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Case Report
A first case report of diffuse acneiform eruption caused by capecitabine in a patient with small-cell neuroendocrine lung carcinoma
J Oncol Pharm Practice 0(0) 1–3 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215587542 opp.sagepub.com
Asude Kara1, EmineTugba Alatas2, Gursoy Dogan2, Serkan Y Celik3 and Ozgur Tanriverdi4
Abstract Capecitabine is a chemotherapeutic agent which is converted to fluorouracil by thymidine phosphorylase in human body. It is one of the commonly used agents in colorectal and metastatic breast cancers. Hand-foot syndrome is most commonly observed adverse effect of capecitabine; however, it has several adverse cutaneous and mucosal effects. To the best of our knowledge, no case with acneiform eruption has been reported so far. Here, we presented a 54-year-old man with development of capecitabine-related acneiform drug eruption.
Keywords Capecitabine, chemotherapeutic agent, acneiform drug eruption
Introduction Capecitabine is a chemotherapeutic agent which is converted to fluorouracil (FU) by thymidine phosphorylase in human body. It is one of the widely used agents in colorectal cancer and metastatic breast cancer due to oral use and less adverse effects compared to 5FU.1 The most common dose-limiting adverse effects include hyperbilirubinemia, diarrhea and hand-foot-and-mouth disease in capecitabine. Myelosuppression, fatigue, weakness, abdominal pain and nausea have been reported as potential adverse effects.2 In the literature, hand-foot syndrome is the most common adverse effect with a frequency ranging from 10% to 50%.3 Here, we present a case in which acneiform drug eruption was developed during capecitabine therapy due to neuroendocrine carcinoma.
Case report A 54-year-old man presented to another facility with abdominal pain that became more severe, altered defecation habits, fatigue and weight loss for three months in June 2013. On abdominal computed tomography (CT) scan, it was seen that there was multiple cystic
metastatic lesion in liver, as largest being 25 20 mm in size. On positron emission tomography (PET) scan, there was a mass lesion causing diffuse thickening in bladder wall that has no boundary with bladder, rectum and prostate, and lymphadenopathies at surrounding and obturator lymphatic chains. A mass lesion extending to proximal rectum was detected in the endoscopic evaluation of lower gastrointestinal tract. Based on the biopsy findings, the patient was diagnosed as small cell neuroendocrine carcinoma which was found as negative for CD3 and CD20, and 1 Department of Dermatology, Mugla Sitki Kocman University Training and Research Hospital, Mugla, Turkey 2 Department of Dermatology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey 3 Department of Pathology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey 4 Department of Medical Oncology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
Corresponding author: Ozgur Tanriverdi, Department of Medical Oncology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla University Training and Research Hospital, Oncology Clinic, Mugla 48000, Turkey. Email: [email protected]
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Figure 1. Diffuse erythematosus, maculopapular lesions and occasional pustules at the back.
positive for TTF-1, NSE, synaptophysin and CD56 positive in immunohistochemical manner. The patient was considered to have stable disease after six cycles of cisplatin plus etoposide by threeweek intervals. The patient received palliative radiotherapy to brain due to newly developed multiple metastatic lesions on the month 10 after diagnosis. On May 2014, palliative chemotherapy including capecitabine (monthly, 1500 mg/m2/day; PO divided BID; D1–14) plus temozolomide (150 mg/m2day; PO divided BID; D10–14) was planned. But the patient did not take temozolomide agent due to eruption, flushing and itching after capecitabine therapy. The patient presented to our outpatient clinic with eruption, flushing and itching over body on day six after initiation of capecitabine therapy. On the dermatological examination, diffuse erythematosus, maculopapular lesions were observed at bilateral arms and forearms on back and trunk. Occasional pustules were also seen on back (Figure I). Laboratory evaluations were normal. On the punch biopsy, it was found that there were orthokeratosis, epidermal acanthosis, hydropic degeneration in basal cells, inflammatory infiltration including lymphocytes, histiocytes, scarce neutrophil and eosinophil at upper dermis (Figure 2). The patient was diagnosed with acneiform drug eruption caused by capecitabine, and topical clindamycin was prescribed. The patient did not use any medication, herbal or alternative-complementary medicine shortly before the reaction and also during the reaction. Additionally, he did not use any anti-emetics, anti-epileptics, steroids, antibiotics or other drugs when the reaction began or shortly before the reaction. As the reaction occurred during capecitabine treatment, the present reaction was associated with capecitabine. We concluded that the reactions were associated with capecitabine because the patient only took capecitabine treatment.
