Surgical treatment and management of cutaneous squamous cell carcinoma in patients with dystrophic epidermolysis bullosa – a case report

Introduction

Epidermolysis bullosa (EB) is a group of rare diseases characterized by blistering of the skin and mucous membranes after mild trauma, friction or even spontaneously. The cause of the disease are mutations in various genes encoding different proteins of the skin. The in­heritance may be of dominant or recessive types. Defective proteins are responsible for insufficient adherence between the epidermis and the dermis, causing blistering of the skin. EB is divided into four main forms according to the layer of the skin of blister formation. Recurrent blistering may lead to chronic wounds or scars. Some forms of EB are associated with the development of cutaneous squamous cell carcinoma (SCC). Unlike in the general population, aggressive SCC can occur in EB patients at a very young age at the site of chronic wounds, recurrent scars or non-healing granulation tissue. The risk of SCC increases with age and SCC is the leading cause of death in patients with recessive dystrophic EB (rDEB), especially in the severe generalized form (rDEB-SG). Patients with rDEB have periodical full skin examination by EB specialist and they are instructed to self-examine their wounds for early SCC detection.

The standard treatment of SCC is surgical excision with wide margins. Prior to the surgical excision, a histological verification of the tumor from biopsy and staging of the patient including evaluation of regional lymph nodes should be done. Wound closure after the excision is questionable, since minimally invasive techniques are required. Management and surgery planning with following check-ups are led by a plastic surgeon and a multidisciplinary approach is required. In this paper we present a clinical management of SCC including multiple surgical excisions of the tumor mass, palliative treatment and end-of-life care.

Description of the case

We present a case of 25-year-old male patient with rDEB-SG diagnosed by histological examination of the skin with electron microscopy within the first year of life. The patient was treated since birth at the Department of Pediatric Dermatology with regular check-ups which later transformed into the national EB Center. The majority of blister formation were localized on the patient’s trunk with the most severe blister formation on his back. At the age of 22, he developed cutaneous SCC in the terrain of chronic wound at the center of his lower back. The histological examination of incisional biopsy showed moderately-differentiated SCC with the classification pT2 pNX pM0. The size of the tumor mass was approx. 10 cm in diameter and had typical clinical manifestations – raised edge, areas of hyperkeratosis and ulceration of the center. Staging of the patient via chest X-ray and ultrasonography of the abdomen including evaluation of regional axillar and inguinal lymph nodes showed no further dissemination of the tumor. Surgical excision of the tumor mass was executed by plastic surgeon under general anesthesia after careful preparation of the operating table. The excision was done with 2 cm margin around the tumor mass. The surgical wound was covered with low adherent polyamide net coated with soft silicon and soft foam dressing to avoid drying up with healing by secondary intention. The wound healed conservatively within the next two months. The histological examination by an experienced pathologist in EB biopsies showed clean resection margins. Regular check-ups and oncological staging were established.

After more than a year, there were several chronic wounds suspicious of SCC in different areas of the back. Incisional ­biopsy showed moderately-differentiated SCC and a plastic surgeon performed several excisions of the tumor mass including multiple excisions around the edge of the tumor (Fig. 1–3). All defects healed by secondary intention (Fig. 4). Despite clean resection margins, in the following months, there was a growth of new SCCs not associated with the previously removed tumors which required multiple surgical excisions. At the age of 25, an enlarged lymph node was observed in the right groin together with new tumors at his back. Ultrasonography of the node showed suspicious metastasis of SCC which was later confirmed by histological examination after surgical excision (Fig. 5). The lymph node was infiltrated by a bulky metastasis of SCC replacing lymphatic tissue and spreading through the lymphatics. The positron emission tomography/computed tomography (PET/CT) scan showed a metastatic disease of the right lateral chest wall with osteolysis of the ribs and central necrosis (Fig. 6).

The patient was reviewed by oncologists at Masaryk Memorial Cancer Institute and at multidisciplinary meeting of EB specialists consisting of a dermatologist, a plastic surgeon, a clinical oncologist, a radiation oncologist, a palliative care specialist, a chest surgeon, a hematologist, a psychologist and a gastroenterologist. The conclusion of the committee was not to continue with further surgical excisions due to metastatic disease with a high risk of secondary damage. The recommendation was to switch to palliative care with the biological treatment with cemiplimab (Libtayo®, Regeneron Pharmaceuticals, Inc., NY, USA). Psychological support of the patient and his family was established through the patient organization Debra Czech Republic.

