nature reviews disease primers https://doi.org/10.1038/s41572-025-00611-8
Primer Check for updates
Mastocytosis
Cem Akin 1
, Michel Arock 2
, Melody C. Carter 3
, Tracy I. George 4
& Peter Valent 5,6
Abstract Sections
Mastocytosis is a spectrum of clonal myeloid disorders defined by Introduction
abnormal growth and accumulation of mast cells in various organ Epidemiology
systems. The disease is divided into cutaneous mastocytosis, systemic Mechanisms/pathophysiology
mastocytosis (SM) and mast cell sarcoma. SM is further categorized
Diagnosis, screening and
into several non-advanced and advanced forms. The prognosis of prevention
cutaneous mastocytosis and non-advanced SM is mostly favourable,
Management
whereas prognosis and survival in advanced SM and mast cell
Quality of life
sarcoma are poor. During the past 15 years, major advances have
been made in the diagnosis, prognosis and management of patients Outlook
with mast cell neoplasms. Management of mastocytosis consists of
symptomatic therapy, including anti-mast cell mediator drugs, and
cytoreductive agents for patients with advanced disease and selected
individuals with non-advanced disease, as well as recognition and
prevention of comorbidities such as osteoporosis and anaphylaxis.
The preclinical and clinical development of KIT-D816V-targeting drugs,
such as midostaurin or avapritinib, mark a milestone in improving
management, the quality of life and survival in patients with SM.
These agents induce major responses or even remission in people
with advanced SM and lead to rapid improvement of mediator-related
symptoms and quality of life in symptomatic patients.
Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor,
1
MI, USA. 2CEREMAST, Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie
University (UPMC), Paris, France. 3Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA. 4Department of
Pathology, University of Utah, Salt Lake City, UT, USA. 5Department of Internal Medicine I, Division of Hematology
and Hemostaseology, Medical University of Vienna, Vienna, Austria. 6Ludwig Boltzmann Institute for Hematology
and Oncology, Medical University of Vienna, Vienna, Austria. e-mail: ; peter.valent@
meduniwien.ac.at
Nature Reviews Disease Primers | (2025) 11:30 1
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,Primer
Introduction Network of Mastocytosis (ECNM) and the American Initiative on Mast
Mastocytosis is characterized by focal accumulations of clonal mast cells Cell Diseases (AIM)17,20,21 and is used in this Primer (Supplementary
in the skin and/or in internal organs such as bone marrow, spleen, lymph Table 1). In 2022, an alternative classification, named the International
nodes or the gastrointestinal tract and is divided into cutaneous mastocy- Consensus Classification (ICC), was proposed22,23. The ICC is largely
tosis (CM), systemic mastocytosis (SM) and the extremely rare mast cell similar to the WHO proposal but has introduced slight changes in
sarcoma (MCS)1–9 (Table 1). SM can further be divided into non-advanced diagnostic criteria and the classification of SM22,23.
SM and advanced SM based on the presence or absence of an associ- During the past decade, insights into the pathogenesis of CM and
ated (non-mast cell lineage) haematological neoplasm, local aggressive SM have been expanded. Both groups of disease are now regarded as
growth of mast cells resulting in organ damage or mast cell leukaemia neoplasms that are derived from lineage-specific and/or multilineage
(MCL)1–13. A special variant is smouldering SM in which the prognosis neoplastic myeloid stem cells2–4. The evolution of CM and SM is trig-
is better than in advanced SM but worse compared with patients with gered by activated KIT (also known as CD117) signalling pathways that
indolent SM5,12,14,15. Another special variant is bone marrow mastocytosis, lead to KIT-ligand-independent growth and expansion of mast cells2–4.
in which skin lesions are absent and the disease is largely restricted to the Indeed, in most cases of CM and SM, neoplastic mast cells carry a
bone marrow3–5,16,17. Well-differentiated SM (WDSM) is a morphological somatic gain-of-function mutation in the KIT oncogene. The most
variation that can be encountered in all categories of SM and that exhibits common KIT mutation encountered in SM is D816V, which confers
distinct molecular, immunological and pharmacological features18,19. ligand-independent activation of the KIT tyrosine kinase18,24–29.
