Case Report
Urologia Internationalis
Urol Int 1996:56:246-249
Erythropoietin-Producing Adrenocortical Carcinoma
Toshitsugu Oka Kenzo Onoe Kenji Nishimura Akira Tsujimura Hideki Sugao Minato Takaha Akihiko Kurata
Department of Urology, Osaka National Hospital, Osaka, Japan
| Key Words | Abstract |
| Erythropoietin | A 62-year-old Japanese male with an erythropoietin-producing adrenocortical |
| Adrenocortical carcinoma | carcinoma is presented. The elevated erythropoietin level and erythrocytosis returned to normal after surgical removal of a huge left adrenal tumor weigh- ing 1,580 g. A histopathological diagnosis of adrenocortical carcinoma was made. Despite adjuvant combined chemotherapy, the patient died of lung and liver metastases 3.5 months after operation. Although the possibility that the elevated plasma erythropoietin level and erythrocytosis resulted from local kidney hypoxia, caused by pressure from the huge adrenal tumor, cannot be completely neglected, the positive cytoplasmatic evidence of immunoreactive erythropoietin in the carcinoma cells and the detection of a high erythropoic- tin level in the tumor extract on radioimmunoassay confirmed that this is a very rare case of erythropoietin-producing adrenocortical carcinoma. |
Introduction
The most common malignant tumor associated with erythropoietin-induced secondary polycythemia is renal cell carcinoma. On the other hand, adrenocortical carci- noma associated with polycythemia is very rare. We present here a very rare case of erythropoietin-producing adrenocortical carcinoma.
Case Report
A 62-year-old Japanese male visited our hospital on January 27. 1989, for cpigastralgia that he had experienced for about 6 months. and a diagnosis of duodenal ulcer was made on endoscopic examina- tion. Routine laboratory examination for duodenal ulcer incidentally revealed erythrocytosis and ultrasonography showed a mass in the left retroperitoneal space. and he was referred to our clinic on April
19. 1989. Hematologic data were as follows: red blood cell count 6.330.000/mm3 (normal range 4.000.000-5.400.000/mm3); hemo- globin 17.5 g/dl (12.5-17.0 g/dl); hematocrit reading 56.0% (34.0- 50.0%): white blood cell count 8.900/mm3(4.000-9.000/mm3). and a platelet count of 162,000/mm3 (120.000-340,000/mm3). Blood elec- trolytes and liver functional data were normal except for alkaline phosphatase (203 U/l. normal range ≤ 110 U/l). A specific gravity of 1.025. pH 6.5. glucose (-). protein (±) and no abnormal cellular ele- ments were found on urinalysis. Physical examination showed a palpable solid mass in the left hypochondrial region and a marked varicocele in the left scrotum. An excretory urography. CT scan and abdominal angiography revealed that the retroperitoneal mass was a huge adrenal tumor (fig. 1). Hormonal data showed high levels of plasma renin activity (8.0 ng/ml/h, normal range 0.3-2.9 ng/ml/h). aldosterone (160 pg/ml, normal range 10.9-62.7 pg/ml) and radioim- munoreactive erythropoietin (48.4 mU/ml. normal range 8.0- 30.0 mU/ml), but the values of serum ACTH, epinephrine, norepi- nephrine, dopamine, cortisol and testerone, and urinary excretions of epinephrine. norepinephrine. vanillylmandelic acid and 17-hydro- corticosterone were normal. The radioimmunoassay method for the
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Toshitsugu Oka Department of Urology Osaka National Hospital 2-1-14. Hoenzaka Chuo-ku. Osaka 540 (Japan)
Received: September 29. 1995 Accepted: November 17. 1995
| EPO standard preparation or Sample + | 100 μl |
| Buffer (Borate buffer 50 mM, pH 8.2) + | 200 μl |
| Anti-EPO antibody 1 | 100 ul |
| Pre-incubation (25℃, 20 h) | |
| 1 | |
| 1251-EPO | 100 μl |
| 1 | |
| First incubation (4 ℃, 4 h) | |
| 1 Immunobead (Goat anti-rabbit serum) 1 | |
| 250 µl | |
| Second incubation (25℃, 1 h) 1 | |
| Centrifuge (4℃, 20 min, 3,000 rpm) 1 | |
| Aspirate and Count |
Fig. 2. Scheme for the radioimmunoassay method of plasma erythropoietin.
measurement of serum erythropoietin using anti-erythropoietin anti- body and 1251-labeled erythropoietin is shown in figure 2.
