Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement Maella Severino, MD,a,b,n Marie-Olivia Chandesris, MD,h,i Stephane Barete, MD, PhD,h,j Emilie Tournier, MD,a,c,f,m Beatrix Sans, MD,b,m,n Camille Laurent, MD, PhD,a,c,f,m Pol Andre Apoil, MD, PhD,g,m Laurence Lamant, MD, PhD,a,c,f,m Claire Mailhol, MD,d,m Michel Laroche, MD, PhD,e,m Sylvie Fraitag, MD,h,k Katia Hanssens, MLT,l Patrice Dubreuil, PhD,l Olivier Hermine, MD, PhD,h,i Carle Paul, MD, PhD,a,b,m,n and Cristina Bulai Livideanu, MDa,b,m,n Toulouse, Paris, and Marseille, France Background: Telangiectasia macularis eruptiva perstans (TMEP) has not been fully characterized. Objective: We sought to estimate the frequency and clinical characteristics of TMEP in a cohort of adult patients with cutaneous mastocytosis, and to assess the presence of systemic involvement. Methods: We included all consecutive patients evaluated for cutaneous mastocytosis in 2 centers: the Mastocytosis Competence Center of the Midi-Pyr en ees from May 2006 to December 2013, and the French Reference Center for Mastocytosis from January 2008 to September 2013. Skin phenotype, histopathology, presence of KIT mutation in the skin, and assessment of systemic involvement according to World Health Organization (WHO) criteria were prospectively investigated. Results: Of 243 patients with cutaneous mastocytosis, 34 (14%) were given a diagnosis of TMEP. The diagnosis of systemic mastocytosis was established in 16 patients (47%) with TMEP. Three patients (9%) had aggressive systemic mastocytosis (C-findings according to WHO). In all, 32 patients (94%) exhibited at least 1 mast cell activationerelated symptom. Limitations: Patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis so that the clinical findings and incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. Conclusion: TMEP accounts for about 14% of patients with cutaneous mastocytosis. The disease manifests as mast cell activation symptoms in almost all patients and can be associated with systemic involvement in about 50% of cases. ( J Am Acad Dermatol 2016;74:885-91.) Key words: aggressive systemic mastocytosis; cutaneous mastocytosis; indolent systemic mastocytosis; mast cell activation symptom; mast cell disease; telangiectasia macularis eruptiva perstans.
Paul Sabatier University, Toulousea; Departments of Dermatology,b Pathology,c Allergy and Pulmonology,d and Rheumatology,e Cancer University Institute of Toulouse Oncopolef; Immunology Laboratoryg; Mastocytosis Competence Center of Midi-Pyr en eesm; Toulouse University Hospitaln; French Reference Center for Mastocytosis, Parish; Department of Hematology, Necker Hospital, Assistance Publique des H^ opitaux de Paris (AP-HP), Parisi; Unit of Dermatology, AP-HP, Piti e-Salp^ etri ere Hospital, Sorbonne Universities- Universite Pierre et Marie CURIE (UPMC) Paris VIj; Department of Pathology, Necker-Enfants Malades Hospital, AP-HP, Parisk; and Centre de Recherche en Cancerologie de Marseille (CRCM) (Signaling, Hematopoiesis, and Mechanism of Oncogenesis), Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille
University, UM105, Centre national de la recherche scientifique (CNRS), Unite mixte de recherche (UMR) 7258, Marseille.l Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 27, 2015. Reprint requests: Cristina Bulai Livideanu, MD, Mastocytosis Competence Center of Midi-Pyrenees, Department of Dermatology, Toulouse University Hospital, 24 Chemin de Pouvourville, 31100, Toulouse, France. E-mail: [email protected]. Published online February 20, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.10.050
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Cutaneous mastocytosis is a result of an accumulatypical skin eruption (small, irregular redtion of abnormal mast cells in the skin.1,2 Cutaneous dish, telangiectatic macules widely distribmastocytosis can be isolated or associated with systemic uted both bilaterally and symmetrically) and involvement.1,2 The frequency of systemic involvement histopathological criteria: an increased numin adults with cutaneous mastocytosis is higher than in ber of mast cells around dilated capillaries children.3,4 There are several clinical phenotypes of and venules of the superficial venous plexus cutaneous mastocytosis.5 Most reports of telangiectasia found in the upper third of the dermis.13 d For other cutaneous mastomacularis eruptiva perstans (TMEP) are single cases or cytosis phenotypes, as CAPSULE SUMMARY small series.6-8 It has been recommended by Valent et al,2 the diagnosis was suggested that TMEP is not There is limited information on systemic associated with systemic determined on the basis of involvement in telangiectasia macularis mastocytosis.9 TMEP is not a typical skin eruption (maeruptiva perstans, a form of cutaneous jor criterion) and 1 of the considered a separate entity mastocytosis. following 2 minor criteria: in the most recent update of Telangiectasia macularis eruptiva (1) monomorphic mast cell the World Health Organization perstans accounted for 14% of adult infiltrate consisting of (WHO) classification of cutapatients with cutaneous mastocytosis at either large aggregates of neous mastocytosis.10 As 2 referral centers for mastocytosis. tryptase-positive mast cells TMEP may sometimes be Systemic mastocytosis was present in ($15 cells/cluster) or scatassociated with urticaria pig47% of these patients. tered mast cells exceeding mentosa, some