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Acromegaly and Bronchial Carcinoid
FIGURE 3. Coronary arteriograms four weeks after the onset of acute myocardial infarction. a, Left coronary arteriogram in the right anterior oblique projection. Minimal luminal irregularities were present in the proximal segment ofthe left anterior descending coronary artery. b, Right coronary arteriogram in the left anterior oblique projection. c, Left coronary arteriogram after ergonovine maleate. Discrete luminal narrowing was provoked (arrow). d, Left coronary arteriogram after isosorbide dinitrate. The narrowing was relieved.
sponse to ergonovine maleate is uncertain. Our patient lacked the coronary arteriographic findings such as saccular aneurysm or development of significant obstructive lesions in a very short period, which are considered to be suggestive of coronary arteritis. 3 However, the minimal luminal irregularities in LAD might have been produced by an arteritic process and might subsequently become the basis for the altered vasomotor response. ACKNOWLEDGMENT: We gratefully acknowledge the help of Shunichi Tamaki, MD, and Ario Yamazato, MD, in performing coronary thrombolytic therapy in the patient, and the help of Alice S. Cary, MD, in preparation of the manuscript. REFERENCES
2 3 4
5 6
Dubois EL. Cause of death in systemic lupus erythematosus. In: Dubois EL, ed. Lupus erythematosus, 2nd ed. Los Angeles: University of Southern California Press, 1974:633-40 Bonfiglio TA, Bontti RE, Hagstrom JWC. Coronary arteritis, occlusion and myocardial infarction due to lupus erythematosus. Am Heart J 1972; 83:153-58 Heibel RH, OToole JD, Curtiss EI, Medsger TA, Reddy Sp' Shaver ]A. Coronary arteritis in systemic lupus erythematosus. Chest 1976; 69:700-03 Meller J, Conde CA, Deppisch LM, Donoso E, Dack S. Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus. Am J Cardiol 1975; 35:309-14 Tsakraklides VG, Blieden LC, Edwards JE. Coronaryatherosclerosis and myocardial infarction associated with systemic lupus erythematosus. Am Heart J 1974; 87:637-41 Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Cardiol 1975;
58:243-64 7 Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56:366-70 8 Hastillo A, Willis HE, Hess ML. The heart as a target organ of immune injury. Curr Probl Cardio11982; 6:1-51 9 Heupler FA Jr, Proudfit WL, Razavi M, Shirey EK, Greenstreet R, Sheldon WC. Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardio11978; 41:631-40
Acromegaly and Bronchial Carcinoid Effect of Removal of the Latter F. Hawkins, M.D.;* V. Sanchez Moro, M.D.;* M. Aguirre, M.D.;* M. Leon, M.D.;* D. Rigopoulou, M.D.;* ]. L. Marlin de Nicolas, M.D.;t and]. Toledo, M.D.t
A patient with a long-standing history of bronchial carcinoid and acromegaly was studied. There was pituitary enlargement with an intrasellar mass (brain computed tomography scan), high basal GH levels, and abnormal GH and other pituitary hormones response to oral glucose and a combined test (LHRH, TRH, insulin). After resection of the bronchial carcinoid, basal GH was normal, GH was normally suppressed during OGTT, pituitary function was within exFrom the *Endocrine Unit and tThoracic Surgical Unit, Hospital I· de Octubre, Faculty of Medicine Complutense, Madrid, Spain. Reprint requests: Dr: Toledo, Principe de Vergara 204, Madrid, Spain 28002 CHEST I 88 I 1 I JULY. 1985
149
pected normal range, and there was regression of the pituitary tumor together with clinical improvement. These data suggest that the patient's acromegaly was secondary to pituitary stimulation due to the bronchial carcinoid. he clinical association of acromegaly and bronchial carT cinoid tumor can be coincidental or can be related, but it
is still rarely reported. Pituitary adenomas and carcinoids can
be part ofa pluriglandular syndrome with or without tumors
in other endocrine glands. 1 Ectopic production of growth hormone (GH) by nonpituitary tumors, even ifuncommon, is well documented. 2 Only one case ofacromegaly produced by the secretion ofa GH-like substance by a bronchial carcinoid has been described. 3 Bronchial carcinoids can produce acromegalic disease secreting a peptide with growth hormone-releasing activity (GHRA), as recently demonstrated by bioassay4.5 and partially characterized. 6 Similar peptides have been isolated from other extrapituitary tumors. 6 •7 It has been suggested that biologically active amines produced by the tumor could playa role in the pathogenesis of acromegaly, but there is no conclusive evidence of this fact. Elevated levels of serum serotonin and increased urinary 5 hydroxyindole acetic acid (5 HIAA) are not a constant feature in patients with carcinoid tumor and acromegaly;8 therefore, it cannot be postulated that 5 HIAA is the only factor responsible for pituitary dysfunction. The present report describes a patient with clinical acromegaly, high basal GH levels and abnormal hormone response to glucose tolerance test, pituitary tumor and bronchial carcinoid. Removal ofthe latter led to the return ofGH levels to normal and to regression of the pituitary tumor as demonstrated by brain computed tomography, together with clinical improvement. With our data, we believe it is possible that acromegaly in our patient could be due to the production of a peptide with GHRA by the carcinoid tumOI: CASE REPORT
