Paraneoplastic syndrome is usually associated with neurological dysfunctioning, endocrine and cutaneous disorders.

The following are the signs and symptoms of the syndrome:

• Walking difficulty
• Difficulty in maintaining balance
• Seizures
• Vision disturbances
• Muscle coordination loss
• Fever [6]
• Vertigo
• Dizziness
• Sleep disturbances
• Loss of fine motor skills
• Loss of memory
• Trouble in eating and swallowing food
• Cognitive impairment 
• Weakness
• Cutaneous itching [7]

• Cervical Lymphadenopathy

  PET/CT showed a hypermetabolic mass in the upper lobe of the left lung and the left hilar region with central necrosis and contralateral cervical lymphadenopathy in the high jugular region. [healio.com]

• Anemia

  Three types of paraneoplastic anemias may be described, as follows: Chronic anemia resulting from an anti-erythropoietin factor, reduction in mean red blood cell (RBC) life, and poor iron availability Microangiopathic hemolytic anemia resulting from diffuse [emedicine.medscape.com]

• Fatigue

  The authors present a case report of a woman with presumed contact dermatitis who was diagnosed with breast cancer in the setting of progressive fatigue and muscle weakness. DM was subsequently diagnosed. [ncbi.nlm.nih.gov]

  Hypercalcemia can cause a range of symptoms, such as confusion, nausea, constipation, fatigue, weakness, dehydration, muscle pain and — in extreme cases — kidney failure. [curetoday.com]

  SIADH is a euvolemic hypoosmolar hyponatremic state in which the patient can present with nonspecific symptoms such as nausea, vomiting, decreased oral intake, and fatigue. [cancertherapyadvisor.com]

  Signs and symptoms include pelvic and lower extremity muscle weakness, fatigue, difficulty swallowing, difficulty speaking, irregular eye movement, and double vision. Autonomic nervous system problems can include dry mouth and impotence. [mayoclinic.org]

• Amyloidosis

  Renal syndromes Secondary kidney amyloidosis and sedimentation of immunocomplexes in nephrons (and subsequent membranoproliferative glomerulonephritis) is thought to be the underlying mechanism of nephrotic syndrome and, frequently, neoplastic hypoalbuminemia [emedicine.medscape.com]

• Buffalo Hump

  Due to its rapid onset, patients generally are found to have electrolyte imbalances rather than having a cushingoid appearance, although typical cushingoid characteristics such as moon face and buffalo hump generally do not manifest, as hypercortisolism [intechopen.com]

  Characteristic findings on physical examination include abnormal fat deposition (moon facies, buffalo hump, centripetal obesity) and violaceous striae (20). [atm.amegroups.com]

• Dyspnea

  Review of systems was significant for hemoptysis, dyspnea on exertion and dull achy left anterior chest and shoulder pain. He denied any headaches, double vision or blurred vision. [healio.com]

  Typical presentations include cough, dyspnea, and weight loss. However, SCLC can present in more atypical ways. [bmcpulmmed.biomedcentral.com]

  Infants and children with a small PDA are generally asymptomatic; infants with a large PDA present with signs of heart failure (eg, failure to thrive, poor feeding, tachypnea, dyspnea with feeding, tachycardia). [merckmanuals.com]

  Cutaneous necrosis, heliotrope erythema, dysphagia, dyspnea, muscle weakness, arthralgia, and positive anti-155/140 antibodies are considered as risk factors for cancer. [pulmonologyadvisor.com]

• Nausea

  A 64 year-old 20-pack year smoker presented to the emergency department with nausea and vomiting for 3 days. No inciting events were elicited. [ncbi.nlm.nih.gov]

  vomiting, abdominal pain, postprandial fullness, nausea, and early satiety in patients with advanced cancer. [hindawi.com]

  At initial presentation he had nausea, vomiting and positive mild right nystagmus on dix-hallpike maneuver and was thought to have peripheral vertigo, especially in the presence of negative brain MRI/MRA imaging. [neurology.org]

