journal oflnternal Medicine 1991: 2 3 0 : 355-359
Case report Extra-adrenal phaeochromocytoma presenting as fulminant malignant disease with tumour positive sputum cytology R. S. DE JONG, H. A. V A N DEN BERGEN*, C. A. BOENDER & T. TJABBES From the Department of lnternal Medicine and the *Department of Pathology, Sophia Hospital. Zwolle, The Netherlands
Abstract. de Jong RS, van den Bergen HA, Boender CA, Tjabbes T (Department of Internal
Medicine and Department of Pathology, Sophia Hospital, Zwolle. The Netherlands). Extra-adrenal phaeochromocytoma presenting as fulminant malignant disease with tumour positive sputum cytology. Journal of Internal Medicine 1991: 230 : 3 5 5-3 59. A case of a 69-year-old man with an extra-adrenal malignant phaeochromocytoma is described. Sputum cytology revealed metastatic cells, which have not been reported previously in malignant phaeochromocytoma. This case is also remarkable for the short duration of disease, rapid progression and extensive spread of metastases, the radiological aspect of metastatic lesions shown by chest X-ray, hypercalcaemia and extremely high levels of circulating catecholamines and urinary metabolites.
Keywords: catecholamines, malignant phaeochromocytoma. metastases, paraganglioma. sputum cytology.
Introduction Phaeochromocytomas are rare tumours that arise from chromaffin cells, and in most cases secrete catecholamines. Early investigations [ 1,21 reported malignancy in 10-1 5 %of phaeochromocytomas, but in more recent studies using newer techniques for localization of metastases, this percentage rises to almost 50% [3]. A clear distinction between benign and malignant disease cannot be made by histopathological examination, and a diagnosis of malignant disease is based on the presence of recurrent or metastatic disease [41. Most tumours are localized in the adrenal glands. Extra-adrenal localization has been reported in 10-20% of adult patients [l,2, 51. There have been few reports of patients presenting with metastatic disease at multiple sites [6, 71. The general picture that emerges from the literature is one of a patient presenting with a history of hypertension and typical symptoms over a period of several years, few metastases at presentation, and subsequent survival for several years with only palliative treatment [6, 8, 91.
We here describe the case of a patient with an extra-adrenal phaeochromocytoma with extensive and rapidly progressive metastatic disease.
Case report The patient was a 69-year-old man who was known to have suffered from mild hypertension for several years. He was treated with verapamil by his general physician, resulting in satisfactory blood pressure control. He was reported to be in good health until 2 months prior to admission to our hospital. The patient complained of headache, sweating, nausea, loss of appetite, weight loss, constipation, fatigue, muscle pain, hoarseness and haemoptysis. There was no mention of flushing or palpitations. His medication was recently changed to methyldopa because initially his complaints were thought to be side-effects of verapamil. He was receiving no other medication. The patient stopped smoking 14 years ago. There was no family history of endocrinological disease. Physical examination showed a cachectic patient (height 1.95 m, weight 79 kg) with some dyspnoea. His blood pressure was 140/100 mmHg, pulse rate 355
356
R. S. DE JONG et al.
Fig. 1. Chest X-ray showing multiple nodular abnormalities in both lungs.
Fig. 2. Sputum cytology showring tumour cells (see text).
