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Skin and Skin Diseases PHM 480D Normal Physiology, Pathophysiology II Spring 2024 John DiGiovanni, Ph.D. Professor and Coulter R. Sublett Endowed Chair Division of Pharmacology & Toxicology Director, Center For Molecular Carcinogenesis and Toxicology Associate Director for Basic Research, LiveSTRONG...

Skin and Skin Diseases PHM 480D Normal Physiology, Pathophysiology II Spring 2024 John DiGiovanni, Ph.D. Professor and Coulter R. Sublett Endowed Chair Division of Pharmacology & Toxicology Director, Center For Molecular Carcinogenesis and Toxicology Associate Director for Basic Research, LiveSTRONG Cancer Institutes Learning Objectives Understand normal skin structure and function. Discuss and understand pathophysiology of selected inflammatory skin diseases/disorders. Discuss skin cancer types and our current understanding of the their pathogenesis. Briefly discuss some potential therapeutic strategies and targets. The Integumentary System (Skin) Integument is skin Skin and its appendages make up the integumentary system A fatty layer (hypodermis) lies underneath Two distinct regions Epidermis Dermis Functions of Skin Protection Cushions and insulates and is waterproof Protects from chemicals, heat, cold, bacteria Screens UV Synthesizes vitamin D with UV Regulates body heat Prevents unnecessary water loss Sensory reception (nerve endings) Skin Structure Epidermis Keratinized stratified squamous epithelium Four types of cells Keratinocytes – deepest, produce keratin (tough fibrous protein) Melanocytes - make dark skin pigment melanin Merkel cells – associated with sensory nerve endings Langerhans cells – macrophage-like dendritic cells Layers (from deep to superficial) Stratum basale or germinativum – single row of cells attached to dermis; youngest cells Stratum spinosum – spinyness is artifactual; tonofilaments (bundles of protein) resist tension Stratum granulosum – layers of flattened keratinocytes producing keratin (hair and nails made of it also) Stratum lucidum (only on palms and soles) Stratum corneum – horny layer (cells dead, many layers thick)primary protective layer of epidermis (see figure on next slide) Epithelium: Layers (on left) and Cell Types (on right) Remember… Four basic types of tissue Epithelium – epidermis just discussed Connective tissue - dermis Muscle tissue Nervous tissue Dermis Strong, flexible connective tissue Cells: fibroblasts, macrophages, mast cells,Tcells Fiber types: collagen, elastic, reticular Rich supply of nerves and vessels Critical role in temperature regulation (the vessels) Two layers (see next slides) Papillary – areolar connective tissue; includes dermal papillae Reticular – “reticulum” (network) of collagen and reticular fibers *Dermis layers *Dermal papillae * * Epidermis and dermis of (a) thick skin and (b) thin skin Hypodermis “Hypodermis” (Gk) = below the skin “Subcutaneous” (Latin) = below the skin Also called “superficial fascia” “fascia” (Latin) =band; in anatomy: sheet of connective tissue Fatty tissue which stores fat and anchors skin (areolar tissue and adipose cells) Different patterns of accumulation (male/female) Skin color Three skin pigments Melanin: the most important Carotene: from carrots and yellow vegies Hemoglobin: the pink of light skin Melanin in granules passes from melanocytes (same number in all races) to keratinocytes in stratum basale Digested by lysosomes Variations in color Protection from UV light vs vitamin D? Skin appendages Derived from epidermis but extend into dermis Include Hair and hair follicles Sebaceous (oil) glands Sweat (sudoiferous) glands Nails Hair and hair follicles: complex Derived from epidermis and dermis Everywhere but palms, soles, nipples, parts of genitalia * *“arrector pili” is smooth muscle Hair bulb: epithelial cells surrounding papilla Hair papilla is connective tissue________________ Functions of hair Warmth – less in man than other mammals Sense light touch of the skin