Chapter 144:  Dermatologic Complications of Cancer Chemotherapy

Alopecia

Alopecia is the most common dermatologic complication associated with chemotherapy. Whereas most drug-induced alopecias involve a telogen effluvium pattern by inducing normal hairs into a premature resting phase, the anagen effluvium pattern of hair loss is the most common type of alopecia produced by chemotherapeutic agents, with the exception of interleukin-2 (IL-2)and interferon-α (IFN-α) therapy. In chemotherapy, anagen effluvium is caused by the abrupt cessation of the high mitotic activity of hair matrix cells in the anagen phase of hair follicles; this induces the follicles to produce either no hair, or narrow defective hair sheaths which are predisposed to fracture and breaking.¹ This type of alopecia can be seen to some degree in most antineoplastic therapies, depending on dosage and route of administration.^2,3 However, there are certain agents, such as doxorubicin, which induce alopecia more frequently and severely (Table 144.3).^2–6 These agents display a synergistic effect when used in combination and may cause severe and complete alopecia.⁶ Anagen effluvium manifests within 1 to 2 weeks after the beginning of chemotherapy but is most noticeable 1 to 2 months later.³ Initially, there may not be total hair loss, since approximately 10% of follicles will not be in anagen phase at the start of chemotherapy. However, total hair loss eventually occurs with prolonged therapy, which can also induce hair loss in other areas of the body. Hair regrowth can usually be expected after the end of chemotherapy, although hair color and texture may change.⁷ Permanent alopecia has also been reported with busulfan/cyclophosphamide therapy.⁸

As hair loss often has emotional impact on patients receiving chemotherapy, issues such as prevention and treatment of alopecia are of high importance. Unfortunately, there are currently no widely accepted methods of prevention and treatment for alopecia. To prevent alopecia, scalp hypothermia and tourniquets have been used with some demonstrated success; of the two, hypothermia is relatively easier to use. Drugs such as doxorubicin, vincristine, vinblastine, dactinomycin, and mechlorethamine, which have short administration periods and half-lives, are particularly well suited for scalp hypothermia.² Despite a reported 47% rate of success in preservation of hair, scalp cooling has been controversial. Widespread use of hypothermia has been limited by the possibility that the decreased scalp perfusion—and thereby decreased drug exposure—could increase the risk of scalp metastasis in certain patients with solid tumors.^7,9 However, confirmatory reports of this risk are lacking.⁹ In patients with hematologic malignancies and cutaneous T-cell lymphoma, this modality is contraindicated. Although topical 2% minoxidil has been shown to be ineffective in the prevention of chemotherapy-induced hair loss, there is evidence that the treatment can augment the regrowth process and decrease the duration of alopecia by an average of 50 days.¹⁰

Stomatitis

Stomatitis is a common and potentially dose-limiting mucocutaneous reaction seen in chemotherapy administration. This reaction along with other oral complications related to cancer chemotherapy are discussed in another chapter of this textbook.

Nail Reactions

There are several types of nail changes which may be expected in the patient receiving chemotherapy. The most common nail abnormality encountered, particularly in dark-skinned patients, is hyperpigmentation.² Vertical bands, horizontal bands, or diffuse hyperpigmentation of nails have been known to occur to some degree in the use of the following medications: bleomycin, cyclophosphamide, daunorubicin, doxorubicin, fluorouracil, hydroxyurea, aminoglutethimide, busulfan, cisplatin, dacarbazine, docetaxel, idarubicin, ifosfamide, melphalan, methotrexate, mitomycin, and mitoxantrone.⁵ This hyperpigmentation generally grows out with the nail. Other common nail manifestations include Beau’s lines (horizontal depressions of the nail plate which can occur a few weeks after a course of chemotherapy), Mee’s lines (white horizontal discoloration of the nail plate involving the entire nail width), leukonychia (white horizontal discoloration involving partial nail width), onycholysis, and onychodystrophy. Associations between bleomycin and nail loss, hydroxyurea and brittle nails, and etoposide and nail bed pigmentation have also been reported in the literature.^2,5 Patients can be reassured about these nail changes, which are generally benign and eventually resolve once administration of the causative agent ceases and the affected nails grow out.