was 104 beatsmin-', and body temperature was 37.6 "C. There was a multinodular goitre. There were no palpable lymph nodes. Local pain was elicited by pressure on the tenth rib on the right side. There was no vertebral bone pain. Examination of heart and lungs revealed no abnormalities. Abdominal examination revealed liver enlargement (3 cm palpable), but there were no palpable tumours. Rectal examination was normal. Laboratory analyses were as follows: ESR 53 mm in the 1st hour: Ca 2.99 mmol-' 1 ( n < 2.60); ASAT
79 U 1-' (n < 30); ALAT 58 U I-' (n < 3 0 ) ; gammaglutamyl transpeptidase 1 7 7 U I-' (n < 30) ; alkaline phosphatase 218 U 1-' (n < 100); LDH 830 U I-' (n < 320) : no haematological abnormalities, normal renal function, normal phosphate and bilirubin values. Electrocardiography showed left ventricular strain. A chest X-ray (Fig. 1) revealed numerous nodular abnormalities in both lungs with suspected metastases of a n extra-pulmonary malignancy, a goitre, and no cardiac enlargement. On cytological exam-
FULMINANT MALIGNANT PHAEOCHROMOCYTOMA
ination of the sputum, tumour cells were seen with pleiomorphic hyperchromatic nuclei and nuclear moulding (Fig. 2). These tumour cells were indicative of small cell anaplastic lung carcinoma, and further analysis in part followed the pattern for this kind of disease, although the chest X-ray was atypical. Abdominal ultrasound revealed diffuse liver metastases and a possible mass in the region of the right kidney. Computer tomography (Fig. 3) confirmed these abnormalities and showed skeletal metastasi; in all lumbar vertebrae. A bone scan showed multiple hot-spots. Computer tomography of the brain indicated suspected brain metastasis. Thyroid scanning revealed a solitary cold nodule and a goitre. Puncture of the nodule revealed no malignancy. Because of the patient's deteriorating condition, bronchoscopy was not performed. In summary, there was widespread malignancy with a possible tumour near the right kidney. Because the patient was only known to have mild hypertension and, during his stay in the hospital, his blood pressure proved difficult to control despite Labetolol, with values up to 250/150 mmHg, a phaeochromocytoma was suspected. The rate of vanillylmandelic acid (VMA) excretion (measured after termination of medication with methyldopa) and serum levels of epinephrine, norepinephrine and dopamine were very high [VMA excretion 1730 pmol 24 h-' ( n 10-30), norepinephrine 110.7 nmol I-' ( n < 3.5), epinephrine 0.87 nmol I-'
357
( n < 0.55),dopamine 1.76 nmoll-'(n < 0.35)],thus confirming the diagnosis of phaeochromocytoma. In order to localize the phaeochromocytoma, a 1311meta-iodobenzylguanidine scan was planned. However, the patient's general condition deteriorated rapidly during hospitalization and he died after 2 weeks. Autopsy was performed, but his relatives did not give permission for examination of the brain. At autopsy there were about 300 nodular tumour metastases in all the lobes of the lungs, of maximum diameter 2 cm. There was also pleuritis carcinomatosa. All the bronchi showed a normal cylindrical epithelium without metaplasia. Tumour metastases in all lumbar vertebrae were also observed, and these were osteolytic. In the abdomen there were multiple metastases with central necrosis in the liver, of maximum diameter 6 cm. Both adrenals had a normal configuration with a normal aspect of medulla and cortex. A tumour was situated below the right adrenal gland with a diameter of 7 cm and a grey-white appearance. There was no continuity with the right adrenal gland. On microscopic examination of formalin-fixed, paraffin-embedded tissue the tumour showed cells with polymorphic round to polygonal nuclei. Several mitoses were seen. The morphological appearance was similar to that of the tumour cells found in the sputum. The tumour was arranged in
358
R. S. DE JONG et al.
Fig. 4. Morphology of the tunnour shown in Fig. 3. A mitosis is shown at the centre. Note thc similarity of the tumour cells to those shown in Fig. 2.
fields and cords around many blood vessels (Fig. 4). The cells had eosinophil cytoplasm. A positive Grimelius stain and diffuse immunoreactivity for Chromogranin A and Synaptofysin (Dakopatts monoclonal anti-human antibodies) were seen. These findings are compatible with a neuro-endocrine carcinoma, in this case an extra-adrenal phaeochromocytoma, and not with metastasized small-cell lung carcinoma. The multiple metastases in lungs, liver and lumbar vertebrae were morphologically identical to this tumour, and gave the same positive reaction with Grimelius stain, Chromogranin A and Synaptofysin. These metastases demonstrate the malignant nature of this extra-adrenal phaeochromocytoma. All the parathyroid glands were of normal appearance and size. In the left lobe of the thyroid there was a nodule with a diameter of 4 cm. Microscopic examination revealed bleeding and fibrosis. There were no papillary configurations or signs of a medullary tumour. These findings are consistent with a dysplastic nodule. A definite diagnosis of functioning malignant extra-adrenal phaeochromocytoma with liver, pulmonary, bone and possible cerebral metastases was made.