Protection - scalp Parts Root imbedded in skin Shaft projecting above skin surface Make up of hair – hard keratin Three concentric layers Medulla (core) Cortex (surrounds medulla) Cuticle (single layers, overlapping) Sebaceous (oil) Glands Entire body except palms and soles Produce sebum by holocrine secretion (holocrine secretions are produced in the cytoplasm of cells and released by the rupture of the plasma membrane which destroys the cell with subsequent release of the product into the lumen) Oils and lubricates Sweat Glands Entire skin surface except nipples and part of external genitalia Prevent overheating 500 cc to 12 l/day! (is mostly water) Humans most efficient (only mammals have) Produced in response to stress as well as heat Types of Sweat Glands Eccrine or merocrine Most numerous True sweat: 99% water, some salts, traces of waste Open through pores Apocrine Axillary, anal and genital areas only Ducts open into hair follices The organic molecules in it decompose with time - odor Modified apocrine glands Ceruminous – secrete earwax Mammary – secrete milk Skin Disorders/Diseases Inflammatory Urticaria Contact dermatitis Atopic dermatitis Psoriasis Acne Vulgaris Acne Rosacea Skin Cancer Benign Tumors Actinic keratosis Basal cell carcinoma Malignant tumors Squamous cell carcinoma melanoma Psoriasis Follows exposure to pollens, foods, drugs, pressure, temperature, etc Ag  IgE  mast cell degranulation  inflammation Perivascular inflammatory infiltrate: lymphocytes, neutrophils or eosinophils Histamine release Spongiosis = intracellular epidermal edema Treatment of Hives The best treatment for hives and angiodema is to identify and remove the trigger, but this is not always an easy task. Antihistamines are usually prescribed to provide relief from symptoms. Chronic hives may be treated with antihistamines or a combination of medications. When antihistamines don't provide relief, oral corticosteroids may be prescribed. A biologic drug, omalizumab (Xolair), is also approved to treat chronic hives in those at least 12 years of age. This is a type of anti-IgE antibody that binds to free IgE and prevents degranulation of mast cells. For severe hive or angioedema outbreaks, an injection of epinephrine (adrenaline) or a cortisone medication may be needed. Dermatitis (Also known as Excema) Defined: Inflamed, pruritic skin (dermatitis) not due, exclusively, to external factors (allergens, sunlight, cold, heat, fungus, etc.). Types: Allergic Contact, Atopic, Hand, Nummular, Stasis Dermatitis. Primary Lesion: ill-defined scaly red patch. Keys to Dx: Rule out external factors as the sole cause of the eruption. Allergic Contact Dermatitis Atopic Dermatitis Hand and Nummular Eczema Eczema: Pathophysiology Etiology not completely understood: both genetic and environmental factors play a strong role. Histology: Spongiosis = intercellular edema within the epidermis. Acute and chronic inflammatory cells. T cell mediated cytokine release (TH2 type) drives pathology Epidermal hyperplasia Atopic Dermatitis Effects of cytokines on epidermis in AD. Disrupted epidermal barrier and environmental triggers stimulate keratinocytes to release IL-1 , IL-25, IL-33, MDC, TARC, and TSLP, which activate dendritic cells and Langerhans cells. Activated dendritic cells stimulate Th2 cells to produce IL-4, IL-5, IL-13, IL-31, and IL-33, which leads to barrier dysfunction, decreased AMP production, impaired keratinocyte differentiation, and itch symptoms. Chronic AD is characterized by recruitment of Th1, Th22, and Th17 subsets, which results in epidermal thickening and abnormal keratinocyte proliferation. AD atopic dermatitis; AMP antimicrobial peptide; DC dendric cell; IFN interferon; IL, interleukin; KC, keratinocyte; LC, Langerhans cell; MDC, macrophage-derived chemokine; S100A, S100 calcium-binding protein A; Th, T-helper type; TARC thymus and activationregulated chemokine; TSLP, thymic stromallymphopoietin. Taken from Allergy and Asthma Proceedings 