Improving Melanoma Classification by Integrating Genetic and Morphologic Features

Abstract

Background

In 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 Findings

We 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).

Conclusions

Refined 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.

Abstract

Boris Bastian and colleagues present a refined morphological classification of primary melanomas that can be used to improve existing melanoma classifications by defining genetically homogeneous subgroups.

Editors' Summary

Background.

Skin cancers—the most commonly diagnosed cancers worldwide—are usually caused by exposure to ultraviolet (UV) radiation in sunlight. UV radiation damages the DNA in skin cells and can introduce permanent genetic changes (mutations) into the skin cells that allow them to divide uncontrollably to form a tumor, a disorganized mass of cells. Because there are many different cell types in the skin, there are many types of skin cancer. The most dangerous type—melanoma—develops when genetic changes occur in melanocytes, the cells that produce the skin pigment melanin. Although only 4% of skin cancers are melanomas, 80% of skin cancer deaths are caused by melanomas. The first signs of a melanoma are often a change in the appearance or size of a mole (a pigmented skin blemish that is also called a nevus) or a newly arising pigmented lesion that looks different from the other moles (an “ugly duckling”). If this early sign is noticed and the melanoma is diagnosed before it has spread from the skin into other parts of the body, surgery can sometimes provide a cure. But, for more advanced melanomas, the outlook is generally poor. Although radiation therapy, chemotherapy, or immunotherapy (drugs that stimulate the immune system to kill the cancer cells) can prolong the life expectancy of some patients, these treatments often fail to remove all of the cancer cells.

Why Was This Study Done?

Now, however, scientists have identified some of the genetic alterations that cause melanoma. For example, they know that many melanomas carry mutations in either the BRAF gene or the NRAS gene, and that the proteins made from these mutated genes (“oncogenes”) help cancer cells to grow uncontrollably. The hope is that targeted drugs designed to block the activity of oncogenic BRAF or NRAS might stop the growth of those melanomas that make these altered proteins. But how can the patients with these specific tumors be identified in the clinic? The expression of altered proteins is likely to affect the microscopic growth patterns (“histomorphology”) of melanomas. However, the current histomorphology-based classification system for melanomas, which distinguishes four main types of melanoma, does not help clinicians choose the best treatment for their patients. In this study, the researchers have tried to improve melanoma classification by looking for correlations between histomorphological features and genetic alterations in a large collection of melanomas.

What Did the Researchers Do and Find?

The researchers examined several histomorphological features in more than 300 melanoma samples and used statistical methods to correlate these features with the mutation status of BRAF and NRAS in the tumors. They found that some individual histomorphological features were strongly associated with the BRAF (but not the NRAS) mutation status of the tumors. For example, melanomas with BRAF mutations had more melanocytes in the upper layers of the epidermis (the outermost layer of the skin) than did those without BRAF mutations (melanocytes usually live at the bottom of the epidermis). Then, by combining several individual histomorphological features, the researchers built a model that correctly predicted the BRAF mutation status of more than 90% of the melanomas. They also found that, among the variables routinely recorded in cancer registries, being younger than 55 years old was the single most predictive factor for BRAF mutations. Finally, in another large group of patients with melanoma, the researchers found that those patients predicted to have a BRAF mutation on the basis of their age survived longer than those patients predicted not to have a BRAF mutation using the same criterion.

What Do These Findings Mean?

These findings suggest that an improved classification of melanomas that combines an analysis of known genetic factors with histomorphological features might divide melanomas into subgroups that are likely to differ in terms of their clinical outcome and responses to targeted therapies when they become available. Additional studies are needed to investigate whether the histomorphological features identified here can be readily assessed in clinical settings and whether different observers will agree on the scoring of these features. The classification model defined by the researchers also needs to be validated and refined in independent groups of patients. Nevertheless, these findings represent an important first step toward helping clinicians improve outcomes for patients with melanoma.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050120.

• A related PLoS Medicine Research in Translation article is available

• The MedlinePlus encyclopedia provides information for patients about melanoma

• The US National Cancer Institute provides information for patients and health professionals about melanoma (in English and Spanish)

• Cancer Research UK also provides detailed information about the causes, diagnosis, and treatment of melanoma