Ectopic Hormone Production Research Articles

Ectopic Secretion of Peptides of the Proopiomelanocortin Family

A wide spectrum of clinical and biochemical presentations characterize ectopic POMC syndrome. It is presently postulated that ectopic POMC production results from increased expression of the activity of a POMC gene normally occurring in a variety of tissues outside the pituitary gland. The syndrome is rapidly progressive and is characterized by severe clinical manifestations in patients with a more aggressively developing oat cell carcinoma of the lung. However, in patients with slower growing nonpituitary tumors, the presentation may overlap that seen in patients with pituitary ACTH-dependent Cushing's syndrome. In cases in which the biochemical testing results overlap with those seen in pituitary ACTH-dependent disease, a combination of lack of suppression with high-dose dexamethasone and absent response to CRH stimulation greatly increases the diagnostic accuracy. Abnormal alternative processing of POMC in nonpituitary neoplasms may render unusual POMC-derived peptides that could be used as markers in the diagnosis and follow-up of patients with this syndrome. The prognosis of patients afflicted with ectopic POMC syndrome is largely determined by the nature of the underlying tumor. However, the clinical course can be greatly modified by control of the metabolic manifestations of hypercortisolemia. A variety of surgical and pharmacologic options are available, including adrenalectomy and the use of adrenal inhibitors. Cushing's syndrome of long duration, the finding of ectopic pituitary adenomas, and the combined secretion of CRH and POMC by nonpituitary tumors constitute interesting variants of the classic picture.

Small Cell Carcinoma of the Uterine Cervix Showing Cushing's Syndrome Caused by Ectopic Adrenocorticotropin Hormone Production

A uterine cervical cancer is reported in a woman who developed Cushing's syndrome. The tumor measured 1.3 x 0.7 cm, and was a pure small cell carcinoma, identical to that in the lung. The primary tumor cells showed argyrophilia with Grimelius staining and reacted positively to the anti-chromogranin antibody. Clinically, the neoplasm behaved in an aggressive manner in spite of adjuvant chemotherapy and radiotherapy, and the patient died of widespread metastasis. Cushing's syndrome was noted after the occurrence of liver metastasis with an elevation of the serum adrenocorticotropin hormone (ACTH) level. At autopsy, metastatic tumor cells from the liver reacted immunohistochemically positively not only to anti-ACTH but also to antichromogranin, anti-gastrin and anti-calcitonin antibodies. This is the first report of an immunohistochemical analysis of, and comparison of primary and metastatic sites in cervical carcinoma showing Cushing's syndrome.

Small cell carcinoma of the prostate

This report details clinical and pathologic aspects of a patient with small cell undifferentiated carcinoma of the prostate and systemic hyperglucagonemia. A panel of potential serologic markers was evaluated in order to document additional evidence of ectopic hormonal production. Immunocytochemical markers were sought in tissue samples from the primary neoplasm and a lung metastasis. Stains were positive for corticotropin (ACTH) and gastrin in both the prostate and in the lung, but no evidence of excess secretion was documented. These findings are consistent with the notion that neuroendocrine activity is common in undifferentiated small cell carcinomas, regardless of their site of origin.

Aberrant hormone production from ovarian neoplasms: Strategies for diagnosis and therapy

Syndromes involving peptide or nonsex steroid hormone secretion due to aberrantly located tumors are rare. We report a collected series of 16 patients with ectopic hormone production from ovarian neoplasms, including 3 patients recently encountered at our institution as well as 13 additional cases identified in the recent literature. These tumors included 2 insulin-producing ovarian carcinoids, 1 ACTH-producing pituitary adenoma within a benign ovarian cystic teratoma, 2 cortisol-producing ovarian neoplasms, 8 gastrin-producing ovarian cystadenomata or cystadenocarcinomata, and 3 thyroxine-producing ovarian strumal carcinoids. All patients presented with syndromes of hormone excess. Only 62% of all tumors were localized preoperatively. Following ovarian resection, 87% of patients remained disease-free with a median follow-up period of 1.5 years. In addition to ovariectomy, 8 additional unnecessary ablative procedures were performed in 7 patients. These included distal pancreatectomy, pancreaticoduodenectomy, adrenalectomy, total gastrectomy, selective vagotomy, and subtotal thyroidectomy. Failure to localize the ovarian neoplasm preoperatively was associated with a significantly higher risk of subsequent unnecessary ablative procedures. Because of the potential for the ovary to act as a source of aberrant hormone secretion, we recommend complete preoperative evaluation of the pelvis in female patients presenting with nonlocalizable endocrine tumors.

