Editors: Felig, Philip; Frohman, Lawrence A.

Title: Endocrinology & Metabolism, 4th Edition; Ectopic Hormone Production Glenn
D. Braunstein

Paraneoplastic Syndromes

Most clinical abnormalities found in patients with cancer are directly related to the growth of the primary tumor and to metastases,
infections, or therapy. In addition, these patients may exhibit one or more remote effects of cancer. Such remote effects, or
paraneoplastic syndromes, include the signs, symptoms, and biochemical abnormalities that occur in patients as a result of cancer
which are not due to the mass effects of the primary neoplasm or its metastases. The spectrum of paraneoplastic syndromes is large
and covers every organ system (Table 28-1). Paraneoplastic syndromes are relatively common in patients with cancer, being found
in approximately 7-10 percent of patients at the time of diagnosis, 20 percent at any time period, and in up to 50 percent at some
time during the course of disease.1, 2 The most common paraneoplastic syndromes involve ectopic hormone production, neurologic
dysfunction, and hematologic abnormalities.
Many of the nonendocrine paraneoplastic syndromes result from immunologic abnormalities. Some syndromes are associated with
the production of site-specific antibodies. Examples include subacute cerebellar degeneration, which is associated with anti-
Purkinje cell cytoplasmic antibodies (anti-Yo antibody), the Lambert-Eaton syndrome with antibodies directed against the voltage-
gated calcium channels, the antiacetylcholine receptor antibodies found in patients with myasthenia gravis associated with
thymomas, and autoantibodies to desmoplakin I and other skin antigens in paraneoplastic pemphigus. 3, 4 Circulating antibodies may
also cause a paraneoplastic syndrome through the formation of immune complexes. The deposition of an immune complex
composed of carcinoembryonic antigen and anticarcinoembryonic antigen has been described in patients with nephrotic syndrome
associated with cancer.5 Similarly, glomerular membrane deposition of IgG and IgM in patients with the nephrotic syndrome and
lung carcinoma has been noted.6, 7 Cell-mediated immune dysfunction in patients with cancer is well known and accounts for the
anergy found with late-stage disease. Lymphocytes that are cytotoxic for muscle cells have been found in patients with cancer-
associated dermatomyositis.8 The alterations in normal immunity found in cancer patients also account for some of the unusual
infections encountered. For many years the syndrome of progressive multifocal leukoencephalopathy was thought to be a
paraneoplastic syndrome primarily found in lymphoproliferative and myoproliferative neoplasms. However, it is now known that
this syndrome is the consequence of central nervous system (CNS) infection with a papovavirus (JC virus or SV40-PML virus).9
Another mechanism by which tumors may give rise to a paraneoplastic syndrome is through the depletion of substrates. Examples
include a pellagra-like dermatitis secondary to the niacin deficiency found in some patients with carcinoid tumors and the
necrolytic migratory erythema from amino acid depletion in the hypercatabolic state induced by glucagon-secreting tumors. Also,
the hypoglycemia found in markedly cachectic patients may result from a lack of sufficient quantities of gluconeogenic amino acids
to allow the liver to synthesize adequate quantities of glucose during fasting. 10
Tumors also may secrete excessive quantities of normally occurring proteins. A number of growth factors that are considered to be
local or paracrine regulators of cell function may be secreted in sufficient quantities to act systemically. Eosinophilopoietin
production in lymphoproliferative disorders may be responsible for the eosinophilia associated with these tumors.11 Disseminated
intravascular coagulation has been associated with mucin-producing adenocarcinomas in which the mucin appears to activate
factor X.12 These examples illustrate the wide range of pathophysiologic mechanisms that may give rise to nonendocrine
paraneoplastic syndromes.

Eutopic versus Ectopic Hormone Production

Until recently, the definition of eutopic and ectopic hormone production was relatively straightforward. Eutopic hormone
production referred to the secretion of a hormone by a neoplasm derived from a tissue or organ that normally produces the
hormone, while ectopic hormone production was defined as the secretion of a hormone by a neoplasm derived from a tissue or
organ that does not normally produce that hormone. Using these definitions, excessive production of adrenocorticotropin (ACTH)
by a corticotrope adenoma of the pituitary represents eutopic production of ACTH, while Cushing's syndrome resulting from
production of ACTH by a small cell carcinoma of the lung represents ectopic production. However, many normal tissues, including
lung, contain small amounts of immunoreactive ACTH or pro-opiomelanocortin (POMC).13 This finding has resulted in the
hypothesis that the elevated serum and tumor levels of immunoreactive ACTH or POMC are due to a quantitative difference in the
amounts of ACTH/POMC synthesized by tumor cells in contrast to normal cells. In addition, if cancer cells contain the enzymes that
process the biologically inactive POMC to the biologically active ACTH molecule, Cushing's syndrome may result.13 Growth
hormone, prolactin, insulin, corticotropin releasing factor (CRF), human chorionic gonadotropin (hCG), somatostatin, calcitonin,
vasoactive intestinal peptide (VIP), and parathyroid hormone-related protein (PTH-rp) have also been demonstrated in normal
nonendocrine tissues. In an effort to maintain the concept of ectopic hormone production while recognizing the possibility that all
normal tissues may secrete small quantities of at least immunoreactive forms of peptide hormones, ectopic hormone production
may be redefined as the excessive secretion of a hormone by a neoplasm derived from a tissue or organ that is not the known
physiologic source of that hormone. This definition is not wholly satisfactory because the small quantities of peptide hormones that
are secreted by normal tissues may have a physiologic autocrine or paracrine function. Nevertheless, this is a satisfactory working
definition that encompasses the current state of knowledge.

TABLE 28-1. Spectrum of Paraneoplastic Syndromes

Ectopic hormone syndromes (see Table 28-2) T- and B-cell dysfunction
Neurologic syndromes Thrombocytopenia
Dementia Thromobocytosis
Dermatomyositis-polymyositis Renal syndromes
Lambert-Eaton syndrome Glomerulonephritis
Limbic encephlalitis Nephrotic syndrome
Myesthenia gravis Renal tubular acidosis
Necrotizing myelopathy Secondary amyloidosis
Opsoclonus-myoclonus Dermatologic syndromes
Paraneoplastic retinopathy Acanthosis nigricans
Peripheral neuropathies Acquired icthyosis
Stiff-man syndrome Acquired tylosis
Subacute cerebellar degeneration Bazex's syndrome
Subacute sensory neuropathy Bowen's disease
Myopathies Dermatitis herpetiformis
Acute necrotizing myopathy Erythemia annulare centrifugum
Carcinomatous neuromyopathy Erythemia gryatum repens
Dermatomyositis-polymyositis Erythromelalgia
Hematologic syndromes Exfoliative dermatitis
Acquired von Willebrand disease Extramammary Paget's disease
Autoimmune hemolytic anemia Hypertrichosis lanuginosa
Circulating anticoagulant Leser-Trelat sign
Cold hemagglutinin disease Melanosis
Cryoglobulinemia Pachydermoperiostosis
Disseminated intravascular coagulation Pemphigoid
Eosinophilia Pityriasis rotunda
Erythrocytosis Pruritis
Granulocytopenia Pyoderma gangrenosum
Granulocytosis Sweet's syndrome
Hyperviscosity syndrome Tripe palms
Hypogammaglobulinemia Gastrointestinal syndromes
Megaloblastic anemia Anorexia-cachexia
Microangiopathic hemolytic anemia Dysguesia/hypogeusia
Red cell aplasia Protein-losing enteropathy
Rheumatologic syndromes
Hypertrophic pulmonary osteoarthropathy
Polyarteritis
Rheumatoid arthritis-like arthropathy
Secondary gout
Vascular syndromes
Nonbacterial thrombotic endocarditis
Venous thrombosis
Miscellaneous syndromes
Fever
Hyperlipidemia
Lactic acidosis
Porphyria cutanea tarda

A large number of hormones are produced ectopically, although not all are associated with clinical syndromes (Table 28-2). It is of
interest that neither the thyronines nor the steroid hormones are on this list. Presumably, the synthesis of these classes of hormones
requires orderly enzymatic steps absent in tumors that are not derived from the thyroid, adrenals, or steroid-secreting gonadal cells.
Although nonendocrine tumors do not synthesize steroid hormones from cholesterol, they may have enzyme systems that convert
one steroid hormone to another. Indeed, the gynecomastia found in some males with lung, gastric, and hepatic carcinomas is caused
by the conversion of dehydroepiandosterone to estrone and estradiol by the tumors.23, 24

Importance of Ectopic Hormone Production

Consideration of ectopic hormone production is important for several reasons. First, the recognition of the syndrome may lead to the
diagnosis of the tumor. Although most patients are known to harbor a tumor when the ectopic hormone syndrome is diagnosed,
there are many examples of ectopic hormone syndromes occurring months to years before the diagnosis of a tumor. This is most
commonly seen in patients who have slowly growing neoplasms such as bronchial carcinoids, malignant thymomas, or islet-cell
carcinomas. With these tumors, Cushing's syndrome from ectopic production of ACTH or CRF or acromegaly from secretion of
growth hormone releasing factor (GHRF) commonly antedates the other manifestations of the underlying malignancy, and it is
during the evaluation of these patients for this syndrome that the underlying tumor is discovered. In some patients, the tumor may
be discovered at such an early stage that the patient can be cured through surgical resection.

TABLE 28-2. Hormones Produced Ectopically and Their Associated Clinical Syndromes
Eutopic Source of HormoneHormone Syndrome
Hypothalamus Corticotropin releasing factor Cushing's syndrome
Growth hormone releasing hormone Acromegaly
Somatostatin None
Gonadotropin releasing hormone None
Thyrotropin releasing hormone None
Antidiuretic hormone SIAD
Oxytocin None
Pituitary Pro-opiomelanocortin/ACTH Cushing's syndrome
Growth hormone Acromegaly
Prolactin Galactorrhea
Placenta Human chorionic gonadotropin Precocious puberty (childhood)
Gynecomastia (adults)
Placental lactogen None
 Heart Atrial natriuretic factor Hyponatremia
Gastrointestinal tract Gastrin Zollinger-Ellison syndrome
Glucagon Glucagonoma syndrome
Vasoactive intestinal peptide Diarrhea, hypokalemia
Cholecystokinin None
Bombesin/gastrin-releasing peptide Cushing's syndrome
Secretin None
Kidney Erythropoietin Polycythemia
Prorenin/renin Hypertension, hypokalemia
Parathyroid Parathormone Hypercalcemia
Parafollicular cells Calcitonin None
Liver Insulin-like growth factors Hypoglycemia
Multiple sites Parathyroid hormone-releated peptideHypercalcemia
Transforming growth factor ?Hypercalcemia
Epidermal growth factor ?Hypercalcemia
Platelet-derived growth factor ?Hypercalcemia
Tumor necrosis factor ?Hypercalcemia
Interleukins ?Hypercalcemia
Unknown Phosphatonin Oncogenic osteomalacia

Ectopic hormone production is also important because the patient may succumb to the metabolic effects of the hormone rather than
to the direct effects of the neoplasm. The intense catabolic state induced by the full-blown ectopic ACTH syndrome, the severe
hyponatremia that may occur with the syndrome of inappropriate antidiuresis (SIAD), and the hypercalcemic crisis that occurs with
excessive production of PTH-rp are examples. Prompt treatment of these metabolic abnormalities can be expected to prolong
survival, assuming that the patient is not preterminal from the other effects of the neoplasm.
Aditionally an understanding of ectopic hormone syndromes is important because failure to recognize the presence of a syndrome
may lead to an erroneous diagnosis in a patient with known cancer. The hypercortisolemia found with ectopic ACTH production,
the hyponatremia found with SIAD, and humoral hypercalcemia are each associated with neurologic abnormalities, including
behavioral disorders and alterations of consciousness. These conditions may be mistaken for the presence of CNS metastases or
infections that in turn may result in inappropriate therapy.
Furthermore, the hormone itself may serve as a tumor marker for localizing the neoplasm, monitoring the effects of therapy, and
detecting a recurrence. For example, approximately 70 percent of tumors associated with the clinical ectopic ACTH syndrome are
located between the jaw and the diaphragm. The finding of an elevated, nonsuppressible ACTH level in such a patient should lead to
a careful search for a lung, thymic, or thyroid tumor. Once a tumor is identified, serial measurements of the ectopic hormone may
provide objective evidence of the effects of therapy. In many instances, the changes in the serum or plasma concentrations of a
hormone accurately reflect changes in the mass of the tumor. Although a persistently elevated hormone level is indicative of a
persistent tumor, the reverse is not always true, as the ectopically produced hormone may decrease at a time when the tumor mass
is increasing. Immunohistologic staining for hormone-secreting cells in tumor tissues has demonstrated that most tumors are quite
heterogeneous, with much variability in the proportion of cells that synthesize the hormone. 25 Either selective loss of the hormone-
producing cells from overgrowth by more rapidly dividing cells that do not secrete the hormone or selective destruction of
hormone-producing cells by chemotherapy or radiotherapy may account for the discordance between changes in the marker levels
and tumor growth.26 This phenomenon is also illustrated by studies in which multiple tumor markers were measured.27, 28 Indeed, it
is the exception rather than the rule that all tumor markers and tumor growth remain concordant throughout the course of disease.
Nevertheless, a rising level of the ectopically produced hormone is almost always indicative of recurrence or progression of the
disease. The only exception occurs immediately after surgical manipulation of the tumor or shortly after radiation therapy or
induction chemotherapy. In these situations, necrosis of tumor tissue may lead to the release of preformed hormone into the
circulation, which may result in a transient increase in the hormone level.
The presence of an ectopic hormone syndrome may provide prognostic information. Patients with hypercalcemia associated with
cancer and PTH-rp have a shorter life expectency than patients without elevations of serum calcium or elevated PTH-rp
concentrations.29, 30 Similarly, paraneoplastic Cushing's syndrome in patients with small cell lung cancer is associated with a shorter
survival than in patients without ectopic ACTH production. 31
Finally, ectopic hormone syndromes are important because their study may lead to the discovery of new hormones. The discovery,
purification, and structural characterization of GHRF and PTH-rp are recent examples of hormones that were initially isolated from
cancers causing acromegaly and hypercalcemia, respectively. The humoral factor responsible for oncogenic osteomalacia has not
yet been identified, but the existence of this phospaturetic hormone, termed phosphatonin, is clearly predicted from the studies
carried out with tumor extracts from patients with this syndrome. 32,

Criteria for Ectopic Hormone Production

Multiple criteria have been developed to establish ectopic hormone production (Table 28-3). Most of the clinical criteria are
sufficient to lead to a presumptive diagnosis of ectopic hormone production but not to an unequivocal diagnosis. Both the presence
of an endocrine syndrome associated with a nonendocrine neoplasm and the finding of increased quantities of a circulating
hormone associated with a neoplasm derived from the tissue that is not the physiologic source of the hormone are not definitive
because of the possibility of coexistence of an endocrine neoplasm with a nonendocrine cancer. For example, several studies have
shown that hyperparathyroidism due to parathyroid adenomas or hyperplasia occurs with a greater than expected frequency in
patients with cancer.34,35,36,37 A patient with an ectopic CRF-producing neoplasm will present with Cushing's syndrome associated
with elevated plasma ACTH. In this situation, it may be erroneously concluded that the tumor was secreting ACTH when in fact the
source of the ACTH was actually the anterior pituitary corticotropes responding to the ectopic CRF. A third example of how an
erroneous conclusion may be reached utilizing clinical criteria alone is seen in the case of the SIAD in association with some
neoplasms. Chemotherapeutic drugs such as cyclophosphamide and vincristine may cause hyponatremia, which could be
mistakenly attributed to the secretion of antidiuretic hormone (ADH) by the tumor. A lung tumor associated with SIAD may actually
not be secreting ADH but may have so altered intrathoracic pressure that the stretch receptors present in the great pulmonary veins
and left atrium may be inappropriately stimulated, which in turn may lead to the release of ADH from the hypothalamus and
posterior pituitary. Removal of the lung tumor may reestablish normal intrathoracic pressure, and the excessive ADH release will
cease. Recurrence of the tumor may again alter intrathoracic pressure in such a manner that ADH release from the hypothalamus
and posterior pituitary is again stimulated. Thus, recurrence of the syndrome or an elevation of ADH levels cannot be used as
evidence that the tumor is secreting the hormone directly.

TABLE 28-3. Criteria for Ectopic Hormone Production

1. Presence of an endocrine syndrome associated with a neoplasm
derived from a tissue that is not the physiologic source of the hormone
known to cause the syndrome
2. Disapperance of the endocrine syndrome after removal or effective treatment
of the tumor recurrence of syndrome with relapse of tumor
3. Excessive quantities of circulating hormone associated with a
neoplasm derived from a tissue that is not the physiologic source of
the hormone
4. Return of circulating hormone to normal or subnormal levels after
removal or effective treatment of the tumor; recurrence of elevated
hormone levels with relapse of tumor
5. Persistence of syndrome or excesssive hormone production after
removal or suppression of the normal physiologic endocrine source
of the hormone
6. Extraction of the hormone from the tumor tissue in quantities greater
than expected from blood contamination
 7. Greater concentration of the hormone in the tumor than in the
surrounding nonneoplastic tissue
8. Immunochemical or histochemical localization of the hormone in the
tumor cells, especially in secretory granules
9. Arteriovenous hormone concentration difference across the tumor,
with higher levels in the venous effluent
10. Detection of messenger RNA for the hormone in the tumor tissue by
Northern analysis, in situ hybridization, or in vitro cell-free translation
systems
11. In vitro synthesis and secretion of the hormone by the tumor,
especially with incorporation of radiolabeled precursors into the
hormone
12. Demonstration of in vivo hormone production after tumor transplantation
into an animal model

Although persistence of a syndrome of excessive hormone production after the removal or suppression of the normal physiologic
endocrine source of that hormone is indicative of ectopic production of the hormone in most instances, there are exceptions. The
most frequent exceptions are seen in some patients with Cushing's disease in whom ACTH is not suppressed after the administration
of even very high doses of dexamethasone. Another example is the presence of hyperparathyroidism due to a parathyroid adenoma
in an accessory parathyroid gland in a patient who also harbors a cancer. A neck exploration may reveal four suppressed
parathyroid glands, and it may be erroneously concluded that the cancer is responsible for elaborating the parathyroid hormone.
If the tumor contains a greater concentration of the hormone than does the surrounding normal tissue or than can be accounted for
by the amount of contaminating blood, a stronger case can be made for ectopic production of the hormone by the tumor. However,
there are potential exceptions. Several tumors have been shown to possess receptors for hormones, and it is conceivable that some
concentrate hormones from the circulation.38, 39 A much stronger criterion is the specific localization of the hormone in secretory
granules within the tumor tissue. Although the presence of a hormone in such secretory granules does not necessarily indicate that
the hormone is secreted, a reasonable cause-and-effect relation may be assumed if the tumor contains the hormone in the secretory
granules and the patient exhibits the appropriate clinical syndrome with an elevation of the same hormone in the blood.
The last four criteria for ectopic hormone production in Table Table 28-3 unequivocally establish the production of the hormone by
the tumor. Of course, each criterion assumes that the methods used for detecting the hormone or its messenger RNA are specific.
An example of how these various criteria may be used to establish the presence of an ectopic hormone syndrome is provided in the
reports of Melmed and colleagues, who described a 60-year-old male with acromegaly and elevated serum growth hormone and
insulin-like growth factor-I (IGF-I) concentrations.40, 41 The finding of a normal pituitary on high-resolution CT scan prompted a
search for a possible GHRF-producing neoplasm. A CT scan of the abdomen (Fig. 28-1) revealed a large mass in the region of the
head of the pancreas, which at surgery was found to be a partially cystic vascular mass consistent with an intramesenteric
pancreatic islet cell tumor. At the time of surgery, an arteriovenous gradient of growth hormone was present across the tumor; the
growth hormone concentration in a peripheral artery was 34 ng/ml, and that in a tumor vein was 368 ng/ml. Postoperatively, the
serum growth hormone levels rapidly fell from 34 to 2 ng/ml over the expected rate of disappearance based on the half-life of
growth hormone (Fig. 28-2). GHRF was not detected in the peripheral blood or in a tumor vein. Elevated levels of immunoreactive
growth hormone were found in the tumor tissue, and immunoreactive growth hormone was localized in juxtanuclear granules in
the tumor cells by both immunohistochemistry and immunoelectron microscopy (Fig. 28-3). The tumor growth hormone
comigrated with pituitary growth hormone on Sephadex column chromatography. In addition, dispersed tumor cells secreted
immunoreactive growth hormone into tissue culture medium for several weeks, and the tumor cells were able to synthesize growth
hormone. Finally, messenger RNA extracted from the tumor cells hybridized with a cDNA probe for human growth hormone and
migrated as a 0.9 Kb transcript on Northern gel electrophoresis, consistent with the size of pituitary growth hormone mRNA. Six
months postoperatively, the acromegaly had remitted, the serum growth hormone was 1.4 ng/ml, the serum IGF-I was normal, and
dynamic growth hormone response to glucose normalized. One year after tumor resection, the patient had the return of the clinical
features of acromegaly associated with a rising growth hormone and IGF-I level, coinciding with the presence of multiple
intraperitoneal and liver metastasis. Injection of GHRF or TRH did not stimulate growth hormone secretion as is often seen in
patients with eutopic growth hormone hypersecretion from a pituitary somatotrope adenoma. 41 Thus, virtually all the criteria for
ectopic hormone production outlined in Table 28-3 were satisfied in this case study.
FIGURE 28-1. Abdominal CT scan of the acromegalic male described in the text showing an 8.16.6-cm mass adjacent to the
liver. T = tumor mass; L = liver; P = pancreas. (Reprinted from Melmed and coworkers,40 with permission.)