Extravasation Reactions

Extravasation injury is a well-known adverse event associated with intravenous chemotherapy administration and occurs when drugs escape from the veins or intravenous catheters into subcutaneous tissues. Accidental extravasation occurs in approximately 0.1 to 6% of patients receiving intravenous chemotherapy.¹¹ Cancer patients are inherently at high risk of extravasation for several reasons. These patients often require multiple venipuncture sites and have thin and fragile veins, concomitant peripheral vascular disease, and malnutrition. In addition, the number of optimal intravenous sites may be reduced due to previous chemotherapy, cutaneous radiation therapy changes, and lymphedema secondary to surgery.^2,12 The cutaneous manifestations of extravasation may range from discomfort and mild erythema to severely painful skin necrosis, ulcerations, and invasion and damage of deep tissue structures. Further necrotic complications, which may lead to significant morbidity, include damage to nerves and tendons, resulting in neurologic deficits, contractures, and joint stiffness. The extent of tissue damage in extravasation largely depends on the concentration, volume, and vesicant nature of the extravasated agent.^11,12

Extravasated cytotoxic agents generally cause two types of local cutaneous reactions: irritant and vesicant reactions. Irritants cause a short-lived and self-limited phlebitis and tender, warm, erythematous reaction along the vein or at the site of intravenous administration. A variant of this local irritation is an erythematous and urticarial hypersensitivity “flare reaction” that has been associated with the anthracyclines. The reaction caused by vesicants is often referred to as chemical cellulitis, which initially presents in a similar way to irritation but may worsen, depending on the amount of drug that has extravasated. In contrast to small-volume extravasations, in which the erythema usually resolves over a few weeks, large-volume extravasations may induce necrosis within a matter of days. Eschars generally follow with subsequent development of painful ulcerations with red, raised edges. Antibiotics, such as doxorubicin, dactinomycin, daunorubicin, and mitomycin, are probably the most common, potent, and well-documented vesicants (Table 144.4). On the other hand, chemical cellulitis is rare with fluorouracil and less severe with vinblastine and vincristine. While almost all vesicants exhibit some degree of irritation on a spectrum of injury, carboplatin, cyclophosphamide, docetaxel, ifosfamide, menogaril, and thiotepa are known to produce irritation, but have not been reported to cause chemical cellulitis.⁵ If these agents do have vesicant activity, it is likely to be very minimal and rare. Paclitaxel can induce an extravasation recall reaction, in which extravasation of the agent at one site has induced a cutaneous reaction, ranging from erythema to ulcerations, at a previous extravasation site.¹³

Chemical cellulitis displays poor healing activity and often continues to worsen and progress, necessitating surgical intervention. Rudolph and Larson have reported that vesicant-induced damage to the skin delays fibroblastic wound contraction.¹² The ability of these vesicants to bind to DNA may allow them to be recycled and retained in the tissue, thereby inducing damage for a longer duration.¹² As it has been estimated that about one-third of all vesicant extravasations will develop into ulcerations, vigilance in the proper and timely recognition and management of extravasation plays a major role in limiting tissue injury.¹⁴ When extravasation is suspected, prompt discontinuation of the infusion is recommended, followed by aspiration of residual drug and removal of the catheter. Local cold application and elevation of the affected extremity is commonly used and helpful.¹² Intermittent local cooling alone has an 89.1% success rate in preventing ulceration.¹⁵ For the vinca alkaloids, heat application is recommended instead, as cold application may actually induce ulceration.¹⁴