Pituitaries Transplanted under the Renal Capsule Contain Functional Growth Hormone (GH) Secretors and Suppress GH and Prolactin Release from Individual Eutopic Pituitary Cells*

The extent to which pituitary explants secrete GH requires clarification. In the present study GH release from ectopic pituitary tissue was assessed using the reverse hemolytic plaque assay. In addition, the effects of this tissue on eutopic GH and PRL release were simultaneously investigated. Anterior pituitary glands from adult female donor rats were grafted beneath the kidney capsule of adult male hosts. Four weeks later, this ectopic pituitary tissue and the eutopic pituitary glands of the host animals were removed, dispersed with trypsin, and subsequently assayed for GH and PRL release. Contrary to expectations, we found that 37% of the ectopic pituitary cells were GH secretors. Furthermore, these GH cells remained highly responsive to GRF (10(-7) M), which evoked a 7-fold increase (P less than 0.05) in mean GH plaque area. By comparison, only 28% of these ectopic cells secreted PRL, and this release was not consistently augmented by exposure to TRH (10(-7) M). In the second half of this study we found that the presence of ectopic pituitary tissue severely compromised the secretory capacity of the eutopic pituitary cells. More specifically, GH-releasing factor induced a 3-fold increase in GH secretion from the eutopic pituitary cells of sham-operated control animals, but it enhanced the release from cells of host animals by only 2-fold. Moreover, the response to TRH by the eutopic PRL cells from explant-bearing animals was curtailed to such an extent that it was not significantly greater (P greater than 0.05) than basal release in that group. We conclude that the potential of pituitary explant cells to release GH is far greater than previously believed and that this ectopic hormone production may inhibit hormone release from the eutopic pituitary cells.

Abdominal computed tomography in patients with small cell lung cancer.

The results of abdominal computed tomography in 38 patients with small cell lung cancer are reported. 47% patients had abnormal scans. Liver metastases were present in 24%, adrenal enlargement in 24% and lymphadenopathy in 8%. Two of the three patients (8%) with bilateral adrenal enlargement had ectopic hormone production. Overall 11% patients with retroperitoneal metastases had their staging changed from limited to extensive disease due to computed tomography.

7 Ectopic hormone production

Current understanding of the phenomenon of ectopic hormone production is largely based on a histopathological and immunocytochemical analysis of peptide hormone secreting tumours arising in non-endocrine tissues. Recent advances in the study of gene regulation show that the tissue-specific expression of genes is a highly sophisticated process and is unlikely to be disturbed by a spontaneous event such as point mutation in DNA. Study of several genes for frequently found ectopic hormones, i.e. prop-opiomelanocortin, vasopressin/neurophysin II, gastrin-releasing peptide, parathyroid hormone-related peptide, calcitonin gene-related peptide and beta-chorionic gonadotropin, suggests they are transcribed as they would be in their natural cell of origin. It is argued therefore that these data are compatible with the concept that the tumour cell of origin was capable of expressing these peptides, if only in a minor or transient manner. In one example, the ectopic ACTH syndrome, it is also necessary to explain the non-suppression of this gene's expression by elevated levels of glucocorticoids. Recent work suggests that this may result from physically present, but biologically inactive glucocorticoid receptors, a phenomenon that has occasionally been noted in hormonally inactive tumour tissue and cell lines.

Anaesthesia for phaeochromocytoma.