The patient was a 50-year-old man with a known right lung field found 20 years previously on routine chest x-ray examination. He related a typical history ofacromegaly of15 years' duration. Physical examination revealed clear acromegalic signs together with a slight diffuse goiter. Blood pressure was 140/80 mm Hg and visual fields were normal. The following data were within normal limits: blood count and red cell sedimentation rate, creatinine clearance, electrolytes, liver function tests, serum calcium, phosphate, alkaline phosphatase, uric acid, cholesterol and triglycerides. Levels of thyroid hormones (free and total thyroxine and triiodothyronine), midnight and basal cortisol, testosterone and urinary 17 oxo- and oxogenic steroids were also normal. Basal plasma serotonin level was 113 ng/ml and urinary excretion of 5 hydroxyindole acetic acid was 8.5 mg/24 h, epinephrine 2.69 ..,g/24 h, and norepinephrine 21.15 ..,g/24 h; all of these results were within normal laboratory range. Chest x-ray examination showed a large opacity in the right middle zone. Bonchoscopy revealed an obstruction of the right middle lobe bronchus by a tumor, and biopsy showed it to be a bronchial carcinoid. Heel pad thickness was increased (33 mm). Skull x-ray examination showed an enlarged sella turcica with double Boor. In brain computed tomography, pituitary fossa was increased in size, and there was a hyperdense image in the right halfofthe sellar space that was enhanced after contrast injection. Oral glucose tolerance
150
Table I-Combined Testing of Pituita,." Gland before Surgery* Tune (Min)
Glycemia
GD
PRL
-15
103
>75 >75
69 63 145 115 100 79 79 79 79 63.5
o
20 30 60
SO 90
100
120
ISO
104
73 56 43 71 96
>75 65 55 37.5 >75
ACTH
TSH
73
3.15 4.40 4.60 4.20 4.60
105 80 73 85 55
FSH
LH
3.7 3.5
2.2 1.6
5.2 8.0
5.7 6.0
6.1
5.0
6.0
4.4
*Normal basal values in men: glycemia: 60-115 mg%; GH: <5 ng/ml; PRL: <15 ng/ml; ACTH: 20-60 pg/ml; TSH: <5 ..,U/ml; FSH: 1.80 ± 0.5 ng/ml (mean ± SD); LH: 1.46 ± 0.7 ng/ml (mean ±SD). test (OGTIj was performed with 75 g ofglucose: basal, 30, 60, 90 and 120 minute plasma glycemia (glucose-oxidase) levels were 96, 181, 230,232 and 174 mg% respectively. Basal serum GH was 75 ng/ml (normal values <5ng/ml), with elevated levels along the OGTT and there was an exaggerated insulin response. A combined test of anterior pituitary gland was performed using l00..,g ofLHRH, 4OO..,g ofTRH and 0.3 U/kg of insulin because of resistance. LHRH and TRH were injected iv 60 minutes before. Blood samples withdrawn at intervals shown in Table 1 were assayed (RIA) for serum LH, FSH, TSH, GD, prolactin and ACTH (normal values in 11lbles 1 and 2); plasma glycemia was also determined. GH levels were abnormally high during the test; prolactin basal levels (69 ng/ml) (normal values <15 ng/ml) and responsive levels showed increments; AcrH response to hypoglycemia was minimal; and there was no TSH response to TRH stimulus. FSH and LH basal and stimulated levels were slightly higher than those found in younger men, according to our experience. The diagnosis ofacromegaly and bronchial carcinoid was made and right middle lobectomy performed. The patient had an uneventful recovery. The lobectomy specimen showed a well circumscribed encapsulated 6 x 5 x 4 cm tan tumor. Histologically, the tumor was made of small to medium eosinophilic cells with argyrophilic, nonchromaffin cytoplasmic granules, arranged forming predominantly an alveolar pattern, but also rosettoid and trabecular. The nuclei were not atypical and mitosis was not found. The bronchial wall was infiltrated by the neoplasm. The neighboring pulmonary parenchyma was compressed, but not infiltrated by the tumor. The histologic diagnosis was bronchial carcinoid. The patient was evaluated again one and six months after surgery. As shown in Figure 1, postoperative OGTT glycemia and insulinemia
Table 2-Combined Testing of Pituita,." Gland after Surgery* TIme (Min)
Glycemia
GH
PRL
-15
78 75
3 3.5
11 10.5 28 27 21 21 18.5 17 19 17
o
20 30 60 80 90
100
120
ISO
55 28 22 38 63
2 3 12 61 42
ACTH
TSH
45
3.50 3.30 3.25 3.65
30 20 95 260 45
FSH
LH
6.4 6.3
2.4 2.7
7.7 7.8
7.2 8.0
7.7
7.5
8.8
4.4
*See Table 1 for normal values. Acromegaly and Bronchial Carcinoid (HtfWldns st 81)
a.G.TT.
