Mast cell disorders comprise a heterogeneous spectrum that ranges from solitary cutaneous mastocytoma to mast cell leukemia. The most common variants are listed below.
Telangiectasia macularis eruptiva perstans (TMEP)
Systemic mast cell disease
Mast cell leukemia
Although clonality has been demonstrated in some mast cell proliferations, their behavior is difficult to predict.
Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION DEAFNESS
Familial mastocytosis associated with neurosensory deafness.
Trevisan G, Pauluzzi P, Gatti A, Semeraro A.
Institute of Dermatology, University of Trieste, Italy.
J Eur Acad Dermatol Venereol 2000 Mar;14(2):119-22 Abstract quote
Mastocytosis is a disease characterized by excessive accumulation of mast cells in different tissues and symptoms caused by the release of mast cell mediators. The skin is frequently directly involved in mastocytosis. The disease is rarely seen in other members of the subjects' family; only 49 cases of familial mastocytosis have been reported. Familial mastocytosis associated with hearing loss may represent a newly described inherited entity.
We describe a brother and sister exhibiting skin mastocytosis and neurosensory deafness, associated with a history of hearing loss in their father's family. The appearance of the mast cell disease in two siblings, who presented with similar clinical features represents a familial form of mastocytosis; the association with an inherited form of deafness may constitute a new syndrome.
Our patients show several features similar to some previously reported cases but different insofar that additional congenital defects and mental retardation are absent.
- Combined mastocytoma-junctional nevus.
Northcutt AD, Tschen JA.
Central Texas Pathology Laboratory, Waco, Texas 76708, USA.
Am J Dermatopathol. 2004 Dec;26(6):478-81. Abstract quote
A unique combined mastocytoma-junctional nevus presented as a 4-mm dark brown macule in the axilla of a 57-year-old white female. Histopathologic examination revealed a proliferation of mast cells partially or completely filling the dermal papillae, hyperpigmentation of the basal keratinocytes and mildly increased basal melanocytes. Overlying the mast cell proliferation, pigmented junctional nevus nests were present. The mast cells were strongly positive with Giemsa stain and mast cell tryptase immunohistochemical stain; nevomelanocytic cells were negative. Nevomelanocytes were strongly immunoreactive for S100, HMB-45, Mart-1, and tyrosinase; mast cells were negative. The clinicopathologic features suggested a synchronous proliferation of 2 cell types in the same small cutaneous field rather than a collision tumor.
While the cutaneous mast cells probably originated as a disseminated clone, it is postulated that local mast cell growth factor induced nevomelanocytic proliferation and modulated mast cell growth. In fact, the tumor exhibited strong immunoreactivity for the mast cell growth factor receptor (CD117) in mast cells, basal melanocytes, and nevus nests. The incidence of dual mast cell-melanocytic tumors appears to be very low, as only 3 total cases have now been reported.
However, since in patients with multiple mastocytomas only a small fraction of lesions are biopsied, the true incidence may be higher than supposed.
Telangiectasia macularis eruptiva perstans and multiple myeloma.
Bachmeyer C, Guillemette J, Blum L, Turc Y, Dhote R, Fermand JP, Aractingi S.
Departement de Medecine Interne, Centre Hospitalier Laennec, Boulevard Laennec, BP 72, F-60109 Creil Cedex, France.
J Am Acad Dermatol 2000 Nov;43(5 Pt 2):972-4 Abstract quote
The association of mast cell diseases and some hematologic malignancies, usually myeloproliferative disorders, myelodysplastic syndromes, and acute leukemia is well recognized.
We report the case of a patient with telangiectasia macularis eruptiva perstans, a rare form of cutaneous mastocytosis, and multiple myeloma, an association that has been described only twice in the literature. Parallel improvement of both conditions was observed under chemotherapy regimens for multiple myeloma.
Pathogenesis remains unclear, although the abnormalities in the c-kit pathway may play a role in the proliferation of cells from both lineages.
Cutaneous mastocytosis associated with a mixed germ cell tumour of the ovary: report of a case and review of the literature.
Miyagawa S, Hirota S, Park YD, Yamasaki M, Daikoku N, Morikawa H, Yoshioka A, Kitamura Y, Ichijima K.
Department of Dermatology, Nara Medical University, Kashihara City, Nara 634-8522, Japan.
Br J Dermatol 2001 Aug;145(2):309-12 Abstract quote
A 10-year-old girl with a mixed germ cell tumour of the ovary, treated by surgery and chemotherapy, developed cutaneous mastocytosis approximately 8 months after starting chemotherapy.
This is the sixth report of a germ cell tumour associated with mastocytosis. c-kit receptor point mutations, including Asp816Val and Val560Gly were absent in a biopsy specimen obtained from lesional skin.
Diffuse cutaneous mastocytosis with bone marrow infiltration in a child: a case report.
Waxtein LM, Vega-Memije ME, Cortes-Franco R, Dominguez-Soto L.
Department of Dermatology, Gea Gonzalez Hospital, Mexico City, Mexico.
Pediatr Dermatol 2000 May-Jun;17(3):198-201 Abstract quote
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.
Mastocytosis complicating pregnancy.
Worobec AS, Akin C, Scott LM, Metcalfe DD.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1881, USA.
Obstet Gynecol 2000 Mar;95(3):391-5 Abstract quote
OBJECTIVE: To review the experience of women who conceived after developing mastocytosis and who were observed at the National Institutes of Health.
METHODS: We reviewed our patient database for the years 1984-1998 to identify women with mastocytosis who had conceived. We then reviewed each woman's record, asked each woman to complete a questionnaire, and with permission wrote outside hospitals to obtain records of each labor and delivery.
RESULTS: We identified eight women who had become pregnant. These women delivered a total of 11 live infants. In approximately a third of the pregnancies, patients experienced worsening of symptoms. They often used fewer medications during pregnancy because of safety concerns, and no greater incidence of adverse reactions was noted. Antihistamines were used most commonly, followed by oral prednisone. Medications used during delivery were well tolerated and included epidural analgesics. Neonates were generally healthy. None to date have developed urticaria pigmentosa or systemic mastocytosis.
CONCLUSION: A subset of women with mastocytosis might have had exacerbated mastocytosis during and after pregnancy, but labor and delivery progressed normally. Infants were born generally healthy and were without mastocytosis. Thus there appears to be no absolute contraindication to pregnancy for women with mastocytosis, although women should be aware that the choice to have a child is not without some added risk.
Urticaria pigmentosa associated with Wilms tumor.
Guler E, Emir S, Kutluk T, Varan A, Buyukpamukcu M.
Department of Pediatric Oncology, Hacettepe University Institute of Oncology, Ankara, Turkey.
Pediatr Dermatol 2001 Jul-Aug;18(4):313-5 Abstract quote
Urticaria pigmentosa is the most common manifestation of mastocytosis, with the majority of cases undergoing spontaneous resolution, especially in children. Several reports have documented hematologic malignancies developing in patients with urticaria pigmentosa.
We present a 4.5-year-old boy with urticaria pigmentosa who developed Wilms tumor. To our knowledge, coexisting urticaria pigmentosa and Wilms tumor have not previously been described.
PATHOGENESIS CHARACTERIZATION APOPTOSIS
Alteration of mast cell proliferation/apoptosis and expression of stem cell factor in the regression of mastocytoma - report of a case and a serial immunohistochemical study.
Inoue T, Yoneda K, Kakurai M, Fujita S, Manabe M, Demitsu T.
Department of Dermatology, Akita University School of Medicine, Akita, Japan, Department of Dermatology, Jichi Medical School, Tochigi, Japan, Omiya Medical Center, Jichi Medical School, Saitama, Japan.
J Cutan Pathol 2002 May;29(5):305-12 Abstract quote
Background: Spontaneous regression of solitary mastocytoma is a well-described phenomenon, but its mechanism is unknown.
Methods: Serial-section immunohistochemical analyses were performed on biopsies of a mastocytoma from a Japanese child during the proliferation stage (PS, 7 months of age) and the regression stage (RS, 5 years old).
Results: Mast cell (MC) density in RS was markedly decreased (406 cells/mm2) compared to that in PS (3554 cells/mm2). MCs in RS were larger than those in PS. With proliferative cell nuclear antigen (PCNA) staining, 1.7% MCs were positive in PS, whereas no positive MCs were seen in RS. TUNEL-labeling index (LI) in RS (2.8%) increased 1.5-fold in PS (1.9%). With stem cell factor (SCF) staining, 57% of lesional MCs in RS revealed strong cytoplasmic immunoreactivity, whereas only 9% of MCs were positive in PS. Epidermal SCF reactivity was found as intracellular and intercellular patterns in both PS and RS.
Conclusions: Loss of MC proliferating activity, an increase in apoptotic MCs, and increased expression of SCF in remaining MCs in RS may play a role in the involution of mastocytomas.
Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia.
Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R, Stein H, Valent P, Horny HP.
Institute of Pathology, University Hospital Tubingen, Germany.
Mol Pathol 2000 Aug;53(4):188-93 Abstract quote
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 cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His.
Pullarkat VA, Pullarkat ST, Calverley DC, Brynes RK.
Division of Hematology, University of Southern California School of Medicine, Los Angeles, California 90033-0804, USA.
Am J Hematol 2000 Dec;65(4):307-9 Abstract quote
Mast cell disease (MCD), a proliferation of mast cells (MC), is occasionally associated with hematologic malignancies. Neoplastic MC have activating c-kit mutations. c-kit is a receptor tyrosine kinase required for the development, proliferation, and survival of MC. Interaction of c-kit with its ligand stem cell factor induces dimerization, receptor phosphorylation, and signal transduction. The most common c-kit mutation detected in neoplastic MCD is Asp816Val, which results in ligand-independent autophosphorylation of the receptor leading to MC proliferation.
