merkel cell carcinoma ( mcc ) is a rare and aggressive tumor of the skin described the first time by toker , in 1972   as a trabecular carcinoma of the skin , suggesting the origin from the cells of the sweat glands , with a later ultrastructural demonstration of neurosecretory granules that places the neoplasm from the merkel cells . at the beginning of the 1980s , other authors contributed to the discussion on the suitability of the term suggested by toker , introducing a great variety of alternative names (  primitive small cell carcinoma of the skin ,   malignant merkel cell carcinoma , murky cell carcinoma ,   merkeloma  ) [ 38 ] . finally , histochemical and histogenetic studies coined the term  neuroendocrine carcinoma of the skin  for this neoplasm placing it , therefore , in the large family of apudomas [ 916 ] , even if the true origin of the tumor from merkel cell has not been proved definitively . it was also postulated the derivation of merkel cell from the neural crest , the separation from the cells of schwann , and the following migration from mesenchyma to epidermis as prolongation of the sensitive nerves of the derma . mcc is currently considered deriving from an epithelial totipotent cell able to differentiate it both in neuroendocrine way , and as cheratinocita . the presence of transitional cells similar both to the cheratinocytis and merkel cells gives support to this theory . the nearby contact with sensitive fibers would make to suppose a role of merkel cell in the process of transition for some nervous stimulus ; an influence is also possible on the secretion of neuropeptides as paracrine regulators on the near structures of the epidermis and adnexa . our observation of a consistent number of cases of mcc has induced us to a review of the literature in order to optimize the diagnostic and therapeutic approach to this tumor , and to emphasize management problems secondary to a cultural limitations that considers in our country mcc like a cancer of little interest with a negative influence in terms of cost and survival . at the rare hormonal tumors group , department of general surgery of cremona hospital , in the last 21 years we have observed 48 patients suffering from mcc in different stages of disease : stage i 28.2% , stage ii 8.6% , stage iii 26% , and stage iv 37% of cases . most of the observed patients came from other institutions as a request for second opinion ( at least 2/3 ) , and for this reason the analysis of data can not be homogeneous ( table 1 ) . in order to stage the disease we have preferred to use the previous staging system from american joint committee on cancer ( ajcc ) 2005 because more simple to use , and because the greatest part of the oldest literature refers to this . there were 26 male ( 54.1% ) and 22 female ( 45.8% ) patients with slight male predominance . in our series mcc affects most frequently elderly patients with a mean age of 70.1 for male , and 71.2 for female ( male plus female equal to 70.6 , range from 52 to 95 years ) . mcc has been observed as a nodule of the skin in most of the cases . the extremities ( 40% of cases ) were the most common site of incidence : follow unknown primary site ( 31% ) , head and neck ( 19% ) , buttock ( 8% ) , and trunk ( 1% ) . half of cases had lesions with diameter < 2  cm , and the other diameter equal to 2  cm or more , with a mean of 2.42  cm , and range from 0.5 to 8  cm . about proliferation cell index ( ki67 , mib1 clone ) , we have separated the series in three different groups ( ki67 1030% , ki67 3050% , and ki67 > 50% ) in which percentage were 13.6% for the group 1 , 22.7% for group 2 , and 63.6% for group 3 ( range from 22% to 90% ) . the group with the most elevated cell proliferation is prevailing , and this confirms that mcc is a particularly aggressive tumor . in our series we have observed 3 patients with associated rheumatoid arthritis , 3 with hepatitis virus c related , 1 transplanted , 1 with kaposi sarcoma , and 4 patients with a personal history of tumor ( 1 non - hodgkin lymphoma and 3 carcinomas ) . in 1 case we have observed mcc associated with squamous - cell carcinoma growing together . about unknown primary site , we observed 15 patients ( 31% ) : 6 with lesion situated in the groin ( 40% ) , 5 in the buttock ( 33% ) , and in 1 case lesions were situated in axilla , thigh , vestibule of nose , and parotid gland , respectively . role of surgery was confirmed as fundamental for treatment of mcc , above all in early stage . in our series all the patients received surgical approach always : as radical and curative method in early stage , or as debulking for local relapse in advanced stages . due to the different origin of patients , surgery was associated with other therapies : radiotherapy ( 12.5% ) , chemotherapy ( 10.4% ) , somatostatin analogues ( 8.3% ) , or more treatments together , as radiotherapy plus somatostatin analogues ( 8.3% ) , chemotherapy plus somatostatin analogues ( 6.2% ) , and radiotherapy plus chemotherapy plus somatostatin analogues ( 6.2% ) , radiotherapy plus chemotherapy ( 2% ) . in only 4% of cases other treatments were considered , as receptor radionuclide therapy ,  interferon ( ifn ) , and imiquimod . this tumor most frequently affects elderly patients over the age of sixty ( range 795 ) , in 78.6% of cases , with a preference for women ( m  :  f = 1  :  3 ) [ 22 , 23 ] ; mcc is most common in caucasian populations , but occasionally is also present among blacks and polynesians . the most common site of the tumor is the skin of the head and neck ( 50% ) ; in 40% of cases extremities are affected , and in 10% trunk and mucosa . cases have also been reported of multiple sites of the disease [ 15 , 23 ] . the markers normally expressed by this tumour are neuron - specific enolase ( nse ) , chromogranins , and synaptophysin . cytoplasmatic granules can be rich of vasoactive intestinal polypeptide ( vip ) , and of met - encephalin . the neoplasm is typically presented as an isolated , raised or flat lesion , red - purplish in colour , with a shiny surface occasionally associated with nearby telangiectasias . the epidermis may be intact or ulcerated the size of the neoplasm can vary greatly , up to 15  cm in diameter , with an average of 3  cm at presentation .   in early stage mcc does n't present specific characters , so that the differential diagnosis can result difficult : in fact mcc can be confused with the baso or spinocellular carcinoma , the pyogenic granuloma , the cheratoacantoma , the melanoma , the cutaneous linfoma , cutaneous metastasis from anaplastic carcinoma , carcinoid tumors , retinoblastoma , sarcoma of ewing , and neuroblastoma . a high incidence of the tumor ( over 600 cases ) was reported in transplanted patients with a mean of 53 years ( range 3378 ) . mcc was observed after 5286 months from transplant ( average 91.5 ) with characteristics of greater aggressiveness probably secondary to the immunosuppression of the patient [ 3032 ] . the immunosuppressive situation could be the cause of metastatic mcc also in an hiv patient . in our series 3 cases reported of rheumatoid arthritis associated with mcc could be secondary to immunosuppression . since rheumatoid arthritis is considered an autoimmune disease , it is possible a predisposition to mcc among elderly patients with immune defenses reduced because of the prolonged use of steroid molecules . the staging of mcc considers a whole - body ct spiral scan because of the frequent high - proliferation index and poor differentiation of the tumor , with the aim of identifying metastatic involvement of soft tissues , sometimes associated with lytic bone lesions . positron emission tomography ( f - fdg - pet - ct ) is an highly useful whole - body - staging method compared to conventional imaging methods , also when used as a single procedure [ 36 , 37 ] . octreoscan , using a labelled analogue of somatostatin ( in - pentetreotide ) , is still considered an highly sensitive method also when compared with other conventional imaging techniques . laboratory diagnosis considers the plasmatic dosage of chromogranin a and nse , more specific in posttreatment followup rather than during the stage of the tumor . patients affected by mcc can be classified using the last classification ajcc 2010 , more online with other skin malignancies , although more complicated to use . because of this , the literature often refers to the previous staging system from ajcc 2005 , more simple to use , but making comparison is difficult with newer studies that consider the last classification . for this reason , we preferred to refer to the classification ajcc 2005 in order to give more homogeneity to our older cases staged by this classification ( table 2 ) . in stage i and ii , surgical is the treatment of choice represented by the excision of the primitive lesion [ 15 , 4144 ] . in order to avoid local recurrence , an adequate resection margin of at least 2  cm a more wide excision provides a significant reduction in local recurrence rate by increasing the margin from 1 to 3  cm [ 15 , 47 , 48 ] . in our series of 8 cases from other institutions , a wide excision was not considered after histological examination causing a local relapse to distance . tumor size > 1  cm was found to be a poor prognostic factor , and 2  cm can be a significant cut off for poor prognosis [ 34 , 40 ] . for these reasons , and also in relationship with our experience , we suggest that sentinel lymph node biopsy ( slnb ) should always be considered . slnb detects mcc spread in one - third of patients understaged , and those who did not receive treatment that involved nodes ; this method identifies occult nodal metastases in 29% of patients with localized mcc . about this method , in our series we have observed a higher sensibility using f - scan rather than tc - scan . finally , in absence of slnb , adjuvant radiotherapy to the primary and nodal region should be delivered . this choice is associated with a reduced risk of local recurrence [ 53 , 54 ] . radiant treatment ( 4060  gy ) should follow surgical excision   in order to prevent the progression of disease in stage i and ii with development of lymph nodal metastases in 4073% of the cases and local relapse in 2360% of the cases , with a disease free survival only up to 8 months . in these cases surgical debulking can be associated with more sustained radiant regimes with survival