Ectopic Hormone Syndromes

chapter

152

Ectopic Hormone Syndromes David W. Ray

CHAPTER OUTLINE HISTORY, 2628 THEORETICAL CONSIDERATIONS,  2629 Theories of the Origin of Ectopic Hormones,  2629 Hormones in Small-Cell Lung Carcinoma,  2630 ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME, 2630 The POMC Gene,  2630 Regulation of POMC Gene Expression,  2630 Ectopic Adrenocorticotropic Hormone Syndrome,  2631 Pro-opiomelanocortin Processing,  2631 Dysregulation of POMC Gene Expression in Extrapituitary Tumors,  2632 Diagnosis, 2632 Treatment, 2633 ECTOPIC CORTICOTROPIN-RELEASING HORMONE SECRETION, 2633 SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION,  2633

Diagnosis, 2634 Management, 2634 HUMORAL HYPERCALCEMIA OF MALIGNANCY,  2635 Parathyroid Hormone–Related Protein,  2635 Hypercalcemia in Hematologic Malignancy,  2636 Diagnosis, 2636 Treatment, 2636 ONCOGENIC OSTEOMALACIA,  2637 ECTOPIC GROWTH HORMONE–RELEASING HORMONE, 2637 NON–ISLET CELL TUMOR HYPOGLYCEMIA,  2637 Diagnosis, 2638 Management, 2638 OTHER PITUITARY ECTOPIC HORMONES,  2638 Gonadotropins, 2639 ECTOPIC GUT HORMONE SYNDROMES,  2639 Ectopic Renin Secretion,  2639

KEY POINTS • E  ctopic hormone–producing syndromes result from aberrant regulation of genes with roles in tissue development or physiology. • Simple single-peptide hormone ectopic expression (e.g., POMC) is more prevalent than multigene, or extensively modified hormone production (e.g., FSH) • Diagnosis may be delayed if presentation is dominated by malignant disease. • Management requires attention to the underlying disease process and treatment of the endocrine manifestation. • New specific assay technology permits earlier confident diagnosis.   

HISTORY Tightly regulated production of hormones from specialized endocrine glands is usually under the control of higher centers, ultimately the brain, and is normally subject to negative feedback. This affords a mechanism for influencing diverse tissue function throughout the body. Inappropriate hormone production by nonendocrine tissue causes a spectrum of rare syndromes. These disorders are important because they may be the first manifestation 2628

of an underlying tumor, and the hormonal manifestations can induce morbidity and affect quality of life. Ectopic hormone secretion also sheds light on mechanisms of tissuespecific gene expression and regulation. Ectopic hormone production reveals important linkages between cell differentiation and gene expression. Ectopic expression of a peptide may also be useful as a tumor marker (e.g., human chorionic gonadotropin, α-fetoprotein). Initial reports of endocrine activity associated with tumors appeared in the 1920s. These examples included

152  ECTOPIC HORMONE SYNDROMES

features of parathyroid-like activity with disseminated carcinoma and adrenocortical activity in patients with lung and thymic tumors.1,2 At the same time, initial reports of tumor-associated hypoglycemia were documented.3,4 Later, based on the metabolic similarities to hyperparathyroidism, Albright and Reifenstein5 proposed the secretion of parathyroid-like hormone activity in a patient with renal cell carcinoma as the cause of hypercalcemia. Proof of tumor-derived endocrine factors had to await development of accurate and sensitive hormone assays. These assays allowed identification of adrenocorticotropic hormone (ACTH) and antidiuretic hormone (ADH) secretion from tumors causing ectopic ACTH syndrome and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), respectively.6-9 Since these breakthroughs, further advances in cell and molecular biology have sought to explain how and why such ectopic hormone production occurs and its consequences.

THEORETICAL CONSIDERATIONS Circulating hormones are almost exclusively derived from specialized cells in endocrine glands. However, low-level hormone production or gene expression can be found much more widely. For example, the gene encoding ACTH is expressed at a high level in anterior pituitary corticotroph cells, but its expression has also been detected in a wide array of normal and tumoral extrapituitary tissues. This “ectopic” expression can give rise to the clinical syndrome of ectopic ACTH production, a cause of Cushing’s syndrome. However, it is also possible that POMC gene expression may have a role in healthy tissue, especially in the placenta, lymphocytes, testes, and lung. There must be compelling evidence that the hormone is produced by the tissue or tumor in question for the diagnosis of ectopic hormone production to be secure. Production is the most fundamental level of hormone control. Thus, mRNA or the peptide should be demonstrated in tissue sections, or hormone secretion can be shown to persist in vitro in primary cell culture, or there may be an arteriovenous gradient of hormone across the tissue in vivo. Other criteria, such as reduction in hormone level postresection, are weaker because the tumor may express a hormone secretogogue (e.g., growth hormone– releasing hormone [GHRH] rather than growth hormone [GH] itself). Hormones most frequently associated with ectopic production tend to be those with the most widespread distribution. The POMC gene is widely expressed in nontumorous, nonendocrine tissues and is frequently overexpressed in tumors, giving rise to the ectopic ACTH syndrome. Insulin is almost never produced ectopically by tumors, consistent with its restricted expression only in specialized β cells within the pancreatic islets. Peptide hormones are often processed differently in tumors compared with their usual organs of production. They may undergo incomplete proteolytic cleavage

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or altered glycosylation, but the peptides themselves are the products of the same genes responsible for their production in their normal cells. Tumors that produce one hormone ectopically frequently express other hormones and proteins inappropriately; however, it is rare to have clinically significant secretion of more than one peptide.

Theories of the Origin of Ectopic Hormones With the development of sophisticated molecular techniques, low levels of hormone gene expression have been documented in a wide range of normal tissues.10 Therefore, it is not surprising that tumors arising from these tissues can give rise to ectopic hormone–producing syndromes. If hormone production in the tumor remained under physiologic control, ectopic hormone production would not pose a clinical problem. Sometimes aberrant control has an obvious mechanism (e.g., lack of specific neural connection, physical distance from a portal system, absence of receptors for hormonal modulators of gene expression). Several theories have been proposed to explain ectopic hormone production. Amine Precursor Uptake and Decarboxylation Hypothesis11,12 A number of endocrinologically active cells are dispersed through normal tissues, but they are not usually considered to be endocrinologically active. These cells share amine precursor uptake and decarboxylation (APUD) properties. At one time, these cells were thought to derive from a common source in the embryonic neural crest. Although an appealing concept, evidence of this common origin is lacking. Nonetheless, their common features suggest that they may respond to transformation in a similar way. Many ectopic hormone-producing tumors have features of APUD cells, and these tumors may originate from APUD precursor cells. However, other ectopic hormone-producing tumors have no features of APUD tissue, and these tumors are often the most aggressive, secreting high levels of hormone, evidence that contradicts the importance of APUD characteristics for hormone production. Dysdifferentiation Theory13-15 Problems with previous theories have led to the dysdifferentiation hypothesis. It proposes that neoplastic changes occur in progenitor cells rather than in terminally differentiated cells. As a result of one or more mutations, the transformed progenitor cell undergoes variable differentiation. If this theory holds true, it predicts a tumor with a mixed population of cells at different stages of development. Depending on the blocks to normal differentiation, a subset of cells may develop into an endocrine cell type and give rise to an endocrine-type tumor. This model explains why some tissues produce particular hormones, since the tumor would tend to transcribe the same genes as its parent tissue, although these may be expressed aberrantly (Fig. 152-1). Extrapituitary expression of the ACTH gene (proopiomelanocortin [POMC]) is described in detail in the following section. Ectopic ACTH production shares many features of other ectopic hormone syndromes and

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Differentiation pathway

Progenitor cell

Differentiated cells

Dysdifferentiated malignant cell clone

Figure 152-1  Dysdifferentiation

results in aberrant gene expression. The malignant transformation of a progenitor cell results in a clonal population of cells that have undergone atypical differentiation. These cells share some features with their progenitor cells (shaded areas) and may continue to express genes associated with these immature, incompletely differentiated cells. Malignant transformation of a cell can lead to persistent, or enhanced, hormone gene expression in the clone of proliferating cells (heavily shaded area).

may provide a paradigm for understanding general mechanisms of ectopic hormone production.

Hormones in Small-Cell Lung Carcinoma Small-cell lung carcinoma (SCLC) is the most common and aggressive neuroendocrine tumor. Patients with SCLC seldom present to the endocrinologist, but because there is evidence of hormone expression, it is a useful model from which to extrapolate to other less common syndromes. The normal adult lung contains a diffuse population of cells that synthesize very low levels of peptide hormones, including ACTH, GHRH, and gastrin-releasing hormone. In fetal life, these cells are more densely represented and produce higher concentrations of hormones, suggesting a possible role in differentiation. These scattered endocrine cells have APUD properties and compose part of a diffuse neuroendocrine system. SCLC, a bronchogenic tumor, produces most of the hormones found in normal bronchial epithelium. ACTH, vasopressin, and calcitonin secretion have been studied most extensively because of the clinical syndromes they cause and because they produce potential disease markers that can be used for diagnosis or response to treatment. In a study of 157 primary lung tumor extracts, 83% expressed at least one peptide hormone. Multiple hormone production is common and includes ectopic ACTH syndrome in 20% of cases, although production of one hormone tends to dominate the clinical picture.16,17 However, only about 1% of patients with SCLC have clinical features of cortisol excess, possibly because of the short duration of disease.18 Peptide hormones often undergo incomplete processing. In particular, POMC is not efficiently cleaved to ACTH, resulting in high–molecularweight forms of ACTH in tumor extracts and in the circulation.16,19 It is now clear that these alternate forms represent the prohormones POMC and pro-ACTH. The abnormal protein processing may result from a lack of specific cleavage enzymes, prohormone convertases 1 and

2, which are expressed only in specialized endocrine tissue or from a switch from the regulated secretory pathway to the constitutive one.20

ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME The POMC Gene Pituitary corticotroph cells are the only cells that express the POMC gene at a high level. The human POMC gene is encoded in three exons on chromosome 2. The first exon is noncoding. The second exon contains the signal peptide, which targets the protein product to the regulated secretion pathway. The third exon encodes the majority of the mature protein, including ACTH.21 The mature mRNA from the POMC gene is 1200 nucleotides. In addition, a short form of the mRNA has been found at low levels in most tissues analyzed. This arises from a transcription start site 5′ to exon 3 and thus only includes the coding sequence for exon 3.22 Therefore, this transcript lacks a signal peptide and does not give rise to the mature POMC molecule. There is no evidence that this transcript produces a peptide product, and its physiologic role is unclear. A third POMC transcript has also been described that is longer than the pituitary form (–1500 nucleotides). It arises from a site (or multiple sites) within the 5′ flanking region of the human POMC promoter.23,24 This mRNA species includes the entire coding region of the peptide and does give rise to a secreted peptide product. This “long” form of the POMC mRNA is particularly found in extrapituitary tissues and tumors.