  SIADH is a euvolemic hypoosmolar hyponatremic state in which the patient can present with nonspecific symptoms such as nausea, vomiting, decreased oral intake, and fatigue. [cancertherapyadvisor.com]

  The patient’s nausea and vomiting had resolved as his sodium levels improved, which later was attributed to his hyponatremia from SIADH. [bmcpulmmed.biomedcentral.com]

• Diarrhea

  Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. [ncbi.nlm.nih.gov]

  Excessive production of other hormones, usually by pancreatic carcinoid tumors, can cause carcinoid syndrome—flushing, wheezing, diarrhea, and heart valve problems. [msdmanuals.com]

  Carcinoid tumors produce serotonin degradation products that lead to flushing, diarrhea, and breathing difficulty. Protein-losing enteropathies may result from tumor mass inflammation, particularly with lymphomas. [merckmanuals.com]

• Dysphagia

  This 59-year-old man developed ophthalmoplegia, dysarthria, dysphagia, pruritus, ataxia, corticobulbar and corticospinal signs in association with prostate cancer. [ncbi.nlm.nih.gov]

  In this instance the symptoms that the patient had were dysarthria, dysphagia, ataxia and possible encephalitis with cerebellar signs. Final diagnosis was 'high grade serous pelvic carcinoma with paraneoplastic cerebellar syndrome'. [remote.health.vic.gov.au]

  About six months, later the patient started having dysphagia, regurgitation and weight loss, and was evaluated by gastroenterology. Barium swallow showed poor motility, poor emptying and distal esophageal narrowing. [healio.com]

  […] example, cancer of the thyroid gland may cause symptoms due to compressions of certain structures of the head and neck; pressure on the laryngeal nerves may cause voice changes, narrowing of the windpipe may cause stridor, pressure on the gullet may cause dysphagia [en.wikipedia.org]

• Hypertension

  Hypertension and hypercalcemia occurring as single PNS, although also correlated with advanced stage, require further investigation. Copyright © 2012 S. Karger AG, Basel. [ncbi.nlm.nih.gov]

  To the Editor: Hyperaldosteronism is the cause of about 0.5 to 2 percent of all cases of hypertension. [doi.org]

  Larger, untreated defects could cause: High blood pressure in the lungs (pulmonary hypertension). [mayoclinic.org]

• Muscle Twitch

  Myelitis is a term used to describe inflammation of the spinal cord and is characterized by weakness, muscle wasting, and involuntary muscle twitches. [brighamandwomens.org]

  PTHRP causes hypercalcemia and its associated symptoms (polyuria, dehydration, constipation, muscle weakness); calcitonin causes a fall in the serum calcium level, leading to muscle twitching and cardiac arrhythmias. [merckmanuals.com]

  Over the course of time, fine muscle twitching can progress to more pronounced abnormal movements and postures of the arms and legs (choreoathetosis). Many patients develop abnormal movements with the face, mouth or tongue (orofacial dyskinesias). [rarediseases.org]

• Arthralgia

  Sweet’s Syndrome  Acute febrile neutrophilic dermatosis  Associated with leukemia  Acute tender red nodules or plaques  Fever, arthralgia, oral lesions, eye involvement  Almost all organs can be involved  Neutrophil mediated, with role for TNF, [slideshare.net]

  Inflammation of the heart (myocarditis), joints (arthralgias), and lungs (interstitial lung disease) can occur. [rarediseases.org]

  Other manifestations include arthralgia, myocarditis and congestive heart failure, and interstitial lung disease. Clinical, electromyographical, and pathological findings of dermatomyositis are similar in patients with and without cancer. [theoncologist.onlinelibrary.wiley.com]

  Cutaneous necrosis, heliotrope erythema, dysphagia, dyspnea, muscle weakness, arthralgia, and positive anti-155/140 antibodies are considered as risk factors for cancer. [pulmonologyadvisor.com]

• Diplopia

  One year later he presented with a month history of progressive dysarthria, diplopia and fast beating horizontal nystagmus accompanied by severe limb and gait ataxia. Repeat imaging with brain MRA was unrevealing. [neurology.org]