Abdominal exploration was undertaken on May 15, 1989, and the huge left adrenal tumor with tumor thrombus in the dilated infe- rior adrenal vein extending into the left renal vein was removed. The enlarged infrarenal hilar lymph nodes were also removed. During the operation, we found that the marked varicocele in the left scrotum
resulted from the anomaly of the left spermatic vein entering the dilated inferior adrenal vein with tumor thrombus. We also supposed that the elevations in plasma renin activity and aldosterone level resulted from compression of the left renal artery by the enlarged infrarenal hilar lymph nodes. During the operation a large amount of blood loss occurred and blood transfusion of 4,000 cm3 was per- formed. The surgical specimen measured 19 x 15.5 x 9 cm and weighed 1.580 g. Grossly its cut surface revealed that the tumor had a variegated pattern with soft friable nodules in association with necro- sis and hemorrhages. Microscopic study showed that the tumor cells closely resembled normal adrenocortical cells and that they were arranged in nodules and trabeculae with a sinusoidal vascular struc- ture. Furthermore, it revealed that in some tumor portions atypical cells with hyperchromatia and prominent nucleoli were present (fig. 3). A histopathological diagnosis of adrenocortical carcinoma was made. The enlarged infrarenal hilar lymph nodes contained met- astatic lesions from adrenocortical carcinoma.
Elevated plasma erythropoietin levels and erythrocytosis, as well as the elevated plasma renin activity and aldosterone values returned to almost normal 1 month after operation: radioimmunoreactive erythropoietin 19.0 mU/ml; red blood cell count 3,780,000/mm3; hemoglobin 11.6 g/dl: hematocrit reading 34.5%: plasma renin activ- ity 2.1 ng/ml/h. and aldosterone 39.0 pg/ml. Despite combined adju- vant chemotherapy including cisplatinum, doxorubicin, cyclophos- phamide and 5-fluorouracil added to oral op’-DDD. the patient died of lung and liver metastases 3.5 months after operation on September 4. 1989. Autopsy was not donc.
The erythropoietin concentration of 73.8 mU/g in the tumor material frozen at - 70°℃ was measured using the same radioimmu- noassay method as the measurement of serum erythropoietin. On the other hand. the tissue erythropoietin concentrations of extracts of normal adrenal cortices obtained by radical nephrectomy from 2 patients with renal cell carcinoma measured at the same time were 19.2 and 28.2 mU/g.
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Some sections of the formalin-fixed paraffin-embedded speci- mens of the adrenocortical carcinoma were analyzed for the presence of human erythropoietin by the immunoperoxidase method using a commercial monoclonal mouse anti-human erythropoietin pur- chased from CosmoBio Labo (Product Code: AE7A5). This immuno- histochemical stain of erythropoietin was employed according to the method described by Hsu et al. [1] (= ABC method). Immunorcactive erythropoietin positivitics were demonstrated in the adrenocortical carcinoma cells, especially in the cells with abundant clear cytoplas- ma (fig. 4a). For the erythropoietin-positive control slide a normal kidney obtained by total nephroureterectomy from a patient with ureteral tumor was used (fig. 4b).
Finally the diagnosis of erythropoietin-producing adrenocortical carcinoma was made.
Discussion
Erythropoietin is a glycoprotein with a molecular weight of approximately 30,000 daltons, which consists of 165 amino acids and regulates red blood cell production [2-4]. Since it is mainly produced in the kidney [5], tumor-associated secondary erythrocytosis most com- monly occurs in renal tumors, especially renal cell carci- noma [6, 7]. Adrenocortical carcinoma associated with erythrocytosis, however, is very rare. Hammond and Winnick [8] stated that of 340 reported cases 120 were associated with renal cell carcinoma and 11 adrenal tumors were associated with erythrocytosis. In the studies reported by Waldman et al. [9] saline extracts of 2 adreno-
cortical tumors from patients with erythrocytosis and the sera from 3 such cases were negative in the erythropoietin assay. On the other hand, in 1969 Meincke [10] showed that the erythropoietically active material in the rat bear- ing a transplantable adrenocortical carcinoma is erythro- poietin and that the site of production of erythropoietin is the tumor itself. To our knowledge, however, no case of erythropoietin-producing adrenocortical carcinoma has been reported until now.
As possible mechanisms by which the tumors provoke erythrocytosis, Balcerzak and Bromberg [11] described the following five items: (1) renal or hepatic hypoxia induced by impaired circulation; (2) systemic hypoxia; (3) impairment of erythropoietin catabolismo (4) produc- tion of erythropoietin by the tumor itself, and (5) produc- tion by the tumor of erythropoietic substances other than erythropoietin. In our present case we could not complete- ly neglect the possibility that erythrocytosis and the eleva- tion of plasma erythropoietin levels resulted from local kidney hypoxia caused by pressure from the huge adrenal tumor mass causing impairment of kidney microcircula- tion or constriction of the renal artery or vein, as Ham- mond and Winnich [8] described. Since a large amount of blood loss occurred during the operation and blood trans- fusion of 4,000 cm3 was performed, we did not examine the serum erythropoietin level until 1 month after opera- tion. After that, the patient’s condition extremely rapidly deteriorated associated with a large amount of hemotho- rax caused by lung metastasis. The patient died only 3.5 months after operation. Due to the broad metastatic dis- ease, the serum erythropoietin level could not be re- peatedly studied after operation in order to see whether the erythropoietin level remains in the normal range. However, the evidence of positive immunohistochemical erythropoietin in the cytoplasma of the adrenocortical carcinoma cells, as well as the high erythropoietin level in the tumor extract on radioimmunoassay, confirmed that this is a very rare case of erythropoietin-producing adre- nocortical carcinoma.
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