a) Lipodermatosclerosis (10 Marks)

Definition

Epidemiology

• Most common form of panniculitis
• Predominantly affects overweight women > 40 years (F:M ratio up to 12:1)
• 85% of patients have BMI > 30
• Associated comorbidities: hypertension, diabetes mellitus, prior DVT/cellulitis, thyroid disease, obstructive sleep apnea

Etiopathogenesis

• Elevated hydrostatic pressure → increased vascular permeability → extravascular fibrin deposition
• Microthrombi formation; defects in fibrinolysis (protein C/S abnormalities)
• Hypoxia → macrophage infiltration, inflammatory cytokines → fibrosis
• Upregulation of TGF-β1 → collagen I/III stimulation → fibrosis
• Occasionally drug-induced (gemcitabine, pemetrexed)

Clinical Features

Acute Phase

• Painful, poorly demarcated, cellulitis-like red-to-purple indurated plaques on the lower medial leg/anteromedial calf
• Bilateral in many cases
• DDx: cellulitis, thrombophlebitis, erythema nodosum, inflammatory morphea

Chronic Phase

• Woody, sclerotic induration with hyperpigmentation in a stocking distribution
• Classic "inverted champagne bottle" or "bowling pin" deformity — calves taper at the ankles from fibrosis of the subcutaneous fat
• Skin is tight, tethered, and depressed

Histopathology

• Dermis: Stasis changes — nodular proliferation of thick-walled vessels, hemosiderin deposition, fibrosis, lymphohistiocytic infiltrate
• Early lesions: Ischemic necrosis at the center of fat lobules → "ghost cells" (pale cell walls with no nuclei); thickened septa; sparse lymphocytic septal infiltrate
• Evolving lesions: Mixed infiltrate (lymphocytes, plasma cells, macrophages); foamy histiocytes around fat necrosis
• Lipomembranous fat necrosis: Pathognomonic small fat microcysts with feathery eosinophilic remnants of adipocytes lining the cyst cavity ("frost on a window")
• Late lesions: Microcysts collapse → replaced by dense fibrosis; lobular panniculitis without vasculitis

Diagnosis

• Primarily clinical
• Doppler/duplex ultrasound to confirm venous insufficiency
• MRI preferred over biopsy to avoid poor wound healing
• If biopsy needed: take from the most proximal edge of involvement
• Lab: rarely required; may reveal genetic mutations in the fibrinolytic system

Treatment

⚠ Fibrosis may be irreversible. Rare complication: angiosarcoma in the setting of postphlebitic LDS.

b) Sézary Syndrome (10 Marks)

Definition

1. Generalized erythroderma
2. Generalized lymphadenopathy
3. Circulating neoplastic T cells (Sézary cells) with cerebriform nuclei in peripheral blood, skin, and lymph nodes

Epidemiology

• Accounts for < 5% of all CTCL (some sources cite ~3%)
• Occurs exclusively in adults; slightly more common in males
• Unlike MF (which may progress to SS), most SS patients present with erythroderma from onset
• Poor prognosis: 5-year overall survival only 24–43%

Pathogenesis

• Neoplastic CD4+ T cells (helper T cells); origin: central memory or other T cell subsets
• Th2 phenotype → elevated IgE, eosinophilia, reduced delayed-type hypersensitivity
• Resistance to Fas-ligand and TNF-related apoptosis
• Chromosomal aberrations common; high degree of single-cell heterogeneity
• HTLV-1 has not been conclusively implicated

Clinical Features

Diagnostic Criteria (ISCL/EORTC)

• Absolute Sézary cell count ≥ 1000 cells/µL
• CD4/CD8 ratio > 10 in peripheral blood
• CD4+CD7⁻ cells ≥ 40% or CD4+CD26⁻ cells ≥ 30%

Laboratory & Histopathology

• Histology: May mimic MF — bandlike/epidermotropic dermal infiltrate with Pautrier microabscesses; often nonspecific/spongiotic in up to 1/3 of biopsies
• Bone marrow: May be involved (often sparse, interstitial)
• Lymph nodes: Dense monotonous Sézary cell infiltrate with effacement of normal architecture
• T-cell gene rearrangement studies: Identical clone in skin and blood — key diagnostic criterion
• Flow cytometry: CD3+/CD4+/CD7−/CD26− expanded population
• Novel biomarkers: PD-1, TOX, KIR3DL2 (CD158k)
• Eosinophilia and elevated IgE — from Th2 cytokines

Differential Diagnosis

Key: Demonstration of identical T-cell clone in skin and blood distinguishes SS from non-neoplastic erythroderma. Actinic reticuloid: predominant CD4−/CD8+ (inverted ratio).

