INTRODUCTION — Systemic and local treatments for cancer can cause a number of changes in the skin, mucous membranes, hair, and nails [1-6]. When dermatologic lesions arise in patients being treated for cancer, they may represent an adverse effect of therapy, but other etiologies need to be considered. These include a cutaneous reaction to other drugs, exacerbation of a previously existing condition, infection, metastatic tumor involvement, a paraneoplastic phenomenon, graft-versus-host disease, or a nutritional disorder.
The accurate diagnosis and management of chemotherapy-related side effects requires the clinician to be knowledgeable about the most common cutaneous reaction patterns for the drugs the patient is receiving. The clinician must also be familiar with the cutaneous manifestations of certain cancers, as well as the dermatologic effects of other forms of cancer treatments. In some cases, diagnostic uncertainty can only be clarified with a rechallenge, and the clinician must determine whether a rechallenge with a lower dose, if appropriate, is safe and medically justifiable.
The cutaneous adverse effects of conventional cytotoxic cancer therapy agents are presented here. Other mucocutaneous complications of cancer treatment are discussed separately. Infusion reactions are also discussed separately.
TOXIC ERYTHEMA OF CHEMOTHERAPY — The term "toxic erythema of chemotherapy" refers to a group of cutaneous reactions induced by conventional chemotherapy agents (most frequently doxorubicin, pegylated liposomal doxorubicin, fluoropyrimidines [fluorouracil, capecitabine], cytarabine, and docetaxel) with overlapping clinical and histopathologic features . The most frequently seen clinical presentation involves the hands and feet and is known as "hand-foot syndrome" (picture 1). Other terms that have been used include acral erythema, palmar-plantar erythrodysesthesia, toxic acral erythema, and Burgdorf's reaction.
The pathogenesis, clinical presentation, diagnosis, treatment, and prevention of toxic erythema of chemotherapy are discussed separately. (See "Toxic erythema of chemotherapy (hand-foot syndrome)".)
NEUTROPHILIC ECCRINE HIDRADENITIS — Neutrophilic eccrine hidradenitis (NEH) is a reactive, self-limited disorder that may occur in association with malignancy (with or without chemotherapy), infections, and certain medications . (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.)
The original description of drug-induced NEH was in a patient receiving cytarabine for acute myeloid leukemia . Since then, a variety of chemotherapeutic agents have been associated with this entity that may be considered within the spectrum of toxic erythema of chemotherapy (table 1) [1,10,11]. However, the cause of NEH in patients receiving chemotherapy remains elusive. It is postulated that a high concentration of the drug in sweat has a direct toxic effect on the eccrine glands [12,13]:
●Clinical presentation – Patients present with the eruption one to two weeks after therapy with the offending agent. The clinical presentation is nonspecific. Lesions are typically asymptomatic, erythematous, edematous plaques but may be purpuric and painful. They can be located on the extremities (picture 2A), trunk, and face (picture 2B), including the periorbital region, where severe lesions may mimic cellulitis. Generalized, erythema multiforme-like lesions have been reported .
●Diagnosis – Because the clinical picture is nonspecific, a biopsy should be performed in cases of suspected NEH to confirm the diagnosis. Histopathologic examination shows neutrophils surrounding the eccrine glands, vacuolar degeneration in glands and ducts, along with necrosis of lining cells, and squamous syringometaplasia of eccrine ducts (picture 3) . Epidermal keratinocyte atypia is a common associated finding . If chemotherapy-induced neutropenia is present, neutrophils may be absent on histologic examination. However, other characteristic findings, such as eccrine gland necrosis, are still identifiable .
●Management – The natural history is that of spontaneous resolution in one to two weeks . While the reaction is self-limited and resolves without therapy, some studies support the use of systemic corticosteroids . However, efficacy has not been established in randomized trials . One case report suggests that oral dapsone may be useful for prophylaxis . The majority of patients with NEH will develop the same eruption with rechallenge.
PHOTOSENSITIVITY REACTIONS — An increased sensitivity to ultraviolet (UV) light exposure (photosensitivity) has been associated with a variety of chemotherapy agents [1,19-22]. Photosensitivity reactions can be manifested in a variety of ways, including phototoxic reaction, photoallergic reaction, photorecall, and photoenhancement.
