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Paraneoplastic syndrome

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Paraneoplastic syndrome
SpecialtyOncology
FrequencyRare[1]

A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one).[1] It is specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by tumor cells or by an immune response against the tumor.[2] Unlike a mass effect, it is not due to the local presence of cancer cells.[3]

Paraneoplastic syndromes are typical among middle-aged to older people, and they most commonly occur with cancers of the lung, breast, ovaries or lymphatic system (a lymphoma).[4] 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 (e.g., neuronal proteins), triggering an anti-tumor immune response which may be partially or, rarely, completely effective[5] in suppressing tumor growth and symptoms.[6][7] 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.

The abbreviation PNS is sometimes used for paraneoplastic syndrome, although it is used more often to refer to the peripheral nervous system.

Signs and symptoms

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Symptomatic features of paraneoplastic syndrome cultivate in four ways: endocrine, neurological, mucocutaneous, and hematological. The most common presentation is a fever (release of endogenous pyrogens often related to lymphokines or tissue pyrogens), but the overall picture will often include several clinical cases observed which may specifically simulate more common benign conditions.[8]

Endocrine

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The following diseases manifest by means of endocrine dysfunction: Cushing syndrome, syndrome of inappropriate antidiuretic hormone, hypercalcemia, hypoglycemia, carcinoid syndrome, and hyperaldosteronism.[8]

Neurological

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The following diseases manifest by means of neurological dysfunction: Lambert–Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, encephalomyelitis, limbic encephalitis, brainstem encephalitis, opsoclonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and polymyositis.[8]

Mucocutaneous

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The following diseases manifest by means of mucocutaneous dysfunction: acanthosis nigricans, dermatomyositis, Leser-Trélat sign, necrolytic migratory erythema, Sweet's syndrome, Florid cutaneous papillomatosis, pyoderma gangrenosum, and acquired generalized hypertrichosis. Mucocutaneous dysfunctions of paraneoplastic syndromes can be seen in cases of itching (hypereosinophilia), immune system depression (latent varicella-zoster virus in sensory ganglia), pancreatic tumors (leading to adipose nodular necrosis of subcutaneous tissues), flushes (prostaglandin secretions), and even dermic melanosis (cannot be eliminated via urine and results in grey to black-blueish skin tones).[8]

Hematological

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The following diseases manifest by means of hematological dysfunction: granulocytosis, polycythemia, Trousseau sign, nonbacterial thrombotic endocarditis, and anemia. Hematological dysfunction of paraneoplastic syndromes can be seen from an increase of erythropoietin (EPO), which may occur in response to hypoxia or ectopic EPO production/altered catabolism. Erythrocytosis is common in regions of the liver, kidney, adrenal glands, lung, thymus, and central nervous system (as well as gynecological tumors and myosarcomas).[8]

Other

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The following diseases manifest by means of physiological dysfunction besides the categories above: membranous glomerulonephritis, tumor-induced osteomalacia, Stauffer syndrome, Neoplastic fever, and thymoma-associated multiorgan autoimmunity. Rheumatologic (hypertrophic osteoarthropathy), renal (secondary kidney amyloidosis and sedimentation of the immunocomplexes in nephrons), and gastrointestinal (production of molecules that affect the motility and secretory activity of the digestive tract) dysfunctions, for example, may relate to paraneoplastic syndromes.[8]

Mechanism

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The mechanism for a paraneoplastic syndrome varies from case to case. However, pathophysiological outcomes usually arise when a tumor does. Paraneoplastic syndrome often occurs alongside associated cancers as a result of an activated immune system. In this scenario, the body may produce antibodies to fight off the tumor by directly binding and destroying the tumor cell. Paraneoplastic disorders may arise in that antibodies would cross-react with normal tissues and destroy them.[9]

Diagnosis

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Diagnostic testing in a possible paraneoplastic syndrome depends on the symptoms and the suspected underlying cancer.[citation needed]

Diagnosis may be difficult in patients in whom paraneoplastic antibodies cannot be detected. In the absence of these antibodies, other tests that may be helpful include MRI, PET, lumbar puncture and electrophysiology.[10]