authors have 20 cells per microscopic suggested that TMEP is not a Although selection bias may have high-power field (340); or distinct entity.11 affected our analysis, evaluation for (2) detection of a KIT muThe main objectives of our systemic involvement should be tation at codon 816 in RNA study were to estimate the undertaken in patients with extracted from a lesional frequency of TMEP in a cohort telangiectasia macularis eruptiva skin biopsy specimen. of adult patients with cutaperstans. neous mastocytosis, and to All diagnostic criteria describe its clinical characterwere verified by dermatoloistics and association with systemic involvement. gists (C. B. L., C. P., or S. B.) and/or hematologists (MO. C. or O. H.), and pathologists (E. T., L. L., or S. F.) METHODS with a special interest in mast cell diseases. Patient population Mast cells were identified and quantified in skin We included all consecutive adult patients evalubiopsy sections by immunohistochemical analysis ated for cutaneous mastocytosis in 2 referral centers: with anti-CD117 antibodies (polyclonal rabbit; the Mastocytosis Competence Center of the Dako, Glostrup, Denmark). The detection of a KIT Midi-Pyr en ees region from May 2006 to December point mutation at codon 816 in skin was performed 2013, and the French Reference Center for by sequencing the 816 region of the KIT gene after Mastocytosis from January 2008 to September 2013. RNA extraction from a lesional skin biopsy specAs part of a standardized evaluation procedure, imen. Total serum tryptase was determined by a patients underwent 2 skin biopsies, 1 for histology standardized fluoroenzyme immunoassay on a (including routine histopathology and immunohisPhadia 250 automated analyzer (ThermoFisher tochemical analysis with anti-CD117 antibodies), Scientific, Villebon sur Yvette, France) in accordance and 1 for detection of skin KIT mutations by with the recommended procedures of the reagent sequencing the 816 region of the KIT gene. supplier and good laboratory practice (International This study was approved by the Institutional Organization for Standardization 15189). Review Board of the Necker-Enfants Malades The diagnosis and classification of systemic Hospital, and was carried out in accordance with mastocytosis were made using the diagnostic criteria the Declaration of Helsinki. Written informed defined by WHO1 (Supplemental Table I; available at consent was obtained from all patients. http://www.jaad.org). d
d
d
Diagnostic criteria Cutaneous mastocytosis was defined as follows. 12 d For TMEP, as recommended by Ackerman, the diagnosis was assessed on the basis of a
Data collection and analysis Clinical data on cutaneous mastocytosis were prospectively recorded on a specific case report
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Abbreviations used: IQR: TMEP: WHO:
interquartile range telangiectasia macularis eruptiva perstans World Health Organization
form. Patients who had telangiectatic macules associated with urticaria pigmentosa at initial diagnosis were not included. The following characteristics were recorded: demographics, main reason for initial consultation, time between first clinical signs and
Severino et al 887
cutaneous mastocytosis diagnosis, TMEP localizations, disease course, type and severity of systemic involvement if any, systemic mastocytosis classification, presence of mast cell activationerelated symptoms, presence of dilated capillaries in the papillary dermis, number of mast cells/mm2 and KIT mutation status in skin, and serum tryptase levels. A comparison of the following clinical characteristics was performed in patients who had TMEP with and without systemic involvement: age at diagnosis, sex, presence of at least 1 mast cell activation symptom, number of mast cells/mm2 in skin biopsy
Fig 1. Localization of telangiectasia macularis eruptiva perstans lesions. A, Telangiectatic, erythematous macules distributed on the upper aspect of the back. B, Rust-colored macules and papules arranged in clusters and in plaques on the back. C, Widely distributed telangiectatic erythematous lesions of 1.0 to 1.5 cm diameter both bilaterally and symmetrically on the chest and arms. D, Erythematous and telangiectatic lesions on the thighs. E, Telangiectatic, erythematous macules distributed on the neck. F, Telangiectatic macules on the palms of the hands.
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Fig 2. Histologic analysis of a telangiectasia macularis eruptiva perstans lesion. A, Dilated capillaries of the superficial venous plexus found in the upper third of the dermis with a surrounding moderate inflammatory reaction, mainly composed of mast cells. (Hematoxylineosin stain; original magnification: 360.) B, Spindle mast cells identified by immunohistochemistry around dilated capillaries in the papillary dermis. (Anti-CD117 antibodies; original magnification: 3100.)
specimen, serum tryptase levels, and presence of a KIT mutation in skin. Prism software (Version 5.01, Graphpad, Irvine, CA) was used for statistical analysis. The distribution of patient characteristics was expressed as median and interquartile range (IQR) for continuous variables, and as absolute number and percentage for categorical variables. Continuous variables were compared using the Mann-Whitney test and categorical variables (percentages) were compared using the x 2 test. P less than .05 was considered significant.
