Disorders of pigmentation: melanoma

Published on May 4, 2014   50 min
0:00
This is Dr. David Fisher from the Department of Dermatology at Massachusetts General Hospital. I'm pleased to present today's lecture, entitled Disorders of Pigmentation and Melanoma.
0:13
Probably the first comprehensively presented series of melanoma patients appeared way back in 1857, as depicted in this particular report by Dr. William Norris, who was describing a set of patients with a condition associated with a hyper pigmented, atypical, melanocytic disorder that probably represented one of the initial descriptions of human melanoma.
0:40
This slide presents a depiction in graphical form of the anatomy and architecture of human skin. You will notice the word epidermis describes the most superficial layers of the skin. We will see in a moment greater detail of the structure of the epidermis. But it is the epidermis which is visible to the outside. It's the epidermis through which other organ structures, such as hairs, protrude. And it is really the epidermis that represents the most crucial functional barrier that protects the inside of our bodies from the outside environment. Deep into the epidermis lies the dermis and the hypodermis. Within these structures reside numerous other organelles that have specialized function, both in maintaining the skin itself, and also in permitting communication and protection to the organism through their specific interactions. The skin is frequently described as the largest organ in the human body, given its cumulative surface area. And it carries out numerous highly differentiated and specialized functions that are vital for human health.
1:53
This slide contains two histologic images of human skin. On the left, we see a hematoxylin and eosin stain, which reveals, starting at the top, the most superficial layer, known as the stratum corneum, which is derived from the progressive differentiation, and eventually did derivative of highly differentiated keratinocytes. Primarily, this is a proteinaceous and lipid containing highly cross linked layer, which functions a highly specialized and extremely important role as a barrier to the most superficial layers the epidermis. Deep to the stratum corneum is the purplish appearing epidermis. Most of the layers of cells within the epidermis consist of keratinocytes, which are progressively differentiating as they go from the most basal layers up to the more superficial layers. Down at the very base of the epidermis, at the junction between the epidermis the dermis, reside melanocytes. In the image to the left, the melanocytes can be seen to have a small halo around their bluish nuclei. This is caused by a staining artifact. But the arrows are pointing to each of these melanocytes. And in the image to the right , one can see a spectralized stain, the antibody against MITF, which identifies the nuclei of melanocytes. Once again, melanocytes can be seen at the base of the epidermis, just near the dermal junction. The melanocytes are seen to be relatively few in number within the epidermis. But it's notable that each melanocyte through dendrites, which are too small to be visualized in these histologic images. These dendrites are thought to make between 25 and 35 contacts with different keratinocytes. So while the melanocytes are significantly fewer in number than keratinocytes, they are highly communicative with keratinocytes. And this is a two way communication. Keratinocytes communicate to melanocytes and are thought to modulate melanocytic activities, including pigmentation. And in reverse, melanocytes then communicate back to keratinocytes. For example, in the very process of transferring melanin containing vesicles back out to the keratinocytes. So in fact, in pigmented human skin, the vast majority of pigment typically resides within keratinocytes, although it was originally synthesized within melanocytes.
4:24
The developmental biology of melanocytes is a fascinating and, in fact, even clinically important area of biology. The melanocyte lineage is derived from neural crest related development. The cells, which will give rise eventually to the pigments population, the melanocytic and cutaneous pigment population, originates in the neural crest, and then migrates out from the neural crest, where that progenitor population will give rise to a number of different lineages. Cellular lineages, which include neurons, as well as glial cells, or Schwann cells, are all related by a common precursor cell population. The migration out of the neural crest occurs in a process that first involves the migration to a region near the neural crest, known as the staging area. And then, from this staging area, a progressive migratory route, known as the dorsolateral migration route, will occur, through which the neural crest precursor cells are progressively differentiating and limiting their differentiative capacity among the pluripotent capacities of the cell, neuronal glial or melanocyte, eventually differentiating and specifying in a specific fashion the formation of melanocytes as they migrate by the dorsolateral pathway, eventually to the skin. An alternative differentiation pathway has more recently been identified, in which it was shown that Schwann cell precursors have the capacity, under conditions of both normal development as well as pathologic responses, to undergo a differentiation response from Schwann cell precursors into epidermal or dermal melanocytes. These have also been identified in hair follicle, among the hair follicle melanocyte populations. So in fact, there are several pathways which appear to function. And the precise means by which these alternative developmental pathways and migratory pathways occur in comprising the eventual population of mature melanocytes in skin or hair follicles remains, in many cases, the details of this process remain to be fully understood. If one looks at the developmental biology from head to tail, one notes that the migration appears to occur primarily in a rostral to caudal set of temporal waves. That is to say that the upper part of the body appears to migrate from the neural crest in these precursor dorsolateral migratory routes, somewhat earlier in development than the more caudal portions of the anatomy.
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Disorders of pigmentation: melanoma

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