Dermatology

Mastocytosis (Urticaria Pigmentosa, Telangiectasia Macularis Eruptiva Perstans)

Mastocytosis (Urticaria Pigmentosa, Telangiectasia Macularis Eruptiva Perstans) (ICD-9-CM 757.33)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Many children and adults have few, if any, symptoms. When symptoms do occur, they are due to the diverse physiologic effects of secreted mast cell mediators, such as histamine, eicosanoids and cytokines. These complaints and findings may range from pruritus and flushing, to abdominal pain and diarrhea, to palpitations, dizziness and syncope. Of interest is the relative absence of pulmonary symptoms in mastocytosis.

Complaints of fever, night sweats, malaise, weight loss, bone pain, epigastric distress, and problems with mentation (cognitive disorganization) often signal the presence of extracutaneous disease. Deaths associated with extensive mast cell mediator release also are rare, but have been reported in both children and adults.

Symptoms of mastocytosis can be exacerbated by exercise, heat, or local trauma to skin lesions. In addition, alcohol, narcotics, salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs), polymyxin B, and anticholinergic medications have been implicated in precipitating symptoms of mastocytosis. Some systemic anesthetic agents may precipitate anaphylaxis.

Characteristic findings on physical examination

Skin lesions of childhood mastocytosis patients include a solitary tan or yellow-tan plaque or nodule (mastocytoma) frequently appearing on the distal extremities (Figure 1), or variable numbers of tan to brown macules or papules (urticaria pigmentosa) commonly appearing on the trunk but often sparing the central face, scalp, palms, and soles. Some infants will develop diffuse erythematous, edematous plaques termed diffuse cutaneous mastocytosis. These patients, along with some infants with urticaria pigmentosa may develop non-scarring vesicles or bullae.

Figure 1.

Cutaneous mastocytosis. Papules, plaques, and vesicular morphologies. (Courtesy of Bryan Anderson, MD)

Skin lesions in adult mastocytosis patients differ significantly from those in children. The most common cutaneous lesions of mastocytosis in adults are reddish-brown macules and papules that measure a half centimeter or less in diameter. These lesions are most numerous on the trunk and proximal extremities and appear less frequently on the face, distal extremities, or palms and soles. A rare form of adult cutaneous is telangiectasia macularis eruptiva perstans (TMEP), which is characterized by macules and patches composed of telangiectasias with minimal if any hyperpigmentation (Figure 2).

Figure 2.

Telangiectasia macularis eruptiva perstans (TMEP). (Courtesy of Bryan Anderson, MD)

The presence of mast cell hyperplasia in the skin of mastocytosis patients can be confirmed clinically by firmly rubbing a characteristic lesion. The formation of an urticarial wheal (Darier's sign) at the lesion site is indicative of mast cell mediator release. Darier's sign is readily demonstrated in mastocytomas and childhood urticaria pigmentosa lesions, whereas it may be less apparent in common adult mastocytosis lesions and barely detectable in TMEP. This is due to the fact that adult onset lesions have significantly fewer mast cells than those appearing in children.

Expected results of diagnostic studies

The diagnosis of mastocytosis is established by demonstrating increased numbers of mast cells in one or more organs (Figure 3). For patients with cutaneous lesions, mast cell infiltrates can be demonstrated in a biopsy of lesional skin. Special stains, such as toluidine blue, Giemsa, Leder (chloroacetate esterase), or monoclonal antibodies that recognize tryptase or CD117 (KIT) are helpful for identifying tissue mast cells.

Figure 3.

TMEP: Histopathology. Geimsa stain highlights the perivascular mast cells. (Courtesy of Bryan Anderson, MD)

Biopsy specimens of normal-appearing skin from patients with mastocytosis have normal concentrations of mast cells, and thus are not helpful in establishing the diagnosis in patients without skin lesions. A biopsy of the bone marrow or gastrointestinal (GI) tract may be indicated for patients lacking skin lesions in which the diagnosis of systemic mastocytosis is a possibility.

Detection of circulating mast cell mediators and/or their metabolites can offer indirect evidence of mastocytosis escpeically in patients without characteristic skin lesions. Total (α and β) serum tryptase levels have been correlated with the extent of mast cell disease. Fifty percent of patients with total serum tryptase levels between 20 and 75 ng/ml have evidence of systemic mastocytosis, whereas all patients with levels higher than 75 ng/ml have proven systemic involvement.

