Science and Research
Caroline A. Nelson, MD
Structure and Function
Basic Concepts
The skin consists of three layers: the epidermis, the dermis, and the subcutis.
Key functions include maintenance of the skin barrier, pre-vention of infection, wound healing, nutrition, thermoregulation, and physical and interpersonal communication.
Skin (Figure 1.1)
Epidermis
Keratinocytes
The cytoskeletal network of keratinocytes is made up of actin microfilaments and keratin (K) intermediate filaments.
Keratin intermediate filaments are coexpressed as heterodimers:
Type I: low molecular weight, acidic, K9-28, K31-40, gene locus on chromosome 17.
Type II: high molecular weight, basic, K1-8, K71-86, gene locus on chromosome 12.
Keratinocyte stem cells are located at the base of rete ridges in the interfollicular epithelium and the bulge region of hair follicles.
Figure 1.1. SKIN. a-epidermis, b-papillary dermis, c-reticular dermis, d-subcutis. Epidermal layers: e-stratum corneum, f-stratum granulosum, g-stratum spinosum, h-stratum basale.
(Illustration by Caroline A. Nelson, MD; Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
Terminal keratinocyte differentiation (Figure 1.2) is mediated by p63 and NOTCH signaling along with an increase in extracellular calcium. Phospholipids decrease and sphingolipids increase. The lipid composition in the stratum corneum is ˜45% to 50% ceramide, 25% cholesterol, 10% to 15% free fatty acids (FFAs), 5% cholesterol sulfate, and other lipids. Ceramide is the major lipid component of the cornified lipid envelope, while loricrin is the major protein component of the cornified cell envelope.
Phospholipids are on the phloor.
The total transit time of a keratinocyte through normal epidermis is ˜28 days (14 days from stratum basale to stratum corneum and 14 days from stratum corneum to desquamation).
Keratinocyte transit time decreases in hyperproliferative disease states such as psoriasis.
Melanocytes
Melanocytes are derived from the neural crest. KIT and KIT ligand signaling is an important mediator of melanocyte migration.
Sporadic mutation of the gene encoding KIT disrupts melanocyte migration leading to piebaldism. Autosomal dominant (AD) gain-of-function mutation
in the gene encoding KIT ligand increases melanocyte migration, leading to familial progressive hyperpigmentation.
Table 1.1. DISORDERS OF KERATIN
Type II
Type I
Location of Expression
Associated Disordersa
1
10
Suprabasal layers
EI, ichthyosis with confetti, ichthyosis hystrix Curth-Macklin (K1)
1
9
Palmoplantar suprabasal layers
Vörner-Unna-Thost epidermolytic PPK, nonepidermolytic PPK (K1), striate PPK (K1)
2b
10
Upper spinous and granular layers
Superficial EI (K2)
3
12
Cornea
Meesmann corneal dystrophy
4
13
Mucosa
White sponge nevus
5
14
Basal layer
DDD (K5), EBS, EBS with mottled pigmentation (K5 > K14), NFJ syndrome/DPR (K14)
6a, 6b, 6c
16, 17
Hair follicle isthmus, nail bed
Hyperproliferative disease states such as psoriasis (increased K6 and K16), PC,c steatocystoma (K17), vellus hair cyst (K17)
81, 83, 86d
Hair cortex
Monilethrix
DDD, Dowling-Degos disease; DPR, dermatopathia pigmentosa reticularis; EBS, epidermolysis bullosa simplex; EI, epidermolytic ichthyosis; K, keratin; NFJ, Naegeli-Franceschetti-Jadassohn; PC, pachyonychia congenita; PPK, palmoplantar keratoderma.
a Illustrative examples provided for clinical correlation.
b Previous name K2e.
c Historical classification divided PC into type I (Jadassohn-Lewandowsky) due to mutations in K6a and K16 and type II (Jackson-Lawler) due to mutations in K6b and K17.
d Previous names Hb1, Hb3, Hb6; monilethrix is also due to mutations in desmoglein-4.
Figure 1.2. THE LIFE CYCLE OF KERATINOCYTES. Filaggrin, filament aggregating protein; K, keratin; KHGs, keratohyalin granules; NMF, natural moisturizing factor; TGs, transglutaminases; UVR, ultraviolet radiation.
Melanocytes are primarily located in the stratum basale in a ratio of 1 melanocyte to 10 keratinocytes. Other sites include the mucous membranes, hair, uveal tract of the eye (choroid, ciliary body, iris, retina), inner ear (striae vascularis of the cochlea), and leptomeninges.
Congenital melanocytic nevi may be associated with increased melanocytes at other sites, such as neurocutaneous melanosis.
Under the influence of melanocyte-stimulating hormone (MSH), a product of the proopiomelanocortin (POMC) polypeptide, melanocytes synthesize melanin pigment. POMC is also the precursor of adrenocorticotropic hormone (ACTH).
Stimulation of POMC is the mechanism of hyperpigmentation in Addison disease.
Melanocytes synthesize melanin in melanosomes (specialized lysosomes). Tyrosinase, a product of the TYR gene, is the copper-dependent rate-limiting enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone.
Oculocutaneous albinism (OCA) may result from defective vesicle assembly, trafficking, or transport (eg, Chédiak-Higashi syndrome) or defective melanin synthesis (eg, TYR mutation in OCA, type I). Tyrosinase is also impaired in copper-deficient states such as Menkes kinky hair disease.
Synthesis of pheomelanin versus eumelanin is primarily determined by the melanocortin-1 receptor (MC1R):
Pheomelanin: red-yellow, synthesized in spherical melanosomes with microvesicular structure.
Eumelanin: brown-black, synthesized in elliptical melanosomes with lamellar structure.
Dysfunction of the MC1R can lead to red hair, inability to tan following ultraviolet radiation (UVR) exposure, and increased risk of melanoma and nonmelanoma skin cancer.
Table 1.2. DISORDERS OF CORNIFICATION
Target
Associated Disordersa
Lamellar granules
ARCI (decreased or absent), EI (increased but abnormal), Flegel disease (decreased or absent), steroid sulfatase deficiency
Filaggrin
AD, ichthyosis vulgaris, KP
Involucrin
Psoriasis (increased)
Loricrin
Loricrin keratoderma, psoriasis (decreased)
TG-1b
LI
AD, atopic dermatitis; ARCI, autosomal recessive congenital ichthyosis; DH, dermatitis herpetiformis; EI, epidermolytic ichthyosis; filaggrin, filament aggregating protein; KP, keratosis pilaris; LI, lamellar ichthyosis; TG, transglutaminase.
a Illustrative examples provided for clinical correlation.
b The auto-antigen in DH is TG-3.
