Ectopic ACTH syndrome caused by bronchial carcinoid

A 35-year male patient with clinical and biochemical manifestations of severe hypercorticism was thought to have Cushing's syndrome of pituitary origin. However, the surgically removed pituitary adenoma was not confirmed by pathological examination. There was no improvement after transsphenoidal microsurgery Chest CT scan showed a small mass located at the upper-lobe of the right lung. This tumor (1.8 x 1.0 x 1.0 cm) was removed and one course of radiotherapy with linear accelerator was given. Remission was achieved clinically and biochemically after these therapies. The diagnosis of bronchial carcinoid was confirmed by pathological findings. Metastasis of a lymph node was also proved. The tumor cells was found to contain ACTH and related peptides with radioimmunoassay, immunocytochemistry and electron microscopy. Gel filtration of the tumor extracts showed molecular heterogeniety of ACTH related peptides and that the big-form were in large percentage.     

Ectopic ACTH production by a bronchial carcinoid tumour responsive to desmopressin in vivo and in vitro

A desmopressin-induced ACTH increase has been recently suggested to be specific for pituitary-dependent Cushing's disease. We present the case of a 47-year-old woman with Cushing's syndrome due to ectopic ACTH production by a bronchial carcinoid. While CRH failed to induce an ACTH or cortisol response, intravenous administration of desmopressin led to a 47% increase in serum ACTH and a 42% increase in serum cortisol concentration. After surgical removal of the tumour, the desmopressin response became negative. In vitro , ACTH production by tumour cells obtained at surgery was also stimulated by desmopressin but not by CRH. Additional receptor mRNA expression studies using RT-PCR revealed expression of both V2 and V3 vasopressin receptor subtypes in the carcinoid tumour at a level comparable to that recently described in pituitary corticotroph adenomas. This case illustrates that ACTH stimulation by desmopressin is not specific for pituitary-dependent Cushing's syndrome as vasopressin receptor subtypes known to interact with desmopressin may also be found in ectopic tumours producing ACTH.     

Octreoscan in patients with bronchial carcinoid tumours

OBJECTIVES: Scintigraphy with radiolabelled octreotide (octreoscan) is useful for imaging various neuroendocrine tumours, especially in patients with midgut carcinoids. We were interested in estimating the efficacy of octreoscan for detection of the primary tumour and metastases in patients with bronchial carcinoids. PATIENTS AND METHODS: Twenty-eight patients with histologically verified bronchial carcinoids underwent octreoscan and the imaging results were compared to CT regarding soft tissue metastases, and to bone scan and MRI regarding bone metastases. The primary tumour had been removed prior to the octreoscan in 12 patients. Metastatic disease was diagnosed in 22 patients. RESULTS: Altogether, 20 patients (71%) had octreoscan-positive tumours, including 2/5 patients with ectopic ACTH secretion resulting in Cushing's syndrome and 8/9 patients with carcinoid syndrome. The primary tumour was octreoscan-positive in 13/16 patients and could be detected on CT in 15/16 patients. CT failed to localize the primary tumour in one octreoscan-positive patient, presenting with ectopic ACTH secretion and Cushing's syndrome. Intrathoracic recurrences/metastases were visualized by octreoscan in 7/9 patients and by CT in 8/9 patients. CT showed liver metastases in 14 patients; nine of these patients (64%) had octreoscan-positive liver metastases. Ten patients had bone metastases; octreoscan was positive in seven and bone scan in nine of these 10. CONCLUSIONS: Octreoscan may be used for follow-up and detection of recurrent disease in patients with somatostatin receptor-positive bronchial carcinoids. In our limited patient material, CT however, seems to be better than octreoscan for visualization of the primary tumour as well as liver metastases.     

Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor

Cushing's syndrome due to bronchial carcinoid tumors that secrete adrenocorticotropin (ACTH) may be difficult to distinguish from pituitary Cushing's disease, since the responses to dexamethasone and metyrapone are sometimes similar. Recently, the ACTH and cortisol responses to ovine corticotropin-releasing factor (oCRF) have been shown to be different in pituitary Cushing's disease than in Cushing's syndrome due to other causes. It is not known if the response to oCRF can distinguish pituitary Cushing's disease from those ACTH-secreting bronchial carcinoid tumors that respond to dexamethasone and metyrapone. A case of Cushing's syndrome due to an ACTH-secreting bronchial carcinoid is described in which the responses to dexamethasone, metyrapone, and oCRF were indistinguishable from the responses observed in pituitary Cushing's disease. A bronchial carcinoid tumor should be considered even when responses to dexamethasone, metyrapone, and oCRF suggest pituitary Cushing's disease.     

