Luigi Santacroce, MD,
Assistant Professor, Medical School, State
University at Bari, Italy
Nothing to disclose.
University of Bari School of Medicine,
Nothing to disclose.
Lodovico Balducci, MD,
Professor of Oncology and Medicine,
University of South Florida College of Medicine; Division
Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer
Center and Research Institute
Nothing to disclose.
Silvia Gagliardi, MD,
Consulting Staff, Department of Surgery,
Medical Center Vita, Italy
Nothing to disclose.
Benjamin Movsas, MD,
Vice-Chairman, Department of Radiation
Oncology, Fox Chase Cancer Center
Nothing to disclose.
Francisco Talavera, PharmD, PhD,
Senior Pharmacy Editor,
eMedicine Salary Employment
Michael Perry, MD, MS, MACP,
Nellie B Smith Chair of Oncology Emeritus,
Professor, Department of Internal Medicine, Division of
Hematology and Oncology, University of Missouri/Ellis Fischel
Nothing to disclose.
Rajalaxmi McKenna, MD, FACP,
Southwest Medical Consultants, SC, Department
of Medicine, Good Samaritan Hospital, Advocate Health
Nothing to disclose.
Jules E Harris, MD,
Clinical Professor of Medicine, Division of
Hematology/Medical Oncology, Department of Internal Medicine,
University of Arizona College of Medicine at Tucson;
Consulting Staff, Arizona Cancer Center
The first report of a paraneoplastic syndrome dates back to the 19th century. The description of the relationship between neurological disorders and systemic tumors has been attributed to a French physician, M. Auchè, who described peripheral nervous system involvement in cancer patients in 1890.
Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm. They are defined as clinical syndromes involving nonmetastatic systemic effects that accompany malignant disease.
In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, and they occur remotely from the tumor itself. The symptoms may be endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature.
Although fever is the most common presentation, several clinical pictures may be observed, each of which specifically simulates more common benign conditions. These syndromes vary from dermatomyositis-polymyositis to Cushing syndrome to the malignant carcinoid syndrome. A large number of cancer patients show CNS involvement.
Paraneoplastic syndromes may be the first or most prominent manifestation. When a patient without a known cancer presents with one of the “typical” paraneoplastic syndromes, a diagnosis of cancer should be considered and investigated.
The pathophysiology of paraneoplastic syndromes is complex and intriguing. When a tumor arises, the body may produce antibodies to fight it by binding to and destroying tumor cells. Unfortunately, in some cases, these antibodies cross-react with normal tissues and destroy them, which may result in a paraneoplastic disorder. For example, antibodies or T cells directed against the tumor may mistakenly attack normal nerve cells. The detection of paraneoplastic anti-neural antibody was first reported in 1965.
In other cases, paraneoplastic syndromes result from the production and release of physiologically active substances by the tumor. Tumors may produce hormones, hormone precursors, a variety of enzymes, or cytokines. Several cancers produce proteins that are physiologically expressed in utero by embryonic and fetal cells but not expressed by normal adult cells. These substances may serve as tumor markers (eg, carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], carbohydrate antigen 19-9 [CA 19-9]). More rarely, the tumor may interfere with normal metabolic pathways or steroid metabolism. Finally, some paraneoplastic syndromes are idiopathic.
The reported frequency of paraneoplastic syndromes ranges from 10-15% to 2-20% of malignancies, However, these could be underestimates. Neurological paraneoplastic syndromes are estimated to occur in fewer than 1% of patients with cancer.
The true incidence of deaths and complications related to paraneoplastic syndromes is unknown.
No race predilection is reported.
No sex predilection is known.
People of all ages may be affected by cancers and their related paraneoplastic syndromes.
Paraneoplastic syndromes most commonly occur in patients not known to have cancer, as well as in those with active cancer and those in remission after treatment. A complete history and physical examination findings can suggest neoplasia. Persons with a family history of malignancies (eg, breast,[7, 8] colon) may be at increased risk and should be screened for cancer. Nonspecific syndromes can precede the clinical manifestations of the tumor, and this occurrence is a negative prognostic factor.
