- Email: [email protected]
Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy
CASE
& REVIEW
Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy Katherine L. Goldfeder, BA,a Joshua M. Levin, MD,b Kenneth A. Katz, MD, MSc,b Loren E. Clarke, MD,c Alison W. Loren, MD, MS,d and William D. James, MDb Philadelphia and Hershey, Pennsylvania Ultraviolet (UV) reactivation reactions are rare and can occur in areas of prior sunburn or UV light therapy after the administration of chemotherapy, antibiotics, and other medications. Reactions may occur within days, as described after methotrexate therapy, or may appear months later, as described with ampicillin. Such reactions have been variably termed ‘‘UV recall,’’ ‘‘sunburn recall,’’ ‘‘photo recall,’’ and ‘‘photodermatitis reactivation,’’ making classification difficult. We report a UV reactivation reaction in a patient with acute lymphocytic leukemia treated with total body irradiation, etoposide, and methotrexate. We propose the terms ‘‘UV recall’’ and ‘‘UV enhancement’’ be used in future reports to classify UV reactivation reactions in a scheme analogous to the terminology for cutaneous reactions after radiotherapy. ( J Am Acad Dermatol 2007;56:494-9.)
CASE REPORT A 49-year-old man with pre-B cell acute lymphocytic leukemia was admitted to the hospital for allogeneic bone-marrow transplantation. One month earlier he completed 3 cycles of therapy with cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate. His transplant was conditioned with total body irradiation (1200 cGy) given in 6 fractions over 3 days, beginning 4 days before transplantation; and etoposide (60 mg/kg) given in a single dose 2 days before transplantation. In addition, he received trimethoprimsulfamethoxazole (TMP-SMX) prophylaxis 3 times per week, beginning 2 weeks before transplantation, with his last dose 1 day before transplantation. He received an allogeneic bone-marrow transplant from his 10/10 HLA-matched sibling, followed by
From the University of Pennsylvania School of Medicinea; Department of Dermatology, Hospital of the University of Pennsylvaniab; Department of Pathology, Penn State/Milton S. Hershey Medical Centerc; and Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania Cancer Center, Philadelphia.d Funding sources: None. Conflicts of interest: None identified. Reprint requests: Joshua M. Levin, MD, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Maloney Bldg, Philadelphia, PA 19104. E-mail: joshua. [email protected]. Published online December 30, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.11.009
494
Abbreviations used: RR: TMP-SMX: UV: UVR:
radiation recall trimethoprim-sulfamethoxazole ultraviolet ultraviolet recall
methotrexate given as graft-versus-host disease prophylaxis on posttransplantation days 1, 3, 6, and 11 with doses of 15 mg/m2 on day 1, 10 mg/m2 on days 3 and 6, and 5 mg/m2 on day 11. The last dose was a reduction from the planned dose of 10 mg/m2 because of severe oropharyngeal mucositis. On the fourth day posttransplantation the patient developed pruritic macules and papules on the superior aspect of his chest, shoulders, superior aspect of his back, lateral aspects of arms, face, and ears with sparing of the submental area (Figs 1 and 2). He had been sunburned many times in this same distribution, having worn tank-top shirts during decades of work as a roofer. The most recent sunburn had been 8 months earlier. There was no history of diarrhea or gastrointestinal symptoms suggestive of graft-versus-host disease. A punch biopsy specimen obtained from the right arm revealed epidermal dysmaturation with apoptotic, necrotic keratinocytes (Fig 3). Laboratory data were remarkable for a white blood cell count of less than 0.1 3 109/L (normal 4.0-11.0). Bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were within normal limits. We diagnosed a UV recall (UVR) reaction. The eruption resolved after 4 days with treatment of
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Fig 1. Erythematous macules and papules on upper aspect of chest, shoulders, outer aspect of arms, with sparing of submental area.
Fig 2. Erythematous macules and papules on outer aspect of arm, shoulder, and upper aspect of back.
triamcinalone 0.1% ointment twice daily. There was no exacerbation or recurrence of his eruption with subsequent methotrexate doses on posttransplantation days 6 and 11.