Frequency of Ectopic Hormone Production

The frequency of ectopic hormone production varies considerably, depending to a great extent on the population of patients studied
and whether clinical or biochemical criteria are utilized for making the diagnosis. Table 28-4 summarizes a number of studies that
have examined the frequency of the most common paraneoplastic endocrine
syndromes.42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65 Hypercalcemia is the most frequently recognized syndrome, being
found in 10-14 percent of patients with cancer. However, the frequency among the different types of cancer varies considerably.
Thus, patients with multiple myeloma and breast carcinoma tend to have a higher incidence of hypercalcemia than do patients with
lung carcinoma. Even among patients with lung carcinoma, there is substantial variability in the frequency of hypercalcemia;
patients harboring squamous cell carcinomas have a much higher frequency than do patients with small cell carcinoma. If the
incidence of hypercalcemia in carcinoma patients is assessed in a population in which breast carcinoma is overrepresented, the
incidence of hypercalcemia will be higher than that in a population in which breast carcinoma is underrepresented. Thus, the
incidence figures are heavily prone to ascertain-
ment bias. In addition, the various reported frequencies are dependent on the criteria used to diagnose ectopic hormone production.
Incidence figures based on clinical criteria are uniformly lower than are those based on biochemical criteria. For example, less than
5 percent of patients with small cell carcinoma of the lung have clinically recognizable Cushing's syndrome. 45,53,57,58 In contrast,
between 24 and 78 percent of patients with small cell carcinoma of the lung have elevated ACTH levels, and between one-quarter
and one-half of these patients have elevated serum cortisol concentrations that do not suppress appropriately after dexamethasone
administration.45,53,54,66,67,68,69,70 The same phenomenon is also true in regard to SIAD in patients with small cell carcinoma of the
lung. Approximately 10-15 percent of patients with this tumor have symptomatic or asymptomatic hyponatremia. 50,55,57,59
However, 40-68 percent fail to excrete a standardized water load appropriately, 55,64,70 and close to half of these patients have
elevated plasma or urinary ADH or neurophysin levels. Thus, reliance only on the presence or absence of a clinical syndrome will
give a spuriously low frequency of ectopic hormone production.

FIGURE 28-2. Serum growth hormone levels in the patient with a growth hormone-secreting islet-cell tumor described in the text.
Preoperative growth hormone levels varied between 25 and 60 ng/ml. Abdominal surgery was begun at 22 h and just before
tumor removal at 0 h (*), blood was drawn from a tumor vein and peripheral artery for growth hormone measurements. The
simultaneous arteriovenous gradient of GH levels across the tumor: peripheral artery, 34 ng/ml; tumor vein, 368 ng/ml. (Reprinted
from Melmed and coworkers,40 with permission.)
TABLE 28-4. Frequency of Paraneoplastic Endocrine Syndromes
Syndrome Tumor Frequency %
Cushing's syndromeSmall cell lung carcinoma 1.34.8
Squamous cell lung carcinoma0
Adenocarcinoma of lung 0
SIAD Small cell lung carcinoma 9.514
Lung carcinoma (all) 1.6
Head and neck cancers 3%
Hypercalcemia Carcinomas in general 1014
Breast carcinoma 7.222.8
Multiple myeloma 21.228.1
Renal cell carcinoma 512.7
 Lung cancer (all) 6.812.5
Squamous cell carcinoma 24
Small cell carcinoma 1
Adenocarcinoma 3
Large cell carcinoma 8
Lymphoma 9.8
Leukemia 11.5
Polycythemia Renal cell carcinoma 0.93.5
Cerebellar hemangioblastoma 920

TABLE 28-5. Factors Responsible for the Low Frequency of Diagnosis of Ectopic Hormone Production
Low index of clinical suspicion
Minimal clinical expression
Ectopic hormone replaces eutopic hormone
Syndrome obscured by other effects of cancer
Inadequate long-term follow-up of patient
Periodic hormonogenesis
Hormone production without clinical expression
Hormone excess not associated with clinical syndromes
Secretion of hormone precursor without processing to active hormone
Secretion of hormone subunits
Secretion of hormone fragments
Ectopic secretion of unidentified hormones
Hormone assay factors
Insensitive assay
Assay specificity issues
Presence of interfering substances

Several other factors are responsible for the low frequency of diagnosis of ectopic hormone production (Table 28-5). The physician
caring for the patient may have a low index of clinical suspicion that an ectopic hormone syndrome is present. Patients with the
ectopic ACTH syndrome, SIAD, or hypercalcemia may complain of weakness and anorexia that may be attributable to other effects
of cancer or therapy rather than to the hypokalemic alkalosis and catabolic effects of large amounts of circulating cortisol seen with
the ectopic ACTH syndrome, the hyponatremia seen with excessive ADH, or the direct effects of an increase in serum calcium. Early
in the course of ectopic hormone production, the ectopic hormone may actually replace the eutopic hormone, and therefore a
hormone excess syndrome may not be clinically apparent. Low levels of ACTH from a tumor may stimulate cortisol production from
the adrenals, and the cortisol will suppress pituitary ACTH production. The patient will not exhibit the signs or symptoms of
Cushing's syndrome until the cortisol production rate rises above normal for several weeks or months. In addition, the clinical
features of an ectopic hormone syndrome may actually be obscured by other manifestations of the neoplasm. One reason why
patients with the ectopic ACTH syndrome associated with small cell carcinoma of the lung generally do not have cushingoid
features with centripetal redistribution of fat may be the coexistence of cancer cachexia. Also, some paraneoplastic endocrine
syndromes occur as a late manifestation of the neoplasm and therefore may not be apparent to the clinician unless the patient is
followed over a long period. The phenomenon of periodic hormonogenesis may account for an underdiagnosis of ectopic hormone
production. Bailey originally described this phenomenon in which some neoplasms secrete excessive quantities of their hormones
intermittently and in an autonomous fashion.76 This has been well described for the ectopic ACTH syndrome. Biochemical testing
during the intervals between excessive hormone production may give normal results.
There are many situations in which hormones are produced ectopically without clinical expression, and a diagnosis of ectopic
hormone production will thus be missed unless a battery of hormone determinations are made in blood or urine samples from such
patients. In some instances, the hormone excess may not be associated with a clinical syndrome. Mild hypercalcemia is usually
asymptomatic and is detected as part of a multiphasic panel of tests run on a blood sample. In addition, there may be situations in
which the body's homeostatic mechanisms are able to compensate for the excessive concentration of the ectopic hormone. For
instance, prolonged elevation of human chorionic gonadotropin (hCG) may lead to down regulation of testicular Leydig cell
receptors, which in turn may lead to a decrease in the Leydig cells' responsiveness to the effects of hormones. 77 There are numerous
examples of tumors that secrete hormone precursors that do not undergo processing to the active hormone. One of the best studied
examples concerns the ectopic ACTH syndrome, in which the major form of the hormone circulating in the blood and present in the
tumor tissue is a large molecular form (big ACTH; proACTH, POMC) that is immunologically active but biologically
inactive. This precursor of ACTH may be converted into biologically active ACTH by trypsin exposure. Indeed, a high frequency
(17-88 percent) of elevated concentrations of immunoreactive ACTH has been found in the circulation of patients with all types of
lung cancer.54,67,69,78,79,80,81 This is in contrast to the low (<5 percent) prevalence of clinical Cushing's syndrome in such patients. It
has been proposed that this difference is due to the inability of the majority of lung cancers to convert POMC to ACTH. In addition
to hormone precursor molecules, some tumors secrete biologically inactive hormone subunits, such as the and subunits of hCG,
or biologically inactive fragments of hormones.
Ectopic hormone production may be undiagnosed if the tumor secretes an unidentified hormone. For instance, before the discovery
of PTH-rp, ectopic production of the PTH-like hormone was diagnosed only when the patient developed hypercalcemia. Since the
advent of immunoassays for measuring PTH-rp, it has been found that some patients with cancer but without hypercalcemia also
have elevated levels of this hormone.20 Alternatively, the patient may exhibit a full-blown syndrome from the ectopic production of
an unidentified hormone. In this situation, the fact that the syndrome is actually a paraneoplastic syndrome may not be appreciated.
This was the case with the description of the first patient with a hypoglycemia-inducing mesenchymal tumor who had an
intrathoracic fibrosarcoma associated with neuroglucopenic symptoms that responded to a rectal glucose drip.82 The symptoms
were attributed to the mechanical displacement of the heart and blood vessels by the tumor, which resulted in lack of
nourishment to the brain and accumulation of toxemia in the brain [which] could induce mental disturbance.82 Another theory
stated that such tumors, being quite large, consume more glucose than the body's homeostatic mechanisms can cope with. 83 It is
now recognized that the hypoglycemia occurring with these non-islet cell tumors is primarly due to excessive production of
insulin-like growth factors, especially insulin-like growth factor-II.84
Hormone assay factors may also be responsible for the low frequency of diagnosis of ectopic hormone production. Some assays may
be too insensitive to detect ectopic hormone production, especially when the hormone levels are too low to elicit a clinical
syndrome. Thus, before the advent of a sensitive and relatively specific RIA for hCG based on antibodies generated against the
subunit of the hormone, hCG RIAs exhibited substantial cross- reaction with human luteinizing hormone. Therefore, hCG could not
be measured with confidence until the quantities measured exceeded the normal physiologic levels of luteinizing hormone. This
resulted in the development of pregnancy tests that required that 500 mIU of hCG/ml of urine or serum be reached or exceeded
before the test would become positive. The beta-hCG RIA allowed the detection of 5 mIU/ml of hCG in the presence of physiologic
concentrations of luteinizing hormone, a 100-fold increase in sensitivity over the earlier pregnancy tests.85 Because most patients
with ectopic hCG production have levels under 15 mIU/ml of blood, the earlier urinary pregnancy tests would not have been
sufficiently sensitive to detect the ectopic production of this hormone. 86 Assay specificity issues may also result in low detection of
ectopic hormone secretion. Thus, two-site immunomimetric assays that are highly specific for biologically active ACTH may fail to
recognize the large molecular weight pro-ACTH molecule that is the predominant form of ACTH present in the circulation of
patients with the ectopic ACTH syndrome.87,88 Another problem with immunomimetric assays is their susceptibility to interference
by many different substances, including proteases, circulating binding proteins for the ligand, heterophilic antibodies,
hyperlipidemia, contaminant radioactivity in serum, and other nonspecific serum factors.

Etiology of Ectopic Hormone Production

Any etiologic theory of the mechanisms of ectopic hormone production must provide an adequate explanation for two observations.
First, the ectopically produced hormones closely resemble the eutopic hormone, at least in their amino acid sequences. Some tumors
produce prohormones, hormone subunits, or fragments of hormones. When analyzed, these proteins are structurally identical to the
analogous sequence in the native hormone or prohormone. Alterations in the carbohydrate composition of several ectopically
produced glycoproteins have been noted.89,90,91 These findings indicate that the translation of the RNA sequence into the protein
proceeds normally and that the differences between ectopically and eutopically produced hormones relate to posttranslational
modifications such as glycosylation and enzymatic modification of prohormones or of the hormone itself.
TABLE 28-6. Levine-Metz Classification of Tumors Producing Ectopic Hormones
Group I (APUD) Group II Transitional
Tumors Foregut carcinoid Hepatoma Pheochromocytoma
Small cell carcinoma Cholangioma Melanoma
Pancreatic islet-cell tumors Wilms' tumor
Some tumors of pancreatic and biliary ductsHypernephroma
Thyroid medullary carcinoma Adrenocortical carcinoma
Malignant epithelial thymomas Nongerminal gonadal tumors
Vascular tumors
Connective tissue and mesodermal tumors
Reticuloendothelial tumors
Non-small-cell lung carcinoma
GI tumors (except APUD)
Melanoma
HormonesInsulin PTH-rp Biogenic amines
Calcitonin Erythropoietin ACTH
ACTH/POMC hCG Calcitonin
ADH hPL Glucagon
Gastrin PRL Secretin
Glucagon GH hPL
Secretin IGF PTH-rp
Biogenic amines Renin Erythropoietin
74
Source: Adapted from Levine and Metz.

Second, ectopic hormone production is not random. Certain tumor types are associated with specific clinical syndromes and
hormone production. Even within the same organ system, different histologic varieties of a tumor give rise to different syndromes.
Thus, hypercalcemia is found with squamous cell carcinoma of the lung, while Cushing's syndrome is associated primarily with
small cell carcinoma of the lung (Table 28-4). In a thorough analysis of the literature, Levine and Metz concluded that the majority
of the ectopic hormone-producing tumors could be segregated into two main groups (Table 28-6).74 The tumors in each group
share embryologic, morphologic, and hormone-producing capabilities. Each of the group I tumors is capable of secreting any of the
hormones characteristic of that group, and several have been shown to secrete multiple hormones. 49 The group I tumors are derived
from neuroectoderm cells, which constitute the APUD system of Pearse (see later discussion). The group II tumors are derived from
endoderm and mesoderm and primarily secrete glycoprotein hormones, peptides, and growth factors. A small group of tumors of
neural crest origin that embryologically and histologically resemble group I tumors are associated with the secretion of hormones of
groups I and II and therefore constitute a transitional group. Although the Levine-Metz classification is reasonably accurate for the
association between tumor types and clinical syndromes, it is not as useful when ectopic hormone production per se is considered.
Thus, hCG or its -subunit is produced by a wide variety of neoplasms, not just those associated with group II, even though the
clinical syndromes of gynecomastia in adults and precocious puberty in children are seen only with group II tumors. Similarly,
elevated concentrations of proACTH are found in patients with squamous cell carcinoma of the lung (a group II tumor) as well as
small cell carcinoma of the lung (a group I tumor), although clinical Cushing's syndrome is seen primarily in association with group
I tumors.

De Novo Synthesis from Gene Mutation

According to this theory, the process of oncogenesis involves a variety of gene mutations. The resulting alterations in the DNA may
then lead to the synthesis of new proteins, some of which may possess biological activity resembling that found with hormones.
Because hormone production is not entirely random and the tumor hormones, prohormones, fragments, and subunits that are
produced ectopically are identical to the eutopic hormones, at least in regard to the translated protein, this theory cannot explain
ectopic hormone production.

Sponge Theory
In 1964, Unger and colleagues suggested that some tumors concentrate hormones from the circulation and release them at the time
of cell death.38 Support for this hypothesis includes the observation that some adrenocortical carcinomas apparently develop
ectopic receptors for gonadotropins and beta-adrenergic hormones.39, 92 As virtually all the ectopically produced hormones
described to date have been shown to be synthesized and secreted by tumor cells in culture, this hypothesis cannot account for
ectopic hormone production.

Endocrine Cell Hypothesis

In a series of studies, Pearse and colleagues showed the wide distribution of cells of neuroectodermal origin that have the properties
of concentrating amine precursors such as dopa and 5-hydroxy-tryptophan, decarboxylating them, and converting them into
biogenic amines.93, 94 These APUD (amine precursor uptake and decarboxylation) cells contain multiple decarboxylating enzymes
and chromogranin A.93,94,95 Histologically, these cells exhibit secretory granules, a prominent rough endoplasmic reticulum, and a
Golgi apparatus indicating active peptide synthesis. As was noted above, these cells are widely distributed throughout the body
(Table 28-7), and all neoplasms of these cells can produce a variety of polypeptides, primarily those associated with group I tumors
of the Levine-Metz classification (Table 28-6), as well as biogenic amines. A substantial amount of experimental evidence indicates
that APUD cells are derived from the neural crest.96 However, some studies suggest that the gastrointestinal (GI) tract and pancreatic
APUD cells, and possibly those found in the respiratory tract, may be of endodermal origin.97, 98 In addition, the finding that thyroid
C cells contain immunoreactive thyroglobulin99 and that both islet cell granules and zymogen granules may coexist in the same
pancreatic cell100,101 raises the possibility that cells may develop APUD characteristics through cellular differentiation of
totipotential local tissue progenitor cells rather than through migration of cells from the neural crest.

TABLE 28-7. APUD Cell Distribution

APUD Cell Type Tumor
Thyroid parafollicular cells Medullary carcinoma of the thyroid
Adrenal medullary cells Pheochromocytoma
Gastrointestinal neuroendocrine cells Gastrointestinal carcinoids
Pancreatic neuroendocrine cells Islet-cell tumors
Respiratory tract Kultschitsky's cells Small cell carcinoma; bronchial carcinoid
Argyrophil cells of the thymus Thymomas
Anterior pituitary cells Pituitary adenomas
Carotid body and sympathetic ganglia cellsParagangliomas; neuroblastoma
Melanocytes Melanomas
Urogenital neuroendocrine cells Prostate carcinoma
?Parathyroid chief cell Parathyroid adenoma

It has been hypothesized that ectopic hormone production is a result of secretion of the hormones by APUD cells in tumors. 96
Certainly this is a viable hypothesis for the group I tumors of the Levine-Metz classification (Table 28-6) and the tumors listed in
Table 28-7. However, this theory cannot account for the production of the hormones by the Levine-Metz group II tumors, which do
not have APUD cell characteristics, or explain the ectopic production of APUD (group I) hormones by group II tumors. The APUD
cells contain convertases and other processing enzymes that allow the secretion of biologically active hormones. This may explain
why clinical syndromes due to the ectopic secretion of group I hormones are seen more frequently with tumors that have APUD
characteristics than with group II tumors, which may not be capable of appropriately processing group I prohormones.
A variation of the APUD hypothesis of ectopic hormone production is the cell hybridization hypothesis of Warner 102 who proposed
that ectopic hormone production represents the fusion of a malignant cell with an APUD-type bystander cell, which results
in the malignant cell secreting the polypeptide that APUD-type cells can secrete. Warner further suggested that the production of
the hormones by these fused cells may give the clone of hormone-producing cells a survival advantage. Support for this theory is
circumstantial and based on histologic and histochemical findings such as the demonstration of mucin-secreting carcinoid tumors,
the presence of argentophil cells in some adenocarcinomas of the GI tract, and the existence of carcinosarcomas and
adenocanthomas. There is no direct evidence that such cell hybridization takes place in vivo; even if it did, the same criticisms that
have been used to discount the APUD theory as a unifying hypothesis for ectopic hormone production would apply to the cell
hybridization theory.

Gene Derepression
All nucleated diploid cells in any individual contain the same genetic information that was initially present in the zygote. During the
process of cellular differentiation and specialization, portions of the genome become repressed and are no longer expressed. It has
been estimated that the average cell expresses <10 percent of its genetic information. 103 According to the derepression hypothesis,
portions of the tumor cell's DNA become derepressed during the process of neoplastic transformation allowing the gene to be
expressed. If the derepressed portion of the genome normally codes for a hormone, that tumor may express the hormone
ectopically. The possibility of derepression has clearly been shown in the frog experiments of Gurdon, who transplanted the nucleus
from a differentiated adult frog cell into an enucleated frog egg which subsequently developed into an adult frog. 104 Similarly, when
the nucleus from a frog kidney carcinoma is placed into an enucleated frog ovum, differentiation to the tadpole stage occurs.105
Derepression is an attractive concept because it could account for the production of hormones by nonendocrine tumors that are
structurally identical to the hormone secreted by the normal endocrine gland and could also account for the production of
prohormones, fragments, and subunits. The production of prohormones could reflect the lack of derepression of the genes
responsible for directing the synthesis of the cytoplasmic hormone- processing enzymes. However, this hypothesis does not account
for the nonrandom association of certain tumors with specific hormones or explain why polypeptide hormones such as calcitonin,
ACTH, and hCG are more frequently produced than are hormones such as growth hormone and placental lactogen.

Cellular Dedifferentiation
The cellular dedifferentiation hypothesis is an extension of the gene derepression hypothesis. This theory suggests that tumor tissues
regress from a differentiated state to an undifferentiated state. 106, 107 At each step in this process, the dedifferentiated cell resembles
a stage in normal cell development during the process of differentiation. The dedifferentiated cell will have the ability to make all
the products normal for that particular stage of differentiation. The nonrandom nature of ectopic hormone production provides
strong evidence against this hypothesis.

