Paraneoplastic syndromes often present as a constellation of signs and symptoms triggered by an altered immune system response to a tumor or substances produced by a tumor. These substances may include biologically active products that could cause abnormal hormonal function, blockade of normal hormone function, autoimmunity, immune complex production, and/or immunosuppression. For instance, the body’s immune response to a tumor may produce antibodies to fight tumor cells. These antibodies may cross-react with other normal tissue and subsequently damage normal cells. Another example is when tumor cells produce biologically active substances that are cross-reactive with normal tissue causing a cascade of reactions altering normal metabolic pathways resulting in paraneoplastic syndromes.
Paraneoplastic syndrome signs and symptoms may be nonspecific or have organ-specific presentations. They may present with neuromuscular, rheumatologic, hematologic, cutaneous, cardiac, endocrine, renal, gastrointestinal, or generalized nonfocal signs. Up to 20% of cancer patients experience paraneoplastic syndromes, but often, these syndromes are unrecognized (27). Interestingly, there is no known race or gender predisposition to developing paraneoplastic syndrome, and people of all ages may be affected. However, they typically affect middle-aged to older people and are most common in individuals with lung, ovarian, lymphatic, or breast cancer (22). The most common tumor associated with paraneoplastic syndrome is small cell lung cancer (SCLC). Other common cancers associated with paraneoplastic syndromes include renal carcinoma, hepatocellular carcinoma, ovarian tumors, neural, gastric, and pancreatic cancers. Paraneoplastic syndromes may be the first or most prominent manifestation of an underlying malignancy. When a patient without a known cancer presents with one of the “typical” paraneoplastic syndromes, a diagnosis of cancer should be considered and investigated (1).
It is important to emphasize that paraneoplastic syndrome may initially present with nonspecific symptoms such as fever, night sweats, dysgeusia, malaise, and anorexia. Fever is the most common presentation (1) often associated with lymphomas, acute leukemia, sarcomas, renal cell carcinomas, and gastrointestinal malignancies (27). These intermittent fevers generally occur at night. Anorexia is another common symptom often resulting in weight loss and cachexia. Dysgeusia, an alteration in the sense of taste, may manifest in a variety of ways, such as ageusia (loss of taste) or an aversion to protein (in particular, meat proteins). These symptoms may be due to the release of cytokines such as interleukins 1, 6, and 10, which are involved in the inflammatory response or from mediators involved in tumor cell death, such as tumor necrosis factor-α. Treatment is directed usually toward detection and management of the underlying malignancy. And, of course, the actual treatment of an underlying cancer, such as with chemotherapy, may cause some of the same symptoms (such as dysgeusia, malaise, anorexia, and the like).
The key objectives of this article are to review the signs and symptoms of paraneoplastic syndromes in relationship to organ-specific presentations and to discuss diagnostic evaluation and treatment methods.
Neuromuscular Paraneoplastic Syndromes
Paraneoplastic syndromes may affect specific organ systems, but when they affect the neuromuscular system, tumor-related substances are produced, which attack or interact with nerve and muscle cells. Neuromuscular disorders related to cancers affect 6% of all patients with cancer and are prevalent in breast, ovarian, and pulmonary cancers (1). The location of cell damage can cause abnormal muscle movement, abnormal coordination, and dysfunction causing difficulty walking, and loss of muscle tone or muscle weakness. Symptoms also may include abnormal sensory perception such as vision problems, numbness or tingling, vertigo or dizziness, memory loss, cognitive dysfunction, seizures, or sleep disturbances. They develop quickly over weeks to months depending on the affected areas and may progress rapidly. Common paraneoplastic syndromes of the nervous system include myasthenia gravis, Lambert-Eaton myasthenic syndrome, peripheral neuropathy, opsoclonus-myoclonus syndrome, stiff-man syndrome, limbic encephalitis, encephalomyelitis, and cerebellar degeneration.
