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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3504-3505 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3322
Tamoxifen-Related VasculitisDepartments of Breast Medical Oncology, Pathology, Dermatology, and Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX A 67-year-old woman was diagnosed with left breast cancer (T2, N1, M0) in 1998 and underwent a modified radical mastectomy. Postoperatively, the patient received adjuvant chemotherapy (fluorouracil, doxorubicin, and cyclophosphamide followed by paclitaxel) and radiation therapy to the left chest wall. The primary tumor was estrogen-receptor–positive and progesterone-receptor–negative. The patient refused adjuvant tamoxifen because of a history of deep venous thrombosis. She did well until December 2002, when she was found to have left supraclavicular lymph node metastasis. A biopsy of the affected lymph node showed an invasive carcinoma consistent with breast primary. The metastatic cancer cells were estrogen-receptor–positive, progesterone-receptor–negative, and HER-2–negative. The patient received letrozole from January 2003 until January 2004, when a bone scan and magnetic resonance imaging revealed multiple bony metastases. The patient was started on zoledronic acid and received exemestane until February 2005. At that time positron emission tomography and computed tomography scans showed progressive disease and the patient was treated with fulvestrant until May 2005, when she developed progressive disease in multiple bones. Fulvestrant was discontinued and tamoxifen was started. After taking tamoxifen for 4 weeks the patient noticed a rash in her lower extremities and face, and discontinued tamoxifen on her own. Physical examination 4 days after tamoxifen discontinuation revealed multiple erythematous, crusted plaques on her face and legs. A 14 cm x 8 cm erythematous, indurated plaque with overlaying petechiae was noted in the patient's left lateral lower leg, suggestive of vasculitis (Fig 1). Computed tomography scans of the chest, abdomen, and brain showed no evidence of metastatic disease. A bone scan showed stable bone metastases. Serum chemistry and coagulation studies were within normal limits. The tumor marker CA27.29 was stable. Punch biopsies were obtained from the larger left lateral lower leg plaque. Microscopic evaluation of the skin biopsies revealed superficial dermal edema, with a superficial and deep, predominantly perivascular lymphocytic infiltrate with prominent eosinophils and focal extravasated red cells. There was no evident endothelial cells necrosis or leukocytoclasis (Fig 2). Numerous eosinophils in a perivascular arrangement were noted (Fig 2, inset). Thus, the findings were those of a dermal hypersensitivity reaction with vasculopathic changes, consistent with a reaction to an internal antigen such as a medication. Bacterial, fungal, and atypical mycobacterial cultures were all negative. One week after tamoxifen discontinuation the cutaneous eruption disappeared completely. A retrospective chart review with waiver of informed consent was approved by the institutional review board at M.D. Anderson (Houston, TX).
Tamoxifen, a nonsteroidal antiestrogen, has been used in the treatment of breast cancer since the early 1970s.1,2 Tamoxifen binds to estrogen receptor (ER) and inhibits estradiol binding to ER, resulting in decreased tumor cell proliferation and cell death.3 In addition to antitumor responses, tamoxifen can also exert antiangiogenic effects.4 Potential life-threatening events such as thromboembolic events and endometrial cancers may occur during tamoxifen use. More common, nonlife-threatening adverse events include hot flashes, nausea, vomiting, vaginal discharge, and irregular menses. Skin changes caused by tamoxifen were reported in 19% of tamoxifen-treated patients.2 A search of the published medical literature identified occasional reports of skin reactions (eg, urticaria or hives) in patients receiving tamoxifen therapy.5-7 Rare hypersensitivity-type reactions, including angioedema, have occurred (personal communication, AstraZeneca). However, the development of purpura due to antiestrogen therapy is extremely unusual.8 The quick resolution of this toxicity after tamoxifen discontinuation strongly supports a cause–effect in our patient. Interestingly, the patient did not experience similar reactions to prior endocrine therapies, including the antiestrogen fulvestrant and several aromatase inhibitors. Studies have shown that tamoxifen can induce skin fibrosis and dermal chronic inflammatory cell infiltration in rats.9 However, the biologic mechanism underlying the development of tamoxifen-induced skin toxicity in humans remains unknown. In summary, to the best of our knowledge, we describe for the first time dermal vasculopathic changes secondary to tamoxifen treatment in a patient with metastatic breast carcinoma. Therefore, tamoxifen should be included in the list of medications capable of inducing palpable purpura. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Hortobagyi GN: Treatment of breast cancer. N Engl J Med 339:974-984, 1998 2. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989[Abstract] 3. Lippman ME, Bolan G: Oestrogen-responsive human breast cancer in long term tissue culture. Nature 256:592-593, 1975[CrossRef][Medline] 4. Gagliardi A, Collins DC: Inhibition of angiogenesis by antiestrogens. Cancer Res 53:533-535, 1993 5. Fentiman IS, Caleffi M, Hamed H, et al: Studies of tamoxifen in women with mastalgia. Br J Clin Pract Symp 68:34-36, 1989 (suppl); discussion 49-53, 1989 6. Rendina GM, Donadio C, Fabri M, et al: Tamoxifen and medroxyprogesterone therapy for advanced endometrial carcinoma. Eur J Obstet Gynecol Reprod Biol 17:285-291, 1984[CrossRef][Medline] 7. Bonte J, Ide P, Billiet G, et al: Tamoxifen as a possible chemotherapeutic agent in endometrial adenocarcinoma. Gynecol Oncol 11:140-161, 1981[CrossRef][Medline] 8. Erbagci Z, Tuncel A, Erkilic S, et al: Progressive pigmentary purpura related to raloxifene. Saudi Med J 26:314-316, 2005[Medline] 9. Inaloz HS, Deveci E, Inaloz SS, et al: The effects of tamoxifen on rat skin. Eur J Gynaecol Oncol 23:50-52, 2002[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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