We describe the rare occurrence of MCD associated with acute myeloid leukemia, report a novel c-kit mutation Asp816 His, and discuss the pathogenesis of MCD associated with hematologic malignancies.
Cytogenetic studies in patients with mastocytosis.
Swolin B, Rodjer S, Roupe G.
Department of Clinical Chemistry and Transfusion Medicine, Ostra, Sahlgrenska University Hospital, Goteborg University, Goteborg, Sweden.
Cancer Genet Cytogenet 2000 Jul 15;120(2):131-5 Abstract quote
Chromosomal aberrations in hematopoietic cells are common in malignant hematological disorders and have also been reported in some patients with mastocytosis.
In this study, 34 patients with either urticaria pigmentosa or systemic mastocytosis were investigated by cytogenetic analysis of bone marrow cells. A follow-up investigation was performed in 22 patients. Clones with chromosome abnormalities were found in 32% of the patients at the first examination and in 27% at the second examination; in total, 41% of the patients had an abnormal clone in at least one examination. No clinical correlation was found with regard to cytogenetic results, with the exception of four patients who had an associated hematological disease and poor prognosis. In the second examination, only 6 patients had an unchanged chromosome pattern, and 4 of the patients with an initial normal pattern had appearance of abnormal clones; however, in 7 patients, the initial abnormal cells disappeared.
The abnormalities were, among others, deletions of chromosomes 5, 7, 11, and 20. The proportion of cells with structural or numerical chromosome changes was higher in comparison with reported control groups.
The frequency and type of chromosome abnormalities in bone marrow cells from patients with mastocytosis was about the same as observed in other chronic myeloproliferative disorders and myelodysplastic syndromes, diseases which also developed in 4 of our patients. An association between malignant hematological disorders and mastocytosis have been suggested by us and others. The chromosome abnormalities maybe reflect a genetic instability of the hematopoietic cells in mastocytosis.
Mastocytosis: molecular mechanisms and clinical disease heterogeneity.
Metcalfe DD, Akin C.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 11C205, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881, USA.
Leuk Res 2001 Jul;25(7):577-82 Abstract quote
Systemic mastocytosis has one unifying feature: an unexplained and pathologic increase in mast cells in specific tissues. This observation, along with clinical disease heterogeneity has long suggested that mastocytosis is a disease of complex etiology. At the same time, the last decade has witnessed significant progress in identifying the critical elements that regulate mast cell growth and development.
Human mast cells are now known to arise from CD34(+) progenitors, particularly under the influence of stem cell factor (SCF). This information in turn led to the critical observation that a substantial number of patients with mastocytosis exhibit activating mutations in c-kit, the receptor for SCF. And while this observation may well be key in understanding mastocytosis, this mutation alone does not explain all heterogeneity.
It now appears that other influences such as genetic polymorphisms within the host may influence the course of disease in those with KIT mutations; and that the search for additional molecular events capable of creating disease diversity must continue.
Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.
Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C, Larizza L.
Department of Biology and Genetics, Medical Faculty, University of Milan, via Viotti 3/5, 20133 Milan, Italy.
Cancer 2001 Aug 1;92(3):657-62 Abstract quote
BACKGROUND: Gain-of-function mutations of the c-kit protooncogene, mainly clustered in the juxtamembrane domain, have been reported in a significant fraction of gastrointestinal (GI) stromal tumors (GISTs) that represent the most common mesenchymal tumor of the GI tract. Two families also have been described with a GIST predisposition syndrome with a germline c-kit mutation affecting either the juxtamembrane domain or the tyrosine kinase domain. Here, the authors report on a family in which the dominantly inherited trait of hyperpigmented spots was inherited from an individual who developed multiple GISTs with diffuse hyperplasia of the myenteric plexus by his son, who was affected with urticaria pigmentosa.
METHODS: Screening for the c-kit mutation was performed by means of polymerase chain reaction-based denaturing gradient gel electrophoresis/constant denaturing gel electrophoresis followed by direct sequencing of abnormal conformers. Expression of KIT and CD34 was determined by immunohistochemistry.
RESULTS: In peripheral blood DNA samples, both affected family members showed a previously undescribed c-kit mutation in the juxtamembrane domain, resulting in the substitution of alanine for valine(559). Mutation and polymorphic marker analyses on DNA samples from three GISTs and two skin biopsy specimens evidenced the same mutation in the heterozygous condition. Immunohistochemical examination showed coexpression of CD117 (c-kit) and CD34 in all independent GISTs and CD117 positivity in mast cells from the skin lesions.
CONCLUSIONS: Comparative analysis of clinical presentation and mutation mapping in the families described to date point to the peculiar association of mast cells, melanocytic dysfunction, and GIST predisposition in carriers of c-kit mutations within the juxtamembrane domain.
Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis.
Fritsche-Polanz R, Jordan JH, Feix A, Sperr WR, Sunder-Plassmann G, Valent P, Fodinger M.
Department of Laboratory Medicine, Division of Endocrinology and Metabolism, University of Vienna, Vienna, Austria.
Br J Haematol 2001 May;113(2):357-64 Abstract quote
The proto-oncogene C-KIT encodes a tyrosine kinase receptor that is expressed on mast cells and haematopoietic stem cells and can show somatic mutations in patients with mastocytosis. Only scattered information is available about mutations in C-KIT in patients with other myeloid neoplasms. Moreover, the prevalence of mutations in C-KIT in bone marrow specimens of individuals with systemic mastocytosis is largely unknown.
Using sequence analysis, we have screened cDNAs of the C-KIT domain encompassing codon 510-626 and codon 763-858 in bone marrow (BM) mononuclear cells (MNCs) of patients with myelodysplastic syndromes (n = 28) and patients with systemic mastocytosis (n = 12) for the presence of mutations. Furthermore, restriction fragment length polymorphism analysis was applied for identification of the C-KIT 2468A-->T and the C-KIT 1700T-->G mutation, as well as the C-KIT 1642A-->C polymorphism. All 11 patients with systemic indolent mastocytosis tested positive for C-KIT 2468A-->T. In contrast, no mutation was identified in the case of aggressive mastocytosis. Among patients with myelodysplastic syndromes, no patient showed a somatic mutation in C-KIT. The allele frequency for C-KIT 1642A-->C among the entire patient population was 0.038 and was 0.125 among age- and sex-matched healthy controls.
Our data demonstrate that myelodysplastic syndromes without histological or cytological evidence of mastocytosis do not exhibit somatic mutations in exons 10, 11, 12, 16, 17 and 18 of C-KIT. In contrast, BM MNCs of patients with systemic indolent mastocytosis were all positive for C-KIT 2468A-->T and negative for additional mutations in these exons. The C-KIT 1642A-->C polymorphism is not associated with myelodysplastic syndrome or systemic mastocytosis.
Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology.
Akin C, Schwartz LB, Kitoh T, Obayashi H, Worobec AS, Scott LM, Metcalfe DD.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA.
Blood 2000 Aug 15;96(4):1267-73 Abstract quote
Systemic mastocytosis is a disease of mast cell proliferation that may be associated with hematologic disorders. There are no features on examination that allow the diagnosis of systemic disease, and mast cell-derived mediators, which may be elevated in urine or blood, may also be elevated in individuals with severe allergic disorders. Thus, the diagnosis usually depends on results of bone marrow biopsy.
To facilitate evaluation, surrogate markers of the extent and severity of the disease are needed. Because of the association of mastocytosis with hematologic disease, plasma levels were measured for soluble KIT (sKIT) and soluble interleukin-2 receptor alpha chain (sCD25), which are known to be cleaved in part from the mast cell surface and are elevated in some hematologic malignancies. Results revealed that levels of both soluble receptors are increased in systemic mastocytosis. Median plasma sKIT concentrations as expressed by AU/mL (1 AU = 1.4 ng/mL) were as follows: controls, 176 (n = 60); urticaria pigmentosa without systemic involvement, 194 (n = 8); systemic indolent mastocytosis, 511 (n = 30); systemic mastocytosis with an associated hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3). Plasma sCD25 levels were elevated in systemic mastocytosis; the highest levels were associated with extensive bone marrow involvement. Levels of sKIT correlated with total tryptase levels, sCD25 levels, and bone marrow pathology.
These results demonstrate that sKIT and sCD25 are useful surrogate markers of disease severity in patients with mastocytosis and should aid in diagnosis, in the selection of those needing a bone marrow biopsy, and in the documentation of disease progression.
Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis.
Escribano L, Diaz-Agustin B, Bellas C, Navalon R, Nunez R, Sperr WR, Schernthaner GH, Valent P, Orfao A.
Servicio de Hematologia, Mast Cell Unit, Hospital Ramon y Cajal, Carretera de Colmenar Km 9,1, Madrid 28034, Spain.
Leuk Res 2001 Jul;25(7):563-70 Abstract quote
The diagnosis of bone marrow (BM) involvement in mastocytosis has mainly been based on conventional histology. Nevertheless, in recent years, three major methodological advances have been made: the measurement of serum tryptase levels, the immunohistochemical assessment of mast cell (MC) tryptase, and the immunophenotypical characterization of BMMC using flow cytometry (FCM).
The most characteristic immunophenotypic feature in mastocytosis is the coexpression of CD2 and CD25 antigens, which are never present in normal BMMC and constitute a phenotypic hallmark of BMMC in adult mastocytosis. Such observations would support the need to include the immunophenotypic analysis of MC in the diagnosis of mastocytosis.