DISCUSSION UV reactivation, also referred to as UVR,1,2 sunburn recall,3 photo recall,4,5 and photodermatitis reactivation6 among others, is a rare phenomenon that can occur with chemotherapy or antibiotics. Identifying the specific triggering agent can be difficult, because most cancer patients receive multidrug chemotherapy and often require antibiotics during the course of treatment. Some patients also receive total body irradiation, which has also been
Fig 3. High magnification shows numerous apoptotic keratinocytes. There are pleomorphic keratinocytes with enlarged, irregular, hyperchromatic nuclei distributed throughout spinous layer. Loss of keratinocyte polarity is also present. (Hematoxylin-eosin stain; original magnification: 3400.)
implicated in causing reactivation of a prior sunburn.7 We have identified 21 additional reports of UV reactivation reactions after chemotherapy, antibiotics, other medications, or radiotherapy in the literature (Table I). In this review we describe clinical and histopathologic features of UV reactivation reactions and suggest a classification scheme for them based on the terminology used to describe cutaneous reactions after radiotherapy. Reactions in areas of prior radiation therapy after administration of chemotherapeutics (ie, radiation enhancement and radiation recall [RR]) have been well documented.8,9 Radiation enhancement occurs when the drug is administered within several days of radiotherapy and is considered an exacerbation of acute radiation dermatitis, presenting with pain, edema, erythema, bullae, and hemorrhagic crusting.8 In contrast, RR occurs weeks to years after radiotherapy and clinically presents with pruritus or pain, erythema, edema, macules and papules, vesiculation, and ulceration and necrosis in more severe cases.8-10 When reviewing the cases of UV reactivation reactions, those reactions that occurred within 1 week of UV exposure were associated with pain and burning, and erythematous, violaceous, and bullous skin lesions (Table I). In contrast, those reactions that occurred weeks to months after UV exposure were associated with pruritus and macular and papular lesions, although bullae were present in two patients and one patient experienced burning. Given the similarities to radiotherapy reactions, the sunburnlike reactions that occurred when the drug was administered within several days of UV exposure could be described as UV enhancement, and the macules, papules, and other eruptions that occurred when the drug was given months after UV exposure
Study
Moller13 (1969) Corder et al14 (1976) Jaffe15 (1976) Korossy et al16 (1981) Andersen et al17 (1984)
Putative associated agent
Morphology of eruption
Symptoms
Pathology
Time from UV exposure to causative agent*
Time from causative agent to eruption
MTX, 6-MP MTX, leucovorin
Dusky erythema with bullae Violaceous, blanching erythema
Not described Pain
Not described Not described
1 day 5 days
2 days 24 h
MTX, citrovorum MTX
Erythema, peeling, hemorrhage Erythema, edema, vesicles
Not described Great discomfort
Not described Not described
Not described 2 days
Not described 48 h
MTX, cyclophosphamide, 5-FU
Red-violet erythema
None
1 day
2-3 days
Neiman et al18 (1985)
MTX
Not described
48 h
23 h
Nedorost et al19 (1989) Okamoto et al20 (1994) Khan et al6 (2000)
MTX
Dusky red dermatitis, bullae superficial ulcerations of buccal mucosa Bullae and severe eczemitization
Few basal cells with hydropic degeneration and dyskeratotic cells; papillary dermis with slight perivascular lymphocytic infiltrate Not described
Not described
MTX
Erythema
MTX
Kaya et al21 (2006) Williams et al2 (1993)
MTX, cytarabine
Erythematous to violaceous skin with bullae, desquamation, and hemorrhagic crusting Erythema, vesicles
24-48 h after sunburny 1 mo after topical PUVA 2 days
Lowitt et al22 (1995) Ee et al4 (2003)
Etoposide, cyclophosphamide, ceftazidime, tobramycin, vancomycin Suraminz
Paclitaxel
Progression of Not described sunburn symptoms Not described Not described Burning
Not described
Burning
Not described
No history of sunburn 1 wk
496 Goldfeder et al
Table I. Summary of cases of ultraviolet reactivation reactions
3 days 2 days
Not described
Exanthematous, urticarial, and eczematous eruptions in an actinic pattern Erythema and bullae
Not described
Not specified
Not described
12 days for etoposide and cyclophosphomide; 3 days for ceftazidime, tobramycin, and vancomycin Not described
Not described
Epidermis with focal parakeratosis, acanthosis, spongiosis, and occasional apoptotic cells; dilated dermal vessels, extravasated red blood cells, and perivascular infiltrate of lymphocytes, histiocytes, and few neutrophils