The use of antidotes is controversial, and some antidotes such as sodium bicarbonate may be harmful or ulcerative. Sodium thiosulfate and hyaluronidase have been recommended for mechlorethamine and vinca alkaloids, respectively. The success of locally injected corticosteroids has also been variable. As few inflammatory cells are involved in extravasation reactions, these reactions may not be inflammatory and would not, hypothetically, benefit from locally injected corticosteroids.¹⁶ Locally injected granulocyte macrophage colony-stimulating factor (GM-CSF), which has been used to promote healing of doxorubicin ulcerations, and pyridoxine, which has been used to treat mitomycin extravasation, are both worthy of further study.^17,18 Whether a local antidote has a specific effect or acts as a dilutant is hard to determine. Locally injected saline alone has proven successful in resolving extravasation reactions and preventing ulceration.¹⁹ While conservative treatment is preferable for most vesicant extravasations, early excision is sometimes favored, especially when the most potent vesicants are involved.^19,20 Surgical consultation for wide local excision and flap reconstruction is invariably necessary when ulcerations become evident, or if extravasation lesions prove unresponsive to therapy. For topical therapy, the free-radical scavenger (DMSO) has shown consistent therapeutic success. In 1995, an analysis of 96 cumulative patients from multiple studies showed that DMSO protected 98.3% of extravasation cases from ulceration.²¹

Prevention is always the most effective measure in managing extravasation and includes use of a central line or a carefully chosen site of administration. The use of a central venous catheter (CVC) or port is recommended for continuous infusion therapies. However, the use of CVC administration does not prevent extravasation injury, since devices may be dislodged, or venous vessels may be perforated with potentially disastrous consequences, including mediastinitis.²² Thus, central extravasation should be considered in the differential in the presentation of fever, severe pleuritic pain, upper extremity and neck swelling, and a widened mediastinum. In the case of peripheral intravenous administration, the selection of sites should be in the order of forearm, dorsal hand, wrist, and antecubital fossae, on the basis of the presence of vital underlying structures. Optimally, vesicants should not be given in areas of recent administration, irradiation, or lymphedema.¹¹ It is also wise to avoid sites, which are distal to a recent site of venipuncture, as leakage could occur at these sites.

Hyperpigmentation

Hyperpigmentation is a common cutaneous manifestation, which may be of cosmetic concern to patients. The skin, mucous membranes, hair, teeth, and nails may be affected, and the reaction may be diffuse or localized. Hyperpigmentation most commonly accompanies use of alkylating agents and antitumor antibiotics (Table 144.5).⁵ Agents commonly associated with oral mucosal hyperpigmentation include busulfan, fluorouracil, tegafur, doxorubicin, hydroxyurea, cisplatin, and cyclophosphamide.⁵

Among the antimetabolites, methotrexate may produce a characteristic “flag sign” on the hair: horizontal hyperpigmented bands alternating with normal hair color in light-haired individuals.⁵ Tegafur can induce hyperpigmentation of the palms, soles, nails, and glans penis in a third of patients receiving the drug. A “flagellate,” band-like hyperpigmentation in areas of trauma also occurs with high incidence in 8 to 20% of patients receiving bleomycin. Busulfan’s hyperpigmentation can mimic Addison’s disease, with symptoms of weakness, weight loss, and diarrhea, but with normal melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) serum levels.⁷

Hyperpigmentation in areas of occlusion, such as cutaneous areas under electrocardiogram (EKG) pads, tape, or dressings, with or without preceding erythema, has been reported with ifosfamide, topical carmustine, thiotepa, docetaxel, and combinations of etoposide and carboplatin with either cyclophosphamide or ifosfamide.⁵ Finally, localized, serpentine, supravenous hyperpigmentation is often seen at the intravenous administration sites of fotemustine, fluorouracil, vinorelbine, and various combined chemotherapy regimens. The mechanism of chemotherapy-induced hyperpigmentation reactions is currently unknown but may involve direct toxicity, melanocyte stimulation, and postinflammatory changes. Although these reactions may occasionally be permanent, in most cases, discoloration will gradually resolve after the discontinuation of the chemotherapy.