Glucocorticoid receptors and glucocorticoid effects in rat Sertoli cells

In this report we demonstrate glucocorticoid receptors in seminiferous tubules of the rat testis, and that these receptors are localized in Sertoli cells and peritubular cells. The receptors had high affinity for [3H]dexamethasone (Kd = 0.5 - 1 x 10(-9) M), and similar Kd values were calculated from equilibrium analysis and from rate studies (k1 = 1.5 x 10(6) M-1 min-1 and k-1 = 1.4 x 10(-3) min-1, O C). Binding specificity was typical for glucocorticoid receptors (affinity: dexamethasone greater than corticosterone greater than cortisol approximately R5020 approximately progesterone greater than aldosterone = R1881 greater than 17 beta-estradiol approximately cortisone approximately testosterone greater than 5 alpha-dihydrotestosterone). The concentration of glucocorticoid receptors in rat seminiferous tubules revealed an age-dependent decrease, coinciding with the increase in the number of germ cells. Glucocorticoid receptor levels were higher in Sertoli cells from immature rats than in cells from adult rats. Cultured peritubular cells from immature rats contained levels of glucocorticoid receptors similar to cultured Sertoli cells from rats of the same age. With a nick-translated human glucocorticoid receptor complementary DNA probe, a messenger RNA (mRNA) species of approximately 7 kilobase was clearly detected in both Sertoli cells and peritubular cells. In peritubular cells, a smaller mRNA species (5 kilobase) was also clearly detectable. In mRNA from whole testis tissue, a similar developmental pattern as for dexamethasone binding was found. Dexamethasone caused a concentration-dependent stimulation of mRNA levels for androgen binding protein and for the cAMP-dependent protein kinase regulatory subunit type II beta in cultured immature rat Sertoli cells. On the other hand, mRNA levels for glucocorticoid receptor decreased, whereas mRNA levels for beta-actin remained constant. This report documents for the first time the presence of glucocorticoid receptors and glucocorticoid effects in rat Sertoli cells, and is also the first demonstration of glucocorticoid receptors in peritubular cells of the rat testis.     

Expression of the neuroendocrine cell marker 7B2 in human ACTH secreting tumours

OBJECTIVE AND DESIGN: Pro-opiomelanocortin gene expression is a ubiquitous phenomenon which takes place not only in the pituitary but also in many normal and tumoral non-pituitary tissues. However, the clinical features of the ectopic ACTH syndrome are rarely encountered. To further investigate this problem we examined series of normal human pituitaries and endocrine tumours evaluating the tissue content of pro-opiomelanocortin peptides, and the state of neuroendocrine differentiation as indicated by the biochemical marker 7B2. PATIENTS AND MEASUREMENTS: Tissue concentration of 7B2, pro-opiomelanocortin products (joining peptide and beta-endorphin) were measured in 13 pituitary corticotrophic adenomas and 13 non-pituitary tumours associated with the ectopic ACTH syndrome (five out of 20 bronchial carcinoid tumours, two out of 19 phaeochromocytomas, one out of 11 medullary thyroid carcinomas, three pancreatic and two thymic carcinoid tumours). Molecular weight forms of immunoreactive 7B2 and 7B2 RNA messenger were determined using Western and Northern blot analysis respectively. RESULTS: In all tissues examined, concentrations of immunoreactive beta-endorphin (fmol/mg tissue wet weight) showed widely distributed values from less than 0.7 to 1,340,000, which were correlated (r = 0.975, P less than 0.01) with that of immunoreactive joining peptide, another pro-opiomelanocortin fragment. In the 13 non-pituitary tumours associated with the ectopic ACTH syndrome, immunoreactive beta-endorphin concentrations ranged from 8.6 to 548,000, whereas in normal and tumoral pituitaries they varied from 16,600 to 364,800, and 5000 to 1,340,000, respectively. Immunoreactive 7B2 was detected in 67 of 68 neuroendocrine tumours. Tissue concentrations (fmol/mg tissue wet weight) of immunoreactive 7B2 varied from 135 to 1787 in pituitary tumours; from less than 0.5 to 555 in bronchial carcinoids; from 21.7 to 793 in phaeochromocytomas; from less than 1.6 to 948 in medullary thyroid carcinomas. Western blot analysis showed a predominant molecular weight form of immunoreactive 7B2 at 22 kDa. Northern blot analysis of RNA extracted from ACTH secreting pituitary and non-pituitary tumours showed a predominant signal hybridizing at 1.5 kb with a 7B2 probe. CONCLUSION: These results show that all ACTH secreting tumours have biochemical markers for neuroendocrine differentiation. Tissue concentrations of pro-opiomelanocortin peptides are variable, being extremely high in the most benign tumours and low in those with an aggressive growing pattern, and are not correlated with the biochemical neuroendocrine markers.     

