Mastocytosis 2022 Flashcards
- A 43-year-old woman with indolent systemic mastocytosis has been experiencing worsening,
generalized pruritus over the past 2-3 months which is not responding to her once daily
fexofenadine (180 mg).
Which cytokine, released by mast cells, has been most strongly implicated in her condition?
A. IL-4
B. IL-13
C. IL-18
D. IL-31
Answer: IL-31
(Pages 1218-9) IL-31 has emerged as a highly pruritogenic cytokine released from mast cells. It has been well documented in associated with atopic dermatitis as well as mastocytosis. IL-4 and IL-13 are part of the Th2 pathway with major role in isotype switching to IgE and are cytokines also released by mast cells. Sharing the common IL-4α receptor subunit they both produce downstream effects on vasculature and mediator function to include histamine, platelet activating factor, and leukotrienes. IL-4 contributes to mast cell proliferation and survival. IL-13 is commonly associated with driving increased mucous production from goblet cells. IL-18, of the IL-1 family of cytokines, acts on mast cells to stimulate production of IL-4 and IL-13.
Chapter 74: Mastocytosis
Middleton’s Allergy Principles and Practice, 9th Edition
- A 7-month-old infant boy presents with concern for food allergy secondary to recurrent
rashes. Routine exam is significant for a 1.6 cm by 1.1 cm reddish-brown, painless nodule on
the child’s left posterior shoulder that exhibits a positive Darier sign. He has no other skin
lesions or hepatosplenomegaly and is otherwise healthy.
What is the most appropriate next step in the management?
A. Obtain a bone marrow biopsy
B. Obtain a skin biopsy
C. Prescribe a low-to-mid potency topical steroid twice daily for two weeks
D. Provide reassurance that the lesion is likely to resolve during childhood
Answer: Provide reassurance that the lesion is likely to resolve during childhood
(Pages 1219, 1224) The vignette provides a classical description of a solitary lesion that urticates within 10 minutes following gentle stroking of the lesion (Darier’s sign). Solitary mastocytomas (SM) often appear at an early age (under 3 months) and spontaneously resolve during childhood. Diagnosis of SM is clinical. Though some practitioners might prefer to have definitive proof via skin biopsy revealing mast cell infiltrate of the papillary dermis, skin biopsy is not necessary and should be weighed against consideration of lesion location, scar formation, and parental concerns. Without other clinical history to suggest systemic symptoms of mast cell degranulation and/or proliferation (eg, cutaneous flushing/pruritus, gastrointestinal abdominal pain/diarrhea/nausea/vomiting, musculoskeletal pain, organomegaly, cognitive impairment and/or anxiety), a bone marrow biopsy would not be indicated to evaluate for systemic mastocytosis. Topical steroids have been used with variable success in hastening the resolution of SM, however, resolution takes months.
Reassurance and monitoring for new lesions, lymphadenopathy, organomegaly, and/or new concerning review of systems is appropriate.
- A 37-year-old man presents for follow-up of anaphylaxis immediately following sting from a
flying insect. A baseline tryptase is 26 ng/mL and he had a bone marrow biopsy completed 1
week ago showing greater than 25% of the mast cells are atypical or spindle-shaped without
evidence of dense aggregates. Polymerase chain reaction (PCR) testing for a D816V KIT
mutation was negative in his serum and marrow.
What additional World Health Organization (WHO) criteria is necessary to make the diagnosis
of systemic mastocytosis?
A. Bone marrow sample detection of CD25+/CD117+ mast cells
B. Evidence of one or more cytopenias (eg, ANC<1.0 x 109
/L, Hb <10 g/dL, and or platelet count
<100 x 109
/L)
C. Hepatomegaly, splenomegaly, or evidence of lymphoproliferation
D. No further criteria needed
Answer: Bone marrow sample detection of CD25+/CD117+ mast cells
(Page 1217) Diagnosis of systemic mastocytosis requires confirmation of either 1 major and 1 minor OR 3 minor criteria as outlined in Box 74.1. This patient lacks major criteria but has (2) minor criteria with ≥25% atypical (or spindle shaped) mast cells in marrow and he has a baseline serum tryptase ≥20 ng/mL. Bone marrow immunohistochemistry showing CD25+ mast cells (CD 117+, normal mast cell marker). Cytopenia is a “C” finding used in differentiating aggressive systemic mastocytosis whereas organomegaly/lymphoproliferation “B” finding of smoldering systemic mastocytosis.
