Paraneoplastic Erythrocytosis in a Young Adult With an Erythropoietin-Producing Wilms’ Tumor ROBERT DREICER, M.D., MS., JAMES DONOVAN, M.D., JO ANN BENDA, M.D., JAMES LUND, M.D., RICHARD L. DEGOWIN, M.D., /owa city, /ma
Paraneoplastic erythrocytosis in patients with Wii’ tumors is exceedingly rare, with only three reported casea in the literature. We report acaseofayoungmanwithWilms’tumorwitha significant erythrocytosis but a normal serum eryfhropoietin level and a tumor that elaborated erythropoietin.
From the Department of Medicine (RD. RLD). Department of Urology (JD. JL), and Department of Pathology (JAB), University of Iowa Hospitals and Clinics, Iowa City, Iowa. Requests for reprints should be addressed to Robert Dreicer, M.D., MS., Department of Medicine, University of Iowa, Iowa City, Iowa 52242. Manuscript submitted February 26, 1991, and accepted in revised form July 5. 1991.
CASE REPORT A 20-year-old nonsmoking man was found to have a hemoglobin level and hematocrit of 207 g/L and 0.62, respectively, prior to removal of an ingrown toenail. He gave a history of cold intolerance, fatigue, and weight loss of 4.5 kg. Physical examination demonstrated a thin man with plethoric facies, normal vital signs, and otherwise unremarkable findings. Laboratory values were as follows: leukocyte count 7.7 X log/L, platelet count 188 X log/L, creatinine 106 pmol/L, thyroid-stimulating hormone 0.82 mu/L, oxygen tension 13.2 kPa (99 mm Hg), 1% carboxyhemoglobin, normal hemoglobin oxygen affinity studies, red cell mass 51.1 mL/kg (normal 30 f 5 ml/kg), plasma volume 42.0 mL/kg (normal 40 f 5 ml/kg), and serum erythropoietin 8 mU/mL (normal 4 to 24 mU/mL; radioimmunoassay performed by SmithKline Bio-Science Lab, Van Nuys, CA). Abdominal ultrasonography demonstrated a 4-cm mass in the upper pole of the right kidney. An abdominal computed tomographic (CT) scan confirmed the presence of a solid mass confined within the renal capsule (Figure 1) without regional lymphadenopathy or extension into the renal vein. Staging studies including chest radiograph, chest CT scan, and bone scan did not demonstrate metastatic disease. The patient donated 2 units of blood for autologous transfusion and had a preoperative hematocrit of 0.57. The patient underwent a right radical nephrectomy with regional lymph node dissection. The left kidney was palpably normal. The surgery was uncomplicated and the patient made an uneventful recovery. Pathologic study revealed a favorable-histology Wilma’ tumor confined to the kidney with negative nodes. Samples of tumor and adjacent, histologically normal renal parenchyma were taken for erythropoietin analysis. Tissue samples (0.5 g) were minced and added to 10 mL of isotonic saline and agitated, and aliquota of supernatant were analyzed for erythropoietin. Erythropoietin levels were 60 mU/mL in the tumor aliquot and less than 2 mU/mL in the normal renal parenchyma. The patient had a stage I favorable-histology Wilms’ tumor and was registered into a National
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PARANEOPLASTIC ERVTHROCVTOSISAND WILMS’ TUMOR / DREICERET AL
ropoietin secretion occurred, making the results of determination of a single erythropoietin level deceptive [6]; or alternatively, that a patient’s “normal” erythropoietin level may in fact be inappropriately elevated when found in association with an increased red cell mass [7]. There are at least three lines of evidence confiiming that our patient’s Wilma’ tumor elaborated erythropoietin that led to erythrocytosis. First, removal of the tumor corrected the erythrocytosis. Second, an extract of the tumor contained high levels of erythropoietin, but the adjacent normal kidney tissue did not. Finally, the “normal” plasma erythropoietin concentration (8 mU/mL) in our patient was inappropriately elevated in the presence of a greatly increased erythrocyte mass of 170% of normal. It is of interest that 30 years ago, Gurney [8] reported the first case of erythrocytosis induced by a renal tumor, an adenocarcinoma, secreting erythropoietin. His patient was a 62-year-old man whose erythrocytosis was ameliorated by removal of the tumor. A saline extract of the tumor contained large amounts of erythropoietin, but normal kidney tissue adjacent to the tumor and plasma from the patient had no erythropoietic activity in the relatively insensitive polycythemic mouse assay. This unusual case of paraneoplastic erythrocytosis in an adult with Wilma’ tumor underscores the need for caution in the interpretation of “normaI” erythropoietin levels in patients with secondary polycythemia [5]. Isolated erythrocytosis in a patient who is not hypoxic should, in itself, prompt an evaluation of the kidneys and other potential sites of excessive production of erythropoietin.
Figure
1. Computed tomographic (CT) scan image demonstrates the right renal mass (arrow) confined within the renal capsule. The contralateral kidney is within normal limits. Additional CT scan images (not shown) did not reveal evidence of tumor involving either the renal vein or regional lymph nodes.
