Table 2.
Immune checkpoint inhibitor-induced adverse events in the oral cavity.
| First Author | Age/Sex | Cancer Type | ICIs | Time to irAE | Clinical Feature (Distribution) | Pathological | Immunological | Other irAEs | Tumor | Treatment of irAEs | Clinical Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|
| [Ref.] | M/cycle | Feature | Data | Response | |||||||
| Oral lichenoid reaction | |||||||||||
| Shi | F | RCC | Nivolumab | 1.6 M | Papular (mouth) | Lichenoid | Papular (palms, soles) | SD | ICI continued | ||
| [107] | F | Lung cancer | Nivolumab | 10.2 M | Mucositis (mouth) | Lichenoid | None | PR | ICI continued | ||
| M | Melanoma | Nivolumab | 0.5 M | Erosive lichen planus | Lichenoid | None | SD | ICI discontinued | |||
| (mouth, penis) | |||||||||||
| F | RCC | Atezolizumab | 8.3 M | Papular (mouth) | Lichenoid | Papular (plams, arms) | PR | ICI discontinued | |||
| Sibaud | 53/M | Multiple myeloma | Nivolumab | 2 cycles | Papule, Reticular streaks | Cutaneous lichenoid | DEX | Resolved after | |||
| [108] | (lip, tongue, buccal) | eruption | Mouth wash | several weeks | |||||||
| 62/M | RCC | Nivolumab | 23 cycles | White streaks (buccal), | No dermal lesions | None | Resolved after ICI | ||||
| White plaque (tomhue) | ICI discontinued | discontinuation | |||||||||
| 42/M | Glioblastoma | Nivolumab | 2 cycles | White papule (lip, tongue, | No dermal lesions | Topical corticosteroids | |||||
| multiforme | buccal) | Anti-fungal lozenges | |||||||||
| 70/F | Lung cancer | Nivolmab | 6 cycles | White streaks (buccal, lip, mouth | Cutaneous lichenoid | Topical and oral | Resolved after | ||||
| floor, soft palate, tongue), | eruption | corticosteroids | several weeks | ||||||||
| Erythema/atrophy (tongue) | Pneumonitis | ||||||||||
| 41/F | Breast cancer | Pembrolizu mab |
10 cycles | White plaque-like lesion | No dermal lesions | None | |||||
| (tongue) | |||||||||||
| 63/M | Lung carcinoma | Nivolumab | 3 cycles | Reticular white streaks | Nonspecifc maculo- | Topical coticosteroids | |||||
| (buccal, soft palate) | papular rash | ||||||||||
| 56/M | Renal cell | Atezolizumab | 11 cycles | White plaque-like lesions | Cutaneous lichenoid | Topical corticosteroids | Resolved after | ||||
| carcinoma | (tongue), Reticular white | reaction | ICI discontinued | ICI discontinuation | |||||||
| streaks (hard palate) | |||||||||||
| 66/M | Adenocarcinoma | Atezolizumab | 14 cycles | Reticular white streak | Xerostomia | None | |||||
| of esophagus | (buccal) | ||||||||||
| 54/M | RCC | Atezolizumab | 5 cycles | Ulcers (floor of mouth) | No dermal lesions | Topical corticosteroids | Resolved eventually | ||||
| Sensitive tongue | |||||||||||
| 58/M | Lung carcinoma | Pembrolizu mab |
12 cycles | Reticular white streaks | Cutaneous | Topical corticosteroids | Resolved eventually | ||||
| Oral lichenoid reaction | |||||||||||
| Namiki | 84/F | Melanoma | Nivolumab | 3 M | Ulcers (buccal, tongure) | Epithelial necrosis, | None | Methylprednisolone, | Resolved after | ||
| [109] | Lichenoid lymphocyte | Oral prednisolone | a month | ||||||||
| infiltration | |||||||||||
| Shazib | 74/F | Melanoma | Nivolumab | 4 doses | Lichenoid (buccal, lip, | Lichenoid mucositis | Pneumonitis | PR | Topical CLO | ||
| [112] | gingiva) | ||||||||||
| 55/F | Melanoma | Nivolumab | 16 doses | Lichenoid (palate) | Pneumotitis | PR | Topical FLUOC | ||||
| 68/M | OSCC | Nivolumab | 2 doses | Lichenoid (buccal, gingiva) | Lichenoid mucositis | PR | Topical DEX | ||||
| 39/M | OSCC | Nivolumab | 2 doses | Oral erythema | Topical DEX | ||||||
| multiforme (bucal, lip, palate) | Prednisolne | ||||||||||
| 60/F | Breast cancer | Pembrolizumab | 2 doses | Lichenoid (tongue, buccal, | Topical DEX | ||||||
| gingiva, lip) | Prednisolone | ||||||||||
| Severe immune mucositis | |||||||||||
