Staging in skin cancer
SETTING THE STAGE
Changes to TNM system enhance prognostication for cutaneous cancers
Feature
By Jan Bowers, Contributing Writer, October 1, 2021
When French surgeon Pierre Denoix, MD, pioneered the development of a simple staging system for breast cancer in the 1940s and '50s, he opened a path for physicians treating many other types of cancer to plan their management strategy based on a clear set of parameters. Dr. Denoix conceived of the system known as TNM, which specifies the size and invasiveness of the primary tumor; the status of regional lymph nodes; and the presence or absence of distant metastases. Building on his work, medical societies such as the Union for International Cancer Control, the American Cancer Society, the International College of Radiology, and the American College of Surgeons organized the precursor to the group now known as the American Joint Committee on Cancer (AJCC). Comprised of 22 member organizations, the AJCC has published eight editions of its Cancer Staging Manual; the most recent edition was implemented in 2018.
The AJCC 8th edition (AJCC 8) includes updated information for the staging of cutaneous melanoma and for cutaneous squamous cell carcinoma (cSCC) of the head and neck. DermWorld spoke with dermatologists who specialize in the diagnosis and treatment of cutaneous malignancies and discussed the changes in AJCC 8 and their significance in the management of melanoma and SCC.
Melanoma
The panel of experts appointed by the AJCC to revise the melanoma staging criteria for AJCC 8 worked from a database of more than 46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. In addition to drawing on a larger dataset than was available for the 7th edition, the panel analyzed results from patients for whom a sentinel node biopsy was available. "Up until the mid-90s, the sentinel node procedure wasn't considered to be standard, so some people in the previous dataset had the procedure and some did not," said Michael E. Ming, MD, FAAD, associate professor of dermatology at the Hospital of the University of Pennsylvania. "In the newer dataset, a lot more people would have had it." Dr. Ming added that the members of the panel for AJCC 8 are different from the group that produced AJCC 7, which may underlie some of the changes in the newer edition.
A group of authors representing the AJCC Melanoma Expert Panel and the International Melanoma Database and Discovery Platform published a detailed discussion of the updates to the melanoma staging criteria in AJCC 8 (CA Cancer J Clin. 2017;76:472-92). Among the numerous changes to and clarifications of criteria set forth in AJCC 7, the authors highlight the following:
In Dr. Ming's view, the changes in staging criteria for patients with Stage I and Stage II melanoma will likely have the most significance for dermatologists, as "those are the patients for whom we as dermatologists are most likely to be taking primary responsibility." Specifically, Dr. Ming pointed to the changes from AJCC 7 to AJCC 8 affecting T1 tumors as particularly noteworthy. "In the previous system, if you had a lesion that was 1 mm or less in thickness and the lesion had a mitosis or ulceration, you moved from T1a to T1b. Now, if you have a lesion with a thickness between 0.8 mm and 1 mm or if the lesion has ulceration, you move from T1a to T1b. If you have a lesion that's less than 0.8 mm, then it will be T1a if it's not ulcerated, but T1b if it is ulcerated."
In addition, "mitotic rate is not in the staging system at all at this point, although it's still important," said Dr. Ming. "The committee members did say that it should still be reported, but it was thought that the 0.8 mm thickness cutoff was a better reflection of survival than the mitotic rate, if only one of them were to be included." A colleague of Dr. Ming's, Emily Y. Chu, MD, PhD, FAAD, agreed that the changes to T1a and T1b are the most impactful and "maybe the most confusing. The biggest change on our part as dermatopathologists is the lack of inclusion of mitoses in distinguishing between the T1a vs. the T1b melanomas." Dr. Chu, who is associate professor of dermatology at the Hospital of the University of Pennsylvania, maintained that "it is still recommended that the mitotic rate be included in pathology reports, even though this is no longer part of the staging system. In a number of ways, the change does make some sense because the survival difference between a thin melanoma with 0 versus 1 mitosis/mm₂ may not be great, but the question may be: Do we need to stratify between one and two? In practice, if a patient has a thinner melanoma, less than 0.8 mm in depth, but they have three or four mitotic figures, that's a melanoma I'm going to worry a lot more about than if they have one mitotic figure per mm₂."
