A case of ectopic ACTH syndrome due to DDAVP-sensitive but V1b receptor-negative bronchial typical carcinoid with lymphatic metastasis and plasma ProGRP elevation.

Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing's syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

[Bronchopulmonary ACTH-producing tumors].

Neuroendocrine tumors have the ability to produce the hormones and vasoactive peptides. Excess of these hormones leads to different symptoms and syndromes because of organs' injuries. Detection of ACTH origin by using of modern diagnostic methods is not always possible. Lungs and bronchi are one of the most frequent localization of ACTH-producing tumors. It is considered that carcinoids with bronchopulmonary localization like a benign tumors in the clinical course. But at the same time carcinoid tends to metastasize, so timely diagnostics and treatment improve quality of life significant and increase the life expectancy of patients. The modern state of diagnostics and surgical treatment problem of ACTH-producing tumors with bronchopulmonary localization is presented in the article. It was described the brief historical background, clinical symptoms, instrumental and biochemical methods of diagnosis. The principles of surgical treatment are presented in the article.

Pulmonary arterial sampling was useful for localizing ectopic ACTH production in a patient with bronchial carcinoid causing Cushing syndrome.

OBJECTIVE: We report a 44-year old man with ectopic adrenocorticotropic hormone (ACTH) syndrome caused by bronchial carcinoid that developed Cushing syndrome. METHODS: We performed several imaging studies, including chest and abdominal CT, for exploration of nodules and selective pulmonary arterial sampling for localizing a source of ectopic ACTH production. RESULTS: The patient was diagnosed as Cushing syndrome due to ectopic production of ACTH without identification of its source(s). After 2 years' follow-up with repeated CT scans every 6-12 months and treatment with metyrapone, chest CT revealed two small nodules respectively in the segment (S) 4 and 10 of the right lung. We performed selective pulmonary arterial sampling from branches of the right pulmonary artery to obtain blood from the nodules in a reverse flow fashion: wedged sampling from the basal branch (A8, 9 and 10) revealed significant elevation of ACTH, whereas sampling from the lateral branch (A4) did not, indicating that the S10 nodule produced ACTH ectopically. The video-assisted thoracoscopic surgery removing the right inferior lobe normalized plasma ACTH, serum cortisol and 24-hour urinary free cortisol. The S10 nodule was histologically diagnosed as atypical bronchial carcinoid containing immunoreactive ACTH. CONCLUSIONS: Selective pulmonary arterial sampling was useful for localizing the lesion of ectopic ACTH production and helped make the decision for its surgical removal. This procedure should be considered once lung nodules suspicious for ectopic ACTH production are identified in patients with EAS.

Selected neuroendocrine tumour markers, growth factors and their receptors in typical and atypical bronchopulmonary carcinoids.

INTRODUCTION: Bronchopulmonary neuroendocrine tumours (BP NET) cause many diagnostic and therapeutic problems. There is an ongoing search for biochemical markers of activity of these tumours. The use of polypeptide growth factors seems potentially feasible in establishing the diagnosis, prognosis and treatment of these tumours. MATERIAL AND METHODS: We included 41 patients aged 25 to 78 years with histopathologically confirmed typical and atypical bronchopulmonary carcinoid tumours and 20 healthy volunteers. We assessed the levels of specific and non-specific markers of these tumours and of selected growth factors relative to TNM classification. RESULTS: The levels of specific markers (serotonin and its metabolite, 5-hydroxyindoleacetic acid [5HIAA]) and non-specific markers (chromogranin A [CgA]) were significantly higher in patients with atypical carcinoid tumours. The serum levels of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1) were significantly higher in patients with carcinoid tumours versus the control group. The levels of VEGFR-1 closely correlated with TNM classification. No such correlation could, however, be confirmed for the levels of HGF, VEGF or VEGFR-2. CONCLUSIONS: Determination of CgA, serotonin and 5HIAA may be useful in the diagnosis of BP NET, particularly in atypical carcinoid tumours, and their levels depend on the presence of distant metastases. Determination of growth factors (VEGF and its receptor, VEGFR­1, and HGF) may prove useful in the clinical diagnosis of these tumours, while the assessment of VEGFR­1 expression may be helpful in tumour staging.

Acromegaly caused by ectopic growth hormone-releasing hormone production from a bronchial carcinoid tumor.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma. In rare cases, however, it is caused by the ectopic production of growth hormone-releasing hormone (GHRH). We report a case of acromegaly due to ectopic production of GHRH from a bronchial carcinoid in a 42-year-old female. The carcinoid tumor was successfully treated with bilobectomy.

Successful localization of ectopic ACTH-secreting bronchial carcinoid by selective pulmonary arterial sampling.