Because of their complexity and variety, the clinical presentations of these syndromes may vary greatly. Usually, paraneoplastic syndromes are divided into the following categories: (1) miscellaneous (nonspecific), (2) rheumatologic, (3) renal, (4) gastrointestinal, (5) hematologic, (6) cutaneous, (7) endocrine, and (8) neuromuscular.
Fever, dysgeusia, anorexia, and cachexia are included in this category.
Fever is frequently associated with lymphomas, acute leukemias, sarcomas, renal cell carcinomas (Grawitz tumors), and digestive malignancies (including the liver).
Paraneoplastic arthropathies arise as rheumatic polyarthritis or polymyalgia, particularly in patients with myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the colon, pancreas, prostate, and CNS.
Hypertrophic osteoarthropathy may be observed in patients with lung cancers, pleural mesothelioma, or phrenic neurilemmoma.
Scleroderma may precede direct evidence of tumor
The widespread form is typical of malignancies of the breast, uterus, and lung (both alveolar and bronchial forms).
The localized form is characteristic of carcinoids and of lung tumors (bronchoalveolar forms).
Systemic lupus erythematosus (SLE) may develop in patients with lymphomas or cancers of the lung, breast, or gonads.
Secondary amyloidosis of the connective tissues is a rare presentation in patients with myeloma, renal carcinoma, and lymphomas.
Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20 mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone (ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the lung (ie, small cell lung cancer ).
Hypokalemia, hyponatremia or hypernatremia, hyperphosphatemia, and alkalosis or acidosis may result from other types of tumors that produce ACTH, antidiuretic hormone (ADH), or gut hormones (see Endocrine and neuromuscular, below).
Nephrotic syndrome is observed, although infrequently, in patients who have Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); leukemias; melanomas; or malignancies of lung, thyroid, colon, breast, ovary, or pancreatic head.
Secondary amyloidosis of the kidneys, heart, or CNS may rarely be a presenting feature in patients with myeloma, renal carcinoma, or lymphomas. The clinical picture of secondary amyloidosis is related to renal and cardiac injuries.
Watery diarrhea accompanied by an electrolyte imbalance leads to asthenia, confusion, and exhaustion.
These problems are typical of patients with proctosigmoid tumors (both benign and malignant) and of medullary thyroid carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2 and F2) that lead to malabsorption and, consequently, unavailability of nutrients.
These alterations also can be observed in patients with melanomas, myelomas, ovarian tumors, pineal body tumors, and lung metastases.
Symptoms related to erythrocytosis or anemia, thrombocytosis, disseminated intravascular coagulation (DIC), and leukemoid reactions may result from many types of cancers.
In some cases, symptoms result from migrating vascular thrombosis (ie, Trousseau syndrome) occurring in at least 2 sites.
Leukemoid reactions, characterized by the presence of immature WBCs in the bloodstream, are usually accompanied by hypereosinophilia and itching. These reactions are typically observed in patients with lymphomas or cancers of the lung, breast, or stomach.
Cryoglobulinemia may occur in patients with lung cancer or pleural mesothelioma.
Itching is the most frequent cutaneous manifestation in patients with cancer.
Herpes zoster, ichthyosis, flushes, alopecia, or hypertrichosis also may be observed.
Acanthosis nigricans and dermic melanosis are characterized by a blackish pigmentation of the skin and usually occur in patients with metastatic melanomas or pancreatic tumors.
Endocrine symptoms related to paraneoplastic syndromes usually resemble the more common endocrine disorders (eg, Cushing syndrome). Neuromuscular symptoms may mimic common neurological conditions (eg, dementia).
Cushing syndrome, accompanied by hypokalemia, very high plasma ACTH levels, and increased serum and urine cortisol concentrations, is the most common example of an endocrine disorder linked to a malignancy.[16, 17, 3, 18] This is related to the ectopic production of ACTH or ACTH-like molecules from many tumors (eg, small cell cancer of the lung).
Neuromuscular disorders related to cancers are now included among the paraneoplastic syndromes. Such disorders affect 6% of all patients with cancer and are prevalent in ovarian and pulmonary cancers. Examples include the following:
Myasthenia gravis is the most common paraneoplastic syndrome in patients with thymoma, a malignancy arising from epithelial cells of the thymus. Indeed, thymoma is the underlying cause in approximately 10% to 15% of cases of myasthenia gravis. Rarely, hypogammaglobulinemia and pure red cell aplasia occur as paraneoplastic syndromes in patients with thymoma.
