Therapeutics of xeroderma pigmentosum: A PRISMA-compliant systematic review

Introduction

Xeroderma pigmentosum is a rare inherited autosomal recessive genodermatosis, first described in 1874 by Hebra and Kaposi.¹ In 1932, de Sanctis and Cacchione reported neurological degenerative diseases associated with xeroderma pigmentosum.² In 1968, Cleaver established the molecular origin of the disease, demonstrating numerous DNA repair defects in fibroblast cultures irradiated with ultraviolet light.^3,4 In particular, the p53 gene mutation was identified in skin tumors in xeroderma pigmentosum patients.^3,4

The estimated global incidence of xeroderma pigmentosum is 1:1,000,000.⁵ In Japan, the prevalence is 1:22,000,⁶ and in countries in North Africa^7-9 and the Middle East^10,11 the prevalence is increasing, especially where consanguinity is common.¹² However, there is no predilection for any gender.¹² In Brazil, 48 cases of xeroderma pigmentosum were reported between 1953 and 1995 with consanguinity reported in eight of them.^13-15 The poor prognosis of this genodermatosis is due to the high incidence of skin tumors, approximately 1,000 times higher than the population mean, with a predominance of basal cell carcinoma and squamous cell carcinoma.¹² Melanoma in xeroderma pigmentosum usually occurs in adolescence, with patients having a worse prognosis and shorter survival time.¹²

In clinical practice, xeroderma pigmentosum is characterized by severe skin sensitivity to sunlight, resulting in burns, dry skin, depigmentation, poikiloderma, early skin aging and skin malignancies.¹⁶ Systemic changes may also occur which compromise development and growth in childhood.^12,13,16 Thus, patients with xeroderma pigmentosum must initiate aggressive protective measures against sunlight exposure as soon as the diagnosis is made.^12,16,17

Currently, there are many treatment options for xeroderma pigmentosum, covering medical/procedural, surgical and combined modalities.^12,18,19 In clinical practice, antioxidant drugs, retinoic acid derivatives,²⁰ isotretinoin,^20,21 imiquimod 5%,²² acitretin,²² 5-fluorouracil,^12,23 immunomodulators,^12,22,23 topical liposome lotion containing T4N57 bacteriophage endonuclease,²⁴ photodynamic therapy²⁵ with aminolevulinic acid¹⁸ and cryotherapy²⁶ have been used. The surgical approaches most often performed include excision of skin lesions with primary closure or the use of skin grafts and local flaps, simple or composite, or distant flaps.²⁷ However, the literature is silent with regard to the efficacy of various treatment options in xeroderma pigmentosum. The objective of the present study was to perform a systematic review of the literature regarding the medical/procedural and surgical treatment of xeroderma pigmentosum.

Methods

A systematic review of the literature was performed in EMBASE/ Elsevier, Scopus, Medline, PubMed, BVS, SciELO and Lilacs, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.²⁸ The search strategy was as follows: (“xeroderma pigmentosum”[MeSH Terms] OR (“xeroderma”[All Fields] AND “pigmentosum”[All Fields]) OR “xeroderma pigmentosum”[All Fields]) AND (“therapy”[Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields]) AND (“surgical procedures, operative”[MeSH Terms] OR (“surgical”[All Fields] AND “procedures”[All Fields] AND “operative”[All Fields]) OR “operative surgical procedures”[All Fields] OR (“surgical”[All Fields] AND “procedures”[All Fields]) OR “surgical procedures”[All Fields]).

The present review was registered in the international prospective register of systematic reviews (PROSPERO-CRD 42018114858). All articles found, based on the title and abstract, were tabulated, then read and separated into two categories, medical/procedural and surgical treatment and analyzed in detail. The article selection and reading process was carried out by two of the authors. All articles selected by the two authors (FAGA and FCI) were definitively included in the systematic review. Articles selected by only one of the authors were analyzed by a third (senior) author (LMF) and included only if there was concordance between all three authors. The full text was obtained for complete evaluation and final inclusion of the articles.

The inclusion criteria comprised randomized clinical trials, prospective and retrospective cohort studies, case-control studies, case series and case reports, published from January 2000 to April 2019.

The study design classification was based on the definition described by Dekkers et al.²⁹ The level of evidence of the studies were scored by the authors according to the levels determined by the 2011 Oxford center for evidence-based medicine.³⁰

The data contained in the included articles was extracted by the researchers independently and evaluated together to obtain consensus on the information. Experimental studies using cell culture and animal models were not included, even if applicable as xeroderma pigmentosum treatment strategies. Articles published in languages other than Portuguese, Spanish and English were not included. Studies involving transplant patients, preliminary and pilot studies and studies with conflicts of interest of any nature were excluded. The data collected is summarized in Table 1.

