Palmar plantar erythrodysesthesia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Palmar plantar erythrodysesthesia (PPE), also known as hand-foot syndrome, is a dermatological side effect of a number of chemotherapeutic drugs. In 1974, Zuehlke was the first to describe palmar plantar erythrodysesthesia (PPE) in a patient receiving mitotane for hypernephroma. A number of different classifications have been used for grading the severity of palmar plantar erythrodysesthesia (PPE). The classifications suggested by the National Cancer Institute (NCI), and the World Health Organization (WHO) are the two most commonly used. 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. Several different chemotherapeutic agents have been associated with palmar plantar erythrodysesthesia (PPE). Most frequently associated drugs include cytarabine, docetaxel, doxorubicin, liposomal-encapsulated doxorubicin, 5-fluorouracil, and capecitabine. Palmar plantar erythrodysesthesia (PPE) must be differentiated from other skin disorders that involve palms and/or soles, such as Graft-versus-host disease, contact dermatitis, palmoplantar plaque psoriasis, dyshidrotic eczema, and palmoplantar pustulosis. Palmar plantar erythrodysesthesia (PPE) has been reported to occur in 6 – 64% of patients treated with different chemotherapy regimens. However, the exact incidence of PPE is unknown, as most reports are isolated case reports or short case series. The most common and established risk factors are chemotherapeutic agents. The severity of the condition depends on the dose and frequency of the agent. There is insufficient evidence to recommend routine screening for palmar plantar erythrodysesthesia. Prognosis is generally good and symptoms usually resolve within 1 – 2 weeks after stopping the causative chemotherapeutic agent. If left untreated, palmar plantar erythrodysesthesia (PPE) can progress rapidly. PPE is not life-threatening, but it can be very debilitating and can significantly impair quality of life. There is no single diagnostic study of choice for the diagnosis of palmar plantar erythrodysesthesia (PPE). PPE is primarily diagnosed based on the history and clinical presentation. The most common symptoms of PPE include tingling, burning pain, edema, and erythema. Less common symptoms of PPE include sensory impairment, paresthesia, and pruritus. Physical examination of patients with PPE depends on the grade of the disease. Determination of toxicity grading of PPE requires both visual assessment and patient description of symptoms. Skin findings include erythema, edema, hyperkeratosis, peeling, blisters, bleeding, and fissures. There are no diagnostic laboratory findings associated with palmar plantar erythrodysesthesia. There are no ECG findings associated with palmar plantar erythrodysesthesia. There are no x-ray findings associated with palmar plantar erythrodysesthesia. There are no echocardiography/ultrasound findings associated with palmar plantar erythrodysesthesia. There are no CT scan findings associated with palmar plantar erythrodysesthesia. There are no MRI findings associated with palmar plantar erythrodysesthesia. There are no other imaging findings associated with palmar plantar erythrodysesthesia. There are no other diagnostic studies associated with palmar plantar erythrodysesthesia. Dose reduction, lengthening the interval between dose administration, and ultimately drug withdrawal are the most effective strategies. Specific treatment strategies include cooling the extremities during drug administration, vitamin B6, topical and oral corticosteroids, and topical 99% dimethyl sulfoxide. Surgical intervention is not recommended for the management of palmar plantar erythrodysesthesia. Avoiding excessive manual work and walking, wound care to prevent infection, limb elevation, cold compresses, avoiding extreme temperatures, analgesics, and creams/emollients are suggested to prevent, delay onset, and/or decrease the severity of palmar plantar erythrodysesthesia (PPE). There are no established measures for the secondary prevention of palmar plantar erythrodysesthesia.

In 1974, Zuehlke was the first to describe palmar plantar erythrodysesthesia (PPE) in a patient receiving mitotane for hypernephroma.

A number of different classifications have been used for grading the severity of palmar plantar erythrodysesthesia (PPE). The classifications suggested by the National Cancer Institute (NCI), and the World Health Organization (WHO) are the two most commonly used.

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.

Several different chemotherapeutic agents have been associated with palmar plantar erythrodysesthesia (PPE). Most frequently associated drugs include cytarabine, docetaxel, doxorubicin, liposomal-encapsulated doxorubicin, 5-fluorouracil, and capecitabine.