Discussion Our patient had a histologically proven metastasized malignant phaeochromocytoma. The localization of what we think is the primary tumour was extraadrenal, near the right kidney. Some of the patient’s symptoms, such as sweating, headache, tachycardia and fluctuating hypertension, were strongly indicative of phaeochromocytoma [lo]. However, sweating and headache did not occur
in a typical paroxysmal manner, and may be manifested in many other diseases. With the exception of hypertension, most symptoms of patients with phaeochromocytoma. when persistent in nature, are also consistent with a diagnosis of widespread malignant disease. The short duration of the disease and extensive dissemination suggest that this patient had a very aggressive tumour, in contrast to the general picture of malignant phaeochromocytoma as a slowly progressive disease. However, the patient was known to have had mild hypertension for several years, and we cannot exclude the possibility that this was due to an underlying phaeochromocytoma that did not develop into malignant disease until very recently. A remarkable feature was the presence of metastatic cells in the patient’s sputum, a finding that emphasizes the high grade of malignancy in this case. This is the first published report of a patient with tumour positive sputum cytology due to malignant phaeochromocytoma. Although sputum cytology was indicative of small-cell lung carcinoma, chest X-ray findings were typical of metastases of an extra-pulmonary tumour and not of a primary smallcell lung carcinoma. Autopsy findings ruled out this last diagnosis because the metastases were histologically identical to the primary tumour. The patient also hadremarkably high levelsofcirculating catecholamines, particularly norepinephrine, and high urinary concentrations of metabolites. These findings confirm the diagnosis of phaeochromocytoma, and possibly reflect high tumour load and functioning metastases. Hypercalcaemia was a striking feature of this case, and we consider that it was due to metastatic bone disease. Humoral factors, such as PTH related-
FULMINANT MALIGNANT PHAEOCHROMOCYTOMA
protein, produced by phaeochromocytomas have been reported to be a cause of hypercalcaemia [l11, and we cannot rule out such a possibility in this patient, because serum levels of PTH and PTH related-protein were not determined.
6
7
8
9
References Remine WH. Chong GC. van Heerden JA, Sheps SG. Harrison EG. Current management of phaeochromocytoma. Ann Surg 1974: 1 7 9 ( 5 ) : 740-8. Sutton MG. Sheps SG. Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981 : 56 ( 6 ) :354-60. Beierwaltes WH. Sisson JC, Shapiro B. Lloyd RV. Dmuchowski C. Rabbani R. Malignant potential of pheochromocytoma : implications for follow-up. Proc AACR 1986: 2 7 : 61 7. Norton JA. Doppman JL. Jensen RT. In: DeVita VT. Hellman S. Rosenberg SA. eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott. 1 9 8 9 : 1298-303. Goldfarb DA. Novick AC. Bravo EL, Straflon RA, Montie JE,
10
1I
359
Kay R. Experience with extra-adrenal pheochromocytoma. / Urol 1 9 8 9 : 142: 931-6. Lewi HJE. Reid R. Mucci B et al. Malignant phaeochromocytoma. flr / Urol 1 9 8 5 ; 57: 394-8. Melicow MM. One hundred cases of pheochromocytoma (107 tumors) at the Columbia-Presbyterian Medical Center, 1926-1976. Cancer 1 9 7 7 : 40 (5): 1987-2004. Scott HW. Reynolds V, Green N et al. Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 1982 : 1 5 4 ( 6 ) : 801-1 8 . Shapiro B. Sisson JC, Lloyd R, Nakajo M. Satterlee W. Beierwaltes WH. Malignant pheochromocytoma : clinical, biochemical and scintigraphic characterization. Clin Endocrinol 1 9 8 4 : 2 0 : 189-203. Bravo EL., Giflord RW. Pheochromocytoma : diagnosis, localhation and management. N Engl J Med 1 9 8 4 ; 31 1 : 1298-303. Kimura S. Nishimura Y. Yarnaguchi K. Nagasaki K, Shimada K. Uchida H. A case of pheochromocytoma producing parathyroid hormone-related protein and presenting with hypercalcemia. / Clin Endocrinol Metab 1990: 7 0 ( 6 ) : 1559-63.
Received 5 February 1991, accepted 12 April 1991.
Correspondence: R. S . de Jong. MD. Sophia Hospital. Department of Internal Medicine, P.O. Box 10400. 8 0 0 0 GK. Zwolle, The Netherlands.