RESULTS Frequency of TMEP In all, 243 patients with cutaneous mastocytosis were included, of whom 34 (13.9%) were given a diagnosis of TMEP. Patient characteristics There were 16 men (47.0%) and 18 women (53.0%) with a median age of 50 years (IQR 27-55). The median age at disease onset was 42 years (IQR 25-53) and the median time from first signs and/or symptoms to diagnosis was 24 months (IQR 12-63). The main reason for initial consultation was: skin lesions for 23 patients (67.4%), mast cell activatione related symptoms for 9 patients (26.4%) including anaphylactic shock in 2 cases, and bone fracture for 2 patients (5.9%). The lesions were localized (Fig 1) on the back in 15 patients (44.1%) (Fig 1, A and B), front of chest in 23 patients (67.6%) (Fig 1, C ), upper limbs in 19 patients (55.9%) (Fig 1, C ), lower limbs in 10 patients (29.4%) (Fig 1, D), neck in 9 patients (26.5%) (Fig 1, E ), abdomen in 8 patients (23.5%), and palms in 3 patients (8.8%) (Fig 1, F ). Follow-up data on the
course of the skin lesions were available for all patients: 1 patient (2.9%) developed a mixed form of cutaneous mastocytosis combining TMEP and urticaria pigmentosa after 5 years of follow-up. Histologic examination showed dilated vessels with a moderate inflammatory reaction in the dermis (Fig 2, A) in all cases. The median number of mast cells/mm2 in papillary dermal tissue on skin biopsy specimen was 40 (IQR 29-52) (Fig 2, B). KIT point mutations at codon 816 in skin biopsy specimens were present in 10 patients (29.4%), and 24 patients (70.6%) had no KIT mutation. The median serum tryptase level was 8.3 g/L (IQR 5.5-27). Systemic mastocytosis was diagnosed in 16 patients (47.0%), and organ injury with dysfunction was present in 3 patients (8.8%) (C-findings according to the WHO), indicating aggressive systemic mastocytosis. This involved bone fractures in 2 patients (5.9%), and gastrointestinal tract injury consisting of malabsorption with weight loss as a result of specific mast cell infiltrates in 1 patient (2.9%). Among patients with systemic mastocytosis, 8 (50%) had a serum tryptase level less than 13.5 g/L (median 7; IQR 6.7-9.2) and 8 (50%) a serum tryptase level greater than 13.5 g/L (median 47; IQR 36-94). In total, 32 patients (94.1%) had at least 1 mast cell activationerelated symptom, and 24 patients (70.6%) had at least 2 mast cell activation symptoms. Table I summarizes the characteristics of patients with TMEP. Comparisons of the different clinical characteristics between the 2 groups of patients who had TMEP with and without systemic involvement are summarized in Table II. Significantly higher serum
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Table I. Clinical characteristics of patients with telangiectasia macularis eruptiva perstans Characteristics
No. of patients (%)
Median (IQR)
Total no. of patients with TMEP 34 WHO mastocytosis subtypes Cutaneous 18 (53) Systemic 16 (47) Indolent systemic 13 (38.1) Aggressive systemic 3 (8.9) Demographic data Female 18 (53) Age at diagnosis, y 50 Age at disease onset, y 42 Time from first signs and 24 symptoms to diagnosis, mo Main reason for initial consultation Skin lesions 22 (67.4) Mast cell activationerelated 9 (26.4) symptoms Bone fracture 2 (5.9) Clinical findings Mediators release symptoms Fatigue 6 (17.6) Flush 16 (47.0) Pruritus 22 (64.7) Diarrhea 16 (47.0) Abdominal pain 4 (11.8) Neuropsychiatric symptoms 2 (5.9) Chronic headache 4 (11.8) Urinary symptoms 7 (20.6) Dyspnea 5 (14.7) Fever 2 (5.9) Localization of TMEP lesions Neck 9 (26.5) Upper limbs 19 (55.9) Chest 23 (67.6) Abdomen 8 (23.5) Back 15 (44.1) Lower limbs 10 (29.4) Palms 3 (8.8) Mast cells systemic infiltration symptoms/signs (C-sign finding) Bone fracture 2 (5.9) Weight loss and 1 (2.9) hypoalbuminemia Skin histologic findings Dilated capillaries and venules 34 (100) in papillary dermis No. of mast cells/mm2 34 (100) 40 No. of mast cells/mm2 11 (32.4) 64 for case with [20 cells/microscopic high-power field (340) Biological findings Serum tryptase level, g/L 34 (100) 8.3 Serum tryptase level [20 9 (26.5) 48
(27-55) (25-53) (12-63)
Table I. Cont’d Characteristics
KIT 816 mutation detected From bone-marrow aspiration in 31 patients From skin biopsy specimen in 34 patients
-
Median (IQR)
12 (35.3) 10 (32.3)
-
12 (35.3)
-
IQR, Interquartile range; TMEP, telangiectasia macularis eruptiva perstans; WHO, World Health Organization.
Table II. Clinical characteristics of telangiectasia macularis eruptiva perstans with and without systemic involvement
-
No. of patients (%)
Characteristics
Female, n (%) Age at diagnosis, y, median (IQR) Age at disease onset, y, median (IQR) At least a mediator release symptom, n (%) Mast cells/mm2, n (IQR) Serum tryptase level, g/L (IQR) KIT 816 mutation detected from skin biopsy specimen, n (%)
Patients without Patients with systemic systemic P involvement involvement N = 18 value N = 16
6 (37.5) 49 (29-54)
12 (66.7) 51 (25-58)
.1 .8
45 (27-52)
39 (24-56)
.9
14 (87.5)
18 (100)
.2
47 (30-54) 36 (29-58) .4 16 (7-47) 6.7 (5.3-11) .02 6 (37.5)
3 (16.6)
.2
Bold value indicates statistical significance. IQR, Interquartile range.
tryptase levels were observed in patients with systemic involvement.