The clinical course and symptoms in mastocytosis range from Management of mastocytosis includes avoidance of patient-
asymptomatic to recurrent anaphylaxis and from a stable and indolent specific triggers of mast cell activation, prophylactic therapy with
course over decades to a rapidly progressive course or even leukaemic mediator-targeting or mast cell-stabilizing agents, in addition to drugs
transformation and short survival1–13. Whereas childhood-onset CM that support bone density in those with osteoporosis, and Hymenop-
usually improves or even resolves by adolescence, CM and SM in adults tera venom immunotherapy for those with anaphylactic sensitivity to
are generally persistent4–7. Hymenoptera venom. KIT-targeting tyrosine kinase inhibitors (TKIs)
There are currently two classification schemes for mastocytosis. are often recommended in patients with advanced SM or those with
The WHO classification is in line with the proposal of the EU–US con- indolent SM with severe refractory symptoms despite anti-mediator
sensus group, which consists of experts of the European Competence therapy, whereas in drug-resistant advanced SM chemotherapy and
Table 1 | WHO classification of mastocytosis3,5,17,20 and estimated prevalence
Variants and subvariants Predominant Estimated prevalence (%) Individuals with KIT D816V
age group mutation (%)
Cutaneous mastocytosis – 0.01 –
MPCM a
Polymorphic form of MPCM Children 0.005 20b
Monomorphic form of MPCM Children and 0.01 30 (children)b and 80
adults (adults)
Diffuse CM – Children 0.0001 <10b
Mastocytoma of skin – Children 0.02 Not known
Systemic mastocytosis – 0.005 –
Non-advanced SM Bone marrow mastocytosis Adults 0.002 80
Indolent SM Adults 0.005 90
Smouldering SM Adults 0.0005 95
Well-differentiated SM subsets Adults <0.0001 <5c
Advanced SM SM with an associated haematological Adults 0.001 95
neoplasm
Aggressive SM Adults 0.0001 80
Mast cell leukaemia Adults <0.0001 70
Well-differentiated subsets of Adults <0.0001 <5c
advanced SM
MCS – Adults <0.0001 <5
MCS-like SMd Adults <0.0001 50
Extracutaneous mastocytomae – Adults <0.0001 Not known
CM, cutaneous mastocytosis; MCS, mast cell sarcoma; MPCM, maculopapular cutaneous mastocytosis; SM, systemic mastocytosis. aMPCM was formerly termed urticaria pigmentosa.
b
In childhood-onset MPCM and diffuse cutaneous mastocytosis, other KIT mutations (outside of codon 816) may be found. cIn patients with well-differentiated SM, mutations in other codons
of KIT (other than 816) may be detected. dIn patients with advanced SM with MCS-like progression, KITD816V is often detected in neoplastic mast cells. However, in patients with true MCS without
systemic involvement, neoplastic mast cells usually lack KIT mutations, including KITD816V. eExtracutaneous mastocytoma is an extremely rare category, which is not included in the WHO
classification.
Nature Reviews Disease Primers | (2025) 11:30 2
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, Primer
stem cell transplantation may be considered. Among the TKIs, the rates are much higher in patients with advanced SM or MCS compared
great majority of variants are only sensitive to strong inhibitors of with those with CM or non-advanced SM, and despite the availability of
KIT-D816V, whereas in rare cases of WDSM without a codon 816 KIT new potent KIT-D816V-targeting drugs and stem cell transplantation,
mutation, imatinib may be an effective option. This Primer outlines these patients have shortened life expectancy8–13. The estimated 5-year
the epidemiology, mechanisms of disease, diagnosis and treatment mortality rate of patients with advanced SM in Europe and in the USA
of mastocytosis with an emphasis on the common categories of CM is about 50% and the mortality rates in MCL and SM–acute myeloid
and SM. leukaemia (AML) are even higher12.
