Clinical utility of intralesional methotrexate to distinguish crateriform keratinocytic tumors before surgeryDear Editors,Keratoacanthoma (KA) and cutaneous squamous cell carci-noma  (CSCC)  may  adopt  an  identical  crateriform  morpho-logy.  Nowadays,  the  debate  about  whether  KA  is  a  distinct  entity,  or  a  low-grade  variant  of  cutaneous  squamous  cell  carcinoma  (CSCC)  still  persists.  Since  CSCC  is  a  more  ag-gressive  neoplasm,  misdiagnosing  crateriform  lesions  may  have a negative impact on the patient's prognosis. Evaluating a partial biopsy is extremely challenging to confidently dis-tinguish KA from CSCC [1]. No distinctive gene expression profiles have been identified and no pathognomonic criteria to  unequivocally  differentiate  between  KA  and  CSCC  exist  [2].  Consequently,  the  surgical  approach  remains  the  gold  standard  in  the  management  of  crateriform  tumors,  especi-ally those arising on the face

González-Menchen, A. (Alberto)

Nuñez-Cordoba, J.M. (Jorge M.)

Redondo, P. (Pedro)

Salido-Vallejo, R. (Rafael)

Sanz-Cabanillas, J.L. (Juan Luis)

Vélez, A. (Antonio)

English

Redondo-Bellón, P. (Pedro)

