Paraneoplastic syndrome
Encyclopedia
A paraneoplastic syndrome is a disease
or symptom
that is the consequence of the presence of cancer
in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors (by hormone
s or cytokine
s) excreted by tumor cells or by an immune response against the tumor
. Paraneoplastic syndromes are typical among middle aged to older patients, and they most commonly present with cancers of the lung
, breast
, ovaries
or lymphatic system (a lymphoma
). Sometimes the symptoms of paraneoplastic syndromes show before the diagnosis of a malignancy
, which has been hypothesized to relate to the disease pathogenesis. In this paradigm, tumor cells express tissue-restricted antigens (such as neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective in suppressing tumor growth and symptoms. Patients then come to clinical attention when this tumor immune response breaks immune tolerance
and begins to attack the normal tissue expressing that (e.g. neuronal) protein.
) may improve with treatment of the condition or the tumour. Symptoms of paraneoplastic neurological disorders may include ataxia
(difficulty with walking and balance), dizziness
, nystagmus (rapid uncontrolled eye movements), difficulty swallowing, loss of muscle tone
, loss of fine motor coordination
, slurred speech, memory loss, vision problems, sleep disturbances, dementia
, seizure
s, sensory loss in the limbs.
The most common cancers associated with paraneoplastic neurological disorders are breast
, ovarian
and lung cancer
, but many other cancers can produce paraneoplastic symptoms as well.
Treatment options include:
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
or symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
that is the consequence of the presence of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors (by hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s or cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s) excreted by tumor cells or by an immune response against the tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. Paraneoplastic syndromes are typical among middle aged to older patients, and they most commonly present with cancers of the lung
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovaries
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
or lymphatic system (a lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
). Sometimes the symptoms of paraneoplastic syndromes show before the diagnosis of a malignancy
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
, which has been hypothesized to relate to the disease pathogenesis. In this paradigm, tumor cells express tissue-restricted antigens (such as neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective in suppressing tumor growth and symptoms. Patients then come to clinical attention when this tumor immune response breaks immune tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
and begins to attack the normal tissue expressing that (e.g. neuronal) protein.
Classification
Paraneoplastic syndromes can be divided into four main categories: Endocrine, neurological, mucocutaneous and hematological paraneoplastic syndromes, as well as others that may not fit into any of the above categories:| Syndrome class | Syndrome | Main causal cancers | Causal mechanism |
|---|---|---|---|
| Endocrine | |||
| Cushing syndrome |
|
Ectopic ACTH and ACTH-like substance | |
| SIADH Syndrome of inappropriate antidiuretic hormone The syndrome of inappropriate antidiuretic hormone hypersecretion is characterized by excessive release of antidiuretic hormone from the posterior pituitary gland or another source. The result is hyponatremia and sometimes fluid overload... |
Small cell carcinoma Small cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate.... |
antidiuretic hormone | |
| Hypercalcemia |
Lung cancer Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary... (typically squamous cell) Multiple myeloma Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies... (may occur independent of osteolytic lesions) |
PTHrP Parathyroid hormone-related protein Parathyroid hormone-related protein is a protein member of the parathyroid hormone family. It is occasionally secreted by cancer cells . However, it also has normal functions.- Function :PTHrP acts as an endocrine, autocrine, paracrine, and intracrine hormone... (Parathyroid hormone-related protein), TGF-α TGF alpha Transforming growth factor alpha is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. It is closely related to EGF, and can also bind to the EGF receptor with similar effects... , TNF Tumor necrosis factor Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction... , IL-1 |
|
| Hypoglycemia Hypoglycemia Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"... |
Fibrosarcoma Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells.Usually in males ages 30 to 40. Originates in fibrous tissues of the bone. Invades long or flat bones such as femur, tibia,... Hepatocellular carcinoma Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States... |
