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Adrenocortical adenomas: Nonfunctioning?
LETTERS TO THE EDITOR EFFECT OF BETA BLOCKADE AND STIMULATIONON STAGE FRIGHT
TABLE II
BETA
Charles 0. Brantigan, M.D., in a letter to the editor, has stated that the dosages of propranolol and terbutaline were inadVUtently Ot’tIitkd from his article on “stage fright” (Am J Med 1982; 72: 88-94). The dosage of propranolol was 40 mg and that of terbutaline was 5 mg. ADRENOCORTICAL
ADENOMAS:
NONFUNCTIONING? To the Editor: Recently an excellent review by Bertagna and Orth [I] on adrenocortical tumors was published by the Journal. The authors stated that “nonfunctional” tumors probably merely secreted insufficient steroids to cause signs and symptoms, The purpose of this letter is to document two cases that extend their observations but do not entirely conform to that conclusion. In one patient with a massive benign tumor, large amounts of “inactive” compounds were produced. In the other, a typical adrenal adenoma was found during evaluation of hematuria. Serum and urinary results in this patient are consistent with its being nonsecretory. Methods. Serum and urinary steroid levels were measured by specific radioimmunoassays. Urinary 17-hydroxycorticoid (17-OHCS) levels were measured by the Porter-Silber reaction as was the urinary tetrahydro-compound-S (THCS) level. The 17-ketosteroid (17-KS) levels were assayed by the Zimmermann reaction. The dihydrotestosterone precipitation index (DHT-PI), a measure of testosterone-binding globulin, was measured as previously described [2]. Case 1. A 30 year old woman was found to have hypertension on a periodic examination. There was a strong paternal history of hypertension. The patient also gave a history of hirsutism since menarche. The weight was stable and she had regular menses. On physical examination, her blood pressure was 1807 120 mm Hg, she weighed 180 pounds, and her height was 69’/* inches. There was hirsutism of the chin and abdominal wall. There were no Cushingoid stigmata and no virilization of the external genitalia. An intravenous pyelogram revealed a large left suprarenal mass. Arteriograms documented a large neovascular tumor of the left adrenal area. The serum potassium level was 4.0 meq/liter. Endocrine results are shown in Tables I and II. TABLE I
DHEA
I?-A5P
21.2 4.2 f 1.6
22.5 1.5 f 0.5
DHEA-S 23,300 1,700 f 400
DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiadrosterone sulfate; 17-AS-P = 17-hydroxypregnenolone.
Through a thoracoabdominal incision, a 620 g tumor was removed. It measured 14 X 10.5 X 7 cm in the greatest dimensions. The capsule was intact. There was no gross or microscopic venous involvement. The ultrastructural features of the tumor confirmed that it was an adrenocortical tumor. The patient became normotensive shortly folfpwing surgery, and this has persisted. In addition, the hirsutism diminished. The urinary 17-KS level is now 5.9 mg/24 hours. Comment. The patient has been followed for five and a half years and there is no evidence of recurrence despite the initial secretion of large amounts of 17-KS. Major secretory products were AS C19, free and conjugated steroids and free A5 C-2, steroids. Another interesting charadteristic of this tumor was a normal excretion of 17-OHCS with a high cortisol excretion but nonsuppressibility with low- and high-dose dexamethasone of the 17-DHCS. In addition, the 8 AM plasma cortisol level was 20 Fgldl and remained at that level after 1 mg of dexamethasone the night before. There were no Cushingoid stigmata, other than hirsutism, which is associated with an elevated free testosterone level (serum testosterone 48 ng/dl, DHT-PI 0.02, with normal for females being 0.8 to 1.2). The patient did, however, have abnormal results of glucose tolerance testing (1 hours 242 mg/dl, 2 hour 183 mg/dl). Despite