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Advances in dermatology and venereology Acta Dermato-Venereologica
Ramucirumab-induced Multiple Haemangiomas of the Skin: Two Case Reports
Hideyuki KOSUMI 1, Wataru NISHIE 1 *, Tatsuro SUGAI 1, 2, Ellen TOYONAGA 1, Norihiro YOSHIMOTO 1, 2, Hiroyuki NAKAMURA 2, Ryota HORIBE 3, Yasuo KITAMURA 3, Hiroshi NAKATSUMI 4 and Hiroshi SHIMIZU 1
1
Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo 060-8638, Departments of 2 Dermatology and 3 Respiratory Medicine and Allergology, Kushiro City General Hospital, Kushiro and 4 Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan. * E-mail: nishie @ med. hokudai. ac. jp Accepted Dec 20, 2017; Epub ahead of print Dec 20, 2017
Ramucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extracellular domain of vascular endothelial growth factor receptor 2( VEGFR-2). Ramucirumab is mainly used as a second-line treatment for advanced cancers, such as gastric, colorectal and nonsmall-cell lung cancers( 1 – 4). Various adverse events due to ramucirumab have been reported, including hypertension, deep vein thrombosis, headaches, anorexia, vomiting and dyspnoea( 5). Tanibirumab and alacizumab, which are reagents targeting VEGFR-2, are known to induce haemangiomas as a paradoxical reaction( 6, 7); however, only 2 cases of multiple haemangiomas associated with ramucirumab have been reported in a phase I study( CP12-0401), and these had no detailed clinical or histopathological descriptions( 8). Moreover, tanibirumab and alacizumab are not commercially available. Therefore, we clinicians have limited opportunity to observe this phenomenon. We report here 2 cases of ramucirumab-induced multiple haemangiomas of the skin.
CASE REPORTS
Case 1. A 61-year-old woman presented to our department with multiple reddish macules over the body. She was on FOLFIRI( 5-fluorouracil, leucovorin, irinotecan) and ramucirumab treatment as a second-line chemotherapy for refractory metastatic caecal adenocarcinoma. Eighteen months earlier, caecal adenocarcinoma with multiple liver metastases had been found and she had received mFOLFOX6( oxaliplatin, 5-fluorouracil( 5-FU), folic acid) plus bevacizumab therapy. After 5 cycles of the regimen, she had undergone a right hepatic and caudal lobectomy. New liver metastases were found 5 months after the operation, and mFOLFOX6 plus bevacizumab treatment was re-started. Unfortunately, the metastatic lesion of the liver enlarged and the treatment was changed to FOLFIRI plus ramucirumab. Two months after the treatment, reddish papules developed.
Physical examination revealed numerous reddish papules approximately 2 – 3 mm in diameter on the scalp, neck, trunk and limbs( Fig. 1a, b). There was a slightly elevated red macule of 30 × 20 mm on the right shoulder( Fig. 1a). Dermoscopy revealed red homogenous globules surrounded by telangiectasia( Fig. 1c). Histopathological findings of the skin specimen obtained from a red papule on the neck revealed local proliferation of vascular endothelial cells in the superficial dermis( Fig. 1d). Enlarged capillary vessels and fibrosis surrounding the endothelial cells were also observed( Fig. 1d). We made a diagnosis of capillary haemangioma, and the other lesions were not removed. The FOLFIRI plus ramucirumab therapy was switched to panitumumab because of severe neutropaenia. Approximately 3 months after discontinuing the treatment, the haemangiomas disappeared gradually( Fig. 1b).
Case 2. A 65-year-old woman presented to our department with slowly growing nodules on the limbs and the face. She had been receiving docetaxel and ramucirumab as a second-line therapy for refractory metastatic lung adenocarcinoma for 2 months. Three years earlier, she had been diagnosed with lung adenocarcinoma with bone metastasis of the right sixth rib and thoracic vertebrae. The patient had received radiation( total dose: 30 Gy) to the right rib, and thoracic vertebrae and afatinib was started. One month later, the afatinib was changed to gefitinib due to drug-related ileus. One year later, carboplatin and pemetrexed were started because of metastasis to the skull. Unfortunately, cerebellar metastasis was found after 3 cycles of the regimen, which was
Fig. 1. Clinical and histopathological characteristics of case 1.( a) Sporadic reddish papules approximately 2 – 3 mm in diameter are seen on the neck and right shoulder( black arrows). There is also a slightly elevated red macule measuring 30 × 20 mm on the right shoulder( white arrow).( b) Three months after the cessation of FOLFIRI( 5-fluorouracil, leucovorin, irinotecan) and ramucirumab. Note the haemangioma has spontaneously regressed.( The lesion of the right neck has been excised.)( c) Dermoscopy shows red homogenous globules surrounded by telangiectasia( arrowheads).( d) The skin specimen of the red papule on the neck shows local proliferation of vascular endothelial cells in the superficial dermis. Enlarged capillary vessels( arrowheads) and fibrosis surrounding the endothelial cells are also seen. Scale bar: 200 μm. doi: 10.2340 / 00015555-2869 Acta Derm Venereol 2018; 98: 454 – 455
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.