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A Kaposi-like variant of splenic angiosarcoma lacking association with human herpesvirus 8. (Case Report).

Splenic angiosarcomas are the most common malignant primary nonlymphoid tumors, although their occurrence is rare. (1,2) Microscopic findings are highly variable, both within tumors and between cases. While a spongiform or honeycomb-like proliferation of endothelial cells is the most common finding, Kaposi sarcoma--like proliferation is infrequent. (3,4) Recently, human herpesvirus 8 (HHV-8) was detected in a case of acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma, (5) and now it is considered to be present in all Kaposi sarcomas, regardless of any association with AIDS. (6) Furthermore, HHV-8 DNA detection using polymerase chain reaction (PCR) or in situ hybridization is now considered to be a critical test for the diagnosis of Kaposi sarcoma. (6,7) We encountered a case of splenic angiosarcoma showing Kaposi-like spindle cell proliferation. We report here the examination of HHV-8 DNA by PCR analysis and discuss differences between splenic angiosarcomas and Kaposi sarcomas.


A 28-year-old housewife without any particular past individual or familial medical history experienced persistent left flank pain. Abdominal ultrasonography and computed tomography revealed splenomegaly (Figure 1, a), and she was admitted to Kitasato University Hospital, Sagamihara, Japan. Laboratory examination revealed slight anemia (red blood cell count, 3.58 x [10.sup.12]/L; hemoglobin, 107 g/L; hematocrit, 0.32), and because a malignant lymphoma was initially suspected, splenectomy was performed.


The resected spleen weighed 530 g and showed diffuse dark-reddish enlargement (Figure 1, b) without nodular lesions. Histologically, the splenic normal structure was entirely replaced by diffuse proliferation of spindle cells arranged in a fascicular pattern with erythrocytes containing slit formations (Figure 1, c). Occasionally, markedly dilated spongelike spaces filled with erythrocytes were seen (Figure 1, d). Nuclear pleomorphism was minimal. Several calcium deposits were found within the remaining splenic trabeculae. The accessory spleen, measuring 1.5 cm in diameter, also exhibited the spindle cell proliferation.

Although Kaposi sarcoma was suspected from the pathologic findings, serologic examination revealed no human immunodeficiency virus infection. After 13 months, follow-up computed tomography and gallium scintigraphy revealed focal hepatic and bone marrow involvement without clinical symptoms except for slight anemia. Liver and bone marrow biopsies were performed. In the liver, spindle cells showed focal nodular proliferation, especially along Gleason sheaths. Occasionally, the spindle cells invaded the sinusoids, replacing the normal endothelium (Figure 2, a). In the bone marrow, the spindle cells were located in the myxoid mesenchyma and were separated from each other (Figure 2, b). She was then treated with adriamycin. Although the metastatic lesions had not completely disappeared, the patient was still alive 21 months after the first operation.




Tissue samples from the spleen were fixed in buffered formalin and embedded in paraffin. To investigate the tumor cell character, immunohistochemical staining of tissue sections was performed using the labeled streptavidin-biotin method (commercial kit, Dakopatts, Glostrup, Denmark), with anticytokeratin (monoclonal, clone CAM 5.2, Becton Dickinson, San Jose, Calif), antivimentin (monoclonal, clone v9, Dako), anti-factor VIII--associated antigen (polyclonal, Dako), anti-CD34 (monoclonal, clone QBEND 10, Immunotech, Marseille, France), anti-CD68 (monoclonal, clone PG-M1, Dako), anti-ct-smooth muscle actin (monoclonal, clone 1A4, Dako), antilysozyme (polyclonal, Dako), and anti-Ki-67 (polyclonal, Dako) primary antibodies. To compare the cell proliferation activity of the tumor with data for vascular tumors, 11 cases of cavernous hemangioma and 15 cases of hemangiosarcoma of scalp were retrieved from the pathology files of Kitasato University Hospital, and immunohistochemistry for Ki-67 antigen was performed. At least 1000 tumor cells were examined for each case, and the percentage of positively stained nuclei was calculated as the labeling index.

Proliferating spindle cells and lining cells of the cavernous spaces showed immunoreactivity for factor VIII-associated antigen and CD34 (Figure 3, a and b). They were negative for cytokeratin, CD68, a-smooth muscle actin (Figure 3, c), and lysozyme. The Ki-67 labeling index for the present case was 5.4%, while the labeling indices of the cavernous hemangiomas and the hemangiosarcomas of the scalp were 1.3% [+ or -] 1.5% (mean [+ or -] standard deviation) and 20.8% [+ or -] 10.9%, respectively.


