Search

Endobronchial plasmacytoma is a rare manifestation of extramedullary plasmacytoma. A 49-year-old woman with a history of multiple myeloma consulted to our pulmonary service with progressive dyspnoea and cough and abnormal chest X-ray. A lesion measuring 6 × 5 cm in size existed in anterior baseline of the right lung's lower lobe in thoracic computed tomography in addition to right bronchial narrowing and atelectasis distal in lesions. Diagnostic bronchoscopy was performed previously for the obstruction and biopsy was taken from the lesion in the right middle lobe bronchus. Endobronchial biopsies showed extensive tumour infiltration with plasmocytoid cells. Immunohistochemistry was positive CD138 and Lamda. Microscopic and immunohistochemical findings supported the diagnosis of extramedullary endobronchial plasmacytoma., (© 2015 John Wiley & Sons Ltd.)

Bronchial endocrine neoplasms causing acromegaly due to ectopic production of growth hormone (GH)-releasing hormone (GHRH) have been reported. We describe the case of a 39-year-old man with clinical and biochemical acromegaly. Magnetic resonance imaging revealed an enlarged pituitary, which was confirmed histologically to harbour somatotroph hyperplasia. Further investigations identified a circumscribed central mass in the right lung which was surgically resected and histologically confirmed to be an endocrine tumour with strong immunopositivity for GHRH, synaptophysin and chromogranin; the lesion also exhibited mild positivity for peptide YY, calcitonin gene-related peptide (CGRP), glucagon-like peptide (GLP)-1, corticotrophin-releasing hormone (CRH), tyrosine hydroxylase, vasoactive intestinal peptide (VIP) and enkephalin. S100 protein was identified in stellate cells surrounding nests of epithelial tumour cells. The MIB-1 antibody labelled about 10% of the tumour cells. We established that the tumour not only produced GHRH but the GHRH-receptor (GHRH-R) as well. GHRH and GHRH-R mRNA were identified and the latter was characterized as two variants, a full-length transcript and a truncated splice variant that has been described in human pituitary somatotroph adenomas. We suggest that GHRH expression by this tumour and the presence of its receptor may be responsible for enhanced growth. The expression of a truncated splice variant that is unable to transduce GHRH signalling may be implicated in the less aggressive behaviour of well-differentiated endocrine tumours that produce GHRH compared with small-cell lung carcinomas that are very responsive to GHRH growth stimulation.

Objective: The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA., Design: RT-PCR, denaturing gradient gel electrophoresis and S1 nuclease protection experiments were used to analyse V3 mRNA structure in ACTH-secreting tumours. We also developed a competitive RT-PCR system to compare the levels of expression of POMC, V3 and CRH-R genes. This system used as competitor a single mutant template (termed multi-mutant) containing primers for the three genes flanking an unrelated core sequence allowing multiple quantifications from the same cDNA preparations. We analysed 12 normal pituitaries, 15 corticotroph pituitary adenomas and 6 ACTH-secreting bronchial carcinoids., Results: The V3 mRNA structure and sequence were found to be identical in normal and tumoural pituitary indicating that the tumoural Vs mRNA codes for a normal receptor. POMC RT-PCR signals in the pituitary tumour group were approximately 7-fold higher than in the normal pituitary group. Similarly, V3 and CRH-R signal were increased in pituitary tumors (mean +/- SEM: 5.87 x 10(-6) +/- 1.73 x 10(-6), and 2.33 x 10(-4) +/- 1.4 x 10(-4), respectively), when compared to normal pituitaries (1.19 x 10(-7) +/- 2.39 x 10(-8), and 1.7 x 10(-6) +/- 4.65 x 10(-7), respectively) suggesting that these two genes are expressed at very high levels in corticotroph tumours. When expressed relative to the corresponding POMC signals, increases in V3 and CRH-R signals reached 49-fold and 137-fold, respectively, in pituitary tumours. In ACTH-secreting bronchial carcinoids V3 gene expression level was also higher than in normal pituitary, whereas CRH-R signals were detected in only 4 of the 6 tumours with wide variations., Conclusion: Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.

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.

Ectopic ACTH secretion due to occult carcinoid tumours is an occasional cause of ACTH dependent Cushing's syndrome. In many cases the ectopic source may be obvious, but sometimes no obvious source is evident, the so-called occult ectopic syndrome. Due to their small size, localization of such occult tumours, particularly bronchial carcinoids, may be extremely difficult. Whole body CT and venous sampling studies have been used but are not always successful in determining the site of such lesions. We report a 40-year-old patient with the ectopic ACTH syndrome due to a 0.6-cm bronchial carcinoid tumour which was successfully localized by 111indium-DTPA labelled octreotide scintigraphy.

Cushing's syndrome due to a bronchial ACTH secreting carcinoid tumour may be difficult to distinguish from a pituitary microadenoma (corticotrophinoma) causing Cushing's disease, since in both disorders ACTH secretion may be responsive to glucocorticoids. Why some bronchial carcinoid tumours are responsive is unknown but it could be because of co-secretion of corticotrophin releasing factor (CRF) and/or expression of glucocorticoid receptors. We report two patients with glucocorticoid responsive ACTH secreting bronchial carcinoid tumours, neither of whom produced or responded to CRF. Significant glucocorticoid receptor binding capacity (92 and 102 pmol/g protein), compared with control lung tissue, was found in extracts from both tumours. These findings suggest that corticotrophinoma-like responses to glucocorticoids observed in some ACTH secreting bronchial carcinoids result from expression of glucocorticoid receptors and are not necessarily related to the production of CRF.

