42: Mastocytosis Flashcards
What is the hallmark of mastocytosis?
The hallmark of mastocytosis is the pathologic accumulation of mast cells in tissues.
What are the common cutaneous findings in children with mastocytosis?
Common cutaneous findings in children with mastocytosis include hyperpigmented macules, papules, or nodules, and diffuse infiltration of the dermis.
What is the significance of c-kit mutations in mastocytosis?
c-kit mutations, particularly in codon 816, are significant as they lead to amino acid substitutions and cause constitutive activation of KIT, which results in continued mast cell growth and development.
What cytokines are important in regulating mast cell growth and differentiation?
The important cytokines in regulating mast cell growth and differentiation include:
Cytokine | Function |
|———-|———-|
| IL-3 | Signal transduction pathways with SCF, minimal direct effects on proliferation |
| IL-4 | Enhances mast cell function in mature cultures |
| IL-6 | Increases mast cell mediator concentrations |
| IL-9 | Increases the number of mast cells in culture |
| IFN-gamma| Inhibits mast cell proliferation and influences phenotype and function |
What are the common extracutaneous tissues involved in mastocytosis?
The most common extracutaneous tissues involved in mastocytosis include the bone marrow, liver, spleen, and lymph nodes.
What is the typical age of onset for mastocytosis in children?
Most cases of mastocytosis arise in children, with 70% occurring by 6 months of age and 90% by the first 2 years of life.
How does mastocytosis present in children compared to adults?
In children, it typically presents with cutaneous findings such as hyperpigmented macules, papules, or nodules, and most children only have skin involvement. In contrast, adults are more likely to have systemic disease.
What role do c-kit mutations play in mastocytosis, particularly regarding codon 816?
Mutations in c-kit, specifically in codon 816, lead to amino acid substitutions that cause constitutive activation of KIT. This results in continued mast cell growth and development.
How do cytokines influence mast cell growth and differentiation in mastocytosis?
Cytokines play a crucial role in regulating mast cell growth and differentiation:
Cytokine | Effect on Mast Cells |
|———-|———————|
| IL-3 | Minimal direct effects on proliferation, important in early cultures |
| IL-4 | Enhances mast cell function in mature cultures |
| IL-6 | Increases mast cell mediator concentrations |
| IL-9 | Increases the number of mast cells in culture |
| IFN-gamma| Inhibits mast cell proliferation and influences phenotype and function |
What are the common clinical manifestations of cutaneous mastocytosis (CM) in children?
Children with cutaneous mastocytosis (CM) commonly present with urticaria pigmentosa (UP), which appears as tan to brown papules or macules, ranging from 1.0 to 2.5 cm in size.
What are the differences in cutaneous lesions between children and adults with mastocytosis?
The cutaneous lesions in children and adults with mastocytosis differ in size and appearance:
Age Group | Lesion Characteristics |
|———–|———————–|
| Children | Tan to brown papules and macules, 1.0 to 2.5 cm in diameter, often on the trunk. |
| Adults | Smaller reddish-brown macules and papules (approximately 5 mm or less), with variable hyperpigmentation and fine telangiectasias, most numerous on the trunk and proximal extremities. |
What is the significance of Darier sign in mastocytosis?
Darier sign is a reaction that occurs when skin lesions are scratched or rubbed, leading to urtication and erythema. This sign is readily demonstrated in childhood urticaria pigmentosa (UP) and mastocytomas.
What hematologic disorders are associated with systemic mastocytosis with associated clonal hematologic non-mast-cell-lineage disease (SM-AHNMD)?
Hematologic disorders associated with SM-AHNMD include:
- Polycythemia rubra vera
- Chronic myeloid leukemia
- Chronic myelomonocytic leukemia
- Idiopathic myelofibrosis
- Chronic eosinophilic leukemia
- Hypereosinophilic syndrome
- Acute and chronic lymphocytic leukemia
- Non-Hodgkin and Hodgkin lymphoma
What are the clinical manifestations of cutaneous mastocytosis (CM) in children, and how do they differ from those in adults?
In children, cutaneous mastocytosis (CM) is primarily manifested as urticaria pigmentosa (UP), which appears as tan to brown papules or macules, ranging from 1.0 to 2.5 cm in diameter. In contrast, adult cutaneous lesions are smaller (approximately 5 mm or less), reddish-brown macules and papules.
