Toxic erythema of chemotherapy: A useful clinical term

COMMENTARY

Toxic erythema of chemotherapy: A useful clinical term Jean L. Bolognia, MD,a Dennis L. Cooper, MD,b and Earl J. Glusac, MDa,c New Haven, Connecticut

he administration of chemotherapy can lead to a host of cutaneous findings, ranging from adverse reactions to specific drugs to infectious complications caused by immunosuppression and neutropenia. While some of the drug reactions are allergic in nature, there is a group of overlapping toxic reactions that is characterized by areas of painful erythema (and oftentimes edema) which usually involve the hands and feet, intertriginous zones (eg, axillae, groin), and, less often, the elbows, knees, and ears.1,2 The eruptions may have a bullous component,3,4 are self-limited,5 and often resolve with desquamation and postinflammatory hyperpigmentation. Frequently, they are misdiagnosed as hypersensitivity reactions, including allergic drug eruptions and contact dermatitis, as well as graft versus host disease (GVHD), vasculitis, or cutaneous infections (both primary and embolic).6 Clinical recognition of toxic erythema is especially important in the case of high-dose chemotherapy because the lesions develop during a critical 2- to 3week period following administration when patients are often receiving multiple medications, including antibiotics, and are at risk for infections and GVHD (if they also received an allogeneic hematopoietic stem cell transplant). Therefore an accurate diagnosis is critical, not just from a prognostic standpoint, but also because it avoids unnecessary, potentially harmful therapeutic interventions (eg, systemic corticosteroids) and erroneous assignment of drug allergies, especially to antibiotics, which then restricts future treatment options. Unfortunately, over the past 3 decades, multiple, sometimes confusing diagnostic names have been applied to these eruptions (Table I),1,7-18 including ones that reflect the histologic, but not clinical,

T

findings (Table II).2,3,18-28 The latter is best exemplified by the designations ‘‘eccrine squamous syringometaplasia,’’19,26 ‘‘epidermal dystrophy,’’25 and ‘‘epidermal dysmaturation,’’29,30 terms that, while clearly apt and insightful, may not even be that familiar to dermatologists and are certainly foreign to hematologists and oncologists. We are recommending a new clinically descriptive term, toxic erythema of chemotherapy (TEC), in order to emphasize the overlapping features of the entities outlined in Table II and to provide a straightforward, easily understood clinical name that enhances communication and patient care. The diagnostic terms outlined in Table III are those that are cited most frequently in the literature. By listing the characteristic clinical (Table III) and histologic features (Table IV), significant overlap becomes readily apparent. For example, eccrine squamous syringometaplasia can be seen histologically in patients diagnosed with acral erythrodysesthesia31-33 and in those with chemotherapy-associated eccrine neutrophilic hidradenitis.34 In addition, intertriginous eruptions caused by chemotherapy can have evidence of epidermal dysmaturation23 and eccrine squamous syringometaplasia.26 It is also noteworthy that the inciting chemotherapeutic agents for each of these entities also exhibit significant overlap. Of note, some of the currently used terms can also prove a bit restrictive. For example, while the majority of patients with erythrodysesthesia secondary to chemotherapy have just hand and foot involvement, some will also have areas of painful erythema at sites of pressure,35 an intertrigo-like eruption,21 facial edema and erythema,36 or involvement of flexural areas.37 For these patients, use of the terms acral erythema, acral erythrodysesthesia,

From the Department of Dermatology,a Yale University School of Medicine; Section of Medical Oncology,b Yale Comprehensive Cancer Center; and the Department of Pathology,c Yale University School of Medicine. Funding sources: None. Conflicts of interest: None declared. Presented at the 66th Annual Meeting of the American Academy of Dermatology, San Antonio, Texas, February 1-5, 2008.