Regulation of POMC Gene Expression Expression of the POMC gene appears to be predominantly controlled at the level of gene transcription.25 The rat POMC gene has been most extensively studied, and pituitary expression is conferred by the 5′ flanking region of the gene. It has recently been found that pituitary corticotroph expression of POMC requires the action of a tightly restricted transcription factor, a member of the T-box family, termed Tpit.26 This factor acts with the homeodomain protein PitX1 and promotes recruitment of SRC-family coactivators to the POMC promoter, leading to enhanced gene transcription.27 Corticotropin-releasing hormone (CRH) acts on pituitary corticotroph cells to increase cyclic adenosine monophosphate (cAMP) accumulation and activates mitogen-activated protein kinases. There is also evidence of activation of the orphan nuclear receptor nerve growth factor–induced clone B (or Nur 77),28-30 leading to enhanced POMC transcription through the recruitment of SRC coactivators to nerve growth factor–induced clone B.27,31 As nerve growth factor–induced clone B and Tpit act synergistically, this suggests the formation of a regulatory complex on the POMC promoter with Tpit, NGFI-B, and SRC coactivators.27 It is important that expression of Tpit promotes corticotroph cell differentiation and that its expression is more limited than that of POMC. Therefore, there is no Tpit expression in hypothalamic POMC-expressing neurons, suggesting that Tpit is specific for corticotroph-specific expression of

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POMC; other mechanisms are responsible for expression elsewhere. Tpit expression has been found specifically in human pituitary corticotroph adenomas.26 Glucocorticoids repress transcription of the POMC gene by binding to two DNA elements in the 5′ flanking region of the promoter. The more proximal element, an imperfect palindrome 63 nucleotides upstream from the transcription start site, is thought to bind three glucocorticoid receptor molecules in an unusual trimer formation.32-34 This conformation of receptors on DNA directs repression of transcription rather than enhancement. Further upstream, between –480 and –320, there is another glucocorticoid-regulated element, suggesting that these two DNA elements interact to achieve the full effect of glucocorticoid repression.35 It is interesting that Tpit expression, essential to the corticotroph cell type and to POMC expression, is not affected by glucocorticoids, in contrast to POMC, which is repressed.36 However, it now appears clear that the activated glucocorticoid receptor can antagonize the actions of Nur77 and, by removing a positive transactivator, lead to POMC gene repression.37 The mechanism of glucocorticoid receptor interaction with Nur77 requires the chromatin remodeling protein Brg1, which stabilizes their binding. Furthermore, Brg1 assists recruitment of a further chromatin remodeling enzyme, HDAC2, to the glucocorticoid receptor bound to the POMC gene. The pathophysiologic importance of Brg1 and HDAC2 are illustrated by finding deficient expression of one or both in 50% of glucocorticoid-resistant pituitary corticotroph adenomas.38 The expression of Brg1 and HDAC2 in ectopic ACTH syndrome has not been explored. A number of other hypothalamic factors act on the pituitary corticotroph to influence POMC expression. However, their modes of action are not well defined. In particular, arginine vasopressin stimulates POMC expression rather weakly but augments CRH action. The intracellular pathways activated by arginine vasopressin appear to be protein kinase C–dependent, but arginine vasopressin also potentiates the action of CRH on cAMP generation.25,39 However, many other peptide growth factors and cytokines are capable of activating cAMP, mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades and thus are potentially capable of regulating POMC expression in nonpituitary tissue. Although extrapituitary tissues lack expression of corticotroph-specific transcription factors, activation of common signaling cascades might be expected to result in POMC gene expression. In extrapituitary tissues, the POMC gene may be modified to render it transcriptionally silent. One such irreversible modification is DNA methylation. The loss of methylation in tumor tissue may allow transcription of the gene to be activated by the common signaling pathways described previously. There is some evidence that such changes in DNA methylation occur in cell-line models of ectopic ACTH syndrome.40,41 It seems likely that POMC expression per cell is lower in most extrapituitary tumors compared with the pituitary corticotroph, but this relative inefficiency of expression is compensated for by

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TABLE 152-1  Tumors Associated with Ectopic Adrenocorticotropic Hormone Secretion Small-cell lung carcinoma Carcinoid tumors (bronchus, thymus, small intestine) Pancreatic islet cell tumor Pheochromocytoma Medullary carcinoma of the thyroid gland Carcinomas (breast, gastrointestinal tract [esophageal, gastric, colorectal], ovarian, cervical, prostate)

the greater number of cells expressing the gene in extrapituitary tumors.

Ectopic Adrenocorticotropic Hormone Syndrome ACTH immunoreactivity has been recognized to show size heterogeneity for many years, with the presence of high– molecular-weight forms detected in human plasma.42,43 Ectopic ACTH syndrome was the first of the ectopic hormone syndromes to be recognized. In its most florid form, it is rare, in one study affecting 4.5% of patients with SCLC, although there is evidence of derangement in the hypothalamic-pituitary-adrenal axis in the majority of patients with SCLC42,44 (Table 152-1). Analysis of tumor tissue surprisingly suggests the presence of immunoreactive ACTH, even in the absence of clinical features of hormone excess. ACTH is present predominantly in a high–molecular-weight form of approximately 20 kD, but this purified material can be cleaved to mature ACTH (4.5 kD) by the action of trypsin. Further work identified the presence of immunoreactive ACTH-like peptide in a variety of normal tissues, suggesting that extrapituitary ACTH expression is less ectopic than it is inappropriately regulated. The ACTH immunoreactivity was found to have no biological activity and was assumed to be “big” ACTH. However, identification of predominantly high– molecular-weight forms of ACTH in the circulation of patients with clinically apparent Cushing’s syndrome suggests that the precursors of ACTH may have some activity at the ACTH receptor.

Pro-opiomelanocortin Processing The POMC gene leads to the generation of a pre-prohormone, POMC. This protein undergoes a series of proteolytic cleavages at dibasic amino acid residues to give rise to a series of small molecules, including ACTH, melanocytestimulating hormone, and β-endorphin.45-47 In the anterior pituitary gland, ACTH is cleaved by the action of a specific protease termed prohormone convertase type 1 (PC1).48 In the rodent intermediate lobe melanotroph, the POMC molecule undergoes more comprehensive digestion to give smaller fragments, including melanocyte-stimulating hormone, β-endorphin, and corticotropin-like intermediate lobe peptide as a result of cleavage by prohormone convertase 2. Expression of prohormone convertase 2 and thus detection of circulating ACTH fragments have been described in ectopic ACTH-syndrome tumors.49 In the majority of extrapituitary tumors that cause ectopic ACTH syndrome, processing of the preprohormone is incomplete. Therefore, ectopic ACTH syndrome is characterized by high–molecular-weight forms of

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ACTH in the circulation.17,19 It is likely that the extent of processing correlates with the degree of neuroendocrine differentiation of the tumor, and hormonal manifestations are probably only seen in tumors with significant hormone-processing capacity. A number of small, highly differentiated, slow-growing tumors (typically bronchial carcinoid) have been shown to process POMC in the neurointermediate lobe manner, giving rise to small fragments in the circulation, such as corticotropin-like intermediate lobe peptide and α-melanocyte–stimulating hormone. These have been used to aid diagnosis in some cases of Cushing’s syndrome, although the series are small.8,50

Dysregulation of POMC Gene Expression in Extrapituitary Tumors In contrast to POMC gene expression in pituitary corticotroph cells, expression in extrapituitary tumors is characteristically resistant to glucocorticoids.7,51 This is the basis of the high-dose glucocorticoid suppression test used to distinguish eutopic from ectopic sources of ACTH in Cushing’s syndrome. Because the test has approximately 10% false-positive and 10% false-negative rates, it has largely been superseded by sophisticated imaging and inferior petrosal sinus sampling for differential diagnosis.52 With the availability of recombinant CRH, responses of extrapituitary tumors to this peptide have been measured. In general, only pituitary corticotrophs stimulate POMC expression in response to CRH, but exceptions are increasingly being identified.53 Pituitary expression of POMC was defined with the aid of a cell-line model, so a cell-line model was sought for extrapituitary expression. To this end, a panel of human SCLC cell lines was established. These cell lines express the POMC gene, and expression is resistant to glucocorticoid suppression.16,54-58 Further, the cell lines secrete predominantly unprocessed POMC and partially processed forms, again reflecting the pattern of activity characterized in vivo.54 It is intriguing that the majority of extrapituitary tumors are resistant to glucocorticoid inhibition of POMC expression. Receptors for glucocorticoids are present in most cells, including malignant cells, so exploring the mechanisms of glucocorticoid resistance was important. Using the panel of cell lines, expression of glucocorticoid receptor was identified using both Western blot with a polyclonal antiglucocorticoid receptor antibody, and ligand-binding assays using tritiated dexamethasone.56-58 To determine whether the receptors were sufficient for glucocorticoid signaling, a synthetic, glucocorticoidresponsive gene was used. This gene was transfected into the cells, and the effects of glucocorticoid incubation on expression of the reporter measured. In contrast to the brisk induction of expression seen in control pituitary cells, none of the human SCLC cells responded to either natural or synthetic glucocorticoids.56,58 Thus, resistance of the POMC gene to glucocorticoids is only part of a global resistance of malignant cells to glucocorticoid action. High concentrations of wild-type receptor in the cells was found to be sufficient to restore glucocorticoid signaling, thereby suggesting that resistance resides at the

TABLE 152-2  Laboratory Investigation of Ectopic Adrenocorticotropic Hormone Syndrome Investigation

Test Results

ACTH

Higher in ectopic disease; partially processed forms more common in ectopic disease Higher in ectopic disease Nearly 100% in ectopic ACTH secretion; –10% (<3.2 mmol/L) in Cushing’s disease and alkalosis No suppression in 89% of ectopic disease; suppression in 78% of pituitary-dependent disease Absent response in ectopic disease; exaggerated response in pituitarydependent disease Presence of elevated calcitonin, hCG, α-fetoprotein, 5-HIAA suggests ectopic disease

Cortisol Hypokalemia High-dose dexamethasone testing (8 mg) CRH test Tumor markers

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; hCG, human chorionic gonadotropin, 5-HIAA, 5-hydroxyindoleacetic acid.

