Paraneoplastic Syndromes – Causes, Symptoms, Treatment

Paraneoplastic Syndromes are a group of rare disorders that are triggered by an abnormal immune system response to a cancerous tumor known as a “neoplasm.” Paraneoplastic syndromes are thought to happen when cancer-fighting antibodies or white blood cells (known as T cells) mistakenly attack normal cells in the nervous system.

Paraneoplastic syndromes are rare disorders with complex systemic clinical manifestations from underlying malignancy due to the altered immune system. In other words, malignant cells do not directly manifest symptoms with metastasis; rather they generate autoantibodies, cytokines, hormones, or peptides that affect the multiple organ systems such as neurological, dermatological, gastrointestinal, endocrine, hematologic, and cardiovascular system.[rx]Symptoms can manifest before or after the diagnosis of cancer. Therefore, it is critical to recognize these syndromes to identify the hidden malignancy which can affect the clinical outcome in patients.

Types of Paraneoplastic Syndromes

Examples of paraneoplastic syndromes of the nervous system include:

Paraneoplastic disorders can be divided into four groups, roughly in order of their recognition.

• (1) The neuromuscular paraneoplastic disorders, typified by myasthenia gravis, generally involve autoantibodies to a neuromuscular junction or peripheral nerve membrane proteins that have direct pathophysiological effects. For this reason, and due to the strong reparative abilities of the PNS, these disorders respond to immunotherapy.
• (2) The classical paraneoplastic disorders, such as anti-Hu, involve T-cell processes targeting neurons of the CNS or PNS. Cancer associations are relatively strong and the prognosis is poorer.
• (3) The next group involves autoantibodies to intracellular synaptic proteins such as GAD65 and amphiphysin. These both associated with stiff person syndrome and other CNS disorders. It is controversial whether these antibodies are directly pathogenic, or mark a T-cell response, or both.
• (4) The newest group involves antibodies to CNS synaptic and other neuronal membrane proteins such as the NMDA receptor. These disorders involve direct effects of the antibodies, have variable tumor associations, and tend to improve with immunotherapy.

Pathophysiology

Tumor cells are immunogenic and lead to the activation of both cell-mediated and humoral immune systems. It has been observed that cytotoxic T cells recognize antigens on tumor cells and attack those cells or generate antibodies against tumor cells.[rx] However, the body’s immune system can also attack normal tissue with a similar antigen presentation and lead to symptoms. Most cases exhibit paraneoplastic syndrome with immunologic mechanisms; however, there are non-immunologic mechanisms of paraneoplastic syndrome. Paraneoplastic syndrome has heterogenous manifestations affecting multiple organ systems in the body, and clinical manifestation does not necessarily associate with the clinical or pathological stage of the underlying malignancy nor is it a prognostic indicator.[rx]

Immunologic Mechanism

Cell-mediated immunity, T cells attack tumor cells antigens as well as similar antigens in normal cells.

Paraneoplastic antibodies, also known as onconeural antibodies, direct against target antigen (onconeural antigen) such as type-1 antineuronal nuclear antibodies (ANNA-1), type-2 antineuronal nuclear antibodies (ANNA-2), collapsing response mediator protein-5 (CRMP-5), Purkinje cell cytoplasmic antibody type-1 (PCA-1), anti-amphiphysin, anti-recoverin, anti-bipolar cells of the retina, N-methyl D-aspartate (NMDA) receptor antibodies, acetylcholine receptor antibodies, and gamma-aminobutyric acid A (GABA-A) receptor antibodies.

Non-Immunologic Mechanism

Tumor cells produce hormones or cytokines leading to metabolic abnormalities such as hyponatremia due to antidiuretic hormone or hypercalcemia due to the parathyroid-hormone-related peptide. Hematological malignancies producing immunoglobulins affect the peripheral nervous system manifested as peripheral neuropathy.

Causes of Paraneoplastic Syndromes

Paraneoplastic syndromes are accompanied with underlying malignancy, but the exact mechanism remains unclear. The syndromes commonly manifest in lung cancer, breast cancer, hematological malignancies, medullary thyroid cancer, gynecological malignancies, and prostate cancer. [rx][rx]

Symptoms of Paraneoplastic Syndromes

Signs and symptoms of paraneoplastic syndromes of the nervous system can develop relatively quickly, often over days to weeks. Signs and symptoms of paraneoplastic syndromes of the nervous system often begin even before a cancer is diagnosed.