Myasthenia gravis is the most common paraneoplastic syndrome in patients with a thymoma, a neoplasm originating within the epithelial cells of the thymus. A thymoma is the underlying cause of 10% to 15% of cases of myasthenia gravis (1). However, myasthenia gravis also may be associated with other malignancies such as lung cancer. Symptoms occur due to a blockade at the neuromuscular junction caused by autoantibodies to acetylcholine receptors and are most commonly seen in older men with an associated thymoma. Clinical signs and symptoms include difficulty chewing or swallowing, respiratory distress, and weakness, which may be generalized or localized to a few muscle groups but often affecting the ocular muscles. Physical examination findings include ptosis, diplopia, and confirmation of weakness and fatigability of affected muscles. Sustained activity of affected muscles causes increased weakness, and rest improves muscle strength. It is important to note that normal pupillary response, sensation, and reflexes are usually preserved.
Diagnostic serologic findings include elevated serum acetylcholine receptor antibodies; some patients have antibodies to muscle-specific tyrosine kinase. This small subset of people with muscle-specific tyrosine kinase antibodies often has associated facial, respiratory, and proximal muscle weakness in comparison to patients with antibodies to acetylcholine receptors (20). Imaging studies include computerized tomographic scans of the chest with and without contrast to evaluate for a thymoma. Electromyography (EMG) studies may show decreasing muscle response with repetitive electrical stimuli over the affected muscles. Symptomatic treatment with anticholinesterase drugs (e.g., neostigmine and pyridostigmine) is utilized often, as well as glucocorticoids, chemotherapeutic agents, plasmapheresis, or intravenous immunoglobulin therapy for patients with major disabilities or acute crisis (causing respiratory weakness) (20). Definitive treatment is directed toward the eradication of the underlying malignancy. In the instance that the disease slowly progresses, it is acceptable to monitor symptoms for approximately 1 year in the hope that spontaneous remission may occur (20).
Lambert-Eaton myasthenic syndrome is associated with cancer 40% to 70% of the time, most commonly, SCLC (1). It is due to the disruption in release of acetylcholine in response to nerve impulses. An immunologic attack against presynaptic voltage-gated calcium channels causes weakness especially in proximal limb muscles. The clinical presentation includes weakness, often of the scapular and pelvic girdles, which typically improves with activity. Physical examination findings show that strength steadily increases with sustained contraction, decreased tendon reflexes, xerostomia, sexual impotence, myopathy, and peripheral neuropathy. Electromyography reveals that muscle response increases significantly with repetitive stimulus of the affected muscle group or nerve. Symptomatic treatment involves plasmapheresis and immunosuppressive medication (prednisone and azathioprine) and potassium channel antagonists. Definitive treatment involves targeting the underlying malignancy or tumor. The athlete should try to maintain submaximal fitness training while undergoing work up and treatment.
Paraneoplastic peripheral neuropathy is due to axonal degeneration of unclear etiology in the setting of a malignancy. Involvement of the autonomic nervous system could result in dysfunction of the heart (dysrhythmias), vascular system (blood pressure regulation), bowel, and bladder. The damage to nerves of the somatic nervous system could affect the voluntary motor function and sensory function. Neuropathies that present in the early stages of cancer frequently show a rapid progression and sometimes have a relapsing and remitting course (5). Multiple myeloma, Waldenstrom’s macroglobulinemia, B-cell lymphoma, and chronic B-cell lymphocytic leukemia may cause neuropathy associated with a paraneoplastic syndrome. Approximately 50% of people with sclerotic myeloma develop sensorimotor neuropathy with predominately motor deficits (5). And 5% to 10% of patients with Waldenstrom’s macroglobulinemia will develop distal symmetric sensorimotor neuropathy (5).
Clinical findings are based on the affected nerve or nerve root; sensorimotor neuropathy may present with muscle weakness, cramps, muscle twitching, stiffness, delayed muscle relaxation (pseudomyotonia), and muscle spasms. Involved muscles may be hypertrophic or atrophic, and patients may develop associated paresthesias. Damage to the autonomic nerves could cause cardiac dysrhythmias, postural hypotension, abnormal pupillary response, dry mouth, anhidrosis, erectile dysfunction, and bowel or bladder dysfunction. Athletes should have cardiology clearance prior to continuing their training regimen. These disorders are associated with several tumors such as small cell lung carcinoma, pancreatic cancer, testicular cancer, carcinoid tumors, and lymphomas. Further evaluation with axonal biopsy may reveal inflammatory infiltrates and changes consistent with axonal demyelination; occasionally, patients may have positive serum anti-CV2/CRMP5 antibodies and anti-Hu antibodies (5). Glucocorticoids, plasma exchange, and intravenous immunoglobulin infusion may help to decrease inflammation and subsequently improve symptoms. Definitive treatment is directed toward treating the underlying malignancy.