Phaeochromocytomas are functionally active cateeholamine-seereting tumours of chromaffin tissue. These tumours are usually found in the adrenal medullae but may occur anywhere where chromaffln tissue exists. Chromaffin tissue occurs in association with the celiac, mesenteric, renal, adrenal, hypogastric, testicular and paravertehral sympathetic nervous plexuses. Although most phaeochromocytomas are found in the adrenal medulla (in 90 per cent of cases), they can occur anywhere in the body where paraganglion ceils of the sympathetic nervous system are found. Multiple and extra-adrenal tumours are far more common in children (35 per cent) than in adults (eight per cent).t Although about 90 per cent are benign and surgically curable, they are of special interest because of the profound physiological effects produced by the release of large quantities of catechnlamines. Phaeochromocytomas can also contain a variety of peptides including enkephalins, somatostatin, calcitonin, oxytocin and vasopressin and, rarely, can be a source of clinically important ectopic hormone production. 2 Although these turnouts account for elevated arterial pressure in only 0.1 per cent of the population with diastolic hypertension, the diagnosis should be suspected in any patient who develops hypertension at an early age, who has hypertension resistant to conventional therapy, or in anyone with a history of paroxysmal headaches, palpitations, sweating and pallor. Phaeochromocytomas can also be part of an autosomaldominant multiglandular neoplastic syndrome known as Multiple Endocrine Adenomatosis (Table). This syndrome can be categorized as Type ll-a (SippLe's syndrome comprising medullary carcinoma of the thyroid, parathyroid adenoma/hyperplasia and phaeochromocytoma) or

Purification and characterization of the glycoprotein hormone .alpha.-subunit-like material secreted by HeLa cells

The protein secreted by HeLa cells that cross-reacts with antiserum developed against the alpha-subunit of human chorionic gonadotropin (hCG) has been purified approximately 30,000-fold from concentrated culture medium by organic solvent fractionation followed by ion exchange, gel filtration, and lectin affinity chromatography. The final preparation had a specific activity (by RIA) of 6.8 x 10(5) ng of alpha/mg of protein and appeared homogeneous by electrophoresis on reducing/denaturing polyacrylamide gels (SDS-PAGE). Amino acid analysis indicated that HeLa-alpha had a composition very similar to that of the urinary hCG alpha-subunit. Peptide fingerprints of the HeLa protein and hCG-alpha revealed that several of the Tyr-, Met-, and Cys-containing tryptic peptides were held in common, thus identifying the tumor protein as a glycoprotein hormone alpha-subunit with a primary structure similar to that of hCG-alpha. However, comparison of hCG-alpha and HeLa-alpha demonstrated that the tumor-associated subunit was not identical with its normal counterpart. Only two of the three Tyr-containing tryptic peptides present in hCG-alpha could be detected in HeLa-alpha after iodination with 125I. HeLa-alpha eluted prior to hCG-alpha during Sephadex G-75 chromatography, but the subunits coeluted when the tumor protein was first subjected to mild acid hydrolysis. The purified tumor protein had an apparent molecular weight greater than that of the urinary alpha-subunit when analyzed by SDS-PAGE (Coomassie blue staining), and this difference was even greater when a partially purified preparation was examined by an immunoblot technique (Western). Isoelectric focusing of the HeLa and hCG subunits demonstrated that the tumor protein had a lower pI (4.7-5.5 compared to 6.5-7.8), and removal of sialic acid by mild acid hydrolysis did not entirely eliminate this difference. Immunoprecipitation and electrophoresis of alpha-subunit from HeLa cultures labeled with [3H]fucose indicated that the tumor subunit was fucosylated, whereas analysis of hCG-alpha hydrolysates by HPLC confirmed previous reports that the placental subunit does not contain fucose. HeLa alpha-subunit was unable to combine with hCG beta-subunit to form holo-hCG under conditions where the hCG alpha-subunit was able to do so. The results indicate that, regardless of whether or not a single alpha-subunit gene is being expressed in both normal and neoplastic tissues, posttranslational modifications lead to a highly altered subunit in the tumor. The differences observed may be useful in diagnosing neoplastic vs hyperplastic conditions and may lend insight into the mechanism of ectopic hormone production by tumors

Ectopic hormone production by a prostatic small cell carcinoma xenograft line

The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, β-endorphin and somatostatin in vivo and ACTH and β-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.

