James Grichnik, MD, PhD, explains a new hypothesis that melanoma springs from mutant stem cells. The model could help demystify the often strange behaviors of melanoma and offer more clues toward detection and treatment.

Our studies of metastatic melanoma cell lines support the hypothesis that melanoma develops from mutated stem cells.

The idea is that there are stem cells sitting in the skin, and they accumulate mutations. When these stem cells are called upon to produce melanocytes (cells that produce pigment), if they have a benign complement of mutations, they’re going to produce a benign mole.

If they have a malignant complement of mutations, they’re going to form a melanoma. This explains why three-fourths of melanomas develop directly from normal skin.

The mutated stem cell may also start growing with a benign complement of mutations but suffer an additional malignant mutation during that growth that results in the secondary development of a melanoma within a mole.

This may explain the one-fourth of melanomas that develop in moles. What is also interesting is that through the use of dermoscopy (surface microscopy) we can identify specific growth patterns of different moles and melanoma types.

We anticipate that someday we will be able to look at a lesion and, based on its growth pattern, be able to immediately predict what underlying pathways have been mutated and whether it is benign or malignant.

The stem cell model is consistent with the clinical phenomena that we’re seeing. It could more easily explain behaviors like delayed onset and tumor dormancy. Cells could exist unstimulated for long periods in the body, and then when environmental conditions are appropriate, those mutated stem cells could again give rise to differentiating daughter cells and the tumor would become apparent.

It might also explain death from melanoma despite a strong immunologic response. The immune system might easily destroy the malignant daughter cells but overlook the stem cells themselves.

We still have yet to conclusively prove the existence of these cells, but there are lots of papers being published now identifying different types of dermal stem cells, so I think it’s just a matter of time.

If the stem cell hypothesis turns out to be true, it will have major ramifications for the diagnosis, prognosis, and treatment of melanoma.