Systemic mastocytosis with involvement of the pelvis: a radiographic and clinicopathologic study--a case report.
Siegel S, Sadler MA, Yook C, Chang V, Miller J.
Department of Radiology, UMDNJ-Newark, University Hospital, New Jersey, USA.
Clin Imaging 1999 Jul-Aug;23(4):245-8 Abstract quote
The musculoskeletal manifestations of systemic mastocytosis have been described in the literature.
We present a case of systemic mastocytosis involving the pelvis. Conventional radiographs and CT imaging may demonstrate diffuse sclerotic, or mixed lytic and sclerotic lesions. On MRI, the lesions, if sclerotic, may show low signal on T1- and T2-weighted images. However, if lytic, the lesions may demonstrate low signal on T1, and increased signal on T2. As there are numerous disease entities included within the differential diagnosis, the clinical and pathological findings are crucial for establishing the correct diagnosis.
Systemic mastocytosis: MRI of bone marrow involvement.
Roca M, Mota J, Giraldo P, Garcia Erce JA.
Department of Radiology, Hospital Miguel Servet, Isabel la Catolica 1-3, E-50009 Zaragoza, Spain.
Eur Radiol 1999;9(6):1094-7 Abstract quote
Systemic mastocytosis (SM) is an abnormal proliferation of mast cells, located in different structures: skin, bone marrow, spleen, liver and lymph nodes. Magnetic resonance imaging was prospectively performed in ten patients diagnosed by bone marrow biopsy in order to describe the different patterns of bone marrow involvement. Coronal T1-weighted spin-echo images were obtained in vertebral, pelvic, humeral and femoral bones.
Depending on the extension of the cell infiltration, three patterns of bone marrow involvement were used: normal/no involvement (N), non-homogeneous (NH) and homogeneous (H). All ten patients presented bone infiltration. The patterns observed were: spine (50 % NH, 50 % H), pelvis (70 % NH), humerus 100(NH) and femur 40 % (NH). T1-weighted MR imaging is a sensitive technique for detecting marrow abnormalities in patients with systemic mastocytosis.
There is no correlation between percentage of mast cells in bone marrow biopsy and extent or pattern of bone marrow involvement.
CHARACTERIZATION GASTROINTESTINAL TRACT
- Systemic Mastocytosis Mimicking Inflammatory Bowel Disease: A Case Report and Discussion of Gastrointestinal Pathology in Systemic Mastocytosis.
Departments of *Pathology daggerMedicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA.
- Am J Surg Pathol. 2006 Nov;30(11):1478-1482. Abstract quote
Gastrointestinal (GI) symptoms are present in up to 80% of patients with systemic mastocytosis (SM). GI symptoms include mainly abdominal pain, diarrhea, nausea, and vomiting. It is believed that most of the GI symptoms are due to the secondary effect of mast cell mediators on the GI tract. Direct involvement of the GI tract by neoplastic mast cell infiltration has not been well documented.
We report a case of SM that initially mimicked inflammatory bowel disease based on clinical, radiographic, endoscopic, and histopathologic findings. On routine histologic sections of small bowel and colonic mucosal biopsies, there was expansion of the lamina propria by mononuclear inflammatory cells, foci of erosions with associated acute inflammation, and evidence of chronic mucosal injury with architectural distortion and gland foreshortening. Only on repeat biopsies and with ancillary tests for mast cells was a diagnosis of SM made, with extensive involvement of the GI tract.
This is the first reported case of SM presenting as and mimicking inflammatory bowel disease. It is critical that clinicians and pathologists are aware that neoplastic mast cells in patients with SM can infiltrate the mucosa throughout the GI tract and that this infiltration can lead to symptoms and findings that can mimic inflammatory bowel disease.
Arch Pathol Lab Med. 2006 Mar;130(3):362-7. Abstract quote
CONTEXT: In some adult patients with chronic intractable diarrhea, the diagnosis remains elusive even after detailed evaluations, and colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining.
OBJECTIVES: To assess the concentration of mast cells in colonic or duodenal biopsy specimens by immunohistochemical analysis for mast cell tryptase from patients with chronic intractable diarrhea and to evaluate their response to drugs affecting mast cell function.
DESIGN: Mast cells per high-power field were assessed in biopsy specimens from 47 patients with chronic intractable diarrhea, from 50 control subjects, and from 63 patients with other specific diseases that cause chronic diarrhea (inflammatory bowel disease, celiac disease, collagenous colitis, and lymphocytic colitis). Patients with chronic intractable diarrhea who had more than 20 mast cells per high-power field were administered drugs affecting mast cell mediator function and release.
RESULTS: The mean +/- SD concentration of mast cells in the 50 control subjects was 13.3 +/- 3.5 cells per high-power field; hence, patients with more than 20 mast cells per high-power field were considered to have increased mast cells. Thirty-three (70%) of 47 patients with chronic intractable diarrhea had increased mast cells, and symptoms were controlled by drug therapy in 22 (67%) of the 33 patients. No patient had systemic or cutaneous mastocytosis. No increase in mast cells was seen in patients with other common causes of chronic diarrhea.
CONCLUSIONS: In chronic intractable diarrhea, colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining, but increased mast cells may be demonstrated by immunohistochemistry for mast cell tryptase, with the novel term mastocytic enterocolitis describing this condition. Similar increases in mast cells are not apparent in control populations or in patients with other specific diseases that cause chronic diarrhea. The cause of the increased mast cells remains to be elucidated.
Presentation of cutaneous mastocytosis in 173 children.
Hannaford R, Rogers M.
New Children's Hospital, Sydney, New South Wales, Australia.
Australas J Dermatol 2001 Feb;42(1):15-21 Abstract quote
This is a retrospective review of the case files and clinical photographs of 173 children diagnosed with cutaneous mastocytosis by a dermatologist in an exclusively paediatric practice.
Of the 98 males and 75 females, 51% had mastocytomas, 47% had urticaria pigmentosa and three patients had diffuse cutaneous mastocytosis. Of these cases, 87% first appeared prior to or at 6 months of age. Flushing occurred in 26% of urticaria pigmentosa cases, 29% of mastocytomas and 100% of diffuse cutaneous mastocytosis. Blistering was noted in 23% of urticaria pigmentosa, 31% of mastocytomas and 100% of diffuse cases. Neither symptom was noted in 59% of urticaria pigmentosa and 49% of mastocytomas. There were three cases with a positive family history.
The finding of a palmar mastocytoma has only once been previously reported. Illustrated descriptions of our cases are provided.
Nodular and bullous cutaneous mastocytosis of the xanthelasmoid type: case report.
Husak R, Blume-Peytavi U, Pfrommer C, Geilen CC, Goerdt S, Orfanos CE.
Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Br J Dermatol 2001 Feb;144(2):355-8 Abstract quote
Severe generalized nodular and bullous mastocytosis of the xanthelasmoid type is described in a 7-month-old boy. Reddish to yellowish-brown xanthelasmoid papules and nodules first developed in the inguinal region a few weeks after birth and then progressively spread to cover nearly the entire body surface. There was severe pruritus and recurrent episodes of blistering.
The diagnosis of cutaneous mastocytosis of the xanthelasmoid type with subepidermal bullae was confirmed by skin biopsies showing solid and deeply penetrating infiltrates of metachromatic mast cells under light and electron microscopy. Systemic involvement of other organs, however, was excluded by bone scintigraphy, abdominal ultrasound, bone marrow aspiration and echocardiography. The extensive skin involvement was reflected in highly elevated urinary levels of histamine (263.4 microg L(-1)) and its metabolite N-methylimidazole acetic acid (20.8 mg L(-1)).
The patient was systematically well and received only symptomatic treatment. Over a period of 1 year, the condition gradually improved, and the skin lesions began to flatten and regress.
Clinical and histopathological aspects of cutaneous mastocytosis.
Wolff K, Komar M, Petzelbauer P.
Department of Dermatology, Division of General Dermatology, University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Leuk Res 2001 Jul;25(7):519-28 Abstract quote
The organ most frequently involved in mastocytosis is the skin. Cutaneous mastocytosis (CM) is classified according to clinical presentation and is further defined by onset of disease.
CM tends to appear early in life but adult onset CM occurs. CM in children has a low incidence of systemic involvement whereas systemic mastocytosis occurs in >25% of CM in adults. Almost all patients with CM belong into the indolent category of the consensus revised classification (Valent et al., Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leukemia Research 2001;25:603-625.) and thus have a good prognosis.
CM of infancy and childhood frequently involutes spontaneously, CM of adults does not. The prevalence of the disease is unknown and familiar occurrence is very rare.
Familial cutaneous mastocytosis.
Chang A, Tung RC, Schlesinger T, Bergfeld WF, Dijkstra J, Kahn TA.
Department of Dermatology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Pediatr Dermatol 2001 Jul-Aug;18(4):271-6 Abstract quote
Cutaneous mastocytosis appears to occur sporadically; however, familial inheritance has been reported in 50 families since the mid-1880s.
We report four cases of telangiectasia macularis eruptiva perstans (TMEP) occurring in three generations of a family. Whereas most patients with TMEP manifest in adulthood, all of the members of this family developed initial lesions during childhood.
This is the third documented instance of familial mastocytosis affecting members of three generations, and the first report of familial TMEP. Although the inheritance pattern is unknown, the presentation of disease in this family further supports the hypothesis of an autosomal dominant mode of transmission with incomplete penetrance.
Complex karyotype and absence of mutation in the c-kit receptor in aggressive mastocytosis presenting with pelvic osteolysis, eosinophilia and brain damage.