What is the significance of Darier sign in the context of mastocytosis?
Darier sign is a reaction that occurs when scratching or rubbing skin lesions leads to urtication and erythema. This sign is readily demonstrated in childhood urticaria pigmentosa (UP) and mastocytomas.
What hematologic disorders are associated with systemic mastocytosis with an associated clonal hematologic non-mast-cell-lineage disease (SM-AHNMD)?
Hematologic disorders associated with SM-AHNMD include:
- Polycythemia rubra vera
- Chronic myeloid leukemia
- Chronic myelomonocytic leukemia
- Idiopathic myelofibrosis
- Chronic eosinophilic leukemia
- Hypereosinophilic syndrome
- Acute and chronic lymphocytic leukemia
- Non-Hodgkin and Hodgkin lymphoma
A child presents with tan-brown nodules on the distal extremities that urticate upon rubbing. What is the likely diagnosis and its typical onset age?
The likely diagnosis is solitary mastocytomas, which are tan-brown nodules that frequently appear on the distal extremities. Their onset is generally before 6 months of age.
What explains the difference in lesional skin reactivity between children and adults with cutaneous mastocytosis (CM)?
Mast cell concentrations in mastocytomas and childhood urticaria pigmentosa (UP) are 150 to 40 fold greater than in normal skin, while in adult mastocytosis, mast cell concentrations are only 8 fold greater than controls.
What are the common symptoms and signs of mastocytosis?
Symptoms and signs of mastocytosis may include:
- Pruritus
- Flushing
- Diarrhea
- Abdominal pain
- Nausea
- Bloating
- Vomiting
- Gastric reflux
- Palpitations
- Dizziness
- Syncope
What are the potential triggers that can exacerbate symptoms of mastocytosis?
Symptoms of mastocytosis can be exacerbated by:
- Exercise
- Heat
- Local trauma to skin lesions
What is the significance of gastrointestinal (GI) symptoms in adults with mastocytosis?
GI symptoms in adults with mastocytosis range from 25% to 70%, with diarrhea being the most common symptom. This may result from gastric hypersecretion, increased motility, and/or malabsorption.
What is Diffuse Cutaneous Mastocytosis (DCM) and its characteristics?
Diffuse Cutaneous Mastocytosis (DCM) is seen almost exclusively in infants and may persist into adult life. The skin often has a peau d’orange appearance and yellowish-brown discoloration.
What are the common symptoms associated with mastocytosis, particularly in children with diffuse cutaneous mastocytosis (DCM)?
Symptoms may include pruritus, flushing, diarrhea, abdominal pain, nausea, bloating, vomiting, gastric reflux, palpitations, dizziness, and syncope.
How can trauma to mastocytomas affect systemic symptoms in patients?
Trauma to mastocytomas can lead to systemic symptoms such as flushing and hypotension.
What is the significance of total serum tryptase levels in the diagnosis of mastocytosis?
Total serum tryptase levels of >20 ng/mL are considered abnormal and represent one of the minor criteria for systemic mastocytosis (SM).
What neuropsychiatric abnormalities are associated with mastocytosis?
Neuropsychiatric abnormalities in mastocytosis may include decreased attention span, memory impairment, headache, and irritability.
What is the major urinary metabolite of histamine that is often elevated in systemic mastocytosis patients?
The major urinary metabolite of histamine that is often persistently elevated in systemic mastocytosis patients is 1,4-methylimidazole acetic acid.
What foods should be avoided during the collection of urinary histamine metabolites in mastocytosis patients?
Foods high in histamine content, such as spinach, eggplant, cheeses (e.g., Parmesan, Roquefort, and blue), and red wines, should be avoided.
What are the WHO criteria for systemic mastocytosis (SM)?
The WHO criteria for SM include:
- Bone marrow findings of multifocal dense mast cell aggregates
- Atypical mast cell morphology
- Expression of CD2 and/or CD25 by bone marrow mast cells.
What is the role of bone marrow biopsies in the diagnosis of mastocytosis?
Bone marrow biopsies are indicated for patients suspected of having more advanced disease forms such as SM-AHNMD, ASM, and MCL.
What percentage of mastocytosis patients experience musculoskeletal pain?
Musculoskeletal pain affects 19% to 28% of mastocytosis patients.