Although not considered a classic comorbidity, AHNs, such as
Epidemiology AML, appear to be the most important fatal non-SM-related patholo-
Incidence and prevalence gies recorded in patients with SM8–13. Other relevant comorbidities to
Mastocytosis is a rare disease, with an annual incidence of about 1–10 impact survival include infections in advanced SM with disease-induced
per 100,000 and a prevalence of 1–3 in 10,000 (refs. 4,21,30–33). The and/or therapy-related neutropenia and severe bleeding caused
incidence and prevalence vary between the variants of mastocytosis by disease and/or drug-induced thrombocytopenia. In those with
(Table 1). For example, in comparison with childhood CM, a higher non-advanced mastocytosis (CM, bone marrow mastocytosis and
prevalence is found in adults with SM (1.7–2.7 in 10,000)32,33. Of note, indolent SM), the most relevant comorbidities are anaphylaxis and
these estimates are mostly derived from retrospective data collected osteoporosis. Lifetime prevalence of anaphylaxis is approximately
in Europe and North America30–33, and no information about the global 30–40% in patients with SM and <10% in those with CM. Anaphylaxis
incidence and prevalence of mastocytosis is available. In the USA, mas- may result from IgE-dependent allergies, other triggers of anaphy-
tocytosis has been reported more predominantly in individuals with laxis or can occur without an identifiable cause1–4,34,50–55. Especially in
European ancestry34,35. Most of the literature is derived from European patients with Hymenoptera venom allergy, the risk of fatal anaphylaxis
and US databases, representing a potential reporting bias. In addition, is higher1–4,34,50–55. Although anaphylaxis may also occur in patients with
lack of access to certain diagnostic methods such as mutational analy- advanced SM, it is more commonly reported in non-advanced SM.
sis, tryptase levels, flow cytometry as well as disease registries or data- Osteoporosis is detected in approximately 30% of patients with SM,
bases in some parts of the world, such as parts of Africa, South America often presenting with pathological fractures56–58.
or the Indo-Pacific region, may contribute to limited knowledge on the
true prevalence of disease in those areas36. Awareness of mastocytosis Risk factors
and the application of clinical and research tools, such as KIT mutation Mutagenic triggers. Risk factors for development of mastocytosis
assays, tryptase tests, genetic studies or assessment of patient-specific have not been well characterized. Although exposure to any mutagenic
variables and assessments, are currently growing in non-US/EU coun- trigger such as ionizing radiation or mutagenic chemicals may result in
tries worldwide, which is also supported by patient-based ‘open innova- a higher risk of developing cancer in general and may promote somatic
tion in science (OIS)’ projects36. In these OIS projects, patients and their lesions such as KIT mutations that drive mastocytosis, most cases
representatives provide recommendations (based on their perception remain sporadic with an unidentifiable causative exposure. Overall,
of disease and unmet needs) to the scientific community in general, genetic background factors that facilitate the occurrence of KIT D816V,
and specifically to ECNM and AIM network members, who can in turn the major driver in SM, or facilitating expansion of KIT D816V+ clones
use and exploit these recommendations to develop new scientific and remain unknown.