40:84-92, 2019 Allergic Contact Dermatitis Pathophysiology of allergic contact dermatitis (ACD). After penetrating the skin, contact allergens react with or modify self-proteins into immunogenic proteins. Contact allergen-stressed KC produce profound amount of IL-1b and IL-18 and activated DETC produce IL-17A and IFN-g. Simultaneously, APC are activated and can subsequently carry contact allergen-modified self-proteinMHC complexes to the dLN, where the priming of naïve T cells occur. Activated CD8+ T cells undergo clonal expansion and several memory subsets are developed. One specific subset of memory CD8+ T cells e.g., TRM cells migrates back to the site of primary allergen exposure. At the second exposure to the contact allergen, a faster and stronger inflammatory response is induced. Activated DETC and TRM cells produce significant amounts of IL-17A and IFN-g and stressed KC produce large amounts of IL-1b. Additionally, TRM cells can induce apoptosis in allergen-modified KC via either the Fas-FasL-dependent or the perforin-dependent pathway. DETC, dendritic epidermal gd T cell; APC, antigen presenting cell; TRM cells, tissue-resident memory T cells; KC, keratinocyte. Taken from Frontiers in Immunol., 11:1-9, 2020 JAK-STAT Signaling Pathway Cytokines = Interleukins e.g., IL-1,IL-4, IL-13, IL-17, IL18,IL-22, etc Therapy of Mild to Severe Eczema Rule out allergic or irritant contact dermatitis, dermatophyte infections, drug reactions, etc. Good skin care: Mild superfatted skin cleanser (, lukewarm not hot showers, lubricate skin frequently with unscented lotions/creams. Topical steroids only for flares Class I or II for short term (14 days) control of severe flares in adults. Class III or IV for children. Class IV - VII for mild flares in adults. Class VI or VII in children. Consider topical or oral antibiotics if crusted Antihistamines Consider topical tacrolimus or topical pimecrolimus ($$$) for refractory disease. Both are calcineurin inhibitors that inhibit T cell proliferation Calcineurin is a protein serine/threonine phosphatase For severe/widespread also may consider oral methotrexate (immune supression) New Drugs for Atopic Dermatitis Eucrisa (Crisaborole)- inhihibits PDE4 Dupixent (Dupilumab)- mAb that blocks IL4R and thus blocks IL-4 and IL-13 signaling Adbry (tralokinumab-ldrm)- IgG4 mAb that specifically binds to human IL-13 Cibinqo (abrocitinib) reversibly inhibits JAK1 by blocking the ATP binding site. Opzelura (ruxolitinib) is a topical cream formulation of ruxolitinib, a Janus kinase (JAK) inhibitor. It inhibits JAK1 and JAK2 Rinvoq (upadacitinib) is a JAK1 and 2 inhibitor. Acne Vulgaris (vs Rosacea) Defined: Chronic papulopustular eruption affecting the pilosebaceous units of the face and trunk. Types: Comedonal, Papulopustular, Nodulocystic, Conglobata, Fulminans, Rosacea. Primary Lesion: red papule/nodule, pustule, comedones (white and black heads). Keys to Dx: Age, Flushing? Acne Vulgaris Often referred to as “acne”. Is a disorder of pilosebaceous follicles. Typically presents at ages 8-12 (often the first sign of puberty); peaks at ages 15-18 and resolves by age 25. Affects 90% of adolescents and affects races equally. Family history is often positive. ~12% of women and ~3% of men will have acne until age 40 In women, not uncommon to have first outbreak at 20-35 years of age Acne Vulgaris – con’t Affects mainly face, neck, upper trunk and upper arms (where sebaceous glands are abundant). Acne begins with clogged pilosebaceous units aka comedones. Debris and bacteria (P. Acnes) collect in these clogged “pores” which then leads to inflammation: papules and pustules with erythema and edema. These pressurized follicles can rupture in the dermis resulting in tender deep nodulocystic ACNE Acne results when excess sebum and dead cells clog the pores of the hair follicle followed by infection by propionibacterium acnes and inflammation. Excess sebum results from environment stress and especially during puberty with