Paraneoplastic syndrome

Paraneoplastic syndromes are diseases or symptoms that are the consequence of a cancer in the body, but are unrelated to the local presence of actual cancer cells. They have one of two major causes:
*The release of hormones or cytokines by the tumor cells.
*A response by the immune system to the tumor.
Paraneoplastic syndromes are more common in older patients, and tend to occur mostly in patients who are middle age and older. They are also more common with certain types of cancer than others. Cancers of the lungs, breasts, ovaries, and lymphatic system are more likely to cause such conditions. In some cases, the syndromes caused by a faulty immune system response will present with symptoms before the cancer becomes malignant and starts exhibiting its own symptoms. However, both malignant and benign tumors can have associated paraneoplastic syndromes.
Paraneoplastic syndromes are fairly common on House, M.D., occurring in many episodes where cancer is the final diagnosis. However, many critics of the series, including the popular medical blog about House Polite Dissent, have noted that paraneoplastic syndromes, which are in any event rare even when a patient has cancer (roughly 1% of cancer patients exhibit such syndromes), are too often used as a way of explaining the patient's symptoms that can't be explained by the underlying cancer.
==Classification==
There are four main categories of paraneoplastic syndromes:
===Endocrine===
These syndromes are generally caused when a tumor is found in one of the organs that produces hormones starts creating the hormone itself, but can also be caused by tumors elsewhere in the body. Some of the best known of these are:
*Cushing's syndrome, which caused uncontrolled weight gain. This can be caused by a tumor that secretes ACTH. It can be caused by small-cell carcinoma, tumor on the pancreas, a tumor on the nerves or a thymoma.
*Syndrome of inappropriate antidiuretic hormone secretion or SIADH. This results in low urine volume and a buildup of fluids in the body. It can be caused by small-cell carcinoma or tumors of the central nervous system
*Hypercalcemia or high calcium levels. Several cancers can cause this condition, including squamous cell carcinoma of the lungs, breast cancer, kidney cancer, myeloma, cancers of the T cells, and ovarian cancer.
*Hypoglycemia or low blood sugar. The most obvious cause is an nesidioblastoma (such as the one in TB or Not TB), but it can also be caused by sarcomas of the connective tissue, bones, fat, bone marrow, and other similar tissues, as well as by hepatocellular carcinoma.
*Carcinoid syndrome, which causes high levels of serotonin and kallikrein. It can be caused by a bronchial adenoma, pancreatic carcinoma, or stomach carcinoma.
*Hyperaldosteronism, or an excess of the hormone aldosterone which controls the processing of sodium and potassium in the kidneys. It leads to hypokalemia - low potassium levels. It can be caused by an adenoma of the adrenal gland, non-Hodgkin's lymphoma, an ovarian carcinoma, or cancers of the lung.
*Doege-Potter syndrome, a very rare condition caused by an excess of insulin like human growth hormone, usually from a tumor in the pleural cavity. This causes severe hypoglycemia that leads to behavior and personality changes.
===Neurological===
These syndromes affect the brain and nervous system. These are generally far more severe than the other types and can be debilitating all on their own. They can often persist even after the underlying cancer is treated. They can cause ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine muscle control, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, and peripheral neuropathy. These syndromes include:
*Lambert-Eaton myasthenic syndrome or LEMS. It is caused when antibodies created to fight the tumor instead attack calcium channels in the muscles. It's usually caused by small-cell carcinoma.
*Paraneoplastic cerebellar degeneration. It's caused when the immune system attacks the central nervous system. It's caused by cancers of the lungs, ovaries and breast.
*Encephalomyelitis. This can be the result of several conditions, but can also be caused by excess inflammation due to an underlying cancer.
*Limbic encephalitis and Brainstem encephalitis. These can be caused by small-cell lung carcinoma.
*Paraneoplastic opsoclonus-myoclonus. This is caused when antibodies attack an RNA binding protein called Nova 1. It can be caused by breast carcinoma, ovarian carcinoma, small-cell lung carcinoma, and, in children, neuroblastoma.
