The exact pathogenesis of palmar plantar erythrodysesthesia (PPE) is not completely understood. It is thought that PPE is caused by direct toxic effect of the chemotherapeutic drugs against keratinocytes, excretion of the drugs in eccrine sweat glands, or type I allergic reaction. The pathological features of PPE are non-specific. However, since PPE involves a cytotoxic reaction primarily affecting keratinocytes, the histopathologic findings are similar to histologic manifestation of direct toxic reactions.

• The exact pathogenesis of palmar plantar erythrodysesthesia (PPE) is not completely understood.
• Suggested explanations include:

• Direct toxic effect of the chemotherapeutic drugs against epidermal cells (keratinocytes).^[1]

• Concentration and excretion of cytotoxic drugs in eccrine sweat glands causing damage or architectural insult.^[2][3]

• A type I (immunoglobulin E [IgE]-mediated) allergic reaction. This explanation is based on the occasional co-occurrence of facial erythema/edema, papular rash, and fever.^[4]

• Unique characteristics of the palms and the soles which justify their involvement as the preferred sites of involvement include: ^{[2] [5] [6]}

• High density of eccrine sweat glands^[7]

• Absence of folliculo–sebaceous units (hair follicles and sebaceous glands)^[7]
• Thick stratum corneum ^[7]
• Wide dermal papillae ^[7]
• High proliferation rate of epidermal basal cells
• The temperature and pressure gradient
• Gravitation forces
• Vascular anatomy peculiar to these areas
• In cases caused by capecitabine, higher expression of the capecitabine-activating enzyme thymidine phosphorylase in the skin of the palms^[8]

• The pathological features of PPE are non-specific.
• However, since PPE involves a cytotoxic reaction primarily affecting keratinocytes, the histopathologic findings are similar to histologic manifestation of direct toxic reactions:

• Dominantly an interface dermatitis with a cell-poor infiltrate
• A variable degree of epidermal (keratinocytes) necrosis^[9]

• Generally, in mild cytotoxic reactions (PPE WHO grades 1 and 2), necrosis is restricted to basal keratinocytes.
• In severe cytotoxic reactions (WHO grades 3 and 4) destruction of the entire basal layer occurs, and a blister along with complete epidermal necrosis may also be seen.^[10]

• Other histologic manifestations in epidermis include:

• Vacuolar degeneration of the basal cell layer of epidermis
• Mild spongiosis
• Hyperkeratosis
• Lymphohistiocytic infiltrates
• Apoptosis of keratinocytes
• Partial separation of the epidermis from the dermis

• Dermal changes include:

• Superficial perivascular infiltration of dermis by lymphocytes and eosinophils
• Papillary dermal edema
• Neutrophilic eccrine hidradenitis
• Eccrine squamous syringometaplasia, in severe PPE (WHO grades 3 and 4)

• Histologic evidence of small-fiber neuropathy, as shown by reduced epidermal nerve fiber density, has been suggested to be responsible for occurrence of neuropathic pain, dysesthesias, paresthesias, and temperature intolerance in PPE. ^[11]