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Mastocytosis

Mastocytosis is a general term referring to a heterogeneous group of disorders associated with enhanced survival and autonomous growth of mast cells. The main types of mastocytosis are cutaneous mastocytosis (CM), which is limited to the skin and more frequently diagnosed in children, and systemic mastocytosis (SM), which is characterized by the involvement of extracutaneous tissues and more often seen in adults. While SM is generally related to mutations of the KIT gene, the etiology of CM remains unknown. Beyond CM and SM, there is the rare entity of mast cell sarcoma, a malignant mast cell neoplasm presenting as a solitary mass lesion.


Presentation

Skin lesions are observed in about 80% of patients with mastocytosis. They are characteristic of CM and very common in indolent SM [1]. Patients may present with solitary or multiple hyperpigmented macules, papules or nodules, with generalized erythroderma, or peau d'orange-like skin. In infants and young children, skin blistering may be noted. When lesions are stroked, mast cell degranulation may occur and urticaria may be triggered. This phenomenon has been named after the dermatologist who first described it and is known as Darier's sign. Dermatographism, pruritus, and flushing may also be observed in response to the secretion of mast cell mediators.

It is important to note that the more aggressive subtypes of SM rarely present with cutaneous symptoms. These patients may show symptoms related to organ function impairment, may display systemic responses to mast cell degranulation, or suffer from constitutional symptoms [1]. The latter comprise fatigue, fever, and weight loss, among others. Mast cell granules contain histamine, heparin, prostaglandins, leukotrienes, and other vasoactive and proinflammatory mediators, which may induce headaches and abdominal pain, hypotension, tachycardia, and respiratory distress if they reach the circulation. Patients may experience syncopes and life-threatening complications such as anaphylaxis, particularly upon exposure to Hymenoptera venoms.

Extracutaneous tissues most frequently involved in SM are the bone marrow, lymph nodes, liver, spleen, and gastrointestinal mucosa. Bone marrow failure may lead to anemia, leukopenia, and thrombocytopenia. These conditions are accompanied by symptoms such as pallor, loss of energy, and poor performance, recurrent infections, and hemorrhagic diathesis. Lymphadenopathy, hepatomegaly, and splenomegaly may be diagnosed during the clinical examination, while gastrointestinal complications frequently result in nausea, pyrosis, abdominal pain, bloating, and diarrhea. In this context, it may not always be feasible to clinically distinguish between the effects of mast cell degranulation and the direct consequences of mast cell infiltration.

Additionally, mastocytosis predisposes to myalgia, arthralgia, and bone pain. Affected individuals are at higher risks of developing osteopenia, osteoporosis, and pathological fractures.

Rigor
  • The efficacy of Rydapt was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by six cycles of treatment per the modified Valent criteria (n 89), in which CR and ICR are the two most rigorous subcategories of[novartis.com]
Inguinal Lymphadenopathy
  • On abdominal exam there was no organomegaly, masses, tenderness, or inguinal lymphadenopathy. A ventral hernia was noted.[doi.org]
Sore Throat
  • The patient had a sensation of a “sore throat” for years along with more frequent bowel movements and increased flatus. There were no other gastrointestinal complaints.[doi.org]
  • throat; chronic kidney failure grade 1; dermatographism; longitudinal ridging in all nails; mood disturbances; recurrent impaired vision Mast cell clusters ( 15 MCs) in gastro-intestinal biopsies; 14% were stained CD25-positive; somatic KIT D816V mutation[f1000research.com]
Eructation
  • When the analysis was limited to patients whose mastocytosis was validated by a central review, there was some variability in whether certain symptoms (i.e., aerophagia/eruction, ocular discomfort, erectile function/ability to make love, and dysuria)[doi.org]
Diplopia
  • CASE REPORT: A patient presented with bilateral eyelid edema with exophthalmos associated with binocular diplopia.[ncbi.nlm.nih.gov]
Dysuria
  • ., aerophagia/eruction, ocular discomfort, erectile function/ability to make love, and dysuria) were statistically significant or not (data not shown); however, except for dysuria, when only severe or intolerable disabilities (grades 3 or 4) were considered[doi.org]

Workup

The diagnosis of CM is based on clinical and histopathological findings and the exclusion of SM. Skin biopsy samples need to be examined and typically reveal prominent mast cell infiltration in the dermis. Mast cells tend to aggregate around blood vessels and are readily recognized by their dense granular cytoplasm containing numerous metachromatic vesicles.

SM is characterized by the involvement of at least one extracutaneous organ, and the suspicion of systemic complications may be based on observations like organ dysfunction, organomegaly, severe clinical symptoms, and elevated serum tryptase levels. While it is generally recommended to carry out a bone marrow biopsy and to obtain tissue specimens from the organs assumed to be infiltrated by mast cells, molecular testing of peripheral blood cells for the KIT D816V mutation may constitute a less invasive approach to diagnosis. This is particularly the case for pediatric patients who are unlikely to suffer from the systemic variant and where serum tryptase levels may be associated with extensive skin involvement without underlying SM [2] [3].

