Mastocytosis is a clonal disorder characterized by the accumulation of abnormal
mast cells in the skin and/or in extracutaneous organs.
To present all cases of mastocytosis seen in the Porto Hospital Center and
evaluate the performance of World Health Organization diagnostic criteria for
The cases of twenty-four adult patients with mastocytosis were reviewed. Their
clinical and laboratorial characteristics were assessed, and the properties of the
criteria used to diagnose systemic mastocytosis were evaluated.
The age of disease onset ranged from 2 to 75 years. Twenty-three patients had
cutaneous involvement and 75% were referred by dermatologists. Urticaria
pigmentosa was the most common manifestation of the disease. One patient with
severe systemic mast cell mediator-related symptoms showed the activating V560G
KIT mutation. The bone marrow was examined in 79% of patients, and mast cell
immunophenotyping was performed in 67% of the participants. Systemic disease was
detected in 84% of cases, and 81% of the sample had elevated serum tryptase
levels. All the diagnostic criteria for systemic mastocytosis had high specificity
and positive predictive value. Bone marrow biopsy had the lowest sensitivity,
negative predictive value and efficiency, while the highest such values were
observed for mast cell immunophenotyping. Patients were treated with regimens
including antihistamines, sodium cromoglycate, alpha-interferon, hydroxyurea and
Cutaneous involvement is often seen in adult mastocytosis patients, with most
individuals presenting with indolent systemic disease. Although serum tryptase
levels are a good indicator of mast cell burden, bone marrow biopsy should also be
performed in patients with normal serum tryptase, with flow cytometry being the
most adequate method to diagnose systemic disease.
Flow cytometry; Mast cells; Mastocytosis, cutaneous; Mastocytosis, systemic; Tryptases
Mastocytosis is a disease with many variants, all of which are characterized by a pathologic increase in mast cells in cutaneous tissue and extracutaneous organs such as the bone marrow, liver, spleen and lymph nodes. The disease presents in two primary age-related patterns: pediatric-onset mastocytosis and adult-onset mastocytosis, which may differ in their clinical manifestations and disease course. Pediatric-onset mastocytosis commonly is diagnosed prior to 2 years of age, and usually consists of cutaneous disease, with urticaria pigmentosa (UP) the most common pattern. The course of pediatric-onset mastocytosis is variable. This is in contrast to adult onset disease which generally presents with systemic findings and increases in extent and severity over time. Because pediatric forms of mastocytosis often differ in presentation and prognosis from adult variants, it is most important to understand pediatric mastocytosis and not rely on adult approaches as a guide on how to identify and manage disease. This is especially important in selecting therapy where antiproliferative agents have a very different set of concerns when used to treat adult mastocytosis compared to pediatric mastocytosis, especially in terms of long-term toxicity. This review is directed at providing age-specific information surrounding the care of the child with mastocytosis.
Mastocytosis; pediatric; urticaria pigmentosa; treatment
Mastocytosis is a disorder characterized by an abnormal proliferation of mast cells and release of cell mediators. The incidence is 1 per 1000 skin diseases attending in dermatology services. Mastocytosis can be divided into 3 different clinical variants: cutaneous, systemic and malign mastocytosis. Urticaria pigmentosa is the most common variety (70–90%) of mastocytosis. Of all cases 55% ocurr during the first 2 years of life. When the bone marrow, lymph nodes, liver and spleen are affected the disorder is called systemic mastocytosis.
Case 1: A 20 month old male with history of penicillin and erythromycin allergy, as well atopic family history. Began at 4 months with itchy brown-marrow papules in the back, then generalizated except palms and soles. The lesions were exacerbated by heat and rubbing. There was no fever, weight loss, or any other systemic symptoms in the history. Blood count and biochemical laboratories were normal. Skin biopsy reported the presence of mast cells, confirming urticaria pigmentosa diagnosis. The management included antihistamines, restricted diet and emollients with improved of symptoms. Case 2: A 9 month old male with no history of atopy. At the first visit he had 4 months with skin lesions characterized by hyperpigmented maculopapular eruption, scattered on head, over trunk and extremities. Darier´s sign was positive. Skin biopsy is performed with confirming the diagnosis of mastocytosis.
