The bone marrow in urticaria pigmentosa and systemic mastocytosis. Cell composition and mast cell density in relation to urinary excretion of tele-methylimidazoleacetic acid

The bone marrow sections from five normal subjects and 18 patients with mastocytosis were examined to establish criteria to distinguish urticaria pigmentosa from systemic mastocytosis. Nine patients had increased numbers of mast cells in bone marrow sections stained with a long toluidine blue staining technique specific for mast cells, whereas five patients exhibited increased numbers of mast cells on May-Grünwald-Giemsa-stained smears of bone marrow. A positive correlation between the number of mast cells in sections of the bone marrow and the urinary excretion of the main histamine metabolite tele-methylimidazoleacetic acid was found. In ten of the examined bone marrow specimens, focal lesions containing mast cells, lymphocytes, and eosinophils appeared. The presence of these focal lesions together with either an increased number of mast cells in bone marrow sections and/or increased urinary excretion of telemethylimidazoleacetic acid is considered diagnostic of systemic mastocytosis. No patient exhibited myeloproliferative condition or other major hematologic abnormality.     

Death from mast cell leukemia: a young patient with longstanding cutaneous mastocytosis evolving into fatal mast cell leukemia

Mastocytosis is a broad term used for a group of disorders characterized by accumulation of mast cells in the skin with or without extracutaneous involvement. The clinical spectrum of the disease varies from only cutaneous lesions to highly aggressive systemic involvement such as mast cell leukemia. Mastocytosis can present from birth to adulthood. In children, mastocytosis is usually benign, and there is a good chance of spontaneous regression at puberty, unlike adult-onset disease, which is generally systemic and more severe. Moreover, individuals with systemic mastocytosis may be at risk of developing hematologic malignancies. We describe a girl who presented to us with a solitary mastocytoma at age 5 and later developed maculopapular cutaneous mastocytosis. At age 23, after an episode of anaphylactic shock, a bone marrow examination revealed mast cell leukemia. She ultimately died despite aggressive chemotherapy and bone marrow transplantation.     

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

BACKGROUND

Mastocytosis is a clonal disorder characterized by the accumulation of abnormal mast cells in the skin and/or in extracutaneous organs.

OBJECTIVES

To present all cases of mastocytosis seen in the Porto Hospital Center and evaluate the performance of World Health Organization diagnostic criteria for systemic disease.

METHODS

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.

RESULTS

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 phototherapy.

CONCLUSIONS

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.     

"Smoldering systemic mastocytosis. "Successful therapy with cladribine

Mastocytoses are a heterogenous group of diseases characterized by proliferation and accumulation of mast cells in the skin and other organs. They are subdivided into cutaneous mastocytoses; systemic forms, which may appear with or without skin lesions; mast cell sarcomas and extracutaneous, localized, benign mastocytomas. Systemic mastocytoses apart from the skin mainly involve bone marrow, gastrointestinal tract, bones, lymph nodes, spleen and liver. Whereas indolent forms of systemic mastocytosis are mainly treated with antihistamines, glucocorticosteroids and PUVA therapy, the more aggressive forms, including mast cell leukemia, often require cytostatic chemotherapy. A 53-year old patient with beginning "smoldering systemic mastocytosis" failed to respond to high-dose systemic glucocorticosteroids and interferon-alpha. Treatment with cladribine led to an impressive improvement of skin lesions, a significant decrease in tryptase serum levels and stabilization of bone marrow infiltrates.     

„Smouldering systemic mastocytosis“

Mastocytoses are a heterogenous group of diseases characterized by proliferation and accumulation of mast cells in the skin and other organs. They are subdivided into cutaneous mastocytoses; systemic forms , which may appear with or without skin lesions; mast cell sarcomas and extracutaneous, localized, benign mastocytomas. Systemic mastocytoses apart from the skin mainly involve bone marrow, gastrointestinal tract, bones, lymph nodes, spleen and liver. Whereas indolent forms of systemic mastocytosis are mainly treated with antihistamines, glucocorticosteroids and PUVA therapy, the more aggressive forms, including mast cell leukemia, often require cytostatic chemotherapy. A 53-year old patient with beginning “smoldering systemic mastocytosis” failed to respond to high-dose systemic glucocorticosteroids and interferon-α. Treatment with cladribine led to an impressive improvement of skin lesions, a significant decrease in tryptase serum levels and stabilization of bone marrow infiltrates.     