Jost E, Michaux L, Vanden Abeele M, Boland B, Latinne D, Godfraind C, Scheiff JM, Vaerman JL, Lecouvet F, Ferrant A.
Department of Hematology, Universite Catholique de Louvain, Bruxelles, Belgium.
Ann Hematol 2001 May;80(5):302-7 Abstract quote
Aggressive mastocytosis is a form of systemic mast cell disease (SMCD) characterized by organ infiltration, bone lesions. eosinophilia and lymphadenopathies.
Here we report a patient with unusual clinical features, namely osteolysis without other bone lesions commonly found in SMCD, major eosinophilia and cerebral infarction. The mast cells exhibited a classical immunophenotype (CD2+, CD9+, CD13+, CD25+, CD35+, CD45c+ and CD117+). Cytogenetic investigation showed novel complex aberrations, and clonal evolution was correlated with clinical progression. The screening for recurrent point mutations affecting the c-kit gene was negative. Mainly, the ASP816VAL substitution was not detected in our patient. Treatment with steroids and interferon was only temporarily effective.
Slowly progressive systemic mastocytosis with high mast-cell burden and no evidence of a non-mast-cell hematologic disorder: an example of a smoldering case?
Akin C, Scott LM, Metcalfe DD.
Room 11C205, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, MSC-1881, Bethesda, MD 20892, USA.
Leuk Res 2001 Jul;25(7):635-8 Abstract quote
A 43-year-old man with extensive systemic mastocytosis with poor prognostic indicators but no overt hematologic abnormality is described.
This patient's clinical presentation and course are consistent with the newly proposed 'smoldering mastocytosis' category. Long-term follow-up of patients is needed to determine whether they may be at higher risk for progression into more aggressive categories.
A case of 'smouldering' mastocytosis with high mast cell burden, monoclonal myeloid cells, and C-KIT mutation Asp-816-Val.
Jordan JH, Fritsche-Polanz R, Sperr WR, Mitterbauer G, Fodinger M, Schernthaner GH, Christian Bankl H, Gebhart W, Chott A, Lechner K, Valent P.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Vienna, Austria.
Leuk Res 2001 Jul;25(7):627-34 Abstract quote
Mastocytosis is a term used for a group of disorders characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems. In patients with systemic mastocytosis (SM) the clinical course may be indolent or aggressive or even complicated by leukemic progression or an associated clonal hematologic non mast cell lineage disease (AHNMD). However, at first presentation (diagnosis) it may be difficult to define the category of disease and the prognosis.
We report on a 48-year-old female patient with SM with urticaria pigmentosa-like skin lesions and mediator-related symptoms. She was found to have splenomegaly, a high infiltration grade (MC) in bone marrow biopsies (>30%), mild anemia, and a high serum tryptase level (>500 ng/ml). In addition, she exhibited discrete histologic signs of myeloproliferation in the 'non-affected' marrow and monoclonal blood cells established by C-KIT 2468A-->T mutation (Asp-816-Val) -analysis and HUMARA assay. Despite these findings, however, the clinical course was stable over years and no AHNMD or organ impairment developed.
Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'.
VARIANTS ALOPECIA, SCARRING
Scarring alopecia associated with mastocytosis.
Xu X, Solky B, Elenitsas R, Cotsarelis G.
Departments of Pathology and Laboratory Medicine, Hospital of University of Pennsylvania, Philadelphia, PA, Department of Dermatology, Harvard Medical School, Boston, MA, and Department of Dermatology, Hospital of University of Pennsylvania, Philadelphia, PA, USA.
J Cutan Pathol. 2003 Oct;30(9):561-565. Abstract quote
BACKGROUND: Mastocytosis is comprised of a group of heterogeneous diseases involving various organs. Urticaria pigmentosa is the most common manifestation of cutaneous mastocytosis; others include mastocytoma, diffuse mastocytosis, and telangiectasia macularis eruptiva perstans.
METHODS: We describe a case of indolent mastocytosis presenting as scarring alopecia. The scalp biopsy revealed a perifollicular and dermal inflammatory infiltrate composed predominantly of mast cells, which was confirmed by tryptase and Giemsa stains.
RESULTS: The preponderance of mast cells in the biopsy prompted testing for urine N-methylhistamine levels, which were elevated and confirmed the diagnosis of mastocytosis. This is the first report of mastocytosis presenting as scarring alopecia.
CONCLUSIONS: This case suggests that the diagnosis of mastocytosis should be entertained in patients presenting with scarring alopecia accompanied by an intense mast cell infiltrate on scalp biopsy and also supports the notion that mast cells may be involved in the pathogenesis of alopecia.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Diagnostic criteria and classification of mastocytosis: a consensus proposal.
Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nunez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM.
Department of Internal Medicine I, Division of Hematology, University of Vienna, Wahringer Gurtel 18-20 Vienna, Austria.
Leuk Res 2001 Jul;25(7):603-25 Abstract quote
The term 'mastocytosis' denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis.
Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement.
Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin.
Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an associated clonal hematologic non-mast cell lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a 'high-grade' leukemic disease defined by increased numbers of MC in bone marrow smears (>or=20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to >or=10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another.
In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.
Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings.
Horny HP, Valent P.
Institute of Pathology, Medical University of Lubeck, Ratzeburger Allee 160, D-23538 Lubeck, Germany.
Leuk Res 2001 Jul;25(7):543-51 Abstract quote
An increase in mast cell (MC) numbers in hemopoietic tissues may be associated with (a) primary neoplastic MC disease (mastocytosis); (b) non-mast cell lineage myelogenous disorders (myelodysplastic or myeloproliferative syndromes and myeloid leukemias); or (c) reactive, i.e. non-clonal states (MC hyperplasia and reactive mastocytosis).
However, the histologic discrimination between hyperplastic states and neoplastic MC proliferative disorders is sometimes very difficult.
MC hyperplasia is characterized by a diffuse increase in mature, round or spindle-shaped, metachromatic MC that are loosely scattered throughout the tissue and do not form dense focal infiltrates, even in states of marked hyperplasia. However, loosely scattered MC are also a prominent feature of many cases of myelodysplastic syndromes and acute leukemia involving the MC lineage.
In contrast, the demonstration of dense, focal and/or diffuse MC infiltrates can be regarded as indicative of primary MC disease/mastocytosis. In addition to the highly diagnostic focal MC infiltrates, mastocytosis may also present with a predominantly diffuse or a mixed (diffuse and focal) infiltration pattern. The relatively rare diffuse pattern is usually dominated by atypical, often hypogranulated or even non-metachromatic MC and is associated with the aggressive or frankly malignant subtypes of systemic mastocytosis and MC leukemia.
Although the demonstration of MC infiltrates in Giemsa-stained tissue sections is still very important for the diagnosis of mastocytosis, immunohistochemical techniques using antibodies against MC-associated antigens such as tryptase or c-kit (CD117) are essential for the identification of highly atypical, hypogranulated MC, especially in MC leukemia, and for the detection of small and even minute MC infiltrates.
Mast cells with bilobed or multilobed nuclei in a nodular lesion of a patient with urticaria pigmentosa.
Hu S, Kuo TT, Hong HS.
Am J Dermatopathol 2002 Dec;24(6):490-2 Abstract quote
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.
SKIN Cutaneous mastocytoma Urticaria pigmentosa Telangiectasia macularis eruptiva perstans SYSTEMIC DISEASE Systemic mast cell disease (SMCD) Hum Pathol 1985;16(8):808-814 Type 1 (Benign Systemic Mastocytosis)
Generally involves the skin as well as the reticuloendothelial system
Paratrabecular aggregates of mast cells accompanied by dense reticulin, thickening of the adjacent bony trabeculae, and increased lymphocytes and plasma cells within the aggregates
A rim of increased eosinophils often surrounds the aggregates
The non-infiltrated marrow fat and hematopoeisis are normal
Type 2 disease (Malignant Mastocytosis)
In addition to the marrow findings seen with Type 1 disease, marked fibrosis and osteosclerosis, but does not usually demonstrate increased lymphocytes and plasma cells within the mast cell aggregates
The non-mast cell infiltrated marrow shows decreased fat content and increased granulocytopoiesis or myeloid blast cells
Type 3 disease (Malignant Mastocytosis) Characterized by diffuse marrow infiltration with atypical mast cells, hypoplasia of the marrow hematopoietic cells, and may demonstrate mast cell leukemia VARIANTS SKIN-BULLOUS
Bullous mastocytosis: a fatal outcome.
Murphy M, Walsh D, Drumm B, Watson R.
Department of Dermatology, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
Pediatr Dermatol 1999 Nov-Dec;16(6):452-5 Abstract quote
A 6-week-old boy was referred with a generalized bullous rash since birth. Examination revealed bullous mastocytosis with initially no evidence of systemic involvement. Hepatosplenomegaly was noted at 6 months, and at 12 months he was found to have generalized lymphadenopathy. He developed bouts of vomiting associated with increased blistering. At 17 months he had sudden collapse following a brief bout of vomiting and was apneic and asystolic on arrival at the emergency department. The cause of death was attributed to massive hypotension secondary to mast cell degranulation.
Although childhood mastocytosis has a favorable course in general, the subset of children with congenital bullous mastocytosis is at higher risk of sudden death and a more guarded prognosis should be given.
- Delineation of Patterns of Bone Marrow Mast Cell Infiltration in Systemic Mastocytosis : Value of CD25, Correlation With Subvariants of the Disease, and Separation From Mast Cell Hyperplasia.
Krokowski M, Sotlar K, Krauth MT, Fodinger M, Valent P, Horny HP.
