Syndrome of the sea-blue histiocyte--the first case report in Japan and review of the literature--.

A case of the syndrome of sea-blue histiocyte is presented in a 53-year-old Japanese woman, which is the first recorded case in Japan. The patient had hepatosplenomegaly, bleeding manifestations, mild thrombocytopenia, fatty metamorphosis and cirrhosis of the liver, as well as abnormal serum lipid profiles. Her parents were consanguineous and her maternal grandmother with hepatomegaly died of hepatic failure. Histologically, peculiar histiocytes containing numerous, intracytoplasmic sea-blue stained granules on May-Giemsa stain were demonstrated in biopsy materials of the bone marrow, lymph node and liver. The sea-blue granules in these histiocytes proved to have histochemical staining characteristics of lipogenic ceroid-like pigment. Ultrastructurally, these granules showed membrane-bound, pleomorphic inclusions of heterogeneous nature, including electron-dense amorphous or variegatedly osmiophilic, frequently laminated materials. Enzyme cytochemically, localization of acid phosphatase activity was demonstrated in and around the intracytoplasmic inclusions. With regard to the pathogenesis of the sea-blue histiocytes in this case, it may be suggested that the existence of the abnormality in lipid metabolism plays an important role in intralysosomal ceroidogenesis in these histiocytes.     

TWO DISTINCTIVE TYPES OF LIPID HISTIOCYTES APPEARING IN THE SPLEEN OF IDIOPATHIC THROMBOCYTOPENIC PURPURA — SEA-BLUE HISTIOCYTE AND FOAM CELL —

In 11 of 18 spleens surgically removed from patients with idiopathic thrombocytopenic purpura (ITP), the occurrence of sea-blue histiocytes or foam cells was observed. In a few cases, sea-blue histiocytes were found in the lymph nodes or bone marrow. Histochemically the sea-blue histiocytes were proved to contain ceroid or ceroid-like pigments in their cytoplasm. Ultrastructurally, numerous intracytoplasmic membrane-bound inclusions, mostly containing tightly laminated materials and intermingling electron-dense amorphous materials or osmiophilic lipid droplets, were present in these cells. In the foam cells, accumulation of excess amounts of phospholipids was histochemically demonstrated in frozen sections, often accompanied by deposition of cholesterol, particularly in advanced cases. Electron microscopically, vacuolar membrane-bound inclusions were found to predominate in their cytoplasm, most of which contained irregularly or loosely laminated materials. Transitonal cells between both types of cells were also found light -or electron microscopically and ultrastructural transition of sea-blue histiocytes to foam cells was traced. Enhanced phagocytosis of blood cells, including platelets, by sea-blue histiocytes, and gradual transition of the ingested blood cells to the inclusions were confirmed. ACTA PATH. JAP. 27 : 447–462, 1977.     

Two distinctive types of lipid histiocytes appearing in the spleen of idiopathic thrombocytopenic purpura. Sea-blue histiocyte and foam cell

In 11 of 18 spleens surgically removed from patients with idiopathic thrombocytopenic purpura (ITP), the occurrence of sea-blue histiocytes or foam cells were observed. In a few cases, sea-blue histiocytes were found in the lymph nodes or bone marrow. Histochemically the sea-blue histiocytes were proved to contain ceroid or ceroid-like pigments in their cytoplasm. Ultrastructurally numerous intracytoplasmic membrane-bound inclusions, mostly containing tightly laminated materials and intermingling electron-dense amorphous materials or osmiophilic lipid droplets, were present in these cells. In the foam cells, accumulation of excess amounts of phospholipids was histochemically demonstrated in frozen sections, often accompanied by deposition of cholesterol, particularly in advanced cases. Electron microscopically, vacuolar membrane-bound inclusions were found to predominate in their cytoplasm, most of which contained irregularly or loosely laminated materials. Transitional cells between both types of cells were also found light or electron microscopically and ultrastructural transition of sea-blue histiocytes to foam cells was traced. Enhanced phagocytosis of blood cells, including platelets, by sea-blue histiocytes, and gradual transition of the ingested blood cells to the inclusions were confirmed.     

