Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2025;15(4):5564 1 PRAME Immunohistochemical Expression in Recurrent/Traumatized Melanocytic Nevi and the Pitfall of Expression by Reactive Fibroblasts Emma Carraturo1, Giuseppe D’Abbronzo1, Giuseppe Argenziano2, Gabriella Brancaccio2, Camila Scharf2, Elvira Moscarella2, Renato Franco1, Andrea Ronchi1 1 Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy 2 Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy Key words: PRAME, Recurrent nevus, Recurrent/traumatized melanocytic nevi Citation: Carraturo E, D’Abbronzo G, Argenziano G et al. PRAME immunohistochemical expression in recurrent/traumatized melanocytic nevi and the pitfall of expression by reactive fibroblasts. Dermatol Pract Concept. 2025;15(4):5564. DOI: https://doi.org/10.5826/ dpc.1504a5564 Accepted: July 9, 2025; Published: October 2025 Copyright: ©2025 Franco et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Renato Franco, Via Luciano Armanni 5, 80100, Naples. ORCID: 0000-0002-8340-3184. E-mail: renato.franco@unicampania.it Introduction: The recurrent/traumatized melanocytic nevus (RTMN) refers to melanocytic lesions that reappear following incomplete removal or trauma to a previous nevus, often presenting clinically and dermoscopically similar to melanoma, which complicates differential diagnosis. Histologically, RTMN exhibit melanocytic proliferation and scar tissue from prior trauma or excision. PRAME (pref- erentially expressed antigen in melanoma) immunohistochemistry (IHC) is emerging as a diagnostic tool for distinguishing between nevi, melanoma, and nevus-associated melanomas. However, its role in RTMN has not yet been established. Objectives: This study aimed to evaluate the expression of PRAME in RTMN, specifically in the melanocytic and fibroblastic components, to explore its potential diagnostic utility. Methods: A series of 22 RTMN cases from the Pathology Unit of the University of Campania Luigi Vanvitelli Hospital were reviewed. PRAME IHC was performed on formalin-fixed, paraffin-embedded tissue, and staining was evaluated in three compartments: junctional melanocytic, intradermal mela- nocytic, and fibroblastic scar tissue. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2025;15(4):5564 Introduction The recurrent nevus phenomenon describes the reappearance of a melanocytic proliferation at the site of a previously biop- sied melanocytic nevus [1]. A closely related entity, the trauma- tized nevus, refers to a melanocytic lesion that has undergone physical trauma and typically exhibits reparative junctional melanocytic proliferation [2]. Owing to their overlapping his- topathological features, these entities are collectively referred to as recurrent/traumatized melanocytic nevi (RTMN). RTMN represent a significant diagnostic challenge in both clinical and dermoscopic practice due to their potential to mimic melanoma, including melanoma arising in associ- ation with a preexisting nevus  [3]. Clinically, these lesions often manifest as hyperpigmented or hypopigmented areas with scar-like characteristics and asymmetrical borders [4]. The underlying biological mechanisms driving RTMN development remain poorly elucidated. However, it is pos- tulated that recurrence may result from incomplete excision of the initial nevus, followed by subsequent skin trauma. In particular, shave excisions, frequently performed for aes- thetic purposes, have been strongly associated with the emer- gence of recurrent nevi [5]. Histologically, RTMN may present as a junctional or compound melanocytic proliferation with mild to moderate cytologic atypia. This proliferation is frequently accompanied by dermal fibroblastic proliferation, indicative of scar forma- tion from the prior biopsy, along with a perivascular chronic inflammatory infiltrate composed predominantly of lympho- cytes and melanophages, often with melanin pigment deposi- tion [1,6]. These histopathological features can raise concern about malignancy, particularly in the absence of clinical doc- umentation of a previous excision [7]. Notably, intermediate- and late-stage melanomas commonly exhibit features of re- gression such as fibrosis and neovascularization within the papillary dermis, which may further obscure the distinction be- tween benign reactive changes and malignant transformation. RTMN are most commonly observed in females between the ages of 20 and 30, with the back being the most fre- quently affected anatomical site. Recurrence typically occurs within approximately six months following excision of the original nevus. However, there is currently no