Dysdifferentiation or Blocked Ontogenesis

According to this theory, every tissue in the body contains stem or renewal cells that are either totipotential or relatively
undifferentiated. These cells are normally responsible for replenishing cells that are lost through disease or injury. The genome of
these cells is either unrepressed or not fully repressed. During the process of differentiation, the genome of the stem cells undergoes
progressive repression until the adult, specialized state is reached. At each stage, the differentiating cell may express a variety of
proteins specific for that stage. Thus, a stem cell in the skin may be capable of secreting fetal and placental proteins, while in the
adult state these cells are not able to produce these proteins. According to this theory, neoplasia takes place in these progenitor cells
and the morphologic and functional characteristics of the tumor depend on the stage of the differentiation process in which
oncogenesis occurs.108, 109 This theory differs from the dedifferentiation theory in that the neoplasm is derived from cells that have
not fully differentiated rather than from cells that have gone from a differentiated state to a less differentiated state.
This theory is attractive because it accounts for several phenomena that are observed with cancer. It is well established that tumor
populations are heterogeneous, and immunohistochemical studies have shown that different tumors contain variable numbers of
hormone-secreting cells.25 This theory also accounts for the phenomenon of hormone production by granulomas and inflammatory
lesions.110, 111 It also provides a possible explanation for the nonrandom association of certain hormones with specific tumors. Local
factors such as cell surface contact and the presence of growth factors or other paracrine substances may modulate the proliferation
and differentiation of the stem cells in a particular organ. The experimental work with small cell carcinoma carried out by Baylin
and colleagues has shown how the dysdifferentiation theory can account for the APUD characteristics of tumor cells. This does not
necessarily indicate that the tumor originated from a neuroectodermal cell but rather that APUD characteristics may be a feature of
the degree of cell differentiation.112

Excessive Expression of Normal Genes

As was previously noted, many immunoreactive polypeptide hormones have been detected in normal nonendocrine tissues using
sensitive immunoassay techniques. The low levels of these hormones may represent incomplete repression of the portion of the
genome that is responsible for the hormone production (gene leakage) or may reflect the production of the hormones from the stem
cells present in the tissues. If the process of repression is incomplete, ectopic hormone production may merely represent excessive
expression of normal genes and may be directly related to proliferation of the neoplastic cells and tumor mass. If this is correct,
ectopic peptide synthesis may be a universal concomitant of neoplasia, as suggested by Odell and colleagues.72 Clinical
syndromes occur only when tumors elaborate bioactive forms of hormones.

Therapy
Specific therapies have been devised for the treatment of each of the ectopic hormone syndromes and will be discussed later under
the specific syndromes. In general, several therapeutic approaches may be used for the treatment of ectopic hormone syndromes.
The first approach is to remove the tumor, if possible. If the primary neoplasm is unresectable or if metastases are present, hormone
production may be inhibited through the use of chemotherapy or radiation therapy. If these approaches are unsuccessful and the
metabolic derangements from the ectopic hormone syndrome substantially contribute to morbidity, therapy directed at the target
organ or target organ products may be instituted. Using the ectopic ACTH syndrome as an example, Cushing's syndrome may be
reversed through bilateral adrenalectomy and the administration of physiologic doses of glucocorticoids and mineralocorticoids. In
some patients, a medical adrenalectomy may be accomplished through the use of mitotane (o,p'-DDD). Alternatively, the function of
the target organ, in this case the adrenal, may be blocked. The block may take place at the target organ receptor or at an
intracellular step in target organ activity. In some tissues, it is possible to block the cell membrane receptors for hormones through
hormone antagonists or agonists, with the agonists causing down regulation of the receptor. In the case of the ectopic ACTH
syndrome, there are no clinically effective ACTH agonists or antagonists that are useful for the treatment of Cushing's syndrome.
Instead, target organ activity is blocked through the use of inhibitors of the enzymatic pathways required for steroid hormone
production. Such inhibitors include aminoglutethimide, ketoconazole, and metyrapone. Finally, if the metabolic derangements are
due to overproduction of a target organ product, this product may be antagonized. For the ectopic ACTH syndrome, mifepristone
(RU-486) is an effective glucocorticoid antagonist and has been useful in the treatment of some patients with Cushing's
syndrome.113 As we gain further insight into the biochemical mediators of hormone action, it is likely that additional approaches to
therapy will be forthcoming.

Hormones as Tumor Markers

The experience gained from the use of hCG as a tumor marker in patients with gestational and nongestational trophoblastic disease
served as a major impetus for the search for hormones, enzymes, oncofetal proteins, and other cellular components that could be
used as markers of neoplasms. In fact, in patients with gestational trophoblastic disease, hCG measurements fulfill virtually all the
criteria for an ideal tumor marker (Table 28-8). hCG may be measured in the blood or urine through rapidly performed, technically
simple, and inexpensive immunomimetric assays. If one uses a toff level of 25 mIU/ml of serum, only pregnancy and an occasional
nontrophoblastic neoplasm will be positive and virtually all patients with trophoblastic disease will have measurable quantities of
hCG (no false negatives). The levels of hCG in the serum and urine accurately reflect tumor burden and fluctuate concordantly with
changes in tumor growth. In addition, the approximately 24-h half-life of hCG allows for an assessment of the efficacy of therapy
within a few days of the initiation of treatment. After the initial disappearance of the hormone, an early recurrence of the
trophoblast disease may be detected through serial measurements of hCG levels. 114

TABLE 28-8. The Ideal Tumor Marker

1. Present in blood or urine
2. No false positives (specific)
3. No false negatives (sensitive)
4. Levels fluctuate appropriately with changes in tumor growth
5. Rapid half-life in blood
6. Rapidly performed
7. Technically simple
8. Inexpensive

Unfortunately, the excellent experience with the use of hCG as a marker of gestational trophoblastic disease has not been duplicated
for most other tumor markers, including carcinoembryonic antigen, alpha-fetoprotein, CA-125, and prostate-specific antigen. The
major limitations to the use of tumor markers involve sensitivity and specificity. To detect as many cancers as possible, the method
of measuring the tumor marker should be highly sensitive. However, as the sensitivity of the test increases, the number of patients
without cancer who are either normal or have benign disease processes and test positive increases. Therefore, the test loses its
specificity, or the ability to rule out disease when none is present. In fact, the sensitivity and specificity of a test, along with the
prevalence of the disease in the population being studied, determine the utility of that test as a screen for cancer.

TABLE 28-9. Immunoreactive hCG or hCG-Subunit in Sera of Patients with Cancer

N Percent Positive Biliary 26 30.7
Tumor or Site Pancreatic 200 20.0
Islet cell 104 39.4 Lung 1,365 17.4
Gynecologic 2,010 28.6 Breast 3,031 16.8
Ovary 633 28.6 Melanoma 244 13.9
Endometrium 348 16.7 Genitourinary 658 11.8
Cervix 976 33.8 Renal 119 6.7
Vulva/vagina 37 27.0 Bladder 176 23.3
Carcinoid 41 26.8 Prostate 363 8.0
Gastrointestinal2,165 18.0 Sarcoma 136 11.8
Oropharynx 298 14.8 Hemopoietic 544 6.1
Esophagus 124 17.7 Lymphoma 399 5.3
Gastric 232 20.7 Miscellaneous 576 10.4
Small intestine 24 16.7 Total 11,213 18.0
114
Colon/rectum 693 9.8 Source: From Braunstein, with permission.
Hepatic 281 22.1
TABLE 28-10. Immunoreactive hCG or hCG-Subunit in Sera of Control Patients without Cancer
Type of Control N Percent Positive

Premenopausal females 430 0.7

Postmenopausal females242 0
Normal males 438 0.2
Castrate males 4 0
Blood donors 165 2.4
Benign disease 1,963 3.6
Gynecologic 528 6.6
Gastrointestinal 318 6.0
Breast 254 4.3
Lung 174 2.9
Genitourinary 84 0
Neurologic 10 0
Hypothyroid 10 0
Unspecified 650 0
Other normal 172 0
Miscellaneous 691 2.7
Total 4,105 2.4
114
Source: From Braunstein, with permission.
TABLE 28-11. Predictive Value of hCG Measurements for Cancer Screening

The interaction of test sensitivity and specificity and cancer prevalence can be illustrated by examining the experience with the use
of measurements of immunoreactive hCG (or its -subunit) in the sera of patients with nontrophoblastic neoplasms. The combined
data from 66 published studies are shown in Tables 28-9 and 28-10 for patients with and without cancer, respectively.114 Overall,
approximately 18 percent of patients with cancer are found to have immunoreactive hCG in circulation, while 2.4 percent of
control patients without cancer have circulating immunoreactive hCG by assays that have a sensitivity of 5 mIU/ml. Thus, the
sensitivity of hCG measurements as a tumor marker is 18 percent, while the specificity is 97.6 percent (100 percent -2.4 percent).
Table 28-11 illustrates the effect of cancer prevalence on the diagnostic accuracy of hCG measurements. If we assume that the
prevalence of cancer in the population being examined is 1 percent (Table 28-11, top), we find that for every 100,000 patients
screened, 1,000 will have cancer. Of this 1,000, 18 percent (180) will have immunoreactive hCG present in the circulation (true
positives), while 820 patients with cancer will not have immunoreactive hCG detected by these tests (false negatives). Of the 99,000
patients without cancer, 96,624 (99,00097.6 percent) will not have hCG detected in their circulation (true negatives), while
2,376 patients without cancer (99,0002.4 percent) will have hCG detected (false positives). In this situation, the predictive value
of a positive testthat is, the percentage of patients who have immunoreactive hCG in the circulation who actually have
canceris 7 percent, while the false-positive rate (100 percent -7 percent) is 93 percent. The predictive value of a negative test
(the percentage of noncancerous patients with negative hCG results) is 99 percent with only 1 percent false negatives. Thus, in this
population, the number of false positives markedly exceeds the number of true positives; therefore, approximately 9 of every 10
patients with detectable immunoreactive hCG in the circulation will undergo unnecessary further diagnostic evaluation.
If the prevalence of cancer in the population being evaluated is 10-fold higher (10 percent) (Table 28-11, bottom), the predictive
value of a positive test rises to 45 percent and the number of false positives decreases to 55 percent. However, the number of false
negatives rises dramatically to 9 percent. In this population, a patient with a positive test result is more likely to harbor a neoplasm
than is the case in a population with a 1 percent prevalence of cancer, but almost 10 percent of patients with a negative test will
have cancer.
These calculations suggest that hCG measurements are not particularly useful as a screening test for nontrophoblastic cancer. In
actuality, hCG and other potential tumor markers generally perform worse in a screening situation than is suggested in much of the
medical literature. This occurs because of biases in the ascertainment of many of the patient populations that have been the subject
of reports. To establish the value of a tumor marker, investigators usually measure the marker in the blood or urine of patients with
well-established neoplasms. Most markers are more likely to be positive in patients with advanced disease than in patients with
minimal disease. Therefore, the sensitivity of the test established in research laboratories with well-defined populations often
overestimates the actual sensitivity of the test in terms of detection of early cancer, a stage when the disease is potentially curable
and not diagnosable with other screening tests. Some investigators have tried to increase the sensitivity of tumor marker tests by
measuring multiple markers in the blood and evaluating patients further if any of the markers are positive. This strategy (parallel
testing) increases the sensitivity of the test but markedly decreases the specificity because each test will give false-positive results.
Another strategy is to measure a tumor marker and subject all samples that give positive test results to measurements of a different
tumor marker and to consider a combined test positive only if both are positive (serial testing). This increases the specificity of
tumor marker testing but reduces the sensitivity. Indeed, for any test that is <100 percent sensitive or 100 percent specific, an
increase in sensitivity of the testing strategy will lead to a decrease in specificity and vice versa.115

SPECIFIC SYNDROMES

Hypercalcemia of Malignancy
Hypercalcemia is the most frequently encountered paraneoplastic endocrine abnormality, being found in 10 to 14 percent of
patients with cancer (Table 28-4). A wide spectrum of neoplasms are associated with hypercalcemia (Table 28-
12).29,116,117,118,119,120,121,122 Metastatic adenocarcinoma of the breast and squamous cell carcinoma of the lung and head and neck
region account for more than half the patients with tumor-associated hypercalcemia. If patients with documented bony metastases
are excluded, approximately half of patients with tumor-associated hypercalcemia have a squamous cell carcinoma of the lung or
clear cell carcinoma of the kidney.123,124,125

Pathophysiology of Hypercalcemia(Table 28-13)

Bony Metastases
The idea that osseous metastases are directly associated with calcium abnormalities was first suggested by Virchow, who in 1855
described three patients with bone metastases who had ectopic calcification in various tissues.125 The association of hypercalcemia
with tumor types such as breast carcinoma and multiple myeloma, almost exclusively when the tumors involve the bone, led to the
hypothesis that direct tumor-induced osteolysis can account for the hypercalcemia.126 Indeed, various tumor cells have been shown
to release prostaglandins, epidermal growth factor, lymphotoxins, PTH-rp, and other substances that are capable of stimulating
osteoclastic bone resorption.20,118,127,128 Thus, some tumor cells may directly stimulate osteoclastic bone resorption and lead to an
uncoupling of bone resorption and formation characteristic of the hypercalcemia of malignancy. 129 In addition, monocytes and
lymphocytes in close proximity to the tumor cells may be responsible for the release of bone-resorbing cytokines.

TABLE 28-12. Tumor Types Associated with Hypercalcemia

Tumor Type Percent
Breast 36
Lung 15
Head and neck 8
Lymphoma 7
Multiple myeloma 7
Kidney 6
Gastrointestinal tract 4
Leukemia 2
Ovary 1
Miscellaneous* 15
*Carcinomas of the endometrium, cervix, vagina, vulva, penis, testis, adrenal, and
prostate; pheochromocytoma; neuroblastoma; melanoma; thymoma; osteogenic sarcoma;
lymphosarcoma; reticulum cell sarcoma; hemangiosarcoma; fibrosarcoma;
rhabdomyosarcoma; leiomyosarcoma.

TABLE 28-13. Pathophysiologic Mechanisms of Hypercalcemia in Cancer

Bony metastasis
Elaboration of humoral substances
Parathyroid hormone
Parathyroid hormone-related protein
Prostaglandins
Cytokines
Conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D
Coexistence of cancer and another disease
Primary hyperparathyroidism
Other causes of hypercalcemia

It is clear that the presence of tumor cells in bone alone is not sufficient to cause hypercalcemia. Some tumors, such as small cell
carcinoma of the lung, adenocarcinoma of the colon, and adenocarcinoma of the prostate, metastasize to the bone and are only
rarely associated with hypercalcemia (Table 28-4),125 indicating that the tumor cell type is an important factor determining
whether the patient will develop hypercalcemia with bone metastases. Ralston and coworkers demonstrated that there was no
association between the presence or extent of osseous metastases and the frequency or severity of hypercalcemia in a large group of
cancer patients assessed by bone scan.126 In fact, patients with a light bone tumor load had a higher mean serum calcium level than
did those with a heavy bone tumor load. When analysis was restricted to patients who had hypercalcemia, the highest mean serum
calcium levels were found in patients without evidence of metastatic bone disease. These data indicate that although 60-80 percent
of patients with hypercalcemia and cancer have skeletal metastases,118, 126 the cause of the hypercalcemia is probably multifactorial
and includes both direct and indirect local production of stimulators of osteoclastic bone resorption, including prostaglandins and
cytokines, as well as the secretion of PTH-rp, the substance responsible for the majority of cases of humoral hypercalcemia in
patients with nonmetastatic solid tumors (see later discussion).

Systemic Elaboration of Humoral Substances

Historical Perspective The development of our understanding of the humoral hypercalcemia of cancer and the mediators involved
parallels the history of endocrinology. The early studies were observational. In 1924, Zondek and coworkers described a patient
with hypercalcemia who at autopsy was found to have normal parathyroid glands and carcinoma of the gallbladder. 130 In 1936,
Gutman and associates described a patient with symptomatic hypercalcemia and bronchogenic carcinoma who had normal
parathyroid glands, no skeletal metastases, and a small focus of monostotic Paget disease. 131 The next major step was conceptual and
was provided by Albright in his discussion of a 51-year-old man with a renal cell carcinoma that was metastatic to the ilium. 132
Because of the presence of hypophosphatemia associated with the hypercalcemia, this patient underwent a parathyroid exploration
with a finding of three normal parathyroid glands. Subsequently, the patient's tumor and iliac metastases were treated with
radiation therapy, which led to a concomitant decrease in the serum calcium concentration and a rise in the serum phosphate
concentration. A normal fourth parathyroid gland was found at necropsy. Albright hypothesized that the tumor was secreting a
parahormone (PTH)-like substance, as hypercalcemia resulting from osteolysis alone would be expected to be associated with
hyperphosphatemia. However, bioassay of the tumor tissue for the presence of PTH was negative. In 1956, two groups reported
several patients with malignancies, normal bone x-rays, hypercalcemia, and hypophosphatemia whose biochemical abnormalities
normalized after surgical resection of the tumors. With tumor recurrence, there was a temporally associated increase in serum
calcium.133, 134 No parathyroid bone or renal abnormalities were found at surgery or autopsy in the patients studied. These
observations supported Albright's contention that the tumors were producing a PTH-like substance that was responsible for the
hypercalcemia. As additional patients with the syndrome were reported, the term pseudohyperparathyroidism was applied to this
condition.135 After the purification of PTH, immunoassays were developed, and in 1964 the presence of a material immunologically
similar to bovine PTH was extracted from several tumor tissues.123,136,137
With the advent of RIAs, there was initial support for the concept that the PTH-like substance is actually PTH. One study found that
95 percent of patients with hypercalcemia associated with cancer had inappropriately high PTH levels as measured by an RIA
directed against the carboxy-terminal portion of the molecule.138 Sherwood and colleagues demonstrated immunoreactive PTH in
several tumor extracts, and other investigators showed arteriovenous differences in PTH concentrations across tumors. 139,140,141
However, several investigators found that there were differences between the immunoreactive PTH-like substances in the sera of
patients with cancer and hypercalcemia and in the sera of patients with hypercalcemia from primary hyperparathyroidism. 142, 143
Because both amino- and carboxy-terminal fragments of PTH were known to be present in circulation, it was conceivable that the
differences between pseudohyperparathyroidism and hyperparathyroidism reflected differences in the processing of the hormone at
the time of or after secretion. The difficulties in interpreting RIA data were highlighted by the study of Raisz and colleagues, who
had the same serum samples from patients with primary hyperparathyroidism and humoral hypercalcemia of cancer measured for
immunoreactive PTH by four different laboratories.144 There were marked differences in the results. However, it was generally
found that PTH assays that used antisera generated against amino-terminal portions of the molecule gave lower serum
concentrations of PTH than did RIAs that used antisera against the carboxy-terminal portion of the molecule. Because the carboxy-
terminal fragment of PTH is elevated in patients with renal insufficiency and also appears to be released continuously even when
the amino-terminal fragment of PTH release is suppressed, it is understandable how some of these immunoassay discrepancies
could occur.
An important study was reported in 1973 by Powell and coworkers who described 11 patients with nonparathyroid neoplasms
associated with hypercalcemia and hypophosphatemia in the absence of bony metastases. 145 Remission of biochemical abnormalities
occurred in nine patients after antitumor therapy. These investigators were unable to demonstrate PTH in the patients' blood or the
tumor tissue despite using three different RIAs that covered virtually all regions of the PTH molecule. However, the tumor extracts
did cause bone resorption by bioassay, leading to the conclusion that the humoral hypercalcemia factor was not PTH. During the
1970s a variety of other substances were found to stimulate osteoclastic bone resorption in vitro, and this fueled the effort to
determine whether one or more of these substances could be the humoral hypercalcemic factor produced by cancers. The two
substances that received the most attention were prostaglandins of the E series and osteoclastic activating factor.146,147,148
Major strides in unraveling the pathogenesis of humoral hypercalcemia of malignancy were made during the 1980s through the
use of molecular biological tools. Early studies showed the absence of PTH messenger RNA by in situ hybridization in tumors
associated with nonmetastatic hypercalcemia.149 Subsequently, several tumor cell lines derived from patients with this syndrome
were established and secreted a biologically active bone-resorbing factor.150, 151 This led to purification and sequencing of the PTH-
rp protein and the cloning of the gene.152 Synthetic peptides based on the structure of the PTH-rp protein were used as immunogens
for the development of immunoassays to measure the concentrations of the protein in body fluids and tissues. The use of these
assays has established the fact that the majority of patients with humoral hypercalcemia of malignancy have elevated levels of PTH-
rp, establishing this factor as Albright's predicted PTH-like substance that is responsible for the syndrome.

