Possible causes of an enlarged or edematous tongue include allergic reactions and bradykinin-mediated angioedema (2). However, in this case, there was no sudden worsening of symptoms at the time of the visit, no new medications were started or foods ingested, and no symptoms such as urticaria were present, suggesting that an allergic reaction was not likely. Bradykinin-mediated angioedema can be hereditary angioedema, acquired C1 inhibitor deficiency, drug-induced, or idiopathic (3). However, no abnormalities related to C1 inhibitors were observed in this patient. Drug-induced causative agents have been reported in drugs such as penicillin, aspirin, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), oral contraceptives, and others (4, 5).
Considering that the patient had concurrent hypertension and had been taking an ARB before SOX and trastuzumab therapy, ARB-induced drug-induced angioedema was considered. Angioedema caused by ARBs and ACE-Is has been implicated in bradykinin (6). The mechanism of the development of vascular edema in ACE-Is is thought to be due to the accumulation of bradykinin (2). Increased levels of bradykinin lead to vasodilation, which in turn increases the permeability of endothelial cells, resulting in the swelling of peripheral tissues (7). However, although an increase in bradykinin concentration is also observed in ARBs, the mechanism behind this is still largely unknown (8).
The onset of ACE-I and ARB-induced angioedema has been reported to vary from early administration to several years later (9). While there have been reports of chemotherapy-triggered angioedema in hereditary angioedema (10), there have been no reports of chemotherapy-triggered angioedema in drug-induced angioedema, such as ACE-I and ARBs, although there have been cases of triggered by dental treatment (11).
In this case, the patient did not develop angioedema immediately after starting SOX and trastuzumab but later developed oral mucositis and a swollen tongue, which suggests that the oral mucositis caused by SOX and trastuzumab triggered ARB-induced angioedema and caused the tongue to swell. However, the lack of significant improvement in tongue swelling, in this patient, is inconsistent with previous case reports of angioedema treated with ARBs and ACE-Is, most of which reported rapid improvement in edema symptoms after discontinuation of ARBs and ACE-Is (12).
Finally, there is idiopathic angioedema, the cause of which has not been identified. Idiopathic angioedema is thought to be induced by contact with substances or ingestion of food (13). However, there have been no reports of chemotherapy being a contributing factor.
This case study suggests that angioedema may be caused by oral mucositis following chemotherapy. Notably, when chemotherapy was resumed, fluoropyrimidine was switched from S-1 to capecitabine. The reason was that capecitabine was reported to cause less oral mucositis than S-1 in a comparison of adverse events between S-1 and capecitabine.
In summary, we report a case of significant tongue enlargement after SOX and trastuzumab treatment for unresectable advanced gastric cancer. Angioedema of the tongue, pharyngeal and laryngeal mucosa can lead to asphyxia with airway obstruction, and caution should be exercised because tongue enlargement may occur due to chemotherapy-induced oral mucositis, as in this case (15, 16).