Introduction: Keloid is an abnormal proliferation of scar tissue that grows beyond the original margins of the injury. Even after complete resection, recurrences are common and pose a poorly understood challenge in dermatology. There is lack of large prospective clinical trials; thus, treatment recommendations are based on retrospective analyses and small cohort studies. Superficial radiotherapy is recommended in recurrent keloids; however, the successful treatment rates vary greatly. The aim of this study was to evaluate the keloid recurrence rate after post-excision soft X-ray radiotherapy and the associated factors. Methods: We reviewed retrospective data of all patients, treated with adjuvant post-excision soft X-ray radiotherapy with 12 Gy in 6 sessions at the tertiary referral center, Department of Dermatology, University Hospital Zurich, Switzerland, between 2005 and 2018. We analyzed individual keloids as separate cases. Successful treatment was defined as no sign of recurrence within 2 years. Results: Of the 200 identified patients, 90 met the inclusion criteria and were included in the final analysis. In 90 patients, 104 cases of treated keloids were analyzed. Keloids were mainly located on the trunk (49%) and were mostly caused by previous surgery (52.2%). 50% of the keloids did not relapse within 2 years after therapy. A significant factor leading to recurrence was the presence of previous therapy, with prior topical therapies, such as steroid injections or 5-fluorouracil, leading to most relapses. 69.2% of keloid cases who relapsed were pretreated. Soft X-ray radiotherapy was well tolerated, with posttreatment hyperpigmentation noted in 34% of patients, particularly in patients with non-Caucasian origin (61.3%). Conclusion: Treatment of refractory keloids is difficult. Post-excision radiotherapy is an established adjuvant treatment option; nevertheless, recurrence rates are high, especially in pretreated keloids. Prospective studies determining the exact dosage and fraction of post-excisional radiotherapy are needed to determine the optimal radiation parameters.

Keloid is a type of scar, characterized by excessive growth outside the wound edges after tissue injury. The exceeding outside the borders of the initial injury differentiates the keloid from common hyperplastic scars [1, 2]. Keloids are often perceived to be aesthetically displeasing, as well as impairing for the patient due to intense itching, pain or mechanical irritation [3]. They may develop in any area of the body but tend to form on the upper trunk and auricular area [4]. Especially areas with increased mechanical tension have an increased risk for keloid formation and recurrence [5]. Keloids most commonly develop in patients between 10 and 30 years [6, 7], with a higher prevalence of keloids in people with darker skin type [8].

The etiopathogenesis of keloids is not entirely clear. Possible etiologies include abnormal growth factor activity, excessive fibroblast proliferation and collagen synthesis in the dermis, and tension-caused misalignment of collagen fibers during tissue repair [9, 10]. Abundant fibroblast proliferation in keloids is believed to be caused by multiple factors. One of them is an excess of high-mobility group box protein-1 (HMGB1), which triggers pro-inflammatory cytokines and acts as a mediator for fibrosis. This results in increased synthesis of misaligned type I and especially type III collagen, as well as elastin and fibronectin. This further differentiates keloids from hyperplastic scars, which show little production of type I collagen [11‒13].

