Squamous cell carcinoma in a patient with hereditary dystrophic bullous epidermolysis

Rajovic M1, Radevic T2, Zolotarevski L, Mickovic M2, Stepic N1, Kandolf Sekulovic L*2

1Department of Plastic Surgery and Burns, 2Department of Dermatology and Venereology, Medical Faculty, Military Medical Academy, Belgrade, Serbia

*corresponding author

Case presentation

The patient first presented at our Department in 2007 at the age of 39 when hereditary dystrophic bullous epidermolysis was diagnosed based on personal history, clinical manifestation (Figure 1, 2, 5) and genetic testing. At birth, congenital absence of skin (aplasia cutis congenita, ACC) at the left calf was present, treated surgically with skin grafting until complete healing. From birth, blisters and erosions developed on the skin on minimal pressure that healed with atrophy and scarring, but there were also evident areas with healthy appearing skin.

On regular follow-up, the patient was treated with a local skin care with antiseptic wet compresses, silver sulfadiazine cream and gentamycin ointment, non-adhesive gauzes, courses of antibiotics when secondary infection was suspected, while secondary anemia was treated with iron supplements.

In 2015, at the age of 45, a year after the last examination, the patient complained of the non-healing erosion on the left calf and on examination verrucous eroded plaques were evident Skin biopsy was performed and histopathological examination revealed well differentiated infiltrative squamous cell carcinoma G1 (Figure 4a and 4b). Staging of the disease was performed (ultrasound, MSCT of the thorax, abdomen and pelvis) without the evidence of regional or distant metastases. The patient was diagnosed with stage II at initial diagnosis.

Figure 1. a. Multiple blisters, erosions and areas of atrophy and scarring. b. Complete absence of nail on index finger, but no nail changes evident on other fingers. c. Healthy appearing skin on the right inguinofemoral region

Figure 1. a.

Figure 1. b.


Figure 1. c.


Figure 2. Verrucous eroded plaques on the left calf.


Diagnostic work-up and management

On initial diagnosis, skin biopsy was performed and on immunofluorescence electron microscopy were consistent with the diagnosis of dystrophic bullous epidermolysis, further confirmed with genetic analysis at the National diagnostic epidermolysis bullosa laboratory in London that revealed the presence of paternal missense mutation in exon 94 (G2413E) and maternal in exon 3 of the COL7A1 gene coding for collagen VII. The patient was diagnosed with recessive dystrophic bullous epidermolysis and aplasia cutis congenita known as Bart syndrome. Esophagogastroduodenoscopy also revealed circular narrowing at the upper third of the esophagus.

In 2015, when verrucous eroded plaque developed, complete excision with a skin graft from the healthy appearing skin of the right inguinofemoral region was done, and in a postoperative follow-up complete healing was evident. At the last follow-up in February 2017 there were no signs of disease recurrence and progression (Figure 4).

Figure 3a and 3b. Histopathological analysis of the skin biopsy sample revealing subepidermal cleft andwell-differentiated squamous cell carcinoma, G1

Figure 3a


Figure 3b


Figure 4. At the last follow-up, there was no signs of tumor recurrence, and patient noted less blistering at recipient site.

Figure 4. 


Key messages

Dystrophic epidermolysis bullosa (DEB, OMIM #226600) caused by the mutation in COL7A1 gene is characterized by a broad spectrum of clinical severity from very mildly affected patients with only nail dystrophy to the severe generalized form with widespread blisters, scarring, and deformities. Diagnosis was confirmed in our patient with genetic testing that revealed mutations in COL7A1. Mild clinical manifestations of the disease in our patient where probably related to the type of mutation that led to the incomplete absence of collagen VII expression, or expression of not completely functional protein. When bullous epidermolysis is associated with congenital aplasia cutis (ACC) it is also known as Bart syndrome, that was first described in 1966 (1). It comprises a triad of congenital localized absence of the skin on the lower extremities, mucocutaneous blistering due to bullous epidermolysis and nail abnormalities, as was the case in our patient. ACC is most commonly associated with dystrophic bullous epidermolysis (2).

 One of the well-recognized complications in patients with hereditary epidermolysis bullosa

(EBH) is development of cutaneous squamous cell carcinoma (cSCC). In a recent systematic review of the literature, 117 cases of EBH and cSCC were analyzed (3). cSCC developed in all types of EBH, but predominantly in cases of recessive dystrophic EB (69.2%), and on the extremities, as was the case in our patient (4). The median age of the patient in this systematic review was 36 years, and tumor diameter greater than 2 cm was evident in majority of patients (52/117, 59.1% patients). Regional metastases at initial diagnosis were evident in 14/117 (11.9%) cases and visceral in 20/117 (17.1%) cases, and death related to cSCC was noted in 32/117 (27.3%) patients (4).  In our patient, tumor diameter was also greater than 2 cm, without the metastatic spread at diagnosis. After a 24-month follow-up there was no evidence of local recurrence, nor the disease progression at regular radiological examinations.

In majority of published cases, most commonly employed surgical treatment was limb amputation without preventing the disease relapse and progression (4). There are only single cases published with successful use of skin grafting (5). In our case, mild clinical manifestations of hereditary epidermolysis bullosa, with relative sparing of inguinofemoral region led to the possibility to harvest skin graft from this site and to use it successfully at the left calf where wide surgical excision of the cSCC was performed with 1 cm margins. Healthy looking patches of the skin on the inguinofemoral region, but also on fingers in this patient, could also be related to the revertant mosaicism, which was described in several types of EB (6). During the follow-up, the patient noted far less blistering at the recipient site, pointing out to the possibility of revertant mosaicism, that should be confirmed in the future at the molecular level. Transplantation of the revertant skin was proved to be successful for the treatment of chronic wounds in these patients (6).

In conclusion, regular monitoring of the patients with hereditary epidermolysis bullosa is necessary for the early diagnosis of cutaneous squamous cell carcinoma that develops at far earlier age than in patient without EBH. Complete surgical excision with skin grafting can be successfully employed in patients with EBH, but close monitoring of the patients is necessary, since cSCC in these patient can be highly aggressive.

References:


1. Bart BJ, Gorlin RJ, Anderson VE, et al. Congenital localized absence of skin and associated abnormalities resembling epidermolysis bullosa. A new syndrome. Arch Dermatol 1966;93:296-304.

2. Browning JC. Aplasia cutis congenita: approach to evaluation and management. Dermatol Ther 2013;26:439-44.

3. Montaudié H, Chiaverini C, Sbidian E, Charlesworth A, Lacour JP. Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases. Orphanet J Rare Dis. 2016 Aug 20;11(1):117

4. Gostyński A, Pasmooij AM, Jonkman MF. Successful therapeutic transplantation of revertant skin in epidermolysis bullosa. J Am Acad Dermatol. 2014 Jan;70(1):98-101. 

5. Laimer M, Bauer JW, Klausegger A, Koller J, Pohla-Gubo G, Muss W, Sadler E,Emberger M, Lanschuetzer CM, Hametner R, Wally V, Oender K, Hinter H. Skin grafting as a therapeutic approach in pretibially restricted junctional epidermolysis bullosa. Br J Dermatol. 2006 Jan;154(1):185-7.

6. Kiritsi D, Garcia M, Brander R, Has C, Meijer R, Jose Escámez M, Kohlhase J,van den Akker PC, Scheffer H, Jonkman MF, del Rio M, Bruckner-Tuderman L,Pasmooij AM. Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa. J Invest Dermatol 2014;134(8): 2097-104.