| Cardona | 93/M | Pharyngeal carcinoma | Nivolumab | 10 cycles | Ulcers (buccal, tongue, | Infiltration of | Hypothyroidism | CR | Topical triamcinolone | Complete resolution | |
| [119] | 50% of oral mucosa) | lymphocytes and | Dysphagia | Oral prednisolone | Cyclophosphamide | ||||||
| silimar to GVHD, | macrophage-like cells | Methylprednisolone | and colchicine | ||||||||
| Behcet’s disease | Cyclophosphamide, Colchicine | ||||||||||
| Acero Brand | 69/M | Layngeal carcinoma | Pembrolizumab | 14 cycles | Oral and pharynx | Ulcerative esphoagitis | None | CR | ICI discontinued | Marked improvement | |
| [117] | mucositis, esphagitis | with granulation tissue | Methylprednisolone | within 48 h | |||||||
| Miyagawa | 75/M | Gastric cancer | Nivolumab | 19 cycles | Erosion and ulcers | Infiltration of band-like | Dsg1 (-), Dsg3 (-) | Perianal erosions | ICI discontinued | Improved gradually | |
| [118] | (buccal mucosa, tongue, lip) | inflammatory cells | BP180 (-), BP230 (-) | Erosion (glans, | Pednisolone | ||||||
| IIF (-), DIF (-) | penis) | ||||||||||
| Wang | 32/M | Gastric cancer | Camrelizu mab |
15 cycles | Behchet’s disease, Ulcers (lip, | ICI discontinued | Lip lesion healed | ||||
| [120] | penis, abdominal, skin), | Oral prednisolone | after few days | ||||||||
| folliculitis/acne (hands, feet) | and thalidomide | ||||||||||
| Oral lichenoid reaction | |||||||||||
| Obara | 67/M | Lung adenocarcinoma | Nivolumab | 0.5 M | Ulcers (entire oral mucosa, | Epithelial necrosis, | Dsg1 (-), Dsg3 (-) | None | PD | Topical triamcinolone | Resolved afer |
| [106] | lip, tongue) | Lichenoid lymphocyte | BP180 (-) | 3 weeks | |||||||
| infiltration | |||||||||||
| 74/F | Lung adenocarcinoma | Nivolumab | 5 M | Ulcers (entire oral mucosa, | Epithelial necrosis, | Dsg1 (-), Dsg3 (-) | Erythromatous | PR | Oral prednisolone | Resolved after | |
| lip, tongue) | Lichenoid lymphocyte | papule | 2 weeks | ||||||||
| Enomo to |
52/M | Lung adenocarcinoma | Nivolumab | 5.5 M | Erosion (buccal, mouth floor, | Dsg1 (-), Dsg3 (-) | None | Oral prednisolone | Resolved within | ||
| [107] | gingiva) | BP180 (+) | 3 weeks | ||||||||
| Economopoulou | 66/M | OSCC | Nivolumab | 8 cycles | Ulcers (lower lip) | Bethamethasone cream | Responded well | ||||
| [109] | ICI continued | ||||||||||
| Shazib | 82/F | Melanoma | Pembrolizumab | 1 dose | Lichenoid (buccal, tongue) | Papular rash | PR | Topical DEX | [12/13 of patients | ||
| [108] | Knee arthralgia | reported greater than | |||||||||
| 68/M | NSCLC | Pembrolizumab | 9 doses | Lichenoid (buccal, tongue) | Lichenoid mucositis | None | PR | Topical DEX | 80% improvement in pain scores, | ||
| 43/F | Melanoma | Pembrolizumab | 2 doses | Lichenoid (palate, buccal, | Papular rash, | PR | Topical DEX | but there was | |||
| tongue) | Adrenal crisis | Topical FLUOC | minimal | ||||||||
| 57/M | Melanoma | Nivolumab | 11 doses | Lichenoid (tongue) | Papular rash, | PR | objective | ||||
| Acute nephritis | Topical CLO | improvement] | |||||||||
| 76/M | NSCLC | Nivolumab | 6 doses | Lichenoid (tongue) | Papular rash, | PD | DEX | ||||
| Diarrhea | |||||||||||
| 70/M | OSCC | Pembrolizumab | 4 doses | EM-like (tongue, | Dermatitis | PR | Topical DEX | ||||
| buccak mucosa, lip | Prednisolone | ||||||||||
| 73/F | NSCLC | Nivolumab | 8 doses | Lichenoid (palate, buccal) | Lichenoid mucositis | Pneumonitis | PR | Topical CLO | |||
| Vaginal ulcers | |||||||||||
| 57/M | Colon cancer | Pembrolizumab | 1 dose | Acute GVHD | Papular rash | PD | Topical DEX | ||||
| reactivation (palate, | M-prednisolone | ||||||||||
| tongue, buccal, lip) | |||||||||||
| Phemphigoid with oral lesions | |||||||||||
| Zumelzu | 83/F | Melanoma | Pembrolizumab | 16.5 M | MMP, erosion, blister | Subepithelial cleavage | DIF (+) | No skin lesions | CR | Doxycycline | Controled MMP |
| [63] | of gingiva | Perivascular infilitrate of | BP180 (-) | within 2 weeks | |||||||