In many instances, unmetabolized urinary histamine levels may be normal in asymptomatic systemic mastocytosis patients, whereas the major metabolite of histamine, 1,4-methylimidazole acetic acid (MeImAA) is often persistently elevated. When urinary MeImAA levels are correlated with the extent of mast cell disease, patients with widespread systemic involvement have the highest concentrations, and patients with only cutaneous disease have normal or only slightly elevated MeImAA.

When MeImAA levels are not commercially available, determining urinary methyl histamine levles may prove useful. It is important to note that certain foods with high histamine content, such as spinach, eggplant, cheeses (Parmesan, Roquefort and blue) and red wines, can artificially elevate the levels of urinary histamine and its metabolites.

The urinary excretion of the major urinary metabolite of prosta-glandin D2 (PGD2), 9α, 11β-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-diolic acid (PGD2M), has also been reported to be increased in some systemic mastocytosis patients. Plasma levels of IL-6 has also been shown to be elevated in patients with mastocytosis, correlating with severity of bone marrow pathology, organomegaly, and extent of skin involvement.

Diagnosis confirmation

Childhood lesions of urticaria pigmentosa may spontaneously urticate and thus may be mistaken for urticaria. However, lesions of urticaria last only a few hours and do not have the associated hyperpigmentation seen in urticaria pigmentosa.

Some childhood mastocytosis patients may develop bullae and the differential diagnosis for blisters in these children includes bullous arthropod bites, bullous impetigo, herpes simplex infection, linear IgA bullous dermatosis and, less often, other autoimmune bullous dermatoses. In addition, children with diffuse cutaneous mastocytosis may develop widespread blisters early in their course, which may be mistaken for epidermolysis bullosa or toxic epidermal necrolysis. Mastocytomas in children may be confused with cafe-au-lait macules, arthropod bites, Spitz nevi, pseudolymphomas and juvenile xanthogranulomas.

Demonstration of an increased concentration of mast cells in either the blister fluid or skin biopsy of the mastocytosis patient helps to establish the correct diagnosis. Rarely, nodular scabies has been misdiagnosed as mastocytosis. Lastly, lesions of urticaria pigmentosa may rarely mimic histocytosis clinically (red-yellow-brown lesions), but, histologically, demonstrate increased mast cells admixed with eosinophils, neutrophils and nuclear debri.

Skin lesions of adult mastocytosis patients may at first glance appear as lentigines or melanocytic nevi, but mastocytosis lesions usually have an associated erythema.

Who is at Risk for Developing this Disease?

The true incidence of this disease is unknown. Most cases occur in early childhood with 60-80% presenting within the first year of life. Most patients with mastocytosis have no family history. However, there are reports of familial cases, including monozygotic twins, some of which are discordant for this disease. This disorder has no gender preference, and has been reported in all races. Currently no known risk factors for acquisition of disease exist.

What is the Cause of the Disease?

Etiology

Mast cells are derived from pluripotent CD34+ precursors in the bone marrow and circulate in the peripheral blood as agranular, monocytic-appearing cells. After migrating into tissues, these immature mast cells assume their typical granular morphology. Circulating mast cell precursors express CD34, and the tyrosine kinase KIT (CD117). KIT is the protein product of the proto-oncogene c-KIT located on chromosome 4q12, and belongs to the type III receptor tyrosine kinase subfamily.

KIT is expressed on mast cells, melanocytes, primitive hematopoietic stem cells, primordial germ cells, and interstitial cells of Cajal. Activation of KIT induces cellular growth and extends cell survival by preventing apoptosis. The ligand for KIT is stem cell factor (SCF), which is an important growth factor for mast cells. SCF is produced by bone marrow stromal cells, fibroblasts, keratinocytes, endothelial cells, and reproductive Sertoli and granulosa cells.

Pathophysiology

Alterations in KIT structure and activity are central to the pathogenesis of some forms of mastocytosis. Somatic mutations in codon 816 of the c-KIT proto-oncogene, resulting in amino acid substitutions (D816V, D816Y, D816F and D816H), have been identified in children and adult mastocytosis patients without familial disease. This mutation causes constitutive activation of KIT, thereby leading to continued mast cell development.