  […] respond to treatment of the underlying tumors Cerebellar degeneration Definition / general: Destruction of Purkinje cells (antibody mediated) with perivascular lymphocytes Causes progressive bilateral leg and arm ataxia, dysarthria, variable vertigo and diplopia [pathologyoutlines.com]

  Clinically the disease is characterized by limb weakness (especially of the legs), muscle stiffness, drooping eyelids (ptosis), and double vision (diplopia). [brighamandwomens.org]

  Avramova et al. described an eight-year-old boy presenting with dysarthria and diplopia and subsequently diagnosed with HL. [touchoncology.com]

• Flushing

  Excessive production of other hormones, usually by pancreatic carcinoid tumors, can cause carcinoid syndrome—flushing, wheezing, diarrhea, and heart valve problems. [msdmanuals.com]

  During her hospital stay, she was given fluids to flush the calcium out of her blood. [curetoday.com]

   Symptoms:  Episodes of flushing: hypotension and tachycardia (histamine and bradykinin)  Cutaneous venous teleangiectasia  Secretory diarrhoea (serotonin)  Cardiac valvular lesions (serotonin)  bronchospams 16. [slideshare.net]

  Flushing may also occur and is likely related to tumor-generated circulating vasoactive substances (eg, prostaglandins). [merckmanuals.com]

• Sweating

  These syndromes' symptoms may include fever, loss of appetite and weight, and night sweats. [my.clevelandclinic.org]

  The most common cancers associated with paraneoplastic syndromes include People with cancer often experience fever, night sweats, loss of appetite, and weight loss. The syndromes below are less common. [msdmanuals.com]

  Symptoms of congestive heart failure include rapid breathing, feeding problems, slow weight gain, low energy, and cold, clammy sweating. [mottchildren.org]

  Dysautonomia refers to a wide range of signs and symptoms resulting from injury to the nerves that regulate involuntary body functions (autonomic nervous system), such as heart rate, blood pressure, sweating, and bowel and bladder functions. [mayoclinic.org]

• Hyperhidrosis

  Neuroendocrine tumors Renal Cell Carcinoma Endocrinology Acromegaly Precocious puberty Severe primary IGF-1 deficiency Growth hormone deficiency Turner syndrome Neurosciences Blepharospasm Cervical dystonia Cerebral palsy Equinus deformity Hemifacial spasm Hyperhidrosis [ipsennordic.com]

  Amygdala, Diencephalic, Tegmental & Dentate nuclei Tumor associations Testicular germ-cell or seminoma: May be occult Breast: Occasional CSF: Abnormal MRI: Temporal lobe ± Hypothalamic change Morvan's fibrillary chorea : Thymoma Clinical Neuromyotonia Hyperhidrosis [neuromuscular.wustl.edu]

• Pruritus

  This 59-year-old man developed ophthalmoplegia, dysarthria, dysphagia, pruritus, ataxia, corticobulbar and corticospinal signs in association with prostate cancer. [ncbi.nlm.nih.gov]

  An Austrian dermatologist, Ferdinand von Hebra, underlined the significance of internal disease in the etiology of several skin manifestations such as urticaria, generalized pruritus, xanthoma, and pemphigus. [intechopen.com]

  Cutaneous system: Skin involvement may present with acanthosis nigricans, dermatomyositis, leukocytoclastic vasculitis, pseudoscleroderma, erythema multiform, Sweet syndrome, pruritus and urticaria, tylosis, erythema gyratum repens, Immunoglobulin A pemphigus [pulmonologyadvisor.com]

• Keratosis

  Dermatology: Leser Trelat sign  Explosive onset of multiple sebarrhoic keratosis on erythematous skin  Gastro-intestinal adenocarcinoma  breast/ lung/urinary tract cancer  Often associated with acanthosis nigricans 25. [slideshare.net]

• Aggressive Behavior

  The Teenage Supermodel Edit In Skin Deep, Alex was suffering from double vision, catoplexy, sudden aggressive behavior, nausea, twitching, short term memory loss and elevated protein levels in her CSF. [house.wikia.com]

• Peripheral Neuropathy

  Abstract POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a rare multisystem paraneoplastic disorder. [ncbi.nlm.nih.gov]

