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Paraneoplastic Syndromes

  • Author: Luigi Santacroce, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
 
Updated: Sep 30, 2015
 

Background

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.[1, 2, 99]

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,[3] 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[4] to the malignant carcinoid syndrome.

A large number of cancer patients show central nervous system (CNS) involvement.[5] The first report of a paraneoplastic syndrome has been attributed to a French physician, M. Auchè, who described peripheral nervous system involvement in cancer patients in 1890.[6]

Paraneoplastic syndromes may be the first or most prominent manifestation of a cancer. When a patient without a known cancer presents with one of the “typical” paraneoplastic syndromes, a diagnosis of cancer should be considered and investigated. Because of their protean manifestations, paraneoplastic syndromes should be managed by a coordinated team of physicians, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.

For discussion of specific paraneoplastic syndromes, see the following Medscape Reference articles:

For patient education information, see the Cancer Center, as well as Brain Cancer, Bladder Cancer, and Breast Cancer.

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Pathophysiology

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.[7] 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.[8]

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.

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Etiology

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.

Miscellaneous syndromes

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.

Rheumatologic syndromes

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).

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, which is revealed by increased serum levels of creatine kinase and lactic dehydrogenase (LDH) and an elevated erythrocyte sedimentation rate (ESR).

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 syndromes

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.

Gastrointestinal syndromes

Gastrointestinal paraneoplastic disorders are related to production of molecules that affect the motility and secretory activity of the digestive tract, as follows:

  • 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

Hematologic syndromes

Erythrocytosis results from an increase of erythropoietin (EPO), which may occur in response to hypoxia, or may 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 red blood cell (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

Cutaneous syndromes

Causes of cutaneous paraneoplastic syndromes are as follows:

  • Itching results from hypereosinophilia and is typical of Hodgkin lymphoma, in which it has specific diagnostic and prognostic significance [9]
  • 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, medullary thyroid cancer, 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

Endocrine syndromes

The pathogenesis of paraneoplastic endocrine syndromes results from aberrant production by tumors of protein hormones, hormone precursors, or hormonelike substances. Cancers generally do not synthesize steroid hormones, except those arising in organs with physiological steroidogenesis (ie, gonads or adrenals).

Neurologic/neuromuscular syndromes

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.[100]

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 Eaton-Lambert myasthenic syndrome (ELMS). According to some recent reports, ELMS may be related to production of tumor proteins that may provoke production of anti–calcium-channel antibodies.

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 analysis 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 lymphocyte levels 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 two 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.

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Epidemiology

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. Similarly, the true incidence of deaths and complications related to paraneoplastic syndromes is unknown.

No race predilection for paraneoplastic syndromes is reported. No sex predilection is known. People of all ages may be affected by cancers and their related paraneoplastic syndromes.

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Prognosis

Because paraneoplastic syndromes differ widely from individual to individual, prognosis may vary greatly. For example, disseminated intravascular coagulation indicates a poor prognosis, whereas hypertrophic osteoarthropathy is one of the few paraneoplastic syndromes that may indicate a more favorable prognosis. Some paraneoplastic disorders may resolve spontaneously.

Death may result from the underlying cancer or from an irreversible system impairment, usually acute heart failure or kidney failure. In a review of patients with paraneoplastic pemphigus, infection was a major cause of death.[10]

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Contributor Information and Disclosures
Author

Luigi Santacroce, MD Assistant Professor, Medical School, State University at Bari, Italy

Disclosure: Nothing to disclose.

Coauthor(s)

Lodovico Balducci, MD Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine

Lodovico Balducci, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American College of Physicians, American Geriatrics Society, American Society of Hematology, New York Academy of Sciences, American Society of Clinical Oncology, Southern Society for Clinical Investigation, International Society for Experimental Hematology, American Federation for Clinical Research, American Society of Breast Disease

Disclosure: Nothing to disclose.

Laura Diomede University of Bari School of Medicine, Italy

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD 

Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Radiation Oncology

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, FACP, FRCPC Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acknowledgements

Silvia Gagliardi, MD Consulting Staff, Department of Surgery, Medical Center Vita, Italy

Disclosure: Nothing to disclose.

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