DISCUSSION -
(29-52) (51-110)
(5.5-27) (37-94)
Continued
This article provides a detailed description of the clinical presentation and frequency of systemic involvement associated with TMEP in adults. There is a median 2-year delay in the diagnosis of TMEP. In most patients TMEP is associated with a relatively low-density mast cell infiltrate in the skin and normal tryptase levels. However, most patients with TMEP may experience mast cell activation symptoms (94%), and almost half of them have evidence of systemic mastocytosis. TMEP is a specific form of cutaneous mastocytosis.6,7,9,14-18 In our study, the frequency of TMEP was higher (14%) than previously reported in adults.8,18 The median age at diagnosis (50 years), disease onset
890 Severino et al
(42 years), or both corresponds to the peak incidence of mastocytosis in adult patients.18 The low number of mast cells in dermal tissue (40/mm2), the low frequency of KIT point mutations at codon 816 in skin biopsy specimens (29%), and the low serum tryptase levels (median of 8.3 g/L) suggest that the mast cell burden is lower in TMEP than in other forms of cutaneous mastocytosis. There is a need to consider the use of more sensitive criteria for TMEP diagnosis such as the diagnostic criteria defined by Ackerman.12 One original aspect of this work is the high frequency of systemic manifestations in TMEP (47%), including 3 patients with signs of aggressive systemic mastocytosis (9%), underlining the importance of accurate diagnosis and treatment of patients with TMEP.19 It also validates the clinical spectrum of TMEP as an individualized form of mastocytosis.20-22 Although high serum tryptase levels appear to be the only factor associated with systemic involvement, some patients who have TMEP with systemic involvement have normal serum tryptase levels. This might be explained by high polymorphism of genes (tryptase 1/tryptase 2) encoding the production, maturation, and/or secretion of tryptase in human beings.23-26 In addition, the sample size is too small to rule out the potential role of other factors, such as number of mast cells in skin biopsy specimen and presence of a KIT mutation in skin. This study has several potential limitations: firstly, patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis. It is likely that mild forms of TMEP were underdiagnosed and the relative frequency of TMEP in our cohort might not represent the true relative frequency in the general population. On the other hand, the incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. Secondly, not all patients had a systematic examination by dermoscopy to confirm the findings considered characteristic of TMEP, telangiectatic vessels arranged in a reticular pattern.27 Finally, treatment data were not available for all patients. This precludes any conclusions about treatment efficacy and strategy in this group of patients. Conclusion TMEP is a cutaneous form of mastocytosis that is difficult to diagnose. Although mast cell burden is low in TMEP, the frequency of systemic mast cell involvement is high and should be
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investigated systematically. More work is needed to better define diagnostic criteria in this patient population and to develop specific treatment recommendations. REFERENCES 1. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625. 2. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostic, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435-453. 3. Arock M, Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol. 2010;3:497-516. 4. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74:121-132. 5. Hartmann K, Henzb B. Classification of cutaneous mastocytosis: a modified consensus proposal. Leuk Res. 2002; 26:483-484. 6. Biedermann T, Ru€eff F, Sander CA, Przybilla B. Mastocytosis associated with severe wasp sting anaphylaxis detected by elevated serum mast cell tryptase levels. Br J Dermatol. 1999; 141:1110-1112. 7. Lee HW, Jeong YI, Choi JC, et al. Two cases of telangiectasia macularis eruptiva perstans demonstrated by immunohistochemistry for c-kit (CD 117). J Dermatol. 2005;32:817-820. 8. Vano-Galvan S, Alvarez-Twose I, De Las Heras E, et al. Dermoscopic features of skin lesions in patients with mastocytosis. Arch Dermatol. 2011;147:932-940. 9. Sarkany RPE, Monk BE, Handfield-Jones SE. Telangiectasia macularis eruptiva perstans: a case report and review of the literature. Clin Exp Dermatol. 1998;23:38-39. 10. Pettigrew HD, Teuber SS, Kong JS, Gershwin ME. Contemporary challenges in mastocytosis. Clin Rev Allergy Immunol. 2010;38:125-134. 11. Williams KW, Metcalfe DD, Prussin C, Carter MC, Komarow HD. Telangiectasia macularis eruptiva perstans or highly vascularized urticaria pigmentosa? J Allergy Clin Immunol Pract. 2014;2:813-815. 12. Ackerman AB. Urticaria pigmentosa. In: Ackerman AB, ed. Histologic diagnosis of inflammatory skin diseases. An algorithmic method based on pattern analysis. 2nd ed. Baltimore: Williams and Wilkins; 1997:877-881. 13. Fraitag-Spinner S. Mastocytoses cutanees. Ann Dermatol Venereol. 2007;134:589-592. 14. Weber FP, Hellenschmied R. Telangiectasia macularis eruptiva perstans. Br J Dermatol Syphilol. 1930;42:374-382. 15. Bonnefoy M, Rouchouse B, Clavreul C, Decousus D, Claudy A. Prolonged losses of consciousness disclosing mastocytosis of the telangiectasia macularis eruptiva perstans type. Ann Dermatol Venereol. 1986;113:259-262. 16. Altiner A, Tzu J, Patel R, Meehan S, Sanchez M. Telangiectasia macularis eruptiva perstans. Dermatol Online J. 2011;17:7. 17. Costa DL, Moura HH, Rodrigues R, Pinero-Maceira J, RamosE-Silva M. Telangiectasia macularis eruptiva perstans. A rare form of adult mastocytosis. J Clin Aesthet Dermatol. 2011;4:52-54. 18. Watkins C, Bokor W, Leicht S, Youngberg G, Krishnaswamy G. Telangiectasia macularis eruptiva perstans: more than skin deep. Dermatology Reports. 2011;3:e12. 19. Marrouche N, Grattan C. TMEP or not TMEP: that is the question. J Am Acad Dermatol. 2014;70:581-582.
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20. Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537-545. 21. Cohn MS, Mahon MJ. Telangiectasia macularis eruptiva perstans. J Am Osteopath Assoc. 1994;94:246-248. 22. Smith JH, Butterfield JH, Pardanani A, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg. 2011;113:570-574. 23. Johnson MR, Verstovsek S, Jorgensen JL, et al. Utility of the World Health Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow. Mod Pathol. 2009;22:50-57.
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24. Guida M, Riedy M, Lee D, Hall J. Characterization of two highly polymorphic human tryptase loci and comparison with a newly discovered monkey tryptase ortholog. Pharmacogenetics. 2000;10:389-396. 25. Hernandez-Hernandez L, Sanz C, Garcıa-Solaesa V, et al. Tryptase: genetic and functional considerations. Allergol Immunopathol. 2012;40:385-389. 26. Vitte J. Human mast cell tryptase in biology and medicine. Mol Immunol. 2015;63:18-24. 27. Akay BN, Kittler H, Sanli H, et al. Dermatoscopic findings of cutaneous mastocytosis. Dermatol. 2009;218:226-230.