level of the endogenous receptor.56 Because one of the actions of glucocorticoids on pituitary corticotrophs is to inhibit proliferation, and in the developing lung glucocorticoids act to promote differentiation, it is possible that evasion of glucocorticoid signaling confers a survival advantage on the malignant cells. Indeed, it has recently been shown that overexpressing the wild-type glucocorticoid receptor in human small-cell lung cancer cells powerfully induces apoptosis. Intriguingly, this effect occurs even in the absence of added glucocorticoid.59 As yet, a single, unifying molecular mechanism of glucocorticoid resistance in the human SCLC cell lines remains to be defined. It is interesting that well-differentiated carcinoid tumors causing ectopic ACTH syndrome sometimes show appropriate POMC suppression to supraphysiologic glucocorticoid levels, as in pituitary-dependent Cushing’s disease, but these tumors express high levels of the glucocorticoid receptor.60

Diagnosis The diagnosis of Cushing’s syndrome and the differential diagnosis of ACTH-dependent Cushing’s syndrome are described elsewhere (see Chapter 13). Dynamic endocrine testing is required to diagnose Cushing’s syndrome, and detection of ACTH using a sensitive two-site immunoradiometric assay is useful for making the diagnosis of ACTH-dependent Cushing’s syndrome. A variety of dynamic endocrine and imaging protocols may be used to identify a pituitary or extrapituitary source of the ACTH excess (Tables 152-2 and 152-3). These all have variable sensitivity and specificity, but combined tests afford nearly 100% diagnostic accuracy.61 Most occult tumors are carcinoid, pheochromocytoma, or medullary thyroid carcinoma and originate in the neck, chest, or abdomen. Computed tomography or magnetic resonance imaging can be used to detect chest tumors in patients with a normal chest radiograph. There has been

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TABLE 152-3  Features of Different Causes of Ectopic Cushing’s Syndrome Small-Cell Lung Carcinoma ACTH

Very high

Cortisol

Very high

Features Potassium

Not cushingoid Marked hypokalemia

TABLE 152-4  Medical Therapy of Cushing’s Syndrome Caused by Ectopic Adrenocorticotropic Hormone

Carcinoid

Drug

Mechanism of Action

Similar to pituitarydependent disease Similar to pituitarydependent disease Cushingoid Potassium <3.2 mmol/L

Metyrapone Ketoconazole

Inhibition of 11 β-hydroxylase Inhibition of several steps of cortisol synthesis Inhibition of cholesterol conversion to pregnenolone Inhibition of adrenocorticotropic hormone secretion Adrenolytic agent Glucocorticoid receptor antagonist Adrenolytic agent

ACTH, Adrenocorticotropic hormone.

some success in using indium-labeled octreotide scanning to identify occult neuroendocrine tumors, although its diagnostic performance is poor, tending only to confirm the presence of tumors found with conventional imaging.61,62

Treatment Treatment is based on two objectives: controlling endocrine manifestations and managing the underlying tumor. Individual patients will present with different priorities. The ideal treatment is curative resection of the primary tumor, achieving both objectives. If this is not possible, patients with small occult primary tumors may be managed by chemical or surgical adrenalectomy; in most cases, the primary tumor is not life-threatening. Patients with extensive carcinoma (e.g., small-cell carcinoma in which ACTH excess coexists) may be best managed by chemotherapy, which indirectly reduces ACTH expression. Chemotherapy should be tailored for the cell type and tumor stage, regardless of hormone excess. In some patients with florid Cushing’s syndrome, control of cortisol production may help in preparation for surgery. In these cases, treatment with metyrapone, mitotane, or ketoconazole, in combination or individually, is helpful.63,64 Side effects are common with these agents in the doses required, and so combinations (e.g., ketoconazole and metyrapone) may allow more effective control. Rapid control of hypercortisolemia may require intravenous etomidate.61 There are case reports of good responses to long-acting somatostatin analogues65 and the c-kit inhibitor imitinib66 (Table 152-4).

ECTOPIC CORTICOTROPIN-RELEASING HORMONE SECRETION It has been more than 30 years since the original description of ectopic CRH secretion, and it is now clear that true isolated secretion of CRH is very rare (Table 152-5). In tumors secreting ACTH peptides, there are frequent reports of CRH immunoreactivity, which may play a paracrine role in the development of the hormone syndrome, but such a role has not been defined.67,68 CRH is expressed outside the central nervous system, particularly in sites of inflammation, and may subserve other roles, including vasodilatation. CRH is seldom measured in the peripheral blood during the workup of Cushing’s syndrome or in inflammatory disease, so evidence of a true endocrine role of this hormone in the peripheral circulation is lacking.

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Aminoglutethimide Octreotide Etomidate RU486 Mitotane

TABLE 152-5  Tumors Associated with Ectopic Corticotropin-Releasing Hormone Secretion Pancreatic tumors Small-cell lung carcinoma Prostate carcinoma Hypothalamic gangliocytoma Medullary thyroid carcinoma Bronchial carcinoid

The clinical features are typical of Cushing’s syndrome, and the hormonal features may resemble either pituitary secretion of ACTH (if the ectopic source secretes purely CRH) or ectopic ACTH syndrome (if the tumor co-secretes ACTH-related peptides). Measurement of CRH is probably best left to cases with definitive pituitary ACTH production and confirmed corticotroph hyperplasia by histology.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION SIADH is the most common cause of hyponatremia and one of the most frequent hormone syndromes associated with malignant disease (Table 152-6). It may be caused by a wide range of underlying disorders that can be categorized into several broad groups: malignancies, neurologic disorders, lung disease, and drugs. These conditions cause hyponatremia as a result of abnormal hypothalamic vasopressin, when secretion comes under aberrant control from either neuronal inputs or circulating humoral factors. The vasopressin gene is expressed in a number of separate neuronal nuclei and peripheral tissues. Regulation of vasopressin expression is dependent on the site. For example, hyperosmolality increases vasopressin expression in the supraoptic nucleus and the magnocellular division of the paraventricular nucleus, but vasopressin mRNA in other sites is unaltered. For example, vasopressin expression in the suprachiasmatic nucleus is under diurnal regulation. Androgens upregulate expression of vasopressin in the striae terminalis, and glucocorticoids suppress expression in the parvocellular division of the paraventricular nucleus. Differential regulation, even within anatomically related sites, likely results from differential expression

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TABLE 152-6  Diagnostic Criteria for Syndrome of Inappropriate Antidiuretic Hormone Secretion Hyponatremia Inappropriately increased urine osmolality (>100 mOsm/kg) Persistent sodium excretion in urine (>20 mmol/L) Normal renal, thyroid, and adrenal function No hypovolemia, edema, or diuretic use

TABLE 152-7  Tumors Associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion Small-cell lung carcinoma Pancreas Duodenum Urethra Prostate Bladder Lymphoma and other hematologic malignancies

of hormone receptors in the cells and different neuronal afferents. Vasopressin gene transcription is under positive regulation by cAMP and protein kinase C pathways. Little is known about regulation of vasopressin outside the central nervous system, but glucocorticoids have been shown to suppress its expression in an SCLC cell line. Ectopic secretion of vasopressin occurs in squamous cell carcinoma; small cell carcinoma; neuroblastoma; pancreatic, duodenal, prostatic, and urothelial tumors; and undifferentiated carcinoma68-71 (Table 152-7). In one series, 16% of patients with SCLC had hyponatremia (<130 mmol/L) at diagnosis, compared with 0% of patients with non-SCLC. Hyponatremia was found to be an independent predictor of poor prognosis in extensivestage disease. In vitro studies found that 7 of 11 tumors in culture produced vasopressin, 9 of 11 tumors produced atrial natriuretic factor, and 5 of 11 tumors produced both hormones. All the cells studied from patients with hyponatremia produced one of the two hormones.68 The active hormone, vasopressin, is the product of a precursor peptide cleavage, which also gives rise to neurophysin II, and a C-terminal glycopeptide. Similar to the identification of partially processed forms of ACTH in the circulation in ectopic ACTH syndrome, the vasopressin-neurophysin precursor has been found in plasma from patients with SIADH due to SCLC.72 This is in contrast to patients with SIADH caused by central nervous system disease. Differential hormone processing may provide an additional diagnostic test for the underlying cause of SIADH.

Diagnosis Hyponatremia presents with features of neuropsychiatric dysfunction in most cases (Table 152-8). Older adults and young individuals are more likely than others to be symptomatic. The absolute sodium concentration is less reliable as a predictor of symptoms than the rate of decrease in sodium concentration, although almost all symptomatic patients will have plasma sodium concentration of less than 120 mmol/L. Clinical features include lethargy, fatigue, impaired consciousness level, coma,

TABLE 152-8  Clinical Features of Hyponatremia Headache Lethargy Weakness Nausea/vomiting Mood swings Confusion Drowsiness Hyporeflexia Positive Babinski’s sign Convulsions Coma

seizures, and psychosis. Hyponatremia may cause death as a result of cerebral edema, uncontrolled seizures, and the consequences of coma. Although mild hyponatremia (>125 mmol/L) is usually regarded as a straightforward condition that may not require specific treatment, hyponatremia should not be regarded as benign. A set of diagnostic criteria must be fulfilled before a secure diagnosis is reached (see Table 152-8). The underlying cause is then sought. Neurologic, lung-related, drug-related, and miscellaneous causes can result in dysregulation of vasopressin regulation in the hypothalamus and should not, therefore, be regarded as ectopic hormone–secretion states. In contrast, a variety of tumors (see Table 152-7) has been shown to aberrantly secrete vasopressin and express the vasopressin gene inappropriately. There is evidence from T1-weighted magnetic resonance imaging scans of the pituitary gland that such ectopic vasopressin secretion results in central suppression of vasopressin synthesis.

Management The management of this disorder falls into two parts. The first is to diagnose and treat the underlying cause, and the second is to remove excess free body water. Discussion of specific therapy on the variety of underlying tumors is beyond the scope of this chapter, but surgical cure or debulking, chemotherapy, and radiotherapy have all been applied. In general, the circulating vasopressin concentration bears a direct relationship to tumor bulk in an individual patient, but there is a low correlation across a patient cohort, presumably reflecting intertumoral differences in cellular differentiation and hormone production. Decisions about the acute correction of hyponatremia are complicated by the occurrence of both pontine and extrapontine myelinolysis as consequences of therapy. The risk for myelinolysis is linked to the rate of change in sodium concentration. Therefore, a prudent approach is always justified, with an increase of between 0.5 and 1.0 mmol/L sodium per hour and a maximum of 8 mmol/L over 24 hours. This requires close monitoring every 2 to 3 hours.73 In symptomatic patients, treat with furosemide and hypertonic saline until convulsions cease and the level of consciousness improves. This is usually achieved by an increase in sodium concentration of 10% (–10 mmol/L) and subsequent water restriction. In asymptomatic patients, the condition is almost always chronic; these patients should be treated by water deprivation initially.