Results

Totally, 298 articles on the treatment of xeroderma pigmentosum, published between 2000 and 2019, were found [Figure 1]. Of these, 86 articles were selected for their relevance to the topic of the systematic review according to the title and abstract, after removing duplicates. Of these 53 studies were excluded because they did not meet the inclusion criteria, while the remaining 33 studies were included, after complete reading and analysis. [Table 1].

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Figure 1:

Study recruitment details

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Of the 33 articles included, 16 reported medical/procedural and 17 surgical treatments of xeroderma pigmentosum, as depicted in Table 1 Studies reporting medical and procedural treatments were evaluated and classified with a low evidence level, except one.⁶⁰ As for studies with surgical treatments, all were evaluated and classified with a low evidence level.

Three illustrative cases are described below, in which the patients presented malignant neoplastic lesions, mainly in the face. The therapeutic proposal was the complete resection of each lesion followed by closure by second intention surgeon-assisted healing. These cases serve to demonstrate the multiple number of times that surgical intervention may be required, as well as the efficacy of this procedure.

Illustrative case 1

L.S.S., is a Caucasian female, born in 2001 in Maceió, Alagoas, Brazil. Her parents are first cousins. In 2003, at 2 years of age, the patient was seen at the Plastic Surgery Outpatient Clinic of the Professor Alberto Antunes University Hospital (UFAL HUPAA), Federal University of Alagoas, where a diagnosis of xeroderma pigmentosum was made. On the same date, instructions for continuous solar photoprotection were emphatically given but not followed by the parents or relatives. Almost 3 years after diagnosis, in October 2006, at 4 years of age, the patient underwent incisional biopsy and subsequently, regular excision of multiple basal cell carcinomas and actinic keratoses on the nose, back and nostrils. The entire aesthetic unit of the nose (dorsum, sidewall, ala, lobule, soft triangle facet and columella) was operated and the material was sent for histopathology during surgery which showed that the margins were not compromised. The wound area was closed with a full-thickness skin graft taken from the inguinocrural region (sun-hyposensitized region) [Figure 2]. In November 2006, 1 month later, a basal cell carcinoma in the malar region and a squamous cell carcinoma in the eyelid were excised. Total skin grafting of the left inguinal region was also performed to cover the defects. In March 2007, 4 months later, resection of a posterior cervical basal cell carcinoma with primary suture was done. Another basal cell carcinoma and multiple squamous cell carcinomas located in the left malar region were treated by excision and total skin grafting with skin taken from the inguinal region [Figure 3]. In September 2007, May 2008, March and September 2009 and October 2010, basal cell carcinomas and a squamous cell carcinoma on the face were excised. Circular tumor excision was performed. The wound area was left open for second-intention healing [Figures 4 and 5]. In December 2010, May and December 2011, March and September 2012, June and October 2013 and February 2014, other lesions were excised with diagnoses of cutaneous hemangioma, basal cell carcinoma, actinic keratosis and pyogenic granuloma. Total skin grafting was then performed in the aesthetic unit (dorsum, sidewall and ala) of the nose and malar regions using the inguinocrural region as the donor area. After 7 years of follow-up, the skin grafted in these regions remains distinct from the adjacent “natural” skin.

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Figure 2a:

Preoperative image of the lesion in the nasal dorsum and surgical marking of the nose esthetic unit and medial subunit of the genic unit

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Figure 2b:

Patient under tarsorrhaphy, demarcation of the total skin graft needed

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Figure 2c:

Inguinal area hyposensitized to the sun as a donor area of the total skin graft

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Figure 3a:

Frontal postoperative image of 3 months

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Figure 3b:

Right profile postoperative of 3 months

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Figure 3c:

Left profile postoperative of 3 months

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Figure 4a:

Frontal intraoperative photograph - frontal, left eyelid and mental lesions

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Figure 4b:

Right profile intraoperative - frontal, left eyelid and mental lesions

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Figure 4c:

Intraoperative patient: lesion exertion in frontal region, left eyelid and mental region (left profile view)

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Figure 5a:

Patient at the postoperative period of 5 months, showing the result of surgeon-assisted healing in frontal view

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Figure 5b:

Patient at the postoperative period of 5 months, showing the result of surgeon-assisted healing in right profile view

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Figure 5c:

Patient at the postoperative period of 5 months, showing the result of surgeon-assisted healing in left profile view

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Illustrative case 2

D.L.S.S., a caucasian female, born in 2005,^the sister of L. S. S. (case 1), presented at 3 months of age, with a gradually progressive poikiloderma mainly on the face, shoulders and anterior thoracic region. The mother denied excessive sun exposure and claimed significant use of sun protection when outside the home. At 3 years of age, the patient underwent excision of lesions on the right thigh and side of the face, with a histopathological diagnosis of junctional melanocytic nevi. In March 2012, at 7 years of age, seven basal cell carcinomas were excised with tumour free surgical margins [Figure 6]. In December 2012, 9 months later, another nine basal cell carcinomas on the face were excised with free margins. In July 2013 and February 2014, solid basal cell carcinomas were excised in the right and left temporal regions. The patient receives monthly outpatient follow-up.

