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Mastocytosis

Chapter 366 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Mastocytosis is defined by accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut.
  2. Prevalence is estimated at ~1 in 10,000 people.

  3. 90% of patients carry the KIT D816V mutation; somatic gain-of-function mutations in the stem cell factor receptor (KIT) gene are characteristic.

  4. Cutaneous mastocytosis (CM) is the most common diagnosis in children and indicates disease limited to skin with absence of pathologic infiltrates in internal organs.
  5. Systemic mastocytosis (SM) refers to involvement of an extracutaneous site (most often bone marrow).
  6. Darier's sign: Rubbing or irritation of a mastocytoma lesion may lead to systemic symptoms such as flushing and urticaria.
  7. Diagnosis of Smoldering Systemic Mastocytosis (SSM) requires 2 or more B findings in the absence of any C findings.
  8. Diagnosis of Aggressive Systemic Mastocytosis (ASM) requires 1 or more C findings attributable to high tissue MC infiltration.
  9. Life expectancy for patients with cutaneous mastocytosis and indolent systemic mastocytosis (ISM) is normal.
  10. Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) have a poor prognosis.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Figure / Illustration

1. DEFINITION & OVERVIEW

Mastocytosis is defined by accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut. Diagnostically, mast cell expansion is most readily identified in skin and/or bone marrow. Mastocytosis occurs at any age, although it is most commonly diagnosed in infancy and young adulthood.

1.1 Pathophysiology

Most forms of the disease are characterized by somatic gain-of-function mutations in the stem cell factor receptor (KIT) gene. KIT mutations are observed in patients with all forms of systemic mastocytosis but are also present in some children with cutaneous mastocytosis in lesional skin. Familial occurrence is rare, and atopy is not increased compared with the general population.

2. EPIDEMIOLOGY

The prevalence of mastocytosis is estimated at ~1 in 10,000 people. Most forms of the disease are characterized by somatic gain-of-function mutations in the stem cell factor receptor (KIT) gene, and >90% of patients carry the KIT D816V mutation. Familial occurrence is rare, and atopy is not increased compared with the general population.

3. CLASSIFICATION & PATHOPHYSIOLOGY

A consensus classification for mastocytosis recognizes cutaneous mastocytosis with variants, systemic mastocytosis with five variants, and mast cell sarcoma. Cutaneous mastocytosis is the most common diagnosis in children and indicates disease limited to skin with absence of pathologic infiltrates in internal organs. Systemic mastocytosis (SM) refers to involvement of an extracutaneous site (most often bone marrow).

3.1 Cutaneous Mastocytosis (CM)

Cutaneous mastocytosis is the most common diagnosis in children and indicates disease limited to skin with absence of pathologic infiltrates in internal organs. It is usually diagnosed within the first year of life with demonstration of fixed, maculopapular, polymorphic, and hyperpigmented lesions (known as maculopapular cutaneous mastocytosis [MPCM]), solitary mastocytoma(s), or diffuse cutaneous mastocytosis. Although mast cell accumulation is limited to the skin, children often have systemic symptoms. Systemic mastocytosis (SM) refers to involvement of an extracutaneous site (most often bone marrow).

Table 1 — Table 366-1 Classification of Mastocytosis

Category Subtypes
Cutaneous mastocytosis (CM) Maculopapular cutaneous mastocytosis (MPCM), Solitary mastocytoma of skin, Diffuse cutaneous mastocytosis
Systemic mastocytosis Indolent systemic mastocytosis (ISM), Smoldering systemic mastocytosis, Systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD), Aggressive systemic mastocytosis (ASM), Mast cell leukemia (MCL), Mast cell sarcoma (MCS)

