Paraneoplastic Syndrome: Causes, Symptoms, Treatment, Pathogenesis, Types

Paraneoplastic syndrome is a set of signs and symptoms, which develop at distant sites from a tumor/cancer. This syndrome occurs as a result of cancer in the body. Paraneoplastic syndromes are commonly seen in the middle-aged to older patients and are often seen in association with breast cancer, lung cancer, lymphatic or ovarian cancer. In some patients, symptoms of paraneoplastic syndrome can be seen before the diagnosis of cancer.

Paraneoplastic Syndrome does not occur due to presence of cancer cells locally. The cause of development of Paraneoplastic Syndrome is humoral factors, such as cytokines or hormones that are excreted by an immune response against the tumor or by the tumor cells themselves.

The tumor cells produce antigens, which are tissue-restricted and this triggers an anti-tumor immune response in the body, which can partially or in rare cases can completely suppress the growth of the tumor and the cancer symptoms. When this immune response of the tumor breaks the immune tolerance of the body, then the normal tissue of the body gets attacked resulting in generation of neuronal protein. At this point, the patient consults the doctor.

The pathogenesis of Paraneoplastic Syndrome is not clear. Paraneoplastic Syndrome can develop secondary to substances that are secreted by the tumor or can occur as a result of antibodies produced against the tumors, which produce a cross-reaction with other tissues. Paraneoplastic Syndrome patient can experience symptoms in any physiologic system or any organ. About 20% of the patients suffering from cancer also have paraneoplastic syndromes; however, this condition usually goes unrecognized.

Some of the common cancers which are associated with Paraneoplastic Syndrome include:

• Lung carcinoma (commonest).
• Hepatocellular carcinoma.
• Renal carcinoma.
• Leukemia.
• Breast cancer.
• Lymphomas.
• Ovarian cancer.
• Neural cancers.
• Pancreatic cancer.
• Gastric cancer.

Common symptoms seen in patients with Paraneoplastic Syndrome are fever, anorexia, night sweats and cachexia. These symptoms of Paraneoplastic Syndrome occur due to release of cytokines that are involved in the immune response or inflammatory response. They can also be produced from mediators that are associated with tumor cell death. Other factors such as changes in the liver function and steroidogenesis can also contribute to the symptoms of Paraneoplastic Syndrome.

Cutaneous Paraneoplastic Syndrome: In this type of Paraneoplastic Syndrome, the patient has symptoms related to skin. The commonest cutaneous symptom experienced is itching and this can occur from hypereosinophilia. The patient may also have flushing, which is often related to vasoactive substances produced by the tumor such as prostaglandins. Other symptoms of Cutaneous Paraneoplastic Syndromes include keratosis or pigmented skin lesions. Patients suffering from gastrointestinal cancer can have acanthosis nigricans. Patients having cancers such as lymphoma, hepatocellular carcinoma and melanoma can have dermal melanosis. Bowen disease can be seen in the patients having genitourinary, lung and gastrointestinal cancer. Patients with gastrointestinal cancer and lymphoma can also experience large multiple seborrheic keratoses.

Gastro-Intestinal Paraneoplastic Syndrome: Secretion of prostaglandins from a tumor or vasoactive intestinal peptide can result in watery diarrhea with electrolyte imbalances and dehydration in the patient. Some of the causative tumors include pancreatic islet cell tumors. Carcinoid tumors are responsible for producing serotonin degradation products, which produces symptoms such as diarrhea, flushing, breathing difficulties. Inflammatory tumor mass, especially lymphomas, can result in protein-losing enteropathies.

Endocrine Paraneoplastic Syndrome: Paraneoplastic syndrome also affects the endocrine system. Patients having small cell cancer of the lung will commonly have ectopic production of ACTH-like or ACTH molecules, which results in Cushing syndrome. Patient suffering from endocrine paraneoplastic syndrome can also have electrolyte and water imbalances such as hyponatremia. Patients having hemangiopericytomas or pancreatic islet cell tumors can generate insulin production or production of growth factors similar to insulin, which can result in hypoglycemia. In Endocrine Paraneoplastic Syndrome, the patients can have refractory hyperglycemia from glucagon-producing pancreatic tumors.

Pheochromocytoma or ACTH-secreting tumors lead to abnormal secretion of norepinephrine and epinephrine, which can result in hypertension in the patient. There are other hormones which can be ectopically produced, such as parathyroid hormone-related peptide from head and neck cancer, squamous cell lung cancer and bladder cancer. Parathyroid hormone-related peptide can also cause hypercalcemia and other related symptoms, such as dehydration, polyuria, muscle weakness and constipation. Calcitonin can be produced in the body from small cell lung cancer, breast cancer and medullary thyroid cancer. Calcitonin can also cause a decrease in the serum calcium level resulting in cardiac arrhythmias and twitching of the muscles. Patient can also have ectopic production of thyroid-stimulating hormone due to gestational choriocarcinoma.

Hematologic Paraneoplastic Syndromes: Patients suffering from cancer can develop anemia of chronic disease, pure red cell aplasia, leukocytosis eosinophilia, thrombocytosis, basophilia along with disseminated intravascular coagulation. Other than this, if the patient has Coombs-positive hemolytic anemia and immune thrombocytopenia then he/she will have a complicated course of Hodgkin lymphoma and lymphoid cancers. Erythrocytosis can develop in different types of cancers, particularly hepatomas and renal cancers. This is due to ectopic production of erythropoietin or substances similar to erythropoietin. In some cases monoclonal gammopathy can also be seen.

Renal Paraneoplastic Syndrome: Patients with ovarian cancer, colon cancer and lymphoma can develop membranous glomerulonephritis due to circulating immune complexes.

