirrhosis. Six autopsy cases (five women and one man) of primary biliary cirrhosis associated with hepatocellular carcinoma were obtained from several Japanese institutions and examined. All cases were in an established cirrhotic stage of primary biliary cirrhosis. Hepatocellular carcinoma was incidentally found at autopsy in four cases and, in these, the carcinomas were small in size and number. The other two cases showed advanced hepatocellular carcinoma and one case showed extrahepatic metastasis. Histologically, all cases showed well-differentiated hepatocellular carcinomas. Fatty changes or bile plugs were frequently seen within the tumors. Mallory body clusters and focal deposition of copper-binding protein were consistently found in cirrhotic liver tissues and also in the carcinoma tissues of almost all cases. The presence of atypical adenomatous hyperplasia in the peripheries of some carcinomas suggested that hepatocellular carcinoma in primary biliary cirrhosis may evolve through multiple steps.

We describe herein the morphologies of three cases of ciliated hepatic cysts and compare them with those of normal bronchi and intrahepatic bile ducts. Grossly, the hepatic cysts were located in the subcapsular region. They were solitary, unilocular, and rather small (less than 4 cm in diameter). Histologically, the cyst wall consisted of four layers: pseudostratified ciliated columnar epithelia with mucous cells, subepithelial connective tissue, smooth-muscle bundles, and an outermost fibrous capsule. The epithelial cytoplasm contained neutral, carboxylated, and sulfated mucus. We noted moderate immunoreactivity to keratin, epithelial membrane antigen, carcinoembryonic antigen, DU-PAN-2 and secretory component; weak immunoreactivity to cytokeratin CAM 5.2, cytokeratin AE1 + 3, and carbohydrate antigen 19-9; and faint or negative immunoreactivity to IgA and IgM. Cilia were immunoreactive to actin and tubulin; smooth muscles were immunoreactive to actin and desmin. Ultrastructural observations revealed definite cilia arranged in a 9 + 2 pattern as well as mucous cells. These morphologic features of the hepatic cysts were similar to those of normal bronchi but different from those of normal bile ducts. Our findings suggest that ciliated hepatic cysts arise from the embryonic foregut and differentiated toward bronchial structures in the liver.

Cavernous vessels in the liver have been rarely described in the liver with hepatocellular carcinoma. We report the morphology and distribution of cavernous vessels in an autopsy liver of hepatocellular carcinoma, using a whole liver slice. In this case, antemortem angiography disclosed obstruction of portal veins at the hepatic hilus and portal trunk as well as many hepatopetal collaterals, mainly at the hepatic hilus. Tumor thrombi were diffusely distributed in the liver from the portal trunk to peripheral portal branches at autopsy. The cavernous vessels, which were positive for Factor VIII-related antigen, were also distributed throughout the liver from the hepatic hilus to the subcapsular regions, especially around the occluded portal veins by hepatocellular carcinoma, suggesting that these vessels were collaterals that developed as the result of portal obstruction. This study suggests that these vessels might be present from the hepatic hilus to the subcapsular regions, even if antemortem imaging techniques disclose collateral vessels only at the hepatic hilus.

To determine the prevalence and clinicopathologic features of cholangiocarcinoma (CC) associated with nonbiliary cirrhosis, we performed a clinicopathologic study. Among the 5,563 autopsies in our laboratories during the past 14 years, 85 (1.5%) were CCs. Four (4.7%) were associated with cirrhosis, due to hepatitis B virus in one case and cryptogenic (probably non-A non-B hepatitis virus) in the remaining three. Clinically, patients with CC and cirrhosis were characterized by male preponderance, lower age, past history of liver injury, and elevated values of zinc sulfate and thymol turbidity tests. Pathologically, all CCs with cirrhosis were basically adenocarcinoma; other histologic features included adenocarcinoma resembling bile ductules without mucin (one case), adenocarcinoma with broad areas of signet ring cell carcinoma (one case), adenocarcinoma with extensive sarcomatoid transformation (one case), and adenocarcinoma associated with hepatoliths (one case). Immunohistochemically, immunophenotypes of carcinoma cells of CC with cirrhosis were not different from those of CC without cirrhosis. Carcinoembryonic antigens, CA19-9, DU-PAN-2, and biliary-type cytokeratins were positive and alpha-fetoprotein was negative, suggesting that our CCs are not hepatocellular neoplasms but true CCs. It must be stressed that there are actual CCs arising in nonbiliary cirrhotic livers.

A rare autopsy case of small hepatocellular carcinoma presenting as an intrabiliary pedunculated mass is reported. The patient, 60-year-old man, presented with obstructive jaundice and died 1 month later. At autopsy, an intrabiliary pedunculated tumor measuring 3.5 x 2.0 x 2.0 cm was found in the hepatic, right hepatic, and right posterior segmental bile ducts. The intraductal tumor was attached to the segmental bile ductal wall, where a tumor measuring 2.0 x 0.9 cm was found in the parenchyma. The parenchymal tumor was continuous with the intrabiliary mass. Histologically, the tumor was a hepatocellular carcinoma showing acidophilic granular cytoplasm with occasional hyaline globules and was structurally arranged in a vague trabecular pattern. Immunohistochemically, tumor cells were positive for alpha-fetoprotein and alpha 1-antitrypsin, but was negative for keratin. We present a brief review of the literature of such icteric hepatocellular carcinomas.