Palmar Plantar Erythrodysesthesia
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Synonyms and keywords:Palmar plantar erythrodysesthesia, Palmar-Plantar Erythrodysesthesia; Palmoplantar Erythrodysesthesia; Hand-Foot Syndrome, peculiar AE, chemotherapy-induced AE, toxic erythema of the palms and soles, palmar-plantar erythema, and Burgdorfs reaction.

# Overview
Palmar Plantar Erythrodysesthesia or Hand-Foot syndrome is a skin-related reaction involving the palms an soles. It commonly occurs due to a reaction to different kinds of chemotherapeutic agent used to treat cancer. The first s. PPE may be classified into grade1, grade 2, grade 3, or grade 4 depending on toxicity rating. The pathophysiologic mechanism of Palmar Plantar Erythrodysesthesia is under active investigation and different mechanisms have been postulated.  Histologic biposy is consistent with toxic reaction. After extensive studies, it has been determined that Pegylated Liposomal doxorubicin deposits into the eccrine glands which is concentrated in the palms and soles which then causes a drug reaction and development of PPE.. Several Different types of Chemotherapeutic agents have been associated with the development of Palmar Plantar Erythrodysesthesia. PPE must be differentiated from Acute Graft Versus Host Response, Tinea manuum and Hand-Foot reaction due to tyrosine kinase inhibitor.

# Historical Perspective
In 1974, Zuehlke was the first to report a case of Palmar Plantar Erythrodysesthesia which was associated with mitotane therapy.

# Classification
Palmar Plantar Erythrodysesthesia may be classified according to toxicity or severity of symptoms into 4 grades.

# Pathophysiology
The pathophysiologic mechanism of Palmar Plantar Erythrodysesthesia is under active investigation and different mechanisms have been postulated. Factors that have been implicated involve rapid cell division in palms and soles, gravitational forces, vascular anatomy peculiar to these areas and temperature gradients that may be present in distal end of extremities. The higher drug concentration in the eccrine glands of palms and soles also play a role in this condition. PPE Biopsies appear histologically nonspecific, but a consistenty toxic reaction is seen.
In Palmar Plantar Erythrodysesthesia associated with Pegylated liposomal doxorubicin (PLD), it has been determined that the drug is present is deposited in sweat then smeared onto the skin surfaces. The sweat glands are present in high concentration on the palms and soles. The drug then infiltrates the stratum corneum which is a thick layer in the body. This layer acts as a reservoir for the drug leading to the symptoms of PPE.

## Associated Conditions
Palmar Plantar Erythrodysesthesia is commonly associated with chemotherapy that is used for the treatment of different cancers.

## Gross Pathology
PPE commonly affects the palms more commonly than the soles. The lesion starts as just a sensation in the palms and soles, progressing to painful, tingling, symmetric, well-demarcated swelling and erythematous plaques. This is then followed by a desquamative phase that happens on resolution.

## Microscopic Pathology
On histopathology non-specific features seen in Palmar Plantar Erythrodysesthesia. Features include:
- Vacuolar degenration of the basal cell layer
- Mild spongiosis, keratinocytes necrosis
- Papillary dermal edema
- Lymphocytic infiltrates
- Partial separation of epidermis from the dermis
- Dermis shows perivascular infiltrates made up of eosinphils and lymphocytes
- May have presence of eccrine squamous syringometaplasia or netruophilic eccrine hidradenitis.
- Some data suggests that small-fibre neuropathy may cause the pain and dysesthesia.

# Causes

## Risk Factors
Exposure to chemotherapeutic agents has been proven to be an established risk factor. Occurrence of this condition has been linked to dose and prolonged chemotherapeutic drug exposure especially with more continuous IV infusion, daily ingestion and liposomal encapsulationg of PLD which prolong half-life of drug. The use of cooling mechanism, higher number of PLD cycles, and occurrence of mucositis, neutropenia and peripheral neuropathy are possible predictors of PPE. 
Several agents may be linked with the condition but the Most frequently associated are:
- Doxorubicin (Pegylated liposomal Doxorubicin)
- 5-Flurouracil
- Cytarabine.

