January 14, 2007

Paraneoplastic Syndromes

Synonyms and related keywords: paraneoplastic disorders, tumors, cancer, dermatomyositis-polymyositis, Cushing syndrome, malignant carcinoid syndrome


Background: Paraneoplastic syndromes 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 one specifically simulating more common benign conditions. These syndromes vary from dermatomyositis-polymyositis to Cushing syndrome to the malignant carcinoid syndrome. Currently, the mechanisms of how cancers affect distant sites are not understood precisely. 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 stimulate the onset of paraneoplastic disorders. However, not all paraneoplastic syndromes are associated with these antibodies. In the future, physicians who deal with cancer-associated syndromes should be able to differentiate the paraneoplastic syndromes and the benign disorders that mimic paraneoplastic syndromes.

Pathophysiology: The relationships between malignancies and other diseases are complex and intriguing.

As already reported, a paraneoplastic syndrome may result from production and release of antibodies and physiologically active substances, or it may be idiopathic. In fact, any tumor may produce hormones and protein hormone precursors, or a variety of enzymes and fetal proteins, or cytokines. More rarely, the tumor may interfere with normal metabolic pathways or steroid metabolism.

Several cancers also produce fetal proteins that are physiologically expressed in embryonic cells during fetal life but not expressed by normal adult cells. These substances may help laboratories detect malignancies and usually are used as tumor markers (eg, carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], cancer antigens [CA 19.9]).

Increased comprehension of the molecular mechanisms of paraneoplastic syndromes will permit earlier diagnoses of cancer and also be useful for following the response to antineoplastic therapy, using cancer products as tumor markers of the progression or remission of disease.


Mortality/Morbidity: The real 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: Because of their complexity and variety, the clinical pictures of these syndromes may vary greatly. Paraneoplastic syndromes may or may not be characteristic of a specific system. Usually, the 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.

A complete history and physical examination can suggest neoplasia. Persons with a family history of malignancies (eg, breast, 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.

    • Patients with myeloma, renal carcinoma, or lymphomas present rarely with secondary amyloidosis of the kidneys, heart, or CNS. The clinical picture of secondary amyloidosis is related to renal and cardiac injuries.
  • Gastrointestinal
    • 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.
  • Hematologic
    • 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, usually are accompanied by hypereosinophilia and itching. These reactions typically are observed in patients with lymphomas or cancers of the lung, breast, or stomach.
    • Patients with lung cancer or pleural mesothelioma may have cryoglobulinemia.
  • Cutaneous
    • 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.


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.


Antithrombin Deficiency
[Attention-Deficit/Hyperactivity Disorder]

Bone Marrow Failure
Chronic Fatigue Syndrome
Diabetes Mellitus, Type 1
Glomerulonephritis, Acute
Mixed Connective-Tissue Disease
Myelodysplastic Syndrome
Nephrotic Syndrome
Personality Disorders
Polycythemia Vera
Polymyalgia Rheumatica
Superficial Thrombophlebitis
Systemic Lupus Erythematosus
Undifferentiated Connective-Tissue Disease

Other Problems to be Considered:

Antiglomerular basement membrane disease


Lab Studies:

Imaging Studies:


Histologic Findings: The histologic findings vary depending on the injured 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: The surgical procedures that usually are applied to neoplastic disorders also are applied to those with paraneoplastic syndrome. On the other hand, some paraneoplastic disorders may disappear rapidly without surgery on the primary tumor (eg, in patients with hypertrophic osteoarthropathy, resection of the tumor or the ipsilateral vagus nerve leads to rapid remission of symptoms).

Consultations: Because of their protean manifestations, paraneoplastic syndromes should be evaluated clinically by a coordinated team of doctors, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.


Therapeutic protocols are those that usually are applied to neoplastic disorders without the presence of a paraneoplastic syndrome. If autoantibodies are detected, the best drug to use may be cyclosporine.

Drug Category: Immunosuppressives -- These agents promote immune suppressor cell function related to production of autoimmune reactions.
Drug Name
Cyclosporine (Neoral, Sandimmune) -- 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.
Adult Dose5-6 mg/kg/d PO
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; uncontrolled hypertension or malignancies; concurrent PUVA or UVB radiation in psoriasis, because it may increase risk of cancer
InteractionsCarbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; lovastatin increases acute renal failure, rhabdomyolysis, myositis, and myalgias
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsMay induce cholestasis, hyperuricemia, and hyperbilirubinemia; evaluate renal and liver function often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; avoid in women who are breastfeeding
Drug Category: Lymphocyte immune globulins -- These agents may help suppress immune reactions.
Drug Name
Antithymocyte globulin (Atgam) -- 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.
Adult Dose40 mg/kg/d IV over 4 h for 4 d, for least for 10 mo
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay increase effects of NSAIDs
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsAdminister ID test prior to initial dose because of risk of anaphylaxis; avoid any vaccination 2 wk prior to and during therapy; avoid in women who are breastfeeding; may cause leukopenia, thrombocytopenia, and hemolysis
Drug Category: Corticosteroids -- These agents may be useful in suppressing immune cell function.
Drug Name
Prednisone (Deltasone, Meticorten, Orasone, Sterapred) -- 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.
Adult Dose5-60 mg/d PO
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease; Cushing disease; cardiovascular diseases
InteractionsEstrogens may decrease clearance; may cause digitalis (ie, digoxin) toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsAbrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use


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