Lambert-Eaton myasthenic syndrome (LEMS), which manifests as asthenia of the scapular and pelvic girdles and a reduction of tendon reflexes. LEMS sometimes can be accompanied by xerostomia, sexual impotence, myopathy, and peripheral neuropathy. It is associated with cancer 40-70% of the time, most commonly small cell lung cancer (SCLC). It seems to result from interference with the release of acetylcholine due to immunologic attack against the presynaptic voltage-gated calcium channel.
Opsoclonus-myoclonus syndrome usually affects children younger than 4 years. It is associated with hypotonia, ataxia, and irritability. One in two patients has neuroblastoma.
Paraneoplastic limbic encephalitis is characterized by depression, seizures, irritability, and short-term memory loss. The neurologic symptoms develop rapidly and can resesmble dementia. Paraneoplastic limbic encephalitis is most commonly associated with SCLC.
Paraneoplastic encephalomyelitis is characterized by a complex of symptoms derived from brainstem encephalitis, limbic encephalitis, cerebellar degeneration, myelitis, and autonomic dysfunction. Such neurologic deficits and signs seem to be related to an inflammatory process involving multiple areas of the nervous system.
Paraneoplastic cerebellar degeneration causes gait difficulties, dizziness, nausea, and diplopia, followed by ataxia, dysarthria, and dysphagia. Paraneoplastic cerebellar degeneration is frequently associated with Hodgkin lymphoma, breast cancer, SCLC, and ovarian cancer; it may occur in association with prostate carcinoma.
Paraneoplastic sensory neuropathy affects lower and upper extremities and is characterized by progressive sensory loss, either symmetric or asymmetric. It seems to be related to the loss of the dorsal root ganglia with early involvement of major fibers responsible for detecting vibration and position.
Fever generally occurs in the evening and is of a continual-remittent type.
Dysgeusia manifests in a variety of ways, from ageusia to aversion to protein (in particular, meat proteins).
Anorexia is common among patients with neoplastic syndromes and is responsible, along with dysgeusia, for weight loss and even cachexia.
Hypertrophic osteoarthropathy presents as digital clubbing and painful swelling of the hip, wrist, and knee, accompanied by an articular effusion.
The long bones may also be involved. In such cases, patients complain of pain and x-rays show a typical elevation (thickening and detachment) of the periosteum.
For patients with scleroderma or systemic lupus erythematosus (SLE), the clinical picture is characteristic of nonparaneoplastic conditions.
Urinary symptoms related to paraneoplastic disorders are characterized by edema resulting from hypoalbuminemia and proteinuria (>3 g/24 h).
Hypercholesterolemia may be present.
The clinical picture of paraneoplastic disorders affecting the GI system is similar to that of nontropical sprue.
Thrombocytosis (>500,000 platelets per dL) can be observed in patients with cancer of the lung, breast, digestive organs, or reproductive organs. This thrombocytosis leads to the following 2 phenomena:
Migrating thrombophlebitis that is resistant to standard anticoagulant therapy and involves the arm veins, the inferior vena cava, and the jugular veins. It usually appears as oval formations along small and medium-size veins, accompanied by cutaneous necrosis.
Marantic (nonbacterial) endocarditis characterized by growths developing on the heart valves that may break off and form emboli.
Herpes zoster and alopecia presenting as part of a paraneoplastic syndrome are similar to their equivalent benign forms.
Flushes appear that are similar to those related to benign conditions such as stress.
Hypertrichosis is not different from the form it takes when related to an endocrine imbalance (usually, adrenal dysfunction). Paraneoplastic hypertrichosis is characterized by a sudden appearance of wooly hair on the face and ears that disappears promptly after the tumor is removed.
Acanthosis nigricans and dermic melanosis are often pathognomonic for the presence of a malignancy. They are similar but differ by location. Dermic melanosis is diffuse; acanthosis nigricans usually is accompanied by confluent papillomas and affects the oral, umbilical, axillary, and inguinal areas. Three types of acanthosis nigricans are described: benign, pseudoacanthosis, and malignant. The malignant form is characterized by rapid growth of hyperkeratotic warts (Leser-Trélat sign).