Institute of Pathology, University of Lubeck, Lubeck, Germany.
Am J Clin Pathol. 2005 Oct;124(4):1-10. Abstract quote
In most cases, the diagnosis of systemic mastocytosis (SM) is based on histomorphologic evaluation of the bone marrow.
We analyzed mast cell (MC) infiltration patterns in 57 cases of SM and 31 cases of mast cell hyperplasia (MCH). Tryptase immunohistochemical analysis was used for MC detection and CD25 to distinguish neoplastic from normal MCs. The following infiltration patterns were found: I, diffuse interstitial; II, focal, dense; III, focal, dense with an additional diffuse component, located preferentially around focal infiltrates; IV, focal, dense with an additional diffuse component evenly distributed throughout; and V, diffuse, dense.
In 29 cases of MCH, MCs formed the type I pattern. The majority of SM cases exhibited patterns II to V; type IV was the most frequent (n = 36). Type V was seen in 3 cases of MC leukemia and 1 case of smoldering SM. In 1 case of SM, type I infiltration was found; the SM diagnosis was based on 3 minor SM criteria.
Our data show that the infiltration pattern in SM correlates with the disease subtype and should be recognized as an important aspect in the histomorphologic evaluation of the bone marrow.
Bone Marrow Biopsies for the Diagnosis of Systemic Mastocytosis Is One Biopsy Sufficient?
Joseph H. Butterfield, MD, and Chin-Yang Li, MD
Am J Clin Pathol 2004;121:264-267 Abstract quote
The medical records of 21 patients evaluated for mastocytosis and 2 patients seen for follow-up of known mastocytosis who underwent bilateral iliac crest aspirations and biopsies were reviewed retrospectively to determine whether mastocytosis could be confirmed in each of a patient's biopsy specimens.
In 19 cases (83%), each biopsy specimen showed evidence of mastocytosis; however, in 4 cases (17%), only 1 of 2 biopsy sites revealed mastocytosis. Compared with the 4 patients with only a unilateral positive biopsy result, the bilateral group had significantly higher urinary excretion of 11 b -prostaglandin F 2a , higher serum tryptase levels, and higher serum calcitonin values, and a higher percentage had splenomegaly (37% [7/19] vs 0% [0/4]). The 2 groups could not be distinguished by the main initial symptom(s), presence of urticaria pigmentosa, or other laboratory findings (alkaline phosphatase, aspartate transaminase, or hemoglobin concentrations or total WBC, total eosinophil, or platelet counts).
Bilateral biopsies might be useful for diagnosing early systemic mastocytosis or detecting minimal bone marrow involvement.
An Immunohistochemical Study of the Bone Marrow Lesions of Systemic Mastocytosis
Expression of Stem Cell Factor by Lesional Mast Cells
Cem Akin, MD, PhD
Elaine S. Jaffe, MD
Mark Raffeld, MD
Arnold S. Kirshenbaum, MD
Trisha Daley, MD
Pierre Noel, MD
Dean D. Metcalfe, MD
Am J Clin Pathol 2002;118:242-247 Abstract quote
The bone marrow biopsy in mastocytosis often reveals characteristic mast cell collections associated with lymphoid cell aggregates. There is limited information on the composition of these aggregates and whether they contain cytokines important to mast cell growth and development.
We thus performed an immunohistochemical characterization of bone marrow lesions in 7 patients with systemic indolent mastocytosis. In nodular lesions, the collections of mast cells were surrounded by lymphoid aggregates; these aggregates consisted of a mixture of B and T cells. Immunohistochemical staining for stem cell factor (SCF) revealed the presence of this cytokine in the lesional mast cells with a granular staining pattern.
These results show that the characteristic nodular lesions observed in bone marrow biopsy specimens of patients with mastocytosis bear features of benign lymphoid aggregates and that SCF is present in these lesions, creating a potential autocrine or paracrine growth and differentiation loop for mast cells and lymphoid progenitors.
Bone Marrow Mast Cell Morphologic Features and Hematopoietic Dyspoiesis in Systemic Mast Cell Disease
Eric C. Stevens, MD, and Nancy S. Rosenthal, MD disorders.
Am J Clin Pathol 2001;116:177-182 Abstract quote
Systemic mast cell disease (SMCD) cannot be distinguished from reactive mastocytosis (RM) by quantitation of mast cells in aspirate smears, and few studies have analyzed systematically the morphologic features of mast cells in SMCD vs RM. In addition, although SMCD is associated with myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS), it is not known whether subtle signs of dysplasia or MPD can be found in SMCD, suggesting most cases are part of a dysplastic or myeloproliferative process.
We compared 18 bone marrow specimens with SMCD with 10 bone marrow specimens from patients with RM. Mast cells in SMCD were more likely to show cytoplasmic hypogranularity, uneven granule distribution, and fusiform morphologic features. Eight cases of SMCD (44%) demonstrated MPD/MDS, and 9 cases (50%) showed subtle evidence of dyspoiesis, with megaloblastic change, nuclear budding of erythroid precursors, and/or atypical megakaryocytes. Mast cells in SMCD appear morphologically different from those in reactive proliferations. Dyspoietic features were present in most cases of SMCD, suggesting that SMCD is part of a spectrum of chronic myeloproliferative/myelodysplastic disorders.
- An unusual mastocytoma with massive eosinophilic infiltration: identification with immunohistochemistry.
Ueng SH, Kuo TT.
Department of Pathology, Chang Gung Memorial Hospital, Taipei 105, Taiwan.
Am J Dermatopathol. 2004 Dec;26(6):475-7. Abstract quote
A cutaneous mastocytoma excised from a 6-month-old male infant was found to have unusual massive eosinophilic infiltrates.
The mast cells were identified with the aid of immunohistochemistry with antibodies to tryptase and KIT protein (CD117).
Massive eosinophilic infiltration in a cutaneous tumor could be a diagnostic clue of an eosinophil-rich mastocytoma.
MAST CELL SARCOMA
Morphologic and immunophenotypic properties of neoplastic cells in a case of mast cell sarcoma.
Chott A, Guenther P, Huebner A, Selzer E, Parwaresch RM, Horny HP, Valent P.
Am J Surg Pathol. 2003 Jul;27(7):1013-9 Abstract quote
Mast cell sarcoma is an extremely rare and aggressive type of mast cell disease. Only a few cases have been described so far, and little is known about the biology and phenotype of afflicted cells.
We describe morphologic and immunophenotypic properties of neoplastic mast cells in a case of an intracranial mast cell sarcoma. In Wright-Giemsa-stained cytospin preparations, the morphology of dispersed cells appeared to be highly atypical with a considerable percentage of metachromatic blasts and mast cells with bilobed or multilobed nuclei. Combined toluidine blue/immunofluorescence staining revealed expression of CD13, CD45, CD88, CD116, and CD117 (c-KIT) on neoplastic mast cells. As assessed by immunohistochemistry, mast cells were immunoreactive for tryptase and CD68R, In contrast, the CD2 antigen that is expressed in mast cells in patients with indolent systemic mastocytosis was not detectable. Mast cells also failed to display the c-KIT mutation Asp-816-Val, which is typically found in systemic mast cell disorders.
Together, neoplastic mast cells in a case of mast cell sarcoma were found to exhibit unique morphologic, phenotypical, and molecular features when compared with mast cells in indolent mastocytosis or normal tissue mast cells.
MYELOMASTOCYTIC OVERLAP SYNDROME
Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis.
Valent P, Sperr WR, Samorapoompichit P, Geissler K, Lechner K, Horny HP, Bennett JM.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Wahringer Gurtel 18-20, 1090 Vienna, Austria.
Leuk Res 2001 Jul;25(7):595-602 Abstract quote
Although mast cells (MC) appear to be myeloid cells, MC lineage involvement in myelogenous malignancies has been described only rarely. Based on clonal evolution, biology of afflicted cells, and disease criteria, three major groups of patients have been recognized:
The first meets criteria for both diagnoses 'systemic mastocytosis' and 'associated hematologic clonal non-mast cell lineage disease (AHNMD)'. In such patients, myeloproliferative (MPS) or myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML) is diagnosed apart from mastocytosis.
In a second group of patients, large numbers of very immature MC-lineage cells (metachromatically granulated blast-like cells) are detectable, but the criteria to diagnose mastocytosis are not met. These patients have advanced myeloid neoplasms (MDS or MPS with blast cell increase, or AML) and variably suffer from mediator-related symptoms (flush, GI-tract ulcer, diarrhoea, coagulopathy).In some cases, the disease mimics mast cell- or basophilic leukemia. In contrast to basophilic leukemia, however, the metachromatic cells are strongly KIT+ and tryptase+. In contrast to true mast cell leukemia (MCL), MC do not form multifocal dense infiltrates in the bone marrow. Also, MC lack CD2 and CD25, and the C-KIT mutation Asp-816-Val. We propose the term 'myelomastocytic leukemia' or 'myelodysplastic mast cell syndrome' for these cases.
In a third group of patients, myeloid neoplasms (MDS, MPS, AML) show constitutive expression of MC-associated antigens (tryptase, histamine) or mastocytosis-related gene defects (mutated C-KIT) without significant increase in metachromatic cells or criteria of mastocytosis. Whether these neoplasms display aberrant gene expression (or gene defects) or represent 'pre-pre-mast cell leukemias', remains unknown.
CHARACTERIZATION Special stains Leder stain
Immunoperoxidase Paraffin Section Immunophenotype of Cutaneous and Extracutaneous Mast Cell Disease
Comparison to Other Hematopoietic Neoplasms
Fan Yang, M.D., Ph.D.; Tien-Anh Tran, M.D.; J. Andrew Carlson, M.D.; Eric D. Hsi, M.D.; Charles W. Ross, M.D.; Daniel A. Arber, M.D.