The management of keloids is challenging as despite the established treatment guidelines, recurrence rates are as high as 55% [1, 14, 15]. The choice of treatment option is influenced by the number, size, and location of the keloid, as well as the keloid’s propensity to recur [16]. First-line therapy encompasses compression, intralesional corticosteroid injection (with or without cryotherapy) in combination with silicone gel or sheeting. In refractory or severe cases therapy with intralesional 5-fluorouracil injections in combination with corticosteroids is recommended. A secondary measure is laser therapy [17, 18]. Surgical procedures may be used for debulking larger lesions or the removal of narrow-based keloids [16]. However, as surgery alone can result in very high recurrence rates, adjuvant measures such as post-excision radiotherapy (PER) are implemented [2, 19, 20]. The aim of dermal tissue irradiation is to damage the target cell DNA, to cause premature senescence, irreparable cell injury, and initiation of apoptosis, which should result in inhibition of uncontrolled proliferation of fibroblasts and production of collagen [21‒23]. In PER of keloid, this effect occurs due to increased expression of the reduced cell-lifespan associated genes, such as p21, p16, and p27, and the increase in duration of the G0/G1 phase in the irradiated fibroblasts [24]. In the Swiss healthcare system, soft X-ray radiotherapy (XRT) with low energy photons is usually administered by dermatologists, whereas electron beam irradiation or brachytherapy is administered by radiation oncologist. The advantage of external beam radiotherapy with low-voltage photons from orthovoltage devices allows a much simpler treatment planning and calculation compared to irradiation with high electron beams from linear accelerators. Compared to brachytherapy, low-voltage photon therapy is noninvasive and requires significantly less logistical effort in radiation protection. Although there are several studies on radiation-based treatments used for keloid management, a treatment consensus for radiotherapy is still lacking [25‒27]. The purpose of this study was to analyze the efficacy and safety of PER in patients with keloids treated at a tertiary referral center.

We reviewed all cases of patients with keloids who were treated with PER at the Department of Dermatology, University Hospital Zurich, between 2005 and 2018. Patients who qualified for PER were males and females over the age of 12, who have undergone a narrow margin surgical excision of a keloid. Pregnant and lactating women were not candidates for PER. Out of 200 identified patients, 90 patients with total 104 keloids have met the inclusion criteria of being treated with PER after surgical removal of keloid and having a follow-up of at least 2 years and were analyzed. Each keloid was analyzed as individual case. Demographic data, keloid-specific data (e.g., etiology of keloid, time since keloid development – keloid age (KA), localization), and data on previous treatments were collected. Previous treatments were grouped into topical therapy (intralesional steroids, 5-fluorouracil), destructive therapy (cryosurgery, ablative laser therapy), and surgery (prior to PAR preceding surgery). Recurrence was defined as presence or absence of a pathologic elevated tissue growth within or beyond the borders of postsurgical wound, i.e., a hypertrophic scar or keloid, and was assessed by the treating physician or reported by the patient. Based on reports in the literature, successful treatment was defined as the absence of recurrence within 2 years of PER [16, 27‒30]. Data on recurrence were recorded in the electronic healthcare records and confirmed by phone consultation in case the last follow-up was longer than 2 years ago. Adverse events were defined as an undesirable experience, such as pain, discomfort, or ulceration of the irradiated area, associated with PAR and reported by patient or documented by physician. Dyspigmentation was defined as an increase (hyperpigmentation) or decrease (hypopigmentation) of pigmentation of irradiated area compared to surrounding skin and was assessed as present or absent by the treating physician. Hyperpigmentation which was still present at the last 2-year follow-up was classified as persistent.

All patients were treated according to the PER protocol used at the University Hospital Zurich. The PER was started within 24–48 h after the total excision of the keloid using a D3100 X-ray device (Gulmay, UK). A total dose of 12 Gy (Gy) was administered in 6 fractions of 2 Gy each. The tube voltage was 30 kV (kV) for areas with thin wound dressing, increased to 40–50 kV for thicker wound dressings, and reduced to 20 kV for more sensitive anatomic areas such as the ear lobe or the areola. Field size was calculated by summarizing the individual fields in cm2.

Statistics

A χ2 test was performed to compare clinical factors between patients with and without keloid recurrence. To test the effect of relevant clinical parameters (age, localization of keloid, pretreatment) on recurrence, generalized linear regression was performed using a binomial link function. A p value of less than 0.05 was considered statistically significant. Data were analyzed using R statistical software.