1 day
1 wk
MARCH 2007
Vacuolar degeneration and perivascular mononuclear cell infiltrate with hemorrhage
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Violaceous blanching patches with Not described peripheral petechiae
Erythema
Not described
TMP-SMX
Erythema with initial reaction; bullae with rechallenge
Not described
Flax et al24 (1990) Lee et al25 (1998)
Cefazolin and gentamicin Aspirin, dialuminate
‘‘Maculopapular’’
Pruritus
Erythema and purpura in sun-exposed areas; targetoid lesions in sun-protected areas; vesicular and erosive lesions in vulvar and oral mucosa
Burning
Krishnan et al1 (2001) Blanco et al26 (2002) Hill et al7 (2002) Garza et al5 (2004)
Piperacillin, tobramycin, ciprofloxacin Ampicillin
Morbilliform
Not described
(Biopsy specimen from 8 mo lesion in sun-exposed area) increased number of melancytes, intact epidermis, dense extravasation of red blood cells Not described 1 mo
Erythema, bullae
Pruritus
Not described
2 mo
3 days
Pruritus Not described
Not described Mild perivascular lymphocytic infiltrate with rare apoptotic keratinocytes
50 y Several wk
3 wk 1 day
Pruritus
8 mo Apoptotic, necrotic keratinocytes; keratinocyte atypia with loss of polarity; minimal vacuolar degeneration; mild superficial perivascular inflammatory cell infiltrate
Current case
Radiotherapy ‘‘Maculopapular’’ Cefazolin, codeine, Erythema ondansetron, acetaminophen, phenytoin, ranitidine, dexamethasone Etoposide, Erythematous macules MTX, TMP-SMX, and papules radiotherapy
Atrophic epidermis with 1 wk after UVB necrotic keratinocytes therapy Extensive epidermal cell 7 mo necrosis with intraepidermal bulla formation; perivascular inflammatory cell infiltrate, predominantly lymphocytes, in reticular dermis Not described 1 mo
‘‘Almost immediately’’ 12 days for initial reaction; 24 h for rechallenge
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Badger et al23 (2005) Shelley et al11 (1984)
5 days for cefazolin, 48 h for gentamicin Initial reaction not described; 1 h after rechallenge
3 days
7 days for etoposide, 3 days for MTX, 8 days for radiotherapy, 11 days for TMP-SMX§
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FU, Fluorouracil; MP, mercaptopurine; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; TMP-SMX, trimethoprim-sulfamethoxazole; UV, ultraviolet; UVB, ultraviolet B. *UV exposure was sunburn unless otherwise specified. y Sunburn thought to be a drug-induced photosensitivity reaction from ciprofloxacin plus sun exposure. z In a case series of 60 patients receiving suramin for metastatic solid tumors, 21 patients (35%) reported as having ‘‘UV recall.’’ § TMP-SMX was stopped 6 days before eruption.
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could be described as UVR. This would create a simple classification scheme that is analogous to the existing scheme for radiotherapy reactions. Our patient fits into the category of UVR, given the delay of 8 months from sunburn to drug administration, pruritus, and macular and papular morphology. Similar to the patient reported by Williams et al,2 there are multiple potential putative agents for his UVR. Our patient received etoposide 7 days before the eruption, methotrextate 3 days before the eruption, and total body irradiation 8 days before eruption. He also completed a 2-week course of alternate-day TMP-SMX 6 days before the onset of skin lesions. Methotrexate seems unlikely to be the single responsible agent, because the patient received much larger doses of methotrexate during chemotherapy several months before admission without developing any cutaneous lesions. In addition, he received 3 subsequent doses of methotrexate without exacerbation or recurrence of his eruption during his admission. A case of a severe bullous eruption after the 12th day of receiving TMP-SMX in an area severely sunburned 7 months earlier has been reported.11 Although our patient did receive TMP-SMX, the medication was stopped 6 days before the onset of lesions and he did not have a bullous eruption. Etoposide has been previously reported with a UV reactivation reaction; however, in that case the reaction occurred only 1 week after UV exposure and was characterized by violaceous blanching patches with petechiae.2 Futhermore, that patient received multiple other medications, including cyclophosphamide and several antibiotics (Table I). Finally, there is a report of UVR induced by radiation therapy 50 years after sunburn.7 It is difficult to determine which of these therapies, either alone or in combination, triggered our patient’s UVR. Histolopathologic features of reactivation reactions to radiotherapy and UV light are not well described in