Introduction
Systemic mastocytosis is a rare clonal neoplastic proliferation of mast cells characterized by diverse skin and systemic manifestations. These varied clinical signs and symptoms can contribute to delays in medical care and diagnosis. We report a case of a previously healthy man with a 25-year history of skin lesions consistent with telangiectasia macularis eruptiva perstans, later progressing to mast cell leukemia. This case highlights the diagnostic challenges of mast cell disease and the importance of early recognition and consideration of targeted therapy in advanced cases.
Case report
A 52-year-old male presented with a 25-year history of persistent, intermittently pruritic, red-brown macules on the lower extremities, which eventually spread to the trunk and upper extremities (Fig 1). For over a decade, the eruption was misattributed to environmental triggers and behavioral causes. The patient reported chronic symptoms of mast cell mediator release, including abdominal pain, near-syncope, cognitive dysfunction (“brain fog”), and arthralgias, exacerbated by heat, stress, and spicy foods.
Fig 1.
Telangiectasia macularis eruptive perstans; photographs showing widespread symmetric red-brown telangiectatic macules and thin papules, with focal confluence on the proximal lower extremity (A) and abdomen (B).
In late 2014, a dermatology evaluation revealed widespread telangiectatic macules, which raised concern for maculopapular cutaneous mastocytosis, specifically, telangiectatic macularis eruptiva perstans. Skin punch biopsy demonstrated mast cells in the papillary dermis with oval nuclei and abundant eosinophilic cytoplasm. Serum tryptase was elevated at 62 ng/mL (normal: 1-15 ng/mL). A bone marrow (BM) biopsy performed in 2015 confirmed indolent systemic mastocytosis by fulfilling the diagnostic criteria set by the National Comprehensive Cancer Network. The patient showed no “C-findings”–such as cytopenias, palpable hepatosplenomegaly with functional impairment or malabsorption–and Sanger sequencing tests for KIT mutations were negative. Medical management varied over the following decade (See Table I) as his condition remained overall stable, with persistently elevated tryptase levels (Fig 2).
Table I.
Progression of medical management of the patient during 2014-2024
| Date | Management | Clinical notes |
|---|---|---|
| December 2014 | Epinephrine 0.3 mg autoinjector | Prescribed to use as needed due to a high risk of anaphylaxis |
| 2015 | Cetirizine, fexofenadine, and hydroxyzine 25 mg tacrolimus 0.1% & hydrocortisone | Antihistamines were used for symptomatic control of pruritus and rash. Topical steroids were used in short, alternating courses with tacrolimus to prevent steroid atrophy |
| 2020 | Diphenhydramine 25 mg daily | Added to the regimen for further symptomatic control of the patient's cutaneous flares |
| May 2022 | Naproxen | Instructed to take as needed with food to manage flares of generalized arthralgias and myalgias (bone/joint pain) |
| November 2022 | Prednisone (Prolonged taper) | Prescribed to manage a severe systemic mastocytosis flare, starting at 80 mg and gradually walking down over several weeks |
| January 2024 | Vitamin D3 (50,000 units) weekly methylprednisolone 4 mg |
Vitamin D3 was prescribed to treat a documented deficiency. The patient also kept a methylprednisolone 4 mg at home for acute unforeseen symptom events |
| April 2024 | Meloxicam 15 mg quercetin, diamine oxidase, and Low-histamine diet | Meloxicam was initiated for escalating bone pain. Instead of starting high-dose steroids for worsening symptoms and rising tryptase, the patient opted for dietary changes, quercetin, and diamine oxidase supplementation |
| June/July 2024 | Omeprazole 40 mg Ketorolac 40 mg | Omeprazole replaced OTC omeprazole for GI symptoms. A trial of Ketorolac was started to manage escalating bone pain, replacing previous NSAIDs. |
| September 2024 | Montelukast 5 mg Fenoxfenadine 180 mg | The patient discontinued night-time Benadryl and added Montelukast and an additional dose of Fenoxfenadine at bedtime to manage symptoms during cooler weather better |
Table I outlines the decade-long progression of therapeutic interventions for a patient with systemic mastocytosis. It highlights key supportive care measures before escalation to tyrosine kinase inhibitors.
Fig 2.
Serial serum tryptase levels of the index patient, 2014-2026. Levels were elevated at presentation (62 ng/mL), then rose progressively to a peak of 171 ng/mL in 2025, and declined to 25 ng/mL in 2026 after intervention with a small daily dose of avapritinib (25 mg).
In the summer of 2020, his course was complicated by concomitant Rocky Mountain spotted fever and COVID-19 infections, both of which were associated with significant systemic inflammatory flares consisting of pruritus, arthralgias, myalgias, anxiety, and abdominal pain. In 2022, a repeat BM biopsy confirmed systemic mastocytosis with roughly 10% to 15% mast cell cellularity, favoring the indolent form, and positron emission tomography/computed tomography revealed widespread sclerotic bone foci. A repeat flow cytometry test detecting KIT mutations was negative.
By early 2024, the patient developed worsening exercise intolerance, near-syncope, palpitations, and severe episodic panic attacks, prompting urgent reassessment. Skin examination revealed stable lesions, with no new lesions detected. However, the tryptase levels had risen to 114 ng/ml. In May 2025, a next-generation sequencing test showed a negative KIT mutation, and a BM biopsy showed 90% hypercellularity with 20% to 30% mast cells, meeting the WHO diagnostic criteria1 for mast cell leukemia. An initial trial of imatinib (up to 400 mg daily) was discontinued due to debilitating side effects.