What are the common skeletal lesions observed in patients with systemic mastocytosis (SM)?
Skeletal lesions in patients with SM may appear as radiopacities, radiolucencies, or a mixture of both, with the skull, spine, and pelvis being the most commonly involved areas.
What is the significance of total serum tryptase levels in the diagnosis of mastocytosis, and how often should they be measured?
Total serum tryptase levels of >20 ng/mL are considered abnormal and represent one of the minor criteria for systemic mastocytosis.
What are the common skeletal lesions observed in mastocytosis patients?
Common skeletal lesions include radiopacities, radiolucencies, or a mixture of both, primarily affecting the skull, spine, and pelvis.
What percentage of mastocytosis patients experience musculoskeletal pain?
Musculoskeletal pain affects 19% to 28% of mastocytosis patients.
What is the significance of total serum tryptase levels in the diagnosis of mastocytosis?
Total serum tryptase levels of >20 ng/mL are considered abnormal and represent one of the minor criteria for systemic mastocytosis (SM). Serial measurements should be taken every 6 to 12 months to monitor disease progression.
How do neuropsychiatric abnormalities relate to mastocytosis?
Neuropsychiatric abnormalities in mastocytosis may include decreased attention span, memory impairment, headache, and irritability. Additionally, depression may occur as a consequence of chronic disease or due to mast cell mediators.
What role do urinary histamine metabolites play in the diagnosis of mastocytosis?
Determinations of urinary histamine metabolite levels may be useful in diagnosing mastocytosis, especially in patients without cutaneous lesions. The major urinary metabolite, 1,4-methylimidazole acetic acid, is often persistently elevated in systemic mastocytosis patients and correlates with the extent of mast cell disease.
What are the WHO criteria for systemic mastocytosis?
The WHO criteria for systemic mastocytosis include findings of multifocal dense mast cell aggregates, atypical mast cell morphology, and the expression of CD2 and/or CD25 by bone marrow mast cells, indicating more advanced disease.
What diagnostic steps should be taken for a patient with unexplained osteoporosis and vertebral fractures?
The diagnosis of mastocytosis should include radiographs of the skull, spine, and pelvis to detect bone involvement. Additionally, a bone marrow biopsy is indicated to check for multifocal dense mast cell aggregates, atypical mast cell morphology, and the expression of CD2 and/or CD25 by bone marrow mast cells. Total serum tryptase levels (>20 ng/mL) and urinary histamine metabolite levels should also be evaluated.
What is the likely cause of cognitive disorganization and memory impairment in a patient with mastocytosis?
The likely cause is neuropsychiatric abnormalities associated with mastocytosis, potentially mediated by mast cell mediators.
What does elevated urinary levels of 1,4-methylimidazole acetic acid indicate?
Elevated levels of 1,4-methylimidazole acetic acid, the major urinary metabolite of histamine, indicate an increased mast cell burden and are diagnostic of systemic mastocytosis (SM).
What are the most commonly affected bones in mastocytosis patients with skeletal lesions?
The most commonly affected bones are the proximal long bones, skull, spine, ribs, and pelvis.
What does a serum tryptase level of 25 ng/mL indicate in a patient with mastocytosis?
A serum tryptase level >20 ng/mL is considered abnormal and represents one of the minor criteria for systemic mastocytosis (SM). It also provides an estimate of the overall mast cell burden.
What is the likely cause of worsening symptoms after consuming red wine and cheese in a patient with mastocytosis?
The likely cause is the high histamine content in red wine and cheese, which can exacerbate mastocytosis symptoms.
What are the initial diagnostic tests recommended for adolescents or adults with suspected mastocytosis?
The initial diagnostic tests include a complete blood count (CBC) with differential, liver function test, total serum tryptase level, and skeletal radiographs.
What are the first-line treatment options for cutaneous mastocytosis?
The first-line treatment options for cutaneous mastocytosis include topical glucocorticoids, avoidance of triggering factors such as heat, friction, or drugs, and H1 and H2 antihistamines.
What should be investigated if the CBC becomes abnormal in an adult patient with mastocytosis?
If the CBC becomes abnormal in an adult patient, the cause of this abnormality should be investigated by examining the bone marrow.
What systemic anesthetic agents should be avoided in patients with mastocytosis?
