Paraneoplastic Syndrome

Original Editors - Brittany Chorley & Seth Chorley from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Seth Chorley, Brittany Chorley, Lucinda hampton, Admin, Kim Jackson, Priya Gulla, Elaine Lonnemann, WikiSysop, Rujuta Naik, 127.0.0.1, Vidya Acharya, Claire Knott, Wendy Walker, Mariam Hashem and Adam Vallely Farrell  

Definition/Description

Paraneoplastic syndrome is a group of rare disorders that is triggered by an abnormal immune system response caused by a neoplasm. It is hypothesisized that paraneoplastic syndrome occurs when cancer-fighting antibodies or white blood cells (known as T cells) mistakenly attack normal cells in the nervous system.  Another hypothesis is that the neoplasm secretes hormones or cytokines that cause the symptoms to occur.  Neurologic symptoms can develop over a period of days to weeks and usually occur prior to the tumor being discovered.

Prevalence

You will see symptoms of this disorder typically in the middle-aged to older population. It is most common in individuals with lung, ovarian, lymphatic, or breast cancer.  The most common cancer associated with paraneoplastic syndrome is small cell cancer of the lungs.

Characteristics/Clinical Presentation

Paraneoplastic syndrome is typically characterized by symptoms that include difficulty in walking or swallowing, decreased muscle tone, decreased fine motor coordination, memory loss, slurred speech, visual symptoms, sleep disturbances, dementia, seizures, loss of sensation in the limbs, and vertigo/dizziness. Paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis, myasthenia gravis, cerebellar degeneration, limbic or brainstem encephalitis, neuromyotonia, opsoclonus, and sensory neuropathy.

Paraneoplastic syndromes most commonly occur in patients with undiagnosed cancer, as well as in those with active cancer, or those in remission. Persons with a family history of malignancies such as breast or colon cancer may be at an increased risk and should be screened for cancer.

Paraneoplastic syndrome has several different clinical presentations due to the complexity of the syndrome. Paraneoplastic syndromes are most commonly divided into the following categories: 1) miscellaneous (nonspecific), 2) rheumatologic, 3) renal, 4) gastrointestinal, 5) hematologic, 6) cutaneous, 7) endocrine, and 8) neuromuscular.

Miscellaneous (nonspecific)
-Fever

     -Often associated with lymphomas, acute leukemias, sarcomas, renal cell carcinomas (Grawitz tumors), and digestive malignancies (including the liver).

-Dysgeusia

-Anorexia

-Cachexia

Rheumatologic
-Paraneoplastic arthropathies can present as rheumatic polyarthritis or polymyalgia, specifically 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. So it is important to keep this in the back of your mind when treating someone who has a history or family history of cancer.
The widespread form of paraneoplastic syndrome is typically associated with malignancies of the breast, uterus, and lung.
The localized form of paraneoplastic syndrome is typically associated with carcinoids and of lung tumors (bronchoalveolar forms).

Renal
Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20 mEq per 24 hours, can develop in patients with tumors secreting adrenocorticotropic hormone (ACTH) or ACTH-like substances. This occurs in 50% of people with ACTH-secreting tumors of the lung (ie, small cell lung cancer ).
Hypokalemia, hyponatremia, hypernatremia, hyperphosphatemia, and alkalosis or acidosis may result from other types of tumors that produce ACTH, antidiuretic hormone (ADH), or hormones formed in the gut.
Nephrotic syndrome at times is observed in patients who have Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), leukemia, melanomas, malignancies of the thyroid, colon, lung, breast, ovary, or pancreatic head.
Secondary amyloidosis of the kidneys, heart, or CNS can be a presenting feature in patients with myeloma, renal carcinoma, or lymphomas. 

Gastrointestinal
Paraneoplastic syndrome can cause watery diarrhea which can lead to symptoms such as asthenia, confusion, and exhaustion.
Gastro intestinal symptoms are most common in patients with proctosigmoid tumors and of medullary thyroid carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2 and F2) that lead to malabsorption.
In addition, the previously listed symptoms can also can be observed in patients with melanomas, myelomas, ovarian tumors, pineal body tumors, and lung metastases.

Hematologic
In patients with cancers of the lung, stomach, or breast symptoms related to a hematological nature can be observed. These symptoms can be erythrocytosis, anemia, thrombocytosis, disseminated intravascular coagulation (DIC), and leukemoid reactions may result from many types of cancers.
In some patients, hematologic symptoms result from a migrating vascular thrombosis that occurs in at least 2 sites.
Leukemoid reactions can occur and are characterized by the presence of immature WBCs in the bloodstream. These reactions are usually accompanied by hypereosinophilia and itching.

Cutaneous
Cutaneous symptoms resulting from paraneoplastic syndrome commonly present themselves as itching.
Other symptoms associated with the cutaneous aspect of paraneoplastic syntrome are herpes zoster, ichthyosis, flushes, alopecia, or hypertrichosis.
Patients with metastatic melanomas and pancreatic tumors can present with acanthosis nigricans or dermic melanosis which are characterized by blackish pigmentation of the skin.