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TABLE 152-9  Mechanisms of MalignancyAssociated Hypercalcemia

TABLE 152-10  Tumors Associated with Ectopic Calcitonin Secretion

Mechanism

Agent

Tumor Type

Lytic metastases

TGF-β

Humoral effects

IL-1 TNF Lymphotoxin PTHrP PTHrP

Squamous cell carcinoma of the lung Breast Kidney Myeloma

Pheochromocytomas Pancreatic neuroendocrine tumors Adrenocortical carcinoma Neuroendocrine tumor of esophagus Acute leukemia Lung cancer (27% small cell lung carcinoma or adenocarcinoma) Cervical carcinoma Prostatic carcinoma Breast cancer Renal carcinoma Gastrointestinal tract tumors

PGE TNF TGF-β IL-1 Lymphotoxin 1,25-Dihydroxyvitamin D

Ectopic PTH Coexistent other causes of hypercalcemia

Primary hyperparathyroidism Sarcoidosis Vitamin D–mediated

Solid tumors, particularly squamous cell carcinoma of the skin, lung, kidney, head, and neck Solid tumors Multiple myeloma

T-cell lymphoma Non-Hodgkin’s lymphoma Hodgkin’s lymphoma Melanoma Small-cell lung carcinoma Small-cell lung carcinoma (very rare) Ovarian cancer

1,25-DHCC, 1,25-Dihydroxycholecalciferol; IL-1, interleukin 1; PGE, prostaglandin E; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related protein; TGF-β, transforming growth factor β; TNF, tumor necrosis factor.

Specific approaches to antagonize the action of vasopressin with demeclocycline are now supplemented by the vaptan class of vasopressin V2 receptor antagonists. Alternatively, oral sodium supplementation, up to 3 g daily, with furosemide, 40 to 80 mg, results in net loss of free water. The vaptans can be effective, but treatment is best initiated in a hospital setting, as rapid changes in serum sodium can follow administration.74 Current clinical experience is limited with the vaptans, which are licensed for short-term use only.75

HUMORAL HYPERCALCEMIA OF MALIGNANCY Hypercalcemia is a common complication of malignancy (Table 152-9). It may result from the direct lytic effect of bony metastases or the action of tumor-derived humoral factors, although it is now clear that a spectrum of disorders lies between these two extremes, and in most cases, there is a humoral component. Calcitonin has been detected in peripheral blood in a number of patients with malignancy and appears to be incompletely processed, in a manner similar to ACTH, with higher–molecularweight variants.76 However, there is no clinical syndrome ascribed to such ectopic production. Calcitonin secretion

appears to be most commonly associated with a multihormonal secretory phenotype, with other peptide hormones including ACTH and gastrin55,76-79 (Table 152-10).

Parathyroid Hormone–Related Protein The humoral syndrome has been explained by the isolation and characterization of a peptide hormone, parathyroid hormone–related protein (PTHrP). This hormone is closely related in amino acid sequence to parathyroid hormone (PTH) in its N-terminal region (amino acids 1 to 34), but after residue 34, the two peptides have unique sequences. The discovery of PTHrP as the circulating mediator of hypercalcemia in malignancy ruled out earlier theories that ectopic production of PTH was the cause. There have been isolated reports of ectopic PTH production by tumors, but these are rare. There is convincing evidence of PTH production in SCLC,80 an ovarian tumor,81 thymoma,82 and neuroectodermal tumor.83 In most cases, patients with malignancy and hypercalcemia with increased PTH concentrations will have coincident primary hyperparathyroidism rather than ectopic PTH secretion. As many as 70% of cases of hypercalcemia in malignancy are caused by excess PTHrP secretion.84-89 PTHrP is seldom detectable in the circulation of normal subjects, but its expression has been shown in a number of normal tissues. PTHrP may be regarded as a product of the diffuse paracrine system and may have evolved to perform quite different physiologic roles compared with the structurally related PTH. Indeed, mutations in PTHrP result in both a skeletal phenotype, and also failure of mammary gland development.90 Under these circumstances, it is hard to describe production of PTHrP from a tumor arising from any tissue as truly ectopic, because no definite eutopic source for the peptide has been defined. However, humoral hypercalcemia of malignancy is most conveniently considered with the group of ectopic hormone–secretion syndromes. PTH and PTHrP share the type I PTH/PTHrP receptor that they recognize through their homologous N-terminal sequences. The PTH/PTHrP receptor mediates the action of both peptides in bone and kidney and is a member of the G protein–coupled seven-transmembrane receptor family. The common receptor explains 1) how PTHrP is able to generate cAMP in membrane preparations of PTH-sensitive renal tubule and 2) why the humoral

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PART 15  MULTISYSTEM ENDOCRINE DISORDERS

hypercalcemia of malignancy syndrome results in hypercalcemia with hypophosphatemia.90 PTHrP may also play a role in hypercalcemia related to osseous metastases, in that the hypercalcemia associated with bony metastases has a significant humoral component. Furthermore, expression of PTHrP by primary tumors is a predictor of bony metastatic disease development. This suggests that the local production of PTHrP by bone micrometastases may facilitate bony invasion and destruction.91-94 PTHrP expression is under complex regulation. A number of cytokines and growth factors have been shown to induce its expression, and both glucocorticoids and 1,25-dihydroxycholecalciferol, which have an antiproliferative effect on epithelial cells, inhibit expression.95-98

Hypercalcemia in Hematologic Malignancy Hypercalcemia occurs in as many as 30% of patients with multiple myeloma. Skeletal involvement causes extensive bone destruction, with pain and risk for pathologic fracture. Histological evidence suggests that the bone disease is caused by increased osteoclastic activity in the absence of significant osteoblastic activity. Loss of osteoblastic activity is also supported by the characteristically negative bone scan and suppressed circulating osteocalcin concentration. A number of cytokines produced by activated immune cells have been shown to have direct effects on promoting bone resorption. Such cytokines include tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), interleukin-1, and leukemia inhibitory factor. A superseded generic term for these factors was osteoclast-activating factor. However, it is noteworthy that in three of nine patients with multiple myeloma complicated by hypercalcemia, there was an elevation in circulating PTHrP, suggesting that a mechanism similar to humoral hypercalcemia of malignancy syndrome may be operating in at least some patients with hematologic malignancy-associated hypercalcemia.88,99,100 Generally, hypercalcemia is rare in lymphoma, with the exception of adult T-cell leukemia/lymphoma. This disease occurs in Japan and the West Indies and is caused by infection with the human T-cell lymphotrophic virus type 1. At least one fourth of patients will develop hypercalcemia, which is associated with suppressed 1,25-dihydroxyvitamin D. Hypercalcemia predicts outcome and is implicated in causing patient mortality. There is strong evidence that the hypercalcemia is mediated by PTHrP.101-104

itself. Patients may be nonspecifically unwell and may complain of constipation, nausea, vomiting, confusion, or dehydration. Hypercalcemia induces a diuresis and may cause profound dehydration, particularly in association with vomiting or drowsiness. Further manifestations include lethargy, depression, poor concentration, and drowsiness. It is sometimes necessary to distinguish malignancyinduced hypercalcemia from other causes of hypercalcemia such as hyperparathyroidism. PTH levels are low in hypercalcemia of malignancy. An elevated PTHrP level confirms the diagnosis, and it is increased in approximately 80% of patients with hypercalcemia with cancer. 1,25-Dihydroxyvitamin D levels may be increased in patients with lymphoma. Recognition of hypercalcemia and its appropriate treatment allow retrospective allocation of symptoms in an individual patient. Therefore, it is almost always worth treating such patients, irrespective of their underlying disease prognosis.

Treatment There is little evidence that hypercalcemia is a significant cause of premature mortality in cancer, but it is a significant cause of morbidity.105 Even if the underlying malignancy is beyond cure, effective relief of hypercalcemia is a most useful palliative intervention. There are few patients in whom treatment should not be seriously considered, because intervention is quick, easy, and largely free of serious complications. In the past, calcitonin and/or mithramycin were used, but these have been replaced by the bisphosphonate drugs in conjunction with rehydration with intravenous saline.106 Saline infusion promotes calcium diuresis. Usually, single infusions of pamidronate or clodronate are sufficient, with a suggestion that pamidronate is slightly more effective.107,108 There are newer bisphosphonates that have become available (e.g., ibandronate), but further head-to-head comparisons are lacking.109 These drugs are usually administered by slow intravenous infusion. There may be a transient febrile reaction within the first 24 hours, but this is usually selflimiting. The calcium response is typically rapid and may last as long as 1 month. In patients in whom a more rapid acute effect is desired, bisphosphonates can be combined with calcitonin.110 The bisphosphonates are rapidly cleared from the circulation and concentrated in bone. They appear to inhibit osteoclast activity and may induce osteoclast apoptosis. Their duration of action is significantly longer than

Diagnosis Hypercalcemia is the most common metabolic complication of malignant disease and the cause of much morbidity (Table 152-11). Most cases are due to humoral mechanisms, principally PTHrP, rather than direct damage of bone by malignant cells. This is clear from the observation that even patients who have bone metastases and hypercalcemia have a poor correlation between extent of skeletal involvement and calcium concentration in the circulation. The presentation of hypercalcemia may be confusing and may be attributed to the underlying disease process

TABLE 152-11  Symptoms and Signs of Hypercalcemia Polyuria Thirst Nausea Anorexia Constipation Confusion Drowsiness Headache Coma

152  ECTOPIC HORMONE SYNDROMES

predicted by their plasma half-life, reflecting their distribution and mode of action.109

ONCOGENIC OSTEOMALACIA Osteomalacia associated with typically benign tumors is characterized by hypophosphatemia, normal or low calcium, elevated alkaline phosphatase, and suppressed 1,25-dihydroxyvitamin D. It is usually found with benign mesenchymal tumors, of which hemangiopericytomas are the most common. The disorder is caused by excessive production of FGF23, which acts on the renal tubule to promote phosphaturia.111 The disorder exhibits biochemical features similar to those seen with inactivating mutations in the PHEX gene, the cause of hereditary X-linked hypophosphatemia. The PHEX gene encodes a protease that inactivates phosphatonins, including the protein fibroblast growth factor type 23, which seems to be the phosphaturic factor produced by tumors that cause oncogenic osteomalacia.