increased production of the androgen - Testosterone. Hyperactivity of 5-alpha reductase [especially in acne prone skin] converts Testosterone to the more active Dihydrotestosterone [DHT] leading to excess sebum production. The increased sebum levels and dead cells clog the follicles with reduced aeration of the skin providing ideal conditions for the action of Propionibacterium acnes [p. acnes] ever present on the skin, resulting in the formation of irritating free fatty acids and other inflammatory mediators. The end result is usually red, inflamed acne lesions - whiteheads/blackheads [pimples/papules]. Low levels of co-enzyme A [CoA] results in decreased metabolism of the irritating free fatty acids produced by the action of p. acnes while the action of damaging UV irradiation further compounds the condition with the resultant and almost inevitable post inflammatory hyper-pigmentation Acne Vulgaris Therapeutic Agents Classes of Topical Agents Retinoids: tretinoin, adapalene (micro gels, gels, creams, solutions)- comedolytic, shrink sebaceous glands Should not be used in pregnant women Antibiotics: Clindamycin & Erythromycin (solution, gel, pads, lotion)antibacterial Sulfur-containing products (lotion, cream)- antibacterial Benzoyl Peroxide (cream, gel)- antibacterial, comedolytic Acne Vulgaris Therapeutic Agents Classes of oral agents Antibiotics Retinoid (Isotretinoin) Spironolactone (blocks androgen receptor) Uncommonly used Oral contraceptives (low progesterone) Yasmin, Orthotricyclen Only for adjunctive therapy Reduce sebum production Acne Vulgaris Therapeutic Agents Oral Antibiotics Tetracycline: 500mg bid - tid (Photosensitivity, GI upset- empty stomach) Doxycycline: 100mg qd - bid (Photosensitivity, $$) Minocycline: 100mg qd (Dizziness, skin pigmentation, $$$) Erythromycin: 500mg bid-tid (GI upset) Trimethoprim/sulfamethoxazole: 800/160mg (1 DS tab) bid (Photosensitivity, renal effects) Acne Rosaecea Also called rosacea. Chronic inflammatory condition. located at the “flush” areas of the face (nose, cheeks, brow and chin). Papules and pustules superimposed on a background of telangiectasias and general erythema. More common in women. Age of onset 30-50 years (later than acne vulgaris). Affected persons flush easily Patients often report very sensitive skin. Telangiectasia = small dilated capillaries near skin surface; can appear spidery Acne Rosacea Pathophysiology Woo et al, Int. J. Mol. Sci. 2016, 17, 1562 Representation of proposed mechanisms for rosacea. Predisposing factors are associated with dysregulated immune responses and neurovascular dysregulation. Among the triggering factors, demodex proliferation directly disrupts the epidermal barrier. Demodex and ultraviolet radiation can cause the elevated expression of TLR-2. TLR-2 regulates the release of KLK-5, which disrupts the epidermal barrier and activates the cleavage of hCAP-18 into LL-37. LL-37 stimulates tissue inflammation, vasodilation, and angiogenesis in rosacea. LL-37 also facilitates the degranulation of mast cells, which further enhances the expression of MMP-1, MMP-9, and IL-6. Furthermore, Th1 and Th17-mediated immune reactions affect inflammation in rosacea. In addition, Erdr1 is related to the upregulation of IL-18 and angiogenesis. Heat and stress can induce the release of various neuromodulators, such as PACAP, VIP, substance P, CGRP, and the TRP family. These cause neurovascular dysregulation, which consequently results in inflammation, vasodilation, and angiogenesis in rosacea. Blue solid lines indicate pathophysiological pathways involved in rosacea. Dashed lines denote the proposed mechanisms for triggering factors and predisposing factors in rosacea. Upward arrows indicate increased expression of certain protein. Abbreviation: TLR, Toll-like receptor; KLK-5, Kallikrein-5; MMP, Matrix metalloproteinase; PACAP, Pituitary adenylate cyclase-activating polypeptide; VIP, Vasoactive intestinal peptide; CGRP, Calcitonin gene-related peptide; TRP, Transient