Mastocytosis is a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in the skin and sometimes in other organs. The summary is: 1. Mast cells are derived from bone marrow precursors and mature in tissues where they play roles in both innate and acquired immunity. 2. Mastocytosis includes cutaneous and systemic forms, with cutaneous forms showing mast cell infiltration of the skin and systemic forms showing infiltration of other organs. 3. Symptoms result from mast cell mediator release and can include skin lesions, gastrointestinal issues, bone pain, and constitutional symptoms. Diagnosis involves skin biopsy, serum tryptase levels, and bone marrow biopsy in systemic forms.

1. MASTOCYTOSIS
DrY SRI HARSHA

2. Introduction
• Mature mast cells are 10μm in size
with a life span of 6 months-1year
• Mature mast cells have prominent
cytoplasmic granules that contain
histamine, and other chemical
mediators, and surface receptors
that bind the Fc portion of IgE with
high affinity
• Mast cell nuclei are round with
surrounding ample cytoplasm
producing a “FRIED EGG”
appearance

3. MAST CELLS

Mast cells are the primary effector cells in immunoglobulin E (lgE)
mediated inflammatory reactions.

Mast cells are widely distributed, long lived cells found predominately in
connective and mucosal tissues and often in proximity to blood
vessels, nerves, and lymphatic tissue

Mast cells are abundant in the skin, respiratory tract, gastrointestinal
tract.

They are implicated in both acquired and innate immune
responses, wound healing, fibrosis, angiogenesis, and autoimmune
diseases.

4. Mast cells have been classified into two types
1. TC mast cells: Mast cells that contain tryptase and chymase are referred
to as TC mast cells (MCTC)

Such cells tend to be located in submucosal tissues.

Increased numbers of these cells are found in fibrotic diseases
2. T mast cells: Mast cells that contain tryptase but not chymase are
referred to as T mast cells(MCT)

are increased in allergic and parasitic diseases and decreased in the
gastrointestinal mucosa in patients affected with HIV


5. Development of Mast cells





Mast cells are derived from pluripotent CD34+ precursor cells in the bone
marrow
complete maturation in vascularized peripheral tissues
c-kit (proto-oncogene) encodes Kit (CD117) : trans membrane tyrosine
kinase receptor for SCF
Cross linking KIT by stem cell factor (SCF) is essential for these precursor
cells to differentiate into mast cells
Other cytokines that regulate SCF-dependent mast cell differentiation
and proliferation include interleukin 13 (lL-13), IL-4,-5, and interferon-ϒ
(lFN-ϒ)

6. Mastocytosis

Definition: A heterogeneous group of disorders characterized by
abnormal growth and accumulation of mast cells in the skin and
sometimes in other organs(bones, GIT, liver, spleen)

Epidemiology:

Age: can present at the time of birth or develop anytime thereafter into
late adulthood

sex: no gender preference and is reported in all races

7. History

The original description of mastocytosis was given by Nettleship and Tay
on a 2 yr old girl with hyper pigmented papules that spontaneously
urticated in 1869

Later in 1877, Paul Ehrlich discovered the mast cell

Unna was the first to demonstrate the mast cells were responsible for the
cutaneous eruption in mastocytosis patients

In 1949, Ellis reported the first patient with systemic disease

8. Etiopathogenesis




Alteration in KIT structure and activity are central to the pathogenesis of
mastocytosis
Somatic point mutations in codon 816 of the c-kit proto-oncogene have been
identified in adult mastocytosis without familial disease which causes
constitutive activation of KIT leading to continued mast cell production(most
commo mutation consists of a substitution of valine for aspartic acid (ASP
816 VAL))
Increased local concentrations of soluble SCF are believed to stimulate mast
cell proliferation, melanocyte proliferation and melanin pigment production.
Impaired mast cell apoptosis has been postulated to be involved as
evidenced by up-regulation of the apoptosis preventing protein BCL-2
demonstrated in patients with mastocytosis

9. PATHOLOGIC EFFECTS OF INCREASED MAST
CELLS

The pathologic changes observed in mastocytosis are the result of the
increased number of mast cells residing within tissues, and the release of
mast cell-dependent mediators within tissues

Mast cell-derived mediators also circulate through the bloodstream and
lymphatic system to produce biologic effects

11. Mastocytosis

1.
There are 2 main categories:
CUTANEOUS MASTOCYTOSIS(CM):
MC infiltrate is confined to one or more lesions on the skin
2.
SYSTEMIC MASTOCYTOSIS(SM):
MC infiltration of at least one extracutaneous organ with or without
evidence of skin involvement

