Mastocytosis is a disease characterized by proliferation and accumulation of apparently normal mast cells in the skin and occasionally, in other organs. It can occur in two forms – cutaneous and systemic. Cutaneous (skin) mastocytosis constitutes 90 percent of cases of mastocytosis that are not associated with a hematologic disorder (Gruchalla, 1995 as cited by Alto and Clarcq, 1999). Types of cutaneous mastocytosis include solitary mastocytoma, diffuse erythrodermic mastocytosis, paucicellular mastocytosis and urticaria pigmentosa. Urticaria pigmentosa is the most common type and is characterized by oval or round red-brown macules, papules, or plaques that range in number from a few to thousands (Hogan and Lewis, 2006). The macules initially appear at the trunk and rapidly spread symmetrically and centripetally (Alto and Clarcq, 1999). The palms, soles, face and scalp are the parts not usually affected. Exposure to certain environmental stimuli such as heat, cold or pressure usually results to localized urticaria (Darier’s sign). When the macules heal, they usually do not produce any scarring unless superinfection occurs.
While cutaneous mastocytosis involve only the skin, systemic mastocytosis is characterized by mast cell infiltration of extracutaneous organs (Krishnan and Ramu, 2006). Before 1949, mastocytosis was thought to manifest only in the skin. Ellis was the first to establish an autopsy proving that the disease also involved other organs. An autopsy of a 1-year-old infant revealed that mastocytosis occurred in the bone marrow, lymph nodes, spleen, kidneys and pancreas. At present, mast cell infiltration has also been observed in the kidney and in the gastrointestinal (GI) tract.
The most obvious manifestation of mastocytosis is the appearance of macules, papules, nodules and plaques in the skin. Mast cells however produce chemicals (histamine being one of the most significant) that change the body’s functioning and a large number of mast cells in the body result in abdominal pain, vomiting and diarrhea severe enough to cause malabsorption (Alto and Clarcq, 1999). Headache, hypotension leading to syncope, bleeding diathesis, peptic ulcer and even psychological changes such as irritability and difficulty in concentrating are also symptoms associated with the disorder. In patients with systemic mast cell disease, GI symptoms are usually exhibited. Abdominal pain is the most common GI symptom, while diarrhea, nausea and vomiting follow abdominal pain in rank, respectively (Krishnan and Ramu, 2006). There are also symptoms and signs of gastroesophageal reflux disease noted in some cases. Symptoms of pruritus and flushing and signs of urticaria are also exhibited especially when the mast cell accumulation is associated with cutaneous abnormalities. If the skeletal system is involved, mastocytosis can be manifested as bone pain or the onset of a new bone fracture (Hogan and Lewis, 2006). Involvement of the central nervous system may result in neuropsychiatric symptoms and in nonspecific changes such as malaise or irritability.
Systemic mast cell disease has also been associated with a number of hematologic diseases, including hypereosinophilic syndrome, Castleman disease, monoclonal gammopathy, and hairy cell leukemia. Certain hematologic disorders such as non-Hodgkin lymphoma, polycythemia vera and primary thrombocythemia occur in conjuction with systemic mastocytosis (Krishnan and Ramu, 2006). Hematologic manifestations in fact make the diagnosis of mastocytosis possible. In systemic mast cell disease, the peripheral blood picture shows anemia, leucopenia, thrombocytopenia, and lymphopenia, with anemia being the most common abnormality. In some patients, these hematologic diseases have also been found: eosinophilia, leukocytosis, basophilia, thrombocytosis and monocytosis.
Assessment of certain factors or results in the laboratory also aids in the diagnosis of mastocytosis. Urticaria pigmentosa can be diagnosed when history and physical examination reveal the characteristic lesions that demonstrate the Darier sign (Hogan and Lewis, 2006). A skin biopsy should however be done in order to confirm the diagnosis of mastocytosis since Darier sign is not pathognomonic (Alto and Clarcq, 1999). Anaesthesizing the skin should be done by injecting a local anaesthetic without epinephrine below the biopsy site and not directly into it. When direct trauma or epinephrine is applied, the mast cells are degranulated making their identification more difficult. Special stains such as toluidine blue, Giemsa or fluorescein isothiocyanate-avidin are required because routine histological staining may not clearly reveal the excess number of mast cells (Miner, 1991 as cited by Alto and Clarq; Alto and Clarcq, 1999).