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MINUTES
60
~
120
Figure 1. Serum growth hormone (GD), plasma glucose and serum insulin response to oral glucose tolerance test (OGTT) before and after bronchial carcinoid lobectomy in a patient with acromegaly. profiles were normal after the six-month period. Postoperative basal GH levels were normal in both evaluations (2.0 and 2.5 nglml), and there was suppression of GD levels during the OGn as found in normal subjects. As shown in Table 2, there was a return to normal values and normal response of pituitary hormones during the combined test of anterior pituitary gland (this time, only 0.1 U of insulinJkg), except for TSH, which remained hyporesponsive. Computed tomography of the brain was performed one and six months after lobectomy, with and without contrast, revealing the absence of the previous intrasellar tumor. The patient experienced clinical improvement as well. DISCUSSION
To our knowledge, there have been eight cases reported which claim that acromegaly can be secondary to bronchial
carcinoid.3-5·8-11 Only six of these cases are well documented with hormonal studies before and after the carcinoid excision. 3,4.lO.11 The initially accepted concept was that this association was either fortuitous or was part of a pluriglanit was also accepted that bronchial dular syndrome. 1 Late~ carcinoids belong to the functionally and stnlcturally heterogeneous group oftumors derived from neuroectodermal cells of the neural crest, capable of synthesizing polypeptide hormones and biologically active amines. 1I It became possible, therefore, that substances produced by the carcinoid could be responsible for the acromegaly in patients with these tumors. In our patient, there was a clear relationship between acromegaly and the bronchial carcinoid. It is the first case in which normalization of endocrinologic parameters (nonsuppression of GH after OGn altered pituitary response to combined test) regression of intrasellar tumor (brain computed tomography) and clinical improvement after the bronchial carcinoid resection is reported. Up to now, Dabel(J presented the only report of a carcinoid tumor containing elevated amounts ofGH, but the fact that there was also pituitary fossa enlargement seems to indicate that GH release by the tumor was not the sole factor in developing the acromegalic features. Later reports have not found GH increased in carcinoid tumors in similar patients. 4.5.10 The first evidence ofthe secretion ofa peptide with GHRA by a bronchial carcinoid in this association was the simultaneous reports of Saeed uz Zafar et a14 and Shalet et a15 describing two patients. Recently, Frohman et a16 have reported the partial purification and characterization of this GHRA in carcinoid and other extrapituitary tumors. Our patient's decreased TSH reserve is in accord with previous descriptions in acromegalic subjects related to suppression of TSH secretion rather than destnlction ofthyrotrophic cells. 13 We cannot explain the lack ofpostoperative response, but it is possible that a considerable period is required for recovery. The cause of hyperprolactinemia reported in some of these patients4.5 and in our case, is unknown. From high basal levels (69 and 63 nglml) our patient had hyperresponse to TRH (145 nglml) that was normalized after surgery. The possibility of a prolactin-releasing factor secreted by the carcinoid cannot be excluded. It is still controversial that certain biogenic amines produced by the carcinoid have a role in the development of acromegaly. Dopamine seems to have no effect on GH secretion in culture systems. 5 Very few reports have identi8ed norepinephrine and epinephrine in bronchial carcinoids. 14 Our patient had catecholamine excretion within normal range. Urinary excretion of 5-HIAA and plasma serotonin were also normal in our patient, in agreement with the majority of reports. Therefore, 5-hydroxytryptamine seems not to be related to the acromegaly in these patients. The fact that patients with carcinoid tumors that do not secrete 5-hydroxytryptamine can have raised GH levels seems to support this view 8 In summary, we suggest that in our patient, as well as in other cases, the acromegaly was secondary to the bronchial carcinoid (probably by secretion of a GHRH). The demonstration of normal GH values, normal pituitary tumor and improvement of acromegalic features after resection of the CHEST I 88 I 1 I JULY, 1885
151
carcinoid resection seems to support this hypothesis. ACKNOWLEDGMENTS: The authors wish to thank Drs. L. Larrodera and M. Fernandez SaJa of the Biochemistry Department for the RIA ofpituitary hormones, and Prof. F: Martinez Tello, Head, Pathology Department, for his assistance in preparation of the manuscript.
