Most TEN cases result from hypersensitive reaction to drugs, and sulfonamides, pyrazolones, barbiturates, and antiepileptics are the most frequent triggers[9]. TEN usually occurs between 7 days to 8 weeks after drug administration. Upon readministration of the implicated drugs, it may develop within hours.

TEN is a T-cell-mediated disease with CD8⁺ T cells acting as the major mediator of keratinocyte death. Drug-induced CD8⁺ T-cell activation is highly specific for particular human leukocyte antigen (HLA) allotypes, placing certain populations at a greater risk of developing TEN. Granulysin is the main mediator of apoptosis, and soluble Fas ligand (sFasL), tumor necrosis factor-alpha (TNF-α), and granzyme B/perforin are important in the pathogenesis of TEN[10].

The diagnosis of TEN is made based on clinical and histological findings. Schwartz et al.[11] put forward that the clinical features of TEN include (1) constitutional symptoms such as fever, malaise, anorexia, and pharyngitis; (2) erythematous, dusky, violaceous macules, morbilliform, or atypical targetoid macules starting on the trunk and spreading distally, confluence on the face, trunk, and elsewhere [the skin lesion area of TEN is greater than that of Stevens-Johnson syndrome (SJS)]; (3) manifests in flaccid bullae, epidermal sloughing, and necrosis with gray hue; (4) exfoliation of the epidermis involving 10% of body surface area for SJS, 10%–30% for SJS/TEN overlap, and >30% for TEN; (5) oral, genital, and ocular mucositis in nearly all patients; (6) tender skin and painful mucosal erosions; (7) positive Nikolsky sign; (8) positive Asboe-Hansen sign; (9) systemic symptoms always present in SJS/TEN overlap and TEN; and (10) respiratory tract epithelial involvement in 25% of patients with TEN. Histological features were described as follows: (1) full thickness epidermal necrosis; (2) subepidermal split, lymphocytic infiltrate at the dermoepidermal junction, CD4⁺ T cells in the dermis, and CD8⁺ T cells in the epidermis; and (3) endothelial apoptosis[11].

For mild and early stage TEN, the main differential diagnoses includes SJS, acute generalized exanthematous pustulosis (AGEP), erythema multiforme major (EMM), staphylococcal scalded skin syndrome (SSSS), drug-induced linear immunoglobulin A (IgA) dermatosis, acute graft versus host disease (GVHD), and a generalized morbilliform drug eruption, among other conditions[12,13]. Our patient’s clinical characteristics were consistent with the above criteria except items (8) and (10). Because the patient’s exfoliation was almost systemic, SJS and EMM were excluded; SSSS were excluded due to negative blood and rash cultures for bacteria and fungus as well as the presence of conjunctiva and oral mucosa damage. In addition, the patient’s rash mainly appeared as blisters and bullae due to erythema in the beginning stage, without pustules. Accordingly, AGEP and other diseases were also excluded.

Therefore, the patient was diagnosed with TEN according to typical clinical features. After treatment with glucocorticoids combined with immunoglobulin, her condition gradually improved, which verified the diagnosis of TEN. However, there also exists some deficiency in the diagnosis of this case, primarily the lack of mucocutaneous biopsy and immunologic examination to aid in the diagnosis.

There is currently no standardized treatment for TEN. An effective treatment requires early diagnosis, immediate discontinuation of the causative drugs, and supportive and specific treatment. Recently, the systematic application of glucocorticoids has been the major therapeutic regimen, and glucocorticoids combined with immunoglobulin can quickly control symptoms and shorten hospitalization time and is especially suitable for patients with concurrent infection[11].

Because this case of TEN occurred after AP and gefitinib sequential combination treatment, it is difficult to determine which drug was responsible for this toxicity. Thus far, there has been no report of TEN induced by cisplatin, whereas there has only been one case of SJS related to bleomycin-cisplatin combination treatment[14] and another case of exfoliative dermatitis associated with cyclophosphamide-cisplatin combination treatment[15]. To the best of our knowledge, 4 cases of TEN due to pemetrexed have been reported thus far: 1 due to pemetrexed alone, 1 related to pemetrexed plus carboplatin, and the other 2 related to pemetrexed plus cisplatin. The mucocutaneous disorder occurs between 2 days after the first cycle and 15 days after the second cycle of drug administration. Pemetrexed seems to be the most likely cause for our TEN case. Although our patient received gefitinib after AP chemotherapy, TEN occurred at the expected time and the patient did not develop mucocutaneous disorder after readministration of another EGFR-TKI, which supports pemetrexed as the initiator.

Although there is no report of EGFR-TKI-induced TEN thus far, gefitinib could not be ruled out for the cause of this case as EGFR-TKIs alter keratinocyte proliferation, differentiation, migration, and attachment, and cutaneous toxicity occurs in more than 50% of patients. Meanwhile, TEN occurring after 8 days of gefitinib administration has also increased the suspicion of gefitinib as the initiator. Another possible mechanism may be the synergistic effect on dermal toxicity for pemetrexed and gefitinib combination therapy. The basic skin toxicity of EGFR-TKIs may facilitate the occurrence of TEN induced by pemetrexed. Meanwhile, is there any possibility for the enhancement of EGFR-TKI-induced mucocutaneous disorder based on the alternation of folic acid metabolism of epithelial cells by pemetrexed? It is still unknown.

In summary, we report this case with the intent to further understand the potential rare mucocutaneous adverse effects of AP with gefitinib combination therapy. This case report also warns of the possibility of gefitinib as a potential initiator agent of TEN.