One melanocyte transfers melanin to ˜30 to 40 keratinocytes via phagocytosis of melanocyte tips. This constitutes an epidermal melanin unit. Melanin absorbs UVR, thereby protecting against UVR-induced mutations. Melanocyte density is consistent across all skin phototypes (Table 1.3); however, melanosomes in darker skin are larger, darker, more stable, more numerous, and transferred as individual organelles as opposed to membrane-bound clusters, ultimately exhibiting a higher degree of dispersion within keratinocytes.
Merkel Cells
Merkel cells are primarily located in the stratum basale in areas with high tactile sensitivity such as the hair follicle outer root sheath (ORS), lips, oral cavity, fingertips, and anogenital region.
Merkel cells function as mechanoreceptors and contain neuropeptides such as calcitonin gene-related peptide, chromogranin A, met-enkephalin, neuron-specific enolase, synaptophysin, and vasoactive intestinal peptide.
Junctions
Intercellular Junctions (Figure 1.3)
Keratinocytes are bound together by a variety of cell-cell junctions:
Tight junctions (zonula occludens): seal the intercellular space with claudins and occludins to prevent the free diffusion of macromolecules (eg, water loss in the granular layer).
Adherens junctions (zonula adherens): bind cells together with actin cytoskeleton linked to α-catenin linked to armadillo family proteins (β-catenin or plakoglobin) linked to transmembrane proteins (classic cadherins E and P).
Desmosomes: bind cells together with keratin cytoskeleton linked to plakin family protein (desmoplakin) linked to armadillo family proteins (plakoglobin or plakophilin) linked to calcium-dependent transmembrane proteins (cadherins desmocollin 1/2/3 and desmoglein 1/3). Plakoglobin, also known as γ-catenin, is the only common protein between adherens junctions and desmosomes. Desmoglein 1 is 160 kDa and desmoglein 3 is 130 kDa.
Table 1.3. FITZPATRICK SCALE OF SKIN PHOTOTYPES
Skin Phototype
Response to UVR
I
Always burns, does not tan
II
Burns easily, tans with difficulty
III
Mild burns, tans gradually
IV
Rarely burns, tans easily
V
Very rarely burns, tans very easily
VI
Never burns, tans very easily
UVR, ultraviolet radiation.
Figure 1.3. KERATINOCYTE INTERCELLULAR JUNCTIONS. a-claudins and occludins, b-actin monofilaments, c-α-catenin d-β-catenin and plakoglobin, e-classic cadherins E and P, f-keratin intermediate filaments, g-desmoplakin, h-plakoglobin and plakophilin, i-cadherins desmocollin 1/2/3 and desmoglein 1/3, j-6 connexins forming a connexon. Ultrastructure of a desmosome.
(Electron microscopy image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
The name of a protein may provide a clue to its family. Armadillos are covered in plates (plakoglobin, plakophilin, plus β-catenin); plakins often end with plakin (desmoplakin, envoplakin, periplakin, plus bullous pemphigoid antigen 1 [BPAG1] and plectin). Cadherins are calcium-dependent.
Gap junctions: facilitate intercellular communication through connexons (six connexins).
Basement Membrane Zone (Figure 1.4)
The basement membrane zone (BMZ) consists of dermo-epidermal junction (DEJ) and dermal blood vessels.
The DEJ can be divided into four layers with the following key components:
Basal keratinocyte hemidesmosomes: keratin cytoskeleton linked to plakin family proteins (BPAG1 and plectin) linked to transmembrane proteins (bullous pemphigoid antigen 2 [BPAG2] and α6β4 integrin).
Lamina lucida: transmembrane proteins linked to anchoring filaments (eg, laminin 332).
Lamina densa: anchoring filaments linked to collagen IV linked to anchoring fibrils (collagen VII) along with heparin sulfate (provides a selective permeability barrier).
Sublamina densa: anchoring fibrils linked by anchoring plaques to collagen I and III along with elastic fibers.
Based on molecular weight (kDa), BPAG1 is also known as BP230 and BPAG2 is also known as BP180. Another name for BPAG2 is collagen XVII. The amino terminus of BPAG2 is intracellular, the NC16A domain is the first extracellular segment, and the carboxy terminus extends into the lamina lucida.
The risk of scarring associated with subepidermal blistering disorders increases with depth. For example, antibodies may preferentially target the carboxy terminus of BPAG2 in cicatricial pemphigoid (CP).
In addition to their structural role, integrins transduce signals from keratinocytes to the extracellular matric (ECM) to control cell proliferation, differentiation, and migration.
Figure 1.4. THE BASEMENT MEMBRANE ZONE. a-keratin intermediate filaments, b-BPAG1, c-plectin, d-BPAG2, e-integrin subunit α6, f-integrin subunit β4, g-anchoring filaments (laminin 332), h-collagen IV, i-anchoring fibrils (collagen VII), j-anchoring plaques (collagen IV), k-collagens I and III. A, The BMZ stained with PAS separating the epidermis and the dermis. Solid arrow: basement membrane zone. B, Ultrastructure of the BMZ. BMZ basement membrane zone; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2; PAS, periodic acid-Schiff.
(Histology and electron microscopy images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
The lamina lucida is the weakest layer of the BMZ. Laminin 332 was previously known as epiligrin and laminin 5. Like integrins, laminins are also involved in cell signaling.
The lamina lucida is the cleavage plane in salt-split skin immunofluorescence testing for autoimmune blistering disorders.
In focal adhesion complexes, the actin cytoskeleton is linked via intracellular proteins such as kindlins, talin, and vinculin to α3β1 integrin, which binds laminins 311 and 332.
Dermis
The dermis is divided into a superficial papillary layer and a deep reticular layer.
Fibroblasts synthesize a variety of ECM components, primarily regulated by growth factors in the transforming growth factor (TGF) β family:
Collagen (75% of dry weight) is configured in a triple helix with each chain containing Gly-X-Y repeats (glycine, X often proline, Y often hydroxylysine or hydroxy-proline). It provides structural stability to the skin and other tissues.
Elastin (4% of dry weight) contains desmosine and isodesmosine cross-links and is surrounded by a fibrillin scaffold. Oxytalan fibers run perpendicular to the skin surface in the papillary dermis, while elaunin fibers run parallel to the skin surface in the reticular dermis. Elastin provides elasticity to the skin (capacity to resume its normal shape after deformation).
Oxytalan elastic fibers are like a “talon heel” (perpendicular); elaunin elastic fibers lay flat (parallel).
Elastin mutation causes cutis laxa.