REFERENCES 1 Williams ED, Celestin LR. The association of bronchial carcinoid and pluriglandular adenomatosis. Thorax 1962; 17:120-27 2 Beck C, Burger HG. Evidence for the presence of immunoreactive growth hormone in cancers of the lung and stomach. Cancer 1972; 30:75-9 3 Dabek.n: Bronchial tumor with acromegaly in two patients. J Clin Endocrinol Metah 1974; 38:329-33 4 uz Zafar MS, Mellinger RC, Fine G, Szabo M, Frohman LA. Acromegaly associated with a bronchial carcinoid tumor: Evidence for ectopic production of growth hormone-releasing activity. J Clin Endocrinol Metab 1979; 48:66-71 5 Shalet SM, Beardwell CG, MacFarlane lA, Ellison ML, Norman CM, Rees LH, et al. Acromegaly due to production of a growth hormone releasing factor by a bronchial carcinoid tumour. Clinical Endocrinol 1979; 10:61-7 6 Frohman LA, Szabo M, Berelowitz M, Stachura ME. Partial purification and characterization ofa peptide with growth hormonereleasing activity from extrapituitary tumors in patients with acromegaly. J Clin Invest 1980; 65:43-54 7 Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone releasing factor from a human pancreatic islet tumour. Nature 1982; 300:276-78 8 Feldman JM, Plonk JW, Bivens CH, Lebovitz HE, Handwerger S. Growth hormone and prolactin secretion in the carcinoid syndrome. Am J Med Sci 1975; 269:333-46 9 Altmann H~ Schutz W. Uber ein knochenhaJtiges Bronchuscarcinoid (Morphologische und klinische Beobachtungen bei einer akromegalen Patientin). Beitr Pathol Anat 1959; 120:455-73 10 Sonksen PH, Ayres AB, Braimbridge M, Corrin B, Davies DR, Jeremiah GM, et ale Acromegaly caused by pulmonary carcinoid tumours. Clin Endocrinol (Oxf) 1976; 5:503-13 11 Scheithauer BW, Carpenter PC, Bloch B, Brazeau R Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med 1984; 76:605-16 12 Frolich JC, Margolius HS. Prostaglandins, the Kallikreinkinin system, Bartters syndrome, and the carcinoid syndrome. In: Felig ~ Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and metabolism. New York: McGraw-Hill, 1981, 1265 13 IOijn JGM, Lamberts SWJ, Docter R, De Jong FH, Van Dongen KJ, Birkenhager JC. The function of the pituitary-thyroidal axis in acromegalic patients V. patients with hyperprolactinaemia and a pituitary tumour. Clin Endocrinol 1980; 13:577-85 14 Hinterberger H, Smith A, Bartholomew RJ, Scholtz C. Biochemical diagnosis of malignant carcinoid tumours. Pathology 1973; 5:1-8
152
Transbronchlal Needle Aspiration of a Bronchial Carcinoid TUmor* C. Delp Givens, ]r., M.D.;t and]ohn]. Marini, M.D.,
F.C.C.~+
We biopsied a suspected bronchial carcinoid tumor with a transbronchial aspiration needle and obtained cytologic diagnosis without signi6cant hemorrhage. This technique may prove valuable in sampling highly vascular endobronchial neoplasms.
B
ronchial carcinoid tumors are located proximally within the airway in approximately 80 percent of cases. 1 Viewed through the bronchoscope, these highly vascular neoplasms have a characteristic appearance described as smooth, polypoid, and non-ulcerated. 2 Forceps biopsy through the 6beroptic bronchoscope is reported to have a high incidence ofmajor hemorrhage, and rigid bronchoscopy has been the preferred diagnostic approach. 3 We used a transbronchial aspiration needle to obtain a biopsy in suspected bronchial carcinoid tumor, obtaining diagnostic cellular material without incurring signi6cant hemorrhage. CASE REPORT A 68-year-old man retired from farming five years prior to admission because of exertional dyspnea. He had noted occasional wheezing, but little cough or sputum production and no constitutional symptoms. He had discontinued smoking 15 years previously after a 20 pack-year exposure. Two weeks before admission, he coughed blood-streaked phlegm and consulted his physician. A chest roentgenogram showed left hilar prominence, and he was referred for evaluation. On admission, his temperature was 37°C; the blood pressure, 170/95 mm Hg without pulsus paradoxus; the pulse rate, 641min, regular; and respirations, 2O/min. An expiratory wheeze was audible intermittently over the left chest on forced expiration. Breath sounds were symmetrical. His digits were not clubbed, and he had no lymphadenopathy. The hemoglobin and leukocyte count were 14.3 gldl, and 6,400/cu mm, respectively. Arterial blood gas levels on room air were pH, 7.42; Peo., 40 mm Hg, and Po., 71 mm Hg. Chest roentgenogram showed a prominent left hilum with the shadow ofan endobronchial mass visible in the left mainstem bronchus (Fig 1). A flow-volume loop demonstrated a fixed airway obstruction pattern. Three specimens of expectorated sputum were cytopathologically negative. At 6beroptic bronchoscopic examination, a mass nearly occluded the entire left main bronchus at the level of the left upper lobe. Its smooth, glistening capsule bled easily when touched with the tip of bronchoscope. We used a transbronchial aspiration needle (MillRose) to puncture the center of the mass and to aspirate a specimen for cytopathologic analysis. Minor hemorrhage was easily controlled with topical 1 percent epinephrine. The aspiration biopsy (Fig 2) included a core of tissue that showed features characteristic of a carcinoid tumor: small uniform cells, round central nuclei with finely granular chromatin, cellular rosettes, and cells distributed in ribbons around vessels." 