receptor potential, VEGF, Vascular endothelial growth factor; FGF, Fibroblast growth factor; ROS, reactive oxygen species. Woo et al, Int. J. Mol. Sci. 2016, 17, 1562 Acne Rosacea: Treatment Considerations NO COMEDONES: No place for topical comedolytics (tretinoin, benzoyl peroxide). P. acnes bacteria not important: Topical erythromycin and clindamycin not helpful. Vascular instability leads to flushing. Therapy of Acne Rosacea Topical metronidazole (antibiotic) cream or gel bid If moderately severe add oral antibiotics * Tetracycline , Doxycyline, Minocycline * Erythromycin Topical sulfur containing lotions/creams are occasionally helpful. Brimonidine (Mirvaso), a gel that tightens blood vessels in the skin to get rid of redness. α2 adrenergic receptor agonist Azelaic acid, a gel and foam that clears up bumps, swelling, and redness. What is Psoriasis A chronic eruption of scaly plaques on the extensor surfaces that may involve the scalp and nails. Koebner phenomenon- the appearance of new skin lesions on previously unaffected skin secondary to trauma. Types of psoriasis include Vulgaris, Guttate, Pustular, Erythrodermic, Scalp, Palmoplantar, Nail. Primary Lesion: well-defined plaque with thick silvery scale. Keys to Dx: Distribution-Most often located on the scalp, trunk, and limbs, with a predilection for extensor surfaces, such as the elbows and knees. Pitting of nails. Psoriasis: Statistics, etc Psoriasis can occur at any age, including childhood There are two main peaks of onset, 20-30 years of age and 50-60 years of age. Psoriatic arthritis usually develops between ages of 30-50 years. It is estimated that 125 million people worldwide have psoriasis (~2-3% of total population; 8 million in the U.S.) Although less frequent in pediatric vs adult patients, some estimates suggest that 30% of psoriasis patients present with their first symptoms during childhood and adolescence. The most common form of pediatric psoriasis is psoriasis vulgaris. Impact on emotional and psychosocial well-being can be significant, especially in children and adolescents with psoriasis. Plaque-type Psoriasis Vulgaris Plaque-type Psoriasis Vulgaris Pitted Nails of Psoriasis Clinical Features of Psoriatic Arthritis Histopathology of Psoriasis Layered parakeratosis with neutrophils between the layers Neutrophils in the epidermis Acanthosis (thickening of the epidermis) Elongated rete ridges Prominent dermal papillae with thinned overlying suprapapillary plates Psoriasis: Pathophysiology Multifactorial: genetic factors and immune system Strong association with HLA-C w*0602 allele (PSORS1 locus on Chr6) Sensitized T-cells infiltrate skin and secrete cytokines and growth factors (e.g., TNFα, IL-17) that drive the plaques Hyperplasia and hyperkeratosis Inflammation Vascular proliferation and angiogenesis Trauma precipitates lesions-Koebner phenomenon Activation of keratinocytes Main defect: rapid turnover of epidermal maturation (differentiation). Normal epidermal transit time = 30 days Psoriasis epidermal transit time = 7-14 days Cross-talk between keratinocytes and T-cells essential Multisystem disorder Arthritis, myopathy, enteropathy, immune deficiency HLA (Human Leukocyte Antigen) is part of the MHC (major histocompatablity complex) which regulates immune function and responses Summary of the Initiation and Maintenance of Psoriasis Taken from Noor et al, Biomedicines10:498, 2022 Psoriasis: Therapeutic Agents/Modalities Topical steroid creams and ointments Topical calcipotriene cream and ointment (vit D analog) Topical tazarotene (retinoid) gel Topical tar containing ointments Phototherapy (UVB & PUVA) Oral methotrexate, acitretin (retinoid), or cyclosporine Systemic (s.c. injection) biologic response modifiers (antibodies) -Etanercept (Enbrel),, adalimumab (Humira), infliximab (Inflecta)-TNF-α -Ustekinumab (Stelara)-IL12/23; Risankizumab (Skyriza), Guselkumab (Tremfya)- IL23 -Secukinumab (IL-17)- Cosentyx Apremilast (PDE4)-Otezla Oral JAK