Discussion

EB represents a rare complex disease which can be classified into 4 main forms with more than 30 different clinical subtypes. The most common form is EB simplex (EBS), which represents approx. 70% of all EB cases, followed by 20% of dystrophic EB (DEB), 10% of junctional EB (JEB) and very rare Kindler syndrome (up to 1%) [1]. While EBS has mild clinical manifestations and is not associated with an increased risk of SCC, patients with DEB suffer from severe recurrent blistering leading to chronic wounds and scars. DEB form is caused by a mutation in the COL7A1 gene, which encodes defective collagen VII making insufficient anchoring fibrils between dermis and epidermis [2]. Patients with DEB are at high risk of developing SCC which is a leading cause of death in a group of patients with severe generalized forms of recessive dystrophic epidermolysis bullosa (rDEB-SG) [3].

In general population, cutaneous SCC is the second most common form of skin cancer. It is considered as a slow growing malignancy of elderly people and it is usually found on the areas of the body which have been exposed to the UV rays [4]. On the contrary, SCC in patients with DEB behaves more aggressively and may firstly occur in their adolescence. The cumulative risk of having SCC rises with age, from 7.5% by the age of 20, through 67.8% at 35 years to 90.1% at 55 years. Alongside with this, the cumulative risk of death increases to 38.7%, 70.0% and 78.7% by the age of 35, 45 and 55 years, respectively [5]. SCC usually arises from chronic wounds, non-healing defects and recurrent scarring with no causal relationship with the exposure to UV rays. SCC may be well-differentiated (grade I), moderately-differentiated (grade II) and poorly-differentiated (grade III). In situ SCC, such as actinic keratosis or Bowen’s disease, are extremely rare in patients with EB [6].

Since SCC in patients with DEB usually origins from chronic non-healing wounds or scars, it is hard to distinguish between a non-tumorous ulceration and SCC [7]. Patients with DEB have large areas of blister formations at various predilection sites resembling the tumor mass. It is recommended that patients with DEB should undergo a full skin examination every 3–6 months by an EB specialist. It is important to mention that EB patients know the process of healing of their wounds and they are instructed to see a specialist whenever they encounter a non-healing or atypically healing wound. A wound suspicious of SCC growth includes rapidly growing granulation tissue, hyperkeratosis, raised edges or sensitivity change in the wound or its neighborhood [3]. Modern bandage materials contributed to faster and safer wound healing, so any prolonged healing may also be a sign of a growing tumor. If there is a suspicion of SCC, incisional biopsy should be performed by an EB plastic surgeon [8]. At our workplace, we take multiple biopsies under local anesthesia from the center and margins of the lesion. If the lesion is smaller than 2 cm in diameter, we usually perform a total excision. Every excision should be examined by a pathologist experienced in EB biopsies since the microscopic picture of the granulation tissue or hyperplasia may be similar to the tumor mass.

In case of SCC confirmation from incisional biopsy, the plastic surgeon in cooperation with other EB specialists leads the subsequent treatment. Surgical removal of the tumor mass with wide margins is the method of choice. Prior to the surgery, evaluation of regional lymph nodes and staging for distant metastases is necessary [9]. The radicality of excision is limited by the localization on the patient’s body. Extensive SCC localized on the patient’s limb without clear margins may be an indication for amputation of the digit or limb [10]. On the contrary, extensive tumor mass localized on patient’s trunk is limited by the anatomical location and involvement of underlying structures.

The surgical excision is usually performed under general anesthesia with respect to the patient skin – at our workplace, the operating table is padded out, patient’s skin being in contact with oxygen mask or electrodes is covered in soft foam dressings and the patient does not have endotracheal intubation, but deep sedation with monitored anesthesia by an experienced EB anesthesiologist [11]. After marking the outline of the incision (Fig. 1), the tissue surrounding and underlying the tumor mass is infiltrated with local anesthe­tics consisting of trimecaine (Mesocain®, Zentiva, Prague, Czech Republic) with epi­nephrine to prevent bleeding and reduce pain. The tumor mass is removed in one part and the orientation is marked perioperatively in at least two directions with different colors of surgical suture. Attention must be paid to the surrounding skin with no-touch technique in order to avoid massive blistering after the surgery. Bleeding from the wound is stopped by electrocoagulation, ligature and surgical gauze with hydrogen peroxide. Several biopsies of the underlying tissue are taken and all samples are separately sent to the histopathological examination.