Systemic anesthetic agents that should be avoided in patients with mastocytosis include systemic lidocaine, D-tubocurarine, metocurine, etomidate, thiopental, succinylcholine hydrochloride, enflurane, and isoflurane.
What potential mast cell degranulating agents should mastocytosis patients avoid?
Mastocytosis patients should avoid potential mast cell degranulating agents such as ingested alcohol, anticholinergic preparations, aspirin, NSAIDs, narcotics, and polymyxin B sulfate. Additionally, heat and friction should also be avoided as they can induce local or systemic symptoms.
What laboratory tests are necessary for diagnosing mastocytosis in adolescents or adults with noncutaneous symptoms?
A complete blood count (CBC) with differential, liver function test, total serum tryptase level, and skeletal radiographs are necessary for diagnosing mastocytosis in adolescents or adults with noncutaneous symptoms.
What precautions should mastocytosis patients take regarding medications and environmental factors?
Mastocytosis patients should avoid potential mast cell degranulating agents such as ingested alcohol, anticholinergic preparations, aspirin, NSAIDs, narcotics, and polymyxin B sulfate. Additionally, they should avoid heat and friction, which can induce local or systemic symptoms.
What are the safe alternative systemic anesthetics for mastocytosis patients?
The safe alternative systemic anesthetics for mastocytosis patients include fentanyl, sufentanil, remifentanil, paracetamol, midazolam, propofol, ketamine, desflurane, sevoflurane, cis-atracurium, pancuronium, and vecuronium bromide.
What is the role of H1 antihistamines in the treatment of mastocytosis?
Chronic administration of H1 antihistamines is often helpful in reducing cutaneous symptoms and gastrointestinal (GI) symptoms. Second-generation H1 antihistamines like cetirizine, loratadine, and fexofenadine have advantages over first-generation due to their longer half-lives and more specific activity on the H1 receptor.
What are the potential benefits of using H2 antihistamines in mastocytosis patients?
H2 antihistamines may be beneficial in patients with symptoms of gastric acid hypersecretion and malabsorption, as well as controlling pruritus, flushing, and wheal formation when administered with an H1 agent.
What is the significance of using Omalizumab in mastocytosis treatment?
Omalizumab is a monoclonal antibody against immunoglobulin E that has proven effective in reducing or eliminating symptoms of mastocytosis in adults who are recalcitrant to antihistamines and leukotriene inhibitors. Effective doses range from 150 to 450 mg/month.
What precautions should be taken when using Doxepin in mastocytosis patients?
Doxepin should be used with caution in older patients and those with a history of cardiac arrhythmias, renal insufficiency, or hepatic disease due to its potential to cause cardiac QT interval prolongation.
What are the advantages of using second-generation H1 antihistamines over first-generation antihistamines in the treatment of mastocytosis?
Second-generation H1 antihistamines have distinct advantages over first-generation antihistamines due to their longer half-lives and more specific activity on the H1 receptor, which can lead to more effective symptom control.
How do H2 antihistamines assist in the management of mastocytosis symptoms?
H2 antihistamines may help manage symptoms of gastric acid hypersecretion and malabsorption, as well as assist in controlling pruritus and flushing. If GI symptoms persist despite H2 antihistamine use, proton pump inhibitors may be effective.
What role does Omalizumab play in the treatment of mastocytosis?
Omalizumab is effective in reducing or eliminating symptoms of mastocytosis in adults who are resistant to antihistamines and leukotriene inhibitors. Effective doses range from 150 to 450 mg per month.
What are the potential risks associated with low-dose aspirin use in patients with mastocytosis?
Low-dose aspirin can reduce symptoms like flushing and tachycardia in some patients, but it must be used with caution in those with a history of NSAID intolerance, as it may cause vascular collapse and exacerbate peptic ulcer disease.
What alternative treatments can be considered for a patient with mastocytosis experiencing severe flushing and tachycardia after taking aspirin?
Alternative treatments include chronic administration of H1 antihistamines, H2 antihistamines, leukotriene inhibitors, and omalizumab. Low-dose aspirin should be avoided in patients with NSAID intolerance.
What topical treatment can be considered for a patient with mastocytosis experiencing persistent pruritus and whealing?
