Ocular PEComas are frequently melanotic and TFE3-translocated: report of two cases including the first description of PRCC-TFE3 fusion in PEComa.

Ocular perivascular epithelioid cell tumor (PEComa) is exceedingly rare. We reported two examples involving the choroid and subconjunctival tissue, respectively, in patients aged 17 and 20 years. Both tumors comprised packets and sheets of large polygonal cells with moderately pleomorphic nuclei and prominent nucleoli, traversed by delicate fibrovascular septa. Melanin pigmentation was present in one case. The tumors showed HMB45 and TFE3 immunoreactivity. TFE3 gene translocation was confirmed by FISH break-apart probes. RNA seq revealed PRCC-TFE3 and NONO-TFE3 fusions, with the former representing the first description of PRCC-TFE3 in PEComa. Critical reappraisal of the reported cases showed that ocular PEComa frequently affected young patents with melanin pigmentation, frequent TFE3 protein expression, and/or TFE3 gene translocation. No recurrence or metastasis was reported after complete excision despite the presence of cytologic atypia.

cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).

Expression of MUC1 and MUC2 and carbohydrate antigen Tn change during malignant transformation of biliary papillomatosis.

AIM: Biliary papillomatosis is characterized by papillary proliferations of biliary lining cells without invasion or metastasis. The neoplastic character and biological behaviour of this disease remain still speculative. These issues were examined in this study. METHODS AND RESULTS: Mucin core protein MUC1, MUC2, MUC3, MUC5AC and carbohydrate antigens (T, Tn and sialosyl Tn) were immunohistochemically examined, using 11 lesions of biliary papillomatosis from seven patients, and five lesions of biliary papillomatosis with foci of carcinoma from four patients. Five cases of papillary intrahepatic cholangiocarcinoma and 12 histologically normal livers were used as a control. Patients with biliary papillomatosis alone or with carcinoma were middle-aged or elderly (five men and six women). Microscopically, biliary papillomatosis showed a villous, papillo-tubular, papillary, or papillo-villous pattern with a thin fibrovascular core. Cytologically, they were classifiable into biliary epithelial or pyloric gland-like type. The former was frequent in the cases associated with carcinoma. Expression of MUC1, Tn antigen and sialosyl Tn antigen was frequent and marked in biliary papillomatosis alone and with carcinoma and also intrahepatic papillary carcinoma. In addition, marked expression of MUC1 and Tn antigen were rather frequent in biliary papillomatosis with carcinoma and intrahepatic biliary papillary carcinoma compared with biliary papillomatosis. MUC2 was rather frequent and marked in biliary papillomatosis alone compared to other two disease groups. Focal expression of MUC5AC and MUC2 was rather frequent and infrequent irrespective of disease group, respectively. Focal expression of T antigen was frequent in papillary ICC. CONCLUSION: Biliary papillomatosis could undergo overt malignant transformation along with altered phenotypic expression of MUC proteins and mucin carbohydrate antigens.

The C282Y mutation of the HFE gene is not found in Chinese haemochromatotic patients: multicentre retrospective study.

OBJECTIVE: To detect two novel mutations (C282Y and H63D) of the HFE gene in Chinese patients with hepatic iron overload. DESIGN: Multicentre retrospective study. SETTING: Four public hospitals, Hong Kong. PARTICIPANTS: Fifty Chinese patients who presented from January 1987 through December 1999 with hepatic iron overload from various causes. MAIN OUTCOME MEASURES: The DNA from liver biopsy samples was tested for HFE mutations by restriction fragment length polymorphism analysis. RESULTS: The sample DNA quality was unsatisfactory for analysis of the C282Y mutation in one case and the H63D mutation in nine cases. The C282Y mutation was not detected in any of the 49 satisfactory samples. Three of the 41 samples were heterozygous for the H63D mutation and only one was homozygous, giving an allele frequency of 6.1%. Of the three H63D-heterozygotes, one had beta-thalassaemia major, one had beta-thalassaemia minor, and one had hereditary spherocytosis. None of the 12 patients who were presumed to have primary haemochromatosis were positive for either mutation. CONCLUSIONS: The classical form of human leukocyte antigen-linked hereditary haemochromatosis appears to be absent form this locality. The H63D mutation is found in a minority (9.8%) of the patients, in whom it may act synergistically with an erythropoietic factor.