By late 2025, tryptase peaked at 171 ng/mL. By late 2025, tryptase peaked at 171 ng/mL. A KIT mutation was eventually identified via High-sensitivity droplet digital PCR. A subsequent Droplet PCR test in February 2026 was also positive, with a quantitative value of 0.25%. While the exact variant detected in 2025 is not detailed, the background clinical information from his earlier lab reports indicates that these diagnostic tests typically analyze KIT exons 8, 9, 11, and 17. The lab documentation specifically notes that the KIT exon 17 D816V mutation is commonly reported in patients with systemic mastocytosis. The patient was started on 25 mg of avapritinib daily (vs typical 200 mg daily) –due to concerns of medication sensitivity and tolerability. Within 4 months, a follow-up BM biopsy showed a dramatic reduction in mast cell burden to 5%, and tryptase plummeted to 25 ng/mL. The patient reported significant symptomatic improvement and remains on therapy. Finally, his lesions improved markedly, with near-resolution on his trunk and back, leaving only persistence on the lower extremities. He reported no pruritus (Fig 3).
Fig 3.
Clinical response following avapritinib therapy. The patient’s trunk and abdomen four months after initiation of avapritinib (25 mg daily). The image demonstrates near-complete resolution of the previously persistent, widespread telangiectatic macules characteristic of his systemic mastocytosis correlating with the patient's clinical improvement and the significant reduction in mast cell burden observed on the follow-up bone marrow biopsy.
Discussion
This case highlights 3 main issues relevant to dermatologists:
-
1.
Adult mastocytosis may present with subtle cutaneous findings and prolonged diagnostic delay. Telangiectasia macularis eruptiva perstans-like lesions–now recognized as a variant of maculopapular cutaneous mastocytosis1,2– may be overlooked, particularly when the Darier sign (localized urtication and erythema induced by rubbing a lesion) is absent or minimal. Recognition of widespread telangiectatic macules, with or without mediator-related symptoms (eg, pruritus, abdominal pain, hypotension, cognitive dysfunction, “brain fog”) should prompt a systemic workup for mastocytosis, including a bone marrow biopsy.2, 3, 4, 5
-
2.
Negative initial molecular testing does not rule out systemic mastocytosis. While the majority of systemic mastocytosis cases document a KIT mutation, most often KIT D816V, detection of this mutation is not required for diagnosis, although it does represent a minor criterion.6 Mutations can be missed by low-sensitivity tests such as Sanger Sequencing, especially when the allele burden is low.7 More sensitive molecular methods can find KIT D816V in over 80% to 90% of patients with suspected systemic mastocytosis; on the other hand, about 5% to 10% of patients may test negative for KIT D816V, which highlights the risk of false negatives with less sensitive tests. For patients with compatible clinical signs, elevated tryptase levels, and supportive tissue analysis, repeat testing with a high-sensitivity method may be necessary.4,8
-
3.
Serial serum tryptase measurements were clinically informative but not in isolation. Although elevated baseline tryptase may reflect mast cell burden, a marked change from baseline, along with objective clinical findings such as cytopenias, hepatosplenomegaly, liver dysfunction, ascites, elevated alkaline phosphatase, and pathological fractures, may indicate an increasing mast cell burden and should prompt reassessment in symptomatic patients.3,4,8 In this patient, the marked increase from baseline coincided with worsening clinical disease and subsequent leukemic transformation. A long-standing baseline range of ∼ 50 to 100 ng/mL was followed by a rise to 171 ng/mL at the time of leukemic transformation and coincided with reports of bone pain. The KIT inhibitor avapritinib elicited a rapid biochemical response, consistent with published trial data reporting high response rates in advanced systemic mastocytosis.9,10
Conflicts of interest
None disclosed.
Footnotes
Funding sources: None.
Patient consent: The authors obtained written consent from the patient(s) for their photographs and medical information to be published in print and online, with the understanding that this information may be publicly available. Patient consent forms were not provided to the journal but are retained by the authors.
IRB approval status: Not applicable.
References
- 1.Khoury J.D., Solary E., Abla O., et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–1719. doi: 10.1038/s41375-022-01613-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hartmann K., Escribano L., Grattan C., et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35–45. doi: 10.1016/j.jaci.2015.08.034. [DOI] [PubMed] [Google Scholar]
- 3.Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508–525. doi: 10.1002/ajh.26118. [DOI] [PubMed] [Google Scholar]
- 4.Gotlib J., Gerds A.T., Bose P., et al. Systemic mastocytosis, version 2.2023, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2023;21(7):759–781. doi: 10.6004/jnccn.2023.0031. [DOI] [Google Scholar]
- 5.Severino M., Chandesris M.O., Georgin-Lavialle S., et al. Telangiectasia macularis eruptiva perstans (TMEP): a form of cutaneous mastocytosis with potential systemic involvement. J Am Acad Dermatol. 2016;74(5):885–891. doi: 10.1016/j.jaad.2015.10.050. [DOI] [PubMed] [Google Scholar]
- 6.Valent P., Akin C., Metcalfe D.D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420–1427. doi: 10.1182/blood-2016-09-731893. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Shomali W., Gotlib J. The new tool "KIT" in advanced systemic mastocytosis. Hematology Am Soc Hematol Educ Program. 2018;2018(1):127–136. doi: 10.1182/asheducation-2018.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ustun C., Keklik Karadag F., Linden M.A., Valent P., Akin C. Systemic mastocytosis: current status and challenges in 2024. Blood Adv. 2025;9(9):2048–2062. doi: 10.1182/bloodadvances.2024012612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gotlib J., Reiter A., Radia D.H., et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27(12):2192–2199. doi: 10.1038/s41591-021-01539-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.DeAngelo D.J., Radia D.H., George T.I., et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021;27(12):2183–2191. doi: 10.1038/s41591-021-01538-9. [DOI] [PMC free article] [PubMed] [Google Scholar]