Splenic angiosarcoma following chemotherapy for follicular lymphoma

A case of splenic angiosarcoma in a patient who had been treated for a follicular lymphoma with chemotherapy over a period of about nine years is reported. The etiologic agents for angiosarcomas at various sites, and their associations with other tumors, are reviewed. The most important of these associations are radiotherapy and lymphedema with tumors of the skin and soft tissues; and vinyl chloride, arsenic, and thorium dioxide with hepatic tumors. For splenic angiosarcomas, only isolated associations with breast carcinoma and thorium dioxide exposure have been reported. In the present case long-term combination chemotherapy seems to be the most likely etiologic association.     

Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti's syndrome) to Angiosarcomas.

Histologic examination of liver tissue (eight autopsy and 18 biopsy specimens) and five spleens from 20 workers with vinyl chloride polymerization showed hepatic angiosarcomas in 15. In addition, a peculiar pattern of progressive portal-tract, inconspicuous intralobular and conspicuous capsular fibrosis was observed in the five workers without angiosarconma, in all the seven patients with angiosarcoma from whom tumor-free portions of the liver were available, and in two tumor-free biopsies from patients subsequently found to have angiosarcoma. The fibrosis was accompanied by splenomegaly. Hypertrophy and hyperplasia of both hepatocytes and hepatic and splenic mesenchymal cells were also seen. The histologic similarity to chronic inorganic arsenical poisoning, in which angiosarcomas also occur, and to idiopathic portal hypertension (Banti's syndrome) suggests that the latter syndrome at times results from unknown toxic, possible environmental, chemicals.     

Precursor stage of hepatocellular neoplasm following long exposure to orally administered contraceptives

Hepatic neoplasms and peliosis are known to occur in women taking contraceptives orally. We observed hyperplasia of hepatocytes combined with hypertrophy of sinusoidal lining cells and sinusoidal dilatation with progression to peliosis in the liver of a patient who had been taking such contraceptives for 10 years. These changes resembled the precursor stage in the development of hepatic angiosarcoma induced by vinyl chloride, Thorotrast, and arsenic. In users of orally administered contraceptives these findings may precede the development of hepatocellular neoplasms.     

Thorium dioxide-related angiosarcoma of the liver. Pathomorphologic study of 29 autopsy cases

We describe the pathomorphologic features of 29 autopsy cases of thorium dioxide-related angiosarcoma (AGS) of the liver. The average (+/- SD) latent period after thorium dioxide injection was 36.2 +/- 5.2 years. Macroscopically, thorium dioxide-related AGS was divided into four types as follows: diffuse micronodular, multinodular, massive, and mixed multinodular and massive. Diffuse-micronodular and multinodular types were the most common. Histologically, thorium dioxide-related hepatic AGS was characterized by two cell types (spindle-shaped cells and polyhedral cells) and two structural patterns (sinusoidal and solid). There was no case composed of a solid pattern only. Immunohistochemically, factor VIII-related antigen was found to be positive in the endothelial cells of normal blood vessels and in the hyperplastic endothelial cells of the sinusoids, but negative in the tumor cells. Extramedullary hematopoiesis was found in both the tumorous and nontumorous areas in four cases. Erythrophagocytosis by the tumor cells was found in three cases. In the nontumorous area, varying degrees of sinusoidal dilatation with frequent hyperplastic changes of the sinusoidal lining cells were observed in all cases. These sinusoidal changes were frequently contiguous to AGS foci and were considered as a precursor change. In addition to the dominant sinusoidal changes, nodular hepatocytic hyperplasia was observed in two cases.     

Splenic angiosarcoma: a clinicopathologic and immunophenotypic study of 28 cases.

