CASE REPORTS
Danazol-Induced Hepatocellular Adenoma JEAN PAUL FERMAND, M.D., YVES LEVY, M.D., DIDIER BOUSCARY, M.D., MARIE FRAN(~OISED'AGAY, M.D., PHILIPPE CLOT, M.D., JACQUES FRIJA, M.D., JEAN CLAUDE BROUET, M.D., Ph.D., Paris, France
D
anazol is currently used in the treatment of various conditions such as endometriosis, angioneurotic edema, and idiopathic thrombocytopenic purpura (ITP). In contrast to other C-17 alkylated anabolic steroids, this androgen has been rarely implicated in the development of primary liver tumors. We report the occurrence of an hepatocellular adenoma in one patient with ITP receiving long-term danazol therapy.
sinusoids supported by a close reticulin network, thinwalled vessels, and large central areas of hemorrhagic necrosis. A diagnosis of hepatocellular adenoma was made. The postoperative course was uneventful. Several months after surgery, the patient was well and thrombocytopenic and biological and ultrasonographic examinations of the liver were normal.
CASE REPORT
COMMENTS
A 34-year-old woman was found to have ITP in 1978. Successive treatments (prednisone, high-dose intravenous immunoglobulins, vincristine sulfate, and splenectomy) induced only transient improvement. Danazol, 600 mg daily, was begun in September 1983, and platelet counts increased from 5,000 to 90,000/ mm 3. A relapse occurred when the dose of the androgen was tapered, and danazol was continued at 400 mg per day. The patient took no other drugs, notably no oral contraceptives. The results of an ultrasonographic examination of the liver, performed in 1985, were normal, and until 1987, there was no clinical or biologic evidence of a liver abnormality. In 1987, the serum alkaline phosphatase level slightly increased, and clinical examination disclosed an abdominal mass despite the patient's obesity. Ultrasound study showed a large solid hepatic tumor, which, on liver scintigraphy, took up technetium-labeled sulfur colloid. A magnetic resonance imaging scan confirmed the existence of a large, wellcircumscribed tumoral lesion in the right hepatic lobe; on T2-weighted images, it had a heterogeneous bright texture with several areas of higher-signal intensity indicating vascular lakes and necrotic lesions (Figure 1). An angiographic examination corroborated magnetic resonance data; the mass was nonhomogeneous, and hypervascular and displaced normal vascular structures; the adjacent hepatic parenchymal pattern was normal. Serum a-fetoprotein levels were not increased. Treatment with danazol was stopped. A 4-day course of intravenous immunoglobulins induced a transient increase in platelet counts, and laparotomy with excision of the mass, which was 16 cm in diameter, was performed. Histologically (Figure 2), the tumoral lesion was separated by fibrous tissue from the surrounding parenchyma, which was normal, without peliosis hepatis; the tumor was composed of irregular cords of hepatocytes without mitoses and cellular atypia; it did not contain any bile ducts but numerous
In addition to hepatic dysfunction, cholestatic jaundice, and peliosis hepatis, therapy with synthetic 17alkylated androgenic steroids may lead to the development of primary liver tumors [1]. Hepatocellular carcinomas [2], hepatic angiosarcomas [3], and adenomas [4] occur in patients treated with androgens, most often over long periods of time. A causal relationship is supported by experimental data in animals and by the observation, in a few patients, of tumor regression after withdrawal of the androgen [5]. Danazol is a derivative of C-17 ethinyltestosterone
Fromthe HSpitalSaintLouis,Paris, France.Requestsfor reprintsshouldbe addressedto Jean Paul Fermand,M.D., Serviced'lmmuno-H6matologie, H6pitalSaintLouis, 1, Av. ClaudeVellefaux,75475ParisCedex10 France. ManuscriptsubmittedAugust3, ]989, and acceptedOctober2, 1989.
