Mastocytosis in the Skin: Approach to Diagnosis, Evaluation, and Management in Adult and Pediatric Patients

Abstract

Mastocytosis is characterized by the clonal infiltration and proliferation of neoplastic mast cells into target organs. Clinical features of mastocytosis are based in large part on dysregulated mast cell mediator release. Affected individuals may present with isolated skin involvement or multisystemic disease with a spectrum of symptoms including anaphylaxis, pathologic fractures, and chronic gastrointestinal, neurocognitive, musculoskeletal, and constitutional symptoms. The term “mastocytosis in the skin” refers to individuals with cutaneous infiltration and encompasses both localized and systemic forms of disease. Cutaneous involvement is further categorized into cutaneous mastocytoma, diffuse cutaneous mastocytosis, and maculopapular cutaneous mastocytosis based on morphology. In ~95% of patients with systemic mastocytosis, the disease is driven by the KIT D816V somatic variant. The aim of this clinical review is to highlight the diagnostic considerations, management complexities, and evolving treatment landscape that must be considered when evaluating a patient presenting with mastocytosis in their skin. Clinical manifestations, histopathology, and laboratory parameters are essential to diagnosis and determining the disease burden in those with known or suspected systemic mastocytosis. Once appropriately staged, both skin-directed therapy as well as novel systemic treatment options, including selective tyrosine kinase inhibitors, can be considered with the potential to improve patient outcomes.

Key Points

This clinical review presents an updated approach to the diagnosis, evaluation, and management of patients presenting with mastocytosis in the skin.

As systemic and prognostic implications differ between adult and pediatric populations, careful attention to the unique features that impact an evaluation in these groups is imperative and is outlined within.

Introduction

Mastocytosis is a clonal mast cell (MC) disease driven by mutations in the KIT gene in the majority of cases [1, 2]. It is characterized by MC proliferation and activation in one or more of the following organs: the bone marrow (BM), liver, spleen, lymph nodes, gastrointestinal tract, and skin. Clinically, the disease may manifest with recurrent pruritus, flushing, urtication, abdominal pain, nausea/vomiting, diarrhea, musculoskeletal pain, vascular instability, headache, and neuropsychiatric difficulties [3]. It is estimated to affect 1 in 10,000 individuals [4], although the precise incidence in the USA remains uncertain and limited by under-diagnosis, which is at least partially attributed to a lack of recognition and awareness of mastocytosis. Mastocytosis may present at any age without sex predilection and familial occurrence may occur but is uncommon [4–6].

Mastocytosis represents a spectrum of phenotypic expression with pathologic and genetic findings affecting presentation and prognosis. In children, the skin is the most common organ involved and, in the vast majority of cases, is the only manifestation of the disease. Pediatric-onset mastocytosis occurs as early as birth, with 85% presenting by age 2 years [7]. Children may be diagnosed with all mastocytosis variants, though the clinical presentation and underlying pathogenesis may differ from adults. For example, most children lack the KIT c.2447 C>T (p.D816V) exon 17 activating mutation often found in adults. Additional distinct KIT genetic alterations have been found in skin biopsies of children with skin-limited disease (cutaneous mastocytosis [CM]), including alterations in exons 8 and 9, partially explaining the differences in the disease course [8]. Although systemic mastocytosis (SM) rarely presents during childhood, recognition is paramount to improving outcomes for these patients. In contrast to children, the vast majority of adults and late adolescents presenting with abnormal MC proliferation in the skin have concurrent SM characterized by extracutaneous neoplastic MC hyperplasia [9]. For this reason, adults found to have cutaneous disease are termed to have “mastocytosis in the skin (MIS)” until staging is complete as cutaneous-limited disease (CM) cannot be definitively diagnosed in this population otherwise.