Figure 2. Orthokeratosis at surface, acanthosis at epidermis, perivascular and interstitial inflammatory cell infiltration at upper dermis. Hematoxylin and Eosin (HE) 40.
After the reaction, capecitabine treatment was stopped. Then the third day of discontinuation of capecitabine treatment, we observed that the rash began to resolve. We did not begin capecitabine and other chemotherapeutic agents because we determined that progression of brain metastases got worse. We decided to follow up our patient with the best supportive care. Three weeks after the reaction occurred, the patient died because of the cerebral herniation due to the progression of brain metastases.
Discussion Capecitabine is a pro-drug of 5-FU. Hand-foot syndrome is the most frequently seen dermatological adverse effect. In a previous study, it was reported that hand-foot syndrome was developed in 116 (64.8%) of 179 patients who received capecitabine.3 In addition several dermatological entities including lichenoid drug eruption, pyogenic granuloma-like lesion, subacute lupus erythematosus, palmoplantar keratoderma, alopecia, nail abnormalities, cutaneous hyper-pigmentation, radiation recall dermatitis, xerosis and photosensitivity have been observed due to capecitabine.4–6 To the best of our knowledge, no case with acneiform eruption has been reported so far. Drug-related acne is a specific subgroup of acne which is distinguished from classical acne by monomorphic pattern, localization at non-seborrheic regions, unusual age of onset, resistance to acne therapies and history of drug use.7 Several drugs such as corticosteroids, neuropsychiatric drugs, anti-tuberculosis drugs and immunomodulatory drugs can cause such clinical presentation.7 The diagnosis is always based on history and clinical characteristic in acneiform drug eruption. Pustules usually appear within one to three weeks
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following drug use.8 In our case, lesions appeared on day six of the therapy. Pustules are sterile; thus, bacterial and fungal cultures are not needed.7 There is no accompanying comedones contrary to acne vulgaris.8 Although the term ‘‘papulopustular reaction’’ is being proposed instead of terms ‘‘acne, acne-like or acneiform’’ as it is different from acne vulgaris in pathological and etiological aspects, it has been stated as ‘‘acneiform eruption’’ in many publication. Lesions cover seborrheic areas such as hairy scalp, mid-face, neck, chest, shoulders and postauricular areas. Rarely, it involves extremities, waist and abdomen, but palm or sole has never been involved. In severe cases, diffuse erythematous plagues and pustules, hemorrhagic crusts, ulcers and scarring can be observed. It may produce an appearance mimicking rosacea accompanied by telangiectasias or pyoderma faciale. Telangiectasia regresses with mild hyper-pigmentation after several months.9 Histopathologically, T-cell infiltration is seen in follicular infundibulum at an early period. Subsequently, suppurative folliculitis is observed which destruct hair follicle and cause granuloma formation in severe cases.7 In our case, inflammatory cell infiltration was detected at upper dermis in histopathological evaluation. In differential diagnosis, it is distinguished from acne vulgaris by lack of accompanying comedone. In addition, it is more acute and inflammatory on contrary to classical acneiform drug eruption caused by systemic corticosteroid use. Pruritus may be present in some cases, which is helpful to distinguish from both acne vulgaris and corticosteroid acne. Involvement of skin folds is not prominent as in acute generalized exanthematous pustulosis; pustules do not display tendency to fuse and do not cause fever.9 In particular, Malassezia furfur folliculitis should be kept in mind in the differential diagnosis in immunocompromised patients.9 Treatment includes humidification of skin and sun protection products for hyper-pigmentation. In cases with mild clinical presentation, topical metronidazole, topical clindamycin or topical salicylic acid can be prescribed. If there is pruritus, systemic antihistamines can be used. Tetracycline can be used in moderate to severe acneiform lesions.10
Conclusion Many advantages of oral capecitabine regarding improved quality of life and reduced healthcare costs have been stressed. Due to increased use in oncologic conditions, dermatologists should be aware of skin reactions that can develop in association with capecitabine use in terms of early diagnosis and treatment. Here, we aimed to present acneiform drug eruption caused by capecitabine, which is rarely seen in the literature.
