Paraneoplastic Syndromes

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Author

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

Nothing to disclose.

Coauthor(s)

Laura Diomede, University of Bari School of Medicine, Italy

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.

Specialty Editor(s)

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center

Nothing to disclose.

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

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 Cancer Center

Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Nothing to disclose.

Chief Editor

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

GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

Background

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.[1]

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,[2] 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[3] to the malignant carcinoid syndrome. A large number of cancer patients show CNS involvement.[4]

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.

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.[5] 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.[6]

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.

Epidemiology

Frequency

International

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.

Mortality/Morbidity

The true incidence of deaths and complications related to paraneoplastic syndromes is unknown.

Race

No race predilection is reported.

Sex

No sex predilection is known.

Age

People of all ages may be affected by cancers and their related paraneoplastic syndromes.

History

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.

Physical

Miscellaneous (nonspecific)

Rheumatologic

Renal

Gastrointestinal

Hematologic

Cutaneous

Endocrine

Neuromuscular

Causes

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.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

The histologic findings vary depending on the involved system. More details are included in Causes.

Medical Care

Treatment varies with the type and location of the paraneoplastic disorder. Two treatment options exist, as follows:

Surgical Care

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).

Consultations

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.

Medication Summary

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.

Class Summary

These agents promote immune suppressor cell function related to production of autoimmune reactions.

Cyclosporine (Neoral, Sandimmune)

Clinical Context:  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.

Class Summary

These agents may help suppress immune reactions.

Antithymocyte globulin (Atgam)

Clinical Context:  Polyclonal IgG cluster against human T lymphocytes. Obtained from horses or rabbits hyperimmunized with human thymus lymphocytes.

Reduces lymphocyte count 85-90% after first dose, as long as circulating antibody concentrations remain high.

Class Summary

These agents may be useful in suppressing immune cell function.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Clinical Context:  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.

Inpatient & Outpatient Medications

Deterrence/Prevention

As with most cancers, no primary preventive or deterrence measures are known for paraneoplastic syndromes.

Complications

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.

Prognosis

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.

References

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