Among patient with ACTH-dependent Cushing's syndrome, about 10-20% of those with ectopic ACTH syndromes (EAS) have occult or unknown tumors. Despite the intensive search for the culprit tumors by dynamic endocrine tests and imaging tests, it is often difficult to localize and confirm the source of occult ectopic ACTH secretion. We report a patient with EAS caused by a small bronchial carcinoid tumor, which was successfully localized by a selective pulmonary arterial sampling for the first time. A 69-year-old woman presented with typical Cushingoid features and elevated plasma ACTH and cortisol levels, which showed lack of circadian rhythm, no suppression by high-dose dexamethasone, and no response to CRH stimulation. No mass lesion was detected by pituitary MRI, and inferior petrosal sinus sampling showed no central to peripheral ACTH gradient. Although CT scan of the chest revealed a very small nodule in the right lung, it could not be confirmed by either somatostatin receptor scintigraphy or fluorodeoxyglucose positron emission tomography. Selective pulmonary arterial sampling of the wedged blood from a pulmonary artery branch affecting the nodule showed a marked ACTH gradient, and the lobectomy of the right middle lung resulted in dramatic decreases in plasma ACTH and cortisol levels. The resected tumor was diagnosed as a bronchial carcinoid tumor with positive immunostaining for ACTH. Thus, selective pulmonary arterial sampling, because of its more site-selective measurement of hormonal secretion, could be one of the useful tools to localize and confirm the ectopic ACTH production by a small pulmonary tumor.

Salvage therapy with (177)Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors.

UNLABELLED: Regular therapy with the radiolabeled somatostatin analog (177)Lu-octreotate (22.2-29.6 GBq) in patients with gastroenteropancreatic or bronchial neuroendocrine tumors results in tumor remission in 46% of patients, including minor response. We present the effects of additional therapy with (177)Lu-octreotate in patients in whom progressive disease developed after an initial benefit from regular therapy. METHODS: Thirty-three patients with progressive disease after an initial radiologic or clinical response were treated with additional cycles of (177)Lu-octreotate. The intended cumulative dose of additional therapy was 14.8 GBq in 2 cycles. Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of >or=25% and <50%). RESULTS: Median time to progression (TTP) after regular therapy was 27 mo. In 4 patients, the intended cumulative dose was not achieved (2 had progressive disease, 2 had long-lasting thrombocytopenia). Hematologic toxicity grade 3 was observed in 4 patients, and grade 4, in 1. The median follow-up time was 16 mo (range, 1-40 mo). No kidney failure or myelodysplastic syndrome was observed. Renewed tumor regression was observed in 8 patients (2 partial remission, 6 minor response), and 8 patients had stable disease. Median TTP was 17 mo. Treatment outcome was less favorable in patients with a short TTP after regular cycles. Treatment effects in patients with pancreatic neuroendocrine tumors were similar to those in patients with other gastroenteropancreatic neuroendocrine tumors. CONCLUSION: Most patients tolerated additional cycles with (177)Lu-octreotate well. None developed serious delayed adverse events. Additional cycles with (177)Lu-octreotate can have antitumor effects, but effects were less than for the regular cycles. This may be because of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. We conclude that this salvage therapy can be effective and is safe.

Dual bronchial carcinoids and Cushing's syndrome with a paradoxical response to dexamethasone and a false positive outcome of inferior petrosal sinus sampling.

CONTEXT: Establishing the cause of Cushing's syndrome (CS) can be a considerable challenge, in particular in ectopic adrenocorticotropic hormone (ACTH) syndrome, and often requires a combination of biochemical tests and imaging procedures. SUBJECT: A 27-year-old man presented with signs of CS. P-ACTH levels were three times above the upper limit of normal (ULN) and free urinary cortisol around 2000 nmol/24 h. The work-up showed remarkable results. RESULTS: A 2-day low-dose dexamethasone suppression test demonstrated paradoxical increases in cortisol. Sampling from the bilateral inferior petrosal sinus sampling (BIPSS) showed a central to peripheral ACTH ratio of 4.7 after corticotrophin-releasing hormone (CRH) stimulation, i.e. indicated pituitary disease, but magnetic resonance imaging of the pituitary was normal. Computed tomography (CT) scan of the lungs showed two oval-shaped masses, 1.3 x 1.8 and 1.3 x 2 cm, in the middle lobe. Both were positive at somatostatin receptor scintigraphy, compatible with tumors or inflammatory lesions. Subsequently, (11)C-5-hydroxytryptophan-PET showed distinct uptake in the tumors but not elsewhere. Two carcinoids situated 3 cm apart, both staining for ACTH, were removed at surgery. CONCLUSION: This unique case with dual bronchial carcinoids inducing hypercortisolism illustrates the problems with identifying the source of ACTH in CS. Possibly, an abnormal regulation of ACTH production in response to dexamethasone, or steroid-induced tumor necrosis, explains the paradoxical outcome at dexamethasone suppression, and the false positive result at BIPSS reflects an unusual sensitivity of the pituitary corticotrophs to CRH in this patient. The work-up illustrates the great value of (11)C-5-hydroxytryptophan-PET as a diagnostic procedure when other investigations have produced ambiguous results.