Fibrillin mutations cause Marfan syndrome and congenital contractural arachnodactyly.
The extrafibrillar matrix (previously known as ground substance) consists of glycosaminoglycans (GAGs). GAGs can be protein free (eg, chondroitin sulfate, dermatan sulfate, heparin sulfate, and keratan sulfate). Versican, a negatively charged proteoglycan bound to chondroitin/dermatan sulfate, forms aggregates with hyaluronic acid (HA) in the dermis.
Figure 1.5. DISORDERS OF JUNCTIONS. Illustrative Examples Provided For Clinical Correlation. BP, bullous pemphigoid; BPAG1, bullous pemphigoid antigen 1; DEB, dystrophic epidermolysis bullosa; EBA, epidermolysis bullosa acquisita; EBS, epidermolysis bullosa simplex; EKV, erythrokeratoderma variabilis; GJB2, gap junction beta-2; JEB; junctional epidermolysis bullosa; KID, keratitis-ichthyosis-deafness; LABD, linear IgA bullous dermatosis; LE, lupus erythematosus; MMP, mucous membrane pemphigoid; PF, pemphigus foliaceus; PNP, paraneoplastic pemphigus; PPK, palmoplantar keratoderma; PV, pemphigus vulgaris; SSSS, staphylococcal scalded skin syndrome.
Table 1.4. DISORDERS OF COLLAGEN
Collagen
Location
Associated Disordersa
Ib
Bone, dermis, ligament, tendon, wound healing (remodeling phase)
EDS type VII (arthrochalasia), morphea/SSc, OI
II
Cartilage, vitreous humor
Morphea/SSc, relapsing polychondritis
III
Blood vessels, fetal skin, gastrointestinal tract, wound healing (proliferative phase)
EDS type III (vascular), keloid, morphea/SSc
IV
Basement membrane
Alport syndrome, Goodpasture disease
V
Dermis
EDS type I (classic)
VIIb
Amnion, anchoring fibrils
Bullous SLE, DEB, EBA
XVII
Hemidesmosome
BP/pemphigoid gestationis, CP, generalized intermediate JEB, LABD
BP, bullous pemphigoid; CP, cicatricial pemphigoid; DEB, dystrophic epidermolysis bullosa; EBA, epidermolysis bullosa acquisita; EDS, Ehlers-Danlos syndrome; JEB, junctional epidermolysis bullosa; LABD, linear IgA bullous dermatosis; OI, osteogenesis imperfecta; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.
a Illustrative examples provided for clinical correlation.
b Retinoids upregulate synthesis of collagen I and collagen VII.
GAGs on a proteoglycan are arranged like “bristles on a hairbrush.”
The mucopolysaccharidoses, such as Hunter syndrome and Hurler syndrome, are caused by mutations in enzymes that catabolize GAGs.
Prolyl hydroxylases are involved in collagen synthesis. Lysyl oxidase, a copper-dependent enzyme, is important for collagen and elastin cross-linking. Vitamin C is an essential cofactor for these enzymes.
Lysyl hydroxylase is impaired in Ehlers-Danlos syndrome (EDS) type VI (kyphoscoliotic).
Lysyl oxidase is impaired in copper-deficient states such as Menkes kinky hair disease.
Subcutis (Hypodermis)
The subcutis contains lobules of adipose (fat) cells within loose connective tissue.
The subcutis provides padding, insulation, and an energy reserve.
Figure 1.6. VITAMIN C. Scurvy was a feared complication of sailing, resulting in bleeding, impaired wound healing, “a strange dejection of the spirits,” and death. In 1747, the Scottish surgeon James Lind conducted one of the first known controlled trials. He randomized 12 scorbutic sailors to receive a quart of cider daily, 25 drops of elixir of vitriol (sulfuric acid), six spoonfuls of vinegar, half a pint of seawater, two oranges and one lemon, or a spicy paste plus a drink of barley water. Vitamin C in the citrus fruit reversed the blood vessel fragility due to impaired collagen synthesis. Unfortunately, Lind’s discovery was ignored for 42 y, but the admiralty eventually issued lemon juice to every sailor.
(Illustration by Caroline A. Nelson, MD.)
Brown (immature) fat produces heat. It is more prominent in children.
Blood Vessels (Figure 1.7)
Anatomy of blood vessels (arteries, veins, and lymphatics):
Capillaries: supply the papillary dermis and adnexa.
Superficial plexus: located in the upper part of the reticular dermis.
Deep plexus: located in the lower part of the reticular dermis.
Communicating blood vessels: connect the superficial and deep plexuses.
Cutaneous small vessel vasculitis (CSVV) is mediated by immune complex deposition in postcapillary venules, while cutaneous polyarteritis nodosa (PAN) primarily involves medium-sized arteries in the deep plexus.
The walls of arteries have three layers: intima, media, and adventitia. The walls of veins are thinner and less clearly divided. Lymphatics do not have well-developed walls.
Vascular endothelial growth factor (VEGF) is the primary mediator of angiogenesis (formation of new blood vessels).
Mutation of FLT4, which encodes VEGF receptor 3, causes hereditary lymphedema.
VEGF is the target of angiogenesis inhibitors such as bevacizumab.
Blood vessels function to deliver oxygen, nutrients, and leukocytes to the skin and to regulate body temperature and blood pressure.
Endothelial cells contain Weibel-Palade bodies that serve as storage organelles for the blood clotting protein von Willebrand factor.
Vimentin is the intermediate filament preferentially expressed over desmin in vascular smooth muscle, which is under adrenergic control.
Glomus cells are modified smooth muscle cells enriched on the distal extremities, particularly the nail beds, palms, and soles. They permit shunting of blood from arterioles to venules, bypassing capillaries. A glomus body consists of an afferent arteriole, Sucquet-Hoyer canal, efferent venule, and nerve fibers.
The subungual region of the finger is the leading site for glomus cell tumors. Temperature changes and pressure may provoke severe paroxysmal pain due to myofilament contraction.
Nerves (Figure 1.8)
Nonencapsulated (Free) Nerve Endings
Aβ-type fibers: large diameter myelinated fibers that innervate dermal corpuscles and hair follicles. Aβ-type fibers detect light touch and moving stimuli.
Aδ-type fibers: small diameter myelinated fibers that lose their myelin sheath as they terminate in the epidermis. Aδ-type fibers detect sharp pain, pruritus, temperature, and mechanical stimuli.
Figure 1.7. BLOOD VESSELS. a-capillary in the papillary dermis, b-superficial plexus, c-deep plexus. A, Artery. B, Vein. C, Lymphatic vessel.