inhibitors currently approved for treatment of psoriasis/ psoriatic arthritis. Tofacitinib, Baricitinib, Ruxolitinib Types of Skin Cancer Basal cell carcinoma Squamous cell carcinoma Melanoma Merkel Cell Carcinoma (rare) Basal Cell Carcinoma (BCC) Basal cell carcinoma is the most frequently diagnosed skin cancer (2.8 million every year in U.S.). BCC occurs in heavily sun-exposed areas of the skin, especially face, neck, ears, lips, nose and arms. BCC rarely results in death, but it can spread and cause more serious health problems. For example, they can grow to the point where disfiguring surgery is necessary to remove them. BCC typically occur as light pink or flesh-colored bumps with pearly or waxy appearances. Although common in all areas of the country, BCC is especially prevalent in southern states. Cutaneous Squamous Cell Carcinoma (cSCC) cSCC is the second most common skin cancer (750,000 cases every year in U.S.). It is more aggressive than BCC and can spread to other parts of the body and may result in death (approximately 2,500/year). cSCC also tends to occur in the most heavily sun-exposed areas of the skin. cSCCs often start as flat red or brown splotches which become rough, dry, and scaly. If not treated, they may eventually grow large enough to spread to lymph nodes and internal organs and can be fatal. cSCC occurs in all areas of the country, but is more prevalent in southern states. BCC and cSCC Approximately 3.5 million cases of basal and squamous cell carcinomas are estimated in the U.S. (2023 statistics from American Cancer Society ) Note that the incidence of both is projected to increase world wide over the next 20 years. The Good News: With early detection and treatment, BCC and SCC have cure rates of more than 95%. Melanoma Melanoma cases are increasing faster than any other cancer. Melanoma is the most common cancer among 25-29 year-olds and second for 15-29 year-olds. Vulnerability to melanoma begins at age 12, much earlier than other skin cancers. If not removed early, while thin (primary tumor), melanoma often grows rapidly, spreads to distant internal organs, and is nearly always fatal. It is equally likely to occur in all areas of the country. Source: CDC http://www.cdc.gov/cancer/skin/ http://www.skincancer.org/ Melanoma Malignant melanoma is the most deadly of the three types of cancer. Melanoma accounts for less than 5% of the skin cancer cases. It causes more than 75% of the skin cancer deaths. About 100,640 new melanomas will be diagnosed (about 59,170 in men and 41,470 in women) in 2024. About 8,290 people are expected to die of melanoma in 2024 (about 5,430 men and 2,860 women)(American Cancer Society). What Causes Skin Cancer? ▪ Solar ultraviolet (sUV) radiation is the main cause of skin cancer. ▪ Artificially-produced UV radiation, such as from sunlamps and tanning booths, also can cause skin cancer. ▪ Predisposition (genetics). ▪ Chemicals (e.g., trivalent inorganic arsenic). UV Radiation and Skin Cancer Ultraviolet A (UVA) is made up of wavelengths 320 to 400 nanometers (nm) in length. Ultraviolet B (UVB) wavelengths are 280 to 320 nm in length. Ultraviolet C (UVC) wavelengths are 100 to 280 nm in length. Only UVA and UVB ultraviolet rays reach the earth's surface. The earth's atmosphere absorbs UVC wavelengths.UVB rays cause a much greater risk of skin cancer than UVA. However, UVA rays cause aging, wrinkling, and loss of elasticity. UVA also increases the damaging effects of UVB, including skin cancer and cataracts. Types of Skin Cancer Caused by UV Exposure Basal Cell Carcinoma (BCC)- most common form. Found on sun exposed parts of the body. Does not metastasize. Squamous Cell Carcinoma (SCC)-second most common skin cancer. Found typically on sun exposed parts of the body. Can metastasize. Melanoma- less common but accounts for about 75% of deaths associated with skin cancer. Found on sun exposed parts of the body but some can also be found in areas with little sun exposure. Very aggressive