Because histamine is usually released by mast cells, an accumulation of mast cells produce elevated levels of histamine in the blood. Unusually high levels of histamine may also be revealed in the urine if it contains high level of histamine metabolites (products) as well as metabolites of prostaglandin D2 (“Mastocytosis”, n.d.). There are also other tests for elevated mast cell mediators and degradation products that aids in ascertaining the diagnosis of mastocytosis. Serum tryptase levels should be tested because these are elevated in patients with mastocytosis (Hogan and Lewis, 2006). Testing for tryptase levels is actually more useful than histamine levels, because histamine can be elevated during hypereosinophilic state. Urinary N-methylhistamine (NMH) and N-methylimidazoleacetic acid levels are also more specific and sensitive than urinary histamine levels. Furthermore, levels of NMH are directly correlated with the extent of skin lesions. Urinary prostaglandin levels are also important basis in diagnosing mastocytosis. Even during asymptomatic periods, urinary prostaglandin levels may range from 1.5-150 times higher than normal levels.
In patients with suspected systemic mastocytosis, bone marrow aspiration and biopsy are essential tests. These tests are also performed when their peripheral blood test shows abnormalities such as hepatomegaly, splenomegaly, or lymphadenopathy to determine if they have an associated hematologic disorder (Hogan and Lewis, 2006). Bone densitometry is also performed especially to elderly patients to determine whether osteoporosis is present. Osteoporosis in individuals who have mastocytosis is believed to be secondary to elevated prostaglandin D2 and heparin levels (Alto and Clarcq, 1999). When GI symptoms are present, especially when these are unresponsive to treatment, endoscopy is strongly recommended. Liver biopsy is also done to patients with hepatomegaly to gather evidence of mast cell infiltration (Krishnan and Ramu, 2006).
Histologic examination of mastocytosis patients reveal dermal mast cell infiltrates especially in the papillary dermis around the blood vessels (Hogan and Lewis, 2006). A typical mast cell contains a spindle-shaped nucleus and fine eosinophilic granules which can be seen at high magnification (Krishnan and Ramu, 2006). Such cells are likely to be identified by Geimsa or toluidine blue staining. Other stains used to identify mast cells are chloroacetate asterase, aminocaproate asterase, and tartrate-resistant acid phosphatase.
Histologic findings have also shown spleen and lymphoid involvement in systemic mast cell disease. Mast cell accumulation in the spleen can cause nodular areas that could be confused with lymphomas. Biopsy specimen from the spleen shows findings similar to myeloproliferative disorder or hair cell leukemia (Krishnan and Ramu, 2006). Histopathology of the spleen show two types of involvement: focal infiltration of the white pulp, and diffuse infiltration of the red pulp and sinuses.
In summary, the criteria used for diagnosis of systemic mastocytosis are as follows (Krishnan and Ramu, 2006):
· Dense infiltrates of mast cells should be seen in bone marrow or other extracutaneous tissues. Mast cells should be in aggregates of 15 or more.
· Tryptase immunohistochemistry or metachromatic staining (Geimsa, toluidine blue) should be used to confirm diagnosis. Immunohistological staining is more sensitive and reliable than metachromatic straining.
The major criteria mentioned above may be lacking in early diseases. In such cases, minor criteria will be used to make pathological diagnosis. Three of the four minor criteria should be present in order to make and confirm diagnosis. The criteria are as follows (Krishnan and Ramu, 2006):
· Uncharacteristic mast cell morphology
· Anomalous mast cell phenotype
· Serum or plasma tryptase levels that are greater than 20 ng/mL
· A codon-816 c-kit mutation in peripheral blood, bone marrow or involved tissue.