Radiation-Associated Reactions

With the widespread use of combined modality regimens involving both chemotherapy and radiation therapy, two types of radiation-associated cutaneous reactions have been well described: radiation enhancement and radiation recall (Table 144.6). Radiation enhancement refers to the augmentation of radiation therapy effects, which may occur when both chemotherapy and radiation therapy are given within 1 week of each other. The agents most commonly involved include bleomycin, dactinomycin, doxorubicin, fluorouracil, hydroxyurea, and methotrexate. Although other organs are also affected in this potentiation, the skin is the most common site of this toxicity. The reaction may appear as dry or moist desquamation, or as erythema and edema. Bullae can sometimes be observed with erosions or ulcerations. Staphylococcus infection may also be associated with all of the latter (Duvic, personal communication). Upon resolution, postinflammatory hyperpigmentation may develop. The degree of enhancement of radiation damage depends on, and is inversely related to, the time interval between administration of the drug and radiation. The less time there is between chemotherapy and irradiation, the greater the enhancement effect will be.²³ Enhancement is also dependent on drug dosage and the pharmacologic mechanism of the drug.²

Radiation recall is an erythematous inflammatory reaction in areas of previously irradiated skin. Whereas radiation enhancement reactions usually occur with short intervals between treatment modalities, radiation recall occurs from 8 days up to 15 years after radiation therapy and may also occur in other organs, such as the lung, gastrointestinal track, and heart.⁵ The most commonly associated agents are the antitumor antibiotics dactinomycin and doxorubicin.²⁴ Dosage and treatment intervals also influence recall reactions. The time interval between irradiation and chemotherapy administration and the radiation dosage seem to be significant in determining the severity and occurrence of recall, respectively.²⁴ The mechanism of the recall reaction is currently unknown, although it has been theorized that impaired tissue repair may be induced by inadequate stem cell reserve or mutations in surviving cells from the late effects of radiation.²⁵ Generally, the treatment for radiation-associated reactions is symptomatic with an effort to avoid or treat secondary infections with appropriate cultures and antibiotics. Severe ulcerative and necrotic reactions may necessitate débridement. Systemic corticosteroids may have a place in the treatment of radiation recall and may even allow continuation of the offending drug without further recall effects.²⁵

Photosensitivity Reactions

Cutaneous reactions related to chemotherapy and UV light exposure have been well documented, though they are relatively infrequent. Generally, most of these reactions involve exogenous phototoxicity with the agents acting as chromophores.²⁶ Dacarbazine, fluorouracil, methotrexate, and vinblastine are the cytotoxic agents which are commonly associated with phototoxicity (Table 144.7).²⁶ Both clinically and histologically, these phototoxic reactions appear as exaggerated sunburns. Phototoxicity has also been reported to affect the nails in the form of mercaptopurine-induced photo-onycholysis, which usually involves the distal third of the nail and can be tender to palpation. Another form of photosensitivity is the photoallergy that has been described with flutamide and tegafur, in which the cutaneous reaction recurs with re-administration of the implicated agent. A third type of photosensitivity, the UV recall reaction, is observed with suramin (35% incidence), methotrexate, and etoposide/cyclophosphamide therapy which causes a sunburn reactivation if the drugs are administered within 1 week of obtaining a sunburn.²⁷ The UV recall reaction may actually be more severe than the primary sunburn.

Photosensitivity is suspected when an eruption involves sun-exposed areas and may resolve with hyperpigmentation lasting several months. Susceptibility to phototoxic reactions depends on both host and environmental factors and is hard to predict, with the exception of porphyrin drugs, such as hematoporphyrin derivative (Hpd) and Photofrin polyporphyrin. These agents are highly sensitizing, causing 74% incidence of photosensitivity with Hpd and 20 to 40% incidence with Photofrin.^26,28,29 Interventions for phototoxicity reactions are aimed at reducing inflammation and include cool wet dressings, lotions, topical corticosteroids, and antipruritics. Severe cases may require systemic steroids. Furthermore, as the agent may remain in the patient’s skin for several weeks, patients should be advised to take preventative measures, such as wearing sunscreens, and protective clothing and avoiding sunlight. In the case of porphyrins, sunblock with physical barriers, such as zinc oxide, should be used, as these agents are highly phototoxic to visible light.²⁹

