By Abby S. Van Voorhees, MD, January 02, 2012
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Nanette Liegeois, MD, PhD, about her recent Journal of the American Academy of Dermatology article, “A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: Creation and rationale for inclusion of tumor (T) characteristics.”
Dr. Van Voorhees: Why is this new staging system important? Why should cutaneous squamous cell carcinomas (cSCCs) be separated from other non-melanoma skin cancers? What is it hoped that this will achieve?
Dr. Liegeois: The incidence of SCC is increasing in the U.S. The increase in frequency reflects the demographics of our population — increased numbers of older people who’ve had excessive sun exposure and are now developing skin cancers. The second aspect of the demographics is that we have an increasing population of solid-organ transplant survivors. Along with their now-improved survival come secondary medical problems such as skin cancers. SCC is the most common skin cancer in the solid-organ transplant population, occurring frequently, and the disease can be much more aggressive [in these patients]. So it’s important to understand not only the treatment options but also to understand which patients are most at risk for metastatis or poor prognosis so we can offer them the most definitive therapies.
We must remember that SCC is a potentially metastatic disease often diagnosed and treated by dermatologists. We’re seeing more of this disease and we’re also seeing advanced disease. When SCC becomes advanced, it is associated with high morbidity and often high mortality.
Dr. Van Voorhees: Does the new system more specifically include features that are thought to increase the risk of metastatic disease in cSCC? What are these features?
Dr. Liegeois: Absolutely. The previous model, the sixth AJCC edition, had not been updated in almost 20 years and was virtually irrelevant to non-melanoma skin cancers (NMSCs). I am unaware of any practitioner who relied on the sixth edition AJCC staging system. The reason it wasn’t helpful is because it encompassed very benign appendageal tumors along with often fatal carcinomas such as Merkel cell carcinoma. We have completely overhauled the AJCC staging system for NMSC. We’ve separated Merkel cell carcinoma from the rest — it has its own chapter — and used evidence-based medicine that has been published in the literature to create an entirely new grading system that is more prognostically relevant. [pagebreak]
Dr. Van Voorhees: What features have you identified as high-risk features for cSCC?
Dr. Liegeois: There is excellent prospective data in the literature to suggest that tumors greater than 2cm are at high risk of metastasis. That stratifies our T1 vs. T2 tumors. Previously we had a grading system solely based on size. We know now through very good studies that there are multiple parameters that can predispose a tumor for metastasis. One is depth of invasion greater than 2 mm in thickness. Perineural invasion also has a definite association with advanced or metastatic disease. Anatomic sites such as the ear or lip are extremely important. Tumor differentiation also plays a role; if it is poorly differentiated or undifferentiated, that is associated with advanced disease.
Dr. Van Voorhees: What are the advantages of making our tumor staging system congruent with other head and neck staging systems?
Dr. Liegeois: Because this is a UV, sun-induced tumor, most of these tumors occur on the head and neck and many of the published studies have actually been reported by head-and-neck surgeons who have stratified nodal disease and tested the cSCC model against their model, which grades staging based on the burden of nodal metastasis. The preliminary studies for the seventh edition staging manual were consistent with the head-and-neck findings in that prognosis decreased with increasing nodal disease. For instance, a very small, solitary lymph node had a much better prognosis than multiple lymph nodes or a single very large lymph node. Since these preliminary results appear to be consistent with the head and neck experience, we adopted that staging system. I believe it provides a sound basis so that future prospective studies can test and further refine the model as we collect more multivariate data.
Melanoma serves as a nice example of a staging system that has evolved beautifully over a period of 20 years. We now have a very good understanding of that disease and its prognostic variables. What we need to do is keep studying SCC so that when therapeutics are developed, they can be properly tested and patients can be properly stratified according to the risks.
Dr. Van Voorhees: Let’s consider tumor diameter this variable remains important in the new staging system. How is this changed from the prior AJCC guidelines?
Dr. Liegeois: The sixth edition T staging relied entirely on the size of the tumor. In the new version we realized that it’s not just size; various histologic features appear to be important. The real challenge is that we as a dermatologic community are seeing the patients with T1 and T2 tumors. What we need to do is take all the variables and perform a prospective multivariate analysis so we can see which clinical or pathologic criteria determine the prognosis of this disease.
In this analysis we recognize that 2 cm is an adequate cutoff — but there are instances where 2 cm is too big a cutoff. We know solid-organ transplant patients can have a poor prognosis with tumors smaller than 2 cm. This is a good example of how more data and more multivariate analysis can help us refine these criteria as we go forward in the future.
Dr. Van Voorhees: Depth of invasion and tumor thickness are now listed as important staging variables in the new staging system. What do we know about these features and their interplay with diameter?
Dr. Liegeois: There are two very nice studies in the literature. One was published in 1997 in Cancer; another was published in 2008 in Lancet Oncology. Both are referenced in our paper and show that a tumor thickness greater than 2 mm is an important independent variable in whether a tumor will metastasize. In terms of the Clark level greater than or equal to four being a predictor, that is a consensus opinion among all of the committee members. There is less data to support that, but because many of these tumors occur in areas where the skin is quite thin, we felt that 2 mm might not represent areas where the skin is thin such as the ear or the lip. [pagebreak]
Dr. Van Voorhees: What are the other features that are also now included in the seventh staging system that were not a part of the sixth staging system?
Dr. Liegeois: Perineural invasion came up in multiple studies and was universally felt to be a criterion for poor prognosis disease. There have been many reports, most of which are retrospective in nature, citing the anatomic ear and lip as being high risk sites. In the previous edition the tumors were graded in terms of poorly differentiated or undifferentiated; in our version we included that within the staging system as a key criterion rather than separately from the staging system. Multiple reports suggest that poorly differentiated or undifferentiated tumors have a poor prognosis.
Dr. Van Voorhees: Were there any features that you thought would be important to include that turned out to not have enough validity to stand on their own?
Dr. Liegeois: The criterion we felt was most important for prognosis was immune suppression, such as in solid-organ transplant recipients. By the nature of the staging system, which is defined by very strict criteria for what defines T (primary tumor), N (lymph nodes), and M (distant metastasis), there is only one example of a clinical factor being used to stage thyroid cancer, where the clinical factor of male sex is such an overwhelming factor that it was given an exception. In our instance, although we all felt that immune suppression was the most important prognostic determinant in cSCC, the rules of the AJCC did not allow us to include that. Having said that, the whole process is evolving as more and more molecular markers are determining prognosis and so the current T, N, and M criteria may change over the next several years to allow a more diverse array of parameters.
The second thing that we wanted to include that we were unable to add was in-transit metastasis, a type of disease that occurs mostly in transplant patients. An in-transit metastasis is when the tumor is thought to be traveling along the lymphatic system but has not reached a lymph node yet.
Dr. Van Voorhees: How can dermatologists help advance the science of SCC?
Dr. Liegeois: I encourage the dermatologic and dermatopathology community to participate in reporting poor-outcome disease. Additionally, we need studies to include as many patients as possible with multivariate analysis to ensure that our next AJCC staging system is as accurate as it can be.
Dr. Ligeois practices at Northwest Dermatology, SC, in Hoffman Estates, Ill., and is Adjunct Assistant Professor at Johns Hopkins University Department of Oncology and Plastic Surgery. Her article was published in the Journal of the American Academy of Dermatology, 64(6), 1051-1059 (June 2011). doi:10.1016/j.jaad.2010.08.033.