Types

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Syndrome class Syndrome Main causal cancers Causal mechanism
Endocrine[11]
Cushing syndrome Ectopic ACTH and ACTH-like substance
Syndrome of inappropriate antidiuretic hormone Antidiuretic hormone[12]
Hypercalcemia PTHrP (Parathyroid hormone-related protein), TGF-α, TNF, IL-1[12]
Hypoglycemia Insulin or insulin-like substance[12] or "big" IGF-II
Carcinoid syndrome Serotonin, bradykinin[12]
Hyperaldosteronism Aldosterone[14]
Neurological[15] Lambert–Eaton myasthenic syndrome
  • Small-cell lung cancer
 Immunologic
Paraneoplastic cerebellar degeneration
Encephalomyelitis Inflammation of the brain and spinal cord
Limbic encephalitis
  • Small-cell lung carcinoma
Brainstem encephalitis
  • Lung cancer
  • Testicular cancer
 Antineuronal antibodies (anti-Hu, anti-Ri, and anti-Ma2). Some forms are amenable to immunotherapy while others are not.[16]
Opsoclonus myoclonus ataxia syndrome
  • Breast carcinoma
  • Ovarian carcinoma
  • Small-cell lung carcinoma
  • Neuroblastoma (in children)
 Autoimmune reaction against the RNA-binding protein Nova-1[17]
Anti-NMDA receptor encephalitis Autoimmune reaction against NMDA-receptor subunits
Polymyositis
Mucocutaneous[19] Acanthosis nigricans
Dermatomyositis Immunologic[12]
Leser-Trélat sign
Necrolytic migratory erythema Glucagonoma
Sweet's syndrome
Florid cutaneous papillomatosis
Pyoderma gangrenosum
Acquired generalized hypertrichosis
Hematological[21] Granulocytosis G-CSF
Polycythemia Erythropoietin[12]
Trousseau sign Mucins that activate clotting,[12] others
Nonbacterial thrombotic endocarditis
  • Advanced cancers[12]
 Hypercoagulability[12]
Anemia Unknown[12]
Others Membranous glomerulonephritis
Tumor-induced osteomalacia
Stauffer syndrome
Neoplastic fever[23]
Thymoma-associated multiorgan autoimmunity

A specifically devastating form of (neurological) paraneoplastic syndromes is a group of disorders classified as paraneoplastic neurological disorders (PNDs).[24] These PNDs affect the central or peripheral nervous system; some are degenerative,[25] though others (such as LEMS) may improve with treatment of the condition or the tumor. Symptoms of PNDs may include difficulty with walking and balance, dizziness, rapid uncontrolled eye movements, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, and sensory loss in the limbs.[citation needed]

The most common cancers associated with PNDs are breast, ovarian, and lung cancers, but many other cancers can produce paraneoplastic symptoms, as well.[citation needed]

The root cause is extremely difficult to identify for paraneoplastic syndrome, as there are so many ways the disease can manifest (which may eventually lead to cancer)[citation needed]. Ideas may relate to age-related diseases (unable to handle environmental or physical stress in combination with genetic pre-dispositions), accumulation of damaged biomolecules (damages signaling pathways in various regions of the body), increased oxygen free radicals in the body (alters metabolic processes in various regions of the body), etc. [citation needed].

However, prophylactic efforts include routine checks with physicians (particularly those that specialize in neurology and oncology) especially when a patient notices subtle changes in his or her own body.[citation needed]

Treatment

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Treatment options include:[citation needed]

  1. Therapies to eliminate the underlying cancer, such as chemotherapy, radiation and surgery.
  2. Therapies to reduce or slow neurological degeneration. In this scenario, 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 paraneoplastic neurological disorders (PNDs). Therefore, PND patients should consult with a specialist with experience in diagnosing and treating paraneoplastic neurological disorders.

A specific prognosis for those with paraneoplastic syndromes links to each unique case presented. Thus, prognosis for paraneoplastic syndromes may vary greatly. For example, paraneoplastic pemphigus often included infection as a major cause of death.[26] Paraneoplastic pemphigus is one of the three major subtypes that affects IgG autoantibodies that are characteristically raised against desmoglein 1 and desmoglein 3 (which are cell-cell adhesion molecules found in desmosomes).[27] Underlying cancer or irreversible system impairment, seen in acute heart failure or kidney failure, may result in death as well.[citation needed]

Research directions

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Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. Paraneoplastic syndromes of this nature tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes (endocrine manifestations, neurological entities, dermatological conditions, and other syndromes). A vast majority of prostate cancer cases (over 70%) document paraneoplastic syndrome as a major clinical manifestation of prostate cancer; and (under 20%), the syndrome as an initial sign of disease progression to the castrate-resistant state.[28] Urologist researchers identify serum markers that are associated with the syndrome in order to specific what type of therapies may work most effectively.[citation needed]