*Anti-NMDA receptor encephalitis, caused by an autoimmune reaction to certain types of glutamate receptors. It is usually caused by a teratoma.
*Polymyositis. The autoimmune reaction against muscles can be triggered by Non-Hodgkin lymphoma and cancers of the lung and bladder.
===Mucocutaneous===
These syndromes affect the skin and the layer where the skin and underlying tissues meet. Unfortunately, most of these can be caused by conditions other than cancer, and in most cases cancer would be a zebra diagnosis for these symptoms. These include:
*Acanthosis nigricans. Although this can have several underlying causes, the skin discoloration can be caused by carcinomas of the stomach, lungs and uterus which cause the production of a hormone, EGF, which causes uncontrolled cell growth.
*Dermatomyositis. This is caused by an immune response that causes inflammation of the skin and underlying tissues. Although it has other causes, it can also be caused by several cancers including those of the breast, ovaries, pancreas, stomach, large intestine, and Non-Hodgkin's lymphoma.
*Leser-Trelat sign, a series of dark spots underneath the surface of the skin resembling liver spots. These are often a sign of colon cancer.
*Necrolytic migratory erythema, a red blistering rash that usually appears on the abdomen. It's usually caused by a glucagonoma, a glucagon producing tumor.
*Sweet's syndrome or febrile neutrophilic dermatosis, characterized by a certain type of papule. These can be caused by blood cancers such as leukemia.
*Florid cutaneous papillomatosis, a sudden appearance of multiple papillomas that look like warts. These can be caused by many types of cancer, but are most commonly associated with stomach carcinomas.
*Pyoderma gangrenosum, a type of necrosis that leads to large skin ulcers. These can be caused by multiple myeloma.
*Acquired generalized hypertrichosis, where the body grows an unusually large amount of hair. Although hypertrichosis has many causes, it can be caused by several different types of cancer.
===Hematological===
These syndromes affect the blood. Almost any general blood condition can be caused by an underlying cancer. These syndromes include:
*Granulocytosis, from an excess production of the hormone that encourages blood production. This syndrome is common with leukemia.
*Polycythemia, from the excess production of erythropoietin. It can be caused by cancers of the kidneys, brain, and liver.
*Trousseau sign of malignancy, characterized by tender nodules in the veins which characterize clotting . It is characteristic of cancers of the pancreas and lungs.
*Nonbacterial thrombotic endocarditis, where vegetations grow on the heart valves due to the blood being very susceptible to clotting. This can happen with any cancer, but is more likely with cancers of the pancreas. It usually only appears in very advanced stages of cancer.
*Anemia. Although anemia can be caused by many conditions, it is also possible with neoplasms of the thymus gland.
===Other===
Some syndromes do not fit neatly into any of the main categories. These include:
*Membranous glomerulonephritis, a progressive disease of the kidneys. It can be caused by a tumor in the lungs or large intestine, although the vast majority of cases are idiopathic.
*Tumor-induced osteomalacia. This condition causes the kidneys to excrete phosphates at a higher than normal rate, leading to weaknesses in the bones. It is often caused by benign tumors in the connective tissues.
*Stauffer syndrome, liver dysfunction usually caused by a tumor in a kidney, and more rarely by other malignancies.
*Neoplastic fever, a fever attributable to an underlying cancer.
==On the series==
Although cancer is by far the most common diagnosis on the series, in many of those cases, the actual symptoms being suffered by the patient were attributed to paraneoplastic syndrome and not the underlying cancer. However, as has been noted, this storytelling device often starts lumping a zebra onto another zebra. Most paraneoplastic syndromes are associated with one or a few cancers, and most cancers are associated with one or a few paraneoplastic syndromes. Although it is theoretically possible that any of the paraneoplastic syndromes can be triggered by any type of cancer, on the series this is usually not a good fit.