The urticaria pigmentosa diagnosis is mainly clinical, with emphasis on the Darier´s sign, which is pathognomonic and positive in 90% of cases. In some cases a skin biopsy is required to confirm the diagnosis. Antihistamines are the first line of treatment. Symptoms relieve spontaneously before adolescence in 50% of pediatric patients. In some cases, a malignant transformation of mastocytosis could occur, condition that is called “mast cell leukemia”.
Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient’s course and the serum tryptase levels are examined in the follow-up.
Mastocytosis; tryptase; KIT D816V; diagnostic algorithm; staging
Mastocytosis is a heterogeneous disease, with abnormal accumulation of mast cells in one or more organs. Hyperplasia is often found in the bone marrow and peripheral sites such as skin, gastrointestinal mucosa, liver and spleen. The clinical manifestations are due to release of mast cell mediators and tissue infiltration; however, there is no direct relationship between total mast cell mass and symptoms of liberation.
Describe 2 cases of mastocytosis that manifest with anaphylactic shock and also have IgE-dependent allergy.
Case1: Man of 62 years consulting for intraoperative anaphylaxis with an expected elevated serum tryptase (54 mg/L) during episode. The skin test were positive to vecuronium, rocuronium and Izofran and the other drugs and latex were negative. Specific IgE to quaternary ammonium latex and beta-lactams were negative. The tryptase remains elevated (23 mg/L) 6 weeks after surgery. Bone marrow biopsy showed mast cell infiltration of 10% CD 34 staining less than 1% and 10% CD117. Co-CD25 and CD117 were 25% compatible with mastocytosis. CT neck, thorax, abdomen and pelvis were normal. The upper and lower endoscopy revealed polyps in gastric antrum, the histology was nodular foveolar hyperplasia. Case 2: Female, 38 years consulted for 3 episodes of anaphylaxis following the ingestion of fish, shellfish and quinoa. The skin prick test was positive to white fish and shrimp, specific IgE were positive to white and blue fish and shrimp. The initial serum tryptase was 11 mg/L, 3 months was 14 mg/L. Later, patient had a new anaphylaxis episode, after unnoticed consumption of fish. Bone marrow biopsy compatible with mastocytosis. The study with lower and upper endoscopy with chest and abdominal CT scan ruled out visceral involvement.
Both cases of systemic mastocytosis show an IgE sensitization to drugs and to food whose main manifestation was anaphylactic shock. In the literature, anaphylaxis was reported in up to 22% of mastocytosis, mostly men, associated with different triggering stimuli such as muscle relaxants, but not food. Therefore it is essential to rule out the presence of mastocytosis in patients complaining of anaphylaxis even in those with allergy study showing IgE-dependent sensitization.
Is a heterogeneous disorder characterized by clonal proliferation of mast cells (MCs) leading accumulation in different organs. Pathologic activation of KIT due to a mutation in codon 816 replacing aspartic acid for valine: KIT-D816V (>93%) has been identified. Cutaneous Mastocytosis (CM), Classified in Urticaria Pigmentosa (UP), solitary mastocytoma, diffuse, and telangiectasia macularis eruptiva perstans (TMEP). The most common is the Urticaria Pigmentosa as fixed, reddish brown macular or papular, urticate in physical irritation (Darier's sign). WHO Diagnostic Criteria for cutaneous Mastocytosis: Presence of at least 1 of skin lesions with Focal dense MC infiltrates (>15 MCs per cluster) or diffuse (>20 cells per high-power field).
We report 2 cases of patients with this disease who were not diagnosed at first. A 51 years old female, who noticed 20 years ago, the appareance of itchy "spots” in thorax, abdomen and extremities, progressively increasing in number and size, receiving unspecified treatments without improvement. On examination, we found brown macules with sharp borders, 0.3 to 0.5 cm erythema and Darier´s sign, disseminated lesions on thorax, shoulders and extremities. A 45 year old female, who noticed 2 years ago, the appareance of freckles in neck, arms, thorax and legs progressively increasing in number, who in stress are itchy. Receiving multiple treatments without improvement. On examination disseminated brown macules with sharp borders <0.5 cm with Darier´s sign.
In both patients, the biopsies taken had findings compatible with mastocytosis (inflammatory infiltrate with perivascular lymphocytes, histiocytes and mast cells). Mast cells were not quantified. We realized a genetic study in search of c-kit mutation. Once the diagnosis was considered and treated accordingly, they had a good control of symptoms.