Dadun, University of Navarra

Correspondence Clinical Letter102 © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2022/2001DOI: 10.1111/ddg.14637Clinical utility of intralesional methotrexate to distinguish crateriform keratinocytic tumors before surgeryDear Editors,Keratoacanthoma (KA) and cutaneous squamous cell carci-noma (CSCC) may adopt an identical crateriform morpho-logy. Nowadays, the debate about whether KA is a distinct entity, or a low-grade variant of cutaneous squamous cell carcinoma (CSCC) still persists. Since CSCC is a more ag-gressive neoplasm, misdiagnosing crateriform lesions may have a negative impact on the patient's prognosis. Evaluating a partial biopsy is extremely challenging to confidently dis-tinguish KA from CSCC [1]. No distinctive gene expression profiles have been identified and no pathognomonic criteria to unequivocally differentiate between KA and CSCC exist [2]. Consequently, the surgical approach remains the gold standard in the management of crateriform tumors, especi-ally those arising on the face.With intralesional methotrexate (il-MTX) in monothe-rapy, neoadjuvant to surgery or administered with palliative intent [3], a remarkable reduction in the size of tumors could be shown, both for KA and for CSCC. Nevertheless, the re-sponse of KA to il-MTX appears higher than that of CSCC [4, 5]. In the absence of reliable diagnostic tools to clinically discriminate between KA and CSCC, the aim of this study was to evaluate whether crateriform tumors can be accura-tely classified as KA or SCC according to the reduction in tumor size occurring after a single il-MTX infiltration.A retrospective cohort study was conducted from 2014 to 2019 at Reina Sofía University Hospital (Spain). The study protocol was approved by the Pharmacy and Therapeutics Institutional Review Board of this institution.We included immunocompetent adults ≥ 18 years with a primary solitary crateriform tumor with no regressing featu-res treated with il-MTX prior to conventional surgery. Exclu-sion criteria were history of glomerular filtration < 30 mg/mL, bone marrow or hepatic failure, hypersensitivity to me-thotrexate, pregnancy or breastfeeding and genetic disorders associated with cancer.Neoadjuvant intralesional MTX was administered during the waiting period ahead of the scheduled surgery after informed consent was obtained. A diagnostic punch-biopsy was performed before administration of il-MTX in all tumors. Syringes pre-filled with MTX (25 mg/mL) were injected intralesionally using a 30-gauge needle until the tu-mor blanched. All lesions were excised by the same surgeon (R.S.V.).The primary outcome was the reduction of tumor area defined as the difference between the initial area (before il-MTX) and the final area (pre-surgery).We used logistic regression to estimate odds ratios (OR) and 95 % confidence intervals (95 % CI) for KA comparing groups of relative area lesion change after il-MTX, adjusting for age, sex, and location of tumor. The area under the recei-ver operating characteristic (ROC) curve (AUC) was used to evaluate the power of relative area lesion change after il-MTX to discriminate between patients with KA and CSCC. P values < 0.05 indicated statistical significance.Table 1 displays baseline characteristics of CSCC and KA groups. The average volume of MTX infiltrated was 0.57 ml (95 % CI: 0.51–0.62). The mean time between di-agnosis and surgery was 18.4 days (95 % CI: 16.2–20.7) for CSCC patients and 21.9 days (95 % CI: 18.1–25.8) for KA patients (P = 0.119). The mean initial major diameter was 1.9 cm (95 % CI: 1.7–2.1) in CSCC and 1.4 cm (95 % CI: 1.2–1.6) in KA (P = 0.001). The mean initial area was 2.6 cm2 (95 % CI: 2.0–3.1) in CSCC and 1.7 cm2 (95 % CI: 1.0–2.3) in KA (P =  0.038).After il-MTX infiltration, a reduction in tumor lesion area was observed in 31 CSCC patients (68.9 %) and 42 KA patients (95.5 %) (P = 0.001). No area variation was ob-served in three CSCC patients (6.7 %) and one KA patient (2.3 %). An area increase was observed in eleven CSCC pati-ents (24.4 %) and in one KA patient (2.3 %). The mean valu-es of final greatest diameter in the CSCC and KA patients were 1.76 cm (95 % CI: 1.53–1.99) and 0.71 cm (95 % CI: 0.50–0.92), respectively (P < 0.001).The average percentage of area lesion change after il-MTX in KA (mean: –63.4 %; 95 % CI: –75.2 to –51.5) dif-fered significantly