clinical concepts, examples being research on mast cell activation and
studies on genetic predisposition36. Prevalence of KIT D816V and other gene mutations. Most KIT muta-
Mastocytosis has been reported in roughly equal ratios in male and tions detected in CM and SM are somatic mutations and are regarded
female individuals, although adult-onset SM has a slight female pre- as being major disease drivers. The genome aggregation database
dominance whereas cases with paediatric-onset disease and advanced notes the highest frequency of the KIT D816V mutation in the European
SM, especially SM with an associated haematological neoplasm (AHN), non-Finnish cohort (https://gnomad.broadinstitute.org/). This muta-
have a slightly higher prevalence in male individuals12,30,34,37–40. Patients tion is documented in >80% of patients with SM5,18,24–29. The prevalence
with WDSM have a female preponderance and may have familial disease of KIT D816V is lower in patients with CM (about 30%), which is mainly
with onset in childhood19. diagnosed in children17,27–29 (Table 1). However, in paediatric CM, other
KIT mutations at codon 816 and KIT mutations outside of codon 816,
Mortality and comorbidities may be detected17,27–29. Among these KIT variants, the most frequently
Children and adults with CM, bone marrow mastocytosis or indolent reported are Del419 (10–20%), ITD502–503 (3–5%), K509I (<3%), F522C
SM, have a normal or near-normal life expectancy12,16,17,37. The main (<3%) and V560G (<3%)17. Of note, KIT D816V is not specific for SM but
disease morbidity in non-advanced SM is due to symptoms caused by may rarely be detected also in patients who have AML or other myeloid
release of mast cell mediators1,4,41,42. In these patients, the only events neoplasms without evidence of concomitant SM59–62.
that have an impact on disease-related mortality are progression to Most important risk factors for progression to advanced SM are
an advanced form of SM and life-threatening anaphylaxis12,16,37. Some other somatic mutations within the KIT gene (other than KIT D816V) or
studies also reported cancer and cardiovascular diseases as poten- additional mutations in other driver genes (other than KIT ), and/or
tially life-threatening comorbidities in SM43,44. Overall, patients with adverse karyotype patterns detected in neoplastic cells, organomegaly
paediatric-onset or adulthood CM and those with non-advanced SM (lymphadenopathy and/or hepatosplenomegaly), age, male sex and
have a favourable prognosis. In general, children have a better progno- resistance to standard antineoplastic therapy used to treat patients
sis as most of these patients have CM. However, in a very few children, with advanced SM, especially KIT-D816V-targeting drugs2–4,11–13,28,63–68.
advanced SM may develop45–49. MCS and MCL have also been described In a recent ECNM registry study, the authors examined the relation-
but are exceptionally rare in children47–49. Regardless of age, mortality ship between sex, cytogenetics and survival in 3,403 patients with
Nature Reviews Disease Primers | (2025) 11:30 3
0123456789();:
Primer Check for updates
Mastocytosis
Cem Akin 1
, Michel Arock 2
, Melody C. Carter 3
, Tracy I. George 4
& Peter Valent 5,6
Abstract Sections
Mastocytosis is a spectrum of clonal myeloid disorders defined by Introduction
abnormal growth and accumulation of mast cells in various organ Epidemiology
systems. The disease is divided into cutaneous mastocytosis, systemic Mechanisms/pathophysiology
mastocytosis (SM) and mast cell sarcoma. SM is further categorized
Diagnosis, screening and
into several non-advanced and advanced forms. The prognosis of prevention
cutaneous mastocytosis and non-advanced SM is mostly favourable,
Management
whereas prognosis and survival in advanced SM and mast cell
Quality of life
sarcoma are poor. During the past 15 years, major advances have
been made in the diagnosis, prognosis and management of patients Outlook
with mast cell neoplasms. Management of mastocytosis consists of
symptomatic therapy, including anti-mast cell mediator drugs, and
cytoreductive agents for patients with advanced disease and selected
individuals with non-advanced disease, as well as recognition and
prevention of comorbidities such as osteoporosis and anaphylaxis.
The preclinical and clinical development of KIT-D816V-targeting drugs,
such as midostaurin or avapritinib, mark a milestone in improving
management, the quality of life and survival in patients with SM.
These agents induce major responses or even remission in people
with advanced SM and lead to rapid improvement of mediator-related
symptoms and quality of life in symptomatic patients.
Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor,
1
MI, USA. 2CEREMAST, Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie
University (UPMC), Paris, France. 3Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA. 4Department of
Pathology, University of Utah, Salt Lake City, UT, USA. 5Department of Internal Medicine I, Division of Hematology
and Hemostaseology, Medical University of Vienna, Vienna, Austria. 6Ludwig Boltzmann Institute for Hematology
and Oncology, Medical University of Vienna, Vienna, Austria. e-mail: ; peter.valent@
meduniwien.ac.at
Nature Reviews Disease Primers | (2025) 11:30 1
0123456789();:
,Primer
Introduction Network of Mastocytosis (ECNM) and the American Initiative on Mast
Mastocytosis is characterized by focal accumulations of clonal mast cells Cell Diseases (AIM)17,20,21 and is used in this Primer (Supplementary
in the skin and/or in internal organs such as bone marrow, spleen, lymph Table 1). In 2022, an alternative classification, named the International
nodes or the gastrointestinal tract and is divided into cutaneous mastocy- Consensus Classification (ICC), was proposed22,23. The ICC is largely
tosis (CM), systemic mastocytosis (SM) and the extremely rare mast cell similar to the WHO proposal but has introduced slight changes in
sarcoma (MCS)1–9 (Table 1). SM can further be divided into non-advanced diagnostic criteria and the classification of SM22,23.
SM and advanced SM based on the presence or absence of an associ- During the past decade, insights into the pathogenesis of CM and
ated (non-mast cell lineage) haematological neoplasm, local aggressive SM have been expanded. Both groups of disease are now regarded as
growth of mast cells resulting in organ damage or mast cell leukaemia neoplasms that are derived from lineage-specific and/or multilineage
(MCL)1–13. A special variant is smouldering SM in which the prognosis neoplastic myeloid stem cells2–4. The evolution of CM and SM is trig-
is better than in advanced SM but worse compared with patients with gered by activated KIT (also known as CD117) signalling pathways that
indolent SM5,12,14,15. Another special variant is bone marrow mastocytosis, lead to KIT-ligand-independent growth and expansion of mast cells2–4.
in which skin lesions are absent and the disease is largely restricted to the Indeed, in most cases of CM and SM, neoplastic mast cells carry a
bone marrow3–5,16,17. Well-differentiated SM (WDSM) is a morphological somatic gain-of-function mutation in the KIT oncogene. The most
variation that can be encountered in all categories of SM and that exhibits common KIT mutation encountered in SM is D816V, which confers
distinct molecular, immunological and pharmacological features18,19. ligand-independent activation of the KIT tyrosine kinase18,24–29.
The clinical course and symptoms in mastocytosis range from Management of mastocytosis includes avoidance of patient-
asymptomatic to recurrent anaphylaxis and from a stable and indolent specific triggers of mast cell activation, prophylactic therapy with
course over decades to a rapidly progressive course or even leukaemic mediator-targeting or mast cell-stabilizing agents, in addition to drugs
transformation and short survival1–13. Whereas childhood-onset CM that support bone density in those with osteoporosis, and Hymenop-
usually improves or even resolves by adolescence, CM and SM in adults tera venom immunotherapy for those with anaphylactic sensitivity to
are generally persistent4–7. Hymenoptera venom. KIT-targeting tyrosine kinase inhibitors (TKIs)
There are currently two classification schemes for mastocytosis. are often recommended in patients with advanced SM or those with
The WHO classification is in line with the proposal of the EU–US con- indolent SM with severe refractory symptoms despite anti-mediator
sensus group, which consists of experts of the European Competence therapy, whereas in drug-resistant advanced SM chemotherapy and
Table 1 | WHO classification of mastocytosis3,5,17,20 and estimated prevalence
Variants and subvariants Predominant Estimated prevalence (%) Individuals with KIT D816V
age group mutation (%)
Cutaneous mastocytosis – 0.01 –
MPCM a
Polymorphic form of MPCM Children 0.005 20b
Monomorphic form of MPCM Children and 0.01 30 (children)b and 80
adults (adults)
Diffuse CM – Children 0.0001 <10b
Mastocytoma of skin – Children 0.02 Not known
Systemic mastocytosis – 0.005 –
Non-advanced SM Bone marrow mastocytosis Adults 0.002 80
Indolent SM Adults 0.005 90
Smouldering SM Adults 0.0005 95
Well-differentiated SM subsets Adults <0.0001 <5c
Advanced SM SM with an associated haematological Adults 0.001 95
neoplasm
Aggressive SM Adults 0.0001 80
Mast cell leukaemia Adults <0.0001 70
Well-differentiated subsets of Adults <0.0001 <5c
advanced SM
MCS – Adults <0.0001 <5
MCS-like SMd Adults <0.0001 50
Extracutaneous mastocytomae – Adults <0.0001 Not known
CM, cutaneous mastocytosis; MCS, mast cell sarcoma; MPCM, maculopapular cutaneous mastocytosis; SM, systemic mastocytosis. aMPCM was formerly termed urticaria pigmentosa.