===The Mom To Be===
In Babies & Bathwater, Naomi Randolph suffered from fainting, impaired function of the liver and kidneys, increased levels of BUN and creatinine, cramps, difficulty swallowing, myasthenia, and one drooping eyelid. After quickly ruling out that her pregnancy was responsible for her symptoms, they found a granuloma on her lung indicating small-cell carcinoma. The doctors told her that her other symptoms were the result of Lambert-Eaton myasthenic syndrome.
This is a plausible diagnosis. Lambert-Eaton does cause muscle weakness, and small-cell lung carcinoma is the most common cause. Lambert-Eaton also causes double vision, drooping of the eyelids and difficulty swallowing. Although the usual way of confirming Lambert-Eaton is electromyography, the existence of the granuloma most likely made the test unnecessary given her other symptoms. In addition, the doctor's recommendation to immediately treat the underlying cancer was probably her best treatment option to eliminate the paraneoplastic syndrome.
===The Teenage Supermodel===
In Skin Deep, Alex was suffering from double vision, cataplexy, sudden aggressive behavior, nausea, twitching, short term memory loss, and elevated protein levels in her CSF. Her symptoms were attributed to paraneoplastic syndrome which was eventually traced to testicular cancer.
Apart from the unlikely combination of paraneoplastic syndrome and testicular cancer in a person with male pseudohermaphroditism, this one is actually plausible. The most common paraneoplastic syndrome associated with testicular cancer is limbic encephalitis, which causes short term memory deficit, headaches, irritability, sleep disturbance, delusions, hallucinations, agitation, seizures, and psychosis. No treatment is sure-fire, but House's choice of intravenous immunoglobulin is the usual course of action. In addition, the syndrome can also be caused by ovarian cancer, so House was right to ensure that Wilson had checked for it.
House's diagnosis of paraneoplastic syndrome was a bit of a stretch, however. It was essentially just a guess that turned out right. Paraneoplastic limbic encephalitis can only be confirmed with test of antibodies found in the CSF.
===The Big Man===
In Que Será Será, George suffered from unexplained self-resolving coma, fever, anorexia, blindness, and clubbing. He was diagnosed with small-cell carcinoma and the blindness and coma were blamed on paraneoplastic syndrome.
In an article in the Los Angeles times, Marc Siegel also asked about the plausibility of this diagnosis. He had to admit that although it wasn't an exact fit, antibodies can attack both the limbic system, resulting in the coma, and the retina, resulting in vision loss.
===The Fake Mom===
In It's a Wonderful Lie, Maggie suffered from paralysis, rapid onset blindness, swollen lymph nodes, a low platelet count, and osteopetrosis. Chris Taub immediately suggested paraneoplastic syndrome for the paralysis, but it was only at the end of the episode that they could prove that Maggie developed breast cancer despite having had a preventative mastectomy.
This one is a stretch. The most common paraneoplastic syndrome that causes paralysis is Brown-Sequard syndrome, and it almost always is caused by a tumor on the spine.
===Chosen by the Cat===
In Here Kitty, Morgan West exhibited persistent cold symptoms, malaise, bronchospasm, rash, and spider veins. House finally realized that paraneoplastic syndrome from colon cancer could cause a bronchospasm, but her colon was completely examined without seeing a tumor. However, House finally realized the tumor was in her appendix.
This diagnosis is also maddeningly non-specific. Bronchospasm can result from a paraneoplastic cause, but it shouldn't be the first diagnosis anyone would spring to. A carcinoid tumor of the heart would be much more likely to cause a bronchospasm than colon cancer. In addition, paraneoplastic syndromes with colon cancer are rare even by the standards of this disease.
===The Prospect===
In Moving the Chains, Daryl suffered from sudden attacks of rage, increased GNRH levels, tachycardia, Raynaud's phenomenon, inflamed liver, increased clotting, and excess production of human growth hormone. The doctors believed the last symptom pointed to a paraneoplastic syndrome and Daryl was eventually diagnosed with a melanoma.
