Dermatology - Disorders of Pigmentation and Melanocytes

Topics covered:

1. Review of basics
2. Freckle (Ephelis)
3. Lentigo
4. Melanocytic Nevus (Mole)
5. Dysplastic Nevi
6. Melanoma


Review of Basics:

Melanocytes

• Melanocytes are a type of dendritic cell
• Melanoblasts, the precursors to melanocytes, are derived from neural crest. Wnt, expressed by the neural tube, directs neural crest cells to migrate and mature into melanoblasts. 
• Wnt --> binds to Frizzled, a transmembrane receptor, activating it --> this causes dissociation of GSK3beta from beta-catenin --> beta-catenin translocates to the nucleus where it binds with Tr factor to initiate MITF (microphthalmia-associated transcription factor) transcription.
• MITF --> important in differentiation of melanoblasts. MITF induces transcription of tyrosinase, tyrosinase-related protein-1 (TRP-1) and DOPA (aka TRP-2). 
• Tyrosinase (TYR gene) is responsible for the first step in melanin production, tyrosine conversion to DOPA. 
• Oculocutaneous albinism (OCA) -- TYR mutations. Patients have fair skin, light coloured eyes, white/ pale coloured hair and are at increased risk of skin cancers like melanoma. Patients also have vision problems. Further reading: GHR reference, NIH library article. 
• Type 1 - as described above
• Type 2 - less severe form
• Type 3 (Rofus oculocutaneous albinism) - affects dark skinned people. Patients have reddish-brown skin, red hair, hazel or brown eyes. Rofus = brown. Further reading here, and here. 
• Type 4 - similar to type 2
• BMPs (bone morphogeneti proteins) act in an opposite way to Wnt, they suppress neural crest differentiation into melanocytes. Melanocytes are formed when BMP levels are low. 
• Endothelins, like Wnt, are essential for neural crest differentiation into melanocytes, particularly in their migration.
• Steel Factor (SF) and c-kit -- SF is a cytokine which binds to c-kit, a tyrosine kinase transmembrane receptor. SF is expressed by epidermal keratinocytes and c-kit is expressed by melanoblasts. This is important in migration of melanoblasts to their final destination, e.g. skin, hair follicle, etc.  
• Piebaldism -- aka partial albinism. This is an autosomal dominant mutation of SF or c-kit causes failure of melanoblast migration to their final destination i.e. skin, hair follicles, etc. Patients have patches of skin and hair that are lighter than normal - most often the front of the trunk, mid region of the extremities, forehead, and middle front of the scalp. These patches are present from birth, this condition is not progressive. Most, ~90%, have a "white forelock", a section of hair near the front that is white. Further reading: detailed Piebaldism review article here, and GHR reference.
• Waardenburg's syndrome [1/40,000]-- Piebladism associated with congenital neurosensory hearing loss (due to lack of melanocytes in cochlea). This condition accounts for 2-5% of all cases of congenital hearing loss. Patients often have a white forelock with pale blue eyes, or different coloured eyes. The main 2 features of Waardenburg's syndrome are Piebaldism and hearing loss. Each type has extra features as described below. Further reading: GHR reference, and review article. 
• Type 1 -- eyes are further apart, hearing loss is less common. Due to PAX3 gene mutation. 
• Type 2 -- hearing loss is more common. Due to mutation of MITF or SNAI2 genes. 
• Type 3 (Klein-Waardenburg syndrome) -- patients also have abnormalities of the arms and hands. Due to PAX3 gene mutation. 
• Type 4 (Waardenburg-Shah syndrome) -- patients also have Hirschprung disease. Due to mutation of SOX10, EDN3 or EDNRB gene. 
• Cadherins -- cadherin expression by melanocytes matches expression by surrounding cells like keratinocytes, and the theory is that this allows for proper ratios of cell types.  
• Melanocytes are found in the epidermis, hair follicles, eyes, cochlea and meninges
• Skin and hair -- Melanocytes here transfer melanin to keratinocytes. Hair and skin colour is determined by the amount of melanin transferred and the ratio of eumelanin (black-brown) to pheomelanin (red-yellow). 
• Ocular -- Melanocytes are found in the uveal tract (iris, choroid, stroma of the ciliary body), where they are thought to protect against oxidative damage.
• Cochlea -- Melanocytes here are thought to help maintain the endolymph by regulating K+ transport. Loss of these melanocytes can lead to sensorineural hearing loss. Further reading: article explaining melanocytes in the cochlea here. 
• Melanocytes make melanin, the primary pigment responsible for skin colour, and store it in melanosomes. Melanin is a derivative of 3,4 di-hydroxy-phenyalanine (DOPA).
• eumelanosomes - large, and contain eumelanin
• pheomelanosomes - small, and contain pheomelanin
• Melanosomal protein sorting -- tyrosinase and tyrosinase-related protein-1 
• Melanosomes are transported to melanocyte dendrite tips and transferred to epidermal keratinocytes in a process called apocopation
• Melanosomes absorb UV radiation, thereby protecting the skin