5 At thoracotomy, a 2.5 x 1.5 x 1.0 cm mass obstructed the left main bronchus and extended into the left upper lobe, causing distal bronchiectasis. Lobectomy was performed. The tumor did not *From the Division of Pulmonary Medicine, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville. tFellow in Pulmonary Medicine. +Associate Professor of Medicine. Transbronchlal Needle Aspiration (Givens, Marini)
sponse to ergonovine maleate is uncertain. Our patient lacked the coronary arteriographic findings such as saccular aneurysm or development of significant obstructive lesions in a very short period, which are considered to be suggestive of coronary arteritis. 3 However, the minimal luminal irregularities in LAD might have been produced by an arteritic process and might subsequently become the basis for the altered vasomotor response. ACKNOWLEDGMENT: We gratefully acknowledge the help of Shunichi Tamaki, MD, and Ario Yamazato, MD, in performing coronary thrombolytic therapy in the patient, and the help of Alice S. Cary, MD, in preparation of the manuscript. REFERENCES
2 3 4
5 6
Dubois EL. Cause of death in systemic lupus erythematosus. In: Dubois EL, ed. Lupus erythematosus, 2nd ed. Los Angeles: University of Southern California Press, 1974:633-40 Bonfiglio TA, Bontti RE, Hagstrom JWC. Coronary arteritis, occlusion and myocardial infarction due to lupus erythematosus. Am Heart J 1972; 83:153-58 Heibel RH, OToole JD, Curtiss EI, Medsger TA, Reddy Sp' Shaver ]A. Coronary arteritis in systemic lupus erythematosus. Chest 1976; 69:700-03 Meller J, Conde CA, Deppisch LM, Donoso E, Dack S. Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus. Am J Cardiol 1975; 35:309-14 Tsakraklides VG, Blieden LC, Edwards JE. Coronaryatherosclerosis and myocardial infarction associated with systemic lupus erythematosus. Am Heart J 1974; 87:637-41 Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Cardiol 1975;
58:243-64 7 Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56:366-70 8 Hastillo A, Willis HE, Hess ML. The heart as a target organ of immune injury. Curr Probl Cardio11982; 6:1-51 9 Heupler FA Jr, Proudfit WL, Razavi M, Shirey EK, Greenstreet R, Sheldon WC. Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardio11978; 41:631-40
Acromegaly and Bronchial Carcinoid Effect of Removal of the Latter F. Hawkins, M.D.;* V. Sanchez Moro, M.D.;* M. Aguirre, M.D.;* M. Leon, M.D.;* D. Rigopoulou, M.D.;* ]. L. Marlin de Nicolas, M.D.;t and]. Toledo, M.D.t
A patient with a long-standing history of bronchial carcinoid and acromegaly was studied. There was pituitary enlargement with an intrasellar mass (brain computed tomography scan), high basal GH levels, and abnormal GH and other pituitary hormones response to oral glucose and a combined test (LHRH, TRH, insulin). After resection of the bronchial carcinoid, basal GH was normal, GH was normally suppressed during OGTT, pituitary function was within exFrom the *Endocrine Unit and tThoracic Surgical Unit, Hospital I· de Octubre, Faculty of Medicine Complutense, Madrid, Spain. Reprint requests: Dr: Toledo, Principe de Vergara 204, Madrid, Spain 28002 CHEST I 88 I 1 I JULY. 1985
149
pected normal range, and there was regression of the pituitary tumor together with clinical improvement. These data suggest that the patient's acromegaly was secondary to pituitary stimulation due to the bronchial carcinoid. he clinical association of acromegaly and bronchial carT cinoid tumor can be coincidental or can be related, but it
is still rarely reported. Pituitary adenomas and carcinoids can
be part ofa pluriglandular syndrome with or without tumors
in other endocrine glands. 1 Ectopic production of growth hormone (GH) by nonpituitary tumors, even ifuncommon, is well documented. 2 Only one case ofacromegaly produced by the secretion ofa GH-like substance by a bronchial carcinoid has been described. 3 Bronchial carcinoids can produce acromegalic disease secreting a peptide with growth hormone-releasing activity (GHRA), as recently demonstrated by bioassay4.5 and partially characterized. 6 Similar peptides have been isolated from other extrapituitary tumors. 6 •7 It has been suggested that biologically active amines produced by the tumor could playa role in the pathogenesis of acromegaly, but there is no conclusive evidence of this fact. Elevated levels of serum serotonin and increased urinary 5 hydroxyindole acetic acid (5 HIAA) are not a constant feature in patients with carcinoid tumor and acromegaly;8 therefore, it cannot be postulated that 5 HIAA is the only factor responsible for pituitary dysfunction. The present report describes a patient with clinical acromegaly, high basal GH levels and abnormal hormone response to glucose tolerance test, pituitary tumor and bronchial carcinoid. Removal ofthe latter led to the return ofGH levels to normal and to regression of the pituitary tumor as demonstrated by brain computed tomography, together with clinical improvement. With our data, we believe it is possible that acromegaly in our patient could be due to the production of a peptide with GHRA by the carcinoid tumOI: CASE REPORT