## Genetics
No genetic association has been found as of yet as the data on this condition is limited.

## Common Causes
- Several different Chemotherapeutic agents have been associated with acral erythema. Common ones are listed below.
Most frequently associated with:
Doxorubicin (Pegylated liposomal Doxorubicin)
5-Flurouracil
Cytarabine.
Methotrexate - even low dose used to treat ALL
Mitotane
PLD, Docetaxel, Capecitabine, vinorelbine, gemcitabine and Sorafenib
- Most frequently associated with:
Doxorubicin (Pegylated liposomal Doxorubicin)
5-Flurouracil
Cytarabine.
- Doxorubicin (Pegylated liposomal Doxorubicin)
- 5-Flurouracil
- Cytarabine.
- Methotrexate - even low dose used to treat ALL
- Mitotane
- PLD, Docetaxel, Capecitabine, vinorelbine, gemcitabine and Sorafenib
Less Common Causes
- Capacitabine-based chemotherapy
- Docetaxel 

## Causes in Alphabetical Order
- 5-Flurouracil
- Capecitabine
- Capacitabine-based chemotherapy
- Cytarabine
- Docetaxel
- Doxorubicin (Pegylated liposomal Doxorubicin)
- Gemcitabine
- Methotrexate - even low dose used to treat ALL
- Mitotane
- PLD
- Sorafenib
- Vinorelbine

# Differentiating Palmar Plantar Erythrosysesthesia from other Diseases
- Palmar Plantar Erythrosysesthesia must be differentiated from Tinea manuum which can also present in patients being treated with chemotherapy. Tinea Manuum infection responds to antifungal therapy.
- Palmar Plantar Erythrosysesthesia should be differentiated from Acute Graft Versus Host Response commonly seen in bone marrow transplanted patients who are on chemotherapy such as in leukemia. In graft-versus-host disease the condition progresses to involve other regions of the body. Palmar Plantar Erythrosysesthesia, on the the other hand is limited to hands and feet. Differentiating the two disorders is possible with either clinical features or serial biopsies every 3 - 5 days.
- Palmar Plantar Erythrosysesthesia can have similar presentation to Hand-foot skin reaction due to tyrosine kinase inhibitor. They can be differentiated with clinical presentation. PPE presents with diffuse erythema due to cytotoxic reaction while Hand-foot skin reaction has focal hyperkeratotic lesions.

# Epidemiology and Demographics

## Age

## Gender

## Race

## Developed Countries

## Developing Countries

# Risk Factors
Palmar Plantar Erythrosysesthesia has been linked with The occurrence of this condition has been linked to dose and prolonged chemotherapeutic drug exposure especially with more continuous IV infusion, daily ingestion and liposomal encapsulationg of PLD which prolong half-life of drug. The use of cooling mechanism, higher number of PLD cycles, and occurrence of mucositis, neutropenia and peripheral neuropathy are possible predictors of PPE.

# Screening

# Natural History, Complications and Prognosis
Initially, the patient of Palmar Plantar Erythrosysesthesia experiences a sensation of numbness/tingling in the palms and soles. This progresses into a painful, tingling, symmetric, well-demarcated swelling with an erythematous plaques. It is followed by a phase of desquamation upon resolution.
One of the complications associated with PPE is loss of fingerprints. It is documented in a patient who was treated with capecitabine and detained at an airport while travelling because of lack of finger prints.

# Diagnosis

## Diagnostic Criteria
In cancer patients receiving chemotherapy, swelling of hands and feet that is painful is enough to make the diagnosis. The differentials stated above should also be considered.

## History
A directed history should be obtained to ascertain

## Symptoms
"Type symptom here" is pathognomonic of the "type disease name here".
Erythematous changes of the palms with associated oedema, blistering and desquamation.

## Past Medical History

## Family History

## Social History

### Occupational

### Alcohol
The frequency and amount of alcohol consumption should be characterized.

### Drug Use

### Smoking

## Allergies

## Physical Examination

### Appearance of the Patient

### Vital Signs

### Skin

### Head

### Eyes

### Ear

### Nose

### Mouth

### Throat

### Heart

### Lungs

### Abdomen

### Extremities

### Neurologic

### Genitals

### Other

## Laboratory Findings

### Electrolyte and Biomarker Studies

### Electrocardiogram

### Chest X Ray

### CT

### MRI

### Echocardiography or Ultrasound

### Other Imaging Findings

## Other Diagnostic Studies

# Treatment

## Pharmacotherapy

### Acute Pharmacotherapies

### Chronic Pharmacotherapies

## Surgery and Device Based Therapy

### Indications for Surgery

### Pre-Operative Assessment

### Post-Operative Management

### Transplantation

## Primary Prevention
- Dr Kuznecovs with his colleagues came to the conclusion that atorvastatin and polyprenol combination can prevent PPE due to capecitabine. 
- Application of ointment containing antioxidants with high radical protection factors can effectively prevent the development of PPE.
- In a randomized control trial in patients that were using pegylated liposomal doxorubicin, it was proven that reduction of dose intensity can effectively prevent PPE. When the dose of PLD is not in excess of 10mg/m(2) weekly, PPE can be easily managed. As the literature support is limited, panel of experts advise patient education and supportive measures for prevention and treatment of PPE.

## Secondary Prevention

## Cost-Effectiveness of Therapy

## Future or Investigational Therapies