Mastocytosis

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Mastocytosis
Mastocytosis - cropped - very high mag.jpg
Micrograph of mastocytosis. Skin biopsy. H&E stain.
Specialty Oncology, allergology, hematology

Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called mastocytes) and CD34+ mast cell precursors.[1]

People affected by mastocytosis are susceptible to a variety of symptoms including itching, hives, and anaphylactic shock, caused by the release of histamine and other pro-inflammatory substances from mast cells.[2]

Classification[edit]

Mastocytosis can occur in a variety of forms:

Cutaneous mastocytosis (CM)

  • The most common cutaneous mastocytosis is maculopapular cutaneous mastocytosis, previously named papular urticaria pigmentosa (UP), more common in children, although also seen in adults. Telangiectasia macularis eruptiva perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.[2] MPCM and TMEP can be a part of indolent systemic mastocytosis. This should be considered if patients develop any systemic symptoms[3]
  • Generalized eruption of cutaneous mastocytosis (adult type) is the most common pattern of mastocytosis presenting to the dermatologist, with the most common lesions being macules, papules, or nodules that are disseminated over most of the body but especially on the upper arms, legs, and trunk[4]
  • Diffuse cutaneous mastocytosis' has diffuse involvement in which the entire integument may be thickened and infiltrated with mast cells to produce a peculiar orange color, giving rise to the term "homme orange."[5]

Cutaneous mastocytosis in children usually presents in the first year after birth and in most cases vanishes during adolescence.

Systemic mastocytosis (SM)

Systemic mastocytosis involves the bone marrow in the majority of cases and in some cases other internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs where mast cells do not normally inhabit such as the liver, spleen and lymph nodes, and organs which have normal populations but where numbers are increased. In the bowel, it may manifest as mastocytic enterocolitis.[6]

There are five types of systemic mastocytosis:[7]

  • Indolent systemic mastocytosis (ISM). The most common SM (>90%)
  • Smouldering systemic mastocytosis (SSM)
  • Systemic mastocytosis with associated haematological neoplasm (SM-AHN)
  • Aggressive systemic mastocytosis (ASM)
  • Mast cell leukemia (MCL)

Signs and symptoms[edit]

When mast cells undergo degranulation, the substances that are released can cause a number of symptoms which can vary over time and can range in intensity from mild to severe. Because mast cells play a role in allergic reactions, the symptoms of mastocytosis often are similar to the symptoms of an allergic reaction. They may include, but are not limited to[8]

Pathophysiology[edit]

Mast cells are located in connective tissue, including the skin, the linings of the stomach and intestine, and other sites. They play an important role in the immune defence against bacteria and parasites. By releasing chemical "alarms" such as histamine, mast cells attract other key players of the immune defense system to areas of the body where they are needed.[citation needed]

Mast cells seem to have other roles as well. Because they gather together around wounds, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by histamine released by mast cells. Researchers also think mast cells may have a role in the growth of blood vessels (angiogenesis). No one with too few or no mast cells has been found, which indicates to some scientists we may not be able to survive with too few mast cells.[citation needed]

Mast cells express a cell surface receptor, c-kit[11] (CD117), which is the receptor for stem cell factor (scf). In laboratory studies, scf appears to be important for the proliferation of mast cells. Mutations of the gene coding for the c-kit receptor (mutation KIT(D816V)), leading to constitutive signalling through the receptor is found in >90% of patients with systemic mastocytosis.[12]

Diagnosis[edit]

Diagnosis of urticaria pigmentosa (cutaneous mastocytosis, see above) can often be done by seeing the characteristic lesions that are dark-brown and fixed. A small skin sample (biopsy) may help confirm the diagnosis.[citation needed].

In case of suspicion of systemic disease the level of serum tryptase in the blood can be of help. If the base level of s-tryptase is elevated, this implies that the mastocytosis can be systemic. In cases of suspicion of SM help can also be drawn from analysis of mutation in KIT(D816V) in peripheral blood using sensitive PCR-technology

To set the diagnosis of systemic mastocytosis, certain criteria must be met. Either one major + one minor criterium or 3 minor criteria has to be fulfilled:[7]

Major criterium[edit]

  • Dense infiltrates of >15 mast cells in the bone marrow or an extracutaneous organ

Minor criteria[edit]