Extrapulmonary Small-Cell Carcinoma

We report 18 patients with extrapulmonary small-cell carcinoma, which we regard as a distinct clinicopathologic entity. The natural history of this disease in some sites appears to differ from that of small-cell lung cancer. One patient with small-cell carcinoma of the esophagus was treated with combination chemotherapy and survived for 1 year. Another patient had ectopic adrenocorticotropic hormone production with small-cell carcinoma of the rectum. Two patients with small-cell bladder carcinoma are also reported in this series. Another patient with small-cell carcinoma in a cervical lymph node metastasis has survived more than 7 years after receiving radiation as the only modality of therapy. This case further substantiates the observations of others that extrapulmonary small-cell carcinoma may pursue an indolent course. Furthermore, in certain sites, local modalities of therapy may result in long-term survival or cure. This is particularly true for small-cell neoplasms of the head and neck region. An association between smoking and extrapulmonary small-cell carcinoma is postulated. The therapy and outcome of this disease is also discussed, with particular emphasis on the effectiveness of combined strategies of surgery, radiation, and chemotherapy.

Fat Metabolism and Cancer

Progressive weight loss and anorexia are frequent phenomena in cancer patients. Although cachexia is an expected occurrence in the terminal stages of nearly all malignancies, it may be a presenting sign when the tumor burden is quite small. Lipid depletion occurs out of proportion to the protein loss and accounts for most of the weight loss in cancer. Lipids, more specifically fatty acids, are the major source of fuel in mammals and may also be used in the synthesis of new cell products. Lipolysis and lipogenesis are under the influence of several important enzymes and peptide hormones that may be modulated by a variety of exogenous factors. There is evidence that cancer patients have lost the normal homeostatic responses to decreased energy intake or starvation that allow a decrease in oxygen consumption and protein sparing. An increase in Cori cycle activity or futile recycling of metabolic products occurs with a net energy expenditure rather than energy production. Clinical studies have shown that the body lipid depletion accompanying tumor progression is not solely secondary to decreased food intake and may be reproduced by the transplantation of certain noninvasive tumors to normal hosts. Elevated basal lipolysis has occasionally been seen early in tumor growth. Such findings suggest the presence of a tumor-associated factor responsible for this increase in lipid mobilization. Some of the potential mechanisms for the altered lipid metabolism seen in cancer have been discussed. Metabolic substrates may be remodeled and directed away from fuel-efficient into energy-requiring pathways. An increased energy expenditure may occur as a result of the energy costs of tumor synthesis, an uncoupling of oxidative phosphorylation, or energy-requiring futile cycling. An overall depletion of lipid may be the final outcome of the inhibition of lipid deposition. TNF/cachectin has recently been found to suppress the activity and synthesis of several key lipogenic enzymes, including lipoprotein lipase. Abnormalities in insulin secretion or sensitivity may be involved in the decrease of fat storage in malignancy. Insulin also exerts a significant antilipolytic effect by its antagonism of hormone-sensitive lipase. Mediators of lipolysis and abnormal lipid metabolism may occur in a number of clinical conditions and include ectopic hormone production, growth factors, and tumor-associated lipolytic factors (lipid mobilizing factor, toxohormone).

Immunocytochemical study of 18 tumours causing ectopic Cushing's syndrome.

Eighteen cases of Cushing's syndrome caused by ectopic production of peptide hormones were investigated by histological and immunocytochemical methods and the findings correlated with clinical and biochemical observations. Immunocytochemistry showed immunoreactive adrenocorticotrophic hormone (ACTH) or peptides derived from the ACTH precursor (pro-opiomelanocortin (POMC], or both, in a total of 10 cases: five of these also contained immunoreactive-alpha-melanocyte stimulating hormone, indicating more extensive translational processing of POMC than normally occurs in healthy corticotrophs of the anterior pituitary; in two further cases peptides capable of stimulating ACTH release from the anterior pituitary were present. In the remaining six cases immunocytochemistry failed to show the presence of ACTH, other POMC derived peptides, or peptides with ACTH releasing properties. These findings correlate well with the histological and clinical observations, in that the six tumours had been clinically overt, caused rapid death, and histologically seemed to be highly malignant. In contrast, the 12 other tumours were occult to radiological examination, patients had a much improved survival rate, and histologically the tumours seemed to be less aggressive. All but one of the tumours in this series showed a degree of neuroendocrine differentiation, indicated by the presence of neuron specific enolase. These results suggest that one feature of highly malignant tumours, which cause an ectopic endocrine syndrome, is a high secretion of peptide hormones, leaving amounts that are too small to be shown by immunocytochemistry.