Acromegaly secondary to the secretion of ectopic growth hormone releasing hormone (GHRH) is rare. We have documented the presentation and unusual clinical course of a patient with a disseminated GHRH-secreting bronchial carcinoid tumour associated with acromegaly over a 17-year period. Recurrent widespread metastatic lesions have been treated over a 10-year period by repeated cycles of the nitrosourea CCNU and 5-fluorouracil with evidence of tumour regression and reduction of circulating growth hormone (GH) and urinary 5HIAA excretion. This cytotoxic regimen, which has been well tolerated, may prove valuable in the management of disseminated carcinoid tumours.

We have studied growth hormone production in a patient with a bronchial carcinoid and acromegaly. The absence of growth hormone from the carcinoid tumour was demonstrated by extraction, cell culture and immunoperosidase techniques. Using a linked perfusion culture system, effluent from the bronchial carcinoid tumour culture stimulated a rapid release of growth hormone from a rat pituitary monolayer. This is the first time evidence of growth hormone releasing activity by a bronchial carcinoid has been demonstrated in a production.

Many patients with advanced non-thyroid malignancies have elevated plasma immunoreactive calcitonin concentrations. Breast and bronchial carcinomas contain immunoreactive calcitonin and an epidermoid bronchial carcinoma has been shown to produce immunoreactive calcitonin in vitro. We have established monolayer cultures of breast carcinomas and eight out of fifteen consecutive carcinomas released immunoreactive calcitonin; some released HCG (human chorionic gonadotrophin) or CEA (carcinoembryonic antigen). In addition, a primary human breast carcinoma has been shown to release and contain calcitonin after being passaged in 'nude' mice over 1 year. Chromatography of extracts and culture media of a bronchical carcinoma demonstrated that, in contrast with the other tumours, it secreted a form or forms of calcitonin having size, charge and immunological differences when compared to calcitonin M. Preliminary evaluation of plasma immunoreactive calcitonin estimations in patients with breast carcinoma showed that twenty-three out of twenty-eight patients with metastatic disease had elevated plasma calcitonin concentrations, whereas only one out of thirteen with localized disease had high levels.

Monolayer tissue culture has been used as a system in which to study aspects of ectopic hormone secretion. Of a series of twenty-four human bronchial carcinomas, nineteen were successfully established in culture and the supernatant medium from each tested for peptide hormones by radioimmunoassay. Six tumours were found to produce adrenocorticotrophin (ACTH), four to release calcitonin (CT) and one to release both of these hormones. No growth hormone or insulin was detected throughout the series. Net in vitro synthesis of both ACTH and CT was demonstrated by recovery of more hormone during culture than was originally contained in the explanted tumour tissue. The production of hormone by four out of six proliferative cultures established, and its persistence through many subculture passages, confirms ectopic hormone production as a stable heritable characteristic of some lung tumours. The ability of hormone-producing bronchial tumour cells to respond to factors known to influence hormone output from normal endocrine cells was tested. ACTH release was stimulated in one tumour by Pitressin and CT in another by gastrin. In addition, the release of CT from the same tumour cell line was shown to be inhibited by the accumulation of high external concentrations of CT as has been reported for normal C-cells.

A young female patient, with clinical and biochemical manifestations of severe hypercorticism and with the presence of a pituitary adenoma shown by computerized tomography, was thought to have Cushing's syndrome of hypophysial origin. However, the surgically-removed pituitary adenoma contained no ACTH, by immunocytology, and hypercorticism persisted after transsphenoidal adenomectomy. The patient died and autopsy demonstrated an ACTH and corticotrophin releasing factor (CRF)-containing bronchial carcinoid. It can be concluded that bronchial carcinoids can produce ACTH and CRF and can mimic the clinical and biochemical manifestations of pituitary Cushing's syndrome. Thus, the localization of the primary site of hypercorticism can be extremely difficult in patients who have an insidious, occult extrapituitary tumour. Further work is required to establish whether CRF plays a role in the causation of Cushing's syndrome and whether the simultaneous secretion of this peptide can modify the clinical and biochemical manifestations of the ectopic ACTH syndrome.

In order to evaluate which of human (h) corticotrophin-like intermediary lobe peptide (CLIP) or h beta-melanocyte stimulating hormone5-22 (h beta MSH5-22) was the better marker of alternate pro-opiomelanocortin (POMC) processing, both peptides were simultaneously sought in the same tissue extracts from a normal human pituitary, six corticotrophic adenomas, and four non-pituitary tumours responsible for an ectopic ACTH syndrome. Human CLIP was detected using a combination of gel exclusion chromatography and two different radioimmunoassays (RIAs): a mid-ACTH RIA which recognized ACTH but not CLIP, and a COOH-ACTH RIA which recognized both molecules. Human beta MSH5-22 had been measured previously. Neither hCLIP nor h beta MSH5-22 were detected in the normal or tumoural pituitaries. The four non-pituitary tumours, in contrast, contained both peptides; the hCLIP and h beta MSH5-22 ratios (CLIP/CLIP + ACTH and h beta MSH5-22/h beta MSH5-22 + h gamma LPH) ranged from 40 to 94% and from 24 to 46%, respectively. In a given tissue the hCLIP ratio was always higher than the h beta MSH5-22 ratio. hCLIP is therefore the better marker of alternate POMC processing.

A patient is described with malignancy, hypercalcaemia and radiological evidence of severe parathyroid bone disease but undetectable concentrations of circulating immunoreactive PTH. Autopsy showed the tumour to be a metastatic bronchial carcinoid with no evidence of primary parathyroid disease. Extracts of the tumour had no PTH immunoreactivity but had high concentrations of a substance with identical activity to PTH in a cytochemical bioassay. The biological activity of the extract was not inhibited by PTH antibodies but was inhibited by an antagonist to PTH bioactivity.