Bone marrow involvement in cutaneous mastocytosis

BACKGROUND: Cutaneous mastocytosis is considered a relatively benign and indolent form of mast cell disease, which either ultimately regresses, remains stable or is only slowly progressive. Previously, it has been purported that no more than 60% of adult patients with cutaneous mastocytosis will have occult bone marrow involvement. OBJECTIVES: To investigate the frequency of bone marrow involvement in patients with mastocytosis but without systemic symptoms. METHODS: Bone marrow aspirate and trephine biopsy were performed in 13 consecutive patients with cutaneous mastocytosis attending our department. RESULTS: All but one of these patients had evidence of bone marrow involvement. Bone marrow cytogenetic abnormalities have been found in patients with cutaneous mastocytosis: all our patients who were analysed showed a normal karyotype. CONCLUSIONS: Bone marrow involvement is common in adults with cutaneous mastocytosis.     

Mast cells with bilobed or multilobed nuclei in a nodular lesion of a patient with urticaria pigmentosa

Mast cells with bilobed or multilobed nuclei have only rarely been observed in the bone marrow of patients with systemic mastocytosis and in a case of subdural mast cell sarcoma. To our knowledge, they have not been reported in cutaneous mast cell disease. We report a rare occurrence of mast cells with bilobed or multilobed nuclei (atypical mast cell type II) in a nodular lesion of a 24-year-old woman with urticaria pigmentosa. The typical and atypical mast cells were confirmed by Giemsa and Leder's naphthol-AS-D-chloroacetate esterase stains and by immunohistochemical staining for tryptase and KIT protein (CD117). Although the nodular lesion with atypical mast cells did not appear to be cytologically malignant, the occurrence of atypical mast cells in a nodular lesion but not in a papular lesion might denote progression of the disease as suggested by the emergence of cells positive for p53.     

Mastocytosis – pathogenesis,clinical manifestation and treatment

The term mastocytosis designates a group of rare disorders characterized by typical skin lesions, frequently associated episodes of anaphylaxis, and clinical symptoms related to the release of various mediators. Dermatologists/allergists are frequently the first to establish the diagnosis. The condition is based on clonal mast cell proliferation, usually in the skin or bone marrow and only rarely in the gastrointestinal tract or other tissues. In general, mastocytosis has a good prognosis in terms of life expectancy. Rare variants – including mast cell leukemia, aggressive mastocytosis, and the exceedingly rare mast cell sarcoma – require cytoreductive therapy. In cases associated with hematological neoplasms, the prognosis depends on the underlying hematologic disorder.     

Urinary N-methylhistamine as an indicator of bone marrow involvement in mastocytosis

Thirty-seven patients with mastocytosis and unexplained elevated levels of urinary N-methylhistamine who were undergoing bone marrow biopsy were studied with respect to the diagnosis of mastocytosis and the manifestations of the disease. These patients were from a group of 66 patients from whom a bone marrow biopsy was obtained and urinary N-methylhistamine levels were measured in the period 1990-1998. In seven (19%) of the 37 patients, mastocytosis was limited to the skin. Five (14%) of the 37 patients showed accumulation of mast cells in the bone marrow without characteristic skin lesions, whereas seven (19%) of the 37 patients showed increased numbers of mast cells both in the skin and the bone marrow. Eighteen (49%) of the 37 patients with elevated N-methylhistamine did not have mast cell accumulation in either the skin or the bone marrow biopsy. The median level of N-methylhistamine in the urine of patients with mastocytosis limited to the skin was 245 micro mol/mol creatinine. The average level of N-methylhistamine was 509 micro mol/mol creatinine in patients with mast cell accumulation in the bone marrow and cutaneous mastocytosis. There was a significant difference in the levels of N-methylhistamine in patients with mast cell accumulation in the bone marrow biopsy compared with those without. The likelihood of mastocytosis with mast cell accumulation in the bone marrow biopsy at a given level of N-methylhistamine was calculated. It was established that an N-methylhistamine level of 297 micro mol/mol creatinine or higher may be considered as a threshold indicator for obtaining a bone marrow biopsy in patients suspected of mastocytosis with mast cell accumulation in the bone marrow. For practical purposes, we propose to consider the cut-off level of approximately 300 micro mol/mol N-methylhistamine creatinine for this assay.     

Effect of granulocyte macrophage colony-stimulating factor in a patient with benign systemic mastocytosis

We report the in vitro and in vivo effects of granulocyte macrophage colony stimulating factor (GM-CSF), a known inhibitor of in vitro mast cell differentiation, in a patient with benign, adult-onset systemic mastocytosis. In vitro effects of GM-CSF on bone marrow cultures before the start of treatment showed a marked inhibition of mast cell marker expression [tryptase, Kit, and high-affinity IgE receptor (FcepsilonRIalpha)] at both protein and mRNA levels. Therefore, the patient was treated with daily injections of GM-CSF for 10 weeks. After an initial improvement, increasing worsening of clinical symptoms was noted, and the patient refused further treatment. Lesional skin biopsies showed an increase of toluidine blue-positive mast cells, compared with uninvolved skin, with further significant increase after treatment. Similar results were obtained on staining for mast cell-specific tryptase and Kit, as well as for CD1a and FcepsilonRIalpha. These findings show that GM-CSF inhibits human bone marrow mast cell differentiation in vitro, and also in mastocytosis. However, GM-CSF apparently enhances recruitment of mast cell as well as dendritic cell precursors into the tissue during systemic treatment. These findings and the observed adverse clinical effects in the present patient make it unlikely that GM-CSF monotherapy will be beneficial for the treatment of mastocytosis.     