Tobacco as an allergen in bronchial disease.

BACKGROUND: Skin testing and sera measurements have verified the existence of tobacco specific IgE. However, the few published studies on this matter report conflicting results concerning their clinical significance. OBJECTIVE: To verify if a specific clinical allergenic response against tobacco might be possible in allergenic and nonallergenic bronchial diseases. METHODS: We performed a cross-sectional observational case-control analysis on 180 patients with asthma, chronic obstructive pulmonary disease (COPD), and bronchial carcinoma and controls who were randomly chosen. Skin prick tests and serum specific IgE to tobacco and related allergens, bronchial challenge with cigarettes and tobacco extract, patch tests with tobacco and nicotine, sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting, and Enzyme AllergoSorbent Test (EAST) inhibition were performed. RESULTS: Twenty-eight patients had positive tobacco skin prick test results. The association among positive skin prick test results, IgE, and bronchial challenge was strong (P < .001). Tobacco sensitivity was higher in patients with pollen asthma than in patients with COPD and carcinoma and negative in patients with intrinsic asthma and controls. A positive bronchial challenge result was related to the length of habit (P < .001) and the tobacco index in patients who had stopped smoking (P < .001). Delayed bronchial and patch response was more common in patients with COPD (P < .001). Tobacco IgE response (EAST) was related to sensitivity to Lolium perenne (rye grass) pollen (P < .001) but not to other vegetables that belong to the Solanaceae family. EAST inhibition showed cross-reactivity between tobacco and Lolium pollen. CONCLUSIONS: Tobacco may be responsible for a specific IgE response. Patients with pollen asthma were those with more positive responses to tobacco due to cross-reactivity between Lolium and tobacco allergens.

Adrenomedullin is a novel marker of tumor progression in neuroendocrine carcinomas.

Adrenomedullin is a multi-functional polypeptide hormone. Its involvement in angiogenesis and vasodilator action support the hypothesis that adrenomedullin may be a secretory product of neuroendocrine tumors and contribute to tumor progression. Plasma levels of adrenomedullin were measured by radioimmunoassay in 46 patients with neuroendocrine carcinomas of the gastroenteropancreatic and bronchial system. Tissue expression of adrenomedullin was studied using monoclonal antibodies on pretreated paraffin embedded tissues in a group of 31 patients. Adrenomedullin plasma levels were significantly elevated in patients compared to healthy age-matched controls (p < 0.001). The highest plasma levels were found in patients with neuroendocrine carcinomas of bronchial, midgut and unknown origin. Patients with progressive disease had higher plasma levels than patients with stable disease (p < 0.001). Of the examined tumor samples, 55 % showed cytoplasmic staining for adrenomedullin > 5 % of the total tumor area. Plasma levels and tissue expression of adrenomedullin did not correlate with functional activity of the tumors or presence of the carcinoid syndrome, but did with tumor progression (p < 0.001 and p < 0.014). In conclusion, plasma and tissue expression of the angiogenic peptide adrenomedullin are predictive of tumor progression in patients with neuroendocrine carcinomas. Adrenomedullin might represent a useful prognostic marker in patients with neuroendocrine carcinomas.

The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up.

CONTEXT: There are few large series of patients with ectopic, nonpituitary, corticotropin (ACTH) secretion (EAS). OBJECTIVE: The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS. DESIGN: This was a retrospective case-record study. SETTING: The setting for this study was a tertiary referral hospital center. PATIENTS: Forty patients with EAS were studied. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological features and response to therapy and survival were measured. RESULTS: The median follow-up was 5 yr (range, 2-30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5% of patients, the source of EAS was never found. Octreotide scintigraphy and whole-body venous sampling were of limited value. Surgical attempt at curative resection was successful in 83% (10 of 12) of patients with bronchial carcinoid tumors; others responded generally well to adrenolytic therapy or bilateral adrenalectomy. Tumor histology and the presence of distant metastases were the main predictors of overall survival (P < 0.05). CONCLUSIONS: A variety of tests and imaging studies are necessary for the correct diagnosis of the EAS, but even then, up to 20% of cases present a covert or occult EAS syndrome. These cases require a prolonged follow-up, review, and repetition of diagnostic tests and scans.

Tumor markers (pregnancy protein 1, placental-specific tissue protein 10, placental-specific tissue protein 12, alpha1-fetoprotein) in patients with bronchial carcinoma.