the massive size of this tumor and the high excretion of 17-KS, the normal excretion of compound-S, plus the absence of malignant characteristics such as vascular involvement, supports our belief that this was a massive benign adrenal tumor. The major characteristics of this tumor were (1) massive production of AS steroids by a large but benign tumor [3,4]; (2) abnormal coritsol kinetics without the usual clinical features of Cushing’s syndrome and not requiring replacement after the immediate postoperative period; (3) the production of a presumed but unidentified hypertensive compound. Case II. The second patient was a 69 year old man, who was found to have a left suprarenal mass during evaluation for microscopic hematuria. There were no symptoms of endo-
Preoperative Urinary Steroid Values
Dexamethasone
l
Preoperative Normal
Serum Steroids (ng/dl)
THCS (mg/24 hours)
17-KS (mg124hours)
0 0.5 mg every 6 hours 2.0 mg every 6 hours 7 days postoperative
1.0 1.0 1.0
144
-
3.6
Normal values
1.0
5-15
Measured as acid-fluorescent
138 180
17.OHCS (mg124hours)
Cortisol’ @g/24 hours)
8.1 8.3 8.1
717 728 343
l-9
<320
steroids (Continued on page 830)
May 1982
The American Journalof Medicine Volume 72
829
LETTERS TO THE EDITOR (Cont’d) crine dysfunction. Blood pressure was 135185 mm Hg. He was a normal appearing male. Laboratory results are found in Table Ill. TABLE III
Hormone Studies in a Nonfunctioning Adenoma
lo the Editor:
Measured by radioimmunoassay. t Normal male values in parentheses. If not specified, values are serum. l
The left adrenal mass was removed in toto and there were two adenomas, the largest being 4 X 4 X 3 cm, the second adenoma being 1 cm in the greatest diameter. Histologic features were variable, showing mainly abundant foamy cytoplasm; however, in some places, cells possessed eosinophilic cytoplasm with little or no vacuolation. This case is presented because the three patients with adenomas discussed by Bertagna and Orth [l] without clinical endocrine syndromes, except possibly hypertension, showed in one instance, laboratory values typical of Cushing’s syndrome and in two others normal or slightly increased glucocorticoid production, and absence of a normal plasma coritsol diurnal rhythm. In our patient, there was diurnal variation. In addition, the cortisol level shortly following surgery indicates the remaining adrenocortical tissue and the pituitary were not suppressed. Although a completely exhaustive search for steroids was not accomplished, the extensive studies on this patient are consistent with his having a true nonfunctioning adrenocortical tumor. Acknowledgment. The A5 steroids from the first patient were kindly measured by Dr. Guy Abraham. RALPH G. WIELAND, M.D. Chairman, Department of Medicine Case Western Reserve University Medical School Cleveland, Ohio 44112 1. BertagnaC, Orth DN: Clinical and laboratory findings and results of
030
therapy in 58 patients with adrenoccrtical tumors admitted to a single medical center (1951-1978). Am J Med 1981; 71: 855. Wieland RG, Zorn EM, Johnson MW: Elevated testosterone-binding globulin in Klinefelter’s syndrome. J Clin Endocrinol Metab 1980; 51:1199.
May 1982
The American Journal of Medicine
4.
Fukanshima DK, Gallagher TF: Steroid production in “nonfunctioning” adrenocortical tumors. J Clin Endocrinol Metab 1963; 23: 923. Wieland RG. de Courcy C, Hirschmann HK: Detection of 3 @,17dihydroxy-preng-5-en-20-one in blood from a human adrenal tumor. Steroids 1983; 2: 61.
CHLORAMPHENICOL: INEFFECTIVE FOR TREATMENT OF LISTERIA MENINGITIS
Urinary cortisol’ 61 wg/24 hours (18-120)t Urinary 17-KS 12.8 mg124 hours 8 AM cortisoi preoperative 19.3 pg/dl 4 PM cortisol preoperative 11.1 pg/dl 8 AM cortisol postoperative 18.6 pgldl Aldosterone 8.9 ngldl(3-10) Testosterone 345 ng/dl(300-800) Estradiol 27 pg/dl (10-50) DHEA-S 620 ngldl(1,900-3,340)
2.
3.