Figure 1. Sagittal magnetic resonance imaged slice (spin-echo: 1,600-100) passing through the right lobe of the liver and the adenoma.
May 1990 The American Journal of Medicine Volume 88
529
DANAZOL-INDUCEDHEPATOCELLULARADENOMA/ FERMANDET AL
Figure 2. Histologic pattern of the hepatic lesion. Liver cells are arranged in tightly packed trabeculae intermixed with acini-like structures (hematoxylin and eosin; original magnification x 2 0 0 ; reduced by 50%).
and, accordingly, may induce hepatic injury. In our experience with 30 patients with ITP treated by danazol alone (400 to 600 mg daily), an increase in transaminase values was observed in 40% of cases but was usually mild and reversible when the dose of the drug was decreased (unpublished data). Other investigators have reported danazol-induced cholestatic hepatitis [6], and a few cases of hepatic and/or splenic peliosis have been documented [7]. To date, two cases of hepatocellular carcinoma have been reported, one in a patient with endometriosis treated with danazol (200 mg daily) for 2 years [8], the other in a patient with systemic lupus erythematosus who received 400 mg of danazol daily for 4 years [9]. Our observation provides further evidence for a tumorogenic role of long-term therapy with danazol. Our patient's adenoma had the usual features of this tumor: rapid growth, large size, and intratumoral hemorrhages, which can rupture through the capsule leading to hemoperitoneum [10]. Interestingly, the technetium-99m sulfur colloid scan performed in our patient demonstrated uptake of the colloid by the tumor; this scintigraphic pattern, although more suggestive of focal nodular hyperplasia than of an adenoma, has already been found in a few cases of hepatocellular adenoma [11]. Thus, danazol, although considered a weak androgen, exhibits all the adverse effects that could be expected from its 17-alkylated steroid structure. Wheth-
530
May 1990 The American Journal of Medicine Volume88
er the incidence of liver damage, and, particularly, of primary liver tumors, is lower than with other anabolic steroids remains unknown. However, long-term treatment with danazol, when justified, should be performed at a minimal effective dosage and should be carefully monitored, preferably by periodic ultrasonic examinations of the liver. REFERENCES 1. Westaby D, Williams R: Androgen and anabolic steroid-related liver tumours. In: DavisM, Tredger JM, Williams R, eds. Drug reactions and the liver. London: Pitman Medical, ]981; 284-289. 2. Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H: Androgeninduced hepatoma. Lancet 1975; 1: 430-431. 3. Falk H, Thomas LB, Popper H, Ishak KG: Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 1979; 2: ] 120-1130. 4. Westaby D, Portmann B, Williams R: Androgen related primary hepatic tumors in non-Fanconi patients. Cancer ]983; 51: 1947-1952. 5. McCaughanGW, Bilous MJ, Gallagher ND: Long-term survival with tumor regression in androgen-induced liver tumors. Cancer 1985; 56: 2622-2626. 6. Boue F, Coffin 8, Delfraissy JF: Danazol and cholestatic hepatitis. Ann Intern Med 1986; ]05: 139-140. 7. Nesher G, Dollberg L, Zimran A, Hershko C: Hepatosplenic peliosis after danazol and glucocorticoids for ITP (letter). N Engl J Med 1985; 3]2: 242. 8. Buamah PK: An apparent danazol-induced primary hepatocellular carcinoma: case report. J Surg Oncol ]985; 28: 114-116. 9. Weill BJ, Menkes CJ, Cormier C, Louvel A, DougadosM, HoussinD: Hepatocelluo lar carcinoma after danazol therapy. J Rheumatol ]988; 15: 1447-1449. 10. Goldfarb S: Sex hormones and hepatic neoplasia. Cancer Res 1976; 36: 25842588. 11. Goodman ZD, Mikel UV, Lubbers PR, Ros PR, LanglossJM, Ishak KG: Kupffer cells in hepatocellular adenomas. Am J Surg Pathol ]987; 11: 191-]96.