Opsoclonus-myoclonus syndrome is associated often with lung, breast, and ovarian cancer in adults, and approximately 50% of children have an underlying neuroblastoma (30). Patients present with rapid, irregular eye movements (opsoclonus) frequently associated with myoclonus. Rarely, some patients may develop ataxia, muscle rigidity, autonomic dysfunction, and dementia. Children may present with hypotonia, ataxia, and behavioral changes including irritability. Testing for serum anti-Ri antibodies may be appropriate since some patients will form these autoantibodies. If the underlying tumor is not treated successfully, the disease may lead to encephalopathy, coma, and death. Symptomatic treatment includes glucocorticoids, plasma exchange, and intravenous immunoglobulin infusion. Even after treatment of the underlying tumor, many patients will have psychomotor retardation and behavioral and sleep problems (30).
Stiff-man or stiff-person syndrome is associated with SCLC and breast cancer in which antibodies typically target proteins involved in inhibiting synapses at the neuromuscular junction. The presenting symptoms include severe muscle stiffness, rigidity, and painful muscle spasm often affecting the spine and legs or the arms and legs. They are triggered by auditory, sensory, or even emotional stimuli (30). A paraneoplastic variant of the disease is associated with amphiphysin antibodies, which are often related to SCLC and breast cancer. EMG results show continuous motor unit activity. The optimal treatment of stiff-man syndrome is directed toward the therapy of the underlying tumor. Glucocorticoids, along with medication that enhances GABAergic transmission (diazepam, baclofen, valproic acid, tiagabine, and vigabatrin), are used for symptomatic relief (30).
Paraneoplastic limbic encephalitis is impairment of the limbic system, which controls behavior, memory, and emotion. This syndrome is associated most often with SCLC. Patients may have personality changes, mood disturbances, and impairment of recent memories. Global dementia, seizures, sleep disturbances, and hallucinations may be seen also. Cerebrospinal fluid (CSF) tests may show mononuclear pleocytosis and elevated protein levels, and approximately 60% of patients have antineuronal antibodies in the CSF (30). SCLC is associated also with anti-Hu antibodies, and testicular cancer is associated with anti-Ta antibodies. Electroencephalogram studies may reveal diffuse slowing or bitemporal slow waves and spikes (30). A brain magnetic resonance imaging (MRI) may show abnormal signal intensity in the affected areas. In the absence of head injury, paraneoplastic limbic encephalitis should be considered in the differential of an athlete with acute personality changes.
Paraneoplastic cerebellar degeneration is due to the damage of Purkinje cells and cerebellar neurons often associated with SCLC, breast cancer, ovarian cancer, and Hodgkin’s lymphoma. The clinical presentation may involve impaired gait, limb ataxia, inability to maintain posture, dizziness, nausea, involuntary eye movement, diplopia, dysarthria, and dysphagia. The physical examination findings include a positive Babinski sign, nystagmus, ataxia, and tremors. Later in the disease course, the brain MRI may reveal an atrophic cerebellum. The serum tests may be positive for anti-Yo antibodies, which are associated with gynecologic cancer, including breast cancer. Serum tests positive for anti-Tr antibodies are associated often with Hodgkin’s lymphoma. A number of case reports have described neurologic improvement after tumor removal, plasma exchange, intravenous immunoglobulin infusion, glucocorticoids, and chemotherapeutic agents. However, in patients who are antibody positive, paraneoplastic cerebellar degeneration rarely improves with any form of treatment (14).
