Hitting the Spot in Squamous Cell Carcinoma

Maureen Lennon was just 35 when she began developing red scaly patches at an alarming rate. Called actinic keratosis, the lesions typically arise on sun-damaged skin, but in rare cases, they can be a precursor to a type of skin cancer, cutaneous squamous cell carcinoma (CSCC). Within months, Lennon received her first CSCC diagnosis.

A lifelong swimmer, Lennon spent summer days basking in the sunshine beginning at age 8. “I was out from 7 a.m. to 7 p.m. every day, all summer long, without sunblock, until about age 21,” she says. When she was in her 20s and 30s, she visited tanning beds nearly every month. Fair skinned with light-colored eyes and plenty of freckles, Lennon was at high risk of developing CSCC.

“Squamous cell carcinoma (SCC) is not just one type of cancer but, rather, a whole gamut of cancers that have a common origin: the epithelial lining cells, not just on the skin, but also in the mucosal surfaces,” a membrane that lines body cavities and coats internal organs, says Dr. Larisa Geskin, director of the Comprehensive Skin Cancer Center at New York-Presbyterian/ Columbia University Irving Medical Center. Squamous cells are shaped like small fish scales. They’re thin and flat and exist in many places in the body, including the skin, throat, mouth, genitals and cervix, particularly in areas of rapid cell turnover.

The primary cause of skin SCC is sun exposure. Carcinogens such as cigarette smoke and other environ- mental toxins usually play a role in head and neck SCC, whereas SCC in the genitals and oropharynx is often caused by HPV. SCC in the lining of the cervix is called cervical cancer, not SCC. Similarly, SCC in the urethra (male or female) is called urothelial cancer.

“The terminology can be confusing,” says Dr. Sarah Arron, associate professor of dermatology at the University of California, San Francisco. “Lesions on the skin of the head and neck are CSCC, (whereas) lesions inside the mouth or throat are an entirely different type of cancer called head and neck SCC. So, head and neck SCC is not the same as a skin squamous cell carcinoma that happens to be on the skin of the head and neck.”

CSCC is the second most common skin cancer in the United States, just after basal cell carcinoma, and especially prevalent in regions where people have near-constant exposure to the sun. Experts estimate that more than 1 million cases are diagnosed in the U.S. each year. Most of these cancers can be cut out and don’t require further treatment. But in people with weakened immune systems or those — like Lennon — with a perfect storm of risk factors, obliterating CSCC and preventing its recurrence can be a challenge.

Fortunately, with targeted treatments, a newly approved immunotherapy drug and a growing body of research investigating combination therapies, the treatment landscape is slowly shifting.

THE ABCS OF SCC

All forms of SCC are caused, at least in part, by an environ- mental insult, most commonly ultraviolet radiation from the sun. HPV, arsenic, coal tar and other environmental toxins are also culprits. In fact, SCCs — then called soot wart — were first described in 1775 when little boys who worked as chimney sweeps began developing the cancers on their scrotal skin. “The soot would get into the scrotal folds, leading to cancer. It was the first occupational link to cancer,” Geskin says.

Other risk factors include age, most likely because of accumulated skin damage, and weakened immunity. A compromised immune system can’t prevent cancerous cells from growing and spreading in patients such as organ transplant recipients or those who have HIV infection or had prior radiation to treat previous lymphoma or leukemia.

When squamous cells on the skin regenerate at a fast clip due to chronic inflammation or sun damage, there’s more room for error and a greater chance of CSCC. “The vast majority of CSCCs arise in a primary site on the skin, and they’re found and treated surgically,” Arron says.

In a 2013 review of 12 studies published in the British Medical Journal, researchers reported an overall local recurrence rate of 5.4% after standard surgical removal. But CSCCs usually don’t occur as a single malignant cancer on otherwise healthy skin. “The entire area surrounding the SCC is affected, so treating just one cancer on one site is not enough,” Geskin says. Instead, after surgical removal, doctors often treat the entire carcinogenic field with light therapy, or photodynamic therapy; other options are radiation and topical drugs, such as the immunotherapy imiquimod and the chemotherapy 5-fluorouracil.