Ichthyosis, which in the early stages could mimic a benign dermatosis, is characterized by desquamation of the extensory surface of the limbs (resembles the scales of a fish, from the ancient Greek ichthus, meaning fish).
Patients with glucagonoma may have necrotizing migrating erythema (NME) resulting from erythematous and exfoliative injuries that differ from exfoliative erythrodermia. This is typical of leukemias and lymphomas and results in blushing and diffuse skin desquamation that affects cutaneous adnexa, which subsequently results in alopecia and nail fragility but which rarely is accompanied by fever, chills, and itching.
This is a heterogeneous group of disorders characterized by clinical signs that vary greatly according to the specific disorder.
Patients with Cushing syndrome as part of a paraneoplastic syndrome appear similar to patients with Cushing disease, with the typical moon facies and obesity of the trunk. Symptoms caused by human chorionic gonadotropin and urinary gonadotropin peptide are absent. Gynecomastia may occur in males.
Hyponatremia may occur in patients with tumors that produce hormones that affect water and electrolyte balance (ie, antidiuretic hormone [ADH]).
Hypercalcemia mediated by the secretion of parathyroid hormone–related peptide has been reported in a variety of cancers, including gynecologic malignancies.[29, 30]
Hypoglycemia seems related to production of insulinlike growth factor (IGF)-1 and IGF-2.
One or more neurological paraneoplastic syndromes may be present in patients with cancer, especially those suffering from lung cancer.
Neuropathies may be sensory, motor, or mixed.
Sensory neuropathy, which usually affects only patients with lung cancer, originates from ganglionic degeneration, and its onset is characterized by paresthesias and tabeticlike pain, acute hyporeflexia with a reduction of proprioceptive sensitivity and ataxia (both static and dynamic), vibratory anesthesia, deafness, cutaneous hypoesthesia or anesthesia, dysgeusia, and dysosmia.
Mixed neuropathy may occur with several malignancies and has an extremely variable presentation, with motor or sensory symptoms either preceding the clinical onset of tumor disease or accompanying it. The spinal cord can be affected by either subacute necrotic myelitis or subacute myelitis. These conditions lead to a progressive flaccid paraplegia with areflexia, lack of sphincteric control, and anesthesia of the lower limbs. A lateral amyotrophic syndrome (LAS) may occur, presenting as the typical muscular asthenia and atrophy, hyperreflexia with pyramidal fasciculations, and degeneration of the second motor neuron. This form of LAS differs from the nonparaneoplastic form because it includes sensory involvement (ie, proprioception and pallesthesia).
The cerebellum may be the site of subacute neuronal degeneration in patients with small cell carcinoma or breast or gynecologic tumors. Such degeneration presents clinically as cerebellar ataxia, dysarthria, and nystagmus. Dysphagia, palpebral ptosis, deafness, and a positive Babinski sign may also occur.
The cerebellum of patients with lung cancer also may be affected by encephalitis. In such cases, the clinical picture is characterized by convulsions, delirium, and a lack of long-term memory. In other patients, the pathological process involves the medulla (ie, encephalomyelitis).
In some patients with leukemias, lymphomas, or epithelial cancers, a rare degenerative process involving the semioval center may be observed. This degenerative process is characterized by convulsions, cerebellar ataxia, progressive dementia, aphasia, hemiparesis, hemihypoesthesia, dysphagia, and nystagmus. The process develops rapidly, leading to death within 6 months of onset.
Eaton-Lambert myasthenic syndrome (ELMS) may occur in patients with lymphomas; thymomas; or cancers of the pancreas, rectum, kidney, breast, prostate, or uterus. ELMS may resolve after surgical resection of the primary tumor but not after radiotherapy or chemotherapy.
Patients with lymphomas or cancers of the lung, stomach, breast, or uterus may have polymyositis and dermatomyositis characterized clinically by asthenia, pain, and progressive hypertrophy of proximal muscles affecting, then involving, the dermis and the skin. This leads to violet-colored rashes of the face and hands.
A retrospective study by Fardet et al identified independent factors associated with an underlying malignancy in patients with dermatomyositis :
Age at diagnosis >52 years (hazard ratio [HR], 7.24; 95% confidence interval [CI], 2.35-22.31)
The causes of the paraneoplastic syndromes associated with underlying cancers are not well known. Only a few cases clearly demonstrate an etiologic and a pathogenetic factor.