13. SYMPTOMS

The symptoms of SM are usually grouped into 4 categories:
(1) constitutional symptoms : fatigue, weight loss, sweats, and fever
(2) skin symptoms
(3) MC mediator-related symptoms
(4) musculoskeletal symptoms, which include bone, muscle, and joint
pain

15. Skin

Urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis
(MPCM)

Diffuse cutaneous mastocytosis (DCM)

Solitary mastocytoma of the skin

Telangiectasia macularis eruptiva perstans(TMEP)

16. URTICARIA PIGMENTOSA

Commonest form of mastocytosis

Onset: is generally before 2 years of age and a few infants born with few skin
lesions , also seen in adults where it is more chronic and associated with systemic
involvement

Lesion: multiple, monomorphic, oval, yellowish tan to reddish-brown macules
and slightly elevated papules of variable size(1mm to several cm) with a
characteristic border which is not sharp

Site: commonly on trunk but can occur anywhere
central face, scalp, palms and soles are spared

Nodules and plaques are less common

A generalized blistering variety has been reported in patients less than 2 years
which subsides spontaneously by 3-5 years

17. 
Darier’s sign : rubbing of the lesions usually leads to urtication and
erythema over and around the macules( due to local release of histamine
from mast cells )

UP is sometimes associated with pruritus that is exacerbated by
 changes in temperature, local friction, ingestion of hot beverages or
spicy foods, ethanol, and certain drugs

18. URTICARIA PIGMENTOSA

19. Urticaria
pigmentosa
Typical lesions of urticaria pigmentosa in a child.

20. HISTOPATHOLOGY:
Characterized by accumulation of mast cells
in dermis particularly around the blood vessels
Mast cells are basophilic, granular and they
may appear elongated like fibroblast or
cuboidal
In macular and Papular lesions the infiltrate is
relatively sparse and located in the upper
dermis whereas in nodular lesions it is massive
and tumor like
In the bullous variety the blister is sub
epidermal and the blister cavity often contains
numerous eosinophils
The epidemis shows increased melanization

21. DIFFUSE CUTANEOUS
MASTOCYTOSIS







Extremely rare form of CM
Characterized by diffuse infiltration of virtually the entire skin by mast cells
Onset : children younger than 3 years , but also in adults
Lesions: numerous erythematous to yellow tan papules and plaques with
areas of confluence that have a leathery texture
Skin may be normal or thickened with exaggerated skin markings
Large blisters may develop on apparently normal skin spontaneously or
following pressure or mild trauma
Because of enormous mast cell load, serious complications such as
hypotension, shock, GI bleeding, and severe diarrhea may occur

22. Diffuse
cutaneous
mastocytoma
Spontaneous blister in an infant with diffuse cutaneous
mastocytosis.

23. Extensive diffuse skin involvement
Bullous eruption
DIFFUSE CUTANEOUS MASTOCYTOSIS

24. HISTOPATHOLOGY:
• Epidermis shows increased
melanization
• Full-thickness infiltration of
skin or a band like
involvement of the upper
dermis are seen in diffuse
cutaneous mastocytosis

25. SOLITARY MASTOCYTOMA

Onset: before the age of 6 months, but may appear at any age(extremely
rare in adults)

Lesions: solitary, reddish brown or grayish yellow smooth surfaced
plaques or nodules, often lobulated , up to 3-4 cm in diameter

Site: often appear at distal extremities but can occur in any location

Surface may have an orange peel appearance

They may be itchy, tender, or even asymptomatic

Darier’s sign is positive

26. SOLITARY MASTOCYTOMA

27. Histopathology:
• Epidermis shows increased
melanization
• Diffuse, dense interstitial infiltrate
of mast cells around blood vessels
are seen

28. Telangiectasia macularis eruptiva perstans








A rare form of mastocytosis seen < 1% of cases
Age: usually appears in the adults
Lesion: patients develop crops of numerous itchy, ill
defined, telangiectatic, brown macules, 3-8mm in size
Longstanding lesions develop hyperpigmentation
It may co exist with Urticaria pigmentosa
Darier’s sign and dermatographism are present
Associated with bone lesions and peptic ulcers
Site: primarily on the trunk(especially the chest), but also on the extremities

29. Telangiectasia macularis eruptiva perstans

30. Telangiectasia macularis eruptiva
perstans

31. Telangiectasia
macularis eruptiva
perstans
Multiple lesions composed of telangiectasias are present.
Telangiectasia macularis eruptiva perstans