Another significant change for dermatopathologists, Dr. Chu noted, is "the issue of microsatellites and how those are reported. It used to be that microsatellites were defined as tumor deposits that are separated from the primary melanoma by a distance of at least 0.3 mm and with a diameter of at least 0.05 mm, and now the size and distance criteria are no longer included. Now, because the distance and size thresholds have been removed, you could see more calls of microsatellites than in the past, which would then prompt some melanomas to be staged upward compared to in the prior editions." Dr. Ming explained that while Stage III wasn't expanded in AJCC 8, "they moved people around within Stage III. The possible staging options for patients with microscopic satellites or in-transit metastases are much wider than they had previously been. Research has shown that the thickness of the original lesion and the number of involved nodes influence survival for these patients, so that information is included in more detail now."
Cutaneous squamous cell carcinoma
Although cSCC is the second most common cancer among the white population in the U.S., the majority of patients are at very low risk of recurrence once the primary tumor has been removed. But in large part because it is so common, staging cSCC in a way that helps dermatologists target the small proportion of cases at high risk of a poor outcome has posed a serious challenge, said Chrysalyne D. Schmults, MD, FAAD, associate professor and vice chair of surgical oncology, department of dermatology, at Harvard Medical School. "The problem with squamous cell staging is that we don't have large-scale data to validate it. SEER seeks to record every melanoma case, for example, that's seen at the SEER contributing centers, and that's not feasible with a disease like squamous cell because there are just too many. It was considered too much manpower for a disease that was thought to not kill very many people."
Dr. Schmults said she developed a special interest in staging cSCC while at the University of Pennsylvania, "where I was seeing patients with large tumors, who I was really worried about having risk of metastasis and death. But without good staging, you can't really start to develop guidelines on, say, which people need radiologic nodal staging, which people need adjuvant therapy in addition to surgery. That's overkill for most patients with squamous cell cancer, but you're not sure how to define that group of patients who do have a risk of things going badly." Dr. Schmults developed a cohort of cSCC patients for study at Penn, then moved to Brigham and Women's Hospital (BWH) and started a similar cohort there. Using data from both cohorts, her group sought to validate AJCC staging. "What we found was that it was performing quite poorly in the 7th edition because they had taken a lot of staging parameters from head and neck mucosal squamous cell cancers, but those are quite different," she explained. "The biggest problem with AJCC 7 was that to get into the upper stages, T3 and T4 tumors, you had to have bone invasion, and most of our bad squamous cell cancers don't have that. What our data showed was that almost all the poor outcomes were happening in T2 tumors. So, you had this big, heterogenous T2 group that included a lot of people who were very likely to do well, and almost all the people who did do poorly."
"The problem with squamous cell staging is that we don't have large-scale data to validate it."
A subset of the BWH cohort — those with cSCC of the head and neck — were analyzed for a comparison of AJCC 7 and AJCC 8 (JAMA Dermatol. 2018;154(2):175-181). Shortcomings of the AJCC 7 classification, the authors state, were that it "lacked distinctiveness (outcomes differ between categories), homogeneity (outcomes are similar within categories), and monotonicity (outcomes worsen with increasing categories), which are three categories set forth by the AJCC to describe an ideal staging system." Significant changes in AJCC 8 cited in the article include:
"In AJCC 8, the big changes were that the depth of invasion considered to be significant was changed to be deeper, and the perineural invasion was classified as large caliber," said Emily S. Ruiz, MD, FAAD, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women's Cancer Center and assistant professor of dermatology at Harvard Medical School. "Also, it now uses a 2- and 4-cm cutoff to distinguish between T2 and T3. The 7th edition is quite outdated now." At first, the AJCC committee tasked with developing the 8th edition planned to omit an update of cSCC staging, Dr. Ruiz said, "but the head and neck surgeons said they needed a staging system, so they took it into their section. That's why the staging system is written for head and neck tumors, but it will be extrapolated to the trunk."
AJCC 8, while an improvement over the previous version, still has shortcomings, Dr. Schmults maintained. "They expanded T3 a lot, which helped because it moved a lot of the poor outcomes out of T2 and up into T3. But now the problem is that the T2 and T3 groups have about equal risks. And if you group all the tumors that are AJCC T2 and T3 together, it's about 25% of all squamous cell cancers that are being called high-risk — and that's too big a group. You're inappropriately upstaging too many people who are really low risk."