Other activating mutations in c-KIT have also been reported in adults and children with mastocytosis but these appear to be less common. Recent animal and clinical studies strongly suggest that factors in addition to mutated-autoactivated KIT are important for the full clinical expression of this disorder.

Systemic Implications and Complications

A new classification scheme has been established by the World Health Organiation (WHO) with the following seven disease variants: cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD), aggressive SM (ASM), mast cell leukemia (MCL), mast cell sarcoma and extracutaneous mastocytomas.

Patients with CM represent the largest group and include most children and some adults. Patients with SM by definition have focal accumulations of mast cells in other organs, including the bone marrow. Patients with ISM frequently have cutaneous lesions but few, if any systemic symptoms. Mast cell infiltrates can be detected in various organs (spleen, liver, lymph nodes and/or bone marrow) but organ impairment is usually absent.

Patients with SM-AHNMD often do not have cutaneous lesions but have increased BM mast cells and may have liver, spleen, and/or lymph node involvement. Hematologic disorders associated with this group of patients include: myeloproliferative and myelodysplastic disorders (eg. polycythemia rubra vera, chronic myeloid leukemia, chronic myelo-monocytic leukemia, idiopathic myelofibrosis), chronic eosinophilic leukemia and the hypereosinophilic syndrome, lymphocytic leukemia (acute and chronic), and lymphoma (non-Hodgkin and Hodgkin disease).

Secondary acute myeloblastic or myelomonocytic leukemias may also occur in this patient group. The overall prognosis of SM-AHNMD patients appears directly dependent upon the severity of the hematologic disease.

Aggressive systemic mastocytosis patients have one or more of the following signs: BMMC infiltrates with abnormal myelopoiesis resulting in peripheral blood abnormalities (cytopenias, leukocytosis including eosinophilia, basophilia and monocytosis and thrombocytosis), hepatomegaly with liver function impairment, bone involvement with bone pain and increased risk of pathologic fractures, malabsorption secondary to mast cell infiltration of the GI tract, and/or splenomegaly with hypersplenism or life threatening organ dysfunction. The overall prognosis for this patient group is not well-defined but appears dependent upon response to treatment. Mast cell leukemia is rare.

The diagnosis of mast cell leukemia requires the peripheral blood nucleated cell population to be composed of at least 10% mast cells and BM smears to contain at least 20% mast cells. Most patients with MCL do not have cutaneous lesions, but frequently experience recurrent fever, weight loss, abdominal pain, diarrhea, nausea and vomiting. Multiorgan failure, including the BM, is common over weeks to a few months in these patients. The prognosis for MCL is extremely poor, with an expected survival of a year or less from the time of diagnosis.

Mast cell sarcomas and extracutaneous mastocytomas are extremely rare. Sarcomas containing poorly differentiated mast cells have been described in the larynx, colon and brain. The prognosis appears poor since the terminal phase of patients with these lesions is similar to patients with ASM or MCL. In contrast, extracutaneous mastocytomas contain well- differentiated mast cells and arise primarily in the lung. These lesions appear to have a benign course and a good prognosis.

Skeletal lesions occur more frequently in adult patients with mastocytosis, and are rare in childhood onset disease. Even when they occur in children they appear to resolve over time. Bony lesions may appear as radio-opacities, radiolucencies, or a mixture of the two. The skull, spine, and pelvis are most commonly involved, with reported changes such as demineralization, osteosclerosis, osteosclerosis, and osteoporosis.

The bone marrow is commonly involved in adult patients with mastocytosis. Recently WHO has established criteria for the diagnosis of systemic mastocytosis and include the following bone marrow abnormalities: multifocal, dense aggregrates of mast cells (> 15/aggregrate), > 25% atypical (including spindle-shaped) mast cells in the infiltrate, co-expression of BMMC CD117 with CD2 and/or CD25 and/or the presence of the D816 activating c-KIT mutation in BMMCs. Observations have led to the recommendation that bone marrow biopsies should not be routinely performed in children with mastocytosis and in patients with indolent mastocytosis and normal hematologic parameters.