Signs and symptoms vary depending on the body part being injured, and may include:

• Difficulty walking
• Difficulty maintaining balance
• Loss of muscle coordination
• Loss of muscle tone or weakness
• Loss of fine motor skills, such as picking up objects
• Difficulty swallowing
• Slurred speech or stuttering
• Memory loss and other thinking (cognitive) impairment
• Vision problems
• Sleep disturbances
• Seizures
• Hallucinations
• Unusual involuntary movements

Diagnosis of Paraneoplastic Syndromes

History and Physical

The paraneoplastic syndrome involves a multi-organ system in the body with heterogeneous and complex clinical manifestations in the setting of underlying malignancy.

Clinical presentations are categorized based on the organ system as follows.

Nervous System

Signs and symptoms are based on the part of the nervous system that is affected by a paraneoplastic syndrome, for example, central nervous system, neuromuscular junction, or peripheral nervous system. A patient may present with seizure, cognitive dysfunction, personality change, psychosis, insomnia, ataxia, dysarthria, dysphagia, cranial nerve deficits, and sensorimotor abnormalities.

Central Nervous System

Paraneoplastic encephalitis/encephalomyelitis

Diverse and complex symptoms arising from cerebellar encephalitis, brainstem encephalitis, limbic encephalitis, and myelitis. Characterized by cognitive dysfunction, depression, personality changes, hallucinations, seizures, somnolence, autonomic dysfunction, and less common endocrine dysfunction if the hypothalamus is involved.[rx]

Subacute cerebellar degeneration

It is commonly associated with breast cancer, small cell lung cancer, Hodgkin lymphoma, and ovarian cancer. Clinically manifested as ataxia, dysarthria, dysphagia, diplopia, dizziness, nausea, and vomiting.

Opsoclonus-myoclonus syndrome

Clinically characterized by uncontrolled rapid eye movement, body jerks, ataxia, hypotonia, irritability, and commonly affects children less than 4 years. Opsoclonus is a common manifestation in children whereas ataxia is more prominent in adults.

Neuromuscular Junction

Myasthenia Gravis

Most commonly seen in patients with thymoma and is clinically manifested as a weakness of voluntary muscles and diaphragmatic weakness. Anti-AchR (acetylcholine receptor) antibody is positive in those patients, and electromyography (EMG) shows a decremental response to repetitive nerve stimulation.[rx]

Lambert-Eaton myasthenic syndrome (LEMS)

It is caused due to impairment of voltage-gated calcium channels (VGCC) due to autoantibodies on the presynaptic membrane at neuromuscular junction which leads to decreased acetylcholine release. [rx] LEMS is strongly associated with small cell lung cancer (SCLC), about 3% of patients develop LEMS, and it can occur at any stage of the disease. Clinically LEMS is characterized by weakness of the proximal muscles predominantly affecting thigh and pelvic muscles; patient generally have difficulty in strenuous activity; moreover, patients also have difficulties in basic activities such as climbing stairs, walking, and getting up from a chair. Symptoms are gradual in onset with slow progression. Patients also demonstrate autonomic symptoms such as dry mouth, decreased sweating, and constipation. Clinical examination is positive for diminished tendon reflexes.  The blood anti-VGCC antibodies are positive in approximately 85% of patients with LEMS.

Peripheral Nervous System

Autonomic neuropathy

Frequently associated with SCLC and thymoma. Autonomic neuropathy affects parasympathetic, sympathetic, and enteric nervous systems. Characterized by dry mouth, eyes, altered pupillary reflexes, bladder and bowel dysfunction, orthostatic hypotension. A patient may also manifest as chronic gastrointestinal (GI) pseudo-obstruction leading to constipation, nausea, vomiting, dysphagia, and abdominal distension.

Subacute sensory neuropathy

Characterized by paresthesia, pain, decreased sensation and deep tendon reflexes. It affects both upper and the lower extremities; distribution can be either multifocal, asymmetric or symmetric.

Endocrine

Cushing syndrome

Manifested as muscle weakness, weight gain, peripheral edema, centripetal fat distribution, and high blood pressure.[rx] Blood workup significant for hypokalemia elevated cortisol level and elevated ectopic adrenocorticotropic hormone (ACTH) due to tumor cells.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

SIADH is more frequently seen in SCLC patients due to ectopic anti-diuretic hormone (ADH) by tumor cells.[rx] Clinical manifestations vary from mild symptoms such as nausea, anorexia, fatigue, and lethargy to severe symptoms like confusion, seizures, respiratory depression, and coma. Laboratory findings are positive for hyponatremia, hyperosmolality and increased urine osmolality.