Parathyroid Hormone
As was noted earlier, the majority of patients who had been diagnosed as having pseudohyperparathyroidism due to the ectopic
production of PTH most likely had the syndrome on the basis of excessive production of PTH-rp. The close homology between the
PTH and PTH-rp molecules in their first 13 amino acids might have accounted for some of the positive results reported in early PTH
immunoassays. In addition, the presence of renal insufficiency in some patients and the inability to completely shut off the release of
the carboxy-terminal fragments of PTH even in the face of hypercalcemia might have been important factors in accounting for the
spurious diagnosis of ectopic PTH production by tumors.118 Finally, the coexistence of hyperparathyroidism and cancer may have
accounted for some of the examples of pseudohyperparathyroidism.
Although the bona fide ectopic production of PTH appears to be exceedingly rare, it does occur. For instance, Yoshimoto and
associates described a 70-year-old man with a small cell carcinoma of the lung, multiple metastases, and normal parathyroid
glands at autopsy. He had markedly elevated serum PTH levels by three separate assays as well as high concentrations of PTH in a
tumor extract that cochromatographed with human PTH on gel filtration chromatography. Northern blot analysis also showed the
presence of PTH mRNA in the tumor.153 Similarly, authentic ectopic PTH secretion has been reported in patients with ovarian
carcinoma, a primitive neuroectodermal tumor, squamous cell carcinoma of the lung, and thymoma. 154,155,156,157

Parathyroid Hormone-Related Protein

After the 1973 report of Powell and colleagues,145 which demonstrated that the syndrome of humoral hypercalcemia of malignancy
is not due to the production of immunoreactive PTH, several groups of investigators sought the putative PTH-like factor. In 1980,
Stewart and associates examined 50 consecutive patients with humoral hypercalcemia of malignancy and found that they
segregated into two groups that were distinguishable primarily on the basis of nephrogenous cyclic AMP excretion. 119 More than
80 percent of these patients had elevated nephrogenous cyclic AMP and harbored squamous cell carcinomas of the head and neck,
lung, esophagus, and vulva; squamous metaplasia; renal cell carcinomas; or transitional cell carcinomas. The patients with low
cyclic AMP excretion had hematologic malignancies including myeloma and lymphoma as well as breast carcinoma. The patients
with elevated nephrogenous cyclic AMP excretion exhibited hypercalcemia, hypophosphatemia, decreased tubular reabsorption of
phosphate, increased fasting calcium excretion for a given level of serum calcium and low 1,25(OH)2D3 serum concentrations
compared with patients with primary hyperparathyroidism, and undetectable serum immunoreactive PTH levels. 119, 158 The sera
from patients in this group were active in a kidney cortex cytochemical bioassay for PTH, and the biological activity could not be
completely inhibited by preincubation with antiserum against PTH. 159 Several tumor cell lines elaborating the PTH-like substance
were established.150, 151 One such line, when transplanted into nude mice, led to the development of hypercalcemia,
hypophosphatemia, and elevation of 1,25(OH)3D3 serum concentrations.160 The biochemical abnormalities were inhibited by
analogs to PTH that also inhibited PTH activity in vitro and in vivo. The biologically active components of these cell lines were
purified and found to reside in a protein with a molecular mass of 17-18 kDa. Amino-terminal sequence analysis demonstrated
significant homology with the first 13 amino acids of PTH and also allowed the preparation of synthetic oligonucleotides which
were used to isolate the cDNA for PTH-rp.152 The full-length DNA coding for the protein was isolated, and the amino acid structure
was predicted.151
PTH-rp has been found to exist in three isoforms of 139, 141, and 173 amino acids resulting from alternate splicing of exons. There
is a 36-amino acid prepropeptide. Eight of the first 13 amino-terminal amino acids are homologous with those found in PTH, and
this accounts for the PTH-like biological activity both in vivo and in vitro. The amino acid sequence of PTH and PTH-rp diverges
completely after the first 13 amino acids. It is likely that the genes for both PTH and PTH-rp are derived from a common ancestral
gene. Synthetic amino-terminal peptides containing the first 34 amino acids retain full biological activity, while no biological
activity has been demonstrated for the carboxy-terminal fragments.20,151,161
PTH-rp fulfills the criteria for the humoral hypercalcemic factor for the majority of nonmetastatic solid tumors. First, serum
immunoreactive PTH-rp is elevated in 53-83 percent of patients with nonmetastatic hypercalcemia, and serum concentrations of
PTH-rp have been correlated with total serum calcium concentrations. 120, 163 Second, therapy for tumors associated with
hypercalcemia has led to a decrease in serum calcium and a parallel reduction in PTH-rp levels.122, 162 Third, serum PTH-rp
concentrations have been correlated with nephrogenous cyclic AMP excretion in patients with this syndrome.162 Fourth, PTH-rp has
been isolated from tumors associated with this syndrome, and the tumors contain PTH-rp mRNA.164, 165 Fifth, the infusion of PTH-rp
into animals leads to the development of hypercalcemia, and the administration of anti-PTH-rp antibodies reverses the
hypercalcemia in animal models.166,167,168 Finally, infusion of PTH-rp (1-36) into human volunteers increased serum ionized
calcium, decreased serum phosphorous, increased the fractional excretion of phosphorous, increased nephrogenous cAMP
excretion, increased plasma 1,25-dihydroxy vitamin D levels, and suppressed endogenous PTH (1-84).
PTH-rp production by tumors is not limited to nonmetastatic solid neoplasms, and elevated levels have been found in patients with
metastases to the bone as well as in one-third to one-half of patients with hematologic malignancies.120,121,122,170
Depending on the assay utilized, between 5 and 90 percent of normal individuals have detectable concentrations of
immunoreactive PTH-rp in their blood.171 Normal concentrations are generally below 2.5 pmol/L with assays based on antisera to
the 1-34 fragment of PTH-rp, and below 2.1 pmol/L for carboxy-terminal assays (amino acids 109-138).120,121,122,162 PTH-rp is
widely distributed throughout the body as assessed by immunoassay, immunohistochemistry, and mRNA determinations. Thus, it is
present in keratinocytes of the epidermis, pancreatic islet cells, stomach, adrenal cortex and medulla, hypothalamus, pituitary, brain,
thyroid, bone marrow, myometrium, placenta, and lactating mammary glands.172,173,174,175 In fact, the highest concentrations of the
protein are found in milk.162, 174 Although the physiologic functions of PTH-rp are unknown, it has been speculated that it may play
a role in calcium transport in the breast, where the production of PTH-rp is under the control of prolactin, and in transplacental
calcium transport.175,176,177 PTH-rp may also have an important autocrine function. The protein has been shown to be produced by
lectin-stimulated T lymphocytes. Incubation of lymphocytes with synthetic PTH-rp (1-34) led to suppression of DNA synthesis.178
The widespread distribution of PTH-rp raises the possibility that production of the hormone by neoplasms is not strictly ectopic but
may represent excessive eutopic production.

Prostaglandins
In 1970, prostaglandins of the E series (PGEs) were found to stimulate osteoclastic bone resorption and increase cyclic AMP in
vitro.179, 180 A few years later, Tashjian and associates studied mouse HSDM1 fibrosarcoma and rabbit VX2 carcinoma tumors, which
are associated with nonmetastatic hypercalcemia.181, 182 The tumor tissues from these animals contain high quantities of PGE 2, and
the tumor cells secrete the prostaglandin in vitro and stimulate osteoclastic bone resorption. Arteriovenous concentration
differences of PGE2 across the tumor confirm the in vivo production, and the administration of an inhibitor of prostaglandin
synthesisindomethacinto tumor-bearing animals lowers the elevated serum calcium and plasma PGE2 levels in a parallel
fashion.183 Indomethacin also inhibits PGE2 and bone resorption-stimulating activity produced by tumor cells grown in vitro.
Finally, infusion of PGE2 into rats was found to produce hypercalcemia.184 These studies provided strong support for the concept
that some tumors may cause hypercalcemia through osteoclastic bone resorption stimulated by the excessive production by
prostaglandins.
The first study in humans appeared in 1974 with the description of a hypercalcemic patient with a renal cell carcinoma associated
with a high concentration of E-type prostaglandin in liver metastases and a low plasma prostaglandin level. 185 The administration
of indomethacin was associated with a decline in serum calcium, which again rose after the cessation of the medication. Additional
cases of patients with renal cell carcinoma and hypercalcemia who were responsive to indomethacin were reported 147,186 In 1975,
Seyberth and colleagues studied 29 patients with solid tumors, including 14 with hypercalcemia.146 They evaluated prostaglandin
production in these patients by measuring the urinary excretion of the major urinary metabolite of PGE 1 and PGE2, 7 alpha-
hydroxy-5,11-diketotetranorprostane-1,16-dioic acid (PGE-M). They found that 12 of the 14 patients with humoral hypercalcemia
associated with solid tumors had elevations of urinary PGE-M, as did 2 patients who were normocalcemic at the time of study but
subsequently developed hypercalcemia. Patients who were hypercalcemic as a result of hyperparathyroidism or hematologic
malignancies had normal urine concentrations of PGE-M. Five of 13 normocalcemic patients who had solid tumors also had
elevations of this urinary metabolite. Six hypercalcemic patients with solid tumors received inhibitors of prostaglandin synthesis
and had a concomitant decrease in serum calcium and urinary PGE-M levels. These investigators subsequently found that urinary
cyclic AMP excretion was normal in patients with elevated PGE-M levels, in contrast to patients who had nonmetastatic
hypercalcemia with normal PGE-M levels, who demonstrated elevated urinary cyclic AMP concentrations. 187
Despite this initial positive report, relatively few hypercalcemic patients with neoplasms have been found to have a reduction in
serum calcium with the use of inhibitors of prostaglandin synthesis. 188, 189 In addition, it has been noted that there is no correlation
between PGE levels and the degree of hypercalcemia or the presence or absence of metastases. 125, 190 It is of interest that
indomethacin may lower the urinary excretion of PGE without consistently altering plasma PGE levels or serum calcium. 190 Because
PGE is extensively metabolized during the first pass through the lungs and liver, it has been calculated that the venous blood
concentration of PGE2 would need to be greater than 10 times the upper limit of normal to result in an arterial PGE 2 blood
concentration that is the minimal effective concentration required to increase bone resorption in vitro. 190 Concentrations of that
magnitude have not been found in patients with hypercalcemia associated with nonmetastatic solid tumors.
As noted earlier, prostaglandin production by tumor cells is probably most important in inducing osteolysis in the region
surrounding osseous tumor deposits. It is clear that tumors do synthesize and secrete prostaglandins, as do monocytes and
macrophages, which are also found in the area of bone metastases.118 In this regard, it has long been known that after the initial
administration of estrogens or antiestrogens, patients with breast cancer metastatic to the bone may develop acute, severe
hypercalcemia. Breast cancer cells have been shown to release E-series prostaglandins after exposure to estrogens in vitro, and there
is a concomitant increase in bone resorbing activity, which can be inhibited by indomethacin and flufenamic acid. 191 Unfortunately,
the administration of prostaglandin synthesis inhibitors has not been shown to be effective in lowering serum calcium in
hypercalcemic patients with metastatic breast cancer. Although the reasons for this are unclear, concentrations of the prostaglandin
synthesis inhibitors in the area of the bone metastases that can be achieved after oral administration may be insufficient to inhibit
prostaglandin synthesis in vivo. Alternatively, because elevated concentrations of PTH-rp have been found in some patients with
metastatic breast cancer, the hypercalcemia associated with such tumors may be multifactorial.

Cytokines
Interest in cytokines as potential mediators of hypercalcemia in patients with cancer began in 1974, when Mundy and associates
described the production of an osteoclast-activating factor produced in vitro by multiple myeloma cells.148 This substance was
similar to a material produced by phytohemagglutinin-transformed normal lymphocytes. Similar osteoclast-activating-factor
activity was found in cells derived from hypercalcemic patients with Burkitt's lymphoma, T-cell lymphoma, and some leukemias.
Subsequent work has indicated that the osteoclast-activating-factor activity can be accounted for by a group of cytokines and
growth factors including interleukin-I, interleukin-I, intraleukin-6, transforming growth factor-, transforming growth
factor-, tumor necrosis factor- (lymphotoxin), colony-stimulating factors, and epidermal growth factor.20, 127 These cytokines
may be produced by the tumor cells or by transformed lymphocytes, monocytes, or macrophages in the vicinity of the tumor cells.
Several different mechanisms for stimulation of bone reabsorption by the cytokines have been described, including the activation of
preexisting osteoclasts, stimulation of the proliferation of osteoclast progenitor cells without activation of preexisting osteoclasts,
and stimulation of PGE2 synthesis in the bone.192 Thus, as is the case with prostaglandins, cytokines appear to be local mediators of
bone resorption in patients with metastatic solid tumors associated with hypercalcemia as well as in patients with hematologic and
lymphoproliferative disorders involving the bone.

Conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D

In addition to renal tubular cells, the vitamin-D-1-hydroxyl-ase enzyme is present in keratinocytes, fibroblasts, trophoblasts,
alveolar macrophages, and lymphocytes. Several tumors, including HIV-I-associated and unassociated lymphomas, HTLV-I-
mediated adult T-cell leukemia/lymphoma, small cell carcinoma of the lung, and melanoma, have been found to be associated with
elevated 1,25(OH)2-vitamin D levels with dysregulated 25(OH)-1-vitamin D hydroxylase activity.193,194,195,196,197,198 High levels of
1,25(OH)2-vitamin D have been found in more than half of patients with lymphomas.198, 199 In patients with lymphomas associated
with elevated 1,25-dihydroxy vitamin D levels and hypercalcemia, therapy with glucocorticoids reduces both the serum calcium
and 1,25-dihydroxy vitamin D concentrations in a parallel fashion.193

Coexistence of Cancer and Primary Hyperparathyroidism

The association of hyperparathyroidism and nonparathyroid malignancies is well established in patients with both type I and type II
multiple endocrine neoplasia syndromes. Additionally, numerous investigators have reported an increased incidence of malignant
breast, thyroid, GI, genitourinary, and pulmonary neoplasms in patients with hyperparathyroidism. 34,35,36,37,200,201,202,203 These
studies have suggested that between 34 and 42 percent of patients with parathyroid adenomas or hyperplasia have an associated
neoplasm, raising the possibility that hypercalcemia or hyperparathyroidism predisposes a patient to neoplasia. Alternatively,
neoplasms may produce a parathyrotropic substance that leads to the development of parathyroid hyperplasia or adenoma(s).
However, caution should be exercised in interpreting the literature because of three considerations. First, both hyperparathyroidism
and neoplasms are relatively common, and the frequency of both increases with age.204 This, coupled with the increased scrutiny
that a patient undergoes during an evaluation for one of the conditions which incidentally could uncover the other, may account
for the apparent association. Second, some of these studies utilized histologic criteria for the diagnosis of parathyroid hyperplasia or
adenoma in patients with cancer. One of the major criteria for parathyroid chief cell hyperplasia is a reduction in stromal fat. In a
study of hypercalcemic patients with nonmetastatic tumors and undetectable parathyroid hormone who exhibited the clinical
features of the humoral hypercalcemia of cancer syndrome, 70 percent had markedly reduced amounts of parathyroid stromal fat,
giving a histologic appearance that was indistinguishable from that of chief cell hyperplasia. Similar data were found in 20 percent
of normocalcemic cancer patients.129 These histologic findings undoubtedly represent the effects of weight loss and cachexia on the
parathyroid glands rather than functional parathyroid abnormalities. Third, the association between well-differentiated thyroid
cancer and hyperparathyroidism in some of these series may have been due to the inclusion of patients who received head and neck
irradiation for benign disorders during childhood and adolescence, a known risk factor for both problems.205, 206

Clinical Manifestations and Diagnosis

Hypercalcemia is generally a late and often preterminal manifestation of malignancy, with death usually occurring within 3 months
of the diagnosis.29,30,37,207,208,209
The signs and symptoms of hypercalcemia fall into four groups. Nonspecific general complaints of fatigue, weakness, headaches,
behavioral abnormalities, and malaise are present in more than half the patients and are an especially prominent complaint in
individuals with calcium concentrations below 14 mg/dl.29 Gastrointestinal manifestations include anorexia, nausea, vomiting,
constipation, and abdominal discomfort and are present in one-half to three-quarters of patients at the time of presentation.29, 117
Neurologic abnormalities are also prominent, especially in patients with serum calcium above 14 mg/dl. 29, 117 Patients often
complain of drowsiness, visual abnormalities, confusion, and memory impairment and are frequently found to be lethargic,
confused, stuporous, or comatose. There are usually no localizing signs. Finally, the hypercalcemia may lead to a nephrogenic
diabetes insipidus resulting in polyuria, thirst, and polydipsia. If fluid intake is insufficient, findings of dehydration may be present.
Patients who have humoral hypercalcemia of malignancy share many of the clinical and biochemical findings of primary
hyperparathyroidism, although there are clinical and biochemical differences between these diseases (Table 28-14).123,210,211,212
Considering the close biochemical similarity in the actions of PTH and PTH-rp, it is of interest that three laboratory abnormalities
cannot be explained on the basis of the direct biochemical effects of these two hormones. 213 Patients with hyperparathyroidism
generally have hyperchloremic acidosis, while individuals with humoral hypercalcemia of malignancy have hypochloremic
alkalosis and do not exhibit the renal bicarbonate wasting found with primary hyperparathyroidism. Although in vitro both PTH
and PTH-rp stimulate renal 25(OH)-vitamin D1-hydroxylase activity, clinically patients with primary hyperparathyroidism have
elevated levels of 1,25(OH)2 vitamin D while patients with the humoral hypercalcemia of malignancy generally have normal or low
levels. Finally, patients with malignancy-associated hypercalcemia exhibit uncoupling of bone resorption and bone formation as
assessed through histomorphometric evaluation, while patients with primary hyperparathyroidism usually demonstrate coupling of
the resorption and formation activity. Thus, some of the clinical manifestations of humoral hypercalcemia of malignancy may not be
explained by simply implicating excessive production of PTH-rp. Instead, it is likely that other humoral factors, nutritional
deficiencies, and metabolic abnormalities contribute to the observed differences between the two diseases.

Figure 28-4 provides an algorithm for evaluating patients with hypercalcemia and cancer. A bone scan is the most sensitive
screening test for detecting osteolytic metastases. If lytic lesions are found, the hypercalcemia may be due to local prostaglandin or
cytokine production or may represent osteoclastic reabsorption from secretion of PTH-rp. If the bone scan is normal, a
determination of serum concentrations of PTH and PTH-rp should be performed. Elevated levels of PTH are almost always due to the
coexistence of primary hyperparathyroidism, while elevations of PTH-rp point to the neoplastic production of PTH-rp as the
etiology of the hypercalcemia. If the PTH and PTH-rp concentrations are normal or low, a measurement of 1,25(OH) 2 vitamin D
should be performed; if it is elevated, this suggests the presence of lymphoma or leukemia or the possibility of an associated
granulomatous disease or vitamin D intoxication. If the 1,25(OH) 2 vitamin D levels are normal, a therapeutic trial of indomethacin
or another prostaglandin synthesis inhibitor may be given. A decrease in calcium provides presumptive evidence of prostaglandin-
mediated hypercalcemia. An absence of change in the calcium concentration suggests the presence of bony micrometastases that are
too small to be seen by bone scan or the coexistence of another cause of hypercalcemia.

TABLE 28-14. Comparison of Primary Hyperparathyroidism and Humoral Hypercalcemia of Malignancy

Humoral Hypercalcemia
Feature Primary Hyperparathyroidism of Malignancy
History Long, indolent course (125 years) Short, rapidly progressive course (weeks to months)
Sex 60 percent female 75 percent male
Major symptoms None; renal stones, peptic ulcer, pancreatitis, bone pain, Weight loss, lethargy, obtundation, polyuria,
memory impairment nocturia, nausea, vomiting
Serum calcium Rarely >14 mg/dl Often >14 mg/dl
Urine calcium/serum Lower Higher
calcium
Serum phosphate Normal or decreased Normal or decreased
Serum chloride Often >102 mEq/L Often 102 mEq/L
Serum HCO3 Normal or low Elevated
Serum Cl/PO4 Usually >35 Usually <35
Alkaline phosphatase Usually normal Often elevated
Nephrogenous cAMP Elevated Elevated
1,25(OH)2D3 Normal to elevated Normal to low
Hematocrit >38 percent in 90 percent <38 percent in 75 percent
Serum PTH Normal to elevated Low
Serum PTH-rp Low High
Bone biopsy Elevated osteoclastic bone resorption and osteoblastic Elevated osteoclastic bone resorption, depressed
bone formation (coupled resorption formation) bone formation (uncoupled resorption formation)

Therapy
The mainstays of therapy for humoral hypercalcemia include the treatment of the underlying tumor and therapies directed toward
directly reducing serum calcium. Hydration with normal saline not only expands intravascular fluid volume, which decreases the
serum calcium, but also promotes urinary calcium excretion. The rate of urine flow may be enhanced with diuretics such as
furosemide or ethacrynic acid with careful attention to and replacement of the potassium lost in urine. Concurrently, medications
may be administered to inhibit bone resorption. Glucocorticoids are effective in patients with prostaglandin-mediated
hypercalcemia and patients with hematologic and lymphoproliferative neoplasms with cytokine production or enhanced
conversion of 25(OH)-vitamin D to 1,25(OH)2 vitamin D. Calcitonin, mithramycin, bisphosphonates, and gallium nitrate are
medications that inhibit osteoclastic bone resorption. Finally, if these measures are not effective, a dangerously elevated serum
calcium may be reduced through peritoneal dialysis or hemodialysis using a calcium-free dialysis solution.214,215,216,217,218
Once the acute hypercalcemia has been effectively treated, further exacerbations of hypercalcemia may be prevented through the
maintenance of adequate hydration, ambulation, and exercise and the administration of oral bisphosphonates or phosphates. In the
rare patient with prostaglandin-mediated hypercalcemia due to systemic overproduction of prostaglandin, indomethacin or another
prostaglandin synthesis inhibitor may be effective.