the literature. Smith et al12 examined skin biopsy specimens from 8 patients with RR and two patients with radiation enhancement. They reported similar findings in both groups, with variable degrees of ballooning degeneration characteristic of cellular necrosis, occasional nuclear and cytoplasmic contraction consistent with apoptosis, acanthosis, and variable mixed inflammatory cell infiltrate in the dermis. Six of the biopsy specimens taken from patients with RR also revealed features of chronic radiodermatitis, with dermal sclerosis, vascular dilatation with atypia of endothelial cells, and variable degrees of atypia in other stromal cells. Biopsy of UV reactivation reactions is not routinely performed (Table I). Tissue from both UVR and UV
enhancement show similar features, with necrotic keratinocytes and a perivascular inflammatory cell infiltrate of varying degrees in most specimens (Table I). The pathogenesis of radiotherapy and UV reactivation reactions remains poorly understood. Proposed mechanisms include inhibition of DNA repair and cellular recovery, reduction of proliferative capacity and impairment of surviving stem cells, and low-level secretion of various inflammatory cytokines that are up-regulated with a precipitating medication.9,10 Other hypotheses, such as local vascular changes induced by radiotherapy, and mast cells in irradiated skin as mediators of reactivation reactions, have also been advanced.4 Nomenclature for reactivation reactions to UV exposure is inconsistent and confusing. Given the similarities to radiotherapy reactions, we propose the terms ‘‘UV recall’’ and ‘‘UV enhancement’’ be used in future reports to classify UV reactivation reactions in a scheme analogous to the terminology for cutaneous reactions after radiotherapy. REFERENCES 1. Krishnan RS, Lewis AT, Kass JS, Hsu S. Ultraviolet recall-like phenomenon occurring after piperacillin, tobramycin, and ciprofloxacin therapy. J Am Acad Dermatol 2001;44:1045-7. 2. Williams BJ, Roth DJ, Callen JP. Ultraviolet recall associated with etoposide and cyclophosphamide therapy. Clin Exp Dermatol 1993;18:452-3. 3. Guzzo C, Kaidby K. Recurrent recall of sunburn by methotrexate. Photodermatol Photoimmunol Photomed 1995;11:55-6. 4. Ee HL, Yosipovitch G. Photo recall phenomenon: an adverse reaction to taxanes. Dermatology 2003;207:196-8. 5. Garza LA, Yoo EK, Junkins-Hopkins JM, VanVoorhees AS. Photo recall effect in association with cefazolin. Cutis 2004;73:79-80, 85. 6. Khan AJ, Marghoob AA, Prestia AE, Spector IJ. Methotrexate and the photodermatitis reactivation reaction: a case report and review of the literature. Cutis 2000;66:379-82. 7. Hill HZ, Hill GJ, Cathcart C. Photo-recall of sunburn induced by radiation therapy 50 years later. J Med 2002;33:115-8. 8. Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999;40: 367-400. 9. Azria D, Magne N, Zouhair A, Castadot P, Culine S, Ychou M, et al. Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 2005;31:555-70. 10. Ristic B. Radiation recall dermatitis. Int J Dermatol 2004;43: 627-31. 11. Shelley WB, Shelley ED, Campbell AC, Weigensberg IJ. Drug eruptions presenting at sites of prior radiation damage (sunlight and electron beam). J Am Acad Dermatol 1984;11: 53-7. 12. Smith KJ, Germain M, Skelton H. Histopathologic features seen with radiation recall or enhancement eruptions. J Cutan Med Surg 2002;6:535-40. 13. Moller H. Reactivation of acute inflammation by methotrexate. J Invest Dermatol 1969;52:437-41. 14. Corder MP, Stone WH. Failure of leucovorin rescue to prevent reactivation of a solar burn after high dose methotrexate. Cancer 1976;37:1660-2.
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15. Jaffe N. Reactivation of a solar burn with high-dose methotrexate and citrovorum rescue [letter]. Cancer 1976;38:1036-7. 16. Korossy KS, Hood AF. Methotrexate reactivation of sunburn reaction. Arch Dermatol 1981;117:310-1. 17. Andersen KE, Lindskov R. Recall of UVB-induced erythema in breast cancer patient receiving multiple drug chemotherapy. Photodermatology 1984;1:129-32. 18. Neiman RA, Fye KH. Methotrexate induced false photosensitivity reaction. J Rheumatol 1985;12:354-5. 19. Nedorost ST, Dijkstra JW, Handel DW. Drug-induced photosensitivity reaction. Arch Dermatol 1989;125:433-4. 20. Okamoto H, Fukuda A, Mizuno K, Matsuyoshi N, Fujii K, Imamura S. Reactivation of phototoxicity test for psoralens plus ultraviolet A by low-dose methotrexate. Photodermatol Photoimmunol Photomed 1994;10:134-6. 21. Kaya TI, Tiftik N, Tursen U, Ikizoglu G, Yalcin A. Ultraviolet recall phenomenon associated with methotrexate and cytarabine. J Eur Acad Dermatol Venereol 2006;20:353-4.
