8.1 Dermatopathology High-Yield Lesions

Skin Architecture: Layers and Cell Types

Skin is a barrier, immune organ, and thermoregulatory surface. Exam vignettes encode disease level by which layer fails.

Epidermis (avascular, stratified squamous)

From deep to superficial:

Non-keratinocyte cells:

• Melanocytes (neural crest) in basal layer: synthesize melanin in melanosomes transferred to keratinocytes. Melanoma is malignant melanocyte neoplasia.
• Langerhans cells (bone-marrow–derived dendritic cells) in mid-epidermis: CD1a+, Birbeck granules ("tennis racket" on EM); present antigen and migrate to nodes. Depleted by UV.
• Merkel cells: mechanoreceptors in basal epidermis; Merkel cell carcinoma is rare but aggressive (neuroendocrine skin tumor).

Dermis and Subcutis

The dermis contains collagen (type I predominant), elastic fibers, vessels, nerves, adnexa (hair follicles, sebaceous and sweat glands), and immune cells. Superficial papillary dermis interfaces basement membrane; deeper reticular dermis is denser. Subcutis (hypodermis) is adipose tissue—site of panniculitis (e.g., erythema nodosum).

Basement membrane zone (BMZ) is the critical split plane for many blistering diseases: hemidesmosomes link basal keratinocytes to lamina lucida/densa; autoantibodies against BMZ components produce subepidermal blisters.

Primary Lesion Terminology

Use precise morphology—vignettes often hinge on one word.

Secondary changes (scale, crust, erosion, ulcer, lichenification, scar) describe evolution after the primary process. Nikolsky sign (shear-induced epidermal separation) is positive when cohesion within epidermis or just above BMZ is lost (pemphigus, SJS/TEN, staphylococcal scalded skin)—not classic for bullous pemphigoid.

Autoimmune Blistering: Level of Split Decides the Clinic

Mechanism logic: antibodies against desmosomes dissolve keratinocyte–keratinocyte adhesion → acantholysis and fragile blisters. Antibodies against hemidesmosomes detach the entire epidermis from dermis → tense fluid-filled bullae. IgA variants (dermatitis herpetiformis—granular IgA in dermal papillae; associated with celiac disease) and epidermolysis bullosa acquisita (type VII collagen) appear less often but share "level of split + immunofluorescence pattern" reasoning.

Severe Cutaneous Adverse Drug Reactions: SJS and TEN

The blueprint carries adverse effects of drugs on skin and subcutaneous tissue as its own category, and Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) is its highest-stakes entry. The two are one disease on a single severity spectrum, separated only by the body surface area (BSA) of epidermal detachment:

Mechanism. A drug or reactive metabolite is presented to CD8+ cytotoxic T cells, which kill keratinocytes via granulysin, perforin/granzyme B, and Fas–FasL signaling. The result is full-thickness epidermal necrosis with a subepidermal split and only a sparse dermal lymphocytic infiltrate — histologically distinct from the eosinophil-rich subepidermal blister of bullous pemphigoid and from the intraepidermal acantholysis of pemphigus vulgaris described above.

Classic triggers in a stem: sulfonamides (especially trimethoprim-sulfamethoxazole), allopurinol, aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine), nevirapine, and oxicam NSAIDs. Onset is typically 1–3 weeks after the drug is started, opening with fever and a flu-like prodrome before painful skin and mucosal erosions appear.

High-yield discriminators.

• Nikolsky sign is positive (lateral pressure shears the epidermis) — shared with pemphigus vulgaris and staphylococcal scalded skin syndrome (SSSS), but not with bullous pemphigoid.
• SSSS splits in the granular layer from exfoliative toxin and spares mucous membranes; TEN splits at the dermal–epidermal junction and essentially always involves mucosa. Add age (SSSS in young children) and that pair becomes an easy two-point discrimination.
• Erythema multiforme is a separate, milder entity most often triggered by HSV, defined by true target lesions on acral surfaces; it is no longer classified as the mild end of the SJS spectrum.
• HLA-B*15:02 predicts carbamazepine-induced SJS/TEN in patients of Han Chinese and Southeast Asian ancestry; HLA-B*58:01 predicts allopurinol reactions. Pharmacogenomic screening is the preventive answer when a stem offers it.

The immediate action tested is invariant: stop the culprit drug, then support the patient as a burn — fluid resuscitation, thermoregulation, wound care, and early ophthalmology involvement for ocular mucosa.

Psoriasis Pathogenesis

Psoriasis is a chronic immune-mediated disease of keratinocyte hyperproliferation and incomplete differentiation.

Key pathway: dendritic cells and macrophages drive a Th1/Th17 axis. IL-12 and IL-23 promote Th1/Th17 differentiation; IL-17, IL-22, and TNF-α stimulate keratinocyte proliferation and chemokine production that recruits more leukocytes—a self-amplifying loop. Biologics targeting TNF, IL-17, or IL-23 exploit this axis (pharmacology overlap).