Phototoxic reactions — A phototoxic reaction is a nonimmunologically mediated reaction that resembles an exaggerated sunburn, with erythema, edema, pain, and tenderness in sun-exposed areas, such as the face, the "V" area of the upper chest, and the dorsa of the hands. In severe cases, blistering can occur. Severe erythema develops within minutes to hours following light exposure. Postinflammatory hyperpigmentation is common.
The most common chemotherapeutic agent associated with phototoxic reactions is methotrexate, although other antineoplastic agents, such as fluorouracil and related compounds, dacarbazine, and vinblastine, may also be associated [22,23]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
●Pathogenesis – The pathogenesis of phototoxic chemotherapy reactions is thought to involve concentration of the drug within the skin and subsequent absorption of UV light, resulting in apoptosis of keratinocytes. Characteristic histologic findings include dyskeratotic keratinocytes, a vacuolar interface dermatitis, and papillary dermal edema with minimal inflammation .
●Clinical diagnosis – The clinical diagnosis is based upon the distribution of the eruption (ie, a sharp demarcation between sun-exposed versus protected sites) (picture 4A-B) and the temporal relationship to the administration of the offending agent. If the diagnosis is in doubt, photo patch testing can be used as adjunctive diagnostic measures .
●Treatment – The treatment of phototoxic reactions involves the discontinuation of the offending agent and avoidance of direct exposure to sunlight by using protective clothing and a topical sunscreen for at least two weeks. Physical sunscreens containing titanium oxide or zinc oxide are preferred because chemical sunscreens, especially oxybenzone, can be associated with photoallergic reactions (see "Selection of sunscreen and sun-protective measures"). Symptomatic treatment with cool compresses and topical steroids may be helpful. Severe cases may require systemic steroids.
Patients receiving photosensitizing drugs should be counseled regarding the risk of adverse reactions to sunlight and encouraged to use UV protection with sunscreens and protective clothing.
Photoallergic reactions — Photoallergic reactions are type IV, delayed hypersensitivity reactions that develop at least 24 hours after light exposure. In contrast to phototoxic reactions, a photoallergic reaction is characterized by a pruritic, papulovesicular eruption that involves sun-exposed areas but may spread to non-sun-exposed areas. Photosensitivity reactions to flutamide (an antiandrogen) and ftorafur (also called tegafur, a prodrug of fluorouracil) are typically photoallergic rather than phototoxic [19,25,26]. Symptoms generally clear within four to eight weeks after drug discontinuation. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
Photorecall and photoenhancement — A photorecall phenomenon (also called "UV reactivation reaction" or "solar burn reactivation reaction") occurs when the administration of a chemotherapy drug (typically methotrexate but also taxanes) triggers a sunburn-like reaction in the absence of light exposure in the same distribution as a sunburn that the patient may have sustained months to years before [27-31]. Symptoms are usually reproduced with rechallenge.
In contrast, photoenhancement occurs when patients who receive a drug (typically high-dose methotrexate) within two to five days of exposure to UV light develop severe erythema within the sun-exposed areas. In contrast to photoreactivation, retreatment with methotrexate does not usually reproduce this reaction. (See "Therapeutic use and toxicity of high-dose methotrexate".)
Inflammation of actinic keratoses — There are isolated reports of patients receiving systemic chemotherapy, particularly cytotoxic chemotherapies, who developed erythematous papules and plaques in photodamaged areas that, on closer inspection, were actually inflamed actinic keratoses [36-39].
RADIATION RECALL DERMATITIS AND RADIATION ENHANCEMENT
●Radiation recall dermatitis – Radiation recall dermatitis (RRD) is an uncommon, inflammatory skin reaction that develops in an area of previously irradiated skin after administration of certain promoting agents . Most cases have been associated with chemotherapy. There may be a long interval between the administration of the causative agent and the appearance of RRD. The frequency of these reactions is unclear. In one study, RRD occurred in 8 of 91 patients (9 percent) who received chemotherapy following radiation therapy . (See "Radiation dermatitis", section on 'Radiation recall reaction'.)
RRD was originally described with dactinomycin . Since then, a number of other drugs have also been associated with this phenomenon (table 2), particularly anthracyclines and anthracycline-like drugs [43-47].
The pathogenesis of RRD is controversial. An idiosyncratic hypersensitivity reaction has been proposed, with the "trauma" of prior radiation therapy sensitizing an area of skin into manifesting an immune reaction when there is little or no systemic activation (akin to the Koebner phenomenon) . However, the occurrence of many of these reactions after the first drug exposure argues against an immune mechanism, and defects in deoxyribonucleic acid (DNA) repair  as well as toxic drug effects  have also been proposed as causative factors.
