A rare case of Cushing syndrome by cyclic ectopic-ACTH

ACTH-dependent Cushing syndrome (CS) due to ectopic ACTH production is most times difficult to manage. The identification of the source of ACTH may take many years. Surgery or chemotherapy for the primary tumor is not always possible. Control of Cushing symptoms is many times achieved using medication, or bilateral adrenalectomy in refractory cases. This case presents a Brazilian male who showed severe hypertension, mood changes, muscle weakness, darkening of skin, and increased abdominal fat. An investigation for Cushing syndrome was carried out and, after a four-year follow-up, a carotid glomus tumor (chemodectoma) was confirmed, a rare ectopic ACTH-producing tumor. Besides, the patient presented cyclic Cushing syndrome that was exacerbated by diverticulitis episodes. This case presents interesting pitfalls on diagnosis and management of ACTH-dependent CS. This is the only report of a chemodectoma that produced ACTH in the literature.     

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.     

Genetics of neuroendocrine and carcinoid tumours

Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-alpha and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-beta, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.     

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.

     

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.     

Failure of somatostatin analogue to control Cushing''s syndrome in two cases of ACTH-producing carcinoid tumours

OBJECTIVE--To determine the effectiveness of somatostatin analogue (octreotide) in controlling hypercortisolism in two patients with ectopic ACTH-producing carcinoid tumours, and to review the literature. DESIGN--The two patients were treated with octreotide administered by subcutaneous injection, for 5 days with 150 micrograms three times daily and for 7 days with 100 micrograms three times daily respectively. They were subsequently treated with oral metyrapone 250 mg three times daily. PATIENTS--Patient 1 had a metastatic carcinoid tumour but the primary was not identified. Patient 2 had a pulmonary carcinoid. Cushing's syndrome due to ectopic ACTH syndrome was established by demonstration of failure of cortisol suppression by dexamethasone, elevated ACTH levels, and immunoperoxidase staining for ACTH within the tumours. MEASUREMENTS--Urinary free cortisol (UFC) was measured on consecutive days during treatment with octreotide. Serum cortisol and ACTH levels were taken daily in patient 2, and on days 0 and 3 in patient 1. RESULTS--Patient 1 had a baseline 24-hour urinary free cortisol of 5340 nmol/24 h, serum cortisol of 915 nmol/l, and serum ACTH of 163 ng/l (ACTH ng/l x 0.23 = pmol/l). After 3 days of octreotide, serum cortisol was 782 nmol/l and ACTH 164 ng/l. Twenty-four hour urinary free cortisol was 4136 nmol/24 h after 7 days of treatment. Metyrapone, however, resulted in a rapid fall in urinary free cortisol to 290 nmol/24 h, with marked clinical improvement. Patient 2 had a baseline 24-hour urinary free cortisol of 2520 nmol/24 h, serum cortisol of 747 nmol/l, and ACTH of 103 ng/l. Urinary free cortisol rose to 2970 nmol/24 h on day 6 of treatment with octreotide. Serum cortisol and ACTH levels fell slightly to 611 nmol/l and 70 ng/l respectively. On changing to metyrapone, the urinary free cortisol fell to 821 nmol/24 h in 4 days. CONCLUSIONS--Octreotide failed to significantly reduce 24-hour urinary free cortisol, serum cortisol and ACTH in the two patients reported. We conclude that it should probably not be regarded as primary treatment for control of hypercotisolism in patients with ACTH-producing carcinoids, but reserved as adjunctive therapy.     

The diagnosis of pulmonary carcinoid tumours.

Carcinoid tumours of the lung are commonly misdiagnosed as carcinoma and even if they are recognized their behaviour may be unexpected. In a series of ten cases which had caused diagnostic difficulty there had been an incorrect interpretation of broncial biopsy material in four, of the resected tumours in another four, of a needle biopsy core in one and of autopsy material in another. In some cases these errors led to needless radiotherapy and to an unnecessarily poor prognosis being given. In all cases the diagnosis of carcinoid tumour was made retrospectively by the demonstration of argyrophil granules in the tumour cells or by electron microscopy. Electron-dense bodies could be found in material that had been fixed in formol saline or even embedded in paraffin so that this method may be used retrospectively. Two of these ten tumours behaved in a malignant fashion but progressed much more slowly than most samples of bronchial carcinoma. The possibility of carcinoid tumour should be considered in any patient with a tumour of the lung who is unusually young, or who is a non-smoker or where bone or calcification are present in the tumour. It is also suggested that unrecognized cases of carcinoid tumour may be found amongst long-term survivors with lung tumours which havebeen treated by radiotherapy or chemotherapy without surgery.     

Management of disseminated midgut carcinoid tumours.

Forty-one patients with disseminated midgut carcinoid tumours were treated over a 6-year period according to a strict programme including primary surgical treatment. In 10 patients, a total remission of the disease was obtained. Patients with bilobar hepatic disease had ischaemic treatment of their liver metastases by hepatic arterial embolisation after primary surgical and medical treatment (low dose octreotide). Thus, by combining surgical, radiological and medical treatment modalities, we wanted to offer these patients optimal palliation. This treatment programme resulted in good symptomatic relief in all patients accompanied by a marked reduction in 5-hydroxyindoleacetic acid (5-HIAA) levels. At recurrence of symptoms in combination with rising 5-HIAA levels, embolisation was repeated. Ten of the treated patients have deceased during the observation period, but only 5 from their carcinoid disease.     