Fine-needle aspiration cytologic diagnosis of intrahepatic biliary papillomatosis (intraductal papillary tumor): report of three cases and comparative study with cholangiocarcinoma.

Biliary papillomatosis is a rare tumor of the intrahepatic and extrahepatic biliary tree, and its FNA findings have not been reported. The cytologic features of 3 cases of intrahepatic biliary papillomatosis were studied and compared with 5 cases of cholangiocarcinoma. The distinctive features include: 1) hypercellular smear, 2) very broad and often double-cell layered sheets of ductal columnar epithelium, 3) papillary configuration, 4) preserved honeycomb pattern with even nuclear spacing, and 5) dysplastic but not frankly malignant nuclear features. The constellation of these features is highly characteristic of biliary papillomatosis and helpful in distinguishing it from cholangiocarcinoma and other differential diagnoses. A firm preoperative diagnosis can thus be achieved, allowing better planning in management of this borderline malignant tumor.

Absence of Epstein-Barr virus (EBV) in intrahepatic cholangiocarcinoma confirmed by lack of EBV-coded nuclear RNA and latent membrane protein-1.

AIMS: Studies are disclosing that Epstein-Barr virus (EBV) is involved in the aetiology of various neoplasms including undifferentiated carcinomas of the aerodigestive tract. The aetiology of intrahepatic cholangiocarcinoma (ICC), a malignant neoplasm arising from intrahepatic biliary epithelia, has yet to be fully evaluated. To date, two cases of EBV-related ICC have been reported, and they presented foci of lymphoepitheliomatous undifferentiated carcinoma components. METHODS AND RESULTS: To determine whether EBV is commonly involved in the developments of ICC, we performed in-situ hybridization and immunohistochemistry for EBV in 215 cases of ICC in Japan, using a probe against EBV-coded nuclear RNA (EBER) and a specific antibody against latent membrane protein-1 (LMP-1), respectively. We did not detect EBV-infected carcinoma cells in any of the ICC cases examined. No lymphoepitheliomatous undifferentiated carcinoma components were found either. CONCLUSION: The results suggest that EBV infection is unlikely to be involved in the pathogenesis of ICC.

Hepatic angiomyolipoma: a clinicopathologic study of 30 cases and delineation of unusual morphologic variants.

Hepatic angiomyolipoma (AML) is frequently misdiagnosed. HMB-45 is a promising immunomarker for this tumor that leads to recognition of some AMLs with unusual morphology. The purpose of this collaborative study is to better define the morphologic variations of AML. Thirty AMLs were examined, including four biopsy specimens and two fine-needle aspirates. The diagnosis was confirmed by the presence of HMB-45-positive myoid cells. Almost half the cases were originally misdiagnosed as carcinomas or sarcomas. There was marked female predominance (25:5), and the mean age was 48.7 years (range 29-68). Three patients (10%) had evidence of tuberous sclerosis and all had renal AML. According to the line of differentiation and predominance of tissue components, the tumors was subcategorized into mixed, lipomatous (> or = 70% fat), myomatous (< or = 10% fat), and angiomatous type. The mixed type was the most common (11 resected cases), comprising sheets of epithelioid muscle cells admixed with islands of adipocytes, abnormal vessels, and frequently, hematopoietic cells. Six tumors (including three from biopsy specimens) were heavily fatty and showed predominantly adipocytes with epithelioid and short spindle myoid cells webbed between fat cells. Of 10 myomatous AMLs, five tumors showed a pure sinusoidal trabecular pattern and comprised mainly epithelioid cells. Typically, mature adipocytes were absent or scanty, but fat was seen as fine droplets within cytoplasm or as occasional large globules in sinusoids. Pelioid and inflammatory pseudotumor-like patterns were identified focally. Regarding cellular features of the myoid cells, most of the epithelioid cells were either eosinophilic or clear with spiderweb cell morphology. Three AMLs showed an almost purely oncocytic appearance with scanty fat. Large pleomorphic epithelioid cells existed as small foci. Spindle cells arranged in long fascicles were uncommon. D-PAS-positive globules were common around pelioid areas. Brown pigments with staining characteristics of hemosiderin and/or melanin were noted. In conclusion, we propose HMB-45-positive myoid cells as the defining criterion of hepatic AML, which is a tumor capable of dual myomatous and lipomatous differentiation and melanogenesis. Because of its protean morphologic appearance, recognition of the various variant patterns and cell types is important for a correct diagnosis, assisted by immunohistochemical confirmation with HMB-45. Trabecular and oncocytic cell tumors appear to stand out as distinctive subtypes.

Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma.

AIMS: To examine the usefulness of Hep Par 1 together with selected antibodies in the separation of hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC), combined tumours (HCC-CC) and metastatic carcinoma. METHODS AND RESULTS: Antibodies to Hep Par 1, CK19, CK20 and factor XIIIa were applied to 32 HCCs, 27 CCs, five HCC-CCs and 19 metastatic carcinomas from a variety of sites. Hep Par 1 produced distinctive granular staining of all benign hepatocytes and stained 30 HCCs in a heterogeneous manner, irrespective of the degree of differentiation. While labelling all cases of combined HCC-CC, the antibody also stained the mucus-secreting cells of four cases of pure CC. Anti-CK19 produced distinctive staining of bile ducts and CC but also decorated four HCCs and 10 metastatic tumours. Factor XIIIa was not found in normal, reactive or neoplastic hepatocytes. CK20 was found in some cases of HCC and CC and in all cases of metastatic carcinomas from the colon. CONCLUSIONS: Hep Par 1 was a sensitive marker of hepatocytes but its variable staining in HCC may produce false negative results in small biopsies and it was occasionally found in CC. The highest diagnostic yield was obtained when anti-Hep Par 1, CK19 and CK20 were used in a panel. Factor XIIIa staining has no role in the diagnosis of liver cancers.

Cystic dysplasia of the testis associated with ipsilateral renal agenesis and high anorectal anomalies.

Scrotal masses in young children are often caused by hydrocoeles and hernias. When they arise from the testis, testicular tumor or orchitis, although rare in this age group, is often the diagnosis. Cystic dysplasia of the testis, a rare condition frequently associated with renal anomalies, is another possible differential diagnosis. Herein the authors describe a case in which cystic dysplasia of the testis is associated with ipsilateral renal agenesis as well as high anorectal anomalies.

Intravascular lymphomatosis: a case presenting with encephalomyelitis and reactive haemophagocytic syndrome diagnosed by renal biopsy.

AIMS: To report an unusual instance of intravascular lymphomatosis presented with encephalomyelitis and reactive haemophagocytic syndrome. There was no skin involvement. The diagnosis was made on a renal biopsy. METHODS AND RESULTS: The marrow smear was air dried and stained with Diff-Quik. The tissue sections were stained with haematoxylin and eosin. Masson trichrome, periodic acid-Schiff's reagent, Elastic van Gieson's stain, modified hexamine-silver technique and Martius scarlet blue. Immunohistochemistry for CD45, CD20, CD45RO, Factor VIII related antigen, CD31 and CD34 was performed on paraffin-processed tissue. The marrow smear showed active haemophagocytosis in the histiocytes. The renal biopsy showed intravascular lymphomatosis with tumour cells positive for CD45 and CD20. CONCLUSION: The possibility of intravascular lymphomatosis should be considered in patients with reactive haemophagocytic syndrome where the underlying cause cannot be found after thorough investigation.

Fine-needle aspiration cytologic diagnosis of lymphoepithelioma-like carcinoma of the lung. Report of two cases with immunohistochemical study.