  • Aberrant phenotype on the mast cells (pos. for CD2 and/or CD25)
  • Aberrant mast cell morphology (spindle-shaped)
  • Finding of mutation in KIT(D816V)
  • S-tryptase >20 ng/ml

Other mast cell diseases

Other types of mast cell disease include:

  • Monoclonal mast cell activation, defined by the World Health Organisation definitions 2010, also has increased mast cells but insufficient to be systemic mastocytosis (in World Health Organisation Definitions)
  • Mast cell activation syndrome – has normal number of mast cells, but all the symptoms and in some cases the genetic markers of systemic mastocytosis[13]
  • Another known but rare mast cell proliferation disease is mast cell sarcoma.[14]

Epidemiology[edit]

The true incidence and prevalence of mastocytosis is unknown, but mastocytosis generally has been considered to be an "orphan disease" (orphan diseases affect 200,000 or fewer people in the United States). Mastocytosis, however, often may be misdiagnosed, especially because it typically occurs secondary to another condition, and thus may occur more frequently than assumed.[[citation needed]

Treatment[edit]

There is currently no cure for mastocytosis, but there are a number of medicines to help treat the symptoms:[citation needed]

Anti-mediator therapy

  • Antihistamines block receptors targeted by histamine released from mast cells. Both H1 and H2 blockers may be helpful.
  • Leukotriene antagonists block receptors targeted by leukotrienes released from mast cells.
  • Mast cell stabilizers help prevent mast cells from releasing their chemical contents. Cromoglicic acid is the only medicine specifically approved by the FDA for the treatment of mastocytosis. Ketotifen is available in Canada and Europe and more recently in the U.S. It is also available as eyedrops (Zaditor).
  • Proton pump inhibitors help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
  • Epinephrine constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused anaphylaxis.
  • Salbutamol and other beta-2 agonists open airways that can constrict in the presence of histamine.
  • Corticosteroids can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.
  • Drugs to prevent/treat osteoporosis include Calcium-Vitamine D, bisphosphonates and in rare cases inhibitors of RANK-L

Antidepressants are an important and often overlooked tool in the treatment of mastocytosis. Depression and other neurological symptoms have been noted in mastocytosis.[15][16] Some antidepressants, such as doxepin, are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

Cytoreductive therapy

In cases of advanced systemic mastocytosis or rare cases with indolent systemic mastocytosis with very troublesome symtoms, cytoreductive therapy can be indicated.[17][17]

  • ɑ-interferon. Given as subcutaneous injections. Side effects include fatigue and influenza-like symtoms
  • Cladribine (CdA). Chemotherapy which is given as subcutaneous injections. Side effects include immunodeficiency and infections.
  • Tyrosine kinase inhibitors (TKI)
    • Midostaurin. TKI acting on many different tyrosine kinases, approved by FDA and EMA for advanced mastocytosis
    • Imatinib. Can have effect in rare cases without mutation in KIT(D816V)
    • Masitinib. Is being tested in trials. Not approved.

Allogeneic stem cell transplantation has been used in rare cases with aggressive systemic mastocytosis in patients deemed to be fit for the procedure.

Prognosis[edit]

Patients with indolent systemic mastocytosis have a normal life expectancy. The prognosis for patients with advanced systemic mastocytosis differs depending on type of disease with MCL being the most serious form with short survival.[17]

Research[edit]

National Institute of Allergy and Infectious Diseases scientists have been studying and treating patients with mastocytosis for several years at the National Institutes of Health (NIH) Clinical Center.[citation needed]

Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production. Researchers are currently evaluating approaches to improve ways to treat mastocytosis.[citation needed]

Scientists also are focusing on identifying disease-associated mutations (changes in genes). NIH scientists have identified some mutations, which may help researchers understand the causes of mastocytosis, improve diagnosis, and develop better treatments.[citation needed]

In Europe the European Competence Network on Mastocytosis (ECNM) coordinates studies, registries and education on mastocytosis.