32. HISTOPATHOLOGY:
• Mast cells are brick shaped or
spindle shaped
• The infiltrate tends to be
predominantly perivascular
and there is also vascular
ectasia

33. Systemic mastocytosis(SM)

refers to the condition in which patients have an abnormal increase in
mast cells in non cutaneous tissues

Usual sites affected: bone marrow, liver, spleen, lymph nodes
, GIT, skeletal system but any tissue can be affected

CNS is not effected

Usually seen in adults but rarely seen in children

34. GIT symptoms

Most common chronic symptoms

It includes:
1.
Abdominal pain: pain may be epigastric(due to hypersecretion of
gastric juices due to elevated plasma histamine) or cramping , lower
abdominal pain(due to bowel wall edema)
2.
Diarrhea: episodic (caused by malabsorption, increased motility of the
gut and hypersecretion)
3.
GI hemorrhage: occurs secondary to gastritis or peptic ulcer

35. Skeletal system involvement







Occurs in 70% of patients
It is common in adults , but rare in children
Patients complain of localized bone pain(can be due to osteosclerosis or
osteoporosis)
The proximal long bones, pelvis, ribs, skull are most often effected
Bone marrow is commonly involved in adult patients with mastocytosis
There is increased number of spindle shaped bone marrow with focal
perivascular, peritrabecular and/or intertrabecular accumulations
Scattered lymphocytes and eosinophils have been associated with these mast cells
leading to the term MEL(mast cell, eosinophil, lymphocytes) lesion which helps in
differentiating mastocytosis from other hematological disorders such as
myeloproliferative and myelodysplastic diseases

36. Other features






Hepatomegaly: is reported in up to 72% of patients but is of no consequences
as liver function tests are normal
Fibrosis, portal hypertension, and ascites can result from mast cell infiltration
Splenomegaly is seen in 50-60% of the patients
Lymph node enlargement is seen in patients with advanced systemic disease
Hematological abnormalities like mild normochromic normocytic
anemia, leukocytosis or leukopenia, eosinophilia, monocytosis, and
thrombocytosis are seen(may be due to the involvement of bone marrow)
Systemic mastocytosis may be associated with dysplastic and neoplastic
disorders of myeloid cells

37. Malignant Mastocytosis

A rare condition which may be mistaken for systemic mastocytosis with
or without the cutaneous signs

It is usually associated with a corresponding proliferation of
atypical(malignant) mast cells in the bone marrow

Atypical cells have a larger nuclei, mitotic activity, fewer granules and
increased toluidine metachromasia at a higher ph

Prominent constitutional symptoms, severe peptic ulcer disease, and
hepatosplenomegaly are common features

40. Differential Diagnosis
1. Urticaria pigmentosa:

Histiocytosis

Secondary syphilis

Papular sarcoidasis

Xanthomas

Nevoxantho-endotheliomas
Macular lesions of UP

Pigmented nevi, Multiple lentigens
Bullous lesions of UP

Bullous insect bites, Epidermolysis bullosa, linear IgA disease and early
incontinentia pigmenti

41. Differential Diagnosis
2. Mastocytoma:

Juvenile xanthogranuloma, pigmented nevi and connective tissue nevi
3. TMEP:

Hereditary hemorrhagic telangiectasia

43. Investigations

If the age of onset of mastocytosis is below 5 years , then skin biopsy is sufficient to
determine the diagnosis

If systemic signs are present or later age of onset ,then
1.
A complete blood count(anemia, leukocytosis, thrombocytopenia)
2.
Serum tryptase levels (elevated in mastocytosis)
3.
Bone marrow biopsy
4.
USG Abdomen/CT Scan abdomen ( to rule out liver and spleen pathology)
5.
Radiologic and endoscopic studies of GIT(if GI symptoms are present)
6.
Radiological skeletal survey(if bone pain or h/o of fracture is present)
7.
Liver Function tests
8.
Urinary levels of major histamine metabolites(methylimidazoleacetic acid,MIAA)
9.
Plasma or urinary histamine levels(2-3 times more in pts with mastocytosis)

44. Serum Tryptase Levels



1.
2.
3.

Normal range is 1-15ng/ml
It is slightly elevated in patients with CM’s and isolated bone marrow
mastocytosis
It is significantly elevated(>20ng/ml) in case of multi organ involvement
and also in other conditions like
Acute and chronic myeloid leukemia
Myelodysplastic disorders
During a severe allergic reaction
So, in adult patients with a persistently elevated tryptase, the likelihood
of SM is significant, and a bone marrow examination warranted.

