Chemotherapy-induced acral erythema (also known as "palmar-plantar erythrodysesthesia" or "hand-foot syndrome") is reddening, swelling, numbness and desquamation

Desquamation

Desquamation , also called skin peeling, is the shedding of the outermost membrane or layer of a tissue, such as the skin.-Skin:Normal, nonpathologic desquamation of the skin occurs when keratinocytes, after moving apically over about 14 days, are individually shed unnoticeably...

 on palms and soles that can occur after chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 in patients with cancer. These skin changes usually are well demarcated. Acral erythema typically disappears within a few weeks after discontinuation of the offending drug.

Synonyms

Synonyms for acral erythema (AE) include: hand-foot syndrome, palmar-plantar erythrodysesthesia, peculiar AE, chemotherapy-induced AE, toxic erythema of the palms and soles, palmar-plantar erythema, and Burgdorf’s reaction.

History

Hand-foot syndrome was first reported in association with chemotherapy by Zuehlke in 1974.

Pathogenesis

The cause of PPE is unknown. Existing theories are based on the fact that only the hands and feet are involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells (rapidly dividing epidermal cells and eccrine glands).

Offending drugs

The offending drug leading to acral erythema as an adverse drug reaction

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 usually is a cytotoxic drug, very commonly fluorouracil

Fluorouracil

Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...

, capecitabine, cytarabine

Cytarabine

Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia and non-Hodgkin lymphoma. It is also known as Ara-C...

, sorafenib, or pegylated liposomal doxorubicin

Doxorubicin

Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

.

New drugs: Targeted agents against cancer, especially two tyrosine kinase inhibitors, sorafenib

Sorafenib

Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....

 and sunitinib

Sunitinib

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...

, have also been associated with a high incidence of acral erythema. However, acral erythema due to tyrosine kinase inhibitors seems to differ somewhat from acral erythema due to classic chemotherapy drugs.

Clinical symptoms

The symptoms can occur anywhere between days to months after administration of the offending medication, depending on the dose and speed of administration (Baack and Burgdorf, 1991; Demirçay, 1997;). The patient first experiences tingling and/or numbness of the palms and soles that evolves into painful, symmetric, and well-demarcated swelling and red plaques. This is followed by peeling of the skin and resolution of the symptoms (Apisarnthanarax and Duvic 2003).

Diagnosis

Painful red swelling of the hands and feet in a patient receiving chemotherapy is usually enough to make the diagnosis. The problem can also arise in patients after bone marrow transplant

Bone marrow transplant

Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...

s, as the clinical and histologic features of PPE can be similar to cutaneous manifestations of acute (first 3 weeks) graft-versus-host disease

Graft-versus-host disease

Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...

. It is important to differentiate PPE, which is benign, from the more dangerous graft-versus-host disease. As time progresses, patients with graft-versus-host disease progress to have other body parts affected, while PPE is limited to hands and feet. Serial biopsies every 3 to 5 days can also be helpful in differentiating the two disorders (Crider et al., 1986).

Prevention

The cooling of hands and feet during chemotherapy may help prevent PPE (Baack and Burgdorf, 1991; Zimmerman et al., 1995). Support for this and a variety of other approaches to treat or prevent acral erythema comes from small clinical studies, although none has been proven in a randomised controlled clinical trial of sufficient size.

Treatment

The main treatment for acral erythema is discontinuation of the offending drug, and symptomatic treatment to provide analgesia, lessen edema

Edema

Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

, and prevent superinfection

Superinfection

In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which...

. However, the treatment for the underlying cancer of the patient must not be neglected. Often, the discontinued drug can be substituted with another cancer drug or cancer treatment.

Symptomatic treatment can include wound care, elevation, and pain medication. Corticosteroid

Corticosteroid

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

s and pyridoxine

Pyridoxine

Pyridoxine is one of the compounds that can be called vitamin B6, along with pyridoxal and pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...

 have also been used to relieve symptoms.

Prognosis

PPE invariably recurs with resumption of chemotherapy. Long-term chemotherapy may also result in reversible palmoplantar keratoderma

Palmoplantar keratoderma

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by abnormal thickening of the palms and soleAutosomal recessive and dominant, X-linked, and acquired forms have all been described.There are also acquired forms of the condition....

. Symptoms resolve 1–2 weeks after cessation of chemotherapy (Apisarnthanarax and Duvic 2003).