(Illustration by Caroline A. Nelson, MD. A, Histology images courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
C-type fibers: small diameter nonmyelinated fibers that terminate in the epidermis. C-type fibers detect dull pain, pruritus, temperature, and mechanical stimuli. They may be histaminergic or nonhistaminergic.
Merkel cells: see above.
Primary mediators of pruritus include histamine, tryptase, cathepsin S, and interleukin (IL)-31, while secondary mediators of pruritus include prostaglandin E1,2, substance P, µ-opioid receptor agonists, nerve growth factor, and IL-2.
Opioids cause pruritus.
Antihistamines relieve pruritus.
Capsaicin, found in chili peppers and other night-shades (Solanaceae), releases and depletes substance P from C-type fibers. It initially causes erythema, edema, and burning but ultimately relieves pruritus.
Nemolizumab, a monoclonal antibody targeting IL-31, is under investigation for the treatment of pruritus associated with atopic dermatitis (AD).
Encapsulated Nerve Endings
Meissner corpuscles: mechanoreceptors located in the dermal papillae. Meissner corpuscles detect light pressure and vibration and are enriched on sensitive areas such as the palms and soles.
Meissner corpuscles are shaped like “pine cones.”
Ruffini corpuscles: mechanoreceptors located in the deep dermis. Ruffini corpuscles detect sustained pressure or stretch and are concentrated around fingernails.
Ruffini corpuscles are shaped like “spindles.”
Pacinian (lamellar) corpuscles: mechanoreceptors located in the deep dermis and subcutis. Pacinian corpuscles detect deep pressure and vibration and are enriched on sensitive areas such as the palms and soles.
Pacinian corpuscles are shaped like “onions.”
Pacinian Pressure.
Krause end bulbs (mucocutaneous end organs): mechanoreceptors located in the dermis. Krause end bulbs detect pressure and temperature and are enriched on the conjunctiva, mucosal lip, tongue, nipple, and anogenital region.
Glands (Figure 1.9)
Sebaceous Glands
Sebaceous glands are present nearly everywhere except the palms and soles, but are enriched on the scalp, face, chest, and upper back. Free sebaceous glands (not associated with a hair follicle) are on the superficial eyelid margin (glands of Zeis), eyelid tarsal plate (meibomian glands), buccal mucosa and vermillion border of the lips (Fordyce
granules), nipple and areola (Montgomery tubercles), and prepuce and labia minora (Tyson glands).
Figure 1.8. NERVES. a-free nerve endings, b-Merkel disks, c-Meissner corpuscle, d-Ruffini corpuscle, e-Pacinian corpuscle. A, Dermal nerve fibers demonstrated by S100 immunohistochemical staining. B, Meissner corpuscle within dermal papillae of human palm skin. Solid arrow: Meissner corpuscle. C, Pacinian corpuscle with characteristic concentric pattern.
(Illustration by Caroline A. Nelson, MD. A and C, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
Zeis is on the zurface.
Fordyce granules present as multiple asymptomatic yellow to white papules on the buccal mucosa/vermilion upper lip. They are considered a normal anatomic variant.
Sebaceous glands are under adrenergic hormonal control. They are transiently stimulated in infancy and mature under the influence of androgens during puberty.
Androgen stimulation explains the appearance of infantile acne between 2 and 12 months of age and the onset of acne vulgaris during adolescence.
The primary functions of sebaceous glands are to promote skin barrier function and modulate inflammation. They exhibit holocrine secretion. Sebocytes in lobules shed into the lumen of the excretory duct, which opens into the hair follicle at the junction between the isthmus and infundibulum.
Sebum is roughly 57% triglycerides, 26% wax esters, 12% squalene, 3% cholesterol esters, and 1.5% cholesterol.
Do NOT get confused! Ceramide predominates in the cornified lipid envelope. Triglycerides predominate in sebum.
Sebaceous follicles harbor bacteria, for example, Staphy-lococcus epidermidis and Cutibacterium acnes (formally Propionibacterium acnes), fungi, for example, Malassezia species, and Demodex mites.
C. acnes contributes to the pathogenesis of acne.
Malassezia species cause tinea versicolor (TV) and Malassezia folliculitis and have been implicated in confluent and reticulated papillomatosis (CARP), seborrheic dermatitis, and neonatal acne.
Demodex mites cause folliculitis and have been implicated in the pathogenesis of rosacea.
Apocrine Glands
Apocrine glands are present on the vermillion border of the lip, axilla, nipple and areola, periumbilical region, and anogenital region. Modified apocrine glands are present on the superficial eyelid margin (Moll glands),
external auditory canal (ceruminous glands), and areola (mammary glands).
Figure 1.9. GLANDS. a-eccrine gland secretory coil, b-eccrine gland straight duct, c-eccrine gland acrosyringium, d-apocrine gland, e-sebaceous gland. A, Eccrine gland secretory coil and straight duct. B, Eccrine gland acrosyringium. C, Apocrine glands. Solid arrow: decapitation secretion. D, Sebaceous gland.
(Illustration by Caroline A. Nelson, MD. A, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. C, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. D, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
Apocrine glands are under adrenergic control (circulating catecholamines). They are present at birth but become functional under the influence of androgens during puberty.
Apocrine glands are thought to play a role in olfactory communication. They exhibit decapitation secretion. Vesicles pinch off from secretory cells in the subcutis and degrade in the lumen of the excretory duct, which typically opens into the infundibulum of the hair follicle above the sebaceous duct. Fatty sweat, mixed with sebum, is odorless until it reaches the skin surface and is degraded by bacteria. Specialized apocrine glands open directly to the skin surface.
Eccrine Glands
Eccrine glands are present nearly everywhere except the external auditory canal, vermillion lip, nail bed, prepuce, glans penis, labia minora, and clitoris.
Eccrine glands are functionally cholinergic (acetylcholine neurotransmitter), but anatomically adrenergic (enervated by postganglionic sympathetic fibers).
Sympathectomy is a treatment for hyperhidrosis, but may cause compensatory hyperhidrosis.
The primary function of eccrine glands is thermoregulation. They exhibit merocrine secretion. Sweat is secreted via exocytosis from the secretory coil in the subcutis or reticular dermis
and transported through the straight duct into the intraepidermal spiral acrosyringium. Sweat is initially isotonic but becomes hypotonic due to sodium absorption. When it reaches the skin surface, it cools the body by evaporation.
Heat intolerance is a prominent feature of hypohidrotic ectodermal dysplasia. Decreased electrolyte reabsorption by the eccrine duct in cystic fibrosis (CF) results in electrolyte loss that poses a risk in hot environments.
