Cutaneous Reactions to Chemotherapy: Commonly Seen, Less Described, Little Understood
Section snippets
Alopecia
The pathogenesis of hair loss is perhaps the best understood of the cutaneous reactions to chemotherapy. Most chemotherapeutic agents affect cells undergoing mitosis by inducing varying types of DNA damage or by interfering with the function of mitotic spindle formation. Because most hair follicles, particularly those of the scalp, are in the active anagen phase most of the time, chemotherapeutic agents will interrupt replication of the hair matrix cells inducing premature catagen involutionary
Acral erythema
The condition of acral erythema is also referred to as Burgdorf's syndrome, hand-foot syndrome, palmar-plantar erythrodysesthesia, or toxic erythema of the palms and soles. This condition refers to the development of dysesthesia over the palms and soles, followed by swelling and the formation of well-circumscribed erythematous macules [9], [11], [12], [13]. These lesions can progress to involve the entire palm and sole, and can involve the dorsal surfaces of hands or feet [1], [2], [13].
Neutrophilic eccrine hidradenitis
Neutrophilic eccrine hidradenitis (NEH; also known as drug-induced eccrine hidradenitis) typically involves the trunk, extremities, head, and neck. The condition may manifest as either a painful or nonpainful macular, papular, plaquing, or pustular erythematous rash, within 1 to 2 weeks of starting chemotherapy, typically in concurrence with a fever [1], [8], [9]. The rash resolves with desquamation, usually without subsequent hyperpigmentation or scarring [1], [9].
Histologically, NEH is
Epidermal dysmaturation
The term epidermal dysmaturation refers to a constellation of disrupted keratinocyte maturation with altered epidermal polarity, nuclear pleomorphism, mitoses above the basal layer and focal apoptosis (Fig. 4) [3], [21]. It may be shown on biopsy to occur in the context of acral erythema, or, in the case of docetaxel, simultaneously with acral erythema or NEH [17], [35].
The lesions may consist of scattered discrete maculopapular eruptions [36]. Docetaxel administration has been associated with
Eccrine squamous syringometaplasia
Eccrine squamous syringometaplasia is characterized by erythematous macules, papules, plaques, or vesicles, developing between 2 days and 5 weeks after chemotherapy. The eruption may be limited or generalized. The clinical picture is similar to neutrophilic eccrine hidradenitis, and in a similar fashion spontaneously resolves without scarring within 4 weeks [1], [38].
The histologic pattern is that of squamous metaplasia of the eccrine ducts with relative sparing of the eccrine coils (Fig. 5) [3]
Hyperpigmentation
Cutaneous hyperpigmentation may manifest with a variety of presentations, and may be caused by numerous chemotherapeutic agents, with discoloration of the skin, mucous membranes, nails, or hair. The mechanism of the toxicity has not been studied or established, but is postulated to be a result of direct toxic effects on melanocytes, stimulating increased melanin secretion [1], [8], [9]. The histologic appearance may be varied, but may demonstrate a subtle increase in pigmented melanocytes at
Chemotherapy and radiation recall and sensitivity reactions
Cutaneous recall reactions are most commonly thought to occur as a result of exposure to the combination of chemotherapy and radiation, with an inflammatory chemotherapy-induced reaction occurring at sites of previous radiation therapy. This may include recall of previous significant, or even mild, sunburn [4], [46], [47]. Chemotherapeutic agents may also induce recall reactions at sites of previous chemotherapy extravasation, or at locations of previous chemotherapy infusion [19], [48]. Table 6
Phototoxic dermatitis
Increased sensitivity to sun exposure may be manifested with exposure to multiple chemotherapeutic agents. Sun sensitivity may manifest in a variety of ways, including increased tendency for erythematous sunburn, hyperpigmentation in areas of sun exposure, and rash occurring on sun-exposed skin [42], [55], [56].