Pathological, histochemical and ultrastructural studies on sea-blue histiocytes and Gaucher-like cells in acquired lipidosis occurring in leukemia

Smears of bone marrow aspiration from 82 patients with leukemia and major hematopoietic organs, such as bone marrow, spleen, liver and lymph nodes, obtained from 97 autopsy cases of the disease, were light-microscopically examined. As the results, occurrence of either sea-blue histiocytes or Gaucher-like cells, or of both, was observed in bone marrow smears of 23 patients and in the hematopoietic tissues of 44 out of the examined cases, particularly marked in those of chronic myelogenous leukemia. In acute myelogenous leukemia, these lipid storage cells were also confirmed though less in frequency or degree. Histochemically, the sea-blue histiocytes were substantiated to contain ceroid-like pigments in their cytoplasm uhile the lipid materials stored in the Gaucher-like cells were presumed to be glycolipids. Ultrastructural morphology of the inclusions in the sea-blue histiocytes uas almost consistent with that of ceroid previously reported, but showed more marked variegated and heterogeneous features. Intracytoplasmic inclusions of the Gaucher-like cells differed from those of Gaucher cells seen in Gaucher's disease and were dominated by fibrillar or linear deposits. Transitions from phagocytized leukemic cells to the inclusions characteristic of each type of the cells were traced.     

PATHOLOGICAL, HISTOCHEMICAL AND ULTRASTRUCTURAL STUDIES ON SEA-BLUE HISTIOCYTES AND GAUCHER-LIKE CELLS IN ACQUIRED LIPIDOSIS OCCURRING IN LEUKEMIA

Smears of bone marrow aspiration from 82 patients with leukemia and major hematopoietic organs, such as bone marrow, spleen, liver and lymph nodes, obtained from 97 autopsy cases of the disease, were light-microscopically examined. As the results, occurrence of either sea-blue histiocytes or Gaucher-like cells, or of both, was observed in bone marrow smears of 23 patients and in the hematopoietic tissues of 44 out of the examined cases, particularly marked in those of chronic myelogenous leukemia. In acute myelogenous leukemia, these lipid storage cells were also confirmed though less in frequency or degree. Histochemically, the sea-blue histiocytes were substantiated to contain ceroid-like pigments in their cytoplasm, while the lipid materials stored in the Gaucher-like cells were presumed to be glycolipids. Ultrastructural morphology of the inclusions in the sea-blue histiocytes was almost consistent with that of ceroid previously reported, but showed more marked variegated and heterogeneous features. Intracytoplasmic inclusions of the Gaucher-like cells differed from those of Gaucher cells seen in Gaucher's disease and were dominated by fibrillar or linear deposits. Transitions from phagocytized leukemic cells to the inclusions characteristic of each type of the cells were traced. ACTA PATH. JAP. 27: 775-797, 1977.     

CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD AND SEA-BLUE HISTIOCYTOSIS: A Pathologic Study of an Autopsy Case

A boy, who started remittent fever reaching 40°C at the age of 4 years and 9 months and gradually developed hepatosplenomegaly, lymphadenopathy, pancytopenia, and hypergammaglobulinemia, is reported. Aspirated bone marrows contained sea-blue histiocytes, and nitroblue tetrazolium test was abnormal. X-ray examination revealed a tumor mass in the right lung, uremia occurred terminally, and he died at the age of 10 years and 3 months. Surgical specimens, obtained by splenectomy, and necropsy revealed the presence of characteristic sea-blue cells in the bone marrow, spleen, lymph nodes, liver, and kidneys, and pseudotuberculous granulomas with or without aspergillus in the lungs, epicardium, liver, and lymph nodes. Histochemically, sea-blue granules accumulating in the cytoplasm of the histiocytes were proved to be a lipogenic ceroid-like pigment. Electron microscopically, these granules were comprised of round or ovoid, membrane-bound or free lipid droplets of various sizes and electron densities, occasionally containing poorly oriented, lamellar structures. The nature and possible pathogenesis of the sea-blue histiocytosis in this case are discussed briefly. ACTA PATHOL. JPN. 34 : 1385–1401, 1984.     