Mastocytosis is diagnosed by clinical features and histological infiltrate of mast cells. The skin is the organ most frequently affected. These patients previously received multiple treatments with no clinical improvement suggest inadecuate diagnosis. Histologically, compatible although no quantificate mast cells, but a mutation of c-kit was found. It is important to consider this disease in the differential diagnosis of pruritic skin disorders since an appropriate treatment with an improvement in quality of life also must be aware of the risk of anafylaxis and its potential triggers.
Despite the good prognosis of pediatric mastocytosis, some patients suffer from severe mast cell (MC) mediator-associated symptoms. The aim of this study was to identify predictors for severe MC mediator release symptoms in children with mastocytosis in the skin (MIS).
Serum baseline total tryptase (sbT) levels in 111 children with MIS – 80 maculopapular cutaneous mastocytosis/plaque mastocytosis, 22 nodular mastocytosis, and nine diffuse cutaneous mastocytosis – were investigated as a predictive biomarker for the occurrence of MC mediator-related signs and symptoms within the first 18 months after disease onset.
Twelve children (11%) who showed extensive cutaneous disease involving >90% of body surface area (BSA) suffered from severe symptoms requiring hospitalization, with (n = 5) or without (n = 6) management in the intensive care unit (ICU) owing to life-threatening complications. The median sbT was significantly (P < 0.001) higher in patients with extensive cutaneous disease vs those with <90% of BSA involved (45.5 vs 5.2 µg/l, respectively), as well as in children with grade 4 (severe mastocytosis-related symptoms requiring emergency therapy and hospitalization) vs those with grade <4 (46.2 vs 5.2 µg/l, respectively). Receiver operating characteristics curve analyses showed that the optimal cutoff s for sbT to predict the need for daily antimediator therapy, hospitalization, and the management in an ICU were 6.6, 15.5, and 30.8 µg/l, respectively (sensitivity and specificity of 77% and 79%, 100% and 95%, and 100% and 96%, respectively).
Increased sbT in association with extensive cutaneous involvement identifies patients at risk for severe MC activation events in pediatric mastocytosis.
mast cell; mastocytosis, pediatric; skin; tryptase
Mastocytosis is a rare disease of mast-cell proliferation with involvement of the reticuloendothelial systems including skin, bone, gastrointestinal tract, liver, lungs, spleen, and lymph nodes. Systemic mastocytosis is characterized by a combination of symptoms that relate to the mast cells' release of vasoactive substances, such as histamine. These symptoms include urticaria pigmentosa, flushing, syncope with hypotension, headaches, nausea, vomiting, diarrhea, and occasional bronchospasm. The diagnosis of mastocytosis is typically based on the presence of the characteristic extraosseus manifestations. A well recognized roentgenographic feature seen in 70-75% of patients with mastocytosis is diffuse osteolysis and osteosclerosis, affecting primarily the axial skeleton and the ends of the long bones. Rarely, the bony involvement consists of generalized osteoporosis, which may lead to pathologic fracture, or solitary lesions (mastocytomas) which may cause symptoms of localized pain. Four patients with previously diagnosed systemic mastocytosis had unusual skeletal lesions. Clinical and laboratory evaluation of these patients eventually led to the correct diagnosis of systemic mastocytosis. We report these four cases to emphasize the need for thorough evaluation of unusual musculoskeletal findings in association with extraosseus symptoms that are characteristic of mastocytosis. Knowledge of a wide differential diagnosis of unusual skeletal lesions should include systemic mastosytosis.
It is known that patients with mastocytosis have an increased risk of anaphylaxis. This also appears to be the case with patients with evidence of a clonal mast cell disorder resulting in the monoclonal mast cell activation syndrome (MMAS) who do not express the full mastocytosis phenotype. Most patients with mastocytosis are recognized by their characteristic skin lesions. An increased level of baseline serum mast cell tryptase is also an indicator for a possible clonal mast cell disorder including mastocytosis. Other markers for mast cell clonality and for mastocytosis include abnormal immunostaining of mast cells with CD25 and CD2, clustering of mast cells in tissues, abnormal mast cell morphology, and the presence of a mutation in the proto-oncogene c-kit encoding for the mast cell growth receptor KIT. As recognition depends on an understanding of mastocytosis, and this disease should be considered in patients with recurrent anaphylaxis, we describe the features of mast cell clonality, MMAS and mastocytosis; and review recent findings.
