By Terri D'Arrigo, contributing writer, December 01, 2015
Most patients with cutaneous squamous cell carcinoma (CSCC) have good outcomes. But for those in a small subset, CSCC can be lethal. According to research cited in a paper in the Feb. 1, 2014 issue of the Journal of Clinical Oncology, up to 5.2 percent of patients with CSCC will develop nodal metastasis and up to 2.1 percent will die from CSCC.
Predicting the risk of potentially fatal metastasis can be challenging, particularly when there is a dearth of population-based data, said Thomas Stasko, MD, professor and chair of the department of dermatology at the University of Oklahoma Health Sciences Center. "Squamous cell carcinoma is usually not part of cancer registries like the Surveillance, Epidemiology, and End Results Program [SEER] because it's so common, in the vicinity of 700,000 new diagnoses per year. The deaths range between 3,000 and 7,000, a very small subset. That makes it tough to pick out who we have to worry about and who we don't."
Studies going back to the 1990s suggest that immunocompromised patients have a higher risk of developing CSCCs and of CSCC metastasis, particularly organ transplant recipients. Tumor staging (T staging) is another tool to help dermatologists sort out metastasis risk, although there are no treatment protocols or recommendations based on prospective trials after that risk is assessed, Dr. Stasko said.
"T staging is where the focus is in dermatology, compared to overall staging. Once the patient moves to N [nodal involvement] or M [metastasis] staging, that is when we've usually lost the patient to other specialties," Dr. Stasko said.
Cutaneous squamous cell carcinoma in patients who are medically immunosuppressed, such as those being managed for Crohn's disease, rheumatoid arthritis, or cancers like leukemia and lymphoma, can signal issues that should be addressed with the patient's health care team, said Chrysalyne D. Schmults, MD, MSCE, assistant professor of dermatology at Harvard Medical School and director of the Mohs and dermatologic surgery center at Dana Farber/Brigham and Women's Cancer Center in Boston.
"If the patient starts to form multiple dermally invasive CSCCs, the patient may be more immunosuppressed than the care team thinks," Dr. Schmults said. "Dermatologists should speak with other members of the team and see if there is an option to correct the immunosuppression or see if another less immunosuppressive therapy will work."
T staging
The two major T staging scoring systems used in the U.S. are the American Joint Committee on Cancer (AJCC) system and an alternative system by Brigham and Women's Hospital (BWH) in Boston.
The AJCC system has four stages:
T1. The tumor is 2 cm in dimension or smaller with fewer than 2 high-risk features
T2. The tumor is larger than 2 cm across, or is any size with 2 or more high-risk features
T3. The tumor has invaded maxilla, mandible, orbit, or temporal bone
T4. The tumor has invaded the skeleton (axial or appendicular) or there is perineural invasion of the skull base
The AJCC's high-risk features include a depth of more than 2 mm, Clark level of IV (reticular dermis) or deeper, perineural invasion, location (primary site ear; primary site nonglabrous lip), and differentiation (poorly differentiated or undifferentiated).
The BWH system divides stages according to the number of BWH high-risk factors present which include tumor diameter of at least 2 cm, poorly differentiated histology, perineural invasion of nerves at least 0.1 mm wide, and tumor invasion beyond fat. There are three stages, but T2 is split into T2a and T2b.
T1. No high-risk factors
T2a. One high-risk factor
T2b. Two to three high-risk factors
T3. Four or more high-risk factors or bone invasion.
"The newest AJCC staging system is the first system unique to cSCC and is congruent with the head and neck staging system. The main limitation with the AJCC system is that it doesn't give us any population-based information on outcomes for each stage," said Thuzar M. Shin, MD, PhD, assistant professor of dermatology at the University of Pennsylvania. "The BWH system more accurately stratifies low-risk and high-risk patients and imparts the ability to predict risk of nodal metastasis and death based on tumor stage."
In a paper in the April 2013 JAMA Dermatology, Dr. Schmults and her colleagues sought to identify risk factors for metastasis and death in CSCC, and evaluate the AJCC system's ability to stratify occurrences of these outcomes. They found that fewer than 2 percent of cases were in AJCC stages T3 or T4, and the bulk of poor outcomes occurred in stage T2, indicating that the AJCC T-stages do not risk-stratify most patients well.