in approximately 60% of cases , and a disease free survival from 3 to 30 months ( average 8 months ) . the largest series from seer data shows median survival for adjuvant radiotherapy up to 63 months compared with median survival without radiant therapy up to 45 months . radiotherapy is associated with an increased survival particularly for primary lesions greater than 2  cm . in another series from canada and australia , combined surgery and radiotherapy improves both loco - regional control and disease - free survival . on the contrary , adjuvant chemotherapy we have observed 10 cases from other institutions with local relapse due to the absence of prior radiant therapy that were in need of surgical debulking . radiotherapy as primary treatment is essential in cases of locally advanced tumors or invasion of critical structures with difficult resectability . it was reported , a study on 3 cases with complete response after primary radiotherapy , and the absence of local relapses for up to 3 years . in a retrospective study there were no statistical differences and disease - free survival between two different groups ( radiotherapy alone versus conventional therapy ) . in a series of 50 patients , lymph node radiation alone in metastatic nodes has resulted in a great percentage of local control compared with lymphadenectomy alone on both microscopic and palpable nodes , and no differences for overall survival . chemotherapy treatment considers a wide range of molecules used both in monotherapy and in combination , as etoposide , carbo / cisplatin , doxorubicin , dacarbazine , vincristine , cyclophosphamide , and methotrexate . chemotherapy shows a surprising objective response at beginning of treatment ( 61% ) with a progressive drop during a second ( 45% ) , and a third line of therapy ( 20% )   with a very short duration , from 3.5 to 12 months [ 64 , 65 ] . in the trog study , synchronous carboplatin / etoposide plus radiation have been achieved high levels of locoregional control and survival , in contrast with a retrospective study from the same group . local infiltration of -2b ifn , tumor necrosis factor ( tnf ) , hyperthermia in association with low doses of radiotherapy , or radiotherapy with tnf- , ifn  , and melphalan , have showed occasional remissions with relatively long , but anecdotal , disease - free survival . among the immunomodulatory molecules , imiquimod combined with radiotherapy has suggested the possible use effective with a complete response up to 7 months in a case reported of mcc of the head . about somatostatin analogues treatment , there is a few number of reports in literature . in one case of metastatic mcc from our series , the treatment with octreotide showed an immediate objective response with a moderate dose ( 1  mg / day subcutis ) , in absence of significant side effects and survival over 10 months from the start of therapy ; moreover , in 2 cases observed , octreoscan was been able to determine a partial regression of local relapse , even before starting treatment with somatostatin analogues . in another case reported of local advanced and recurrent mcc of the head , treatment with lanreotide at the dose of 15  mg intramuscular every two weeks showed a favorable course after 17 months from the start of therapy . in other case of metastatic mcc reported treated with octreotide has been observed a favorable course up to 3 years with a good quality of life . somatostatin analogues can play a role in the therapy of metastatic mcc , in alternative to chemotherapy , limited to selected cases with mild aggressive disease , and with significant density in vivo for somatostatin receptors . in our series , somatostatin analogues represent a wide slice in the treatment of mcc ( 29% of cases ) in different modalities of association . receptor radionuclide therapy is reported only in one case after relapse from mcc in a elderly patient , with a good response . in our series we have treated only one elderly patient suffering from mcc with lu - dotatate ( 1.5  gbq ) , already submitted to other therapies , and probably in a too advanced stage to consent a response . the incidence in usa has increased threefold and became the second common cause of nonmelanoma skin cancer death . the most common features were used to create a simple acronym : aeiou ( asymptomatic / lack of tenderness , expanding rapidly <3 months , immunosuppression , older than 50 , and location on an ultraviolet - exposed site ) . these criteria can allow as a clue in the diagnosis of mcc , with three or more criteria in 89% of cases in a series of 195 patients . in relation to the current knowledge , the correct management for mcc is the aggressive and radical excision of the lesion in its early stage in order to reduce the rate of relapse , and to improve survival . outcome depends mainly on the early and wide excision , and on sequential radiotherapy , in order to avoid local relapse and/or progressive disease , as also confirmed from our personal observations . in this way , the role of slnb is in our opinion fundamental also in stage i , given that size of lesion may not match the malignancy of the tumor . about chemotherapy , its role should be revisited