History[edit]

Urticaria pigmentosa was first described in 1869.[18] Systemic mastocytosis was first reported by French scientists in 1936.[19]

See also[edit]

References[edit]

  1. ^ Horny HP, Sotlar K, Valent P (2007). "Mastocytosis: state of the art". Pathobiology. 74 (2): 121–32. doi:10.1159/000101711. PMID 17587883. 
  2. ^ "Mastocytosis & mast cell disorders". Mastocytosis Society Canada. Archived from the original on 2013-12-28. Retrieved 2017-11-02. 
  3. ^ Ellis DL (1996). "Treatment of telangiectasia macularis eruptiva perstans with the 585-nm flashlamp-pumped dye laser". Dermatol Surg. 22 (1): 33–7. doi:10.1016/1076-0512(95)00388-6. PMID 8556255. 
  4. ^ Noack F, Escribano L, Sotlar K, Nunez R, Schuetze K, Valent P, Horny HP (2003). "Evolution of urticaria pigmentosa into indolent systemic mastocytosis: abnormal immunophenotype of mast cells without evidence of c-kit mutation ASP-816-VAL". Leuk Lymphoma. 44 (2): 313–9. doi:10.1080/1042819021000037967. PMID 12688351. 
  5. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  6. ^ Ramsay DB, Stephen S, Borum M, Voltaggio L, Doman DB (2010). "Mast cells in gastrointestinal disease". Gastroenterology Hepatology (N Y). 6 (12): 772–7. PMC 3033552Freely accessible. PMID 21301631. 
  7. ^ a b Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (May 2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254. 
  8. ^ Hermine O, Lortholary O, Leventhal PS, et al. (2008). Soyer HP, ed. "Case-Control Cohort Study of Patients' Perceptions of Disability in Mastocytosis". PLOS One. 3 (5): e2266. doi:10.1371/journal.pone.0002266. PMC 2386235Freely accessible. PMID 18509466.  open access publication – free to read
  9. ^ Moura DS, Sultan S, Georgin-Lavialle S, Pillet N, Montestruc F, Gineste P, Barete S, Damaj G, Moussy A, Lortholary O, Hermine O (2011). "Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy". PLOS One. 6 (10): e26375. doi:10.1371/journal.pone.0026375. PMC 3198767Freely accessible. PMID 22031830. 
  10. ^ Lee, JK; Whittaker, SJ; Enns, RA; Zetler, P (Dec 7, 2008). "Gastrointestinal manifestations of systemic mastocytosis". World Journal of Gastroenterology. 14 (45): 7005–8. doi:10.3748/wjg.14.7005. PMC 2773867Freely accessible. PMID 19058339. 
  11. ^ Orfao A, Garcia-Montero AC, Sanchez L, Escribano L (2007). "Recent advances in the understanding of mastocytosis: the role of KIT mutations". Br. J. Haematol. 138 (1): 12–30. doi:10.1111/j.1365-2141.2007.06619.x. PMID 17555444. 
  12. ^ Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. (March 2017). "Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future". Cancer Research. 77 (6): 1261–1270. doi:10.1158/0008-5472.CAN-16-2234. PMC 5354959Freely accessible. PMID 28254862. 
  13. ^ Akin C, Valent P, Metcalfe DD (2010). "Mast cell activation: proposed diagnostic criteria". The Journal of Allergy and Clinical Immunology. 126 (6): 1099–104. doi:10.1016/j.jaci.2010.08.035. PMC 3753019Freely accessible. PMID 21035176. 
  14. ^ National Organization for Rare Disorders (NORD) "Mastocytosis", 2017
  15. ^ Moura DS, Sultan S, Georgin-Lavialle S, Pillet N, Montestruc F, et al. (2011). "Depression in Patients with Mastocytosis: Prevalence, Features and Effects of Masitinib Therapy". PLOS One. 6 (10): e26375. doi:10.1371/journal.pone.0026375. PMC 3198767Freely accessible. PMID 22031830.  open access publication – free to read
  16. ^ Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF (1986). "Mixed organic brain syndrome as a manifestation of systemic mastocytosis". Psychosom Med. 48 (6): 437–47. doi:10.1097/00006842-198607000-00006. PMID 3749421. 
  17. ^ a b Pardanani A (November 2016). "Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management". American Journal of Hematology. 91 (11): 1146–1159. doi:10.1002/ajh.24553. PMID 27762455. 
  18. ^ Nettleship E, Tay W (1869). "Reports of Medical and Surgical Practice in the Hospitals of Great Britain". Br Med J. 2 (455): 323–4. doi:10.1136/bmj.2.455.323. PMC 2260962Freely accessible. PMID 20745623. 
  19. ^ Sézary A, Levy-Coblentz G, Chauvillon P (1936). "Dermographisme et mastocytose". Bull Soc Fr Dermatol Syphilol. 43: 359–61. 

External links[edit]

Classification
External resources