from that in CSCC (mean: –11.5 %; 95 % CI: –22.3 to –0.6) (P < 0.001). Some examples are shown in Figure S1 (online supporting information). We estima-ted that for a one-percentage point reduction in lesion area after il-MTX, a statistically significant 3.96 % (95 % CI: 2.22–5.72 %) increase in the odds of having KA would be expected. Patients were categorized into two groups accor-ding to relative area lesion change (median = –36.2 %). When comparing with the group of patients in the lowest category (relative lesion area reduction lower than 36.2 %), patients in the highest category (relative area reduction greater than or equal to 36.2 %) showed a 10.5-fold increased odds of having a KA (95 % CI: 3.8–28.0). This association remained after adjusting for age, sex, or tumor location (Table 2).The percentage of area lesion change showed a good ability to discriminate between KA and CSCC [AUC (95 % CI): 0.84 (0.76–0.92), P < 0.001] (Figure 1). We used two  Clinical LetterThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Correspondence Clinical Letter103© 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2022/2001Table 1 Baseline characteristics of eligible patients with crateriform keratinocytic tumors.PatientsTotal (n = 89)CSCC (n = 45)KA (n = 44)n (%)Mean  (95 % IC)Median (range)n (%)Mean (95 % IC)Median (range)n (%)Mean  (95 % IC)Median  (range)P valueAge (years)76.4  (73.6 to 79.3)79  (40 to 103)80.2 (76.9 to 83.4)83  (54 to 95)72.7 (68.0 to 77.4)74.5 (40 to 103)0.010Men52 (58.4)31 (68.9)21 (47.7)0.043Phototype0.251I–II23 (25.8)14 (31.1)9 (20.5)III–IV66 (74.2)31 (68.9)35 (79.5)Tumor lesionsSun-exposed location66 (74.2)38 (84.4)28 (63.6)0.025Tumor evolution time (months)2.8  (2.0 to 3.6)2.0  (0.5 to 24.0)3.5  (2.1 to 5.0)2.0  (0.5 to 24.0)2.1  (1.5 to 2.6)2.0  (0.5 to 12.0)0.066Initial major diameter (cm)*1.6  (1.5 to 1.8)1.5  (0.5 to 4.2)1.9  (1.7 to 2.1)1.8  (0.7 to 4.0) 1.4  (1.2 to 1.6)1.2 (0.5 to 4.2)0.001Initial minor diameter (cm)*1.4  (1.2 to 1.5)1.3  (0.5 to 4.2)1.6  (1.4 to 1.8)1.5  (0.5 to 3.0)1.2  (1.0 to 1.4)1.0 (0.5 to 4.2)0.007Initial area (cm2 )**2.1  (1.7 to 2.6)1.4  (0.2 to 13.9)2.6  (2.0 to 3.1)2.1  (0.4 to 9.4)1.7  (1.0 to 2.3)0.9  (0.2 to 13.9)0.038Time to surgery (days)20.0  (17.9 to 22.1)18.0  (7.0 to 60.0)18.4  (16.2 to 20.7)15.0  (7.0 to 37.0)21.9  (18.1 to 25.8)20.0  (7.0 to 60.0)0.119MTX infiltrated (ml)0.57  (0.51 to 0.62) 0.50  (0.15 to 1.20)0.64  (0.56 to 0.71)0.60  (0.20 to 1.20)0.49  (0.42 to 0.57)0.50  (0.15 to 1.20)0.008Abbr.: 95 % CI, 95 % confidence interval; CSCC, cutaneous squamous cell carcinoma; KA, keratoacanthoma. *Tumor diameters were meticulously measured with a standardizer ruler by two board-certified physicians. **Tumor area measurements were calculated using the formula π x r x s [largest (r) and smallest (s) radius] after assuming a circular or elliptical morphology for all tumors.Correspondence Clinical Letter104 © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2022/2001alternative methods to explore the estimation of cut-points for relative area reduction after il-MTX with potential cli-nical usefulness to discriminate between KA and CSCC (Table 2).Intralesional methotrexate has been shown to be a suc-cessful treatment for keratinocytic tumors. However, effec-tiveness rates vary considerably depending on which tumor is treated [4–6]. Successive il-MTX infiltrations have shown higher resolution rates in KA. Moss et al. reported that of the 64 KA that resolved after il-MTX, 70 % of cases needed > 1 infiltration [5]. We used a single dose of il-MTX as neoad-juvant therapy to surgery rather than as a main treatment, which may explain our lower response rates. Thus, when a significant reduction in size of a crateriform keratinocytic Table 2 Estimated odds ratios for KA by level of relative lesion area change after il-MTX.Relative area lesion  change categoryLess than 36.2 % reduction Greater than or equal to 36.2 % reductionRelative area lesion  change (%)Mean Median Range Mean Median Range–0.5 –9.4 73.8 to –35.3 –72.9 –75.0 –36.2 to –100KA cases (%) 22.7 75.6 P valueModel 1: OR (95 % CI)* 1 (reference) 10.5 (3.9 to 28.0) < 0.001Model 2: OR (95 % CI)** 1 (reference) 10.5 (3.8 to 29.1) < 0.001Model 3: OR (95 % CI)*** 1 (reference) 16.9 (5.1 to 55.7) < 0.001Model 4: OR (95 % CI)**** 1 (reference) 15.1 (4.9 to 46.8) < 0.001Abbr.: 95 % CI, 95 % confidence interval; KA, keratoacanthoma; OR, Odds ratio.