A 70-year-old man with masses on his tongue and lower lip was referred to our hospital. He had no significant past history unless hypertension. On initial examination, the patient had three independent masses with induration at the right dorsum tongue, left lateral edge of the tongue, and left lower lip. Each tumor showed different characteristics (a 53 × 45 × 10 mm pedunculated tumor on his right dorsum of tongue, a 27 × 24 × 8 mm introverted tumor on the left lateral edge of tongue, and a 14 × 13 × 6 mm pedunculated tumor with partial keratinization on his lower lip) (Fig. 1A–C). 18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) images revealed abnormal uptake of FDG (SUVmax = 6.2–11) by each legion of mass and bilateral cervical lymph nodes. Besides, multiple abnormal accumulations showed in the bilateral parotid glands (Fig. 1D, E), which were diagnosed with Warthin’s tumor and a follow-up examination was performed at the Department of Otolaryngology in our hospital. Contrast-enhanced MR image (T1-weighted) showed a 23 × 20 × 9 mm mass with high signal intensity on the left margin of tongue, and the tumor of right tongue and lip were unclear (Fig. 1F). Contrast-enhanced computed tomography (CE-CT) images showed the high density presented in level IIA at the right side and level IIB at the left side (Fig. 1G, H). The masses at right dorsum tongue, left side edge of tongue, and lower lip were diagnosed as well-differentiated squamous cell carcinoma (SCC) on pathologic examination of biopsy specimens (Fig. 1I–L). The distance between the tumor at the right dorsal tongue and that at the left side edge of the tongue was 34 mm. According to the 8th Edition of the UICC TNM classification of oral cavity cancers, the patient was definitively diagnosed with right tongue cancer “T3”, left tongue cancer “T2”, and lower left lip cancer “T1”, N2cM0.

Representative images and pathology of synchronous multifocal oral squamous cell carcinomas. Three independent tumors were found in left tongue (A), right dorsal tongue (B), and left lower lip (C). D, E PET/CT image showed abnormal uptake of FDG (arrows, SUVmax: tongue = 8–11, lip = 6.2). Multiple abnormal accumulations also showed in the bilateral parotid glands at the same time. F Contrast T1-weighted image showed a mass with high signal intensity on the left margin of tongue (arrow). G, H CECT images showed the high density presented in right level IIA and left level IIB lymph node (arrows). I–L Microinvasion and cancer pearl, epithelial funiculus dysplasia and atypical mitotic figure can be seen in histopathology of the tumors (I, J right tongue; K, L, lip). Scale bars indicate 1 mm (I), 500 μm (K), and 50 μm (J, L)

The patient received IACRT combined with intravenous (IV) administration of cetuximab. Catheterization from the superior temporal artery (STA) was performed as previously reported [9]. Before the treatment, 3-dimensional computed tomography angiography of the carotid artery was performed to identify the tumor-feeding arteries and examine the morphology of the tumor-feeding artery arising from the external carotid artery. A hook-shaped catheter (Medikit Corp., Tokyo, Japan) was superselectively inserted into the target artery under radiographic guidance and fixed to the periauricular skin. When catheterization using a hook-shaped catheter was not stable, we replaced it with a P–U catheter that is flexible, reducing long-lasting damage to blood vessels (Toray Medical Co., Ltd., Tokyo, Japan). The catheters were superselectively inserted into the bilateral lingual arteries (LA) via STA. Due to preventing the reduction of chemo-drug concentration by distribution through several routes, we decided to exclude the infusion of chemo-drug into left facial artery (FA) targeting lower lip cancer. Treatment was performed for 7 weeks as following schedule (Fig. 2): After catheterization, flow-check digital subtraction angiography and angiographic CT were performed to confirm the appropriate catheter placement and enhancement of the feeding areas (Fig. 3A–D). Sodium indigotindisulfonate was utilized weekly as another confirmation of feeding areas via dyeing of the tongue and oral floor (Fig. 3E, F). Cetuximab was weekly IV administered 1 week prior to the initiation of IACRT; the patient received seven times (400 mg/m2 as an initial dose, followed by 250 mg/m2, in week 2–7, Fig. 2). To minimize the risk of infusion reaction, antihistamine and corticosteroids were premedicated, and the patient was monitored vital signs [10]. Docetaxel (DTX) and cisplatin (CDDP) were injected as a slow bolus over 1 h through the catheter during the irradiation. The dose of DTX was 10 mg/m2/week, for a total of 60 mg/m2 during the whole treatment course, and that of CDDP was 5 mg/m2/day, for a total of 150 mg/m2. Sodium thiosulfate, a CDDP neutralizing agent, was also administered intravenously at 1 g/m2 immediately after arterial infusion of CDDP. Radiotherapy was performed 5 times per week using 2 Gy per fraction of 6-MV photon beams with a linear accelerator with a total dose of 60 Gy. The irradiation field was set up to cover the primary lesions and the whole neck. After a total dose of 40 Gy was delivered to the initial field, an additional 20 Gy was delivered to the primary tumors and metastatic lymph nodes within the shrunken field [11].

Treatment schedule of IACRT combined with systemic cetuximab administration. IACT: intra-arterial chemotherapy, Cisplatin (C): 5 mg/m2/day (Total: 150 mg/m2/6 weeks), Docetaxel (D): 10 mg/m2/week (Total: 60 mg/m2/6 weeks), RT: Radiotherapy, 2 Gy/day (Total: 60 Gy), C-mab: cetuximab, initial dose at 400 mg/m2, followed by the dose at 250 mg/m2 (Total: 1900 mg/m2/7 weeks)

Representative images of DSA, angio CT and indigotindisulfonate-staining. Two catheters were superselectively inserted into the lingual arteries (arrows) via the superfacial temporal arteries (A, B: flow-check digital subtraction angiography (DSA), C, D: angiographic CT images). EF, photograph representing the flow areas stained by injection of indigotindisulfonate sodium (A, C, E: right, B, D, F: left side)

During the treatment, there were some adverse events: grade 3 oral mucositis, grade 3 cheilitis and grade 2 radiation dermatitis, classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events ver. 4.0. There were no significant hematological and kidney toxicities or major complications, such as cerebral infarction or other neurological disorders observed.

About 1 month after the completion of initial treatment, no residual local tumors were found by CT and MRI imaging and biopsy, demonstrating that the patient achieved a complete response (Fig. 4A, B). There was a mild FDG accumulation on the left upper deep cervical lymph nodes (Fig. 4A), hence the left modified radical neck dissection was conducted. No viable cancer cells in the dissected lymph nodes were found, resulting in pathological complete response. During the subsequent follow-up period, no evidence of recurrence and metastasis was suggested, and the patient did not show dysarthria and masticatory disturbance for four years so far (Fig. 4C, D).

Representative images of synchronous multifocal oral squamous cell carcinomas following completion of treatment. Result of PET/CT one month after the treatment (A), local finding one month after the treatment (B), and local finding 3 years after the treatment (C, D)