Mastocytosis

Question 1

What are the differenti categories of

Mastocytosis ?

Answer 1

• Cutaneous mastocytosis
• Systemic mastocytosis
• Mast cell sarcoma

Question 2

What subcategories are listed

under cutaneous mastocytosis ?

Answer 2

• urticaria pigmentosa/maculopapular cutaneous mastocytosis
• diffuse cutaneous mastocytosis
• mastocytoma of the skin

Question 3

What are the different subcategories of

systemic mastocytosis ?

Answer 3

• indolent systemic mastocytosis (including the bone marrow)
• smouldering systemic mastocytosis
• systemic mastocytosis with an associated hematological neoplasm
• aggressive systemic mastocytosis
• mast cell leukemia

Question 4

When can the diagnosis of

systemic mastocytosis be rendered ?

Answer 4

• when the major criterion and at least 1 minor criterion are present
• OR
• when >3 minor criteria are seen

Question 5

What is the basic definition of

Mastocytosis?

Answer 5

• clonal neoplastic proliferation of mast cells that accumulate in one or more organ systems
• disorder can be heterogeneous
  
  • can have skin lesions that spontaneously regress to overtly aggressive systemic disease with poor survival
• Cutaneous mastocytosis
  
  • cellular infiltrate remains localized to the skin
• Systemic mastocytosis
  
  • involement of at least one extracutaneous organ with or witout evidence of skin lesions

Question 6

What must be distinguished in mast cell disease?

Answer 6

• neoplastic vs. mast cell hyperplasia and mast cell activation states
  
  • the reactive mast cells do not have the IHC and molecular abnormalities that the neoplastic ones do

Question 7

What is the epidemiology of mast cell disease ?

Answer 7

• mastocytosis can occur at any age but certain types occur at different time periods
• cutaneous mastocytosis
  
  • more comon in children and can present at birth
  • much less common than adults with slight male predominance
• systemic mastocytosis
  
  • diagnosed after the second decade
  • equal M:F

Question 8

Review localization

p. 62 other notes next slide

Answer 8

• >80% with mastocytosis have skin involvement
• systemic mastocytosis
  
  • BM is always involved
  • rarely have circulating mast cells
  • any tissue can be affected in systenic disease
  • note: aggressive variants usually do not have skin lesions

Question 9

What are key clinical features of

cutaneous mastocytosis ?

Answer 9

• the three types all can urticate when stroked (Darier’s sign)
  
  • intraepidermal accumulation of melanin pigment also occurs
• Urticaria Pigmentosa
  
  • blistering usually in patients < 3 years old
  • but blistering is non-specific

Question 10

What are the 4 clinical groups of

presenting symptoms of

systemic mastocytosis ?

Answer 10

1. Constitutional symptoms
   
   1. fatigue, weight loss, fever, diaphoresis
2. Skin manifestations
   
   1. pruritus, urticaria, dermatographism, flushing
3. Mediator-related systemic events
   
   1. abdmonal pain, GI distres, syncope, headache, hypotension, tachicardia, respiratory symptoms
4. Muskuloskeletal symptoms
   
   1. bone pain, osteopenia/osteoporosis, fractures, arthralgias, and myalgias

Question 11

What physical findings can be seen

at diagnosis in mastocytosis ?

Answer 11

• splenomegaly (often minmal)
• lymphoadenopathy
• hepatomegaly
• Organomegaly is often absent in indolent systemic mastocytosis
  
  • impaired organ function is seen in aggressive systemic mastocytosis

Question 12

What is Mast Cell Activation Syndrome ?

Answer 12

• severe mediator related symptoms occurring in temporal association with increased serum tryptase levels
• this is NOT a subset of systemic mastocytosis
  
  • but it can occur in that setting as well as in other disorders
    
    • including IgE dependent allergic reactions
• diagnosis in some patients does not fulfill criteria for systemic mastocytosis
  
  • but can have clonal mast cells with aberrant CD25 and KIT D816V mutations
  • these are called monoclonal MCAS

IMP: if there is diagnosed systemic mastocytosis it is key to mention MCAS because the symptoms are critical

Question 13

What are the hematological manifestations

of systemic mastocytosis ?

Answer 13

• anemia, leukocytosis, eosinophilia (common), neutropenia and thrombocytopenia
• bone marrow failure can occur in patients with systemic disease
• circulating mast cells are rare and should raise the possibility of mast cell leukemia

Note: in 30% of cases of there is an associated hematological neoplasm

• myeloid neoplasms are more common
• prognosis depends on the hematological disorder and the mastocytosis but outcome usually determined by myeloid neoplasm

Question 14

What is the significance of elevated

serum tryptase levels ?

Answer 14

• elevated serum tryptase levels >20 ng/mL suggests systemic mastocytosis and is one of the minor criterion
  
  • IMP: if there is an associated myeloid neoplasm paramter is not valid
• in cutaneous mastocytosis
  
  • serum tryptase levels are not that elevated

Question 15

Review microscopic findings

p. 64

Question 16

What are morphologic features of

atypical mast cells ?

Answer 16

• marked spindling or hypogranularity
• in high-grade mastocytosis
  
  • cytological atypia is pronounced
  • metachromatic blast cells are often seen in mast cell leukemia
  • bilobed or multilobed mast cells = promastocytes
    
    • generally indicate an aggressive mast cell proliferation
• Mitosis can occur but even in high grade disease are not frequent
• normal morphology can also been seen in neoplastic processes

Question 17

What immunohistochemical findings

are helpful in identifying neoplastic mast cells ?

Answer 17

• tryptase
• CD117
• CD2, CD25 and CD30

Question 18

What is the definition of

cutaneous mastocytosis ?