4. Which category of mastocytosis typically has the worst prognosis? A. Aggressive systemic mastocytosis B. Cutaneous mastocytosis C. Indolent systemic mastocytosis D. Mast cell leukemia
Answer: Mast cell leukemia
(Page 1225) Mast cell leukemia has the worst prognosis with mean survival of less than 1 year. In order of more favorable to worst prognosis, the categories of mastocytosis are as follows:
Cutaneous mastocytosis > indolent systemic mastocytosis > aggressive systemic mastocytosis > mast cell leukemia. Systemic mastocytosis with associated hematologic neoplasm has a variable prognosis and often related to the underlying hematologic condition.
- A 3-year-old toddler girl recently diagnosed with diffuse cutaneous mastocytosis has been
experiencing flushing and pruritus symptoms that are not controlled with cetirizine 5 mg taken
once daily.
What is the most appropriate next step in medication management?
A. Disodium cromoglycate (Cromolyn sodium) 100 mg orally up to four times per day
B. Famotidine 0.5-1 mg/kg orally daily
C. Omalizumab 150 mg subcutaneous every 4 weeks
D. Start prednisolone 1-2 mg/kg orally daily for 1 week
Answer: Famotidine 0.5-1 mg/kg orally daily
(Page 1224) Cutaneous mastocytosis symptoms of flushing and pruritus are primarily managed with oral antihistamine. Though individual provider preferences exist, the mainstay of treatment to target pruritus and flushing is some mix of H1 and H2 antagonists. Options include:
• increasing to off label dosing of a single second generation H1 antagonists
• adding a second H1 antagonist (either first or second generation)
• adding a H2 antagonist (eg famotidine) to the H1 regimen
Additionally, a leukotriene modifying agent may be prescribed. Disodium cromoglycate targets gastrointestinal symptoms and is not thought to have significant impact on cutaneous symptoms. Omalizumab is not FDA approved at this age – it is approved for pediatric use in asthma down to age 6 and for chronic spontaneous urticaria down to age 12.
- A 20-year-old man is in for follow-up after being stung on his foot while mowing his lawn. He
recalls feeling lightheaded and within minutes lost consciousness. Medical reports confirm
hypotension as well as lack of any cutaneous findings aside from the erythema over the sting
site. You suspect yellow jacket and order venom IgE testing.
Based on 2016 practice parameter for stinging insect hypersensitivity, what additional
laboratory evaluation is indicated?
A. 24-hour urine histamine
B. Serum cortisol
C. Serum tryptase
D. Total immunoglobulin E
Answer: Serum tryptase
(Pages 1222, 1224; Ch 76 – page 1254) Mastocytosis, particularly indolent systemic mastocytosis, can present with sting anaphylaxis as the inciting feature of the diagnosis. Around 2% of individuals with sting anaphylaxis will have a diagnosis of mastocytosis and up to 10% have some form of mast cell disease. Sting reaction with hypotensive shock without hives, especially in a male, is one indication to screen for mastocytosis. Baseline serum tryptase is the preferred testing and recommended in the 2016 practice parameter update on stinging insect sensitivity and Table 5 in the parameter specifies when it is recommended to measure basal serum tryptase levels (eg severe reaction to a sting, hypotensive reaction, lack of urticarial in a systemic reaction to a sting, systemic reaction to a sting with negative venom IgE test results). Though 24-hour urine antihistamine can be elevated in mast cell disorders, it is less clinically useful in the context of evaluating sting reactions and therefore not part of the practice parameter. Serum cortisol is not part of the evaluation for sting reaction or mastocytosis. The practice parameter addresses total IgE levels in the context of interpretation of serum IgE levels to specific venoms as a ration of the total IgE, though it is not a specific recommendation to routinely obtained total IgE.
- A 31-year-old woman with a baseline tryptase of 5 ng/mL and normal bone marrow biopsy
presents with a history of shortness of breath, throat tightness, and generalized pruritus
approximately 45 minutes after wearing a new brand of face mask as part of her COVID
precautions. In the emergency department her vitals were:
• Temperature 99.1
• Heart Rate: 84
• Blood Pressure 108/74
• Respiratory Rate 14
• Oxygen saturation: 99% in room air
A serum tryptase level was obtained two hours after symptom onset.
What minimum level would strongly support a diagnosis of mast cell activation syndrome?
