merkel cell carcinoma ( mcc ) is a rare neuroendocrine carcinoma of the skin that preferentially occurs in sun - exposed areas in elderly patients . the age - adjusted incidence of this disease increased from 0.15 per 100,000 persons in 1986 to 0.44 per 100,000 persons in 2001 based on data from the u.s . surveillance , epidemiology , and end results ( seer ) program ( 1 ) . a strain of polyomavirus , merkel cell polyomavirus , is known to be involved in the carcinogenesis of mcc in some cases ( 2 ) . mcc has an aggressive natural history , with the majority of patients developing locoregional recurrence and distant metastases within two years from curative - intent surgical resection ( 1 ) . the role of chemotherapy for mcc remains controversial , as the rare nature of mcc has made it difficult to perform prospective randomized controlled trials in patients with mcc . anthracycline - based and platinum - based chemotherapies have been used empirically because these agents are effective against another neuroendocrine carcinoma , small cell lung cancer . the overall response rate of a combination of cyclophosphamide , doxorubicin , and vincristine in patients with advanced mcc was 76% , and that of cisplatin and etoposide was 60% ( 3 ) . however , no data on second - line or salvage chemotherapy have been reported . despite the high response rates of the first - line chemotherapy , the median overall survival period was 9 months , with a 2-year survival rate as low as 20% ( 4 - 6 ) , urging the establishment of second - line chemotherapy . we herein report a patient with platinum - refractory mcc who was successful treated with amrubicin . a 73-year - old man was referred to our institution because of back pain , fatigue , and a weight loss of 11 kg over the previous 3 months . ten years prior to presentation , he underwent surgical treatment for stage ib ( pt1n0m0 ) mcc in his left forearm at another hospital . one year after the surgery , the mcc relapsed to the left neck lymph nodes . he received chemotherapy with carboplatin at a fixed dose of 300 mg with irregular intervals , for a total of 10 cycles in 5 years , which led to the complete remission of the disease . he remained in remission for four years until three months prior to the presently reported admission . on admission , his abdomen was soft and flat , and no tenderness was noted on a physical examination . there were no signs of metastatic lesions in the skin except for a scar on the left forearm . laboratory examinations revealed normal findings except for a decreased hemoglobin concentration of 8.3 g / dl and an elevated neuron - specific enolase ( nse ) level of 212 ng / ml , with normal carcinoembryonic antigen ( cea ) and ca 19 - 9 values . no antibodies to human immunodeficiency virus were detected . a computed tomography ( ct ) scan revealed a conglomerated lesion at the abdominal lymph nodes that was 120 mm in size and located adjacent to the pancreatic tail , with smaller masses in the abdomen and retroperitoneal space . an [ f ] fluorodeoxyglucose positron emission tomography ( fdg - pet ) scan showed enhanced uptake in all the lesions and the absence of metastases in other organs . endoscopic ultrasound - guided fine - needle aspiration biopsy was performed for a histological examination , showing tumor nests of small round cells with scanty cytoplasm , round - to - oval nuclei , finely dispersed chromatin , and inconspicuous nucleoli ( fig . the tumor cells were diffusely positive for cytokeratin 20 ( ck 20 ) in a dot - like paranuclear pattern ( fig . 1b ) , in addition to being positive for neuroendocrine markers , including the cluster of differentiation ( cd ) 56 ( neural cell adhesion molecule ) , nse , and chromogranin a ( fig . in contrast , the tumor cells were negative for thyroid transcription factor 1 ( ttf-1 ) ( fig . the patient tested negative for polyomavirus in an immunohistochemistry study ( data not shown ) . fine - needle aspiration biopsy of the abdominal mass revealed tumor nests consisting of small round tumor cells with scanty cytoplasm , round - to - oval nuclei , finely dispersed chromatin , and inconspicuous nucleoli ( a : hematoxylin and eosin staining , original magnification , 20 ) . an immunohistochemical evaluation showed the small round tumor cells to exhibit membranous and paranuclear dot - like staining with cytokeratin 20 ( b : 20 ) as well as neuroendocrine markers consisting of chromogranin a ( c : 20 ) , cd56 , and synptophysin ( data not shown ) and negative staining for thyroid transcription factor 1 ( d : 20 ) , indicating a neuroendocrine carcinoma . the patient received one cycle of carboplatin ( at a dose targeting an area under the curve of 5 , which was calculated by the calvert formula ( 7 ) , on day 1 ) plus etoposide ( 100 mg / m on days 1 - 3 ) . shortly after the chemotherapy , however , the patient complained of worsened back and abdominal pain . a second ct scan obtained at this time showed further enlargement of the abdominal lesion to a size of 144 mm ( fig . 