Reprint requests: Jean L. Bolognia, MD, Department of Dermatology, Yale Medical School, 501 LCI, 333 Cedar St, New Haven, CT 06510. E-mail: [email protected]. J Am Acad Dermatol 2008;59:524-9. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.05.018

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Table I. Initial descriptive terms for erythrodysesthesia1,7-17 Author, year

Zuehlke, 1974 Burgdorf, 1982 Herzig, 1983 Cordonnier, 1982 Lokich, 1983 Silver, 1983 Doyle, 1983 Levine, 1985 Walker, 1985 Feldman, 1985 Crider, 1986 Cox, 1986

Chemotherapeutic agents

Names

Mitotane Cytarabine, doxorubicin Cytarabine Cytarabine, doxorubicin, CCNU 5-Fluorouracil (continuous infusion) Hydroxyurea Methotrexate, cyclophosphamide, doxorubicin, VP-16 Cytarabine Cytarabine 5-Fluorouracil (continuous infusion) Cyclophosphamide 6 cytarabine Mercaptopurine*

Erythematous eruption of the palms and soles Peculiar acral erythema Unusual and dramatic palmar and plantar erythema Acral erythema Swelling of the distal fingers with paresthesias Acral erythema Erythema and desquamation of the hands Distinctive acral erythema Palmar-plantar erythema Dermatitis of the hands and feet Chemotherapy-induced acral erythema Toxic erythema of palms and soles

The term ‘‘chemotherapy-associated palmareplantar erythrodysesthesia syndrome’’ was coined by Lokich and Moore.18 CCNU, N-(2-chloroethyl)-N9 -cyclo-hexyl-N-nitrosourea; VP-16, etoposide. *Combined with allopurinol.

chemotherapy-induced acral erythema, handefoot syndrome, and palmareplantar (palmoplantar) erythrodysesthesia may cause confusion and an unwarranted search for a second diagnosis. Beyond the multiple sites of cutaneous involvement, analogous changes may develop internally. For example, it is well established that similar chemotherapy-induced cytotoxic effects occur routinely in the gastrointestinal tract, often termed ‘‘mucositis.’’ The histologic findings within the intestinal tract caused by chemotherapy are similar to those seen in the skin. They include mucosal cell atypia, necrosis, and delayed regeneration, with loss of polarity.38 Clinically, this may be accompanied by one or more of the following: diarrhea, ileus, abdominal pain, hematemesis, melena, or proteinlosing enteropathy. In addition, there was one report of acral erythema occurring in association with spontaneously resolving pleuropericarditis in which the authors raised the possibility of a syndrome with both cutaneous and serosal toxicity.39 Recognition of this association allows the clinician to consider a cause other than an infection, hypersensitivity reaction, or GVHD, which then can be supported by further studies, including histologic evaluation. The chemotherapeutic agents most commonly associated with TEC are listed in Table V.40 There have been several proposals regarding pathophysiology (eg, friction, trauma, temperature gradient, and vascularity), but a toxic insult to the cells of the straight portion of the eccrine duct and the acrosyringium and the epidermis is the favored explanation. Excretion of chemotherapeutic agents via eccrine sweat provides a plausible explanation,34,41,42 and in

Table II. Entities within the spectrum of toxic erythema of chemotherapy2,3,18-28 AraC (cytarabine) ears Burgdorf’s reaction Chemotherapy-associated eccrine reactions Eccrine squamous syringometaplasia, chemotherapyinduced Epidermal dysmaturation, chemotherapy-induced Epidermal dystrophy (secondary to cytotoxic agents*) Erythrodysesthesia Acral erythema Acral erythrodysesthesia Chemotherapy-induced acral erythema (CIAE or CAE) Handefoot syndrome Palmareplantar erythema Palmareplantar (palmoplantar) erythrodysesthesia Toxic acral erythema Toxic erythema of the palms and soles Intertriginous eruption associated with chemotherapy Intertrigo-like eruption, chemotherapy-induced Flexural erythematous eruption (following autologous PBSCT) Intertrigo dermatitis Neutrophilic eccrine hidradenitis, chemotherapyassociated Chemotherapy-induced hidradenitis Drug-induced hidradenitis PBSCT, Peripheral blood stem cell transplant. *Also seen with radiation therapy (reflects cytoreductive therapy).

the case of at least one drug, thiotepa, enhanced concentration in the sweat (as compared to the serum) has been demonstrated.43 Sites of predilection could be explained in part by the high density of eccrine glands on the palms and soles (although the periungual region and the dorsal surfaces of the

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Table III. Clinical features of the major entities within the spectrum of toxic erythema of chemotherapy Clinical features Erythematous patches or plaques

Entity

Acral Intertriginous (hands, (eg, axillae, feet) groin)