b
In childhood-onset MPCM and diffuse cutaneous mastocytosis, other KIT mutations (outside of codon 816) may be found. cIn patients with well-differentiated SM, mutations in other codons
of KIT (other than 816) may be detected. dIn patients with advanced SM with MCS-like progression, KITD816V is often detected in neoplastic mast cells. However, in patients with true MCS without
systemic involvement, neoplastic mast cells usually lack KIT mutations, including KITD816V. eExtracutaneous mastocytoma is an extremely rare category, which is not included in the WHO
classification.
Nature Reviews Disease Primers | (2025) 11:30 2
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, Primer
stem cell transplantation may be considered. Among the TKIs, the rates are much higher in patients with advanced SM or MCS compared
great majority of variants are only sensitive to strong inhibitors of with those with CM or non-advanced SM, and despite the availability of
KIT-D816V, whereas in rare cases of WDSM without a codon 816 KIT new potent KIT-D816V-targeting drugs and stem cell transplantation,
mutation, imatinib may be an effective option. This Primer outlines these patients have shortened life expectancy8–13. The estimated 5-year
the epidemiology, mechanisms of disease, diagnosis and treatment mortality rate of patients with advanced SM in Europe and in the USA
of mastocytosis with an emphasis on the common categories of CM is about 50% and the mortality rates in MCL and SM–acute myeloid
and SM. leukaemia (AML) are even higher12.
Although not considered a classic comorbidity, AHNs, such as
Epidemiology AML, appear to be the most important fatal non-SM-related patholo-
Incidence and prevalence gies recorded in patients with SM8–13. Other relevant comorbidities to
Mastocytosis is a rare disease, with an annual incidence of about 1–10 impact survival include infections in advanced SM with disease-induced
per 100,000 and a prevalence of 1–3 in 10,000 (refs. 4,21,30–33). The and/or therapy-related neutropenia and severe bleeding caused
incidence and prevalence vary between the variants of mastocytosis by disease and/or drug-induced thrombocytopenia. In those with
(Table 1). For example, in comparison with childhood CM, a higher non-advanced mastocytosis (CM, bone marrow mastocytosis and
prevalence is found in adults with SM (1.7–2.7 in 10,000)32,33. Of note, indolent SM), the most relevant comorbidities are anaphylaxis and
these estimates are mostly derived from retrospective data collected osteoporosis. Lifetime prevalence of anaphylaxis is approximately
in Europe and North America30–33, and no information about the global 30–40% in patients with SM and <10% in those with CM. Anaphylaxis
incidence and prevalence of mastocytosis is available. In the USA, mas- may result from IgE-dependent allergies, other triggers of anaphy-
tocytosis has been reported more predominantly in individuals with laxis or can occur without an identifiable cause1–4,34,50–55. Especially in
European ancestry34,35. Most of the literature is derived from European patients with Hymenoptera venom allergy, the risk of fatal anaphylaxis
and US databases, representing a potential reporting bias. In addition, is higher1–4,34,50–55. Although anaphylaxis may also occur in patients with
lack of access to certain diagnostic methods such as mutational analy- advanced SM, it is more commonly reported in non-advanced SM.
sis, tryptase levels, flow cytometry as well as disease registries or data- Osteoporosis is detected in approximately 30% of patients with SM,
bases in some parts of the world, such as parts of Africa, South America often presenting with pathological fractures56–58.