Case report Extra-adrenal phaeochromocytoma presenting as fulminant malignant disease with tumour positive sputum cytology R. S. DE JONG, H. A. V A N DEN BERGEN*, C. A. BOENDER & T. TJABBES From the Department of lnternal Medicine and the *Department of Pathology, Sophia Hospital. Zwolle, The Netherlands
Abstract. de Jong RS, van den Bergen HA, Boender CA, Tjabbes T (Department of Internal
Medicine and Department of Pathology, Sophia Hospital, Zwolle. The Netherlands). Extra-adrenal phaeochromocytoma presenting as fulminant malignant disease with tumour positive sputum cytology. Journal of Internal Medicine 1991: 230 : 3 5 5-3 59. A case of a 69-year-old man with an extra-adrenal malignant phaeochromocytoma is described. Sputum cytology revealed metastatic cells, which have not been reported previously in malignant phaeochromocytoma. This case is also remarkable for the short duration of disease, rapid progression and extensive spread of metastases, the radiological aspect of metastatic lesions shown by chest X-ray, hypercalcaemia and extremely high levels of circulating catecholamines and urinary metabolites.
Keywords: catecholamines, malignant phaeochromocytoma. metastases, paraganglioma. sputum cytology.
Introduction Phaeochromocytomas are rare tumours that arise from chromaffin cells, and in most cases secrete catecholamines. Early investigations [ 1,21 reported malignancy in 10-1 5 %of phaeochromocytomas, but in more recent studies using newer techniques for localization of metastases, this percentage rises to almost 50% [3]. A clear distinction between benign and malignant disease cannot be made by histopathological examination, and a diagnosis of malignant disease is based on the presence of recurrent or metastatic disease [41. Most tumours are localized in the adrenal glands. Extra-adrenal localization has been reported in 10-20% of adult patients [l,2, 51. There have been few reports of patients presenting with metastatic disease at multiple sites [6, 71. The general picture that emerges from the literature is one of a patient presenting with a history of hypertension and typical symptoms over a period of several years, few metastases at presentation, and subsequent survival for several years with only palliative treatment [6, 8, 91.
We here describe the case of a patient with an extra-adrenal phaeochromocytoma with extensive and rapidly progressive metastatic disease.
Case report The patient was a 69-year-old man who was known to have suffered from mild hypertension for several years. He was treated with verapamil by his general physician, resulting in satisfactory blood pressure control. He was reported to be in good health until 2 months prior to admission to our hospital. The patient complained of headache, sweating, nausea, loss of appetite, weight loss, constipation, fatigue, muscle pain, hoarseness and haemoptysis. There was no mention of flushing or palpitations. His medication was recently changed to methyldopa because initially his complaints were thought to be side-effects of verapamil. He was receiving no other medication. The patient stopped smoking 14 years ago. There was no family history of endocrinological disease. Physical examination showed a cachectic patient (height 1.95 m, weight 79 kg) with some dyspnoea. His blood pressure was 140/100 mmHg, pulse rate 355
356
R. S. DE JONG et al.
Fig. 1. Chest X-ray showing multiple nodular abnormalities in both lungs.
Fig. 2. Sputum cytology showring tumour cells (see text).
