Oxymetholone

A 72-year-old man with no previous history of liver disease was admitted to our university hospital with severe dyspnea, edema of the lower limbs, and weight loss. Within a few days of hospitalization, he died due to severe bleeding in the upper digestive tract. At autopsy, the liver displayed typical gross features of peliosis hepatis. In addition, a diffuse infiltration of liver, spleen, bone marrow, and lymph nodes by lymphoplasmacytic lymphoma was disclosed by light microscopy. In the liver, the neoplastic cells partially filled the peliotic cavities. Peliosis hepatis is a rare liver disease characterized by multiple blood-filled, dilated cavities within the liver parenchyma. Association of lymphoplasmacytic lymphoma and peliosis hepatis has rarely been reported in the literature. The pathologic findings of such an unusual association and a review of the literature are presented.

(Arch Pathol Lab Med. 2004;128:1283-1285)

Peliosis hepatis is characterized by the presence of blood-filled cavities in the liver1 and was first described by Wagner in 1861. Various unrelated conditions have been reported to be associated with peliosis hepatis, the most important of them being the administration of steroid hormones.2 Other conditions include Castleman disease,3 Hodgkin lymphoma,4 malnutrition,5 Bartonella species infection,6 hairy cell leukemia,7 malignant histiocytosis,8 and renal transplantation.9,10 We report an autopsy case of peliosis hepatis in a patient affected by lymphoplasmacytic lymphoma. We found only 2 previous reports of a similar association in the literature.11,12

REPORT OF A CASE

A 72-year-old man presented to the emergency room with severe dyspnea at mild effort, edema of the lower limbs, and a 4-kg weight loss within the preceding 20 days. He had no known history of chronic obstructive lung disease and had no past medical history of liver disease or steroid hormone use. On admission, routine hematological laboratory tests included an erythrocyte count of 1.6 × 10^sup 6^/µL; hemoglobin, 6.4 g/dL; and white blood cell count, 8.89 × 10^sup 6^/µL. A differential count showed 44% neutrophils, 42% lymphocytes, 13.4% monocytes, 0.3% eosinophils, and 0.6% basophils. No atypical lymphocytes were detected in the peripheral blood smear. Serum aspartate aminotransferase and alanine transferase levels were within normal reference ranges. A roentgenogram of the thorax revealed a large mediastinal mass, suggestive of lymph node enlargement. During hospitalization, the patient experienced severe bleeding in the upper digestive tract, with consequent hemorrhagic shock. He received several erythrocyte-concentrated blood transfusions without response and died on the 12th internment day.

MATERIALS AND METHODS

The tissue samples were fixed in 10% buffered formalin and embedded in paraffin. Four-micrometer-thick sections from the paraffin blocks were stained with hematoxylin-eosin. Masson trichrome and silver stains were also prepared. Immunohistochemistry was performed using the avidin-biotin-peroxidase method after heat-induced antigen retrieval. Stains for CD3 (clone PS1, Novocastra, Newcastle upon Tyne, United Kingdom), CDS (Novocastra), CD20 (clone L26, Dako Corporation, Carpinteria, Calif), CD138 (clone B-B4 Serotec, Oxford, United Kingdom), κ light chain, and λ light chain, as well as immunoglobulin (Ig) M, IgG, IgA, and IgD heavy chains (Dako) were performed.

PATHOLOGIC FINDINGS

At autopsy, the main macroscopic findings were hepatomegaly (3205 g), splenomegaly (295 g), and mediastinal adenomegaly. The liver contained many small empty spaces intermingled and very often mixed to confluent hemorrhagic dots (Figure 1).

Microscopically, the liver displayed numerous dilated, randomly distributed, blood-filled spaces, bordered by atrophie liver cell plates, characterizing peliosis hepatis (Figure 2). The cavities were also irregularly filled with a monotonous dense infiltrate of neoplastic small lymphocytes, most with lymphoplasmacytic features, characterized by small round nuclei with granular chromatin and light eosinophilic cytoplasm (Figure 3). The same neoplastic lymphoid infiltrate was also present in mediastinal lymph nodes, spleen, and bone marrow.

Immunohistochemistry revealed diffuse positivity of the neoplastic cells for CD20 (Figure 4), κ light chain, and IgG heavy chain, and faint focal positivity for CD138. The immunostains for CD3, CDS, λ light chains, IgM, IgD, and IgA heavy chains were all negative. The combination of morphologic and immunohistochemical features of the neoplastic cells were diagnostic of lymphoplasmacytic lymphoma.