Ectopic POMC/ACTH Syndrome

The first recorded example of the ectopic POMC/ACTH syndrome was reported in 1928 by Brown, 4 years before Cushing's classic
paper describing the syndrome which bears his name.219 Brown's patient was a 45-year-old obese female with hyperpigmentation,
glucose intolerance, hypertension, hirsutism, weakness, and plethora who was found to have bilateral adrenal hyperplasia
associated with a small cell carcinoma of the lung. In 1961, Christy demonstrated the presence of an adrenal weight-maintaining
factor in the plasma of two patients with neoplasms and this syndrome. 220 This was followed shortly by the demonstration of
immunoreactive ACTH in tumor tissue and plasma.221, 222 Subsequent studies by Liddle and colleagues showed that the ACTH
present in tumors from patients with Cushing's syndrome closely resembled the biologically active hormone in the pituitary. 223

Prevalence and Tumor Types

Cushing's syndrome is a relatively uncommon paraneoplastic syndrome associated with cancer. The ectopic production of
POMC/ACTH accounts for 15-20 percent of patients with Cushing's syndrome.125, 224 Close to half the patients with this syndrome
have a small cell carcinoma of the lung, while an additional 11 percent harbor a bronchial carcinoid and 13 percent have an
epithelial thymic neoplasm or thymic carcinoid (Table 28-15).225,226,227,228 Thus, close to 70 percent of patients presenting with this
syndrome have a tumor between the clavicles and the diaphragm. Islet cell tumors of the pancreas, carcinoid tumors arising from
sites other than the lung, pheochromocytomas and other tumors of chromaffin tissue, ovarian neoplasms, and medullary carcinoma
of the thyroid account for the majority of the remaining 30 percent of tumor types associated with this syndrome.225,226,227,228
Altogether, 84 percent of the tumor types have APUD characteristics, while the remaining 16 percent are squamous cell tumors,
adenocarcinomas, or hepatomas.226

TABLE 28-15. Tumors Associated with the Ectopic POMC/ACTH Syndrome (N = 220)
Tumor Percent
Small cell carcinoma of lung 45
Thymic carcinoma/carcinoid 13
Bronchial carcinoid 11
Islet-cell tumor 10
Other carcinoid 4
Pheochromocytoma 2
Ovarian carcinoma 2
Other* 13
* Esophageal, gastric, ileal, appendicular, colonic, cervical, breast, prostate, and laryngeal carcinoma; medullary carcinoma of the
thyroid; acute myelogenous leukemia.

Between 1.3 and 4.8 percent of patients with small cell carcinoma of the lung have clinically recognizable ectopic POMC/ACTH
syndrome (Table 28-4).43,53,54,57,58 In contrast, 19 percent of patients with small cell carcinoma of the lung examined at autopsy
have unequivocal pathologic evidence of ACTH excess as reflected by bilateral adrenal hyperplasia and the presence of Crooke's
hyaline changes in the pituitary.229 Using biochemical criteria, between one-fourth and one-half of patients with small cell
carcinoma of the lung have elevations of plasma or urine cortisol and do not show appropriate suppression of plasma cortisol after
an overnight dexamethasone suppression test.43,53,70,230 In addition, between 24 and 78 percent of patients with small cell
carcinoma have elevated concentrations of immunoreactive POMC/ACTH in the serum or plasma. The dichotomy between the high
prevalence of elevated blood immunoreactive ACTH concentrations and the low frequency of the clinical ectopic POMC/ACTH
syndrome is due to the secretion by these tumors of immunologically active forms of POMC/ACTH with little or no biological
activity.

POMC Products Produced by Tumors

In the anterior pituitary, the 1,200-base POMC mRNA encodes for the pre-POMC protein, which contains a 26-amino acid signal
peptide along with the 241-amino acid POMC protein (Fig. 28-5). POMC is glycosylated and has a molecular mass of
approximately 31 kDa. In the anterior pituitary it undergoes posttranslational processing through convertases, with the generation
of ACTH, N-terminal fragment, joining peptide, and beta-lipotropin (-LPH). -LPH is further processed to -LPH and -
endorphin.90, 224 A small quantity of pro-ACTH, a 22-kDa glycosylated form of ACTH, has also been detected in pituitary extracts. 90,
232
In the human fetal pituitary intermediate lobe, the amino-terminal peptide is further processed to generate gamma melanocyte
stimulating hormone (-MSH), and ACTH is cleaved to form -MSH [N--acetyl-(ACTH1-13)-NH2] and corticotropin-like
intermediate peptide (CLIP). -LPH is also cleaved to form the 18-residue -MSH (Fig. 28-5). Each of the POMC-derived peptide
produced by the normal anterior pituitary and the fetal intermediate lobe has been found in extracts of tumors removed from
patients with the ectopic PMOC/ACTH syndrome. Met-enkephalin has also been found in tumor extracts.240, 241 Although this
molecule was originally thought to be derived from -lipotropin molecules since it shares a common amino acid sequence with the
C-terminal portion of -LPH, met-enkephalin is actually derived from a separate precursor, pro-enkephalin.

In patients with the clinical syndrome, both the biologically active nonglycosylated 39-amino acid ACTH moiety and ACTH
precursors are present in the tumor and circulation.87 As has been noted previously, a number of investigations have found that the
majority of patients with lung cancer of any histologic type have elevations of immunoreactive ACTH in the circulation but do not
exhibit any clinical syndrome. In addition, the majority of extracts derived from lung cancers of all histologic types, including
squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and poorly differentiated carcinoma, have been found to contain
immunoreactive ACTH, and over one-third also contain immunoreactive -LPH.68 The immunoreactive ACTH in the tumors and
blood of patients without the clinical syndrome lacks biological activity, as reflected by absent or reduced binding in a radioreceptor
assay.67 This form of ACTH represents the glycosylated 22,000-dalton pro-ACTH molecule initially described by Yalow as big
ACTH.90,231 Digestion of this intermediate form of ACTH with trypsin generates biologically active ACTH.
It is of interest that POMC mRNA has been found to be widely distributed in normal tissues, including the stomach, pancreas, brain,
placenta, adrenal medulla, and testis.242 In addition, POMC peptides have been found in many normal tissues.68,72,243,244 In this
regard, Odell and colleagues hypothesized that all normal tissues produce small amounts of the ACTH precursor and carcinomas
produce increased quantities of this material. Selected carcinomas are capable of converting this ACTH precursor into biologically
active ACTH, thereby producing the ectopic POMC/ACTH syndrome.72, 245 However, recent studies suggest an alternative
mechanism. The POMC mRNA in nonpituitary tissues and tumors that is not associated with the ectopic POMC/ACTH syndrome is
smaller (approximately 800 bases) than the 1,200-base POMC mRNA present in the pituitary.242,246,247,248 In contrast, the 1,200-
base POMC mRNA has been found in tumors associated with the clinical syndrome. 249 This, together with the observation that the
ratio of POMC mRNA to POMC peptides present in nonpituitary tissues is much greater than that in the pituitary, suggests that
POMC gene expression in normal tissues and tumors not associated with the clinical syndrome is inefficient or defective. 224

Clinical Manifestations
There are two major modes of presentation of patients with the ectopic PMOC/ACTH syndrome. The first is found in individuals
with clinically apparent neoplasms, especially small cell carcinoma of the lung, in which there is rapid onset of clinical and
biochemical aberrations. The usual patient is a male 45-60 years old, often with a cigarette smoking history of multiple packs over
many years, who has the acute onset of profound proximal muscle weakness; pitting edema of the lower extremities;
neuropsychiatric symptoms such as mood change, mania, depression, and obtundation; and hypertension. Either weight loss from
the underlying neoplasm or weight gain may be present. Polyuria and polydipsia may also be present as a result of glucose
intolerance. Women may note the onset of acne and hirsutism. Biochemically, these patients generally exhibit a profound
hypokalemic (K <3 mEq/L) alkalosis (HCO328 mEq/L) due to a combination of increase secretion of cortisol, corticosterone, and 11-
deoxycorticosterone, all of which interact with the mineralocorticoid receptor. In addition, the inactivation of cortisol is reduced
because of an ACTH-induced inhibition of 11-hydroxysteroid dehydrogen-ase, which converts cortisol to cortisone, the latter
being devoid of mineralocorticoid activity.250 The patients usually have either overt diabetes mellitus or glucose intolerance.
Although some patients may appear to be cushingoid, most presenting in this manner do not, presumably because they have not had
enough time to develop the centripetal fat redistribution and moon facies characteristic of Cushing's disease. Alternatively, the
highly malignant nature of the underlying neoplasm in these patients, along with the attendant weight loss and cachexia, may
obscure the more typical cushingoid features. The average survival of patients presenting in this manner is 4 months or
less.31,227,228,229,251
The second major mode of presentation is seen primarily in patients with occult tumors, especially pulmonary and thymic
carcinoids.228 These patients usually harbor small neoplasms, some of which may be benign, and generally present with signs and
symptoms closely mimicking Cushing's disease. Thus, typical cushingoid features are common, with centripetal obesity, moon facies,
buffalo hump, increased supraclavicular fat pads, thinning of the skin with purplish stria, easy bruising, plethora, hirsutism, acne,
psychiatric symptoms, polydipsia, polyuria, and hypertension. Virtually all these patients have significant proximal muscle
weakness, and approximately one-half exhibit hyperpigmentation. Hypokalemic alkalosis may also be present, but it is generally of
a milder degree than in patients with more overt neoplasms. 227,228,252 This group of patients is most difficult to differentiate
clinically and biochemically from patients with

Cushing's disease.
The Ectopic Corticotropin Releasing Hormone Syndrome
In 1971, Upton and Amatruda described two patients, one with a pancreatic tumor and the other with a small cell carcinoma of the
lung, who exhibited the clinical ectopic POMC/ACTH syndrome but whose tumors contained bioactive corticotropin releasing
hormone (CRH).253 Subsequently, several additional patients have been reported with the spectrum of tumors including bronchial
carcinoid, prostatic carcinoma, medullary carcinoma of the thyroid, and intrasellar gangliocytoma. 254, 255,256,257,258,259,260 Both the
rapid-onset and slow-onset types of presentation described above have been noted in these patients. Some but not all of these
tumors also contain POMC and related peptides, including biologically active ACTH. The pituitary in these patients demonstrates
corticotroph hyperplasia, indicating that the CRH is biologically active. 254,255,261 It appears that the clinical features of Cushing's
syndrome result from CRH stimulation of pituitary ACTH secretion with or without concomitant secretion of biologically active
ACTH from the tumor. It is also of interest that materials closely related immunologically to CRH have been found in normal
stomach, pancreas, and adrenal glands, along with various tumors, including those not associated with Cushing's syndrome.262

Diagnosis
In patients with overt neoplasms and a rapid onset of the ectopic POMC/ACTH syndrome, the biochemical diagnosis does not
present difficulties (Fig. 28-6). The 24-h urine free cortisol concentration is generally four or more times above the upper limit of
normal, and these patients fail to demonstrate a 50 percent or greater suppression of serum or urine cortisol concentrations after
the administration of either low-dose (1 mg overnight; 0.5 mg orally every 6 h for eight doses) or high-dose (2 mg orally every 6 h
for eight doses) dexamethasone because of the autonomous secretion of ACTH from the tumor. Measurement of plasma ACTH can
differentiate between the ectopic POMC/ACTH syndrome and the presence of an adrenal adenoma or carcinoma that autonomously
secretes excessive quantities of cortisol. In the latter group of patients, plasma ACTH levels are suppressed, while in patients with the
ectopic POMC/ACTH syndrome, the levels usually exceed 200 pg/ml.125, 227
FIGURE 28-6. Algorithm for the evaluation of a patient with suspected Cushing's syndrome. See text for details. (*The rare pure
CRH-secreting tumor potentially may give similar results. Plasma CRH levels should help differentiate these entities.)
Unfortunately, not all patients with the ectopic POMC/ACTH syndrome follow this classical scheme. Close to 80 percent of patients
with pituitary-dependent Cushing's disease have more than 50 percent suppression of plasma or 24-h urine cortisol levels after 2
days of ingesting 8 mg of dexamethasone each day, while 11 percent of patients with the ectopic POMC/ACTH syndrome also show
such suppression.228 Similarly, close to 90 percent of patients with Cushing's disease and 63 percent of patients with ectopic
POMC/ACTH syndrome demonstrate a 100 percent or greater rise in either plasma ACTH or urinary 17-hydroxysteroids after
metyrapone administration.228 This overlap in biochemical responses between patients who have Cushing's disease and those with
the ectopic POMC/ACTH syndrome is seen primarily in individuals who have occult neoplasms as well as patients with the ectopic
CRH syndrome. Indeed, in the group of patients with occult tumors and Cushing's syndrome, an incorrect diagnosis is initially made
in approximately 70 percent.263
When CRH is administered as an intravenous bolus over 30 s at a dose of 1 g/kg, normal individuals show a prompt rise in ACTH
followed by an increase in plasma cortisol (Fig. 28-7).264 As expected, patients with ACTH-independent Cushing's syndrome
resulting from primary adrenocortical disease demonstrate little or no rise in either ACTH or cortisol. In contrast, individuals with
pituitary ACTH-dependent Cushing's disease have elevations of basal ACTH and cortisol concentrations and exhibit an exuberant
rise in both hormones after CRH administration. Patients with ectopic POMC/ACTH Cushing's syndrome also have elevated plasma
ACTH and cortisol concentrations but demonstrate no further increase after receiving CRH. Unfortunately, only 90 percent of
patients with pituitary ACTH-dependent Cushing's disease show a rise in ACTH, while 8 percent of patients with the ectopic
POMC/ACTH syndrome show a similar rise. Because of the four- to six-fold greater prevalence of pituitary ACTH-dependent
Cushing's disease, the predictive value of a positive CRH test in identifying Cushing's disease is 99 percent, but the predictive value
of a negative test (with an insufficient rise in ACTH) is only 63 percent. 265 Thus, this test is not as useful in differentiating between
the two diseases as the initial reports suggested. It is of interest that CRH has been found in tumors from patients with the ectopic
POMC/ACTH syndrome who have an increase in ACTH after a CRH test, suggesting that the false-positive responses in this
syndrome are due to the ectopic production of CRH by the tumor, which leads to hyperplasia of the pituitary corticotrophs which
are responsive to exogenous CRH.
Another technique developed to differentiate eutopic pituitary ACTH-dependent Cushing's syndrome from ectopic POMC/ ACTH
Cushing's syndrome is selective venous blood sampling from multiple sites with measurement of ACTH. Because the pituitary
venous effluent drains into the inferior petrosal sinuses, catheterization of the sinuses with simultaneous blood sampling of both
sinuses and a peripheral vein will show a gradient of 2 or greater in the unstimulated state or 3 or greater during a simultaneous
infusion of CRH in patients with an ACTH-secreting pituitary adenoma.265,266,267 In contrast, patients with the ectopic POMC/ACTH
syndrome have a gradient below 2 in the basal state or during CRH infusion. The localization of the tumor producing the syndrome
may be accomplished through sampling of blood from a variety of other sites throughout the venous vascular tree. Because of the
potential for microsecretory bursts of ACTH secretion, it is important to carry out the procedure as rapidly as possible. 266, 268
Serum serotonin or urine 5-hydroxyindolacetic acid measurements are occasionally useful in patients with the ectopic
POMC/ACTH syndrome due to carcinoid tumors or small cell carcinoma of the lung. 269 Because the majority of patients with this
syndrome harbor a neoplasm within the chest, a CT or MRI scan of the chest and mediastinum should be performed on all patients
who do not have an overt tumor but fulfill the biochemical criteria for the ectopic POMC/ACTH syndrome. Similarly, patients who
appear to have classical Cushing's disease should also have a CT or MRI scan of the chest unless radiographic procedures or inferior
petrosal sinus studies have clearly demonstrated the presence of an ACTH-secreting pituitary adenoma.
Treatment
Slow-growing, well-localized bronchial or thymic carcinoids may be successfully removed surgically. However, between one-
quarter and one-half of the patients will have lymph node metastasis and thus will not be cured unless a lymph node dissection is
carried out and/or postoperative mediastinal irradiation given. 252 Bilateral adrenalectomy is certainly effective in reversing the
metabolic abnormalities but may be inappropriate in a patient with a highly malignant neoplasm such as small cell carcinoma of
the lung. Inhibitors of glucocorticoid synthesis including aminoglutethimide, metyrapone, and ketoconazole have been used
successfully in treating some, but not all, patients with this syndrome. 224,270,271,272 Combinations of inhibitors and the adrenlytic
agent o,p'-DDD have also been used.273 Similarly, glucocorticoid receptor blockade with the glucocorticoid antagonist RU-486 has
been effective in a limited number of patients.113 Finally, octreotide, a long-acting somatostatin analog has been used in patients
with the ectopic POMC/ACTH syndrome and led to the rapid correction of the hypercortisolemia in less than half of the subjects.274
Syndrome of Inappropriate Antidiuresis in Cancer
The first description of the syndrome of inappropriate antidiuresis (SIAD) in patients with cancer appeared in 1938. 275 In 1957,
Schwartz and coworkers published the classic description of two patients with bronchogenic carcinoma who exhibited
hyponatremia, continual loss of sodium in urine, and an impaired ability to dilute their urine. 276 Recognizing the similarity in the
biochemical features between the two patients with lung cancer and normal subjects given injections of pitressin tannate-in-oil and
free access to fluid, Schwartz et al. proposed that the syndrome is due to the inappropriate secretion of antidiuretic hormone
[arginine vasopressin (AVP)].277 In 1963, an increased concentration of antidiuretic hormone was found to be present in the urine
of a patient with a lung tumor and this syndrome278 and in tumor tissue by bioassay.279 That a tumor could be the source of AVP
was suggested by the finding in 1964 of increased concentrations of AVP in the plasma and tumor tissue of a patient with a
bronchogenic carcinoma who also exhibited destruction of the posterior pituitary from a metastatic lesion. 280 More direct evidence
of tumor production was provided by the studies of George et al., who demonstrated the incorporation of radiolabeled amino acids
into AVP by lung tumor cells in vitro.281 The similarity of the biosynthetic pathway for tumor and hypothalamic production of AVP
was shown by Yamaji and colleagues in 1981 with the in vitro production of provasopressin by a small cell carcinoma of the lung
maintained in vitro.282 In the same year, a nude mouse bearing a small cell carcinoma of the lung derived from a patient with SIAD
exhibited increased blood and tumor levels of AVP, excessive sodium loss in the urine, and decreased free water clearance,
mimicking the human syndrome.283
Prevalence and Tumor Types
Between one-half and two-thirds of patients in reported series of SIAD have an underlying malignancy as the etiology.284, 285 This
undoubtedly represents a reporting bias, as transient SIAD is frequently seen in patients with conditions such as meningitis and
head trauma. The vast majority of patients with SIAD associated with cancer have a bronchogenic carcinoma, especially small cell
carcinoma, which accounts for three-quarters of the patients with cancer-associated SIAD (Table 28-16).226,284,285,286,287 Other
histologic types of lung tumors, lymphomas, and an array of different types of tumors account for the remaining cases.

TABLE 28-16. Tumor Types Associated with SIAD

Cases Percent
Bronchogenic carcinoma 83
Small cell carcinoma 59
Non-small-cell carcinoma 24
Lymphoma 3
Pancreatic carcinoma 2
Laryngeal carcinoma 1
Duodenal carcinoma 1
Miscellaneous tumors * 10
*Prostate (small cell), cervic al (small cell), bladder, colon, thymoma, mesothelioma,
olfactory neuroblastoma, sarcoma, lymphosarcoma, reticulum cell sarcoma, Ewing's
sarcoma, malignant histiocytosis.
The prevalence of SIAD depends on how the condition is defined. The clinical syndrome associated with small cell carcinoma of the
lung occurs in 7-14 percent of patients.50,53,54,55,64,288 Even within this group, the patients may be asymptomatic and merely
demonstrate hyponatremia and a urinary concentrating defect. On the basis of an abnormal water load test, between 35 and 66
percent of patients with small cell carcinoma of the lung are classified as having SIAD.55,64,70,284 However, close to 70 percent of
patients with other malignancies also exhibit abnormalities in the ability to excrete a water load, raising the possibility that this test
gives nonspecific results in all patients.70 Increased concentrations of plasma or urinary AVP levels are found in 33-71 percent of
these patients.52,53,54,55,64,72 Elevated AVP levels have also been noted in 43 percent of patients with colon carcinoma who do not
exhibit clinical SIAD.72 Using immunoassays for neurophysins, North and colleagues found that approximately 65 percent of
patients with small cell carcinoma of the lung have elevated concentrations of neurophysins in the circulation. 71, 289 Close to one-
third have increased quantities of vasopressin-associated neurophysin alone, 12 percent have elevations of oxytocin-associated
neurophysin alone, and 22 percent have elevations of both neurophysins. 71 Approximately 20 percent of patients with non-small-
cell carcinoma of the lung also have elevations of neurophysins in the serum. Because AVP and AVP-associated neurophysin are
synthesized together, along with a glycopeptide as provasopressin, and are normally secreted in equimolar amounts, it is not
surprising that both are elevated in about half the patients with small cell carcinoma of the lung. Immunohistologic staining for
AVP-associated neurophysin in small cell carcinoma of the lung has shown the presence of the antigen in 72 percent of the tissue
specimens examined.290 Thus, it appears that many patients with small cell carcinoma of the lung have a propensity for developing
SIAD, although only a minority exhibit the clinical syndrome.