Cutaneous involvement characterized by urticarial lesions with or without angioedema and itch is commonly observed in routine medical practice. The clinical approach may still remain complex in real life, because several diseases may display similar cutaneous manifestations. Urticaria is a common disease, characterized by the sudden appearance of wheals, with/without angioedema. The term Chronic Urticaria (CU) encompasses a group of conditions with different underlying causes and different mechanisms, but sharing the clinical picture of recurring wheals and/or angioedema for at least 6 weeks. Hereditary Angioedema (HAE) is a rare disorder characterized by recurrent episodes of non-pruritic, non-pitting, subcutaneous or submucosal edema affecting the extremities, face, throat, trunk, genitalia, or bowel, that are referred as “attacks”. HAE is an autosomal dominant disease caused by a deficiency of functional C1 inhibitor, due to a mutation in C1-INH gene (serping 1 gene) characterized by the clonal proliferation of mast cells, leading to their accumulation, and possibly mediator release, in one or more organs. In childhood there are two main forms of mastocytosis, the Systemic and the Cutaneous. The clinical features of skin lesions in urticaria, angioedema and mastocytosis may differ depending on the aetiologic factors, and the underlying pathophysiological mechanisms. The diagnostic process, as stepwise approach in routine clinical practice, is here reviewed for CU, HAE and mastocytosis, resulting in an integrated method for improved management of these cutaneous diseases. Taking into account that usually these conditions have also a relevant impact on the quality of life of children, affecting social activities and behavior, the availability of care pathways could be helpful in disentangle the diagnostic issue achieving the most cost-effective ratio.
Urticaria; Angioedema; Mastocytosis; Skin; Itch; Children; Epidemiology; Diagnosis; Management; Clinical practice
Counting mast cells in gastrointestinal (GI) mucosal biopsies is becoming an increasingly common practice. The primary reason for this exercise is to evaluate for possible involvement by systemic mastocytosis (SM). However, the features of mastocytosis in GI biopsies are not well described. In addition, recent studies have suggested that increased mast cells may be involved in the pathogenesis of some cases of diarrhea-predominant irritable bowel syndrome (IBS); the term “mastocytic enterocolitis” has been proposed for such cases. As the baseline mast cell density in colonic biopsies from normal patients has not been established in large cohorts, there is no widely accepted threshold for what constitutes increased mucosal mast cells. The aims of this study were (1) to determine the utility of GI biopsies for the diagnosis of SM, (2) to characterize the clinical, histologic, and immunohistochemical features of mastocytosis in the GI tract, (3) to determine mast cell density in normal colonic mucosa from a large cohort of asymptomatic patients, and (4) to compare these findings with those from patients with diarrhea-predominant IBS. Twenty-four patients with SM involving the GI tract, 100 asymptomatic patients, and 100 patients with IBS (the latter 2 groups with histologically normal colonic biopsies) were included. For the mastocytosis group, 107 biopsies (70 involved by mastocytosis; 67 mucosal, 3 liver) from 20 women and 4 men were evaluated (median age 59 y). The most commonly involved site was the colon (19 patients, 95%), followed by ileum (86%), duodenum (80%), and stomach (54%). In 16 cases (67%), the first diagnosis of SM was made on the basis of GI biopsies. Seventeen patients had documented cutaneous mastocytosis. Fifteen of 17 patients who underwent bone marrow biopsy had marrow involvement by SM. Eighteen patients had indolent disease, and 6 had aggressive disease (including all 3 with liver involvement). The most common GI symptom was diarrhea, followed by abdominal pain, nausea, weight loss, bloating, vomiting, or reflux. Liver disease presented with hepatomegaly and ascites. Endoscopic abnormalities (observed in 62%) included erythema, granularity, and nodules. Histologically, involved biopsies were characterized by infiltrates of ovoid to spindle-shaped mast cells in aggregates or sheets in the lamina propria, sometimes forming a confluent band underneath the surface epithelium; 25% of biopsies had only focal involvement (single aggregate). Prominent eosinophils were seen in 44% of involved colonic/ileal biopsies and 16% of duodenal biopsies. Mast cells were highlighted by diffuse membranous staining for KIT and CD25. In the nonmastocytosis groups, all biopsies contained singly dispersed mast cells with no aggregates. The mean highest mast cell counts (in a single high-power field) for asymptomatic patients and IBS patients were 26 (range, 11 to 55) and 30 (range, 13 to 59), respectively. In summary, GI (especially colonic) biopsies can establish a diagnosis of SM in patients with GI symptoms. GI involvement is usually subtle and is often associated with prominent eosinophils, which may obscure the mast cell infiltrate. KIT and CD25 are invaluable markers for the diagnosis. Mast cell density in colonic mucosa from asymptomatic patients is highly variable. Although patients with diarrhea-predominant IBS on average have mildly increased mast cells, the overlap in range with that of control patients is too great for this difference to be clinically useful. These findings argue against the utility of counting GI mucosal mast cell in patients with chronic diarrhea.