3.2 Systemic Mastocytosis (SM) Variants

There are five distinct variants of SM. Indolent systemic mastocytosis (ISM) accounts for >70% of adult patients. ISM is diagnosed when there is no evidence of organ dysfunction due to mast cell infiltration, an associated hematologic disorder, or mast cell leukemia. Smoldering systemic mastocytosis (SSM) is characterized by high mast cell burden including bone marrow infiltration of >30% and a baseline serum tryptase >200 ng/mL, but absence of systemic mastocytosis associated with clonal hematologic non–mast cell lineage disease (SM-AHNMD) or aggressive systemic mastocytosis (ASM). In SM-AHNMD, the prognosis is determined by the nature of the associated disorder, which can range from dysmyelopoiesis to leukemia. In ASM, mast cell infiltration may occur in multiple organs such as liver, spleen, gut, bone, and bone marrow but not in gastrointestinal tissue or skin. Mast cell leukemia (MCL) is the rarest form of SM and is invariably fatal at present; the peripheral blood contains circulating, metachromatically staining, atypical mast cells. An aleukemic form of MCL is recognized without circulating mast cells when the percentage of high-grade immature mast cells in bone marrow smears exceeds 20% in a nonspicular area. Mast cell sarcoma is a rare solid mast cell tumor with malignant invasive features.

4. CLINICAL FEATURES

The clinical manifestations of SM are due to the release of bioactive substances acting at both local and distal sites, tissue infiltration by mast cells, and the tissue response to the cellular infiltrate. Clinical manifestations include intermittent urticaria, flushing, tachycardia and vascular collapse, gastric acid hypersecretion, crampy lower abdominal pain, and diarrhea. The increased local mast cell burden in the skin (MPCM), bone marrow, and gastrointestinal tract may be a direct cause of pruritus, bone pain, and malabsorption, respectively. Mast cell–mediated fibrotic changes may occur in liver, spleen, and bone marrow resulting in one or more C findings and a poor prognosis. The cutaneous lesions of MPCM are reddish-brown macules, papules, or plaques that respond to trauma with urtication and erythema (Darier's sign). Two distinct forms of MPCM are recognized: polymorphic MPCM and monomorphic MPCM. Children with CM may present with MPCM, mastocytomas, or diffuse cutaneous mastocytosis (DCM). Mastocytomas are generally solitary elevated lesions that are yellow, brown, or red in color. Their size may vary from a few millimeters to several centimeters. Rubbing or irritation of a mastocytoma lesion may lead to systemic symptoms such as flushing and urticaria. Children with DCM present without distinct lesions, but rather a generalized thickening of skin and "peau d'orange" appearance due to diffuse mast cell infiltration. DCM is associated with bullae formation and more severe systemic symptoms, including upper gastrointestinal irritation and vascular collapse in the first few years of life. Maculopapular skin lesions of mastocytosis may be present in patients with adult-onset systemic disease. The apparent incidence of cutaneous lesions is ≥80% in patients with ISM and <50% in those with SM-AHNMD or ASM. In the upper gastrointestinal tract, gastritis and peptic ulcer are significant problems. In the lower intestinal tract, the occurrence of diarrhea and abdominal pain is attributed to increased motility due to mast cell mediators. The periportal fibrosis associated with mast cell infiltration may lead to portal hypertension. In some patients, anaphylaxis may occur with rapid and life-threatening vascular collapse. Anaphylaxis is most commonly induced by Hymenoptera stings and nonsteroidal anti-inflammatory drugs (NSAIDs). The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and "migraine-like" headaches. Patients may experience exacerbation of a specific clinical sign or symptom variably with alcohol ingestion, temperature changes, stress, use of mast cell–interactive opioids, or ingestion of NSAIDs.

4.1 Cutaneous Lesions

The cutaneous lesions of MPCM are reddish-brown macules, papules, or plaques that respond to trauma with urtication and erythema (Darier's sign). Two distinct forms of MPCM are recognized: polymorphic MPCM and monomorphic MPCM. Children with CM may present with MPCM, mastocytomas, or diffuse cutaneous mastocytosis (DCM). Mastocytomas are generally solitary elevated lesions that are yellow, brown, or red in color. Their size may vary from a few millimeters to several centimeters. Rubbing or irritation of a mastocytoma lesion may lead to systemic symptoms such as flushing and urticaria. Children with DCM present without distinct lesions, but rather a generalized thickening of skin and "peau d'orange" appearance due to diffuse mast cell infiltration. DCM is associated with bullae formation and more severe systemic symptoms, including upper gastrointestinal irritation and vascular collapse in the first few years of life.