Hair (Figure 1.10)
Hair anatomy and histopathology (cross-sectional from inner to outer): medulla, cortex, cuticle (hair shaft), cuticle of the inner root sheath (IRS), Huxley layer of the IRS, Henle layer of the IRS, ORS, vitreous or glassy layer, fibrous root sheath.
Figure 1.10. HAIR. A, Low-power view of a hair follicle: a-bulb, b-suprabulbar zone, c-isthmus, d-infundibulum, e-papillary mesenchymal body, f-matrix, g-critical line of Auber, h- Adamson fringe, i-arrector pili muscle insertion site (bulge), j-sebaceous gland ostium. B, High-power view of the suprabulbar zone: k-medulla, l-cortex, m-cuticle (hair shaft and IRS), n- Huxley layer of the IRS, o- Henle layer of the IRS, p- ORS, q-vitreous layer, r-fibrous root sheath. IRS, inner root sheath; ORS, outer root sheath.
(Illustration by Caroline A. Nelson, MD. Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
Huxley layer overlying the cuticle is like the “husk on a corncob.”
Hair anatomy and histopathology (longitudinal from bulb to epidermal surface):
Bulb: base to Adamson fringe. The bulk of mitotic activity happens below the critical line of Auber (widest diameter) in the matrix, which receives its blood supply from the dermal papilla. Adamson fringe is the point above which the hair shaft is completely keratinized. The IRS keratinizes first and contains citrulline.
Suprabulbar zone (lower segment): Adamson fringe to arrector pili muscle insertion site. The arrector pili muscle is under adrenergic control.
Piloerection (eg, during the fight or flight response) causes goose bumps.
Isthmus: arrector pili muscle insertion site to sebaceous gland ostium. The IRS disappears. The ORS keratinizes without a granular layer (trichilemmal keratinization) and expresses K6, K16, and K17.
The absence of a granular layer is a histopathological feature that distinguishes pilar cysts arising from the isthmus from epidermoid cysts arising from the infundibulum.
Infundibulum: sebaceous gland ostium to epidermal surface. The ORS keratinizes with a granular layer and is contiguous with the epidermis.
Keratinocyte stem cells are primarily located at the bulge (arrector pili muscle insertion site) of hair follicles. Stem cells contribute to hair cycling, tissue regeneration, and wound healing. The enzyme ornithine decarboxylase (ODC) plays a role in cellular growth and differentiation and is a marker of proliferative activity.
ODC is inhibited by eflornithine, a treatment for hypertrichosis.
Sonic hedgehog (SHH) and the Wnt, bone morphogenic protein (BMP), and fibroblast growth factor (FGF) families are important mediators of hair follicle development and cycling.
Gardner syndrome, caused by APC mutation in the Wnt/β-catenin signaling pathway, is associated with epidermoid cysts.
There are ˜100,000 hairs on the scalp and ˜100 to 200 are lost each day. The hair cycle has three phases:
Anagen (85%-90%): growth phase. Hair grows at a rate of ˜0.4 mm/d. The length of the anagen phase determines hair length (2-6 years on the scalp).
Anagen effluvium (AE) occurs when a trigger such as cytotoxic chemotherapy leads to shedding of anagen hairs.
Catagen (<1%): regression phase. The bulb regresses, the IRS is lost, and melanocytes apoptose. This is the shortest phase (2-3 weeks on the scalp).
Telogen (10%-15%): rest phase. After the telogen phase (˜3 months on the scalp), hairs are shed (exogen) leaving behind an empty follicle (kenogen).
Unlike animals that molt, humans have asynchronous hair cycling to maintain a fairly uniform density of hair. Telogen effluvium (TE) occurs when triggers such as systemic diseases reset the hair follicle biological clock, leading to synchronous shedding.
Melanocytes, enriched in the matrix, transfer melanin to hair keratinocytes during anagen (ratio 1:5). Follicular melanocyte stem cells contribute to interfollicular repigmentation. Hair graying is due to a decline in the number of melanocytes with aging.
Perifollicular repigmentation is the predominant pattern in vitiligo vulgaris.
The hair follicle represents a site of immune privilege.
Collapse of immune privilege is implicated in alopecia areata (AA).
The cortex contains the majority of hair keratins; while the cuticle maintains the integrity of hair fibers.
Excessive heat and mechanical stress can damage the cuticle, leading to trichoptilosis (split ends).
Hair strength is primarily proportional to the number of disulfide bonds. Round follicles produce straight hair, while oval (elliptical) follicles produce curly hair.
There are three types of hair: lanugo (fine hairs shed in first wave during the third trimester and in a second wave 3-4 months after birth), vellus (fine hairs over face and body), and terminal hairs (long, thick, and dark-colored hairs on scalp, eyebrows, and eyelashes).
Hypertrichosis lanuginosa may be congenital or acquired (paraneoplastic).
Excess of lanugo-like hair may occur in nutritional deficiencies (eg, marasmus).
During puberty, androgens cause vellus hair follicles to be replaced with terminal hair follicles in the axillae and anogenital region. Men and women with increased androgens will also develop terminal hairs on the face (moustache and beard), chest, back, arms, thighs, pubic and lower abdominal areas, and buttocks. Terminal hair follicles on the scalp exposed to the same androgens revert to vellus hair follicles in genetically susceptible individuals. 5α-reductase type 2 converts testosterone to its more potent metabolite dihydrotestosterone (DHT). Androgen signaling does not influence eyebrow and eyelash hair growth. Estrogen signaling prolongs anagen but reduces the hair growth rate.
The paradoxical effect of androgens on body versus scalp hair explains the excess of terminal hairs in hirsutism and the miniaturization of terminal hairs in androgenetic alopecia (AGA). Finasteride blocks 5α-reductase type 2.
Nails (Figure 1.12)
Nail anatomy and histopathology:
Nail matrix: wedge-shaped epithelium that synthesizes the nail plate. The proximal matrix synthesizes 80% of the nail plate. It begins at the mid-distal phalanx, while the
distal matrix may be visible under the nail plate (lunula). The matrix keratinizes without a granular layer.
Figure 1.11. DISULFIDE BONDS. Ammonium thioglycolate and glyceryl thioglycolate are reducing agents used in permanent waves. They dissolve disulfide bonds, allowing keratin molecules to rearrange into curls, reformed by neutralizers. Unfortunately, they also cause contact dermatitis.
(Illustration by Caroline A. Nelson, MD.)
The lunula looks like a “crescent moon” under the thumbnail.