Electron Microscopy

Electron microscopy was performed with fresh tissues fixed in glutaraldehyde and postfixed in osmium tetroxide. Ultrathin sections were stained with uranyl acetate and lead citrate and examined with a transmission electron microscope (H-600, Hitachi, Tokyo, Japan).

The proliferating spindle cells were observed to form primitive junctional complexes with neighboring cells. Pinocytotic vesicles were found beneath the plasma membranes, and cytoplasmic organelles were sparse, although swollen mitochondria, rough endoplasmic reticulum, lysosomes, and occasional collections of intermediate filaments were noted (Figure 4). Some cells contained intracytoplasmic lumina filled with erythrocytes.


Polymerase Chain Reaction Analysis for HHV-8

DNA was extracted from fresh frozen tumor tissue and sections of formalin-fixed, paraffin-embedded tumor tissues by proteinase K digestion, phenol-chloroform extraction, and ethanol precipitation. Using the primer set (5'-AGCCGAAAGGATTCCACCAT-3' and 5'-TCCGTGTTGT CTACGTCCAG-3'), (8) 35 cycles of PCR amplification of a section of the HHV-8 genome were carried out. These primers amplify a 233-base pair (bp) fragment located from base pair 987 to base pair 1219 of the reported HHV-8 sequence. (5) As a substitute for template DNA, distilled water was added to the reaction solution as a negative control. As a positive control, DNA samples from 3 cases of AIDS-associated Kaposi sarcoma were used.

After electrophoresis, the agarose gels were stained with ethidium bromide and visualized by ultraviolet light. While the PCR product of 233 bp was detected for the 3 samples from Kaposi sarcomas, no product of this size was seen with our present case (Figure 5).



Splenic angiosarcoma is a rare tumor, and most details concerning this tumor have been published in case reports. In 1993, Falk et al (3) reported a clinicopathologic study of 40 collected cases. More recently, Neuhauser et al (4) described the clinicopathologic findings with a detailed immunohistochemical study of 28 cases. According to these 2 articles, the histology of splenic angiosarcoma is highly variable. Although the most common type features a spongiform proliferation of endothelial cells forming irregular capillary networks. Other pseudosinusoidal, pseudopapillary, and spindle cell sarcoma-like patterns have been documented. (3,4) Neuhauser et al (4) reported that only 2 of their collected cases showed Kaposi sarcoma--like spindle cell proliferations with slitlike spaces. In the present case, the tumor was composed of 2 characteristic components: spongelike, dilated, thin-walled endothelium and Kaposi sarcoma--like spindle cells. Immunohistochemically, the spindle cells were immunopositive for factor VIII--associated antigen and CD34 and were immunonegative for [alpha]-smooth muscle actin, although Kaposi sarcomas generally express [alpha]-smooth muscle actin but lack expression of factor VIII--associated antigen. (9,10) Ultrastructural findings confirmed an endothelial differentiation of the proliferating cells. We therefore concluded that the present case is a rare variant of the splenic angiosarcoma, a Kaposi-like variant.

In the literature, although some controversial findings were reported, (11) most studies were unable to detect HHV-8 DNA in mesenchymal and vascular tumors other than Kaposi sarcoma, including hemangiomas, hemangioendotheliomas, infantile capillary hemangioma, and hemangiosarcoma. (6) Identification of HHV-8 DNA is now regarded as the diagnostic criterion for Kaposi sarcoma. (6) In the present case, HHV-8 DNA was not detected with PCR analysis. Accordingly, a distinct entity of splenic angiosarcoma--different from Kaposi sarcoma but with similar histologic findings--may exist.

To our knowledge, Sarode et al (12) reported the only case of splenic Kaposi sarcoma to date. The histologic components of the case, judging from the description and the photographs, comprised spindle cell proliferation and thin-walled, dilated vascular channels lined by flattened endothelium. The authors came to a diagnosis of Kaposi sarcoma only from the former component. Their tumor metastasized to the liver, the mesenterium, the pleura, and the lymph nodes. Although the authors did not investigate for HHV-8 DNA (the report was published before the discovery of the virus), we believe that the splenic tumor they reported belongs to the same category as our case because of the similar histologic findings and the malignant behavior.