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Supplemental Table I. World Health Organization diagnostic criteria of systemic mastocytosis: Major and 1 minor or 3 minor criteria are fulfilled Major criterion Minor criteria
Multifocal dense infiltrates of MC ([15 MC aggregating) detected in sections of BMB and/or of other extracutaneous organ(s) by tryptase immunohistochemistry or other stains a. MCs in bone marrow or other extracutaneous organs show an abnormal (spindling) morphology ([25%). b. Detection of a KIT point mutation at codon 816 in bone marrow or blood or other extracutaneous organ(s) c. Kit1 MC in bone marrow or blood or other extracutaneous organ(s) co-express CD2 or/and CD25 d. Serum total tryptase concentration persistently [20 g/L
BMB, Bone-marrow biopsy specimen; MC, mast cells.
Paul Sabatier University, Toulousea; Departments of Dermatology,b Pathology,c Allergy and Pulmonology,d and Rheumatology,e Cancer University Institute of Toulouse Oncopolef; Immunology Laboratoryg; Mastocytosis Competence Center of Midi-Pyr en eesm; Toulouse University Hospitaln; French Reference Center for Mastocytosis, Parish; Department of Hematology, Necker Hospital, Assistance Publique des H^ opitaux de Paris (AP-HP), Parisi; Unit of Dermatology, AP-HP, Piti e-Salp^ etri ere Hospital, Sorbonne Universities- Universite Pierre et Marie CURIE (UPMC) Paris VIj; Department of Pathology, Necker-Enfants Malades Hospital, AP-HP, Parisk; and Centre de Recherche en Cancerologie de Marseille (CRCM) (Signaling, Hematopoiesis, and Mechanism of Oncogenesis), Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille
University, UM105, Centre national de la recherche scientifique (CNRS), Unite mixte de recherche (UMR) 7258, Marseille.l Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 27, 2015. Reprint requests: Cristina Bulai Livideanu, MD, Mastocytosis Competence Center of Midi-Pyrenees, Department of Dermatology, Toulouse University Hospital, 24 Chemin de Pouvourville, 31100, Toulouse, France. E-mail: [email protected]. Published online February 20, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.10.050
885
J AM ACAD DERMATOL
886 Severino et al
MAY 2016
Cutaneous mastocytosis is a result of an accumulatypical skin eruption (small, irregular redtion of abnormal mast cells in the skin.1,2 Cutaneous dish, telangiectatic macules widely distribmastocytosis can be isolated or associated with systemic uted both bilaterally and symmetrically) and involvement.1,2 The frequency of systemic involvement histopathological criteria: an increased numin adults with cutaneous mastocytosis is higher than in ber of mast cells around dilated capillaries children.3,4 There are several clinical phenotypes of and venules of the superficial venous plexus cutaneous mastocytosis.5 Most reports of telangiectasia found in the upper third of the dermis.13 d For other cutaneous mastomacularis eruptiva perstans (TMEP) are single cases or cytosis phenotypes, as CAPSULE SUMMARY small series.6-8 It has been recommended by Valent et al,2 the diagnosis was suggested that TMEP is not There is limited information on systemic associated with systemic determined on the basis of involvement in telangiectasia macularis mastocytosis.9 TMEP is not a typical skin eruption (maeruptiva perstans, a form of cutaneous jor criterion) and 1 of the considered a separate entity mastocytosis. following 2 minor criteria: in the most recent update of Telangiectasia macularis eruptiva (1) monomorphic mast cell the World Health Organization perstans accounted for 14% of adult infiltrate consisting of (WHO) classification of cutapatients with cutaneous mastocytosis at either large aggregates of neous mastocytosis.10 As 2 referral centers for mastocytosis. tryptase-positive mast cells TMEP may sometimes be Systemic mastocytosis was present in ($15 cells/cluster) or scatassociated with urticaria pig47% of these patients. tered mast cells exceeding mentosa, some authors have 20 cells per microscopic suggested that TMEP is not a Although selection bias may have high-power field (340); or distinct entity.11 affected our analysis, evaluation for (2) detection of a KIT muThe main objectives of our systemic involvement should be tation at codon 816 in RNA study were to estimate the undertaken in patients with extracted from a lesional frequency of TMEP in a cohort telangiectasia macularis eruptiva skin biopsy specimen. of adult patients with cutaperstans. neous mastocytosis, and to All diagnostic criteria describe its clinical characterwere verified by dermatoloistics and association with systemic involvement. gists (C. B. L., C. P., or S. B.) and/or hematologists (MO. C. or O. H.), and pathologists (E. T., L. L., or S. F.) METHODS with a special interest in mast cell diseases. Patient population Mast cells were identified and quantified in skin We included all consecutive adult patients evalubiopsy sections by immunohistochemical analysis ated for cutaneous mastocytosis in 2 referral centers: with anti-CD117 antibodies (polyclonal rabbit; the Mastocytosis Competence Center of the Dako, Glostrup, Denmark). The detection of a KIT Midi-Pyr en ees region from May 2006 to December point mutation at codon 816 in skin was performed 2013, and the French Reference Center for by sequencing the 816 region of the KIT gene after Mastocytosis from January 2008 to September 2013. RNA extraction from a lesional skin biopsy specAs part of a standardized evaluation procedure, imen. Total serum tryptase was determined by a patients underwent 2 skin biopsies, 1 for histology standardized fluoroenzyme immunoassay on a (including routine histopathology and immunohisPhadia 250 automated analyzer (ThermoFisher tochemical analysis with anti-CD117 antibodies), Scientific, Villebon sur Yvette, France) in accordance and 1 for detection of skin KIT mutations by with the recommended procedures of the reagent sequencing the 816 region of the KIT gene. supplier and good laboratory practice (International This study was approved by the Institutional Organization for Standardization 15189). Review Board of the Necker-Enfants Malades The diagnosis and classification of systemic Hospital, and was carried out in accordance with mastocytosis were made using the diagnostic criteria the Declaration of Helsinki. Written informed defined by WHO1 (Supplemental Table I; available at consent was obtained from all patients. http://www.jaad.org). d