Patient Population and Keloids Characteristics

Between 2005 and 2018, 104 keloids in 90 patients were treated with PER. The patient population included 37 males (41.1%). Median patient age at PER was 37 years (range, 13 78 years). Most patients were Caucasians (61.1%) followed by Hispanic (11.1%), Black (10.0%), Asian (10.0%), Indian (4.4%), and Middle Eastern (3.3%) ethnicity. Skin types II–V were the most represented in our cohort. The median KA was 3.0 years (range, 0.08–37 years). The location of keloids was the trunk in 51 keloids (49.0%), the ear in 22 keloids (21.2%), the upper extremities in 16 keloids (15.4%), followed by the head in 9 keloids (8.7%) and neck in 6 keloids (5.8%). The most common cause of keloid development was surgical procedures in 47 patients (52.2%), piercing in 18 patients (20%), and trauma in 14 patients (15.6%). 54.4% of the analyzed cases were previously treated with other treatment modalities. Demographic data are detailed in Table 1.

Table 1.

Patient characteristics

Patient characteristicsn = 90
Age, median (range), years 37 (13–78) 
Gender, n (%) 
 Female 53 (58.9) 
 Male 37 (41.1) 
Race, n (%) 
 Asian 9 (10.0) 
 Black 9 (10.0) 
 Caucasian 55 (61.1) 
 Hispanic 10 (11.1) 
 Indian 4 (4.4) 
 Middle East 3 (3.3) 
Skin type, n (%) 
 I 1 (1) 
 II 26 (28.9) 
 III 25 (27.8) 
 IV 22 (24.4) 
 V 13 (14.4) 
 VI 2 (2.2) 
 Unknown 1 (1.1) 
Previous therapy, n (%) 
 No 41 (45.6) 
 Yes 49 (54.4) 
  Topical therapy 25 (27.8) 
  Destructive therapy 12 (13.3) 
  Excision 29 (32.2) 
Relapse, n (%) 
 No 44 (48.9) 
 Yes 46 (51.1) 
Patient characteristicsn = 90
Age, median (range), years 37 (13–78) 
Gender, n (%) 
 Female 53 (58.9) 
 Male 37 (41.1) 
Race, n (%) 
 Asian 9 (10.0) 
 Black 9 (10.0) 
 Caucasian 55 (61.1) 
 Hispanic 10 (11.1) 
 Indian 4 (4.4) 
 Middle East 3 (3.3) 
Skin type, n (%) 
 I 1 (1) 
 II 26 (28.9) 
 III 25 (27.8) 
 IV 22 (24.4) 
 V 13 (14.4) 
 VI 2 (2.2) 
 Unknown 1 (1.1) 
Previous therapy, n (%) 
 No 41 (45.6) 
 Yes 49 (54.4) 
  Topical therapy 25 (27.8) 
  Destructive therapy 12 (13.3) 
  Excision 29 (32.2) 
Relapse, n (%) 
 No 44 (48.9) 
 Yes 46 (51.1) 

Topical therapy including topical steroids, silicone dressings; destructive therapy including cryosurgery, clips.

Recurrence

Following PER, 51.1% of patients (n = 46) have developed a relapse within 2 years. The relapse of individual keloids was 50% (n = 52) at a median time of 6.5 months. Among the patients who experienced a recurrence, 69.6% (n = 32) were Caucasian, and 30.4% (n = 14) were non-Caucasian. A significant factor (p = 0.007) in regression leading to relapse was the presence of prior therapy (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000539782) with 69.2% (n = 36); topical therapy led to most relapses (Table 2). Out of 8 spontaneous keloids treated with PER, 7 have relapsed (Table 2). We found no association between the age of the keloid, the location of the keloid or the size of the lesion (represented by field size) and the recurrence rate. Relapses in clinical groups are seen in online supplementary Figure 1. An example of treated patients can be seen in Figure 1.

Table 2.