Palmar plantar erythrodysesthesia (PPE) must be differentiated from other skin disorders that involve palms and/or soles, such as Graft-versus-host disease, contact dermatitis, palmoplantar plaque psoriasis, dyshidrotic eczema, and palmoplantar pustulosis.

Palmar plantar erythrodysesthesia (PPE) has been reported to occur in 6 – 64% of patients treated with different chemotherapy regimens. However, the exact incidence of PPE is unknown, as most reports are isolated case reports or short case series.

The most common and established risk factors are chemotherapeutic agents. The severity of the condition depends on the dose and frequency of the agent.

There is insufficient evidence to recommend routine screening for palmar plantar erythrodysesthesia.

Prognosis is generally good and symptoms usually resolve within 1 – 2 weeks after stopping the causative chemotherapeutic agent. If left untreated, palmar plantar erythrodysesthesia (PPE) can progress rapidly. PPE is not life-threatening, but it can be very debilitating and can significantly impair quality of life.

There is no single diagnostic study of choice for the diagnosis of palmar plantar erythrodysesthesia (PPE). PPE is primarily diagnosed based on the history and clinical presentation.

The most common symptoms of PPE include tingling, burning pain, edema, and erythema. Less common symptoms of PPE include sensory impairment, paresthesia, and pruritus.

Physical examination of patients with PPE depends on the grade of the disease. Determination of toxicity grading of PPE requires both visual assessment and patient description of symptoms. Skin findings include erythema, edema, hyperkeratosis, peeling, blisters, bleeding, and fissures.

There are no diagnostic laboratory findings associated with palmar plantar erythrodysesthesia.

There are no ECG findings associated with palmar plantar erythrodysesthesia.

There are no x-ray findings associated with palmar plantar erythrodysesthesia.

There are no echocardiography/ultrasound findings associated with palmar plantar erythrodysesthesia.

There are no CT scan findings associated with palmar plantar erythrodysesthesia.

There are no MRI findings associated with palmar plantar erythrodysesthesia.

There are no other imaging findings associated with palmar plantar erythrodysesthesia.

There are no other diagnostic studies associated with palmar plantar erythrodysesthesia.

Dose reduction, lengthening the interval between dose administration, and ultimately drug withdrawal are the most effective strategies. Specific treatment strategies include cooling the extremities during drug administration, vitamin B6, topical and oral corticosteroids, and topical 99% dimethyl sulfoxide.

Surgical intervention is not recommended for the management of palmar plantar erythrodysesthesia.

Avoiding excessive manual work and walking, wound care to prevent infection, limb elevation, cold compresses, avoiding extreme temperatures, analgesics, and creams/emollients are suggested to prevent, delay onset, and/or decrease the severity of palmar plantar erythrodysesthesia (PPE).

There are no established measures for the secondary prevention of palmar plantar erythrodysesthesia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

In 1974, Zuehlke was the first to describe palmar plantar erythrodysesthesia (PPE) in a patient receiving mitotane for hypernephroma.

• In 1974, Zuehlke was the first to describe palmar plantar erythrodysesthesia (PPE) in a patient receiving mitotane for hypernephroma.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

A number of different classifications have been used for grading the severity of palmar plantar erythrodysesthesia (PPE). The classifications suggested by the National Cancer Institute (NCI), and the World Health Organization (WHO) are the two most commonly used.

• Palmar plantar erythrodysesthesia (PPE) may be classified into 3 grades according to the National Cancer Institute (NCI).^[1]

Classification of PPE severity according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0

GRADES
1	Minimal skin changes (e.g, erythema, edema, or hyperkeratosis) without pain
2	Skin changes (e.g, peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting instrumental ADL
3	Severe skin changes (e.g, peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting self care ADL

• Palmar plantar erythrodysesthesis (PPE) may be classified into 4 grades based on the World Health Organization (WHO). ^[2]

Classification of PPE severity according to WHO criteria

GRADES
1	Dysesthesia/paresthesia, tingling in the hands and feet
2	Discomfort in holding objects and upon walking, painless swelling or erythema
3	Painful erythema and swelling of palms and soles, periungual erythema and swelling
4	Desquamation, ulceration, blistering, severe pain

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

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]
  

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Palmar plantar erythrodysesthesia (PPE) has been reported to occur in 6 – 64% of patients treated with different chemotherapy regimens. However, the exact incidence of PPE is unknown, as most reports are isolated case reports or short case series.

