Derm - Patho PDF - Fall 2024

Structure, Function, and Disorders of the Integument Prof. Paul Shreve, MPAS, PA-C Pathophysiologic Processes I Fall 2024  Objectives Describe the pathophysiologic basis for changes in color, surface texture, swelling, temper...

Structure, Function, and Disorders of the Integument Prof. Paul Shreve, MPAS, PA-C Pathophysiologic Processes I Fall 2024  Objectives Describe the pathophysiologic basis for changes in color, surface texture, swelling, temperature, and sensitivity of the skin (LO-A) Apply knowledge of the anatomic and immunologic structure of the skin to discuss the role of the skin in protecting against direct invasion of the skin and appendages by pathogens (LO-A) Explain the anatomic basis for the skin as a barrier and the role of normal flora that colonize the skin in this function (LO-A) Distinguish between common skin lesions or infections and their underlying pathophysiologic cause (immunologic, inflammatory, bacterial, viral, fungal, parasitic, exogenous) (LO-A) Apply knowledge of the molecular basis of neoplasia to an understanding of the clinical presentation, biologic behavior, morphologic appearance, classification, diagnosis, prognosis, and therapy of benign and malignant skin neoplasms (LO-A) Explain the role of ultraviolet light and other environmental factors in the development of various skin cancers (LO-A)  Clinical Manifestations of Skin Abnormalities Macule Vesicle Keloid Papule Bulla Scar Patch Pustule Excoriation Plaque Cyst Fissure Wheal Telangiectasia Erosion Nodule Scale Ulcer Tumor Lichenification Atrophy  Pathophysiology Atrophy Hyperplasias Dysplasias Neoplasias Genetic factors Inflammation – Immunologic – Infection-viral, bacterial, fungal Physical injury – Burns – Pressure ulcers – Toxic exposures  Disorders of Pigmentation & Melanocytes Freckle Caused by a focal abnormality in pigment production, enhanced melanin transfer to keratinocytes, or a combination of both Lentigo Benign localized hyperplasia of melanocytes Freckles Lentigo  Melanocytic Nevus (Pigmented Nevus, Mole) Caused by acquired activating mutations in components of the RAS signaling pathway Pathogenesis Types of Melanocytic Nevi Nevus Variant Diagnostic Cytologic Features Clinical Significance Architectural Features Congenital nevus Deep dermal and Identical to ordinary Present at birth; sometimes acquired nevi large variants have subcutaneous increased melanoma growth around risk adnexa, neurovascular bundles, and blood vessel walls Blue nevus Non-nested dermal Highly dendritic, Black-blue nodule; infiltration, often heavily pigmented often confused with with associated nevus cells melanoma clinically fibrosis Spindle and Fascicular growth Large, plump cells Common in children; epithelioid cell with pink-blue red-pink nodule; nevus (Spitz nevus) cytoplasm; fusiform often confused with cells hemangioma clinically Halo nevus Lymphocytic Identical to ordinary Host immune infiltration acquired nevi response against surrounding nevus nevus cells and cells surrounding normal melanocytes Dysplastic nevus Coalescent Cytologic atypia Potential marker or intraepidermal nests precursor of melanoma Congenital Nevus Blue Nevus Spindle & Epithelioid Cell Nevus (Spitz Nevus) Halo Nevus  Dysplastic Nevi Can be direct precursors of melanoma Caused by acquired activating mutations in NRAS and BRAF genes as well as increased CDK4 activity Dysplastic Nevus  Melanoma Caused by acquired mutations caused by exposure to UV radiation Most frequent driver mutations affect cell cycle control, pro-growth pathways, and telomerase  Melanoma Mutations affecting cell cycle control Mutation of CDKN2A gene causing decreased production of P15, P16, and ARF Normally, CDKN2A encodes p15, p16, and ADP- ribosylation Factor (ARF) P16 inhibits CDK4 and CDK6 allowing retinoblastoma (RB) tumor suppressor to block cells in G1 phase ARF enhances activity of p53 by inhibiting MDM2 (stimulates p53 degradation)  Melanoma Mutations affecting pro-growth signaling pathways Aberrant increases in RAS and PI3K/AKT signaling promote cell growth and survival Melanoma  Melanoma Mutations that activate telomerase Mutations of TERT gene encodes the catalytic subunit of telomerase This results in upregulation of telomerase resulting in immortality of the cells due to constant addition of telomeres at the terminal ends of chromosomes Melanoma  Benign Epithelial Tumors Seborrheic Keratosis Activating mutations in fibroblast growth receptor factor-3 (FGFR3) drive the growth of the tumor Seborrheic Keratosis  Acanthosis Nigricans Important cutaneous sign of underlying benign and malignant conditions (Type II