Keloid characteristics and distribution by recurrence of individual keloids (n = 104)

Keloid characteristicsNo relapse (n = 52)Relapse (n = 52)p value
Keloid age, median (range), years 2 (0.08, 30) 3 (0.08, 40) 0.533 
Localization, n (%)   0.093 
 Ear 12 (23.1) 10 (19.2)  
 Head 5 (9.6) 4 (7.7)  
 Neck 6 (11.5)  
 Trunk 26 (50.0) 25 (48.1)  
 Upper extremities 9 (17.3) 7 (13.5)  
Etiology, n (%)   0.025 
 Piercing 12 (23.1) 9 (17.3)  
 Spontaneous 1 (1.9) 7 (13.5)  
 Surgery 26 (50.0) 26 (50.0)  
 Trauma 12 (23.1) 7 (13.5)  
 Unknown 1 (1.9) 3 (5.8)  
Previous therapy, n (%) 
 No 31 (59.6) 16 (30.8) 0.02 
 Yes 21 (40.4) 36 (69.2)  
  Topical therapy 7 (13.5) 23 (44.2)  
  Destructive therapy 3 (5.8) 13 (25.0)  
  Excision 14 (26.9) 19 (36.5)  
Keloid characteristicsNo relapse (n = 52)Relapse (n = 52)p value
Keloid age, median (range), years 2 (0.08, 30) 3 (0.08, 40) 0.533 
Localization, n (%)   0.093 
 Ear 12 (23.1) 10 (19.2)  
 Head 5 (9.6) 4 (7.7)  
 Neck 6 (11.5)  
 Trunk 26 (50.0) 25 (48.1)  
 Upper extremities 9 (17.3) 7 (13.5)  
Etiology, n (%)   0.025 
 Piercing 12 (23.1) 9 (17.3)  
 Spontaneous 1 (1.9) 7 (13.5)  
 Surgery 26 (50.0) 26 (50.0)  
 Trauma 12 (23.1) 7 (13.5)  
 Unknown 1 (1.9) 3 (5.8)  
Previous therapy, n (%) 
 No 31 (59.6) 16 (30.8) 0.02 
 Yes 21 (40.4) 36 (69.2)  
  Topical therapy 7 (13.5) 23 (44.2)  
  Destructive therapy 3 (5.8) 13 (25.0)  
  Excision 14 (26.9) 19 (36.5)  

Topical therapy included topical steroids, silicone dressings; destructive therapy included cryosurgery, clips.

Fig. 1.

Examples of keloids treated with PER. a Keloid on the lower abdomen prior to surgery. b PER setting of the keloid covered with bandage. c Clinical presentation after PER. d Keloid after piercing of the ear. e Post-surgical presentation. f Partial response of the keloid after PER.

Fig. 1.

Examples of keloids treated with PER. a Keloid on the lower abdomen prior to surgery. b PER setting of the keloid covered with bandage. c Clinical presentation after PER. d Keloid after piercing of the ear. e Post-surgical presentation. f Partial response of the keloid after PER.

Close modal

Hyperpigmentation

Mild local hyperpigmentation of the skin (grade 1 according to CTCAE v5.0) was documented in 31 patients (34.4%) after radiotherapy (Table 3). This completely regressed in 22 of them (71.0%) and was no longer detectable at the time of follow-up. The regression analysis showed that race has impacted the hyperpigmentation (p = 0.0009): Hispanics were most commonly affected by hyperpigmentation, with 8 of 10 patients of Hispanic origin developing it. This is reflected significantly (p = 0.009) in the skin type, and 64% of patients with documented hyperpigmentation had skin types IV and V. The localization of the keloid also had an influence on the development of hyperpigmentation (p = 0.007) in regression analysis. The trunk and upper extremities were most commonly affected by hyperpigmentation. Development of hyperpigmentation did not differ among patients with different age, gender, KA, and radiotherapy-specific parameters (Table 3).

Table 3.