Cholesterol ester storage disease and sea-blue histiocytes

A case of cholesteryl ester storage disease (CESD) was found by liver biopsy in a 5-year-old boy. Hepatosplenomegaly, varying elevations of serum transaminases and hyperlipoproteinemia, type IIb, were detected clinically. The liver tissue was yellow. The cytoplasm of hepatocytes and Kupffer cells was foamy. In frozen sections these cells stained with dyes and histochemical methods for neutral lipids, unsaturated lipids, and cholesterol, but not with dyes for phospholipids and glycosaminoglycans. Under polarized light a large quantity of birefringent storage material was visible. We determined the lipid composition histochromatographically and found a very substantial increase in cholesteryl ester content and a moderate increase in triglycerides compared to control liver tissue. These findings are in agreement with our former case of CESD (1979). But in contrast to the liver tissue of the first patient there was more pronounced hepatic periportal and intralobular fibrosis in the second case. Remarkable amounts of ceroid storing histiocytes, so called "sea-blue histiocytes" were visible within the fibrous tissue. The granules of these cells stained with dyes for neutral lipids, phospholipids, glycosaminoglycans, and sea-blue with Giemsa in both frozen sections and paraffin-embedded liver tissue. They showed a yellow autofluorescence and were partly birefringent. Ceroid is believed to be the product of lipid peroxidation, binding to protein and polymerization. Therefore we suggest an additional deficiency of tissue antioxidants at the storage sites in such cases of CESD and this may potentiate liver fibrosis.     

CEROID-LIKE HISTIOCYTIC GRANULOMA OF GALL-BLADDER — A PREVIOUSLY UNDESCRIBED LESION —

In the present study, 13 cases of a peculiar gall-bladder granuloma characterized by marked proliferation of ceroid-fllled brown histiocytes were pathomorphologically, histochemically and ultrastructurally examined to define the pathologic features of such a lesion previously undescribed in the literature. The lesion grossly showed a granulomatous appearance of yellow brown to dark brown color developing in the wall of gall-bladder. Histologically, there was proliferation of histiocytes containing abundant brown pigment granules In their cytoplasm. The pigment granules proved to have staining characteristics closely resembling those of lipogenic ceroid-like pigment. Ultrastructurally, these granules showed membrane-bound, pleomorphic osmiophilic inclusions of heterogenous materials. With regard to the pathogenesis of this granuloma, it may be suggested that lipid components of bile juice, particularly unsaturated fatty acids and phospholipids, play an Important role as a source of ceroidogenesis In the proliferating histiocytes.     

Ceroid-like histiocytic granuloma of gall-bladder --a previously undescribed lesion--.

In the present study, 13 cases of a peculiar gall-bladder granuloma characterized by marked proliferation of ceroid-filled brown histiocytes were pathomorphologically, histochemically and ultrastructurally examined to define the pathologic features of such a lesion previously undescribed in the literature. The lesion grossly showed a granulomatous appearance of yellow brown to dark brown color developing in the wall of gall-bladder. Histologically, there was proliferation of histiocytes containing abundant brown pigment granules in their cytoplasm. The pigment granules proved to have staining characteristics closely resembling those of lipogenic ceroid-like pigment. Ultrastructurally, these granules showed membrane-bound, pleomorphic osmiophilic inclusions of heterogenous materials. With regard to the pathogenesis of this granuloma, it may be suggested that lipid components of bile juice, particularly unsaturated fatty acids and phospholipids, play an important role as a source of ceroidogenesis in the proliferating histiocytes.     

Ground-glass hepatocytes with Lafora body like inclusions—histochemical, immunohistochemical and electronmicroscopic characterization

We report two adult patients whose liver biopsy specimens revealed numerous ground-glass hepatocytes due to inclusions resembling Lafora bodies. The inclusions were large, intracytoplasmic, pale, eosinophilic and kidney-shaped and were periodic acid-Schiff positive and HBsAg negative. Immunoperoxidase studies showed that the inclusions were positive for cytokeratins and alpha 1-antitrypsin. In case 1, the inclusions were not membrane-bound and consisted of secondary lysosomes and degenerate organelles including rough and smooth endoplasmic reticulum. In case 2, electronmicroscopy showed the inclusions were not membrane-bound, but consisted of dense granules, fibrils and vacuoles, with appearances very similar to Lafora bodies. Neither patient had myoclonus or epilepsy. Electronmicroscopy is important in differentiating the type of Lafora body like inclusions found in liver biopsies.     

Diffuse histiocytosis of the spleen and idiopathic thrombocytopenic purpura (ITP): histochemical and ultrastructural studies

A case of ITP where the spleen was infiltrated diffusely and extensively by foamy macrophages is described. Among these macrophages were also clusters of cells with the morphologic and tinctorial characteristics of ceroid or "sea-blue" histiocytes. The ultrastructural characteristics of the foamy and ceroid histiocytes are described. Transition of ceroid cells into foamy macrophages is demonstrated, and intermediate forms were observed. It is postulated that the ceroid or sea-blue histiocytes are macrophages that contain platelets at an early stage of digestion, and when the phagocytosis of these platelets is completed, the macrophages become foamy. Therefore, it is suggested that the foamy cells and ceroid or sea-blue histiocytes seen in the spleen in cases of ITP are macrophages that have ingested and metabolized the abnormal platelets.     

