Advances in Diagnosing Non-melanoma Skin Cancers

Biopsy remains the gold standard, but newer tools are useful adjuncts.NMSC

More than 3.5 million skin cancers are diagnosed in more than 2 million patients in the United States each year,1 and evidence from the American Academy of Dermatology (AAD) suggests that 20% of Americans will develop skin cancer. Basal cell and squamous cell carcinomas (BCC and SCC, respectively) are the two most common forms, accounting for about 96% of non-melanoma skin cancer (NMSC), and are easily treated,2,3 with the latter more likely to spread to the lymph nodes. Both BCC and SCC are increasingly being diagnosed in people under age 40; BCC is more common in younger women than younger men.4 NMSCThe AAD notes that the total direct costs for treating these NMSCs is more than $1.5 billion yearly. The correlation between SCCs and actinic keratosis (AK) is well established; patients with AKs can benefit from earlier diagnosis and treatment as well. More than 3,000 deaths can be directly attributed to aggressive or high-risk SCC that metastasize.5  

Figure 1, above: An example of a high-risk squamous cell carcinoma. Photo courtesy of D. Geist, MD

When it comes to diagnosis, “the most important tools we have are our eyes and hands,” says Gary Goldenberg, MD, assistant professor of dermatology and pathology and medical director of the Dermatology Faculty Practice at Mount Sinai School of Medicine in New York. “You have to know what you’re looking at — is it AK or is it SCC in situ? Is it an invasive squamous cell, is it a basal cell? There’s often a sandpaper feel to AKs that can help narrow it down, but pathology will help make the definitive diagnosis.”

As with any disorder, the diagnosis will dictate the treatment.

“I’m not an observer, I’m a treater,” Dr. Goldenberg says. “The treatment of AKs is so easy I don’t think it’s worth not doing.”

Before Biopsy

That said, Dr. Goldenberg and other experts agree: while the gold standard remains biopsy, receiving the pathology report from an outside lab can take time. In the interim, other tools can be useful as adjuncts to the initial screening.

Dr. GeistFor one, “dermoscopy doesn’t play a significant role in the identification of SCCs, but it’s a helpful tool to differentiate benign nevi from things that could be melanoma,” says David E. Geist, MD, medical director of the University of Massachusetts Medical School dermatology clinic in Worchester, MA. When it comes to diagnosing SCC, “other than clinical acumen and biopsy, there are not a lot of other diagnostic tricks,” he adds.

Erin Gilbert, MD, PhD, assistant professor of dermatology at SUNY Downstate Medical Center in New York who is also in practice at Gramercy Park Dermatology, says dermoscopy is “used consistently in my practice. I find it very helpful in distinguishing between NMSC subtypes (basal and squamous and AKs). I do adjunctively use optical coherence tomography (OCT). If I’m clinically confident that I’m looking at a superficial basal cell, I’ll perform OCT, treat the patient topically and, if it’s still present after treatment, I’ll do a follow-up biopsy then. The key here is close patient follow-up.”

Dr. Goldenberg says the magnification aspects of the dermatoscope makes it a useful adjunctive tool, “but, if you’re still uncertain after using a dermatoscope, the best course of action is to biopsy the skin and have a definitive diagnosis.”

Since integrating the VivoSight OCT (Michaelson Diagnostics) into her practice, Dr. Gilbert says her diagnostic preferences have slightly shifted to use dermoscopy, followed by OCT and, ultimately, biopsy.

NMSC“These three technologies used together give a very safe and complete diagnostic picture,” she says. “OCT is still in its early days of use in clinical dermatology, and clinicians need to know there’s a long learning curve for image interpretation,” mainly because the images generated are cross-sectional black-and-white. Dr. Gilbert adds it took her about a year to rapidly determine what each image represented.

Figure 2, above:  Patient’s hand as presented for diagnosis (top) and a basal cell carcinoma visualized using optical coherence tomography (bottom). Photos courtesy of Gramercy Park Dermatology.

She cautions about adding OCT to the diagnostic armamentarium: the depth of visualization “is somewhat limited — only about 2 mm to 3 mm into the skin. Clinicians have to be wary with deeper lesions and/or recurrent lesions.” So, for example, elements of an infiltrative basal cell within the deeper hair follicles are nearly impossible to visualize.

“But when you get good at reading the images, it’s an instantaneous diagnosis that allows you to make clinical decisions on management of superficial lesions quickly without necessarily having to wait a week for the biopsy to come back,” Dr. Gilbert says.

High-risk NMSCFor high-risk SCC (Figure 3, left), Dr. Geist explains that biopsy not only confirms the diagnosis but can give clinicians a treatment plan simply by divulging if the carcinoma is well, moderately or poorly differentiated. He says that if a biopsy reveals a moderately or poorly differentiated SCC, “it needs to be treated aggressively with Mohs micrographic surgery. Mohs provides the highest cure rate and that is why it is recommended by the National Cancer Center Network for these cases.”

Unfortunately, “great data doesn’t exist” to guide pre-set treatment times.

“In my practice, if I think the patient has an aggressive SCC, it needs to be treated in a matter of a few weeks. Eight weeks is too long, and the same goes for melanomas,” Dr. Geist says.

Developing Treatment Plans

For most clinicians, patients with one or two AKs or an isolated BCC or SCC are not overly challenging.