gastrointestinal tract; liver; mast cells; mastocytosis; mast cell activation syndrome; irritable bowel syndrome; urticaria pigmentosa; KIT
Background/Aims—The occurrence of myeloid leukaemia in patients with systemic mastocytosis is a well recognised phenomenon. However, the pathophysiological basis of such a coevolution has not been clarified. Recent data have shown that the c-kit mutation Asp 816 to Val is detectable in neoplastic mast cells in most patients with systemic mastocytosis, including those who have associated haematological disorders. The aim of this study was to study clonal disease evolution by analysing bone marrow cells from a patient with systemic mastocytosis and associated chronic myelomonocytic leukaemia (CMML) for the presence of this mutation.
Methods—The DNA of microdissected bone marrow cells from a patient with systemic mastocytosis and associated CMML was analysed for the presence of the c-kit mutation Asp 816 to Val by means of HinfI digestion and direct sequencing of semi-nested polymerase chain reaction (PCR) products.
Results—The two neoplasms could easily be identified and discriminated in paraffin wax embedded bone marrow sections by tryptase and chloroacetate esterase staining. A total number of 10 tryptase positive systemic mastocytosis infiltrates and 10 tryptase negative CMML infiltrates were removed by microdissection. As assessed by HinfI digestion and direct sequencing of semi-nested PCR products, the c-kit mutation Asp 816 to Val was detected in five of seven systemic mastocytosis infiltrates and four of six CMML infiltrates. By contrast, no c-kit mutation Asp 816 to Val was found in bone marrow infiltrates in patients with CMML without associated systemic mastocytosis (n = 20).
Conclusion—These data support a monoclonal evolution of systemic mastocytosis and concurrent CMML in the patient studied.
mast cells; microdissection; c-kit point mutation
Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. It is a rare hematologic disorder in all its forms. The exact incidence is unknown; it affects patients of any age and males and females equally. Its molecular pathogenesis is incompletely understood. The clinical features of mastocytosis result from both chronic and episodic mast cell mediator release, signs and symptoms arising from diffuse or focal tissue infiltration, and, occasionally, the presence of an associated non-mast cell clonal hematologic disease. The histopathologic analysis is essential for definitive diagnosis but there is no curative treatment. The authors report a clinical case of a 72-year-old woman with no history of allergies, with bicytopenia, weight loss, and diffuse axial osteolytic lesions. This is a rare clinical case of aggressive systemic mastocytosis for which palliative treatment can improve survival and quality of life. A brief review of the literature about this pathology is also included.
Biopsy; Allergy and immunology; Bone marrow cells
Mastocytosis is a heterogeneous group of disorders characterized by a clonal proliferation and accumulation of mast cells in one or more organ, primarily in the skin and bone marrow. The clinical spectrum of the disease varies from relatively benign forms with isolated skin lesions to very aggressive variants with extensive systemic involvement and poor prognosis. The growth and proliferation of clonal mast cells is caused by an activating mutation of the tyrosine kinase receptor Kit for Stem Cell Factor, the main growth factor for mast cells. Clinical symptoms are related to mast-cell mediator release, to the tissue mast cell infiltration or both. The degree of infiltration and cell activation determines the highly variable clinical and morphological features. Current treatment of mastocytosis includes symptomatic, antimediator drugs and cytoreductive targeted therapies.