consensus regarding which specific histological subtype of nevus is most susceptible to recurrence [1,8]. Immunohistochemistry (IHC) for PRAME (preferentially expressed antigen in melanoma) is increasingly recognized as a useful adjunct in the differential diagnosis of melano- cytic lesions, particularly in distinguishing between benign nevi, melanoma, and nevus-associated cutaneous melanoma [9-12]. PRAME plays a role in multiple cellular processes, including apoptosis, differentiation, growth regulation, tran- scriptional control, and ubiquitination. It is expressed in a range of both epithelial and non-epithelial neoplasms and has emerged as a promising target for immunotherapeutic approaches, with ongoing clinical trials investigating its po- tential applications. In the context of melanocytic pathology, PRAME im- munohistochemistry serves as a valuable diagnostic aid. The identification of a PRAME-positive melanocytic population within a nevus may support a diagnosis of melanoma arising in association with that nevus. However, a negative PRAME result does not definitively exclude melanoma, and interpre- tation should be integrated with clinical, histological, and additional immunohistochemical findings [13]. Although PRAME IHC holds potential in differentiat- ing RTMN from melanoma, recent evidence indicates that PRAME expression may also be observed in reactive and cic- atricial fibroblastic proliferations. This finding underscores a potential limitation in the specificity of PRAME IHC within the context of melanocytic lesions, particularly when evalu- ating recurrent or traumatized nevi [14,15]. The aim of this study was to evaluate a series of RTMN cases to assess PRAME expression in both melanocytic and fibroblastic cell populations, with the goal of elucidating PRAME’s potential diagnostic utility in this specific histo- pathological context. Methods and Materials Case Selection All cases included in this study were retrospectively selected from the archives of the Pathology Unit at the University Hospital of Campania Luigi Vanvitelli in Naples, Italy, cov- ering the period from January 2019 to November 2024. Results: PRAME IHC showed no positivity in the junctional or intradermal melanocytic components of any case. However, five out of 22 cases (22.7%) demonstrated PRAME positivity in the fibroblastic component, which was statistically significant (P=0.0169). Conclusions: This study suggests that PRAME IHC is negative in the melanocytic components of RTMN, distinguishing it from melanoma. However, PRAME positivity in the fibroblastic scar compo- nent warrants careful interpretation to avoid diagnostic pitfalls. These findings emphasize the impor- tance of considering the histological context when using PRAME as a diagnostic marker in RTMN. Original Article | Dermatol Pract Concept. 2025;15(4):5564 3 The inclusion criteria were: i) diagnosis of recurrent melanocytic nevus or traumatized melanocytic nevus; ii) formalin-fixed and paraffin-embedded (FFPE) tissue blocks and histological slides available; iii) histological evidence of fibroblastic proliferation. Twenty-two cases satisfied the criteria. All the cases were reviewed by two experienced dermatopathologists and eval- uated in their appropriate clinical setting. The diagnosis was confirmed in all cases. PRAME Immunohistochemistry Immunohistochemical staining was performed on 5 μm-thick sections obtained from formalin-fixed, paraffin- embedded (FFPE) tissue blocks using the automated Ventana Bench- Mark ULTRA system (Ventana-Roche Diagnostics, Meylan, France), according to the manufacturer’s protocol. The antibody employed was anti-PRAME (rabbit monoclonal antibody, clone EPR20330, Ventana-Roche), provided in a prediluted, ready-to-use format with a standardized con- centration. Sebaceous glands served as internal positive controls. PRAME immunoreactivity was independently evaluated by two experienced pathologists. Assessment focused on three distinct compartments: the junctional (recurrent/pro- liferative) melanocytic component, the intradermal (mature) melanocytic component, and the scar-associated fibroblastic component. Nuclear staining was considered positive when more than 50% of the cells in a given compartment exhib- ited immunoreactivity, irrespective of staining intensity, in accordance with previously established criteria [16]. Statistical Analysis To calculate the statistical significance of fibroblast positiv- ity for the marker, a two-tailed binomial test was applied, assuming that the proportion of positive fibroblasts deviates significantly from a random distribution