Encephalomyelitis is the inflammation of the central nervous system: the brain, brain stem, cerebellum, and spinal cord. The disease is associated often with SCLC, and the rapid progression of the disease may lead to limbic encephalitis and/or cerebellar degeneration. Clinical presentation depends on the affected areas, but symptoms may include numbness, seizures, mood changes, cranial nerve palsies, gait disturbances, upper and lower motor neuron symptoms, and autonomic dysfunction. Encephalomyelitis associated with SCLC may be positive for serum and CSF anti-Hu antibodies and less frequently associated with anti-CV2/CRMP5 antibodies and anti-Ma2 antibodies. There is poor response to treatment; only about 30% of patients with anti-Ma-2-associated encephalitis respond to treatment of tumor and immunotherapy (30).
Rheumatologic Paraneoplastic Syndromes
Paraneoplastic syndrome also may have rheumatologic presentations. These disorders may include inflammatory myopathies such as polymyositis, seronegative rheumatoid arthritis, scleroderma-like syndrome, lupus-like syndrome, polymyalgia rheumatica, and hypertrophic osteoarthropathy. Although it is difficult to differentiate between idiopathic rheumatologic disorders and paraneoplastic rheumatologic disorders, the main distinguishing feature is in response to treatment. Surgical removal or pharmacological treatment of the cancer will result in the resolution of symptoms in paraneoplastic rheumatologic disorders.
Paraneoplastic inflammatory myopathies such as polymyositis- and dermatopolymyositis-type symptoms have been reported as early clinical manifestations of melanoma, ovarian, renal, lung, and colorectal cancers (28). Poor response to immunosuppressive treatment should raise clinical suspicion for an underlying malignancy. Blood tests may reveal anemia, thrombocytopenia, and hypergammaglobulinemia. Collected data support the hypothesis that circulating autoantibodies reactive to tissue proteins are involved in the clinical manifestation (28). If strength is intact and the anemia is mild, the athlete can continue to train as tolerated.
Paraneoplastic seronegative rheumatoid arthritis-like syndrome is associated often with acute myeloblastic leukemia, lung, colon, breast, ovarian, stomach, and oropharynx cancers (28). Rapid onset of rheumatoid arthritis symptoms and lack of response to treatment should cause concern for an underlying malignancy. Rheumatoid-like symptoms may develop 8 to 12 months before the manifestation of the cancer. There is rapid symptom onset that can present with asymmetric arthritis. Diagnostic tests are negative for rheumatoid factor, and there is poor response to treatment with disease-modifying antirheumatic drugs; the goal is to treat the underlying malignancy.
Scleroderma-like syndrome and Raynaud’s phenomenon are associated with T-cell lymphoma, osteosclerotic myeloma, stomach, lung, skin, and breast cancer (28). This syndrome is often resistant to vasodilator therapy and progresses rapidly, sometimes leading to necrosis of the digits. Cold-weather athletes are at particular risk. Patients may develop acute onset of Raynaud’s phenomenon, progressive sclerosis, and sclerodactyly. Quantitative blood tests reveal high levels of antinuclear antibodies (ANA) and antitopoisomerase antibodies in the absence of autoimmune disease symptoms.
Lupus-like syndrome is associated with hairy cell leukemia, lymphomas, ovarian, breast, and head and neck cancers (28). Signs and symptoms include polyserositis, Raynaud’s phenomena, and cutaneous lupus manifestations. Blood tests are positive for ANA, and treatment is directed toward the underlying malignancy.
Paraneoplastic polymyalgia rheumatic-like disorders have been known to be associated with an underlying malignancy of myelodysplastic and myeloproliferative syndrome; kidney, prostate, breast, colon, and lung cancers; and hepatic hemangiomas (28). Clinical presentation may include asymmetric involvement and pain, stiffness, and fatigue of the shoulder girdle as well as other proximal muscle groups. Diagnostic tests may reveal anemia of chronic disease, severe anemia, erythrocyte sedimentation rate <40 or >100 mm·h−1, and proteinuria. Identification and treatment of the underlying cancer is the most definitive form treatment.
Hypertrophic osteoarthropathy is a rapidly progressive disease associated most commonly with underlying lung cancer, pleural mesothelioma, and phrenic neurilemmoma (1). Patients may have clubbing of the fingers and toes, painful polyarthritis associated with noninflammatory intraarticular effusion, and periostitis of long bones (21). X-rays may reveal elevation of the periosteum over the affected areas. Nonsteroidal anti-inflammatory medications or other analgesics may help with pain control, but conclusive treatment involves surgical removal of the tumor or effective chemotherapy. If an athlete has a rapid onset of painful joints and atraumatic effusions, consider hypertrophic osteoarthropathy in the differential.