If the suspicion of systemic involvement is substantiated, biopsy samples as described above have to be obtained. The multifocal presence of dense infiltrates of mast cells in the bone marrow and/or other extracutaneous organs is the single most important feature and major criterion of SM [4]. According to the World Health Organization, one major and one minor diagnostic criterion must be fulfilled for the diagnosis of SM. This same diagnosis may be established in the presence of three minor criteria. In this line, the following minor criteria should be considered:

  • Presence of atypical mast cells in affected tissues
  • Presence of KIT D816V mutation
  • Aberrant expression of CD25 with or without CD2 on neoplastic mast cells
  • Persistently elevated serum tryptase levels (> 20 ng/ml)

Since serum tryptase levels reflect the actual mast cell burden, they are also determined during follow-ups [4].

Liver Enzymes Abnormal
  • The main biological features were anemia (79.2%), thrombocytopenia (50.9%), leucopenia (20.8%), and liver enzyme abnormalities (32.1%).[ncbi.nlm.nih.gov]

Treatment

Treatment of mastocytosis is mostly symptomatic and tailored on an individual basis [5]:

  • Treating physicians should work in close cooperation with the patient to identify potential triggers leading to the exacerbation of symptoms. Common triggers include physical stimuli, emotional stress, spicy and hot foods, alcohol, drugs, and pathogens.
  • The use of antihistamines, steroids, and cromolyn is recommended to alleviate symptoms related to mast cell degranulation. While adults may require lifelong treatment, medical therapy may be ceased eventually in the majority of pediatric patients.
  • Cytoreductive drugs are generally reserved for those suffering from aggressive SM, whereby the decision in favor or against chemotherapy should be based on the recommendations of the World Health Organization. Here, B and C findings have been defined that indicate a high mast cell burden, possible dysplasia or excess proliferation of non-mast cell lineages, bone marrow dysfunction, and the involvement of liver, spleen, digestive tract, or skeleton [1]. Chemotherapeutic agents available for the management of mastocytosis include imatinib, masitinib, nilotinib, dasatinib, midostaurin, cladribine, and interferon α, but KIT D816V mutation may confer resistance to drug therapy [6].
  • Hematopoietic stem cell transplantation may be considered as a viable and potentially curative therapeutic option for advanced SM [6] [7].
  • Mastocytosis-related anaphylaxis should be treated in the same way as other cases of anaphylaxis. Beyond that, CM patients with extensive skin involvement, those diagnosed with SM, and every patient with a history of anaphylaxis should be provided an emergency kit containing an epinephrine autoinjector, corticosteroids, and antihistamines.

Prognosis

The prognosis for cutaneous and indolent SM is excellent. With regard to CM, regression is common in children and typically occurs before puberty. According to a retrospective study based on a long term clinical follow-up of childhood mastocytosis, complete regression may be achieved by 67% of all patients, major regression by 20%, and partial regression by 13% [8]. The persistence of skin lesions is to be expected in adult patients, but the disease can usually be managed with symptomatic treatment, and affected individuals have a normal life expectancy. On the other end of the spectrum are the most aggressive subtypes of SM, namely mast cell leukemia, SM with an associated hematological neoplasm, and aggressive SM. Median survival times of 2, 24, and 41 months, respectively, have been reported [9].

Under circumstances yet to be clarified, mild mastocytosis may aggravate and transform into a more aggressive type. Distinct factors have been identified that allow for a more reliable, yet not infallible risk stratification, and these factors include the type and subtype of mastocytosis, clinical findings, and molecular features [10]. For instance, the presence of KIT D816V mutation has been related to an increased likelihood of CM patients developing systemic complications during the course of the disease, but the parameter is lacking sensitivity [2]. Furthermore, up to 3% of patients who present with indolent SM, the least aggressive subtype of the disease, eventually develop mast cell leukemia. Predictors of disease progression are elevated serum β2‐microglobulin levels and the presence of KIT D816V mutation in multiple lineages [10].

Etiology

SM is related to spontaneous mutations of the KIT proto-oncogene, which is located on the long arm of chromosome 4 and encodes for a receptor tyrosine kinase. The latter is activated by stem cell factor, a cytokine otherwise known as mast cell growth factor, and plays a key role in the regulation of mast cell differentiation, maturation, and survival. Gain-of-function mutations underlie the increase of mast cell numbers observed in mastocytosis, with mutation D816V being the most prevalent variant in these patients. Apart from KIT mutations, other gene defects, gene polymorphisms, and chromosomal aberrations may account for SM [11].

Little is known about the etiology of CM. Mutations as described in the previous paragraph can rarely be confirmed in patients diagnosed with CM.

Epidemiology

The overall incidence of mastocytosis has been estimated at 1 in 10,000 inhabitants, but the underdiagnosis is still assumed [9]. CM is most commonly diagnosed in pediatric patients. While children of all ages may be affected, the majority of cases develops during the first year of life. CM may even be present at birth. By contrast, SM is generally an adult disease, with a peak incidence between the third and fifth decade of life. Slight preference for males or females has been reported for some subtypes of mastocytosis, but the gender distribution may be considered approximately equal at a general level.