| lymphocytes and histiocytes | BP230 (-) | ||||||||||
| Haug | 62/M | Merkei cell carcinoma | Pembrolizumab | 3.3 M | MMP, erosion, aphthous | DIF (+), IIF (+) | None | ICI discontinued | Erosion healed after | ||
| [125] | ulcers (tongue, buccal) | BP180 (+) | Doxycycline | 6 weeks | |||||||
| Topical mometasone | |||||||||||
| Naidoo | 80/M | Melanoma | Nivolumab | 6 M | BP, bucal mucosa | Subepithelial vesicular | BP180 (+) | CR | Topical tacrolimus | ||
| [121] | dermatitis with | BP230 (+), DIF (+) | and DEX | ||||||||
| eosinophils | |||||||||||
| 78/F | Melanoma | Durvalumab | 13 M | BP, bucal mucosa | Subepithelial cleft | BP180 (+) | PR | Topical steroids | |||
| BP230 (+), DIF (+) | |||||||||||
| Hwang | 68/M | Melanoma | Pembrolizumab | 19.5 M | BP, bucal mucosa | Dermal chronic | DIF (+) | Papules on trunks, | PR | Topical methyl- | Responded promptly |
| [122] | inflammation with | backs, legs | prednisolone | ||||||||
| eosinophils | Doxycycline | ||||||||||
| 72/M | Melanoma | Pembrolizumab | 6.8 M | BP, bucal mucosa | Subepithelial blister | DIF (+) | Excorated blisters | PD | ICI stop, Doxcycline | ||
| with eosinophils | on trunk, back, legs | Topical prednisolone | |||||||||
| Methotrexate | |||||||||||
| Jour | 63/M | HNSCC | Nivolumab | 3.5 M | BP, bucal mucosa | Subepithelial blisters | DIF (+) | Vesiclees and bulae | PD | Topical fluocinonide | Progressive |
| [123] | with eosinophils | on neck, chin, trunk, | Oral prodnisolone | improvement | |||||||
| four extremities | ICI discontinued | ||||||||||
| Sowerby | 80/M | Lung adenocarcinoma | Nivolumab | 20 M | BP, gingival bulla | Subepithelial vesicle | DIF (+) | Vesicles and bullae | CR | ICI discontinued | Cleared within 2 |
| [124] | with eosinophils | Dsg1 (+), BP180 (+) | on 4–5% of body | Oral steroids, Rituximab | months by rituximab | ||||||
| surface | |||||||||||
| Phemphigoid with oral lesions | |||||||||||
| Wang | 70/M | Melanoma | Pembrolizumab | 35 cycles | BP, hard palate | Detachment of the | DIF (+) | Erosions (trunk, limbs) | CR | Oral prednisolone | Disappered 4 weeks later |
| [126] | epidermis | Blisters (hands, legs) | |||||||||
| Sadik | 62/M | Melanoma | Pembrolizumab | 6.8 M | BP, vesicular lesions of the oral mucosa |
Interface dermatitis, | IIF (IgG+) BP180 (+), | Scattered skin papules | CR | Topical clobetasol, Oral prednisolone | Minor alleviation |
| [127] | Focal epidermal | BP230 (+) | with central vesicles | , Rituximab | |||||||
| necrosis | |||||||||||
| 76/M | RCC | Nivolumab | 4.8 M | BP, vesicular and white | Lichenoid interface | DIF (C3+), IIF (IgG+) | Palmoplanter hyper- | SD | Topical clobetasol (skin) | Alleviated but not completely | |
| reticular lesions of the | dermatitis | BP180 (+), BP230 (+) | keratosis, Polygonal | Topical triamcinolone, | resolved | ||||||
| oral mucosa | papules, and vesicles | Dexpanthenol | |||||||||
| Paraneoplastic pemphigus | |||||||||||
| Yatim | 64/M | Cutaneous SCC | Pembrolizumab | 0.7 M | Paraneoplastic pemphigus, | Suprabasal acantholysis | DIF (+) | Extensive cutaneous | ICI discontinued | Complete healing | |
| [130] | blisters, pustules, | Intraepithelial blisters | Dsg1 (+), Dsg3 (+) | involvement | Oral prednisolone | ||||||
| Severe stomatitis | |||||||||||
ICIs, immune checkpoint inhibitors; irAEs, immune-related adverse events; M, month; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; RCC, renal cell carcinoma; NR, not reported; DEX, Dexamethasone; Dsg1, desmoglein1; Dsg3, desmoglein 3; OSCC, oral squamous cell carcinoma; NSCLC, non-small cell lung cancer; FLUOC, flucinonide; CLO, Clobetasol; GVHD, graft-versus-host disease; DIF, direct immunofluorescence; IIF, indirect immunofluorescence; MMP, mucous membrane pemphidoid; BP, bullous pemphigoid; HNSCC, head and neck squamous cell carcinoma.