Paraneoplastic Dermatologic Syndromes
The conditions discussed in this section most commonly occur without any associated malignancy. They are clinical syndromes involving nonmetastatic effects that are accompanying malignant disease. When newly diagnosed, the incidence of cancer is sufficient to warrant an age-appropriate screening evaluation. The management of these syndromes consists of cancer-directed therapy plus standard treatments of the nonparaneoplastic counterparts (26). The paraneoplastic syndromes are less responsive to therapy. Development of these disorders often precedes a diagnosis of cancer or recurrence of a previously treated malignancy (34).
Acanthosis nigricans is a velvety, hyperpigmented skin lesion, most often in the axilla and neck region. This is associated often with insulin resistance and other endocrine disorders. As a paraneoplastic condition, acanthosis nigricans is associated most commonly with gastric adenocarcinoma. It is seen in lung and uterine cancer as well. Up to 90% of the cases affecting the palms, termed tripe palms, have been found to be associated with cancer (19). Up to half of the patients with paraneoplastic acanthosis have mucosal involvement (4). The usual topical treatments are of minimal benefit. If the underlying malignancy is treated successfully, the acanthosis may resolve or improve.
Dermatomyositis is a rare inflammatory myopathy involving the skin and proximal muscles. The cutaneous findings include a heliotrope (pink-purple color) rash on the upper eyelids; an erythematous rash on the face, neck, back, chest, and shoulders; and a scaly eruption over the phalangeal joints that may mimic psoriasis (26). More than a fifth of these eruptions are paraneoplastic. The malignancies often associated with dermatomyositis include breast, ovarian, lung, and prostate cancer (34).
When evaluating this disease, elevated creatine phosphokinase, characteristic electromyography, and muscle biopsy findings demonstrating mixed B-cell and T-cell perivascular infiltrate all suggest dermatomyositis. Because of the association between dermatomyositis and malignancy, expedited age-appropriate screening for cancer is warranted in all patients with dermatomyositis (10). One study concluded that dermatomyositis patients with constitutional symptoms, absence of Raynaud’s phenomena, rapid onset myositis, high sedimentation rate, and high creatine kinase warranted a more extensive search for malignancy. Glucocorticoids are the mainstay of treatment, but paraneoplastic dermatomyositis requires immune-modulating therapies and successful tumor-directed treatment. Up to one third of the patients will have substantial residual motor impairment. If motor impairment is controlled with treatment, the athlete should be allowed to continue to train.
Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease characterized by painful, erosive stomatitis and cutaneous eruption consisting of papules, bullae, and erosions. Two thirds of the cases present with known or preexisting malignancy. One third of these will present before the neoplasm is detected. Circulating autoantibodies confirm the diagnosis of PNP. This condition is referred also to as paraneoplastic autoimmune multiorgan syndrome because of its high mortality rate and the fact that the autoantibodies target many other organ systems (34).
In the adult population, PNP is associated with benign and malignant lymphoproliferative tumors. Although rare in children, the majority of cases are associated with Castleman’s disease. Although a benign lymphoproliferative disorder, Castleman’s disease must be distinguished from lymphoma. Early identification is important because the mortality rate is as high as 90%, often due to respiratory failure.
Sweet’s syndrome is characterized by the sudden onset of painful, erythematous plaques, papules, and nodules on the face, trunk, and extremities as well as leukocytosis and fever (8). Approximately 10% to 20% of patients with Sweet’s syndrome have a neoplasm, most commonly leukemia. Other associated solid tumors include breast, genitourinary, and gastrointestinal cancers (8). Initial treatment of paraneoplastic Sweet’s syndrome includes corticosteroids and colchicine, but they tend to be less responsive than the nonparaneoplastic cases.
Paraneoplastic Hematologic Syndromes
Hematologic manifestations of paraneoplastic syndrome are rarely symptomatic and often can be a sign of advanced disease. Additionally, they rarely require specific treatment and may improve when the underlying malignancy is addressed.