COMMENT

Peliosis is defined as the presence of cystic blood-filled spaces in the liver, spleen, and lymph nodes, as well as in other organs.1 When occurring in the liver, it is referred to as peliosis hepatis. It is usually asymptomatic, frequently discovered only as a result of abnormal liver function tests. Liver rupture, either spontaneous or after minor trauma, can occur, albeit rarely. Of the different conditions associated with the onset of peliosis hepatis, the most common is the use of steroid hormones.2 Other conditions include Castleman disease,3 Hodgkin disease,4 malnutrition,5 Bartonella species infections in immunosuppressed patients (especially those with acquired immunodeficiency syndrome),6 hairy cell leukemia,7 malignant histiocytosis,8 and renal transplantation, presumably secondary to cyclosporine and azathioprine therapy.13 Our case of peliosis hepatitis was associated with massive liver infiltration by lymphoplasmacytic lymphoma.

Lymphoplasmacytic lymphoma is a rare B-cell neoplasm that accounts for only 1.5% of nodal lymphomas.13 When a monoclonal IgM serum paraprotein is present, the designation Waldenström macroglobulinemia is applicable. This neoplasm usually involves bone marrow, lymph nodes, and spleen.13 It occurs predominantly in older individuals and exhibits a slight male predominance. In the Revised European-American Lymphoma Classification clinical study, the mean age was 63 years and 53% of the patients were male.14 Microscopically, the neoplastic cells are small lymphocytes with plasmacytic features, lacking expression of CD5 and CD23, with strong expression of B-cell markers, as well as surface and cytoplasmic immunoglobulin. Differential diagnosis with plasmacytoma/multiple myeloma based on pure morphologic grounds is sometimes difficult. In these cases, immunohistochemistry is a very helpful tool. The strong diffuse positivity of the neoplastic cells for CD20, with only focal positivity for CD138, associated with the morphologic and clinical features, helped to exclude the diagnosis of plasmacytoma/multiple myeloma in the present case.

To the best of our knowledge, only 2 previous reports of peliosis hepatis in association with lymphoplasmacytic lymphoma have been published. Ginestal-Cruz et al11 reported a case of Waldenström macroglobulinemia that presented as a bleeding duodenal ulcer. After several months of therapy with oxymetholone, peliosis was diagnosed through a fine-needle liver biopsy. The biopsy disclosed a portal infiltrate by lymphoma cells, surrounded by typical peliotic cavities, which did not contain neoplastic cells. Voinchet et al12 reported a case of a 54-year-old woman with persistent elevated levels of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Liver biopsy demonstrated peliosis without infiltration by neoplastic cells.

The present case differs from the 2 aforementioned cases by its unique pattern of infiltration, with the presence of neoplastic cells inside the peliotic cavities. The case reported by Ginestal-Cruz et al11 was most probably due to the therapy with oxymetholone, a steroid known to induce peliosis both in vitro and in vivo,15 although neoplastic cells were present in the portal tracts. On the other hand, in the case reported by Voinchet et al,12 the lesions most probably resulted from liver damage by circulating immunoglobulins, as demonstrated by the presence of κ-chain deposits along the sinusoids.

The unusual sinusoidal pattern of infiltration by neoplastic cells seen in the present case in association with peliosis hepatis, to our knowledge has only been reported previously in hairy cell leukemia7 and was attributed to the presence of VCAM-1 in the wall of the hepatic sinusoids. In the few published cases of lymphoma-associated peliosis hepatis, such a pattern of infiltration was absent.4,11,12

The pathogenesis of peliosis hepatis is still not well understood. Possible mechanisms include obstruction of the sinusoidal blood flow, as in neoplastic infiltration, and sinusoidal wall damage by infectious agents or drugs, as in Bartonella infections and steroid hormone administration. The loss of reticulin fibers in the wall of the peliotic cavities is demonstrated in most situations, supporting the concept that some kind of damage to its structure is the cause of the lesions, but it has not been clearly verified yet.

Previous reports of peliosis hepatis arising in patients with Castleman disease of plasma cell type in which monoclonal gammaglobulinemia was present3 also point toward a possible role of abnormally high concentrations of circulating immunoglobulins in the pathogenesis of peliosis hepatis. The high concentration of serum immunoglobulins probably exerts its effect through increasing blood viscosity and decreasing sinusoidal blood flow.11 In 1 case,3 although photomicrographs were not shown, plasma cells were present in both the portal tracts and sinuses, similar to our case. One could hypothesize that the cells present in the sinusoids in that case and in our case could be the source of the lesions either obstructing the blood flow through the sinusoids or damaging its walls.

