Skin and Cell Components

Skin and Cell Components

• Keratinocytes are squamous epithelial cells tightly bound by cell junctions
• Melanocytes in the epidermis produce melanin
• Dendritic cells (Langerhans cells) provide the first line of defense against microorganisms via antigen presentation
• Lymphocytes include T cells, which mediate inflammation, and B cells, which mediate humoral response
• The skin is a large and complex ecosystem, with specialized structures for neural end organs, enabling physical sensations
• Adnexal components, such as sweat glands, help regulate body temperature

Nomenclature of Skin Lesions: Macroscopic Lesions

• Excoriation involves a traumatic break in the epidermis, causing a raw, linear defect often self-induced
• Lichenification involves thickened, rough skin similar to lichen on a rock, resulting from repeated rubbing
• Macules are circumscribed, flat lesions distinguished by color, measuring 5mm or less in diameter, while patches are larger than 5mm
• Onycholysis is the separation of the nail plate from the nailbed
• Papules are elevated dome-shaped or flat-topped lesions, measuring 5mm or less across; nodules are larger than 5mm
• Plaques are elevated flat-topped lesions usually greater than 5mm across, potentially from coalescent papules
• Pustules are discrete, pus-filled, raised lesions
• Scales are dry, horny, plate-like excrescences resulting from imperfect cornification
• Vesicles are fluid-filled raised lesions measuring 5mm or less across, whereas bullae are greater than 5mm across; blisters are a general term for either
• Wheals are itchy, transient, elevated lesions with variable blanching and erythema due to dermal edema

Nomenclature of Skin Lesions: Microscopic Lesions

• Dyskeratosis is abnormal, premature keratinization within cells below the stratum granulosum
• Erosion is a discontinuity of the skin showing incomplete loss of the epidermis
• Exocytosis is the infiltration of the epidermis by inflammatory cells
• Acanthosis is the irregular hyperplasia of the epidermis
• Orthokeratosis is the thickening of the stratum corneum devoid of nuclei
• Hypergranulosis is the increased thickness of the granular layer
• Hyperkeratosis is the thickening of the keratin layer
• Parakeratosis is keratinization with retained nuclei in the stratum corneum, which is normal on mucous membranes
• Hydropic swelling (ballooning) involves intracellular edema of keratinocytes, often seen in viral infections
• Lentiginous refers to a linear pattern of melanocyte proliferation within the epidermal basal cell layer
• Papillomatosis is a surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae
• Spongiosis is intercellular edema of the epidermis
• Ulceration is discontinuity of the skin marked by complete loss of the epidermis, revealing the dermis or subcutis
• Vacuolization is the formation of vacuoles within or adjacent to cells, often referring to the basal cell-basement membrane zone area

Disorders of Pigmentation and Melanocytes

• Skin is vulnerable to the harmful effects of sunlight as in albinism
• Changes in preexisting skin pigmentation may signify important primary skin disorders
• Pigmentation disorders include freckles (ephelis), lentigo, melanocytic nevus (pigmented nevus or mole), dysplastic nevi, and melanoma

Freckles (Ephelis)

• Freckles are common pigmented lesions of childhood
• They are tan-red to brown macules (1-10 mm) that appear after sun exposure, fading and recurring with seasonal cycles
• They have a normal melanocyte number, possibly slightly enlarged, with increased melanin within basal keratinocytes

Lentigo

• Lentigo is a benign hyperpigmented macule on skin and mucous membranes
• Macules do not darken with sun exposure
• Linear basal hyperpigmentation (melanocytic hyperplasia) and elongation and thinning of the rete ridges are present

Vitiligo

• Vitiligo presents as irregular, well-demarcated macules devoid of pigmentation, common in darkly pigmented individuals
• Common sites include the wrists, axillae, and perioral, periorbital, and anogenital regions
• Its pathogenesis involves autoimmune etiology (-COX2, autoimmune regulator genes), neurohumoral factors, and toxic intermediates in melanin synthesis
• There is a general loss of melanocytes

Melanocytic Nevus (Pigmented Nevus, Mole)

• Melanocytic nevus, or moles, are benign neoplasms caused in most cases by acquired mutations in components of the RAS signaling pathway
• Typically, they are tan to brown, uniformly pigmented, small (<6mm), solid regions that are relatively flat (macules) to elevated (papules) with defined, rounded borders
• Numerous clinical and histologic types of moles exist
• Moles progress through a series of morphologic changes over time, proceeding through Junctional, Compound, and Intradermal Nevi stages