cancer and highly metastatic. Actinic keratosis (premalignant skin lesions for SCC) Rough ,scaly spots on sun-damaged skin Represent abnormal skin development due to exposure to UV radiation Should be considered potentially precancerous(>10 AKs = 10-15% risk SCC) Common on exposed sites eg backs of hands,face,scalp and ears of bald men A certain percentage progress to SCC Actinic keratosis-treatment Diclofenac gel (Solaraze) -NSAID Cryotherapy Curettage/Excision 5-Fluorouracil cream (Efudix) Imiquimod 5% cream (Aldara) Photodynamic therapy Bowen’s disease Bowen’s disease is intraepidermal squamous cell carcinoma It is effectively carcinoma-in situ It may progress into squamous cell carcinoma (approximately 5%) Because of this, it is very important to treat it effectively Bowen’s disease Presents as a pink or red ,irregular scaly patch Usually develops in a sun –exposed area of skin Common sites include hands and face in both sexes, scalp in men, lower legs in women Diagnosis should be confirmed by biopsy Bowen’s disease Bowen’s disease-causes: UV radiation causes mutation in genes controlling skin cell growth UV radiation suppresses immune response in skin Arsenic ingestion Ionising radiation-very common in early 20th century radiologists Bowen’s disease-treatment: Cryotherapy Curettage/excision 5 Fluorouracil cream (Efudix) Imiquimod 5% cream (Aldara) Photodynamic therapy Basal cell carcinoma (BCC) Affects fair skinned adults who have had a lot of sun exposure or repeated episodes of sunburn Gorlin’s syndrome-inherited tendency to multiple BCCs BCCs usually arise in normal-looking skin BCCs grow slowly over months or years Metastasis exceedingly rare but BCCs can cause destructive changes in surrounding tissues Basal cell carcinoma-types: Nodular BCC-most common type Superficial BCC-common Morphoeic BCC-waxy,scar-like Pigmented BCC- can resemble melanoma Basisquamous BCC-mixed BCC/SCC First two most common. Nodular BCC Most common type on face Small, shiny, skin-coloured swelling Telangiectasia cross the edge May have central ulcer or scab so edges appear rolled Often bleed spontaneously, then heal over Rodent ulcer is an open sore Facial BCC should be referred to plastic surgeon Nodular BCC Superficial BCC Often multiple Upper trunk or shoulders commonest site but can appear anywhere Pink or red scaly patch with raised edge on close examination Slowly growing over months or years Bleed or ulcerate easily Superficial BCC Upregulation of the Hedgehog Signaling Pathway in BCC Mutations in Ptch1 lead to its activation driving BCC development BCC- treatment: Shave,curettage,cautery Excision biopsy, may need grafting or flap. Moh’s micrographic excision Photodynamic therapy Imiquimod 5% cream-highly effective for superficial BCCs Cryotherapy Radiotherapy Cutaneous Squamous Cell Carcinoma (cSCC) ▪ More than 750,000 new cases of squamous cell carcinoma diagnosed each year in the U.S.. ▪ Often develop from actinic keratosis (AKs). ▪ Can look similar to basal cell carcinoma, and even actinic keratosis. ▪ Cancer that begins in squamous cells (keratinocytes) in the epidermis. Cutaneous Squamous Cell Carcinoma cSCC is a common type of skin cancer It develops in the epidermis from squamous cells which produce keratin Usual presentation is a slowly –growing scaly or crusted lump Can present as a non-healing sore or ulcer “punched out” in appearance Sometimes growth is rapid over a matter of weeks. Squamous Cell Carcinoma ▪ Similar in appearance to actinic keratosis and basal cell carcinoma. Squamous Cell Carcinoma-causes: UV radiation-damages DNA in skin SCC may develop in an actinic keratosis or patch of Bowen’s disease Genetic predisposition to develop SCCs Smoking-especially SCC lip Thermal burns Chronic leg ulcers Immunosuppression-Azathioprine/Cyclosporin. Organ transplantation patients highly susceptible HPV infection implicated in genital SCCs Pre-existing skin conditions eg lichen sclerosus and lichen planus can predispose to