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  

Introduction

Paraneoplastic syndromes (PNS) are rare clinical syndromes due to the systemic effects of tumours; they are unrelated to tumour size, invasiveness or metastases. Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors See image R

• Recent years have seen considerable advances leading to improved understanding of their pathophysiology and increased recognition of new PNS entities and PNS associated tumours.
• Diagnosis is still frequently missed or delayed.
• Diverse organs and systems are affected by the associated tumours- which may be benign or malignant.
• PNS can occur concurrently with tumour diagnosis, before tumour is diagnosed and even after tumours have been resected.
• It is hypothesized 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. Neurological symptoms can develop over a period of days to weeks and usually occur prior to the tumor being discovered.
• The symptoms typically presents in the middle-aged to older population. Also, it is 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.

Etiology

PNS are largely due to two main causes:

1. Those due to tumour secretions of hormones, functionally active peptides, enzymes cytokines
2. Those due to tumours operating through auto-immune/immunological mechanisms with cross-reacting antibodies between neoplastic and normal tissues. Nb Remission of symptoms often follows resection of humoral secretory tumours but not always of tumours due to immunological mechanisms.

Epidemiology

• Precise incidence and prevalence of the paraneoplastic syndrome are unknown (due to the rarity of disease). Can occur with any malignancy.
• A review of the literature suggests that paraneoplastic syndrome occurs in up to 8% of cancer patients.
• Neurological manifestation in the form of neuropathies is common.
• Males and females are affected equally.

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.

Management

• Management of the patients is based on type, severity, and location of the paraneoplastic syndrome. First, therapeutic options are to treat underlying malignancy with chemotherapy, radiation, or surgery.
• Other therapeutic options are immunosuppression with corticosteroids or other immunosuppressive drugs, intravenous immunoglobulins, plasma exchange, or plasmapheresis.

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. 

Physical Therapy Management

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

1. Abdominal Aortic Aneurysm
2. Anemia
3. Antithrombin Deficiency
4. Attention Deficit Hyperactivity Disorder
5. Bone Marrow Failure
6. Chronic Fatigue Syndrome
7. Dermatomyositis
8. Diabetes Mellitus, Type 1
9. Glomerulonephritis, Acute
10. Mixed Connective-Tissue Disease
11. Myelodysplastic Syndrome
12. Nephrotic Syndrome
13. Personality Disorders
14. Polycythemia Vera
15. Polymyalgia Rheumatica
16. Scleroderma
17. Superficial Thrombophlebitis
18. Systemic Lupus Erythematosus
19. 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

Conclusion

The diagnosis and management of paraneoplastic syndromes is difficult.

• In most cases, there is an underlying malignancy responsible.
• Due to the numerous causes, the condition is best managed by an interprofessional team (including a pathologist, oncologist, radiologist, hematologist, nurse specialist, and an internist).
• Once the cause is discovered, it needs to be treated.

The management of the patients is based on type, severity, and location of the paraneoplastic syndrome.

• First, therapeutic options are to treat underlying malignancy with chemotherapy, radiation, or surgery.
• Other therapeutic options are immunosuppression with corticosteroids or other immunosuppressive drugs, intravenous immunoglobulins, plasma exchange, or plasmapheresis.