22. Lowitt MH, Eisenberger M, Sina B, Kao GF. Cutaneous eruptions from suramin: a clinical and histopathologic study of 60 patients. Arch Dermatol 1995;131:1147-53. 23. Badger J, Kang S, Uzieblo A, Srinivas S. Double diagnosis in cancer patients and cutaneous reaction related to gemcitabine, case 3: photo therapy recall with gemcitabine following ultraviolet B treatment. J Clin Oncol 2005;23: 7224-5. 24. Flax SH, Uhle P. Photo recall-like phenomenon following the use of cefazolin and gentamicin sulfate. Cutis 1990;46: 59-61. 25. Lee SG, Matsuyoshi N, Ohta K, Horiguchi Y, Imamura S. Drug eruption due to Bufferin showing erythema exsudativum multiforme with a photo-recall-like phenomenon. Eur J Dermatol 1998;8:280-2. 26. Blanco J, Manzanedo L, Gutierrez MC, Fuentes M. Ultraviolet recall phenomenon following the use of ampicillin. J Investig Allergol Clin Immunol 2002;12:215-6.
& REVIEW
Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy Katherine L. Goldfeder, BA,a Joshua M. Levin, MD,b Kenneth A. Katz, MD, MSc,b Loren E. Clarke, MD,c Alison W. Loren, MD, MS,d and William D. James, MDb Philadelphia and Hershey, Pennsylvania Ultraviolet (UV) reactivation reactions are rare and can occur in areas of prior sunburn or UV light therapy after the administration of chemotherapy, antibiotics, and other medications. Reactions may occur within days, as described after methotrexate therapy, or may appear months later, as described with ampicillin. Such reactions have been variably termed ‘‘UV recall,’’ ‘‘sunburn recall,’’ ‘‘photo recall,’’ and ‘‘photodermatitis reactivation,’’ making classification difficult. We report a UV reactivation reaction in a patient with acute lymphocytic leukemia treated with total body irradiation, etoposide, and methotrexate. We propose the terms ‘‘UV recall’’ and ‘‘UV enhancement’’ be used in future reports to classify UV reactivation reactions in a scheme analogous to the terminology for cutaneous reactions after radiotherapy. ( J Am Acad Dermatol 2007;56:494-9.)
CASE REPORT A 49-year-old man with pre-B cell acute lymphocytic leukemia was admitted to the hospital for allogeneic bone-marrow transplantation. One month earlier he completed 3 cycles of therapy with cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate. His transplant was conditioned with total body irradiation (1200 cGy) given in 6 fractions over 3 days, beginning 4 days before transplantation; and etoposide (60 mg/kg) given in a single dose 2 days before transplantation. In addition, he received trimethoprimsulfamethoxazole (TMP-SMX) prophylaxis 3 times per week, beginning 2 weeks before transplantation, with his last dose 1 day before transplantation. He received an allogeneic bone-marrow transplant from his 10/10 HLA-matched sibling, followed by
From the University of Pennsylvania School of Medicinea; Department of Dermatology, Hospital of the University of Pennsylvaniab; Department of Pathology, Penn State/Milton S. Hershey Medical Centerc; and Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania Cancer Center, Philadelphia.d Funding sources: None. Conflicts of interest: None identified. Reprint requests: Joshua M. Levin, MD, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Maloney Bldg, Philadelphia, PA 19104. E-mail: joshua. [email protected]. Published online December 30, 2006. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.11.009
494
Abbreviations used: RR: TMP-SMX: UV: UVR:
radiation recall trimethoprim-sulfamethoxazole ultraviolet ultraviolet recall
methotrexate given as graft-versus-host disease prophylaxis on posttransplantation days 1, 3, 6, and 11 with doses of 15 mg/m2 on day 1, 10 mg/m2 on days 3 and 6, and 5 mg/m2 on day 11. The last dose was a reduction from the planned dose of 10 mg/m2 because of severe oropharyngeal mucositis. On the fourth day posttransplantation the patient developed pruritic macules and papules on the superior aspect of his chest, shoulders, superior aspect of his back, lateral aspects of arms, face, and ears with sparing of the submental area (Figs 1 and 2). He had been sunburned many times in this same distribution, having worn tank-top shirts during decades of work as a roofer. The most recent sunburn had been 8 months earlier. There was no history of diarrhea or gastrointestinal symptoms suggestive of graft-versus-host disease. A punch biopsy specimen obtained from the right arm revealed epidermal dysmaturation with apoptotic, necrotic keratinocytes (Fig 3). Laboratory data were remarkable for a white blood cell count of less than 0.1 3 109/L (normal 4.0-11.0). Bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were within normal limits. We diagnosed a UV recall (UVR) reaction. The eruption resolved after 4 days with treatment of
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Fig 1. Erythematous macules and papules on upper aspect of chest, shoulders, outer aspect of arms, with sparing of submental area.
Fig 2. Erythematous macules and papules on outer aspect of arm, shoulder, and upper aspect of back.
triamcinalone 0.1% ointment twice daily. There was no exacerbation or recurrence of his eruption with subsequent methotrexate doses on posttransplantation days 6 and 11.