Endocrine

Endocrine symptoms associated with paraneoplastic syndrome typically resemble the more common endocrine disorders such as Cushing syndrome.
The most common example of an endocrine disorder linked to a malignancy and paraneoplastic syndrome is Cushing syndrome accompanied by hypokalemia, very high plasma ACTH levels, and increased serum and urine cortisol concentrationss. This is due to the ectopic production of ACTH or ACTH-like molecules from many tumors (eg, small cell cancer of the lung).

Neuromuscular
-Neuromuscular symptoms related to paraneoplastic syndrome are rare and only affect 6% of all patients with cancer. These symptoms are most commonly seen in patients with ovarian or pulmonary cancers. Examples include the following:
-Myasthenia gravis is the most common paraneoplastic syndrome in patients with thymoma. Thymoma has been shown to be the underlying cause in approximately 10% to 15% of cases of myasthenia gravis.
-Lambert-Eaton myasthenic syndrome (LEMS) is another syndrome of paraneoplastic syndrome which manifests as asthenia of the scapular and pelvic girdles and a reduction of tendon reflexes. LEMS can be accompanied by xerostomia, sexual impotence, myopathy, and peripheral neuropathy. LEMS is also associated with 40-70% of cancer; most commonly small cell lung cancer (SCLC). As stated before, the most comon cancer associated with paraneoplastic syndrome.  LEMS seems to be a result from interference with the release of acetylcholine due to immunologic attack against the presynaptic calcium channel.
-Opsoclonus-myoclonus syndrome most commonly affects children younger than 4 years old. It is also associated with hypotonia, ataxia, and irritability.
-Paraneoplastic limbic encephalitis is most commonly associated SCLC and is characterized by depression, seizures, irritability, and short-term memory loss. The neurologic symptoms usually develop rapidly and can resesmble dementia.
-Paraneoplastic encephalomyelitis is characterized by a complex of symptoms derived from limbic encephalitis, brainstem encephalitis, myelitis,cerebellar degeneration, and autonomic dysfunction. These signs and symptoms related to the paraneoplastic encephalomelitis seem to be related to an inflammatory process involving multiple areas of the nervous system.
-Paraneoplastic cerebellar degeneration generally causes gait difficulties, dizziness, nausea, and diplopia, which then is followed by ataxia, dysarthria, and dysphagia. Paraneoplastic cerebellar degeneration is often associated with Hodgkin lymphoma, breast cancer, SCLC, and ovarian cancer. 
Paraneoplastic sensory neuropathy affects both the lower and upper extremities. It is characterized by progressive sensory loss that can be either symmetric or asymmetric. Paraneoplastic sensory neuropath seems to be related to the loss of the dorsal root ganglia with early involvement of major fibers which are responsible for detecting vibration and position of the body in space.

Associated Co-morbidities

Associated Co-morbidities

HTN	Categorized as BP 140/90 or higher for either systolic or diastolic
Endocarditis	Inflammation of the inner layer of the heart
Thrombophlebitis	A blood clot that causes swelling in one or more veins. Typically observed in the legs
Polyarthritis	Arthritis of several joints
Anemia	Lack of healthy red blood cells causing decrease oxygen delievered to the body
Anorexia	Eating disorder characterized by starving one's self to lose weight

Medications

Medications will depend on what type of paraneoplastic syndrome the patient has.  In addition to chemotherapy for the underlying cancer, medications could include:

Corticosteroids, such as prednisone, inhibit inflammation. Long-term use of corticosteroids may cause weakening of the bones (osteoporosis), diabetes, high blood pressure, high cholesterol and other serious side effects.

Immunosuppressants inhibit the production of disease-fighting white blood cells. Side effects include an increased risk of infections. Drugs with immunosuppressant properties that may be used include azathioprine (Imuran) and cyclophosphamide (Cytoxan).

Anti-seizure medications may help control seizures associated with syndromes affecting nerve cells in the brain. A number of anti-seizure medications are available, including carbamazepine (Tegretol, Carbatrol, others) and valproic acid (Depakene, Stavzor).

Medications to enhance nerve to muscle transmission may improve symptoms of syndromes affecting muscle function. Some drugs, such as 3,4-diaminopyridine, enhance the release of a chemical messenger that transmits a signal from nerve cells to muscles. Other drugs, such as pyridostigmine (Mestinon, Regonol), prevent the breakdown of these chemical messengers.

Because depression can be common in these patients, anti-depressent drugs may be prescribed.

File:Paraneoplastic Syndromes Treatment Pros and Cons.gif

Diagnostic Tests/Lab Tests/Lab Values

First, a health care provider will perform a clinical exam that would include a general physical and neurological screening. Tests that would be involved in the neurological screening could include reflexes, sensation, myotomes, balance, and coordination.