Fever is thought to result from the release of endogenous pyrogens (ie, lymphokines or tissue pyrogenes). Fever may also be related to necrotic-inflammatory phenomena of the tumor and/or to alterations in liver function and consequent disorders of steroidogenesis.
Dysgeusia seems to be related to alterations in the body's level of copper and zinc or to a morphofunctional variation of the tasting bodies (ie, gustative papillae).
Cachexia is thought to be caused by bioactive molecules produced by the tumor, such as alpha-lymphotoxin (tumor necrosis factor [TNF] alpha), peptides, and nucleotides, which are able to affect metabolism. Such modifications include an increase in the serum levels of fatty acids; a decrease in urea, alanine, and carbon dioxide; and alterations of glucose metabolism.
The causes of hypertrophic osteoarthropathy remain unknown, although several hypotheses have been developed (eg, estrogen or growth hormone [GH] production by the tumor, vagal hyperactivity).
Onset of scleroderma and SLE could be related to production of antinuclear antibody (ANA), because antigens normally restricted to connective tissues are expressed aberrantly in cancer.
Renal: Secondary kidney amyloidosis and sedimentation of immunocomplexes in nephrons (and subsequent membranoproliferative glomerulonephritis) is thought to be the underlying mechanism of nephrotic syndrome and, frequently, neoplastic hypoalbuminemia, which is also related to reduced albumin synthesis.
GI paraneoplastic disorders are related to production of molecules that affect the motility and secretory activity of the digestive tract.
Medullary thyroid carcinomas (MTCs) may produce several prostaglandins (PGs) (eg, PGE2 and PGF2) that lead to malabsorption and, consequently, unavailability of nutrients.
Malignancies of the digestive system, especially those in the stomach or intestine, may lead to a protein-losing enteropathy resulting from tumor-mass inflammation and exudation.
Erythrocytosis results from an increase of erythropoietin (EPO), which may occur in response to hypoxia, or result from ectopic production of EPO or EPO-like substances or from altered catabolism of EPO itself. Erythrocytosis is common in cancers of the liver, kidney, adrenal glands, lung, thymus, and CNS as well as in gynecologic tumors and myosarcomas. It always disappears after removal of the primary tumor.
Anemia is a common presenting symptom of several neoplasms and results from chronic hemorrhages from ulcerated tumors, altered intestinal absorption of vitamins B-6 and B-12, and increased destruction or insufficient production of RBCs. Three types of paraneoplastic anemias may be described, as follows:
Chronic anemia resulting from an anti-erythropoietin factor, reduction in mean RBC life, and poor iron availability
Microangiopathic hemolytic anemia resulting from diffuse intravascular coagulation (DIC), with formation of fibrin filaments in capillary vessels and consequent mechanical hemolysis
Autoimmune hemolytic anemia resulting from anti-RBC antibodies that can be either produced by lymphomatous clones or directed against novel antigens produced by teratomas and ovarian cystadenocarcinomas
DIC is typical of epithelial tumors, leukemias, and lymphomas (in particular, acute promyelocytic leukemia). Usually, DIC has a slow and gradual onset, but in some cases, DIC appears in an acute and severe form, characterized by typical thrombotic and/or hemorrhagic manifestations, and sometimes leading to thrombocytopenia.
Thrombocytopenia may also be caused by autoantibodies. The causes of thrombocytosis are still unknown.
Marantic endocarditis is typical of mucous adenocarcinomas of lung, stomach, and pancreas.
Leukemoid reactions are probably caused by mechanical stimulation of bone marrow, resulting from bone metastases, or they may be caused by humoral stimuli resulting from neosynthesized blastic factors or factors released from the foci of tumor necrosis.
Leukopenia is not common and is essentially related to metastatic compression of bone marrow.
Gammopathies occurring in cancer patients may be monoclonal (immunoglobulin G [IgG] or the rarer immunoglobulin M [IgM]), monoclonal secondary (IgG + IgM), or polyclonal (IgG). Gammopathies probably are related to an antigenic stimulus of the tumor on some immune clones.
Itching results from hypereosinophilia and is typical of Hodgkin lymphoma, in which it has specific diagnostic and prognostic significance.