From the Division of Pathology, City of Hope National Medical Center, Duarte, California, U.S.A. (F.Y., D.A.A.); the Departments of Pathology Albany Medical Center, Albany, New York, U.S.A. (T.A.T., J.A.C.) and Cleveland Clinic, Cleveland, Ohio, U.S.A. (E.D.H.); and University of Michigan Medical School, Ann Arbor, Michigan, U.S.A. (C.W.R.).
Am J Surg Pathol 2000;24:703-709 Abstract quote
Mast cell disease (MCD) is a rare proliferation that may be easily confused with other hematopoietic tumors. Several paraffin section antibodies immunoreact with mast cells but most are not specific. Tryptase, a specific marker of mast cells, may not be cost-effective to maintain in a laboratory because of the rarity of these lesions.
This study was undertaken to assess the immunoreactivity of MCD and attempt to select a limited antibody panel for diagnosing MCD among hematopoietic tumors that morphologically mimic MCD.
Immunophenotyping of cutaneous (10 cases) and extracutaneous (18 cases) MCD, as well as 94 other hematopoietic neoplasms, was performed on paraffin sections. All cases of MCD showed strong and diffuse positivity for CD68 and tryptase. In the vast majority of the cases, the mast cells were also positive for CD117 (27 of 28) and CD43 (25 of 27). Four cases (40%) of cutaneous MCD demonstrated a subpopulation of mast cells expressing myeloperoxidase (MPX), whereas all extracutaneous MCD were negative for MPX. Two (40%) extramedullary myeloid tumors (EMT) expressed CD43, CD68, CD117, and MPX, but none expressed tryptase. CD43, CD68, CD117, and tryptase were expressed by 25%, 1%, 15%, and 1%, respectively, of all B-cell lymphoid neoplasms, and none expressed more than one of these four antigens.
We conclude that (1) cutaneous MCDs may demonstrate a subpopulation of MPX antigen expressing tumor cells and may be confused with cutaneous involvement by myeloid leukemia if other antibodies are not used; (2) tryptase is the most specific mast cell marker among the antibodies studied; and, (3) the detection of tryptase, together with CD68, CD117, and usually CD43, is unique to MCD among hematopoietic tumors.
Utility of Paraffin Section Immunohistochemistry for C-KIT (CD117) in the Differential Diagnosis of Systemic Mast Cell Disease Involving the Bone Marrow
Am J Surg Pathol 2000;24:81 Abstract quote
Immunohistochemistry for the C-KIT encoded tyrosine kinase receptor protein, CD117, for detection of mast cells on paraffin sections of 89 bone marrow specimens including systemic mast cell disease and other disorders. CD117 staining was found in all cases of mast cell disorders (seven of seven), and in one case of chronic myelogenous leukemia in blast crisis. None of the other myeloid disorders tested (0 of 16), or any of the cases of Hodgkin's disease (0 of 12), B-cell lymphomas (0 of 32), T-cell lymphomas (0 of 3), or histiocytic proliferations (0 of 3) showed staining for CD117.
CD117 expression is effective in the separation of mast cell disease from disorders that may simulate it histologically.
Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L).
Jordan JH, Walchshofer S, Jurecka W, Mosberger I, Sperr WR, Wolff K, Chott A, Buhring HJ, Lechner K, Horny HP, Valent P.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Vienna, Austria.
Hum Pathol 2001 May;32(5):545-52 Abstract quote
In an attempt to identify novel diagnostic markers for mast cell (MC)-proliferative disorders, serial bone marrow (bm) sections of 22 patients with mastocytosis (systemic indolent mastocytosis, n = 19; mast cell leukemia [MCL], n = 1; isolated bm mastocytosis, n = 2) were analyzed by immunohistochemistry using antibodies against CD2, CD15, CD29, CD30, CD31, CD34, CD45, CD51, CD56, CD68R, CD117, HLA-DR, bcl-2, bcl-x(L), myeloperoxidase (MPO), and tryptase.
Staining results revealed expression of bcl-x(L), CD68R, and tryptase in neoplastic MCs (focal dense infiltrates) in all patients. Mastocytosis infiltrates were also immunoreactive for CD45, CD117 (Kit), and HLA-DR. In most cases, the CD2 antibody produced reactivity with bm MCs in mastocytosis, whereas in control cases (reactive bm, immunocytoma, myelodysplastic syndrome), MCs were consistently CD2 negative. Expression of bcl-2 was detectable in a subset of MCs in the patient with MCL, whereas no reactivity was seen in patients with SIM or bm mastocytosis. Mastocytosis infiltrates did not react with antibodies against CD15, CD30, CD31, CD34, or MPO.
In summary, our data confirm the diagnostic value of staining for tryptase, Kit, and CD68R in mastocytosis. Apart from these, CD2 may be a novel useful marker because MCs in mastocytosis frequently express this antigen, whereas MCs in other pathologic conditions are CD2 negative.
- CD25 Expression on Cutaneous Mast Cells From Adult Patients Presenting With Urticaria Pigmentosa is Predictive of Systemic Mastocytosis.
*Department of Pathology, Brigham and Womenʼs Hospital and Harvard Medical School, Boston, MA †Department of Pathology, Western General Hospital, Edinburgh, UK.
- Am J Surg Pathol. 2008 Jan;32(1):139-145. Abstract quote
Urticaria pigmentosa (UP) is a clinicopathologic term used to describe reddish-brown cutaneous macules and papules, characterized histologically by mast cell infiltration of the papillary and upper reticular dermis and reactive basal hyperpigmentation of the overlying epidermis. Although typically a benign, self-limited disorder of childhood, a significant proportion (up to 30%) of adolescent and adult-onset UP represents cutaneous involvement by underlying systemic mastocytosis (SM). Predicting the course of cutaneous mast cell disease has been limited by a lack of diagnostic and prognostic markers. In patients with SM, neoplastic bone marrow mast cells show aberrant surface expression of CD25. However, whether CD25 expression on cutaneous mast cells is associated with underlying SM is unknown.
In this study, we performed a clinicopathologic analysis of 30 adult patients presenting with UP between 1987 and 2007. Cutaneous mast cell infiltration pattern, cytomorphology, density, and CD25 immunoreactivity were correlated with underlying or subsequent SM. On the basis of clinical and pathologic follow-up, 10 of 30 (33%) patients were diagnosed with SM and 20 of 30 (67%) with limited cutaneous mastocytosis (CM). Although cutaneous mast cell density was slightly higher in patients with SM compared to those with limited CM (P=0.047), neither mast cell cytomorphology nor infiltration pattern correlated with underlying systemic disease. However, cutaneous mast cells from all 10 patients with SM (100%) were immunoreactive for CD25, compared to only 5 of 20 (25%) with limited CM (P<0.001).
Our findings suggest that immunoreactivity for CD25 in cutaneous mast cells may be useful for stratifying adult patients presenting with UP for additional clinical evaluation.
CD25 Indicates the Neoplastic Phenotype of Mast Cells: A Novel Immunohistochemical Marker for the Diagnosis of Systemic Mastocytosis (SM) in Routinely Processed Bone Marrow Biopsy Specimens.
Sotlar K, Horny HP, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, Valent P.
*Institute of Pathology, University of Tubingen, Tubingen, Germany; daggerInstitute of Pathology, University of Lubeck, Lubeck, Germany; double daggerDepartments of Clinical Pathology and Internal Medicine I, section signDivision of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria; and paragraph signSt. Anna Childrens Hospital, Vienna, Austria.
Am J Surg Pathol. 2004 Oct;28(10):1319-1325 Abstract quote
The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available.
We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit.
CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.
- Immunohistochemical detection of histidine decarboxylase in neoplastic mast cells in patients with systemic mastocytosis.
Krauth MT, Agis H, Aichberger KJ, Simonitsch-Klupp I, Mullauer L, Mayerhofer M, Bohm A, Horny HP, Valent P.
Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Austria.
Hum Pathol. 2006 Apr;37(4):439-47. Epub 2006 Feb 7. Abstract quote
Synthesis of histamine in hematopoietic progenitor cells may be one of the earliest events in mastopoiesis. We therefore asked whether the key enzyme involved in histamine production, histidine decarboxylase (HDC), can be used as an immunohistochemical marker for the detection of immature neoplastic mast cells (MC) in patients with MC-proliferative disorders.
To address this question, we examined bone marrow biopsy specimens in a cohort of 102 patients with mastocytosis using an antibody against HDC. Independent of the maturation stage of MC, the anti-HDC antibody produced clear diagnostic staining results in all patients with systemic MC disease examined including those with MC leukemia and MC sarcoma, in which MCs are particularly immature. In these patients, expression of HDC was reconfirmed at the messenger RNA level by reverse transcriptase polymerase chain reaction analyses performed with RNA of highly enriched CD117(+) MC.
In summary, HDC is expressed in neoplastic MC in patients with systemic mastocytosis independent of the maturation stage of cells or the variant of disease. Histidine decarboxylase should therefore be considered as a new MC marker in the screen panel of antigens used to diagnose high-grade MC malignancies.
Synaptotagmin I expression in mast cells of normal human tissues, systemic mast cell disease, and a human mast cell leukemia cell line.
Kimura N, Shiraishi S, Mizunashi K, Ohtsu H, Kimura I.
Department of Pathology, Second Department of Internal Medicine, First Department of Pharmacology, Tohoku University, Sendai, Japan.