Glucocorticoid dose dependent downregulation of glucocorticoid receptors in patients with rheumatic diseases

OBJECTIVE: The therapeutic success of low doses of glucocorticoids is mediated entirely by classical genomic effects, whereas that of high doses is also mediated to an as yet unknown extent by nongenomic effects. We assessed the relative therapeutic importance of these nongenomic effects in pulse therapy. METHODS: A [3H]dexamethasone radioligand binding assay was used to measure the number of glucocorticoid receptor sites (R, given as number of sites per cell) and glucocorticoid receptor binding affinity (Kd, given in nM) in peripheral blood mononuclear cells isolated from 26 healthy control blood donors and 27 patients with rheumatic diseases. Patients were divided into 4 groups on the basis of their glucocorticoid dose: 0 mg (Group A), < or = 0.25 mg (Group B), 0.25 to 1 mg (Group C), and > 1 mg (Group D) of prednisolone equivalent per kg per day. RESULTS: Sex independent normal values of 3605 +/- 1136 for R and 5.39 +/- 3.4 for Kd were found. At 5407 +/- 1968, the number of receptor sites in patients not receiving glucocorticoid therapy (Group A) was significantly higher than that of controls (p < 0.01). In patients receiving glucocorticoid therapy this value was reduced at 3855 +/- 866 (Group B), 3358 +/- 963 (Group C), and 2685 +/- 962 (Group D). The values in Groups C and D were significantly lower than those in untreated patients (p < 0.02). CONCLUSION: In pulse therapy doses of glucocorticoids that exceed receptor saturation are administered for several days, but in addition significant receptor downregulation occurs. Therefore, we assume an increase in the relative contribution of the nongenomic effects of glucocorticoids to the therapeutic success under these conditions.     

Thallium-201 scintigraphy was useful in diagnosing ectopic ACTH syndrome due to bronchial carcinoid

Abstract. Initial investigations of a 70-year-old woman with clinical Cushing's syndrome, including overnight dexamethasone suppression test, CRH test, and pituitary MRI, suggested the presence of ectopic ACTH production. Thoracic computed tomography (CT) scan revealed a mass measuring 7 mm in the right lung, but it was thought to be an incidental opacity, leaving the source of ectopic ACTH undetermined for several years. During this period, although the size of the lung opacity did not change remarkably, serum cortisol levels became elevated to 43 microg/dl, and the patient's symptoms worsened. Tl-201 SPECT demonstrated intense accumulation in the right lung. The mass was surgically resected using thoracoscopy to investigate it as the focus of ACTH production. Histological and immunohistochemical examination confirmed that the area of intense Tl-201 uptake was an ACTH-producing bronchial carcinoid. Plasma ACTH and cortisol levels decreased immediately after the surgery. In conclusion, this case demonstrated Tl-201 scintigraphy as a useful tool in identifying the location of an ACTH-producing bronchial carcinoid.     

Glucocorticoid resistance following herpes simplex-1 infection: role of hippocampal glucocorticoid receptors

Herpes simplex-1 (HSV-1) is a sporadic cause of viral encephalitis. We have previously demonstrated that corneal HSV inoculation markedly activates the hypothalamo-pituitary-adrenal (HPA) axis. This activation depends on host derived brain interleukine-1 and was resistant to pretreatment with dexamethasone (dex), possibly because immune factors such as pro-inflammatory cytokines can modify the binding capacity of glucocorticoids in the hippocampus. In the present study, we examined whether resistance of the HPA axis activation following intracerebral HSV-1 infection to dex-induced suppression is associated with modifications in hippocampal or pituitary glucocorticoids (GC) receptors or GC receptors in cultured astrocytes. Male rats were injected intracerebroventricularly with purified HSV-1 or vehicle. 48 h later, dex or vehicle was injected intraperitoneally. Rats were sacrificed 3.5 h later. ACTH and corticosterone (CS) were measured in the serum. Specific binding of 3H-dex was measured in the cytosolic fraction of the hippocampus and the pituitary. Dex failed to reduce ACTH and CS responses to HSV-1 infection. In contrast, dex significantly reduced ACTH and CS responses to acoustic neural stimuli. Infection with HSV-1 markedly reduced the hippocampal maximal specific binding of dex with no effect on the dissociation constant (Kd) values. HSV-1 had no effect on the binding of dex in the pituitary. Infection of cultured astrocytes with HSV-1 also reduced the maximal specific binding of dex, but increased the Kd value. The results suggest that HSV-1 induced GC resistance may be mediated by downregulation of GC receptors in hippocampal tissue. These results may clarify a mechanism responsible for GC resistance following immune challenges.     