Volume 72
In the August 1981 issue of the Journa/(Am J Med 1981; 71: 199-209), Cherubin et al. reported a mortality rate of 75 percent in patients with Listeria meningitis treated with chloramphenicol alone or combined with a penicillin, versus 50 percent in patients treated with a penicillin without chloramphenicol. Three-quarters of these patients were older than 50 years of age and one-half had chronic immunocompromising diseases. We recently reviewed the results of antimicrobial therapy in 70 renal transplant recipients with central nervous system disease due to Listeria monocytogenes [ 11. Five patients were specified to have received chloramphenicol without a penicillin; three died after three, eight and 13 days of therapy, and two had relapses following 19- and 24-day courses of treatment. Chloramphenicol was ineffective in 100 percent of cases. In contrast, in the other 65 patients, there were 23 deaths during therapy and four relapses; antimicrobial therapy failed in only 42 percent of cases. Additionally, chloramphenicol was reported to be ineffective in a murine model of Listeria meningitis [2]. Thus, these investigations suggest chloramphenicol is not effective against listeriosis of the central nervous system. We recommend treatment of Listeria meningitis with ampicillin plus gentamicin intravenously [I]. Patients allergic to penicillins should be treated with tetracycline [3,4]; this has been successful even in the compromised host with meningitis [5]. During pregnancy and childhood, erythromycin should be substituted for tetracycline in the penicillin-allergic
[41. ALAN M. STAMM,
M.D.
University of Alabama in Birmingham Birmingham, Alabama 35294 1. 2.
3.
4.
5.
Stamm AM, Dismukes WE, Simmons BP, et al.: Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982; 4: (in press). Tsai YH, Hirth RS, Leitner F: A murine model for listerial meningitis and meningoencephalitis: therapeutic evaluation of drugs in mice. Chemotherapy 1980; 26: 196-206. Buchner LH. Schneierson SS: Clinical and laboratory aspects of Lisferia monocyfogenes infections: with a report of ten cases. Am J Med 1968; 45: 904-92 1. Seeliger HPR, Finger H: Listeriosis. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: WB Saunders. 1976: 333-365. Christensen E: Clinical listeriosis in renal allotransplantation. Acta Med Stand 1975; 197: 235-239.
TABLE II
BETA
Charles 0. Brantigan, M.D., in a letter to the editor, has stated that the dosages of propranolol and terbutaline were inadVUtently Ot’tIitkd from his article on “stage fright” (Am J Med 1982; 72: 88-94). The dosage of propranolol was 40 mg and that of terbutaline was 5 mg. ADRENOCORTICAL
ADENOMAS:
NONFUNCTIONING? To the Editor: Recently an excellent review by Bertagna and Orth [I] on adrenocortical tumors was published by the Journal. The authors stated that “nonfunctional” tumors probably merely secreted insufficient steroids to cause signs and symptoms, The purpose of this letter is to document two cases that extend their observations but do not entirely conform to that conclusion. In one patient with a massive benign tumor, large amounts of “inactive” compounds were produced. In the other, a typical adrenal adenoma was found during evaluation of hematuria. Serum and urinary results in this patient are consistent with its being nonsecretory. Methods. Serum and urinary steroid levels were measured by specific radioimmunoassays. Urinary 17-hydroxycorticoid (17-OHCS) levels were measured by the Porter-Silber reaction as was the urinary tetrahydro-compound-S (THCS) level. The 17-ketosteroid (17-KS) levels were assayed by the Zimmermann reaction. The dihydrotestosterone precipitation index (DHT-PI), a measure of testosterone-binding globulin, was measured as previously described [2]. Case 1. A 30 year old woman was found to have hypertension on a periodic examination. There was a strong paternal history of hypertension. The patient also gave a history of hirsutism since menarche. The weight was stable and she had regular menses. On physical examination, her blood pressure was 1807 120 mm Hg, she weighed 180 pounds, and her height was 69’/* inches. There was hirsutism of the chin and abdominal wall. There were no Cushingoid stigmata and no virilization of the external genitalia. An intravenous pyelogram revealed a large left suprarenal mass. Arteriograms documented a large neovascular tumor of the left adrenal area. The serum potassium level was 4.0 meq/liter. Endocrine results are shown in Tables I and II. TABLE I
DHEA
I?-A5P
21.2 4.2 f 1.6
22.5 1.5 f 0.5
DHEA-S 23,300 1,700 f 400
DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiadrosterone sulfate; 17-AS-P = 17-hydroxypregnenolone.