Across all ages, SM is diagnosed based on BM and extracutaneous organ histopathologic changes as outlined by the World Health Organization and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias [10–13]. A BM biopsy should therefore be considered in all adult-onset cases and in children demonstrating features suggestive of systemic involvement. Mastocytosis is classified into different subtypes [11]. Bone marrow mastocytosis, indolent SM (ISM), and smoldering SM comprise non-advanced SM, whereas aggressive SM, SM with an associated myeloid hematologic neoplasm, and MC leukemia comprise advanced SM [14]. Indolent SM is the most common form of SM and is diagnosed when criteria for SM are met without evidence of an associated clonal hematologic disorder or MC-related end-organ damage such as severe liver disease, hypersplenism, or significant lymphadenopathy. Patients with CM and ISM have survival rates similar to the general population, whereas survival in patients with advanced SM is reduced owing to a higher disease burden, an associated hematologic neoplasm, or MC-related end-organ damage [15]. Approximately 50% of patients with SM with an associated myeloid hematologic neoplasm and aggressive SM do not display typical cutaneous lesions [9], nor are typical skin lesions common in MC leukemia. Bone marrow mastocytosis, often associated with venom-induced anaphylaxis, also lacks typical skin lesions but has more favorable survival [16]. Well-differentiated SM, when seen in a setting of ISM, may present with a familial pattern and variable cutaneous manifestations [17]. A summary of mastocytosis subtypes is presented in Table 1.

Table 1.

Mastocytosis types and subtypes

WHO 5th Editiona	International Consensus Classification
Cutaneous mastocytosis
Subtypes
Maculopapular cutaneous mastocytosis (urticaria pigmentosa)	Maculopapular cutaneous mastocytosis (urticaria pigmentosa)
Monomorphic	Diffuse cutaneous mastocytosis
Polymorphic	Mastocytoma of skin
Diffuse cutaneous mastocytosis
Cutaneous mastocytoma
Isolated mastocytoma
Multi-localized mastocytoma
Systemic mastocytosis (SM)
Subtypes
Bone marrow mastocytosisb
Indolent SM
Smoldering SM
Aggressive SM
SM with an associated hematologic neoplasmc
Mast cell leukemia
Mast cell sarcoma

SM systemic mastocytosis, WHO World Health Organization

^aWell-differentiated SM is a morphologic variant present in all subtypes of SM

^bBone marrow is now considered a separate subtype of SM in the WHO 5th ed classification of hematolymphoid tumors characterized by no mastocytosis skin lesions, no B-findings, and a basal serum total tryptase level <125 ng/mL, whereas in the International Consensus Classification it is considered a clinicopathologic variant of indolent SM

^cIn the International Consensus Classification, SM with an associated hematologic neoplasm has been modified such that the associated hematologic neoplasm is defined as an associated myeloid neoplasm only

Adapted from Arber et al. Blood. 2022;140(11):1200–8 [10]; Khoury et al. Leukemia. 2022;36:1703–19 [11]; National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Systemic mastocytosis. 2024; version 3.2024 [14]

Presentation

Morphology

Classically, affected individuals present with red-brown macules, papules, nodules, and/or plaques that produce dermal edema and erythema upon mechanical stimulation (Darier’s sign) [18, 19]. To perform this test accurately, the lesion is stroked five times with moderate pressure using a tongue depressor. Within several minutes, erythema and edema will develop that will be absent in surrounding unaffected skin (thus differentiating this from dermatographism) [20]. The presence of a positive Darier’s sign is particularly useful when establishing a diagnosis in the setting of classic morphology, although in cases of diagnostic uncertainty, histopathology with appropriate staining will be more definitive. Notably, a positive Darier’s sign is more likely to be absent in adults, in patients concurrently receiving antihistamines, and if performed incorrectly [20]. Testing too aggressively may also result in false-positive results or rarely in systemic symptoms—flushing, wheezing, or hypotension—in children with nodular skin lesions.

Atypical presentations require a high index of suspicion and expertise. Skin lesions may have atypical distribution—intertriginous [21, 22], acral [23], unilateral localization [24]—and additional cutaneous features may be present, including pseudoxanthomatous/xanthelasmoid morphology [25–27]. Secondary changes such as acquired cutis laxa and leonine facies are seldomly observed [28, 29]. Non-specific features, including flushing and pruritus, are frequently present and may be the most prominent features of the disease, particularly when the burden of fixed skin lesions is low.

Historically, morphologic classification centered around terms such as urticaria pigmentosa and telangiectasia macularis eruptiva perstans. Recent reclassification has challenged the validity of these as unique variants and instead favors the encompassing term “maculopapular cutaneous mastocytosis” (MPCM). Current guidelines recommend dividing the cutaneous manifestations of mastocytosis into three subtypes, namely, cutaneous mastocytoma, diffuse cutaneous mastocytosis (DCM), and MPCM; this terminology will be utilized throughout this article [20].

