Risk stratification tools for cutaneous SCC
Nomograms, gene expression profiling, and ctDNA help personalize risk stratification, treatment, and follow-up protocols in high-risk cSCC.
Cutaneous squamous cell carcinoma (cSCC) is currently the second most common type of skin cancer, and cases continue to rise largely due to cumulative UV exposure combined with an aging population. Current staging systems and guidelines — such as those from the National Comprehensive Cancer Network (NCCN) and Brigham and Women’s Hospital (BWH) — label patients as either high or very high risk for recurrence based on clinical and pathological risk factors.
Gaurav Singh, MD, MPH, FACMS, FAAD
Dr. Singh is a board-certified Mohs micrographic surgeon and dermatologist at City of Hope Cancer Center in Chicago and assistant professor at Chicago Medical School. He has seen an increase in cSCC among patients with immunosuppression, including solid organ transplant recipients. A small percentage of these cases — approximately 5% — can recur locally and metastasize to the lymph nodes leading to distant metastasis or even death. That, Dr. Singh said, is where risk stratification can play a crucial role.
“The purpose of risk stratification is to avoid overtreating low-risk disease. In other words, ensuring nonsurgical treatments are used appropriately and ensuring that high-risk patients receive appropriate escalation beyond the surgery including imaging, radiation, and immunotherapy,” he said. “Risk stratification also guides surveillance intensity and frequency, and informs patient counseling that leads to honest, evidence-based discussions.”
Shadi Khalil, MD, PhD, FAAD
“Dermatopathological evaluation for high-risk features such as poor differentiation and perineural invasion is an effective tool for risk stratification, but it is vulnerable to subjectivity and misses,” he said. “Ancillary tests can supplement these features for better and more accurate classification of high-risk squamous cell carcinoma.”
Emerging, auxiliary tools
Session presenter Stan Tolkachjov, MD, FAAD, FACMS, director of Mohs micrographic and reconstructive surgery at Epiphany Dermatology and Baylor University Medical Center in Dallas, said one of the tools physicians can use to support the NCCN or BWH staging systems is a nomogram — a visual graphical and statistical tool that can be used to predict the probability of a clinical event, such as cSCC.
“Nomograms use clinicopathologic factors to create a scoring system which can help with prognosis or risk stratification,” he said. “These do not take the place of staging systems, but rather, they give more information to physicians and patients to make a more informed decision.”
Dr. Singh said there are limitations in the NCCN guidelines that nomograms can address, such as the fact that NCCN does not weigh individual tumor risk factors and handles continuous variables in a limited fashion.
“Different risk factors have varying risk. For example, a tumor that is 2.1 cm is considered equally as risky as a tumor with perineural invasion,” he said. “The NCCN also does not consider patient risk factors such as immunosuppression history. Nomograms help improve stage heterogeneity within T2b tumors, consider additional variables that are often absent in staging, present individualized probability, can be updated dynamically, and predict local recurrence, which staging does not predict.”
Stan Tolkachjov, MD, FAAD, FACMS
“No staging system is fully inclusive at this time,” Dr. Tolkachjov said. “[The BWH] also does not take into account that some tumors are biologically or genetically either more or less aggressive than others.”
Other useful tools like molecular tests — gene expression profile testing (GEP) and circulating tumor DNA (ctDNA) — can provide more personalized information when used with existing guidelines and staging systems.
“Patients now want more personalized care and more information than staging,” Dr. Tolkachjov said. “They ask questions like: ‘What are you doing for me personally, doctor?’ or ‘What is unique about my case?’ or ‘What else can I know or do about my skin cancer?’”
These tools provide more knowledge to the physician regarding the risk of recurrence and the risk of metastases, which Dr. Tolkachjov said allows patients and dermatologists to come up with a more personalized plan of care. For example, he said that if staging of a skin cancer like cSCC suggests radiation is needed, but the patient refuses it based on prior experience with family or friends or reading online, and the GEP shows a higher risk, then physicians have one more piece of evidence to reinforce the recommendation of staging and adjuvant radiation therapy to benefit the patient.
