Squamous cell carcinomas (SCCs) are highly aggressive in patients with epidermolysis bullosa (EB). Non–ultraviolet-related SCCs are the leading cause of death in patients with recessive dystrophic EB, particularly recessive dystrophic EB-generalized severe subtype (RDEB-GS). The mechanism of SCC development in patients with RDEB continues to be investigated and several theories have been reported in the literature.
Squamous cell carcinomas (SCCs) are highly aggressive in patients with epidermolysis bullosa (EB). Non–ultraviolet-related SCCs are the leading cause of death in patients with recessive dystrophic EB, particularly recessive dystrophic EB-generalized severe subtype (RDEB-GS). The mechanism of SCC development in patients with RDEB continues to be investigated and several theories have been reported in the literature.
Regular skin checks
Regular skin checks are imperative to assess potential premalignant or malignant lesions. Dermatologists recommend 3-monthly full body detailed skin checks for patients with RDEB to be performed after the age of 12 years. Along with the skin check, patients can also receive multidisciplinary care for the wide array of other medical conditions that patients with RDEB suffer from.
The skin checks often last for 2 hours and begin with the patient removing their dressings with or without a bath. Once the patient is undressed and dressings have been removed, digital photography is performed as a baseline for current wounds, to compare with previous photos, and determine any suspicious areas. Biopsies are generally taken from areas of concern during the same visit. Patients and family members are also encouraged to keep a personal account of ulcers that have become symptomatic or are long standing, associated with either poor or no healing. The skin check is performed by several staff members including the dermatologists and supportive dermatology personnel, nursing staff, and family members.
Some institutions offer home services by an experienced nurse who takes photos; these are then assessed by medical staff. However, this process does not allow the clinician to palpate or directly visualize the suspicious area, or ask questions about individual lesions.
Epidemiology
The cumulative risk of developing SCCs in RDEB patients is 90.1% by the age of 55 years; the most common site of involvement is chronic wounds, followed by long-term cutaneous scars. Multiple SCCs are common in patients with a median of 3 to 3.5 tumors. The leading cause of death in RDEB-GS patients is metastatic SCCs with a staggering 87.3% cumulative risk of death by the age of 45 years.
Patients with RDEB-GS develop SCCs at a much earlier age compared with healthy individuals, often in their adolescence. The trend in onset during adolescence suggests that the skin’s mechanism of constant repair may be the culprit for SCC development. In healthy patients, Marjolin ulcers take several years to become malignant ranging between several weeks in burn patients to several years in long-term ulcers.
The histologic grading of SCCs does not correlate well with the clinical behavior of these malignancies. SCCs in RDEB patients invariably behave in an anaplastic manner despite histopathology reports confirming well or moderate differentiation. The main predictor of mortality in these patients is the extent of SCC at diagnosis. Evidence of local or distant metastasis is associated with a poor outcome because of the aggressive nature of the malignancy. However, early detection of potential SCCs before local tissue invasion coupled with effective treatment results in a more favorable outcome. The earliest report of SCC development in EB is 12 years.
Epidemiology
The cumulative risk of developing SCCs in RDEB patients is 90.1% by the age of 55 years; the most common site of involvement is chronic wounds, followed by long-term cutaneous scars. Multiple SCCs are common in patients with a median of 3 to 3.5 tumors. The leading cause of death in RDEB-GS patients is metastatic SCCs with a staggering 87.3% cumulative risk of death by the age of 45 years.
Patients with RDEB-GS develop SCCs at a much earlier age compared with healthy individuals, often in their adolescence. The trend in onset during adolescence suggests that the skin’s mechanism of constant repair may be the culprit for SCC development. In healthy patients, Marjolin ulcers take several years to become malignant ranging between several weeks in burn patients to several years in long-term ulcers.
The histologic grading of SCCs does not correlate well with the clinical behavior of these malignancies. SCCs in RDEB patients invariably behave in an anaplastic manner despite histopathology reports confirming well or moderate differentiation. The main predictor of mortality in these patients is the extent of SCC at diagnosis. Evidence of local or distant metastasis is associated with a poor outcome because of the aggressive nature of the malignancy. However, early detection of potential SCCs before local tissue invasion coupled with effective treatment results in a more favorable outcome. The earliest report of SCC development in EB is 12 years.