Cutaneous mastocytomas are characterized by solitary or a few raised, yellow, red, or brown rubbery ovoid nodules or plaques that may develop secondary blistering and frequently demonstrate a positive Darier’s sign. This form of disease presents in early childhood, is defined by remission during adolescence, and lacks an association with systemic disease [20, 30].

Diffuse cutaneous mastocytosis also generally presents in early childhood. Children with DCM often lack individual lesions and instead manifest with generalized skin thickening (pachydermia) with alteration of skin color. Mechanical irritation frequently produces erythema and cutaneous edema and may evoke blistering. Anaphylaxis may also occur [31]. There is often an elevated serum tryptase level at presentation, but most children lack internal organ involvement. A tendency toward prolonged cutaneous bleeding may be present in the setting of local heparin release, but blood parameters are characteristically normal. Reassuringly, DCM also classically resolves by adolescence [20, 31, 32].

Maculopapular cutaneous mastocytosis represents the most heterogeneous subtype. A consensus statement from the European Competence Network on Mastocytosis, the American Academy of Allergy, Asthma, & Immunology, and the European Academy of Allergology and Clinical Immunology recommended further division of MPCM into polymorphic and monomorphic categories [20]. The polymorphic form predominates in children and is defined by findings of red-brown lesions of varying sizes (Fig. 1). These are often fewer in number compared with monomorphic MPCM, with a predilection for the head and neck in addition to the trunk and extremities [20]. As with cutaneous mastocytoma and DCM, polymorphic MPCM is usually temporary and generally lacks an association with systemic disease. Rarely, adults may also present with polymorphic MPCM or skin lesions consistent with DCM. These individuals are more likely to have an earlier age at onset, BM features of well-differentiated SM, and present with non-D816V KIT mutations [17].

Fig. 1.

Polymorphic maculopapular cutaneous mastocytosis and monomorphic maculopapular cutaneous mastocytosis in children of varied skin phototypes

Monomorphic MPCM is characterized by small uniform red-brown macules and papules with a predilection for the trunk and proximal extremities, classically sparing the face (Fig. 2). This is the predominant presentation of adult-onset MIS, although children may also be affected. In adults, it is strongly associated with SM and requires surveillance and staging. The monomorphic pattern in pediatric patients has also been associated with more severe and persistent disease beyond adolescence [20, 33, 34]. The number of lesions ranges from less than a dozen to near-universal involvement [20]. This morphology is persistent over time and carries a risk of anaphylaxis [20, 35]. Notably, as this classification schema is largely intuitive and based on experience, limitations in distinguishing monomorphic and polymorphic disease exist. In one small study, interobserver variability in the classification of MPCM in pediatric patients was demonstrated even among experts [36].

Fig. 2.

Monomorphic maculopapular cutaneous mastocytosis in adults of different skin types

Systemic Symptoms

Patients with SM frequently present with extracutaneous manifestations including abdominal pain, nausea/emesis, bowel pattern changes, musculoskeletal pain, vascular instability, and neuropsychiatric complaints leading to an impaired quality of life [37–39]. Fifty-six percent of adult patients with SM may also experience anaphylaxis, [40–42] and pathologic fractures, due to premature osteopenia or osteoporosis, are reported in 28–56% of patients with SM [43–45]. The prevalence of idiopathic anaphylaxis in patients with pediatric mastocytosis has also been reported to be higher than the general pediatric population; however, the prevalence of other triggers is lower [46]. Moreover, the prevalence of anaphylaxis in pediatric mastocytosis is lower than in adult patients with mastocytosis [42, 46]. A complete review of systems is imperative in patients presenting with MIS, as the presence of additional features may increase the suspicion for SM [47].

Histopathology

A skin biopsy should be considered in the initial diagnostic work-up if MIS is suspected and clinical manifestations are not conclusive. Pathologists should be notified of the clinical suspicion on the requisition as histopathological features can be subtle [48]. The duration of the lesion typically does not affect pathology; however, older lesions may not be as responsive when testing for Darier’s sign. Given that fibroblasts can be activated by MCs [49], the biopsy site may have an exaggerated fibrotic response. Therefore, the authors tend to biopsy areas covered by clothing such as the trunk.

