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Professor of Oral Medicine Head of the Oral Medicine Unit Department of Odontostomatological and Maxillofacial Sciences School of Medicine and Surgery Federico II University of Naples Via Pansini 5, 80131 Naples, Italy fax 39817462197 mignogna{at}unina.it
Resident, Advanced Program of Oral Medicine Oral Medicine Unit Department of Odontostomatological and Maxillofacial Sciences School of Medicine and Surgery Federico II University of Naples
Clinical Research Oral Medicine Unit Department of Odontostomatological and Maxillofacial Sciences School of Medicine and Surgery Federico II University of Naples
Resident, Advanced Program of Oral Medicine Oral Medicine Unit Department of Odontostomatological and Maxillofacial Sciences School of Medicine and Surgery Federico II University of Naples
Assistant Clinical Professor Oral Medicine Unit Department of Odontostomatological and Maxillofacial Sciences School of Medicine and Surgery Federico II University of Naples
Published Online, February 24, 2009. www.theannals.com, DOI 10.1345/aph.1K592
Case Report: A 57-year-old female with a history of metastatic breast cancer, left mastectomy, and homolateral axillary lymphoadenectomy received an anthracycline-based chemotherapy regimen (fluorouracil/epirubicin/cyclophosphamide) and then exemestane (25 mg orally once daily); this was replaced by fulvestrant (250 mg intramuscularly monthly) because of low tolerability. Due to the progression of metastatic disease, she received sunitinib malate cycles (25 mg orally 3 times per day) for a 14 day-cycle, with 7 days off and, concurrently, zolendronic acid (4 mg intravenously monthly) and omeprazole (20 mg orally twice daily). During the first and second cycles, the patient developed mild face and palmoplantar rash with edema that disappeared spontaneously within 24 hours. Dechallenge and rechallenge procedures were performed to allow a third cycle at a lower sunitinib dosage (25 mg twice daily), but during the second day, she developed persistent and painful bullous mucositis localized on the right ventral surface and edge of the tongue (Figure 1a), as well as lichenoid and necrotizing areas on the hard palate (Figure 1b), which appeared 12 hours after the second day of the third cycle. The Nikolsky's sign, performed on both sites, was positive. Extraoral examination revealed the presence of severe palmoplantar desquamation, with a diffuse facial and axillary rash and edema. The patient refused rechallenge.
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Discussion: Although the frequency of grade 3/4 toxicities occurring with sunitinib is relatively low (<10%) and is most often reported in renal cell cancer rather than metastatic breast cancer studies, the oral adverse event, always described as stomatitis or mucositis, nonetheless occurred with varying frequency (10–30%).4 Our case is unique because, for the first time, it describes the clinical aspects of sunitinib-induced stomatitis, characterized by bullous and erosive lesions with widespread lichenoid and necrotizing areas. The patient discontinued sunitinib and received prednisone (25 mg once daily) for 3 days and topical corticosteroids for 7 days. She was counseled to modify her diet, eat soft foods, avoid alcohol, and maintain meticulous oral hygiene by using a tooth-brush with soft bristles and a diluted solution of chlorhexidine 0.12%. Ten days later she was in complete clinical remission.
The first target of sunitinib is the capillary endothelium, which blocks VEGFR 1/2/3, PDGFR, c-KIT, and FMS-like tyrosine kinase 3. However, the presence of these receptors has also been detected in other tissues, for example, c-KIT in the acini and ducts of salivary glands,5 in human keratinocytes,6 and VEGFR-1 in the epidermal layer of unwounded skin.7
It is likely that the initial damage induced by sunitinib in the oral cavity may affect not only vascular tissue, but also salivary glands and keratinocytes. Once the damage is established, these lesions might self-maintain, due to an impairment of wound-healing mechanisms. Indeed, the wound repair mechanisms are regulated via VEGF, which is expressed by both epithelial cells of salivary glands8 and keratinocytes.7 These are the main sources of VEGF during wound healing, acting in a paracrine and autocrine manner7 and promoting wound healing via stimulation of endothelial cell–mediated angiogenesis. Clinicians should consider sunitinib as a trigger for oral mucositis.
References
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