Histology triad concepts:

1. Hyperkeratosis with parakeratosis (nuclei retained in stratum corneum—accelerated turnover).
2. Acanthosis with elongated rete ridges ("regular" psoriasiform hyperplasia).
3. Munro microabscesses (neutrophils in stratum corneum) and thin/absent granular layer; dilated vessels in dermal papillae → pinpoint bleeding on scale removal (Auspitz sign).

Clinical: well-demarcated erythematous plaques with silvery scale on extensor surfaces, scalp, lumbosacral skin; nail pitting and oil spots; psoriatic arthritis and metabolic associations. Triggers include trauma (Koebner phenomenon), streptococcal pharyngitis (guttate psoriasis), drugs (e.g., β-blockers, lithium, interferon), and withdrawal of systemic steroids.

Eczema / Atopic Dermatitis: Th2 and Barrier

Atopic dermatitis is a type I hypersensitivity–linked, barrier-first disease.

• Barrier defect: loss-of-function filaggrin mutations impair natural moisturizing factor and lipid organization → transepidermal water loss and allergen penetration.
• Immune skew: Th2 cytokines IL-4 and IL-13 drive IgE class switching; IL-5 supports eosinophils. Chronic lesions may recruit more mixed inflammation, but classic acute disease is Th2.
• Clinical: pruritic flexural eczema in children (face/extensors in infants), lichenification with chronic scratching; strong association with asthma and allergic rhinitis ("atopic march"). Secondary infection with S. aureus is common (superantigen exposure can worsen flares).

Contact dermatitis differs: allergic contact dermatitis is type IV (delayed) T-cell response to haptens (e.g., nickel, poison ivy urushiol); irritant contact dermatitis is non-immune direct toxicity.

Acne Pathogenesis

Acne vulgaris is a pilosebaceous unit disease of adolescents and adults with four interacting drivers:

1. Androgen-stimulated sebum production (puberty; also PCOS/endocrine states).
2. Follicular hyperkeratinization plugging the follicle (comedone formation: open = blackhead, closed = whitehead).
3. Cutibacterium acnes (formerly Propionibacterium acnes) colonization of the anaerobic follicle.
4. Inflammation—innate recognition of bacterial products, free fatty acids from sebum lipases, and neutrophil recruitment → papules, pustules, nodules, cysts.

Treatment logic maps to mechanism: retinoids normalize keratinization and reduce sebum signaling; benzoyl peroxide is antimicrobial/keratolytic; antibiotics reduce C. acnes and inflammation; anti-androgens or OCPs in selected female patients; isotretinoin for severe nodulocystic disease.

Melanoma vs Basal Cell Carcinoma vs Squamous Cell Carcinoma

ABCDE for melanoma risk morphology: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm (not absolute), Evolving. Depth (Breslow thickness) is the classic prognostic metric once invasive.

Risk amplifiers: fair skin/inability to tan, family history/CDKN2A and other syndromes, numerous atypical nevi, immunosuppression (especially SCC), arsenic, chronic wounds (Marjolin ulcer = SCC), xeroderma pigmentosum (nucleotide excision repair defect → extreme UV cancers).

Nevi: Growth Pattern and Risk Language

• Junctional nevus: nests at dermoepidermal junction; flat/macular, often pigmented.
• Compound nevus: junctional + dermal nests; raised pigmented.
• Intradermal nevus: nests entirely in dermis; often flesh-colored papule in adults.
• Congenital nevus: present at birth; large congenital nevi carry higher melanoma risk.
• Spitz nevus: spindle/epithelioid melanocytes in children/young adults; can mimic melanoma histologically—clinical context matters.
• Dysplastic (atypical) nevus: architectural/cytologic atypia; marker of increased melanoma risk, especially when numerous or familial.

Transformation is not the usual story for every common mole; exams emphasize changing lesions, high-risk phenotypes, and histopathologic depth once melanoma is diagnosed.

Dermatologic Manifestations of Systemic Disease

Viral Skin and Mucocutaneous Disease

HSV and VZV are herpesviruses with latency and reactivation; HPV is a DNA virus of keratinocytes with type-specific oncogenicity; molluscum is a poxvirus producing cytoplasmic inclusions and characteristic umbilication.

Integrating the Differential on Exam Day

When a stem gives a blister, ask: tense vs flaccid, mucosa, age, Nikolsky, immunofluorescence pattern. When it gives a scaly plaque, separate psoriasis (extensors, silvery scale, Auspitz) from eczema (flexural, itch, atopic history) and fungal infection (annular, KOH-positive). When it gives a pigmented lesion, run ABCDE + risk factors and remember BCC/SCC morphology differs from melanocytic atypia. Systemic disease signs are high-yield "one-look" associations that link dermatology to metabolism, vasculitis, and GI disease.