at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
, a dermatologist, director of the melanoma research program, and senior scientist at the California Pacific Medical Center Research Institute, San Francisco, was first author of a large recently published study that made a strong case for reincorporation of mitotic index into the American Joint Cancer Committee (AJCC) melanoma staging system.
Mitotic index was included in the 7th edition of the AJCC classification system, but was dropped from the8th edition in part because of concern it could potentially lead to overtreatment of patients with very thin melanomas of less than 0.5-mm thickness.
However, mitotic rate, like tumor thickness, is a continuous variable. And like tumor thickness, mitotic rate has a nonlinear relationship with survival. That’s why the AJCC staging system utilizes unequally spaced tumor thickness cut points of 1, 2, and 4 mm to define T1-T4 disease. But until the study led by Dr. Kashani-Sabet, optimal cut points for mitotic rate hadn’t been defined.
He and his coinvestigators at Melanoma Institute Australia collected a dataset comprising 5,050 patients with primary cutaneous melanoma in Australia and Northern California, all of whom either died of metastatic melanoma or remained distant metastasis–free for at least 8 years of follow-up. Median follow-up of the cohort was 9.5 years.
The investigators developed computer-generated cut points for mitotic rate and its impact on survival for each melanoma T category, then assessed their value in randomly split training and validation sets from their large cohort. For T1 melanoma, the optimal cut point proved to be 2 mitoses/mm2; more than two was independently associated with increased mortality risk. For T2 disease, the optimal cut point was 4, for T3 it was 6, and for T4 it was 7 mitoses/mm2.
A keyfinding: In a multivariate regression analysis, tumor thickness was associated with survival, with an odds ratio of 1.58, ulceration had an odds ratio of 1.55, and mitotic rate by cut point had an odds ratio of 5.38. Each of these three characteristics was independently associated with survival (P < .00005). Dr. Kashani-Sabet said that, despite the more than threefold greater odds ratio for mitotic rate, compared with ulceration, in a Kaplan-Meier analysis, the survival impact of ulceration being present was “virtually identical” to an elevated mitotic rate in each T category.
He and his coinvestigators proposed a revised T-category system which incorporates this new insight. There is no change in tumor thickness to define T1-T4 melanoma: T1 is less than 1.0 mm, T2 is greater than 1-2.0 mm, T3 is greater than 2.01-4.0 mm, and T4 is greater than 4.0 mm. But now, within each T category the proposal is that the “a” designation indicates neither ulceration nor an elevated mitotic rate is present, while “b” means ulceration and/or an elevated mitotic rate using the optimal cut point for that T category is present. In their Australian/Northern California dataset, these new T categories showed a distinct separation in cumulative survival.
Dr. Kashani-Sabet and coworkers have submitted a proposal to validate their results using the AJCC database. Based upon a first look at the numbers, “We think it’s really very likely that these observations can be reproduced in this most important of datasets,” he predicted.
During a panel discussion,, offered a recent example from her own practice where an elevated mitotic index as defined by Dr. Kashani-Sabet and coworkers served as a red flag.
“I had a patient with a 0.3-mm melanoma with three mitoses. I did a sentinel lymph node biopsy on the patient, and she was positive,” said Dr. Leachman, professor and chair of the department of dermatology at Oregon Health & Science University, Portland.
Dr. Kashani-Sabet commented that, while an elevated mitotic index is clearly not an absolute requirement for metastasis, when present it’s a prognostically important finding.
Moreover, as adjuvant therapies of proven value in node-positive disease increasingly come under study in node-negative melanoma, it will be critical to identify the high-risk node-negative subgroup for whom such therapies should be targeted.
“While T4 tumors and ulcerated melanomas are clearly high risk, they’re not going to capture every patient who has a very high risk of distant metastases and death. I think mitotic rate is another pathway to identify patients who very well might benefit and should be candidates for inclusion in those adjuvant therapy trials as we’re moving more into node-negative patients,” according to Dr. Kashani-Sabet.
He reported having no financial conflicts of interest regarding his presentation.
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