DR Taxane-induced morphea in a patient with CREST syndrome Susan M. Bouchard, Melinda R. Mohr, Robert J. Pariser Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA, USA Abstract The taxanes, docetaxel and paclitaxel, are microtubule stabilizing chemotherapeutic agents that have demonstrated antineoplastic effects in a variety of solid tumors. They have been linked to the development of localized cutaneous sclerosis in some patients. We pres- ent a case of docetaxel-induced cutaneous scle- rosis of the lower extremities in a patient with pre-existing CREST syndrome. We propose that patients with a history of limited or diffuse sys- temic sclerosis should be given taxane chemotherapy with caution, as these patients may have an immunological predisposition for the development of drug-induced morphea. Case Report A 73-year old Caucasian woman received doc- etaxel and cyclophosphamide chemotherapy for treatment of poorly differentiated infiltrating ductal carcinoma of the breast. Past medical history was significant for osteoporosis, hypothyroidism, and CREST syndrome for 20 to 30 years. Medications included esomeprazole, zoledronate, calcium with vitamin D, levothy- roxine, fish oil, aspirin, and a multivitamin. Prior to initiation of docetaxel, she exhibited physical changes consistent with longstanding CREST syndrome, including sclerodactyly, firm subcutaneous nodules consistent with calci- nosis cutis, teleangiectasias, and gastroe- sophageal reflux without overt esophageal dys- motility. On review of systems, she cited a his- tory of infrequent dyspneic episodes. During therapy with docetaxel, she noticed significant swelling of her legs. Three months after comple- tion of her chemotherapy regimen, she present- ed with firm, erythematous, burning plaques of her lower legs (Figure 1). Additionally, she noticed worsening of her gastroesophageal reflux symptoms. Fluticasone propionate lotion was applied to the legs twice daily for 18 days without benefit. Six months after completion of her chemotherapy, she noticed a slight decrease in pain and stiffness of her legs without any other specific treatment. Discussion Scleroderma is a disease characterized by cutaneous and sometimes visceral sclerosis, vasculopathy, and the presence of autoantibod- ies. Localized cutaneous sclerosis is commonly termed morphea.1 Systemic sclerosis (SSc) may be categorized into diffuse cutaneous systemic sclerosis (dSSc) and limited cutaneous sys- temic sclerosis (lSSc). Diffuse cutaneous SSc is characterized by truncal and acral skin involve- ment, early visceral disease, and a poorer prog- nosis. Alternatively, limited cutaneous SSc is limited to acral cutaneous involvement of the hands, face, feet, and forearms with occasional late visceral (predominately pulmonary) involvement.1 CREST syndrome represents a form of lSSc and is manifested by calcinosis cutis, Raynaud’s phenomenon, esophageal dys- motility, sclerodactyly, and telangiectasias.2 The development of cutaneous sclerosis is typically preceded by tissue inflammation, endothelial cell activation, and edema.3 Histopathological changes include dermal thickening with immense collagen accumula- tion and resulting epidermal atrophy, flattening of rete pegs, and obliteration of hair follicles and sebaceous and sweat glands.2 Inflammatory cells commonly aggregate at the dermal-adi- pose junction, particularly in early lesions.4 Cytokines produced by these inflammatory cells (transforming growth factor-b,2 tumor necrosis factor-a (TNF-a),5,6 interferon gamma (IFN-g),6 and interleukin-6 (IL-6)7) are all present at high levels in the serum of patients with sclero- derma, and are thought to play a central role in the pathogenesis of the disease.8 Several studies have demonstrated an increased incidence of breast and lung cancers in patients with pre-existing SSc. Because the cases studied have typically shown a close tem- poral relationship between the onset of SSc and breast cancer, a number of theories have been proposed to illuminate a pathophysiological link between the two. One theory implicates the aforementioned inflammatory cytokines as pro- moters of breast and lung cancers. Also, increased