An ectopic ACTH-producing carcinoid tumor localized by the measurement of ACTH in the bronchial lavage

We report a case of an ectopic ACTH-producing carcinoid in the lung. Typical Cushingoid appearance, elevated plasma ACTH and serum cortisol, bilateral enlargement of the adrenal glands, absence of pituitary adenoma and negativity in petrosus sinus venous sampling indicated the ectopic ACTH syndrome. Venous samplings from a lung tumor which was detected by the chest X-ray, did not show any step-up of ACTH. However, ACTH concentration in the bronchoscopic lavage was as high as that in the peripheral blood. Removal of the tumor, which was an ACTH producing carcinoid, resulted in normalization of ACTH and cortisol concentrations. Measurement of ACTH in the bronchoscopic lavage was useful for the diagnosis of ectopic ACTH-producing tumor.     

Acromegaly secondary to an incidentally discovered growth-hormone-releasing hormone secreting bronchial carcinoid tumour associated to a pituitary incidentaloma

In this report we emphasize the opportunity of considering the uncommon causes of chronic GH-excess in the initial diagnostic process, such as GHRH hypersecretion, especially in the presence of ambiguous pituitary neuroimaging. This topic may have an important clinical significance in order to plan the most cost-effective diagnostic procedures and management and to avoid unnecessary pituitary neurosurgery.     

Clinical aspects of carcinoid tumours

Carcinoid tumours are the most commonly occurring gut endocrine tumours; they are characterized by relatively slow rate of growth, local spread and distant metastases as compared with other malignant neoplasms. The carcinoid syndrome occurs in less than 10% of patients with carcinoid tumours when liver metastases are present. The combination of symptoms, humoral markers and imaging techniques provide an optimal means for the identification of carcinoid tumours and their metastases.     

Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors

Fourteen hormone-producing gastrointestinal tract tumors were tested for their content of somatostatin (SRIH) receptors, using receptor autoradiography and in vitro binding assay with tumor homogenates. All four gastrinomas tested had high levels of SRIH receptors, as did two of five insulinomas and four of five vasoactive intestinal peptide-producing tumors. Receptor visualization was obtained with two different radioligands, either a SRIH-28 analog, [125I]-[Leu8,D-Trp22,Tyr25]SRIH-28, or a SRIH octapeptide, the [125I]Tyr3 derivative of SMS 201-995 [H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr(ol)], [125I]204-090. In both cases receptors were localized over the tumor cell area only. Biochemical and pharmacological analyses of one insulinoma and two vipomas revealed saturable, high affinity binding sites with pharmacological specificity for SRIH. However, differences in receptor affinity of selected SRIH analogs, in particular SRIH-28 and SRIH octapeptides, were found between the insulinomas and the two other tumor types, vipoma and gastrinoma. The presence of SRIH receptors on various hormone-producing gastrointestinal tumors suggests that at least part of the beneficial effects of chronic therapy with SRIH analogs may be mediated through such membrane-bound receptors located on the tumor itself. SRIH receptor measurement may be of prognostic value in assessment of the therapeutic efficacy of SRIH analogs. They may also be of diagnostic value, if used as in vivo markers for the localization of small hormone-producing gastrointestinal tumors or their metastases.     

The prognosis of rectal carcinoid tumours

Carcinoid tumours of the rectum are very rare, and they may present sprecial therapeutic problems for the surgeon. Tumour size and muscle layer invasion are the two most important factors predicting their malignant potential. A series of 20 patients with carcinoid tumours of the rectum were reviewed. 16 tumours less than 2 cm in diameter had neither muscle layer invasion nor lymph node metastases, with the exception of one tumour. Four patients with tumours larger than 2 cm died from metastatic carcinoid. In order to plan operative management endoluminal ultrasound should be performed preoperatively. Rectal carcinoid tumours should be treated like carcinomas of the rectum if they are 2 cm or more in diameter or if they demonstrate muscularis propria invasion independent of tumour size.

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Résumé Les tumeurs carcinoïdes du rectum sont très rares et peuvent présenter des problèmes thérapeutiques particuliers pour le chirurgien. Le calibre de la tumeur et l'invasion des couches musculaires sont les deux facteurs les plus importants pour prévoir leur potentiel malin. Une série de 20 malades présentant une tumeur carcinoïde du rectum a été revue. Les 16 tumeurs de moins de 2 cm de diamètre ne présentaient ni invasion des couches musculaires, ni métastase lymphatique à l'exception d'une seule. 4 patients avec des tumeurs plus grandes que 2 cm sont morts de métastases carcinoïdes. En vue de planifier la conduite opératoire l'échographie endo-rectale devrait être pratiquée pré-opératoirement. Les tumeurs carcinoïde du rectum devraient être traitées comme des cancers du rectum si leur diamètre dépasse 2 cm où si elles démontrent une invasion de la musculaire propre, indépendamment de la taille de la tumeur.

     

Myocardial metastasis of a bronchial carcinoid

A 78-year-old woman was admitted to the Intensive Care Unitfor cardiogenic shock due to cardiac tamponade. She had no pastmedical history and was