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A 69-year-old man presented to his physician with severe left upper quadrant pain, fevers and night sweats. Imaging revealed a markedly enlarged spleen, without any well-defined mass lesions. A splenectomy was performed and a 1,200 gram spleen was received. The capsular surface was smooth. Sectioning revealed a red and tan heterogeneous cut surface without a well-defined mass lesion.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 9 and is an angiosarcoma.
Criteria for Diagnosis and Comments:
At low power, there is complete effacement of the normal splenic architecture. Prominent small and larger caliber blood vessels are noted, some of which are poorly formed. At higher power, there is a mixture of spindled and epithelioid cells that line these vascular spaces that show high nuclear to cytoplasmic ratios, eosinophilic cytoplasm, prominent nucleoli and significant nuclear atypia. Many of the neoplastic cells bulge into the lumina of the vascular spaces which creates a ‘hobnail’ pattern. Numerous mitotic figures, including many atypical mitoses, are present. Neoplastic cells were immunoreactive with antibodies directed against CD31, CD34, and factor VIII related antigen. They were negative for numerous cytokeratins, smooth muscle actin, desmin, and S-100 protein along with CD68 and CD21. The morphologic and immunophenotypic findings are diagnostic of angiosarcoma.
Primary splenic angiosarcoma is a rare and clinically aggressive lesion. It was first described by Langhans in 1879. A majority of these tumors arise in adults in their 6th-7th decades of life with no sex predilection. Unlike hepatic angiosarcoma, which is associated with exposure to arsenic, vinyl chloride, or thorium oxide (Thorotrast), splenic angiosarcoma has no such exposure associations. Clinically, primary splenic angiosarcomas are associated with significant symptoms, including left upper quadrant pain, fatigue, fever, weight loss, and in some cases, spontaneous splenic rupture. Metastasis is an early and common finding. Favored sites for metastatic deposits include liver, lung, lymph node, and bone.
Grossly, the spleen is markedly enlarged, with mean weights in two large series of 1,073 grams and 1,116 grams. Most frequently, the lesions are multinodular and hemorrhagic. The nodules may be discrete, and in some cases, poorly delineated. Histologically, the tumor can be heterogeneous in its distribution, thus making thorough sampling paramount. Histologically, splenic angiosarcomas show a vasoformative growth pattern, with an intricate network of variably sized slit- or capillary-like vascular spaces. Areas with more cavernous spaces frequently merge with this anastomosing network. The key factor in distinguishing angiosarcoma from other splenic vascular lesions is cytologic atypia of the neoplastic endothelial cells. In general, the nuclear atypia is conspicuous, which makes the diagnosis of malignancy straightforward. Extracellular or intracellular periodic-Schiff positive hyaline globules can sometimes be seen, along with a solid, sheet-like growth pattern which sometimes mimics carcinoma.
Most cases are positive by immunohistochemistry for two or more vascular markers including CD31, CD34, and factor VIII related antigen. CD31 is the most sensitive and specific marker, and is useful in poorly differentiated tumors. Occasionally, focal reactivity can be seen for keratins and S-100 protein.
As noted in the master list, the differential diagnosis includes:
- Littoral cell angiosarcoma: These tumors are regarded as the malignant counterpart of the littoral cell angioma. The key to diagnosis is the presence of malignant nuclear cytology. Immunohistochemistry demonstrates a littoral cell origin (positive for factor VIII related antigen, CD31, CD68, cathepsin D, and CD21, and negative for CD34 and CD8).
- Hemangioma, lymphangioma, littoral cell angioma: Benign splenic vascular tumors are distinguished from angiosarcoma based on nuclear cytology and infiltrative growth pattern. Immunohistochemistry is of little value, since all of these lesions will stain with one or more of the vascular markers.
- Metastases: Metastatic carcinoma, along with lymphoma (Hodgkin and non-Hodgkin), melanoma, and sarcoma, can present as one or multiple splenic lesions. Clinical history and the appropriate immunohistochemical stains (including cytokeratins, S-100, CD45, and CD30) can resolve the question. In poorly differentiated tumors, the finding of poorly formed vascular spaces, along with malignant appearing cells lining vascular spaces, favor a diagnosis of splenic angiosarcoma. One must be cautious in interpreting immunohistochemical stains, since angiosarcomas can show focal reactivity with keratin and S-100 protein.