Danazol-Induced Hepatocellular Adenoma JEAN PAUL FERMAND, M.D., YVES LEVY, M.D., DIDIER BOUSCARY, M.D., MARIE FRAN(~OISED'AGAY, M.D., PHILIPPE CLOT, M.D., JACQUES FRIJA, M.D., JEAN CLAUDE BROUET, M.D., Ph.D., Paris, France
D
anazol is currently used in the treatment of various conditions such as endometriosis, angioneurotic edema, and idiopathic thrombocytopenic purpura (ITP). In contrast to other C-17 alkylated anabolic steroids, this androgen has been rarely implicated in the development of primary liver tumors. We report the occurrence of an hepatocellular adenoma in one patient with ITP receiving long-term danazol therapy.
sinusoids supported by a close reticulin network, thinwalled vessels, and large central areas of hemorrhagic necrosis. A diagnosis of hepatocellular adenoma was made. The postoperative course was uneventful. Several months after surgery, the patient was well and thrombocytopenic and biological and ultrasonographic examinations of the liver were normal.
CASE REPORT
COMMENTS
A 34-year-old woman was found to have ITP in 1978. Successive treatments (prednisone, high-dose intravenous immunoglobulins, vincristine sulfate, and splenectomy) induced only transient improvement. Danazol, 600 mg daily, was begun in September 1983, and platelet counts increased from 5,000 to 90,000/ mm 3. A relapse occurred when the dose of the androgen was tapered, and danazol was continued at 400 mg per day. The patient took no other drugs, notably no oral contraceptives. The results of an ultrasonographic examination of the liver, performed in 1985, were normal, and until 1987, there was no clinical or biologic evidence of a liver abnormality. In 1987, the serum alkaline phosphatase level slightly increased, and clinical examination disclosed an abdominal mass despite the patient's obesity. Ultrasound study showed a large solid hepatic tumor, which, on liver scintigraphy, took up technetium-labeled sulfur colloid. A magnetic resonance imaging scan confirmed the existence of a large, wellcircumscribed tumoral lesion in the right hepatic lobe; on T2-weighted images, it had a heterogeneous bright texture with several areas of higher-signal intensity indicating vascular lakes and necrotic lesions (Figure 1). An angiographic examination corroborated magnetic resonance data; the mass was nonhomogeneous, and hypervascular and displaced normal vascular structures; the adjacent hepatic parenchymal pattern was normal. Serum a-fetoprotein levels were not increased. Treatment with danazol was stopped. A 4-day course of intravenous immunoglobulins induced a transient increase in platelet counts, and laparotomy with excision of the mass, which was 16 cm in diameter, was performed. Histologically (Figure 2), the tumoral lesion was separated by fibrous tissue from the surrounding parenchyma, which was normal, without peliosis hepatis; the tumor was composed of irregular cords of hepatocytes without mitoses and cellular atypia; it did not contain any bile ducts but numerous
In addition to hepatic dysfunction, cholestatic jaundice, and peliosis hepatis, therapy with synthetic 17alkylated androgenic steroids may lead to the development of primary liver tumors [1]. Hepatocellular carcinomas [2], hepatic angiosarcomas [3], and adenomas [4] occur in patients treated with androgens, most often over long periods of time. A causal relationship is supported by experimental data in animals and by the observation, in a few patients, of tumor regression after withdrawal of the androgen [5]. Danazol is a derivative of C-17 ethinyltestosterone
Fromthe HSpitalSaintLouis,Paris, France.Requestsfor reprintsshouldbe addressedto Jean Paul Fermand,M.D., Serviced'lmmuno-H6matologie, H6pitalSaintLouis, 1, Av. ClaudeVellefaux,75475ParisCedex10 France. ManuscriptsubmittedAugust3, ]989, and acceptedOctober2, 1989.
Figure 1. Sagittal magnetic resonance imaged slice (spin-echo: 1,600-100) passing through the right lobe of the liver and the adenoma.