In conclusion, it should be kept in mind that acneiform eruption may develop in patients receiving capecitabine and should be considered in the differential diagnosis. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Acknowledgement We acknowledge our patient in this case who consented to submission of this case report and offered suggestions in the editing process.
References 1. Walko CM and Lindley C. Capecitabine: a review. Clin Ther 2005; 27: 23–44. 2. Cassidy J, Twelves C, van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13: 566–575. 3. Heo YS, Chang HM, Kim TW, et al. Hand-foot syndrome in patients treated with capecitabine-containing combination chemotherapy. J Clin Pharmacol 2004; 44: 1166–1172. 4. Hague JS and Ilchyshyn A. Lichenoid photosensitive eruption due to capecitabine chemotherapy for metastatic breast cancer. Clin Exp Dermatol 2007; 32: 102–103. 5. Pique´-Duran E, Pe´rez-Dı´ az MJ and Pe´rez-Cejudo JA. Pyogenic granuloma-like lesions caused by capecitabine therapy. Clin Exp Dermatol 2008; 33: 652–653. 6. Floristan U, Feltes RA, Sendagorta E, et al. Subacute cutaneous lupus erythematosus induced by capecitabine. Clin Exp Dermatol 2009; 34: e328–e329. 7. Du-Thanh A, Kluger N, Bensalleh H, et al. Drug-induced acneiform eruption. Am J Clin Dermatol 2011; 12: 233–245. 8. Agero ALC, Duzsa SW, Benvenuto-Andrade C, et al. Dermatological side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006; 55: 657–670. 9. ArıcanO¨ and O¨nver N. A case report of cetuximabrelated acneiform eruption. Turk J Dermatol 2011; 5: 29–32. 10. Kimyai-Asadi A and Jih MH. Follicular toxic effects of chimeric antiepidermal growth factor receptor antibody cetuximab used to treat human solid tumors. Arch Dermatol 2002; 138: 129–131.
Downloaded from opp.sagepub.com at OAKLAND UNIV on June 4, 2015
(OPP)
[1–3] [INVALID Stage]
Case Report
A first case report of diffuse acneiform eruption caused by capecitabine in a patient with small-cell neuroendocrine lung carcinoma
J Oncol Pharm Practice 0(0) 1–3 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215587542 opp.sagepub.com
Asude Kara1, EmineTugba Alatas2, Gursoy Dogan2, Serkan Y Celik3 and Ozgur Tanriverdi4
Abstract Capecitabine is a chemotherapeutic agent which is converted to fluorouracil by thymidine phosphorylase in human body. It is one of the commonly used agents in colorectal and metastatic breast cancers. Hand-foot syndrome is most commonly observed adverse effect of capecitabine; however, it has several adverse cutaneous and mucosal effects. To the best of our knowledge, no case with acneiform eruption has been reported so far. Here, we presented a 54-year-old man with development of capecitabine-related acneiform drug eruption.
Keywords Capecitabine, chemotherapeutic agent, acneiform drug eruption
Introduction Capecitabine is a chemotherapeutic agent which is converted to fluorouracil (FU) by thymidine phosphorylase in human body. It is one of the widely used agents in colorectal cancer and metastatic breast cancer due to oral use and less adverse effects compared to 5FU.1 The most common dose-limiting adverse effects include hyperbilirubinemia, diarrhea and hand-foot-and-mouth disease in capecitabine. Myelosuppression, fatigue, weakness, abdominal pain and nausea have been reported as potential adverse effects.2 In the literature, hand-foot syndrome is the most common adverse effect with a frequency ranging from 10% to 50%.3 Here, we present a case in which acneiform drug eruption was developed during capecitabine therapy due to neuroendocrine carcinoma.