*Not adjusted. **Adjusted for age ***Adjusted for sex. ****Adjusted for tumor anatomical location (sun-exposed or unexposed area).Figure 1 Receiver operating charac-teristic (ROC) curve for relative area lesion change after il-MTX treatment to discriminate KA tumors. Two cri-teria were used to estimate potential cut-points of relative area lesion ch-ange after il-MTX to discriminate KA tumors. Compared to the cut-point estimated with the closest to (0.1) criteria, the Youden index method cut-point showed higher Sp and PPV, and lower FPR and Se.  Abbr.: 95 % CI, 95 % confidence interval; AUC, area under the ROC curve; FPR, false positive rate; il-MTX, intralesional methotrexate; KA, kera-toacanthoma; NPV, negative predic-tive value; OA, overall accuracy; PPV, positive predictive value; Se, sensi-tivity; Sp, specificity. Please replace “p<0.01” in the figure with “P < 0.01”.Correspondence Clinical Letter105© 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2022/2001tumor occurs after il-MTX, a second administration could be appropriate given the high probability of an existing KA.Our study is the first to use a standardized clinical practice protocol and to assess the response to il-MTX in KA and CSCC. We observed that relative area lesion change after il-MTX may be a potential indicator for clinical discrimina-tion between KA and CSCC.Misdiagnosis of CSCC as KA may be considered the worst scenario. However, the rate of false positive cases in our study was relatively low. Since il-MTX treatment can ea-sily be performed during the pre-surgery waiting times found in the majority of hospitals, the procedure might not cause additional delay. If a complete response is not achieved, or a minimal reduction in size or even growth is observed, surgi-cal excision should be performed as scheduled.Our results suggest that a single MTX infiltration could help to predict the nature of the keratinocytic tumors before histopathological analysis. This may contribute to conserva-tive management and allow surgery to be avoided in cases showing a significant response to il-MTX. These preliminary findings should be corroborated by additional, larger studies.AcknowledgementsOpen access funding enabled and organized by Projekt DEAL.Conflict of interestNone.Rafael Salido-Vallejo1,2, Juan Luis Sanz-Cabanillas2, Jorge María Núñez-Córdoba3, Alberto  González-Menchen4, Antonio Vélez2,  Pedro Redondo1(1) Department of Dermatology, University Clinic of Navarra, School of Medicine, University of Navarra, Pamplona, Spain(2) Department of Dermatology, Reina Sofía University Hospi-tal, Córdoba, Spain(3) Research Support Service, Central Clinical Trials Unit, University Clinic of Navarra, Pamplona, Spain(4) Department of Pathology, Reina Sofía University Hospital, Córdoba, SpainCorrespondence toRafael Salido-Vallejo, MD, PhDDepartment of DermatologyUniversity Clinic of Navarra, School of MedicineUniversity of NavarraAvda. Pio XII, 3631008 Pamplona, SpainE-mail: rsalidov@unav.esReferences1 Takai T. Advances in histopathological diagnosis of keratoac-anthoma. J Dermatol 2017; 44: 304–14.2 Ra SH, Su A, Li X et al. Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective. Mod Pathol 2015; 28: 799–806.3 Carriere C, Baier S, Campana LG et al. Palliative intralesional tumescent methotrexate for recurrent locally advanced peri-ocular cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2020; 18: 1063–6.4 Salido-Vallejo R, Cuevas-Asencio I, Garnacho-Sucedo G et al. Neoadjuvant intralesional methotrexate in cutaneous squa-mous cell carcinoma: a comparative cohort study. J Eur Acad Dermatol Venereol 2016; 30: 1120–4.5 Moss M, Weber E, Hoverson K, Montemarano AD. Management of keratoacanthoma: 157 tumors treated with surgery or intralesional methotrexate. Dermatol Surg 2019; 45: 877–83.6 Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrexate treatment for keratoacanthoma tumors: a retro-spective study and review of the literature. J Am Acad Derma-tol 2007; 56: 989–93.

Clinical utility of intralesional methotrexate to distinguish crateriform keratinocytic tumors before surgery

Universidad de Navarra

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Clinical utility of intralesional methotrexate to distinguish crateriform keratinocytic tumors before surgery

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