The symptoms in our patient were slight anemia and left flank pain. According to the collected series of Falk et al, (3) the major symptoms are abdominal pain (83%) and cytopenia (91%), including anemia, thrombocytopenia, and pancytopenia. A rare but important presentation of splenic angiosarcoma is spontaneous splenic rupture (13%). The prognosis of splenic angiosarcoma is poor Calculated from the cases in the reports of Falk et al (3) and Neuhauser et al, (4) 1- and 3-year survival rates were 52.1% and 13.5%, respectively. The prognosis of the Kaposi-like variant remains to be determined.

In earlier reports, nuclear atypia varied from case to case. In the present lesion, nuclear atypia was minimal, especially in the spongelike component. However, the cell proliferation rate was between those for hemangiosarcomas of scalp and cavernous hemangiomas. Pathologists should bear in mind that splenic angiosarcomas can show minimal nuclear atypia.

In conclusion, we report here a rare variant of splenic angiosarcoma. Although histologically similar to Kaposi sarcoma in part, it appeared to be a distinct entity because HHV-8 DNA was not detected. We conclude that it should be treated as a Kaposi-like variant of splenic angiosarcoma.

We thank M. Koike, MD, and S. Moriyama, MD, for providing DNA from Kaposi sarcomas in patients with acquired immunodeficiency syndrome. We also thank the staff of the Electron Microscope Centre, Kitasato University School of Medicine (Sagamihara, Japan), and M. Yokozawa for their expert technical support.


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(3.) Falk S, Krishnan J, Meis JM. Primary angiosarcoma of the spleen: a clinicopathologic study of 40 cases. Am J Surg Pathol. 1993;17:959-970.

(4.) Neuhauser TS, Derringer GA, Thompson LDR, et al. Splenic angiosarcoma: a clinicopathologic and immunophenotypic study of 28 cases. Mod Pathol. 2000; 13:978-987.

(5.) Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266:1865-1869.

(6.) Cathomas G. Human herpes virus 8: a new virus discloses its face. Virchows Arch. 2000;436:195-206.

(7.) Brooks LA, Wilson AJ, Crook T. Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV8): a new human tumour virus. J Pathol. 1997; 182:262-265.

(8.) Alkan S, Eltoum IA, Tabbara S, Day E, Karcher DS. Usefulness of molecular detection of human herpesvirus-8 in the diagnosis of Kaposi sarcoma by fine-needle aspiration. Am J Clin Pathol. 1999;111:91-96.

(9.) Weich HA, Salahuddin SZ, Gill P, Nakamura S, Gallo RC, Folkmann J. AIDS-associated Kaposi's sarcoma-derived cells in long-term culture express and synthesize smooth muscle alpha-actin. Am J Pathol. 1991;139:1251-1258.

(10.) Enzinger FM, Weiss SW. Soft Tissue Tumors. 3rd ed. St Louis, Mo: Mosby-Year Book Inc; 1995:658-669.

(11.) McDonagh DP, Liu J, Gaffey MJ, Layfield LJ, Azumi N, Traweek ST. Detection of Kaposi's sarcoma-associated herpesvirus-like DNA sequences in angiosarcoma. Am J Pathol. 1996;149:1363-1368.

(12.) Sarode VR, Datta BN, Savitri K, Singh K, Bhasin D. Kaposi's sarcoma of spleen with unusual clinical and histologic features. Arch Pathol Lab Med. 1991; 115:1042-1044.

Accepted for publication July 12, 2001.

From the Department of Pathology (Drs Mikami, Saegusa, Akino, Iwabuchi, and Okayasu), Kitasato University School of Medicine, Sagamihara, Japan; and the Departments of Pathology (Drs Mikami, Saegusa, Akino, Iwabuchi, and Okayasu, and Mr Machida) and Hematology (Dr Hagiwara), Kitasato University Hospital, Sagamihara, Japan.

Reprints: Tetuo Mikami, MD, Department of Pathology, Kitasato University School of Medicine, 1-15-1, Kitasato, Sagamihara-si, Kanagawa, 228-8555, Japan (e-mail:
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Article Details
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Author:Mikami, Tetuo; Saegusa, Makoto; Akino, Fumiyuki; Machida, Daisuke; Iwabuchi, Keiichi; Hagiwara, Shot
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:9JAPA
Date:Feb 1, 2002
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