with a probability of 50% (P=0.5). The test considered both the exact proba- bility of observing five positive cases out of 22 samples and the cumulative probability. Specifically, the probability of observing exactly five successes was calculated using the bi- nomial distribution formula: P = (X = k) = (n k) . pk . (1 – p)n–k where (n k) is the binomial coefficient. Then, cumulative probability for values P(X≤5) and P(X≥5) was included to account for all outcomes as ex- treme as five observed successes. We applied the following formulas: ( ) ( ) k i k P X k P x i = ≤ = =∑ ( ) ( ) 0 k i P X k P x i = ≥ = =∑ The p-value for the two-tailed test was calculated as: p = 2 . (P(X ≤ k), P (x ≥ k)) The significance threshold was set at α=0.05. Furthermore, we analyzed potential correlations between age, sex, and anatomical site. Age was analyzed as a contin- uous variable using Spearman’s rank correlation. The asso- ciation between sex and fibroblast positivity was evaluated using Fisher’s exact test, and the association with anatomical site was tested using the Chi-squared test. Ethical Statement This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Com- mittee of University “Luigi Vanvitelli” (Naples, Italy) (proto- col code 282/202, approval date 6 October 2020). Informed consent was obtained from all subjects involved in the study. Results The study cohort comprised 22 patients, including eight fe- males (36%) and 14 males (64%), with ages ranging from 14 to 71 years (median age: 36 years). Of the 22 cases, 16 (72.7%) were diagnosed with traumatized melanocytic nevi, while six (27.3%) were classified as recurrent melanocytic nevi. Among the recurrent cases, five had a documented history of prior shave excision, whereas one had undergone a punch biopsy. Anatom- ical distribution of the lesions was as follows: the dorsal region in eight cases (36.4%), the lower limbs in five cases (22.7%), the lumbar region in three cases (13.6%), the shoulder in two cases (9.1%), the gluteal region in two cases (9.1%), the chest in one case (4.5%), and the abdominal region in one case (4.). The clinical findings of the series are detailed in Table 1. The histological findings of an exemplary case of RTMN are shown in Figure 1. PRAME immunohistochemistry was negative in both the junctional and intradermal melanocytic components across all 22 cases (0%). However, PRAME positivity was observed in the fibroblastic component in five cases (22.7%). The re- sults are summarized in Table 2. Fibroblast positivity was observed in five out of 22 cases. The probability of observing exactly five successes under the null hypothesis P(X=5) was 0.00628. The cumulative prob- ability for P(X≤5) was 0.008450, while P(X≥5) was 0.997. Applying the two-tailed binomial test, the overall p-value was computed as: p = 2 . (P(X ≤ 5), P (x ≥ 5)) = 0.0169 4 Original Article | Dermatol Pract Concept. 2025;15(4):5564 Table 1. Clinical Findings. N. Age Location Recurrent or traumatized melanocytic nevus Phototype 1 27 Dorsal Traumatized II 2 36 Right leg Traumatized IV 3 17 Abdominal Traumatized III 4 28 Lumbar Traumatized II 5 34 Dorsal Traumatized III 6 22 Dorsal Traumatized III 7 49 Gluteal Traumatized III 8 34 Dorsal Traumatized III 9 40 Dorsal Traumatized III 10 14 Dorsal Recurrent (previous shaving biopsy) IV 11 41 Dorsal Traumatized III 12 22 Dorsal Traumatized II 13 28 Chest Recurrent (previous shaving biopsy) II 14 42 Gluteal Recurrent (previous shaving biopsy) III 15 41 Left shoulder Traumatized II 16 43 Lumbar Traumatized II 17 32 Right shoulder Traumatized III 18 35 Right leg Recurrent (previous punch biopsy) III 19 58 Right thigh Traumatized III 20 71 Right leg Traumatized II 21 46 Left thigh Recurrent (previous shaving biopsy) III 22 48 Lumbar Recurrent (previous shaving biopsy) II Figure 1. A traumatized nevus localized on the back of a 41-year- old female. Histological analysis revealed a compound melanocytic proliferation. The junctional component was characterized by large melanocytes arranged in small nests, exhibiting a lentiginous pattern (blue star). The dermal component consisted of mature, small me- lanocytes organized in extensive sheets (yellow star). A fibrous scar was present between the two components (red star) (hematoxylin and eosin stain, original magnification 100x). Table 2. PRAME Immunohistochemical Results in the Three Different Components. Component PRAME IHC positivity Junctional 0/22 (0%) Intradermal 0/22 (0%) Fibroblastic 5/22 (22.7%) Since the p-value (0.0169) is below the pre-defined signif- icance threshold (α=0.05), we conclude that the probability