or the Indo-Pacific region, may contribute to limited knowledge on the
true prevalence of disease in those areas36. Awareness of mastocytosis Risk factors
and the application of clinical and research tools, such as KIT mutation Mutagenic triggers. Risk factors for development of mastocytosis
assays, tryptase tests, genetic studies or assessment of patient-specific have not been well characterized. Although exposure to any mutagenic
variables and assessments, are currently growing in non-US/EU coun- trigger such as ionizing radiation or mutagenic chemicals may result in
tries worldwide, which is also supported by patient-based ‘open innova- a higher risk of developing cancer in general and may promote somatic
tion in science (OIS)’ projects36. In these OIS projects, patients and their lesions such as KIT mutations that drive mastocytosis, most cases
representatives provide recommendations (based on their perception remain sporadic with an unidentifiable causative exposure. Overall,
of disease and unmet needs) to the scientific community in general, genetic background factors that facilitate the occurrence of KIT D816V,
and specifically to ECNM and AIM network members, who can in turn the major driver in SM, or facilitating expansion of KIT D816V+ clones
use and exploit these recommendations to develop new scientific and remain unknown.
clinical concepts, examples being research on mast cell activation and
studies on genetic predisposition36. Prevalence of KIT D816V and other gene mutations. Most KIT muta-
Mastocytosis has been reported in roughly equal ratios in male and tions detected in CM and SM are somatic mutations and are regarded
female individuals, although adult-onset SM has a slight female pre- as being major disease drivers. The genome aggregation database
dominance whereas cases with paediatric-onset disease and advanced notes the highest frequency of the KIT D816V mutation in the European
SM, especially SM with an associated haematological neoplasm (AHN), non-Finnish cohort (https://gnomad.broadinstitute.org/). This muta-
have a slightly higher prevalence in male individuals12,30,34,37–40. Patients tion is documented in >80% of patients with SM5,18,24–29. The prevalence
with WDSM have a female preponderance and may have familial disease of KIT D816V is lower in patients with CM (about 30%), which is mainly
with onset in childhood19. diagnosed in children17,27–29 (Table 1). However, in paediatric CM, other
KIT mutations at codon 816 and KIT mutations outside of codon 816,
Mortality and comorbidities may be detected17,27–29. Among these KIT variants, the most frequently
Children and adults with CM, bone marrow mastocytosis or indolent reported are Del419 (10–20%), ITD502–503 (3–5%), K509I (<3%), F522C
SM, have a normal or near-normal life expectancy12,16,17,37. The main (<3%) and V560G (<3%)17. Of note, KIT D816V is not specific for SM but
disease morbidity in non-advanced SM is due to symptoms caused by may rarely be detected also in patients who have AML or other myeloid
release of mast cell mediators1,4,41,42. In these patients, the only events neoplasms without evidence of concomitant SM59–62.
that have an impact on disease-related mortality are progression to Most important risk factors for progression to advanced SM are
an advanced form of SM and life-threatening anaphylaxis12,16,37. Some other somatic mutations within the KIT gene (other than KIT D816V) or
studies also reported cancer and cardiovascular diseases as poten- additional mutations in other driver genes (other than KIT ), and/or
tially life-threatening comorbidities in SM43,44. Overall, patients with adverse karyotype patterns detected in neoplastic cells, organomegaly
paediatric-onset or adulthood CM and those with non-advanced SM (lymphadenopathy and/or hepatosplenomegaly), age, male sex and
have a favourable prognosis. In general, children have a better progno- resistance to standard antineoplastic therapy used to treat patients
sis as most of these patients have CM. However, in a very few children, with advanced SM, especially KIT-D816V-targeting drugs2–4,11–13,28,63–68.
advanced SM may develop45–49. MCS and MCL have also been described In a recent ECNM registry study, the authors examined the relation-
but are exceptionally rare in children47–49. Regardless of age, mortality ship between sex, cytogenetics and survival in 3,403 patients with
Nature Reviews Disease Primers | (2025) 11:30 3
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