J Histochem Cytochem 2001 Mar;49(3):341-6 Abstract quote
Synaptotagmin I (STG I) is a Ca(2+) sensor and one of the synaptic vesicle proteins that mediate exocytosis.
To determine the mechanism of release of large granules from mast cells, we studied by immunohistochemistry the presence of STG I in mast cells in normal human tissues simultaneously with the mast cell markers mast cell tryptase (tryptase) and c-kit. The tumor cells of systemic mast cell disease (SMCD) and a human mast cell leukemia cell line (HMC-1) were also examined. Human mast cells in normal tissues and the tumor cells of SMCD expressed STG I as well as mast cell tryptase (tryptase) and c-kit. STG I mRNA and its products in HMC-1 were examined by RT-PCR analysis and immunocytochemistry, respectively. STG I expression in HMC-1 cells was compared with that in cells stimulated and non-stimulated by phorbol 12-myristate 13-acetate and also with that in NB-1 and PC12 cells, known to express STG I. STG I mRNA was detected in both non-stimulated and stimulated HMC-1 cells and in NB-1 and PC12 cells. STG I immunoreactivity was weaker than NB-1 or PC12 immunoreactivity. However, it increased in the stimulated HMC-1 cells.
Mast cells expressed STG I in various states. STG I may mediate exocytosis of large granules in mast cells.
Ultrastructural morphometric analysis of lesional skin: mast cells from patients with systemic and nonsystemic mastocytosis.
Tharp MD, Glass MJ, Seelig LL Jr.
Department of Dermatology, University of Texas Health Science Center, Dallas.
J Am Acad Dermatol 1988 Feb;18(2 Pt 1):298-306 Abstract quote
Lesional skin mast cells from some patients with mastocytosis appear morphologically atypical; however, these subjective differences have not been quantified.
Herein we describe an objective method for analyzing cutaneous mastocytosis mast cells by a combination of morphometric analysis and electron microscopy. By this technique, lesional mast cells from patients with adult systemic mastocytosis had a significantly larger mean cytoplasmic area (53.3 microns2), nuclear size (20.4 microns2), and granule diameter (0.81 micron) when compared with mast cells from adults with nonsystemic mastocytosis (36.3 micron 2, 15.4 microns2, and 0.67 micron, respectively) and normal age-matched control subjects (34.4 microns2, 14.1 microns2, and 0.67 micron, respectively). Lesional skin mast cells from infants with nonsytemic mastocytosis were very similar to adult nonsystemic mastocytosis mast cells but differed by several parameters from mast cells in adults with systemic involvement.
This study demonstrates that there are quantitative differences between lesional skin mast cells from patients with systemic mastocytosis and those with nonsystemic disease.
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION
Telangiectasia macularis eruptiva perstans presented as a pseudoallergic food reaction.
Vidal C, del Rio E, Suarez-Penaranda J, Armisen M.
Allergy Unit, Complejo Hospitalario Universitario de Santiago de Compostela, Spain.
J Investig Allergol Clin Immunol 2000 Jul-Aug;10(4):248-50 Abstract quote
Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis observed in less than 1% of cases of mastocytosis. Clinically, anaphylaxis may appear as a result of increased mast cell degranulation in different circumstances.
A case of TMEP presented as pseudoallergic reactions to foods is reported in which the appearance of typical lesions on the trunk and their histological analysis together with a negative food allergy study confirmed the diagnosis.
Cutaneous mast cells are altered in normal healthy volunteers sitting in front of ordinary TVs/PCs – results from open-field provocation experiments
Olle Johansson, Shabnam Gangi, Yong Liang, Ken Yoshimura, Chen Jing and Peng-Yue Liu
The Experimental Dermatology Unit, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Background:
Journal of Cutaneous Pathology 2001;28 (10), 513-519 Abstract quote
Background: Considerable controversy has surrounded the question of possible biological responses to electromagnetic fields (EMFs) generated from visual display terminals (VDTs), such as personal computers (PCs) and ordinary television sets (TVs). The cellular and molecular mechanisms for such potential harmful health hazards have not yet been understood, although clues from the literature include mast cells and histamine. The aim of this study was therefore to investigate possible biological mast cell responses to TV/PC screens.
Methods: Using the indirect immunofluorescence technique, we studied the presence of histamine-containing mast cells in the dermis of healthy volunteers. Cutaneous biopsies taken before and after exposure to ordinary TV/PC screens for 2 or 4 h were investigated in 13 healthy subjects.
Results: Our present in vivo study indicates that normal cutaneous mast cells could be altered by exposure from ordinary TV/PC screens. To our great surprise, we found the number of mast cells in the papillary and reticular dermis to increase, to varying degrees, in 5 out the 13 subjects after such an exposure. A migration of mast cells towards the uppermost dermis appeared as the most important event. Thus, the normally upper “empty zone” of the dermis disappeared, and instead, a higher density of mast cells were found in this zone. These cells also seemed to have a tendency to increase in number towards the epidermal-dermal junctional zone and some of them lost their granular content and the cytoplasm shrunk (=degranulation). These findings could only be seen in the exposed skin. Two of the 13 cases instead showed a decrease in mast cell number, but the shift in mast cells towards the upper dermis was still visible. Twenty-four h after the provocation, the cellular number and location were normalized in all subjects.
Conclusions: By definition, normal healthy volunteers are assumed not to react to a TV/PC screen provocation. To our great surprise, this proved not to be true. The present results might lay a foundation to understand the underlying cause of so-called “screen dermatitis” with special reference to mast cells. However, blind or double-blind experiments using patients ought to be further investigated in order to find out the exact cause for the observed changes. Such causes include the effects of surrounding airborne chemicals, stress factors, etc.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS
Assessment of the extent of cutaneous involvement in children and adults with mastocytosis: Relationship to symptomatology, tryptase levels, and bone marrow pathology.
Brockow K, Akin C, Huber M, Metcalfe DD.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
J Am Acad Dermatol 2003 Apr;48(4):508-16 Abstract quote
BACKGROUND: Cutaneous involvement occurs in most patients with systemic mastocytosis.
OBJECTIVE: We sought to determine whether the extent of cutaneous involvement is predictive of systemic disease.
METHODS: In a prospective survey of 48 adults and 19 children, the extent and density of cutaneous lesions were compared with patient history, symptoms, internal organ involvement, serum total mast cell tryptase level, and bone marrow pathology.
RESULTS: Cutaneous lesions in children were of a greater mean and maximum diameter, but similar in extent and density compared with lesions in adults. In adults with skin lesions, the extent of lesions correlated to disease duration. Adults with extensive cutaneous disease experienced more pruritus and flushing. Fatigue, splenomegaly, and hepatomegaly were more frequent in adults without cutaneous involvement; and in those with a greater density of lesions and disease duration. Increased tryptase levels were found in children and adults with systemic disease and correlated to skin lesion density and bone marrow pathology.
CONCLUSION: An examination of the extent and density of cutaneous lesions in adults helps identify those with more extensive extracutaneous disease and, thus, requiring a more thorough evaluation.
Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin.
Daley T, Metcalfe DD, Akin C.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Blood 2001 Aug 1;98(3):880-2 Abstract quote
Gain-of-function mutations in c-kit, which appear to contribute to mast cell hyperplasia, have been detected in both limited and aggressive forms of mastocytosis, suggesting that other mutations or polymorphisms may contribute to the clinical phenotype.
Because addition of interleukin-4 (IL-4) to mast cell cultures is reported to induce apoptosis, the hypothesis was considered that individuals carrying the gain-of-function polymorphism Q576R in the cytoplasmic domain of the alpha-subunit of the IL-4 receptor (IL-4R) might be relatively resistant to the gain-of-function mutation in c-kit. To assess this possibility, 36 patients with either cutaneous or systemic mastocytosis were studied for association with the Q576R polymorphism. The Q576R polymorphism was found more frequently in those with disease limited to skin and who exhibited lower levels of surrogate disease markers.
These data suggest that the Q576R IL-4R alpha- chain polymorphism may mitigate disease expression and confer a better prognosis in patients with mastocytosis.
Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis.
Sperr WR, Escribano L, Jordan JH, Schernthaner GH, Kundi M, Horny HP, Valent P.
Department of Internal Medicine I, Division of Hematology and Hemostaseology, University of Vienna, Wahringer Gurtel 18-20, 1090 Vienna, Austria.
Leuk Res 2001 Jul;25(7):529-36 Abstract quote
In the present study, cytological properties of bone marrow mast cells (MC) were analyzed and correlated with clinical parameters in 69 patients with systemic mastocytosis (SM).
Based on cytomorphological features, four distinct cell types were recorded: (i) typical tissue MC (round cells, well granulated, round central nuclei); (ii) atypical MC exhibiting elongated cytoplasmic extensions, oval nuclei with excentric position, and a hypogranulated cytoplasm with focal granule accumulation ('atypical MC type I'); (iii) atypical MC with bi- or multilobed nuclei ('atypical MC type II'); and (iv) metachromatically granulated blast-like cells. In the majority of cases with SM, the percentage of MC in bone marrow (bm) smears was less than 5% (of all nucleated bm cells), and the predominant types were typical MC or atypical MC type I.
In a smaller group of patients, the percentage of MC was greater than 5% and a significant subset of MC (>or=10%) were classified as 'metachromatic blasts' and/or atypical MC type II. These patients had a significantly shorter survival (P<0.05) and most of them were found to lack UP-like skin lesions. A percentage of MC>or=20% was invariably associated with the diagnosis 'mast cell leukemia'. Multivariate analysis confirmed the prognostic value of the cytology in SM and identified the percentage of MC (of all nucleated bm cells) as an independent prognostic variable.