May 1990 The American Journal of Medicine Volume 88
529
DANAZOL-INDUCEDHEPATOCELLULARADENOMA/ FERMANDET AL
Figure 2. Histologic pattern of the hepatic lesion. Liver cells are arranged in tightly packed trabeculae intermixed with acini-like structures (hematoxylin and eosin; original magnification x 2 0 0 ; reduced by 50%).
and, accordingly, may induce hepatic injury. In our experience with 30 patients with ITP treated by danazol alone (400 to 600 mg daily), an increase in transaminase values was observed in 40% of cases but was usually mild and reversible when the dose of the drug was decreased (unpublished data). Other investigators have reported danazol-induced cholestatic hepatitis [6], and a few cases of hepatic and/or splenic peliosis have been documented [7]. To date, two cases of hepatocellular carcinoma have been reported, one in a patient with endometriosis treated with danazol (200 mg daily) for 2 years [8], the other in a patient with systemic lupus erythematosus who received 400 mg of danazol daily for 4 years [9]. Our observation provides further evidence for a tumorogenic role of long-term therapy with danazol. Our patient's adenoma had the usual features of this tumor: rapid growth, large size, and intratumoral hemorrhages, which can rupture through the capsule leading to hemoperitoneum [10]. Interestingly, the technetium-99m sulfur colloid scan performed in our patient demonstrated uptake of the colloid by the tumor; this scintigraphic pattern, although more suggestive of focal nodular hyperplasia than of an adenoma, has already been found in a few cases of hepatocellular adenoma [11]. Thus, danazol, although considered a weak androgen, exhibits all the adverse effects that could be expected from its 17-alkylated steroid structure. Wheth-
530
May 1990 The American Journal of Medicine Volume88
er the incidence of liver damage, and, particularly, of primary liver tumors, is lower than with other anabolic steroids remains unknown. However, long-term treatment with danazol, when justified, should be performed at a minimal effective dosage and should be carefully monitored, preferably by periodic ultrasonic examinations of the liver. REFERENCES 1. Westaby D, Williams R: Androgen and anabolic steroid-related liver tumours. In: DavisM, Tredger JM, Williams R, eds. Drug reactions and the liver. London: Pitman Medical, ]981; 284-289. 2. Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H: Androgeninduced hepatoma. Lancet 1975; 1: 430-431. 3. Falk H, Thomas LB, Popper H, Ishak KG: Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 1979; 2: ] 120-1130. 4. Westaby D, Portmann B, Williams R: Androgen related primary hepatic tumors in non-Fanconi patients. Cancer ]983; 51: 1947-1952. 5. McCaughanGW, Bilous MJ, Gallagher ND: Long-term survival with tumor regression in androgen-induced liver tumors. Cancer 1985; 56: 2622-2626. 6. Boue F, Coffin 8, Delfraissy JF: Danazol and cholestatic hepatitis. Ann Intern Med 1986; ]05: 139-140. 7. Nesher G, Dollberg L, Zimran A, Hershko C: Hepatosplenic peliosis after danazol and glucocorticoids for ITP (letter). N Engl J Med 1985; 3]2: 242. 8. Buamah PK: An apparent danazol-induced primary hepatocellular carcinoma: case report. J Surg Oncol ]985; 28: 114-116. 9. Weill BJ, Menkes CJ, Cormier C, Louvel A, DougadosM, HoussinD: Hepatocelluo lar carcinoma after danazol therapy. J Rheumatol ]988; 15: 1447-1449. 10. Goldfarb S: Sex hormones and hepatic neoplasia. Cancer Res 1976; 36: 25842588. 11. Goodman ZD, Mikel UV, Lubbers PR, Ros PR, LanglossJM, Ishak KG: Kupffer cells in hepatocellular adenomas. Am J Surg Pathol ]987; 11: 191-]96.