While AJCC 7 was still in effect, Dr. Schmults had spearheaded the development of a new staging system that would "basically break this large T2 group into a high-risk and a low-risk group." Using modeling to isolate risk factors that were the most useful in predicting metastasis and death, Dr. Schmults targeted four with which to build the BWH tumor classification system: a pre-operative tumor diameter of 2 cm or more; depth of invasion beyond the subcutaneous fat; poor differentiation; and perineural invasion of a nerve that is 0.1 mm or larger in caliber. "If you have none of those risk factors, in Brigham staging you're T1," Dr. Schmults explained. "If you have just one of them, you're T2a, if you have two or three of them then you're T2b, and if you have all four of them, or if you have bone invasion, then you're T3." Using the BWH staging system, "we're able to capture the same number of poor outcomes, but in a smaller fraction of patients, about half the percentage of AJCC 8. It's about 10% or so of cSCC patients that are T2b or T3 in Brigham staging, and that's where all the poor outcomes are pretty much happening." A study comparing the performance of the AJCC 8 and BWH staging systems in head and neck cSCC only (JAMA Dermatol. 2019;155(7):819-825) concluded that "use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis and death."
Assessing implications for treatment resulting from the new staging system, Dr. Schmults remarked that, "Dr. Emily Ruiz has put out a couple of papers showing that if you do radiologic imaging to stage the lymph nodes initially, and do surveillance for tumor recurrence for T2b and T3 people, that seems to be associated with better outcomes. So that's one practical thing that we're advocating for." In terms of adjuvant treatment, however, "that remains an open question. Staging hasn't helped us with that because the risk of you having a poor outcome, if you are one of these upper stage people, varies depending on which study you look at." Citing a risk ranging from 10-20% in various studies, Dr. Schmults noted that "a 10% risk isn't high enough for a lot of patients, especially elderly, frail patients, to want to go through, say, a course of adjuvant radiation after surgery."
Why staging matters
For patients with melanoma, staging is a critical first step in planning how to manage the disease, said Dr. Ming. "It helps us stratify people according to their survival risk profile, so people in the same stage, in general, have similar survival. In turn, that helps us understand who should get certain kinds of management. It's probably not cost effective or sensible from a risk-benefit perspective to look for a positive sentinel node in someone who has an extremely low likelihood of having a positive node, but for other people, it's probably worthwhile to do. It also helps in terms of clinical trials, because a lot of times those are done in different centers under different scenarios, but if everyone in the trials is in the same stage, then it's easier to compare the trials to each other." Dr. Chu agreed, noting that "the staging system gives us a common language in terms of thinking about these tumors, and they use parameters that most providers and institutions are going to be able to understand." Both Dr. Chu and Dr. Ming said they believe many dermatologists are taking the step of staging their patients' melanoma. "I think people are probably either sending the patient to someone like myself or Emily [Dr. Chu], who has particular expertise in melanoma, or they would do it themselves," said Dr. Ming. "Because melanoma is potentially life-threatening, and you need to consider who might have more of a problem."
"The crucial advantage to staging is identifying tumors that are high stage and then offering them closer surveillance and, in some tumors, adjuvant therapy."
For dermatologists treating cSCC, "the crucial advantage to staging is identifying tumors that are high stage and then offering them closer surveillance and, in some tumors, adjuvant therapy," said Dr. Ruiz. "One big change in the new NCCN is that they're recommending Mohs surgery for high stage squamous cells, so that's one reason it's important to recognize the high stage tumors." As to whether dermatologists are routinely staging cSCC, Dr. Ruiz said, "I think it's variable. I think there are some who do and a lot who don't. There are a lot of squamous cell carcinomas, and some people just don't see as many aggressive ones and so they're not in the routine of staging them. And then there are few clear guidelines on what to do with high-stage tumors." More dermatologists are staging cSCC "when they know a tumor is bad," said Dr. Schmults. "We've talked a lot at meetings about what constitutes high-risk or high-stage squamous cell. So, I think people have a good handle on what the risk factors are, and when they get a tumor with one or more of those risk factors, increasingly people are starting to formally stage them and use that to try to figure out what to do for a patient."
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posted by dermatica at
December 14, 2021
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