Case report A 54-year-old man presented to another facility with abdominal pain that became more severe, altered defecation habits, fatigue and weight loss for three months in June 2013. On abdominal computed tomography (CT) scan, it was seen that there was multiple cystic
metastatic lesion in liver, as largest being 25 20 mm in size. On positron emission tomography (PET) scan, there was a mass lesion causing diffuse thickening in bladder wall that has no boundary with bladder, rectum and prostate, and lymphadenopathies at surrounding and obturator lymphatic chains. A mass lesion extending to proximal rectum was detected in the endoscopic evaluation of lower gastrointestinal tract. Based on the biopsy findings, the patient was diagnosed as small cell neuroendocrine carcinoma which was found as negative for CD3 and CD20, and 1 Department of Dermatology, Mugla Sitki Kocman University Training and Research Hospital, Mugla, Turkey 2 Department of Dermatology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey 3 Department of Pathology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey 4 Department of Medical Oncology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
Corresponding author: Ozgur Tanriverdi, Department of Medical Oncology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla University Training and Research Hospital, Oncology Clinic, Mugla 48000, Turkey. Email: [email protected]
Downloaded from opp.sagepub.com at OAKLAND UNIV on June 4, 2015
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Journal of Oncology Pharmacy Practice 0(0)
Figure 1. Diffuse erythematosus, maculopapular lesions and occasional pustules at the back.
positive for TTF-1, NSE, synaptophysin and CD56 positive in immunohistochemical manner. The patient was considered to have stable disease after six cycles of cisplatin plus etoposide by threeweek intervals. The patient received palliative radiotherapy to brain due to newly developed multiple metastatic lesions on the month 10 after diagnosis. On May 2014, palliative chemotherapy including capecitabine (monthly, 1500 mg/m2/day; PO divided BID; D1–14) plus temozolomide (150 mg/m2day; PO divided BID; D10–14) was planned. But the patient did not take temozolomide agent due to eruption, flushing and itching after capecitabine therapy. The patient presented to our outpatient clinic with eruption, flushing and itching over body on day six after initiation of capecitabine therapy. On the dermatological examination, diffuse erythematosus, maculopapular lesions were observed at bilateral arms and forearms on back and trunk. Occasional pustules were also seen on back (Figure I). Laboratory evaluations were normal. On the punch biopsy, it was found that there were orthokeratosis, epidermal acanthosis, hydropic degeneration in basal cells, inflammatory infiltration including lymphocytes, histiocytes, scarce neutrophil and eosinophil at upper dermis (Figure 2). The patient was diagnosed with acneiform drug eruption caused by capecitabine, and topical clindamycin was prescribed. The patient did not use any medication, herbal or alternative-complementary medicine shortly before the reaction and also during the reaction. Additionally, he did not use any anti-emetics, anti-epileptics, steroids, antibiotics or other drugs when the reaction began or shortly before the reaction. As the reaction occurred during capecitabine treatment, the present reaction was associated with capecitabine. We concluded that the reactions were associated with capecitabine because the patient only took capecitabine treatment.
Figure 2. Orthokeratosis at surface, acanthosis at epidermis, perivascular and interstitial inflammatory cell infiltration at upper dermis. Hematoxylin and Eosin (HE) 40.
After the reaction, capecitabine treatment was stopped. Then the third day of discontinuation of capecitabine treatment, we observed that the rash began to resolve. We did not begin capecitabine and other chemotherapeutic agents because we determined that progression of brain metastases got worse. We decided to follow up our patient with the best supportive care. Three weeks after the reaction occurred, the patient died because of the cerebral herniation due to the progression of brain metastases.