Nail bed: epithelium tightly apposed to the undersurface of the nail plate. The nail bed extends from the lunula to the onychodermal band. It keratinizes without a granular layer and expresses K6, K16, and K17. The dermis is contiguous with the periosteum of the distal phalanx (no subcutis). Capillaries in the dermis cause nails to be pink and to blanch with pressure. Glomus cells are enriched in the subungual region.
Nail plate: semitranslucent convex sheet of cornified onychocytes that express hair-type keratins.
Figure 1.12. NAILS. a-nail plate, b-onychodermal band, c-lateral nail fold, d-eponychium (cuticle), e-proximal nail fold, f-hyponychium, g-distal phalanx, h-nail bed, i-nail matrix (lunula), j-extensor tendon. A, Low-power view of a transverse section of the distal portion of a finger including the nail unit. Solid arrow: nail plate. Dashed arrow: nail bed. Dotted arrow: lateral nail fold. B, Proximal nail fold forming the roof of the nail groove. C. Nail matrix. Note the lack of a granular layer and presence of multilayered germinative basal cells. D. Nail bed. Note the lack of a granular layer. The epithelium shows a paucity of germinative basal cells.
(Illustration by Caroline A. Nelson, MD. Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
Nail folds: epithelium that folds over the proximal and lateral edges of the nail plate. The nail folds keratinize with a granular layer.
Eponychium (cuticle): cornified layer of the proximal nail fold that creates a seal between the nail plate and the proximal nail fold.
Hyponychium: anatomic region between the nail bed and the distal groove, where the nail plate detaches from the distal digit.
Keratinocyte stem cells are primarily located in the basal layer of the nail matrix. The proximal matrix synthesizes the dorsal aspect of the plate; the distal matrix synthesizes the ventral aspect of the plate.
Figure 1.13. NAIL GROWTH.
(Illustration by Caroline A. Nelson, MD.)
The nail grows out like a “rainbow.” The proximal matrix synthesizes the dorsal aspect of the plate. The distal matrix synthesizes the ventral aspect of the plate.
Figure 1.14. SPECIAL SITES. A, Eyelid skin (top) and transition to eyelid mucosa (bottom). Solid arrow: Zeis gland. Dashed arrow: skeletal muscle bundle. Dotted arrow: meibomian gland. B, Face. Solid arrow: vellus hair follicle. Dashed arrow: sebaceous gland. C, Oral cavity mucosa. Solid arrow: pale keratinocyte containing glycogen. Note the lack of well-formed granular or cornified layers. D, Palmoplantar skin. Solid arrow: stratum lucidum. Note the absence of hair follicles. E, Scalp. Solid arrow: terminal hair follicle extending to the subcutis. Dashed arrow: sebaceous gland. F, Scrotal skin. Solid arrow: smooth muscle bundle in the dartos layer.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
Biopsy of the proximal matrix is more likely to result in visible nail dystrophy than biopsy of the distal matrix.
Fingernails grow 2 to 3 mm/mo and take approximately 6 months to replace. Toenails grow 1 mm/mo and take approximately 18 months to replace.
Melanocytes, enriched in the distal matrix, transfer melanin to nail keratinocytes.
The nail unit represents a site of relative immune privilege.
Special Sites (Figure 1.14)
Areola: histology shows epidermal acanthosis, basilar hyperpigmentation, central invagination leading to a follicle and sebaceous glands, smooth muscle bundles, and apocrine glands.
Polythelia (accessory nipples) are remnants of the embryologic mammary ridges (milk lines).
Ear: histology shows cartilage and vellus hair follicles.
Accessory tragi are remnants of the first branchial arch.
Eyelid: histology shows a thin stratum corneum transitioning to a conjunctival surface with goblet cells, vellus hair follicles, superficial Zeis and Moll glands, Meibomian glands deep within the tarsal plate, and skeletal muscle bundles.
Face: histology shows hair follicles, sebaceous glands, Demodex mites, and solar elastosis (deposition of degenerative elastotic material in the dermis).
Mucosa: (noncornified) histology shows pale keratinocytes containing glycogen and lacking well-formed granular or cornified layers.
Palmoplantar: histology shows a stratum lucidum (lucent layer under the stratum corneum) and Meissner and Pacinian corpuscles with absence of hair follicles (glabrous). Palmoplantar skin is the thickest ˜1.5 mm (compared to ˜0.04 mm eyelid skin).
Scalp: histology shows hair follicles extending to the subcutis associated with sebaceous glands and arrector pili muscles.
Scrotum: histology shows smooth muscle bundles in the dartos layer.
Embryology
Basic Concepts
Gastrulation: formation of three primary germ layers (ectoderm, mesoderm, and endoderm) at 3 weeks estimated gestational age (EGA).
3 layers at 3 weeks.
Skin structures are derived from the following layers:
Ectoderm: epidermis, adnexal structures, melanocytes, Merkel cells, and nerves (neuroectoderm).
Ecto- is derived from the Greek word ektos meaning “outside” (epidermis).
Mesoderm: fibroblasts, Langerhans cells (LCs), blood vessels, and inflammatory cells.
Meso- is derived from the Greek word mesos meaning “middle” (dermis).
Development of the Skin, Hair, and Nails (Figure 1.15)
Infants attain full skin barrier function ˜ 3 weeks after birth. Premature infants, especially those born before 28 weeks’ EGA, have an immature stratum corneum and impaired skin barrier function.
Premature infants have an increased risk of infection, dehydration, and excessive absorption of topical medications or chemicals.
Genetics
Basic Concepts
Allele: alternative forms of a particular gene.
Locus: location on a chromosome.
Genotype: alleles present at a specific locus.
Phenotype: physical manifestation of a particular genotype.
Allelic heterogeneity: mutations in a single gene causing more than one disorder.
An example of allelic heterogeneity is PTEN gene mutation causing both Cowden syndrome and Bannayan-Riley-Ruvalcaba (BRR) syndrome.
Locus heterogeneity: mutations in different genes causing the same disorder.
An example of locus heterogeneity is tuberous sclerosis complex (TSC) caused by mutations in either hamartin or tuberin.
Homozygous: genotype with two identical alleles at a given locus.
Heterozygous: genotype with two different alleles at a given locus.
Hemizygous: genotype with only one allele at a given locus.
Nullizygous: genotype with no alleles at a given locus.
Haploinsufficiency: protein produced by one wild-type allele is not sufficient to sustain normal function.
An example of haploinsufficiency is Hailey-Hailey disease, an AD disorder in which one wild-type allele of the ATP2C1 gene is not sufficient to sustain normal function of a Golgi calcium pump.
Dominant negative effect: mutated protein interferes with normal function of wild-type proteins.
