Paraneoplastic Endocrine Syndromes
Subhash Kukreja
Cancer cells frequently produce peptides that are not normally synthesized by the tissue of origin. In addition, peptides that are normally produced in a paracrine or autocrine manner may be produced in larger quantities by the cancer cells and released into the circulation. Cancer cells frequently lack the machinery to process peptides into mature hormones, and therefore, only precursor or incomplete forms of the protein are released. These partial peptides or precursor forms of the hormones may either be biologically inactive or may have weak biologic activity. Therefore, clinical syndromes due to ectopic production of these hormones are seen less frequently than might be predicted, based on the immunoassay studies. Ectopic production of steroid hormones by cancer cells is rare. However, steroid hormones may be present in higher concentration because of increased production of enzymes by the tumor cells e.g., synthesis of 1α-hydroxylase by certain lymphomas allows increase in the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D]. Another example is an increased aromatase activity in hepatocellular carcinoma with conversion of androgens to estrogens, resulting in gynecomastia.
Paraneoplastic syndrome is defined as the tumor-related clinical manifestations that occur distant from the site of the tumor and are mediated by humoral factors. Hypercalcemia of malignancy (HM) and syndrome of inappropriate antidiuretic hormone (SIADH) are the more common clinical syndromes due to ectopic hormone production. SIADH is covered elsewhere in this volume. The other ectopic endocrine syndromes are described in this chapter. There are other nonendocrine paraneoplastic manifestations of cancer, which are not covered in this chapter (e.g., polycythemia, various neuropathies, cerebellar degeneration, etc.).
HYPERCALCEMIA OF MALIGNANCY
Definition
Under physiologic conditions, serum calcium is maintained within a narrow range. Serum calcium is bound to proteins that are composed predominantly of albumin so that under normal conditions, approximately 45% of the calcium is available in the physiologically active, ionized, or free form. In the presence of hypoalbuminemia,
serum total calcium values may be low, whereas ionized calcium values may be normal or even elevated. Conversely, in some cases of multiple myeloma, abnormal globulins may bind calcium so that serum total calcium is high and ionized calcium is normal [1, 2]. Various correction formulas have been devised to correct serum total calcium for serum protein/albumin concentrations. These correction formulas are derived from regression analysis of serum calcium and albumin/total proteins. None of these formulas accurately predicts the state of ionized calcium [3, 4]; therefore, ionized calcium should be measured to assess the calcium status accurately when protein abnormalities are present.
serum total calcium values may be low, whereas ionized calcium values may be normal or even elevated. Conversely, in some cases of multiple myeloma, abnormal globulins may bind calcium so that serum total calcium is high and ionized calcium is normal [1, 2]. Various correction formulas have been devised to correct serum total calcium for serum protein/albumin concentrations. These correction formulas are derived from regression analysis of serum calcium and albumin/total proteins. None of these formulas accurately predicts the state of ionized calcium [3, 4]; therefore, ionized calcium should be measured to assess the calcium status accurately when protein abnormalities are present.
HM is defined as the presence of elevated serum calcium levels in a patient with cancer (either solid tumor or hematologic) in whom the hypercalcemia is caused by factors produced by the cancer. This implies that the hypercalcemia should be reversed by the removal of the tumor. In practice, however, complete removal or cure of the tumor can rarely be achieved because the disease is often advanced by the time the diagnosis of hypercalcemia is made. Other diseases associated with hypercalcemia (e.g., primary hyperparathyroidism, sarcoidosis, excessive vitamin D intake) can occur coincidentally in patients with malignancy and should be excluded. This is particularly important because the presence of hypercalcemia in a patient with cancer indicates an extremely poor prognosis. If it can be shown that the hypercalcemia in a cancer patient is not due to malignancy, this may indicate a better prognosis.
Etiology
If bone metastases are present in a hypercalcemic cancer patient, it is traditionally assumed that the bone metastases are responsible for the hypercalcemia. In an examination of serum calcium values in patients with bone metastases, however, Ralston et al. [5] demonstrated that contrary to expectations, an inverse correlation existed between serum calcium levels and the number of bone metastatic lesions in patients with various malignancies. Hypercalcemia is frequently observed without significant bone metastases in certain types of tumors (e.g., squamous cell cancers), whereas in other tumors (e.g., small cell carcinoma of the lung and prostate cancer), bone metastases are frequently observed in the absence of hypercalcemia.