of obtaining exactly five successes is very low under the null hypoth- esis, and it is not random but is instead statistically significant. Finally, we conducted exploratory correlative analyses to as- sess potential associations between PRAME fibroblast positiv- ity and patient-related variables, including age (Spearman’s rank correlation = 0.385, P=0.077), sex (Fisher’s exact test, yielding an odds ratio of 1.05 with P=1.000), and anatomical site (Chi- squared test χ² = 6.39, P=0.381). No statistically significant cor- relations was found in our dataset, although the observed trend with age may merit further exploration in larger cohorts. Focal PRAME positivity, defined as staining in fewer than 50% of cells and thus considered negative, was ob- served in the junctional melanocytic component in six/ 22 cases (27.3%), in the intradermal melanocytic component in two/ 22 cases (9.1%), and in the fibroblastic population in 1/ 22 cases (4.5%). Some examples are shown in Figures 2 and 3. Clinical and dermoscopical features of fibroblast-positive cases are shown in Figure 4. Original Article | Dermatol Pract Concept. 2025;15(4):5564 5 rete ridges, mildly disorganized basal melanocytes, and subtle nuclear enlargement or hyperchromasia. Although pagetoid spread, and peri-adnexal dermal extension are uncommon, they can occasionally be observed  [5]. The primary differ- ential diagnosis is superficial spreading melanoma arising within a pre-existing nevus (nevus-associated melanoma). Accurate differentiation can be challenging and necessitates comprehensive integration of clinical, dermoscopic, and his- topathological data. PRAME (preferentially expressed antigen in melanoma) is a cancer-testis antigen expressed by melanoma and vari- ous other malignant neoplasms; it has recently emerged as a valuable marker in the differential diagnosis of melano- cytic lesions. Immunohistochemical detection of PRAME has demonstrated significant differential expression patterns between melanoma and benign nevi  [10,12,20]. Notably, prior studies have indicated that PRAME IHC is particularly useful in diagnosing nevus-associated melanoma, show- ing positivity in melanoma cells while remaining negative in benign nevus cells  [13,21]. Consequently, PRAME may serve as a helpful diagnostic tool in evaluating RTMN, given that the primary differential diagnosis often involves nevus- associated melanoma. However, the presence of fibroblastic proliferation within RTMN can pose a diagnostic challenge, as emerging evidence has documented PRAME expression in reactive fibroblasts and scar tissue [14,15]. In this study, we evaluated PRAME immunohistochem- ical expression in a series of 22 RTMN cases, examining three distinct lesion components: superficial/junctional me- lanocytic proliferation, the intradermal nevus component, and fibroblastic proliferation associated with scar tissue. Notably, none of the cases demonstrated PRAME positivity in the junctional component. While the limited sample size represents a study limitation and constrains the generaliz- ability of these findings, this observation remains clinically significant, given that the principal differential diagnosis for RTMN is melanoma arising from a pre-existing nevus. Discussion Recurrent/traumatized melanocytic nevi (RTMN) are lesions characterized by the regrowth of residual melanocytes fol- lowing incomplete excision or trauma to a preexisting ne- vus. RTMN are relatively common, with reported recurrence rates ranging from 5% to 10% in dermatology settings where nevi are frequently removed [13,17]. These lesions predom- inantly affect females in their second and third decades of life, with the back being the most commonly involved ana- tomical site. Recurrences typically manifest approximately six months post-excision, although consensus is lacking re- garding which specific nevus subtype is most susceptible to recurrence [1,18]. RTMN often exhibit morphological characteristics that closely resemble melanoma, creating significant challenges in differential diagnosis at clinical, dermoscopic, and his- topathological levels. While a history of prior trauma or incomplete removal can aid diagnostic suspicion, this infor- mation is not always available, as patients may be unaware of or unable to recall such events. Clinically and dermoscopically, RTMN frequently dis- play symmetry alongside irregular pigmentation, making them among the benign lesions that often exhibit dermo- scopic features suggestive of malignancy [19]. Histologically, RTMN can be conceptualized as comprising three distinct components: i) a