ECTOPIC GROWTH HORMONE–RELEASING HORMONE Ectopic GHRH-releasing tumors, often the bronchial or upper gastrointestinal carcinoid cell type, are a very rare cause of acromegaly (Table 152-12). In patients who present with acromegaly, the syndrome is usually of several years’ duration to allow development of the typical clinical features. Accordingly, it is not surprising that the underlying tumors are usually small and benign. Clinical features are similar to those of typical acromegaly. Pituitary imaging is unhelpful because the radiographic features reveal an enlarged pituitary gland or an asymmetric mass that can be confused with an adenoma.112 The histological identification of true pituitary somatotroph hyperplasia, with a preserved reticulin network, led to the identification of GHRH in extracts from islet cell tumors.113-116 Since then, many tumors and tumor cell lines have been shown to express or secrete GHRH.117-121 For example, 25 of 97 carcinoid tumors expressed GHRH in one study,122 17% of gastrointestinal and pancreatic tumors stained for GHRH in another,123 and 63% of endometrial adenocarcinomas expressed GHRH.124 In addition, subtle abnormalities in GH secretion and regulation may be found in patients harboring carcinoid tumors.125 GH secretion has been associated with the development of several malignant tumors, notably prostate and colon adenocarcinoma. A complex, long feedback loop may confer survival advantage on these tumors. It has been suggested that all patients with acromegaly should be screened for ectopic GHRH because TABLE 152-12  Tumors Associated with Growth Hormone–Releasing Hormone Secretion Carcinoid tumors (e.g., bronchial) Pancreatic islet tumors Small-cell lung carcinoma

Pheochromocytomas Adrenal adenomas Hypothalamic gangliocytomas

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measurements in the plasma of greater than 0.3 ng/mL are virtually diagnostic of GHRH production by a tumor.126 However, the assays are not widely available and currently remain research tools. In addition, the incidence is rare. In one series of 177 unselected patients with acromegaly, only one had detectable GHRH concentrations in plasma.115,127 Most commonly, the diagnosis is made after hypophysectomy, when histology shows somatotroph hyperplasia. In these cases, measurement of GHRH is necessary, as is the search for its source. The best treatment is curative resection of the primary tumor, but in cases in which the tumor is elusive or metastatic, success has been achieved using long-acting somatostatin analogues. The prognosis for patients with ectopic GHRH appears to be good.128,129

NON–ISLET CELL TUMOR HYPOGLYCEMIA Fasting hypoglycemia may arise as a consequence of non– islet cell tumor formation (Table 152-13). Such tumors do not express insulin, which appears to be very tightly regulated in its tissue distribution, but rather the insulin-related molecules insulin-like growth factor (IGF)-1 or, more commonly, IGF-2 (Table 152-14). This has prompted the suggestion that the syndrome should be renamed as IGF-2oma, based on a molar ratio of IGF2:IGF-1 of >10.130 In normal subjects, IGF-1 and IGF-2 circulate at much higher concentrations than insulin and, if unopposed, cause profound hypoglycemia due to their actions through the insulin receptor. This does not occur due to the presence of high-affinity, high-capacity, TABLE 152-13  Tumors Associated with Non–Islet Cell Tumor Hypoglycemia Carcinoma

Mesenchymal Tumors

Hepatocellular, hepatoma Adrenocortical Pancreatic Gastric Colon Lung (small-cell, squamous) Kidney Prostate

Fibroma, fibrosarcoma Mesothelioma Rhabdomyosarcoma Neurofibroma, neurofibrosarcoma Leiomyosarcoma Others: Hemangiopericytoma Hematologic Lymphoma

TABLE 152-14  Non–Islet Cell Tumor Hypoglycemia vs. Insulinoma

IGF-1 IGF-2 IGFBP-3 Insulin Glucose Growth hormone β-Hydroxybutyrate

Non–Islet Cell

Insulinoma

↔ ↔ ↓ ↓ ↓ ↓ ↓

↔ ↔ ↔ ↑ ↓ ↔ or ↑ ↓

↑, Increased; ↓, decreased; ↔, equivocal; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein.

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PART 15  MULTISYSTEM ENDOCRINE DISORDERS Ternary complex Insulin

GH

IGFII BP3

ALS

Binary complex

GH

Most tumors are large and intraabdominal, although thoracic tumors have also been reported.140 The underlying tumor may be benign, in which case curative resection is the aim. Histological confirmation of the diagnosis is by specific immunostaining of a biopsy for IGF-2.

Management

Insulin

IGFII BP3 ALS

Figure 152-2  Formation of the ternary complex between insulin-like

growth factors (IGFs), IGF-binding protein 3 (BP3), and the acid-labile subunit (ALS). Normal physiology (top) in ectopic production of IGF (usually IGF-2) by tumor (bottom). Increased activity of IGF inhibits pituitary production of growth hormone (GH) and so reduces hepatic production of ALS and IGF-BP3. The resulting binary complex has increased insulin-like activity and, acting through the insulin receptor, causes hypoglycemia.

circulating IGF-binding proteins (IGFBPs).131,132 These result in very low concentrations of free IGFs and act to chaperone the IGFs and deliver them to their tissue beds of action. A number of tumors, typically of mesenchymal origin, have been identified as the cause of non–islet cell hypoglycemia. The apparent mechanism is overproduction of IGF-2.133 In addition to aberrant overproduction of IGF2, there is also secretion of a partially processed form of IGF-2, “big” IGF-2, which includes a C-terminal extension peptide and frequently an abnormal glycosylation pattern.134,135 The circulating IGF-2 would be expected to cause few problems if it were effectively sequestered by IGFBPs, but this does not occur.136,137 IGF-2 exerts a negative feedback at the pituitary somatotroph to suppress GH secretion. GH is the key regulator of hepatic IGFBP3, a component of the principal ternary circulating IGF complex (Fig. 152-2). Therefore, in the absence of effective GH drive to IGFBP-3 production, the tumor-derived IGF-2 is left in a free state and is thus capable of acting through the insulin receptor and causing hypoglycemia.138

Diagnosis The diagnosis is based on the recognition that the patient’s symptoms are due to hypoglycemia, which involves a detailed history and confirmation of either hypoglycemia occurring during a symptomatic episode or fasting hypoglycemia. The diagnosis should be considered in all unconscious cancer patients without signs of vascular events or brain metastases. The typical biochemical accompaniment to hypoglycemia is suppressed insulin, suppressed ketone bodies (β-hydroxybutyrate), and suppressed GH. In addition, IGF-2 is usually elevated or normal, with suppression of IGFBP-3 as a consequence of low GH.133,139

Effective management requires either surgical excision or debulking of the tumor. This is best achieved by close consultation between oncologist, surgeon, and interventional radiologist, who may be able to perform tumor embolization. These tumors tend not to be radiosensitive, although there are isolated case reports of therapeutic response. Because these tumors are rare, management is tailored to the individual patient and is usually based on pragmatic approaches, including multiple small meals, and occasionally requiring glucose infusions. In patients whose tumors are inoperable, relief of hypoglycemia can be achieved by using glucocorticoid, usually dexamethasone, either alone or with recombinant human GH.138,141,142 Glucocorticoids exert a direct anti-insulin and anti-IGF effect, and GH acts by its anti-insulin action and by increasing the IGFBP concentration, which then acts to “mop up” the excess IGF.

OTHER PITUITARY ECTOPIC HORMONES The two pituitary hormones prolactin and GH are of interest because they have wide extrapituitary expression and yet are very seldom the cause of clinically significant ectopic hormone syndromes. Prolactin is expressed in decidualized endometrium, T lymphocytes, mammary epithelial cells, skin, sweat glands, and the brain. It is the same gene that is transcribed in all of these cases, rather than the related placental lactogen-type gene, but the regulation of the gene appears completely different.143 Whereas in the pituitary lactotroph cell, prolactin is under the transcriptional control of the pituitary-specific factor Pit1, in extrapituitary tissues, Pit1 is not expressed, and the pituitary promoter of the prolactin gene is silent. The gene is transcribed from an upstream promoter that gives rise to a slightly longer mRNA with a unique 5′ end, but after processing, the result is a protein with the same amino acid sequence. Because the gene is transcribed from a different promoter, the control of gene transcription, its basal rate, and regulation by external signals is different. For example, in T-lymphocyte prolactin, gene transcription is responsive to the immunophilins, including cyclosporin A. The function of this extrapituitary prolactin is subject to debate, and it is not clear why such widespread expression is accompanied by such rarity of overexpression in malignant disease, in contrast to ACTH or vasopressin expression. Because prolactin receptors are found in a variety of tissues that cannot be reconciled with an exclusive action on mammary milk production, prolactin may have a more diverse role than so far determined. Ectopic prolactin secretion is a rare occurrence.144 There are reports of ectopic prolactin secretion from a bronchial tumor,145 a gonadoblastoma,146 a renal cell carcinoma,147 and undifferentiated lung cancer.147 However, breast cancers have been shown to express both prolactin

152  ECTOPIC HORMONE SYNDROMES

and prolactin receptors.148-150 There is some evidence of a weak tumor-promoting effect of prolactin on breast adenocarcinoma cells151-152 that has led to the suggestion of a paracrine role for prolactin in the development or progression of breast malignancy. Prolactin may have other activities in addition to its best-characterized function on lactation—in particular, a 16-kD fragment of prolactin has antiangiogenic potential and may influence tumorigenesis.153,154 In addition, prolactin can activate nuclear factor-κΒ, a survival-promoting transcription factor.155 GH is also found in extrapituitary tissues, again in cells of hematopoietic lineage. This expression has been suggested to result in paracrine signaling, although hard data are lacking. Ectopic GH secretion was first described in 1968 in a male patient with lung cancer. Resection of the tumor caused a decrease in GH concentrations, although GH was not measured in the primary tumor.156 There are very few cases in which the criteria are met for true ectopic secretion of GH. One such case was described by Melmed and co-workers,157 who carefully showed GH secretion from a pancreatic islet tumor, with demonstration of a gradient of GH across the tumor in vivo and resolution of abnormal GH and IGF-1 after tumor resection. They also showed GH expression in tumor sections, at both the mRNA and protein level. It is interesting that there is hypertrophic osteoarthropathy in cases of ectopic GH secretion, although this is not a feature of acromegaly; it may result from other humoral factors secreted by the tumors or from neural influences.156-159

Gonadotropins Human chorionic gonadotropin is expressed in trophoblasts and from both germ cell and trophoblast tumors. The most frequent nontrophoblast tumor associated with human chorionic gonadotropin overproduction is lung,160 but other tumors have been described, including adrenal, breast, bladder, maxilla, hepatoblastoma, osteosarcoma, and lymphoma.161-165 The production of human chorionic gonadotropin in men causes gynecomastia as a result of increased estrogen secretion and may cause precocious puberty in children.166

ECTOPIC GUT HORMONE SYNDROMES Clinical syndromes associated with ectopic production of gut hormones by tumors are very rare, but vasoactive intestinal polypeptide causing typical watery diarrhea

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TABLE 152-15  Tumors Associated with Ectopic Renin Secretion Kidney (Wilms’ tumor, renal cell carcinoma) Lung (small-cell lung carcinoma, adenocarcinoma, leiomyosarcoma) Pancreatic carcinoma Ovarian tumors Liver (hepatocellular carcinoma, hamartoma) Ileal carcinoma Adrenal paraganglioma Orbital hemangiopericytoma

has been described. Tumors of the lung, medullary thyroid carcinoma, pheochromocytoma, and neuroendocrine tumors of the kidney have all been reported to produce vasoactive intestinal polypeptide.167-169

Ectopic Renin Secretion Renin production is usually tightly restricted to the juxtaglomerular apparatus of the kidney, and true ectopic secretion by nonrenal tumors is very rare (Table 152-15). In cases described, hypertension is a feature, along with hypokalemia.170 As is often the case with ectopic production of usually processed hormones, renin precursors are described with an increased prorenin-to-renin ratio.171-173 If identified, resection of the primary tumor affords cure, but medical therapy with angiotensin-converting enzyme inhibitors or with angiotensin-blocking agents may be beneficial in incurable disease.174 Extrarenal tumors secreting renin include lung,175-177 pancreas,173 ovary,178,179 liver,180 ileum,181 adrenal,182 and orbital hemangiopericytoma.183

Acknowledgments The author is grateful to Professor John Wass and Dr. Helen Turner, who wrote the previous version of this chapter, for inspiration and for the use of tables.