Patient and keloid characteristics and distribution by hyperpigmentation in individual patients (n = 90)

CharacteristicNo hyperpigmentation (n = 59)Hyperpigmentation (n = 31)p value
Race, n (%)   0.009 
 Asian 5 (8.5) 4 (12.9)  
 Black 5 (8.5) 4 (12.9) 
 Caucasian 43 (72.9) 12 (38.7) 
 Hispanic 2 (3.4) 8 (25.8) 
 Indian 2 (3.4) 2 (6.5) 
 Middle East 2 (3.4) 1 (3.2)  
Race group, n (%)   <0.001 
 Caucasian 43 (72.9) 12 (38.7)  
 Non-Caucasian 16 (27.1) 19 (61.3)  
Skin type, n (%)   0.009 
 I 1 (1.7) 0 (0)  
 II 20 (33.9) 6 (19.4) 
 III 21 (35.6) 4 (12.9) 
 IV 8 (13.6) 14 (45.2) 
 V 7 (11.9) 6 (19.4) 
 VI 1 (1.7) 1 (3.2)  
Localization, n (%)   0.007 
 Ear 15 (25.4) 4 (12.9)  
 Head 8 (13.6) 0 (0) 
 Neck 4 (6.8) 2 (6.5) 
 Trunk 28 (47.5) 18 (58.1) 
 Upper extremities 4 (6.8) 7 (22.6)  
Etiology, n (%)   0.182 
 Piercing 14 (23.7) 4 (12.9)  
 Spontaneous 2 (3.4) 5 (16.1) 
 Surgery 33 (55.9) 14 (45.2) 
 Trauma 6 (10.2) 8 (25.8) 
 Unknown 4 (6.8) 0 (0) 
CharacteristicNo hyperpigmentation (n = 59)Hyperpigmentation (n = 31)p value
Race, n (%)   0.009 
 Asian 5 (8.5) 4 (12.9)  
 Black 5 (8.5) 4 (12.9) 
 Caucasian 43 (72.9) 12 (38.7) 
 Hispanic 2 (3.4) 8 (25.8) 
 Indian 2 (3.4) 2 (6.5) 
 Middle East 2 (3.4) 1 (3.2)  
Race group, n (%)   <0.001 
 Caucasian 43 (72.9) 12 (38.7)  
 Non-Caucasian 16 (27.1) 19 (61.3)  
Skin type, n (%)   0.009 
 I 1 (1.7) 0 (0)  
 II 20 (33.9) 6 (19.4) 
 III 21 (35.6) 4 (12.9) 
 IV 8 (13.6) 14 (45.2) 
 V 7 (11.9) 6 (19.4) 
 VI 1 (1.7) 1 (3.2)  
Localization, n (%)   0.007 
 Ear 15 (25.4) 4 (12.9)  
 Head 8 (13.6) 0 (0) 
 Neck 4 (6.8) 2 (6.5) 
 Trunk 28 (47.5) 18 (58.1) 
 Upper extremities 4 (6.8) 7 (22.6)  
Etiology, n (%)   0.182 
 Piercing 14 (23.7) 4 (12.9)  
 Spontaneous 2 (3.4) 5 (16.1) 
 Surgery 33 (55.9) 14 (45.2) 
 Trauma 6 (10.2) 8 (25.8) 
 Unknown 4 (6.8) 0 (0) 

Skin type by Fitzpatrick.

We analyzed a cohort of 90 patients with a total of 104 keloids treated with adjuvant XRT after surgical keloid excision at the University Hospital Zurich. Successful treatment with no documented relapse at 24 months was achieved in 50% of keloids. The PER was well tolerated with 34.4% of patients developing a hyperpigmentation, which was transient in 71% of them.

