Date Published: June 3, 2008
Publisher: Public Library of Science
Author(s): Amaya Viros, Jane Fridlyand, Juergen Bauer, Konstantin Lasithiotakis, Claus Garbe, Daniel Pinkel, Boris C Bastian, Jonathan Rees
Abstract: BackgroundIn melanoma, morphology-based classification systems have not been able to provide relevant information for selecting treatments for patients whose tumors have metastasized. The recent identification of causative genetic alterations has revealed mutations in signaling pathways that offer targets for therapy. Identifying morphologic surrogates that can identify patients whose tumors express such alterations (or functionally equivalent alterations) would be clinically useful for therapy stratification and for retrospective analysis of clinical trial data.Methodology/Principal FindingsWe defined and assessed a panel of histomorphologic measures and correlated them with the mutation status of the oncogenes BRAF and NRAS in a cohort of 302 archival tissues of primary cutaneous melanomas from an academic comprehensive cancer center. Melanomas with BRAF mutations showed distinct morphological features such as increased upward migration and nest formation of intraepidermal melanocytes, thickening of the involved epidermis, and sharper demarcation to the surrounding skin; and they had larger, rounder, and more pigmented tumor cells (all p-values below 0.0001). By contrast, melanomas with NRAS mutations could not be distinguished based on these morphological features. Using simple combinations of features, BRAF mutation status could be predicted with up to 90.8% accuracy in the entire cohort as well as within the categories of the current World Health Organization (WHO) classification. Among the variables routinely recorded in cancer registries, we identified age < 55 y as the single most predictive factor of BRAF mutation in our cohort. Using age < 55 y as a surrogate for BRAF mutation in an independent cohort of 4,785 patients of the Southern German Tumor Registry, we found a significant survival benefit (p < 0.0001) for patients who, based on their age, were predicted to have BRAF mutant melanomas in 69% of the cases. This group also showed a different pattern of metastasis, more frequently involving regional lymph nodes, compared to the patients predicted to have no BRAF mutation and who more frequently displayed satellite, in-transit metastasis, and visceral metastasis (p < 0.0001).ConclusionsRefined morphological classification of primary melanomas can be used to improve existing melanoma classifications by forming subgroups that are genetically more homogeneous and likely to differ in important clinical variables such as outcome and pattern of metastasis. We expect this information to improve classification and facilitate stratification for therapy as well as retrospective analysis of existing trial data.
Partial Text: Cutaneous melanomas can vary significantly in their clinical and histopathological appearance, which has lead to the development and refinement of morphologically based classification systems. The current World Health Organization (WHO) classification of skin tumors , which is an extension of the revised Sydney classification from 1986 [2–4], distinguishes four main types of melanoma; superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), nodular melanoma (NM), and acral lentiginous melanoma (ALM). These distinctions are based on the observation that certain combinations of morphological features of the microscopic growth pattern of melanoma during its early progression phase are associated with clinical features such as anatomic site of the primary tumor, pace of tumor evolution, and patient age. Although these proposed categories undoubtedly represent prototypical instances or archetypes of the clinical and histopathological presentations that are valuable for teaching purposes, their impact on clinical management has been limited. A major reason is that no significant difference in overall survival or treatment responses could be demonstrated between the categories when tumors of equivalent tumor thickness were compared or after metastasis had occurred . Furthermore, these subtypes are defined by multiple criteria, each assessing complex morphological patterns, resulting in a wide range of possible presentations. Thus a considerable portion of melanomas are differentially classified by multiple observers, or are classified as “ambiguous” . Some have questioned the existence of biologically distinct melanoma types altogether, proposing that the morphological differences are entirely secondary to the anatomic site in which the tumor arises , or, in the case of NM, are a consequence of differences in the pace of tumor evolution .
In this study we demonstrate that histopathological features of the primary tumor, many of which have been part of the WHO classification, provide substantial information on the mutation status of an important melanoma gene, BRAF. We found that phenotypic features such as increased upward scatter and nest formation of intraepidermal melanocytes; thickening of the involved epidermis; sharp demarcation from the surrounding skin; as well as the presence of a larger, rounder, and more pigmented tumor cells were distinguishing features of melanomas with BRAF mutation. This finding suggests that further research will reveal additional phenotypic associations with other genetic factors, including both germ line constitution of the patient and the somatic alterations in the tumor. In general it is not to be expected that single morphological parameters will be associated with individual genetic factors since it is likely that there will be interactions, or partial or functional redundancy, among them.