Neonatal mastocytosis with pachydermic bullous skin without c-Kit 816 mutation

BACKGROUND: Bullous mastocytosis is an unusual variant of mast cell disease with widespread bullae as the main cutaneous feature induced by mast cell proteases that cause dermoepidermal separation. CASE REPORT: A rare case of diffuse cutaneous bullous mastocytosis with pachydermia and unusually extensive skin folding is described in a 3-week-old girl. The diagnosis was confirmed by immunohistochemistry with Giemsa stain, the naphthol ASD chloroacetate esterase reaction and elevated blood levels for tryptase, histamine in serum and histamine and 1.4-methylimidazol acetic acid in the 24-hour urine. Blood cell count was normal, as were thrombocytosis and leukocytosis. FACS analysis of the bone marrow aspiration material showed 1% mast cells. No c-Kit 816 [Asp-->Val] somatic mutation was found. Systemic involvement of other organs was excluded. DISCUSSION: The prognosis of c-Kit-negative diffuse bullous mastocytosis is not known. Regular blood controls are mandatory, and screening for germ cell ovarian cancer and bone marrow controls should be performed as well.     

Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine

Systemic mastocytosis (SM) is a myeloproliferative disorder, characterized by a clonal proliferation of abnormal mast cells accumulating in internal organs and sometimes in the skin, leading to cutaneous and systemic symptoms. Mutations within the gene KIT, which encodes the receptor tyrosine kinase (KIT) on mast cells, is found in most patients with SM. We report a case of a 62‐year‐old woman presenting with a pruritic rash on her limbs and trunk. Several years later she developed gastrointestinal symptoms, associated with raised serum tryptase. Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa. Responses to multiple therapies, including potent topical steroids, oral antihistamines, phototherapy and the tyrosine kinase inhibitor, nilotinib, were inadequate. Treatment with cladribine (2‐chlorodeoxyadenosine) produced a marked and sustained reduction in her symptoms and serum tryptase level.     

Cutaneous mastocytosis: A dermatological perspective

Mastocytosis is a rare disease characterised by expansion and collection of clonal mast cells in various organs including the skin, bone marrow, spleen, lymph nodes and gastrointestinal tract. The prevalence of mastocytosis has been estimated to be one in 10 000, while the estimated incidence is one per 100 000 people per year. Cutaneous mastocytosis is classified into (i) maculopapular cutaneous mastocytosis, also known as urticaria pigmentosa; (ii) diffuse cutaneous mastocytosis; and (iii) mastocytoma of the skin. In adults, cutaneous lesions are usually associated with indolent systemic mastocytosis and have a chronic evolution. Paediatric patients, on the contrary, have often cutaneous manifestations without systemic involvement and usually experience a spontaneous regression. Diagnosis of cutaneous mastocytosis may be challenging due to the rarity of the disease and the overlap of cutaneous manifestations. This short review describes pathogenesis and clinical aspects of cutaneous mastocytosis with a focus on diagnosis and currently available therapies.     

Systemic mastocytosis associated with Hodgkin’s lymphoma in a 4-year-old child

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHN) represents a specific subtype of mastocytosis and is extremely rare in children. We describe a 4-year-old child with systemic mastocytosis associated with Hodgkin's lymphoma. The child had cutaneous mastocytosis and lymphadenopathy without other clinical features of SM, which was diagnosed only by bone marrow examination.     

Urticaria pigmentosa--an obligate systemic disease? Results of nuclear medicine studies and etiopathogenetic significance

The objective of the present investigation was to establish the frequency of systemic spreading of urticaria pigmentosa by means of bone and bone marrow scintigraphy as a noninvasive imaging technique with a low radiation exposure. Bone scintigraphy: Seven of nine patients investigated showed diffuse and focal nuclide accumulation. After exclusion of other causes by reference to the case history and the clinical and chemical laboratory findings, these nuclide accumulations were regarded as mastocytosis-specific in accordance with the atypical localization. Bone-marrow scintigraphy: All the patient investigated showed a peripheral expansion of the bone marrow. This must be interpreted as an expansion of the macrophages of the bone marrow on the basis of the method used. Since the mast cell is regarded as a more highly differentiated form of the same cell-type as macrophages/monocytes, on the basis of the scintigraphic results presented, urticaria pigmentosa can be regarded pathogenetically as a hyperplasia of the macrophages of the bone marrow organ, with increased differentiation in mast cells. The extent of this differentiation and its pathological quality then determine the clinical signs and symptoms (cutaneous, systemic, or malignant mastocytosis). Urticaria pigmentosa thus has the character of a systemic disease.     