“The real gap in the treatment plan and how it’s implemented is how to address the patient who has 50 AKs on a bald scalp or 20 AKs on the face,” Dr. Goldenberg says. “The reason these patients are special or important is because the majority have subclinical lesions. Studies have shown between 80% to 90% have lesions under the surface that we don’t see with our eyes because the skin looks normal. In studies, you can see the lesions become visible (white out) after topical agent use.” In addition, the choice of topical treatment is not a factor in bringing out subclinical lesions. AKs that have been present the longest have the highest likelihood of turning malignant, Dr. Goldenberg notes, emphasizing that treating every lesion is crucial.

“It may not be reasonable to freeze all of them, but certainly you’d want to freeze as many as possible and use a topical agent to clean up the rest,” Dr. Goldenberg continues. “The longer you leave remaining AKs untreated, the higher the chance it will progress to invasive skin cancer.”

Patients “can only tolerate so much at a time,” Dr. Geist says. For those who present with multiple lesions over several areas of their body, he suggests finding three or four that seem to be the most serious and begin treating those first, with the caveat the patient will need ongoing therapy.

“You really have to match your treatment to the ‘flavor’ of the cancer,” Dr. Geist says. For thin SCC in situ, chemotherapeutic creams such imiquimod or 5-fluorouracil (5-FU) may be effective.
“Destructive methods such as electrodessication and curettage may be appropriate for thin lesions on the trunk and extremities,” Dr. Geist adds. “Invasive lesions need to be excised with clear margins. And high-risk lesions need special attention with Mohs surgery and possibly adjuvant treatment.”

Electrodessication and curettage may be effective, depending on tumor location.

“As we get more invasive, we do want to ensure clear margins,” Dr. Geist explains.

Dr. GilbertTo ensure the tumor has completely cleared, Dr. Gilbert recommends “early field treatment for diffuse AKs, not only for the therapeutic benefit but for the cosmetic benefits and preventive therapy as well.” Her go-to for AKs is typically the Fraxel Dual 1550/1927 laser, imiquimod or 5-FU, or photodynamic therapy (PDT). Imiquimod is well tolerated by patients and PDT “offers much improved compliance simply because it’s administered in the office.”

“Preliminary data on the Fraxel shows the treatment may be helpful in clearing multiple AKs, with a 63% clearing rate efficacy after one treatment,” Dr. Gilbert says, citing figures from a presentation by Roy Geronemus, MD, at the American Society for Dermatologic Surgery meeting in November 2011. “With any invasive NMSC, I obviously prefer to excise except where Mohs surgery is clinically indicated.”

Dr. Geist says simple excision “does not have as high a cure rate as Mohs in high-risk sites such as the lip or ear that have many nerves and blood vessels and may facilitate spread of SCC.”

For patients with 10 or more AKs, Dr. Goldenberg will freeze the lesions “and bring the patient back in a few months to see how many more they’ve developed.” If they’ve developed about as many as were frozen off, “we’re going to have a conversation about topical therapy and I’ll encourage them to do something that’s going to treat the whole surface. I’ll freeze them on the second visit, and ask to use cream, and I’ll see them back a few months after using the cream.”

Cream can also double as a diagnostic tool, Dr. Goldenberg says. “Sometimes what’s left isn’t AKs at all, but SCC. There can be so much background noise with AKs it’s difficult to discern what’s what.”

PDT is approved for lesion-directed therapy, not field therapy, but Dr. Goldenberg will use it off-label for that purpose. He also advocates 5-FU, diclofenac and imiquimod in both 5% and 3.75% strengths.

In January, ingenol mebutate (Picato) gel (0.015%, 0.05%) received FDA approval for the topical treatment of AKs.

Dr. Goldenberg“An oral drug — vismodegib — for advanced and metastatic BCC has shown real efficacy in the really serious forms of skin cancer,” adds Dr. Goldenberg. In late January, the FDA approved vismodegib (Erivedge) for the treatment of adults with basal cell carcinoma that has spread to other parts of the body or that has come back after surgery or that their healthcare provider decides cannot be treated with surgery or radiation. Vismodegib selectively inhibits signaling in the Hedgehog pathway, which is been implicated in more than 90% of BCC cases, according to Genentech.

Dr. Gilbert said the 2 to 3 day treatment results with ingenol “appear to cause necrosis and a neutrophil-mediated cytotoxic response that results in clearing of multiple AKs. Again, that’s preliminary outcome data and we need further clinical studies to wholeheartedly embrace it as the new ‘go-to’ molecule for treating NMSC.”

The real shift in treatment approaches will come when more clinicians use combination approaches for AKs, Dr. Goldenberg says.

“Patients do better if you combine the modalities of cryosurgery and topical therapy. I think there’s a disadvantage to patients if you only do one or the other,” he adds.

Dr. Gilbert believes the most cutting edge approaches include customized use of classic and new, including molecular approaches, immunostains during Mohs, or combination laser and topical therapy.

“The most interesting and effective way to treat NMSC is to look at our therapeutic toolbox and create a custom treatment for each individual patient that addresses today as well as tomorrow. It just makes the most sense,” she says.

Disclosures: Dr. Geist has no disclosures. Dr. Gilbert is a consultant to Allergan and Merz. Dr. Goldenberg is a consultant for Graceway, Genentech, Leo Pharma, Medicis and Nycomed PharmaDerm.