Potent topical glucocorticoids applied daily under occlusion for 8 to 12 weeks can reduce the number of cutaneous lesions. However, this treatment is impractical for diffuse skin involvement, and lesions often recur after discontinuation.
What alternative medication can be used for GI symptom relief in a patient with mastocytosis intolerant to H1 antihistamines?
Ketotifen and azelastine, which have potential mast cell-stabilizing properties, can be used to relieve GI symptoms.
What medication should be used with caution in a patient with mastocytosis and a history of cardiac arrhythmias?
Doxepin should be used with caution due to its potential to cause cardiac QT interval prolongation.
What is the mechanism behind vascular collapse after taking NSAIDs in patients with mastocytosis?
The mechanism involves mast cell mediator release triggered by NSAIDs. Management includes avoiding NSAIDs and using alternative treatments like H1 and H2 antihistamines or leukotriene inhibitors.
What combination of medications can be used for symptom control in a patient with mastocytosis experiencing severe pruritus and flushing?
A combination of H1 antihistamines and H2 antihistamines can be used to control pruritus and flushing.
What is the next step in management for a patient with mastocytosis who has persistent GI symptoms despite H2 antihistamine use?
If GI symptoms persist, proton pump inhibitors may be effective.
Why is topical glucocorticoid therapy impractical for a patient with mastocytosis and diffuse skin involvement?
Topical glucocorticoid therapy is impractical for diffuse skin involvement because it requires daily application under occlusion for 8 to 12 weeks, and lesions often recur after discontinuation.
What medication can be cautiously used to reduce flushing and tachycardia in a patient with mastocytosis and a history of NSAID intolerance?
Low-dose aspirin can be used cautiously, but it must be avoided in patients with a history of NSAID intolerance due to the risk of vascular collapse.
What medication can be used cautiously to reduce flushing and tachycardia in mastocytosis?
Low-dose aspirin (500 mg twice daily) can be used cautiously, but it must be avoided in patients with a history of NSAID intolerance due to the risk of vascular collapse.
What is the mechanism of vascular collapse after NSAID use in mastocytosis, and how should it be managed?
The mechanism involves mast cell mediator release triggered by NSAIDs. Management includes avoiding NSAIDs and using alternative treatments like H1 and H2 antihistamines or leukotriene inhibitors.
What combination of medications can be used for symptom control in a patient with mastocytosis experiencing severe pruritus and flushing?
A combination of H1 antihistamines (e.g., cetirizine, loratadine) and H2 antihistamines (e.g., ranitidine, famotidine) can be used to control pruritus and flushing.
What is the recommended treatment for osteoporosis in patients with mastocytosis?
Osteoporosis should be treated with calcium and vitamin D supplementation along with bisphosphonates as needed to maintain normal bone density.
What is the prognosis for pediatric-onset cutaneous mastocytosis?
Pediatric-onset cutaneous disease has a favorable prognosis with 45% to 68% of patients experiencing complete disease regression with a median follow-up of 15 to 20 years.
What are the implications of having detectable D816V mutations in adult mastocytosis patients?
Detectable D816V mutations in non-mast cell populations are considered a poor prognostic finding in adult mastocytosis patients.
What is the prognosis for patients with MCL (mast cell leukemia)?
The prognosis for MCL is poor, with a mean survival of less than 1 year.
What treatment should be considered for patients with SM-AHNMD, ASM, MCL, or mast cell sarcoma?
Cytoreductive therapy should be considered in patients with SM-AHNMD, ASM, MCL, or mast cell sarcoma.
How does the prognosis of SM-AHNMD patients with ASXL1 mutations compare to those with wild-type ASXL1?
SM-AHNMD patients who express a mutation in the ASXL1 gene have a poorer overall survival than those who express wild-type ASXL1.
What is the recommended management for patients with recurrent episodes of anaphylaxis in mastocytosis?
Patients with recurrent episodes of anaphylaxis should receive continuous H1 and H2 antihistamines to lessen the severity of attacks.
What are the implications of recurrent episodes of anaphylaxis in mastocytosis patients?
Patients with recurrent episodes of anaphylaxis should receive continuous H1 and H2 antihistamines to lessen the severity of attacks. Episodes may be spontaneous or triggered by insect stings or iodinated contrast media.
How does the prognosis differ between patients with smoldering SM and ISM?