Discussion Capecitabine is a pro-drug of 5-FU. Hand-foot syndrome is the most frequently seen dermatological adverse effect. In a previous study, it was reported that hand-foot syndrome was developed in 116 (64.8%) of 179 patients who received capecitabine.3 In addition several dermatological entities including lichenoid drug eruption, pyogenic granuloma-like lesion, subacute lupus erythematosus, palmoplantar keratoderma, alopecia, nail abnormalities, cutaneous hyper-pigmentation, radiation recall dermatitis, xerosis and photosensitivity have been observed due to capecitabine.4–6 To the best of our knowledge, no case with acneiform eruption has been reported so far. Drug-related acne is a specific subgroup of acne which is distinguished from classical acne by monomorphic pattern, localization at non-seborrheic regions, unusual age of onset, resistance to acne therapies and history of drug use.7 Several drugs such as corticosteroids, neuropsychiatric drugs, anti-tuberculosis drugs and immunomodulatory drugs can cause such clinical presentation.7 The diagnosis is always based on history and clinical characteristic in acneiform drug eruption. Pustules usually appear within one to three weeks
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following drug use.8 In our case, lesions appeared on day six of the therapy. Pustules are sterile; thus, bacterial and fungal cultures are not needed.7 There is no accompanying comedones contrary to acne vulgaris.8 Although the term ‘‘papulopustular reaction’’ is being proposed instead of terms ‘‘acne, acne-like or acneiform’’ as it is different from acne vulgaris in pathological and etiological aspects, it has been stated as ‘‘acneiform eruption’’ in many publication. Lesions cover seborrheic areas such as hairy scalp, mid-face, neck, chest, shoulders and postauricular areas. Rarely, it involves extremities, waist and abdomen, but palm or sole has never been involved. In severe cases, diffuse erythematous plagues and pustules, hemorrhagic crusts, ulcers and scarring can be observed. It may produce an appearance mimicking rosacea accompanied by telangiectasias or pyoderma faciale. Telangiectasia regresses with mild hyper-pigmentation after several months.9 Histopathologically, T-cell infiltration is seen in follicular infundibulum at an early period. Subsequently, suppurative folliculitis is observed which destruct hair follicle and cause granuloma formation in severe cases.7 In our case, inflammatory cell infiltration was detected at upper dermis in histopathological evaluation. In differential diagnosis, it is distinguished from acne vulgaris by lack of accompanying comedone. In addition, it is more acute and inflammatory on contrary to classical acneiform drug eruption caused by systemic corticosteroid use. Pruritus may be present in some cases, which is helpful to distinguish from both acne vulgaris and corticosteroid acne. Involvement of skin folds is not prominent as in acute generalized exanthematous pustulosis; pustules do not display tendency to fuse and do not cause fever.9 In particular, Malassezia furfur folliculitis should be kept in mind in the differential diagnosis in immunocompromised patients.9 Treatment includes humidification of skin and sun protection products for hyper-pigmentation. In cases with mild clinical presentation, topical metronidazole, topical clindamycin or topical salicylic acid can be prescribed. If there is pruritus, systemic antihistamines can be used. Tetracycline can be used in moderate to severe acneiform lesions.10
Conclusion Many advantages of oral capecitabine regarding improved quality of life and reduced healthcare costs have been stressed. Due to increased use in oncologic conditions, dermatologists should be aware of skin reactions that can develop in association with capecitabine use in terms of early diagnosis and treatment. Here, we aimed to present acneiform drug eruption caused by capecitabine, which is rarely seen in the literature.
In conclusion, it should be kept in mind that acneiform eruption may develop in patients receiving capecitabine and should be considered in the differential diagnosis. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Acknowledgement We acknowledge our patient in this case who consented to submission of this case report and offered suggestions in the editing process.
References 1. Walko CM and Lindley C. Capecitabine: a review. Clin Ther 2005; 27: 23–44. 2. Cassidy J, Twelves C, van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13: 566–575. 3. Heo YS, Chang HM, Kim TW, et al. Hand-foot syndrome in patients treated with capecitabine-containing combination chemotherapy. J Clin Pharmacol 2004; 44: 1166–1172. 4. Hague JS and Ilchyshyn A. Lichenoid photosensitive eruption due to capecitabine chemotherapy for metastatic breast cancer. Clin Exp Dermatol 2007; 32: 102–103. 5. Pique´-Duran E, Pe´rez-Dı´ az MJ and Pe´rez-Cejudo JA. Pyogenic granuloma-like lesions caused by capecitabine therapy. Clin Exp Dermatol 2008; 33: 652–653. 6. Floristan U, Feltes RA, Sendagorta E, et al. Subacute cutaneous lupus erythematosus induced by capecitabine. Clin Exp Dermatol 2009; 34: e328–e329. 7. Du-Thanh A, Kluger N, Bensalleh H, et al. Drug-induced acneiform eruption. Am J Clin Dermatol 2011; 12: 233–245. 8. Agero ALC, Duzsa SW, Benvenuto-Andrade C, et al. Dermatological side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006; 55: 657–670. 9. ArıcanO¨ and O¨nver N. A case report of cetuximabrelated acneiform eruption. Turk J Dermatol 2011; 5: 29–32. 10. Kimyai-Asadi A and Jih MH. Follicular toxic effects of chimeric antiepidermal growth factor receptor antibody cetuximab used to treat human solid tumors. Arch Dermatol 2002; 138: 129–131.
Downloaded from opp.sagepub.com at OAKLAND UNIV on June 4, 2015