was 104 beatsmin-', and body temperature was 37.6 "C. There was a multinodular goitre. There were no palpable lymph nodes. Local pain was elicited by pressure on the tenth rib on the right side. There was no vertebral bone pain. Examination of heart and lungs revealed no abnormalities. Abdominal examination revealed liver enlargement (3 cm palpable), but there were no palpable tumours. Rectal examination was normal. Laboratory analyses were as follows: ESR 53 mm in the 1st hour: Ca 2.99 mmol-' 1 ( n < 2.60); ASAT
79 U 1-' (n < 30); ALAT 58 U I-' (n < 3 0 ) ; gammaglutamyl transpeptidase 1 7 7 U I-' (n < 30) ; alkaline phosphatase 218 U 1-' (n < 100); LDH 830 U I-' (n < 320) : no haematological abnormalities, normal renal function, normal phosphate and bilirubin values. Electrocardiography showed left ventricular strain. A chest X-ray (Fig. 1) revealed numerous nodular abnormalities in both lungs with suspected metastases of a n extra-pulmonary malignancy, a goitre, and no cardiac enlargement. On cytological exam-
FULMINANT MALIGNANT PHAEOCHROMOCYTOMA
ination of the sputum, tumour cells were seen with pleiomorphic hyperchromatic nuclei and nuclear moulding (Fig. 2). These tumour cells were indicative of small cell anaplastic lung carcinoma, and further analysis in part followed the pattern for this kind of disease, although the chest X-ray was atypical. Abdominal ultrasound revealed diffuse liver metastases and a possible mass in the region of the right kidney. Computer tomography (Fig. 3) confirmed these abnormalities and showed skeletal metastasi; in all lumbar vertebrae. A bone scan showed multiple hot-spots. Computer tomography of the brain indicated suspected brain metastasis. Thyroid scanning revealed a solitary cold nodule and a goitre. Puncture of the nodule revealed no malignancy. Because of the patient's deteriorating condition, bronchoscopy was not performed. In summary, there was widespread malignancy with a possible tumour near the right kidney. Because the patient was only known to have mild hypertension and, during his stay in the hospital, his blood pressure proved difficult to control despite Labetolol, with values up to 250/150 mmHg, a phaeochromocytoma was suspected. The rate of vanillylmandelic acid (VMA) excretion (measured after termination of medication with methyldopa) and serum levels of epinephrine, norepinephrine and dopamine were very high [VMA excretion 1730 pmol 24 h-' ( n 10-30), norepinephrine 110.7 nmol I-' ( n < 3.5), epinephrine 0.87 nmol I-'
357
( n < 0.55),dopamine 1.76 nmoll-'(n < 0.35)],thus confirming the diagnosis of phaeochromocytoma. In order to localize the phaeochromocytoma, a 1311meta-iodobenzylguanidine scan was planned. However, the patient's general condition deteriorated rapidly during hospitalization and he died after 2 weeks. Autopsy was performed, but his relatives did not give permission for examination of the brain. At autopsy there were about 300 nodular tumour metastases in all the lobes of the lungs, of maximum diameter 2 cm. There was also pleuritis carcinomatosa. All the bronchi showed a normal cylindrical epithelium without metaplasia. Tumour metastases in all lumbar vertebrae were also observed, and these were osteolytic. In the abdomen there were multiple metastases with central necrosis in the liver, of maximum diameter 6 cm. Both adrenals had a normal configuration with a normal aspect of medulla and cortex. A tumour was situated below the right adrenal gland with a diameter of 7 cm and a grey-white appearance. There was no continuity with the right adrenal gland. On microscopic examination of formalin-fixed, paraffin-embedded tissue the tumour showed cells with polymorphic round to polygonal nuclei. Several mitoses were seen. The morphological appearance was similar to that of the tumour cells found in the sputum. The tumour was arranged in
358
R. S. DE JONG et al.
Fig. 4. Morphology of the tunnour shown in Fig. 3. A mitosis is shown at the centre. Note thc similarity of the tumour cells to those shown in Fig. 2.
fields and cords around many blood vessels (Fig. 4). The cells had eosinophil cytoplasm. A positive Grimelius stain and diffuse immunoreactivity for Chromogranin A and Synaptofysin (Dakopatts monoclonal anti-human antibodies) were seen. These findings are compatible with a neuro-endocrine carcinoma, in this case an extra-adrenal phaeochromocytoma, and not with metastasized small-cell lung carcinoma. The multiple metastases in lungs, liver and lumbar vertebrae were morphologically identical to this tumour, and gave the same positive reaction with Grimelius stain, Chromogranin A and Synaptofysin. These metastases demonstrate the malignant nature of this extra-adrenal phaeochromocytoma. All the parathyroid glands were of normal appearance and size. In the left lobe of the thyroid there was a nodule with a diameter of 4 cm. Microscopic examination revealed bleeding and fibrosis. There were no papillary configurations or signs of a medullary tumour. These findings are consistent with a dysplastic nodule. A definite diagnosis of functioning malignant extra-adrenal phaeochromocytoma with liver, pulmonary, bone and possible cerebral metastases was made.