The patient was a 50-year-old man with a known right lung field found 20 years previously on routine chest x-ray examination. He related a typical history ofacromegaly of15 years' duration. Physical examination revealed clear acromegalic signs together with a slight diffuse goiter. Blood pressure was 140/80 mm Hg and visual fields were normal. The following data were within normal limits: blood count and red cell sedimentation rate, creatinine clearance, electrolytes, liver function tests, serum calcium, phosphate, alkaline phosphatase, uric acid, cholesterol and triglycerides. Levels of thyroid hormones (free and total thyroxine and triiodothyronine), midnight and basal cortisol, testosterone and urinary 17 oxo- and oxogenic steroids were also normal. Basal plasma serotonin level was 113 ng/ml and urinary excretion of 5 hydroxyindole acetic acid was 8.5 mg/24 h, epinephrine 2.69 ..,g/24 h, and norepinephrine 21.15 ..,g/24 h; all of these results were within normal laboratory range. Chest x-ray examination showed a large opacity in the right middle zone. Bonchoscopy revealed an obstruction of the right middle lobe bronchus by a tumor, and biopsy showed it to be a bronchial carcinoid. Heel pad thickness was increased (33 mm). Skull x-ray examination showed an enlarged sella turcica with double Boor. In brain computed tomography, pituitary fossa was increased in size, and there was a hyperdense image in the right halfofthe sellar space that was enhanced after contrast injection. Oral glucose tolerance
150
Table I-Combined Testing of Pituita,." Gland before Surgery* Tune (Min)
Glycemia
GD
PRL
-15
103
>75 >75
69 63 145 115 100 79 79 79 79 63.5
o
20 30 60
SO 90
100
120
ISO
104
73 56 43 71 96
>75 65 55 37.5 >75
ACTH
TSH
73
3.15 4.40 4.60 4.20 4.60
105 80 73 85 55
FSH
LH
3.7 3.5
2.2 1.6
5.2 8.0
5.7 6.0
6.1
5.0
6.0
4.4
*Normal basal values in men: glycemia: 60-115 mg%; GH: <5 ng/ml; PRL: <15 ng/ml; ACTH: 20-60 pg/ml; TSH: <5 ..,U/ml; FSH: 1.80 ± 0.5 ng/ml (mean ± SD); LH: 1.46 ± 0.7 ng/ml (mean ±SD). test (OGTIj was performed with 75 g ofglucose: basal, 30, 60, 90 and 120 minute plasma glycemia (glucose-oxidase) levels were 96, 181, 230,232 and 174 mg% respectively. Basal serum GH was 75 ng/ml (normal values <5ng/ml), with elevated levels along the OGTT and there was an exaggerated insulin response. A combined test of anterior pituitary gland was performed using l00..,g ofLHRH, 4OO..,g ofTRH and 0.3 U/kg of insulin because of resistance. LHRH and TRH were injected iv 60 minutes before. Blood samples withdrawn at intervals shown in Table 1 were assayed (RIA) for serum LH, FSH, TSH, GD, prolactin and ACTH (normal values in 11lbles 1 and 2); plasma glycemia was also determined. GH levels were abnormally high during the test; prolactin basal levels (69 ng/ml) (normal values <15 ng/ml) and responsive levels showed increments; AcrH response to hypoglycemia was minimal; and there was no TSH response to TRH stimulus. FSH and LH basal and stimulated levels were slightly higher than those found in younger men, according to our experience. The diagnosis ofacromegaly and bronchial carcinoid was made and right middle lobectomy performed. The patient had an uneventful recovery. The lobectomy specimen showed a well circumscribed encapsulated 6 x 5 x 4 cm tan tumor. Histologically, the tumor was made of small to medium eosinophilic cells with argyrophilic, nonchromaffin cytoplasmic granules, arranged forming predominantly an alveolar pattern, but also rosettoid and trabecular. The nuclei were not atypical and mitosis was not found. The bronchial wall was infiltrated by the neoplasm. The neighboring pulmonary parenchyma was compressed, but not infiltrated by the tumor. The histologic diagnosis was bronchial carcinoid. The patient was evaluated again one and six months after surgery. As shown in Figure 1, postoperative OGTT glycemia and insulinemia
Table 2-Combined Testing of Pituita,." Gland after Surgery* TIme (Min)
Glycemia
GH
PRL
-15
78 75
3 3.5
11 10.5 28 27 21 21 18.5 17 19 17
o
20 30 60 80 90
100
120
ISO
55 28 22 38 63
2 3 12 61 42
ACTH
TSH
45
3.50 3.30 3.25 3.65
30 20 95 260 45
FSH
LH
6.4 6.3
2.4 2.7
7.7 7.8
7.2 8.0
7.7
7.5
8.8
4.4
