Dermatopathology Notes

Objectives for Part 1 include reviewing the anatomy and histology of skin architecture and recognizing key cells of the epidermis, dermis, and subcutis, including their morphologic features and functions, such as keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Normal skin architecture consists of the epidermis with epidermal ridges, the dermis with the papillary layer, dermal papillae, tactile (sensory) receptors, arteries, veins, and the reticular layer, and the subcutaneous layer with areolar connective tissue and adipocytes. The layers are abbreviated as E for Epidermis, D for Dermis, and SC for Subcutaneous Layer, with ED representing the Eccrine Duct and EG the Eccrine Gland.

In thick skin, the epidermis consists of several layers: Stratum Corneum (Horny layer), Stratum Lucidum (Clear layer), Stratum Granulosum (Granular layer), Stratum Spinosum (Spiny layer), and Stratum Basale (Basal cell layer). Rete ridges are epidermal down growths that penetrate the upper dermis, providing stronger tethering and resistance to frictional shearing force, known as the “Velcro effect.” Dermal papillae are responsible for creating fingerprints.

The Stratum Spinosum, or Prickle Cell Layer, contains cells that synthesize intermediate filament cytokeratin, which aggregates into Tonofibrils. Intercellular desmosomal bridges connect keratinocytes together. Desmosomes and hemidesmosomes feature different proteins (Dsg3, Dsc3, PKP2, Dsg1, Dsc1, PKP1) in the stratum corneum, granular layer, spinous layer, and basal layer. Electron microscopy reveals that keratin filaments assemble into microscopically visible bundles called tonofibrils, converging and terminating at numerous desmosomes.

The Basal Cell Layer (Stratum Basale) consists of columnar cells responsible for cellular regeneration. These mitotically active cells are attached to the basement membrane. Electron microscopy shows Tonofilaments (TF), Basal Keratinocytes (BC), Hemidesmosomes (HD), and the Basement Membrane (BM). Hemidesmosomes in the basal cell membranes join these cells to the basal lamina.

Basal cell carcinoma involves basal cell proliferation, seborrheic keratosis involves keratinocyte proliferation, and pemphigus vulgaris results from loss of desmosomal integrity. Epidermal Immigrant Cells include Langerhans cells, Merkel cells, and Melanocytes, the latter two being dendritic cells. Merkel cells are associated with terminal neuronal axons.

Melanocytes, derived from the neural crest, synthesize melanin by converting tyrosine to 3,4-dihydro- phenylalanine (DOPA), which is then polymerized into melanin. They transfer melanin into neighboring keratinocytes through long, branching processes that extend into the spinous layer. Electron microscopy shows Melanocytes with Melanosomes. Disorders of Melanocytes include albinism, vitiligo (lack of melanin), and malignant melanoma.

Melanocytes do not behave as epithelial cells; they are typically isolated or separate cells but can cluster to form nests of benign cells and grow/move into the dermis without being considered as malignant invasion. In Northern Europe, darker-skinned persons are at increased risk for inadequate vitamin $D_3$ synthesis. Tanning occurs in two steps: first, a physiochemical reaction darkens melanin, and second, keratinocytes accelerate melanin synthesis.

A Junctional Nevus occurs in the epidermis, a Compound Nevus in the dermis, and an Intradermal Nevus in the hypodermis. Merkel Cells, also known as Epithelial tactile cells are specialized keratinocytes. Their nerve complex provides low-threshold mechanoreceptors present only in lips, oral cavity, hair follicles, and palmar skin of digits, mediating the sensation of touch through neuro-secretory granules containing serotonin and neuropeptides. Displacement of epidermis causes exocytosis of substances, and cell membrane $Ca^{2+}$ channels initiate neural impulse. Nerve fiber-terminals contain Merkel Granules.

In histo-pathological correlation, a firm, blue-violet, painless lesion on the back, which upon excision reveals malignant Merkel cells, indicates the primary function of these cells is the detection of texture and shape during active touch. Merkel cell carcinoma, also known as Neuroendocrine Carcinoma of Skin, affects older patients on the head, face, and neck. Long-term sun exposure can weaken the immune system and increase risk. The growth is rapid.