Wilma’ Tumor Study Group protocol. The patient’s hemoglobin level and hematocrit were 110 g/L and 0.33, respectively, prior to initiation of chemotherapy with actinomycin D and vincristine. The patient tolerated chemotherapy without difficulty and is alive and free of disease 9 months after his radical nephrectomy. The hemoglobin level and hematocrit obtained 7 months following completion of chemotherapy were 144 g/L and 0.44, respectively.
COMMENTS A search for the cause of an elevated hematocrit in this asymptomatic young man led to the discovery and probable cure of a malignant tumor, rarely found in a 20-year-old person. The incidence of erythrocytosis in patients with renal cell carcinoma is between 3% and 10%; however, elevated erythropoietin levels have been reported in up to 63% of cases [l]. In contrast, approximately 4% of patients with erythrocytosis have renal cell carcinoma [2]. Although there are numerous reports of elevated erythropoietin levels in patients with Wilma’ tumor [3], there are only three cases of associated erythrocytosis reported in the literature [4]. Hypotheses to account for the wide divergence between the numbers of patients with elevated erythropoietin and those with erythrocytosis include the elaboration of an immunologically active, but biologically inert, erythropoietin, or the inability of the target erythroid cell to respond to stimulation [5]. Additional explanations include the possibility that only intermittent abnormal eryth-
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August 1992 The Americen Journal of Medicine
REFERENCES 1. Sufrin G, Chasan S. Golio A, Murphy GP. Paraneoplastic and serolo& syndromes of renal adenocarcinoma. Semin Ural 1989; 7: 158-71. 2. Hocking WG. Hematologic abnormalities in patients with renal diseases. He matol Oncol Clin North Am 1987; 1: 229-60. 3. Kenny GM, Mirand EA. Staubitz WJ, Allen JE, Trudel PJ. Murphy GP. Erythropoietin levels in Wilms tumor patients. J Ural 1970; 104: 758-61. 4. Hammond D, Winnick S. Paraneoplastic erythrocytosis and ectopic erythropoietins. Ann NY Acad Sci 1974; 230: 219-27. 5. Sherwood JB, Burns ER, Shouval D. Stimulation by cAMP of erythropoietin secretion by an established human renal carcinoma cell line. Blood 1987; 69: 1053-7. 6. Cotes MP, Dore CJ, Liu Yin JA, eta/. Determination
erythropoietin
in the investigation
of erythrocytosis.
of serum immunoreactive N Engl J Med 1986; 315:
283-7. 7. Garcia JF, Ebbe SN, Hollander L. Cutting HO, Miller ME, Cronkite
EF. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings. J Lab Clin Med 1982; 99: 624-35. 6. Gurney CW. Erythremia in renal disease. Trans Assoc Am Physicians 1960;
73: 103-12.
Volume 93
Paraneoplastic erythrocytosis in patients with Wii’ tumors is exceedingly rare, with only three reported casea in the literature. We report acaseofayoungmanwithWilms’tumorwitha significant erythrocytosis but a normal serum eryfhropoietin level and a tumor that elaborated erythropoietin.
From the Department of Medicine (RD. RLD). Department of Urology (JD. JL), and Department of Pathology (JAB), University of Iowa Hospitals and Clinics, Iowa City, Iowa. Requests for reprints should be addressed to Robert Dreicer, M.D., MS., Department of Medicine, University of Iowa, Iowa City, Iowa 52242. Manuscript submitted February 26, 1991, and accepted in revised form July 5. 1991.
CASE REPORT A 20-year-old nonsmoking man was found to have a hemoglobin level and hematocrit of 207 g/L and 0.62, respectively, prior to removal of an ingrown toenail. He gave a history of cold intolerance, fatigue, and weight loss of 4.5 kg. Physical examination demonstrated a thin man with plethoric facies, normal vital signs, and otherwise unremarkable findings. Laboratory values were as follows: leukocyte count 7.7 X log/L, platelet count 188 X log/L, creatinine 106 pmol/L, thyroid-stimulating hormone 0.82 mu/L, oxygen tension 13.2 kPa (99 mm Hg), 1% carboxyhemoglobin, normal hemoglobin oxygen affinity studies, red cell mass 51.1 mL/kg (normal 30 f 5 ml/kg), plasma volume 42.0 mL/kg (normal 40 f 5 ml/kg), and serum erythropoietin 8 mU/mL (normal 4 to 24 mU/mL; radioimmunoassay performed by SmithKline Bio-Science Lab, Van Nuys, CA). Abdominal ultrasonography demonstrated a 4-cm mass in the upper pole of the right kidney. An abdominal computed tomographic (CT) scan confirmed the presence of a solid mass confined within the renal capsule (Figure 1) without regional lymphadenopathy or extension into the renal vein. Staging studies including chest radiograph, chest CT scan, and bone scan did not demonstrate metastatic disease. The patient donated 2 units of blood for autologous transfusion and had a preoperative hematocrit of 0.57. The patient underwent a right radical nephrectomy with regional lymph node dissection. The left kidney was palpably normal. The surgery was uncomplicated and the patient made an uneventful recovery. Pathologic study revealed a favorable-histology Wilma’ tumor confined to the kidney with negative nodes. Samples of tumor and adjacent, histologically normal renal parenchyma were taken for erythropoietin analysis. Tissue samples (0.5 g) were minced and added to 10 mL of isotonic saline and agitated, and aliquota of supernatant were analyzed for erythropoietin. Erythropoietin levels were 60 mU/mL in the tumor aliquot and less than 2 mU/mL in the normal renal parenchyma. The patient had a stage I favorable-histology Wilms’ tumor and was registered into a National