The closure of the surgical wound is problematic due to the state of the surrounding tissue and patient’s overall condition. Numerous approaches were described by various authors including healing by secondary intention, autologous split-thickness skin graft transplantation, flaps or artificial skin equivalents [3,12–14]. Every method has its advantages, limits and needs to be selected strictly individually. At our workplace, we always discuss the possibilities with the patient. In our described case, the patient and his family decided to heal the surgical wound by secondary intention since they were used to change the dressings daily and they didn’t want to take care of the donor site. In healing by secondary intention, we must keep the wound moist to prevent drying up, because changing of dried-up gauze is very poorly tolerated by EB patients in general. In our case, we applied low adherent polyamide net coated with soft silicon directly on the surgical wound and soft foam dressing impregnated with antiseptic solution on the top of it (Fig. 2, 3). The family of the patient changed dressing every other day and the defect was fully healed in the next 2 months (Fig. 4). Regular check-ups were established every month with staging twice a year.

Non-surgical treatment is considered in cases where surgical excision of SCC is not possible or if the patient has metastatic dissemination of SCC. Radiotherapy can be used as primary treatment or palliative local treatment of metastases. It should be delivered in smaller fractions to prevent severe skin desquamation. Chemotherapy is used as palliative care and there were only few cases described. Other treatment includes biologic approach, such as monoclonal antibodies blocking programmed cell death protein 1 / programmed death ligand 1 (PD-1/PD-L1) pathway, epidermal growth factor receptor antagonists or tyrosine kinase inhibitors [3,15]. Non-surgical treatment is led by a clinical oncologist, but has dubious results.

The progression of SCC can lead to metastatic dissemination, the treatment of which is no longer curative. The EB specialists need to focus on quality palliative care with effective pain management and complex end-of-life care. Since every patient requires individual treatment, there are no universal oncological protocols and every patient should be discussed at a multidisciplinary meeting consisting of a dermatologist, a plastic surgeon, an oncologist, a palliative care specialist, a psychologist and other EB specialists involved in the treatment. It is an effort to maximize the quality of life while relieving pain. In our described case, the oncologist indicated biological treatment with cemiplimab, which is a monoclonal antibody binding to the PD-1 receptor acting as a checkpoint inhibitor. Palliative care specialist regularly reviewed the patient and his family to adequately increase pain medication. In this stage of the disease, surgical treatment consists of changing the dressing and sanitation of smell. Psychological support is important for both the patient and the family. Complex care concentrated in the national EB center with the support of patient organizations, such as Debra Czech Republic, is a step forward.

Conclusion

Patients with DEB are at a great risk of developing aggressive SCC in their adulthood. Early detection of the tumor is important for overall outcome and patients should be regularly examined by EB specialists. In case of suspicion of SCC, multiple incisional biopsies from the wound are taken by an EB plastic surgeon and examined by a pathologist experienced in EB biopsies. If SCC is confirmed, the method of choice is surgical excision of the tumor mass with wide margins. In some cases, amputation of the limb is necessary. Other treatment options have specific limits and are used as support therapy. If SCC is metastatically spreading, palliative care with the focus on preserving adequate quality of life should be discussed at multidisciplinary meeting of EB specialists. Every patient requires individual approach which is provided by concentrating complex care in the specialized national EB center.

Role of authors: All the authors listed above contributed equally to this article.

Disclosure: The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The authors declare that this manuscript has not been published before and is not currently being considered for publication. The authors declare that the study was conducted in accordance with the Helsinki Declaration. There are no financial conflicts of interest to disclose.

Pavel Rotschein, M.D.

Department of Pediatric Surgery,

Orthopedics and Traumatology

University Hospital Brno

Jihlavská 20

625 00 Brno

Czech Republic

e-mail: rotschein.pavel@fnbrno.cz

Submitted: 30.6.2021

Accepted:28.10.2021