Bone resorption is increased in most patients with HM. Various osteolytic factors secreted by cancer cells have been described. These osteolytic factors may increase bone resorption by both local and endocrine effects. The major osteolytic factor produced by solid tumors is parathyroid hormone-related protein (PTHrP) [6]. The peptide has structural homology to parathyroid hormone (PTH) in only 8 of the first 13 amino acids, and yet a remarkable similarity exists in the biologic actions of the two peptides. Elevated levels of serum PTHrP are observed in patients with hypercalcemia resulting from solid tumors, including breast cancer [6]. Breast cancer cells derived from the bone marrow lesions produce PTHrP with greater frequency than do those derived from other metastatic sites [7].
In the case of multiple myeloma, other hematologic malignancies, various other cytokines, such as tumor necrosis factors, RANK ligand, interleukins (IL)-1 and -6, hepatocyte growth factor, and macrophage inflammatory protein-1α result in locally increased osteolysis [8]. Locally increased PTHrP production has also been demonstrated in these cancers as a mediator of increased osteolysis. In addition, serum PTHrP levels have been shown to be elevated in about onethird of patients with multiple myeloma and other hematologic malignancies [9]; therefore, PTHrP may contribute to the pathogenesis of hypercalcemia in these cancers through both local and endocrine mechanisms. Myeloma cells also produce factors that inhibit bone formation (DKK1, IL-3, IL-7, soluble frizzle-related
protein [FRP]-2), and the bone lesions due to myeloma often lack a reactive osteoblastic component resulting in a negative nuclear bone scan despite the presence of bone metastases [10].
protein [FRP]-2), and the bone lesions due to myeloma often lack a reactive osteoblastic component resulting in a negative nuclear bone scan despite the presence of bone metastases [10].
HM has been classified as either humoral hypercalcemia of malignancy (HHM) based on absent or minimal bone involvement and an elevation in nephrogenous urine cAMP levels (due to increase in PTH-like effects on the kidney) or local osteolytic hypercalcemia (LOH) seen in patients with hematologic malignancies and breast cancer with extensive bone involvement [11]. While this is a useful concept, there may be significant overlap between the mechanisms responsible for these two types of HM.
Another factor that plays a role in the pathogenesis of hypercalcemia in Hodgkin and non-Hodgkin lymphomas is increased serum 1,25(OH)2D production [12]. In these tumors, the lymphomatous tissue is able to convert 25-(OH)D into the active metabolite, 1,25(OH)2D. Serum 1,25(OH)2D levels are elevated in these patients (unlike in hypercalcemia of solid tumors and multiple myeloma, where these levels are suppressed).
Therefore, PTHrP is the main factor responsible for the hypercalcemia in most solid tumors and in some hematologic malignancies. The local effects of PTHrP result in increased bone resorption, whereas the endocrine effects result in increased phosphaturia and relative decrease in urine calcium excretion. Serum PTHrP may be normal in some patients (up to 20% of patients) with HM due to solid tumors without bone metastases [13]. It is not known whether this represents the inability of the current assays to detect the type of PTHrP molecules that are present in these patients; alternatively, hypercalcemia in these patients may be caused by other unknown osteolytic factors. Increased 1α-hydroxylase activity resulting in increased serum 1,25(OH)2D is the responsible factor in many cases of Hodgkin and non-Hodgkin lymphomas, whereas various cytokines may be responsible for the hypercalcemia in multiple myeloma and other hematologic malignancies. In patients with breast cancer, the hypercalcemia usually occurs at a time when there is extensive tumor bony involvement. However, serum PTHrP levels are elevated in many of these patients, suggesting an important role of this peptide in the development of hypercalcemia both in patients with or without bone metastases.
Epidemiology
Hypercalcemia has been reported to affect about 10% to 40% of all patients with cancer at some time during the course of the disease. However, this may reflect a selection bias, especially if the studies are done in hospitalized patients. Hypercalcemia occurs in late stages of cancer, and such patients are more likely to be hospitalized. At the time of initial presentation, the incidence of hypercalcemia in cancer patients is about 1% [14]. Non-small cell lung cancer, renal cancer, lymphoma, multiple myeloma, and breast cancer are the malignancies most commonly associated with hypercalcemia. The highest incidence of hypercalcemia on a percentage basis is observed in renal cell carcinoma [14]. Carcinoma of the prostate and colon and small cell carcinoma of the lung are rarely associated with hypercalcemia, despite a high prevalence of bone metastases in these cancers.