Splenomegaly, detected either clinically or by computed tomography (CT) scan, has been reported in up to 50% to 60% of adult systemic mastocytosis patients. Increased numbers of mast cells and eosinophils are frequently observed in the spleen, as are various degrees of fibrosis and hematopoiesis. Lymph node enlargement is uncommon in most mastocytosis patients, but occurs in patients with more advanced systemic disease. Histologically, early involvement of lymph nodes often consists of just clusters of mast cells, while in more advanced disease, mast cell infiltrates involve the paracortex, and are often accompanied by eosinophils.

GI symptoms, such as abdominal pain, diarrhea, nausea and vomiting, resulting from mast cell mediator release may occur spontaneously in mastocytosis patients or maybe precipitated by alcohol, aspirin, NSAIDs and certain foods. Diarrhea in patients with mastocytosis is usually episodic; it can result from malabsorption, increased motility and/or acid hypersecretion, probably as a result of the release of mast cell histamine and prostaglandins. GI hemorrhage has been reported in some patients with systemic mastocytosis and is often secondary to gastritis or peptic ulcers.

A number of radiographic changes in the GI tract have been described in patients with systemic mastocytosis and they include urticaria-like lesions, thickened gastric, duodenal and jejunal folds, as well as mucosal nodules and/or peptic ulcers. Biopsies of mucosal nodules have demonstrated numerous mast cells with varying numbers of eosinophils. Hepatomegaly has also been documented in several large series of systemic mastocytosis patients, however, liver function abnormalities are typically within normal limits.

A mixed organic brain syndrome with a constellation of symptoms - including irritability, fatigue, headache, poor attention span and motivation, limited short-term memory, inability to work effectively, and difficulty in interacting with other people - has been described in patients with mastocytosis. It has been hypothesized that these symptoms may be secondary to released mast cell mediators. Electro-encephalographic studies in these patients range from normal to changes consistent with a toxic or metabolic process.

Treatment Options

Medical Treatment

-Avoid potential mast cell degranulating agents and environmental factors

-Histamine type 1 (H1) receptor antagonists for skin symptoms, especially second-generation anti-histamines (cetirizine, loratadine and fexofenadine)

-Potent topical corticosteroids

- H2 antagonist (cimetidine, ranitidine, famotidine or nizatidine) for patients with gastric acid hypersecretion

-Oral cromolyn sodium in patients with GI, cutaneous and CNS symptoms associated with mastocytosis

-Systemic corticosteroids

-Interferon-α-2b (IFN-α-2b)

-Imatinib mesylate (Gleevec®) in patients with rare (del419D, V560G, F522C and K509I) c-KIT mutations and patients with the rare FIP1L1-PDGRA fusion gene who are D816 negative

-Cladribine (2-chlorodeoxyadenosine) in patients with advanced systemic mastocytosis who express the D816 c-KIT mutation

Surgical Treatment

-Excision of a treatment resistant, symptomatic mastocytoma

-Splenectomy for patients with hypersplenism

Physical Modalities

-Psoralen plus ultraviolet A (PUVA) therapy given up to four times a week

-Broad band and Narrow band have also been used 2-3 times a week

-Intralesional injections of triamcinolone acetonide

-Premeasured epinephrine preparation (EpiPen®) for emergency use

-Local radiation therapy (approximately 2000 to 30 000 cGy over a 7- to 14-day period) may benefit patients with bone pain

Appropriate referral to a hematologist should be obtained in cases where systemic involvement is considered.

Optimal Therapeutic Approach for this Disease

Treatment of patients with mastocytosis is directed primarily at alleviating symptoms, since there is no cure for this disorder. Many mastocytosis patients have few, if any, symptoms, and therefore require little or no therapy. First and foremost patients, should be cautioned to avoid potential mast cell degranulating agents and environmental factors, such as alcohol, aspirin, anticholinergic medications, NSAIDS, heat, friction, narcotics, and polymxyin B sulfate.

It has been recommended that mastocytosis patients undergoing general anesthesia be monitored postoperatively for at least 24 hours since delayed anaphylaxsis has occurred hours after surgery in some of these patients.