  Subacute sensory neuropathy is a more specific but rare peripheral neuropathy. Dorsal root ganglia degeneration and progressive sensory loss with ataxia but little motor weakness develop; the disorder may be disabling. [merckmanuals.com]

  neuropathy Definition / general: Most common paraneoplastic syndrome May be associated with anti-Hu antibody in lung cancer patients Primary lateral sclerosis Definition / general: Rarely caused by breast cancer 50% develop lower motor neuron signs eventually [pathologyoutlines.com]

  The peripheral neuropathy associated with osteosclerotic myeloma generally resolves when the tumor is treated with radiotherapy. [encyclopedia.com]

• Confusion

  Haematological paraneoplastic syndromes are even rarer, and may be the only presenting feature in these malignancies, producing diagnostic confusion. [ncbi.nlm.nih.gov]

  Small cell carcinoma of the lung may also produce vasopressin, causing water retention, decreased sodium levels, weakness, confusion, and seizures in some people. [msdmanuals.com]

  It is important that those symptoms not be confused with symptoms caused by advanced metastatic disease, as misdiagnosis can lead to… Read More [britannica.com]

  Some patients develop hypoglycemia, or low blood sugar, which causes symptoms such as confusion, sweating and anxiety. [curetoday.com]

  Confusion and dementia. Poor eyesight that gets worse. [thelondonclinic.co.uk]

• Guillain-Barré Syndrome

  Guillain-Barré syndrome is another type of nerve dysfunction that causes a general loss of muscle strength. It is more common in people with Hodgkin lymphoma. [msdmanuals.com]

  Guillain-Barré syndrome, another ascending peripheral neuropathy, is a rare finding in the general population and probably more common in patients with Hodgkin lymphoma. [merckmanuals.com]

  Although the frequency of cancer in patients with Guillain-Barré syndrome is not increased, the association between this neuropathy and HL is well established. 92 Patients with NHL and monoclonal gammopathy can develop typical CIDP or predominantly sensory [bloodjournal.org]

  Anti-CTLA-4 antibody-induced Guillain–Barré syndrome in a melanoma patient. Ann. Oncol. 22, 991–993 (2011). 33. Liao, B., Shroff, S., Kamiya-Matsuoka, C. & Tummala, S. [doi.org]

• Cognitive Impairment

  impairment Weakness Cutaneous itching Diagnosis of paraneoplastic syndrome is a difficult affair and is often misdiagnosed. [symptoma.com]

  […] 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 [mayoclinic.org]

  Subclinical cognitive impairment in autosomal dominant pure' hereditary spastic paraplegia. J Med Genet 1999; 36: 797-798. Ribaï P., Depienne C., Fedirko E. et al. Mental deficiency in three families with SPG4 spastic paraplegia. [mediasphera.ru]

• Altered Mental Status

  Acute (<48 hours), severe (serum sodium <120 meq/L) hyponatremia leads to cerebral edema causing altered mental status, seizures and death. Chronic, mild to moderate, hyponatremia may not produce any significant neurologic symptoms. [atm.amegroups.com]

  In contrast, severe, rapidly progressive hypercalcemia can be associated with significant volume depletion and acute renal insufficiency, as well as dramatic neurocognitive symptoms ranging from altered mental status to coma. [doi.org]

  Hypertonic saline infusion is typically reserved for severe refractory hyponatremia, and hyponatremia that presents with marked alteration of mental status or seizure. [pulmonologyadvisor.com]

Diagnosis of paraneoplastic syndrome is a difficult affair and is often misdiagnosed. The diagnosis begins with preliminary clinical examination to study the reflexes, mental functioning, muscle tone and its strength, balance, coordination and sensory functioning.

Blood work would be done to analyze the antibodies associated with paraneoplastic syndrome [8]. A lumbar puncture examination to test the cerebrospinal fluid (CSF) for antibodies is carried out.

Several imaging tests such as CT scan, MRI, PET and PET-CT are employed for further diagnosis of the syndrome. Positron emission tomography (PET) scan is a method wherein radioactive elements are injected into the body to generate 3D images. This helps in studying the degree of metabolism of tumor cells and also provides information related to brain abnormalities.

