Skin Cancer
in RDEB:
Where to Start, Where to Stop and What the Future May Hold
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.org
is the DebRA site.
www.aad.org
is the American Academy of Dermatology Home Page, a source of many
links.
www.dermis.net/Index_e.htm
is the home of the Dermatology Online Atlas.
Tray.dermatology.uiowa.edu/SuprtGrps.html
is a good source of links to other disease support groups.
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