Inflammation of Keratoses

Several chemotherapeutic agents (Table 144.8) have been known to induce inflammation of pre-existing skin disease, especially actinic keratoses (AKs). Suramin and cytarabine-induced inflammation of seborrheic keratosis and fludarabine-induced squamous cell carcinoma have also been reported. The association between systemic fluorouracil and the irritation of clinical and subclinical AKs is well known and resembles the effect produced by topical application of 5-Fluorouracil (5-FU). AK recall reactions usually appear 1 week following the initiation of drug administration, and usually resolve 1 to 4 weeks following the end of therapy, although they may regress during therapy as well.³⁰ This reaction is thought to be due to the fact that AKs have increased DNA synthesis and take up 5-FU more readily.³⁰ Another hypothesis proposes a similarity to the radiation recall reaction.³¹ Although these lesions are self-limiting, discomfort can be eased with topical corticosteroids. The reaction may or may not recur with re-administration of the same chemotherapeutic drugs. Similar to the effect of topical 5-FU on AKs, systemic fluorouracil often clears the affected AKs after the inflammatory reaction resolves.³²

Hypersensitivity Reactions

Hypersensitivity reactions, mediated by type I, II, III, and IV immune-mediated allergy, can become dose limiting and are reported with most chemotherapeutic drugs. Although they are generally infrequent, these reactions occur more commonly with L-asparaginase, paclitaxel, docetaxel, teniposide, cisplatin (intravesical), procarbazine, and cytarabine.³³ The only cytotoxic drugs without reported hypersensitivity—when used as single agents—are the nitrosureas, altretamine, vinca alkaloids, and dactinomycin.³³ Most reactions involve type I hypersensitivity with associated urticaria, angioedema, flushing, and pruritus. Severe anaphylactic reactions also occur, frequently causing shock, hypotension, and, occasionally, death. Only the most commonly allergenic chemotherapeutic drugs will be discussed.

L-asparaginase is most commonly associated with hypersensitivity, occurring in 10 to 25% of patients receiving the drug.³³ L-asparaginase is a bacterial polypeptide that instigates immunoglobulin E (IgE) and antibody production, causing acute urticaria, angioedema, or anaphylaxis. Hypersensitivity occurs less frequently when the drug is given in combination drug regimens, especially with vincristine and prednisone.³⁴ In up to 40% of patients, paclitaxel and docetaxel induce mild rashes and flushing, although premedication with antihistamines and corticosteroids reduces this frequency. Although hypersensitivities to cisplatin used to be quite common 20 years ago, the incidence has diminished, possibly secondary to premedication and the decreased dosage of current administration. Interestingly, intravesically administered cisplatin in patients with bladder cancer seems to be more allergenic than when the drug is given intravenously and occurs with a 20% incidence. A dose threshold phenomenon may be involved, as more cycles of drug are given intravesically.³⁵ Maculopapular rashes are the most common manifestation of procarbazine hypersensitivity, although urticaria and angioedema, and type III hypersensitivity, with immune complex deposition manifesting as a toxic epidermal necrolysis reaction, may also occur. This hypersensitivity does not seem to respond to corticosteroid therapy, unlike those induced by other cytotoxic drugs. Maculopapular rash is also the most common manifestation of cytarabine type I hypersensitivity (5 to 30% incidence). A variant of the cytarabine reaction, the “cytarabine syndrome,” described by Castleberry and colleagues includes high fever, rigors, myalgia, arthralgias, and a diffuse erythematous maculopapular rash, and responds to corticosteroids.³⁶ A type III hypersensitivity has been hypothesized, since circulating immune complexes were reported in one patient.³⁷