endothelial cell activation seen in SSc may stimulate tumor development by elevating the levels of various growth factors. Others have investigated SSc as a possible paraneoplastic syndrome in these cases. Perhaps the most widely accepted theory is that SSc is often the result of the cancer treatment itself.9 A variety of chemical agents, including rape- seed oil, organic solvents, herbicides, silica, cocaine, bleomycin, penicillamine, L-trypto- phan, pentazocine, ethosuximide,10 and the taxane family of chemotherapeutic medica- tions11 have been associated with scleroderma or scleroderma-like changes of the skin. The taxanes, which include docetaxel and paclitaxel, exert their antineoplastic effects by stabilizing microtubules thus halting mitosis and by inhibiting Bcl-2 to allow apoptosis.12 These medicines are widely used in the treat- ment of breast, lung, and ovarian carcinomas.13 Established toxicities include peripheral edema, neutropenia, and neuropathy.11 In addi- tion to scleroderma-like changes, cutaneous reactions of the taxanes include acral erythe- ma, pustular eruption, bullous fixed drug erup- tion, erythema multiforme, onycholysis, ery- throdyesthesia, and alopecia.11,14 There is a well-established association between the taxanes and scleroderma-like skin changes. Edema characteristically pre- cedes the development of generalized morphea by a few months, and the sclerosis develops most prominently on the lower legs, sparing the hands and feet.11 The taxanes cause an Dermatology Reports 2010; volume 2:e9 Correspondence: Susan M. Bouchard, 7741 Dunfield Place, Apt. 4, Norfolk, VA 23505, USA. E-mail: susan.bouchard@gmail.com Key words: CREST syndrome, scleroderma, mor- phea, docetaxel, taxane. Contributions: SMB primary author; MRM clini- cal investigator and first editor; RJP clinical investigator and second editor. Conflicts of interest: the authors have no conflict of interest to disclose. Received for publication: 29 June 2010. Accepted for publication: 1 July 2010. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright S.M. Bouchard et al., 2010 Licensee PAGEPress, Italy Dermatology Reports 2010; 2:e9 doi:10.4081/dr.2010.e9 Figure 1. Firm, indurated, slightly erythe- matous plaques on bilateral lower legs. [Dermatology Reports 2010; 2:e9] [page 23] No n- co mm er cia l u se on ly [page 24] [Dermatology Reports 2010; 2:e9] increase in the expression of several of the same inflammatory cytokines that are natural- ly increased in patients with scleroderma, including TNF-a, IL-2, IL-6, and INF-g.2,11 This immunological milieu likely contributes to both the taxanes’ therapeutic efficacy and the development of skin sclerosis. Several cases of taxane-induced scleroderma have displayed dramatic improvement with simple withdrawal of chemotherapy.14,15 Alternatively, it may be treated with systemic steroids and/or d-penicillamine.11,16 Ironically, pencillamine has also been implicated as a cause of cutaneous sclerosis.10 We present this case because of our patient’s distinguishing feature of pre-existing CREST syndrome. Patients with a history of scleroderma and subsequent or concurrent neoplasia may be immunologically predisposed to the development of drug-induced morphea. We propose that this population should be given taxane chemotherapy with caution in order to decrease the incidence of this rare, but potentially debilitating, side effect. References 1. LeRoy EC, Krieg T, Black C, et al. Scleroderma (systemic sclerosis): classifi- cation, subsets and pathogenesis. J Rheumatol 1988;15:202-5. 2. Jimenez SA, Derk CT. Following the molec- ular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med 2004;140:441-51. 3. Krieg T, Takehara K. Skin disease: a cardi- nal feature of systemic sclerosis. Rheumatol 2009;48:14-8. 4. Fleischmajer R, Perlish JS, Reeves JRT. Cellular infiltrates in scleroderma skin. Arthritis Rheum 1977;20:975-84. 5. Sharpe RJ, Margolis RJ, Askari M, et al. Induction of dermal and subcutaneous inflammation by recombinant cachectin tumor necrosis factor (TNF-alpha) in the mouse. J Invest Dermatol 1988;91:353-7. 6. Gruschwitz MS, Vieth G. 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