This one is a bit of a stretch. Melanomas are associated with several paraneoplastic syndromes, but there are none that would result in this constellation of symptoms. In addition, paraneoplastic symptoms this bad usually only happen in melanomas that have metastasized.
===The Uncensored Editor===
In The Social Contract, Nick Greenwald suffered from frontal lobe disinhibition, nosebleed, kidney failure, consistently low blood sugar levels, fever, and fluid in the lungs. He improved on antibiotics, except for the frontal lobe disinhibition, which remained. He had brain surgery to try to correct it and recovered without any brain damage, but the disinhibition persisted and his body temperature dropped showing it wasn't originally an infection but a problem regulating body temperature. When his blood sugar suddenly returned to normal, House realized he had Doege-Potter syndrome and what they thought was a cyst near the lungs was actually a fibroma.
Doege-Potter is incredibly rare - about 100 reported cases. However, the story is consistent with the condition as a tumor near the lungs is the most likely cause.
===Other appearances in the differential===
====The Homeless Patient====
In Histories, Victoria Madsen was suffering from numbness, photophobia, disorientation, paranoia, ineffectiveness of sedatives, and hydrophobia. She was thought to be suffering from paraneoplastic syndrome, but her symptoms were eventually traced to Rabies.
====The Locked In Patient====
In Locked In, Lee's MRI shows a lesion which could not have been caused by a trauma from the accident. House thought the lesion was a brain tumor and that Lee's locked-in syndrome was the result paraneoplastic syndrome. However, in the end, Lee's locked-in syndrome was traced to a Leptospirosis infection.
====The Freak====
When trying to diagnose Kenny Arnold in Ugly, Jeffrey Cole suggested that Kenny had stomach cancer and his arrhythmia was the result of a paraneoplastic syndrome. House ordered a search for the tumor, but in the end Thirteen came up with the right diagnosis Lyme Disease.
====Sleepy Head====
In Fidelity, the team sought out help from James Wilson to try to explain Elise Snow's hypersomnia. Being an oncologist, he suggested it was the result of a paraneoplastic syndrome from breast cancer. House agreed, but the resulting mammogram was clear. The hypersomnia turned out to have a rather obvious if unlikely cause - African trypanosomiasis or sleeping sickness.
====The Wild Woman====
In Airborne, Wilson had concentrated on Fran's recent travel to Venezuela when he realized her symptoms could be the result of paraneoplastic syndrome from breast cancer. She was given a mammogram, but it was negative for cancer. Robert Chase got the right diagnosis by going back to her house and finding that the neighbouring house was being treated with methyl bromide which had travelled through a connecting electrical link to her house.
====The Doomed Man====
As part of the differential of Donny in Brave Heart, Foreman suggested that heart failure could be caused by paraneoplastic syndrome from bone cancer. However, his colleagues noted that bone cancer has no genetic component and could not explain the death of his male ancestors.
====The Astronaut====
In The Right Stuff, Greta Cooper was suffering from synesthesia which descended into psychosis. When The Applicants were trying to impress House, Amber Volakis (then only known as Number 24) suggested that her symptoms might be the result of a paraneoplastic syndrome for liver cancer. House reminded her they couldn't scan the patient because it would show up on her chart. Instead, Lawrence Kutner (Number 6) got back into the competition by suggesting they use alcohol to stress her liver. The "test" was negative and her symptoms were eventually traced to multiple small tumors from Von Hippel-Lindau syndrome.
====The Drag Racer====
One of the differential diagnoses that the remaining applicants came up for to diagnose Casey Alfonso in Need to Know was paraneoplastic syndrome. However, House had to leave and instead ordered a full medical history and left Foreman in charge.
====The Soap Stud====
The team was trying to diagnose Evan Greer in Living the Dream and Kutner suggested it might be paraneoplastic syndrome from small-cell lung carcinoma as the patient had been a smoker. However, Foreman noted the patient had not smoked in twenty years and his calcium levels were normal.