Insulin Insulin Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle.... or insulin-like substance or "big" IGF-II |
|
| Carcinoid syndrome Carcinoid syndrome Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction... |
Carcinoid Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing... type) |
Serotonin Serotonin Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans... , bradykinin Bradykinin Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure... |
|
| Polycythemia Polycythemia Polycythemia is a disease state in which the proportion of blood volume that is occupied by red blood cells increases... |
See hematological paraneoplastic syndromes | ||
| Neurological | Lambert-Eaton myasthenic syndrome Lambert-Eaton myasthenic syndrome Lambert–Eaton myasthenic syndrome is a rare autoimmune disorder that is characterised by muscle weakness of the limbs... (LEMS) |
|
Immunologic |
| Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration is a paraneoplastic syndrome associated with lung, ovarian, breast, and other cancers.As is the case with other paraneoplastic syndromes, PCD is believed to be due to an autoimmune reaction targeted against components of the central nervous system... |
|
||
| Encephalomyelitis Encephalomyelitis Encephalomyelitis is a general term for inflammation of the brain and spinal cord, describing a number of disorders:* Acute disseminated encephalomyelitis or postinfectious encephalomyelitis, a demyelinating disease of the brain and spinal cord, possibly triggered by vaccination or viral... |
inflammation of the brain and spinal cord | ||
| Limbic encephalitis Limbic encephalitis Limbic encephalitis is a form of encephalitis.In a small number of cases, the pathogens responsible for encephalitis attack primarily the limbic system , often causing memory deficits similar to those observed in Alzheimer's disease or Creutzfeldt-Jakob disease Limbic encephalitis is a form of... |
|
||
| Brainstem encephalitis | |||
| Paraneoplastic Opsoclonus Opsoclonus Opsoclonus refers to uncontrolled eye movement. Opsoclonus consists of rapid, involuntary, multivectorial , unpredictable, conjugate fast eye movements without intersaccadic intervals. It is also referred to as saccadomania or reflexive saccade... (involving eye movement)-Myoclonus |
|
Autoimmune reaction against the RNA-binding protein Nova-1 | |
| Anti-NMDA receptor encephalitis Anti-NMDA receptor encephalitis Anti-NMDA receptor encephalitis is an acute form of encephalitis, potentially lethal but with high probability for recovery, caused by autoimmune reaction against NR1- and NR2-subunits of the glutamate NMDA receptor... |
Teratoma A teratoma is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three germ layers. There are rare occasions when not all three germ layers are identifiable... |
Autoimmune reaction against NMDA-receptor subunits | |
| Polymyositis Polymyositis Polymyositis is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis.-Signs and symptoms:... |
|||
| Mucocutaneous | Acanthosis nigricans Acanthosis nigricans Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:... |
|
Epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR... |
| Dermatomyositis Dermatomyositis Dermatomyositis is a connective-tissue disease related to polymyositis and Bramaticosis that is characterized by inflammation of the muscles and the skin.- Causes :... |
|
Immunologic | |
| Leser-Trélat sign Leser-Trelat sign The Leser-Trélat sign is the explosive onset of multiple seborrheic keratoses , often with an inflammatory base. This can be an ominous sign of internal malignancy as part of a paraneoplastic syndrome... |
|||
| Necrolytic migratory erythema Necrolytic migratory erythema Necrolytic migratory erythema is a red, blistering rash that spreads across the skin, particularly the lower abdomen, buttocks, perineum, and groin... |
Glucagonoma Glucagonoma A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of the hormone glucagon. Alpha cell tumors are commonly associated with glucagonoma syndrome, though similar symptoms are present in cases of pseudoglucagonoma syndrome in the absence... |
||
| Sweet's syndrome | |||
| Florid cutaneous papillomatosis Florid cutaneous papillomatosis Florid cutaneous papillomatosis is the sudden onset of numerous cutaneous papillomas that are indistinguishable from viral warts, and associated with underlying malignancy.- History :... |
|||
| Pyoderma gangrenosum Pyoderma gangrenosum Pyoderma gangrenosum is a disease that causes tissue to become necrotic, causing deep ulcers that usually occur on the legs. When they occur, they can lead to chronic wounds. Ulcers usually initially look like small bug bites or papules, and they progress to larger ulcers. Though the wounds... |
|||
| Acquired generalized hypertrichosis | |||