2a ) . as the registered regimen in our hospital allowed the use of amrubicin for advanced neuroendocrine carcinoma in general in the second - line setting , the patient , who had provided his written informed consent to undergo this therapy , was treated with salvage chemotherapy consisting of amrubicin at a dose of 40 mg / m on days 1 - 3 every 3 to 4 weeks , depending on the adverse events . ct scans of the abdomen just before the start of amrubicin administration ( a ) and at the completion of two cycles of amrubicin treatment ( b ) showing tumor shrinkage from a maximum diameter of 144 down to 92 mm . the tumor remained progression - free for 9 months . the serum nse levels returned to normal , and a partial response was achieved after two cycles had been administered ( fig . a total of nine cycles of amrubicin were administered over nine months until the tumor progressed . the adverse events were all manageable and included grade 3 neutropenia , grade 3 thrombocytopenia , grade 4 anemia , grade 1 nausea and anorexia , and grade 2 alopecia throughout all of the treatment cycles . he died of the disease 2 months thereafter , which was 11 months after the initiation of amrubicin and 11 years after the resection of the primary site . the autopsy showed multiple metastases to the liver , gall bladder , left adrenal gland , pancreas , para - aortic lymph nodes , peritoneum , and retroperitoneal spaces , but no involvement was observed in the lung or gastrointestinal tract . the absence of a lesion in the thoracic cavity was demonstrated by ct , pet / ct , and autopsy , excluding a newly developed small cell lung cancer lesion . in addition to 10 cycles of first - line carboplatin treatment over 5 years , the re - administration of carboplatin together with etoposide just before the start of amrubicin treatment did not prevent disease progression , confirming the platinum - refractory nature of the patient 's disease . amrubicin is a synthesized anthracycline derivative that has greater antitumor activity than doxorubicin in human tumor xenograft models ( 8) . a phase ii trial of amrubicin in previously untreated patients with extensive small cell lung cancer showed an overall response rate of 76% and a median survival time of 11.7 months ( 9 ) . in second - line settings , amrubicin yielded response rates of 44 - 53% and median survival times of 9.3 - 11.6 months in patients with sensitive relapse of small cell lung cancer , and response rates of 17 - 50% and median survival times of 5.3 - 10.3 months in patients with the refractory relapse of small cell lung cancer ( 10 - 12 ) . given that both mcc and small cell lung cancer are neuroendocrine carcinomas , we considered that amrubicin might be useful as a second - line chemotherapy , even for patients with advanced mcc , as well as for those with small cell lung cancer . consequently , amrubicin yielded a rapid and durable tumor response with remarkable symptom relief . to our knowledge , this is the first report to show the potential effectiveness of amrubicin as a salvage chemotherapy for platinum - refractory advanced mcc . although it might be difficult to perform large - scale clinical trials because of the rarity of this disease
merkel cell carcinoma ( mcc ) is a rare neuroendocrine carcinoma of the skin with an aggressive clinical course . 
 although anthracycline- and platinum - based regimens are empirically used as first - line treatments for metastatic or unresectable cases , no salvage therapy has been established . a 73-year - old man with platinum - refractory recurrent 
 mcc was treated with amrubicin . 
 the symptoms improved soon , and a partial response was achieved . 
 a total of nine cycles of amrubicin were administered in nine months with manageable adverse events until disease progression was finally observed . 
 the present findings suggest the potential of amrubicin monotherapy as a second - line therapy for patients with advanced / recurrent mcc .