Tumor Peptides and Pathophysiology

Early studies demonstrated that the substance with antidiuretic activity extracted from tumors closely resembles that extracted from
the posterior pituitary in terms of the dose-response effect in bioassay and inactivation by thioglycolate, vasopressinase, and
vasopressin antibodies.286,291,292 In addition, these materials appear to be identical to AVP immunologically and physicochemically.
Direct evidence of in vitro synthesis was provided through immunoassay measurements of AVP production in vitro and through the
incorporation of tritiated phenylalanine into a peptide resembling AVP.281,293,294,295 Finally, in carefully performed pulse-chase
experiments using labeled cysteine and glucosamine, Yamaji and associates found a small cell carcinoma of the lung that
synthesized and secreted a 20,000-dalton glycosylated provasopressin which could be cleaved by trypsin to yield neurophysin, AVP,
and a glycopeptide.282, 296 The mRNA for preprovasopressin also has been demonstrated in small cell carcinoma of the lung. 297
Although it is clear that some lung tumors are capable of synthesizing and secreting AVP, it is safe to conclude that many cases of
SIAD cannot be accounted for by ectopic production of AVP by these tumors, because only three-fourths of patients with SIAD
associated with lung cancer have been found to have inappropriately elevated concentrations of AVP.298 Also, some patients with
typical SIAD actually have resetting of the hypothalamic osmostat, as manifested by a lowered osmotic threshold for the release of
AVP from the hypothalamus.299 In the latter situation, the rise of AVP with increasing plasma osmolality during a hypertonic saline
infusion has a normal slope, but the entire curve is shifted to the left.
Because the normal physiologic regulation of AVP secretion from the hypothalamus and posterior pituitary is mediated through
baroreceptors as well as osmoreceptors, there are multiple situations in which neoplasms may lead to a release of hypothalamic-
pituitary AVP as opposed to ectopic production of the hormone by the tumor. Such mechanisms include obstruction of the vena
cava, infiltration of the vagus nerve leading to baroreceptor denervation, hypothalamic metastases, carcinomatous neuropathy, CNS
or pulmonary infections, pain, and alterations of intrathoracic pressure sufficient to stimulate the baroreceptors in the left atrium
and great veins.125,299,300 Similarly, a number of medications used in patients with cancer may be associated with hyponatremia.
These drugs include cyclophosphamide, vincristine, cisplatin, doxorubicin, vinblastine, and bleomycin. 301, 302
It has also been proposed that some tumors may synthesize an AVP-releasing factor.299 In patients who have SIAD without
measurable levels of AVP, another antidiuretic substance may be produced by the tumor. One candidate substance is arginine
vasotocin, a fetal peptide related to AVP, which may be produced by some tumors.72 The natriuresis found in this syndrome may be
due in part to the secretion of atrial natriuretic peptide (ANP), as plasma levels of this hormone are elevated in some patients with
SIAD303,304,305,306 and the mRNA for ANP has been isolated from small cell carcinomas associated with hyponatremia. 307

Criteria for SIAD and Clinical Features

Vasopressin acts on the renal collecting tubule by binding with the AVP V 2 receptor, an interaction that stimulates adenylyl cyclase
activity and ultimately allows the collecting ducts to become permeable to water. This results in the reabsorption of water from the
hypotonic urine entering the collecting ducts that pass through the hypertonic renal medullary region. The net effect is the
excretion of more concentrated urine and the delivery of the reabsorbed water to the intravascular and extravascular spaces.
Normally, the secretion of AVP by the hypothalamus and posterior pituitary is tightly regulated through osmolar and volume
mechanisms. With inappropriate secretion of AVP, inappropriate water retention and a reduction of body tonicity occur. The
cardinal features of SIAD include the following:
Dilutional hyponatremia (Na+1 <130 mEq/L), hypoosmolality (<280 mOsmol/kg), and low serum blood urea nitrogen
(BUN), creatinine, uric acid, and albumin.
The presence of a urine osmolality that is inappropriately high for the serum hypoosmolality. This does not imply that urine
osmolality must always be greater than serum osmolality in patients with SIAD, although it usually is; it implies only that
the urine is not maximally dilute (50-60 mOsmol/kg), which it should be when AVP is suppressed. This criterion is
reflected in the inability of patients with SIAD to excrete a water load normally.
The presence of continued natriuresis with a urine sodium concentration greater than 20 mEq/L despite the hyponatremia.
The urine sodium excretion reflects sodium intake so that the administration of increasing quantities of sodium results in
an equivalent loss of sodium in the urine. The natriuresis may be absent if the patient's sodium intake is severely restricted.
The cause of the natriuresis is multifactorial and includes an increase in the glomerular filtration rate from the expanded
extracellular fluid space, which in turn results in an increased filtered load of sodium. Additionally, serum aldosterone
levels are either normal or low but are inappropriately low relative to the hyponatremia, which is a stimulus for
aldosterone secretion. In the face of extracellular volume expansion, there is a decrease in the proximal tubular sodium
reabsorption because of factors that are incompletely understood. Finally, atrial natriuretic factor levels are increased in
these patients, and this may also enhance the natriuresis.300
Little or no edema despite the approximately 4-5 liters of water retention. There is an escape from the effects of the ADH
that ultimately occurs in these patients. The reasons include a decrease in the tonicity of the normally hypertonic renal
medullary interstitial space as a result of the dilutional effects, an increase in the water delivered to the distal nephron from
the elevated glomerular filtration rate, and the hypokalemia that is present in approximately half the patients, which
antagonizes the effect of AVP at the renal tubular level.286
The absence of a condition that results in a reduced effective vascular volume, including dehydration, congestive heart
failure, and liver disease associated with ascites. These conditions are associated with an appropriate increase in
hypothalamic and posterior pituitary secretion of AVP.
Normal renal, adrenal, thyroid, and anterior pituitary function.
The clinical manifestations of SIAD depend on the rate of development of hyponatremia and hypoosmolality as well as the actual
level of serum sodium. Only a quarter of patients with SIAD exhibit clinical symptoms. 287 Symptoms may be precipitated through
the ingestion of a thiazide diuretic, the administration of excessive oral or intravenous fluids during chemotherapy, or acutely as a
result of tumor lysis with release of stored AVP. Also, water intoxication in predisposed patients may theoretically be precipitated by
the ingestion of nonsteroidal analgesics that potentiate the antidiuretic effect of AVP by blocking PGE 2, an inhibitor of AVP action.300
It is uncommon for symptoms other than nonspecific malaise to occur above a serum sodium of 120 mEq/L. Between 115 and 120
mEq/L, the signs and symptoms of water intoxication include anorexia, nausea, vomiting, abdominal cramps, bloating, ileus,
myoclonus, muscle weakness, restlessness, irritability, hostility, withdrawal, confusion, and headache. Serum sodium levels below
110 mEq/L are associated with severe muscle weakness, hyporeflexia, ataxia, extrapyramidal signs such as rigidity, bulbar or
pseudobulbar palsies, positive Babinski signs, hemiparesis, stupor, coma, and seizures.
The diagnosis of SIAD is rarely difficult in patients with symptoms that fulfill the classical criteria. Secondary causes of
ADH secretion from volume depletion due to adrenal insufficiency, diuretic use, diarrhea, or hemorrhage are associated with typical
signs and symptoms, including orthostatic hypotension and tachycardia, dry mucous membranes, and decreased skin turgor. In
addition, dehydration leads to a low urinary sodium concentration, as do the conditions associated with volume overload and
decreased effective vascular volume, such as congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome.
Pseudohyponatremia from elevations of serum glucose, lipids, or proteins is excluded through the measurement of plasma
osmolality, which is normal rather than decreased, or correction of the serum sodium concentration for the level of glucose,
triglycerides, or protein. Patients with primary polydipsia may have a low plasma osmolality but uniformly have a low urine
osmolality and thus may be easily differentiated from patients with SIAD.
Plasma AVP measurements are of interest but add little to the management of these patients. The presence of an inappropriately
elevated plasma AVP concentration in a patient with a neoplasm does not in itself indicate that the neoplasm is secreting the
hormone ectopically. Tumors may be associated with SIAD through multiple mechanisms, as outlined previously.
In small cell carcinoma of the lung, there is a tendency for patients with more extensive disease to have a higher prevalence of an
inability to excrete a water load than is seen in patients with limited disease. 55 However, taking into account the stage of the disease,
there is no difference in the survival of patients who have SIAD vs. those who do not.55,70,287,288 The abnormalities in water load tests,
as well as the concentrations of AVP and neurophysins, reasonably parallel the clinical course of patients with small cell carcinoma
of the lung and therefore may be used as markers of the disease. 55,289,290

Therapy
Mild water intoxication is treated with fluid restriction to 800 ml per day or less. This reduces intravascular volume, resulting in a
lowering of the glomerular filtration rate and a decrease in renal sodium loss.
For severe water intoxication, especially in patients with serum sodium levels below 110 mEq/L, a combination of 3 percent
hypertonic sodium chloride with a loop diuretic such as furosemide or ethacrynic acid with replacement of urine sodium and
potassium losses usually increases the serum sodium effectively. Because individuals with SIAD are fluid overloaded to begin with,
the administration of hypertonic saline alone may result in congestive heart failure and hypertension. Also, because these patients
excrete an amount of sodium in their urine equivalent to their sodium intake, hypertonic saline alone rarely leads to a sustained
increase in serum sodium. The loop diuretics increase free water clearance and, together with the hypertonic saline, result in a rise
in the sodium concentration.300,301,308
When one is using hypertonic saline and a loop diuretic, it is important to monitor the rate of rise of serum sodium. Overzealous
correction of hyponatremia in severely debilitated patients has been associated with central pontine myelinosis. This problem can be
avoided if the rate of rise of serum sodium is kept at <2 mEq/L per h until a level of serum sodium of 120 mEq/L is achieved, at
which time the rate should be reduced. This therapy should be discontinued before the sodium reaches 130 mEq/L in order to avoid
hypernatremia and hyperchloremia.309
For patients who are mildly symptomatic or exhibit chronic SIAD, three drugs are currently available. The first is demeclocycline, a
tetracycline antibiotic that induces a nephrogenic diabetes insipidus by inhibiting the formation and action of cyclic AMP in the
collecting ducts of the renal tubules. This drug may be initiated at a dose of 1,200 mg a day in divided doses. Urine osmolality
decreases in 3-6 days, at which time the dose may be gradually decreased to a maintenance level of 300-900 mg/day. The goal is to
maintain serum sodium within the normal range while the patient has free access to fluid. The side effects of this medication
include nausea, vomiting, diarrhea, photosensitivity dermatitis, a dose-related rise in BUN without renal dysfunction, and
nephrotoxicity, especially in patients with hepatic insufficiency.
Another drug that induces a nephrogenic diabetes insipidus is lithium carbonate in doses of 900-2,100 mg/day. The CNS, renal, and
cardiac toxicities of this drug render it inferior to demeclocycline as a treatment for SIAD. 310
Oral urea acts as an osmotic diuretic and enhances water clearance. Thirty grams of urea are dissolved in 100 ml of water or juice
and are administered with 15 g of magnesium and aluminum hydroxide once a day.301 The only adverse reaction to this medication
is the potential for hypernatremic dehydration if the patient does not drink enough fluid. This therapy is reasonable to use if
demeclocycline is not tolerated.
Finally, with small cell carcinoma of the lung, chemotherapy is effective in resolving SIAD in the majority of patients at the time of
initial presentation.59 Indeed, Hainsworth and colleagues found that 16 of 17 patients with small cell carcinoma had resolution of
their SIAD between 8 and 26 days after the institution of chemotherapy. 59 Unfortunately, the majority have a return of SIAD at the
time of progression, and one of the other therapies must be administered.
Hypoglycemia Associated with Malignancy
The first reports of hypoglycemia associated with a neoplasm were published in 1929 when Nadler and Wolfer 311 and Elliot312
described a patient with a hepatoma who had neuroglucopenic symptoms and a blood sugar as low as 13 mg/dl. The following year,
Doege and Potter independently described a patient with low-grade fibrosarcoma and hypoglycemia, whose hypoglycemia remitted
after removal of the tumor, only to return with the recurrence of the malignancy. 82, 313
In the same year, Anderson described the association of hypoglycemia and adrenocortical carcinoma. 314 Since that time, hundreds
of patients with the association have been reported and extensively reviewed. 315, 316 Several eponyms have been used to describe
specific associations, including Doege-Potter syndrome (mesenchymal tumors), Nadler-Wolfer-Elliot syndrome (hepatoma),
Anderson's syndrome (adrenocortical tumors), and Rosenfeldt's syndrome (pseudomyxoma). 315
Incidence and Tumor Types
Paraneoplastic hypoglycemia is rare. Hypoglycemia was found to occur in 1.2 percent of hospitalized patients, most often as a result
of complications of diabetes mellitus, renal insufficiency, malnutrition, liver disease, infection, and shock. 317 In the few patients who
had an underlying malignancy, hypoglycemia was associated with insulin therapy, extensive liver metastases, and malnutrition. 317
Despite its low prevalence, hypoglycemia is associated relatively frequently with some tumor types.
Approximately half the patients with tumor-associated hypoglycemia harbor neoplasms of mesenchymal origin, which include
fibrosarcomas, mesotheliomas, leiomyosarcomas, rhabdomyosarcomas, and hemangiopericytomas, as well as a variety of other
histologic types (Table 28-17).315,318,319,320 Approximately 10 percent are benign tumors or of very low grade malignancy.315, 318
Many of these tumors have a spindle cell morphology.315 They tend to be large neoplasms, ranging from 310 g to 20 kg.316, 319 A
third of these tumors are located within the thorax, one-half in the retroperitoneal area, 11 percent intra-abdominally, and
approximately 6 percent in unique sites.321 The sex distribution is equal.315

TABLE 28-17. Tumor Types Associated with Hypoglycemia (N = 246)

Patients, Percent
Sarcoma 46
Fibrosarcoma 24
Mesothelioma 9
Leiomyosarcoma/rhabdomyosarcoma 6
Hemangiopericytoma 4
Other 3
Hepatoma 19
Adrenocortical carcinoma 10
Lymphoma 6
Neuroectodermal tumors 2
Gastric carcinoma 2
Colon carcinoma 1
Other* 14
*
Cholangiocarcinoma, teratomas, pseudomyxoma, Wilms' tumor, lung carcinoma, melanoma..

Hepatocelluler carcinoma is the second most common tumor associated with hypoglycemia. Approximately 1-2 percent of
hepatocellular carcinomas are associated with hypoglycemia, although the incidence is as high as 26 percent in hepatocellular
carcinomas in Asian patients.322,323,324,325 Males are affected approximately four times more frequently than are females. McFadzean
and Yueng divided these patients into two groups.325 The first group consisted of 87 percent of the patients, who had rapidly
growing, poorly differentiated hepatomas with marked replacement of the liver parenchyma. These patients experienced muscle
weakness and wasting, and hypoglycemia was found in the terminal or preterminal state and could easily be controlled with
glucose infusions. In contrast, the second group, composed of 13 percent of the patients, had slow-growing, well-differentiated
neoplasms without evidence of substantial cachexia or muscle weakness when the hypoglycemia appeared. In this group, death
occurred 2-10 months after the onset of hypoglycemia, whereas in the other group, death generally occurred within 2 weeks. 325
Adrenocortical carcinoma accounts for approximately 10 percent of patients with tumor-associated hypoglycemia. The tumors
generally are highly malignant and are associated with metastases at the time of diagnosis. Both sexes are affected equally, and
survival is generally <6 months from diagnosis. The tumors may be otherwise functional or nonfunctional; when they are
functional, about half are associated with Cushing's syndrome and half with virilization. 315

Pathophysiology
Abnormalities of glucose metabolism have been noted in patients with malignancy-associated hypoglycemia. Tumor cells exhibit a
high rate of glycolysis, and it was proposed that large mesenchymally derived tumors weighing multiple kilograms may consume
enough glucose to overwhelm the body's conterregulatory mechanisms. 315, 326 However, calculations based on an arterial-venous
glucose difference across a tumor and in vitro glucose uptake studies suggest that even tumors in the range of 1.4-6.0 kg consume
less than 400 g of glucose per day, while the liver is capable of producing more than 800 g of glucose per day.326, 327 Thus,
overutilization of glucose by the tumor is insufficient to account for the hypoglycemia. These patients also exhibit an increase in
glucose utilization by peripheral tissues, as shown by the large amount of glucose that must be infused to keep the blood glucose
within the normal range.326 Of interest in this regard, Stuart and coworkers demonstrated insulin receptor proliferation in the liver
and muscle of a patient with a hypoglycemia-producing colon carcinoma that metastasized to the liver.327 The threefold to fivefold
increase in insulin receptors associated with elevations of IGF-II, which can act through insulin receptors, may account for the high
total body glucose utilization.
In addition to overutilization of glucose by tumor and peripheral tissues, there is evidence of deficient hepatic glucose production in
these patients.318,326,328,329,330 With the exception of patients with slow-growing hepatomas that extensively replace the normal liver
parenchyma, most patients with tumor-associated hypoglycemia do not exhibit sufficient destruction of the normal liver to account
for the deficient hepatic glucose production, as experimental studies have shown that more than 75 percent of the liver must be
destroyed before hypoglycemia ensues.331 A problem in glycogenolysis is present, as histologic studies have shown that glycogen is
present in the livers of these patients and the administration of glucagon and epinephrine to some patients results in an increase in
hepatic glucose output.331, 332 Also, there is an inadequate amount of gluconeogenesis, as reflected in increased blood lactate levels
and possible reductions in gluconeogenic amino acids. Part of the reduction in hepatic glucose production may reflect an absent or
sluggish response to the hypoglycemia of the insulin counterregulatory hormones. Indeed, growth hormone, ACTH, cortisol, and
glucagon may be inappropriately low considering the level of the blood sugar in these patients, a response that may be due to a slow
decrease in blood sugar which does not activate the sympathetic nervous system and stress-induced release of the counterregulatory
hormones.331 Also, the low levels of growth hormone noted in the basal state in these patients as well as after arginine infusion may
reflect suppression of growth hormone secretion directly by IGF-II.330,333,334,335
Several different humoral factors secreted by these tumors have been implicated in the pathogenesis of the disorder. In 1962, after
the development of the insulin immunoassay, Olefesky and associates reported elevated serum insulin levels in a patient with a
fibrosarcoma.336 During the next two decades, >100 patients were described as having elevated concentrations of bioactive or
immunoactive insulin or insulin-like activity in blood or tumor tissue. An in-depth analysis of the data by Skrabanek and Powell
suggested that insulin production by non-islet-cell tumors is rarely, if ever, responsible for the hypoglycemia.316 Occasional
carcinoid tumors that resemble islet cell tumors have been associated with excessive insulin secretion.337 More recently, a
neuroectodermal pelvic tumor was shown to contain insulin, proinsulin, and secretory granules and to be responsible for elevated
insulin levels and hypoglycemia in a patient.338 Nevertheless, ectopic insulin production is exceedingly rare, and in most series
immunoreactive insulin levels are low and insulin mRNA is absent from tumor tissue. 335 Although there have been occasional
suggestions that tumors may release a pancreatic beta-cytotropic substance that stimulates insulin secretion, no such substance has
been identified in these tumors, and pancreatic hyperplasia has not been found at autopsy. 315,316,339
Before the development of insulin RIAs, insulin biological activity was divided into that which could be suppressed with insulin
antibodies, which represented the true insulin activity, and that which could not be suppressed by these antibodies, designated
nonsuppressible insulin-like activity (NSILA). Subsequently, NSILA was fractionated by acid-ethanol, which separated the activity
into high-molecular-weight proteins, NSILA-p or NSILAP, and a soluble fraction containing low-molecular-weight proteins,
NSILA-s.331, 340 NSILA-s was found to consist of several peptides, including IGF-I and IGF-II, with molecular masses of
approximately 7,650 and 7,500 dalton, respectively.331 In 1974, Megyesi and coworkers used a radioreceptor assay for NSILA-s
that was primarily responsive to IGF-II and noted that three of seven patients with non-islet cell tumors associated with
hypoglycemia had elevated serum concentrations of IGF-II.341 Further studies by this group indicated that nearly 40 percent of
patients with the syndrome had elevated serum IGF-II-like activity.322, 331 Daughaday and coworkers, using a different
radioreceptor assay, found that more than 90 percent of patients had elevated IGF-II concentrations in their serum.84 However, Zapf
and colleagues were unable to demonstrate elevated IGF-II concentrations using a different radioreceptor assay or an RIA.320, 342
These discrepancies were partially explained by Merimee, who noted elevated serum IGF-II concentrations in two patients with
non-islet-cell tumors as measured by a radioreceptor assay; however, 2-4 months later, when the sera were remeasured in the
same assay, the activity was lost, indicating that the IGF-II molecule produced by these tumors was unstable during storage. 334
Chromatography of serum and tumor extracts from these patients has revealed that 60 percent exhibit an increased proportion of a
high-molecular-weight precursor of IGF-II compared to that in normal serum, and in some patients virtually all the IGF-II is in the
big 10- to 15-kDa fraction. Finally, several investigators have shown that tumors contain IGF-II mRNA. Although it has
been suggested that NSILP may be responsible for the hypoglycemia found in some patients, levels of this protein have been
inconsistently elevated and have been noted to increase in some patients after the removal of hypoglycemia-producing tumors at a
time when the blood sugar levels have returned to normal.340, 343
From the available data, it would appear that the pathogenesis of non-islet-cell-tumor-associated hypoglycemia is multifactorial.
These tumors produce an increased quantity of a high-molecular-weight form of IGF-II, probably as a result of incomplete
processing of the protein. This 10- to 15-kDa IGF-II binds poorly to the circulating IGF-binding proteins. In contrast,
approximately 99 percent of normal 7.5-kDa IGF-II binds avidly to IGF-binding proteins, forming a 140-150 kD ternary complex
consisting of IGF-II, IGF-Binding Protein-3 and an acid-labile complexing component. This complex does not cross the capillary
membrane easily. With less protein binding, the high-molecular-weight IGF-II traverses the capillaries readily and is free to
interact with IGF receptors or insulin receptors present throughout the body, leading to an increase in glucose uptake by both the
tumor and peripheral tissues. In contrast to proACTH (POMC), the high-molecular-weight form of IGF-II retains receptor-binding
activity.343 The elevated IGF-II probably inhibits pituitary growth hormone secretion in a manner analogous to the inhibition
observed with IGF-I and insulin that is mediated through IGF-I receptors.348 This would account for the observed reduction in
serum growth hormone levels during periods of hypoglycemia or after arginine infusion and would also account for the lowered
concentrations of IGF-I in patients with this syndrome.349 The decreased growth hormone also lowers some of the species of IGF-
binding proteins, and this would further account for an increase in free IGF-II in the circulation. Finally, the elevated IGF-II
concentrations may lead to an inhibition of the release of gluconeogenic amino acids from muscle tissue, accounting for some of the
decrease in hepatic glucose output observed with this syndrome. 333