Pathophysiology
PTH-related protein, despite its limited homology to PTH, appears to act through the same receptor as PTH (PTH/PTHrP type I receptor). The clinical features of HM due to solid tumors are similar to those of hyperparathyroidism in many respects (e.g., hypercalcemia, hypophosphatemia, relative hypocalciuria, and increased bone resorption). In other aspects, manifestations of hypercalcemia malignancy due to PTHrP overproduction are different from those of primary
hyperparathyroidism, and these include relatively lower serum 1,25(OH)2D and decreased bone formation observed in HM [15]. The decreased bone formation observed in HM may be related to the secretion of other cytokines (e.g., IL-1 and IL-6), although the mechanisms remain largely unexplained. In the case of Hodgkin and non-Hodgkin lymphomas, the elevated serum 1,25(OH)2D levels enhance gastrointestinal (GI) calcium absorption, and serum PTH is suppressed with increased serum phosphate and urine calcium excretion.
hyperparathyroidism, and these include relatively lower serum 1,25(OH)2D and decreased bone formation observed in HM [15]. The decreased bone formation observed in HM may be related to the secretion of other cytokines (e.g., IL-1 and IL-6), although the mechanisms remain largely unexplained. In the case of Hodgkin and non-Hodgkin lymphomas, the elevated serum 1,25(OH)2D levels enhance gastrointestinal (GI) calcium absorption, and serum PTH is suppressed with increased serum phosphate and urine calcium excretion.
Diagnosis
Primary hyperparathyroidism is the most common cause of hypercalcemia in the general population. In most instances, the hypercalcemia has been present for a long time and is mild to moderate. In HM, which is the second most common cause of hypercalcemia, the hypercalcemia is usually more severe and occurs over a relatively short time. This hypercalcemia manifests late in the course of the malignancy, and the tumor is generally advanced by the time diagnosis of hypercalcemia is confirmed. A complete history and physical examination and simple laboratory and radiologic studies would generally reveal the source of malignancy (i.e., lung cancer, head and neck cancer, carcinoma of the esophagus, breast cancer, multiple myeloma, lymphomas). Retroperitoneal tumors (e.g., renal cell cancer and some lymphomas) may not be readily apparent on initial evaluation, but even in these instances, clinical signs and simple imaging studies often reveal cancer. The laboratory test with the highest yield in the differential diagnosis of hypercalcemia is measurement of serum PTH. Serum PTH level is elevated or in the high-normal range in all patients with primary hyperparathyroidism. Conversely, serum PTH levels are suppressed in almost all cases of HM, with the rare exception of a few reported cases of the production of native PTH by cancer [16]. In the presence of a tumor type that is commonly associated with HM, the presence of suppressed PTH level confirms the etiology of hypercalcemia. If serum PTH levels are elevated, then the patient, in all likelihood, has concomitant hyperparathyroidism. If hypercalcemia is observed in association with a tumor type not commonly associated with hypercalcemia (e.g., small cell cancer of the lung, prostate cancer, colon cancer) and serum PTH levels are suppressed, another cause of the hypercalcemia should be sought. Serum PTHrP levels are increased in 80% to 100% of patients with hypercalcemia due to solid tumors, and this assay may be used in patients in whom the cause of hypercalcemia is not readily apparent. Serum 1,25(OH)2D measurements is of value in the diagnosis of hypercalcemia in granulomatous disease and Hodgkin and non-Hodgkin lymphomas, in which these levels are usually elevated. Serum and urine protein electrophoresis is helpful for the diagnosis of multiple myeloma. In the presence of normal renal function, serum phosphate values are low or in the low-normal range in HM, similar to that seen in the primary hyperparathyroidism. Other tests (e.g., 24-hour urine calcium, urinary cyclic adenosine monophosphate [cAMP] measurements) are of limited value in the differential diagnosis.