Lymphoepithelioma is a term used to describe an undifferentiated carcinoma with prominent lymphoid infiltration in the nasopharynx. Recently, tumors with similar histology, designated as lymphoepithelioma-like carcinomas, have been described in other sites including the lung. The authors report two cases of pulmonary lymphoepithelioma-like carcinoma that were correctly diagnosed by fine-needle aspiration cytology. The distinctive cytologic features consist of cohesive sheets and clusters of spindle tumor cells, which possess moderately pleomorphic vesicular nuclei and prominent nucleoli that are intimately intermixed with numerous small lymphocytes. Immunohistochemical study, performed on the cell block preparation, revealed strong positive staining of these tumor cells for epithelial markers. In both cases, the cytologic diagnosis were confirmed subsequently by histologic examination of the resected surgical specimens. Cytologically, the differential diagnoses include granulomatous inflammatory diseases (especially tuberculosis), malignant lymphoma, melanoma, and metastatic sarcoma. The characteristic cytology of the tumor cells, together with their pattern of immunohistochemical staining, are helpful to distinguish lymphoepithelioma-like carcinoma from the differential diagnoses. In these cases, careful examination of the nasopharynx, preferably with multiple random mucosal biopsies, is essential for the exclusion of nasopharyngeal undifferentiated carcinoma because of the obvious differences in treatment and prognosis.

Cytologic features of Kimura's disease in fine-needle aspirates. A study of eight cases.

Kimura's disease is a chronic inflammatory disorder of unknown etiology, presenting usually as painless subcutaneous swellings in the head and neck region or in the salivary glands. The cytologic features of fine-needle aspirates of eight cases of Kimura's disease were studied with reference to the histologic appearance of the subsequent surgical specimens. In the cytologic smears, the prominent feature was the presence of significant numbers of eosinophils in a background of lymphoid cells. Fragments of collagenous tissue and Warthin-Finkeldey polykaryocytes occasionally were seen. In the cell block, vascular proliferation and fibrosis were useful features, providing further support to the diagnosis. The constellation of these features is characteristic of Kimura's disease and should suggest this diagnosis in the appropriate clinical setting. For initial diagnosis, excisional biopsy is important for the exclusion of malignant lymphoma, histiocytosis X, angiolymphoid hyperplasia with eosinophilia and other reactive lymphadenopathies. Nonetheless, fine-needle aspiration cytology may be valuable in the diagnosis of recurrent lesions of Kimura's disease and may spare the patient from repeated biopsies.

Hepatocellular carcinoma metastasizing to the brain and orbit: report of three cases.

Hepatocellular carcinoma rarely metastasizes to the brain or orbit. We report 3 clinically manifest examples, one of which occurred in a 13-yr-old boy. In 2 cases the intracranial metastasis was the initial presenting lesion. The 2 cases of brain metastasis both presented with intracerebral hemorrhage. Light microscopic examination of these tumors revealed a trabecular hepatocellular carcinoma of Edmondson grade II with focal hemorrhage and necrosis. Their immunohistochemical profile was identical to that described for primary hepatocellular carcinoma. The differential diagnosis from other intracranial metastatic tumors is discussed.

Fine needle aspiration diagnosis of angiomyolipoma of the liver using a cell block with immunohistochemical study. A case report.

Fine needle aspiration diagnosis of hepatic angiomyolipoma has been reported rarely. Below we report one such case diagnosed by examination of a cell block. The presence of epithelioid smooth muscle cells, mature adipocytes, thick-walled vessels and extramedullary hematopoiesis established the diagnosis. It was further substantiated by positive staining of the epithelioid cells for muscle-specific actin (HHF-35). The epithelioid cells were also immunoreactive with a melanocytic marker, HMB-45, but not with desmin, vimentin, cytokeratin or S-100 protein. HMB-45 might prove to be a sensitive marker for the epithelioid smooth muscle component of the tumor. The advantage of the routine use of a cell block in fine needle aspiration is emphasized.