Langerhans cells are antigen-presenting cells derived from monocytes and present in the stratum spinosum. Electron microscopy shows Birbeck granules (racket-shaped organelles), important for antigen presentation. The dermis and subcutis layers consist of the Papillary Dermis, which forms the dermal papillae and is composed of areolar (loose) connective tissue and a subpapillary vascular plexus; the Reticular Dermis, which is a deep layer composed of dense connective tissue and elastic fibers with a deep plexus of blood vessels extending into the subcutis; and the Subcutis, composed of areolar and adipose connective tissue. Clinical correlations include wrinkles resulting from loss of elastin function, lipomas composed of adipose tissue, and erythema nodosum, which is inflammation of the subcutis.

Part 2 objectives include recognizing examples of epidermal histopathologic changes such as acanthosis vs. acantholysis, spongiosis vs. bulla, Pautrier microabscess vs. Munro microabscess, parakeratosis vs. hyperkeratosis/keratosis vs. hypergranulosis, and koilocytosis. It also involves listing examples of disorders associated with epidermal cells (ichthyosis vulgaris, psoriasis, vitiligo, melanoma, contact dermatitis, merkel cell carcinoma) and distinguishing between techniques of scrape, shave biopsy, punch biopsy, and excision/incisional biopsy.

Key terminology includes: 1. Acanthosis (D. Hyperplasia of the stratum spinosum), 2. Acantholysis (H. Separation of cells in the stratum spinosum), 3. Bulla (> 5mm) (E. Large fluid-filled blister), 4. Macule (C. Flat, colored lesion), 5. Pagetoid spread (F. Malignant cells within the epidermis), 6. Parakeratosis (G. Retained nuclei within the stratum corneum), 7. Spongiosis (B. Edema within epidermis), 8. Urticaria (Hives, Wheal) (A. Edema within the dermis), and 9. Vesicle (I. Small fluid-filled blister).

Dermatology techniques vary. An excisional biopsy involves the complete removal of a lesion with a margin of normal skin down to adipose tissue, useful for suspected melanoma or skin cancer. An incisional biopsy takes a cross-section wedge of tissue through the center of a lesion, useful when the lesion is too big to excise and the diagnosis is unsure. A shave biopsy horizontally shaves the skin lesion with only a superficial portion of the dermis, used only to remove benign lesions, as it may not get the entire depth of the lesion and leaves the largest scar, and should never be used if melanoma is suspected. A punch biopsy is used for sampling possible cancers, tumors, and inflammatory skin conditions, where multiple biopsies can be done to obtain more extensive sampling.

Ichthyosis Vulgaris (Fishskin) is an autosomal “semi-dominant” inheritance resulting in excessive epidermal cornification due to decreased or absent synthesis of profilaggrin (skin barrier function). Corneocytes are surrounded by a lipid matrix, and Filaggrin plays a role in mechanical integrity, forming a strong scaffolding for the extracellular lipid matrix, and epidermal barrier, providing water-holding capacity and maintaining acid pH. Pathogenesis involves increased cohesiveness of the stratum corneum cells, leading to a thick stratum corneum, reduced keratohyaline granules resulting in a thin stratum granulosum, and abnormal keratinization impairing tonofilament and keratohyaline synthesis. Filaggrin impairment is seen in Icthyosis vulgaris and Eczema.

Psoriasis is a persistent epidermal hyperplasia with increased incidence linked to HLA haplotypes, environmental physical injury, defective epidermal cell surface receptors, and immunologic factors. A small percent of patients can develop psoriatic arthritis (HLA-B27). Histologically, psoriasis presents as a thickened epidermis, hyperkeratosis & parakeratosis, elongated papillae and rete ridges, and neutrophils migrating into the epidermis (Munro abscess), with pustules potentially forming.

In a case of allergic contact dermatitis, a 6-year-old boy presents with an itchy rash on his left lower leg after playing in a wooded area. Physical exam reveals erythematous papules and vesicles in a linear pattern, resulting from topical exposure to allergens like poison ivy/oak, lacquer, jewelry, detergents, or fragrance. This involves a delayed type hypersensitivity reaction where Langerhans cells process the antigen, migrate to the draining lymph node, and present to naïve T cells, leading to T cell sensitization. T cells then migrate to the affected skin site, releasing cytokines that recruit more inflammatory cells and cause epidermal damage.

In a case study, a 26-year-old female presents for an annual exam and reports being sexually active without consistent barrier protection. Examination of the cervix and vagina was normal. The pap smear report indicates mild squamous dysplasia/Low grade squamous intraepithelial lesion (LSIL), with koilocytes identified, and the HPV strain report is pending. This is indicative of a possible HPV infection.