d
d
Diagnostic criteria Cutaneous mastocytosis was defined as follows. 12 d For TMEP, as recommended by Ackerman, the diagnosis was assessed on the basis of a
Data collection and analysis Clinical data on cutaneous mastocytosis were prospectively recorded on a specific case report
J AM ACAD DERMATOL VOLUME 74, NUMBER 5
Abbreviations used: IQR: TMEP: WHO:
interquartile range telangiectasia macularis eruptiva perstans World Health Organization
form. Patients who had telangiectatic macules associated with urticaria pigmentosa at initial diagnosis were not included. The following characteristics were recorded: demographics, main reason for initial consultation, time between first clinical signs and
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cutaneous mastocytosis diagnosis, TMEP localizations, disease course, type and severity of systemic involvement if any, systemic mastocytosis classification, presence of mast cell activationerelated symptoms, presence of dilated capillaries in the papillary dermis, number of mast cells/mm2 and KIT mutation status in skin, and serum tryptase levels. A comparison of the following clinical characteristics was performed in patients who had TMEP with and without systemic involvement: age at diagnosis, sex, presence of at least 1 mast cell activation symptom, number of mast cells/mm2 in skin biopsy
Fig 1. Localization of telangiectasia macularis eruptiva perstans lesions. A, Telangiectatic, erythematous macules distributed on the upper aspect of the back. B, Rust-colored macules and papules arranged in clusters and in plaques on the back. C, Widely distributed telangiectatic erythematous lesions of 1.0 to 1.5 cm diameter both bilaterally and symmetrically on the chest and arms. D, Erythematous and telangiectatic lesions on the thighs. E, Telangiectatic, erythematous macules distributed on the neck. F, Telangiectatic macules on the palms of the hands.
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Fig 2. Histologic analysis of a telangiectasia macularis eruptiva perstans lesion. A, Dilated capillaries of the superficial venous plexus found in the upper third of the dermis with a surrounding moderate inflammatory reaction, mainly composed of mast cells. (Hematoxylineosin stain; original magnification: 360.) B, Spindle mast cells identified by immunohistochemistry around dilated capillaries in the papillary dermis. (Anti-CD117 antibodies; original magnification: 3100.)
specimen, serum tryptase levels, and presence of a KIT mutation in skin. Prism software (Version 5.01, Graphpad, Irvine, CA) was used for statistical analysis. The distribution of patient characteristics was expressed as median and interquartile range (IQR) for continuous variables, and as absolute number and percentage for categorical variables. Continuous variables were compared using the Mann-Whitney test and categorical variables (percentages) were compared using the x 2 test. P less than .05 was considered significant.
RESULTS Frequency of TMEP In all, 243 patients with cutaneous mastocytosis were included, of whom 34 (13.9%) were given a diagnosis of TMEP. Patient characteristics There were 16 men (47.0%) and 18 women (53.0%) with a median age of 50 years (IQR 27-55). The median age at disease onset was 42 years (IQR 25-53) and the median time from first signs and/or symptoms to diagnosis was 24 months (IQR 12-63). The main reason for initial consultation was: skin lesions for 23 patients (67.4%), mast cell activatione related symptoms for 9 patients (26.4%) including anaphylactic shock in 2 cases, and bone fracture for 2 patients (5.9%). The lesions were localized (Fig 1) on the back in 15 patients (44.1%) (Fig 1, A and B), front of chest in 23 patients (67.6%) (Fig 1, C ), upper limbs in 19 patients (55.9%) (Fig 1, C ), lower limbs in 10 patients (29.4%) (Fig 1, D), neck in 9 patients (26.5%) (Fig 1, E ), abdomen in 8 patients (23.5%), and palms in 3 patients (8.8%) (Fig 1, F ). Follow-up data on the
course of the skin lesions were available for all patients: 1 patient (2.9%) developed a mixed form of cutaneous mastocytosis combining TMEP and urticaria pigmentosa after 5 years of follow-up. Histologic examination showed dilated vessels with a moderate inflammatory reaction in the dermis (Fig 2, A) in all cases. The median number of mast cells/mm2 in papillary dermal tissue on skin biopsy specimen was 40 (IQR 29-52) (Fig 2, B). KIT point mutations at codon 816 in skin biopsy specimens were present in 10 patients (29.4%), and 24 patients (70.6%) had no KIT mutation. The median serum tryptase level was 8.3 g/L (IQR 5.5-27). Systemic mastocytosis was diagnosed in 16 patients (47.0%), and organ injury with dysfunction was present in 3 patients (8.8%) (C-findings according to the WHO), indicating aggressive systemic mastocytosis. This involved bone fractures in 2 patients (5.9%), and gastrointestinal tract injury consisting of malabsorption with weight loss as a result of specific mast cell infiltrates in 1 patient (2.9%). Among patients with systemic mastocytosis, 8 (50%) had a serum tryptase level less than 13.5 g/L (median 7; IQR 6.7-9.2) and 8 (50%) a serum tryptase level greater than 13.5 g/L (median 47; IQR 36-94). In total, 32 patients (94.1%) had at least 1 mast cell activationerelated symptom, and 24 patients (70.6%) had at least 2 mast cell activation symptoms. Table I summarizes the characteristics of patients with TMEP. Comparisons of the different clinical characteristics between the 2 groups of patients who had TMEP with and without systemic involvement are summarized in Table II. Significantly higher serum