Paraneoplastic neurological syndromes may be related immune checkpoint inhibitors (ICIs), one of the underlying causes in inflammatory central nervous system diseases (CNS). The central idea around such research pinpoints treatment strategies to combat cancer related outcomes in the clinical arena, specifically ICIs. Research suggests that patients who are treated with ICIs are more susceptible to CNS disease (since the mechanism of ICIs induces adverse effects on the CNS due to augmented immune responses and neurotoxicity).[29] The purpose of this exploration was to shed light on immunotherapies and distinguishing between neurotoxicity and brain metastasis in the early stages of treatment. In other research, scientists have found that paraneoplastic peripheral nerve disorders (autoantibodies linked to multifocal motor neuropathy) may provide important clinical manifestations.[30] This is especially important for patients who experience inflammatory neuropathies since solid tumors are often associated with peripheral nerve disorders. CV2 autoantibodies, which target dihydropyriminase-related protein 5 (DRP5, or CRMP5) are also associated with a variety of paraneoplastic neurological syndromes, including sensorimotor polyneuropathies.[31][32] Patients undergoing immune therapies or tumor removal respond very well to antibodies that target CASPR2 (to treat nerve hyperexcitability and neuromyotonia).[33][34]

References

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  1. ^ a b "Paraneoplastic Syndromes". National Institute of Neurological Disorders and Stroke. Retrieved 5 September 2023.
  2. ^ Sardiña González, Cristina; Martínez Vivero, Clara; López Castro, José (June 2022). "Paraneoplastic syndromes review: The great forgotten ones". Critical Reviews in Oncology/Hematology. 174: 103676. doi:10.1016/j.critrevonc.2022.103676. ISSN 1879-0461. PMID 35378267. S2CID 247934655.
  3. ^ Paraneoplastic Syndromes, 2011, Darnell & Posner
  4. ^ NINDS Paraneoplastic Syndromes Information Page Archived 2015-01-04 at the Wayback Machine National Institute of Neurological Disorders and Stroke
  5. ^ Darnell RB, DeAngelis LM (January 1993). "Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies". Lancet. 341 (8836): 21–22. doi:10.1016/0140-6736(93)92485-c. PMID 8093269. S2CID 205040647.
  6. ^ Roberts WK, Darnell RB (October 2004). "Neuroimmunology of the paraneoplastic neurological degenerations". Current Opinion in Immunology. 16 (5): 616–622. doi:10.1016/j.coi.2004.07.009. PMID 15342008.
  7. ^ Albert ML, Darnell RB (January 2004). "Paraneoplastic neurological degenerations: keys to tumour immunity". Nature Reviews. Cancer. 4 (1): 36–44. doi:10.1038/nrc1255. PMID 14708025. S2CID 7319871.
  8. ^ a b c d e f Santacroce L, Diomede L, Balducci L (3 February 2019). Talavera F, Movsas B (eds.). "Background of Paraneoplastic Syndromes". Medscape. WebMD LLC.
  9. ^ Pittock SJ, Kryzer TJ, Lennon VA (November 2004). "Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome". Annals of Neurology. 56 (5): 715–719. doi:10.1002/ana.20269. PMID 15468074. S2CID 31651589.
  10. ^ Dalmau J, Rosenfield MR (6 December 2016). "Overview of paraneoplastic syndromes of the nervous system". UpToDate. Retrieved 23 December 2017.
  11. ^ Paraneoplastic endocrine syndromes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  12. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap Table 6-5 in: Mitchell RS, Kumar V, Abbas AK, Fausto N (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 978-1-4160-2973-1. 8th edition.
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  14. ^ Mulatero P, Rabbia F, Veglio F (May 2001). "Paraneoplastic hyperaldosteronism associated with non-Hodgkin's lymphoma". The New England Journal of Medicine. 344 (20): 1558–1559. doi:10.1056/NEJM200105173442017. PMID 11368052.
  15. ^ Nervous system paraneoplastic syndromes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  16. ^ Blaes F (April 2013). "Paraneoplastic brain stem encephalitis". Current Treatment Options in Neurology. 15 (2): 201–209. doi:10.1007/s11940-013-0221-1. PMID 23378230. S2CID 21581917.