Clinical Manifestations and Diagnosis

In general, hypoglycemic symptoms may be divided into the sympathomimetic types of symptoms, such as tachycardia, diaphoresis,
piloerection, and tremulousness, which reflect a relatively rapid rate of fall of blood sugar, and the CNS symptoms, which reflect the
actual level of blood sugar. In patients with non-islet cell-tumor hypoglycemia, the neuroglucopenic symptoms predominate
because the rate of fall of blood sugar is generally slow.84,315,318,331 Thus, episodes of behavioral abnormalities, obtundation, seizures,
or coma, especially in the early morning or after fasting, are commonly observed. The symptoms are usually insidious and may be
intermittently present for weeks, months, or years before the diagnosis of the underlying neoplasm.
Other symptoms are related to the location and size of the neoplasm. Mesenchymal tumors are usually located in the
retroperitoneal, intra-abdominal, or thoracic regions and are associated with pain, abdominal fullness, cough, dyspnea, or
peripheral neurologic symptoms. When they are located within the abdomen or retroperitoneal space, a mass is often palpable.
Hepatomegaly, jaundice, fever, abdominal pain, and nonspecific symptoms including malaise, weakness, anorexia, and weight loss
are commonly seen in patients with hepatocellular carcinoma. The other large group of non-islet-cell tumors associated with
hypoglycemiaadrenocortical carcinomasmay have associated clinical findings of excessive glucocorticoids,
mineralocorticoids, or adrenal androgens.
The diagnosis of this syndrome requires the demonstration of fasting hypoglycemia with suppressed serum insulin concentrations
in association with the presence of a non-islet-cell neoplasm. It is important to keep in mind that during a 72-h fast, normal men
generally maintain a plasma glucose above 55 mg/dl, while normal women may have plasma glucose levels of 30 mg/dl or less. 350
The other causes of fasting hypoglycemia with suppressed insulin levels must be ruled out. These include fulminant liver failure,
chronic renal failure, severe malnutrition, adrenal insufficiency, alcohol use, and the ingestion of drugs that interfere with
gluconeogenesis. Measurements of IGF-II may be helpful if the levels are elevated but are not useful in the differential diagnosis if
they are normal, since some patients with this syndrome have normal total levels of IGF-II with an elevated proportion of high-
molecular-weight IGF-II, which binds poorly to the IGF-binding proteins.

Therapy
The only therapy that is uniformly effective in this syndrome is that directed at the primary tumor. Surgical extirpation, radiation
therapy, or chemotherapy may be effective in reducing the tumor bulk to the extent that the hypoglycemia disappears. If such
therapy is ineffective, frequent carbohydrate feedings and the administration of glucocorticoids, growth hormone, or glucagon may
ameliorate the symptoms. Diazoxide, phenytoin, and somatostatin are rarely effective. 330,331,351
The prognosis depends to a great extent on the underlying disease. In a review of mesenchymal tumors associated with
hypoglycemia, Anderson and Lokich noted that approximately 20 percent of the tumors are inoperable and that those which are
operable generally recur locally rather than with distant metastases.321 Most recurrences occur within 2 years of the primary
surgery. A little more than a third of patients with resected thoracic tumors exhibit a recurrence, while close to two-thirds of
abdominal lesions recur locally after the initial surgery. Approximately 25 percent of patients with thoracic tumors die of the
disease, while almost half with abdominal tumors die as a direct result of the neoplasm. The prognosis for patients with primary
hepatocellular carcinomas and malignant adrenocortical carcinomas associated with hypoglycemia is poor, with the majority of
patients succumbing within 1 year of diagnosis.

Oncogenic Osteomalacia
In 1947, McCance described a teenage female with an osteoid tumor of the femur associated with osteomalacia that improved after
removal of the tumor.352 However, it was Prader and coworkers who suggested a cause-and-effect relation while describing an 11-
year-old girl with osteomalacia associated with a giant cell reparative granuloma of a rib. 353 The osteomalacia improved after
removal of the granuloma.353 Subsequently, approximately 85 cases of oncogenic osteomalacia have been reported in the
literature.354
Incidence and Tumor Types
Oncogenic osteomalacia appears to be rare, although it is likely that the association is underreported because these tumors are often
small, usually measuring 1-4 cm in diameter, and are often located in unusual areas.354 Because these tumors may be quite
indolent, it is likely that many patients with mild idiopathic hypophosphatemic osteomalacia may actually have this
syndrome. Indeed, this syndrome may occur relatively frequently with tumors such as prostatic carcinoma. Lyles and associates
studied in detail two hypophosphatemic patients with prostatic carcinoma who had the typical clinical and biochemical findings of
oncogenic osteomalacia.355 They noted that 21 percent of the patients they studied with prostatic carcinoma had
hypophosphatemia, raising the possibility that they also suffered from a milder form of oncogenic osteomalacia.355
The vast majority of tumors associated with this syndrome are mesenchymal-derived neoplasms that contain multinucleated giant
cells, extensive vascularity, fibrous tissue, and often osteoid formation. The spectrum of tumors includes giant cell granulomas and
tumors, hemangiomas, fibromas, hemangiopericytomas, fibroangiomas, osteoblastomas, chondromas or chondroblastomas, and
fibrous xanthanomas.356, 357 Weidner and Santa Cruz classified the majority of these tumors into four groups: mixed connective
tissue tumors in soft tissue with prominent vascularity and osteoclast-like giant cells, osteoblastoma-like tumors in the bone,
nonossifying fibroma-like tumors in the bone, and ossifying fibroma-like tumors in the bone.358 Most but not all tumors fit this
classification. Tumors such as prostatic carcinoma are of endodermal origin, and oat cell carcinoma, which has also been associated
with this syndrome, is of neuroectodermal origin.359 Other tumors associated with this syndrome include sarcoma, multiple
myeloma, fibrous malignant histocytoma, neurofibromatosis, and neurinomas. 360,361,362,363 Electron microscopic studies of these
tumors have not shown the presence of secretory granules.354, 362
Approximately 10 percent of these tumors are malignant, and 5 percent are multiple.356 Fifty-five percent are located in bone,
approximately half of which are found in the long bones, including the femur and tibia. 354, 364 Another common site of involvement
is the head, with lesions being noted in the mandible, maxilla, skull, and ethmoid regions. Approximately 45 percent of these tumors
are found in soft tissues including skin, with two-thirds of the soft tissue tumors being located in the legs.354 The nasopharyngeal
region is another site of soft tissue involvement.
Clinical Features and Biochemical Abnormalities
More than 90 percent of patients present with generalized bone pain, especially involving the weight-bearing bones of the legs,
ankles, hips, and lower back. Profound muscle weakness is present in two-thirds, with approximately 40 percent exhibiting
abnormal gait or being bedridden. Fatigue, myalgias, and multiple fractures are also common complaints. The average age at onset
is 33 years and at the time of diagnosis is 38 years, with a range of 7-73 years, and symptoms are present for an average of 5 years,
with a range of 3 months-17 years. Males and females are affected equally.
Hypophosphatemia is uniformly present, with a mean phosphate level of approximately 1.5 mg/dl. Serum calcium concentrations
are generally normal, and alkaline phosphatase levels are elevated. Virtually all patients have a marked decrease in the renal
tubular reabsorption of phosphate with phosphaturia. Calcium and phosphorus balance studies have also demonstrated a decrease
in GI tract absorption of both minerals.366 Parathy- roid hormone and calcitonin levels are normal,356, 367 as are serum 25(OH)-
vitamin D and 24,25(OH)2-vitamin D levels.356 1,25(OH)2-vitamin D levels are undetectable or low (mean level of 13.4 pg/ml with
the normal range of 19-50 pg/ml) in more than 80 percent of the patients in whom this metabolite has been measured. One-third
of patients have aminoaciduria, and nearly half have glycosuria.

Pathophysiology
These patients exhibit an acquired Fanconi-like proximal renal tubular reabsorption dysfunction manifested by phosphaturia,
glycosuria, and aminoaciduria. In addition, they have a defect in the conversion of 25(OH)-vitamin D levels to 1,25(OH)2-vitamin
D in the proximal tubules, suggesting an inhibition of 25(OH)- vitamin D-1-hydroxylase enzyme.
The etiology of the proximal tubular defect in these patients is unknown but is clearly humoral in nature and is associated with an
underlying neoplasm. The evidence includes the association of the syndrome with the neoplasms, most of which are very similar
pathologically; the disappearance of the syndrome after removal of the tumor; and the recurrence of the syndrome with recurrence
of the neoplasm. The most convincing data come from experimental studies with tumor extracts and heterotransplantation. Saline
extracts of tumors have been shown to induce phosphaturia and decrease tubular reabsorption of phosphate in puppies, rats, and
mice. Tumors propagated in nude mice have resulted in hypophosphatemia, hyperphosphaturia, and a defect in the conversion of
25(OH)-vitamin D to 1,25(OH)-vitamin D.374,375,376 Cell culture medium from two tumors associated with the syndrome inhibited
sodium-dependent phosphate transport in cultured renal cells without stimulating cAMP.377,378 The factor, termed phosphatonin, is
heat labile and lipid insoluble with a mass between 8 and 25 kD. 32,33 One study showed that the activity was destroyed by trypsin.379
Fukumoto and coworkers pointed out the similarity between this syndrome and the features of maleic acid-induced proximal
tubular dysfunction but were unable to demonstrate the presence of maleic acid in the serum or urine of the patient they studied.368
The syndrome shares many similarities with x-linked hypophosphatemic rickets, which may also represent overproduction of
phosphatonin.32,33,378,379
The clinical features clearly reflect the profound hypophosphatemia and reduced 1,25(OH) 2-vitamin D levels. Bone biopsies
demonstrate osteomalacia with increased osteoclastic bone resorption, which probably accounts for the maintenance of the normal
serum calcium and normal parathyroid hormone level.380 The decrease or inhibition of the 25(OH)-vitamin D-1-hydroxylase
enzyme is all the more striking considering the profound degree of hypophosphatemia, which should be a potent stimulus for the
conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D.

Differential Diagnosis
A number of conditions that result in osteomalacia and hypophosphatemia must be considered. These include nutritional deficiency
in elderly house-bound individuals, adult-onset hypophosphatasia, intestinal malabsorption, renal tubular acidosis, vitamin D-
resistant rickets, chronic renal failure, phosphate-binding antacids, familial or acquired defects of renal tubular phosphate
transport seen with X-linked hypophosphatemic rickets, Fanconi's syndrome, heavy metal poisoning, and cystinosis. 354,356,358
These conditions can usually be eliminated from consideration through a careful family history, occupational and drug history,
consideration of the age at onset, and performance of tests for urinary phosphoethanolamine and serum alkaline phosphatase to
rule out adult-onset hypophosphatasia; fecal fat and D-xylose excretion for the evaluation of steatorrhea; ability of the urine to be
acidified after ammonium chloride administration; and a screen for heavy metal poisoning by cadmium, lead, or copper. 366, 381
Therapy
More than 80 percent of patients are cured with removal of the tumor. 354 If one considers only symptomatic patients, more than 90
percent have a complete disappearance of symptoms between 1 day and 1 year after total removal of the tumor. Within 1-2 days,
the serum phosphate usually increases, the tubular reabsorption of phosphate returns to normal, and the phosphaturia ceases.357 If
the tumor recurs, the syndrome generally also recurs.354
Massive doses of vitamin D, 1--(OH)-D3, and dihydrotachysterol have rarely been effective. Similarly, the administration of
phosphate (2 gm/day) alone has not induced symptomatic remissions, although 15-30 percent of patients show some degree of
improvement with the combination of phosphate and vitamin D administration. 354, 356 The most effective medical therapy is
supplementation with 1,25(OH)2-vitamin D (2-4 g), which has led to improvement in up to 70 percent of the patients in whom
it has been tried.354, 356 However, 1,25(OH)2-vitamin D alone rarely completely corrects the syndrome. The prognosis for these
patients is excellent, reflecting the generally benign nature of the majority of the underlying neoplasms.

Ectopic Growth Hormone and Growth Hormone Releasing Hormone Production

Ectopic Growth Hormone Production
In 1968, Steiner and associates described a patient with hypertrophic osteoarthropathy, adenocarcinoma of the lung, and elevated
serum levels of growth hormone, which reverted to normal after removal of the tumor. 382 The following year, Cameron and
coworkers described a similar patient with normal serum concentrations of growth hormone (GH) but elevated concentrations in
the lung tumor in comparison to the surrounding normal lung tissue. 383 Subsequently, Greenberg and coworkers demonstrated the
synthesis and release of GH from a poorly differentiated lung carcinoma associated with hypertrophic osteoarthropathy maintained
in tissue culture for 4 months.384 The tumor incorporated [14C]leucine into growth hormone that comigrated with monomeric
pituitary GH on both paper and Sephadex chromatography.
Immunoreactive GH has been found in 39 percent of bronchogenic carcinomas, including adenocarcinoma, large cell carcinomas,
and small cell carcinoma, although no arterial-venous difference in GH concentrations across the tumors were found. 385 Close to
two-thirds of gastric carcinomas have also been found to contain immunoreactive GH,385 and all 12 breast carcinomas studied
through immunohistochemistry by Ghosh and colleagues showed the presence of growth hormone-containing tumor cells.386 The
significance of these findings is open to question in view of the presence of both immunoreactive GH and receptor- assayable GH-
like material that is present in a number of normal tissues including the liver, kidney, lung, muscle, colon, stomach, and brain.17 In
addition, the possibility that proteolytic enzymes present in tissues may degrade the radiolabeled GH used in the RIAs must be kept
in mind. This possibility was illustrated by Caplan and associates, who described a young woman with acromegaly associated with a
cystic beta cell adenoma of the pancreas.387 The tumor tissue extract contained immunoreactive GH, which comigrated with GH
extracted from normal human pituitary, and serial dilutions of the tumor extract also demonstrated parallelism to the reference GH.
However, further investigation showed that the GH activity was spurious and was due to proteolytic enzyme damage of the tracer
used in the RIA. The acromegaly in that patient was subsequently shown to be due to the secretion of growth hormone releasing
hormone (GHRH) rather than GH.388
The clinical significance of the presence of GH in tumors is unclear. Many patients with lung cancer, carcinoids, and endometrial
carcinoma either fail to suppress serum GH after a glucose load or show a paradoxic increase. 389,390,391 For a time, GH was
considered a prime candidate for the humoral mediator of hypertrophic pulmonary osteoarthropathy. However, growth hormone is
not uniformly elevated in patients with osteoarthropathy. 382, 390 Full-blown acromegaly would be anticipated to be the consequence
of the ectopic secretion of growth hormone. However, to date, only the patient described by Melmed and colleagues with
acromegaly and an intramesenteric pancreatic islet cell tumor fulfills the criteria for ectopic growth hormone production, attesting
to its varity.40, 41 Also, some of the abnormalities in GH secretion in patients with tumors may be due to the secretion of GHRH,
somatostatin, or other substances.

Ectopic Production of Growth Hormone Releasing Hormone

In 1959, Altmann and Schutz described a patient who had acromegaly that did not respond to pituitary radiotherapy but remitted
after the removal of a pulmonary carcinoid tumor.392 In 1976, Sonksen and coworkers reported a patient with acromegaly whose
hormonal abnormalities remitted after the removal of a bronchial carcinoid tumor that did not contain immunoreactive GH.393
Subsequently, Shalet and colleagues described a similar patient and showed that the tumor cells grown in culture released a
substance that stimulated GH secretion from rat pituitary cells. 394 Partial purification and characterization of GHRH was described
by Frohman and associates in 1980, and in 1982 both Rivier and coworkers and Guillemin and colleagues independently isolated
and clinically characterized GHRH from patients with GHRH-secreting pancreatic islet cell tumors associated with
acromegaly.388,395,396,397

Tumor Types
To date, there have been 41 well-described patients with ectopic GHRH production associated with clinical acromegaly (Table 28-
18).398,400,401,402 Most of these patients harbor a carcinoid, especially a bronchial carcinoid, or a pancreatic islet cell tumor.
Elevations of plasma GHRH without acromegaly or marked elevations of growth hormone have been found in 15 of 44 (34 percent)
patients with small cell carcinoma of the lung, 2 of 28 (7 percent) patients with non-small cell lung carcinoma and 1 of 10 (10
percent) patients, with nonmalignant lung disease.403 The absence of acromegaly in these patients probably reflects the relatively
low concentration of GHRH in their sera.
Immunoreactive GHRH is present in a large proportion of carcinoids, islet cell tumors, small cell carcinomas of the lung,
pheochromocytomas, endometrial carcinomas, and medullary carcinomas of the thyroid tumor tissue extracts. 399,400,401,402 GHRH
has been localized immunohistochemically in islet cell tumors; carcinoid tumors of the lung, thymus, appendix, and cecum;
medullary carcinoma of the thyroid; small cell carcinoma of the lung; and pheochromocytoma. 404,405,406,407

TABLE 28-18. Tumors Associated with Ectopic GHRH Production

Immunochemical Studies

Clinical Immunohistochemical Presence of GHRH in Immunoreactive GHRH in

Acromegaly Tumor Tumors

Total (Malignant) N Positive, Percent

Tumor Type N Positive, Percent
Carcinoid 27 (13) 92 17 15 87
Bronchial 21 (8) 10 10 10
Intestinal 3 (2) 82 18 18
Other 3 (3)
Pancreatic islet-cell 9 (3) 81 17 49 37
Small cell carcinoma of lung 2 (2) 13 69
Sympathetic neural tumors 2 (0) 13 15 38 53
Adrenal adenoma 1 (0)
Medullary carcinoma of 8 50
thyroid
Source: From references 398402.

Many of these tumors contain other hormones as assessed by immunohistochemical means. Thus, somatostatin, gastrin, gastrin-
releasing peptide, calcitonin, insulin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and ACTH have been described
in association with GHRH-secreting tumors.399, 400
This is molecular heterogeneity of the GHRH produced by tumors. The predominant forms are GHRH (1-40)OH and GHRH (1-
44)NH2, with lesser amounts of GHRH (1-37)OH.399, 400 Additionally, a single patient was found to have the biologically inactive
GHRH (3-40)OH in his serum.399 These findings suggest that variable posttranslation proteolysis occurs to modify the forms of
GHRH produced by the tumors.
Clinical Features
Patients with GHRH-secreting tumors associated with acromegaly present at an average age of approximately 40 years with typical
acromegalic features. The diagnosis is made approximately 6 years after the onset of the disease and is somewhat shorter in patients
with pancreatic islet cell tumors and longer in patients with pulmonary carcinoid neoplasms. There is a female predominance, with
a female to male ratio of 2.7:1. In addition to the acromegalic features, other endocrine abnormalities may coexist. These include the
Zollinger-Ellison syndrome, insulin-induced hypoglycemia, galactorrhea, and hyperparathyroidism with pancreatic islet cell
tumors; galactorrhea, Cushing's syndrome, and carcinoid syndrome with carcinoid tumors; and catecholamine excess with
pheochromocytomas.400 GHRH-secreting tumors may also be present as part of the multiple endocrine neoplasia 1 (MEN 1)
syndrome. Symptoms from the mass effects of the underlying neoplasm also may be present and are especially apparent with the
bronchial carcinoids, which may produce cough, hemoptysis, atelectasis, and recurrent pneumonias that follow obstructive
pulmonary infections. Slightly more than one-third of these tumors are malignant, although most are slow-growing.