Diagnosis and Treatment of Cutaneous Mastocytosis in Children

Cutaneous mastocytosis in children is a generally benign disease that can present at birth and is often associated with mast cell mediator-related symptoms including pruritus, flushing, and abdominal pain with diarrhea. The most common form of presentation is urticaria pigmentosa, also referred to as maculopapular mastocytosis. Flares of lesions are induced by triggers such as physical stimuli, changes in temperature, anxiety, medications, and exercise. The skin lesions are typically present on the extremities. Symptoms respond to topical and systemic anti-mediator therapy including antihistamines and cromolyn sodium. Remission at puberty is seen in a majority of cases. Progression to systemic mastocytosis with involvement of extracutaneous organs is not common. The cause of cutaneous mastocytosis is unknown and familial cases are rare. Mutations of c-kit have been observed in the skin of those affected. The diagnosis is established on clinical grounds and the findings on skin biopsy. Bone marrow studies are recommended if there is suspicion of progression of disease to an adult form, if cytoreductive therapy is contemplated, or if skin lesions remain present and/or tryptase levels remain elevated after puberty. The use of chemotherapy, including kinase inhibitors, is strongly discouraged unless severe hematologic disease is present, since malignant evolution is extremely rare.     

Unusual cutaneous findings of urticaria pigmentosa and telangiectasia macularis eruptiva perstans associated with marked myelofibrosis

Mastocytosis is a heterogeneous group of disorders characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and skin. We present a patient with malignant mastocytosis of 11 years' duration. This case highlights the cutaneous findings of mastocytosis with systemic involvement, yet the patient maintains a relatively normal lifestyle with only minimal discomfort and only borderline normochromic anemia. Thus his course is not truly that of malignant mastocytosis but of indolent systemic mastocytosis with cutaneous findings of telangiectasia macularis eruptiva perstans (TMEP).     

Neonatal Onset Diffuse Cutaneous Mastocytosis: A Case Report and Review of the Literature

Abstract: Diffuse cutaneous mastocytosis is a rare variant of mast cell disease with widespread erythroderma, which is normally clinically apparent in early infancy. We report the case of a neonate who presented with diffuse erythrodermic rash and bullous lesions. Biopsy specimens showed a dense dermal infiltrate of mast cells. Serum histamine and tryptase levels were elevated. No somatic mutation of the c‐kit gene was found. Blistering ceased at 5 months of age, but atopic dermatitis appeared at 6 months and allergic workup revealed a high level of food‐specific IgE. Herein, we describe the case and provide the first review of the literature on neonatal onset diffuse cutaneous mastocytosis to clarify the prognosis of this condition.     

The role of the mast cell in clinical gastrointestinal disease with special reference to systemic mastocytosis

The gastrointestinal tract is a rich source of mast cells with an enormous surface area that permits a high degree of interaction between the mast cell and intestinal luminal contents. The active metabolic products of the mast cell influence gastrointestinal secretion, absorption, and motility through paracrine effects of local mast cell degranulation and also cause systemic effects through the release of cellular products into the blood stream. Systemic mastocytosis influences physiologic function through the systemic effects of mast cell products released from focal (e.g., bone marrow) or wide spread increases in mast cell number. Local gastrointestinal proliferation of mast cells in response to recognized (e.g., gluten in celiac sprue) or obscure stimuli can alter gastrointestinal function and induce systemic symptoms. Celiac sprue, inflammatory bowel disease, and non-ulcer dyspepsia are three examples of gastrointestinal diseases in which mast cells can be implicated in the pathophysiology of the symptoms.     

Diffuse cutaneous mastocytosis with bone marrow infiltration in a child: a case report

Mastocytosis encompasses a range of disorders characterized by overproliferation and accumulation of tissue mast cells. Mast cell disease is most commonly seen in the skin, but the skeleton, gastrointestinal tract, bone marrow, and central nervous system may also be involved. We present a 10-year-old boy with diffuse cutaneous mastocytosis characterized by disseminated papular, nodular, and infiltrated leathery lesions. The patient presented with chronic diarrhea and malnutrition. Laboratory studies were normal except for an elevated urinary 1-methylhistamine level. The bone marrow aspirate showed a dense mast cell infiltrate confirming systemic involvement.