Paraneoplastic eosinophilia is thought to be due to tumor production of eosinophilic growth factors (3). This is a form of secondary eosinophilia also seen in allergic reactions and collagen vascular disease. Although typically asymptomatic, in some cases wheezing and dyspnea may be seen. Commonly associated tumors include lymphomas and leukemias, but paraneoplastic eosinophilia also may be seen with lung, gastrointestinal, and gynecologic tumors (15). Following successful treatment, eosinophilia may indicate tumor recurrence (3).
Although granulocytosis may occur in as much as 30% of patients with solid tumors, half of those are paraneoplastic, not associated with a left shift and rarely cause vaso-occlusion. Paraneoplastic granulocytosis is associated with many tumors but most commonly seen with large cell lung cancer (6). Once other causes of the granulocytosis have been ruled out, the paraneoplastic form does not require specific therapy (16).
Thrombocytosis, defined as a platelet count greater than 400,000·μL−1, occurs in approximately 35% of patients with a malignancy (16). This can be a reactive thrombocytosis like that seen in infection or acute blood loss, but paraneoplastic thrombocytosis is thought to occur from tumor production of cytokines (32). Cytokine interleukin 6 has been used to distinguish paraneoplastic from other reactive thrombocytoses. Paraneoplastic thrombocytosis is not associated usually with the complications seen with other platelet disorders but is associated often with poor clinical outcomes.
Paraneoplastic Renal Syndromes
Renal manifestations of paraneoplastic syndrome can be divided into two main categories: exogenous abnormalities and anatomic abnormalities. The exogenous abnormalities include all electrolyte and hormonal effects on the kidneys, and the anatomic abnormalities include all the glomerulonephropathies.
Hypercalcemia, which is discussed in detail under endocrine paraneoplastic syndromes, can affect the kidneys in a variety of ways. The most common alteration to renal function with hypercalcemia is diabetes insipidus; this is caused by the elevation of the serum calcium-limiting antidiuretic hormone (ADH) secretion activity in the renal collecting ducts. This leads to hypercalcemia-related polyuria. Also, when hypercalcemia is due to bone lysis, there is an associated elevation of phosphorus, which can lead to precipitation of nephrolithiasis and associated symptoms. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can develop also, which is discussed in detail within the endocrine section. Tumor lysis syndrome, although not a true paraneoplastic syndrome, should be mentioned also under the umbrella of exogenous effects on the kidney. Tumor lysis syndrome can have significant morbidity for patients. It occurs due to the destruction of neoplastic cells by chemo/radiotherapy, or less commonly, it may happen spontaneously. This is seen more in the treatment of hematologic malignancies including Burkitt’s lymphoma, acute lymphocytic leukemia, and high-grade non-Hodgkin’s lymphoma. During the breakdown of the cells, uric acid, phosphate, and potassium are released into the extracellular compartment. Usually, the symptoms of this syndrome develop 1 to 5 days after the cytotoxic therapy of choice is given. Symptoms, usually nonspecific, involve lethargy, nausea, and vomiting. However, with the uric acid being released into the circulation, the most feared complication is the deposition of uric acid crystals in the renal tubules, causing an acute oliguric renal insufficiency.
In the exogenous category of renal effects are the renin-producing tumors. Reninomas (tumors arising in the kidneys from the juxtaglomerular apparatus) are the most common renin-producing tumors with the rare extra-renal tumors making up a small percentage. The extra-renal tumors include ovarian, adrenal, lung, pancreas, and colonic cancers. Clinically, patients will present with a triad of hypertension, hypokalemia, and elevated plasma renin activity. Other symptoms include polyuria, nocturia, headache, polydipsia, fatigue, and nausea. Profound hypokalemia (<2.0 mEq·L−1) can be found in these patients. Definitive treatment for renin-producing tumors is surgery (12). New-onset hypertension in the athlete warrants an appropriate work up with particular attention given to the electrolytes.