*See Table 1 for normal values. Acromegaly and Bronchial Carcinoid (HtfWldns st 81)
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Figure 1. Serum growth hormone (GD), plasma glucose and serum insulin response to oral glucose tolerance test (OGTT) before and after bronchial carcinoid lobectomy in a patient with acromegaly. profiles were normal after the six-month period. Postoperative basal GH levels were normal in both evaluations (2.0 and 2.5 nglml), and there was suppression of GD levels during the OGn as found in normal subjects. As shown in Table 2, there was a return to normal values and normal response of pituitary hormones during the combined test of anterior pituitary gland (this time, only 0.1 U of insulinJkg), except for TSH, which remained hyporesponsive. Computed tomography of the brain was performed one and six months after lobectomy, with and without contrast, revealing the absence of the previous intrasellar tumor. The patient experienced clinical improvement as well. DISCUSSION
To our knowledge, there have been eight cases reported which claim that acromegaly can be secondary to bronchial
carcinoid.3-5·8-11 Only six of these cases are well documented with hormonal studies before and after the carcinoid excision. 3,4.lO.11 The initially accepted concept was that this association was either fortuitous or was part of a pluriglanit was also accepted that bronchial dular syndrome. 1 Late~ carcinoids belong to the functionally and stnlcturally heterogeneous group oftumors derived from neuroectodermal cells of the neural crest, capable of synthesizing polypeptide hormones and biologically active amines. 1I It became possible, therefore, that substances produced by the carcinoid could be responsible for the acromegaly in patients with these tumors. In our patient, there was a clear relationship between acromegaly and the bronchial carcinoid. It is the first case in which normalization of endocrinologic parameters (nonsuppression of GH after OGn altered pituitary response to combined test) regression of intrasellar tumor (brain computed tomography) and clinical improvement after the bronchial carcinoid resection is reported. Up to now, Dabel(J presented the only report of a carcinoid tumor containing elevated amounts ofGH, but the fact that there was also pituitary fossa enlargement seems to indicate that GH release by the tumor was not the sole factor in developing the acromegalic features. Later reports have not found GH increased in carcinoid tumors in similar patients. 4.5.10 The first evidence ofthe secretion ofa peptide with GHRA by a bronchial carcinoid in this association was the simultaneous reports of Saeed uz Zafar et a14 and Shalet et a15 describing two patients. Recently, Frohman et a16 have reported the partial purification and characterization of this GHRA in carcinoid and other extrapituitary tumors. Our patient's decreased TSH reserve is in accord with previous descriptions in acromegalic subjects related to suppression of TSH secretion rather than destnlction ofthyrotrophic cells. 13 We cannot explain the lack ofpostoperative response, but it is possible that a considerable period is required for recovery. The cause of hyperprolactinemia reported in some of these patients4.5 and in our case, is unknown. From high basal levels (69 and 63 nglml) our patient had hyperresponse to TRH (145 nglml) that was normalized after surgery. The possibility of a prolactin-releasing factor secreted by the carcinoid cannot be excluded. It is still controversial that certain biogenic amines produced by the carcinoid have a role in the development of acromegaly. Dopamine seems to have no effect on GH secretion in culture systems. 5 Very few reports have identi8ed norepinephrine and epinephrine in bronchial carcinoids. 14 Our patient had catecholamine excretion within normal range. Urinary excretion of 5-HIAA and plasma serotonin were also normal in our patient, in agreement with the majority of reports. Therefore, 5-hydroxytryptamine seems not to be related to the acromegaly in these patients. The fact that patients with carcinoid tumors that do not secrete 5-hydroxytryptamine can have raised GH levels seems to support this view 8 In summary, we suggest that in our patient, as well as in other cases, the acromegaly was secondary to the bronchial carcinoid (probably by secretion of a GHRH). The demonstration of normal GH values, normal pituitary tumor and improvement of acromegalic features after resection of the CHEST I 88 I 1 I JULY, 1885
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carcinoid resection seems to support this hypothesis. ACKNOWLEDGMENTS: The authors wish to thank Drs. L. Larrodera and M. Fernandez SaJa of the Biochemistry Department for the RIA ofpituitary hormones, and Prof. F: Martinez Tello, Head, Pathology Department, for his assistance in preparation of the manuscript.