Acral Erythema

Acral erythema (AE) was first reported in association with chemotherapy by Zuehlke in 1974.³⁸ Other names include palmoplantar erythrodyesthesia, palmoplantar erythema, hand-foot syndrome, peculiar acral erythema, and Burgdorf reaction. It commonly occurs with fluorouracil, cytarabine, and doxorubicin (Table 144.9). There is a prodrome of dyesthesia of the palms and soles, evolving into painful, tingling, symmetric, well-demarcated swelling and erythematous plaques, followed by a desquamative phase on resolution (Fig. 144.1). Erythema and swelling usually appears on the thenar and hypothenar eminences, lateral aspect of the fingers, and the pads of the distal phalanges. The hands are more often affected than the feet. In its various manifestations, AE may appear as alternating bands of erythema and sparing and may also be accompanied by a mild erythema or a morbilliform eruption on the trunk, neck, chest, scalp, and extremities.³⁹ Methotrexate and cytarabine can reportedly induce a bullous variant of AE which may progress to full-thickness epidermal necrosis before resolving.⁴⁰

AE occurs with an incidence of 6 to 42% in different series, and occurs mostly in adults.⁴¹ AE appears to be dose dependent on peak levels and total cumulative dose, as it occurs earlier and more severely after bolus infusions (24 hours to 3 weeks), as compared with continuous low-dose administration (2 to 10 months).^39,41 AE tends to persist and worsen with further continuation of chemotherapy and may be dose limiting, as the associated pain may progress to become physically and functionally limiting. Cyclosporine infusions have been shown to worsen the pain, possibly due to the therapy’s high alcohol content.⁴² With long-term chemotherapy, reversible palmoplantar keratoderma can also develop.⁴³ Cessation of the causative agent will allow resolution of AE in 1 to 2 weeks, with desquamation and re-epithelialization. AE may or may not recur with re-administration. The treatment of AE is symptomatic, aimed at increasing tolerability to allow continued chemotherapy. Corticosteroids have shown variable success. Supportive treatment includes topical wound care, elevation, and pain medication. Similar to the concept of scalp hypothermia for alopecia, cooling of hands and feet may help prevent AE.^41,44 Pyridoxine may also reduce the dyesthesia and pain of AE and allow the continuation of therapy.⁴⁵

The pathogenesis of AE is currently unknown, but it is likely to be multifactorial. Theories exist based on the fact that the reaction is usually limited to the palms and soles. Temperature gradients, vascular anatomy, the existence of rapidly dividing epidermal cells, and high concentration of eccrine glands are characteristics of this region of the body and may play a role in pathogenesis.⁴¹ It is conceivable that AE may be related to a direct toxic effect. Biopsies of AE also appear histologically nonspecific but are consistent with a toxic reaction.⁴¹ In the setting of chemotherapy, diagnosis of AE is a relatively simple matter. However, it may occasionally be difficult to differentiate between AE and acute graft-versus-host disease (GVHD) in bone marrow transplantation (BMT) patients. There is a 35% incidence of AE in BMT patients, which may be due to the use of higher doses of chemotherapy and total body irradiation.⁴⁶ This concurrence of conditions can make diagnosis difficult, especially since histologically and clinically, AE may resemble acute GVHD in the first 3 weeks. As in AE, the palms are commonly affected in acute GVHD, although GVHD usually progresses with involvement of other areas of the body. Since early biopsies of acute GVHD mimics AE, serial biopsies at 3-to 5-day intervals are helpful in establishing patterns of progression in acute GVHD.⁴⁶ Distinguishing AE from acute GVHD is important, as the latter requires greater intervention with further immunosuppression. Without treatment, GVHD usually progresses and may be fatal.

