during the last years tyrosine kinase inhibitors ( tkis ) have changed the natural history of metastatic non - small - cell lung cancer ( nsclc ) harboring epidermal growth factor receptor ( egfr ) mutations .
eight important studies were conducted to evaluate the efficacy and tolerability of tkis on advanced nsclc in comparison with standard platinum - based chemotherapy .
not surprisingly , the use of tkis was correlated with a higher response rate , a longer progression - free survival and a better quality of life in patients with advanced nsclc activating egfr mutation .
the iressa pan - asia study ( ipass ) , which enrolled 1,217 patients , was the largest trial in which patients were randomized to receive gefitinib or standard chemotherapy , and in the group of tkis therapy the primary endpoints were reached obtaining a statistically significantly higher response rate , a longer progression - free survival and better symptom control .
similar results were reported by first - signal and by west japan thoracic oncology group ( wjtog 3405 ) studies . the north - east japan study group ( nej002 ) trial
was stopped early because gefitinib showed a significantly higher progression - free survival in comparison with standard chemotherapy in patients with advanced lung adenocarcinoma activating egfr mutation .
impressive results were also reported with the use of other tkis such as erlotinib or afatinib versus chemotherapy in patients carrying the same egfr mutations .
better responses were observed in patients with mutations in exons 1821 of the tyrosine kinase domain of egfr .
however , egfr gene mutations were also identified in small - cell lung cancer ( sclc ) [ 3 , 4 ] and in large - cell neuroendocrine carcinoma ( lcnec ) of the lung .
lcnec is a high - grade carcinoma ( > 10 mitoses/2 mm ) belonging to the neuroendocrine tumors of the lung .
it represents about 3% of all pulmonary malignancies and is characterized by neuroendocrine cytologic features ( formation of rosettes , trabeculae and perilobular palisading pattern ) and markers ( neuron - specific enolase , cd56 , synaptophysin , chromogranin and leu7 ) .
in fact , the cytologic and biologic features of lcnec are different from those of large - cell carcinoma .
the molecular alterations that are commonly found in lcnec are p53 , bcl-2 overexpression and rb mutation .
to our knowledge , few cases of lcnec with egfr gene mutation have been described up to now , and only one case was treated with gefitinib , with a good response [ 7 , 8 ] .
a 47-year - old caucasian woman with no family history of neoplastic diseases and no comorbidities was examined by a general practitioner after the appearance of back pain unresponsive to usual non - steroidal anti - inflammatory drugs .
standard chest x - ray showed a left lung perihilar lesion , probably suggesting pneumonia . as a consequence ,
thus , after 2 weeks , chest x - ray was repeated and showed persistence and stability of the left lung lesion .
about 1 month later , the patient came for the first time to our attention for appearance of vomiting , dyspnea , fatigue and abdominal pain ( visual analog scale 7 ) . abdominal physical examination revealed a painful hepatomegaly .
she underwent a total body computed tomography ( ct ) scan that showed multiple focal liver lesions , solid left lung tissue and multiple secondary brain lesions ( two left frontal cerebral lesions , one right parietal lesion and two cerebellar lesions ) ( fig .
1 ) . as a result , a liver biopsy was performed . since all investigated tumor markers ( carcinoembryonic antigen , carbohydrate antigen 19 - 9 , carbohydrate antigen 125 , neuron - specific enolase , glycoprotein hormones alpha polypeptide )
were increased , it was not possible to identify the primary site of localization of the tumor and to reach a definitive diagnosis . given the rapidly progressive impairment of her clinical conditions and performance status , we administered an empirically not targeted chemotherapy with gemcitabine 1,000 mg / m die 1 and oxaliplatin 100 mg / m die 2 q 2 weeks although we did not yet have definitive histopathological results .
although the sample was poor , the diagnosis was evocative of lung adenocarcinoma ( ttf-1 positive , cytokeratin 7 positive ) .
however , since a further deterioration of her clinical condition was observed , a biopsy was repeated in order to have an additional sample for molecular analysis .
therefore , we started tki therapy and gefitinib was administered at 250 mg p.o . once a day .
the patient reports a good quality of life and no relevant side effects ( skin toxicity grade 1 ) have been registered .
a restaging total body ct scan showed a significant improvement of disease , with a partial response > 50% .
particularly , the brain ct scan showed a significantly reduced volume of the lesions ( valuable only 2/5 lesions ) and complete resolution of edema ( fig .
lcnec is a rare tumor which is usually treated with cisplatin - based chemotherapy as sclc   as it shares many characteristics with it . usually , the administration of tkis is considered only for advanced lung adenocarcinoma because the most important studies demonstrating higher activity of tki , in comparison with standard platinum - based chemotherapy , were conducted in patients affected by nsclc with egfr mutations .
some features are associated with a higher possibility that egfr mutations are present in nsclc .
the research of egfr mutations is not performed routinely on lcnec since this mutation is not commonly present in this subtype .
the prognosis of this tumor with standard chemotherapy is poor , thus we need to evaluate alternative diagnostic strategies such as the investigation of egfr mutational status in order to explore new effective treatments .
we report the case of a patient affected by lcnec carrying all of the predictive characteristics associated with egfr mutation ( caucasian , female , never - smoker ) .
when the patient came to our attention she was very symptomatic , so in an attempt to reach a better and faster response , we decided to test egfr mutational status . strikingly , the mutation was present , and we were allowed to administered gefitinib , obtaining an impressive and objective response .
therefore , we suggest the research of egfr mutations also in patients with lcnec to offer them one more therapeutic option .
 large - cell neuroendocrine carcinoma ( lcnec ) of the lung is a high - grade carcinoma belonging to the neuroendocrine tumors of the lung and is different from typical lung large - cell carcinoma . 
 it represents about 3% of all pulmonary malignancies and is characterized by neuroendocrine cytologic features . 
 the treatment usually is platinum - based chemotherapy , however the outcome remains poor . 
 therefore new therapeutic options are needed . 
 tyrosine kinase inhibitors have demonstrated greater efficacy and better tolerability than standard chemotherapy in non - small - cell lung cancer harboring epidermal growth factor receptor ( egfr ) mutations . 
 egfr gene mutations were also rarely identified in lcnec . 
 we report a patient with lung lcnec activating egfr mutations who showed an impressive response to gefitinib . 
Introduction
Case Presentation
Discussion
Disclosure Statement