Mastocytosis in the skin is characterized by the abnormal accumulation of MCs in the dermis of affected skin. In skin biopsies, MC distribution, number, and density, as well as the presence of additional “non-MC” findings, such as pigmentary change, dermal vascular proliferation and dilatation, eosinophilia, and dermal fibrosis, are all of importance. Mast cells can be highlighted by positive cluster of differentiation (CD) 117 (most sensitive) and tryptase (most specific) immunostaining [50]. When suspecting mastocytosis, additional antigens of aberrant expression in MCs, such as CD2, CD25, and more recently, CD30 [51], may be tested though have less utility in the skin than in other organs. The MC receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) may also be analyzed in patients with MPCM [52]. The density of MCs in normal skin is variable and dependent on the location and the presence of other inflammatory dermatoses [53]; thus, an evaluation by an experienced dermatopathologist is important when considering the diagnosis, and a clinicopathologic correlation remains necessary. Discrimination of isolated CM from SM with cutaneous involvement is often not possible based on skin histopathology alone. As discussed previously, the term MIS is favored when describing an abnormal cutaneous proliferation of MC until an appropriate evaluation and staging have been performed [54]. Anecdotally, the authors have found that cases signed out as MIS in the adult population are more likely to prompt an additional evaluation compared with cases signed out as compatible with CM or urticaria pigmentosa.

The patterns of MC distribution were recently updated by Drabent et al. into “sheet-like,” “subepidermal,” and “perivascular” patterns [55]. The former two are strongly specific for mastocytosis. The presence of a dense sheet-like proliferation of MCs makes the histologic diagnosis of DCM and mastocytoma more straightforward than MPCM, which often presents with more subtle histologic findings. When not in a sheet-like or subepidermal pattern, evaluation of the MC component of the inflammatory infiltrate is important to discriminate mastocytosis from other inflammatory disorders associated with increased MCs (Fig. 3). A 40% cut-off for the percentage of MCs among inflammatory cells has been shown to have a sensitivity of >75% and a specificity approaching 100%. In cases wherein the MC component is <40%, additional features (including number of MCs per mm²) may improve sensitivity [55]. A retrospective histopathologic study by King et al. suggests that a MC density >66 per mm² is a useful threshold to distinguish MPCM from chronic urticaria [56].

Fig. 3.

Histopathologic images showing mast cell infiltration in the skin from a maculopapular cutaneous mastocytosis presentation. (a) A brisk infiltrate of mast cells in the superficial and deep reticular dermis is present with a perivascular and interstitial distribution (hematoxylin and eosin, 20×). (b, c) The mast cells reveal an abnormal morphology characterized by a combination of epithelioid and spindle cell features (hematoxylin and eosin, 100× [b] and 200× [c]). (d) The mast cells are diffusely positive for cluster of differentiation 117 (20×)

A recently published scoring model has been proposed by experts in the field (Table 2), though the model does not account for presentations in skin of color [57]. This model has not yet been widely adopted in clinical practice, and further data may validate such tools for implementation in the future. Testing the skin biopsy for the presence of KIT D816V using a high-sensitivity assay enhances the robustness of this model but is not widely available (see Sect. 4 for more details).

Table 2.

Proposed scoring model to assist with the pathologic diagnosis of MPCM

Variable	Score (points)
≥27 subepidermal MC/HPF	3
≥12 subepidermal MC/HPF	2
≥7 subepidermal MC/HPF	1
Intermediate or strong basal pigmentationa	1
Interstitial distribution of MCs	1
≥3 MC clusters	1
Interpretation
MPCM highy likely (Sp = 97.2%, Sn = 90.6%)	4–6
MPCM unconfirmed (Sp = 38.9%, Sn = 100%)	1–3
MPCM excluded	0

HPF high-power field, MC mast cell, MPCM maculopapular cutaneous mastocytosis, Sn sensitivity, Sp specificity

^aApplies to Caucasian individuals only

Adapted from Gebhard et al. J Eur Acad Dermatol Venereol. 2022;36(8):1367–75 [57]

