The first report of Paraneoplastic syndrome is attributed to a French physician, M Auche, who described the involvement in a peripheral nervous system in cancer patients in 1890. This syndrome is a group of signs and symptoms caused by a substance that is produced by a tumor, or in reaction to a tumor. Paraneoplastic syndrome is defined as a rare disorder triggered by a response to neoplasm of an immune system that is altered. These are clinical syndromes produced by tumor although they occur remotely from the tumor itself.
The symptoms may be of any nature – endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal or miscellaneous. Fever is the most common sign. Other clinical symptoms may be benign but syndromes could be varied; from a malignant carcinoid syndrome to Cushing syndrome. In cancer patients, the central nervous system involvement can be detected and it is a prominent manifestation of cancer.
Because of their protean manifestations, Paraneoplastic syndromes are managed by a medical team of physicians, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists and dermatologists.
This syndrome can be due to a number of causes, including hormones or biologically active products, made by tumor, which blocks normal hormone, autoimmunity, immune-complex production and immune suppression. But, this is not caused by the primary tumor itself, or by its metastases, or by compression, infection, nutritional deficiency, or treatment of tumor.
Patients with family history of malignancies are at an increased risk and should be screened for cancer. Paraneoplastic syndromes occur typically among middle-aged to older patients. They are mostly diagnosed with cancers of the lung, breast, ovaries, or lymphatic system or lymphoma.
These symptoms sometimes appear before the diagnosis of a malignancy. When the tumor breaks immune tolerance and begins to attack the normal tissue expressing that protein, this syndrome become prominent.
Types of Paraneoplastic Syndrome
Due to the complexity of this syndrome, its clinical presentations may vary greatly. Hence, Paraneoplastic syndromes is divided into four main categories - endocrine, neurological, mucocutaneous, and hematological syndromes as well as a host of others including rheumatologic, renal, gastrointestinal, Cutaneous and miscellaneous.
Fever, dysgeusia, anorexia, and cachexia are included under miscellaneous category. Fever is associated with lymphomas, acute leukemias, sarcoma and carcinomas.
Rheumatologic syndrome includes polyarthritis, particularly in patients with myelomas, lymphomas, acute leukemia, malignant tumors of the colon, pancreas, prostrate. Scleroderma may precede the evidence of tumor. Widespread form of malignancies of breast, uterus and lung can be observed.
Renal syndrome is characterized by hypokalemic nephropathy, and it occurs in 50% of individuals with ACTH secreting tumors of the lung. Nephrotic syndrome is observed in patients with Hodgkin lymphoma, non Hodgkin lymphoma, malignancies of lung, thyroid, colon, breast, ovary and pancreatic head.
Watery diarrhea and electrolyte imbalance, leads to asthenia, confusion and exhaustion, all characteristic of gastrointestinal syndromes. Severe prostaglandins lead to malabsorption and unavailability of nutrients.
Hematologic syndromes are related to anemia, thrombocytosis, disseminated intravascular coagulation, and leukemoid reactions from several types of cancers. Leukemoid reactions due to immature white blood cells in the blood stream are accompanied by hypereosinophilia and itching.
Cutaneous syndromes are manifested by itching and flushes, alopecia, or hypertrichosis. Blackish pigmentation of the skin usually occurs in patients with metastatic melanomas or pancreatic tumors.
Endocrine syndromes resemble common endocrine disorders. Increased serum and urine cortisol concentrations are common examples of this malignancy.
Neurologic or neuromuscular syndromes relate to cancers and such disorders affect 6% of all patients with cancer. Neuromuscular symptoms mimic common neurological conditions. Myasthenia gravis is a common Paraneoplastic syndrome in patients with thymoma, a malignancy arising from epithelial cells of the thymus.
Paraneoplastic limbic encephalitis is characterized by depression, seizures, irritability and short term memory loss and neurologic symptoms rapidly resemble dementia.
Paraneoplastic cerebellar degeneration causes gait difficulties, dizziness, nausea and diplopia. Sensory neuropathy affects lower and upper extremities and there is progressive memory loss, either symmetric or asymmetric.
As Paraneoplastic syndromes may evolve over weeks to months, they usually stabilize regardless whether the patient's underlying condition improves or worsens. Since this is the first manifestation of cancer, patients should undergo investigation for cancer. Other diagnoses are membrane disease, dementia, encephalopathy, encephalitis, myelitis, anemia, bone marrow failure, chronic fatigue syndrome, mixed connective tissue disease, polycythemia vera and polymyalgia rheumatica among others.
Complete laboratory tests in blood, urine, cerebrospinal fluid, protein electrophoresis, assays for auto antibodies, Endoscopy and imaging studies including whole body scans and FDG-PET scans are prescribed to detect extremely small tumors especially useful for patients with neurologic diseases.