Erythema, which may be painful, is the most common sign [49,50]. Vesiculation, desquamation, and ulceration have also been reported . Histologically, epidermal dysplasia; necrotic keratinocytes; and a mixed, inflammatory reaction  characterize involved areas, with some cases showing psoriasiform dermatitis. Additional dermal changes include fibrosis, vasodilatation, and atypical fibroblasts. Many of these findings mimic the histologic findings of acute, severe sunburn or radiation dermatitis.
RRD typically occurs with the first dose of the chemotherapy agent or combination and may require a minimum threshold radiation dose. In two case reports, patients receiving various doses of radiotherapy with bleomycin or docetaxel had a radiation recall reaction only in those skin sites that had received the highest radiation dose [52,53]. Chemotherapy agents administered by the intravenous route usually produce RRD more rapidly (range, several minutes to 14 days) than oral agents, which have a longer lag period (range, three days to two months) [54,55].
Drug interruption or dose reduction are the primary treatments for RRD. Symptomatic treatment includes topical corticosteroids and oral antihistamines. Rechallenge with the same agent does not always lead to symptom recurrence .
●Radiation enhancement – Enhancement of the cutaneous toxicity of radiation therapy can occur if a radiosensitizing chemotherapy drug is administered concurrently or within one week of radiation therapy . The drugs that have been associated with radiation enhancement (also called radiation sensitizers) are listed in the table (table 2).
Radiation enhancement involving the skin resembles RRD, with painful erythema, edema, superficial desquamation, and, if severe, erosions (wet desquamation). Similar to RRD, the eruption usually localizes to the irradiated field, but there may be local extension to unirradiated areas. Histologically, epidermal dysplasia; necrotic keratinocytes; and a mixed, inflammatory reaction characterize involved areas, with some cases showing psoriasiform dermatitis . (See "Radiation dermatitis".)
Susceptibility to this effect decreases as the time between administration of chemotherapy and radiation therapy lengthens. In one report, superficial desquamation occurred in 50 percent of patients with lung cancer who received doxorubicin within five days of radiation therapy, while no desquamative reactions occurred when the interval between radiation and chemotherapy was increased to three weeks [57,58].
Possible explanations for the radiation-sensitizing effect of some chemotherapy drugs include increased blood supply and cellular reoxygenation to the tissue, interference with repair of radiation damage, competition for repair enzymes, and an increased percentage of cells in sensitive phases of the cell cycle . For example, paclitaxel arrests cell division in the G2 and M phases of the cell cycle, when cells are the most susceptible to ionizing radiation injury .
The eruption is usually self-limiting, resolving over a period of days to months. Treatment of radiation enhancement reactions is symptomatic and includes the application of cold compresses; local wound care to prevent infection; and the avoidance of trauma, irritation, heat, and ultraviolet (UV) light. Long-term sequelae may include skin atrophy, fibrosis, and telangiectasias. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)
The synergistic interaction between chemotherapy and radiation is exploited clinically in situations in which concurrent chemotherapy and radiation are administered to enhance antitumor effect (eg, concomitant fluoropyrimidines and radiation therapy for many gastrointestinal tumors). Since the target of the radiation beam is typically located deep within the body, enhanced skin toxicity is usually not a significant problem. Skin toxicity is seen more commonly with more superficial radiation fields. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)
PIGMENTARY CHANGES — Pigmentary changes involving the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 3) . The area of enhanced pigmentation may be localized or diffuse, and it may affect the skin, mucous membranes, hair, and/or nails. The pigmentary changes usually resolve with drug discontinuation but may persist. As an example, the rare, gingival margin hyperpigmentation seen with cyclophosphamide is usually permanent.
Diffuse hyperpigmentation — Fluorouracil is one of the most ubiquitous drugs used in the treatment of malignancy. It is often associated with a hyperpigmentation reaction that may affect the skin diffusely, locally (in sun-exposed areas), or in a serpentine manner (a pigmentary pattern that follows an underlying vein proximal to an infusion site); darken the nail beds; and induce mucosal pigmentation of the tongue and conjunctiva. Topical fluorouracil can induce hyperpigmentation in treated areas. The fluorouracil derivative tegafur can induce well-circumscribed, brown to black, macular pigmentation that appears on the palms, soles, nails, and glans penis. The localization in these cases is unexplained. Hyperpigmentation associated with fluorouracil usually resolves within weeks to several months after cessation of therapy; however, in certain cases, nail hyperpigmentation may persist for years [62-66].