These data suggest that cytomorphological assessment of bm MC in SM is an important diagnostic approach that may help to delineate between variants of the disease.
Regression of urticaria pigmentosa in adult patients with systemic mastocytosis: correlation with clinical patterns of disease.
Brockow K, Scott LM, Worobec AS, Kirshenbaum A, Akin C, Huber MM, Metcalfe DD.
National Institutes of Health/National Institute of Allergy and Infectious Diseases/LAD, Bldg 10, Room 11C213, 10 Center Dr MSC 1881, Bethesda, MD 20892-1881.
Arch Dermatol 2002 Jun;138(6):785-90 Abstract quote
OBJECTIVE: To determine clinical correlates of urticaria pigmentosa (UP) regression in adult patients with systemic mastocytosis (SM).
DESIGN: Cohort study of the natural history of mastocytosis.
SETTING: National Institutes of Health Clinical Center.
PATIENTS: In a study of adult patients referred to the National Institutes of Health after 1980 and observed for a minimum of 10 years, 12 of 106 adult patients experienced clearance or fading of UP.
MAIN OUTCOME MEASURES: Data from each patient's history and results of physical examination, laboratory evaluation, and organ biopsy at presentation to the National Institutes of Health were compared with findings at the patient's most recent visit.
RESULTS: In the patients in whom clearance of (n = 5) or a decrease in skin lesions (n = 7) was noted, UP had persisted from 4 to 34 years (median, 17 years). Older age was a prognostic feature for regression of UP. Despite improvement of UP, the 2 patients with SM with an associated hematologic disorder experienced a deterioration in clinical condition. In the 10 patients with indolent SM, severity and frequency of symptoms decreased as the UP regressed. However, bone marrow changes consistent with SM remained.
CONCLUSIONS: Urticaria pigmentosa regresses in approximately 10% of the older patients who have SM. In patients with an associated hematologic disorder such as myelodysplasia, this regression may be accompanied by disease progression. In contrast, regression of UP in patients with indolent SM parallels a decrease in disease intensity, although bone marrow findings of indolent SM remain.
SURVIVAL Systemic mast cell disease
The clinical outcome of Type 1 mast cell disease is generally favorable with survival averaging 10 years or more
The prognosis of type 2 and type 3 disease is poor with survival periods usually no more than 1-2 years
Treatment of systemic mast-cell disease with cladribine.
Tefferi A, Li CY, Butterfield JH, Hoagland HC.
N Engl J Med 2001 Jan 25;344(4):307-9 INTERFERON
Effects of interferon-alpha2b treatment on ex vivo differentiation of mast cells from circulating progenitor cells in a patient with systemic mastocytosis.
Schernthaner GH, Spanblochl E, Sperr WR, Sillaber C, Semper H, Jurecka W, Hagen W, Wolff K, Chott A, Lechner K, Valent P.
Department of Internal Medicine I, University of Vienna, Austria.
Ann Hematol 2000 Dec;79(12):660-6 Abstract quote
Interferon (IFN)-alpha, a known inhibitor of myelopoiesis, is increasingly used to treat patients with systemic mastocytosis (SM). However, the mechanisms of IFN-alpha effects on mast cell (MC) growth remain unknown, and the treatment responses may be variable.
In the present study, factor-dependent ex-vivo differentiation of MCs from peripheral blood mononuclear cells (PBMNCs) was analyzed in a patient with SM treated with IFN-alpha2b (3 million U/day). The patient exhibited an extensive MC infiltration in his bone marrow (BM) and increasing serum total tryptase levels (spiking to > 1,400 ng/ml). PBMNCs were collected before and during IFN-alpha2b treatment and cultured in the presence or absence of stem cell factor (SCF, 100 ng/ml) for 42 days. In the absence of SCF, no MC growth was detectable. However, in the presence of SCF, MC containing tryptase appeared in the cultures.
Treatment with IFN-alpha2b resulted in a time-dependent decrease in SCF-inducible formation of MCs from PB progenitor cells in vitro. Also, during IFN-alpha2b treatment, blood histamine concentrations decreased. Serum total tryptase levels initially increased despite IFN-alpha2b treatment. However, after a latency period of a few months, tryptase concentrations declined and then reached a plateau. In healthy individuals, the SCF-induced in vitro growth of MCs from their progenitor cells was also inhibitable by the addition of IFN-alpha2b.
In summary, our data show that IFN-alpha2b can exhibit inhibitory effects on factor-dependent growth of MC progenitor cells. However, it still remains open which of the patients with mastocytosis can benefit from long-term IFN-alpha treatment.
A case of systemic mastocytosis; therapeutic efficacy of ketotifen.
Povoa P, Ducla-Soares J, Fernandes A, Palma-Carlos AG.
Department of Medicine, Santa Maria Hospital, Lisbon, Portugal.
J Intern Med 1991 May;229(5):475-7 Abstract quote
A 68-year-old man presented with a 6-month history of fatigue, rhinorrhoea, pruritic skin lesions, left pleural effusion, ascites, oedema and weight loss of 10 kg.
Investigations revealed hepatosplenomegaly, retroperitoneal lymphadenopathy, anaemia, leucocytosis with eosinophilia, hypoprothrombinaemia, hypocholesterolaemia and elevation of both gamma glutamyltransferase and alkaline phosphatase. Biopsies of a skin lesion, bone marrow and liver revealed mast cell infiltration, allowing the diagnosis of systemic mastocytosis (SM). Hydroxyzine plus ranitidine were given without success. Hydroxyzine treatment was stopped, and ketotifen was initiated; substantial symptomatic improvement was observed within 8 d.
This case report indicates the effectiveness of ketotifen in the symptomatic treatment of SM.
The treatment of urticaria pigmentosa with the frequency-doubled Q-switch Nd:YAG laser.
Bedlow AJ, Gharrie S, Harland CC.
Department of Dermatology, St Helier Hospital, Carshalton, Surrey, UK.
J Cutan Laser Ther 2000 Mar;2(1):45-7 Abstract quote
Urticaria pigmentosa is a chronic benign proliferation of mast cells in the skin that presents considerable cosmetic disability, for which there is no current successful treatment. We describe a 30-year-old woman with urticaria pigmentosa in whom treatment with the Nd:YAG laser produced a significant improvement in the clinical appearance of the eruption, with some recurrence after 9 months.
This procedure has not previously been described, and we propose this as a potential new treatment modality for urticaria pigmentosa.
Response to cyclosporin and low-dose methylprednisolone in aggressive systemic mastocytosis.
Kurosawa M, Amano H, Kanbe N, Igarashi Y, Nagata H, Yamashita T, Kurimoto F, Miyachi Y.
Department of Geriatric Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.
J Allergy Clin Immunol 1999 May;103(5 Pt 2):S412-20 Abstract quote
BACKGROUND: There is no effective treatment for aggressive systemic mastocytosis.
OBJECTIVE: The purpose of this study was to investigate the effect of cyclosporin and low-dose methylprednisolone in a 64-year-old man with aggressive systemic mastocytosis.
METHODS: Immunohistochemical studies were done on biopsy specimens from the skin and other organs. Mast cells, predominantly containing tryptase, were derived from human umbilical cord blood cells cultured in the presence of stem-cell factor and IL-6. IgE-sensitized cultured human mast cells were activated by anti-IgE, and the effect of cyclosporin on histamine release was investigated. In addition, blood and urine levels of various mediators were measured in the patient before and after therapy.
RESULTS: Biopsy specimens of the patient's skin lesions showed an increase of mast cells; cells containing tryptase (but not chymase) comprised 20% to 50% of the skin mast cells. Histamine release from activated cultured mast cells was inhibited by cyclosporin in a concentration-dependent manner. When the patient was treated with cyclosporin and low-dose methylprednisolone, he showed a good response.
CONCLUSION: Cyclosporin combined with low-dose methylprednisolone may be a reasonable therapy for aggressive systemic mastocytosis.
Medium- versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study.
Gobello T, Mazzanti C, Sordi D, Annessi G, Abeni D, Chinni LM, Girolomoni G.
Istituto de Dermopatico dell'Immacolata, IRCCS, Roma, Italy.
J Am Acad Dermatol. 2003 Oct;49(4):679-84. Abstract quote
BACKGROUND: There is currently no definitive cure for urticaria pigmentosa (UP). Psoralen plus ultraviolet A therapy is efficacious in alleviating symptoms and reducing cutaneous lesions.
OBJECTIVE: The purpose of this study was to assess the effect of ultraviolet A1 (UVA1) in adult patients with UP and to compare the effectiveness of high-dose (130 J/cm(2)/day for 10 days) and medium-dose (60 J/cm(2)/day for 15 days) UVA1 radiation.
METHODS: Ten and 12 adult patients with UP were treated with high-dose or medium-dose UVA1, respectively. The number of skin lesions and dermal mast cells, the presence of Darier's sign, the intensity of pruritus, and quality of life measures were evaluated before, at the end of treatment, and 2 and 6 months later.
RESULTS: Baseline characteristics were similar among the 2 groups of patients. In the majority of patients, the number of lesions was not significantly reduced. However, the number of mast cells in lesional skin decreased markedly in most patients by the end of treatment, and it remained low for the whole study period. Pruritus and quality of life improved considerably by the end of treatment, and the improvement was maintained during the 6-month follow up. No significant differences were observed between patients receiving high- or medium-dose UVA1.
CONCLUSIONS: UVA1 phototherapy ameliorates both objective and subjective symptoms of adult patients with UP and induces long-term remission in most cases. Medium-dose UVA1 appears at least as effective as high-dose UVA1.
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