• Objectives for Part 1 include reviewing the anatomy and histology of skin architecture and recognizing key cells of the epidermis, dermis, and subcutis, including their morphologic features and functions, such as keratinocytes, melanocytes, Langerhans cells, and Merkel cells.

• Normal skin architecture consists of:

  • Epidermis with epidermal ridges

  • Dermis with:

  • Papillary layer

  • Dermal papillae

  • Tactile (sensory) receptors

  • Arteries and veins

  • Reticular layer

  • Subcutaneous layer with areolar connective tissue and adipocytes

• Layers abbreviated:

  • E (Epidermis)

  • D (Dermis)

  • SC (Subcutaneous Layer)

  • ED (Eccrine Duct)

  • EG (Eccrine Gland)

• Thick skin epidermis consists of:

  • Stratum Corneum (Horny layer)

  • Stratum Lucidum (Clear layer)

  • Stratum Granulosum (Granular layer)

  • Stratum Spinosum (Spiny layer)

  • Stratum Basale (Basal cell layer)

• Rete ridges are epidermal down growths that penetrate upper dermis, providing stronger tethering and resistance to frictional shearing force, known as “Velcro effect.”

• Dermal papillae are responsible for creating fingerprints.

• Stratum Spinosum (Prickle Cell Layer):

  • Cells synthesize intermediate filament cytokeratin, which aggregates into Tonofibrils.

  • Intercellular desmosomal bridges connect keratinocytes together.

  • Desmosomes and hemidesmosomes feature different proteins (Dsg3, Dsc3, PKP2, Dsg1, Dsc1, PKP1) in the stratum corneum, granular layer, spinous layer, and basal layer.

  • Electron microscopy reveals keratin filaments assemble into microscopically visible bundles called tonofibrils, converging and terminating at numerous desmosomes.

• Basal Cell Layer (Stratum Basale):

  • Consists of columnar cells responsible for cellular regeneration.

  • These mitotically active cells are attached to the basement membrane.

  • Electron microscopy shows Tonofilaments (TF), Basal Keratinocytes (BC), Hemidesmosomes (HD), and Basement Membrane (BM).

  • Hemidesmosomes in the basal cell membranes join these cells to the basal lamina.

• Clinical correlations:

  • Basal cell carcinoma: basal cell proliferation

  • Seborrheic keratosis: keratinocyte proliferation

  • Pemphigus vulgaris: loss of desmosomal integrity

• Epidermal Immigrant Cells:

  • Langerhans cells

  • Merkel cells

  • Melanocytes (dendritic cells)

• Merkel cells:

  • Associated with terminal neuronal axons.

• Melanocytes:

  • Derived from the neural crest

  • Synthesize melanin by converting tyrosine to 3,4-dihydro- phenylalanine (DOPA), which is then polymerized into melanin.

  • Transfer melanin into neighboring keratinocytes through long, branching processes extending into the spinous layer.

  • Electron microscopy shows Melanocytes with Melanosomes.

• Disorders of Melanocytes:

  • Albinism

  • Vitiligo (lack of melanin)

  • Malignant melanoma

• Melanocytes do not behave as epithelial cells; they are typically isolated or separate cells but can cluster to form nests of benign cells and grow/move into the dermis without being considered as malignant invasion.

• Northern Europe: darker-skinned persons are at increased risk for inadequate vitamin $D_3$ synthesis.

• Tanning:

  • Two steps:

  • Physiochemical reaction darkens melanin

  • Keratinocytes accelerate melanin synthesis

• Nevi:

  • Junctional Nevus: occurs in the epidermis

  • Compound Nevus: in the dermis

  • Intradermal Nevus: in the hypodermis

• Merkel Cells (Epithelial tactile cells):

  • Specialized keratinocytes

  • Nerve complex provides low-threshold mechanoreceptors present in lips, oral cavity, hair follicles, and palmar skin of digits, mediating the sensation of touch through neuro-secretory granules containing serotonin and neuropeptides.

  • Displacement of epidermis causes exocytosis of substances, and cell membrane $Ca^{2+}$ channels initiate neural impulse.

  • Nerve fiber-terminals contain Merkel Granules.