• Based on some case series, palmar plantar erythrodysesthesia (PPE) has been reported to occur in 6 – 64% of patients treated with different chemotherapy regimens. ^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

The most common and established risk factors are chemotherapeutic agents. The severity of the condition depends on the dose and frequency of the agent.

• Exposure to chemotherapeutic agents has been proven to be an established risk factor.
• It has a direct relation with the dose of and duration of exposure to chemotherapeutic agents.
• The data is limited to support any other associated risk factors as the pathophysiology of palmar plantar erythrodysesthesia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Several different chemotherapeutic agents have been associated with palmar plantar erythrodysesthesia (PPE). Most frequently associated drugs include cytarabine, docetaxel, doxorubicin, liposomal-encapsulated doxorubicin, 5-fluorouracil, and capecitabine.

Chemotherapy drugs that can cause this syndrome include: ^[1]

Most Frequently Associated:

• Cytarabine (Cytosar-U) ^{[2] [3]}
• Docetaxel (Docefrez, Taxotere) ^{[4] [5]}
• Doxorubicin (Adriamycin) and liposomal-encapsulated doxorubicin (Doxil) ^{[6] [7] [8] [9] [10] [11] [12] [13] [14]}
• 5-Fluorouracil (5-FU, Adrucil) ^{[15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]}
• Capecitabine (Xeloda) ^{[30] [31] [32] [33] [34] [35] [36]}

Less Frequently Associated:

• Cisplatin ^[37]
• Cyclophosphamide ^[38]
• Daunorubicin and liposomal daunorubicin ^[39]
• Doxifluridine
• Etoposide ^{[40] [41] [42] [43]}
• Floxuridine (FUDF) ^[44]
• Hydroxyurea (hydroxycarbamide) ^[45]
• 6-Mercaptopurine ^[46]
• Methotrexate ^{[47] [48] [49] [50] [51] [52]}
• Mitotane ^[53]
• Paclitaxel (Taxol) ^{[54] [55] [56] [57]}
• Tegafur ^{[58] [59] [60]}
• Vinorelbine ^{[61] [62] [63] [64]}
• Idarubicin (Idamycin)
• Vemurafenib (Zelboraf) ^[65]
• 6-thioguanine ^[66]

Targeted Therapy Drugs Causing PPE:

• Axitinib (Inlyta) ^[67]

• Cabozantinib (Cabometyx, Cometriq) ^[68]

• Regorafenib (Stivarga)^[69]

• Sorafenib (Nexavar)^{[70][71] [72]}

• Sunitinib (Sutent) ^{[70][71] [72]}

• Pazopanib (Votrient)^[73]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Palmar plantar erythrodysesthesia (PPE) must be differentiated from other skin disorders that involve palms and/or soles, such as Graft-versus-host disease, contact dermatitis, palmoplantar plaque psoriasis, dyshidrotic eczema, and palmoplantar pustulosis.

Palmar plantar erythrodysesthesia (PPE) must be differentiated from other skin disorders that involve palms and/or soles, such as Graft-versus-host disease, contact dermatitis, palmoplantar plaque psoriasis, dyshidrotic eczema, and palmoplantar pustulosis.