Carcinomas of the lung with neuroendocrine differentiation.

While there are examples of each of the histologic types of bronchogenic carcinoma in which ectopic hormone production has been demonstrated, three groups of lung cancers manifest this type of differentiation with great regularity. These are the carcinoid, atypical carcinoid, and the small cell carcinoma, which have been called neuroendocrine carcinomas of the lung. The carcinoids are neoplasms with a heterogeneous array of histologic appearances that share relatively uniform nuclear features, the absence of both tumor necrosis and mitotic figures, and a good prognosis. Neuroendocrine differentiation is demonstrable with such regularity in carcinoids that the diagnosis is not considered tenable in the absence of at least one of the following features: argyrophilia, the demonstration of neuron-specific-enolase or neuropeptides by immunohistochemistry or other techniques, or the demonstration of numerous dense-core membrane-bound granules, usually 150 to 250 nm in diameter, by electron microscopy. The atypical carcinoids (well or moderately differentiated neuroendocrine carcinomas) share the neuroendocrine differentiation of the carcinoids and many of their histologic features, but are distinguished by the presence of tumor necrosis, more anaplastic large cell nuclei with numerous mitotic figures, and a distinctly worse prognosis. They are a heterogeneous lot with some similarities to carcinoids, small cell carcinomas, and large cell or adenocarcinomas. The demonstration of at least one of the neuroendocrine features listed above is considered necessary for this diagnosis. Small cell carcinoma is also a heterogeneous group of neoplasma primarily distinguished by their finely granular chromatin pattern which correlates with a much worse prognosis but a higher likelihood of response to chemotherapy and radiotherapy. Many small cell carcinomas share the neuroendocrine differentiation of the carcinoids or atypical carcinoids, but some do not and the demonstration of these features is not a requisite for inclusion in the small group. The morphologic demonstration of neuroendocrine differentiation may be more difficult in small cell carcinomas, but they more frequently produce clinically important amounts of ectopic neuropeptides. While the term neuroendocrine carcinoma of the lung includes several quite different entities and does not by itself convey histogenetic or prognostic implications, the demonstration of neuroendocrine differentiation in pulmonary neoplasms is an important procedure when combined with the recognition of other cytologic and histologic features.

Ectopic hormonal production: nursing implications.

Abstract Ectopic hormone production describes a classification of syndromes in which hormone-like substances are produced not by normal parent tissue but by tumor. These ectopically produced hormones are probably the result of gene derepression that corresponds with the neoplastic process. Since their elaboration is controlled by tumor, they do not respond to normal negative feedback mechanisms. The resultant elevation of hormone manifests in clinical and/or laboratory findings. Medical care is aimed at treating the underlying tumor and controlling the fluid and electrolyte problems. Nursing care emphasizes increased observation of physical changes; promoting return of normal body homeostasis; providing physical and emotional support; and teaching the patient and family to recognize the syndromes and how to care for the patient themselves.

Syndromes associated with inappropriate hormone synthesis by tumors: an evolutionary interpretation.

A wide range of tumors derived from nonendocrine cells synthesize and secrete inappropriately large amounts of bioactive peptides, producing in their hosts syndromes typical of hormone excess (Odell and Wolfsen 1982; Fmura 1980; Baylin and Mendelsohn 1980). Table 1 lists some of the theories that have been proposed to explain “ectopic hormone production,” the mysterious ability of these tumors to produce hormonal peptides.

Prospective multicenter study of hormone markers in small cell lung cancer.