  

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REFERENCES

1. Klemperer P. Parathyroid hyperplasia and bone destruction in generalised carcinomatosis. Surg Gynaecol Obstet. 1923;36:11. 2. Brown WH. A case of pluriglandular syndrome: Diabetes of bearded women. Lancet. 1928;2:1022-1028. 3. Nadler WH, Wolfer JA. Hepatogenic hypoglycemia in primary carcinoma of the liver. Arch Intern Med. 1929;44:700. 4. Crawford WH. Hypoglycemia with coma in a case of primary carcinoma of the liver. Am J Med Sci. 1931;181:496. 5. Albright F, Reifenstein EC. The parathyroid glands and metabolic bone disease—selected studies. Baltimore: Williams & Wilkins; 1948. 6. Meador CK, Liddle GW, Island DP, et al. Cause of Cushings syndrome in patients with tumors arising from “nonendocrine” tissue. J Clin Endocrinol Metab. 1962;22:693-703. 7. Liddle GW, Nicholson WE, Island DP, et al. Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res. 1969;25:283-314. 8. Orth DN, Nicholson WE, Mitchell WM, et al. Biologic and immunologic characterization and physical separation of ACTH and ACTH fragments in the ectopic ACTH syndrome. J Clin Invest. 1973;52:1756-1769. 9. Amatruda Jr TT, Mulrow PJ, Gallagher JC, et al. Carcinoma of the lung with inappropriate antidiuresis. Demonstration of antidiuretic-hormone-like activity in tumor extract. N Engl J Med. 1963;269:544-549. 10. DeBold CR, Menefee JK, Nicholson WE, et al. Proopiomelanocortin gene is expressed in many normal human tissues and in tumors not associated with ectopic adrenocorticotropin syndrome. Mol Endocrinol. 1988;2:862-870. 11. Pearse AG. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proc R Soc Lond B Biol Sci. 1968;170:71-80. 12. Pearse AG, Polak JM. Endocrine tumours of neural crest origin: neurolophomas, apudomas and the APUD concept. Med Biol. 1974;52:3-18. 13. Abeloff MD, Eggleston JC, Mendelsohn G, et al. Changes in morphologic and biochemical characteristics of small cell carcinoma of the lung. A clinicopathologic study. Am J Med. 1979;66: 757-764. 14. Baylin SB, Mendelsohn G. Ectopic (inappropriate) hormone production by tumors: mechanisms involved and the biological and clinical implications. Endocr Rev. 1980;1:45-77. 15. Goodwin G, Shaper JH, Abeloff MD, et al. Analysis of cell surface proteins delineates a differentiation pathway linking endocrine and nonendocrine human lung cancers. Proc Natl Acad Sci U S A. 1983;80:3807-3811. 16. White A, Clark AJ. The cellular and molecular basis of the ectopic ACTH syndrome. Clin Endocrinol (Oxf). 1993;39:131-141. 17. White A, Clark AJ, Stewart MF. The synthesis of ACTH and related peptides by tumours. Baillieres Clin Endocrinol Metab. 1990;4:1-27. 18. Delisle L, Boyer MJ, Warr D, et al. Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications. Arch Intern Med. 1993;153:746-752. 19. Stewart PM, Gibson S, Crosby SR, et al. ACTH precursors characterize the ectopic ACTH syndrome. Clin Endocrinol (Oxf). 1994;40:199-204. 20. Gumbiner B, Kelly RB. Two distinct intracellular pathways transport secretory and membrane glycoproteins to the surface of pituitary tumor cells. Cell. 1982;28:51-59. 21. Drouin J, Chamberland M, Charron J, et al. Structure of the rat pro-opiomelanocortin (POMC) gene. FEBS Lett. 1985;193:54-58. 22. Clark AJ, Lavender PM, Coates P, et al. In vitro and in vivo analysis of the processing and fate of the peptide products of the short proopiomelanocortin mRNA. Mol Endocrinol. 1990;4:1737-1743. 23. Clark AJ, Lavender PM, Besser GM, et al. Proopiomelanocortin mRNA size heterogeneity in ACTH-dependent Cushing’s syndrome. J Mol Endocrinol. 1989;2:3-9. 24. De Keyzer Y, Bertagna X, Luton JP, et al. Variable modes of proopiomelanocortin gene transcription in human tumors. Mol Endocrinol. 1989;3:215-223.

25. Lundblad JR, Roberts JL. Regulation of proopiomelanocortin gene expression in pituitary. Endocr Rev. 1988;9:135-158. 26. Lamolet B, Pulichino AM, Lamonerie T, et al. A pituitary cellrestricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell. 2001;104:849-859. 27. Maira M, Couture C, Le Martelot G, et al. The T-box factor Tpit recruits SRC/p160 co-activators and mediates hormone action. J Biol Chem. 2003;278:46523-46532. 28. Drouin J, Maira M, Philips A. Novel mechanism of action for Nur77 and antagonism by glucocorticoids: A convergent mechanism for CRH activation and glucocorticoid repression of POMC gene transcription. J Steroid Biochem Mol Biol. 1998;65:59-63. 29. Philips A, Maira M, Mullick A, et al. Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Mol Cell Biol. 1997;17:5952-5959. 30. Philips A, Lesage S, Gingras R, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol. 1997;17:5946-5951. 31. Maira M, Martens C, Batsche E, et al. Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol. 2003;23:763-776. 32. Drouin J, Trifiro MA, Plante RK, et al. Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. Mol Cell Biol. 1989;9:5305-5314. 33. Drouin J, Sun YL, Nemer M. Glucocorticoid repression of pro-opiomelanocortin gene transcription. J Steroid Biochem. 1989;34:63-69. 34. Drouin J, Sun YL, Chamberland M, et al. Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J. 1993;12:145-156. 35. Riegel AT, Lu Y, Remenick J, et al. Proopiomelanocortin gene promoter elements required for constitutive and glucocorticoidrepressed transcription. Mol Endocrinol. 1991;5:1973-1982. 36. Vallette-Kasic S, Figarella-Branger D, Grino M, et al. Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs. J Clin Endocrinol Metab. 2003;88: 3050-3056. 37. Martens C, Bilodeau S, Maira M, et al. Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor. Mol Endocrinol. 2004;19(4):885-997. 38. Bilodeau S, Vallette-Kasic S, Gauthier Y, et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006;20(2): 2871-2886. 39. Abou-Samra AB, Harwood JP, Manganiello VC, et al. Phorbol 12-myristate 13-acetate and vasopressin potentiate the effect of corticotropin-releasing factor on cyclic AMP production in rat anterior pituitary cells: Mechanisms of action. J Biol Chem. 1987;262:1129-1136. 40. Newell-Price J. Proopiomelanocortin gene expression and DNA methylation: implications for Cushing’s syndrome and beyond. J Endocrinol. 2003;177:365-372. 41. Newell-Price J, King P, Clark AJ. The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression. Mol Endocrinol. 2001;15:338-348. 42. Wolfsen AR, Odell WD. ProACTH: Use for early detection of lung cancer. Am J Med. 1979;66:765-772. 43. Yalow RS, Berson SA. Characteristics of “big ACTH” in human plasma and pituitary extracts. J Clin Endocrinol Metab. 1973;36:415-423. 44. Shepherd FA, Laskey J, Evans WK, et al. Cushing’s syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. 1992;10:21-27. 45. Mains RE, Eipper BA. Biosynthesis of adrenocorticotropic hormone in mouse pituitary tumor cells. J Biol Chem. 1976;251: 4115-4120. 46. Mains RE, Eipper BA, Ling N. Common precursor to corticotropins and endorphins. Proc Natl Acad Sci U S A. 1977;74: 3014-3018.