Primary angiosarcoma of the spleen is a rare neoplasm that has not been well characterized. We describe the clinical, morphologic, and immunophenotypic findings of 28 cases of primary splenic angiosarcoma, including one case that shares features of lymphangioma/lymphangiosarcoma. The patients included 16 men and 12 women, aged 29 to 85 years, with a mean of 59 years and median of 63 years. The majority of patients (75%) complained of abdominal pain, and 25% presented with splenic rupture. The most common physical finding was splenomegaly (71%). Seventeen of 21 patients were reported to have anemia. Macroscopic examination showed splenomegaly in 85% cases. Sectioning revealed discrete lesions in 88% of cases, ranging from well-circumscribed firm nodules to poorly delineated foci of necrosis and hemorrhage associated with cystic spaces. Microscopically, the tumors were heterogenous; however, all cases demonstrated at least a focal vasoformative component lined by atypical endothelial cells. Solid sarcomatous, papillary, and epithelioid growth patterns were observed. The solid sarcomatous component resembled fibrosarcoma in two cases and malignant fibroushistiocytoma in one case. Hemorrhage, necrosis, hemosiderin, extramedullary hematopoiesis, and intracytoplasmic hyaline globules were frequently identified. A panel of immunohistochemical studies revealed that the majority of tumors were immunoreactive for at least two markers of vascular differentiation (CD34, FVIIIRAg, VEGFR3, and CD31) and at least one marker of histiocytic differentiation (CD68 and/or lysozyme). Metastases developed in 100% of patients during the course of their disease. Twenty-six patients died of disease despite aggressive therapy, whereas only two patients are alive at last follow-up, one with disease at 8 years and the other without disease at 10 years. In conclusion, primary splenic angiosarcoma is an extremely aggressive neoplasm that is almost universally fatal. The majority of splenic angiosarcomas coexpress histiocytic and endothelial markers by immunohistochemical analysis, which suggest that some tumors may originate from splenic lining cells.     

Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers

The livers from five vinyl chloride workers are described. They show angioformative and hepatocellular growth disturbance in varying proportions: angiosarcoma in four cases, liver cell hyperplasia in all, hyperplastic nodules in three cases and hepatocellular carcinoma in two cases. In one case the transition between hyperplastic nodule and hepatocellular carcinoma is demonstrated. The relationship between these changes and vinyl chloride exposure is discussed, with evidence that they are causally related.     

Podoplanin is a useful diagnostic marker for epithelioid hemangioendothelioma of the liver.

Podoplanin, which is immunoreactive to D2-40 antibody, is reportedly expressed in lymphatic vessels in non-neoplastic tissues, and also in vascular and non-vascular tumors. However, its expression in non-neoplastic and neoplastic liver tissues has not been well documented. In this study, we examined podoplanin expression in specimens from 10 normal livers and 73 cases of liver tumors: hemangioma (16 cases), epithelioid hemangioendothelioma (9 cases), angiosarcoma (4 cases), angiomyolipoma (7 cases), hepatocellular carcinoma (11 cases), intrahepatic cholangiocarcinoma (11 cases), and metastatic liver cancer (15 cases). We compared levels of podoplanin and other endothelial markers (CD31, CD34, and factor VIII) in liver tumors. In the normal liver, podoplanin was expressed in lymphatic endothelium, nerve fibers, and mesothelium in the hepatic capsule, but not observed in any cells within hepatic lobules. Among liver tumors, podoplanin was specifically expressed in seven of nine cases (78%) of epithelioid hemangioendothelioma but not in other hepatic tumors. The expression of CD31, CD34, and factor VIII was observed in endothelial cells in all cases of hemangioma, epithelioid hemangioendothelioma, angiosarcoma, and angiomyolipoma with one exception, a case of epithelioid hemangioendothelioma which was without CD31 expression. Interestingly, the intensity of podoplanin expression was negatively correlated with the expression of CD34 and factor VIII. In conclusion, podoplanin would be useful as a diagnostic marker for epithelioid hemangioendothelioma in liver tumors.     

Angiosarcoma of the spleen clinically presenting as metastatic ovarian cancer. A case report and review of the literature

Primary angiosarcomas of the spleen are rare and almost always fatal. With no more than 200 cases reported in the literature worldwide, no specific risk factors are strongly associated with the disease. The mean age of patients at presentation is 59 years and the major clinical findings include abdominal pain, splenic rupture, and splenomegaly. Grossly, this neoplasm appears as hemorrhagic and/or cystic nodules, with a low-density signal seen on computed tomographic scans. Histologically, the tumor is characterized by neoplastic proliferation with diffuse or focal areas of a vasoformative component with cavernous and arborizing channels. The vascular spaces are lined by endothelial cells with variable degree of atypia. The differential diagnosis includes a variety of benign and malignant vascular proliferations (littoral cell angioma and Kaposi's sarcoma) as well as metastatic tumors. The worst prognostic factor is splenic rupture with early metastasis. The liver is the most common site. We report a case of the 43-year-old woman with a long-standing history of recurrent ovarian carcinoma treated with surgery and multiple courses of radiation therapy and chemotherapy who clinically appeared to have a metastatic ovarian cancer to the spleen and treated with partial resection of stomach and splenectomy. However, histopathologic examination of the specimen showed the tumor to be of a primary angiosarcoma. We believe that the lengthy exposure to radiation may have played a role in the histopathogenesis of this neoplasm in this patient.     