The concentrations of pregnancy protein 1 (SP1), placental-specific tissue protein 10 (PP10), placental-specific tissue protein 12 (PP12) and alpha1-Fetoprotein (AFP) were analyzed in serum samples of 83 patients with bronchial carcinoma at stages II-IV Protein levels were determined by means of single radial immunodiffusion, rocket immuno-electrophoresis, radioimmunoassay and enzyme- immunoassay. PP12 and AFP serum concentrations were significantly increased in the cancer group compared with the control group. PP12 (control group: x=54.08 microg/l; s=61. 70; tumor group: x = 122.52 microg/l; s = 131.16); AFP (control group: x=3.05 microg/l; s=3. 76; tumor group: x = 8.29 microg/l; s = 17.75). SPI was found in only 22 cases of the tumor group. PP10 (control group: x = 2.25 microg/l; s = 0.866; tumor group: x = 2.503 microg/l; s=1.508). Given that at least two of the tested parameters were determined to be in the pathological range, the sensitivity amounted to 0.64 and the specificity to 0.92.

[Biological variables and stratification of patients with inoperable non-small-cell bronchial cancer: recommendations for future trials]. / Variables biologiques et stratification des patients atteints de cancer bronchique non à petites cellules non opérés: recommandations pour de futurs essais.

OBJECTIVE: To identify, through a review of the literature, the laboratory variables that would allow a more accurate stratification of unresected non small-cell lung cancer patients who participate in clinical trials. METHOD: Systematic review, without meta-analysis, following the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine, and taking into account the Consolidated Standards of Reporting Trials statement. RESULTS: Of 1106 publications retrieved, we were able to include only fourteen studies in our review. Available evidence would support the use of several laboratory variables as prognostic covariables to stratify non resected non small-cell lung cancer patients in clinical trials, but blood haemoglobin would be the only one that could be recommended on a routine basis, and only in patients treated with radiotherapy (three studies out of three). The possible consequences in terms of therapeutic decision of haemoglobin measurements remain however to be clarified. CONCLUSION: Until better designed studies are published, a number of arguments would support the pre-treatment measurements of the following variables in patients participating in clinical trials: blood haemoglobin, white blood cell count with differential, serum LDH, albumin, calcium, and NSE. Further studies would also be necessary to support the addition to this list, of other tumour markers (including Cyfra 21-1), and/or measurements during or after treatment.

Multifocal peripheral bronchial carcinoid tumour.

Peripheral bronchial carcinoids sometimes arise as single solid or nodular lesions in the periphery of the lung. We encountered a 74-year-old Japanese male with bronchial carcinoids that were widely disseminated throughout the lung parenchyma. Pulmonary function tests revealed mild airflow obstruction. A metastatic process was ruled out from primary malignancy and a histological examination revealed findings consistent with a peripheral bronchial carcinoid. Based on these findings, we concluded that this patient had a primary multifocal peripheral bronchial carcinoid. An immunohistochemical examination revealed immunoreactivity for chromogranin A and bombesin. The present case appears to be an unusual case of diffuse multifocal peripheral bronchial carcinoid, confirmed by immunohistochemistry.

Breathing pattern and arterial blood gases during Nd-YAG laser photoresection of endobronchial lesions under general anesthesia: use of negative pressure ventilation: a preliminary study.

STUDY OBJECTIVE: To evaluate the efficacy of negative pressure ventilation (NPV) in avoiding or reducing apneas and related hypoxemia and respiratory acidosis during laser therapy (LT) of endobronchial lesions. DESIGN: A prospective, controlled, randomized study. SETTING: An operating theater of a respiratory endoscopy and laser therapy unit. POPULATION AND INTERVENTION: Twenty-seven consecutive patients referred to LT were entered into the study. Fourteen patients were randomly assigned to LT under general anesthesia and spontaneous assisted ventilation (control group) whereas in 13 cases, NPV by a poncho-wrap ventilator (NPV group) was added to the procedure. MEASUREMENTS AND RESULTS: The prevalence and the duration of apnea/hypopnea periods assessed by respiratory inductive plethysmography during LT were significantly reduced under NPV, compared to the control group. As compared to baseline, during LT, all control patients developed mild to severe hypercapnia (PaCO2 ranging from 55 to 76 mm Hg) and respiratory acidosis (pH from 7.33 to 7.19), whereas only three patients undergoing NPV (23%) developed hypercapnia (PaCO2 from 52 to 68 mm Hg) and related acidosis (pH from 7.29 to 7.21). Optimal oxygenation was achieved in all of the patients; nevertheless, patients under NPV needed a lower mean oxygen supply; five of them (38%) could be treated at a fraction of inspired oxygen of 0.21 for the whole procedure. CONCLUSION: NPV may be useful in reducing apneas during laser therapy under general anesthesia, thus reducing hypercapnia, related acidosis, and need of oxygen supplementation.