• Thrombocytosis

  Paraneoplastic thrombocytosis Thrombocytosis frequency is 13–32% in LC patients. IL-6 is the cytokine that is known to play a role in the development of paraneoplastic thrombocytosis [41]. It requires no specific treatment. 2.7. [intechopen.com]

  Lymphoma may be a cause of secondary thrombocytosis. Renal Paraneoplastic Syndrome About 10% patinets with idiopathic nephrotic syndrome have an underlying maligancy. Most of these patinets have membranoproliferative glomerulonephritis. [allaboutblood.com]

  […] onset, but in some cases, DIC appears in an acute and severe form, characterized by typical thrombotic and/or hemorrhagic manifestations, and sometimes leading to thrombocytopenia Thrombocytopenia may also be caused by autoantibodies; the causes of thrombocytosis [emedicine.medscape.com]

• Erythrocytosis

  In contrast, survival of patients with paraneoplastic erythrocytosis was not significantly reduced. [hindawi.com]

  Erythrocytosis is common in cancers of the liver, kidney, adrenal glands, lung, thymus, and CNS as well as in gynecologic tumors and myosarcomas. It always disappears after removal of the primary tumor. [emedicine.medscape.com]

• Fasting Hypoglycemia

  insulin growth factor 2, non-islet cell tumors, paraneoplastic syndrome, therapy Abstract Paraneoplastic syndrome has a wide range of symptoms and fasting hypoglycemia is one of its possible clinical manifestations. [mattioli1885journals.com]

  Seen in febrosarcoma, haemangiofibropericytoma, hepatoma)  Diagnosis: fasting hypoglycemia  Plasma insulin/pro-insulin/peptide C during hypoglycemia  Treatment:  Anticancer treatment  Glucose/glucagon  Nocturnal meals 12. [slideshare.net]

The primary goal of treatment consists of managing the tumor cells and suppressing the immune system to stop the abnormal behavior. These objectives are carried out through various methods such as:

• Surgical procedures along with chemotherapy and radiation therapy to remove the tumor cells and suppress its growth. Surgery is largely dependent on the nature and the location of the malignant cells.
• Medications like corticosteroids and immunosupressants are employed for treating the condition. Corticosteroids work by reducing the inflammation and immunosupressants suppress the action of the immune system. Based on the type of paraneoplastic syndrome present, other medications are also given to decrease the seizures and enhance the nerve to muscle transmission.
• Plasmaphersis is conducted to rid the body of the antibodies by replacing the blood plasma.
• Individuals are also given intravenous immunoglobulin in which healthy antibodies from donors are transferred to the body [9].

In addition to the above mentioned treatment methods, individuals are also subjected to physical and speech therapies to improvise the walking ability and restore muscle control.

Prognosis of paraneoplastic syndrome is usually poor. There are no available treatments and this syndrome has no known cure. The stage at which the condition is diagnosed generally decides the outcome of the disease. Treatment methods employed to treat the cancer can have some positive effect on the condition. The majority of patients suffering from paraneoplastic syndrome succumbs to secondary infections which is the common cause of mortality [5].

Complications

Complications of paraneoplastic syndrome include the following:

• Permanent neurological damage
• Cerebellar degeneration
• Confusion
• Delirium
• Seizures
• Coma 
• Death

Paraneoplastic syndrome does not occur as a direct effect of the cancer cells [3]. It occurs due to activation of the immune system that behaves in an abnormal fashion in response to cancer cells and in turn attacks the body’s healthy cells giving rise to associated disease conditions.

A secondary phenomenon that explains the development of paraneoplastic syndrome is that the cancer cells releases cellular components which are physiologically active in nature. These components serve as tumor markers paving way for development of paraneoplastic syndrome.

Paraneoplastic syndrome is a rare occurrence that commonly affects the adult and the elderly population. Children seldom fall prey to such syndromes. It has been estimated that about 20% of the population with cancer develop paraneoplastic syndrome. However, the exact incidence of this syndrome is not known.