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Figure 6a:

Preoperative photo showing several lesions in the face

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Figure 6b:

Intraoperative photo after lesion excision

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Figure 6c:

Close-up view

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Illustrative case 3

M.A.S., is a female patient, born in 2006. There was no report of consanguinity between parents. The patient presented with gradually progressive hyperpigmented lesions and dry skin after sun exposure since the first year of life. In 2011, at 5 years of age, the patient was referred to the university hospital, where a diagnosis of xeroderma pigmentosum was made and specific therapy started, on the basis of information about the pathology and the use of sunscreen was advised. In May 2011, a multicentric basal cell carcinoma on the nose and left malar region and a squamous cell carcinoma on the lower lip were excised, with tumour-free surgical margins [Figure 7]. In July, September and December of the same year, multiple lesions on the face and lips were excised with a diagnosis of basal cell carcinoma. Three months later, in March 2012, a new ulcerated squamous cell carcinoma on the lower lip was excised with tumour-free margins. In April 2013, at 6 years of age, the patient underwent excision of solid basal cell carcinomas in the right infraorbital and glabellar regions, superficial basal cell carcinoma in the right temporal region and carcinoma in situ in the upper lip with tumour-free surgical margins. Five months later, in September 2013, the patient underwent excision of an ulcerated basal cell carcinoma in the right periorbital region, pigmented basal cell carcinoma in the lower right eyelid and solid basal cell carcinomas in the upper lip and left malar region with tumour-free surgical margins. In August 2014, 11 months later, the patient underwent excision of squamous cell carcinomas in the left malar and periorbital regions treated by second-intention healing. The patient is on a monthly outpatient follow-up schedule.

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Figure 7a:

Patient preoperatively showing lesions on the back and wings of the nose, on the left malar region and on the lower lip in frontal plane

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Figure 7b:

Patient preoperatively showing lesions on the back and wings of the nose, on the left malar region and on the lower lip in right profile view

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Figure 7c:

Patient preoperatively showing lesions on the back and wings of the nose, on the left malar region and on the lower lip in left profile view

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Figure 7d:

Intraoperative patient after resection of the lesions in frontal plane

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Figure 7e:

Intraoperative patient after resection of the lesions, midface close-up

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Figure 7f:

Intraoperative patient after resection of the lesions, lower face close-up

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Discussion

Xeroderma pigmentosum is an autosomal recessive disorder in which patients exhibit impaired DNA repair.^12,18 Skin lesions are caused by the effect of ultraviolet light on cellular genetic material, causing uncontrolled mutations and proliferation due to the heterogeneity of defects in cell repair mechanisms. This multiplicity is evidenced by the wide variety of genetic variation associated with xeroderma pigmentosum: XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ ERCC4, XPG/ERCC5 and XPV/POLH.^6,12 Patients are therefore classified according to the type of genetic mutation they carry (XPA or XPB, for example). Patients in the XPA to XPG groups have defects in nucleotide excision repair.^6,12 Patients with the XPV mutation have normal nucleotide excision repair but have a deficiency in allowing DNA replication after DNA damage caused by ultraviolet light.¹², Photosensitivity is thus a cardinal characteristic of this genodermatosis.^12,18,25

Approximately 60% of patients with xeroderma pigmentosum report an acute reaction to sunburn after minimal ultraviolet exposure.^25,62 The mean age for the onset of cutaneous signs and symptoms is between the first and second year of life, limited to sun exposed areas.^10,12,25 Continuous sun exposure generates actinic keratoses, and these lesions develop into skin carcinomas. Melanomas also develop but with lower incidence.^12,25

Bradford et al. concluded that individuals up to 20 years of age with xeroderma pigmentosum are at a higher risk for malignant neoplasms of the skin compared to the general population.⁶³ For carcinomas (basal cell carcinomas and squamous cell carcinomas), the risk of developing the disease is approximately 10,000 times higher with a mean age for the onset of lesions at nine years, almost 60 years earlier than in the general population. For melanoma, the risk increases 2,000 times with the mean age for the first lesion at 22 years which is approximately 30 years earlier than in the general population.