development of genital and oral SCCs Metastatic Squamous Cell Carcinoma 5% SCCs metastazise, most commonly from primary lesion on ear, lip or face More common in organ transplant patients Patients with CLL (immunosuppressed) Associated with increasing age More likely if multiple skin cancers present Squamous cell carcinoma-treatment If you suspect a possible SCC, treatment required immediately Surgical removal, skin graft may be necessary depending on size/depth Moh’s surgery with histologic verification best Radiotherapy may be needed again depending on the size/depth Advanced stage (metastatic) will require chemotherapy----not many good options here. Drugs such as cisplatin, doxorubicin, 5fluorouracil (5-FU), capecitabine, topotecan, and etoposide might be used. Recent success with immune checkpoint inhibitors for metastatic disease. --Cemiplimab - anti-PD-1 mAB approved in 2018 for metastatic cSCC --Pemboliziumab (Keytruda)- anti-PD-1 mAb approved in 2020 for metastatic cSCC Genetic alterations Associated with Multistage UV-Induced SCC in Humans INKa-ARF = p16 or CDKN2A Melanoma ▪ ▪ A form of skin cancer that arises in melanocytes, the cells that produce pigment and also are found in the epidermis. Melanomas usually begin in a mole, which is a benign cluster of melanocytes and other tissue. Normal moles: Malignant melanoma Melanoma May be found when a pre-existing mole changes: Early changes - forming a new black area - newly formed fine scales - itching in a mole More advanced changes - texture changes (becomes hard or lumpy) - itch, ooze, or bleed - usually do not cause pain Malignant melanoma-risk factors: Sun exposure, particularly during childhood Fair skin which burns easily Blistering sunburn, especially when young Previous melanoma Family history of melanoma Previous non-melanoma skin cancer Large numbers of moles/ dysplastic moles Common Sites for melanoma: In men commonest site is the back In women commonest site is the leg Can occur on mucous membranes, eg lips or genitals Can occur under the nail Can occur in eye, brain or mouth BEWARE AMELANOTIC MELANOMA Glasgow 7 point checklist: MINOR FEATURES: MAJOR FEATURES: Change in size Irregular shape Irregular colour Diameter > 7mm Inflammation Oozing Change in sensation The ABCDE of melanoma A B C D E Asymmetry Border irregularity Color variation Diameter over 6mm Evolving (enlarging or changing) Malignant melanoma Growth of melanomas Horizontal growth within epidermis=melanoma in situ Vertical growth through basement membrane into dermis=invasive melanoma Once melanoma penetrates dermis,it spreads via lymphatic and blood stream = metastatic melanoma Histological classification: Breslow thickness: This is the thickness of the melanoma in mm Clark’s level: This describes which layer of skin has been breached Clark’s level 1-epidermis-melanoma in situ Clark’s level 2-dermal invasion Clark’s level 5- invasion of subcutaneous fat Molecular Pathology of Melanoma CDKN2A= p16/p14arf; CD1=cyclin D1 Taken from NEJM 355:51-56, 2006 Treatment of Melanoma Refer suspected melanoma via FAST-TRACK pathway Surgical excision with 2-3 mm margin Wider excision if histology confirms melanoma Thicker melanomas> 1mm-wider excision +/- sentinel node biopsy Widespread melanoma-surgery plus chemotherapy (e.g., Dacarbazine, Temozolomide, Paclitaxel, Cisplatin, Carboplatin, Vinblastine) B-raf and MEK inhibitors (debrafenib, vemurafenib,Tramemtinib) Immunotherapy for advanced disease: CTLA-4 inhibitors (e.g., ipilimumab); PD-1 inhibitors (pembrolizumab, nivolumab) and their combinations. Additional References Pathophysiology of Disease, An Introduction to Clinical Medicine, 7th edition, G. Hammer and S. McPhee, Chapter 8, 2014. Pathophysiology, The Basic Basis for Disease in Adults and Children, 7th Edition, K. McCance , S. Huether, V. Brashers and N. Rote, eds., Chapter 46, 2014 The Molecular Basis of Cancer, 4th Edition, J. Gray, P. Howley, M. Israel, C. Thompson, eds. Chapters 41 abd 42, 2105.