Answer 18

• need proof of an abnormal mast cell proliferation of the dermis
• no evidence of systemic involvement
  
  • bone marrow, peripheral organs
  • criteria are not met
• can have one or 2 of the minor diagnostic criteria

Question 19

What is the diagnosis of urticaria pigmentosa/

maculopapular cutaneous mastocytosis ?

Answer 19

• most common form
• in kids lesions are larger and more papular than other skin lesions
  
  • in adults lesions are usually disseminated and red-brown
    
    • generally have fewer mast cells
• Microscopically
  
  • aggregates of spindle shaped mast cells filling the papillary dermis with extension into the reticular dermis
  • often perivascular and periadnexal
  • subset in kids can be non-pigmented

Question 20

What is diffuse cutaneous mastocytosis ?

Answer 20

• much less common than urticaria pigmentosa
• presents almost exclusively in childhood
• skin is diffusely thickened and there are no individual lesions
  
  • peau d’orange look
  • can have a band-like infiltrate of mast cells or if massively infiltrated you will see features similar to a mastocytoma

Question 21

What is typically seen in mastocytoma of the skin ?

Answer 21

• single lesion, almost exclusively in children
  
  • may see up to 2-3 lesions
• histology
  
  • usually sheets of mature mast cells in the papillary or reticular dermis
  • may extend into subcutaneous tissue
  • no cytologic atypia which differentiates from mast cell sarcoma

Question 22

What are the major criteria for

systemic mastocytosis ?

Answer 22

• multifocal, dense infiltrates of mast cells
  
  • >15 mast cells per aggregate
  • detected in sections of bone marrow or other extracutaneous organs

Question 23

What are the minor criteria for

systemic mastocytosis ?

Answer 23

• In biopsy sections of BM or other organs
  
  • >25% of mast cells are spindle shaped or have atypical morphology
  • or >25% of mast cells on the aspirate smear are immature or atypical
• Detection of activating point mutation KIT D816V
• Mast cells express CD25 with or without CD2 in addition to normal mast cell markers
• Serum total tryptase >20 ng/mL
  
  • unless there is an associated myeloid neoplasm and then the paramter is not valid

Question 24

What are the B findings

in systemic mastocytosis ?

Answer 24

• high mast cell burden on bone marrow: >30% of total cells and serum tryptase > 200 ng/mL
• signs of dysplasia or myelofproliferation in non-mast cell lineages but criteria are not met for another neoplasm
• hepatomegaly without impairment of liver function, palpable splenomegaly without hypersplenism or lymphoadenopathy on palpation or imaging

Question 25

What are the C symptoms in systemic mastocytosis ?

Answer 25

* bone marrow dysfunction caused by infiltrating mast cells * \>1 cytopenia * absolute neutrophil count \< 1000 * hemoglobin \<10 * platelet count. \<100 * palpable hepatomegaly with impairment of liver function, ascites or portal hypertension * skeletal involvement with osteolytic lesions with or without pathological fractures (not osteoporosis related) * palpable splenomegaly with hypersplenism * malabsorption with weight loss due to GI mast cell infiltration

Question 26

What are the criteria for indolent systemic mastocytosis ?

Answer 26

* meets general criteria for SM * No C findings * No evidence of associated hematological neoplasm * Low mast cell burden * Skin lesions are almost invariably present * KIT D816V is present \>90% Note: they can have one B finding but not more for this category.

Question 27

What are the criteria for bone marrow mastocytosis ?

Answer 27

* similar findings to indolent SM * burden of neoplastic cells is usually low * serum tryptase levels are often normal or nearly normal

Question 28

What is the morphology of bone marrow mastocytosis ?

Answer 28

* generally lesions have a core of small lymphocytes (target lesion) surrounded by polygonal mast cells with pale, faintly granular cytoplasm * reactive eosinophils are at the edges * lesions are usually well circumscribed * can be paratrabecular or perivascular * sometimes randomly distributed in bone marrow IMP: mast cell proliferations induce fibrosis and osteosclerosis

Question 29

What are the criteria for smoldering mastocytosis?

Answer 29

* meets general criteria for SM * \>2 B findings but NO C findings * No evidence of associated hematological neoplasm * High mast cell burden \*\* * does not meet criteria for mast cell leukemia * but progression to aggressive SM or mast cell leukemia can occur * most have sin lesions * most have KIT D816V * mutation is detectable in many lineages

Question 30

What are the criteria for Systemic Mastocytosis with an associated hematological neoplasm ?

Answer 30

* meets general criteria for SM * meets criteria for a secondary neoplasm as a distinct WHO entity * most common is CMML * lymphoid neoplasms such as MM and lymphoma are rare * most cases have the KIT D816V mutation * also present in the myeloid compartment

Question 31

What are the criteria for Aggressive Systemic Mastocytosis ?

Answer 31

* meets the general criteria for SM * \>1 C finding * does not meet criteria for mast cell leukemia * skin lesions are usually absent \*\*\* * mast cell burden * \<20% in bone marrow but \>5% are diagnosed as ASM in transformation * in these cases progression to mast cell leukemia is common * most have the KIT D816V mutation

Question 32

What are the criteria for mast cell leukemia ?

Answer 32

* meets general criteria for SM * BM biopsy with diffuse infiltration by atypical, immature mast cells * BM aspirate smears show \>20% mast cells * mast cells account for \>10% of the PB WBC * aleukemic variant is more common with only rare if any mast cells in the PB * skin lesions are usually absent

Question 33

What are the criteria for a mast cell sarcoma ?

Answer 33

* extremely rare entity * localized destructive growth of mast cells * distant spread occurs in the terminal phase and it can look like mast cell leukemia