Melanocytes are a type of dendritic cell located in the basal cell layer of the epidermis. Melanosomes, are the organelles inside melanocytes, which contain melanin, the pigment that is responsible for skin colour. The melanosomes are concentrated in the tips of the melanocyte dendritic processes, and these tips are phagocytized by keratinocytes, thereby transferring the melanosomes to the keratinocytes. This process is called apocopation.


Freckle (Ephelis) - small, light brown or tan macules that occur when exposed to sunlight due to increased melanin (pigment) production inside basal keratinocytes.

Lentigo (solar) - benign hyperplasia of melanocytes, found in the skin and mucus membranes, due to sun exposure.

Lentigo maligna - potentially malignant melanocytic neoplasm associated with sun exposure.  The lesion is usually flat and hyperpigmented but with irregular borders and colour variation.

• Management -- Mohs micrographic surgical excision method, which involves immunhistochemical staining of removed tissue and coordination with pathologist. Tissue is removed in layers until there is no cancer on microscopy. 

Pigmented nevus (mole) - aka melanocytic nevus. Benign neoplasm due to activation mutation of the Ras signalling pathway. Various types. Further reading: atypical moles (AAFP).

• Acquired nevi - the most common type of melanocytic nevi, and found on almost everyone. These are tan/ brown small flat macules with well defined borders. As nevi mature they undergo the following stages:
• Junctional nevi - nevi cells grow along the dermo-epidermal junction. These lesions are flat on gross examination.
• Compound nevi - when junctional nevi cells grow deeper into the underlying dermis. These lesions are raised on gross examination.
• Intraderma nevi - when the older epidermal nevi cells are lost and the remaining cells are within dermis. These lesions are raised on gross examination.
• Congential nevus - present at birth, and larger congenital nevi have increased risk of transforming to melanoma
• Blue nevus - black-blue nodule that may be confused with melanoma. Microscopy reveals highly dendritic, heavily pigmented nevus cells. 
• Spitz nevus (spindle and epitheloid) - red-pink nodules commonly seen in children and may be confused with hemangioma. Microscopy shows large plump cells with pink-blue cytoplasm. 
• Halo nevus - there is a whiteish rim around the nevus. In this condition, there is an immune response against the nevus cells and surrounding normal melanocytes. Lymphocytic infiltration is seen on microscope. 
• Dysplastic nevus - potential precursor to melanoma. Larger than most acquired nevi, flat or slightly raised, "pebbly" surface and have variable colour, and irregular borders. They can be found in sun exposed and non-exposed areas. 
• Dysplastic nevus syndrome - patients have many, even hundreds, of dysplastic nevi. 

Melanoma - malignant lesion with irregular margins, colour variation, etc. American Family Physician (melanoma 2012 article).

• Management - surgical removal
• Breslow depth scale to determine surgical margins - measured by pathologist with a micrometer (small ruler). 
• Depth (in situ) - 5 mm margins
• Depth is 2.0 mm or less - 1 cm margins
• Depth is > 2.0 mm - 2 cm margins