since it was first reported by chang et al , in 1994 , endoscopic ultrasound ( eus)-guided fine - needle aspiration ( fna ) of the pancreas has become a popular technique for the diagnosis and staging of cystic and solid lesions of the pancreas because it is relatively safe , accurate , and cost - effective . thus , this diagnostic modality has become essential in the management of patients with symptomatic or incidentally discovered pancreatic masses . eus - guided fna usually serves to confirm the diagnosis of a primary pancreatic malignancy . therefore , it is not surprising that most reports focus on the more common primary pancreatic cystic and solid neoplasms , with little attention given to metastatic lesions . in the literature , metastases comprise at least 2% of pancreatic tumors . these metastases arise from a diverse spectrum of malignancies , including sarcomas , merkel cell carcinoma , squamous cell carcinoma , cardiac rhabdomyosarcoma , ovarian mixed mllerian tumor , melanoma , and phyllodes tumor . in such cases , we review the cases of pancreatic metastases diagnosed by eus - guided fna at our institution in order to characterize the clinico - radiologic features , cytomorphology , results of ancillary studies , and clinical follow - up data of these unusual tumors . during a period of 60 months , between march 2005 and april 2010 , 1172 pancreatic eus - guided fnas were performed at the university of pittsburgh medical center . these cases were identified by searching our institution 's copath computer database for the word pancreas in the final diagnosis of fna biopsies . a case was included if the cytology report contained a diagnosis of metastatic tumor that was confirmed by immunohistochemical ( ihc ) studies or subsequent histologic correlation . the cytomorphology , ihc studies , available clinical information , and histological follow - up were then retrospectively reviewed . fna biopsies were performed by a gastrointestinal physician with specialized training in the endoscopic ultrasound - guided technique . the olympus gf - ue160-al5 radial - array video gastroscope ( olympus imaging america inc . , center valley , pa ) was used in all cases . for each case , immediate on - site adequacy assessment and interpretation by a cytopathologist allowed for appropriate triage of the specimen . this involved examination of a diff - quik ( protocol hema 3 , fisher scientific , kalamazoo , mi ) stained smear from each fna pass . additional material was formalin fixed for a cell block preparation . the number of fna passes varied depending upon the adequacy of the sampled material and patient toleration of the procedure . at the time of final interpretation , papanicolaou and diff - quik stained smears and hematoxylin and eosin ( hande ) stained sections from the formalin - fixed cell block immunohistochemistry ( ihc ) was performed on deparaffinized , formalin - fixed cell block sections using a variety of different antibodies on the ventana benchmark xt system ( ventana medical systems , tucson , az ) . for a large majority of cases , the following immunostains were performed to characterize the cells and rule out a primary neoplasm : ck7 ( clone ov - tl 12/30 , monoclonal antibody ; 1:200 dilution ; dako , carpinteria , ca ) , ck20 ( clone ks20.8 , monoclonal antibody ; 1:50 dilution ; dako , carpinteria , ca ) , ca19 - 9 ( clone 121sle , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) , and cea ( clone tf 3h8 - 1 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . renal cell carcinomas , when suspected , were most often stained with a combination of cd10 ( clone 56c6 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) ; vimentin ( clone v9 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) ; pan - keratin ( clone 80 , monoclonal antibody ; 1:100 ; abcam , cambridge , ma ) ; carbonic anhydrase 9 ( clone n / a , polyclonal antibody ; 1:1000 ; leica , bannockburn , il ) ; and rcc ( clone pn-15 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . small cell and neuroendocrine neoplasms were examined with cd56 ( clone 123c3.d5 , monoclonal antibody ; pre - dilute ; cell marque , rocklin , california ) ; synaptophysin ( clone n / a , polyclonal antibody ; pre - dilute ; cell marque , rocklin , california ) ; and chromogranin ( clone lk2h10 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . all stains were performed according to the standard avidin - biotin - peroxidase complex method . briefly , sections were submitted to heat - induced antigen retrieval in the presence of cc1 ( cell conditioner 1 , ventana medical systems , az , usa ) using an automated tissue immunostainer ( ventana medical systems , az , usa ) , with the appropriate positive and negative controls on the same or an accompanying slide . fna biopsies were performed by a gastrointestinal physician with specialized training in the endoscopic ultrasound - guided technique . the olympus gf - ue160-al5 radial - array video gastroscope ( olympus imaging america inc . , center valley , pa ) was used in all cases . for each case , immediate on - site adequacy assessment and interpretation by a cytopathologist allowed for appropriate triage of the specimen . this involved examination of a diff - quik ( protocol hema 3 , fisher scientific , kalamazoo , mi ) stained smear from each fna pass . additional material was formalin fixed for a cell block preparation . the number of fna passes varied depending upon the adequacy of the sampled material and patient toleration of the procedure . at the time of final interpretation , papanicolaou and diff - quik stained smears and hematoxylin and eosin ( hande ) stained sections from the formalin - fixed cell block were examined and evaluated in conjunction with the results from ancillary studies . immunohistochemistry ( ihc ) was performed on deparaffinized , formalin - fixed cell block sections using a variety of different antibodies on the ventana benchmark xt system ( ventana medical systems , tucson , az ) . for a large majority of cases , the following immunostains were performed to characterize the cells and rule out a primary neoplasm : ck7 ( clone ov - tl 12/30 , monoclonal antibody ; 1:200 dilution ; dako , carpinteria , ca ) , ck20 ( clone ks20.8 , monoclonal antibody ; 1:50 dilution ; dako , carpinteria , ca ) , ca19 - 9 ( clone 121sle , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) , and cea ( clone tf 3h8 - 1 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . renal cell carcinomas , when suspected , were most often stained with a combination of cd10 ( clone 56c6 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) ; vimentin ( clone v9 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) ; pan - keratin ( clone 80 , monoclonal antibody ; 1:100 ; abcam , cambridge , ma ) ; carbonic anhydrase 9 ( clone n / a , polyclonal antibody ; 1:1000 ; leica , bannockburn , il ) ; and rcc ( clone pn-15 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . small cell and neuroendocrine neoplasms were examined with cd56 ( clone 123c3.d5 , monoclonal antibody ; pre - dilute ; cell marque , rocklin , california ) ; synaptophysin ( clone n / a , polyclonal antibody ; pre - dilute ; cell marque , rocklin , california ) ; and chromogranin ( clone lk2h10 , monoclonal antibody ; pre - dilute ; ventana , tucson , az ) . all stains were performed according to the standard avidin - biotin - peroxidase complex method . briefly , sections were submitted to heat - induced antigen retrieval in the presence of cc1 ( cell conditioner 1 , ventana medical systems , az , usa ) using an automated tissue immunostainer ( ventana medical systems , az , usa ) , with the appropriate positive and negative controls on the same or an accompanying slide . of the total 1172 eus - guided fnas of the pancreas , 25 cases ( 2.1% ) of metastases were identified . the average age of the patients was 61 years ( range : 40 - 80 years ) . twenty - one cases ( 84% ) had a previous diagnosis of malignancy of the same type . the mean time between the initial diagnosis of cancer and the development of a pancreatic metastasis was 5.3 years ( range : 0 - 19 years ) . however , in four ( 16% ) cases the eus - guided fnas occurred in patients with no prior diagnosis of malignancy . twenty ( 80% ) of the lesions were solitary , while in five ( 20% ) cases there were multiple lesions . nine ( 36% ) fnas were from the head of the pancreas , six ( 24% ) from the tail , two ( 8% ) from the body , and eight ( 32% ) from an unknown or uncertain location . all cases were confirmed on histological follow - up , ihc stains , and/or clinical follow - up review . the final cytological diagnosis was positive for malignancy in all but two ( 92% ) technically limited cases of conventional renal cell carcinoma . overall , the most common histological type was renal cell carcinoma ( rcc ) , seen in twelve ( 48% ) cases . the other histologic subtypes included malignant melanoma ( 3 cases , 12% ) ; small cell carcinoma ( 3 cases , 12% ) ; and renal leiomyosarcoma , prostatic adenocarcinoma , breast adenocarcinoma , gastric adenocarcinoma , esophageal adenocarcinoma , lung adenocarcinoma , and a non - primary neuroendocrine tumor ( 1 case each ) . the four cases that presented as a mass in the pancreas with no prior history of malignancy included a case of prostatic carcinoma , a small cell carcinoma of the lung , a renal cell carcinoma , and an extrapancreatic neuroendocrine tumor . special stains such as pas , pasd , and mucicarmine were performed in nine ( 36% ) cases . it is well known that primary neoplasms of the pancreas are more common than metastatic tumors . although metastases to the pancreas are rare , our data characterizes the cytomorphological and clinical findings in a large series of patients . our findings demonstrate that metastases to the pancreas frequently present in older patients as a solitary mass , many years after the diagnosis of a primary malignancy . although the majority of lesions were found in the head of the pancreas in our series , they may also be seen in the body and tail as has been described by sellner et al . in a review of 236 rcc resection specimens . in a significant subset ( 16% ) of our cases a pancreatic mass was the first clinically recognized manifestation of an extrapancreatic primary [ figure 1 ] . in two suspicious cases of conventional renal cell carcinoma , material for ancillary studies was inadequate and a diagnosis of  atypical was rendered . these observations illustrate the importance of acquiring material for cell