Acquired lipidosis of marrow macrophages: birefringent blue crystals and Gaucher-like cells, sea-blue histiocytes, and grey-green crystals.

Three varieties of compound lipid inclusions occurring as a secondary phenomenon in marrow macrophages are detectable and distinguishable by Romanowsky staining, ultraviolet fluorescence, and polarised light. Birefringent blue crystals and Gaucher-like cells form one variety, sea-blue granules another, and grey-green crystals a third. All occur chiefly in myeloid leukaemias, either acute or chronic.     

Cholesterol ester storage disease in an adult presenting with sea-blue histiocytosis

An adult patient is described with hepatomegaly and sea-blue histiocytes in the bone marrow. A diagnosis of cholesterol ester storage disease was established following enzyme and lipid analyses on liver biopsy and cultured skin fibroblasts. Acid esterase activity was deficient (approx. 5% of controls) in liver and fibroblasts using [14C]-triolein or 4-methylumbelliferyl palmitate as substrates. Cholesterol ester levels were raised about 70-fold in liver, whereas triglyceride levels were only marginally raised. Marked accumulation of cholesterol esters was also demonstrated in cultured fibroblasts. Clinically, the patient responded favourably to phenobarbitone treatment. However, this was not reflected in liver acid esterase or lipid levels.     

TWO SIBLINGS, INCLUDING A FETUS, WITH TAY-SACHS DISEASE

This report consists of a morphological study on two siblings of Tay-Sachs disease. One is a girl of 3 years of age and the other is a 23-week fetus. In the first case, the nerve cells in the cerebral cortex showed histochemically abnormal accumulation of glycolipids and electron microscopically numerous membranous cytoplasmic bodies characteristic to gangliosidosis. In the fetal case, the nerve cells in the brain stem were well differentiated and here abnormal inclusions were found by histochemical study. The cortical neurons were immature in structure and inclusions were not demonstrated by histochemical study. In electron microscopic study, the cortical neurons also showed a small number of intracytoplasmic inclusions which contained electron dense granules and/or membranous structures. Causes of the differences in amount of abnormal lipid accumulation in the brain stem and the cerebral cortex were discussed.     

Malignant Mixed Exocrine-Endocrine Tumor of the Pancreas with Unusual Intracytoplasmic Inclusions

A case of malignant mixed exocrine-endocrine tumor of the pancreas is reported. Electron microscopy revealed abundant neurosecretory granules in most cells. Zymogen granules indicating acinar differentiation were seen in a few cells. Ductal features, including microvilli with prominent filamentous cores and intracytoplasmic mucin granules, were also noted in this lesion. Immunocytochemical stains were positive for serotonin and glucagon. Unusual intracytoplasmic fibrillary inclusions are described and their possible origin discussed.     

Ungewöhnliche „Fettzysten“ im Labrum acetabulare von Patienten mit Koxarthrose

Diagnostic pathological examination of surgical specimens from patients with hip joint osteoarthrosis occasionally exhibits as yet undescribed pseudocysts consisting of folded granular membranes in necrotic or chondroid tissues. When stained with Sudan red, the content of these cysts indicates the presence of lipid substances. The presence of S100 protein-positive cells with intracytoplasmic fat vacuoles as well as such cells in the walls indicate that they develop from fat inclusions occurring in the chondroid cells of the labrum. Two different wall structures were detected by electron microscopy. The first type exhibited small walls of a granular material similar to the endoplasmic reticulum that surrounds intracytoplasmic fat globules. The second type consisted of broad layers of very tiny granules indicating a more advanced stage of the development of these cysts. The reason for the occurrence of these "chondrocytogenic lipid cysts" remains unknown-it may be assumed that they are due to mechanical labrum destruction that occurs in osteoarthrosis.     