Monitoring
The authors recommend regular skin checks (every 3–6 months) from the age of 10 years and every 3 months from 16 years onwards. Ideally patients remove all dressings first, with or without a bath/shower, as this is most time-efficient routine for the specialist responsible for checking the skin. To assist with this, we have found that comparative digital printed or polaroid photography is useful to detect unhealed potentially premalignant or malignant areas. A thorough history from the patient or carers regarding ulcers that do not heal, are growing larger, becoming increasingly painful, pruritic, or changing in appearance along with serial photography allows dermatologists to detect potential skin cancers early. A body chart for recording the progressive history of SCC in each patient is also useful. A useful chart is available on the DebRA UK Web site ( http://www.debra.org.uk/ ).
Performing the biopsies
The poor compliance of some patients with monitoring for SCCs stems from a combination of the embarrassment of having to remove all the dressings before being checked and the fear of pain when biopsies are taken from nonhealing ulcerated areas. Ideally, a room attached to a private bathing/shower area that is warm, with plenty of room for the dermatologist, nurse, carer, dressings, and assistants doing the biopsies should be available. In an ambulatory hospital facility, oral midazolam may be given to allay anxiety and provide amnesia for the event. The sites of biopsy should be marked on the printed photographs for ease of identification later.
Prevention
Isotretinoin can be used in RDEB patients for chemoprevention up to a dosage of 0.5 mg/kg/d and is tolerated well, however the patient should be monitored for increased skin fragility. In our own experience, several adult RDEB-GS patients have tolerated low dose neotigason well; neotigason has been shown to be more specific for prevention of SCC in the immunosuppressed transplant population.
It is possible that neotigason might reduce the incidence of SCC but this would require a long controlled study, which is difficult in such an orphan disease. Now that there is a mouse model of restricted RDEB, it may be possible to trial this in the mice if they live long enough and develop SCC.
Bowen disease
There are rare reports of in situ SCC in EB. One report used 5-aminolevulinic acid photodynamic therapy for treatment of Bowen disease of the fingers in a patient with RDEB without pseudosyndactyly with no recurrence. We would rather recommend excision of any such areas, given the high mortality rates of SCC in EB and because the biopsy may not have contained all the suspicious area.
Treatment
Surgery
Once an SCC has been confirmed on biopsy, the patient should be managed quickly by a team including the dermatologist and a plastic surgeon familiar with EB. Localized magnetic resonance imaging (MRI) can determine if tendons are involved. These SCCs should be widely excised and in cases that are not caught early, amputation of the distal extremity may be required ( Fig. 1 ). Although Mohs surgery has been reported, this method may have advantages in terms of the pathology to be more sure that the SCC is completely excised, but conservative margins may not be wise given the high risk of recurrence.
Staging
Patients should have staging investigations performed including ultrasound and computerized tomography (CT) scans or MRI. Positron emission tomography (PET) scans can also be used to determine extent and presence of hematogenous and lymphatic metastases. Imaging is guided by the extent of the clinician’s suspicion for metastases. Because of the aggressive nature of the SCCs, if local invasion has been seen on ultrasound and/or biopsy, CT or MRI, further imaging of the chest, abdomen, and pelvis with or without a PET scan, may be warranted. PET scans are particularly useful for determining the presence of localized metastases difficult to visualize on CT or MRI and can also be used to determine local metastases to lymph nodes. Sentinel lymph node biopsies have also been reported in the literature and postulated to be an additional low morbidity tool in staging and prognostic determination.
Surgery
Treatments are largely tailored to the presence or absence of distant metastases and the patient’s general health. The surgical treatment of choice for primary SCCs for patients with RDEB or junctional EB is full thickness excision with wide surgical margins. For patients with localized involvement, the clinician must carefully assess whether limb-sparing treatments such as wide local excision compared with amputation of the hand/foot/part of the limb is warranted. Longitudinal follow-up of EB registry patients in the United States showed that Mohs surgery did not reduce local recurrence or regional metastases and the value of sentinel lymph node biopsy remains inconclusive.