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Table I. Clinical characteristics of patients with telangiectasia macularis eruptiva perstans Characteristics
No. of patients (%)
Median (IQR)
Total no. of patients with TMEP 34 WHO mastocytosis subtypes Cutaneous 18 (53) Systemic 16 (47) Indolent systemic 13 (38.1) Aggressive systemic 3 (8.9) Demographic data Female 18 (53) Age at diagnosis, y 50 Age at disease onset, y 42 Time from first signs and 24 symptoms to diagnosis, mo Main reason for initial consultation Skin lesions 22 (67.4) Mast cell activationerelated 9 (26.4) symptoms Bone fracture 2 (5.9) Clinical findings Mediators release symptoms Fatigue 6 (17.6) Flush 16 (47.0) Pruritus 22 (64.7) Diarrhea 16 (47.0) Abdominal pain 4 (11.8) Neuropsychiatric symptoms 2 (5.9) Chronic headache 4 (11.8) Urinary symptoms 7 (20.6) Dyspnea 5 (14.7) Fever 2 (5.9) Localization of TMEP lesions Neck 9 (26.5) Upper limbs 19 (55.9) Chest 23 (67.6) Abdomen 8 (23.5) Back 15 (44.1) Lower limbs 10 (29.4) Palms 3 (8.8) Mast cells systemic infiltration symptoms/signs (C-sign finding) Bone fracture 2 (5.9) Weight loss and 1 (2.9) hypoalbuminemia Skin histologic findings Dilated capillaries and venules 34 (100) in papillary dermis No. of mast cells/mm2 34 (100) 40 No. of mast cells/mm2 11 (32.4) 64 for case with [20 cells/microscopic high-power field (340) Biological findings Serum tryptase level, g/L 34 (100) 8.3 Serum tryptase level [20 9 (26.5) 48
(27-55) (25-53) (12-63)
Table I. Cont’d Characteristics
KIT 816 mutation detected From bone-marrow aspiration in 31 patients From skin biopsy specimen in 34 patients
-
Median (IQR)
12 (35.3) 10 (32.3)
-
12 (35.3)
-
IQR, Interquartile range; TMEP, telangiectasia macularis eruptiva perstans; WHO, World Health Organization.
Table II. Clinical characteristics of telangiectasia macularis eruptiva perstans with and without systemic involvement
-
No. of patients (%)
Characteristics
Female, n (%) Age at diagnosis, y, median (IQR) Age at disease onset, y, median (IQR) At least a mediator release symptom, n (%) Mast cells/mm2, n (IQR) Serum tryptase level, g/L (IQR) KIT 816 mutation detected from skin biopsy specimen, n (%)
Patients without Patients with systemic systemic P involvement involvement N = 18 value N = 16
6 (37.5) 49 (29-54)
12 (66.7) 51 (25-58)
.1 .8
45 (27-52)
39 (24-56)
.9
14 (87.5)
18 (100)
.2
47 (30-54) 36 (29-58) .4 16 (7-47) 6.7 (5.3-11) .02 6 (37.5)
3 (16.6)
.2
Bold value indicates statistical significance. IQR, Interquartile range.
tryptase levels were observed in patients with systemic involvement.
DISCUSSION -
(29-52) (51-110)
(5.5-27) (37-94)
Continued
This article provides a detailed description of the clinical presentation and frequency of systemic involvement associated with TMEP in adults. There is a median 2-year delay in the diagnosis of TMEP. In most patients TMEP is associated with a relatively low-density mast cell infiltrate in the skin and normal tryptase levels. However, most patients with TMEP may experience mast cell activation symptoms (94%), and almost half of them have evidence of systemic mastocytosis. TMEP is a specific form of cutaneous mastocytosis.6,7,9,14-18 In our study, the frequency of TMEP was higher (14%) than previously reported in adults.8,18 The median age at diagnosis (50 years), disease onset
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(42 years), or both corresponds to the peak incidence of mastocytosis in adult patients.18 The low number of mast cells in dermal tissue (40/mm2), the low frequency of KIT point mutations at codon 816 in skin biopsy specimens (29%), and the low serum tryptase levels (median of 8.3 g/L) suggest that the mast cell burden is lower in TMEP than in other forms of cutaneous mastocytosis. There is a need to consider the use of more sensitive criteria for TMEP diagnosis such as the diagnostic criteria defined by Ackerman.12 One original aspect of this work is the high frequency of systemic manifestations in TMEP (47%), including 3 patients with signs of aggressive systemic mastocytosis (9%), underlining the importance of accurate diagnosis and treatment of patients with TMEP.19 It also validates the clinical spectrum of TMEP as an individualized form of mastocytosis.20-22 Although high serum tryptase levels appear to be the only factor associated with systemic involvement, some patients who have TMEP with systemic involvement have normal serum tryptase levels. This might be explained by high polymorphism of genes (tryptase 1/tryptase 2) encoding the production, maturation, and/or secretion of tryptase in human beings.23-26 In addition, the sample size is too small to rule out the potential role of other factors, such as number of mast cells in skin biopsy specimen and presence of a KIT mutation in skin. This study has several potential limitations: firstly, patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis. It is likely that mild forms of TMEP were underdiagnosed and the relative frequency of TMEP in our cohort might not represent the true relative frequency in the general population. On the other hand, the incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. Secondly, not all patients had a systematic examination by dermoscopy to confirm the findings considered characteristic of TMEP, telangiectatic vessels arranged in a reticular pattern.27 Finally, treatment data were not available for all patients. This precludes any conclusions about treatment efficacy and strategy in this group of patients. Conclusion TMEP is a cutaneous form of mastocytosis that is difficult to diagnose. Although mast cell burden is low in TMEP, the frequency of systemic mast cell involvement is high and should be