REFERENCES 1 Williams ED, Celestin LR. The association of bronchial carcinoid and pluriglandular adenomatosis. Thorax 1962; 17:120-27 2 Beck C, Burger HG. Evidence for the presence of immunoreactive growth hormone in cancers of the lung and stomach. Cancer 1972; 30:75-9 3 Dabek.n: Bronchial tumor with acromegaly in two patients. J Clin Endocrinol Metah 1974; 38:329-33 4 uz Zafar MS, Mellinger RC, Fine G, Szabo M, Frohman LA. Acromegaly associated with a bronchial carcinoid tumor: Evidence for ectopic production of growth hormone-releasing activity. J Clin Endocrinol Metab 1979; 48:66-71 5 Shalet SM, Beardwell CG, MacFarlane lA, Ellison ML, Norman CM, Rees LH, et al. Acromegaly due to production of a growth hormone releasing factor by a bronchial carcinoid tumour. Clinical Endocrinol 1979; 10:61-7 6 Frohman LA, Szabo M, Berelowitz M, Stachura ME. Partial purification and characterization ofa peptide with growth hormonereleasing activity from extrapituitary tumors in patients with acromegaly. J Clin Invest 1980; 65:43-54 7 Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone releasing factor from a human pancreatic islet tumour. Nature 1982; 300:276-78 8 Feldman JM, Plonk JW, Bivens CH, Lebovitz HE, Handwerger S. Growth hormone and prolactin secretion in the carcinoid syndrome. Am J Med Sci 1975; 269:333-46 9 Altmann H~ Schutz W. Uber ein knochenhaJtiges Bronchuscarcinoid (Morphologische und klinische Beobachtungen bei einer akromegalen Patientin). Beitr Pathol Anat 1959; 120:455-73 10 Sonksen PH, Ayres AB, Braimbridge M, Corrin B, Davies DR, Jeremiah GM, et ale Acromegaly caused by pulmonary carcinoid tumours. Clin Endocrinol (Oxf) 1976; 5:503-13 11 Scheithauer BW, Carpenter PC, Bloch B, Brazeau R Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med 1984; 76:605-16 12 Frolich JC, Margolius HS. Prostaglandins, the Kallikreinkinin system, Bartters syndrome, and the carcinoid syndrome. In: Felig ~ Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and metabolism. New York: McGraw-Hill, 1981, 1265 13 IOijn JGM, Lamberts SWJ, Docter R, De Jong FH, Van Dongen KJ, Birkenhager JC. The function of the pituitary-thyroidal axis in acromegalic patients V. patients with hyperprolactinaemia and a pituitary tumour. Clin Endocrinol 1980; 13:577-85 14 Hinterberger H, Smith A, Bartholomew RJ, Scholtz C. Biochemical diagnosis of malignant carcinoid tumours. Pathology 1973; 5:1-8
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Transbronchlal Needle Aspiration of a Bronchial Carcinoid TUmor* C. Delp Givens, ]r., M.D.;t and]ohn]. Marini, M.D.,
F.C.C.~+
We biopsied a suspected bronchial carcinoid tumor with a transbronchial aspiration needle and obtained cytologic diagnosis without signi6cant hemorrhage. This technique may prove valuable in sampling highly vascular endobronchial neoplasms.
B
ronchial carcinoid tumors are located proximally within the airway in approximately 80 percent of cases. 1 Viewed through the bronchoscope, these highly vascular neoplasms have a characteristic appearance described as smooth, polypoid, and non-ulcerated. 2 Forceps biopsy through the 6beroptic bronchoscope is reported to have a high incidence ofmajor hemorrhage, and rigid bronchoscopy has been the preferred diagnostic approach. 3 We used a transbronchial aspiration needle to obtain a biopsy in suspected bronchial carcinoid tumor, obtaining diagnostic cellular material without incurring signi6cant hemorrhage. CASE REPORT A 68-year-old man retired from farming five years prior to admission because of exertional dyspnea. He had noted occasional wheezing, but little cough or sputum production and no constitutional symptoms. He had discontinued smoking 15 years previously after a 20 pack-year exposure. Two weeks before admission, he coughed blood-streaked phlegm and consulted his physician. A chest roentgenogram showed left hilar prominence, and he was referred for evaluation. On admission, his temperature was 37°C; the blood pressure, 170/95 mm Hg without pulsus paradoxus; the pulse rate, 641min, regular; and respirations, 2O/min. An expiratory wheeze was audible intermittently over the left chest on forced expiration. Breath sounds were symmetrical. His digits were not clubbed, and he had no lymphadenopathy. The hemoglobin and leukocyte count were 14.3 gldl, and 6,400/cu mm, respectively. Arterial blood gas levels on room air were pH, 7.42; Peo., 40 mm Hg, and Po., 71 mm Hg. Chest roentgenogram showed a prominent left hilum with the shadow ofan endobronchial mass visible in the left mainstem bronchus (Fig 1). A flow-volume loop demonstrated a fixed airway obstruction pattern. Three specimens of expectorated sputum were cytopathologically negative. At 6beroptic bronchoscopic examination, a mass nearly occluded the entire left main bronchus at the level of the left upper lobe. Its smooth, glistening capsule bled easily when touched with the tip of bronchoscope. We used a transbronchial aspiration needle (MillRose) to puncture the center of the mass and to aspirate a specimen for cytopathologic analysis. Minor hemorrhage was easily controlled with topical 1 percent epinephrine. The aspiration biopsy (Fig 2) included a core of tissue that showed features characteristic of a carcinoid tumor: small uniform cells, round central nuclei with finely granular chromatin, cellular rosettes, and cells distributed in ribbons around vessels." 5 At thoracotomy, a 2.5 x 1.5 x 1.0 cm mass obstructed the left main bronchus and extended into the left upper lobe, causing distal bronchiectasis. Lobectomy was performed. The tumor did not *From the Division of Pulmonary Medicine, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville. tFellow in Pulmonary Medicine. +Associate Professor of Medicine. Transbronchlal Needle Aspiration (Givens, Marini)