Laboratory Studies

As mentioned, the risk of SM is highest in patients with monomorphic MPCM but rarely occurs in those with DCM morphology [58, 59]. Laboratory evaluations are useful in diagnosis, risk stratification, and assessment of disease burden in patients with known or suspected SM (Fig. 4). Evaluation of serum tryptase levels is indicated in all variants of mastocytosis; further laboratory testing is generally not indicated for children with CM alone. Although an elevated basal serum tryptase (BST) level is a valuable clinical parameter, the oft-held view that adults with a serum tryptase level of < 20 ng/mL do not require further evaluation is not supported by the literature or clinical experience [60]. In a retrospective cohort from the Toulouse Excellence Center for Mastocytosis, 27% of adults with cutaneous involvement in the setting of SM were found to have tryptase levels below this metric, with 15% of patients demonstrating levels of < 11.3 ng/mL [61]. Tryptase genotyping is also recommended to interpret whether an elevated BST value is due to different tryptase genotypes (including hereditary alpha tryptasemia) or an MC abnormality [13, 62–64].

Fig. 4.

Evaluation of adult and pediatric patients with mastocytosis in the skin. ABD abdominal, DCM diffuse cutaneous mastocytosis, HαT hereditary alpha-tryptasemia, MC mast cell, MPCM maculopapular cutaneous mastocytosis, PB peripheral blood, SBT serum basal tryptase, yo years old

The KIT D816V somatic variant is the driving mutation in ~ 95% of patients with SM [65, 66]. High-sensitivity (≥ 0.01%) quantitative polymerase chain reaction is recommended over Sanger- or next-generation sequencing-based methods for KIT p.D816V detection [67–69]. Peripheral blood (PB) KIT D816V quantitative polymerase chain reaction and BST are both recommended in the preliminary diagnostic evaluation for SM using the World Health Organization diagnostic criteria [70]. Next-generation sequencing panels focused on myeloproliferative and myelodysplastic neoplasms are also recommended for patients with SM to evaluate for additional mutations suggestive of SM with an associated myeloid hematologic neoplasm.

Treatment and Management

Initial treatment and subsequent evaluation of clinically diagnosed or biopsy-proven MIS are largely based on the subform/variant. All patients should undergo a physical examination to assess for hepatomegaly, splenomegaly, and lymphadenopathy, and a complete review of systems to identify features suggestive of systemic disease. Patients and families should be counseled on the risk of anaphylaxis and be trained in the use of an epinephrine autoinjector. All patients should be offered treatment directed at their cutaneous and extracutaneous symptoms even in the absence of SM or if the SM evaluation is still ongoing. Skin hydration is paramount, and pruritus, wheals, and flushing may be treated with non-sedating second-generation H1 antihistamines (dosed at up to four times the standard dose based on data in patients with chronic spontaneous urticaria) and/or MC stabilizers such as cromolyn [71]. Phototherapy, including the use of narrowband ultraviolet B and 8-methoxypsoralen plus ultraviolet A light, has demonstrated a benefit in adult patients with CM and SM [72–74]; although emerging evidence suggesting susceptibility to a cutaneous malignancy in patients with SM has led to caution with use. Omalizumab, an anti-immunoglobulin E monoclonal antibody, may be considered in patients with urtication and significant mediator symptoms; however, two small prospective clinical trials were unable to prove a definitive advantage, despite a tendency toward symptom reduction [75–77].

Patients with MIS who should be referred for evaluation and consideration of a BM biopsy (preferably at a Center of Excellence [78] with expertise and access to high-complexity molecular testing) are (1) adult patients (onset at ≥18 years of age) with monomorphic MPCM; (2) patients with familial forms of DCM; (3) patients with DCM and features suggestive of systemic disease such as splenomegaly, pathologic fractures, and cytopenias/cytoses; and (4) pediatric patients with monomorphic MPCM wherein there is suspicion of SM such as positive PB KIT D816V or organomegaly (Fig. 4) [79]. As stated previously, BST values do not independently determine whether an adult patient with MIS is a candidate for a BM biopsy as BST values may be less than the < 20 ng/mL (minor criterion) cut-off in patients with SM [61, 67]. Further, the most common etiology of an elevated baseline serum tryptase is hereditary alpha tryptasemia [80]; when possible, genetic testing for hereditary alpha tryptasemia can be included in the work-up. Scoring criteria, such as the European Competence Network on Mastocytosis/Fuchs’ score, can be beneficial in risk stratification and to facilitate informed decision making as patients who lack positivity for KIT D816V mutations and have a low score may be considered for close clinical monitoring alone [81]. Children who are clinically stable with a polymorphic pattern (which is not typically seen in adult-onset disease) can also be followed with PB laboratories including serum tryptase and blood counts at 6- to 12-month intervals. [20, 79]. If there is a suspicion for systemic disease in a child based on an elevated serum tryptase and organomegaly, a PB KIT D816V mutation should be ordered along with an abdominal ultrasound to verify organomegaly [82]. Patients requiring BM studies or additional therapy beyond symptomatic support can be referred to a Center of Excellence or reference center with multidisciplinary expertise to include hematology [83]. A BM evaluation at an experienced center is important as errors in diagnosis and classification occur more frequently in centers with a low case volume [67, 84, 85]. There are currently 21 identified Center of Excellence facilities within the USA along with five additional reference centers [86].