4.2 Systemic Symptoms

Clinical manifestations include intermittent urticaria, flushing, tachycardia and vascular collapse, gastric acid hypersecretion, crampy lower abdominal pain, and diarrhea. The increased local mast cell burden in the skin (MPCM), bone marrow, and gastrointestinal tract may be a direct cause of pruritus, bone pain, and malabsorption, respectively. Mast cell–mediated fibrotic changes may occur in liver, spleen, and bone marrow resulting in one or more C findings and a poor prognosis. In the upper gastrointestinal tract, gastritis and peptic ulcer are significant problems. In the lower intestinal tract, the occurrence of diarrhea and abdominal pain is attributed to increased motility due to mast cell mediators. The periportal fibrosis associated with mast cell infiltration may lead to portal hypertension. In some patients, anaphylaxis may occur with rapid and life-threatening vascular collapse. Anaphylaxis is most commonly induced by Hymenoptera stings and nonsteroidal anti-inflammatory drugs (NSAIDs). The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and "migraine-like" headaches. Patients may experience exacerbation of a specific clinical sign or symptom variably with alcohol ingestion, temperature changes, stress, use of mast cell–interactive opioids, or ingestion of NSAIDs.

5. INVESTIGATIONS & DIAGNOSIS

Diagnostically, mast cell expansion is most readily identified in skin and/or bone marrow. The life expectancy for patients with cutaneous mastocytosis and for most patients with ISM is normal, whereas that for patients with SM-AHNMD is determined by the non–mast cell component. ASM and MCL have a poor prognosis, while patients with SSM have an intermediate prognosis. Progression from ISM to a more advanced form is uncommon (~5% lifetime risk); however, patients should be monitored for emergence of hematologic disease and end-organ manifestations of ASM. In infants and children with cutaneous manifestations, namely, maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement is usually lacking, and spontaneous resolution is common prior to adolescence. Polymorphic maculopapular cutaneous mastocytosis usually resolves spontaneously. Progression from cutaneous mastocytosis (CM) to ISM may occur in ~10% of children, especially in those with high mast cell burden (diffuse cutaneous mastocytosis) or hematologic abnormalities and those who present with smaller uniform lesions with diameters measuring <2 cm (morphomorphic MPCM).

5.1 Diagnostic Criteria: B and C Findings

Diagnosis of Smoldering Systemic Mastocytosis (SSM) requires 2 or more B findings in the absence of any C findings. Diagnosis of Aggressive Systemic Mastocytosis (ASM) requires 1 or more C findings attributable to high tissue MC infiltration. B Findings (2 or more in the absence of any C findings are required for a diagnosis of SSM): 1. High MC burden: MC infiltration in bone marrow of >30%, basal serum tryptase level >200 ng/mL, and/or KIT D816V >10% VAF in bone marrow. 2. Hypercellular bone marrow with signs of dysmyelopoiesis but without cytopenias meeting C criteria or WHO criteria for an MDS or MPN. 3. Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy (on CT or ultrasound: >2 cm) without impaired liver function or hypersplenism. C Findings (1 or more required for a diagnosis of ASM). C findings should be reasonably attributable to high tissue MC infiltration: 1. Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL. 2. Hepatomegaly with ascites and impaired liver function. 3. Palpable splenomegaly with associated hypersplenism and ascites. 4. Malabsorption with hypoalbuminemia and weight loss. 5. Skeletal lesions: large area(s) of osteolysis with pathologic fractures (presence of osteoporosis alone without osteolytic lesions does not satisfy this criterion).

