Toxic erythema of Chemotherapy

TEC is referred to clinically and histologically under various names, which often depend on the primary affected skin region. Synonyms include the following

• Hand-foot syndrome
• Chemotherapy-induced acral erythema
• Palmoplantar erythema or palmoplantar erythrodysaesthesia
• Chemotherapy-induced eccrine reaction
• Intertriginous erythema (with predominant involvement of the body folds)

Toxic erythema following chemotherapy (TEC) is a toxic, non-immune-mediated skin reaction that occurs as a result of the direct cytotoxic effect of chemotherapeutic agents on the epidermis and the ectocrine sweat glands. Clinically, TEC manifests itself in the form of painful, erythematous plaques, often accompanied by oedema, bullous changes, desquamation and post-inflammatory hyperpigmentation. These reactions typically occur within 2 days to 3 weeks after administration of chemotherapy, but can also be delayed (2-10 months) with continuous infusion

• TEC is a frequently observed side effect in patients receiving high-dose or continuous chemotherapy.
• The incidence varies depending on the chemotherapeutic agent and dosage, e.g. palmar-plantar erythema has been reported in 10-67% of patient populations treated with cytarabine depending on the cumulative dose.
• The actual rates may vary depending on the patient population and additional risk factors (such as neutropenia or concomitant antibiotic therapy).
  

Although TEC is regarded as a uniform toxic phenomenon, there are clinically and histologically different forms of presentation that can be regarded as part of a spectrum:

• Acral erythema / hand-foot syndrome: Predominant involvement of the hands and feet.
• Intertriginous erythema: Erythematous changes in body folds (e.g. armpits, groin).
• Epidermal dysmaturia: Histological changes in the epidermis (e.g. bizarre mitotic configurations, loss of cell polarity).
• Eccrine squamous syringometaplasia: Metaplastic transformation of the cells of the ectocrine sweat glands, often in conjunction with the other manifestations.
• Neutrophilic eccrine hidradenitis: A form in which a neutrophilic infiltrate and necrotic changes in the sweat glands are prominent.

These entities often overlap clinically and histologically, making the term TEC a useful descriptive umbrella term.

• Direct cytotoxic effect: Chemotherapeutic agents have a toxic effect on keratinocytes and the cells of the eccrine sweat gland system.
• Sweat secretion as an excretion pathway: The excretion of chemotherapeutic agents via sweat can lead to locally increased concentrations, which can lead to cell damage, especially on hands, feet and intertriginous zones.
• Pathophysiological factors: In addition to the toxic insult, mechanical factors such as friction, local temperature gradients and vascular characteristics play a role.
• Histological correlates: Characteristic changes are apoptosis and necrosis of keratinocytes, dysmaturation processes, vacuolar degeneration of the basal layer and eccrine squamous syringometaplasia.

• Skin changes:
  • Erythematous patches or plaques, often accompanied by oedema
  • Bullous changes may occur in areas of intense erythema and later become erosive.
  • Desquamation and post-inflammatory hyperpigmentation during healing.

• Symptoms:
  • Severe pain, burning, paraesthesia and sometimes pruritus, which can affect the quality of life

• Time course:
  • Typically onset 2 days to 3 weeks after chemotherapy
  • In the case of continuous infusions or oral chemotherapeutic agents, the onset may be delayed (up to several months)

• Systemic side effects:
  • In some cases, mucosal lesions (e.g. mucositis) and gastrointestinal symptoms may also occur, as similar toxic effects are observed in the digestive tract.

• Anamnesis
  • Detailed recording of chemotherapy (type of chemotherapeutic agent, dose, cycle interval) and concomitant medication (e.g. antibiotics)
• Clinical assessment:
  • Typical pattern with infestation of the hands, feet and intertriginous zones, occasionally also generalised distribution.
• Histopathological examination (see below)
• Differential diagnosis:
  • Differentiation from allergic drug reactions, infectious exanthema, graft-versus-host disease (GVHD) and vasculitis, whereby the temporal relationship with chemotherapy and the histological findings are decisive

• Primary infestation:
  • Hands and feet (palmar and plantar) are particularly frequently affected, hence the term "acral erythema".
• Other localisations:
  • Intertriginous areas (armpits, groin)
  • Pressure points and areas with localised friction (e.g. elbows, knees, earlobes)
  • In some cases, the erythema can also spread generalised to the head, neck, trunk and extremities

• Chemotherapeutic treatment:
  • Patients have a history of ongoing or recently completed chemotherapy, often with high-dose regimens or continuous infusion protocols.
• Multidrug therapy:
  • Multiple medications (e.g. chemotherapeutic agents, antibiotics) are often administered, which expands the differential diagnostic spectrum.
• Other risk factors:
  • Previous radiotherapy or stem cell transplantation can represent additional risk factors, as they also affect the skin and the immune system.

The histological findings in TEC typically include

• Keratinocyte changes:
  • Apoptosis, necrosis, mitotic remnants and bizarre mitotic configurations
  • Dysmaturation with loss of cell polarity and keratinocyte crowding
• Basal cell layer:
  • Vacuolar degeneration and partially confluent necrosis of the upper epidermis
• Eccrine glands:
  • Syringometaplasia eccrine squamosa: Metaplastic transformation of the ectocrine type cells (transition to a stratum spinosum-like appearance).
  • Occasionally, apoptotic changes or cancellous reactions are also observed within the eccrine structures.
• Dermis:
  • Frequently only slight, partially neutrophilic inflammatory infiltrate
  • Dermal oedema that supports clinical oedema formation

• Recurrence risk:
  • TEC may recur or worsen with re-exposure to the same or a higher dose of the chemotherapeutic agent.
• Severe symptoms:
  • Severe pain and impairment of quality of life can significantly restrict the patient's daily life.
• Risk of confusion:
  • Misdiagnosis (e.g. GVHD or infectious processes) can lead to unnecessary and potentially harmful therapeutic interventions, such as the use of systemic corticosteroids.

• Adaptation of chemotherapy:
  • Reducing the dose, extending the intervals between chemotherapy cycles or, in individual cases, discontinuing the triggering chemotherapeutic agent can help prevent the recurrence of TEC.
• Preventive measures:
  • Application of cool compresses or local hypothermia to reduce sweat gland activity.
  • Avoid excessive friction and traumatisation of the affected skin areas.
• Medicinal prophylaxis:
  • Case reports have suggested the use of vitamin B6, vitamin E, topical 99% dimethyl sulphoxide (DMSO) and oral celecoxib to reduce the severity and frequency of the reaction

• Self-limiting progression:
  • TEC is usually self-limiting and heals without specific aggressive intervention.
• Healing phase:
  • The initial phase of erythema and oedema formation is often followed by desquamation, which may be accompanied by post-inflammatory hyperpigmentation.
• Risk of recurrence:
  • Re-exposure to the triggering chemotherapeutic agent can lead to a recurrence or intensification of the reaction.
• Long-term prognosis:
  • The skin changes rarely lead to permanent damage, provided that the underlying therapy is continued and appropriate supportive measures are taken.

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