In addition to fluorouracil, many systemic medications induce pigmentary reaction patterns that affect the skin in a diffuse manner:
●Busulfan causes a generalized skin darkening (the so-called "busulfan tan") that can mimic the cutaneous manifestations of Addison's disease. Although busulfan can also cause adrenal insufficiency, the skin pigmentary change is instead thought to be secondary to a toxic effect on melanocytes [67,68]. Features that can help to distinguish cutaneous busulfan toxicity from true Addison's disease include normal levels of melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). (See "Clinical manifestations of adrenal insufficiency in adults".)
●Pegylated liposomal doxorubicin can induce a macular hyperpigmentation over the trunk and extremities, including the palms and soles . This reaction has not been described with unencapsulated doxorubicin.
●Hydroxyurea may induce hyperpigmentation of the face, neck, lower arms, palms, and nails; pigmentation can also be accentuated in areas of pressure or trauma [70,71]. This pressure-induced hyperpigmentation is also reported for cisplatin .
Localized hyperpigmentation — Localized changes in skin pigmentation may be associated with intrinsic, anatomic features of the skin (eg, mucous membranes, skin creases, flexural or intertriginous areas, palms or soles, and the face). However, a suspected local drug reaction may be due to other extrinsic factors that act in combination with the drug. In addition to topical fluorouracil, other drugs that can induce localized hyperpigmentation include thiotepa, ifosfamide, and docetaxel (sites of adhesive placement on the skin); capecitabine, cisplatin, hydroxyurea, and bleomycin (sites of trauma or pressure); and daunorubicin (sun-exposed areas) [1,75]. The hyperpigmentation seen in areas of skin exposed to adhesive may reflect secretion of the drug in sweat.
Some of these reactions may represent postinflammatory hyperpigmentation rather than a local effect of the drug itself, especially if administration of the agent is associated with trauma, skin irritation, or a local allergic reaction (ie, contact dermatitis).
The following are examples of localized, chemotherapy-induced hyperpigmentation:
●The pigmentary changes caused by bleomycin, cyclophosphamide, busulfan, and doxorubicin have a predilection for flexural areas and palmar creases. Ifosfamide hyperpigmentation can occur in flexural areas, the dorsal and plantar surfaces of the feet, the extensor surfaces of the fingers and toes, on the scrotum, and occasionally on large areas of the trunk. It may also occur under occlusive dressings.
●Mitoxantrone hyperpigmentation can affect the face, dorsum of the hands, and nails.
●Mucosal hyperpigmentation has been associated with busulfan, cyclophosphamide (gingiva), tegafur (lower lip as well as glans penis), doxorubicin (tongue and buccal mucosa), cisplatin , and fluorouracil.
Patterned hyperpigmentation (serpentine, flagellate, reticular) — Serpentine hyperpigmentation describes a supravenous, pigmentary pattern that follows the course of an underlying vein proximal to an infusion site. This phenomenon is most commonly seen with fluorouracil but has also been associated with fotemustine, vincristine, vinorelbine, and docetaxel .
Linear (flagellate) hyperpigmentation (picture 5) may be seen with bleomycin [78,79]. Multiple linear, erythematous or hyperpigmented streaks arise at sites of scratching or other minor traumas to the skin. Generalized pruritus is common and may precede the eruption.
Paclitaxel, cytarabine, fluorouracil, and idarubicin may induce a reticular hyperpigmentation predominantly located on the trunk and lower extremities [80,81]. Pruritus is often an accompanying symptom.
Hair color changes — In addition to causing alopecia, chemotherapy can also cause pigmentary changes in hair (see "Alopecia related to systemic cancer therapy"):
●Methotrexate may induce hyperpigmentation of scalp hair, eyebrow hair, and eyelashes. This tends to occur in bands that alternate with the normal color, a feature known as the "flag sign" . This results from alternating periods of treatment and no treatment.
Overview — Nonspecific nail changes are commonly observed during systemic cancer treatment . They include transverse grooves on the nail plate (Beau lines) and onychomadesis (shedding of the nail) due to prolonged inactivation of the nail matrix (picture 6A-B). Fingernails grow approximately 0.1 mm per day. Thus, the distance of a Beau line from the proximal nail fold gives an approximate indication of when the acute insult occurred. (See "Overview of nail disorders", section on 'Transverse grooves (Beau lines)'.)
