Prolonged Fever as a Presenting Symptom in Adrenal Tumors
J. M. Klausner, R. Nakash, M. Inbar, M. Gutman, S. Lelcuk, R. R. Rozin Rokach (Hadassah) Hospital, Tel-Aviv Medical Center, and Sackler School of Medicine, Tel-Aviv University, Israel
Key Words. Fever · Adrenal tumors · Fever of unknown origin
Abstract. Four patients with adrenal tumors in whom prolonged fever was the foremost symptom are presented. Two of the patients had nonfunctional adrenocortical carcinoma, one had a pheochromocytoma without adrenergic hyperactivity, and in the fourth, an aldosteronoma was found. Only in I case was the tumor (pheochromocytoma) resectable and this patient became afebrile post surgery. A review of the literature revealed that fever is encountered in 6-10% of cases with adrenal tumors, sometimes as the first manifestation of disease. However, a survey of the large series of fever of unknown origin revealed no mention of adrenal tumors in that group of solid tumors which many cause prolonged fever.
Introduction
Adrenal tumors usually manifest as endocrine ab- normalities. In patients without endocrine syndromes, abdominal discomfort, pain, distention, and the presence of an abdominal mass or wide-spread metas- tases lead to the diagnosis [1, 2].
Adrenal tumors presenting with prolonged fever as the cardinal symptom are rarely described and studies of fever of unknown origin do not mention adrenal tumors as a possible etiology [3-5]. Four patients with adrenal tumors, in which prolonged fever was the foremost sign, are presented. In addition, the litera- ture on the frequency of fever in adrenal tumors is reviewed.
Clinical Material
Case No. 1 (1984). A 51-year-old male was admitted due to fluctuating fever of 38-39 C of 6 weeks’ duration. Physical exam- ination was unremarkable aside from mild tenderness in the left hypochondrium. Laboratory examinations were all within normal limits. Blood and urine cultures were negative. An abdominal CT demonstrated a 15-cm round. highly vascular mass under the left diaphragm, above the kidney. Repeated scrum and urinary cate- cholamines and steroids taken for a suspected adrenal tumor were within the normal range.
After a 3-week course of diagnostic workup. during which the fever persisted. a laparotomy was performed. A large, encapsulated. homogeneous, yellowish mass was found in the retroperitoneum under the left diaphragm. The tumor was completely removed together with the adrenal gland which appeared as part of it. The following day. the patient was afebrile and remained so.
Histologic examination revealed a benign pheochromocytoma. No necrosis, hemorrhage or abscess formation were found within the tumor. The patient is now. 2 years after surgery, disease-free and afebrilc.
Case No. 2 (1979). A 68-year-old female was hospitalized for fever and abdominal pain. She had been running a 37.5-38.5℃ fluctuating fever for the previous 5 months. On admission, she was extremely weak and febrile (39 ℃). A tender mass was found in her left hypochondrium. A barium enema showed that the splenic flexure had been displaced downwards. No diverticular discase or tumor was seen.
She was operated on 24 h later for a suspected intraabdominal abscess. A large, nonresectable tumor occupying the left hypochon- drium was found. Neither pus nor necrosis were present. Biopsies revealed an adrenocortical carcinoma. Repeated tests for hydroxy and ketosteroids, testosterone, serum and urinary cortisol and the diurnal variation of cortisol were within the normal range. The fever persisted. did not respond to antibiotic trial and was controlled by nonsteroidal antiinflammatory drugs. Blood and urinary cultures during and between the febrile episodes were negative. The patient succumbed to her disease 6 months later.
Case No. 3 (1975). A 54-year-old female had been running a fluctuating fever of 38-38.5 ℃ for 6 months. She was referred to the hospital when abdominal pain appeared.
Physical examination revealed tenderness in the right hypochon- drium and a fever of 39 ℃. Laboratory examinations showed mild
leukocytosis, and SGOT of 180, and alkaline phosphatase of 270 IU. Blood and urine cultures were negative. Ultrasonography (US) demonstrated a wider than normal choledocus with possible biliary stones. Acute cholangitis was suspected and since the high fever persisted. surgery was decided upon. A hard. multilobulated tumor was found in the retroperitoneum on the right side. Liver metastases were not found and the biliary ducts were free of pathology. Histol- ogy revealed an adrenocortical carcinoma. The patient died shortly after the operation from multisystem failure.