In patients who have deeper lesions or cancers on a functionally or cosmetically important site, such as the face, a more measured surgical approach called Mohs is the first-line treatment. During the procedure, surgeons remove one layer of skin at a time and examine the tissue under a microscope. If the margins aren’t free of cancerous cells, doctors repeat the process until the entire area is clear. The pathology happens in real time, so patients know what they’re up against. Plus, there’s less chance of recurrence following Mohs.

Dating back to 1992, a systematic review reported that the five-year local recurrence rate for primary CSCC treated with Mohs was dramatically lower (3.1%) compared with other Food and Drug Administration (FDA)-approved treatments, such as traditional excision and cryosurgery. Most of her early lesions were shallow and didn’t require deep excisions, so Lennon didn’t receive her first Mohs treatment until last year. Now, doctors treat all her CSCCs with Mohs.

In the late ’80s, Lennon had about six CSCCs a year. Now she has about six a month. “My doctor just removed my 166th squam this year,” she says. Her lesions are about the size of a half dollar, much larger than her first CSCC. They’re deeper and more painful, too, and they keep appearing.

TRICKIER TYPES OF TUMORS

Doctors can cure most CSCCs with surgery, but a small percentage of patients with the cancer, like Lennon, develop complicated disease that no longer responds to surgery or radiation. These CSCCs can crop up in multiple locations simultaneously, hide in the lymph nodes and even invade other organs and tissues.

There are two types of complicated CSCC: The first is a tumor that is not easily treatable with surgery and radiation because it has spread to a lymph node or other organ. The second type occurs in patients like Lennon who have extremely sun-damaged skin and multiple primary CSCCs over much of the body.

“Any one of those tumors might be treated individually with surgery, but in total, the numbers of surgeries are exhausting for the patient. In those cases, doctors look at other treatment options,” Arron says. “But it’s important for patients who get lots of skin cancers in sun-damaged skin to understand that these are not the same as one cancer spreading to other areas of the skin.”

Cancer registries tend not to include CSCC. “There are just too many of them to track, so researchers don’t have solid statistics about what percentage of patients with CSCC develop more advanced disease,” Arron explains. Experts estimate that 3% to 5% of patients with CSCC have lymph node involvement, and it’s a higher number among organ transplant recipients and people who are immune suppressed. The risk of CSCC among heart and lung transplant patients, for example, is 198-fold higher than in the general population.

ADDRESSING TOUGHER CASES

Immune-compromised patients are not only more likely to develop CSCC, but their cancers also tend to be more aggressive and less responsive to treatment. Take Lisa Pohl, 59, of Georgetown, Texas: Although she isn’t an organ recipient, she has taken immune-suppressing medication to treat Crohn’s disease for nearly three decades. She was also an avid sunbather in her younger years.

Pohl wasn’t surprised when she developed her first CSCC in 2014. But when lesions began popping up on her left leg, back, chest and right ankle, she started to get spooked. “In early 2018, I had a squamous cell cancer develop in an area that had already been cut twice,” Pohl says. She visited an oncology specialist and endured 13 radiation treatments in one month. Within a week of completing treatment, her right leg was so inflamed that she couldn’t walk. Two weeks later, she developed three more CSCCs on the perimeter of the radiated area. That’s when her doctor referred her to The University of Texas MD Anderson Cancer Center in Houston.

“There are certain types of CSCC that, the more aggressive you are, the more likely they are to recur,” says Dr. Anisha Patel, associate professor in the department of dermatology at MD Anderson.

“Treatments such as radiation and surgery can actually encourage the development of more CSCCs.” This is due in part to the inflammation that occurs during healing and scarring.

Patel treated Pohl’s CSCCs directly with methotrexate injections, a form of chemotherapy, and started her on a drug called acitretin to prevent more CSCCs from forming. “Acitretin is one of the few preventive medications you can use for high-risk, immune-suppressed patients,” Patel says. Originally approved for psoriasis, acitretin works on the regulation of the skin cycle, so cell turnover occurs in a more orderly fashion. The rub: The drug can cause serious birth defects, and if you stop taking it, the CSCCs return. Essentially, it’s lifelong therapy with a drug that causes peeling, itching and scaling skin, hair loss, drowsiness and other side effects.

The medication seems to work for Pohl. When a suspicious spot appeared on her skin last May, it resolved without treatment. “It looked like my other cancers, but within a week the skin around the area just sort of lifted up and peeled off,” she says.