Rheumatologic Paraneoplastic Syndromes: Autoimmune reactions leading to rheumatologic disorders can also be a sign of paraneoplastic syndrome. Patients with hematologic cancers or pancreas, colon or prostate cancer can develop arthropathies. Patients suffering from gynecologic and lung cancers can also develop systemic sclerosis or SLE. Patients with certain lung cancers can have hypertrophic osteoarthropathy with symptoms such as painful swelling of the wrists, knees, elbows, ankles and metacarpophalangeal joints with effusion, and in some cases, clubbing of the fingertips. Secondary amyloidosis may develop in patients with cancers such as lymphomas, myeloma and renal cell carcinomas.

Patients with cancer can also often develop dermatomyositis and to some extent polymyositis, especially in patients above the age of 50. Symptoms consist of progressive proximal muscle weakness with inflammation and necrosis of the muscle. Patient can also develop a butterfly rash, which is dusky and erythematous with pink-purple hue on the cheeks along with periorbital edema. Treatment consists of corticosteroids and treatment of the cancer.

Neurologic Paraneoplastic Syndrome: Paraneoplastic neurological disorders are one of the devastating types of paraneoplastic syndromes. These paraneoplastic disorders affect the peripheral nervous system or the central nervous system. Some of them can be degenerative in nature. Treatment of the cancer may improve the patient’s condition. Signs and symptoms of paraneoplastic neurological disorders include ataxia, nystagmus, dizziness, loss of muscle tone, difficulty in swallowing, loss of fine motor coordination, memory loss, slurred speech, vision problems, dementia, sleep disturbances, sensory loss in the limbs and seizures. Common cancers which are associated with paraneoplastic neurological disorders include ovarian cancer, breast cancer and lung cancer. Other cancers can also lead to paraneoplastic symptoms. There are many different types of peripheral neuropathy which come under the neurologic paraneoplastic syndrome. The commonest neurologic paraneoplastic syndrome is peripheral neuropathy, which is often a distal sensorimotor polyneuropathy resulting in sensory loss, mild motor weakness and absent distal reflexes. Cerebellar syndromes along with other central neurologic paraneoplastic syndrome can also be seen. It is difficult to distinguish, this syndrome from other accompanying chronic conditions.

One of the rare, but specific peripheral neuropathy, is subacute sensory neuropathy. Patient develops degeneration of the dorsal root ganglia with progressive sensory loss and ataxia; however, development of motor weakness is minimal. This disorder can be disabling for the patient. There is no treatment for this syndrome. Another rare ascending peripheral neuropathy is Guillain-Barré syndrome and is usually seen in patients suffering from Hodgkin lymphoma.

Eaton-Lambert syndrome can precede cancer or develop after the diagnosis of cancer or during the cancer. Men having intrathoracic tumors usually get affected with this syndrome. Common signs and symptoms include weakness, fatigue, pain in the muscles of the proximal limb, dry mouth, peripheral paresthesias, ptosis and erectile dysfunction. There is reduction or loss of deep tendon reflexes. This syndrome can be diagnosed by incremental response to repetitive stimulation of the nerves. Treatment consists of treating the underlying cancer first. Guanidine is prescribed, which facilitates the release of acetylcholine release and decreases the severity of the symptoms. However, it also suppresses liver and bone marrow function. Treatment can also be done by plasma exchange and corticosteroids.

Patients with subacute cerebellar degeneration will experience bilateral arm and leg ataxia, dysarthria, and sometimes diplopia and vertigo. Other neurologic signs consist of dementia with or without nystagmus, ophthalmoplegia. There are also extensor plantar signs along with prominent arm involvement and dysarthria. Cerebellar degeneration can occur before the diagnosis of cancer by weeks to years. Cerebellar degeneration worsens and can cause extreme disability in the patient. Investigations such as CT scan or MRI scan will reveal cerebellar atrophy, especially in the late stage of the disease. Other characteristic pathologic changes include lymphocytic cuffing of deep blood vessels and abundant loss of Purkinje cells. Treatment for this syndrome is not specific; however, patient may experience some improvement after successful treatment of cancer.

Patients with childhood neuroblastoma may also have opsoclonus, which is a rare cerebellar syndrome. Patient also has cerebellar ataxia and myoclonus of the extremities and trunk. A circulating autoantibody, anti-Ri, may be present. Treatment of this syndrome consists of treatment of cancer and use of corticosteroids.

Patients having Hodgkin lymphoma and other lymphomas may also have subacute motor neuronopathy and this is a rare condition. There is degeneration of anterior horn cells. Patient can experience spontaneous improvement in this condition.

Encephalitis can develop in some patients as a paraneoplastic syndrome. Depending on the area of the brain involved, encephalitis takes various forms. Patients with small cell lung cancer often experience encephalopathy. The characteristic symptoms of limbic encephalitis include depression, anxiety, loss of memory, confusion, agitation, behavioral abnormalities and hallucinations. The serum and spinal fluid may have Anti-Hu antibodies. MRI scan shows areas with edema and increased contrast uptake.

Treatment of Paraneoplastic Syndrome consists of treating the underlying cancer by therapies such as surgery, radiation therapy and chemotherapy. These cancer treatments will help in slowing the neurological degeneration. For a good prognosis, it is important that rapid diagnosis and treatment be started.

Effective treatment of Paraneoplastic Syndrome can be achieved by controlling and treating the underlying cancer. However, some of the symptoms of Paraneoplastic Syndrome can be controlled with the use of certain drugs, such as somatostatin analogs for carcinoid syndrome or cyproheptadine, corticosteroids and bisphosphonates for hypercalcemia.

As Paraneoplastic Syndrome is comparatively rare, there are only some doctors who have dealt with this condition. Patients suffering from Paraneoplastic Syndrome should consult a specialist who has experience in diagnosing and treating paraneoplastic syndromes.

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