Historically, treatment options were limited for patients with SM and often reserved for those with advanced disease. Within the past decade, there have been significant advancements with the introduction of tyrosine kinase inhibitors (TKIs), which have the potential to induce partial or complete remission and improve patient-reported outcomes. Treatment with TKIs is reserved for patients with SM based on the underlying KIT driving mutation, SM subtype, and symptom burden. If a patient with SM is not adequately staged (e.g., when an appropriate pediatric or adult patient is not referred for a BM biopsy), they may be excluded from meaningful treatment.

Imatinib was the first TKI to be assessed and was found to be effective in some patients with SM who have wild-type or harbor mutations outside of codon 816 in KIT [47, 87–92]. Midostaurin, a multikinase inhibitor capable of inhibiting KIT harboring 816 codon substitutions, is currently US Food and Drug Administration approved for advanced SM. Midostaurin reduced the BM MC burden, spleen volume, and mastocytosis-related organ damage in an open-label phase II study of patients with advanced SM [93, 94]. Toxicity related to midostaurin was frequent, included cytopenias and gastrointestinal problems, and often required a dose reduction. A small phase II, non-randomized, single-center, open-label study of midostaurin treatment for patients with non-advanced disease demonstrated symptom improvement [95]. Avapritinib is a TKI that is selective for KIT harboring 816 codon substitutions and has been approved by the Food and Drud Administration at 200 mg once daily for advanced SM and at 25 mg once daily for ISM. Avapritinib in advanced SM led to complete or partial remission in most patients and improved survival [96–100]. In ISM, avapritinib use was associated with meaningful improvements in patient-reported outcomes and disease biomarkers [101, 102]. Additional targeted TKIs are currently under development and available through clinical trial protocols at experienced centers [103].

Conclusions

Mastocytosis presents in the skin as part of a heterogeneous group of clonal conditions affecting both adults and children. Classification criteria and staging of SM, as well as the treatment landscape, have evolved significantly in recent years. Despite this, many patients who warrant additional evaluation go without an appropriate referral. By addressing knowledge gaps related to diagnosis, terminology, evaluation, and treatment options, dermatologists will be better positioned to identify patients who require additional scrutiny and may benefit from novel therapeutics.

Declarations

Funding

Blueprint Medicines Corporation provided funding for the preparation of this article.

Conflicts of Interest

Lauren M. Madigan served on an international advisory board for Blueprint Medicines and participated as a speaker in a non-Continuing Medical Education (CME) session on recognizing and diagnosis mastocytosis; Section editor, JAMA Dermatology. Nathan A. Boggs participated in a Blueprint Medicines-sponsored patient advocacy summit; participated in developing a Blueprint-sponsored webinar for the College of American Pathologists. Anton V. Rets participated in developing a Blueprint Medicines-sponsored webinar for the College of American Pathologists. Alejandro A. Gru is an investigator for Innate Pharma, Stemline Therapeutics, and Dren Bio; a consultant for Blueprint Medicines; and a speaker for Kyowa Kirin. Tsewang Tashi is a member of the advisory board and a primary investigator in Blueprint Medicines clinical trials, Cogent Biosciences, and PharmaEssentia; a member of the study steering committee for Blueprint Medicines clinical trials. David. A Wada and Melody C. Carter have no conflicts of interest that are directly relevant to the content of this article. Scott R. Florell is a consultant for Orlucent Inc.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Patients or their representatives provided consent for the publication of any identifiable photographs.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Authors’ Contributions

All authors contributed to the concept, research, and writing of the manuscript. All authors read and approved the final manuscript.