Cytotoxic chemotherapeutic agents have also been associated with pigmentary changes (chromonychia) and onycholysis, a detachment of the nail plate from the nail bed. Other inflammatory reaction patterns involving the nail folds include pyogenic granuloma and acute exudative paronychia that may progress to subungual abscess.
The various nail disorders that are associated with individual chemotherapy agents are summarized in the table (table 4), and some are described below. After discontinuation of chemotherapy, all of these conditions generally resolve as the nail grows out.
Melanonychia — Medications may induce diffuse hyperpigmentation or banding/streaking of the nail plate (melanonychia striata) or bed. (See "Longitudinal melanonychia".)
Besides fluorouracil, a wide range of agents have been implicated, including alkylating agents, taxanes, antimetabolites (hydroxyurea, cyclophosphamide), anthracyclines, and other antitumor antibiotics such as bleomycin (table 4) [1,83]. Melanonychia appears one to two months after the initiation of chemotherapy and may be associated with cutaneous and mucosal hyperpigmentations. Taxanes may also induce a red nail discoloration, due to subungual hemorrhages, and true leukonychia (picture 7) . Leukonychia is also observed in patients treated with doxorubicin, cyclophosphamide, or vincristine .
Onycholysis — Onycholysis is caused by inflammation in the nail bed, which leads to detachment of the overlying nail. The cytotoxic drugs most frequently associated with onycholysis are the taxanes paclitaxel and docetaxel (picture 8) . Other medications that have been reported to cause onycholysis include cyclophosphamide, doxorubicin, etoposide, fluorouracil, hydroxyurea, capecitabine, ixabepilone, and the combination of bleomycin plus vinblastine [1,86].
An intriguing association between denervation and protection from chemotherapy-induced nail changes was suggested in a report of a patient with a complete right arm nerve palsy due to advanced breast cancer who developed docetaxel-related nail changes in all extremities except the paretic hand .
A systematic review of 12 studies supports the prophylactic use of frozen gloves and frozen socks for the prevention of taxane-induced nail and skin toxic effects . However, the included studies were generally small and showed considerable methodologic heterogeneity regarding the cooling protocols, chemotherapy regimens, and choice of control limbs. Discomfort from cold may be reduced without changes in efficacy by using frozen gloves prepared at a temperature of -10 to -20°C (14 to -4°F) rather than at the standard temperature of -25 to -30°C (-13 to -22°F) .
A drawback of cold therapy may be a reduced exposure of the extremity to the therapeutic agent, which in theory may permit persistence of metastatic tumor cells in that location. Thus, the use of cold therapy to mitigate skin and nail toxicity must be decided on a case-by-case basis.
Inflammatory changes — A number of infectious and noninfectious, inflammatory changes of the nail folds and nail bed have been reported:
●Painful paronychial inflammation, often associated with pyogenic granulomas, may be induced by etoposide, capecitabine, methotrexate, and doxorubicin. (See "Paronychia" and "Pyogenic granuloma (lobular capillary hemangioma)".)
EXANTHEMATOUS (MACULOPAPULAR) ERUPTIONS — A wide variety of chemotherapy drugs have been associated with a mild, nonspecific, exanthematous drug eruption, including bortezomib, lenalidomide, cladribine, fludarabine, gemcitabine, pemetrexed, and cytarabine. Lesions may be "morbilliform" or may consist of a profuse eruption of small, erythematous papules showing no resemblance to any infective exanthem. Morbilliform eruptions (picture 9A-B) are characterized by monomorphic, erythematous papules and are usually defined as "drug rash" in United States prescribing information and literature references.
The similarity of these rashes to those described for many other drugs underscores the importance of evaluating all medications taken by the patient before concluding that the rash is caused by the chemotherapy agent. (See "Exanthematous (maculopapular) drug eruption".)
The management of patients with a presumptive chemotherapy drug rash is dictated by the severity of the reaction as well as the clinical circumstances surrounding the use of the individual chemotherapy agent. Pertinent issues include whether the offending agent is being used with curative versus palliative intent and whether a therapeutically equivalent substitute from another drug class is available. In mild cases, treatment with topical steroids is usually recommended, without specific modification of the chemotherapy regimen.