Hypercalcemia

It is frequently associated with lung cancer, multiple myeloma, and renal cell carcinoma. Hypercalcemia is mediated by different mechanisms such as the ectopic production of the parathyroid hormone-related peptide (PTHrP) by tumor cells, local osteolytic hypercalcemia and increased excess extrarenal vitamin D. Patients manifest as generalized weakness, lethargy, nausea, vomiting, altered mental status, bradycardia, acute renal failure, hypertonia, and hypertension.

Rheumatological

Paraneoplastic polyarthritis

Commonly involves large joints and is characterized by migratory, non-erosive, asymmetric polyarthritis.

Polymyalgia rheumatica

Manifested as pain and stiffness in the shoulder girdle, neck, and hip girdle.[rx] It is most commonly associated with myelodysplastic syndrome.

Multicentric reticulohistiocytosis

Clinically characterized by papules, nodules, and destructive polyarthritis.

Hypertrophic osteoarthropathy

Clinically manifested as digital clubbing, joint swelling, and pain.

Hematological

Hematologic manifestations of the paraneoplastic syndrome are generally asymptomatic but can be manifested as pallor, fatigue, dyspnea, and venous thromboembolism. Hematologic syndromes are characterized by thrombocytosis, granulocytosis, eosinophilia, pure red cell aplasia, disseminated intravascular coagulation, and leukemoid reactions.

Dermatological

Acanthosis nigricans

Manifested as thickened hyperpigmented skin, usually in the axilla and neck region. Gastric adenocarcinoma is most commonly associated with acanthosis nigricans.[rx]

Paraneoplastic pemphigus

Characterized by blistering and erosion of trunk, palms, and soles; also involves mucous membrane causing pain due to mucosal erosion. Commonly seen in patients with B-cell lymphoproliferative disorder.[rx]

Sweet syndrome

This is also known as acute febrile neutrophilic dermatosis. It manifests as acute onset of painful, erythematous plaques, papules, and nodules accompanied by fever and neutrophilia.

Leukocytoclastic vasculitis

Typically manifests as palpable purpura on the lower extremities, but a patient may also experience cyanosis, pruritus, pain, and ulceration of the affected skin.

Dermatomyositis

Characterized by a heliotrope rash on the upper eyelids, Gottron papules on phalangeal joints, and an erythematous rash on the face, neck back, chest, and shoulders.[rx] Also involves muscles as inflammatory myopathy and is manifested as proximal muscle weakness and muscle tenderness.

Renal

Electrolyte imbalance (hypokalemia, hypo or hypernatremia, hyperphosphatemia) causing nephropathy and acid-base disturbance due to ectopic hormones produced by tumor cells such as ACTH and ADH.[rx] Nephrotic syndrome can also be one of the manifestations of paraneoplastic syndrome.

Miscellaneous

Fever, cachexia, anorexia, dysgeusia

Clinical exam

Your doctor or a neurologist will conduct a general physical, as well as a neurological exam. He or she will ask you questions and conduct simple tests in the office to judge:

• Reflexes
• Muscle strength
• Muscle tone
• Sense of touch
• Vision and hearing
• Coordination
• Balance
• Mood
• Memory

A patient should be evaluated with a complete panel of laboratory, imaging, electrodiagnostic studies and biopsy of specific tissues if required.

• Complete blood count with differential
• Comprehensive metabolic panel
• Urinalysis
• Tumor markers
• Ectopic hormones level like PTHrP, ACTH, ADH
• Cerebrospinal fluid analysis (CSF)
• Protein electrophoresis o serum and CSF
• Assay of paraneoplastic antibodies in blood and CSF
• Skin biopsy
• Muscle biopsy

Laboratory tests

Laboratory tests will likely include:

• Blood tests – You may have blood drawn for a number of laboratory tests, including tests to identify antibodies commonly associated with paraneoplastic syndromes. Other tests may attempt to identify an infection, a hormone disorder or a disorder in processing nutrients (metabolic disorder) that could be causing your symptoms.
• Spinal tap (lumbar puncture) – You may undergo a lumbar puncture to obtain a sample of cerebrospinal fluid (CSF) — the fluid that cushions your brain and spinal cord. A neurologist or specially trained nurse inserts a needle into your lower spine to remove a small amount of CSF for laboratory analysis.
• Computerized tomography (CT) – is a specialized X-ray technology that produces thin, cross-sectional images of tissues.
• Magnetic resonance imaging (MRI) – uses a magnetic field and radio waves to create detailed cross-sectional or 3D images of your body’s tissue.
• Positron emission tomography (PET) – uses radioactive compounds injected into your bloodstream to produce cross-sectional or 3D images of the body. PET scans can be used to identify tumors, measure metabolism in tissues, show blood flow and locate brain abnormalities related to seizures.
• PET plus CT – a combination of PET and CT, may increase the detection rate of small cancers, common in people who have paraneoplastic neurological disorders.

Evaluation

Diagnosis of the suspected paraneoplastic syndromes is based on the exclusion of other etiologies as there are heterogeneous clinical manifestations.

An international panel of neurologists developed criteria for paraneoplastic syndrome affecting the nervous system into definite and possible categories [rx][rx].

Definite paraneoplastic syndromes

A classical neurological syndrome and malignancy which develops within 5 years of neurological disorder. Classical syndromes are encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus syndrome, Lambert Eaton myasthenic syndrome, subacute sensory neuropathy, chronic gastrointestinal pseudoobstruction, and dermatomyositis.

• A nonclassical syndrome that improves significantly with the treatment of underlying malignancy and syndrome is not prone to spontaneous remission.
• A nonclassical syndrome with the detection of paraneoplastic antibodies and malignancy that develops within 5 years of diagnosis of the neurological syndrome.
• A classical or nonclassical neurological syndrome with well-recognized paraneoplastic antibodies. The well-recognized antibodies include anti-Hu, Yo, Ri, CV2/CRMP-5, Ma2, and amphiphysin.

Possible paraneoplastic syndrome

• A classical syndrome without paraneoplastic antibodies and cancer but at high risk for an underlying malignancy.
• A classical or nonclassical neurologic syndrome with partially characterized antibody but no cancer.
• A nonclassical syndrome without paraneoplastic antibodies but with cancer within 2 years of a neurological syndrome.

Treatment of Paraneoplastic Syndromes

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.

Medications

In addition to drugs, such as chemotherapy, to combat your cancer, your doctor may prescribe one or more of the following drugs to stop your immune system from attacking your nervous system:

• Corticosteroids – such as prednisone, inhibit inflammation. Serious long-term side effects include weakening of the bones (osteoporosis), type 2 diabetes, high blood pressure, high cholesterol and others.
• Immunosuppressants – slow the production of disease-fighting white blood cells. Side effects include an increased risk of infections. Drugs may include azathioprine (Imuran, Azasan) and cyclophosphamide.

Depending on the type of neurological syndrome and symptoms, other medications may include:

• Anti-seizure medications – which may help control seizures associated with syndromes that cause electrical instability in the brain.
• Medications to enhance nerve-to-muscle transmission – which may improve symptoms of syndromes affecting muscle function. Some drugs 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.

Other medical treatments

Other treatments that may improve symptoms include:

• Plasmapheresis – This process separates the fluid part of the blood, called plasma, from your blood cells with a device known as a cell separator. Technicians return your red and white blood cells, along with your platelets, to your body, while discarding the plasma, which contains unwanted antibodies, and replacing it with other fluids.
• Intravenous immunoglobulin (IVIg) – Immunoglobulin contains healthy antibodies from blood donors. High doses of immunoglobulin speed up the destruction of the damaging antibodies in your blood.

Other therapies

Other therapies may be helpful if a paraneoplastic syndrome has caused significant disability:

• Physical therapy – Specific exercises may help you regain some muscle function that has been damaged.
• Speech therapy – If you are having trouble speaking or swallowing, a speech therapist can help you relearn the necessary muscle control.

Differential Diagnosis

• Encephalopathy
• Encephalitis
• Personality disorder
• Dementia
• Myelitis
• Anemia
• Myelodysplastic syndrome
• Bone marrow failure
• Polycythemia Vera
• Chronic fatigue syndrome
• Mixed connective tissue disorder
• Dermatomyositis
• Scleroderma
• Systemic lupus erythematosus
• Polymyalgia rheumatica
• Acute glomerulonephritis
• Nephrotic syndrome

References