Treatment of Paraneoplastic Syndrome
Treatment for this syndrome varies depending upon the type and location of tumors. The first option of treatment of the underlying tumor is by therapeutic protocols, a combination of surgery, radiation, chemotherapy. Second therapeutic option is for patients with clearly identifiable antibodies by intravenous immunoglobulins, steroids, or plasma exchange.
Surgical treatment is typically directed toward the underlying neoplasm although some Paraneoplastic disorders may resolve rapidly without surgery on the primary tumor.
Hodgkin's Disease refers to a condition that was first described by British physician Thomas Hodgkin. Hodgkin's disease or Hodgkin's lymphoma is a malignant growth of lymph cells. This uncommon form of cancer of the lymph system is characterized by abnormal growth of cells in the lymph system thereby spreading beyond it. It progressively compromises the body's immune system. While Hodgkin's disease can occur to a person at any time of his life, it is noticed in early adulthood or late adulthood. Usually, Hodgkin's disease begins in the lymph nodes and may spread to other parts of the body. The difference between Hodgkin's disease and non-Hodgkin's lymphoma is that tumors in Hodgkin's syndrome contain large cells called Reed-Sternberg cells.
Patients suffering from Hodgkin's disease notice painless swelling in the lymph nodes of the neck, armpit or groin. There may be fever and fatigue. The patient loses weight and feels drained of energy. Unexplained itching and lower back pain may also be noticed.
Most often diagnosis of Hodgkin's lymphomas is made during physical check-ups. A biopsy is done to test for the presence of Reed-Sternberg cells that are characteristic to Hodgkin's lymphomas. Blood test will reveal abnormal blood cell count and ESR. Bone marrow aspiration is done to aid diagnosis and treatment. Cellular activity can be traced with Positron Emission Tomography (PET) scan. Treatment for Hodgkin's disease depends on the stage that the disease is in. This determines the extent and region of lymph nodes that have been affected.
Radiation therapy is resorted to when a limited area is affected by Hodgkin's disease. Here high-energy rays are used to kill cancer cells and stop their proliferation. Often it is used in combination with chemotherapy. Chemotherapy may involve a combination of drugs that work together.
Immune responses in the human body play a major role during disease or abnormality. The immune system responds according to the stimulus it receives from the brain either to fight a pathogen or to eradicate an unwanted cell in the body. Immunotherapy enhances or suppresses the immune system to act on the respective disease. Immunotherapy varies in types depending upon its administration requirements. In case of allergic reactions or autoimmune diseases, immunotherapy is used to suppress the immune response to control the adverse reactions caused by allergens and abnormal proteins.
Types of Immunotherapeutic Agents
Immunotherapy is selective for each disease. There are many types of immunotherapeutic agents available. Some are used to enhance the immune system in facilitating the process of phagocytosis and some are used to block the allergic reactions and autoimmune responses of the body.
Monoclonal antibodies which are prepared in the lab are used as anticancer agents. These antibodies are unique as they target specific locations of the cancer cells. Monoclonal antibodies can used in many ways depending upon the type of case. Some monoclonal antibodies can be used directly without any additives. Some are coated with a radioactive material or an additional anticancer drug to act on the cancer cells. These antibodies adhere to the target cell thus interfering with the cancer cell activity.
Many conditions such as Hodgkin’s Lymphoma, chronic lymphocytic leukemia have US FDA approved immunotherapy drugs. Rituxan and Campath are the first monoclonal immunotherapy FDA approved drugs in treatment of cancer. The common side effects noticed in the administration of monoclonal antibodies both as single and conjugated forms include fever, headaches, nausea, rash, low red blood cell count as it interferes with the marrow and also liver disorders. Monoclonal antibodies conjugated with radioactive material in case of radio immunotherapy may trigger severe allergic reactions.
Cytokines such as interferon and interleukin are generally used as immunotherapeutic agents because of their involvement with cell signaling pathways. They are naturally secreted by the body and they are also called nonspecific immunotherapeutic agents. They are predominantly used in treating infections, cancers and tumors. Alpha interferon is widely used in the treatment of cancers such as T-cell lymphoma, Chronic myelogenous leukemia and non-Hodgkin lymphomas. They inhibit the proliferation of cancer cells by interfering with the growth factors.
Interleukins are also used in the treatment of cancers such as lymphoma, leukemia and mylomas of various origins. Interleukin 2 (IL2) is a widely recommended agent for myelomas. Interleukin and interferon therapies have side effects such as extreme fluid accumulation, fever, chills and dizziness. Cytokine therapies based on lymphocyte infusion can cause graft versus host disease leading to the destruction of host cells by the induced lymphocyte cells.
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Bibliography / Reference
Collection of Pages - Last revised Date: November 15, 2019