Keloid recurrence after treatment with recommended therapeutic modalities is very common [31]. In line with this, 54.4% of our patient cohort have undergone previous therapy without success. In a study of 387 keloids, the recurrence rates after surgery were reported to be higher for fresh nodular (continuously growing) keloids than after triamcinolone acetonide injections for superficial spreading or mature keloids [32]. However, a meta-analysis of relapse rates after different treatment options is similar [31], suggesting that different keloid biology may be the deciding factor in keloid tendency for relapse. Surgical excision is frequently used for the treatment of mature keloid scars but is considered ineffective as a monotherapy given the recurrence rate of 45–100% [19, 32, 33]. To reduce the risk of recurrence, it is recommended to combine surgical excision with more conservative treatment options, such as cryotherapy, steroids, or radiotherapy. This modality is chosen based on experience, patient characteristics and availability. While there are no limitations for use of cryotherapy or local steroids, pregnant and lactating women or children should not be treated with radiotherapy as the first choice. In a recent meta-analysis systematic review from Mankowski and colleagues [27], the recurrence rates for PER were reported with 23% for XRT, 15% for brachytherapy, and 23% for electron beam modalities. The same results were also shown in another systematic review analyzing surgical excision with adjuvant irradiation with a recurrence rate of 22.2 ± 16% for external radiation [26]. The overall recurrence rate of 50% in our dataset was significantly higher. This high recurrence rate was particularly evident in pretreated keloids: 69.2% of keloids with recurrence after PER were pretreated. We explain the higher recurrence rate in our study with the preexisting refractory keloids. As mentioned, most of our keloids had already been treated one or more times without success and were then referred to our tertiary referral center. Keloids that are relatively easy to treat generally do not reach us. In the other studies mentioned above, no pretreatment information was provided. Also, in comparison, the follow-up period of at least 24 months was quite long in our study. The follow-up time varies widely in different studies and is often not reported at all [28]. Another reason may be the lower total dose, as well as the applied fractionation regimen used in our center.

In contrast to other studies, we did not find a correlation between the location of the keloid and the recurrence rate after PER. Previous observations showed a higher recurrence rate in trunk keloids, especially in the thoracic, sternal, and scapular regions due to higher tension on the scar [16, 33].

Important for the assessment of optimal therapy with PER, also with regard to recurrence, is the total radiation dose and the fractionation scheme. In the standard fractionation regimen, the total radiation therapy dose is administered in several fractions, rather than in a single high-dose application [15, 19, 33]. This allows recovery of normal skin cells and transition of keloid fibroblasts from the radioresistant to radiosensitive phase. At our center, radiation was administered at a total dose of 12 Gy in 6 fractions. However, a higher total dose seems to be more effective in terms of recurrence rate [24]. Protocols used by other institutions recommend a dose of 15–20 Gy in 3–5 fractions [2, 34]. A recent review also suggested hypofractionated radiotherapy, i.e., a higher single dose per session, with a total dose of 28 Gy for a better clinical outcome. However, actual relapse rates were not reported [19]. Many other studies using high-voltage electron beams have also shown that the control rate of keloids after hypofractionated radiotherapy exceeded that of traditional fraction, with good tolerability [35‒38]. Moreover, dose-response analyses even suggested a biologically effective dose of ≥30 Gy administered for a total treatment duration of 1–2 days for 90% control of keloid recurrence with external beam radiotherapy. High doses and limited fraction size may lead to more adverse events, which were not stated in the reports [27, 39]. The accuracy of treatment plans and dose calculations is even more important in this case.

Systemic conditions, such as hypertension, obesity, and high cholesterol, were reported to be associated with keloids [40, 41]. Unfortunately, we do not have data on comorbidities of our cohort and cannot assess the association with response to PAR.