The treatment of xeroderma pigmentosum depends on early diagnosis, starting with immediate and strict prevention of sun exposure and other ultraviolet sources.⁶⁴ This involves minimizing or avoiding staying outdoors without proper protection, even on cloudy days. Even with a clinical suspicion of xeroderma pigmentosum, sun protection measures must be initiated until confirmation or negative diagnosis.²⁵ In addition, because of the extensive ultraviolet protection, patients should be supplemented with vitamin D,⁶⁵ in addition to being given adequate nutritional guidance.¹⁸

The present study is a systematic review of xeroderma pigmentosum treatment, both medical/procedural and surgical. There were 33 included studies. Of these, 17 studies addressed surgical treatment. All studies have a low level of scientific evidence, as they were case reports and case series (level of evidence 4). However, there was consensus regarding skin-sparing resections and the use of skin grafts from donor areas that were not exposed to the sun and/or were poorly pigmented.^36,46,57,58 No study reported continuous, long-term follow-up to determine the incidence of recurrence or new lesions in the grafts or flaps used.

This scientific scenario could be explained by the rarity of xeroderma pigmentosum, making it difficult to perform large randomized clinical trials and meta-analyses. Thus, the long-term follow-up of patients with ongoing surgical treatment, and documenting the evolution of the postoperative period should be encouraged.

As for studies with medical/procedural treatments, most prevalent was the use of topical imiquimod and 5-fluorouracil. Similar to surgical treatment studies, most of the studies presented a low level of scientific evidence. Only one study was a randomized clinical trial. Yarosh et al. tested the ability of the T4 endonuclease V (a bacterial DNA repair enzyme) in a liposomal delivery vehicle applied topically (T4N5 liposome lotion) to lower the rate of new skin cancers in xeroderma pigmentosum patients.⁶⁰ Twenty patients were assigned T4N5 liposome lotion daily for 1 year. The annual rate of new actinic keratoses was 8.2 among the patients who used the lotion and 25.9 for the patients in the control group (P = 0.004). For basal cell carcinomas, the annual rates of new lesions were 3.8 in the treatment group and 5.4 in the control group (difference 1.6 [0.38–2.82], P = 0.006). No significant adverse effects were found among patients. The hypothesis of this study is based on the fact that xeroderma pigmentosum originates in modifications in the genome, and thus a focused treatment could be effective.

For the cutaneous lesions that originate from the failure of DNA repair, there are several studies with a multiplicity of treatments, both medical surgical and combined. Preference is given to less invasive treatments. For example, premalignant lesions are treated with cryotherapy.²⁶ In larger areas of sun-damaged skin, called the cancerization field, topical preparations of 5-fluorouracil or imiquimod may be used.^12,19,23 Isotretinoin or acitretin^20-22 are used for the prevention of skin neoplasms in patients with xeroderma pigmentosum.^66,67 However, due to their toxicity (hepatic, hyperlipidemic and teratogenic effects), these drugs are reserved for patients who are actively developing a large number of new skin tumors.^12,19

When malignant lesions occur, the treatment is similar to that of patients without xeroderma pigmentosum. This involves electrocautery and skin resurfacing, curettage or surgical excision.^44,57,68 Skin cancers that are recurrent or in places with a high risk of recurrence, such as the face, are best treated by Möhs micrographic surgery.¹² Moreover, because a high percentage of these patients undergo multiple surgical procedures, removal of the undamaged skin adjacent to the lesion should be minimized.^57,58 In severe cases or cases needing extensive resections, complete excision followed by skin grafting should be used with a donor area protected from sun exposure.⁵⁸ When the neoplasia is inoperable, the therapeutic option is the use of radiotherapy, such as X radiation and electron therapy, since most patients with xeroderma pigmentosum are not sensitive to this radiation.^69,70

Autologous skin transplantation is not free of risk, and skin previously not exposed to the sun can develop lesions when exposed to ultraviolet light. We emphasize second-intention healing for the closure of wound areas, called “surgeon-assisted healing,” especially for small lesions, which aims to salvage tissue and ensure skin integrity. Furthermore, scar tissue at the site where the lesion was excised may not be affected by neoplasms, preventing the progression of xeroderma pigmentosum, although this tactic limits the aesthetic aspect.

The present study had some limitations, firstly, regarding its methodology, in which only studies since January 2000 were included and with restrictions on their idiom. As for the results, the literature only threw up studies with low evidence levels. For this reason, it was not possible to perform a meta-analysis that could direct treatment guidelines.

Conclusion

Studies with better scientific evidence are needed. Randomized trials or prospective cohort studies should be encouraged in care centers of patients with xeroderma pigmentosum.