Therapy for treatment of mastocytosis is conservative and primarily symptomatic; no known therapy is curative (Krishnan and Ramu, 2006). Certain drugs have to be avoided for they precipitate mediator release. Among these medications are: aspirin, NSAIDs, codeine, morphine, alcohol, thiamine, quinine, opiates, gallamine, decamethonium, procaine, radiographic dyes, dextran, polymyxin B, scopolamine and D-tubocurarine (Hogan and Lewis, 2006).
Pharmacologic treatment of mastocytosis involves stabilizing mast cell membranes in order to reduce the severity of the attacks and at the same time block the action of inflammatory mediators (Alto and Clarcq, 1999). In some cases, surgical removal of isolated mastocytomas may be used. Topical corticosteroid therapy can be used as a treatment for cutaneous lesions involving only a limited part of the body. Intralesional injections of dilute corticosteroid usually resolve skin lesions either temporarily or definitely.Therapy with psoralen plus ultraviolet A (PUVA) to fade multiple pigmented lesions is also an alternative to pharmacologic treatment. PUVA has its risks however – skin cancer may result if more than 200 treatments are required. Currently, PUVa is used in severe unresponsive cases in adults (Hogan and Lewis, 2006).
Histamine H1 and histamine H2 blockers decrease pruritus, flushing and GI symptoms (Hogan and Lewis, 2006). Oral disodium cromoglycate may alleviate cutaneous symptoms such as pruritus, flushing and whealing, as well as systemic symptoms that include diarrhea, abdominal pain, bone pain, and disorders of cognitive function.
Orally administered cromolyn sodium (Gastrocrom) has been known to relieve diarrhea and abdominal pain. It is usually taken four times week and has a 200 mg dose. Several weeks of therapy may be needed before significant improvements become noticeable. Anticholinergic agents also alleviate abdominal cramping (Alto and Clarcq, 1999).
Aspirin, although used cautiously, may be beneficial for patients that are resistant to H1 and H2 antagonists. If the patient has been premedicated with H1 and H2 antihistamines, he could be started on small doses of aspirin. The dose will slowly be increased until it reaches a plasma level of 20-30mg/100 mL. Extreme caution should be exercised in this regimen because aspirin can induce mast cell mediator release and subsequent cardiovascular collapse (Hogan and Lewis, 2006).
Physicians usually advise that the diet of patients with mastocytosis be controlled. Like certain drugs, some food crawfish, lobster, spicy foods, alcohol, hot beverages and cheese are believed to induce mast cell mediator release (Hogan and Lewis, 2006).
Prognosis for individuals with either cutaneous or systemic mastocytosis depends on the age of onset. Patients with urticaria pigmentosa before 2 years old are usually associated with an excellent prognosis, with resolution often setting in at the age of puberty (Hogan and Lewis, 2006). Disease onset after the age of 10 years however has a poorer prognosis. Disease that appears later in life is more persistent and often associated with systemic mast cell disease. For patients with systemic mastocytosis, the severity of urticaria pigmentosa is usually reduced when the frequency and severity of other symptoms are decreased.
Mastocytosis 9
References
Alto, W. & Clarcq, L. (1999 June). Cutaneous and systemic manifestations of mastocytosis. American Academy of Family Physicians. Retrieved November 14, 2007 from http://www.aafp.org/afp/990600ap/3047.html.
Hogan, D. & Lewis, V.P. (2006 May 11). Mastocytosis. eMedicine. Retrieved November 14, 2007 from http://www.emedicine.com/derm/topic258.htm.
Krishnan, K. & Ramu, V. (2006 December 18). Mastocytosis, systemic. eMedicine. Retrieved November 14, 2007 from http://www.emedicine.com/med/topic1401.htm.
Mastocytosis (n.d.). American Osteopathic College of Dermatology. Retrieved November 14, 2007 from http://www.aocd.org/skin/dermatologic_diseases/mastocytosis.html.