The adverse effects of radiotherapy can be divided into acute skin reactions and chronic or late complications. The acute reactions occur during or early after completion of therapy and become evident with cumulative radiation doses [42]. The most common acute adverse event is transient radiodermatitis, which consists of local erythema and often dry or moist desquamation and varies widely in severity [43, 44]. Chronic radiation dermatitis is defined as skin changes that occur longer than 90 days after RT treatment [45]. Depigmentation (more common in darker skin), alopecia, telangiectasia, soft tissue atrophy, and stiffness due to fibrosis may be observed [34]. Frequency and severity of radiodermatitis have been shown to be related to the radiation energy used and the total dose, favored by short treatment intervals, limited fraction size, and large treatment areas [45]. Sakamoto et al. [46] studied 194 keloid lesions treated with PER with a total dose ranging from 16 Gy in 8 fractions to 40 Gy in 8 fractions. They observed a significantly higher incidence of adverse effects in patients who received a cumulative dose greater than 20 Gy [46]. This fact is taken into account in our protocol. We do not use higher doses to minimize long-term adverse effects. Of the 90 patients treated at our institution, 59 (65%) showed no side effects after irradiation. The remaining 31 (35%) patients developed hyperpigmentation of the skin (grade 1, CTCAE Version 5.0), but this was no longer visible in 22 (71%) patients by the 2-year follow-up. As known from post-inflammatory hyperpigmentation, non-Caucasians with a darker skin type are most affected by hyperpigmentation [47, 48], in our cohort, especially Hispanics. The location of the keloid also had an impact on the development of hyperpigmentation. Consistent with other studies, we observed a higher rate of hyperpigmentation on the trunk and upper extremities, whereas there was almost no hyperpigmentation on the ear and head [49]. These factors are relevant when informing patients about the potential adverse events of PER, as darker skin individuals may prefer treatment options that have lower risk of such adverse events, even if they are transient.

By analyzing PER in 104 keloids from 90 patients, all of whom were followed up for at least 24 months, we were able to conduct one of the largest retrospective studies in the field. We observed that after PER with our protocol (6 fractions of 2 Gy, total 12 Gy), 50% of keloids were successfully treated and did not recur within 2 years. PAR was well tolerated with mostly transient hyperpigmentation reported in less than a third of the patients. As post-PAR relapses were higher in pretreated keloids, patients should be educated about risk of recurrence and the potential adverse effects of a higher RT dose.

Strengths and Limitations

The strengths of this analysis are a high case number, homogenous data collected from a single center treated per same protocol, and real-life patient population. The limitations are retrospective analysis and incomplete photodocumentation of relapse assessment. Comparing PAR and other treatment modalities as well as different radiation doses should be investigated in a prospective randomized study to identify the best treatment modality, especially for refractory keloid treatment.

We thank all patients for contributing to the increase in knowledge in PER. We are very grateful to the radiotherapy staff for their help in data collection and Dr. Patrick Turko for technical support.

The study was approved by the Cantonal Ethics Committee Zurich (Project ID: 2017-00067). The patients in this manuscript have given written informed consent to publication of their case details and photographs. For underaged participants, consent was obtained from participant’s parent/legal guardian for patients treated after 2017; for patients treated prior to that, consent was collected whenever possible, otherwise, and given there was no documented refusal, the data were anonymized and used for analysis without consent as per local guidelines.

E.R. has no funding relevant to this research, and has intermittent project-focused consulting and/or advisory relationships or travel support from Sanofi, Pierre Fabre, BMS, Amgen Inc., outside the submitted work. M.W. and F.G. have no conflicts of interest relevant to this research. J.-T.M. has no funding relevant to this research. J.-T.M. is and has served as advisor and/or received speaking fees and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, B.M.S., Celgene, Eli Lilly, LEO Pharma, Janssen-Cilag, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, UCB outside the submitted work. R.D. has no funding relevant to this research. R.D. has intermittent project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touch IME outside the submitted work. L.I. has no conflicts of interest relevant to this research.

No funding received for this study.

E.R., R.D., and L.I. have contributed to the conception and design of the work, interpretation of the data, and finalizing of the manuscript; M.W. and F.G. contributed to acquisition, analysis, interpretation of data for the work and have drafted and finalized the manuscript; and J.T.M. have contributed to writing the manuscript.

Additional Information

Egle Ramelyte and Michèle Welti contributed equally to this work.

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.

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