The pathophysiology of paraneoplastic syndrome is a complex one. There are basically two theories defining the onset of such a kind of syndrome. The preliminary one states that the immune system of individuals with cancer behaves in an abnormal fashion and begins attacking the normal cells along with the tumor cells [4]. Such an activity deteriorates the neurological functioning of the brain giving rise to paraneoplastic syndrome.

In yet another theory, researchers explain that the physiologically active components released by the tumor cells can attack the other body organs giving rise to several associated secondary conditions such as sensory neuropathy, neuromyotonia, myasthenia gravis, cerebellar degeneration, stiff–person syndrome and encephalomyelitis to name a few. These syndromes are collectively referred to as paraneoplastic syndrome.

So far there are no approaches designed to prevent the development of paraneoplastic syndrome. However, if the condition is diagnosed on time then the onset of complications can be prevented to certain extent. Primary screening tests may be used among patients with strong familial history of breast and colon cancer [10].

Paraneoplastic syndrome is characterized by abnormal response of the immune system to the presence of malignant tumors. Patients suffering from cancer of the lungs, breast, lymphatic system or the ovaries are known to contract paraneoplastic syndrome.

Such a kind of a syndrome is also termed as paraneoplastic syndrome of the central nervous system because many affected individuals suffer from neurologic disorders [1]. In some instances, paraneoplastic symdrome involves the peripheral nervous system [2].

The signs and symptoms of the syndrome begin to show effect within days or weeks much before the tumor is diagnosed. Middle aged and the geriatric population fall easy prey to paraneoplastic syndrome.

Definition

Paraneoplastic syndrome is a rare group of disorders that develop in patients suffering from cancer. It however does not occur due to the direct effect of cancer but occurs as a result of abnormal behavior of immune system that attacks the body’s healthy cells. It can also occur due to the release of cellular components of the tumor cells that have an adverse effect on other organs of the body.

Cause

Paraneoplastic syndrome occurs in patients suffering from lung, stomach or breast cancer. The exact cause that triggers the development of such a syndrome is not known. However, researchers believe that the faulty behavior of the immune system can cause paraneoplastic syndrome.

Symptoms

Common symptoms of paraneoplastic syndrome include loss of muscle tone, difficulty in walking, speaking and swallowing, loss of fine motor skills, dementia, seizures, sleep problems, vertigo and dizziness. Individuals also suffer from memory loss, vision problems and loss of sensation in the limbs.

Diagnosis

Diagnosis of the syndrome is done by analyzing the clinical signs and symptoms. In addition, blood test and lumbar puncture test is done for detecting the presence of antibodies. Various imaging tests are carried out for detecting the tumor locations and determining the extent of spread of cancer.

Treatment

Primary mode of treatment consists of removal of the tumors from the body. This is followed by medications to suppress the immune response and also to improve the symptoms. Plasma transfer may also be required in some patients. 

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2. Auche M. Des nevrites peripheriques chez les cancereux. Rev Med. 1890; 10:785-807.
3. Hobbs CB, Miller AL. Review of endocrine syndromes associated with tumours of non-endocrine origin. J Clin Pathol. Mar 1966; 19(2):119-27. 
4. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. Nov 2004; 56(5):715-9.
5. Leger S, Picard D, Ingen-Housz-Oro S, Arnault JP, Aubin F, et al. Prognostic factors of paraneoplastic pemphigus. Arch Dermatol. Oct 2012; 148(10):1165-72.
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7. Rubenstein M, Duvic M. Cutaneous manifestations of Hodgkin's disease. Int J Dermatol. Mar 2006; 45(3):251-6.
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9. Buchwald B, Ahangari R, Weishaupt A, et al. Presynaptic effects of immunoglobulin G from patients with Lambert-Eaton myasthenic syndrome: their neutralization by intravenous immunoglobulins. Muscle Nerve. Apr 2005; 31(4):487-94. 
10. Kawasoe T, Yamamoto Y, Okumura Y, et al. A case report of paraneoplastic neurological syndrome associated with occult breast cancer. Breast Cancer.