with newer molecules including targeted agents . in this way , coexpression of kit in a high percentage of mcc suggests an important role in merkel cell transformation , so that the potential use of kit kinase inhibitor - based therapies , as imatinib , should be also considered in metastatic mcc [ 81 , 82 ] . the finding that polyomavirus ( mcpyv ) is frequently present in mcc ( 6985% of cases ) has been confirmed by several independent groups . the integration of this virus before the tumor development supports a role for polyomavirus in tumorigenesis process . in this way , prophylaxis with vaccination against merkel cell polyomavirus should be possible in high - risk patients , in the future . in our opinion the great number of patients in our case series can suggest the consideration that the mcc , although considered a low - tumor incidence , it is not so quite rare . looking at the cases with advanced disease from other institutions , it is evident that the large number of patients to whom it was not proposed or wide surgical excision , or radiotherapy , or both : thus clearly demonstrates the lack of expertise in the management of mcc , and because of the high aggressiveness of mcc , it is subsequently assumed the highest rate of local relapses or metastastic disease . we have observed several cases where the choice to remove the primary lesion was made after so many months from the onset of disease , and several cases with long latency between histological diagnosis and subsequent treatment decisions . in one case there was not even the histological examination of the primary lesion and in another even that of relapse . these observations are once again due to the lack of experience for mcc , but also towards a management too superficial in regard to a tumor too underestimated . chemotherapy should be considered at present the standard treatment in advanced disease : but in our series we can observe the frequent use of different molecules ( particularly somatostatin analogues ) for patients from other institutions , which can not be considered appropriate to control metastatic disease and even related symptoms . the fifth point relates to the lack of diagnostic and therapeutic protocols , a problem affecting almost the entire management of rare tumors . this question also involves the management of mcc and is highlighted by the large number of second opinion requests . the lack of protocols is partly covered by some guidelines ( in italy by the guidelines from rol , rete oncologica lombarda ) in many cases not known and in many other cases disregarded . the sixth and final point concerns the last classification of mcc , which in our opinion is too complex with the result of a difficult staging , and the consequence of a therapeutic approach to disease not always easy , another reason that makes us still choose the previous staging system from ajcc 2005 . all these reasons lead clearly to the impossibility having concrete data of survival . in our series the survival rate was calculated considering the distance in time between first diagnosis and our last control of patient . since the majority of patients we have considered as second opinion in different stages of disease , and the greatest part of these in advanced disease ( stage iv ) or in presence of local relapse furthermore , in a significant part of cases from other institutions we were not able to get further information about the progress of disease . about mcc from unknown primary site ( 31% in our series ) , survival appears very low ( average 24 months ) but conditioned by a very significant late diagnosis up to 18 months , and few treatment options . finally , we believe that the comprehensive evaluation of the patient integrated with imaging and laboratory parameters can allow to find the right direction for a balanced choice of therapy and not always immediately easy . it will nevertheless require a cultural change in the approach of mcc as in case of other rare tumors ( figures 1 and 2 ) [ 50 , 86 ] .
merkel cell carcinoma ( mcc ) is a rare and aggressive neuroendocrine tumor of the skin . 
 fourty - eight patients with mcc were observed at the rare hormonal tumors group of cremona hospital , 15 of these with unknown primary site . due to rarity of merkel cell carcinoma , 
 clinical experience is generally limited . 
 data from our series confirm the current recommendations . 
 wide surgical excision must be associated with radiotherapy also in early stages in order to avoid local relapse and the rapid progression of disease . in advanced stages chemotherapy 
 is the standard despite the short duration of responses and poor quality of life . 
 the data of our series , characterized by a high demand for second opinion , offer some insight about the real rarity of the tumor , the difficulty of managing of disease in our country secondary to a wrong cultural approach to the problem , the indiscriminate use of molecules unnecessary and often expensive , the lack of protocols , and the presence of guidelines often ignored . 
 this results in very poor survival associated with a very low quality of life , requiring to find the right direction towards a correct management of disease .