| Hematological | Granulocytosis Granulocytosis In medicine, granulocytosis is the presence in peripheral blood of an increased number of granulocytes, a category of white blood cells. Often, the word refers to an increased neutrophil granulocyte count, as neutrophils are the main granulocytes.-Causes:... |
G-CSF Granulocyte colony-stimulating factor Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 .... |
|
| Polycythemia Polycythemia Polycythemia is a disease state in which the proportion of blood volume that is occupied by red blood cells increases... |
Hepatocellular carcinoma Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States... |
Erythropoietin Erythropoietin Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production... |
|
| Trousseau sign Trousseau sign of malignancy The Trousseau sign of malignancy is a medical sign found in certain cancers that is associated with venous thrombosis and hypercoagulability. It is also referred to as Trousseau syndrome and is distinct from the Trousseau sign of latent tetany.-History:... |
|
Mucins that activate clotting, others | |
| Nonbacterial thrombotic endocarditis |
|
Hypercoagulability | |
| Anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... |
|
Unknown | |
| Others | Membranous glomerulonephritis Membranous glomerulonephritis Membranous glomerulonephritis is a slowly progressive disease of the kidney affecting mostly patients between ages of 30 and 50 years, usually Caucasian.It is one of the more common forms of nephrotic syndrome.-Terminology:... |
|
Tumor antigen Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:... s |
| Tumor-induced osteomalacia |
Phosphaturic mesenchymal tumor Phosphaturic mesenchymal tumor is a benign neoplasm of mesenchymal origin, that produces phosphatonin . This tumor may cause tumor-induced osteomalacia, a paraneoplastic syndrome, by the secretion of phosphatonin, which has phosphaturic activity Phosphaturic mesenchymal tumor is a benign neoplasm... |
Fibroblast growth factor Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal... -23) |
|
| Stauffer syndrome Stauffer syndrome Stauffer syndrome was described initially by Maurice H. Stauffer, M.D., a gastroenterologist at the Mayo Clinic in Rochester, MN. This condition is a constellation of signs and symptoms of liver dysfunction that arise due to presence of renal cell carcinoma, and, more rarely, in connection with... |
Renal cell carcinoma Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases... |
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Neurological
A particularly devastating form of paraneoplastic syndromes is a group of disorders classified as paraneoplastic neurological disorders (PNDs). These paraneoplastic disorders affect the central or peripheral nervous system; some are degenerative , though others (such as LEMSLambert-Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome is a rare autoimmune disorder that is characterised by muscle weakness of the limbs...
) may improve with treatment of the condition or the tumour. Symptoms of paraneoplastic neurological disorders may include ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(difficulty with walking and balance), dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, nystagmus (rapid uncontrolled eye movements), difficulty swallowing, loss of muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...
, loss of fine motor coordination
Motor coordination
thumb|right|Motor coordination is shown in this animated sequence by [[Eadweard Muybridge]] of himself throwing a diskMotor coordination is the combination of body movements created with the kinematic and kinetic parameters that result in intended actions. Such movements usually smoothly and...
, slurred speech, memory loss, vision problems, sleep disturbances, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, sensory loss in the limbs.
The most common cancers associated with paraneoplastic neurological disorders are breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovarian
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, but many other cancers can produce paraneoplastic symptoms as well.
Treatment options include:
- Therapies to eliminate the underlying cancer such as chemotherapy, radiation and surgery, and
- Therapies to reduce or slow neurological degeneration. Rapid diagnosis and treatment are critical for the patient to have the best chance of recovery. Since these disorders are relatively rare, few doctors have seen or treated PNDs. Therefore, it is important that PND patients consult with a specialist with experience in diagnosing and treating paraneoplastic neurological disorders.
Organizations
The International Paraneoplastic Association (IPA) is an organization dedicated to providing support and information to those affected by paraneoplastic neurological disorders.External links
- Neuroimmunology, The Medical School, Birmingham University - Paraneoplastic neurological autoantibodies, Birmingham UK
- http://www.antibodypatterns.com/hu.php
- IPA website
- Rockefeller University clinical research laboratory devoted to the paraneoplastic neurologic disorders