Development of hepatic angiosarcoma in man induced by vinyl chloride, thorotrast, and arsenic. Comparison with cases of unknown etiology.

Examples of human angiosarcoma following exposure to vinyl chloride, Thorotrast, or arsenic (medicinal and industrial) and cases, including children, of unknown etiology were studied to establish diagnostic criteria and to study their evolution. The uniform evolution suggests an environmental factor also in the cases of unknown etiology, which may be established by epidemiologic studies. A precursor stage is charaterized by areas of combined hyperlasia of hepatocytes and a variety of sinusoidal and perisinusoidal cells associated with excess of reticulin and with sinusoidal dialation. The diagnostically useful picture in silver impregnations indicated reticulum formation by the perisinusoidal cells, presumably the libocytes. The hepatocytic proliferation suggests a hepatocarcinogenic but usually not fully expressed potential. The mixed hyperplasia of the various sinusoidal cells proceeds to an overgrowth of angiosarcoma cells, presumably derived from endothelial cells. In early stages they are usually in contact with hepatocytes (intralobular growth). A trabecular arrangement results from loosening of the lobular plate arrangement by dilatation of sinusoids, leading to primary peliosis. With disappearance of the hepatocytes, various growth patterns develop, terminating in nodular, solid angiosarcoma composed of either spindle-shaped or polyhedral cells which undergo necrosis or hemorrhage (secondary peliosis). The interaction between hepatocytes and sinusoidal cells requires elucidation.     

Bone marrow metastasis of angiosarcoma

We report a rare finding of bone marrow metastasis from an angiosarcoma. The patient was a 36-year-old man who initially presented with a high-grade angiosarcoma of the spleen and was treated with splenectomy and chemotherapy. He developed leukoerythroblastic anemia three years after splenectomy. Bone marrow biopsy revealed extensive infiltrate by angiosarcoma with typical features of spindle tumor cells and anastomosing vascular channels. The immunohistochemistry showed tumor cells positive for the endothelial markers of CD31, CD34, and von Willebrand factor. Angiosarcomas are rare and aggressive tumors. Although metastases occur commonly, bone marrow findings have been rarely documented. We have found in the literature two other cases of bone marrow metastasis of angiosarcoma, and all these patients had a primary tumor of the spleen. It would seem that splenic angiosarcomas have a virtually unique propensity for infiltration in the bone marrow.     

Vascular neoplasms and non-neoplastic vascular lesions of the spleen

Vascular neoplasms are among the most common conditions affecting the spleen. The majority of these are idiopathic, benign in nature and asymptomatic and therefore treated with a conservative management. Only rare cases cause splenomegaly and/or chronic consumption coagulopathies, thus requiring splenectomy. Among these, the most common is splenic hemangioma, followed by littoral cell angioma and lymphangioma. Peliosis is a peculiar tumor-like non-neoplastic vascular lesion that diffusely affects the spleen and frequently presents with concomitant hepatic involvement. As a distinctive feature, peliosis can occur as a secondary manifestation of infections, malignancies and in individuals using certain drugs. On the opposite spectrum of clinical behavior lies splenic angiosarcoma, a vascular endothelial malignancy with aggressive presentation and poor prognosis. In some cases the endothelial nature of this neoplasm may not be evident on routine histologic examination and immunohistochemistry is used to disclose such phenotype. The term hemangioendothelioma is rarely used to describe borderline vascular neoplasms which appear more aggressive than conventional hemangiomas, but that do not entirely fulfill the diagnostic criteria for angiosarcoma. Some of these neoplasms coexpress endothelial and histiocytic markers and therefore have been proposed as the borderline counterpart of littoral cell angioma. The existence of hemangioendothelioma as a diagnostic entity per se is debated and this diagnosis should be rendered with caution. The current review aims at highlighting the main histologic features of vascular neoplasms and non-neoplastic vascular lesions of the spleen.     