  17. ^ Buckanovich RJ, Posner JB, Darnell RB (October 1993). "Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system". Neuron. 11 (4): 657–672. doi:10.1016/0896-6273(93)90077-5. PMID 8398153. S2CID 22554933.
  18. ^ Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. (January 2007). "Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma". Annals of Neurology. 61 (1): 25–36. doi:10.1002/ana.21050. PMC 2430743. PMID 17262855.
  19. ^ Cohen PR, Kurzrock R (June 1997). "Mucocutaneous paraneoplastic syndromes". Seminars in Oncology. 24 (3): 334–359. PMID 9208889.
  20. ^ Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A, et al. (January 2001). "Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study". Lancet. 357 (9250): 96–100. doi:10.1016/S0140-6736(00)03540-6. PMID 11197446. S2CID 35258253.
  21. ^ Staszewski H (June 1997). "Hematological paraneoplastic syndromes". Seminars in Oncology. 24 (3): 329–333. PMID 9208888.
  22. ^ Zadik Y, Nitzan DW (February 2012). "Tumor induced osteomalacia: a forgotten paraneoplastic syndrome?". Oral Oncology. 48 (2): e9-10. doi:10.1016/j.oraloncology.2011.09.011. PMID 21985764.
  23. ^ Zell JA, Chang JC (November 2005). "Neoplastic fever: a neglected paraneoplastic syndrome". Supportive Care in Cancer. 13 (11): 870–877. doi:10.1007/s00520-005-0825-4. PMID 15864658. S2CID 23992076.
  24. ^ Rees JH (June 2004). "Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (Suppl 2): ii43–ii50. doi:10.1136/jnnp.2004.040378. PMC 1765657. PMID 15146039.
  25. ^ Darnell RB, Posner JB (June 2006). "Paraneoplastic syndromes affecting the nervous system". Seminars in Oncology. 33 (3): 270–298. doi:10.1053/j.seminoncol.2006.03.008. PMID 16769417.
  26. ^ Leger S, Picard D, Ingen-Housz-Oro S, Arnault JP, Aubin F, Carsuzaa F, et al. (October 2012). "Prognostic factors of paraneoplastic pemphigus". Archives of Dermatology. 148 (10): 1165–1172. doi:10.1001/archdermatol.2012.1830. PMID 22801794.
  27. ^ Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M (May 2017). "Pemphigus". Nature Reviews. Disease Primers. 3: 17026. doi:10.1038/nrdp.2017.26. PMC 5901732. PMID 28492232.
  28. ^ Hong MK, Kong J, Namdarian B, Longano A, Grummet J, Hovens CM, et al. (December 2010). "Paraneoplastic syndromes in prostate cancer". Nature Reviews. Urology. 7 (12): 681–692. doi:10.1038/nrurol.2010.186. PMID 21139643. S2CID 25387789.
  29. ^ Yshii LM, Hohlfeld R, Liblau RS (December 2017). "Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives". Nature Reviews. Neurology. 13 (12): 755–763. doi:10.1038/nrneurol.2017.144. PMID 29104289. S2CID 41673022.
  30. ^ Querol L, Devaux J, Rojas-Garcia R, Illa I (September 2017). "Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications". Nature Reviews. Neurology. 13 (9): 533–547. doi:10.1038/nrneurol.2017.84. PMID 28708133. S2CID 24396478.
  31. ^ Graus F, Saiz A, Dalmau J (April 2010). "Antibodies and neuronal autoimmune disorders of the CNS". Journal of Neurology. 257 (4): 509–517. doi:10.1007/s00415-009-5431-9. PMID 20035430. S2CID 19651940.
  32. ^ Hannawi Y, Goldsmith CE, Kass JS, Olar A, Ubogu EE, Kalkonde YV (September 2013). "A case of severe chronic progressive axonal polyradiculoneuropathy temporally associated with anti-CV2/CRMP5 antibodies". Journal of Clinical Neuromuscular Disease. 15 (1): 13–18. doi:10.1097/cnd.0b013e3182a04538. PMID 23965404. S2CID 37917515.
  33. ^ Lancaster E, Huijbers MG, Bar V, Boronat A, Wong A, Martinez-Hernandez E, et al. (February 2011). "Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia". Annals of Neurology. 69 (2): 303–311. doi:10.1002/ana.22297. PMC 3059252. PMID 21387375.
  34. ^ van Sonderen A, Ariño H, Petit-Pedrol M, Leypoldt F, Körtvélyessy P, Wandinger KP, et al. (August 2016). "The clinical spectrum of Caspr2 antibody-associated disease". Neurology. 87 (5): 521–528. doi:10.1212/wnl.0000000000002917. PMC 4970662. PMID 27371488.
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