Mastocytosis is an uncommon disorder defined by increased and abnormal mast cells in one or more tissues. Cutaneous mastocytosis (cm) is limited to the skin, with varying degrees of rash, pruritus, and disfigurement. Systemic mastocytosis (sm) typically involves the bone marrow, sometimes in association with other bone marrow disorders, including chronic myelomonocytic leukemia (cmml). Mastocytosis has been associated with somatic mutations in the gene encoding the tyrosine kinase Kit, leading to identification of Kit as a therapeutic target. The Kit inhibitor imatinib mesylate is approved for aggressive sm. We present an unusual patient with disabling pruritus from telangiectasia macularis eruptiva perstans, a subtype of cm, and cmml, but with no evidence of systemic mast cell disease. She was treated with imatinib and experienced marked improvement in her pruritus. Concomitant cm and cmml have not previously been reported, and the present report is the first of successful imatinib therapy in an adult patient with cm.
Mastocytosis; chronic myelomonocytic leukemia; imatinib; pruritus; cutaneous; tyrosine kinase inhibitor; tmep
Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children.
Mastocytosis is a rare myeloid neoplasm characterized by abnormal proliferation and accumulation of mast cells in one or more organ systems including the skin, bone marrow, liver, spleen, lymph nodes and gastrointestinal tract. An infant presenting with bullous lesions is an even rarer clinical presentation of cutaneous mastocytosis. The symptoms and complications are mostly in proportion to the mast cell degranulation in tissues. Management is focused on preventing and treating this event. We report a three-month-old infant with bullous mastocytosis to enhance awareness about this rare diagnosis.
Infantile bullous mastocytosis; mast cells; urticaria pigmentosa
The authors present a case of telangiectasia macularis eruptiva perstans, an uncommon form of cutaneous mastocytosis, in a 53-year-old man and discuss its clinics, pathophysiology, laboratory results, and treatment. Cutaneous mastocytosis is a proliferation of masts cells on the skin without involvement of other organs. Typically the lesions of telangiectasia macularis eruptiva perstans are telangiectatic macules with color ranging from light to dark brown. It is more frequent in adults, with some reports in children. It is usually insidious, without symptoms at the beginning and, although a manifestation of cutaneous mastocytosis, telangiectasia macularis eruptiva perstans may present systemic involvement. It is very important for dermatologists to know this form of cutaneous mastocytosis and to make an early diagnosis, so they may treat the disorder and improve their patients' quality of life.
Mastocytosis is a clonal disorder associated with an increased mast cell burden. We have recently demonstrated the ability of human mast cells to express and be activated through multiple serotonin receptors; to synthesize and release serotonin; and that mastocytosis patients may have abnormal serotonin levels. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we have now determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters.
Materials and methods
Patients with mastocytosis were categorized according to disease variant. Blood serotonin values were determined and correlated with values reported for normal subjects; and clinical and laboratory features of the disease.
Total blood serotonin levels followed a bimodal distribution in line with our earlier report, unlike the normal distribution reported for normal individuals. Serotonin levels did not correlate with platelet numbers, liver function tests or serum tryptase levels. Patients with lower serotonin values had greater rates of fatigue (P = 0·0001), migraine headaches (P = 0·0028), psychiatric symptoms (P = 0·0001), diarrhoea (P = 0·0407), flushing (0·0085), and abdominal and bone pain (P = 0·0001).
Our study suggests that low blood serotonin levels help define a sub-group of patients with mastocytosis that are more likely to present with neurological and gastrointestinal complaints, and suggests that the use of pharmacologic agents that alter blood serotonin levels could be explored in selected patients.
5HT; mast cells; mastocytosis; platelets; serotonin; tryptase
Pediatric onset mastocytosis usually presents as urticaria pigmentosa; and less often as diffuse cutaneous mastocytosis. While the literature indicates that disease often resolves, there has been a move to more aggressive therapy for mastocytosis early in life. We addressed the long term prognosis of pediatric-onset disease by examining 17 children with mastocytosis which we had reported on in 1989.
We successfully contacted 15 of these patients and data was collected regarding their clinical status. Original bone marrow specimens were re-stained, re-examined, and correlated with disease outcome using consensus criteria. Three of five patients with persistent disease underwent repeat bone marrow biopsies.
There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial morphologic evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis.
This study demonstrates that initial bone marrow biopsies were prognostic in that those without evidence of systemic disease experienced disease regression; and that the long term prognosis for children managed symptomatically with mastocytosis is highly encouraging.