Table 2 — Table 366-2 B and C Findings for Diagnosis of SSM and ASM

Finding Category Criteria
B Findings (2 or more required for SSM) 1. High MC burden: MC infiltration in bone marrow of >30%, basal serum tryptase level >200 ng/mL, and/or KIT D816V >10% VAF in bone marrow; 2. Hypercellular bone marrow with signs of dysmyelopoiesis but without cytopenias meeting C criteria or WHO criteria for an MDS or MPN; 3. Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy (on CT or ultrasound: >2 cm) without impaired liver function or hypersplenism
C Findings (1 or more required for ASM) 1. Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL; 2. Hepatomegaly with ascites and impaired liver function; 3. Palpable splenomegaly with associated hypersplenism and ascites; 4. Malabsorption with hypoalbuminemia and weight loss; 5. Skeletal lesions: large area(s) of osteolysis with pathologic fractures (presence of osteoporosis alone without osteolytic lesions does not satisfy this criterion)

6. MANAGEMENT & TREATMENT

The clinical manifestations of SM are due to the release of bioactive substances acting at both local and distal sites, tissue infiltration by mast cells, and the tissue response to the cellular infiltrate. Management focuses on symptomatic treatment of systemic symptoms. Discontinuing drugs inducing allergic symptoms affects patients for whom second-line therapies may not be available, are more expensive, or do not provide similar therapeutic benefits. DD protocols allow for the safe reintroduction of first-line therapies, and their use should be extended to all patients in need.

7. PROGNOSIS & COMPLICATIONS

The life expectancy for patients with cutaneous mastocytosis and for most patients with ISM is normal, whereas that for patients with SM-AHNMD is determined by the non–mast cell component. ASM and MCL have a poor prognosis, while patients with SSM have an intermediate prognosis. Progression from ISM to a more advanced form is uncommon (~5% lifetime risk); however, patients should be monitored for emergence of hematologic disease and end-organ manifestations of ASM. In infants and children with cutaneous manifestations, namely, maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement is usually lacking, and spontaneous resolution is common prior to adolescence. Polymorphic maculopapular cutaneous mastocytosis usually resolves spontaneously. Progression from cutaneous mastocytosis (CM) to ISM may occur in ~10% of children, especially in those with high mast cell burden (diffuse cutaneous mastocytosis) or hematologic abnormalities and those who present with smaller uniform lesions with diameters measuring <2 cm (morphomorphic MPCM).

7.1 Prognostic Factors

The life expectancy for patients with cutaneous mastocytosis and for most patients with ISM is normal, whereas that for patients with SM-AHNMD is determined by the non–mast cell component. ASM and MCL have a poor prognosis, while patients with SSM have an intermediate prognosis. Progression from ISM to a more advanced form is uncommon (~5% lifetime risk); however, patients should be monitored for emergence of hematologic disease and end-organ manifestations of ASM.

8. SPECIAL CONSIDERATIONS

In infants and children with cutaneous manifestations, namely, maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement is usually lacking, and spontaneous resolution is common prior to adolescence. Polymorphic maculopapular cutaneous mastocytosis usually resolves spontaneously. Progression from cutaneous mastocytosis (CM) to ISM may occur in ~10% of children, especially in those with high mast cell burden (diffuse cutaneous mastocytosis) or hematologic abnormalities and those who present with smaller uniform lesions with diameters measuring <2 cm (morphomorphic MPCM).

9. KEY PEARLS & CLINICAL TRAPS

Darier's sign is a hallmark clinical feature where rubbing or irritation of a mastocytoma lesion may lead to systemic symptoms such as flushing and urticaria. Anaphylaxis is most commonly induced by Hymenoptera stings and nonsteroidal anti-inflammatory drugs (NSAIDs). The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and "migraine-like" headaches. Patients may experience exacerbation of a specific clinical sign or symptom variably with alcohol ingestion, temperature changes, stress, use of mast cell–interactive opioids, or ingestion of NSAIDs.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Clinical appearance of maculopapular cutaneous mastocytosis lesions (reddish-brown macules, papules,...

Caption: Clinical appearance of maculopapular cutaneous mastocytosis lesions (reddish-brown macules, papules, or plaques) demonstrating Darier's sign (urtication and erythema upon rubbing or irritation).

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.