45. Bone marrow biopsy & aspiration

show multifocal, sharply demarcated, compact infiltrates of mast
cells

Mast cells are a mixture of both round and spindle shaped forms

Immunohistochemical and molecular studies are recommended to
distinguish reactive from malignant mast cell infiltrates

46. MCs in Bone marrow

47. Histamine Metabolites detection
MIAA(1,4-methylimidazoleacetic acid) in urine
 Markedly increased, especially in TMEP and SM.

They correlate well with the extent of systemic involvment and their
periodic measurement can be used to monitor disease activity

Other indicators of mast cell degranulation are the mast cell granule
associated tryptase, chronologically elevated urinary metabolite pf
prostaglandin D2 and a prolonged PTT immediately after an attack

48. MANAGMENT
Counseling the patient regarding the nature of the disease
 Avoidance of factors provoking mediator release
 Management of chronic symptoms like pruritis and gastric
hypersecretion (mast cell mediator release symptoms)
 Treatment of acute episodes of vascular collapse
 Cytoreductive therapy to address the sequelae of
disabling organ infiltration by mast cells


49. Factors provocating mediator release








Alcohol intake
Anticholinergic medications
Aspirin
NSAID’S
Heat
Friction
Narcotics (morphine and codeine)
Polymyxin B sulfate

50. Management of mediator release
symptoms






Antihistamines
Corticosteroid
Disodium cromolyn (cromolyn sodium)
Bisphosphonates
UV light irradiation
Epinephrine

51. Anti histamines









H1 receptor antagonists:
classic or non-sedating antihistamines
reduce pruritus and flushing
H2 receptor antagonists:
If H1 is insufficient, especially in cases of gastric hypersecretion
Ex :ranitidine , cimetidine , famotidine
Ketotifen fumarate:(dose :- 1-2 mg/day)
has both antihistamine and mast cell stabilising properties
Effective when combined with ranitidine.

52. 
Disodium cromoglycate (oral cromolyn sodium):

dose:-400-800mg/day

Inhibits mast cell degranulation

may alleviate GI, cutaneous and CNS symptoms

53. UV light irradiation

Psoralen plus UVA (PUVA) can be given 4 times per week

Helps in controlling the pruritis and cutaneous whealing but does not
alter other symptoms associated with this disorder

Photochemotherapy should be used only in instances of extensive
cutaneous disease unresponsive to other forms of therapy

54. 
Corticosteroids:

Topical steroids under occlusion for 6 weeks or more eliminates
pruritis, cutaneous whealing , histamine levels and the no of lesional skin
mast cells

Intralesional injection of Triamcinolone acetonide(30mg/ml) can also be given
to clear mast cell infiltrates in the skin of mastocytosis patients

Systemic corticosteroids can be used in combination with cyclosporine in
patients with aggressive mastocytosis

55.  Specific tyrosine kinase inhibitors


patients who are negative for D816V but have non–codon 816
mutations or wild-type KIT
such as imatinib, or other tyrosine kinase inhibitors

56. Acute episodes of vascular collapse

Treated with self administered premeasured epinephrine
preparations(EPIPEN)

Oral Prednisone(20-40mg/day for 2-4 days) can be given to prevent
recurrence of episodes

57. Cytoreductive therapy

Given for aggressive SM, SM-AHNMD,MCL
1. interferon-α-2b(IFN-α-2b) has been used in treating more aggressive
forms (dose -0.5×106 U/day)

side effects include hypothyroidism, thrombocytopenia, depression
2. Cladribine(2-chlorodeoxyadenosine) IV was effective in eliminating skin
lesions and markedly reducing the no of bone marrow mast cells in patients
with advanced systemic disease

In highly aggressive or relapsed cases : combination chemotherapy
followed by a hematopoietic stem cell transplant should be considered
 cytarabine, fludarabine, and hydroxyurea

58. Bone marrow Transplantation

treatment option for patients with advanced categories of mastocytosis
associated with poor survival in only a few reported instances

may yield a better prognosis if mast cell suppression is attempted prior
to the transplantation

59. Treatment at a glance

61. Prognosis





Patients with CM only have the best prognosis
For children with isolated UP, at least 50% of cases are
reported to resolve by adulthood
UP in adulthood may evolve into systemic disease
Occasionally, ISM converts to SM-AHNMD
The prognosis appears to improve with aggressive
symptomatic management