Regarding anatomic abnormalities, several glomerulonephropathies have been described as part of a paraneoplastic syndrome. The most common type associated with solid tumors is membranous nephropathy. This nephrotic syndrome is described as hyperlipidemia, edema, hypoalbuminemia, and proteinuria (>3.5 g·d−1). This nephropathy is thought to be secondary to immune-mediated with tumor-associated antigens. The most commonly involved tumors causing membranous nephropathy are bronchogenic carcinoma, prostate, renal cell carcinomas, and thymomas. Various other nephropathies can present as paraneoplastic syndrome. Minimal change disease is seen most commonly with Hodgkin’s lymphoma. IgA nephropathy has been seen in various tumors, but the clearest association is with renal cell carcinoma. Focal and segmental glomerulosclerosis is seen with renal cell carcinomas and thymomas. Membranoproliferative glomerulonephritis seems to be associated more commonly with lymphoproliferative disorders. Crescentic glomerulonephritis is associated predominantly with renal cell carcinomas and even more so in patients with antineutrophil cytoplasmic antibody (ANCA)-positive primary vasculitis (12).
Paraneoplastic Endocrine Syndromes
The endocrine system can be affected in many ways with regard to paraneoplastic syndrome. Often times, the endocrine system gets affected by exogenous production of hormones. However, specific criteria must be met prior to calling hormones ectopic. The criteria include more hormones in the tumor than the surrounding tissue, a decrease in the hormones once tumor removal has been completed, increased amount of hormones within the venous vascular bed, and production of the hormones by the tumor in vitro. Ectopic hormones that most often play a role in paraneoplastic syndrome include adrenocorticotropic hormone (ACTH), gonadotropins, ADH, and serotonin.
Paraneoplastic excesses of ACTH may present with polyuria, polydipsia, weakness, edema, and/or mental confusion. The patient also may develop clinical manifestations of Cushing syndrome including centripetal obesity, muscle wasting, diabetes mellitus, hypokalemia, osteoporosis, thinning of skin, hypertension, and mineralocorticoid abnormalities (23). Further evaluation of this possibly paraneoplastic syndrome is by measuring plasma cortisol and urinary 17-hydroxycorticosteroid levels, both of which will be elevated (31). Several neoplasms may produce ACTH with the most common being SCLC, bronchial and thymic carcinoids, pancreatic endocrine tumors, medullary thyroid carcinomas, and pheochromocytomas. Excess ACTH also is seen rarely with neoplasms of the ovary, parotid, testis, gallbladder, breast, colon, prostate, and cervix (11). Regarding treatment, typically, it is directed at not only the tumor but also the symptoms. Pharmacological management of excess ACTH production is aimed at decreasing adrenal steroid secretion, using adrenostatic therapies, i.e., ketoconazole, metyrapone, and aminoglutethimide (13). In the absence of weakness, the athlete may continue to train being mindful of adequate hydration.
Dominant signs in paraneoplastic syndrome of gonadotropins usually consist of precocity and feminization with gynecomastia. Typically, when gynecomastia is present, it tends to be bilateral and painful without associated galactorrhea. In males, interstitial hyperplasia of the testes is also a common finding. Serum and urinary human chorionic gonadotropin (HCG) can be measured if this is suspected, and both will be commonly elevated. This particular paraneoplastic syndrome may be seen with tumors of the reproductive organs and pituitary gland. However, ectopic HCG production has been seen also in hepatoma, cancer of the ovary, and large cell lung cancer (18). Treatment is directed at the causative tumor (31).
Overproduction of ADH from various malignant diseases including small cell lung carcinoma, thymoma, lymphoma, gastrointestinal carcinoma, endometrial, Ewing sarcoma, and brain carcinoma can present in a variety of ways ranging from asymptomatic to comatose. Symptoms typically are related to the degree of hyponatremia. Patients may present with anorexia, nausea, vomiting, confusion, headaches, convulsions, or coma (26). Laboratory findings are consistent with the following urinary and serum values: urinary—high osmolality, normal 17-OHCS, and normal aldosterone; and serum—low sodium, normal potassium, low osmolality, normal plasma cortisone, and normal renal function tests. In the athlete, when considering this diagnosis, other etiologies of hyponatremia should be eliminated (31).
