Cancer/Radiothérapie 18 (2014) 767–769
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Case report
Radiotherapy for breast cancer and erythrokeratodermia variabilis Irradiation mammaire chez une patiente atteinte d’erythrokeratodermia variabilis V. Pernin , Y. Kirova ∗ , F. Campana Département d’oncologie radiothérapie, Institut Curie, 26, rue d’Ulm, 75248 Paris cedex 05, France
a r t i c l e
i n f o
Article history: Received 23 April 2014 Accepted 13 June 2014 Keywords: Radiotherapy Erythrokeratodermia variabilis EKV
a b s t r a c t We report the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities in patient with erythrokeratodermia variabilis after 2 years of follow-up. However, preclinical data showing radiation-induced tumor genesis in case of deficiency of some connexins point out the need of a careful surveillance of these patients. © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Radiothérapie Erythrokeratodermia variabilis EKV
Nous rapportons le premier cas dans la littérature d’une tolérance acceptable d’une irradiation mammaire chez une patiente atteinte d’erythrokeratodermia variabilis avec un suivi de deux ans. Un suivi spécial et adapté est nécessaire pour cette population de patients. © 2014 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Erythrokeratodermia variabilis is a rare autosomal dominant genodermatosis characterized by variable migratory erythematous patches and relatively stable keratotic lesions [1]. Hyperkeratotic plaques may be distributed on the face, extensor surfaces, buttocks, trunk, and extremities [1]. Both types of lesions may be precipitated by either trauma or changes in temperature. The overall health of the patient seems to be unaffected with a normal life-span [2]. Erythrokeratodermia variabilis is linked to mutations in the gene encoding for the gap junction protein, connexin 31 [3]. No data currently described the safety and the locoregional outcome after radiotherapy for patient with erythrokeratodermia variabilis. We report here the first case of radiation therapy for breast cancer in a female patient with erythrokeratodermia variabilis. 2. Case report A 38-year-old caucasian woman with erythrokeratodermia variabilis was diagnosed with cT2N0M0 left breast cancer in
∗ Corresponding author. E-mail address: [email protected] (Y. Kirova).
January 2010. At physical examination, she presented with multiple, irregularly-shaped, well-demarcated, erythematous macules and patches and hyperpigmented, hyperkeratotic plaques located on the upper extremities and the trunk. The histopathological findings of breast biopsy were: invasive ductal carcinoma, grade III and triple negative. She received neoadjuvant chemotherapy, consisting of 12 weekly courses of paclitaxel and 4 courses of epirubicine, cyclophosphamide and 5 fluorouracile followed by breast conservative surgery and axillary dissection. Postoperative pathology showed no residual invasive ductal carcinoma and no lymphatic invasion. Postoperative radiotherapy of 50 Gy in 25 fractions in 5 weeks by a linear accelerator was delivered to left breast with a complementary boost to the surgical bed (16 Gy in 8 fractions). Left supraclavicular region, infraclavicular region and internal mammary chain were also irradiated with a dose of 48 Gy in 24 fractions (Fig. 1). Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events (v3.0). At the end of the radiotherapy, the patient only experienced a grade 1 dermatitis in the irradiated area. Otherwise, erythrokeratodermia variabilis was not exacerbated within the irradiated field and no Köebner phenomenon occurred. At her last follow-up in January 2013, 3 years after the end of radiotherapy, there was no recurrence of ipsilateral breast cancer or in the opposite side. No late toxicities of the radiotherapy such as fibrosis, arm lymphedema or telangiectasia were
http://dx.doi.org/10.1016/j.canrad.2014.06.026 1278-3218/© 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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V. Pernin et al. / Cancer/Radiothérapie 18 (2014) 767–769
reported and erythrokeratodermia variabilis lesions remained stable (Fig. 2).
3. Discussion
Fig. 1. Volumes of irradiation represented by 95% isodose contours in blue. A. Left breast and internal mammary chain. B. Supraclavicular lymph node area. Volumes d’irradiation représentés par l’isodose de 95 % (en bleu). A. Sein gauche et chaîne mammaire interne. B. Région sus-claviculaire.