Dr. Schmults explained the impetus for the BWH system: "We found that if patients had no BWH high-risk factors, they did great. If they had only one, they still did very well as a group. If they had two [what became the BWH stage 2b], then their risk or recurrence or metastatis went up significantly."
Dr. Schmults acknowledged the BWH system's limitations, but is optimistic. "It has only been validated in our own patient cohort. We would like to see it validated in other cohorts. There is currently such a study underway using Mayo Clinic data."
Dr. Shin supports the idea of further research. "The percentage of patients with CSCC who have poor outcomes is so low compared to the overall population diagnosed with CSCC, it limits the ability of a single institution to develop accurate prediction models."
Meanwhile, the AJCC is working on the 8th edition of its staging, with a potential publication date of next year, Dr. Schmults added.
Yet even with two staging systems, predicting the risk of metastasis can be tricky, said Mary Maloney, MD, director of dermatologic surgery at the University of Massachusetts Medical School in Worcester. "A large tumor is a large tumor. You can see it and measure it on the surface of the skin. But the depth is something you can only measure when you remove the tumor. Nothing you can do preoperatively can help you with that."
Dr. Maloney added that characteristics like poor differentiation or perineural involvement are also often diagnosed at the time of treatment. "Sometimes you can find those things out with the biopsy, but sometimes you won't see them until you start treatment. If you do Mohs surgery, that's when you can evaluate the degree of differentiation at the depth, evaluate any clinically undetected spread, and evaluate for nerve invasion."
Dr. Shin agrees. "The higher risk tumors are the larger and deeper ones, and many times they are only partially sampled. Sometimes when we get the pathology report we have incomplete staging, and it's only at the time of surgery that we can completely stage the tumor."
Sentinel lymph node biopsy
There are currently no guidelines on the use of sentinel lymph node biopsy (SLNB), but a literature review of CSCC patients who had undergone SLNB appearing in the January 2014 JAMA Dermatologyfound that 12.3 percent of patients with CSCC had positive SLNBs. Whether the studies reviewed used AJCC staging or BWH staging, most CSCCs associated with positive SLNB occurred when tumors were larger than 2 cm in diameter. The authors noted that the BWH system appeared to more precisely delineate high-risk tumors in stage 2b. However, the review yielded a low number of patients: Just 130 patients had sufficient data for AJCC staging and 117 had sufficient data for BWH staging.
"When considering the usefulness of sentinel lymph node biopsy, the main question is whether it will help you prognosticate and predict risk [of poor outcomes] and if knowledge of that risk can affect outcome. All that has yet to be determined," Dr. Stasko said. "It makes no sense to do this procedure on the 95 percent of patients who will not have problems, but that goes back to why we need to split out high-risk groups in the first place. We need larger, prospective studies over the long-term."
Dr. Maloney agrees. "It's useful for other tumors, like melanoma, but for CSCC, so far it's nothing definitive. We have no guidelines for when SLNB should be done, but for now T2 might be the time to consider doing it."
Dr. Schmults takes a somewhat different view. "If you have someone with a high-stage tumor, stage 2b [in the BWH system], about 20 percent of these patients will have lymph node spread. That's high enough in melanoma that they would get a SLNB. We don't have the data that this is helpful in CSCC, and unfortunately we don't have clear-cut protocols for what to do, but with a 20 percent risk of modal disease some evaluation of lymph nodes beyond palpation may be considered, whether it's radiologic imaging or SLNB."
The future of prognostication
Population-based evidence will go a long way toward helping dermatologists predict the risk of metastasis and other poor outcomes from CSCC, but it will take collaboration, Dr. Shin said.
"It can be a labor-intensive process to collect enough data that it becomes clinically relevant and meaningful," Dr. Shin said. "You'd think electronic medical records would make the process easier, but the real work is in determining which high-risk characteristics to include in the prediction model, and that depends on which staging system you use. We use both systems to stage our patients."
Dr. Shin pointed to the Transplant Skin Cancer Network as an example of the power of teamwork. The network is a multicenter initiative led by the department of dermatology at the University of California, San Francisco. It's dedicated to studying skin cancer outcomes after solid organ transplantation. "Solid organ transplant recipients are at higher risk for developing aggressive cSCC," Dr. Shin said. "The TSCN study is a multi-center collaboration that will help us better understand the true incidence and outcomes of skin cancers after transplantation. The data will be more robust than any single institutional study."