A. 6 ng/mL
B. 8 ng/mL
C. 10 ng/mL
D. 12 ng/mL
Answer: 8 ng/mL
(Page 1223) Objective biomarkers of mast cell release have focused on tryptase and mature (beta) tryptase. Serum tryptase levels can be measured during a suspected mast cell activation episode with an expected rise from baseline. The consensus recommendation for a clinically significant rise in serum tryptase is an increase in total serum tryptase of at least 20% above baseline plus 2 ng/mL in the 4-hour period following onset of an event, or ≥ (baseline tryptase x 1.2) + 2ng/mL
In the above questions stem [5 ng/mL (1.2) + 2 ng/mL] = 8 ng/mL
- A 52-year-old woman with chronic flushing and pruritus without observable skin lesions who
recently met diagnostic criteria for systemic mastocytosis was found to have
hepatosplenomegaly and bilateral thigh pain on exam. Imaging demonstrates
lymphadenopathy and large osteolytic lesions.
What is her most likely diagnosis?
A. Aggressive systemic mastocytosis
B. Indolent systemic mastocytosis
C. Mast cell sarcoma
D. Smoldering systemic mastocytosis
Answer: Aggressive systemic mastocytosis
(Page 1218) This question requires ability to differentiate “B” and “C” criteria in diagnosis of smoldering systemic mastocytosis and aggressive systemic mastocytosis, respectively. Box 74.2 lists the specific findings. This patient has skeletal involvement/lytic lesions which is one of the “C” findings diagnostics of aggressive systemic mastocytosis so long as there are not features of mast cell leukemia (eg marrow with diffuse infiltration by immature mast cells; marrow aspirate with 20% or more mast cells).
Indolent systemic mastocytosis can have not more than 1 of the “B” findings. If 2 or more “B” findings are present, without any “C” findings, then smoldering systemic mastocytosis is the proper diagnosis so long as there is neither any hematologic neoplasm nor features of mast cell leukemia. Mast cell sarcoma does not have evidence of systemic mastocytosis.
- An 8-year-old girl with a history of intermittent flushing with pruritus, multiple food allergies,
and mild persistent asthma presents with 8 weeks of recurring spontaneous urticaria. Her
family history is positive for idiopathic anaphylaxis in her father as well as atopic dermatitis and
chronic gastrointestinal complaints in her 13-year-old brother, although neither has had any
formal work-up. Her paternal grandmother also had chronic spontaneous urticaria, multiple
drug allergies, and long-standing anxiety. Her baseline serum tryptase level is 14.6 ng/mL.
What is the genetic feature associated with her most likely diagnosis?
A. D816V activating mutation in KIT
B. V617F activating mutation in JAK2
C. Increase in germline copies of TPSAB1
D. Presence of FIP1L1-PDGFRA fusion oncogene
Answer: Increase in germline copies of TPSAB1
Hereditary alpha tryptasemia (HαT) is a recently described inherited condition with a relatively high prevalence that should be suspected in patients with a mix of cutaneous (pruritus, urticarial, flushing), gastrointestinal (GERD, diarrhea), and neurocognitive symptoms (brain fog, anxiety, depression), especially in setting of various allergic conditions (eczema, food allergy, drug allergy, asthma). Patients with HαT most often will have elevated serum tryptase at baseline but not typically >20 ng/mL - threshold level for one of the minor criteria in systemic mastocytosis. HαT can be diagnosed by genetic testing looking specifically at the alpha tryptase copy number which is encoded by the TPSAB1 gene on chromosome 16.
D816V activating mutation in KIT is associated with systemic mastocytosis and monoclonal mast cell activation syndrome. V617F activating mutation in JAK2 is a somatic mutation screened for in patients with suspected myeloproliferative disorder/leukemia. Presence of FIP1L1-PDGFRA fusion oncogene can be seen in cases of idiopathic hypereosinophilic syndrome and eosinophilic leukemia.
- A newly diagnosed 26-year-old man with a D816V KIT positive aggressive systemic mastocytosis presents for follow-up discussion and start of treatment.
Which medication would be the most appropriate to start in this patient?
A. Dasatinib
B. Imatinib
C. Midostaurin
D. Nilotinib
Answer: Midostaurin
(Page 1225) Midostaurin is FDA approved and recommended for treatment of aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis associated with hematologic malignancy. Midostaurin can also be prescribed for systemic mastocytosis (SM), regardless of D816V KIT mutation status. Imatinib, a tyrosine kinase inhibitor, should only be utilized in SM patients lacking the mutation. Dasatinib and Nilotinib are both kinase inhibitors approved for Philadelphia chromosome+ chronic myeloid leukemia but have shown limited effectiveness in Phase I/II trials in patients with systemic mastocytosis.