An example of the dominant negative effect is epidermolysis bullosa (EB) simplex, which is most commonly due to mutations in K5 or K14 that interfere with normal wild-type function.
Exon: protein-coding region of a gene.
Intron: non-protein-coding region of a gene.
Epigenetics: heritable changes affecting gene expression that do not result from alterations in the deoxyribonucleic acid (DNA) sequence.
An example of epigenetics is the alteration in DNA methylation, histone modifications, and microribonucleic acid (RNA) profiling that have been found in patients with lupus erythematosus (LE).
Genetic Disorders
Modifying factors to Mendelian inheritance patterns:
Age-dependent penetrance: in late-onset diseases, not all affected individuals are old enough to manifest the disease.
De novo mutations: new mutation in an individual with a negative family history.
Imprinting: epigenetic phenomenon in which the sex of the transmitting parent determines which allele is expressed in the children.
Figure 1.15. DEVELOPMENT OF THE SKIN, HAIR, AND NAILS. Development of the skin, hair, and nails according to approximate EGA in weeks. DEJ, dermal-epidermal junction; EGA, estimated gestational age.
Table 1.5. MENDELIAN INHERITANCE PATTERNS
Pattern
Description
Punnet Square
Notes
AR
If both parents are carriers, children have a 25% risk of being affected.
Risk factors include consanguinity and isolated population.
AD
If one parent is affected, children have a 50% risk of being affected.
De novo mutations. Mechanisms include haploinsufficiency or a dominant negative effect.
XLR
If the mother is a carrier, male children have a 50% risk of being affected. If the father is affected, children have a 0% risk of being affected.
De novo mutations. May be mosaic in female carriers.
XLD
If the mother is affected, children have a 50% risk of being affected. If the father is affected, female children have a 100% risk of being affected.
De novo mutations. Often lethal in affected males and mosaic in affected females.
AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant; XLR, X-linked recessive.
Table 1.6. MNEMONICS FOR X-LINKED GENETIC DISORDERS
XLR: CHADS kinky WIFE CHANdra
XLD: BIG CHOMP
CGDa
Hunter syndrome
Anhidrotic/hypohidrotic ectodermal dysplasiaa
DKCa
SCIDa
Menkes kinky hair disease
WAS
Ichthyosisa
Fabry disease
EDS (V, IX, X)b
Chondrodysplasia punctata (not Conradi-Hünermann)a
Anhidrotic/hypohidrotic ectodermal dysplasia with immune deficiencya
Bruton agammaglobulinemia
Lesch-Nyhan syndrome
Bazex syndrome
IP
Goltz syndrome
CHILD syndrome
Oro-facial-digital syndromea
MIDAS syndrome
Chondrodysplasia punctata (Conradi-Hünermann)a
a Steroid sulfatase deficiency.
b Historical classification. Types V and X have unknown molecular basis.
Type IX has been reclassified as cutis laxa (occipital horn syndrome). CGD, chronic granulomatous disease; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; DKC, dyskeratosis congenita; EDS, Ehlers-Danlos syndrome; IP, incontinentia pigmenti; MIDAS, micrognathia, dermal aplasia, and sclerocornea; SCID, severe combined immunodeficiency; WAS, Wiskott-Aldrich syndrome; XLD, X-linked dominant; XLR, X-linked recessive.
Incomplete penetrance: not all affected individuals manifest the disease.
Loss of heterozygosity (second hit): an individual with a heterozygous loss of function mutation in a tumor suppressor gene develops a cancer following mutation of the wild-type allele.
An example of loss of heterozygosity is Muir-Torre syndrome, which is due to heterozygous germline mutations in DNA mismatch repair genes. Somatic inactivation of the wild-type allele results in microsatellite instability and mutations, leading to sebaceous neoplasms and other malignancies.
Mitochondrial inheritance: a mother transmits a disease, the severity of which is determined by the proportion of mutant versus normal mitochondrial proteins.
Mothers pass on mitochondria.
Mosaicism: presence of two or more populations of cells with different genotypes in an individual who has developed from a single fertilized egg; often manifests as skin lesions following lines of Blaschko, but may take on a variety of patterns including blocklike, dermatomal, garment-like, patchy, phylloid, or segmental (Figure 1.16).
Pseudodominant inheritance: children of an individual homozygous for an autosomal recessive (AR) mutant allele and a carrier have a 50% risk of being affected.
Variable expression: not all affected individuals manifest the same severity of disease.
Figure 1.16. LINES OF BLASCHKO AND DERMATOMES.
(Illustration by Caroline A. Nelson, MD.)
Mosaicism may be divided into three subtypes:
Genomic mosaicism: due to either somatic postzygotic mutations (cannot be transmitted to children) or postzygotic mutations affecting the gonads (may be transmitted to children and result in generalized disease).
Mosaic epidermolytic ichthyosis (EI) is characterized by streaks of hyperkeratosis following lines of Blaschko. It is caused by a postzygotic mutation in K1 or K10 during embryogenesis. If the mutation involves gonadal cells, it can be transmitted to the patient’s children, resulting in generalized EI.
Functional mosaicism: due to variable X-inactivation (lyonization) in females and males with Klinefelter syndrome.
In female patients with X-linked dominant male-lethal genetic disorders such as incontinentia pigmenti (IP), and in female carriers of X-linked recessive disorders, functional mosaicism can produce lesions following lines of Blaschko.
Revertant mosaicism: due to rescue of a mutation in a mosaic clone of cells that regain normal function.
In ichthyosis with confetti, due to K10 mutation, revertant mosaicism is responsible for the appearance of small islands of normal skin on a background of ichthyosiform erythroderma.
Revertant mosaicism is called “natural gene therapy.”
Polygenic disorders are caused by defects in more than one gene.
Complex genetic disorders are caused by interaction of genetic and environmental factors.
Chromosomal genetic disorders are caused by abnormalities in the number, structure, or parental contribution of chromosomes.
Number: one chromosome (monosomy) or extra chromosomes (eg, trisomy) affecting one pair of homologous chromosomes (aneuploidy) or the whole genome (polyploidy).
Structure: inversion (reversal of part of a homologous chromosome) or translocation (rearrangement of parts between nonhomologous chromosomes).
Parental contribution: inheritance of both homologous chromosomes from one parent (uniparental disomy)
resulting in disease due to imprinting or transmission of two AR mutant alleles.
Chromosome 15 provides a classic example of uniparental disomy. Inheritance of the maternal allele causes Prader-Willi syndrome, with features including insatiable appetite and intellectual disability. Inheritance of the paternal allele causes Angelman syndrome, with features including intellectual disability, seizures, and speech impairment.