Cutaneous mastocytosis; pediatric mastocytosis; urticaria pigmentosa; serum tryptase; bone marrow; KIT
Mast cells are now known to derive from CD34+ haemopoietic stem cells in the bone marrow. However, it has not yet been established whether the various types of mastocytosis, which involve tumour-like proliferation of mast cells, are true neoplastic disorders or reactive/hyperplastic conditions. In this study, tissue specimens (five bone marrow, two spleen, one skin) from female patients with histologically confirmed mastocytosis were investigated with a recently developed polymerase chain reaction assay for the determination of clonality of female cells using the human androgen receptor gene (HU-MARA). Mast cells purified to near homogeneity from hysterectomy specimens served as a control. The findings in bone marrow and skin either were not reproducible, or indicated polyclonality. However, both spleen specimens exhibited monoclonality. In addition, DNA analysis by flow cytometry was performed and revealed a diploid chromosome content with proliferation indices of under 8% in all the specimens. This is the first molecular biological study to indicate that mastocytosis is indeed neoplastic in nature.
Mastocytosis is a rare neoplastic disease characterized by a pathologic accumulation of tissue mast cells (MCs). Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor. The contribution of this mutation to mastocytosis development remains unclear. In addition, the clinical heterogeneity presented by mastocytosis patients carrying the same mutation is unexplained. We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs. This disease is characterized by clinical signs ranging from a localized and indolent MC hyperplasia to an invasive MC tumor. In addition, bone marrow–derived MCs from transgenic animals can be maintained in culture for >24 mo and acquire growth factor independency for proliferation. These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis.
Systemic mastocytosis is a rare disease involving the infiltration and accumulation of active mast cells within any organ system. By far, the most common organ affected is the skin. Cutaneous manifestations of mastocytosis, including Urticaria Pigmentosa (UP), cutaneous mastocytoma or telangiectasia macularis eruptive perstans (TMEP), may indicate a more serious and potentially life-threatening underlying disease. The presence of either UP or TMEP in a patient with anaphylactic symptoms should suggest the likelihood of systemic mastocytosis, with the caveat that systemic complications are more likely to occur in patients with UP. TMEP can usually be identified by the typical morphology, but a skin biopsy is confirmative. In patients with elevated tryptase levels or those with frequent systemic manifestations, a bone marrow biopsy is essential in order to demonstrate mast cell infiltration. Further genetic testing for mutations of c-kit gene or the FIP1L1 gene may help with disease classification and/or therapeutic approaches. Rarely, TMEP has been described with malignancy, radiation therapy, and myeloproliferative disorders. A few familial cases have also been described. In this review, we discuss the clinical features, diagnosis and management of patients with TMEP. We also discuss the possible molecular pathogenesis and the role of genetics in disease classification and treatment.
telangiectasia macularis eruptiva perstans; mastocytosis; SCORMA index; serum tryptase; D816V mutation.
Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.
Aims: To investigate mast cell distribution in normal adult skin to provide a reference range for comparison with mastocytosis.
Methods: Mast cells (MCs) were counted in uninvolved skin adjacent to basal cell carcinomas and other dermatological disorders in adults.
Results: There was an uneven distribution of MCs in different body sites using the anti-tryptase monoclonal antibody technique. Numbers of MCs on the trunk, upper arm, and upper leg were similar, but were significantly different from those found on the lower leg and forearm. Two distinct groups were formed—proximal and distal. There were 77.0 MCs/mm2 at proximal body sites and 108.2 MCs/mm2 at distal sites. Adjusted for the adjacent diagnosis and age, this difference was consistent. The numbers of MCs in uninvolved skin adjacent to basal cell carcinomas and other dermatological disorders were not different from those in the control group. Differences in the numbers of MCs between the distal and the proximal body sites must be considered when MCs are counted for a reliable diagnosis of mastocytosis. A pilot study in patients with mastocytosis underlined the variation in the numbers of MCs in mastocytosis and normal skin, but showed a considerable overlap. The observed numbers of MCs in adults cannot be extrapolated to children.
Conclusions: MC numbers varied significantly between proximal and distal body sites and these differences must be considered when MCs are counted for a reliable diagnosis of mastocytosis. There was a considerable overlap between the numbers of MCs in mastocytosis and normal skin.
tryptase monoclonal antibody; body sites; immunohistochemistry; mast cell; mastocytosis