block in cases suspicious for a metastasis to the pancreas . a ) many pleomorphic epithelioid cells with increased nuclear to cytoplasmic ratios are occasionally arranged in an acinar - like formation ( 40 , diff - quik stain ) ; b ) eccentric nuclei with highly prominent macronucleoli , coarsely clumped chromatin , and irregular outlines are highlighted ( 40 , papanicolaou stain ) ; c ) cell block material demonstrates a gland like configuration with prominent nucleoli ( h and e , 20 ) , d ) a psa immunostain is expressed , supporting the diagnosis of metastatic prostatic adenocarcinoma ( 40 , immuno ) in a survey of 4955 adult autopsies , adsay et al . described a rate of metastasis to the pancreas of 3.83% and a significantly different distribution of metastatic neoplasms , with lung and gastrointestinal tumors comprising by far the largest proportion . the study also showed , as might be expected , a higher rate of new diagnoses ( 43% ) . our data demonstrates a similar rate of metastasis ( 2.1% ) , but rcc was the most common metastatic tumor type in our series . this finding is similar to that reported in other fna and resection studies examining metastases to the pancreas . these studies , like ours , may select for tumors with limited spread through the body and/or solitary lesions amenable to resection , as is characteristic of rcc . our data also shows that metastatic rcc may occur many years ( as much as 19 years , according to our data ) after a primary diagnosis.[1618 ] these characteristics of rcc may mimic a primary pancreatic tumor and may explain why metastatic rccs were so common in our series of pancreatic metastases diagnosed by eus - fna . the biologic basis of this distinct and well - documented behavior of rcc is controversial and poorly understood . sellner et al . hypothesize that hematogenous spread and a hospitable pancreatic environment , in combination with the particular biology of rcc , may explain the relatively more common occurrence of this tumor . although rccs may have a broad range of cytologic appearances , the features of clear cell ( conventional type ) rcc are distinctive and include abundant vacuolated cytoplasm with the tumor cells are also frequently seen in association with small blood vessels or basement membrane material . it is important to distinguish this type of rcc from other entities , including primary pancreatic ductal adenocarcinoma with clear cell ( or foamy ) change , well - differentiated neuroendocrine tumors with clear cell changes , and other rare clear cell neoplasms , such as pecomas or clear cell  sugar tumors . in contrast , primary ductal adenocarcinomas of the pancreas are generally characterized by increased cellular pleomorphism , nuclear membrane irregularities , and coarse chromatin . punched out holes ( 40 , diff - quik stain ) , b ) large , cohesive clusters of uniform epithelial cells are seen traveling with endothelial cells and stromal components ( 40 , papanicolaou stain ) , c ) an rcc immunostain is focally expressed , supporting the diagnosis of metastatic renal cell carcinoma ( 40 , immuno ) ihc stains are helpful in that nearly all pancreatic adenocarcinomas express ck7 as well as pasd , ck19 , cea , and ca19 - 9 . in comparison , rcc is typically negative for ck7 , except for many papillary and chromophobe subtypes . immunostains can also distinguish rcc from ambiguous neuroendocrine tumors ( positive for synaptophysin , cd56 , and chromogranin ) and pecomas ( positive for hmb45 ) . the papillary subtype of rcc , frequently seen accompanied by foamy macrophages and fibrovascular cores , is also a potential pitfall . careful interpretation of ihc stains is essential since vimentin and cd10 , for instance , can stain positively in solid pseudopapillary tumor , which may be in the differential . in these cases , beta - catenin , with nuclear expression in nearly all solid pseudopapillary tumors and cytoplasmic or membranous lastly , sarcomatoid dedifferentiation of a rcc should be considered whenever a spindle cell neoplasm or poorly differentiated tumor is present in the pancreas . small cell carcinoma metastatic to the pancreas was another metastatic tumor that was relatively common in our series . the cytomorphological findings in these cases overlap with that of other small round blue cell tumors , including lymphomas , sarcomas ( i.e. , ewing / pnet , alveolar rhabdomyosarcoma , and desmoplastic small round cell tumor ) , and primary neuroendocrine carcinomas of the pancreas . salt - and - pepper chromatin , inconspicuous nucleoli , nuclear molding , crush artifact , and loosely cohesive cells in an apoptotic or necrotic background [ figure 3 ] . although ttf-1 is useful for determining a pulmonary origin for adenocarcinoma , it has been reported in up to 80% of extrapulmonary small cell carcinomas and thus does not differentiate between primary and metastatic neuroendocrine carcinoma . small cell carcinoma of the pancreas is an entity with very few reported cases in the literature and therefore the presence of a tumor with the above described cytomorphology should raise suspicion for an extrapancreatic primary . metastatic small cell carcinoma of the lung ; a ) many loose , small , mildly pleomorphic cells with high nuclear to cytoplasmic ratios