11 Eccrine squamous syringometaplasia, chemotherapyinduced Epidermal NR dysmaturation Erythrodysesthesiay 111 Intertriginous eruption 1z associated with chemotherapy 1 Neutrophilic eccrine hidradenitis, chemotherapyassociated

Extensor surfaces (eg, elbows, knees)/ Pressure points*

Head Petechiae or and dusky neck appearance

Bullae

Spontaneous Desquamation resolution

111

1

1

11

1

11

111

11

11

NR

1

111

111

1 111

1 1

1 1z

11 11

Erosive when intertriginous 11 Erosive when intertriginous

111 11

111 111

e

111

1

1 11 (Under occlusion)

1/

e

Patients may also have evidence of mucositis and, weeks later, Beau’s lines and onychomadesis. ESS, Eccrine squamous syringometaplasia; NR, not reported. *Including sites occluded by tape. y Including types listed in Table II. z May be more common in children.27

Table IV. Histologic features of the major entities within the spectrum of toxic erythema of chemotherapy Histologic features ESS

Apoptosis and necrosis of keratinocytes

111

1

1

1

e 11

1 11

111 11

1 11

Intertriginous eruption associated 11 with chemotherapy Neutrophilic eccrine hidradenitis, 1 chemotherapy-associated

11

111

11

1

e

e

Entity

Eccrine squamous syringometaplasia, chemotherapy-induced Epidermal dysmaturation Erythrodysesthesiay

Keratinocyte Vacuolar dysmaturation* degeneration

Other

Apoptosis of eccrine ductal cells; focal necrosis; NEH occasionally observed

Neutrophilic infiltrate in some patients; necrosis of eccrine ductal cells

ESS, Eccrine squamous syringometaplasia; NEH, neutrophilic eccrine hidradenitis. *Includes distortion of the epidermal maturation process (crowding of keratinocytes, enlarged keratinocytes, nuclear pleomorphism, and loss of polarity). y Including types listed in Table II.

hands and feet, especially that overlying joints, can also be involved), as well as sweating plus occlusive phenomenon in intertriginous zones and in areas of the skin covered by tape. Further support for a toxic insult is the development of localized areas of eccrine squamous syringometaplasia at the sites of extravasation of doxorubicin.44,45

The therapeutic interventions for the various toxic erythemas caused by chemotherapy remain nonspecific and primarily palliative. These include cool compresses, analgesics, bland emollients, topical corticosteroids, and topical antibiotics or ointments for erosions. Based upon case reports or small cases series, the following treatments have also been

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recommended: local hypothermia,14 systemic corticosteroids (with variable success),35,46,47 topical 99% dimethylsulfoxide (DMSO; four times daily for 14 days),48 oral celecoxib,49 oral vitamin B6 (50-150 mg once daily),50 and oral vitamin E (300 mg once daily).51 Prevention of recurrence involves dose reduction, lengthening the interval between cycles, or discontinuation of the offending agents. For example, in an early study by Herzig et al,9 palmar and plantar erythema developed in 10%, 26%, and 67% of patients treated with total doses of 24, 36, and 48 gm/m2 of cytarabine, respectively. Of course, if the patient were able to tolerate the toxic erythema, then the riskebenefit ratio would dictate the continuation of appropriate chemotherapeutic agents. In summary, the clinical characteristics of TEC are as follows: (1) erythematous patches or edematous plaques of the hands and feet, intertriginous zones, and, less often, the elbows, knees, and ears that usually appear 2 days to 3 weeks following the administration of chemotherapeutic agents; (2) associated symptoms of pain (which can be severe), burning, paresthesias, pruritus, and/or tenderness; (3) development of a dusky hue, petechiae (which may reflect thrombocytopenia), and/or sterile bullae (followed by erosions) within areas of intense erythema in some patients; (4) desquamation and spontaneous resolution without specific therapy; and (5) possible recurrence if the same or higher dose is administered. There may be scattered papules at the periphery of the plaques, and papules and plaques can also involve the head and neck (especially in chemotherapy-associated neutrophilic eccrine hidradenitis) and the trunk1 and extremities26 (ie, have a more generalized distribution).19,26 A delayed onset of up to 2 to 10 months52 can be seen in patients who are receiving lower-dose, continuous intravenous infusions (eg, 5-fluorouracil) or oral agents that mimic prolonged infusions. The histologic features of TEC include atypia (enlarged cell and nuclear size and nuclear pleomorphism) and apoptosis of keratinocytes, mitotic arrest and bizarre mitotic configurations (eg, starburst mitoses), loss of polarity of epidermal cells and crowding of keratinocytes, vacuolar degeneration of the basal layer of the epidermis, dermal edema, and eccrine squamous syringometaplasia. The latter is characterized by metaplastic transformation of the cuboidal epithelial cells of the eccrine duct into cells with squamatized cytoplasm that resemble those of the stratum spinosum of the epidermis. Occasionally, there can be eccrine ductal spongiosis, apoptosis, and cytologic atypia.29,31 Additionally, confluent necrosis of the upper epidermis may