Carcinoid syndrome can be a paraneoplastic syndrome characterized by excess serotonin. Classically, carcinoid manifests as a complex involving cutaneous, gastrointestinal, cardiovascular, and pulmonary symptoms (31). Symptoms normally include flushing (pale, red, or purplish), tachycardia or hypotension, diarrhea (watery and explosive), bronchospasm, and right-sided heart disease or failure secondary to tricuspid valvular insufficiency (29). Often times, these symptoms are precipitated by eating or drinking (foods and beverages high in tyramine) or exertion. Detection of this can be obtained by checking a urinary 5-hydroxyindoleacetic acid (29). Carcinoid tumors are typically seen in the small intestine (usually appendiceal or ileal origin), oat cell carcinoma, and undifferentiated carcinoma of the lung. Treatment typically focuses on local excision if the tumor is less than 1 cm; any larger will require nodal dissection.
As a paraneoplastic syndrome, hypoglycemia is encountered more frequently than hyperglycemia. This is mainly due to the types of tumors that cause the symptoms. As regards hypoglycemia, it can be documented when blood glucose levels are below 55 mg·dL−1 and symptoms are present but resolve promptly once blood glucose is raised (9). Symptoms can range from hypotension, cold sweats, confusion, seizures, apathy, and weakness to coma. Tumors responsible for this include pancreatic tumors as well as fibrosarcomas, mesenchymal fibromas, mesotheliomas, and leiomyosarcoma. Hepatomas, adrenal cortex, and gastrointestinal tumors have been implicated also in causing hypoglycemia. In hyperglycemia, most patients will present with mild diabetes and dermatitis. Only glucagon-secreting tumors and functioning islet cell tumors have been implicated as the sole cause of hyperglycemia (31). Controlling sugar levels can allow the athlete to train while undergoing treatment.
One of the more common laboratory abnormalities seen in malignancies is hypercalcemia. Often, hypercalcemia is a direct result of excess production of parathyroid hormone-related protein (PTHrP), accounting for approximately 80% of the cases. Several tumors have been associated with increased production of PTHrP including squamous cell, ovarian, and renal cell carcinomas; endometrial and breast cancers; and human T-lymphotropic-virus (HTLV)-associated lymphomas. Approximately 20% of hypercalcemia-producing malignancies are associated with extensive bone disease, including multiple myeloma, breast cancer, and lymphoma (33). Patients with hypercalcemia can have varying presentations depending on the degree of calcium elevation. Mild hypercalcemia (10.5 to 12 mg·dL−1) may be asymptomatic. If a patient presents with moderate hypercalcemia (12 to 14 mg·dL−1), they may experience a variety of symptoms. GI symptoms can include nausea, abdominal pain, anorexia, peptic ulcer disease, constipation, or pancreatitis. Impaired concentration, confusion, fatigue, and muscle weakness may comprise the neuromuscular manifestations. Renal manifestations may include nephrogenic diabetes insipidus, dehydration, nephrolithiasis, or nephrocalcinosis. Finally, the cardiovascular system also may see the effects of hypercalcemia including hypertension, vascular calcification, and a shortened QT interval on the electrocardiogram, which can lead to arrhythmias (although rare) (7). The first goal of treatment is to correct the hypercalcemia, which is usually a transient effect until the causative tumor has been treated.
As the number of adults who are active and live longer continues to increase, so do the number of patients with a cancer diagnosis who may see a sports medicine physician. A malignancy diagnosis may or may not be known at the time of presentation in the sports medicine office. Although less common, the number of paraneoplastic syndromes presenting in the office will likely increase as well. These syndromes may have nonspecific signs and symptoms and often go unrecognized. There is no known race or gender predisposition, and people of all ages may be affected. Our active sports medicine patients generally maintain an awareness of their bodies and may have good insight as to when something is “off” with them. The earlier a paraneoplastic syndrome is recognized and evaluated, the earlier a cancer diagnosis can potentially be achieved; this could have a substantial beneficial effect on clinical outcomes and improving quality of life in our patients. As part of their treatment, they should be allowed to continue to train as long as it can be done safely.
Sports medicine health care providers should be aware of how paraneoplastic syndromes may present and have a high index of suspicion and a low threshold for further evaluation of these challenging conditions.
The authors declare no conflicts of interest and do not have any financial disclosures.