a 42-year - old woman diagnosed with stage iv nsclc ( adenocarcinoma ) was admitted to our hospital in august 2013 and given an ap regimen ( pemetrexed 500 mg / m on day 1 , cisplatin 75 mg / m on days 1 to 3 , repeated every 3 weeks ) as initial chemotherapy on august 2nd , 2013 .
several days later , her egfr genetic test results demonstrated an exon 19 mutation ( l747-t751>p ) ; thus , she started taking gefitinib ( 250 mg once daily ) on august 15th . on august 23th , which was 21 days after ap chemotherapy and 8 days after gefitinib treatment ,
the patient suddenly developed a widespread eruption including acne - like rash on the face , erythema papules on the trunk and limbs , oral ulcer , and conjunctivitis ( figure 1a and 1b ) , followed by a fever of 39c .
the rash gradually increased and aggravated , accompanied with blisters , pruritus , and ulceration .
gefitinib was immediately stopped , and imipenem , amikacin , and fluconazole were administered intravenously as prophylaxis , and diphenhydramine and loratadine were given as an anti - allergy treatment .
on the 13th day , the patient 's condition deteriorated further with a fever of 42c , fused mucocutaneous rash as well as diffuse vesicles and bullae ( figure 1c and 1d ) , which coalesced and then sloughed , presenting a scalded appearance .
a positive nikolsky sign was present on her back and feet ( figure 1e and 1f ) .
after consulting dermatology doctors , the patient was diagnosed with ten and transferred to the dermatology department at the second affiliated hospital of sun yat - sen university for further treatment .
routine laboratory testing showed a white blood cell ( wbc ) count of 6.26  10/l [ reference value : ( 3.69 - 9.16 )  10/l ] , neutrophil ( neu ) proportion of 73.1% ( reference : 50%-70% ) , and c - reactive protein ( crp ) level of 16.36 mg / l ( reference : 0 - 8.2 mg / l ) ; both the mycoplasma pneumoniae igm antibody and mac strains were negative .
no suspicious fungus was found in the oral swab examination , nor did bacteria grow in the skin secretion culture .
immunosuppressive treatment was started with 100 mg methylprednisolone ( daily injection ) for 9 days and intravenous immunoglobulin ( 20 g / day ) for 5 days , followed by 10 g / day for 5 days , accompanied with imipenem and teicoplanin for anti - infection and other supportive treatment .
this treatment led to a recurrence of the rash and the mucosal lesions , reepithelization of the denuded skin ( figure 2 ) , and improvement of the patient 's general condition within 40 days .
a chest computed tomography ( ct ) scan and brain magnetic resonance imaging ( mri ) showed partial remission after treatment .
the combination of ap and gefitinib was suspended ; accordingly , the patient began treatment with icotinib ( another egfr - tki made in china ) after recovery , without exfoliative dermatitis or other similar toxicities .
stable disease was later achieved . on the 8th day after gefitinib treatment , diffuse erythema papules
were observed on the trunk ( a ) and palms ( b ) ; on the 13th day , fused skin rash and diffuse vesicles and bullae ( c ) as well as erosive lip mucosa ( d ) were observed ; on the 16th day , fused and sloughed systematic herpes ( e ) and plantar blister ( f ) were observed .
the systematic rash gradually crusted and desquamated ( a and b ) ; reepithelization of the denuded skin and ultimate healing were observed ( c - e ) .
most ten cases result from hypersensitive reaction to drugs , and sulfonamides , pyrazolones , barbiturates , and antiepileptics are the most frequent triggers .
ten usually occurs between 7 days to 8 weeks after drug administration . upon readministration of the implicated drugs
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- ) , and granzyme b / perforin are important in the pathogenesis of ten .
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 . 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 , .
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 .
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 .
an effec - tive 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 . 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 and another case of exfoliative dermatitis associated with cyclophosphamide - cisplatin combination treatment . 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 .
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 .
 toxic epidermal necrolysis ( ten ) is a rare acute life - threatening mucocutaneous disorder that is mostly drug - related ( 80%-95% ) . 
 it is clinically characterized as a widespread sloughing of the skin and mucosa . 
 ap regimen ( pemetrexed plus cisplatin ) has been the preferred first - line chemotherapy for metastatic non - squamous non - small cell lung cancer ( nsclc ) . 
 gefitinib , a small - molecule epidermal growth factor receptor ( egfr ) tyrosine kinase inhibitor ( tki ) , has already been recommended as a first - line treatment in egfr - mutant metastatic nsclc . 
 we report rare presentation of ten involving adverse effects of ap and gefitinib combination treatment in a 42-year - old woman diagnosed with metastatic nsclc harboring an egfr mutation . on the 21st day after administration of the first cycle of ap regimen and the 8th day after the initiation of gefitinib treatment 
 , she developed an acne - like rash , oral ulcer , and conjunctivitis , which later became blisters and ultimately denuded . 
 the characteristic clinical courses were decisive for the diagnosis of ten . 
 treatment with systemic steroids and immunoglobulin as well as supportive treatment led to an improvement of her general condition and a remarkable recovery . 
Case Report
Discussion