McKusick’s Online Mendelian Inheritance in Man (OMIM) database provides access to current information on human genes and genetic diseases.
Carcinogenesis
Basic Concepts
Carcinogenesis occurs in four stages (initiation −> promotion −> progression −> malignant conversion).
Telomeres, maintained by the enzyme telomerase, protect the ends of chromosomes. Normal cells enter senescence (a nonproliferative but viable state) and ultimately undergo apoptosis as a consequence of accumulating genetic or epigenetic alterations and telomere shortening.
Telo- is derived from the Greek word telos meaning “end.”
Defective telomere maintenance is a feature of dyskeratosis congenita (DKC).
Apoptosis may be induced by stimuli including DNA damage, withdrawal of growth cytokines, and death-promoting agents. It is mediated by caspases.
“Casper the friendly ghost” (caspases mediate apoptosis).
Cancer cells display a mutator phenotype (higher degree of genomic instability) in comparison to normal cells, often due to decreased efficiency in DNA repair systems.
Driver mutations confer a selective survival advantage to cancer cells, while passenger mutations have no effect on carcinogenesis.
Six hallmarks of cancer:
Sustaining proliferative signaling (eg, gain-of-function mutations in oncogenes such as the RAS family, which behave in a dominant fashion).
Evading growth suppressors (eg, loss-of-function mutations in tumor suppressor genes such as RB, which behave in a recessive fashion [two hits]).
Resisting cell death (eg, mutations that upregulate anti-apoptotic factors like B-cell lymphoma 2 [BCL2]).
Enabling replicative immortality (eg, mutations that upregulate telomerase).
Inducing angiogenesis (eg, mutations that upregulate growth factors such as VEGF).
Activating invasion and metastasis (eg, mutations that downregulate cell adhesion molecules, such as E-cadherin).
Predisposing factors for skin cancer include age, anatomic site, chemical carcinogen exposure (eg, alcohol, arsenic, betel nut, tobacco), gender, genetic disorders, immunosuppression, oncogenic virus infection, scarring or chronic ulceration, skin phototype, and ultraviolet (UV) or ionizing radiation.
Arsenical keratoses on the palms and soles have premalignant potential for aggressive squamous cell carcinomas (SCCs).
The Cell Cycle (Figure 1.17)
The cell cycle is the process of DNA replication and mitosis. It progresses through G1 (gap 1 phase) to S (DNA synthesis phase) to G2 (gap 2 phase) to M (mitosis phase), at which point the cell cycle may repeat or the cell may enter G0 (resting phase).
Conventional antineoplastics may be cell cycle specific or cell cycle nonspecific.
The cell cycle has three primary checkpoints: G1, G2, and M, which are regulated by cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs).
P53 (encoded by the TP53 gene on chromosome 17) is the most common mutation in human cancer. It protects DNA integrity by regulating cell cycle progression, DNA repair, and apoptosis. P53 activates P21, a CKI, leading to cell cycle arrest at G1. P53 also activates P53 unregulated modulator of apoptosis (PUMA), which inhibits BCL2, leading to apoptosis.
Germline TP53 mutation causes Li-Fraumeni syndrome. Somatic TP53 mutation is the leading gene mutation in SCC.
CDKN2A activates P16, a CKI, which leads to cell cycle arrest at G1. CDKN2A also activates P14ARF (alternative reading frame), which inhibits mouse double minute 2 (MDM2), decreasing P53 degradation and leading to cell cycle arrest and apoptosis.
CDKN2A mutation causes familial atypical multiple mole melanoma (FAMMM) syndrome.
The G1 checkpoint is controlled by CDK-cyclin complex-mediated phosphorylation of retinoblastoma (RB) protein. Underphosphorylated RB arrests the cell cycle, while phosphorylated RB releases E2F, which promotes the transcription of cyclins, leading to cell cycle progression.
Human papillomavirus (HPV) co-opts host cell machinery to replicate viral DNA. In high-risk types, the early (E) 6 oncoprotein destroys P53, while the E7 oncoprotein binds underphosphorylated RB, releasing E2F.
Molecular Signaling Pathways (Figure 1.18)
Mitogen-activated protein kinase (MAPK) signaling pathway:
Growth factors (mitogens) bind to and activate receptor tyrosine kinases (RTKs) such as KIT.
Figure 1.17. THE CELL CYCLE. ARF, alternative reading frame; BCL2, B-cell lymphoma 2; CDKN2A, cyclin-dependent kinase inhibitor 2A; G0, resting phase; G1, gap 1 phase; G2, gap 2 phase; M, mitosis phase; MDM2, mouse double minute 2; PUMA, p53 upregulated modulator of apoptosis; RB, retinoblastoma protein; S, deoxyribonucleic acid synthesis phase.
(Illustration by Caroline A. Nelson, MD.)
RTKs activate GTPases in the RAS family.
The RAS family activates kinases BRAF, MEK, and ERK/MAPK.
ERK/MAPK activates cyclin D1, thereby promoting cell proliferation, among other targets.
“Rebecca Brings Matzah Every Passover” (RAS, BRAF, MEK, ERK/MAPK proliferation).
Phosphoinositide 3-kinase (PI3K) signaling pathway:
Growth factors (mitogens) bind to and activate RTKs such as KIT.
RTKs activate PI3Ks.
PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) to active phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
PIP3 activates AKT.
AKT activates the mammalian target of rapamycin (MTOR), thereby promoting cell growth, among other targets.
SHH signaling pathway:
Patched releases smoothened (SMO).
SMO inhibits suppressor of fused (SUFU).
SUFU releases GLI.
GLI activates BCL2, thereby promoting cell survival, among other targets.
Ubiquitin-proteasome pathway:
Enzymes link chains of ubiquitin on to proteins to tag them for degradation.
Tagged proteins are recognized by the 26S proteasome that degrades them into peptides.
Peptides are either degraded by peptidases in the cytoplasm into amino acids or used in antigen presentation.
Proper function of the proteasome is important for protein recycling and therefore cell survival.
Targeted antineoplastics inhibit cellular membrane or intracellular molecular signaling pathways.
 Figure 1.18. MOLECULAR SIGNALING PATHWAYS. A, Unbound state. B, Bound state. GF, growth factor; MAPK, mitogen-activated protein kinase; MTOR, mammalian target of rapamycin; P, proteasome; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RTK, receptor tyrosine kinase; SHH, sonic hedgehog; SMO, smoothened; SUFU, suppressor of fused; Ub, ubiquitin. |
Table 1.7. MOLECULAR SIGNALING PATHWAY MUTATIONS IN NEOPLASMS AND GENODERMATOSES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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