SCCs that have invaded the adjacent tendons or soft tissue structures with or without local lymphogenous spread ideally warrant amputation. Amputation is also warranted for recurrent tumors. The problem in proving that amputation is better than local excision in this situation is not being able to detect small distant metastases that may have already occurred and the lack of randomized evidence, but if the tendons have been invaded, wide excision including the invaded tendon would render the hand or foot nonfunctional, which is the reason most patients wish to preserve their hands and feet.
Adjunctive Radiotherapy and/or Chemotherapy
Because of the anaplastic nature of the malignancy, patients requiring localized wide excision can also be offered chemotherapy and/or radiotherapy to the affected areas. Radiotherapy can be useful in debulking large tumors before surgery. Because of the relative dearth of reports in the literature, there is no clear consensus on adjuvant or neoadjuvant treatment regimes for patients with RDEB who are diagnosed with SCCs with local or distant metastases. In the EB registry in the United States, only 5.7% of patient with RDEB had received chemotherapy and only 17% were given radiotherapy when distant metastases were present, with no clinical benefit noted in single or combined use of chemotherapy and radiotherapy. The problem with this evidence is that it is retrospective and reflects old literature reporting concerns about side effects with these modalities, resulting in delays in treatments that are usually given to patients without EB with metastatic or locally advanced SCC. The Australasian EB Registry includes 5 patients with RDEB-GS with SCC which has metastasized to the axilla who underwent fractionated radiotherapy without significant problems to their skin. Any delay in the initiation of radiotherapy allows the tumor to grow exponentially, reducing the likelihood of disease control with radiotherapy. Delays have occurred in different radiotherapy centers because the older literature reports problems with the skin. Another problem has been that generally oncologists do not encounter RDEB-GS patients until the SCC is advanced, and they may perceive that the patient’s quality of life is not worth the treatments, whereas those taking care of these patients in the long-term know that these patients generally want to keep living and are used to coping with any skin breakdown that might occur. Hence, it is important for experts in EB to publish case reports of their experience with RDEB-GS and tolerability to radiotherapy.
Palliation
If a patient has extensive disease with distant metastases, the treatments offered are predominantly palliative. The management is largely governed by the wishes of the patient and the family. Limb-sparing operations may be offered in these situations to sustain the patient’s quality of life. Adjuvant chemotherapy and radiotherapy can be used; however, there is currently no consensus on the appropriate chemotherapeutic agent and its dosage or duration. Similarly, radiotherapy for EB patients is not routinely recommended because of reports of potential skin breakdown. However, palliative radiotherapy may be particularly useful to treat tumors causing significant impairment to the patient’s quality of life such as neuropathy, large fungating, offensive-smelling tumors or tumors with local invasion into blood vessels.
Epidermal Growth Factor Inhibitors
Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR) and has been used to treat locoregionally advanced head and neck cancers, colorectal cancers, and lung and cutaneous SCCs. EGFR is over expressed in tumor cells and leads to over stimulation of cell growth and tumorigenesis. Cetuximab binds to EGFR receptors and inhibits the action of EGF via these receptors.
Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality, and it has been found that there was no increase in toxic side effects associated with radiotherapy.
Cetuximab can also be used as a single agent in the first-line treatment of patients with unresectable SCCs, and may be considered a therapeutic option. Acneiform rash (in up to 80% of patients) is reported secondary to cetuximab. Other side effects include malaise, nausea, vomiting, diarrhea, constipation, allergic reactions, and susceptibility to infections. Patients should be commenced on pretreatment antihistamines and oral antibiotics, such as minomycin or doxycycline, to prevent an acneiform rash. Cetuximab was well tolerated when given as a weekly intravenous infusion to 1 of our RDEB-GS patients with SCC metastatic to the axilla and chest wall who was taking doxycycline prophylactically.
Related posts:
How to Take Skin Biopsies for Epidermolysis Bullosa
Epidermolysis Bullosa Simplex with Muscular Dystrophy
Genitourinary Tract Involvement in Epidermolysis Bullosa
Growth and Pubertal Delay in Patients with Epidermolysis Bullosa
Epidermolysis Bullosa Care in Germany
Epidermolysis Bullosa Care in Israel
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