superficial/junctional melanocytic compo- nent representing the proliferative portion of the lesion; ii) a dermal melanocytic component corresponding to the resid- ual pre-existing nevus; and iii) an intermediate component characterized by cicatricial fibroblastic proliferation and, occasionally, a chronic inflammatory infiltrate, reflecting the scar tissue resulting from trauma or excision. From a diagnostic perspective, the superficial/junctional melanocytic component is of paramount importance, as it may display atypical morphological features that mimic mel- anoma in situ. These features include thickened and irregular Figure 2. Epigastric region, 48-year-old male. A) Junctional melanocytic proliferation was observed, organized into small nests and exhibiting a lentiginous pattern (blue star). The dermis displayed features of fibrosis, the presence of small vessels, fibroblastic proliferation, and an accumulation of melanophages (red star) (hematoxylin and eosin stain, original magnification 200x). B) PRAME immunohistochemistry resulted negative in the junctional melano- cytes (blue star) and positive in the dermal fibroblasts (red star) (PRAME immunohistochemical stain, original mag- nification 200x). C) PRAME-positive dermal fibroblasts (red star) (PRAME immunohistochemical stain, original magnification 200x). 6 Original Article | Dermatol Pract Concept. 2025;15(4):5564 Figure 4: Clinical and dermoscopical features of fibroblast-positive cases. Case 1: 22-year-old male with a traumatized melanocytic nevus on the back. A) Clinical image: pigmented, asymmetric nevus with a slightly raised central area. B) Dermoscopy: asymmetric lesion with ir- regularly distributed hyperpigmented blotches and structureless brown areas. Case 2: 43-year-old female with a traumatized melanocytic ne- vus on the back. C) Clinical image: pinkish-brown lesion with dome shaped distributed areas and irregular borders. D) Dermoscopy: asym- metric structureless brown pigmentation with whitish-grey central area and crystalline structures. Case 3: 71-year-old female with a trau- matized melanocytic nevus on the right leg. E) clinical image: brown macule with focally hyperpigmented central area. F) Dermoscopy: patchy reticular network with focal area of irregular hyperpigmented network. Case 4: 46-year-old male with a recurrent melanocytic nevus on the left thigh. G) Clinical image: pigmented lesion arising within a hypopigmented scar, with blurred and asymmetric borders. H) Dermoscopy: reticular and structureless pigmentation with radial streaming and central scar-like depigmentation. Case 5: 48-year-old male with a recurrent melanocytic nevus on the back. I) Clinical image: brown macule with irregular pigmentation located within a surgical scar, with blurred borders. J) Dermoscopy: brown structureless areas, atypical pigment network and crystalline structures. PRAME IHC has proven valuable in this diagnostic setting, as prior studies have established its positivity in melanomas developing from nevi [13,21]. Our results, however, indicate that PRAME is consistently negative in the junctional com- ponent of RTMN. The presence of cicatricial fibroblastic proliferation within RTMN introduces a potential diagnostic pitfall when interpreting PRAME staining. Indeed, several reports have documented PRAME expression in benign fibroblasts and scar tissue [14]. Specifically, Plotzke et al. found that 24% of scars exhibited diffuse and strong PRAME expression com- parable to that seen in desmoplastic melanoma [15]. In their cohort, PRAME positivity exceeding 50% of fibroblasts was observed in 11 of 21 (52.4%) scar cases. In contrast, our study identified PRAME positivity above this threshold in the fibroblastic population in five of the 22 cases (22.7%). It is important to highlight that our analysis focused on fibro- blastic proliferations within RTMN lesions rather than on simple scar tissue. We found that PRAME expression in the fibroblas- tic proliferation of RTMN was statistically significant (P=0.0169). Histologically, these cases exhibited a pop- ulation of PRAME-positive spindle-shaped cells within the dermis, embedded in a fibrotic stromal background. Careful morphological assessment using hematoxylin and eosin-stained sections is essential to accurately distinguish these PRAME-positive fibroblasts from melanocytes, thereby preventing potential diagnostic confusion. Distinguishing fibroblasts from spindle-shaped melanocytes in desmoplas- tic melanoma can be challenging due to their similar mor- phology, especially under routine histological examination. However, several key