====Marcus Webly====
In order to get Vince Pearson to stop posting his symptoms on the internet in Epic Fail, the team started reading out some of the faxed diagnosis. One of them was paraneoplastic syndrome from a spinal tumor, but Foreman noted there was no hypocalcemia, muscle spasms, or incontinence.
====The Guy House Couldn't Remember====
In Top Secret, Wilson was called in to help with the case of John Kelley and suggested it might be paraneoplastic syndrome, but the team had already ruled out cancer.
====The Porn Star====
After Hank Hardwick was treated for strongyloides in Teamwork, he got worse and fluid started to build up in his lungs. Foreman suggested that Hank had lymphoma which had caused both peritoneal carcinomatosis and paraneoplastic syndrome. House "agreed" and ordered chemotherapy, but by this time had probably realized that Hank had Crohn's disease which had reasserted itself after his immune system was no longer busy fighting off the strongyloides.
====The Psycho====
In Remorse, Valerie was suffering from severe intermittent ear pain, arrhythmia, antisocial personality disorder, brittle bones, low BUN creatinine levels, and kidney failure. Foreman suggested it was paraneoplastic syndrome from lymphoma. House agreed and ordered radiation therapy. However, she continued to get worse on therapy and she was eventually diagnosed with Wilson's disease.
====The Lucky Man====
In Changes, lottery winner Cyrus Harry was suffering from sudden leg paralysis, vomiting without any associated nausea, focal seizures, and signs of metabolic distress. When they found a mass on his pancreas, they believed it was a tumor and the symptoms were the result of paraneoplastic syndrome. However, Cyrus turned out to have three different tumors, and these were eventually traced to a single teratoma. The symptoms that appeared to be paraneoplastic syndrome were in fact an autoimmune response to cells in the teratoma.
====The Award Winning Artist====
In Moving On it was difficult to determine just what symptoms Afsoun Hamidi had as she faked some to pose a challenge to House as part of her artistic endeavors. However, House realized she had already been diagnosed with a disease and given that, he scanned her and found what appeared to be primary CMS lymphoma. House realized if she had lymphoma, any remaining real symptoms were the result of paraneoplastic syndrome. However, House soon realized that Afsoun's seeming eczema showed she had granulomatosis with polyangiitis, which also explained all her symptoms.
====The Lungs in a Box====
House did a quick examination of Stevie Weathers' body in Transplant and found a mass on his arm that he thought might be a rhabdomyosarcoma that caused paraneoplastic syndrome. However, it was just coagulated plasma that had been given to him on admission.
====The Gun Nut====
In Perils of Paranoia, Tommy suffered from severe chest pain, possible paranoia, an ulcer on his leg that wasn't painful, sudden unexplained aggression, hallucinations, fever, respiratory distress resembling anaphylaxis, and obstruction of the trachea. Chi Park suggested squamous cell carcinoma, which would explain all the symptoms except the hallucinations, but she attributed those to paraneoplastic syndrome. House ordered a biopsy, but soon realized that Tommy was suffering from diphtheria.
====The Runaway====
In Runaways, Callie Rogers suffered from breathing problems resembling asthma and bleeding from her ear. Robert Chase suggested it was squamous cell carcinoma of the middle ear that caused the bleeding and related paraneoplastic syndrome causing the breathing problems. However, her inner ear had already been checked and there were no signs of any sort of mass that could be a tumor.
==In other languages==
Language 	Name
Spanish 	Síndrome paraneoplásico
French 	Syndrome paranéoplasique
Italian 	Sindrome paraneoplastica
Deutsch 	Paraneoplastischen Syndrom
Portuguese	Síndrome paraneoplásica
Turkish 	Paraneoplastik Sendrom
Polski 	Zespół paraneoplastyczny
==Links==
*Paraneoplastic syndrome at Wikipedia - most of the medical text of this article was developed from the article at Wikipedia
*Paraneoplastic syndromes of the nervous system at Mayo Clinic
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Paraneoplastic syndrome