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2639.e2

REFERENCES

47. Mains RE, Eipper BA. Coordinate synthesis of corticotropins and endorphins by mouse pituitary tumor cells. J Biol Chem. 1978;253:651-655. 48. Marcinkiewicz M, Day R, Seidah NG, et al. Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin. Proc Natl Acad Sci U S A. 1993;90:4922-4926. 49. Vieau D, Seidah NG, Mbikay M, et al. Expression of the prohormone convertase PC2 correlates with the presence of corticotropin-like intermediate lobe peptide in human adrenocorticotropinsecreting tumors. J Clin Endocrinol Metab. 1994;79:1503-1506. 50. Vieau D, Massias JF, Girard F, et al. Corticotrophin-like intermediary lobe peptide as a marker of alternate proopiomelanocortin processing in ACTH-producing nonpituitary tumours. Clin Endocrinol (Oxf). 1989;31:691-700. 51. Liddle GW, Givens JR, Nicholson WE, et al. The ectopic ACTH syndrome. Cancer Res. 1965;25:1057-1061. 52. Isidori AM, Kaltsas GA, Mohammed S, et al. Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab. 2003;88:5299-5306. 53. Newell-Price J, Morris DG, Drake WM, et al. Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2002;87:1640-1645. 54. White A, Stewart MF, Farrell WE, et al. Pro-opiomelanocortin gene expression and peptide secretion in human small-cell lung cancer cell lines. J Mol Endocrinol. 1989;3:65-70. 55. Bertagna XY, Nicholson WE, Pettengill OS, et al. Ectopic production of high molecular weight calcitonin and corticotropin by human small cell carcinoma cells in tissue culture: Evidence for separate precursors. J Clin Endocrinol Metab. 1978;47:1390-1393. 56. Ray DW, Littlewood AC, Clark AJ, et al. Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function. J Clin Invest. 1994;93:1625-1630. 57. Clark AJ, Stewart MF, Lavender PM, et al. Defective glucocorticoid regulation of proopiomelanocortin gene expression and peptide secretion in a small cell lung cancer cell line. J Clin Endocrinol Metab. 1990;70:485-490. 58. Ray DW, Davis JR, White A, et al. Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells. Cancer Res. 1996;56:3276-3280. 59. Sommer P, Le Rouzic P, Gillingham H, et al. Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells. Oncogene. 2007;26(5):7111-7121. 60. Florkowski CM, Wittert GA, Lewis JG, et al. Glucocorticoid responsive ACTH secreting bronchial carcinoid tumours contain high concentrations of glucocorticoid receptors. Clin Endocrinol (Oxf). 1994;40:269-274. 61. Isidori AM, Kaltsas A, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management and long-term follow-up. J Clin Endocrinol Metab. 2006;91:371-377. 62. Gözde Özkan Z, Kuyumcu S, Balköse D, et al. The value of somatostatin receptor imaging with In-111 Octreotide and/or Ga-68 DOTATATE in localizing ectopic ACTH producing tumors. Mol Imaging Radionucl Ther. 2013;22(2):49-55. 63. Tabarin A, Navarranne A, Guerin J, et al. Use of ketoconazole in the treatment of Cushing’s disease and ectopic ACTH syndrome. Clin Endocrinol (Oxf). 1991;34:63-69. 64. Donadille B, Groussin L, Waintrop C, et al. Management of Cushing’s syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para’-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. J Clin Endocrinol Metab. 2010;95(2):537-544. 65. De Rosa G, Testa A, Liberale I, et al. Successful treatment of ectopic Cushing’s syndrome with the long-acting somatostatin analog octreotide. Exp Clin Endocrinol. 1993;101:319-325. 66. Bano G, Mir F, Beharry N, et al. A novel medical treatment of Cushing’s due to ectopic ACTH in a patient with neurofibromatosis type 1. Int J Endocrinol Metab. 2013;11(1):52-56. 67. Young J, Deneux C, Grino M, et al. Pitfall of petrosal sinus sampling in a Cushing’s syndrome secondary to ectopic adrenocorticotropin-corticotropin releasing hormone (ACTH-CRH) secretion. J Clin Endocrinol Metab. 1998;83:305-308.

68. Gross AJ, Steinberg SM, Reilly JG, et al. Atrial natriuretic factor and arginine vasopressin production in tumor cell lines from patients with lung cancer and their relationship to serum sodium. Cancer Res. 1993;53:67-74. 69. Ghandur-Mnaymneh L, Satterfield S, Block NL. Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: Morphological, immunohistochemical and clinical expressions. J Urol. 1986;135:1263-1266. 70. Moses AM, Notman DD. Diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Adv Intern Med. 1982;27:73-100. 71. Kaye SB, Ross EJ. Inappropriate anti-diuretic hormone (ADH) secretion in association with carcinoma of the bladder. Postgrad Med J. 1977;53:274-277. 72. Yamaji T, Ishibashi M, Hori T. Propressophysin in human blood: a possible marker of ectopic vasopressin production. J Clin Endocrinol Metab. 1984;59:505-512. 73. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356:2064-2072. 74. Kenz S, Haas CS, Werth SC, et al. High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (­SIADH). Ann Oncol. 2011;22(12):2696. 75. Peri A. Clinical review: the use of vaptans in clinical endocrinology. J Clin Endocrinol Metab. 2013;98(4):1321-1332. 76. Zajac JD, Martin TJ, Hudson P, et al. Biosynthesis of calcitonin by human lung cancer cells. Endocrinology. 1985;116:749755. 77. Asa SL, Kovacs K, Killinger DW, et al. Pancreatic islet cell carcinoma producing gastrin, ACTH, alpha-endorphin, somatostatin and calcitonin. Am J Gastroenterol. 1980;74:30-35. 78. Himsworth RL, Bloomfield GA, Coombes RC, et al. “Big ACTH” and calcitonin in an ectopic hormone secreting tumour of the liver. Clin Endocrinol (Oxf). 1977;7:45-62. 79. Rees LH, Ratcliffe JG. Ectopic hormone production by non-endocrine tumours. Clin Endocrinol (Oxf). 1974;3:263-299. 80. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab. 1989;68:976-981. 81. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med. 1990;323:1324-1328. 82. Rizzoli R, Pache JC, Didierjean L, et al. A thymoma as a cause of true ectopic hyperparathyroidism. J Clin Endocrinol Metab. 1994;79:912-915. 83. Strewler GJ, Budayr AA, Clark OH, et al. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab. 1993;76: 1373-1375. 84. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med. 1989;111:807-812. 85. Broadus AE, Mangin M, Ikeda K, et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med. 1988;319:556-563. 86. Burtis WJ, Wu T, Bunch C, et al. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987;262:7151-7156. 87. Burtis WJ, Brady TG, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med. 1990;322:1106-1112. 88. Firkin F, Schneider H, Grill V. Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Leuk Lymphoma. 1998;29:499-506. 89. Grill V, Ho P, Body JJ, et al. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin ­Endocrinol Metab. 1991;73:1309-1315. 90. Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97(9):2947-2956. 91. Bundred NJ, Walls J, Ratcliffe WA. Parathyroid hormone-related protein, bone metastases and hypercalcaemia of malignancy. Ann R Coll Surg Engl. 1996;78:354-358.

REFERENCES 92. Bundred NJ, Walker RA, Ratcliffe WA, et al. Parathyroid hormone related protein and skeletal morbidity in breast cancer. Eur J Cancer. 1992;28:690-692. 93. Chirgwin JM, Guise TA. Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr. 2000;10:159-178. 94. Guise TA, Yin JJ, Thomas RJ, et al. Parathyroid hormone-related protein (PTHrP)-(1–139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. Bone. 2002;30:670-676. 95. Ikeda K, Lu C, Weir EC, et al. Transcriptional regulation of the parathyroid hormone-related peptide gene by glucocorticoids and vitamin D in a human C-cell line. J Biol Chem. 1989;264: 15743-15746. 96. Lu C, Ikeda K, Deftos LJ, et al. Glucocorticoid regulation of parathyroid hormone-related peptide gene transcription in a human neuroendocrine cell line. Mol Endocrinol. 1989;3:2034-2040. 97. Eto M, Akishita M, Ishikawa M, et al. Cytokine-induced expression of parathyroid hormone-related peptide in cultured human vascular endothelial cells. Biochem Biophys Res Commun. 1998;249:339-343. 98. Urena P, Iida-Klein A, Kong XF, et al. Regulation of parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acid by glucocorticoids and PTH in ROS 17/2.8 and OK cells. Endocrinology. 1994;134:451-456. 99. Seymour JF, Grill V, Martin TJ, et al. Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein. Leukemia. 1993;7: 1672-1675. 100. Zeimer H, Firkin F, Grill V, et al. Assessment of cellular expression of parathyroid hormone-related protein mRNA and protein in multiple myeloma. J Pathol. 2000;192:336-341. 101. Richard V, Lairmore MD, Green PL, et al. Humoral hypercalcemia of malignancy: Severe combined immunodeficient/beige mouse model of adult T-cell lymphoma independent of human T-cell lymphotropic virus type-1 tax expression. Am J Pathol. 2001;158:2219-2228. 102. Obagi S, Derubertis F, Brown L, et al. Hypercalcemia and parathyroid hormone related protein expression in cutaneous T-cell lymphoma. Int J Dermatol. 1999;38:855-862. 103. Moseley JM, Danks JA, Grill V, et al. Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: Implications for the mechanism of hypercalcaemia. Br J Cancer. 1991;64: 745-748. 104. Bunn Jr PA, Schechter GP, Jaffe E, et al. Clinical course of retrovirusassociated adult T-cell lymphoma in the United States. N Engl J Med. 1983;309:257-264. 105. Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990;112:499-504. 106. Ralston SH, Gardner MD, Dryburgh FJ, et al. Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet. 1985;2:907-910. 107. Gallacher SJ, Ralston SH, Fraser WD, et al. A comparison of low versus high dose pamidronate in cancer-associated hypercalcaemia. Bone Miner. 1991;15:249-256. 108. Ralston SH, Gallacher SJ, Patel U, et al. Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia. Lancet. 1989;2:1180-1182. 109. Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer. 1997;75:295-300. 110. Ralston SH, Alzaid AA, Gardner MD, et al. Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin. Br Med J. 1986;292: 1549-1550. 111. Leaf DE, Pereira RC, Bazari H, et al. Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma. J Clin Endocrinol Metab. 2013;98(3):887-891. 112. Drange MR, Melmed S. Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone–releasing hormone-secreting carcinoid. J Clin Endocrinol Metab. 1998;83:3104-3109.