This report deals with good outcome after radiotherapy for a patient affected from erythrokeratodermia variabilis and breast cancer with particularly no dermatological modification. Breast cancer is the most common cancer and the first leading cause of cancer death in women in Europe [4]. After a conservative surgery of the breast, radiotherapy can reduce the risk of breast cancer recurrence by about 70% [5]. Radiation therapy is relatively easy to tolerate and its side effects are limited to the treated area such as dermatitis. This is the first report, which shows good tolerance during and after radiotherapy with a follow-up of 3 years in a patient with erythrokeratodermia variabilis. Nevertheless, late outcomes are unknown. Erythrokeratodermia variabilis is due a mutation of connexin 31, a protein, which is implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in connexin 31 cause the skin disease erythrokeratodermia variabilis and hearing loss with or without neuropathy. Multiple autosomal dominant connexin 31 mutations are associated with erythrokeratodermia variabilis, however mechanisms of pathogenesis remain to be elucidated [6]. In the absence of connexins, it has been shown an increased tumorigenesis in human and animal cells [7]. Deficiency of connexin 43 gap junctions in breast cancer is thought to be a common feature of mammary neoplastic transformation [8]. Furthermore, connexin 32-deficient mice demonstrated increased susceptibility to radiation-induced liver tumorigenesis [9]. Even if no study described an involvement of connexin 31 mutation in breast tumorigenesis, radiotherapy could be involved in tumor
Fig. 2. Good tolerance of radiotherapy on the left breast skin during the treatment and no late skin toxicity was noticed. A. Basal state. B. Grade 1 radiodermatitis. C. One year after irradiation. D. Three years after irradiation. Suivi de la radiothérapie. A. État cutané initial. B. Bonne tolérance de la radiothérapie avec une radiodermite de grade I. C. Une année après la radiothérapie. D. Trois ans après la radiothérapie : aucune toxicité cutanée.
V. Pernin et al. / Cancer/Radiothérapie 18 (2014) 767–769
susceptibility for patient with erythrokeratodermia variabilis, pointing out the need of a careful surveillance of these patients. 4. Conclusion In conclusion, this is the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities after 2 years of follow-up in a patient with erythrokeratodermia variabilis treated for early breast cancer. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Landau M, Cohen-Bar-Dayan M, Hohl D, Ophir J, Wolf CR, Gat A, et al. Erythrokeratodermia variabilis with erythema gyratum repens-like lesions. Pediatr Dermatol 2002;19:285–92.
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[2] Hendrix Jr JD, Greer KE. Erythrokeratodermia variabilis present at birth: case report and review of the literature. Pediatr Dermatol 1995;12:351–4. [3] Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein Jr EH, et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998;20:366–9. [4] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765–81. [5] Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. [6] Wilgoss A, Leigh IM, Barnes MR, Dopping-Hepenstal P, Eady RA, Walter JM, et al. Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol 1999;113:1119–22. [7] Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Güldenagel M, et al. Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem 2002;383:725–37. [8] Laird DW, Fistouris P, Batist G, Alpert L, Huynh HT, Carystinos GD, et al. Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res 1999;59:4104–10. [9] King TJ, Lampe PD. Mice deficient for the gap junction protein connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation. Carcinogenesis 2004;25:669–80.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Case report
Radiotherapy for breast cancer and erythrokeratodermia variabilis Irradiation mammaire chez une patiente atteinte d’erythrokeratodermia variabilis V. Pernin , Y. Kirova ∗ , F. Campana Département d’oncologie radiothérapie, Institut Curie, 26, rue d’Ulm, 75248 Paris cedex 05, France
a r t i c l e
i n f o
Article history: Received 23 April 2014 Accepted 13 June 2014 Keywords: Radiotherapy Erythrokeratodermia variabilis EKV
a b s t r a c t We report the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities in patient with erythrokeratodermia variabilis after 2 years of follow-up. However, preclinical data showing radiation-induced tumor genesis in case of deficiency of some connexins point out the need of a careful surveillance of these patients. © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Radiothérapie Erythrokeratodermia variabilis EKV
Nous rapportons le premier cas dans la littérature d’une tolérance acceptable d’une irradiation mammaire chez une patiente atteinte d’erythrokeratodermia variabilis avec un suivi de deux ans. Un suivi spécial et adapté est nécessaire pour cette population de patients. © 2014 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Erythrokeratodermia variabilis is a rare autosomal dominant genodermatosis characterized by variable migratory erythematous patches and relatively stable keratotic lesions [1]. Hyperkeratotic plaques may be distributed on the face, extensor surfaces, buttocks, trunk, and extremities [1]. Both types of lesions may be precipitated by either trauma or changes in temperature. The overall health of the patient seems to be unaffected with a normal life-span [2]. Erythrokeratodermia variabilis is linked to mutations in the gene encoding for the gap junction protein, connexin 31 [3]. No data currently described the safety and the locoregional outcome after radiotherapy for patient with erythrokeratodermia variabilis. We report here the first case of radiation therapy for breast cancer in a female patient with erythrokeratodermia variabilis. 2. Case report A 38-year-old caucasian woman with erythrokeratodermia variabilis was diagnosed with cT2N0M0 left breast cancer in
∗ Corresponding author. E-mail address: [email protected] (Y. Kirova).