Pretreatment with corticosteroids is not usually recommended to prevent or diminish a chemotherapy-induced drug rash. One exception to this general rule is the drug pemetrexed, a folate analog used in the treatment of mesothelioma and non-small cell lung cancer. In an early phase 2 study, pemetrexed was associated with a papular skin rash in 66 percent of treated patients .
Subsequent phase 1, 2, and 3 trials reported a much lower incidence (less than 20 percent) and severity of skin rash, which was attributed to the routine use of dexamethasone 4 mg twice daily for three days starting the day before treatment [91-94]. As a result, premedication with this schedule of dexamethasone has become a standard practice for patients receiving pemetrexed . Whether fewer doses would suffice is unknown.
FIXED DRUG ERUPTION — Fixed drug eruption is characterized by the rapid formation of a solitary macule, plaque, or bulla after drug exposure in a sensitized individual, although multiple or diffuse lesions can be observed. The cytotoxic drugs most commonly associated with a fixed drug eruption are listed in the table (table 5).
The characteristic early lesion is a sharply demarcated, erythematous, round to oval macule that develops from 30 minutes to 8 hours after drug exposure and arises in the same location after each exposure (picture 10A-B). One-half occur on the oral or genital mucosa (picture 10D). Within hours, the lesion becomes edematous, forming a plaque, which may evolve to bulla (picture 10C) and eventually to erosion. Lesions persist if the drug is continued, but they resolve within days to weeks after the drug is discontinued, leaving a postinflammatory hyperpigmentation.
Fixed drug eruption is discussed in detail separately. (See "Fixed drug eruption".)
DIFFUSE ERYTHEMA AND EXFOLIATIVE DERMATITIS — Diffuse erythema, which can resemble a morbilliform exanthem, has been described with hydroxyurea, busulfan, and cladribine . Many of these eruptions are mild and self-limited, and they do not proceed to exfoliation. Drugs that are more likely to be associated with exfoliative dermatitis include cisplatin, methotrexate, and, rarely, intravesical (but not intravenous) mitomycin [96-99]. At least some of these cases are thought to be immune mediated.
SEVERE CUTANEOUS DRUG REACTIONS — Many antineoplastic agents may cause life-threatening cutaneous adverse reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) .
Whether chemotherapy agents cause erythema multiforme, an immune-mediated reaction in most cases induced by infections and infrequently by drugs, remains uncertain. Similarities in clinical and histopathologic findings between SJS and erythema multiforme (ie, presence of targetoid lesions and keratinocyte necrosis) may have led to a misclassification of limited SJS as erythema multiforme in the few published cases . (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
Stevens-Johnson syndrome/toxic epidermal necrolysis — Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a serious and potentially fatal mucocutaneous drug reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis. Its severity is related to the percentage of body surface area involved, ranging from less than 10 percent in SJS to greater than 30 percent in TEN. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Several anticancer agents have been associated with SJS/TEN (table 6) . Determining the drug causality in patients with cancer may be difficult due to the frequent use of multiple chemotherapy agents in combination and the concurrent use of other drugs to treat underlying conditions and comorbidities. In addition, patients with cancer may have an increased risk of SJS/TEN due to the malignancy itself .
SJS/TEN begins with a prodrome of fever and influenza-like symptoms followed in one to three days by an eruption of ill-defined, coalescing, erythematous macules with atypical target lesions (picture 11). As the disease progresses, vesicles and bullae form, and within days, the skin begins to slough (picture 12C). Mucosal involvement occurs in over 90 percent of cases.
Acute complications may include massive loss of fluids and electrolyte imbalance, hypovolemic shock, sepsis, and multiple organ dysfunction.
Most patients with SJS/TEN require inpatient management, often in a burn unit, because of extensive skin detachment and subsequent risk for hyponatremic dehydration and sepsis. Immediate and permanent discontinuation of the putative offending agent is warranted. Patients who develop SJS/TEN should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)
Drug reaction with eosinophilia and systemic symptoms — Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and potentially life-threatening, drug-induced hypersensitivity reaction that presents with a skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and/or internal organ involvement (liver, kidney, lung). A few antineoplastic agents have been associated with DRESS, including chlorambucil  and lenalidomide .