Immune system depression, which may be observed in most patients with cancer, is often responsible for the reactivation of latent varicella-zoster virus (VZV) in the sensory ganglia and subsequent attacks of herpes zoster.
Pancreatic tumors can release several lipases and lithic enzymes into the bloodstream, leading to adipose nodular necrosis of subcutaneous tissues. This condition is characterized by painful pink to dark-reddish nodules under the skin. These nodules often ulcerate, causing leakage of an oily material.
Flushes can be observed in patients with acute leukemias, mastocytosis, carcinoids, MTC, or pancreatic carcinomas that secrete vasoactive substances, mainly prostaglandins (alpha, E1, E2, F2, I2).
Dermic melanosis results from melanin precursors that enter the bloodstream and, because they cannot be eliminated completely via urine, accumulate in the dermis, which results in a peculiar grey to black-bluish color of the overlying skin.
The pathogenesis of paraneoplastic endocrine syndromes results from aberrant production by tumors of protein hormones, hormone precursors, or hormonelike substances. Generally, cancers, except those arising in organs with physiological steroidogenesis (ie, gonads or adrenals), do not synthesize steroid hormones.
The pathogenesis of neuromuscular paraneoplastic disorders is unknown, but they probably are multifactorial, correlated with a virus becoming virulent, autoantibody formation, or production of substances that alter nervous functions.
The muscular system is involved in myasthenic phenomena (on a toxic and metabolic basis) that can be either simple (affecting the pelvic girdle) or part of an ELMS.
ELMS may be related, according to some recent reports, to production of tumor proteins that may provoke production of anti–calcium-channel antibodies.
The autoimmune basis of polymyositis and dermatomyositis is confirmed by the presence of a lymphoplasma cellular infiltrate of the muscular interstices and by the presence of muscle necrosis revealed by increased serum levels of creatine kinase and lactic dehydrogenase (LDH) and increased erythrocyte sedimentation rate (ESR).
Autoantibodies directed against the central neurons and brain often are present in the serum and cerebrospinal fluid (CSF) of patients with sensory and mixed neuropathies. CSF may reveal increased albumin and immunoglobulins. Patients with mixed neuropathy usually show a distal nervous demyelination, while patients with sensory neuropathy have ganglionic degeneration.
Patients with subacute necrotic myelitis show a characteristic extended necrosis of the spinal cord, while those with the more rare subacute myelitis have characteristic degeneration of the anterior horns of the spinal cord, which sometimes extends to the brain. Both types of myelitis probably have a toxic origin.
Patients with cerebellar paraneoplastic disorders usually have degenerative loss of the molecular, granular, and Purkinje layers of the cerebellar cortex. Sometimes a loss of neurons of the spinocerebellar tract and of the posterior cords of the spinal cord can occur. Elevation of CSF albumin and lymphocytes is usually observed in these patients.
Individuals with paraneoplastic encephalitis commonly have lymphocytic infiltration of the medial sections of the temporal lobes, with a loss of neurons.
Patients with involvement of the semioval center have an acute and ill-defined onset of disease. This condition is often called progressive multifactorial leukoencephalopathy and is related to the site of the nervous injury. This condition probably has a viral origin, resulting from the action of 2 papovaviruses, JV and an SV-40–like virus, both of which have been isolated in the brains of some patients. Some areas of demyelination that tend to be confluent and that spare central axons can be demonstrated by histologic examination.
Patients with a suspected paraneoplastic disorder should receive a complete panel of laboratory studies of blood, urine, and cerebrospinal fluid (CSF).
The CBC may demonstrate anemia. This anemia may be the result of any of several different types of cancer, or it may be the result of different benign conditions. The ESR is usually increased in patients with cancers and in those with infectious diseases. A microscopic study of the WBCs is helpful for diagnosis of leukemia or lymphoma-related disorders. Hypereosinophilia is frequently observed in patients with Hodgkin lymphoma. A platelet count must be performed in any patient with symptoms of DIC.