With regards to the subtypes of mastocytosis, urticaria pigmentosa and indolent SM predominate in pediatric and adult patients, respectively [9].

Sex distribution
Age distribution

Pathophysiology

Mast cells derive from progenitor cells in the bone marrow, circulate in the peripheral blood and eventually home to distinct tissues. Here, they undergo differentiation and maturation, which are complex processes that are regulated by a variety of mediators and feedback mechanisms. In this context, one of the most important cytokines is stem cell factor. It binds to specific, membrane-bound tyrosine kinase receptors expressed by mast cells. These receptors are encoded by the KIT proto-oncogene, and any mutation of this gene may have a profound impact on the development and survival of mast cells. In line with this, loss-of-function mutations of the KIT gene may result in mast cell deficiency, as has been observed in KIT mutant mice. Gain-of-function mutations, however, may promote mast cell growth and survival, giving rise to mastocytosis [11].

Interestingly, KIT mutations can be confirmed in the majority of patients with SM, but have rarely been identified in those suffering from CM. The mechanisms accounting for the abnormal accumulation and distribution of mast cells in the skin of CM patients have yet to be clarified [11].

Prevention

No recommendations can be given to prevent the onset of mastocytosis. KIT mutations arise spontaneously, with familial cases of mastocytosis being increasingly rare [5].

Summary

Mastocytosis has initially been considered a type of myeloproliferative disease but is listed as a separate major disease entity with distinctive clinical and pathological features in the most recent WHO classification of tumors of hematopoietic tissues [1]. This same classification considers three types of mastocytosis, namely the cutaneous and systemic variants of mastocytosis and mast cell sarcoma. Subtypes have been defined as follows:

  • Cutaneous mastocytosis: urticaria pigmentosa/maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, mastocytoma of skin
  • Systemic mastocytosis: indolent systemic mastocytosis (including the bone marrow mastocytosis subtype), smoldering systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, aggressive systemic mastocytosis, mast cell leukemia
  • Mast cell sarcoma without subtypes

It is beyond the scope of this article to provide detailed information on all of these subtypes, which vary with regards to pathogenesis and clinical presentation, which require specific diagnostic measures and treatment strategies. Furthermore, they preferentially affect distinct patient groups and are associated with different outcomes. This article merely aims at giving an overview, and the interested reader is referred to the respective entries on this platform in order to obtain more specific information.

Patient Information

Mastocytosis is a general term referring to a heterogeneous group of disorders that are characterized by an abnormal accumulation and distribution of mast cells. Nearly all children and most adults suffering from mastocytosis present with cutaneous symptoms. They may show hyperpigmented macules, papules or nodules, or other skin lesions that give rise to hives when being stroked. Notwithstanding, mastocytosis may also affect other organs, such as the bone marrow, liver, spleen, or digestive tract. This is more commonly seen in adults and results in a broad spectrum of symptoms, from fatigue to the propensity to infection and bleeding, to abdominal pain and diarrhea. Additional symptoms may be triggered by mast cell-related mediators like histamine and heparin. In this line, patients may complain about headaches, hypotension, palpitations, and respiratory distress. They may also experience anaphylaxis.

The diagnosis of a specific type of mastocytosis is based on a thorough workup and should be considered an indispensable prerequisite for the preparation of an individual treatment plan. Furthermore, the patient's prognosis largely depends on the type of mastocytosis.

References

Article

  1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 ed. Lyon, France: IARC Press; 2017.
  2. Carter MC, Bai Y, Ruiz-Esteves KN, et al. Detection of KIT D816V in peripheral blood of children with manifestations of cutaneous mastocytosis suggests systemic disease. Br J Haematol. 2018; 183(5):775-782.
  3. Lange M, Zawadzka A, Schrörs S, et al. The role of serum tryptase in the diagnosis and monitoring of pediatric mastocytosis: a single-center experience. Postepy Dermatol Alergol. 2017; 34(4):306-312.
  4. Gotlib J, Gerds AT, Bose P, et al. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018; 16(12):1500-1537.
  5. Wagner N, Staubach P. Mastocytosis - pathogenesis, clinical manifestation and treatment. J Dtsch Dermatol Ges. 2018; 16(1):42-57.
  6. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017; 129(11):1420-1427.
  7. Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32(29):3264-3274.
  8. Uzzaman A, Maric I, Noel P, Kettelhut BV, Metcalfe DD, Carter MC. Pediatric-onset mastocytosis: a long term clinical follow-up and correlation with bone marrow histopathology. Pediatr Blood Cancer. 2009; 53(4):629-634.
  9. Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am. 2014; 34(2):283-295.
  10. Pardanani A. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019; 94(3):363-377.
  11. Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006; 26(3):515-534.

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Last updated: 2019-07-11 22:24