DISCUSSION UV reactivation, also referred to as UVR,1,2 sunburn recall,3 photo recall,4,5 and photodermatitis reactivation6 among others, is a rare phenomenon that can occur with chemotherapy or antibiotics. Identifying the specific triggering agent can be difficult, because most cancer patients receive multidrug chemotherapy and often require antibiotics during the course of treatment. Some patients also receive total body irradiation, which has also been
Fig 3. High magnification shows numerous apoptotic keratinocytes. There are pleomorphic keratinocytes with enlarged, irregular, hyperchromatic nuclei distributed throughout spinous layer. Loss of keratinocyte polarity is also present. (Hematoxylin-eosin stain; original magnification: 3400.)
implicated in causing reactivation of a prior sunburn.7 We have identified 21 additional reports of UV reactivation reactions after chemotherapy, antibiotics, other medications, or radiotherapy in the literature (Table I). In this review we describe clinical and histopathologic features of UV reactivation reactions and suggest a classification scheme for them based on the terminology used to describe cutaneous reactions after radiotherapy. Reactions in areas of prior radiation therapy after administration of chemotherapeutics (ie, radiation enhancement and radiation recall [RR]) have been well documented.8,9 Radiation enhancement occurs when the drug is administered within several days of radiotherapy and is considered an exacerbation of acute radiation dermatitis, presenting with pain, edema, erythema, bullae, and hemorrhagic crusting.8 In contrast, RR occurs weeks to years after radiotherapy and clinically presents with pruritus or pain, erythema, edema, macules and papules, vesiculation, and ulceration and necrosis in more severe cases.8-10 When reviewing the cases of UV reactivation reactions, those reactions that occurred within 1 week of UV exposure were associated with pain and burning, and erythematous, violaceous, and bullous skin lesions (Table I). In contrast, those reactions that occurred weeks to months after UV exposure were associated with pruritus and macular and papular lesions, although bullae were present in two patients and one patient experienced burning. Given the similarities to radiotherapy reactions, the sunburnlike reactions that occurred when the drug was administered within several days of UV exposure could be described as UV enhancement, and the macules, papules, and other eruptions that occurred when the drug was given months after UV exposure
Study
Moller13 (1969) Corder et al14 (1976) Jaffe15 (1976) Korossy et al16 (1981) Andersen et al17 (1984)
Putative associated agent
Morphology of eruption
Symptoms
Pathology
Time from UV exposure to causative agent*
Time from causative agent to eruption
MTX, 6-MP MTX, leucovorin
Dusky erythema with bullae Violaceous, blanching erythema
Not described Pain
Not described Not described
1 day 5 days
2 days 24 h
MTX, citrovorum MTX
Erythema, peeling, hemorrhage Erythema, edema, vesicles
Not described Great discomfort
Not described Not described
Not described 2 days
Not described 48 h
MTX, cyclophosphamide, 5-FU
Red-violet erythema
None
1 day
2-3 days
Neiman et al18 (1985)
MTX
Not described
48 h
23 h
Nedorost et al19 (1989) Okamoto et al20 (1994) Khan et al6 (2000)
MTX
Dusky red dermatitis, bullae superficial ulcerations of buccal mucosa Bullae and severe eczemitization
Few basal cells with hydropic degeneration and dyskeratotic cells; papillary dermis with slight perivascular lymphocytic infiltrate Not described
Not described
MTX
Erythema
MTX
Kaya et al21 (2006) Williams et al2 (1993)
MTX, cytarabine
Erythematous to violaceous skin with bullae, desquamation, and hemorrhagic crusting Erythema, vesicles
24-48 h after sunburny 1 mo after topical PUVA 2 days
Lowitt et al22 (1995) Ee et al4 (2003)
Etoposide, cyclophosphamide, ceftazidime, tobramycin, vancomycin Suraminz
Paclitaxel
Progression of Not described sunburn symptoms Not described Not described Burning
Not described
Burning
Not described
No history of sunburn 1 wk
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Table I. Summary of cases of ultraviolet reactivation reactions
3 days 2 days
Not described
Exanthematous, urticarial, and eczematous eruptions in an actinic pattern Erythema and bullae
Not described
Not specified
Not described
12 days for etoposide and cyclophosphomide; 3 days for ceftazidime, tobramycin, and vancomycin Not described
Not described
Epidermis with focal parakeratosis, acanthosis, spongiosis, and occasional apoptotic cells; dilated dermal vessels, extravasated red blood cells, and perivascular infiltrate of lymphocytes, histiocytes, and few neutrophils