Interferon and meta-iodobenzylguanidin combinations in the treatment of metastatic carcinoid tumours

Interferon (IFN) and meta-iodobenzylguanidin (MIBG) are active in metastatic carcinoids. In a phase II study, we evaluated the effect upon diagnostic 131I-MIBG uptake and the clinical response of the combination. 131I-MIBG scintigraphy was performed prior to treatment, after 8 weeks of IFN and after unlabelled MIBG. The tumour over non-tumour (T/NT) ratios were quantitatively determined by comparing counts in the centre of the tumour (liver metastases) with those in an adjacent area of normal liver uptake (T/NT1) and with abdominal background area (T/NT2). The T/NT1 ratio showed an increase of >10% in only four out of 21 patients (19%) after IFN (P = 0.178) and significantly more often in nine out of 18 patients (50%) after unlabelled MIBG (P = 0.016). The absolute uptake in tumour deposits was also increased if compared with the abdominal background (T/NT2: 23% increase after IFN and 83% increase after unlabelled MIBG). The combination produced 91% of patients with stable disease (using World Health Organisation criteria) at computed tomography scan and a biochemical response (a reduction of at least 50% in urinary 5-hydroxyindolacetic acid excretion) in 39%. IFN-alpha did not significantly improve tumour retention of 131I-MIBG. In contrast, unlabelled MIBG significantly improved biodistribution and tumour uptake in 83%. A synergistic effect was not seen.     

Complications of midgut carcinoid tumors and carcinoid syndrome

The carcinoid syndrome, associated with carcinoid tumors of the midgut, consists of symptoms such as diarrhea, flushing, wheezing and cardiovascular symptoms. This review focuses on these symptoms and discusses therapeutic options. The symptoms are caused by the secretion of biogenic amines, polypeptides and other factors of which serotonin is the most prominent. However, diarrhea is also due to factors such as malabsorption. Besides antitumor therapy, more specific interventions such as serotonin receptor blockers can be useful. The carcinoid heart disease involves the tricuspid and pulmonary valve. In the pathogenesis, serotonin plays a central role. The therapeutic approach is mostly symptomatic. Other cardiovascular complications include bowel ischemia and hypertension. Pellagra and psychiatric symptoms are due to a depletion of tryptophan, which is consumed by the carcinoid tumor for serotonin synthesis. Finally, follow-up and clinical practice of patients with carcinoid tumors are discussed.     

Clinical presentation and prognosis of gastrointestinal carcinoid tumours

Clinical data about 104 patients with gastrointestinal carcinoids emphasized the heterogeneous nature of these tumours in different organs. The sites of the primary tumours were the stomach in 12 (11%), the duodenum in 3 (3%), the small bowel in 48 (45%), the appendix in 28 (26%), the colon in 6 (6%), and the rectum in 6 cases (6%). Gastric carcinoids were multiple in 4 (33%) and small-bowel carcinoids in 11 cases (23%). None of the gastric, duodenal, or rectal carcinoids had generated metastases, as contrasted to 34 (72%) small-bowel carcinoids. Twelve patients had symptoms of the carcinoid syndrome caused by hepatic metastases from ileal (11) or appendiceal (1) primary tumours. At least two patients with duodenal carcinoids had Zollinger-Ellison syndrome produced by the tumours. The cumulative 5-year survival rate was 91-100% for gastric, appendiceal, and rectal carcinoids, 77% for small-bowel carcinoids, and 33% for colonic carcinoids. Resectable mesenteric lymph node metastases did not affect the 5-year survival of patients with small-bowel carcinoids as compared with the tumours confined to the bowel wall. Poor prognosis was associated with hepatic metastases at the time of diagnosis. Small-bowel carcinoids remain a challenge in clinical work because of their distinct metastatic propensity and problematic diagnosis.     

Intestinal carcinoid tumours in a father and daughter.

Familial cases of carcinoid tumours that are not associated with any known syndrome or disease are extremely rare. All cases reported in the world literature have involved carcinoid tumours of the gastrointestinal tract. Two cases of carcinoid tumours of the small intestine in a father and daughter are presented. Laboratory analyses did not support the hypothesis that the occurrence of carcinoid tumours in this family is a variant of the multiple endocrine neoplasia type 1 syndrome. A review of the literature on familial occurrence of intestinal carcinoid tumours in the absence of any other known carcinoid tumour-predisposing genetic syndrome is provided.     

Therapy of the malignant carcinoid syndrome

Although usually associated with carcinoid tumors of the small intestine that have metastasized to the liver, the carcinoid syndrome is seen less frequently with primary tumors arising from other organs such as the lung, pancreas, thymus, stomach, and ovary. The clinical features, pathophysiology and diagnosis, and therapeutic considerations of this syndrome are presented. The management of carcinoid crisis and the results of recent chemotherapy trials are also discussed.     

Interventional treatment of the carcinoid syndrome

Liver metastases imply a major problem in patients with carcinoid tumours and hormone overproduction. Patients with distant metastases can undergo resection for potential cure or for symptom palliation. In patients with bilobar liver metastases other interventions are at hand, e.g. local ablation or hepatic arterial embolization. In selected cases liver transplantation can be a treatment alternative. Prior to all interventions patients with midgut carcinoids are protected with somatostatin analogues to reduce hormone secretion. Patients with foregut carcinoids may present special problems with life-threatening release of histamine during interventions.