• Histo-pathological correlation: firm, blue-violet, painless lesion on back, which upon excision reveals malignant Merkel cells, indicates the primary function of these cells is the detection of texture and shape during active touch.

• Merkel cell carcinoma (Neuroendocrine Carcinoma of Skin):

  • Affects older patients on the head, face, and neck.

  • Long-term sun exposure can weaken the immune system and increase risk.

  • Growth is rapid.

• Langerhans cells:

  • Antigen-presenting cells derived from monocytes and present in the stratum spinosum.

  • Electron microscopy shows Birbeck granules (racket-shaped organelles), important for antigen presentation.

• Dermis and Subcutis Layers:

  • Papillary Dermis:

  • Forms the dermal papillae

  • Areolar (loose) connective tissue and a subpapillary vascular plexus

  • Reticular Dermis:

  • Deep layer composed of dense connective tissue and elastic fibers with a deep plexus of blood vessels extending into the subcutis

  • Subcutis:

  • Composed of areolar and adipose connective tissue

• Clinical correlations:

  • Wrinkles: loss of elastin function

  • Lipomas: composed of adipose tissue

  • Erythema nodosum: inflammation of the subcutis

• Part 2 Objectives include recognizing examples of epidermal histopathologic changes.

• Key terminology:

  1. Acanthosis: Hyperplasia of the stratum spinosum

  2. Acantholysis: Separation of cells in the stratum spinosum

  3. Bulla (> 5mm): Large fluid-filled blister

  4. Macule: Flat, colored lesion

  5. Pagetoid spread: Malignant cells within the epidermis

  6. Parakeratosis: Retained nuclei within the stratum corneum

  7. Spongiosis: Edema within epidermis

  8. Urticaria (Hives, Wheal): Edema within the dermis

  9. Vesicle: Small fluid-filled blister

• Dermatology techniques:

  • Excisional biopsy: complete removal of a lesion with a margin of normal skin down to adipose tissue, useful for suspected melanoma or skin cancer.

  • Incisional biopsy: cross-section wedge of tissue through the center of a lesion, useful when the lesion is too big to excise and the diagnosis is unsure.

  • Shave biopsy: horizontally shaves the skin lesion with only a superficial portion of the dermis, used only to remove benign lesions, as it may not get the entire depth of the lesion and leaves the largest scar, and should never be used if melanoma is suspected.

  • Punch biopsy: used for sampling possible cancers, tumors, and inflammatory skin conditions, where multiple biopsies can be done to obtain more extensive sampling.

• Ichthyosis Vulgaris (Fishskin):

  • Autosomal “semi-dominant” inheritance resulting in excessive epidermal cornification due to decreased or absent synthesis of profilaggrin (skin barrier function).

  • Corneocytes are surrounded by a lipid matrix, and Filaggrin plays a role in mechanical integrity, forming a strong scaffolding for the extracellular lipid matrix, and epidermal barrier, providing water-holding capacity and maintaining acid pH.

  • Pathogenesis involves increased cohesiveness of the stratum corneum cells, leading to a thick stratum corneum, reduced keratohyaline granules resulting in a thin stratum granulosum, and abnormal keratinization impairing tonofilament and keratohyaline synthesis.

  • Filaggrin impairment is seen in Icthyosis vulgaris and Eczema.

• Psoriasis:

  • Persistent epidermal hyperplasia with increased incidence linked to HLA haplotypes, environmental physical injury, defective epidermal cell surface receptors, and immunologic factors.

  • A small percent of patients can develop psoriatic arthritis (HLA-B27).

  • Histologically, psoriasis presents as a thickened epidermis, hyperkeratosis & parakeratosis, elongated papillae and rete ridges, and neutrophils migrating into the epidermis (Munro abscess), with pustules potentially forming.

• Allergic Contact Dermatitis:

  • 6-year-old boy presents with an itchy rash on his left lower leg after playing in a wooded area. Physical exam reveals erythematous papules and vesicles in a linear pattern, resulting from topical exposure to allergens like poison ivy/oak, lacquer, jewelry, detergents, or fragrance.

  • This involves a delayed type hypersensitivity reaction where Langerhans cells process the antigen, migrate to the draining lymph node, and present to naïve T cells, leading to T cell sensitization. T cells then migrate to the affected skin site, releasing cytokines that recruit more inflammatory cells and cause epidermal damage.

• Case Study: Possible HPV Infection

  • 26-year-old female presents