2639.e3

113. Guillemin R, Brazeau P, Bohlen P, et al. Growth hormone–releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218:585-587. 114. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone–releasing factor from a human pancreatic islet tumour. Nature. 1982;300:276-278. 115. Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone–releasing ­factor. J Clin Invest. 1982;70:965-977. 116. Thorner MO, Rivier J, Spiess J, et al. Human pancreatic growthhormone–releasing factor selectively stimulates growth-hormone secretion in man. Lancet. 1983;1:24-28. 117. Sano T, Saito H, Yamasaki R, et al. Production and secretion of immunoreactive growth hormone–releasing factor by pheochromocytomas. Cancer. 1986;57:1788-1793. 118. Doga M, Bonadonna S, Burattin A, et al. Ectopic secretion of growth hormone–releasing hormone (GHRH) in neuroendocrine tumors: relevant clinical aspects. Ann Oncol. 2001;12(suppl 2):S89-S94. 119. Othman NH, Ezzat S, Kovacs K, et al. Growth hormone– releasing hormone (GHRH) and GHRH receptor (GHRH-R) isoform expression in ectopic acromegaly. Clin Endocrinol (Oxf). 2001;55:135-140. 120. Sano T, Yamasaki R, Saito H, et al. Growth hormone–releasing hormone (GHRH)-secreting pancreatic tumor in a patient with multiple endocrine neoplasia type I. Am J Surg Pathol. 1987;11:810-819. 121. Schulte HM, Benker G, Windeck R, et al. Failure to respond to growth hormone releasing hormone (GHRH) in acromegaly due to a GHRH secreting pancreatic tumor: Dynamics of multiple endocrine testing. J Clin Endocrinol Metab. 1985;61:585-587. 122. Sano T, Asa SL, Kovacs K. Growth hormone–releasing hormoneproducing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev. 1988;9:357-373. 123. Dayal Y, Lin HD, Tallberg K, et al. Immunocytochemical demonstration of growth hormone–releasing factor in gastrointestinal and pancreatic endocrine tumors. Am J Clin Pathol. 1986;85:13-20. 124. Chatzistamou I, Schally AV, Pafiti A, et al. Expression of growth hormone–releasing hormone in human primary endometrial carcinomas. Eur J Endocrinol. 2002;147:381-386. 125. Oberg K, Norheim I, Wide L. Serum growth hormone in patients with carcinoid tumours: Basal levels and response to glucose and thyrotrophin releasing hormone. Acta Endocrinol (Copenh). 1985;109:13-18. 126. Faglia G, Arosio M, Bazzoni N. Ectopic acromegaly. Endocrinol Metab Clin North Am. 1992;21:575-595. 127. Thorner MO, Frohman LA, Leong DA, et al. Extrahypothalamic growth-hormone–releasing factor (GRF) secretion is a rare cause of acromegaly: Plasma GRF levels in 177 acromegalic patients. J Clin Endocrinol Metab. 1984;59:846-849. 128 Ghazi AA, Amirbaigloo A, Dezfooli AA, et al. Ectopic acromegaly due to growth hormone releasing hormone. Endocrine. 2013;43(2):293-302. 129. Garby L, Caron P, Claustrat F, et al. GTE Group: Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone–releasing hormone (GHRH): a French nationwide series of 21 cases. J Clin Endocrinol Metab. 2012;97(6):2093-2104. 130. Livingstone C. IGF2 and cancer. Endocr Relat Cancer. 2013;20(6):R321-R339. 131. Marks V, Teale JD. Tumours producing hypoglycaemia. Diabetes Metab Rev. 1991;7:79-91. 132. Teale JD. Non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf). 1999;51:147. 133. Teale JD, Marks V. Inappropriately elevated plasma insulin-like growth factor II in relation to suppressed insulin-like growth factor I in the diagnosis of non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf). 1990;33:87-98. 134. Daughaday WH, Wu JC, Lee SD, et al. Abnormal processing of pro-IGF-II in patients with hepatoma and in some hepatitis B virus antibody-positive asymptomatic individuals. J Lab Clin Med. 1990;116:555-562. 135. Daughaday WH, Trivedi B, Baxter RC. Serum “big insulin-like growth factor II” from patients with tumor hypoglycemia lacks normal E-domain O-linked glycosylation, a possible determinant of normal propeptide processing. Proc Natl Acad Sci U S A. 1993;90:5823-5827.

2639.e4

REFERENCES

136. Frystyk J, Skjaerbaek C, Zapf J, et al. Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia. Diabetologia. 1998;41:589-594. 137. Moller N, Frystyk J, Skjaerbaek C, et al. Systemic and regional tumour metabolism in a patient with non-islet cell tumour hypoglycaemia: Role of increased levels of free insulin-like growth factors. Diabetologia. 1996;39:1534-1535. 138. Teale JD, Blum WF, Marks V. Alleviation of non-islet cell tumour hypoglycaemia by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem. 1992;29:314-323. 139. Daughaday WH, Deuel TF. Tumor secretion of growth factors. Endocrinol Metab Clin North Am. 1991;20:539-563. 140. Masson EA, MacFarlane IA, Graham D, et al. Spontaneous hypoglycaemia due to a pleural fibroma: Role of insulin like growth factors. Thorax. 1991;46:930-931. 141. Teale JD, Marks V. Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH). Clin Endocrinol (Oxf). 1998;49: 491-498. 142. de Groot JWB, Rikhof B, van Doorn J, et al. Non-islet cell tumourinduced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer. 2007;14:979-993. 143. Ben Jonathan N, Mershon JL, Allen DL, et al. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev. 1996;17:639-669. 144. Molitch ME, Schwartz S, Mukherji B. Is prolactin secreted ectopically? Am J Med. 1981;70:803-807. 145. Rees LH, Bloomfield GA, Rees GM, et al. Multiple hormones in a bronchial tumor. J Clin Endocrinol Metab. 1974;38: 1090-1097. 146. Hoffman WH, Gala RR, Kovacs K, et al. Ectopic prolactin secretion from a gonadoblastoma. Cancer. 1987;60:2690-2695. 147. Turkington RW. Ectopic production of prolactin. N Engl J Med. 1971;285:1455-1458. 148. Jahnke GD, Trempus CS, Kari FW, et al. Expression of a prolactinlike factor in preneoplastic and neoplastic mouse mammary gland and cells. J Mol Endocrinol. 1996;17:247-256. 149. Clevenger CV, Chang WP, Ngo W, et al. Expression of prolactin and prolactin receptor in human breast carcinoma. Evidence for an autocrine/paracrine loop. Am J Pathol. 1995;146:695-705. 150. Clevenger CV, Furth PA, Hankinson SE, et al. The role of prolactin in mammary carcinoma. Endocr Rev. 2003;24:1-27. 151. Clevenger CV, Plank TL. Prolactin as an autocrine/paracrine factor in breast tissue. J Mammary Gland Biol Neoplasia. 1997;2:59-68. 152. Kwa HG, Cleton F, Wang DY, et al. A prospective study of plasma prolactin levels and subsequent risk of breast cancer. Int J Cancer. 1981;28:673-676. 153. Clapp C, Martial JA, Guzman RC, et al. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology. 1993;133:1292-1299. 154. Ferrara N, Clapp C, Weiner R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology. 1991;129:896-900. 155. Macotela Y, Mendoza C, Corbacho AM, et al. 16K prolactin induces NF-kappaB activation in pulmonary fibroblasts. J Endocrinol. 2002;175:R13-R18. 156. Steiner H, Dahlback O, Waldenstrom J. Ectopic growth-hormone production and osteoarthropathy in carcinoma of the bronchus. Lancet. 1968;1:783-785. 157. Melmed S, Ezrin C, Kovacs K, et al. Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor. N Engl J Med. 1985;312:9-17. 158. Melmed S, Rushakoff RJ. Ectopic pituitary and hypothalamic hormone syndromes. Endocrinol Metab Clin North Am. 1987;16:805-821. 159. Greenberg PB, Martin TJ, Beck C, et al. Synthesis and release of human growth hormone from lung carcinoma in cell culture. ­Lancet. 1972;1:350-352.

160. Yokotani T, Koizumi T, Taniguchi R, et al. Expression of alpha and beta genes of human chorionic gonadotropin in lung cancer. Int J Cancer. 1997;71:539-544. 161. Broder LE, Weintraub BD, Rosen SW, et al. Placental proteins and their subunits as tumor markers in prostatic carcinoma. Cancer. 1977;40:211-216. 162. Scholl PD, Jurco S, Austin JR. Ectopic production of beta-HCG by a maxillary squamous cell carcinoma. Head Neck. 1997;19:701-705. 163. McArthur JW, Toll GD, Russfield AB, et al. Sexual precocity attributable to ectopic gonadotropin secretion by hepatoblastoma. Am J Med. 1973;54:390-403. 164. Ordonez NG, Ayala AG, Raymond AK, et al. Ectopic production of the beta-subunit of human chorionic gonadotropin in osteosarcoma. Arch Pathol Lab Med. 1989;113:416-419. 165. Senba M, Watanabe M. Ectopic production of beta-subunit of human chorionic gonadotropin in malignant lymphoma. Zentralbl Pathol. 1991;137:402-404. 166. Treves N. Gynecomastia; the origins of mammary swelling in the male: an analysis of 406 patients with breast hypertrophy, 525 with testicular tumors, and 13 with adrenal neoplasms. Cancer. 1958;11:1083-1102. 167. Mendelsohn G, Eggleston JC, Olson JL, et al. Vasoactive intestinal peptide and its relationship to ganglion cell differentiation in neuroblastic tumors. Lab Invest. 1979;41:144-149. 168. Said SI, Faloona GR. Elevated plasma and tissue levels of vasoactive intestinal polypeptide in the watery-diarrhea syndrome due to pancreatic, bronchogenic and other tumors. N Engl J Med. 1975;293:155-160. 169. Hamilton I, Reis L, Bilimoria S, et al. A renal vipoma. BMJ. 1980;281:1323-1324. 170. Hollifield JW, Page DL, Smith C, et al. Renin-secreting clear cell carcinoma of the kidney. Arch Intern Med. 1975;135:859-864. 171. Soubrier F, Devaux C, Galen FX, et al. Biochemical and immunological characterization of ectopic tumoral renin. J Clin Endocrinol Metab. 1982;54:139-144. 172. Atlas SA, Hesson TE, Sealey JE, et al. Characterization of inactive renin (“prorenin”) from renin-secreting tumors of nonrenal origin. Similarity to inactive renin from kidney and normal plasma. J Clin Invest. 1984;73:437-447. 173. Ruddy MC, Atlas SA, Salerno FG. Hypertension associated with a renin-secreting adenocarcinoma of the pancreas. N Engl J Med. 1982;307:993-997. 174. Aurell M, Rudin A, Tisell LE, et al. Captopril effect on hypertension in patient with renin-producing tumour. Lancet. 1979;2:149-150. 175. Hauger-Klevene JH. High plasma renin activity in an oat cell carcinoma: a renin-secreting carcinoma? Cancer. 1970;26:1112-1114. 176. Genest J, Rojo-Ortega JM, Kuchel O, et al. Malignant hypertension with hypokalemia in a patient with renin-producing pulmonary carcinoma. Trans Assoc Am Physicians. 1975;88:192-201. 177. Kawai K, Fukamizu A, Kawakami Y, et al. A case of renin producing leiomyosarcoma originating in the lung. Endocrinol Jpn. 1991;38:603-609. 178. Anderson PW, Macaulay L, Do YS, et al. Extrarenal renin-secreting tumors: Insights into hypertension and ovarian renin production. Medicine (Baltimore). 1989;68:257-268. 179. Tetu B, Lebel M, Camilleri JP. Renin-producing ovarian tumor. A case report with immunohistochemical and electron-microscopic study. Am J Surg Pathol. 1988;12:634-640. 180. Cox JN, Paunier L, Vallotton MB, et al. Epithelial liver hamartoma, systemic arterial hypertension and renin hypersecretion. Virchows Arch A Pathol Anat Histol. 1975;366:15-26. 181. Saito T, Fukamizu A, Okada K, et al. Ectopic production of renin by ileal carcinoma. Endocrinol Jpn. 1989;36:117-124. 182. Fried G, Wikstrom LM, Hoog A, et al. Multiple neuropeptide immunoreactivities in a renin-producing human paraganglioma. Cancer. 1994;74:142-151. 183. Yokoyama H, Yamane Y, Takahara J, et al. A case of ectopic renin-secreting orbital hemangiopericytoma associated with juvenile hypertension and hypokalemia. Acta Med Okayama. 1979;33: 315-322.