Endogenous
Cushing's syndrome is a clinical state resulting from prolonged, inappropriate exposure to excessive endogenous secretion of
cortisol and hence excess circulating free
cortisol, characterized by loss of the normal feedback mechanisms of the hypothalamo-pituitary-adrenal axis and the normal circadian rhythm of
cortisol secretion [2]. The etiology of
Cushing's syndrome may be excessive
ACTH secretion from the pituitary gland, ectopic
ACTH secretion by nonpituitary
tumor, or excessive autonomous secretion of
cortisol from a hyperfunctioning adrenal
adenoma or
carcinoma. Other than this broad
ACTH-dependent and
ACTH-independent categories, the syndrome may be caused by ectopic CRH secretion, PPNAD, MAH, ectopic action of GIP or
catecholamines, and other adrenel-dependent processes associated with
adrenocortical hyperfunction.
CASE REPORT: A 31 year-old men with 6-month history of
hyperpigmentation,
weight gain and proximal
myopathy was refereed to Institute of Endocrinology for evaluation of
hypercortisolism. At
admission, patient had classic cushingold habit with plethoric face, dermal and
muscle atrophy, abdominal strie rubrae and centripetal
obesity. The standard laboratory data showed hyperglycaemia and hypokaliemia with high
potassium excretion level. The circadian rhythm of
cortisol secretion was blunted, with moderately elevated
ACTH level, and without
cortisol suppression after low-dose and high-dose dexamethason suppression test. Urinary SHIAA was elevated. Abdominal and sellar region magnetic resonance imaging was negative. CRH stimulation resulted in
ACTH increase of 87% of basal, but without significant increase of
cortisol level, only 7%. Thoracal CT scan revealed 14 mm mass in right apical pulmonary segment. A wedge resection of anterior segment of right upper lobe was performed. Microscopic evaluation showed
tumor tissue consisting of solid areas of uniform, oval cells with eosinophilic cytoplasm and centrally located nuclei. Stromal tissue was scanty, and mitotic figures were infrequent.
Tumor cells were immunoreactive for
synaptophysin,
neuron-specific enolase, and
ACTH. The postoperative course was uneventful and the patient was discharged on
glucocorticoid supplementation. Signs of
Cushing's syndrome were in regression, and patient remained normotensive and normoglycaemic without
therapy.
DISCUSSION: A multitude of normal nonpituitary cells from different organs and tissues have been shown to express the
POMC gene from which
ACTH is derived. The
tumors most commonly associated the
ectopic ACTH syndrome arise from neuroendocrine tissues, APUD cells.
POMC gene expression in non-pituitary cells differs from that in pituitary cells both qualitatively and quantitatively [8]. Aggressive
tumors, like
small cell cancer of the lung (SCCL) preferentially release intact
POMC, whereas
carcinoids rather overprocess the precursor, releasing
ACTH and smaller
peptides like
CLIP. Some
tumors associated with
ectopic ACTH syndrome express other markers of neuroendocrine differentiation like two specific
prohormone convertases (PCs). Assessment of
vasopressin (V3) receptor gene expression in
ACTH-producing nonpitultary
tumors revealed bronchial
carcinoid as a particular subset of
tumors where both V3 receptor and
POMC gene may be expressed in pattern indistinguishable from that in
corticotroph adenoma [9]. In most, but not all, patients with
ectopic ACTH syndrome,
cortisol is unresponsive to high-dose dexamethason suppression test, what is used as diagnostic tool. It is not clear if the primary resistance resulted from structural abnormality of the native
glucocorticoid receptor (GR), a low level of expression, or some intrinsic property of the cell line [9]. It appears that
ectopic ACTH syndrome is made of two different entities. When it is because of highly differentiated
tumors, with highest level of pituitary-like
POMC mRNA, expressing PCs, high level of V3 receptors and GR, like bronchial
carcinoids, it might be called ectopic corticotroph syndrome. In contrast, when it is caused by aggressive, poorly differentiated
tumors, with much lower expression of V3 receptor, like SCCL, it might be called aberrant
ACTH secretion syndrome.
Carcinoid tumors have been reported in a wide range of organs but most commonly involve the lungs, bronchi, and gastrointestinal tract. They arise from neuroendocrine cells and are characterized by positive reactions to markers of neuroendocrine tissue, including
neuron specific enolase,
synaptophysin, and chromogranina [11].
Carcinoid tumors are typically found to contain numerous membrane-bound neurosecretory granules composed of variety of
hormones and
biogenic amines. One of the best characterized is
serotonin, subsequently metabolized to 5-hydrohy-indolacetic
acid (5-HIAA), which is excreted in the urine. In addition to
serotonin,
carcinoid tumors have been found to secrete
ACTH,
histamine,
dopamine,
substance P,
neurotensin,
prostaglandins and
kallikrein. The release of
serotonin and other vasoactive substances is thought to cause
carcinoid syndrome, which manifestations are episodic
flushing, weezing,
diarrhea, and eventual right-sided
valvular heart disease. These
tumors have been classified as either well-differentiated or poorly differentiated
neuroendocrine carcinomas. The term "pulmonary tumorlets" describes multiple microscopic nests of neuroendocrine cells in the lungs [12]. Pulmonary
carcinoids make up approximately 2 percents of primary lung
tumors. The majority of these
tumors are perihilar in location, and patients often presents with recurrent
pneumonia,
cough, hemoptisis, or
chest pain. The
carcinoid syndrome occurs in less than 5 percent of cases. Ectopic secretion of
ACTH from pulmonary
carcinoid accounts for 1 percent of all cases of
Cushing's syndrome. They are distinct clinical and pathologic entity, generally peripheral in location. Although they are usually typical by standard histologic criteria, they have mush greater metastatic potential than hormonally quiescent typical
carcinoids [13]. Surgical treatment therefore should be one proposed for more aggressive malignant
tumors. In all cases of
ACTH-dependent
Cushing's syndrome with regular pituitary MRI and bilateral inferior petrosal sinus sampling, thin-section and spiral CT scanning of the chest should be routine diagnostic procedure [14]. We present thirty-one year old patient with typical pulmonary carcinod with
ACTH ectopic secretion consequently confirmed by histology.