“However, in some cases, if the patient prefers not to do adjuvant care, a lower-risk result may be helpful,” he said. “If the staging is high, then staging is often the data point that guides therapy. If the staging is low and the GEP is low, then this can be more reassuring in cSCC. If staging is low and GEP is high, I may choose to do imaging and a closer follow-up. If staging and GEP are high, I am more likely to send [the patient] to medical oncology for immunotherapy consultation and get immunotherapy on board earlier.”
Dr. Singh said that while the current staging systems inform where the cancer currently is, they do not give personalized insight into where the cancer could be going in the future. GEP and ctDNA help identify the prognosis as well as future challenges.
“CtDNA can be useful in a postoperative setting to monitor disease recurrence or metastasis,” he said. “The circulating DNA levels can often be the first telltale sign of a cancer coming back or traveling, and we like to utilize this individual cancer marker to help make risk-aligned decisions. Rising circulating tumor DNA levels may lead to earlier imaging and detection of disease.”
Dr. Singh said these tools can help identify patients who are at high risk, but who may have been predicted to be at a lower risk by traditional staging, and vice versa.
“Some patients predicted to be at high-risk by traditional staging may have a true risk that is lower and would prefer to avoid immunotherapy and/or radiation,” he said. “While this de-escalation can be uncomfortable from a clinical perspective, having these tools helps shape true shared decision-making.”
Real-world examples
Dr. Tolkachjov presented some real-life cases during the session to illustrate how these tools have helped improve outcomes in some of his patients.
- An elderly patient with high-risk cSCC, was at a high risk of tumor (T2b) according to the BWH staging system. However, the 40-gene expression profile (40-GEP) showed Class 1, which indicates a low risk of metastasis for cSCC. Dr. Tolkachjov decided to forgo radiation and all nonsurgical therapy, and a year later the patient was doing well with no metastasis or recurrence.
- A young woman with a deep cSCC on her lower lip showed T2b on the BWH staging system. She also had a Class 1 40-GEP and refused radiation, and she was doing well more than a year later.
- An older “cowboy” had surgery for a bad T2b tumor with inflammation but wanted no extra therapy. His 40-GEP was Class 2B (the highest risk). Because of this additional data, he ended up getting radiation, imaging, and immunotherapy.
“These are cases where the patient expectation or desire for personalized treatment did not go along with suggestions by guidelines or literature,” Dr. Tolkachjov said. “So, we used GEP and clinicopathologic factors to either better reassure the patient or help encourage further treatment. This does not mean staging isn’t the standard of care and the most important variable at this time, but tumor biology and genetics are a puzzle piece.”
The session also covered recent literature supporting these additions to the decision-making toolbox, including:
- “Incorporation of the 40-Gene Expression Profile (40-GEP) Test to Improve Treatment Discussions in High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients: Case Series and Algorithm,” published in Clinical, Cosmetic, and Investigational Dermatology.
- “Gene Expression Profiling in (GEP) in Dermatology, Part 1: Introduction, Development, Benefits, Limitations, and Future Directions of GEP,” published in the Journal of the American Academy of Dermatology.
- “riSCC: A Personalized Risk Model for the Development of Poor Outcomes in Cutaneous Squamous Cell Carcinoma,” published in the Journal of the American Academy of Dermatology.
Dr. Tolkachjov said these studies demonstrate the usefulness of GEP testing and other tools to help achieve a more personalized level of care — and potentially better outcomes — for these patients.
“The goal is that these GEP and DNA tests can help us personalize workup, treatment, and follow-up plans for patients and give more information than what is already there, specifically based on their tumor genetics,” he said. “Again, these do not take the place of staging systems or guidelines, but rather, they augment management by giving more information for physicians and patients to act upon.”