Laboratory tests that could be utilized to diagnose paraneoplastic syndrome include:

Blood tests: This may identify antibodies typically associated with paraneoplastic syndrome. However, some people who have the syndrome do not have the antibody, and some people who do not have the syndrome actually have the antibody. Blood tests can also identify an infection, disorder of nutrient processing, or hormone disorder.

Spinal tap: A neurologist or nurse will insert a needle into your lumbar spine to extract a small amount of cerebrospinal fluid (CSF). At times, paraneoplastic antibodies may be present in the CSF but not in the blood.

Imaging tests that could be utilized to diagnose paraneoplastic syndrome include:

CT Scan

MRI

PET Scan

PET-CT, which may enhance the detection rate of small cancers

 If the physicians cannot find a malignant tumor, the syndrome may be the cause of a tumor that is too small to locate. In this instance, the physician will continue to have follow-up imaging conducted every three to six months for a several years unless the cause is identified. 

Etiology/Causes

-Paraneoplastic syndrome is not a common occurrence for people with cancer. In addition, paraneoplastic syndrome is not even thought to be caused by the cancer cells directly disrupting the nervous function of the body.

-Instead, it is thought that the white blood cells of the body, or T cells, attack normal cells of the nervous system as well as the cancer itself which then causes paraneoplastic syndrome.

Systemic Involvement

Systemic involvement could affect any of the following systems (specific impairments listed above under Characteristics/Clinical Presentation):

Renal

Gastrointestinal

Hematologic

Cutaneous

Endocrine

Neuromuscular

Medical Management (current best evidence)

Treatment varies with the type and location of the paraneoplastic disorder.

Treatment of the underlying tumor
The therapeutic protocols for treating the paraneoplastic syndrome are typically the same as if the patient did not have paraneoplastic syndrome. Therefore, they would treat the cancer and not the syndrome through surgery, radiation, or chemotherapy, or by some combination of the previously listed.

Treatment of the presumptive immune-mediated disorder
The second therapeutic option is based on immunosuppression which can be accomplished through the use of intravenous immunoglobulins, steroids, plasma exchange, or other immunosuppressive drugs.
This treatment should be reserved for patients with clearly identifiable antibodies in their serum. 

Plasmapheresis (Plasma Exchange)

This process separates the fluid part of the blood, called plasma, from your blood cells through the use of a device called a cell separator. The red and white blood cells, along with your platelets, are returned to your body, while the plasma, which contains unwanted antibodies, is discarded and replaced with other fluids.

File:ComplexPt Plasmapheresis.jpg

Intravenous immune globulin (IVIg)

This can be given to a patient with paraneoplastic syndrome to help aid in the fight against "bad" antibodies. Immune globulin contains healthy antibodies from blood donors. High doses of immune globulin accelerates the destruction of damaging antibodies in your blood.

Physical Therapy Management (current best evidence)

People with paraneoplastic syndrome can have difficulty with walking, coordination, muscle tone, sensory of where the body is in space, and vertigo. All of these symptoms the physical therapist can treat with traditional therapy. Precautions must be taken into account for the cancer or neoplasm that is involved.

Differential Diagnosis

Abdominal Aortic Aneurysm
Anemia
Antithrombin Deficiency
Attention Deficit Hyperactivity Disorder
Bone Marrow Failure
Chronic Fatigue Syndrome
Dermatomyositis
Diabetes Mellitus, Type 1
Glomerulonephritis, Acute
Mixed Connective-Tissue Disease
Myelodysplastic Syndrome
Nephrotic Syndrome
Personality Disorders
Polycythemia Vera
Polymyalgia Rheumatica
Scleroderma
Superficial Thrombophlebitis
Systemic Lupus Erythematosus
Undifferentiated Connective-Tissue Disease

Case Reports/ Case Studies

A case of paraneoplastic syndrome accompanied by two types of cancer: jnnp.bmj.com/content/72/3/408.full.pdf+html

Resources

American Autoimmune Related Diseases Association
22100 Gratiot Avenue
Eastpointe, MI 48021-2227
[email protected]
http://www.aarda.org External link
Tel: 586-776-3900 800-598-4668
Fax: 586-776-3903

National Cancer Institute (NCI)
National Institutes of Health, DHHS
6116 Executive Boulevard, Ste. 3036A, MSC 8322
Bethesda, MD 20892-8322
[email protected]
http://cancer.gov
Tel: 800-4-CANCER (422-6237) 800-332-8615 (TTY)

American Cancer Society
National Home Office
250 Williams Street, NW
Atlanta, GA 30303-1002
http://www.cancer.org External link
Tel: 800-ACS-2345 (227-2345)

National Organization for Rare Disorders (NORD)
55 Kenosia Avenue
Danbury, CT 06810
[email protected]
http://www.rarediseases.org External link
Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291

Recent Related Research (from Pubmed)

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References

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