Hepatocellular carcinoma arising from ectopic liver tissue in the spleen producing insulin-like growth factor II

We report a case of splenic tumor associated with severe hypoglycemia. The patient was a 69-year-old man with a large splenic tumor. He had suffered from relapsing hypoglycemic attacks and the lowest serum glucose level (4 mg/dl). He died 34 months after the onset of symptoms of left abdominal pain. Autopsy revealed large tumors in the spleen, 3 medium sized tumors in the lungs, and several small tumors in the liver. Microscopic studies of the splenic tumors revealed a hepatocellular carcinoma which showed a strongly positive reaction against anti-PIVKA-II and anti-“hepatocyte” antibodies. Several bile ductules thought to be heterotopic remnants of the liver tissues were found in the capsule of the spleen, adjoining the splenic tumor. It was suggested that the tumor originated from one of these ductules. Electron microscopic analysis showed numerous endocrine-like granules of every tumor cell, and 87-165 times stronger mRNA expression of insulin-like growth factor-II was measured in the tumor tissues when compared with normal liver tissue. Owing to these results, we believe that this is the first report of hepatocellular carcinoma that had developed from a liver tissue in the spleen.     

Ultrastructure of hepatic angiosarcoma in rats induced by vinyl chloride

The hepatic angiosarcoma studied was from a male Wistar rat having been exposed to vinyl chloride monomer (VCM) by the oral route for 120 weeks. Widened sinusoids lined by large electron-lucent, spindle-shaped tumor cells and membrane-bound nuclear-free structures were seen in the transitional zone between the tumor mass and the adjacent liver tissue. In areas merely consisting of tumor tissue the tumor cells had a more angular or irregular shape. The origin of the tumor cells is discussed in light of the characteristic differences between endothelial cells and Kupffer cells described in the literature. Although an endothelial origin of the tumor cells could not be established unequivocally, it was concluded that at present there is little reason to doubt such an origin.     

Splenic vascular tumors

Splenic vascular tumors are uncommon and are more typically encountered as benign incidental findings. By contrast, splenic angiosarcoma may present acutely and dramatically and typically pursues a very aggressive clinical course. Vascular tumors in the spleen may show conventional endothelial, specialized endothelial (sinusoidal/littoral cell) or lymphatic differentiation and there is morphologic overlap between some of the currently defined diagnostic categories, within which benign, intermediate, and malignant subsets are recognized. The greatest problem in trying to better define and analyze these tumors is the availability of only relatively small case numbers. This overview describes the diagnosis and differential diagnosis of splenic vascular tumors as presently understood.     

Thorotrast-induced hepatic angiosarcoma with 39 years latency. A pathologic and immunohistochemical study

An autopsy case of hepatic angiosarcoma which occurred in a 64-year-old man who had been examined by Thorotrast angiography 39 years previously, is reported together with the pathologic, radiologic and immunohistochemical findings. Thorotrast deposits were found in the spleen, bone marrow, right elbow joint and lymph nodes as well as the liver. The angiosarcoma was accompanied by markedly distended sinusoids with hypertrophic and hyperplastic endothelial cells, which were considered to be closely associated with angiosarcoma. The results of immunostaining indicated that only a very limited number of tumor cells and not many sinusoidal endothelial cells showed a positive staining reaction to anti-factor VIII-related antigen (anti-F VIII-RAG). On the other hand, endothelial cells lining blood vessels in the portal areas were distinctly positive for anti-F VIII-RAG. This would suggest that production of F VIII-RAG by tumor cells was dependent on the degree of cell dedifferentiation or on the heterogeneity of endothelial cells.     

Long Term Effects of Thorium Dioxide (Thorotrast) Administration on Human Liver Ultrastructual Localization of Thorium Dioxide in Human Liver by Analytical Electron Microscopy

The ultrastructual localization of thorium dioxide was examined in liver biopsy specimens from two patients injected more than 30 years before with thorotrast. An energy dispersive X-ray microanalysis spectrometer (Kevex 5100) was used to identify thorium in the liver tissue. By electron microscopy, most of the thorium particles were found in the cells of the reticuloendothelial system, such as macrophages of the portal triad and Kupffer cells in the hepatic sinusoid. Thorium dioxide particles were mainly located within the phagosomes, but larger aggregates existed in the cytoplasma with no visible limiting membrane. In addition, the deposition of thorium granules in a few hepatocytes was also confirmed by electron microscopy. This fact indicates that two main pathways of elimination are still functioning in the late period, but the hepatocytic pathway appears to be less effective than the reticuloendothelial system.     