Table V. Chemotherapeutic agents associated with toxic erythema* More common Cytarabine (AraC) Anthracyclines (polyethylene glycol-coated liposomal doxorubicin [ doxorubiciny) 5-Fluorouracil (5-FU; prolonged continuous infusion [ bolus) Capecitabine (5-FU prodrug) Taxanes (docetaxel [ paclitaxel) Methotrexate Less common Bleomycin Busulfan (increasing incidence with use of IV form) Carmustine, lomustine Cisplatin, carboplatin Clofarabine Cyclophosphamide, ifosfamide Etoposide Gemcitabine Hydroxyurea Melphalan 6-Mercaptopurine Mitoxantrone Receptor tyrosine kinase inhibitors (imatinib, sunitinib) Tegafur Thiotepa Vinorelbine *This list is not exhaustive, and additional, especially newer, agents will certainly be added to the list. y In contrast, other toxicities (eg, cardiotoxicity, myelosuppression, and alopecia) are observed less frequently with polyethylene glycol-coated liposomal doxorubicin.24,40

occur,29 where the clinical correlate is shellac-like scale reminiscent of that seen in the ‘‘nutritional’’ dermatoses, such as pellagra. Of note, inflammatory infiltrates are usually minimal despite the dramatic clinical appearance. Given this observation, Horn41 has hypothesized that the erythema is secondary to keratinocyte damage with release of cytokines leading to vasodilation. Some may argue that of the entities listed in Table II, it is chemotherapy-induced neutrophilic eccrine hidradenitis that should not be assigned the name TEC. However, there is evidence that this form of neutrophilic eccrine hidradenitis is part of the TEC spectrum. First, in patients with ‘‘erythrodysesthesia’’ and several of the disorders in Table II, similar pauciinflammatory changes of eccrine ducts (and eccrine squamous syringometaplasia) are frequently reported in conjunction with typical chemotherapyinduced epidermal changes (eg, pleomorphism, vacuolar alteration, and necrosis). Furthermore, clinical and histologic overlap with other disorders in the list (eg, eccrine squamous syringometaplasia) can be

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observed in biopsies showing chemotherapy-induced neutrophilic eccrine hidradenitis (Table IV). Lastly, because many patients with eccrine squamous syringometaplasia are neutropenic, it has been suggested that the absence of neutrophils in the reaction is simply a reflection of the inability of the neutropenic patient to mount a secondary neutrophilic response to a primarily cytotoxic process.53 Thus, Greenbaum et al53 and Hurt et al22 have suggested that eccrine squamous syringometaplasia and neutrophilic eccrine hidradenitis are part of a spectrum that might be more accurately termed ‘‘chemotherapy-associated eccrine reactions.’’ We believe there is sufficient evidence to take this a step further. Because the histologic changes in eccrine glands and the surface epidermis are similar (necrosis, pleomorphism, and loss of cellular polarity), and because both are seen concurrently in patients receiving chemotherapy, it seems that the disorders are not separate (ie, they are all part of TEC). In some patients, histologic changes may be more pronounced in eccrine glands, while the epidermis may be more prominently affected in others; however, all appear to be a manifestation of one pathologic process. Use of the term TEC allows for ease in communication with nondermatologists and reflects the nonallergic and noninfectious nature of the eruption as well as providing reassurance that it does not represent GVHD in patients at risk for that process. While TEC and GVHD can usually be distinguished clinically by the significant differences in their distribution patterns (eg, intertriginous GVHD or GVHD that is painful and limited to the palms and soles would be very unusual), there may be some overlap histologically between TEC and GVHD, especially in biopsy specimens obtained within 2 to 3 weeks of chemotherapy administration where GVHD could be superimposed on a background of clinically silent, chemotherapy-induced epidermal dysmaturation. However, unlike TEC, GVHD is a lymphocytemediated phenomenon. In GVHD, an infiltrate of lymphocytes, often sparse, is present within the epidermis and papillary dermis. In particular, intraepidermal lymphocytes (often associated with individual necrotic keratinocytes) are seen in GVHD. By contrast, TEC is a toxic phenomenon, which is not immune-mediated and is generally not associated with inflammation. Occasionally in TEC, inflammatory cells, particularly neutrophils, may be recruited to a site of injury as a secondary phenomenon. Vacuolar change may be seen in both conditions and does not distinguish GVHD from TEC. A more accurate descriptor, such as TEC, may also help prevent the inappropriate use of systemic