Neutrophilic Eccrine Hidradenitis

First described by Harrist and colleagues in 1982, neutrophilic eccrine hidradenitis (NEH) has been associated with a variety of drugs and conditions.⁴⁷ NEH is most often observed with chemotherapy, and cytarabine is most frequently cited along with drugs such as bleomycin, chlorambucil, cyclophosphamide, doxorubicin, lomustine, and mitoxantrone.⁵ It has also occurred in normal individuals, in HIV patients taking zidovudine, in association with acetaminophen, G-CSF, bacterial infections, and in one normal individual prior to the diagnosis of acute myeloid leukemia (AML).^5,48 NEH manifests as erythematous to violaceous macules, papules, plaques, nodules, and pustules, which may be multiple or solitary, and painful or asymptomatic. Unusual presentations occur with involvement of the ears or periorbital inflammation.^48,49 NEH usually begins 2 days to 3 weeks following the initiation of chemotherapy, although it may occur as long as 2 years following therapy.⁵ Fever may also accompany the reaction. The differential diagnosis of NEH includes septic emboli, drug hypersensitivity, metastatic infiltrates, leukocytoclastic vasculitis, erythema multiforme, Sweet’s syndrome, and bullous pyoderma gangrenosum.^7,49 Given the clinical variability of NEH, a skin biopsy is required for diagnosis. The histopathology shows necrosis of eccrine epithelial cells, and neutrophilic infiltrates centered around eccrine sweat glands and ducts, and possibly apocrine glands.⁵⁰ In neutropenic patients, these neutrophilic infiltrates may be sparse. Electron microscopic studies by Brehler and colleagues and evidence of chemotherapeutic drug levels in sweat in a study by Madsen, support the theory that chemotherapy-induced NEH is caused by direct toxicity of the sweat glands.^50,51

NEH is self-limited and resolves spontaneously without scarring within 1 to 4 weeks after the cessation of therapy. However, there is a 60% recurrence rate with the re-administration of the same drug or regimen.⁵ Although therapy is rarely needed for NEH, treatment may alleviate discomfort and perhaps even bring resolution in cases that involve fever and painful lesions. Ibuprofen and systemic corticosteroids may be helpful, despite the incidence of NEH in chemotherapy regimens containing corticosteroids.⁴⁹ Dapsone, which has effects on neutrophil migration, has successfully prevented the recurrence of NEH in a case report.⁴⁹

Eccrine Squamous Syringometaplasia

Eccrine squamous syringometaplasia (ESS) is a relatively uncommon and benign cutaneous reaction, which is defined by pathognomonic noninflammatory metaplasia of the cuboidal epithelial cells of the eccrine sweat ducts. It differs from NEH by the absence of neutrophils on skin biopsy. Like NEH, the cutaneous manifestation of ESS is thought to result from a direct toxic effect from the secretion of chemotherapeutic agents through sweat. Clinically, ESS may give a presentation that is similar to NEH with erythematous macules, papules, plaques, or vesicles, which may be generalized, or localized to the intertriginous areas or the palms and soles. Given these similarities to NEH, ESS is thought to represent the noninflammatory end of the spectrum of chemotherapeutic eccrine gland reactions.⁵² ESS reportedly appears 2 to 39 days after the initiation of chemotherapy and resolves spontaneously without scarring in 7 to 10 days.⁵³ It has been reported in a number of cytotoxic agents, although it is not associated with any one particular drug and also occurs with chronic ulcers, skin tumors, exposure to toxic agents, and inflammatory processes, such as lobular panniculitis, pyoderma gangrenosum, and elastolytic granuloma annulare.^5,53 The reaction may also exist concurrently with other chemotherapy-induced reactions, such as AE, radiation recall, and NEH.^54,55 The differential diagnosis of ESS includes acute GVHD, eruption of lymphocyte recovery, infectious exanthems, and drug reactions.⁵³ A histologic confirmation of ESS changes on biopsy can be a diagnostic aid in differentiating a chemotherapy-induced reaction from acute GVHD or other drug reactions. In any case, ESS deserves consideration in any erythematous eruption during chemotherapy.