Case Report: Meningioma with Granulofilamentous Inclusions

The authors report a case of intracranial meningioma with granulofilamentous inclusions. A 50-year-old man had right trigeminal neuralgia due to trigeminal nerve compression by a petroclival tumor and received tumor resection. Microscopically, tumor cells containing eccentric nuclei and intracytoplasmic hyaline inclusions were arranged in sheets and whorls. The inclusions were negative for periodic acid-Schiff reaction. No histological anaplasia was seen. Immunohistochemistry showed epithelial membrane antigen reactivity on the cytoplasmic membrane. Immunoreactivity for vimentin was recognized in cytoplasm adjacent to inclusions. However, confocal laser microscopic study revealed immunoreactivity for vimentin even inside some inclusions. Ultrastructurally, interdigitation of cytoplasmic processes and desmosomes connecting adjacent cells were noted. Inclusions were composed of numerous fine osmiophilic granules attached by intermediates filaments. These findings were consistent with a meningioma with the granulofilamentous inclusions described earlier. The findings demonstrated by confocal laser microscopy and electron microscopy suggest that these granular materials may be the metabolic products of vimentin filaments.     

Meningioma with granulofilamentous inclusions

The authors report a case of intracranial meningioma with granulofilamentous inclusions. A 50-year-old man had right trigeminal neuralgia due to trigeminal nerve compression by a petroclival tumor and received tumor resection. Microscopically, tumor cells containing eccentric nuclei and intracytoplasmic hyaline inclusions were arranged in sheets and whorls. The inclusions were negative for periodic acid-Schiff reaction. No histological anaplasia was seen. Immunohistochemistry showed epithelial membrane antigen reactivity on the cytoplasmic membrane. Immunoreactivity for vimentin was recognized in cytoplasm adjacent to inclusions. However, confocal laser microscopic study revealed immunoreactivity for vimentin even inside some inclusions. Ultrastructurally, interdigitation of cytoplasmic processes and desmosomes connecting adjacent cells were noted. Inclusions were composed of numerous fine osmiophilic granules attached by intermediates filaments. These findings were consistent with a meningioma with the granulofilamentous inclusions described earlier. The findings demonstrated by confocal laser microscopy and electron microscopy suggest that these granular materials may be the metabolic products of vimentin filaments.     

Cytological features of mammary analogue secretory carcinoma of salivary gland: Fine‐needle aspiration of seven cases

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6‐NTRK3 gene fusion. There have been few case reports on the cytopathologic features of MASC to date. We examined the clinicopathological and cytological features of seven cases of MASC defined by RT‐PCR analysis of the ETV6‐NTRK3 fusion gene. The cases occurred in three men and four women aged between 39 and 68 years, with a mean of 51.6 years. In five of these seven cases, the tumor involved the parotid gland. Histologically, all cases displayed predominantly microcystic patterns, often a mixture of follicular and papillary‐cystic structures. All tumors were immunoreactive for mammaglobin, S‐100 protein, and vimentin. Available fine‐needle aspiration cytology smears were cellular and exhibited many loosely cohesive syncytial clusters or isolated cells. Many histiocytes, some of which contained hemosiderin pigments, and variously shaped mucinous material were evident in the background or within the epithelial clusters. The majority of cases showed small to medium‐sized follicular structures with secreted materials. Papillary clusters were occasionally found. Tumor cells exhibited small to medium‐sized round to oval nuclei, with a smooth contour and indistinct or small nucleoli, and vacuolated cytoplasm. No tumor cells had obvious intracytoplasmic zymogen granules. It appeared that clusters of small to medium‐sized follicular and papillary configurations consisting of bland tumor cells with vacuolated cytoplasm, but lack of intracytoplasmic zymogen granules, in a mucinous or hemosiderin‐laden histiocyte‐rich background, were a characteristic cytological feature highly suggestive of MASC. Diagn. Cytopathol. 2014;42:846–855. © 2014 Wiley Periodicals, Inc.     

Endoplasmic storage disease of liver: characterization of intracytoplasmic hyaline inclusions

Two cases of endoplasmic storage disease of liver are described. The liver tissue in each case showed numerous intracytoplasmic hyaline inclusions of varying sizes with formation of ground-glass hepatocytes. These inclusions were pale eosinophilic in hematoxylin & eosin stained sections, and were periodic acid-Schiff and HBsAg negative. Immunoperoxidase studies revealed strong positivity for fibrinogen and complement components C3 and C4 in case 1 and exclusive positivity for fibrinogen in case 2. On electron microscopy, the inclusions appeared as granular or fibrillar material within dilated cisternae of rough endoplasmic reticulum.