Disease	Clinical manifestation	Histopathology	Additional diagnostic clues
Palmar plantar erythrodysesthesia	Areas of well-defined intense erythema and edema	A variable degree of epidermal (keratinocytes) necrosis [1] Vacuolar degeneration of the basal cell layer of epidermis Spongiosis Hyperkeratosis Lymphohistiocytic infiltrates 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)[2]	History of chemotherapeutic agent use
Graft-versus-host disease (GVHD)	A diffuse macular erythema which may form papules	Histologic features of Graft-versus-host disease and palmar plantar erythrodysesthesia are identical in early stages and serial biopsies may be needed to distinguish between these two entities. Features suggestive of Graft-versus-host disease:[3] Degenerate keratinocytes at all levels of the epidermis Adjacent lymphocytes (satellite cell necrosis)	Extracutaneous manifestations of Acute GVHD, including:[2] Gastrointestinal symptoms, such as diarrhea and abdominal pain Elevated liver enzymes
Allergic contact dermatitis[4]	Well-demarcated, eczematous eruptions localized to the area of skin that in contact with the culprit allergen Acute eruption: Vesicular Chronic eruption: Lichenified and scaly plaques	Eosinophilic spongiosis Exocytosis of eosinophils and lymphocytes	History of allergen exposure Pruritic lesions Patch testing may help to identify allergens
Palmoplantar plaque psoriasis	Sharply defined erythematous, scaly plaques on the palms and/or soles Fissures	Acanthosis Hyperkeratosis Parakeratosis Neutrophilic infiltration in the epidermis and stratum corneum (Kogoj pustules and Munro’s microabscesses) Abundant mononuclear cells (mainly myeloid cells and T cells) in the dermis	Pruritus is common Positive Koebner phenomenon
Dyshidrotic eczema	Deep-seated clear vesicles; later, scaling, fissures and lichenification occur Deep-seated vesicles or blisters on the tips and lateral sides of the fingers, palms, and soles with subsequent scaling, fissures and lichenification	Acute: Intraepidermal spongiotic vesicles or bullae that do not involve the intraepidermal portion of the eccrine sweat duct (acrosyringium) A sparse, superficial perivascular infiltrate of lymphocytes Chronic: Predominance of parakeratosis and acanthosis with minimal or no spongiosis and a dermal lymphocytic infiltrate	Intensely pruritic History of recurrence
Palmoplantar pustulosis	Multiple pustules on the palms and/or soles, with surrounding erythema and hyperkeratosis Fissures Nail changes Brown macules at the site of resolving pustules	Parakeratosis Loss of granular layer Psoriasiform epidermal hyperplasia Spongiosis Pustules filled with neutrophils and eosinophils in the upper epidermis Mast cell and eosinophil infiltration in the upper dermis Mixed perivascular and diffuse infiltrate in the dermis (lymphocytes, neutrophils, eosinophils, and mast cells)	Non-pustular psoriasis-like eruptions may be seen in other areas Nail changes may be seen Arthralgia or unspecified arthritis may be seen in some patients

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Prognosis is generally good and symptoms usually resolve within 1 – 2 weeks after stopping the causative chemotherapeutic agent. If left untreated, palmar plantar erythrodysesthesia (PPE) can progress rapidly. PPE is not life-threatening, but it can be very debilitating and can significantly impair quality of life.

• The symptoms of palmar plantar erythrodysesthesia (PPE) usually develop 1 – 21 days after higher-dose pulse therapies and up to 2 – 10 months after continuous low-dose therapies.
• PPE development appears to be dependent on the dose of the drug.
• Both peak drug concentration and total cumulative dose determine its occurrence since both bolus infusions and continuous low-dose administration can cause a dose-dependent drug reaction.^{[1] [2][3] [4]}
• In addition, combined administration of two chemotherapeutic drugs, both capable of causing palmar plantar erythrodysesthesia (PPE), usually results in an increased frequency of occurrence and severity of PPE.

• PPE is not life-threatening, but it can be very debilitating and can significantly impair quality of life.
• If chemotherapy is continued despite the development of the PPE:
  • The lesions deteriorate, and tenderness and edema may restrict the fine movements of the fingers ^[5]
  • The erythema becomes darker or violaceous and spreads to involve the entire surface of the palms and soles.
  • The pain may be severe enough to limit activities of daily living (ADL).
  • In some patients, lesions may evolve into a palmoplantar keratoderma. ^{[6] [5]}

• If the causative chemotherapeutic agent is stopped within a few days of the development of PPE:
  • Areas of pallor with blisters develop, and eventually desquamate with extensive but superficial cracking and exfoliation.
  • A gradual clearing of symptoms will occur over a period of 2 weeks.
  • Rarely, long term sequelae may occur despite cessation of chemotherapy, with persistence of abnormal sensation of the affected digits. ^[7]
• If appropriate management is not implemented rapidly, PPE can rapidly progress.
• Re-exposure to the causative agent with similar dosage has resulted in the reaction to recur in the majority of the patients.^{[8] [9][10] [11]}