1 day
1 wk
MARCH 2007
Vacuolar degeneration and perivascular mononuclear cell infiltrate with hemorrhage
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Violaceous blanching patches with Not described peripheral petechiae
Erythema
Not described
TMP-SMX
Erythema with initial reaction; bullae with rechallenge
Not described
Flax et al24 (1990) Lee et al25 (1998)
Cefazolin and gentamicin Aspirin, dialuminate
‘‘Maculopapular’’
Pruritus
Erythema and purpura in sun-exposed areas; targetoid lesions in sun-protected areas; vesicular and erosive lesions in vulvar and oral mucosa
Burning
Krishnan et al1 (2001) Blanco et al26 (2002) Hill et al7 (2002) Garza et al5 (2004)
Piperacillin, tobramycin, ciprofloxacin Ampicillin
Morbilliform
Not described
(Biopsy specimen from 8 mo lesion in sun-exposed area) increased number of melancytes, intact epidermis, dense extravasation of red blood cells Not described 1 mo
Erythema, bullae
Pruritus
Not described
2 mo
3 days
Pruritus Not described
Not described Mild perivascular lymphocytic infiltrate with rare apoptotic keratinocytes
50 y Several wk
3 wk 1 day
Pruritus
8 mo Apoptotic, necrotic keratinocytes; keratinocyte atypia with loss of polarity; minimal vacuolar degeneration; mild superficial perivascular inflammatory cell infiltrate
Current case
Radiotherapy ‘‘Maculopapular’’ Cefazolin, codeine, Erythema ondansetron, acetaminophen, phenytoin, ranitidine, dexamethasone Etoposide, Erythematous macules MTX, TMP-SMX, and papules radiotherapy
Atrophic epidermis with 1 wk after UVB necrotic keratinocytes therapy Extensive epidermal cell 7 mo necrosis with intraepidermal bulla formation; perivascular inflammatory cell infiltrate, predominantly lymphocytes, in reticular dermis Not described 1 mo
‘‘Almost immediately’’ 12 days for initial reaction; 24 h for rechallenge
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Badger et al23 (2005) Shelley et al11 (1984)
5 days for cefazolin, 48 h for gentamicin Initial reaction not described; 1 h after rechallenge
3 days
7 days for etoposide, 3 days for MTX, 8 days for radiotherapy, 11 days for TMP-SMX§
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FU, Fluorouracil; MP, mercaptopurine; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; TMP-SMX, trimethoprim-sulfamethoxazole; UV, ultraviolet; UVB, ultraviolet B. *UV exposure was sunburn unless otherwise specified. y Sunburn thought to be a drug-induced photosensitivity reaction from ciprofloxacin plus sun exposure. z In a case series of 60 patients receiving suramin for metastatic solid tumors, 21 patients (35%) reported as having ‘‘UV recall.’’ § TMP-SMX was stopped 6 days before eruption.
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could be described as UVR. This would create a simple classification scheme that is analogous to the existing scheme for radiotherapy reactions. Our patient fits into the category of UVR, given the delay of 8 months from sunburn to drug administration, pruritus, and macular and papular morphology. Similar to the patient reported by Williams et al,2 there are multiple potential putative agents for his UVR. Our patient received etoposide 7 days before the eruption, methotrextate 3 days before the eruption, and total body irradiation 8 days before eruption. He also completed a 2-week course of alternate-day TMP-SMX 6 days before the onset of skin lesions. Methotrexate seems unlikely to be the single responsible agent, because the patient received much larger doses of methotrexate during chemotherapy several months before admission without developing any cutaneous lesions. In addition, he received 3 subsequent doses of methotrexate without exacerbation or recurrence of his eruption during his admission. A case of a severe bullous eruption after the 12th day of receiving TMP-SMX in an area severely sunburned 7 months earlier has been reported.11 Although our patient did receive TMP-SMX, the medication was stopped 6 days before the onset of lesions and he did not have a bullous eruption. Etoposide has been previously reported with a UV reactivation reaction; however, in that case the reaction occurred only 1 week after UV exposure and was characterized by violaceous blanching patches with petechiae.2 Futhermore, that patient received multiple other medications, including cyclophosphamide and several antibiotics (Table I). Finally, there is a report of UVR induced by radiation therapy 50 years after sunburn.7 It is difficult to determine which of these therapies, either alone or in combination, triggered our patient’s UVR. Histolopathologic features of