Treatment
Patients with hypercalcemia are often volume depleted because of nausea, vomiting, and polyuria, which is a result of a decrease in urine-concentrating ability from a direct effect of hypercalcemia on the renal tubules. Infusion of 3 to 4 l/d of normal saline reduces the serum calcium concentration by 1.0 to 1.5 mg/dl. Increased bone resorption is the major mechanism by which the tumors produce hypercalcemia; agents that inhibit osteoclast activity are highly effective in management of these patients. The agents in this class are plicamycin, calcitonin, gallium nitrate, and bisphosphonates [17]. Bisphosphonates are potent antiresorptive agents that have become the drug of choice for treatment of
hypercalcemia. The first bisphosphonate to be used for this purpose was etidronate, but its use has been replaced by the second- and third-generation bisphosphonates (e.g., pamidronate, alendronate, and zoledronate). Intravenous pamidronate and zoledronate are now approved for treatment of HM. Pamidronate, 30 to 90 mg given over a 2- to 4-hour infusion, is as effective as the dose given over 24 hours. A flu-like syndrome is seen in up to 20% of patients, but this adverse effect is transient. Hypocalcaemia may occasionally occur in a small percentage of patients but is usually asymptomatic [18, 19]. Zoledronate appears to be a more potent bisphosphonate than pamidronate [20]. More-rapid administration of zoledronate (i.e., over a 5-minute period) is associated with the risk of development of renal failure and therefore is not recommended. Other bisphosphonates, such as ibandronate and clodronate, are also effective. These latter compounds are not approved for use in the United States but are widely used in other countries [19]. The initial effects of bisphosphonates on reduction in serum calcium are observed within 12 to 24 hours, with peak effect being observed in 4 to 7 days. The effect generally lasts for 1 to 3 weeks, depending on the extent of PTHrP production by the tumor.
hypercalcemia. The first bisphosphonate to be used for this purpose was etidronate, but its use has been replaced by the second- and third-generation bisphosphonates (e.g., pamidronate, alendronate, and zoledronate). Intravenous pamidronate and zoledronate are now approved for treatment of HM. Pamidronate, 30 to 90 mg given over a 2- to 4-hour infusion, is as effective as the dose given over 24 hours. A flu-like syndrome is seen in up to 20% of patients, but this adverse effect is transient. Hypocalcaemia may occasionally occur in a small percentage of patients but is usually asymptomatic [18, 19]. Zoledronate appears to be a more potent bisphosphonate than pamidronate [20]. More-rapid administration of zoledronate (i.e., over a 5-minute period) is associated with the risk of development of renal failure and therefore is not recommended. Other bisphosphonates, such as ibandronate and clodronate, are also effective. These latter compounds are not approved for use in the United States but are widely used in other countries [19]. The initial effects of bisphosphonates on reduction in serum calcium are observed within 12 to 24 hours, with peak effect being observed in 4 to 7 days. The effect generally lasts for 1 to 3 weeks, depending on the extent of PTHrP production by the tumor.
Hypercalcemic patients with Hodgkin and non-Hodgkin lymphomas, by a mechanism associated with increased 1,25(OH)2D production, respond well to glucocorticoid therapy, for example, prednisone 20 to 40 mg/d. Patients with hypercalcemia resulting from multiple myeloma respond well to bisphosphonates and glucocorticoids.
Prognosis
The prognosis is poor for cancer patients by the time hypercalcemia becomes apparent, with a median survival of only 30 to 70 days [21, 22]. In breast cancer with mild hypercalcemia (i.e., ionized serum calcium, 1.36-1.48 mmol/l), the prognosis is better, with a median survival of 17.7 months. Treatment of hypercalcemia is mainly palliative, and a decrease in serum calcium levels in these patients significantly improves symptoms and quality of life without affecting survival [21, 22].
Antiresorptive Agents (Bisphosphonates and Denosumab) for Treatment of Bone Metastases
Laboratory evidence suggests that after the initial seeding and attachment of tumor cells to the bone marrow, increased osteolysis plays a significant role in the establishment and growth of tumor into the bone. In animal models, administration of agents that inhibit bone resorption results in reduction in the incidence and severity of bone metastases [23]. Therefore, a strong rationale exists for antiresorptive therapy to be helpful in the prevention and treatment of bone metastases. Newer bisphosphonates, such as zoledronate, may offer additional beneficial effects in reducing skeletal tumor growth by inhibition of angiogenesis through reduction of vascular endothelial growth factor (VEGF) levels [24]. A recent review of the available literature concluded that bisphosphonates such as pamidronate, zoledronate, ibandronate, and clodronate are effective in reducing the incidence of skeletal events, such as pathologic fracture, spinal cord compression, and hypercalcemia, without a proven benefit on prolonging survival [25, 26, 27]. Similarly, in patients with multiple myeloma and skeletal involvement, there is strong evidence that adding bisphosphonates to standard chemotherapy results in a reduction of future skeletal complications of pathologic fractures, skeletal-related events, and pain without offering a survival benefit [28].