In contrast to systemic anesthetics, local injections of lidocaine can be used safely in mastocytosis patients unless there is a history of a previous adverse reaction.

Potent topical corticosteroids under occlusion for 6 weeks or more eliminate pruritus, cutaneous whealing, and histamine levels, and reduce the number of lesional skin mast cells but cause skin atrophy. Intralesional injections of triamcinolone acetonide have also been successful in clearing mast cell infiltrates in the skin of mastocytosis patients and maybe useful for symptomatic mastocytomas.. The use of systemic corticosteroids in combination with cyclosporine in SM patients has been anecdotal.

Histamine type 1 (H1) receptor antagonists, or combined H1 and H2 receptor antagonists, are safe and often helpful in controlling many of the symptoms associated with mastocytosis. The second-generation anti-histamines cetirizine, loratadine and fexofenadine have distinct advantages over first-generation antihistamines because they have longer half-lives and are more specific H1 antagonists.

The addition of an H2 antagonist (cimetidine, ranitidine, famotidine or nizatidine) may prove beneficial, especially in patients with gastric acid hypersecretion and oral cromolyn sodium (disodium cromoglycate; 400–1000 mg/day) may alleviate GI, cutaneous, and central nervous system (CNS) symptoms in children but appear to be of limited use for adults with mastocytosis.

PUVA therapy given up to four times a week can help to control the pruritus and cutaneous whealing in patients with mastocytosis; however, it does not permanently eliminate cutaneous mast cell infiltrates. The additional risk of cutaneous malignancy must be considered when using PUVA.

Some patients with systemic mastocytosis may experience recurrent, life-threatening episodes of hypotension following mast cell mediator release, and thus should be provided with a premeasured epinephrine preparation (EpiPen®) for emergency use. For patients with advanced systemic mastocytosis, agents such as cladribine, interferon-α-2b, and imatinib mesylate should be considered. These patients need to be managed by a hematologist and allergist. A number of systemic anesthetic agents, including lidocaine, d-tubocurarine, metocurine, etomidate, thiopental, succinylcholine hydrochloride (suxamethonium chloride), enflurane, and isoflurane have been directly or indirectly implicated in precipitating anaphylactoid reactions in mastocytosis patients. Fentanyl, sufentanil, remifentanil, paracetamonl, midazolam, propofol, ketamine, desflurane, sevoflurane, cis-atracurium, pancuronium and vecuronium bromide, appear to be safe alternative systemic anesthetics for patients with mastocytosis.

Patient Management

The initial evaluation of a patient with suspected mastocytosis begins with a thorough history and physical examination. If the history and physical examination are equivocal, then a skin biopsy of lesional skin will help confirm the diagnosis, although special stains (toluidine blue, Giemsa, Leder, or monoclonal antibodies recognizing tryptase or CD177) may be needed.

Patients should be examined for lymphadenopathy and hepatosplenomegaly at each visit, and, if abnormal, receive appropriate screening with ultrasonography, CT imaging, and laboratory evaluation, and referral to hematology. A complete blood cell count (CBC) with differential, liver function tests and a total serum tryptase level (as an indicator of total body mast cell burden) should be performed initially and thereafter every 6 to 12 months. Patients with a solitary mastocytoma should be followed clinically every 6-12 months until resolved.

A hematology consult and bone marrow biopsy are indicated if abnormalities in the CBC (thrombocytopenia, leukopenia) are detected suggesting the presence of a second hematologic disorder . Otherwise the CBC should be monitored every 6 to 12 months.

The bone marrow biopsy sample should undergo immunohistochemical staining for tryptase, mast cell immunophenotyping, cytogenetic studies looking for an associated clonal hematologic disorder, and analysis of c-kit for mutations. A bone scan or, skeletal survey (skull, entire spine and pelvis) should be performed on patients with evidence of lymphadenopathy and hepatosplenomegaly, or patients with evidence of high mast cell burden (eg, consistently elevated serum tryptase >20ng/ml or extensive body surface area involved).

Of note, skin biopsies are not usually necessary in children with characteristic UP, and CBCs and bone marrow biopsies are rarely needed in children with mastocytosis.

At the initial visit and at each follow-up, patients should be questioned about constitutional and other systemic symptoms. Gastrointestinal symptoms should lead to further evaluation as indicated. A history of bone pain or fracture should lead to a radiographic skeletal survey or bone scan as indicated.