For patients who develop aggressive CSCC that’s not oper- able, oral targeted drugs known as EGFR inhibitors, such as Erbitux (cetuximab) and Vectibix (panitumumab), are another option, although they’re not specifically indicated for use in this disease. These drugs block the activity of a protein called epidermal growth factor receptor, or EGFR. Found on the surface of both normal and cancerous cells, EGFR promotes cell growth. Unfortunately, these treatments are not generally curative and have a response rate of just 20% to 25%, with side effects such as rash, hair loss, conjunctivitis (pinkeye) and diarrhea that can be debilitating and make it difficult for patients to stick with the treatment.

Chemotherapy has shown some activity in patients with metastatic CSCC, but the results have been underwhelming. In a study of cisplatin-based chemotherapy, for example, less than 30% of patients achieved complete remission and just 40% experienced partial remission. Although adding radiation post-treatment dramatically improves the odds of complete remission, patients with advanced CSCC need more effective options.

SURVEYING THE TREATMENT LANDSCAPE

The newest player on the CSCC field is Libtayo (cemiplimab), an immunotherapy drug that partners with the body’s immune system to fight cancerous cells. In September 2018, the FDA approved Libtayo injections for patients with advanced CSCC and those with tumors that cannot be surgically removed.

The drug blocks programmed cell death protein 1, or PD-1, which helps cancer cells evade the body’s immune system. When Libtayo blocks PD-1, it acts as sort of a beacon to help the immune system recognize cancerous cells and launch a targeted attack. “Libtayo is a huge para- digm shift in the field,” Arron says. “It’s the first systemic drug approved for CSCC, period.”

The study leading up to its approval reported that 47.2% of all patients with metastatic disease who were treated with Libtayo saw their tumors shrink or disappear. The disease control rate, or the percentage of patients with stable disease, tumor shrinkage or complete remission, was even higher — about 80%. Measuring survival on the drug was a secondary goal of the study. Although the median length of survival had not been reached when the researchers stopped collecting data, the estimated probability of survival at 12 months was 81%, the authors reported.

As with other checkpoint inhibitors, PD-1 can lead to common side effects such as fatigue, rash and diarrhea. Because it interferes with the immune system’s action, it can also spur attacks on healthy organs and tissues, so it may not be an option for patients with autoimmune disease.

“Plus, Libtayo alone only has about a 50% response rate,” Geskin says. “That’s great, considering we didn’t have any solid options before Libtayo, but there’s room for improvement.” There is some suggestion that tumors expressing a lot of the protein PD-L1 may respond better to Libtayo, but that predictor is not 100% accurate, he says.

Like other immunotherapy drugs, Libtayo may produce better responses when combined with other treatments. “But at this point, there is no combination that is well- established and approved,” Geskin says. Investigators are beginning to explore whether using Libtayo after surgery, either alone or in combination with radiation, in patients with localized but aggressive CSCC might prevent the cancer from recurring. The drug may be an option before surgery, too, to shrink the tumor to an operable size.

BEST DEFENSE: SUNSCREEN

The research questions seem endless. Some researchers even wonder if the HPV vaccine may play a role in preventing CSCC. “We know many people carry HPV in their skin, especially people who are immune suppressed,” Arron says. “We also know that many skin tumors have HPV in them, and they’re more likely to have HPV in them than normal skin.” Does that mean an HPV vaccine could protect against or even treat CSCC? Arron says that’s a huge leap but a plausible theory worth investigating.

Researchers are also examining other mutations commonly seen in CSCC, such as alterations in the PTCH1 tumor suppressor gene, to consider whether they may eventually be treated with medications used for advanced basal cell carcinomas that target the PTCH1 protein.

In the meantime, patients like Lennon and Pohl continue to fight off skin lesions while steering clear of the sun.

“UV radiation is the primary cause of these cancers, so protecting our skin from the sun is the best thing you can do,” Arron says.

Now in her 60s, Lennon still frequently appears on pool decks, whether as a coach, official or the parent of a swimmer. When she hears young swimmers complain about applying sunscreen or resisting their parents’ or coaches’ insistence to grease up, she views it as an opportunity to show them the aftermath of sun damage. “I’ll lift up the hem of my skirt or pants or roll up my sleeves and show them what lots of skin cancers look like,” she says. “It can be a gruesome sight, but it almost always causes them to slather up.”