Discussion Our patient had a histologically proven metastasized malignant phaeochromocytoma. The localization of what we think is the primary tumour was extraadrenal, near the right kidney. Some of the patient’s symptoms, such as sweating, headache, tachycardia and fluctuating hypertension, were strongly indicative of phaeochromocytoma [lo]. However, sweating and headache did not occur
in a typical paroxysmal manner, and may be manifested in many other diseases. With the exception of hypertension, most symptoms of patients with phaeochromocytoma. when persistent in nature, are also consistent with a diagnosis of widespread malignant disease. The short duration of the disease and extensive dissemination suggest that this patient had a very aggressive tumour, in contrast to the general picture of malignant phaeochromocytoma as a slowly progressive disease. However, the patient was known to have had mild hypertension for several years, and we cannot exclude the possibility that this was due to an underlying phaeochromocytoma that did not develop into malignant disease until very recently. A remarkable feature was the presence of metastatic cells in the patient’s sputum, a finding that emphasizes the high grade of malignancy in this case. This is the first published report of a patient with tumour positive sputum cytology due to malignant phaeochromocytoma. Although sputum cytology was indicative of small-cell lung carcinoma, chest X-ray findings were typical of metastases of an extra-pulmonary tumour and not of a primary smallcell lung carcinoma. Autopsy findings ruled out this last diagnosis because the metastases were histologically identical to the primary tumour. The patient also hadremarkably high levelsofcirculating catecholamines, particularly norepinephrine, and high urinary concentrations of metabolites. These findings confirm the diagnosis of phaeochromocytoma, and possibly reflect high tumour load and functioning metastases. Hypercalcaemia was a striking feature of this case, and we consider that it was due to metastatic bone disease. Humoral factors, such as PTH related-
FULMINANT MALIGNANT PHAEOCHROMOCYTOMA
protein, produced by phaeochromocytomas have been reported to be a cause of hypercalcaemia [l11, and we cannot rule out such a possibility in this patient, because serum levels of PTH and PTH related-protein were not determined.
6
7
8
9
References Remine WH. Chong GC. van Heerden JA, Sheps SG. Harrison EG. Current management of phaeochromocytoma. Ann Surg 1974: 1 7 9 ( 5 ) : 740-8. Sutton MG. Sheps SG. Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981 : 56 ( 6 ) :354-60. Beierwaltes WH. Sisson JC, Shapiro B. Lloyd RV. Dmuchowski C. Rabbani R. Malignant potential of pheochromocytoma : implications for follow-up. Proc AACR 1986: 2 7 : 61 7. Norton JA. Doppman JL. Jensen RT. In: DeVita VT. Hellman S. Rosenberg SA. eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott. 1 9 8 9 : 1298-303. Goldfarb DA. Novick AC. Bravo EL, Straflon RA, Montie JE,
10
1I
359
Kay R. Experience with extra-adrenal pheochromocytoma. / Urol 1 9 8 9 : 142: 931-6. Lewi HJE. Reid R. Mucci B et al. Malignant phaeochromocytoma. flr / Urol 1 9 8 5 ; 57: 394-8. Melicow MM. One hundred cases of pheochromocytoma (107 tumors) at the Columbia-Presbyterian Medical Center, 1926-1976. Cancer 1 9 7 7 : 40 (5): 1987-2004. Scott HW. Reynolds V, Green N et al. Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 1982 : 1 5 4 ( 6 ) : 801-1 8 . Shapiro B. Sisson JC, Lloyd R, Nakajo M. Satterlee W. Beierwaltes WH. Malignant pheochromocytoma : clinical, biochemical and scintigraphic characterization. Clin Endocrinol 1 9 8 4 : 2 0 : 189-203. Bravo EL., Giflord RW. Pheochromocytoma : diagnosis, localhation and management. N Engl J Med 1 9 8 4 ; 31 1 : 1298-303. Kimura S. Nishimura Y. Yarnaguchi K. Nagasaki K, Shimada K. Uchida H. A case of pheochromocytoma producing parathyroid hormone-related protein and presenting with hypercalcemia. / Clin Endocrinol Metab 1990: 7 0 ( 6 ) : 1559-63.
Received 5 February 1991, accepted 12 April 1991.
Correspondence: R. S . de Jong. MD. Sophia Hospital. Department of Internal Medicine, P.O. Box 10400. 8 0 0 0 GK. Zwolle, The Netherlands.