Unusual Clinical Scenarios to Consider in Patient Management

There is no cure for mastocytosis. Chemotherapeutic agents have been used with limited success in the treatment of patients with extensive systemic disease; however, intravenous cladribine (2-chlorodeoxyadenosine) has proven effective in eliminating skin lesions and markedly reducing the number of bone marrow mast cells in patients with advanced SM who express the D816 c-KIT mutation, thus making it the treatment of choice for this patient group.

Interferon-α-2b (IFN-α-2b) has also been used with limited success in patients with more aggressive forms of mastocytosis.

Imatinib mesylate (Gleevec®) has proven effective in the treatment of KIT-related gastrointestinal stromal tumors (GIST). Unfortunately this drug does not alter the clinical course of mastocytosis patients with the D816 c-KIT mutation.

Imatinib, however, may alleviate the signs and symptoms of mastocytosis in patients with rare (del419D, V560G, F522C , and K509I) c-KIT mutations and has been effective in the treatment of patients with the FIP1L1-PDGRA fusion gene who are D816 negative .Nonmyeloablative allogeneic hematopoietic stem cell transplantation for life-threatening disease is still under investigation.

What is the Evidence?

Longley, BJ, Metcalfe, DD, Tharp, MD, Dang, X, Tyrrell, L, Lu, S-Z. "Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis". Pro Natl Acad Sci. vol. 96. 1995. pp. 1609-14.

(The presence of mutated c-KIT was investigated in skin biopsies from 11 adults and 11 children with mastocytosis and three family members with familial mastocytosis. All 11 adults and four children were heterozygous for mutations in codon 816 (D816) of c-KIT. The presence of these mutations did not discriminate between cutaneous only versus systemic disease.Three children with UP had detectable inactivating c-KIT mutations despite the presence of mast cell disease. No c-KIT mutations were detected in the three patients with familial mastocytosis. This study was the first to report activating and inactivating c-KIT mutations in children with mastocytosis and hypothesizes that mechanisms other than mutated c-KIT may cause mastocytosis.)

Valent, P, Akin, C, Escribano, L, Fodinger, M, Hartmann, K, Brockow, K. "Standards and standardization in mastocyosis: consensus statements on diagnostics, treatment recommendations, and response criteria". Eur J Clin Invest. vol. 37. 2007. pp. 435-53.

(This paper summarizes a consensus conference focusing on the appropriate use of clinical and laboratory tests as well as the selection of appropriate mastocytosis patients for different treatment regimens.)

Tharp, MD, Bolognia, J, Jorizzo, JL, Rapini, RP. "Mastocytosis". Dermatology. Mosby Elsevier Ltd. 2008. pp. 845-53.

(An extensive review of the pathophysiology, clinical manifestations, diagnosis, and management of children and adults with mastocytosis.)

Escribano, L, Alvarez-Twose, I, Sanchez-Munoz, L, Garcia-Montero, A, Nunez, R, Almeida, J. "Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients". J Allergy Clin Immunol. vol. 124. 2009. pp. 514-21.

(One hundred forty-five patients were examined prospectively for parameters predicting the progression of mastocytosis. Multivariate analysis demonstrated that the best predictors of disease progression were elevated serum beta-2 microglobulin levels together with the presence of c-KIT mutations in mast cell, myeloid and lymphoid lineages. Being greater than 60 years old and having an associated clonal hematological non-mast cell disorder were the best predicators of early death [2.2% at 5 years and 11% at 25 yrs].)

Pardanani, A, Tefferi, A. "Systemic mastocyosis in adults: a review of the prognosis and treatment based on 342 Mayo Clinic patients and current literature". Curr Opin Hematol.. vol. 17. 2010. pp. 125-32.