Ectopic production of several peptide hormones in patients with lung cancer has been described repeatedly in recent years. Hormones which are frequently elevated in the sera of patients with small cell lung cancer (SCLC) at diagnosis are summarized in Table 1.KeywordsSmall Cell Lung CancerSmall Cell LungSmall Cell CarcinomaMarker LevelProspective Multicenter StudyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Clinical evaluation of the neurophysins as tumor markers in small cell lung cancer.

Small cell carcinoma of the lung (SCCL) is frequently associated with the ectopic production of peptide hormones, some of which produce significant clinical and laboratory abnormalities in the patient. The syndromes of inappropriate production of antidiuretic hormone (SIADH) and the ectopic secretion of adrenocorticotropic hormone (ACTH) have been well described and occur in 5%–10% of patients suffering from this disease (Kato et al. 1969; Eagan et al. 1974; Lokich 1982). The development of sensitive radioimmunoassays for peptide hormones such as calcitonin, vasopressin, pro-opiomelanocortin and its metabolites (ACTH, lipotropin, B-endorphin), for the neurophysins, and for other proteins, such as carcinoembryonic antigen, neuron-specific enolase, and the BB isoenzyme of creatine kinase, have led to the detection of these substances in SCCL. These peptides and proteins have also been detected in other types of lung cancer, but both the frequency of detection and the quantitative levels are much higher in SCCL. Studies of cell lines of SCCL have contributed to an expansion of the list of hormones detectable in culture. Bombesin is detected in a large percentage of small cell culture lines and may be functioning in an autocrine role (Moody et al. 1981; Sorenson et al. 1982). However, elevated serum levels of bombesin are infrequent (Wood et al. 1982).

ACTH and related peptides in lung cancer.

The study of ACTH and related peptides in lung cancer has had an important influence in formulating current concepts of ACTH biosynthesis and the wider aspects of ectopic hormone production. The fact that tumours arising in tissues traditionally regarded as “nonendocrine”, such as lung, can synthesise and secrete hormones has only been clearly recognised by clinicians in the last 25 years. For some years after the characterisation of the ectopic ACTH syndrome the phenomenon was thought to be very rare. Thus, a critical analysis of nonendocrine tumours associated with Cushing’s syndrome in 1968 showed there to be only about 133 acceptable cases of the syndrome in the literature (Azzopardi and Williams 1968). The majority were due to small cell and carcinoid tumours of the lung, with fewer cases due to endocrine tumours of foregut origin, phaeochromocytoma and related tumours and certain ovarian tumours. Increased clinical awareness and the application of newer methods of hormone assay have fundamentally changed the perspective on the prevalence of ACTH production by extrapituitary tissues, both tumorous and nontumorous. The overt ectopic ACTH syndrome with gross hypercortisolaemia and hypokalaemic alkalosis is still unusual in patients with lung cancer, but biochemical evidence suggests that ACTH production by lung tumours is common.KeywordsSmall Cell CarcinomaPlasma ACTHPlasma ACTH LevelEctopic ACTH SyndromePituitary ACTHThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Opportunistic infections in endogenous Cushing's syndrome.

The cases of 6 patients with endogenous Cushing's syndrome and opportunistic infections were studied, and compared with those of 17 similar patients reported in the literature. Cushing's syndrome was caused by ectopic adrenocorticotrophic hormone production or adrenal tumors in most patients, and hypercortisolism was extreme. Four infectious processes were preponderant: Cryptococcosis, aspergillosis, nocardiosis, or Pneumocystis carinii pneumonia occurred in 21 patients. Signs and symptoms of infection were often masked by the hypercortisolism. Morning plasma cortisol levels correlated with the infection type (rank-order Spearman correlation coefficient = 0.78, p less than 0.01): Levels of less than 70 micrograms/dL or greater than 121 micrograms/dL were associated with cryptococcosis or pneumocystis, respectively, by discriminant analysis. Of the 9 patients who survived their infection, 8 had evidence that cortisol production was reduced to near normal. In contrast, all 14 patients died in whom cortisol production went uncontrolled. In patients with hypercortisolism from endogenous Cushing's syndrome (especially of nonpituitary origin), opportunistic infections should be anticipated and prompt control of cortisol overproduction should be initiated.