Cutaneous Eruption of Lymphocyte Recovery

The cutaneous eruption of lymphocyte recovery (ELR) was first reported by Horn and colleagues in 1989 in leukemic patients receiving intensive marrow aplasia–inducing chemotherapy.⁵⁶ As with ESS, the ELR phenomenon has been observed with various cytotoxic agents but is not associated with a particular agent. Clinically, ELR has the appearance of variably distributed erythematous and pruritic macules, papules, and plaques which may become confluent and erythrodermic and is often associated with a 2- to 3-day episode of fever. In the setting of chemotherapy, this reaction has been found to occur 6 to 21 days after the chemotherapy-induced nadir of the leukocyte count, which correlates with the time of the initial recovery of peripheral lymphocytes.⁵⁶ Although the immunologic mechanism of ELR is poorly understood, it is thought to reflect the return of immunocompetent lymphocytes with heightened alloreactivity to the peripheral circulation and skin.⁵⁶ ELR is self-limited and resolves over several days with desquamation and mild residual hyperpigmentation. Given the nonspecific clinical manifestation of ELR, other causes of an erythematous exanthem must be considered in the differential diagnosis, particularly acute GVHD, sepsis, viral exanthem, leukemia or lymphoma cutis, ESS, and drug hypersensitivity. Of these types of eruptions, acute GVHD is similar in time of onset to ELR in the setting of bone marrow transplantation. The similarity with ELR is especially true in the case of autologous GVHD, as both involve a lymphocytic recovery in which histocompatability is present. However, acute autologous GVHD cannot be reliably distinguished from ELR by skin biopsy, as the nonspecific histologic presentation of ELR may resemble acute autologous GVHD.⁵⁷ As theorized by Horn, GVHD may represent a form of ELR.⁵⁸

Cytokine and Miscellaneous Reactions

With recent advances in biotechnology, there has been a proliferation of cytokines and various immunotherapeutic agents, which have been developed to fight cancer at the cellular level. Roles have already been established for IL-2 as alternative treatment for advanced metastatic melanoma and renal cell cancer and for INF-α as standard treatment for chronic myelogenous leukemia, hairy-cell leukemia, cutaneous T-cell lymphoma, and Kaposi’s sarcoma. Besides other significant toxicities, such as capillary leak syndrome, a plethora of cutaneous reactions (72% incidence) have been reported with IL-2. ⁵⁹ A rather common reaction is a pruritic diffuse macular erythematous eruption which occurs 1 to 3 days after administration and begins to resolve with desquamation 2 days following the cessation of therapy (Fig. 144.2).⁵⁹ This reaction is clinically similar to toxic shock syndrome and has been associated with staphylococcal sepsis in some patients. Intra-arterial IL-2 also causes hypersensitivity to iodine-containing contrast dyes in up to 30% of patients.⁶⁰ Of potential importance, one study of IL-2 for metastatic melanoma has reported a possible correlation between the development of vitiligo and good prognosis.⁶¹

Although INF-α is relatively less toxic than IL-2, several cutaneous reactions have been reported in the literature. In a study of 1,000 patients receiving INF-α, alopecia and herpes labialis exacerbation were common with 10% and 5% incidence, respectively.^60,62 Both INF-α and IL-2 also exacerbate psoriasis and seborrheic dermatitis. INF-α has also been associated with new-onset psoriasis.⁶⁰

There are also case reports of a large number of miscellaneous cutaneous reactions, the incidence rates of which are mostly unknown. Table 144.10 lists and updates many of these reactions, which have been reported in IL-2 and INF-α and in a variety of other cytotoxic drugs.^5,60 This list continues to grow as the numbers of new drugs on the market and in clinical drug trials continue to proliferate. For example, at the M.D. Anderson Cancer Center, chemotherapy-induced acne has been frequently observed during ongoing clinical trials of ZD1839 (tyrosine kinase inhibitor of epidermal growth factor receptor), as well as with C225 (monoclonal [EGFR] antibody). It is clear that new chemotherapy-induced cutaneous reactions such as these will remain a frequently observed and reported phenomenon in the literature.