Patients with ISM who have evidence of hepatosplenomegaly, lymphadenopathy, and/or serum tryptase levels of >200 ng/mL are referred to as smoldering SM, which has a less favorable prognosis compared to the ISM group.
What are the additional poor prognostic findings in adult mastocytosis patients?
Additional poor prognostic findings include:
1. Detectable D816V mutations in non-mast cell populations.
2. Expression of one or more non-c-kit gene mutations (e.g., TETS, SRSF2, ASXL1, ASCL1, RUNXI, and CBL).
What is the prognosis and classification of a 50-year-old patient with systemic mastocytosis (SM) who has elevated serum tryptase levels and hepatosplenomegaly?
The condition is classified as smoldering systemic mastocytosis (SM). The prognosis is less favorable than indolent systemic mastocytosis (ISM), especially if serum tryptase levels exceed 200 ng/mL.
What preventive measures should be taken for a patient with mastocytosis who has a history of recurrent anaphylaxis?
Preventive measures include continuous administration of H1 and H2 antihistamines to lessen the severity of attacks. Patients should also avoid triggers such as insect stings and iodinated contrast media.
How does an ASXL1 gene mutation affect prognosis in a patient with systemic mastocytosis (SM)?
The presence of an ASXL1 gene mutation is associated with poorer overall survival in patients with systemic mastocytosis (SM).
What is the classification of a patient with mastocytosis who has a serum tryptase level of 200 ng/mL and lymphadenopathy?
The condition is classified as smoldering systemic mastocytosis (SM), which has a less favorable prognosis than indolent systemic mastocytosis (ISM).
What medications should be administered continuously for a patient with mastocytosis who has a history of recurrent anaphylaxis?
Continuous administration of H1 and H2 antihistamines is recommended to lessen the severity of anaphylactic attacks.
What are the possible consequences of histamine release from mast cells?
- Hypotension
- Flushing
- Urticaria
- Abdominal pain (peptic, colic, nausea, vomiting, diarrhea, malabsorption)
- CNS symptoms
What are the first-line treatments for gastrointestinal symptoms in noncutaneous mastocytosis?
Treatment | Description |
|———–|————-|
| H1 antihistamines | Block histamine effects |
| H2 antihistamines | Reduce gastric acid secretion |
| Oral cromolyn | Stabilizes mast cells, used in children |
What is the algorithm for diagnosing new-onset mastocytosis based on mast cell mediator symptoms?
- Assess for skin findings: Hyperpigmented papules, macules, or solitary nodules.
- Skin biopsy of lesion: Check CBC with differential, serum tryptase levels, and skeletal radiographs.
- Evaluate serum tryptase: Look for hepatosplenomegaly and other abnormalities.
- Bone marrow biopsy: If abnormalities are found, follow clinically.
- Consider systemic mastocytosis classification if criteria are met.
What are the second-line treatments for cardiovascular symptoms in noncutaneous mastocytosis?
Treatment | Description |
|———–|————-|
| Proton pump inhibitors | Reduce gastric acid secretion |
| Oral glucocorticoids | Used for prophylaxis |
| Leukotriene antagonist | Block leukotriene effects |
| Anticholinergics | Reduce gastrointestinal motility |
What are the newly synthesized mediators from mast cells and their effects?
Mediator | Effect |
|———-|——–|
| Leukotrienes | Increased vascular permeability, bronchoconstriction, vasodilation |
| Prostaglandins | Vasodilation, bronchoconstriction |
How does the presence of elevated tryptase levels influence the diagnostic evaluation of new-onset mastocytosis?
Elevated tryptase and/or urinary histamine metabolites indicate a higher likelihood of systemic mastocytosis, necessitating further evaluation such as a CBC with differential, LFTs, and possibly a bone marrow biopsy.
What is the significance of bone marrow biopsy in the diagnostic evaluation of mastocytosis?
A bone marrow biopsy is crucial for confirming systemic mastocytosis, especially when there are abnormal findings in serum tryptase, CBC, or LFTs, and it helps classify the disease according to WHO criteria.
What second-line treatment options are available for cardiovascular symptoms in noncutaneous mastocytosis?
- Proton pump inhibitors
- Oral glucocorticoids (prophylaxis)
- Leukotriene antagonists
- H1 and H2 antihistamines
- Subcutaneous epinephrine (for anaphylaxis)