Dysplastic Nevi

• Can be direct precursors of melanoma
• There is a higher than 50% chance a person with dysplastic syndrome will develop melanoma by age 60
• Lesions are larger than 5mm, sporadic, and autosomal dominant
• Mutated genes (CDKN2A on chr 9p21), (CDK4 on chr 12q14) are common
• Multiple macules or plaques can be sun exposed or non exposed
• Histologically they exhibit : Large coalescent intraepidermal nests and cytologic atypia as well as lentigenous melanocytic hyperplasia and linear papillary dermal fibrosis
• Other oncogenic mutations and epigenetic changes NRAS and BRAF genes are common

Dysplastic Nevus Syndrome (DNS)

• DNS follows an autosomal dominant pattern
• A high penetrance and variable expressivity are present
• Frequency of DNS is difficult to evaluate
• Characterized by BRAF mutations (p16 & p53)
• DNS defines patients with numerous dysplastic nevi

Melanoma

• Melanoma, the most deadly of all skin cancers, is strongly linked to acquired mutations from UV radiation exposure
• It can be cured when detected and treated in its earliest stages
• Risk factors: Sun exposure, lightly pigmented individuals, Dysplastic nevus syndrome (DNS)
• Driver mutations for cell cycle control, pro-growth pathways, and telomerase
• In about 10% to 15% of affected patients, the risk of melanoma is inherited as an autosomal dominant trait
• In the rest of patients, the risk of melanoma is related to sporatic UV light exposure

Melanoma: Clinical Features

• Asymmetry occurs
• Irregular borders are present
• Variegated colors may appear
• Increasing diameter occurs
• Evolution or change over time, especially if rapid

Melanoma: Growth Phase

• Radial growth phase lacks capacity to metastasize; subtypes include lentigo maligna, superficial spreading, and acral/mucosal lentiginous melanoma
• Vertical growth phase includes extension to deep dermis, loss of cellular maturation, and metastatic capacity

Benign Cutaneous Epithelial Neoplasm

• Derived from the keratinizing stratified squamous epithelium of the epidermis, hair follicles, and the ductular epithelium of cutaneous glands
• Biopsy is required for definitive diagnosis to rule out malignancy if pigmented or inflamed
• Seborrheic keratoses are common epidermal tumors in middle-aged or older individuals, arising spontaneously on the trunk, extremities, head, and neck
• In people of color, multiple small seborrheic keratoses on the face are termed dermatosis papulosa nigra
• Activating mutations in fibroblast growth factor receptor-3 (FGFR3) contribute to it's pathogenesis
• Seborrheic keratoses may suddenly appear in large numbers as part of a paraneoplastic syndrome
• Leser-Trélat sign is present for stimulation of keratinocytes by transforming growth factor-a (TGF-α) produced by tumor cells

Seborrheic Keratosis: Morphology and Histology

• Round, flat, coin-like, waxy plaques (mm-cm) that are tan to brown in color
• Histology shows it is sharply demarcated, exophytic, and with hyperplasia of basal cells, hyperkeratosis, horn cysts

Acanthosis Nigricans

• Acanthosis nigricans can be an important cutaneous sign of several underlying benign and malignant conditions
• A condition marked by thickened, hyperpigmented skin with a velvet-like texture
• It most commonly appears in the flexural areas (axillae, skin folds of the neck, groin, and anogenital regions)
• 80% are benign or malignant middle age and older individuals with adenocarcinoma (GI)
• A familial disease is associated to germline activating mutations in the receptor tyrosine kinase FGFR3

Fibroepithelial Polyp

• Acrochordon or squamous papilloma (skin tag)
• Common in the neck, trunk, or intertriginous zones
• associated with pregnancy, diabetes, or intestinal polyposis

Epithelial Cysts (Wens)

• Well circumscribed, firm subcutaneous nodules formed by down growth and cystic expansion of the epidermal or follicular epithelium
• Subdivided on the basis of the cyst wall characteristics
• Epidermal inclusion cysts are a specific type
• Dermoid cysts are as well
• Steatocystoma simplex (cyst wall resembling sebaceous gland duct from which numerous compressed sebaceous lobules originate) and/or multiplex (dominant heritable condition)

Adnexal Appendage Tumors

• Benign neoplasm arising from skin appendages
• Cylindroma exhibits multiple coalescing nodules of basaloid cells with apocrine differentiation on the scalp and forehead
• Syringoma features multiple, small, tan papules near the lower eyelids, showing tadpole-shaped islands of basaloid epithelium with focal eccrine differentiation
• Trichoepithelioma manifests on the face, scalp, neck, and upper trunk, marked by proliferation of basaloid cells from hair follicle-like structures
• Trichilemmoma is a benign appendage tumor
• Hydradenoma papilliferum is too