In most patients, the reaction begins two to six weeks after the initiation of the offending medication. The eruption starts as a morbilliform eruption that progresses more or less rapidly to a diffuse, confluent, and infiltrated erythema (picture 12A-B). Liver involvement occurs in 60 to 80 percent of patients. Identification and prompt withdrawal of the offending drug is the mainstay of treatment for patients with DRESS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Acute generalized exanthematous pustulosis — Acute generalized exanthematous pustulosis (AGEP) is a rare, acute eruption characterized by nonfollicular, sterile pustules on a background of erythema. It is often accompanied by fever and leukocytosis. AGEP can occur within hours and most commonly occurs within two to three days of starting a medication . Although antimicrobials are the most common culprit, a few chemotherapy agents have been implicated, including bleomycin and taxanes [106,107]. Medications given as premedications for chemotherapy, such as histamine 2 (H2) blockers and acetaminophen, have also been linked with AGEP [108,109]. (See "Acute generalized exanthematous pustulosis (AGEP)".)
SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS AND SCLERODERMA-LIKE CHANGES — Subacute cutaneous lupus erythematosus, which presents with annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 13A-B), has been reported following taxanes [110-112], fluoropyrimidines , doxorubicin plus cyclophosphamide , and gemcitabine . While phototoxicity may play a role in initiating or sustaining active subacute cutaneous lupus erythematosus, the pathogenesis also involves autoimmunity. This is supported by the presence of deposits of immunoglobulin G (IgG) and complement components at the dermal-epidermal junction, immunohistopathologic findings that are identical to those found in idiopathic disease. Another shared feature of drug-induced and idiopathic subacute cutaneous lupus erythematosus is the presence of circulating anti-Ro/SSA antibodies in a majority of cases. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)
Scleroderma-like changes, consisting of edema, tightening, and induration of the skin on the trunk and extremities, have been reported in patients treated with bleomycin , gemcitabine , and docetaxel [118,119]. The presentation of sclerotic changes is a relative contraindication to continued therapy. Data from the World Health Organization (WHO) pharmacovigilance database (VigiBase) found that anticancer drugs were the most represented drug class responsible for the reported cases of drug-induced systemic sclerosis . These included taxane-based agents, bleomycin, vinblastine, dacarbazine, and pemetrexed. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
●Leg ulcers – Treatment-induced leg ulcers occasionally occur in patients taking long-term hydroxyurea for myeloproliferative disorders [121-124]. Lesions are most commonly located near the malleoli and are characteristically painful. The primary mechanism of ulcer formation may involve hydroxyurea-induced inhibition of the synthesis (S) phase of the cell cycle, leading to basal keratinocyte damage and the suppression of collagen synthesis. Discontinuation of therapy is necessary for healing; ulcers recur if treatment is reinitiated .
Whether leg ulcers are more frequent in patients receiving hydroxyurea for sickle cell disease is unclear. Issues related to use of hydroxyurea in this setting are discussed in detail elsewhere. (See "Hydroxyurea use in sickle cell disease".)
●Pseudocellulitis – Pseudocellulitis has been first and most commonly reported following administration of gemcitabine but has also been described with pemetrexed [125-127]. Typically occurring within two to three days of chemotherapy administration, patients present with bright red erythema and pain but usually in a bilateral distribution. The pathogenesis is hypothesized to occur via accumulation of chemotherapy within the interstitial space of edematous extremities, resulting in a toxic effect. The resolution time depends on the causative drug's pharmacokinetics and may persist until the drug is displaced from the tissue . Symptomatic management consists of topical steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antihistamines.
●Grover's disease – Grover's disease, or transient acantholytic dermatosis, has been reported with cytotoxic chemotherapy administration . Clinically and histologically, the findings are indistinguishable from nonchemotherapy-associated presentations, though patients may be less symptomatic. Treatment is with topical steroids, with lotions or creams preferred over ointments given their less occlusive quality. (See "Grover's disease (transient and persistent acantholytic dermatosis)".)
●Other reactions – There are many other rare cutaneous reactions that have been attributed to chemotherapy agents, including Sjögren's disease, dermatomyositis, Raynaud phenomenon, reactivation of varicella-zoster infection, porphyria, and a blistering disorder characterized as a paraneoplastic pemphigus-like phenomenon with fludarabine . (See "Paraneoplastic pemphigus".)
A partial list of such reactions and the associated chemotherapeutic agents can be found in the following table (table 7).