immunosuppressives for presumed hypersensitivity reactions and systemic antimicrobials for presumed infections and the undeserved assignment of drug allergies. Lastly, the term ‘‘toxic’’ emphasizes the risk of recurrence should the same chemotherapeutic regimen be administered, in addition to the possibility of a more intense reaction should the dose be increased. REFERENCES 1. Levine LE, Medenica MM, Lorincz AL, Soltani K, Raab B, Ma A. Distinctive acral erythema occurring during therapy for severe myelogenous leukemia. Arch Dermatol 1985;121:102-4. 2. Krulder JWM, Vlasveld LT, Willemze R. Erythema and swelling of the ears after treatment with cytarabine for leukemia. Eur J Cancer 1990;26:649-50. 3. Azurdia RM, Clark RE, Friedmann PS. Chemotherapy-induced acral erythema (CIAE) with bullous reaction. Clin Exp Dermatol 1999;24:64-6. 4. Waltzer JF, Flowers FP. Bullous variant of chemotherapyinduced acral erythema. Arch Dermatol 1993;129:43-5. 5. Demircay Z, Gu¨rbu¨z O, Alpdogan TB, Yu¨celten D, Alpdogan O, Kurtkaya O, et al. Chemotherapy-induced acral erythema in leukemic patients: a report of 15 cases. Int J Dermatol 1997;36: 593-8. 6. Alonso V, Ramo´n, Monteagudo C, Llombart B, Martı´n JM, Garcı´a L, et al. Eccrine squamous syringometaplasia mimicking a herpetic infection. Int J Dermatol 2006;45:762-3. 7. Zuehlke RL. Erythematous eruption of the palms and soles associated with mitotane therapy. Dermatologica 1974;148: 90-2. 8. Burgdorf WHC, Gilmore WA, Ganick RG. Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. Ann Intern Med 1982;97:61-2. 9. Herzig RH, Wolff SN, Lazarus HM, Phillips GL, Karanes PC, Herzig GP. High-dose cytosine arabinoside therapy for refractory leukemia. Blood 1983;622:361-9. 10. Cordonnier C, Roujeau JC, Vernant JP, Matheron S, Ganem G. Cancer chemotherapy and acral erythema. Ann Intern Med 1982;97:783-4. 11. Lokich J, Fine N, Perri J, Bothe A Jr. Protracted ambulatory venous infusion of 5-fluorouracil. Am J Clin Oncol 1983;6:103-7. 12. Silver FS, Espinoza LR, Hartmann RC. Acral erythema and hydroxyurea. Ann Intern Med 1983;98:675. 13. Doyle LA, Berg C, Bottino G, Chabner B. Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983;98:611-2. 14. Walker IR, Wilson WEC, Sauder DN, Benger AM, Browman G. Cytarabine-induced palmar-plantar erythema. Arch Dermatol 1985;121:1240-1. 15. Feldman LD, Ajani JA. Fluorouracil-associated dermatitis of the hands and feet. JAMA 1985;254:3479. 16. Crider MK, Jansen J, Norins AL, McHale MS. Chemotherapyinduced acral erythema in patients receiving bone marrow transplantation. Arch Dermatol 1986;122:1023-7. 17. Cox GJ, Robertson DB. Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. Arch Dermatol 1986;122:1413-4. 18. Lokich JJ, Moore C. Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1984;101: 798-800. 19. Bhawan J, Malhotra R. Syringosquamous metaplasia. A distinctive eruption in patients receiving chemotherapy. Am J Dermatopathol 1990;12:1-6.

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