By Daniel Mark Siegal MD, MS
Associate Professor, Vice Chair and head of Dermatologic Surgery, Department of Dermatology SUNY@Stony Brook

INTRODUCTION:

     Skin cancer, predominantly Squamous cell Carcinoma (SCC), is a scourge of RDEB. This is a problem that begins with the first blister, the first erosion, the first scar. In a fashion similar to the skin cancers seen in sun worshippers the world over, repeated injury to the skin puts stress upon our largest organ. It is well known that "stress" in the form of injury can induce SCC. It has been postulated that "chronic tissue stress" can cause malignant degeneration. Some investigators have shown a similarity in dysfunction to actinic keratoses seen in severely sun damaged skin and RDEB. Mutations of the p53 gene that has been covered in the lay press lately also have been implicated as playing a role in skin cancer development in RDEB. The best way to deal with SCC at the present time is prevention, which means good skin care and good wound care when blisters arise. Despite the best of efforts, the degeneration to malignancy is relentless. Close surveillance and early treatment offer the best hope at this time.

DIAGNOSIS:

     One hundred thousand SCC are diagnosed each year in the USA. The most commonly afflicted people are elderly individuals with severely sun-damaged skin. On average, on out a hundred metastasizes (spreads) beyond the spot where it first develops. Cancer does what cancer wants to do. You only try to beat it down before it can do something nasty.
      A variety of pre-cancerous conditions may develop into invasive SCC. These include actinic (solar) keratosis, a condition where malignant cells are scattered in the epidermis but not invading any deeper. In Bowen's disease (SCC-in-situ) these cells occupy the full thickness of the epidermis, from top to bottom, but still have not invaded into the dermis. Invasion occurs when these cells protrude down into the dermis and from there, they may extend widely and deeply to other tissues via local extension. In some situations, they may surround nerves and blood vessels and use them as conduits to remote areas. Invasion into blood vessels may allow spread throughout the body. At other times, cells may find there way into lymphatic vessels and travel to regional lymph nodes and the rest of the body. As a rule of thumb, the bigger the tumor, the more likely it is to metastasize.
     Unfortunately, even pre-cancers may metastasize in rare cases. Cancers arising in areas of trauma, such as in RDEB, tend to be more aggressive than the average sun induced skin cancer. Under the microscope, many types of SCC are recognized and categorized by cell appearance and degree of differentiation (which is degree of difference from normal). SCC may be bizarre under the microscope and may mimic other cancers. Melanoma, the most serious type of skin cancer, can occur in RDEB but the incidence is not increased over the normal population.
      Early warning signs include persistent, red, rough scaling patches, open sores that heal very slowly and may not heal completely, with fragile crusts and bleeding with minor trauma. Later signs include thickening of overlying skin to form small horns or plateaus that bleed on picking or peeling. Unfortunately, many of the signs are features of everyday life for people with RDEB and differentiating them from the sequela of everyday minor trauma can be difficult or impossible at times. Even under the best surveillance, despite the best of care from professionals and family, SCC will take its toll over the long haul.
      Common sense is important for RDEB patients and their families, as you are always dealing with wounds. If a wound is not healing as expected, see your dermatologist. If the skin gets rough or thick out of proportion to other adjacent areas, see your dermatologist. If something looks "funny" see your dermatologist. If any question arises, a biopsy can often answer it.

TREATMENT:

     Treatment consists of separating the patient from the tumor. A variety of therapeutic approaches exist. No one approach is perfect; therapy is individualized for each patient. Therapies can be mixed and matched as needed.
      A complicating factor in RDEB is the tendency for patients who have gotten old enough to get SCC to have lots of scars all over and finding "normal" skin for reconstruction, if needed, can be difficult.
      One of the great problems we face is that even if a tumor is completely removed, the skin at the edges of the wound has the same potential to grow a tumor as the tissue removed. Defining endpoints is very difficult in any case, as the periphery beyond the invasive tumor may have changes that look like sun induced pre-cancers, even on non sun-exposed areas. To track margins or to simply "beat them down" with curettage and cautery or cryosurgery as outlined below, or treating with a topical chemotherapy cream (Efudex = 5FU = 5Fluorouracil) are all options.

Curettage and cautery is an approach where tumors are removed by scraping away bulk tumor and burning the edges to achieve additional tissue destruction. The wound then heals on its own over a few weeks. Advantages include low cost to perform; disadvantages include possible failure to obtain a completely clear margin.

Cryosurgery (freezing) with or without curettage is an approach to destroying the tumor by making ice crystals kill cells in the treatment area. Curettage before freezing allows rough definition of the tumor edges. Cryosurgical wounds are always allowed to heal on their own; they ooze and weep a large amount of clear fluid for one to two weeks but are very resistant to infection and healing is usually relatively painless after the first 24 hours.

Surgical excision allows removal and primary closure with stitches of the surgical site. The specimen is reviewed in the laboratory and the pathologist comments on whether or not it is out completely. The pathologist typically cuts the tissue like a loaf of bread. A few random slices are examined and the likelihood of removal is extrapolated from this sample.

Mohs Surgery is a surgical procedure where the tumor margin is fully mapped to maximize the chance of complete tumor removal. Looking at the tumor like a custard pie, the "custard" (bulk tumor) is scooped out and the "pie crust" (sides and bottom) are evaluated microscopically to determine if the entire tumor was removed. If the "pie crust" has leaks (tumor extensions), appropriate pieces of the "pie tin" are removed in the same way. This is an office procedure that may entail spending the better part of a day as tissue is being processed. The wound that is left may be repaired or allowed to heal on it's own.
      Additional reconstructive surgery is an option in many circumstances if necessary for functional or aesthetic reasons. It must be remembered that any extensive procedures carry the risk of placing potentially pre-cancerous skin in otherwise clean areas.

Systemic chemotherapy is not a primary approach to treatment of cutaneous SCC. Chemotherapy for advanced disease often includes cisplatin as a mainstay.

Radiation therapy is not indicated as a primary therapy for skin cancer in RDEB. It may be palliative but results in moist skin desquamation and delayed skin healing. Therapeutic and toxic radiation may be one and the same in RDEB.

SPECIAL CONSIDERATIONS:

Immunotherapy - to vaccinate against the markers of SCC. The obstacle is to make the body differentiate abnormal from normal.

Retinoids - a therapeutic adjunct. Side effects (dry eyes, dry mouth, dry peeling skin) limit their value in RDEB at the present. It is possible that mixtures of different retinoids will have synergistic (additive) effects at lower doses than are currently found to be useful with retinoid monotherapy.

Gene therapy - "Universal Donor" skin - other magic bullet?

REFERENCES AND FURTHER INFORMATION
There are many online resources:

www.ncbi.nlm.nih.gov/PubMed/is a site of free Medline access.

www.ncbi.nlm.nih.gov/Omim/is the Online Mendelian Inheritance Textbook.

www.debra.orgis the DebRA site.

www.aad.orgis the American Academy of Dermatology Home Page, a source of many links.

www.dermis.net is the home of the Dermatology Online Atlas.

Tray.dermatology.uiowa.edu/SuprtGrps.htmlis a good source of links to other disease support groups .