Through a thoracoabdominal incision, a 620 g tumor was removed. It measured 14 X 10.5 X 7 cm in the greatest dimensions. The capsule was intact. There was no gross or microscopic venous involvement. The ultrastructural features of the tumor confirmed that it was an adrenocortical tumor. The patient became normotensive shortly folfpwing surgery, and this has persisted. In addition, the hirsutism diminished. The urinary 17-KS level is now 5.9 mg/24 hours. Comment. The patient has been followed for five and a half years and there is no evidence of recurrence despite the initial secretion of large amounts of 17-KS. Major secretory products were AS C19, free and conjugated steroids and free A5 C-2, steroids. Another interesting charadteristic of this tumor was a normal excretion of 17-OHCS with a high cortisol excretion but nonsuppressibility with low- and high-dose dexamethasone of the 17-DHCS. In addition, the 8 AM plasma cortisol level was 20 Fgldl and remained at that level after 1 mg of dexamethasone the night before. There were no Cushingoid stigmata, other than hirsutism, which is associated with an elevated free testosterone level (serum testosterone 48 ng/dl, DHT-PI 0.02, with normal for females being 0.8 to 1.2). The patient did, however, have abnormal results of glucose tolerance testing (1 hours 242 mg/dl, 2 hour 183 mg/dl). Despite the massive size of this tumor and the high excretion of 17-KS, the normal excretion of compound-S, plus the absence of malignant characteristics such as vascular involvement, supports our belief that this was a massive benign adrenal tumor. The major characteristics of this tumor were (1) massive production of AS steroids by a large but benign tumor [3,4]; (2) abnormal coritsol kinetics without the usual clinical features of Cushing’s syndrome and not requiring replacement after the immediate postoperative period; (3) the production of a presumed but unidentified hypertensive compound. Case II. The second patient was a 69 year old man, who was found to have a left suprarenal mass during evaluation for microscopic hematuria. There were no symptoms of endo-
Preoperative Urinary Steroid Values
Dexamethasone
l
Preoperative Normal
Serum Steroids (ng/dl)
THCS (mg/24 hours)
17-KS (mg124hours)
0 0.5 mg every 6 hours 2.0 mg every 6 hours 7 days postoperative
1.0 1.0 1.0
144
-
3.6
Normal values
1.0
5-15
Measured as acid-fluorescent
138 180
17.OHCS (mg124hours)
Cortisol’ @g/24 hours)
8.1 8.3 8.1
717 728 343
l-9
<320
steroids (Continued on page 830)
May 1982
The American Journalof Medicine Volume 72
829
LETTERS TO THE EDITOR (Cont’d) crine dysfunction. Blood pressure was 135185 mm Hg. He was a normal appearing male. Laboratory results are found in Table Ill. TABLE III
Hormone Studies in a Nonfunctioning Adenoma
lo the Editor:
Measured by radioimmunoassay. t Normal male values in parentheses. If not specified, values are serum. l
The left adrenal mass was removed in toto and there were two adenomas, the largest being 4 X 4 X 3 cm, the second adenoma being 1 cm in the greatest diameter. Histologic features were variable, showing mainly abundant foamy cytoplasm; however, in some places, cells possessed eosinophilic cytoplasm with little or no vacuolation. This case is presented because the three patients with adenomas discussed by Bertagna and Orth [l] without clinical endocrine syndromes, except possibly hypertension, showed in one instance, laboratory values typical of Cushing’s syndrome and in two others normal or slightly increased glucocorticoid production, and absence of a normal plasma coritsol diurnal rhythm. In our patient, there was diurnal variation. In addition, the cortisol level shortly following surgery indicates the remaining adrenocortical tissue and the pituitary were not suppressed. Although a completely exhaustive search for steroids was not accomplished, the extensive studies on this patient are consistent with his having a true nonfunctioning adrenocortical tumor. Acknowledgment. The A5 steroids from the first patient were kindly measured by Dr. Guy Abraham. RALPH G. WIELAND, M.D. Chairman, Department of Medicine Case Western Reserve University Medical School Cleveland, Ohio 44112 1. BertagnaC, Orth DN: Clinical and laboratory findings and results of
030
therapy in 58 patients with adrenoccrtical tumors admitted to a single medical center (1951-1978). Am J Med 1981; 71: 855. Wieland RG, Zorn EM, Johnson MW: Elevated testosterone-binding globulin in Klinefelter’s syndrome. J Clin Endocrinol Metab 1980; 51:1199.