Diagnosis
The diagnosis of GHRH-secreting tumors is often made serendipitously after an attempt at neurosurgical removal of a
suspected growth hormone-secreting pituitary adenoma, at which time somatotrope hyperplasia is found rather than a pituitary
adenoma (with one exception in a patient with MEN).408, 409 Because somatotrope hyperplasia and the excessive secretion of GH
from the hyperplastic somatotropes are direct results of excessive GHRH stimulation, a search for a source of GHRH may then
uncover the neoplasm. In addition to peripheral sources of ectopic GHRH secretion, the possibility that the GHRH excess is due to
eutopic secretion from a hypothalamic hamartoma, choristoma, glioma, or gangliocytoma must be considered. 410
The standard diagnostic tests for acromegaly do not differentiate GH-secreting pituitary adenomas from GHRH-secreting tumors. In
both conditions, the sella turcica may be enlarged and there may appear to be an intrasellar tumor. Similarly, with both conditions,
GH does not suppress appropriately after the administration of glucose, immunoreactive GH in the serum may rise after a bolus
injection of thyrotropin releasing hormone (TRH) of insulin-induced hypoglycemia, and either no response or a rise in serum GH
may occur after the administration of exogenous GHRH.400,401,402,410 A higher percentage of patients with ectopic acromegaly have
elevated prolactin levels than in acromegalic patients with pituitary adenomas (71 vs. 29 percent, p < 0.01). 402 The only test that
clearly differentiates the two conditions is measurement of peripheral levels of GHRH. Normal individuals generally have GHRH
levels of 10 pg/ml or less, while patients with GHRH-secreting tumors have levels that range between 300 pg/ml and 50 ng/ml.400

Therapy
The most effective therapy for these patients is removal of the neoplasm. When this is accomplished, the acromegaly in virtually all
patients remits and the GH secretory dynamics return to normal. Even after partial debulking of tumors in the presence of
metastatic disease, there may be improvement in the acromegaly.400 In patients with persistent disease, the somatostatin analog
octreotide has led to clinical and biochemical improvement in the acromegaly as well as reduction in GH and GHRH levels,
indicating that the drug has a peripheral effect on the tumor as well as its known effect on the pituitary somatotropes. 401, 410
Dopamine agonists are not useful. The long-term prognosis of these patients is unclear, although only approximately 10-15 percent
have died directly from the disease.400

Ectopic Production of Placental Proteins

Human Chorionic Gonadotropin
Human chorionic gonadotropin is a eutopic product of gestational and nongestational trophoblastic disease. Before the development
of the -hCG RIA, several case reports described patients with the ectopic production of hCG. The associated tumors were
bronchogenic carcinoma, hepatoma or hepatoblastoma, adrenocortical carcinoma, melanoma, undifferentiated retroperitoneal
carcinoma, breast carcinoma, and renal cell carcinoma.411 Two clinical syndromes were present in most of the patients reported.
Adult males exhibited gynecomastia and occasionally other signs of feminization, and isosexual precocious puberty was present in
young boys with hCG-secreting hepatoblastomas.411, 412 After the development of sensitive and specific hCG RIAs, immunoreactive
hCG was found to be present in approximately 18 percent of patients with a wide variety of nontrophoblastic neoplasms (Table 28-
9).114 Most of these patients do not have clinical symptoms attributable to the hCG primarily because the quantities of hCG are quite
low in all but a fraction of them. Also, the majority of the hCG assays used in these studies measure both intact hCG and its
biologically inactive -subunit. Recent studies with specific assays have shown that it is the free hCG-subunit that is present in the
circulation of patients with hCG-secreting nontrophoblastic neoplasms.413 Because an hCG-like substance is present in the blood of
normal individuals and patients with a variety of benign diseases (Table 28-10), hCG measurements are not useful as a screening
test for nontrophoblastic neoplasms. In addition, the presence or absence of hCG and the quantitative levels generally show poor
correlation with the stage of disease, may not show concordant changes with disease progression or regression, and have little or no
prognostic value.114 Recently, there has been interest in the measurement of a fragment of the subunit of hCG, the -core
fragment, which is present in the urine of one-half to three-quarters of patients with cancer and 6 percent of nonpregnant healthy
individuals.414

Human Placental Lactogen

Human placental lactogen (hPL), which, like hCG, is normally secreted by the syncytiotrophoblast of the placenta during pregnancy,
is also found in patients with gestational and nongestational trophoblastic disease. However, unlike hCG, serial measurements of
hPL in those conditions are not useful for monitoring the effects of therapy because the concentrations of this hormone are
generally low. hPL has also been noted to be produced ectopically by nontrophoblastic neoplasms, especially those of gynecologic or
GI tract origin (Table 28-19).114 Although overall approximately 14 percent of patients with cancers may have small quantities of
immunoreactive hPL in their sera, close to half the tumor specimens that have been examined immunohistochemically for the
presence of hPL have been found to contain cells that stain positively for this hormone. However, hPL has also been detected by
immunohistochemical techniques in approximately 13 percent of benign breast disease, and the specificity of hPL as a tumor
marker thus is questionable.417, 418 As with hCG, hPL measurements do not consistently correlate with disease stage or changes in
tumor mass or provide prognostic information.27,419,420,421

TABLE 28-19. Immunoreactive hPL in Sera of Patients with Cancer and Control Patients
Tumor or Site N Positive, Percent

Patients with cancer

Gynecologic 344 30.8
Ovary 219 38.4
Cervix 125 17.6
Gastrointestinal 274 13.5
Esophagus 16 0
Gastric 46 26.1
Colon/rectum 174 9.2
Hepatic 24 29.2
Biliary 13 15.4
Leukemia 13 7.7
Lung 64 4.7
Prostate 57 0
Miscellaneous 60 15
Total 812 14.3
Controls N Positive, Percent
Normal volunteers455 0
Benign disease 180 0
Breast 57 0
Gastrointestinal 54 0
Genitourinary 19 0
Other 50 0
Total 630 0

TABLE 28-20. Paraneoplastic Erythrocytosis Associated with Neoplasms and Other Pathologic Conditions in 340 Patients
Percent of Total
Site of Pathology
Kidney 52.6
Hypernephroma 35.3
Cystic kidney 10.3
Hydronephrosis 4.1
Wilms' tumor 0.9
Hemangioma 0.9
Adenoma 0.6
Sarcoma 0.6
Liver (primarily hepatoma) 18.8
Central nervous system (cerebellar 14.7
hemangioblastoma)
Uterus (fibromyoma) 7.4
Adrenal (adrenocortical adenoma, 3.2
carcinoma; pheochromocytoma)
Ovary 2.1
Lung 0.9
Thymus 0.3
422
Source: From Hammond and Winnick, with permission. Also noted with leiomyoma of esophagus and skin,423 fibrous
histiocytoma of parotid,424 hepatic hemangioma,425 and breast cancer.426

Paraneoplastic Erythrocytosis
Polycythemia is associated with benign and malignant lesions of the kidney as well as neoplasms of the liver, cerebellum, uterus,
and adrenal (Table 28-20).422,423,424,425,426 In the majority of the patients studied with erythrocytosis, elevations of the serum or
tissue levels of erythropoietin have been noted (Table 28-21). Approximately 3-4 percent of patients with hypernephroma, 3-12
percent of patients with hepatocellular carcinoma, and 9-20 percent of patients with cerebellar hemangioblastoma exhibit
erythrocytosis. Serum erythropoietin levels are increased in up to one-third of patients wih renal cell carcinoma and 23 percent of
individuals with hepatocellular carcinoma, although the majority of patients in these studies did not have erythrocytosis. 435, 436 This
discrepancy may relate to the conteracting effects of the inhibition of erythrocytosis by malignancy or to the secretion of a
biologically inactive form of erythropoietin. Alternatively, the anemia that often accompanies malignancy may result in tissue
hypoxia that serves as a potent stimulus for physiologic erythropoietin production.437
TABLE 28-21. Proportion of Patients with Paraneoplastic Erythrocytosis Who Exhibit Elevations of Serum and Tissue Erythropoietin
Concentrations
Increased Serum Increased Tissue
Erythropoietin Erythropoietin

Condition N TotalN Elevated (Percent)N TotalN Elevated (Percent)

Cystic kidney 11 5 (45) 12 10 (83)
Hypernephroma 10 9 (90) 13 11 (85)
Hepatoma 9 6 (67) 8 2 (25)
Cerebellar hemangio- blastoma10 6 (60) 6 6 (100)
Uterine fibromyoma 6 0 (0) 6 2 (33)
Hydronephrosis 5 4 (80) 2 0 (0)
Pheochromocytoma 2 2 1 1
Wilms' tumor 2 2 2 2
Source: From references 422 and 427432.

Because erythropoietin is normally produced by the kidney and liver, the production of excessive quantities of this hormone in
benign and malignant renal and hepatic disorders probably represents eutopic production. Most of the data concerning
erythropoietin production by tumors have come from studies of renal cell carcinoma. Several investigators have demonstrated the
secretion of erythropoietin by tumor cells in vitro438,439,440 as well as the presence of erythropoietin mRNA by in situ hybridization in
several hypernephromas with an absence of the mRNA in adjacent normal kidney cells. 432 The erythropoietin from a cerebellar cyst
was physiochemically similar to erythropoietin derived from anemic patients. 441 In addition to the eutopic or ectopic production of
erythropoietin, other mechanisms may be responsible for erythro- cytosis. Thus, virilizing ovarian or adrenal tumors that secrete
androgens may lead to the stimulation of erythropoiesis. Glucocorticoid-producing adrenal tumors may result in stress
polycythemia, and excessive production of prostaglandin A or E may stimulate erythropoiesis through enhancement of
erythropoietin action on the erythrocyte progenitor cells in the marrow.422
The diagnosis of polycythemia is generally made fortuitously when a serum hematocrit is found to be elevated above 55 percent in a
male and 50 percent in a female, reflecting the increase in total red cell mass. In most instances, the erythrocytosis is asymptomatic,
although venous thrombosis may occur as an unusual complication. 429 Paraneoplastic erythrocytosis may be differentiated from
dehydration with hemoconcentration and stress polycythemia through the absence of clinical findings of dehydration and the
presence of an increase in the total red cell mass, which is elevated in paraneoplastic erythrocytosis but normal in stress
polycythemia. Measurements of the partial pressure of oxygen in arterial blood and hemoglobin electrophoresis allow
differentiation from secondary polycythemia due to hypoxia or the presence of a hemoglobinopathy. Erythrocytosis is a prominent
feature of polycythemia vera, but these patients also exhibit pancytosis with elevations of the white cell and platelet counts as well
as splenomegaly. Elevated serum erythropoietin concentrations are found in patients with paraneoplastic erythrocytosis as well as
other secondary causes of polycythemia, while the levels tend to be normal or low in patients with polycythemia vera. Successful
removal of the erythropoietin-producing tumor is associated with a decrease in erythropoietin levels and a decrease in the
erythrocytosis.422 If tumor removal is not possible and the patient develops the symptomatic form of polycythemia, phlebotomy may
relieve the symptoms.429

Ectopic Production of Calcitonin

Serum calcitonin measurements are useful for the diagnosis and monitoring of therapy in patients with medullary carcinoma of the
thyroid or C cell hyperplasia. In 1970, Milhaud and coworkers described a patient with hypercalcitonemia associated with a
bronchial carcinoid tumor.442 Since then, several investigators have measured calcitonin in the serum of patients with neoplasms
and overall have found elevations in approximately half the patients studied and 6.7 percent of patients with benign disorders
(Table 28-22). Many of the tumors associated with hypercalcitonemia have APUD characteristics and include small cell carcinoma
of the lung, carcinoid tumors, pheochromocytomas, melanoma, and islet cell tumors. Elevated tissue calcitonin concentrations have
been found in 95 percent of APUD-type tumors and close to 40 percent of tumors without APUD characteristics. 455 Although some
investigators have been unable to detect calcitonin in normal tissues others have been able to extract calcitonin from a variety of
normal tissues or demonstrate calcitonin by immunohistochemical techniques in normal tissues. 456, 457 Between 16 and 38 percent
of the patients studied have had a rise in serum calcitonin levels after pentagastrin administration, although the increase is
proportionally less than that found in patients with medullary carcinoma of the thyroid. 447,448,545
TABLE 28-22. Serum Immunoreactive Calcitonin Levels in Patients with Malignancies and Benign Diseases
Number Positive/
Total Number Positive, Percent
Tumor
Lung 127/257 49.4
Small cell 91/147 61.9
Squamous 15/55 27.3
Adenocarci- noma 16/38 42.1
Anaplastic/large cell 4/13 30.8
Alveolar 1/4 25.0
Carcinoid 5/11 45.5
Breast 36/73 49.3
Colon 8/30 26.7
Stomach 4/11 36.4
Esophagus 0/2 0
Pancreatic 6/15 40
Melanoma 4/10 40
Leukemia 48/57 84.2
CGL 32/33 97
AML 8/8 100
Other myelopro- liferative 8/11 72.7
CLL 0/10 0
ALL 0/2 0
Miscellaneous 3/10 30
Total 289/540 52.0
Benign
Normal and miscellaneous controls 2/100 2
Benign breast 0/75 0
GI 13/59 22
Benign pulmonary 5/65 7.7
Total 20/299 6.7

The source of the calcitonin excess in patients with nonmedullary cancers is unclear, as a catheterization study in such patients
demonstrated that four of six patients had elevated calcitonin levels emanating from the thyroid rather than from the tumor. The
apparent high frequency of hypercalcitonemia in patients with neoplasms may actually be an artifact in some assays. Roos and
colleagues showed that heating of serum from patients with squamous cell carcinoma and hypercalcitonemia abolished the elevated
immunoreactive calcitonin but did not alter the immunoreactive calcitonin present in patients with small cell carcinoma of the lung
or adenocarcinoma of the lung.Nevertheless, it is clear that some tumors are capable of synthesizing and secreting calcitonin. Tumor
cells derived from squamous cell carcinoma of the lung, small cell carcinoma of the lung, and breast carcinoma have been shown to
produce immunoreactive calcitonin in vitro. A calcitonin-producing breast carcinoma was propagated in nude mice and continued
to proliferate and secrete calcitonin.
In culture, several of these tumors produce high-molecular-mass species of calcitonin including 40-, 13-, and 10-kDa proteins.In
the BEN squamous cell carcinoma of the lung cell line, both high-molecular-mass species and biologically active 3,500-dalton
calcitonin are secreted.461 A greater proportion of the immunoreactive calcitonin present in the circulation of patients with
nonthyroid tumors exists in large-molecular-weight forms than is found in the plasma of patients with medullary carcinoma of the
thyroid.459 The calcitonin mRNA from the BEN cell line closely resembles the calcitonin mRNA from medullary carcinoma of the
thyroid, as do the translation products produced in a wheat germ system. However, other human lung tumor cell lines that contain
mRNA for both calcitonin and calcitonin gene-related product have calcitonin mRNA that is larger than that found in medullary
thyroid carcinoma.464 Thus, as is the case with ectopic ACTH-secreting tumors, some calcitonin-secreting neoplasms may exhibit
abnormalities in transcription of calcitonin mRNA or posttranslational processing of synthesized preprocalcitonin or procalcitonin.
There are no clinical manifestations of calcitonin excess in patients with nonthyroid neoplasms. The differential diagnosis of
hypercalcitonemia in these patients includes the presence of chronic renal failure, acute pancreatitis, sepsis, hypercalcemia, and
pernicious anemia.112, 465
Other Hormones Produced by Tumors
Prolactin
In 1971, Turkington described a 53-year-old male with an undifferentiated bronchogenic carcinoma who exhibited
hyperprolactinemia, which decreased after a course of radiation therapy to the tumor. He also described a 49-year-old woman with
hypernephroma, hyperprolactinemia, and galactorrhea who exhibited a return of prolactin to the normal range after surgical
resection of the tumor. The hypernephroma was grown in culture and continued to release prolactin over a 2-week period.
Turkington noted that only 1 of 21 patients with lung cancer had hyperprolactinemia. In contrast, one-third of 21 patients with
lung cancer studied by Davis and colleagues had hyperprolactinemia, although none exhibited gynecomastia, galactorrhea, or
hypogonadism. In patients who were tested, there was a normal prolactin response to L-dopa and TRH. There was no correlation
with the presence or absence of hyperprolactinemia or the quantitative level of the prolactin elevation and the histology or tumor
burden in these patients. In a larger study, Molitch and coworkers examined 215 patients with cancer and found that 15 (7
percent) had hyperprolactinemia. However, 12 of these 15 patients were receiving phenothiazines or opiates or had undergone
prior radiation therapy to the chest wall or brain, which could account for the prolactin elevation. In fact, only two patients (1
percent) had hyperprolactinemia without another known cause being present. Elevated serum prolactin levels were found in 31
percent (229/743) of patients with uterine cervical carcinoma.The authors did not note whether the patients were taking
medications that could lead to hyperprolactinemia or control their assay for protease activity that can artifically elevate prolactin
levels by degrading the radioiodinated prolactin tracer in the RIA. Thus, the true prevalence of ectopic prolactin secretion in their
study is not known. They also found immunohistochemical localization of prolactin in 22 or 49 (41 percent) cervical carcinoma
specimens and evidence of prolactin secretion into the medium of 5 of 8 primary cervical carcinoma tissue cultures.
Immunoreactive prolactin has been found in a variety of other tumor tissues and cell lines. 2

Vasoactive Intestinal Peptide

The syndrome of pancreatic cholera also referred to as the WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria) or
Wermer-Morrison syndrome, is associated with excessive production of VIP and is usually associated with a non--cell tumor of
the pancreatic islets. Using a sensitive RIA, Said and Faloona found elevated VIP concentrations in five of six patients with lung
carcinoma and in a patient with a ganglioneuroblastoma of the adrenal and another patient with a pheochromocytoma. 473 Elevated
levels of VIP were also present in the tumor tissue.473 Subsequent studies demonstrated an arterial-venous gradient in VIP
concentration across a malignant renal APUDoma associated with this syndrome 474 and the presence of VIP by immunoperoxidase
staining in ganglioneuromas, ganglioneuroblastomas, and neuroblastomas.475, 476 Removal of the tumor is effective in lowering
plasma VIP concentrations and reversing the syndrome. For tumors that are nonresectable, the long-acting somatostatin analog
octreotide may be effective in suppressing VIP production by these tumors, as has been shown in patients with VIP-secreting non-
-islet-cell tumors of the pancreas.477

Somatostatin
Elevated concentrations of plasma immunoreactive somatostatin have been identified in patients with small cell carcinoma of the
lung and carcinoid tumors, often in association with the ectopic production of ACTH. 455, 478 Elevated concentrations of somatostatin
have also been identified in tumor extracts from carcinoids and small cell cancer of the lung as well as in small cell cancer of the
lung cell lines.455,478,479 There is substantial heterogeneity in the somatostatin molecules that have been extracted from tumor tissues,
with species 13,3-4, and 1.6 kDas being noted.478 No clinical manifestations have been described from the excessive production of
somatostatin by these tumors, probably because the actual concentrations of somatostatin in plasma are rather low in comparison to
the concentrations in patients with pancreatic somatostatinomas. 478

Other Gastrointestinal Hormones

Ectopic gastrin production associated with the Zollinger-Ellison syndrome has been reported with an ovarian cystadenoma and a
pancreatic cystadenocarcinoma.480, 481
Glucagon secretion has been described in a patient with a renal endocrine tumor who exhibited edema, rash, malabsorption, villous
hypertrophy of the small intestine, and decreased motility of the jejunum and colon, which reversed after removal of the tumor.482
Hunstein and coworkers reported a 76-year-old male with a glucagon-secreting large cell carcinoma of the lung who exhibited a
typical glucagonoma syndrome with necrolytic migratory erythema, glucose intolerance, and weight loss. 483 Elevated glucagon
levels were present in the patient's plasma, and immunoreactive glucagon was found in the carcinoma cells, with no abnormalities
noted in the pancreas.483 Immunoreactive glucagon also has been found in lung carcinoma and ovarian carcinoid tumors. 483, 484
Immunoreative bombesin-like peptide, which probably represents its mammalian counterpart, gastrin-releasing peptide, has been
found in a variety of tumors, including lung cancers associated with ectopic ACTH, carcinoid tumors, medullary carcinoma of the
thyroid, and pheochromocytoma. Increased levels have also been found in the peripheral circulation of two patients with bronchial
carcinoids and one with medullary carcinoma of the thyroid. 485 No clinical symptoms have been attributed to excessive production
of this peptide.

Renin
Renin production has been associated with several tumors, including Wilms' tumor (nephroblastoma), juxtaglomerular cell tumors
(hemangiopericytomas), and hypernephroma, which may be considered to be eutopic sources of the hormone. Ectopic production
has been found in ovarian carcinomas, pancreatic adenocarcinomas, lung tumors, acute myeloid leukemia, and an adrenal
paraganglioma. Some of the renin-producing tumors are associated with hypokalemic alkalosis and hypertension, while others are
not. In addition to renin, prorenin may be secreted by these tumors. Removal of the tumors cures the hypertension and hypokalemia.
Unresectable lesions may be treated with inhibitors of angiotensin-converting enzyme.