The pathogenesis of peliosis hepatis is still in question. The heterogeneity of the clinical settings in which it develops and its low frequency are factors that make it difficult to establish a single model of pathogenesis. Our case of peliosis hepatis in association with liver infiltration by a lymphoplasmacytic lymphoma is, to the best of our knowledge, the third report of such an association and the first with massive presence of neoplastic cells inside the peliotic cavities. The histopathologic features of the present case suggest a possible role of the neoplastic cells themselves as causative agents of liver damage in peliosis hepatis. Furthermore, this case also emphasizes the strong relationship between peliosis hepatis and malignant neoplasms, especially hematologic neoplasms, which can be helpful in a clinical setting when dealing with a case of peliosis hepatis.

References

1. Wanless IR. Vascular disorders. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, eds. Pathology of the Liver. New York, NY: Churchill Livingstone; 2002:539-573.

2. Nadell J, Kosek J. Peliosis hepatis: twelve cases associated with oral androgen therapy. Arch Palhol Lab Med. 1977;101:405-410.

3. Sherman D, Ramsay B, Theodorou NA, et al. Reversible plane xanthoma, vasculitis, and peliosis hepatis in giant lymph node hyperplasia (Castleman's disease): a case report and review of the cutaneous manifestations of giant lymph node hyperplasia. J Am Acad Dermatol. 1992;26:105-109.

4. Bhaskar KV, Joshi K, Banerjee CK, et al. Peliosis hepatis in Hodgkin's disease: an infrequent association. Am J Gastroenterol. 1990;85:628-629.

5. Simon DM, Krause R, Calambos JT. Peliosis hepatis in a patient with marasmus. Gastroenterology. 1988;95:805-809.

6. Perochka LA, Geaghan SM, Yen TSB, et al. Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med. 1990;323:1581-1586.

7. Zafrani ES, Degos F, Guigui B, et al. The hepatic sinusoid in hairy cell leukemia: an ultrastructural study of 12 cases. Hum Palhol. 1987;18:801-807.

8. Fine KD, Solano M, Polter DE, et al. Malignant histiocytosis in a patient presenting with hepatic dysfunction and peliosis hepatis. Am J Gastroenterol. 1995;90:485-488.

9. Izumi S, Nishiuchi M, Kameda Y, et al. Laparoscopic study of peliosis hepatis and nodular transformation of the liver before and after renal transplantation: natural history and aetiology in follow-up cases. J Hepatol. 1994;20:129-137.

10. Cavalcanti R, Pol S, Carnot F, et al. Impact and evolution of peliosis hepatis in renal transplant recipients. Transplantation. 1994;58:31 5-316.

11. Ginestal-Cruz A, Correia JP, Batista A, et al. Recurrent upper gastro-intestinal bleeding, duodenal and gastric ulcer and peliosis hepatis in a patient with Waldenstrom's macroglobulinemia. Acta Med Port. 1979;1:721-727.

12. Voinchet O, Degott C, Scoazec JY, et al. Peliosis hepatis, nodular regenerative hyperplasia of the liver, and light-chain deposition in a patient with Waldenstrom's macroglobulinemia. Gastroenterology. 1988;95:482-48b.

13. Berger F, Isaacson PG, Piris MA, et al. Lymphoplasmacytic lymphoma/Wäldenström macroglobulinemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:132-134. World Health Organization Classification of Tumours; vol 3.

14. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997;89:3909-3918.

15. Pavlatos AM, Fultz O, Monberg MJ, et al. Review of oxymetholone: a 17alpha-alkylated anabolic-androgenic steroid. Clin Ther. 2001;23:789-801.

Marcus V. N. Corpa, MD; Maura M. Bacchi, MD; Carlos E. Bacchi, MD; Kunie I. R. Coelho, MD

Accepted for publication June 29, 2004.

From the Department of Pathology, Faculdade de Medicina de Botucatu, State University of Sao Paulo, Botucatu, Sao Paulo, Brazil.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Marcus V. N. Corpa, MD, Rua Azevedo Scares 2018, Tatuape, Sao Paulo-SP, Brazil 03322-002 (e-mail: mvncorpa@terra.com.br).

Copyright College of American Pathologists Nov 2004
Provided by ProQuest Information and Learning Company. All rights Reserved