May 1982
The American Journal of Medicine
4.
Fukanshima DK, Gallagher TF: Steroid production in “nonfunctioning” adrenocortical tumors. J Clin Endocrinol Metab 1963; 23: 923. Wieland RG. de Courcy C, Hirschmann HK: Detection of 3 @,17dihydroxy-preng-5-en-20-one in blood from a human adrenal tumor. Steroids 1983; 2: 61.
CHLORAMPHENICOL: INEFFECTIVE FOR TREATMENT OF LISTERIA MENINGITIS
Urinary cortisol’ 61 wg/24 hours (18-120)t Urinary 17-KS 12.8 mg124 hours 8 AM cortisoi preoperative 19.3 pg/dl 4 PM cortisol preoperative 11.1 pg/dl 8 AM cortisol postoperative 18.6 pgldl Aldosterone 8.9 ngldl(3-10) Testosterone 345 ng/dl(300-800) Estradiol 27 pg/dl (10-50) DHEA-S 620 ngldl(1,900-3,340)
2.
3.
Volume 72
In the August 1981 issue of the Journa/(Am J Med 1981; 71: 199-209), Cherubin et al. reported a mortality rate of 75 percent in patients with Listeria meningitis treated with chloramphenicol alone or combined with a penicillin, versus 50 percent in patients treated with a penicillin without chloramphenicol. Three-quarters of these patients were older than 50 years of age and one-half had chronic immunocompromising diseases. We recently reviewed the results of antimicrobial therapy in 70 renal transplant recipients with central nervous system disease due to Listeria monocytogenes [ 11. Five patients were specified to have received chloramphenicol without a penicillin; three died after three, eight and 13 days of therapy, and two had relapses following 19- and 24-day courses of treatment. Chloramphenicol was ineffective in 100 percent of cases. In contrast, in the other 65 patients, there were 23 deaths during therapy and four relapses; antimicrobial therapy failed in only 42 percent of cases. Additionally, chloramphenicol was reported to be ineffective in a murine model of Listeria meningitis [2]. Thus, these investigations suggest chloramphenicol is not effective against listeriosis of the central nervous system. We recommend treatment of Listeria meningitis with ampicillin plus gentamicin intravenously [I]. Patients allergic to penicillins should be treated with tetracycline [3,4]; this has been successful even in the compromised host with meningitis [5]. During pregnancy and childhood, erythromycin should be substituted for tetracycline in the penicillin-allergic
[41. ALAN M. STAMM,
M.D.
University of Alabama in Birmingham Birmingham, Alabama 35294 1. 2.
3.
4.
5.
Stamm AM, Dismukes WE, Simmons BP, et al.: Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982; 4: (in press). Tsai YH, Hirth RS, Leitner F: A murine model for listerial meningitis and meningoencephalitis: therapeutic evaluation of drugs in mice. Chemotherapy 1980; 26: 196-206. Buchner LH. Schneierson SS: Clinical and laboratory aspects of Lisferia monocyfogenes infections: with a report of ten cases. Am J Med 1968; 45: 904-92 1. Seeliger HPR, Finger H: Listeriosis. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: WB Saunders. 1976: 333-365. Christensen E: Clinical listeriosis in renal allotransplantation. Acta Med Stand 1975; 197: 235-239.