August 1992 The American Journal of Medlclne
Volume 93
229
PARANEOPLASTIC ERVTHROCVTOSISAND WILMS’ TUMOR / DREICERET AL
ropoietin secretion occurred, making the results of determination of a single erythropoietin level deceptive [6]; or alternatively, that a patient’s “normal” erythropoietin level may in fact be inappropriately elevated when found in association with an increased red cell mass [7]. There are at least three lines of evidence confiiming that our patient’s Wilma’ tumor elaborated erythropoietin that led to erythrocytosis. First, removal of the tumor corrected the erythrocytosis. Second, an extract of the tumor contained high levels of erythropoietin, but the adjacent normal kidney tissue did not. Finally, the “normal” plasma erythropoietin concentration (8 mU/mL) in our patient was inappropriately elevated in the presence of a greatly increased erythrocyte mass of 170% of normal. It is of interest that 30 years ago, Gurney [8] reported the first case of erythrocytosis induced by a renal tumor, an adenocarcinoma, secreting erythropoietin. His patient was a 62-year-old man whose erythrocytosis was ameliorated by removal of the tumor. A saline extract of the tumor contained large amounts of erythropoietin, but normal kidney tissue adjacent to the tumor and plasma from the patient had no erythropoietic activity in the relatively insensitive polycythemic mouse assay. This unusual case of paraneoplastic erythrocytosis in an adult with Wilma’ tumor underscores the need for caution in the interpretation of “normaI” erythropoietin levels in patients with secondary polycythemia [5]. Isolated erythrocytosis in a patient who is not hypoxic should, in itself, prompt an evaluation of the kidneys and other potential sites of excessive production of erythropoietin.
Figure
1. Computed tomographic (CT) scan image demonstrates the right renal mass (arrow) confined within the renal capsule. The contralateral kidney is within normal limits. Additional CT scan images (not shown) did not reveal evidence of tumor involving either the renal vein or regional lymph nodes.
Wilma’ Tumor Study Group protocol. The patient’s hemoglobin level and hematocrit were 110 g/L and 0.33, respectively, prior to initiation of chemotherapy with actinomycin D and vincristine. The patient tolerated chemotherapy without difficulty and is alive and free of disease 9 months after his radical nephrectomy. The hemoglobin level and hematocrit obtained 7 months following completion of chemotherapy were 144 g/L and 0.44, respectively.
COMMENTS A search for the cause of an elevated hematocrit in this asymptomatic young man led to the discovery and probable cure of a malignant tumor, rarely found in a 20-year-old person. The incidence of erythrocytosis in patients with renal cell carcinoma is between 3% and 10%; however, elevated erythropoietin levels have been reported in up to 63% of cases [l]. In contrast, approximately 4% of patients with erythrocytosis have renal cell carcinoma [2]. Although there are numerous reports of elevated erythropoietin levels in patients with Wilma’ tumor [3], there are only three cases of associated erythrocytosis reported in the literature [4]. Hypotheses to account for the wide divergence between the numbers of patients with elevated erythropoietin and those with erythrocytosis include the elaboration of an immunologically active, but biologically inert, erythropoietin, or the inability of the target erythroid cell to respond to stimulation [5]. Additional explanations include the possibility that only intermittent abnormal eryth-
230
August 1992 The Americen Journal of Medicine
REFERENCES 1. Sufrin G, Chasan S. Golio A, Murphy GP. Paraneoplastic and serolo& syndromes of renal adenocarcinoma. Semin Ural 1989; 7: 158-71. 2. Hocking WG. Hematologic abnormalities in patients with renal diseases. He matol Oncol Clin North Am 1987; 1: 229-60. 3. Kenny GM, Mirand EA. Staubitz WJ, Allen JE, Trudel PJ. Murphy GP. Erythropoietin levels in Wilms tumor patients. J Ural 1970; 104: 758-61. 4. Hammond D, Winnick S. Paraneoplastic erythrocytosis and ectopic erythropoietins. Ann NY Acad Sci 1974; 230: 219-27. 5. Sherwood JB, Burns ER, Shouval D. Stimulation by cAMP of erythropoietin secretion by an established human renal carcinoma cell line. Blood 1987; 69: 1053-7. 6. Cotes MP, Dore CJ, Liu Yin JA, eta/. Determination
erythropoietin
in the investigation
of erythrocytosis.
of serum immunoreactive N Engl J Med 1986; 315:
283-7. 7. Garcia JF, Ebbe SN, Hollander L. Cutting HO, Miller ME, Cronkite
EF. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings. J Lab Clin Med 1982; 99: 624-35. 6. Gurney CW. Erythremia in renal disease. Trans Assoc Am Physicians 1960;
73: 103-12.
Volume 93