diabetes mellitus & gastrointestinal adenocarcinoma) Disturbance leading to increased growth factor receptor signaling Familial form is associated with germline activating mutations in FGFR3 In type 2 diabetes, hyperinsulinemia increases stimulation of insulin-like growth factor receptor-1 (IFGR1) In paraneoplastic acanthosis nigricans cause is uncertain but has been linked to high levels of TGF-α Acanthosis Nigricans  Premalignant & Malignant Epidermal Tumors Actinic keratosis Hyperkeratosis in sun-damaged skin Superficial dermis contains thickened elastic fibers Likely a result of abnormal elastic fiber synthesis by sun- damaged fibroblasts Actinic Keratosis  Squamous Cell Carcinoma Caused by DNA damage from exposure to UV light affecting the function of p53 p53 affects cells in the G1 phase and promotes either DNA repair or elimination of cells damaged beyond repair When protective functions of p53 are lost DNA damage from UV light is repaired by mechanisms prone to error leading to mutations that are passed to daughter cells Squamous Cell Carcinoma  Basal Cell Carcinoma Aggressive cutaneous tumor caused by mutations that activate the Hedgehog signaling pathway Associated with UV light exposure Can be locally invasive Basal Cell Carcinoma Basal Cell Carcinoma  Acute Inflammatory Dermatoses Urticaria Result of antigen-induced release of vasoactive mediators (histamine) from mast cells Mast cell-dependent, IgE-dependent Occurs following exposure to antigen Mast cell-dependent, IgE-independent Results from substances that directly incite degranulation of mast cells Mast cell-independent, IgE-independent Triggered by local factors increasing vascular permeability Urticaria  Acute Eczematous Dermatitis Can be subdivided into: allergic contact dermatitis, atopic dermatitis, drug-related eczematous dermatitis, photoeczematous dermatitis, and primary irritant dermatitis Typically results from T cell-mediated inflammatory reactions (type IV hypersensitivity) Langerhans cells play a central role (especially in contact dermatitis) Acute Eczematous Dermatitis  Erythema Multiforme Self-limited hypersensitivity to certain infections and drugs Characterized by keratinocyte injury mediated by skin-homing CD8+ cytotoxic lymphocytes Erythema Multiforme Chronic Inflammatory Dermatoses Psoriasis Autoimmune chronic inflammatory dermatosis Appears to have an autoimmune basis Sensitized CD4+ Th1 and Th17 cells and CD8+ cytotoxic effector cells enter the skin and accumulate in the epidermis Psoriasis  Seborrheic Dermatitis Chronic inflammatory dermatitis Precise etiology is unknown Possible explanations include increased sebum production in response to androgens or an infection of certain fungal infections of the Malassezia genus Seborrheic Dermatitis  Lichen Planus Usually a self-limited disorder Commonly resolves spontaneously 1 to 2 years after onset Unknown pathogenesis Possibly an expression of altered androgens in basal epidermal cells or dermoepidermal junction causes a cell-mediated cytotoxic (CD8+) T-cell response Lichen Planus  Blistering (Bullous) Diseases Pemphigus Several forms exist, all are autoimmune Caused by IgG autoantibodies against desmogleins disrupting intercellular adhesions resulting in the formation of blisters Pemphigus  Bullous Pemphigoid Caused by antibody to bullous pemphigoid antigen (BPAG) Prevents hemidesmosome from binding to basement membrane causing large blisters Bullous Pemphigoid  Disorders of Epidermal Appendages Acne vulgaris Pathogenesis not well understood 4 factors contribute to development Keratinization of lower portion of the follicular infundibulum and development of a keratin plug blocking sebum outflow Hypertrophy of sebaceous glands under the influence of androgens Lipase-synthesizing bacteria (Propionibacterium acnes) colonizing the upper and mid-portions of the hair follicle converting lipids to proinflammatory fatty acids Secondary inflammation of the involved follicle Acne  Rosacea Caused by high cutaneous levels of the antimicrobial peptide, cathelicidin (mediator of the cutaneous innate immune response) Rosacea  Infection Verrucae (Warts) Caused by human papillomaviruses (HPVs) Some are associated with a high risk for cancer (16 & 18) Produce E6 proteins that abolish p53 function Some are low risk (5 & 8 for example) Produce E6 proteins that don’t affect p53, rather interfere with Notch signaling Warts  Impetigo Caused by group A β-hemolytic Staphylococcus aureus Bacteria produces a toxin specifically cleaving desmoglein Impetigo  Sources Kumar V, Abbas A, Aster J. Robbins & Cotran Pathologic Basis of Disease. 10th ed. Canada. Elsevier Saunders; 2021