Treatment

Prognosis

• 5-year overall survival: ~24–43% (Dermatology 5e: ~35%)
• Average survival: ~5 years (Andrews')
• Most patients die of opportunistic infections due to immunosuppression

a) Epidermotropism vs Exocytosis (10 Marks)

Definitions

Exocytosis

Epidermotropism

Comparison Table

Epidermotropism in Detail (Mycosis Fungoides)

• Solitary or small groups of lymphocytes in the basal cell layer
• Epidermotropism with disproportionately scant spongiosis
• Intraepidermal lymphocytes > what is expected in an inflammatory dermatosis, without acanthosis
• Intraepidermal lymphocytes larger than dermal lymphocytes
• Papillary dermal fibrosis (collagen arranged haphazardly)
• Pautrier microabscesses
• Folliculotropism / syringotropism

Key Distinguishing Mnemonic

"Exo = Inflammation, Epi = Neoplasia"

• Exocytosis + prominent spongiosis = inflammatory
• Epidermotropism + scant spongiosis + nuclear atypia + Pautrier = CTCL/MF

b) Histopathology of Darier Disease vs Hailey-Hailey Disease (10 Marks)

Overview of Both Diseases

Histopathology of Darier Disease

Epidermal Changes:

1. Suprabasal clefts/lacunae: Separation just above the basal layer, forming cleft-like spaces (lacunae) containing acantholytic cells
2. "Villi": Elongated papillary projections lined by a single layer of basal cells, projecting upward into the lacunae (like "villi" of intestinal mucosa)
3. Corps ronds (pathognomonic):
   • Large, rounded, acantholytic dyskeratotic cells in the stratum spinosum (malpighian layer)
   • Characterized by a darkly staining, partially fragmented nucleus surrounded by a clear (pale/blue) halo of cytoplasm, encircled by a bright ring of collapsed keratin bundles (perinuclear eosinophilic shell)
   • Result from apoptosis triggered by loss of adhesion, with nuclear condensation and perinuclear keratin clumping
4. Grains (pathognomonic):
   • Small, oval, flat dyskeratotic cells in the stratum granulosum and stratum corneum
   • Show an intensely eosinophilic cytoplasm of collapsed keratin bundles containing shrunken parakeratotic nuclear remnants
   • Likely derived from corps ronds in later stages
5. Hyperkeratosis and papillomatosis: Overlying epidermis is thickened; surface shows papillomatous hyperplasia with hyperkeratosis
6. Parakeratosis: Adjacent to grains in the stratum corneum

Dermal Changes:

• Mild to moderate perivascular lymphocytic infiltrate in the superficial dermis
• Papillomatous elevation of dermal papillae

Molecular basis of dyskeratosis:

• SERCA2 dysfunction → disrupted ER Ca²⁺ → breakdown of desmosomes → keratin filaments aggregate around nucleus → apoptosis → corps ronds and grains (Dermatology 2-Volume Set 5e, p. 1142–1143; Fitzpatrick's)

Histopathology of Hailey-Hailey Disease

Epidermal Changes:

1. Extensive suprabasilar acantholysis: Begins suprabasally but extends throughout the entire thickness of the spinous layer — this broad, full-thickness involvement is the key distinguishing feature from DD
2. "Dilapidated brick wall" appearance (pathognomonic):
   • Partial loss of intercellular contacts at multiple levels within the epidermis
   • Acantholytic cells remain loosely attached to each other by occasional persistent desmosomal contacts → the epidermis resembles a "dilapidated" or crumbling wall of bricks that are falling apart but still partially connected
3. Dyskeratosis: Present but mild and focal — far less prominent than in Darier disease; individual cell dyskeratosis (corps ronds, grains) are minimal or absent
4. Intraepidermal vesicles: Formed by the extensive acantholysis
5. Overlying crusting: With neutrophilic infiltration in acute phases
6. Mild hyperkeratosis: May be present

Dermal Changes:

• Moderate lymphocytic dermal infiltrate
• No significant papillomatosis (unlike DD)

Molecular basis of acantholysis:

• hSPCA1 dysfunction (Golgi Ca²⁺ ATPase) → impaired Golgi Ca²⁺ sequestration → abnormal protein trafficking → desmosomal breakdown → keratin filament retraction from desmosomes to perinuclear aggregates → pure acantholysis (Dermatology 2-Volume Set 5e, p. 1144; Fitzpatrick's)

Direct Histopathological Comparison Table

Key Points for Exam

• Both diseases show acantholytic dyskeratosis, but in HHD acantholysis dominates and dyskeratosis is minor; in DD dyskeratosis is prominent alongside acantholysis.
• Corps ronds and grains = Darier Disease (the dyskeratotic signature).
• Dilapidated brick wall = Hailey-Hailey Disease (the acantholytic signature).
• DD: focal clefts with villi; HHD: widespread clefts without villi.
• In Grover disease: histology may mimic DD but findings are focal, more acantholysis, fewer corps ronds/grains, eosinophils in dermis favor Grover.

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