Blood enzymes may be altered, even in healthy individuals or those who have benign conditions. Increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, and alkaline phosphatase (ALP) are commonly observed in patients with malignancies of the digestive system as well as in patients with bone or muscle injuries. Protein electrophoresis of serum and CSF may demonstrate alterations of albumin levels and increased beta-globulins and gamma-globulins. Gamma-globulins are always increased in patients with autoimmune disorders, whether neoplastic or not. Oligoclonal bands are seen frequently on CSF electrophoresis.
Tumor markers are very useful for diagnosis of cancers that are clinically silent, but most markers are not specific for determining the origin of the cancer. For example, CEA (carcinoembryonic antigen) is increased in patients with tumors of the breast, lung, and digestive tract, as well as in patients who are heavy smokers. On the other hand, prostate-specific antigen (PSA) is increased only in patients with prostatic disorders, whether benign (including inflammatory diseases) or malignant. Examining the PSA free/total ratio will help ensure a correct diagnosis.
Many patients with paraneoplastic disorders may have autoantibodies against several tissues of the body. Demonstration of these autoantibodies is very important to confirm the diagnosis of a paraneoplastic syndrome and distinguish it from nonneoplastic forms. Most known autoantibodies are directed against nervous system structures. Note that there are 2 systems of nomenclature for onco-neural antibodies in current use: one system designates antibodies by the first two letters of the surname of the patient in whom the antibody was initially discovered, while the other system names antibodies according to their tissue distribution. Such antibodies are screened by indirect immunofluorescence.
Anti-Hu (previously called antineuronal nuclear antibody 1 or ANNA-1) is an autoantibody detected in the serum of patients with paraneoplastic subacute sensory neuronopathy and/or encephalomyelitis.
Anti-Ri (previously called antineuronal nuclear antibody 2 or ANNA-2) may be present in patients with opsoclonus/myoclonus syndrome.
Antibodies directed against amphiphysin (a synaptic vesicle protein) have been detected in the serum of patients with the paraneoplastic form of stiff man syndrome.
The antineuronal antibodies Ma1 and Ma2 (also called anti-Ta) are members of a novel but expanding family of brain-specific or testis-specific proteins. While Ma1 is not found in association with any one type of tumor, Ma2 seems to be associated strongly with testicular cancer.
The anti-Yo or anti-Purkinje cell antibody 1 (APCA-1) has been detected in patients with paraneoplastic cerebellar degeneration.
Any possible imaging study may be useful to detect the primary tumor in patients with paraneoplastic disorders.
CT scanning and magnetic resonance imaging of the whole body allow detection of the site and the extension of the underlying primary tumor and its metastases, if present.
Scintigraphy may be useful in patients with endocrine disorders related to a hormone-producing tumor.
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning may be performed to evaluate patients with neurologic disorders. These examinations allow differentiation of paraneoplastic and nonparaneoplastic neurologic disorders.
Surgical treatment for patients with paraneoplastic syndromes is typically directed toward the underlying neoplasm. On the other hand, some paraneoplastic disorders may resolve rapidly without surgery on the primary tumor (eg, in patients with hypertrophic osteoarthropathy, resection of either the tumor or the ipsilateral vagus nerve leads to rapid remission of symptoms).
In patients with ectopic ACTH syndrome bilateral adrenalectomy with hormone replacement is the most effective treatment.
Patients with thymoma must have complete surgical resection of the tumor to obtain complete remission of paraneoplastic syndromes (ie, myasthenia gravis).
Inoperable patients should have preoperative induction chemotherapy, followed by adjuvant radiation therapy.
Because of their protean manifestations, paraneoplastic syndromes should be clinically evaluated by a coordinated team of physicians, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.
Therapeutic protocols are those that are usually applied to neoplastic disorders without the presence of a paraneoplastic syndrome. If autoantibodies are detected, the best drug to use may be cyclosporine.
Cyclic polypeptide that suppresses some humoral immunity and, to greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for variety of organs. Reserve IV use only for those who cannot take PO.
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Four times as potent as natural glucocorticoids.
Because a paraneoplastic syndrome represents a complication of cancer, the only complication may be death occurring as a result of an irreversible system impairment, usually acute heart failure or kidney failure.
Because paraneoplastic syndromes differ widely from individual to individual, prognosis may vary greatly. For example, DIC indicates a poor prognosis, while hypertrophic osteoarthropathy is one of the few paraneoplastic syndromes that may indicate a more favorable prognosis.