Multiple Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa: A Surgical Challenge

Abstract

The authors have indicated no significant interest with commercial supporters.H ereditary epidermolysis bullosa (EB) is a diverse group of genetic skin disorders having blister formation mostly upon minor trauma as their common feature. They present with a wide clinical spectrum of manifestations because of different underlying molecular defects. EB arises from abnormalities in proteins of the dermoepidermal junction. Three major EB forms can be distinguished on the basis of ultrastructural blistering level: EB simplex, junctional EB (JEB) and dystrophic EB (DEB). EB simplex is a mild form since the defect is located in certain keratins expressed in the keratinocytes of the basal layer, thus causing only superficial blisters. JEB can be associated with defects in the basement membrane protein laminin 5 and thus presents with deeper wounds, which sometimes heal with a distinctive atrophic appearance. DEB is caused by mutations in Type VII collagen, a dermal protein which anchors into the basement membrane. The hallmark features of DEB are deep wounds associated with scarring and severe mutilations. 1 In addition, DEB patients suffer frequently from multiple squamous cell carcinomas (SCC). 1,2 These tumors exert a quite aggressive phenotype with early metastases. 1 Owing to the impaired wound healing and the tendency for mutilating scarring, surgical removal of these tumors is quite problematic.In contrast to DEB, multiple SCC are not a typical feature of JEB. 2 Here we report a patient with JEB who developed multiple SCC. His brother, who was also affected by JEB, died from multiple SCC due to extensive metastasis. Because of the rare association of multiple SCC and JEB, the surgical experiences in this unique setting are very limited. We compared different approaches of wound closure after extensive open excisions in this patient. Case ReportA patient with JEB developed SCC on the lower legs for the first time at the age of 39 years. Clinical diagnosis of JEB was made a few days after birth and confirmed by electron microscopy and antigen mapping. Skin defects by JEB extended mainly over his lower legs. The entire region was almost completely covered with blisters, which were impetiginized mostly by Staphylococcus aureus. Other areas affected but less severely were arms, trunk, and thighs. His younger brother also suffered from JEB with a more pronounced course of the disease. 3 He developed multiple SCC at the age of 32 years. Despite surgical treatment, the aggressive growth of these tumors led to metastasis involving the lymph nodes and the lung and finally to death at the age of 39.In the presented patient, SCC was first diagnosed 11 years previously. He presented with hyperkeratotic areas of approximately 10 Â 12 cm on both shins. Diagnosis was confirmed by multiple punch biopsies. We performed large excisions of the lesions with

Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases

“…5532 + 5G > A 42 p.Arg1753Xaa 9 Frameshift deletion resulting in a premature stop codon 9 p.Arg1933Xaa 41 Splice site mutation resulting in a 45-bp deletion 42 332522noyesNSNSnoNSNSNANSNSNANSLymph nodes metastases but death due to secondary amyloidosis 41 RDEB-nHS COL7A1 ( n  = 3)c.238G > C 13 c.3631C > T 13 NS 43 5818delC 44a p.Ala80Pro 13 p.Gln1211Xaa 13 p.Glu2858Xaa and p.Gly2576Arg 43 p.Gly1815Arg 44 271244nononoNSNSnoNSyesnoNS9NASentinel lymph node performed and negative 13 Follow-up period not specified 43 Follow-up period of 3 years 44 KSNA FERMT1 d ( n  = 3)c.328C > T 45 c.1140-6 T > A 46 p.Arg110Xaa 45 Splice-site mutation 46 >60 ( n  = 2)16NS( n  = 2)yesNS( n  = 2)yesNS( n  = 2)NANS( n  = 2)NAThe patients were siblings 45 Lymph nodes metastases (without histological proof) 46

AR autosomal recessive, DDEB dominant dystrophic epidermolysis bullosa, DEB dystrophic epidermolysis bullosa, DM Dowling-Meara, DNA deoxyribonucleic acid, EBS , EB simplex, JEB junctional epidermolysis bullosa, KS Kindler syndrome, HS hallopeau-Siemens, NH non-Herlitz, n-HS non Hallopeau-Siemens, RDEB recessive dystrophic epidermolysis bullosa, NA not applicable, NS not specified, KRT keratin, LAMB3 laminin subunit beta 3, COL17A1 collagen type XVII alpha 1, COL7A1 , collagen type VII alpha 1, FERMT1 Fermitin family member 1, KIND1 Kindlin-1. All of these genes are named according to the HUGO Gene Nomenclature Committee [47] a We have chosen to write the mutation as it has been mentioned in the article (12,44), in order to do not misinterpret the data b All of these patients had laminin-332 reduced in immunofluorescence, except for the patient from the Mohr et al study [13] with laminin-332 negative c These 2 patients were COL17A negative in immunofluorescence d In the article of Arita et al [20], the gene was named KIND1 , but it is currently known as FERMT1 according to the HUGO Gene Nomenclature Committee [47]

…”

“…All of these genes are named according to the HUGO Gene Nomenclature Committee [47] a We have chosen to write the mutation as it has been mentioned in the article (12,44), in order to do not misinterpret the data b All of these patients had laminin-332 reduced in immunofluorescence, except for the patient from the Mohr et al study [13] with laminin-332 negative c These 2 patients were COL17A negative in immunofluorescence d In the article of Arita et al [20], the gene was named KIND1 , but it is currently known as FERMT1 according to the HUGO Gene Nomenclature Committee [47]…”

“…b All of these patients had laminin-332 reduced in immunofluorescence, except for the patient from the Mohr et al study [13] with laminin-332 negative…”

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines

“…Patients with EB diagnosed with an SCC may require staging to determine the presence and extent of distant metastases, as this will have a bearing on subsequent management . (Strength of recommendation D, quality of evidence III.…”

“…However, the activities of DEBRA International will aid in dissemination of the guidelines and facilitate adoption by the proposed user groups. [11][12][13] Areas of skin clinically suspicious for SCC should be biopsied for histological evaluation D III-IV 12,14,17,22 Tumour evaluation and staging All patients with EB presenting with an SCC should have multidisciplinary review SCCs ≥ 5 cm diameter or overlying difficult anatomical sites should be imaged with magnetic resonance imaging or computed tomography to assess tumour extent D III 15,16,27 Lymphadenopathy should be assessed for potential metastatic SCC D III 2,4,9,13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Patients with EB diagnosed with an SCC may require staging D III 4,13,20,22,24,27,34,35 Surgical treatment Wide local excision is the treatment of choice for EB SCCs D III [2][3][4]…”