Recent studies have shown the critical role of the RANK ligand in the osteoclast recruitment and development. In animal studies, inhibition of RANK ligand by osteoprotegerin results in potent inhibition of bone resorption and reversal
of hypercalcemia in two animal models of HHM [29]. A humanized antibody to RANK ligand, denosumab, has been developed and tested for prevention of skeletal events in malignancy. In recent large phase 3 trials, denosumab (120 mg SC every 4 weeks) when compared to zoledronate (4 mg IV every 4 weeks) showed greater suppression of bone turnover. In addition, denosumab was superior to zoledronate in reducing the rate of skeletal events (fracture, need for radiation treatment to bone, spinal cord compression) in patients with bone metastases due to breast cancer, prostate cancer, other solid tumors [30, 31, 32]. There were no differences in mortality rates. Denosumab is now approved for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. In patients with multiple myeloma with skeletal involvement, denosumab was as effective as zoledronate in preventing skeletal complications. However, in the ad hoc analysis, the mortality was slightly higher in the denosumab treatment group as compared to that in the zoledronate-treated group; the total number of patients in the multiple myeloma group were small [32]. Denosumab is not approved for prevention of bone disease in the patients with multiple myeloma. The incidence of hypocalcemia was greater with denosumab, while that of renal adverse events (AEs) was greater with the zoledronate treatment. There is a small but significant risk of osteonecrosis of the jaw, occurring to 1% to 2% of treated patient with either zoledronate or denosumab treatment.
of hypercalcemia in two animal models of HHM [29]. A humanized antibody to RANK ligand, denosumab, has been developed and tested for prevention of skeletal events in malignancy. In recent large phase 3 trials, denosumab (120 mg SC every 4 weeks) when compared to zoledronate (4 mg IV every 4 weeks) showed greater suppression of bone turnover. In addition, denosumab was superior to zoledronate in reducing the rate of skeletal events (fracture, need for radiation treatment to bone, spinal cord compression) in patients with bone metastases due to breast cancer, prostate cancer, other solid tumors [30, 31, 32]. There were no differences in mortality rates. Denosumab is now approved for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. In patients with multiple myeloma with skeletal involvement, denosumab was as effective as zoledronate in preventing skeletal complications. However, in the ad hoc analysis, the mortality was slightly higher in the denosumab treatment group as compared to that in the zoledronate-treated group; the total number of patients in the multiple myeloma group were small [32]. Denosumab is not approved for prevention of bone disease in the patients with multiple myeloma. The incidence of hypocalcemia was greater with denosumab, while that of renal adverse events (AEs) was greater with the zoledronate treatment. There is a small but significant risk of osteonecrosis of the jaw, occurring to 1% to 2% of treated patient with either zoledronate or denosumab treatment.
HYPOCALCEMIA
Hypocalcemia is not a classic paraneoplastic syndrome in that there are no humoral factors that are released into the circulation, but excessive bone accretion due to local release of osteoblast-stimulating factors from the tumors may result in sequestration of calcium into the skeleton and thus lower serum calcium levels. Based on total serum calcium measurement, hypocalcemia is frequent in patients with cancers related to the low serum albumin and/or renal failure. True hypocalcemia, based on serum ionized calcium measurement, is less frequent and may be seen as a consequence of hyperphosphatemia due to rapid tumor lysis, hypomagnesemia, nephrotoxicity of certain chemotherapy agents, or direct inhibition of bone resorption. Tumor lysis syndrome is a medical emergency that occurs in patients with certain cancers and is caused by the rapid and massive breakdown of tumor cells, either spontaneously or after the initiation of radiation or chemotherapy. The rapid release of intracellular contents causes hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia (due to precipitation of calcium phosphate salts in to the soft tissues), and acute renal failure may develop [33]. Hypocalcemia may occur as a side effect of treatment with antibone resorptive agents such as bisphosphonates and denosumab for prevention of bone metastases.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