●Toxic erythema of chemotherapy – The term "toxic erythema of chemotherapy" refers to a group of cutaneous reactions induced by conventional chemotherapy agents (most frequently doxorubicin, pegylated liposomal doxorubicin, fluoropyrimidines [fluorouracil, capecitabine], cytarabine, and docetaxel) with overlapping clinical and histopathologic features. The most frequently seen clinical presentation involves the hands and feet and is known as "hand-foot syndrome." (See "Toxic erythema of chemotherapy (hand-foot syndrome)".)
●Neutrophilic eccrine hidradenitis – Neutrophilic eccrine hidradenitis (NEH) presents with erythematous, edematous plaques (picture 2A-B) in patients with malignancy (with or without chemotherapy), with infections, or receiving a variety of chemotherapeutic agents (table 1). (See 'Neutrophilic eccrine hidradenitis' above and "Neutrophilic dermatoses", section on 'Palmoplantar eccrine hidradenitis'.)
●Photosensitivity reactions – Phototoxic and photoallergic reactions have been associated with a variety of chemotherapy agents, of which the most common is methotrexate. A phototoxic reaction is a nonimmunologically mediated reaction that resembles an exaggerated sunburn, with erythema, edema, pain, and tenderness in sun-exposed areas (picture 4A-B). Photoallergic reactions are a delayed hypersensitivity reaction characterized by a pruritic, papulovesicular eruption that involves sun-exposed areas but may spread to non-sun-exposed areas. Photorecall and photoenhancement reactions have been reported with methotrexate and taxanes. (See 'Photosensitivity reactions' above.)
●Radiation recall dermatitis and radiation enhancement – Radiation recall dermatitis (RRD) is an inflammatory skin reaction that develops in an area of previously irradiated skin after administration of several chemotherapy agents (table 2). Some drugs may enhance the efficacy and dermatologic toxicity of radiation therapy when administered concurrently or within one week of radiation therapy. They are referred to as radiation sensitizers. This synergistic interaction may be exploited clinically in situations where chemotherapy and radiation therapy are administered together to enhance the therapeutic effect. (See 'Radiation recall dermatitis and radiation enhancement' above.)
●Pigmentary changes – Pigmentary changes involving the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 3). The hyperpigmentation can be localized or diffuse, sometimes with distinctive patterns, such as serpentine or flagellate (picture 5). Hair color changes can occur with cisplatin, cyclophosphamide, and methotrexate. (See 'Pigmentary changes' above.)
●Nail toxicities – Nail changes, such as hyperpigmentation and onycholysis (picture 8), sometimes associated with inflammatory involvement of the periungual tissues, may be induced by many medications, including alkylating agents, taxanes, antimetabolites, anthracyclines, and antitumor antibiotics (table 4). (See 'Nail toxicities' above.)
●Exanthematous eruptions and fixed drug eruptions – Exanthematous (maculopapular) eruptions, including morbilliform rashes (picture 9A-B), and fixed drug eruptions (picture 10A-D) may occur in association with many chemotherapeutic agents (table 5). (See 'Exanthematous (maculopapular) eruptions' above and 'Fixed drug eruption' above and "Exanthematous (maculopapular) drug eruption" and "Fixed drug eruption".)
●Severe cutaneous drug eruptions – A number of antineoplastic agents (table 6) may cause severe cutaneous reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) (picture 12A-D). SJS/TEN is a rare, life-threatening cutaneous reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis (picture 12C). Patients who develop SJS/TEN or DRESS should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See 'Severe cutaneous drug reactions' above and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●Subacute cutaneous lupus erythematosus and scleroderma – Subacute cutaneous lupus erythematosus, manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 13A-B), has been reported in a few cases following docetaxel, fluorouracil, or capecitabine. Scleroderma-like changes, consisting of edema, tightening, and induration of the skin on the trunk and extremities, have been reported in patients treated with taxane-based agents, bleomycin, vinblastine, dacarbazine, and pemetrexed. (See 'Subacute cutaneous lupus erythematosus and scleroderma-like changes' above.)
●Uncommon reactions – Uncommon reactions, including leg ulcers, pseudocellulitis, Sjögren's disease, dermatomyositis, Raynaud phenomenon, reactivation of varicella-zoster infection, porphyria, and a paraneoplastic pemphigus-like phenomenon, have been associated with several chemotherapeutic agents (table 7). (See 'Miscellaneous reactions' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Aimee S Payne, MD, PhD, and Diane MF Savarese, MD, who contributed to earlier versions of this topic review.
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