January 2010. At physical examination, she presented with multiple, irregularly-shaped, well-demarcated, erythematous macules and patches and hyperpigmented, hyperkeratotic plaques located on the upper extremities and the trunk. The histopathological findings of breast biopsy were: invasive ductal carcinoma, grade III and triple negative. She received neoadjuvant chemotherapy, consisting of 12 weekly courses of paclitaxel and 4 courses of epirubicine, cyclophosphamide and 5 fluorouracile followed by breast conservative surgery and axillary dissection. Postoperative pathology showed no residual invasive ductal carcinoma and no lymphatic invasion. Postoperative radiotherapy of 50 Gy in 25 fractions in 5 weeks by a linear accelerator was delivered to left breast with a complementary boost to the surgical bed (16 Gy in 8 fractions). Left supraclavicular region, infraclavicular region and internal mammary chain were also irradiated with a dose of 48 Gy in 24 fractions (Fig. 1). Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events (v3.0). At the end of the radiotherapy, the patient only experienced a grade 1 dermatitis in the irradiated area. Otherwise, erythrokeratodermia variabilis was not exacerbated within the irradiated field and no Köebner phenomenon occurred. At her last follow-up in January 2013, 3 years after the end of radiotherapy, there was no recurrence of ipsilateral breast cancer or in the opposite side. No late toxicities of the radiotherapy such as fibrosis, arm lymphedema or telangiectasia were
http://dx.doi.org/10.1016/j.canrad.2014.06.026 1278-3218/© 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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V. Pernin et al. / Cancer/Radiothérapie 18 (2014) 767–769
reported and erythrokeratodermia variabilis lesions remained stable (Fig. 2).
3. Discussion
Fig. 1. Volumes of irradiation represented by 95% isodose contours in blue. A. Left breast and internal mammary chain. B. Supraclavicular lymph node area. Volumes d’irradiation représentés par l’isodose de 95 % (en bleu). A. Sein gauche et chaîne mammaire interne. B. Région sus-claviculaire.
This report deals with good outcome after radiotherapy for a patient affected from erythrokeratodermia variabilis and breast cancer with particularly no dermatological modification. Breast cancer is the most common cancer and the first leading cause of cancer death in women in Europe [4]. After a conservative surgery of the breast, radiotherapy can reduce the risk of breast cancer recurrence by about 70% [5]. Radiation therapy is relatively easy to tolerate and its side effects are limited to the treated area such as dermatitis. This is the first report, which shows good tolerance during and after radiotherapy with a follow-up of 3 years in a patient with erythrokeratodermia variabilis. Nevertheless, late outcomes are unknown. Erythrokeratodermia variabilis is due a mutation of connexin 31, a protein, which is implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in connexin 31 cause the skin disease erythrokeratodermia variabilis and hearing loss with or without neuropathy. Multiple autosomal dominant connexin 31 mutations are associated with erythrokeratodermia variabilis, however mechanisms of pathogenesis remain to be elucidated [6]. In the absence of connexins, it has been shown an increased tumorigenesis in human and animal cells [7]. Deficiency of connexin 43 gap junctions in breast cancer is thought to be a common feature of mammary neoplastic transformation [8]. Furthermore, connexin 32-deficient mice demonstrated increased susceptibility to radiation-induced liver tumorigenesis [9]. Even if no study described an involvement of connexin 31 mutation in breast tumorigenesis, radiotherapy could be involved in tumor
Fig. 2. Good tolerance of radiotherapy on the left breast skin during the treatment and no late skin toxicity was noticed. A. Basal state. B. Grade 1 radiodermatitis. C. One year after irradiation. D. Three years after irradiation. Suivi de la radiothérapie. A. État cutané initial. B. Bonne tolérance de la radiothérapie avec une radiodermite de grade I. C. Une année après la radiothérapie. D. Trois ans après la radiothérapie : aucune toxicité cutanée.
V. Pernin et al. / Cancer/Radiothérapie 18 (2014) 767–769
susceptibility for patient with erythrokeratodermia variabilis, pointing out the need of a careful surveillance of these patients. 4. Conclusion In conclusion, this is the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities after 2 years of follow-up in a patient with erythrokeratodermia variabilis treated for early breast cancer. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Landau M, Cohen-Bar-Dayan M, Hohl D, Ophir J, Wolf CR, Gat A, et al. Erythrokeratodermia variabilis with erythema gyratum repens-like lesions. Pediatr Dermatol 2002;19:285–92.
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[2] Hendrix Jr JD, Greer KE. Erythrokeratodermia variabilis present at birth: case report and review of the literature. Pediatr Dermatol 1995;12:351–4. [3] Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein Jr EH, et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998;20:366–9. [4] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765–81. [5] Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707–16. [6] Wilgoss A, Leigh IM, Barnes MR, Dopping-Hepenstal P, Eady RA, Walter JM, et al. Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol 1999;113:1119–22. [7] Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Güldenagel M, et al. Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem 2002;383:725–37. [8] Laird DW, Fistouris P, Batist G, Alpert L, Huynh HT, Carystinos GD, et al. Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res 1999;59:4104–10. [9] King TJ, Lampe PD. Mice deficient for the gap junction protein connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation. Carcinogenesis 2004;25:669–80.