reactivation reactions to radiotherapy and UV light are not well described in the literature. Smith et al12 examined skin biopsy specimens from 8 patients with RR and two patients with radiation enhancement. They reported similar findings in both groups, with variable degrees of ballooning degeneration characteristic of cellular necrosis, occasional nuclear and cytoplasmic contraction consistent with apoptosis, acanthosis, and variable mixed inflammatory cell infiltrate in the dermis. Six of the biopsy specimens taken from patients with RR also revealed features of chronic radiodermatitis, with dermal sclerosis, vascular dilatation with atypia of endothelial cells, and variable degrees of atypia in other stromal cells. Biopsy of UV reactivation reactions is not routinely performed (Table I). Tissue from both UVR and UV
enhancement show similar features, with necrotic keratinocytes and a perivascular inflammatory cell infiltrate of varying degrees in most specimens (Table I). The pathogenesis of radiotherapy and UV reactivation reactions remains poorly understood. Proposed mechanisms include inhibition of DNA repair and cellular recovery, reduction of proliferative capacity and impairment of surviving stem cells, and low-level secretion of various inflammatory cytokines that are up-regulated with a precipitating medication.9,10 Other hypotheses, such as local vascular changes induced by radiotherapy, and mast cells in irradiated skin as mediators of reactivation reactions, have also been advanced.4 Nomenclature for reactivation reactions to UV exposure is inconsistent and confusing. Given the similarities to radiotherapy reactions, we propose the terms ‘‘UV recall’’ and ‘‘UV enhancement’’ be used in future reports to classify UV reactivation reactions in a scheme analogous to the terminology for cutaneous reactions after radiotherapy. REFERENCES 1. Krishnan RS, Lewis AT, Kass JS, Hsu S. Ultraviolet recall-like phenomenon occurring after piperacillin, tobramycin, and ciprofloxacin therapy. J Am Acad Dermatol 2001;44:1045-7. 2. Williams BJ, Roth DJ, Callen JP. Ultraviolet recall associated with etoposide and cyclophosphamide therapy. Clin Exp Dermatol 1993;18:452-3. 3. Guzzo C, Kaidby K. Recurrent recall of sunburn by methotrexate. Photodermatol Photoimmunol Photomed 1995;11:55-6. 4. Ee HL, Yosipovitch G. Photo recall phenomenon: an adverse reaction to taxanes. Dermatology 2003;207:196-8. 5. Garza LA, Yoo EK, Junkins-Hopkins JM, VanVoorhees AS. Photo recall effect in association with cefazolin. Cutis 2004;73:79-80, 85. 6. Khan AJ, Marghoob AA, Prestia AE, Spector IJ. Methotrexate and the photodermatitis reactivation reaction: a case report and review of the literature. Cutis 2000;66:379-82. 7. Hill HZ, Hill GJ, Cathcart C. Photo-recall of sunburn induced by radiation therapy 50 years later. J Med 2002;33:115-8. 8. Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999;40: 367-400. 9. Azria D, Magne N, Zouhair A, Castadot P, Culine S, Ychou M, et al. Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 2005;31:555-70. 10. Ristic B. Radiation recall dermatitis. Int J Dermatol 2004;43: 627-31. 11. Shelley WB, Shelley ED, Campbell AC, Weigensberg IJ. Drug eruptions presenting at sites of prior radiation damage (sunlight and electron beam). J Am Acad Dermatol 1984;11: 53-7. 12. Smith KJ, Germain M, Skelton H. Histopathologic features seen with radiation recall or enhancement eruptions. J Cutan Med Surg 2002;6:535-40. 13. Moller H. Reactivation of acute inflammation by methotrexate. J Invest Dermatol 1969;52:437-41. 14. Corder MP, Stone WH. Failure of leucovorin rescue to prevent reactivation of a solar burn after high dose methotrexate. Cancer 1976;37:1660-2.
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22. Lowitt MH, Eisenberger M, Sina B, Kao GF. Cutaneous eruptions from suramin: a clinical and histopathologic study of 60 patients. Arch Dermatol 1995;131:1147-53. 23. Badger J, Kang S, Uzieblo A, Srinivas S. Double diagnosis in cancer patients and cutaneous reaction related to gemcitabine, case 3: photo therapy recall with gemcitabine following ultraviolet B treatment. J Clin Oncol 2005;23: 7224-5. 24. Flax SH, Uhle P. Photo recall-like phenomenon following the use of cefazolin and gentamicin sulfate. Cutis 1990;46: 59-61. 25. Lee SG, Matsuyoshi N, Ohta K, Horiguchi Y, Imamura S. Drug eruption due to Bufferin showing erythema exsudativum multiforme with a photo-recall-like phenomenon. Eur J Dermatol 1998;8:280-2. 26. Blanco J, Manzanedo L, Gutierrez MC, Fuentes M. Ultraviolet recall phenomenon following the use of ampicillin. J Investig Allergol Clin Immunol 2002;12:215-6.