(This was a retrospective analysis of 342 patients with mastocytosis. Forty-two percent of the patients had indolent systemic mastocytosis (ISM) and their prognosis was the same as the control (age-matched, sex-matched) population. Forty percent of the mastocytosis patients had an associated clonal, hematologic non-mast cell disease (AHNMD), and 89% of this group had myeloid neoplasms and the remainder had lymphomas. The overall survival for this AHNMD group was 24 months.Twelve percent of the patients were classified as aggressive systemic mastocytosis (ASM), and the overall survival of this group was 41 months. Four patients had mast cell leukemia with an average survival of 2 months. Treatment for ISM patients was mostly supportive and directed at mast cell mediator related symptoms. In patients with AHNMD, treatment was directed at the secondary myeloid or lymphoid neoplasms. Some patients were treated with either imatinib mesylate or 2-chlorodeoxyadenosine.(2-CdA)The response rate to imatinib was poor in patients with ISM (14%) and AHNMD (9%) but was 50% ASM patients with an average treatment response of nearly 20 months. A 50% response rate was also observed in ASM patients treated with 2-CdA, but the average duration of response was only 11 months.)

Konrad, FM, Schrodeder, h. " Anaesthesia in patients with mastocytosis". Acat Anaesth Scand. vol. 53. 2009. pp. 207-10.

(This paper describes two cases of mastocytosis patients undergoing surgery with general anesthesia. In addition to avoiding specific analgesics and anaesthetics, the authors recommend using combined systemic the prophylatic administration of H1 antihistamines and systemic corticosteroids immediately prior to surgery. In this paper it is recommended to avoid local lidocaine injections; however, this author has used this local anesthetic in over 100 mastocytosis patients without an adverse reaction.)

Butterfield, JH. "Response of severe systemic mastocytosis to interferon-alpha". Br J Dermatol. vol. 138. 1998. pp. 489-95.

(Six patients with systemic mastocytosis were treated with 0.5 to 3.0 mu/d of interferon-alpha (IFN-alpha). Resolution of ascites was seen in 2/2 patients and a decrease in adenopathy was observed in 2/4 patients. There was a 5-10% decrease in bone marrow mast cells in 5/6 patients after 9-12 months of therapy. No changes in hepatosplenomegaly or serum tryptase levels were observed. Side effects included hyothyroidism, thrombocytopenia, and depression. While IFN-alpha had some positive effect on the signs and symptoms of mastocytosis, this agent appears to have limited therapeutic benefit in patients with more aggressive disease.)

Pardanani, A, Hoffbrand, AV, Butterfield, JH, Tefferi, A. " Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine". Leuk Res. vol. 28. 2007. pp. 127-31.

(Four patients with systemic mastocytosis were treated with 2-chlorodeoxyadenosine (2-CdA) after failing to respond to interferon-alpha. Three of the four patients had at least a partial response to treatment with a decrease in mast cell related symptoms and skin lesions after 3- 6 cycles. 2-CdA appears to be an effective treatment for patients with progressive systemic mastocytosis.)

Vega-Ruiz, A, Cortes, JE, Sever, M, Manshouri, T, Quintas-Cardama, A, Luthra, R. " Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis". Leuk Res. vol. 33. 2009. pp. 1481-84.

(Twenty patients with systemic mastocytosis were treated with imatinib mesylate (400-800 mg/d) for a median of 9 months. Only one patient who was negative for the auto-activating (D816V) c-KIT mutation achieved a complete remission (44 months). Six other patients initially noted improvement in episodes of hypotension, flushing, shortness of breath, diarrhea, and fatigue; however, all these patients ultimately discontinued treatment due to loss of response to therapy. While it appears that imatinib mesylate is not effective for mastocytosis patients with the D816V c-KIT mutation, it may be effective for patients with other autoactivating c-KIT mutations.)

Purtill, D, Cooney, J, Sinniah, R, Carnely, B, Cull, G, Agustson, B. Eur J Haematol. vol. 80. 2008. pp. 456-58.

(Four patients with systemic mastocytosis, all expressing the autoactivating (D816V) c-KIT mutation, were treated with increasing doses (20mg twice daily to 110mg twice daily) of the tyrosine kinase inhibitor, dasatinib for 2-11 months. Two patients experienced decreased episodes of diarrhea and pruritus. One patient had a slight improvement of their bone marrow. No significant changes in serum tryptase levels were observed, suggesting a minimal decline in the total body mast cell population in these patients. This small study suggests that dasatinib may be of some, but limited, benefit for mastocytosis patients expressing the D816V c-KIT mutation.)
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