Case No. 4 (1978). A 55-year-old female was admitted due to a persistent fever of 38-39 C which had appeared 2 months previous- ly. She was suffering from weakness and weight loss. A labile hypertension, discovered 13 years previously, had been treated with diuretics. Physical examination disclosed no abnormality. Labora- tory tests revealed a mild hypokalemia (3-3.5 mg/l) which was attributed to the diuretics. She underwent a thorough workup for fever of unknown origin, including abdominal CT. US and radio- isotope scannings, but nothing which could account for the prolon- ged fever was discovered. A therapeutic trial with antibiotics failed. Steroid administration improved her condition and the fever sub- sided. Two months later, while being withdrawn from steroids. the fever reappeared. Soon afterwards mental confusion and hyperex- citability developed. A neurological workup disclosed cortical brain atrophy. The patient deteriorated rapidly and died 4 months after being hospitalized.
Autopsy revealed a small, round 1.5-cm tumor in the right adrenal gland. No abscess nor any other cause for the fever were found. Severe cortical brain atrophy was also found. Histologic examination of the adrenal tumor revealed an aldosteronoma.
Comments
The outstanding feature in the 4 cases presented is the prolonged fever as the first manifestation of an adrenal tumor lasting from 6 weeks to several months. In 1 case (No. 1), the fever was the only symptom indicating the tumor, whilst in the others symptoms and signs such as weakness, weight loss and abdomi- nal mass were also encountered.
Tumor-associated fever is defined [6, 7] as an unex- plained fever which coincides with tumor growth, and which disappears promptly on tumor removal or con- trol. The fever in the patient with pheochromocytoma clearly fulfils this criterion. Alternatively, when the fever persists with an uncontrolled tumor, without any other reasonable cause, the tumor is likely to be the etiology [6, 7] of the fever. We believe that the fever encountered in cases 2-4 meets this definition.
In none of the cases was there any evidence of metastatic spread, which often gives rise to fever [3, 4, 7]. Neither tumor necrosis, abscess formation, infec- tion or hematomata, which may also give rise to fever, were found. This fact was evident in cases 1 and 4,
where the tumors were completely removed and care- fully examined. However, in the remaining cases (No. 2 and 3) this was based on surgical exploration and incisional biopsy only.
In pheochromocytoma, fever is rarely described [8-10] as one of the signs of increased basal metabolic rate when the tumor predominantly secretes ad- renaline. Our patient with pheochromocytoma did not have any clinical signs of increased adrenergic activity and repeated serum and urinary catecholamine levels in this case were normal. The only indication of an adrenal tumor in this patient was the persistent fever.
Fever was not described in patients with aldo- steronomas. Nevertheless we could not find any alter- native cause for the fever in this patient (No. 4). The only pathological findings were the presence of the tumor and cortical brain atrophy.
As for the adrenocortical carcinomas, (No. 2 and 3), a survey of the literature [1, 2, 11-19] showed that fever is associated with these tumors. Out of 462 patients with adrenal carcinomas, 40 (8.6%) did have fever [1, 2, 11-15, 17, 18]. In another series [16, 19] on adrenal carcinomas, fever is described but its exact frequency is not mentioned. In the vast majority of cases, the fever is mentioned as one of many signs. It is almost always found in patients who have nonfunc- tioning endocrinal tumors and in most cases it is a sign of advanced stage disease. Only in 8 cases was pro- longed fever mentioned [1, 2, 15, 17, 18] as the first sign of adrenal carcinoma. To this we add 4 more patients.
The fever in our cases as well as in most of the reviewed cases fulfills the criteria of fever of unknown origin (FUO) as described by Petersdorf [20]. How- ever, a survey of the large series of FUO [3-6, 20, 21] shows no mention of adrenal tumors as a possible etiology. Lymphomas, especially Hodgkin’s disease and renal cell carcinoma, are the prototype of tumors frequently associated with FUO. In addition, hepato- ma, adenocarcinoma of the stomach, pancreas and colon, gastrinoma, myxoma, mesothelioma, leiomyo- sarcoma, osteogenic and spindle cell sarcomas are included in that group of solid tumors which may cause prolonged fever that could only be related to the presence of the tumor.
Fever in a patient with documented malignancy is most commonly due to infection. After excluding in- fection, the etiology of the tumor-associated fever could come from release of pyrogen from tumor cells, leukocytes and a variety of normal cells [22].
We would like to draw attention to the possibility that adrenal tumors can cause prolonged fever, which is sometimes the first manifestation of the disease.
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J. M. Klausner. MD c/o H. B. Hechtman, MD Department of Surgery Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 (USA)