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investigated systematically. More work is needed to better define diagnostic criteria in this patient population and to develop specific treatment recommendations. REFERENCES 1. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625. 2. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostic, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435-453. 3. Arock M, Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol. 2010;3:497-516. 4. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74:121-132. 5. Hartmann K, Henzb B. Classification of cutaneous mastocytosis: a modified consensus proposal. Leuk Res. 2002; 26:483-484. 6. Biedermann T, Ru€eff F, Sander CA, Przybilla B. Mastocytosis associated with severe wasp sting anaphylaxis detected by elevated serum mast cell tryptase levels. Br J Dermatol. 1999; 141:1110-1112. 7. Lee HW, Jeong YI, Choi JC, et al. Two cases of telangiectasia macularis eruptiva perstans demonstrated by immunohistochemistry for c-kit (CD 117). J Dermatol. 2005;32:817-820. 8. Vano-Galvan S, Alvarez-Twose I, De Las Heras E, et al. Dermoscopic features of skin lesions in patients with mastocytosis. Arch Dermatol. 2011;147:932-940. 9. Sarkany RPE, Monk BE, Handfield-Jones SE. Telangiectasia macularis eruptiva perstans: a case report and review of the literature. Clin Exp Dermatol. 1998;23:38-39. 10. Pettigrew HD, Teuber SS, Kong JS, Gershwin ME. Contemporary challenges in mastocytosis. Clin Rev Allergy Immunol. 2010;38:125-134. 11. Williams KW, Metcalfe DD, Prussin C, Carter MC, Komarow HD. Telangiectasia macularis eruptiva perstans or highly vascularized urticaria pigmentosa? J Allergy Clin Immunol Pract. 2014;2:813-815. 12. Ackerman AB. Urticaria pigmentosa. In: Ackerman AB, ed. Histologic diagnosis of inflammatory skin diseases. An algorithmic method based on pattern analysis. 2nd ed. Baltimore: Williams and Wilkins; 1997:877-881. 13. Fraitag-Spinner S. Mastocytoses cutanees. Ann Dermatol Venereol. 2007;134:589-592. 14. Weber FP, Hellenschmied R. Telangiectasia macularis eruptiva perstans. Br J Dermatol Syphilol. 1930;42:374-382. 15. Bonnefoy M, Rouchouse B, Clavreul C, Decousus D, Claudy A. Prolonged losses of consciousness disclosing mastocytosis of the telangiectasia macularis eruptiva perstans type. Ann Dermatol Venereol. 1986;113:259-262. 16. Altiner A, Tzu J, Patel R, Meehan S, Sanchez M. Telangiectasia macularis eruptiva perstans. Dermatol Online J. 2011;17:7. 17. Costa DL, Moura HH, Rodrigues R, Pinero-Maceira J, RamosE-Silva M. Telangiectasia macularis eruptiva perstans. A rare form of adult mastocytosis. J Clin Aesthet Dermatol. 2011;4:52-54. 18. Watkins C, Bokor W, Leicht S, Youngberg G, Krishnaswamy G. Telangiectasia macularis eruptiva perstans: more than skin deep. Dermatology Reports. 2011;3:e12. 19. Marrouche N, Grattan C. TMEP or not TMEP: that is the question. J Am Acad Dermatol. 2014;70:581-582.
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20. Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537-545. 21. Cohn MS, Mahon MJ. Telangiectasia macularis eruptiva perstans. J Am Osteopath Assoc. 1994;94:246-248. 22. Smith JH, Butterfield JH, Pardanani A, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg. 2011;113:570-574. 23. Johnson MR, Verstovsek S, Jorgensen JL, et al. Utility of the World Health Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow. Mod Pathol. 2009;22:50-57.
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24. Guida M, Riedy M, Lee D, Hall J. Characterization of two highly polymorphic human tryptase loci and comparison with a newly discovered monkey tryptase ortholog. Pharmacogenetics. 2000;10:389-396. 25. Hernandez-Hernandez L, Sanz C, Garcıa-Solaesa V, et al. Tryptase: genetic and functional considerations. Allergol Immunopathol. 2012;40:385-389. 26. Vitte J. Human mast cell tryptase in biology and medicine. Mol Immunol. 2015;63:18-24. 27. Akay BN, Kittler H, Sanli H, et al. Dermatoscopic findings of cutaneous mastocytosis. Dermatol. 2009;218:226-230.
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Supplemental Table I. World Health Organization diagnostic criteria of systemic mastocytosis: Major and 1 minor or 3 minor criteria are fulfilled Major criterion Minor criteria
Multifocal dense infiltrates of MC ([15 MC aggregating) detected in sections of BMB and/or of other extracutaneous organ(s) by tryptase immunohistochemistry or other stains a. MCs in bone marrow or other extracutaneous organs show an abnormal (spindling) morphology ([25%). b. Detection of a KIT point mutation at codon 816 in bone marrow or blood or other extracutaneous organ(s) c. Kit1 MC in bone marrow or blood or other extracutaneous organ(s) co-express CD2 or/and CD25 d. Serum total tryptase concentration persistently [20 g/L
BMB, Bone-marrow biopsy specimen; MC, mast cells.