Long term effects of thorium dioxide (thorotrast) administration on human liver. Ultrastructural localization of thorium dioxide in human liver by analytical electron microscopy

The ultrastructual localization of thorium dioxide was examined in liver biopsy specimens from two patients injected more than 30 years before with thorotrast. An energy dispersive X-ray microanalysis spectrometer (Kevex 5100) was used to identify thorium in the liver tissue. By electron microscopy, most of the thorium particles were found in the cells of the reticuloendothelial system, such as macrophages of the portal triad and Kupffer cells in the hepatic sinusoid. Thorium dioxide particles were mainly located within the phagosomes, but larger aggregates existed in the cytoplasma with no visible limiting membrane. In addition, the deposition of thorium granules in a few hepatocytes was also confirmed by electron microscopy. This fact indicates that two main pathways of elimination are still functioning in the late period, but the hepatocytic pathway appears to be less effective than the reticuloendothelial system.     

Angiosarcoma-like metastatic carcinoma of the liver

Two cases of metastatic carcinoma strikingly simulating angiosarcoma in the liver are described. The first case was a 53-year-old female with cystic liver tumors which were found 22 months after surgery for ureteral cancer. The second case was an 81-year-old female with multiple tumors in the liver and the pancreas, and a post-mortem examination was carried out. She had undergone surgery for skin cancer three years before. Both cases had an angiosarcoma-like appearance macroscopically and microscopically. Immunohistochemically, the tumor cells of both cases were negative for CD31, CD34, and Factor VIII-related antigen and positive for several types of cytokeratin, suggesting that they were not angiosarcomas but carcinomas. Angiosarcoma is the most common sarcoma arising in the liver. Thus, metastatic carcinoma, which resembles angiosarcoma, might be mistaken for angiosarcoma.     

Fine-needle aspiration diagnosis of angiosarcoma of the spleen: a case report and review of the literature

Primary angiosarcoma of the spleen is a very rare neoplasm with a poor prognosis. The definitive diagnosis is usually based on the histologic evaluation of the splenectomy specimen. We describe a case of angiosarcoma diagnosed by fine-needle aspiration cytology prior to splenectomy. A 69-year-old white woman presented with heterogeneous lesions in the spleen during a follow-up computed tomographic scan for a history of liposarcoma of the right buttock. A malignant endothelial neoplasm was diagnosed by fine-needle aspiration cytology using immunocytochemistry, and a splenectomy confirmed the presence of angiosarcoma. To our knowledge, this is the first well-documented and confirmed case of primary angiosarcoma of the spleen diagnosed by fine-needle aspiration cytology. This report emphasizes the value of fine-needle aspiration cytology as an important diagnostic tool in splenic neoplasms.     

THOROTRAST-INDUCED HEPATIC ANGIOSARCOMA WITH 39 YEARS LATENCY

An autopsy case of hepatic angiosarcoma which occurred in a 64-year-old man who had been examined by Thorotrast angiography 39 years previously, is reported together with the pathologic, radiologic and immunohistochemical findings. Thorotrast deposits were found in the spleen, bone marrow, right elbow joint and lymph nodes as well as the liver. The angiosarcoma was accompanied by markedly distended sinusoids with hypertrophic and hyperplastic endothelial cells, which were considered to be closely associated with angiosarcoma. The results of immunostaining indicated that only a very limited number of tumor cells and not many sinusoidal endothelial cells showed a positive staining reaction to anti-factor VHI-related antigen (anti-F VIII-RAG). On the other hand, endothelial cells lining blood vessels in the portal areas were distinctly positive for anti-F VIII-RAG. This would suggest that production of F VIII-RAG by tumor cells was dependent on the degree of cell dedifferentiation or on the heterogeneity of endothelial cells. ACTA PATHOL. JPN. 37: 1653-1660, 1987.