With 5-FU, sun exposure may produce any of the above reactions. In patients with erythematous reaction after even mild sun exposure, the reaction may fade over time, or may be followed
Inflammation of actinic keratoses
Preexisting actinic keratoses experience transient inflammation with exposure to certain chemotherapeutic agents. This was first described in patients undergoing therapy with 5-FU [42]. Subsequent to this discovery, 5-FU has been used in the topical therapy of actinic keratoses [58]. Doxorubicin has additionally been identified as a causative agent, as well as sorafenib [59]. In the common situation in which a patient is receiving multiple chemotherapeutic agents simultaneously, identification
Extravasation
Extravasation is defined as the leakage of chemotherapeutic drugs into the surrounding tissues. Extravasation injuries remain uncommon, with estimated incidence published in the literature of between 0.1% and 6% in patients receiving chemotherapy [60]. The published rate is likely an underestimation, however, as many cases of extravasation go unreported.
Chemotherapeutic agents are divided into the classification categories of irritants or vesicants, depending on the potential for localized
Irritants
Irritants are defined as agents that produce local inflammation, pain, tightness, or phlebitis either at the site of injection or along the vein. Irritants may induce local sclerosis or hyperpigmentation, but do not induce tissue necrosis. The symptoms of the local reaction after extravasation are typically self-limiting, most commonly without long-term sequelae [1].
Although case reports of local interventions including glycerine, chlorhexidine, and dimethylsulfoxide (DMSO) have been published
Vesicants
Vesicants have the ability to induce tissue necrosis, with resultant potential for severe and long-lasting injury and local damage. The full effect of the extravasation injury is not usually immediately apparent; but may evolve over days or weeks. Early local symptoms of a vesicant extravasation resemble those of an irritant extravasation: local pain, erythema, burning, pruritis, or swelling [1], [62]. Over the course of the reaction, however, as tissue necrosis evolves and becomes clinically
Hypersensitivity
Although any drug may induce a hypersensitivity reaction in an individual recipient, certain chemotherapeutic and molecularly targeted agents have a higher incidence of hypersensitivity reactions. The hypersensitivity reactions tend to be type I hypersensitivity reactions, and may range from transient urticaria to a pruritic maculopapular rash to an anaphylactic response [4]. The inciting agent may be either the chemotherapeutic drug itself (such as is the case with asparaginase), or may be
Hydroxyurea dermopathy
Hydroxyurea is an oral agent used in the treatment of myeloproliferative disorders, as well as sickle cell disease. The chronicity of these diseases leads to long-term administration of the drug. In addition to lower leg ulcers (typically developing over the malleolar regions and associated with minor trauma), a characteristic dermopathy has been associated with long-term use of hydroxyurea [85], [86], [87].
The dermopathy consists of a lichenoid, papular, erythematous, and scaling eruption
Targeted therapy
The past decade has been marked with the explosive development of new molecularly targeted agents for the treatment of cancer [88]. Although in theory the development of the targeted drugs was intended to improve therapeutic efficacy while reducing toxicity in comparison to standard chemotherapeutic agents, the novel molecularly targeted agents have demonstrated significant toxicity as well. Cutaneous toxicities of the targeted agents fitting the classic chemotherapeutic toxicity descriptions
Nail dystrophy
Chemotherapeutic agents can cause a variety of nail changes, from hyperpigmentation to ridging of the nail plate to premature separation of the nail plate (onycholysis). Nail hyperpigmentation is most commonly associated with doxorubicin, 5-FU, and cyclophosphamide [42], [103], [104]. Transverse leukonychia, also known as Beau-Reil lines, are white transverse lines that develop on the nails during chemotherapy. The appearance of the lines seems to correlate with chemotherapy cycles, with
Summary
Despite the frequency of cutaneous toxicities with chemotherapeutic and molecularly targeted agents used in cancer therapy as well as the stark visibility of these toxicities, little is understood about the pathogenesis of the reactions. Cutaneous toxicities such as acral erythema, hyperpigmentation, and nail dystrophy may occur commonly, yet little is published outside of small patient series and case reports. Many conditions are inadequately histologically described. This is likely because of
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