histological and immunohistochemical features help guide the differential diagnosis. Histologically, fibroblasts typically display small, uniform, elongated or oval nuclei with fine chromatin and inconspicuous nucleoli. Their cytoplasm is scant and often not easily visible. They tend to align in an orderly fashion along collagen bundles, showing a non-infiltrative, reactive pattern. Mitotic figures are usually absent or very rare. In contrast, spindle-shaped melanocytes in melanoma often have larger, more pleomor- phic and hyperchromatic nuclei, frequently with prominent nucleoli [22-23]. These cells may show a more abundant eosinophilic cytoplasm and are arranged in a disorganized, infiltrative pattern. Atypical mitoses may be observed, and there is often evidence of invasion into surrounding struc- tures, such as adnexal elements, nerves, or blood vessels. Immunohistochemistry is crucial to making a definitive distinction. Melanocytic cells in desmoplastic melanoma are typically positive for S100 protein and SOX10, both of which are highly sensitive markers. HMB45 and Melan-A are often negative in desmoplastic variants but may be ex- pressed in other melanoma subtypes. In contrast, fibroblasts Original Article | Dermatol Pract Concept. 2025;15(4):5564 7 with regression. Mod Pathol. 2009;22(5):611-617. DOI:10.1038 /modpathol.2009.22. 2. Selim MA, Vollmer RT, Herman CM, Pham TT, Turner JW. Melanocytic nevi with nonsurgical trauma: a histopathologic study. Am J Dermatopathol. 2007;29(2):134-136. DOI:10.1097 /01.dad.0000246176.81071.a6 3. Briatico G, Brancaccio G, Scharf C, et al. Indications for and Contraindications to Digital Monitoring of Patients with Mela- nocytic Lesions. Dermatol Pract Concept. 2024;14(3):e2024200. Published 2024 Jul 1. DOI:10.5826/dpc.1403a200 4. Blum A, Hofmann-Wellenhof R, Marghoob AA, et al. Recurrent melanocytic nevi and melanomas in dermoscopy: results of a mul- ticenter study of the International Dermoscopy Society.  JAMA Dermatol. 2014;150(2):138-145. DOI:10.1001/jamadermatol .2013.6908 5. Sommer LL, Barcia SM, Clarke LE, Helm KF. Persistent mela- nocytic nevi: a review and analysis of 205 cases. J Cutan Pathol. 2011;38(6):503-507. DOI:10.1111/j.1600-0560.2011.01692.x 6. Hoang MP, Prieto VG, Burchette JL, Shea CR. Recurrent me- lanocytic nevus: a histologic and immunohistochemical eval- uation. J Cutan Pathol. 2001;28(8):400-406. DOI:10.1034 /j.1600-0560.2001.028008400.x 7. Park HK, Leonard DD, Arrington JH 3rd, Lund HZ. Recurrent melanocytic nevi: clinical and histologic review of 175 cases.  J Am Acad Dermatol. 1987;17(2 Pt 1):285-292. DOI:10.1016 /s0190-9622(87)70204-7 8. Castagna RD, Stramari JM, Chemello RML. The recurrent ne- vus phenomenon.  An Bras Dermatol. 2017;92(4):531-533. DOI:10.1590/abd1806-4841.20176190 9. Costessi A, Mahrour N, Tijchon E, et al. The tumour antigen PRAME is a subunit of a Cul2 ubiquitin ligase and associates with active NFY promoters. EMBO J. 2011;30(18):3786-3798. Published 2011 Aug 5. DOI:10.1038/emboj.2011.262 10. Umano GR, Errico ME, D’Onofrio V, et al. The Challenge of Melanocytic Lesions in Pediatric Patients: Clinical- Pathological Findings and the Diagnostic Value of PRAME.  Front On- col. 2021;11:688410. Published 2021 Jun 14. DOI:10.3389 /fonc.2021.688410 11. Gutzmer R, Rivoltini L, Levchenko E, et al. Safety and immuno- genicity of the PRAME cancer immunotherapeutic in metastatic are usually negative for melanocytic markers such as S100 and SOX10, but they may express CD34, which is helpful in identifying dermal fibroblastic populations. Vimentin is pos- itive in both cell types and is therefore not diagnostically use- ful on its own. Clinical context also plays a significant role: the presence of a previous pigmented lesion or ulceration may point towards melanoma, especially if spindle cells are S100- and SOX10-positive in a desmoplastic stroma. On the other hand, spindle cells that are negative for melanocytic markers and positive for CD34 are more likely to represent reactive fibroblasts in a scar. The main limitation of this study is its sample size. How- ever, this is the first study to evaluate the role of PRAME in the diagnosis of RTMN. Conclusions In conclusion, our evaluation of PRAME expression in a series of RTMN highlights its potential diagnostic utility. PRAME was consistently negative in both the junctional and intradermal melanocytic components across all cases, con- trasting with its established positivity in melanoma arising from a nevus and thereby reinforcing its role in differential diagnosis. 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