Premalignant and Malignant Epidermal Tumors

• Actinic keratosis presents as a premalignant dysplastic lesion associated with chronic sun exposure
• It is <1 cm, tan brown, red, or flesh-colored with rough consistency
• Histology shows Hyperkeratosis, parakeratosis and elastosis and keratinocyte dysplasia
• Keratoacanthoma is a self-limited, spontaneously resolving, rapid growing lesion occurring in sun exposed skin of whites >50 y with p53 mutation

Squamous Cell Carcinoma

• 2nd most common tumor ofsun-exposed skin in older individuals, found mostly inmen
• Risk factors are Sunlight (UV), Industrialcarcinogens, Chronic skin ulcers, Old burn scars (Marjolin's ulcer), Draining osteomyelitis, Ionizing radiation, Tobacco, HPV, Xeroderma pigmentosum
• Morphology :in situ: well demarcated, red scaling plaques

Tumor Histology for Squamous Cell Carcinoma

• In situ: full thickness epidermal atypia
• Invasive- well differentiated to anaplastic

Basal Cell Carcinoma

• Most common invasive cancer in human
• It is a slow-growing tumor that rarely metastasizes
• Risk factors include are *Sun-exposure, lightly pigmented people,*Immunosuppression, *Defects in DNArepair-Xeroderma pigmentosum

Merkel Cell Carcinoma

• Neuralcrest-derived cell tumor
• Exhibits Neurosecretory granules
• Exhibits Immunoperoxidase staining pattern
• CK20 dot positivity pattern is present

Tumors of the Dermis

• Dermatofibroma: Neoplasm of dermal fibroblasts and histiocytes that is most common in adults on Legs of young to middle-aged women may have an antecedent of trauma

Benign Fibrous Histiocytoma: Histology

• are Spindle-shaped fibroblasts
• present Mid-dermal nonencapsulated mass extending to subcutaneous fat

Dermatofibrosarcoma Protuberans

• Well differentiated slow growing fibrosarcoma that is Locally aggressive
• Firm nodules may ulcerate
• Most cases are in the the trunk

Mycosis Fungoides (Cutaneous T-Cell Lymphoma)

• Hallmark includes: Sezary-Lutzner cell (a malignant CD4+ cell with cerebriform nuclei) and Pautrier microabscesses

Mastocytosis

• Cutaneous and often visceral mast cell proliferation
• Pruritus, flushing, rhinorrhea, or dermaledema and erythema are common
• Darier sign (wheal when lesional skin is rubbed)

Ichthyosis

• Inherited conditions of Epidermal Maturation
• Associated with cell defects that cause increased scaling
• Defective desquamation: increased cell-cell adhesion

Hives

• Angioedema: dermal and subcutaneous fat edema
• Mediated by antigen-specific IgE which also occurs as independent pathway Hereditary angioneurotic edema- Deficient C1- esterase inhibitor (compliment-mediated urticarial)

Acute Ezematous Dermatitis

• Contact Dermatitis cause- Topically applied Agents (Ags)-- Marked itching, requires antecedent
• The Histology commonly shows spongiotic dermatitis

Erythema Multiforme (EM)

• Uncommon, self-limited hypersensitivity response to drugs (sulfonamides and penicillin), infections or to systemic disorders, Extensive epidermal degeneration and necrosis

EM Histiology

• Dermal-epidermal junction and superficial perivascular lymphocytic infiltrates with dermal edema and focal basal keratinocyte degeneration and necrosis
• Exocytosis: epidermal necrosis occurs in the dermis
• • Target-like lesions present with central necrosis with associated perivenular inflammation

Stevens-Johnson Syndrome

• Extensive and symptomatic febrile form of EM
• A condition is often seen in children
• It includes Extensive Erosions and hemorrhagic crusting involves lips, oral mucosa, conjunctiva, urethra and anogenital regions- and can cause Bacterial superinfection with lifethreatening sepsis

List skin infections

• Verrucae (Warts)-Common lesions and spontaneously regress
• Condyloma acuminatum (venereal wart)- Soles and palms
• molluscum bodies exibit cuplike verrucous epidermal hyperplasia

What is cellulitis, and how is it treated?

• Cellulitis typically is seen around one particular area of the body , and can be treated by antibiotics

Folliculitis versus cellulitis? cellulitis versus impetigo?

• Folliculitius is confined to hair, whereas cellulitis is not

Panniculitis

• Factitial panniculitis- Self-inflicted trauma or administered foreign substances
• Panniculitis is an inflammation of the subcutaneous fat Erythema nodosum-Fever, malaise may accompany cutaneous signs