are seen . some cells are densely crowded into small clusters with nuclear molding ( 40 , diff - quik stain ) ; b ) round nuclear outlines , absent or minimal nucleoli , and smooth , dark chromatin ( 40 , papanicolaou stain ) ; c - e ) cd56 , synaptophysin and ki67 are expressed , supporting the diagnosis of metastatic small cell carcinoma ( 40 , immuno ) in summary , careful scrutiny of the clinical record and radiographic studies is essential when determining the origin of a small cell carcinoma since the morphologic and ihc appearances of primary and metastatic tumors are typically equivalent . if a history of a primary malignancy is available , review of the histology is necessary and molecular studies such as loss of heterozygosity analysis can occasionally be informative . recent examination of pax8 immunohistochemistry suggests a differential staining pattern in pulmonary vs gastrointestinal neuroendocrine tumors . however , further study is required to more definitively characterize the utility of pax8 in these instances . it usually shows a pleomorphic single cell pattern and scattered dark pigment deposition by cytomorphology . when presented with a poorly differentiated neoplasm and a specimen composed of pleomorphic single cells ( e.g. poorly differentiated carcinoma , sarcoma , lymphoma ) , ihc stains for melanocytic markers ( melanin a , hmb45 , tyrosinase , and s100 ) and keratins are essential [ figure 4 ] . these stains are reasonably specific and can help avoid an error and confirm the cytomorphologic impression of melanoma . metastatic melanoma ; a ) a very loose collection of giant cells , multinucleated cells and large pleomorphic cells with a plasmacytoid appearance ( 40 , diff - quik stain ) ; b ) hyperchromatic , coarsely clumped nuclear chromatin with very irregular nuclear outlines . the cytoplasm contains dusty pigmentation ( 40 , papanicolaou stain ) ; c - e ) s-100 , hmb45 , and melanin a are strongly expressed ( 40 , immuno ) the results of this study are important due to the increasing use of eus - guided fna in the preoperative evaluation of pancreatic masses for pathologic diagnosis and because of the paucity of data in the literature characterizing metastases seen in these types of specimens . thus , awareness of the spectrum of metastases seen in the pancreas , in addition to knowledge of the clinicopathologic findings and potential pitfalls , is important for cytopathologists analyzing and triaging these difficult specimens . they can occur as solitary masses , often in the head of the pancreas , and may occur in patients without a known history of malignancy , thus clinically resembling a pancreatic primary . cytopathologists need to be aware of this unusual possibility of a metastasis in the pancreas because a different management approach may be necessary and , typically , the staging and prognosis are different . the combination of detailed clinical history , imaging findings , and cytomorphological features , in addition to the use of immunohistochemistry , can help confirm a diagnosis and thus allow prompt initiation of appropriate treatment . all authors of this article declare that we qualify for authorship as defined by icmje . all authors are responsible for the conception of this study , participated in its design and coordination , and helped to draft the manuscript . this study was conducted with approval from institutional review board ( irb ) ( or its equivalent ) of all the institutions associated with this study . to ensure integrity and highest quality of cytojournal publications , the review process of this manuscript was conducted under a double blind model(authors are blinded for reviewers and reviewers are blinded for authors)through automatic online system .
background : metastases to the pancreas are an uncommon cause of pancreatic masses seen on endoscopic ultrasound ( eus)-guided fine - needle aspiration ( fna ) . 
 the purpose of this study is to retrospectively review the cytomorphology , clinical findings , and results of ancillary studies in a large series of these unusual cases.materials and methods : we searched our institution 's pathology database for eus - guided fnas of the pancreas that were diagnostic of metastatic tumor over a 5-year period . 
 the final cytologic diagnosis , results of ancillary studies , corresponding histological material , and clinical follow - up data were reviewed in these cases.results:a total of 1172 pancreatic eus - guided fnas were identified , of which 25 cases ( 2.1% ) had a confirmed diagnosis of a pancreatic metastasis . 
 this included 12 ( 48% ) cases of renal cell carcinoma , 3 ( 12% ) melanomas , 3 ( 12% ) small cell carcinomas , and 7 ( 28% ) other malignancies . in these metastatic tumors involving the pancreas , 20 ( 80% ) of the lesions were solitary . 
 four ( 16% ) cases had no prior history of malignancy . 
 the average time to diagnosis of pancreatic metastasis was 5.3 years . 
 immunohistochemistry and special stains were performed in 22 ( 88% ) and 9 ( 36% ) cases , respectively.conclusions:our data shows that although metastases to the pancreas are rare , they can present as a solitary mass many years after the primary malignancy is diagnosed and can even be the first manifestation of an extrapancreatic primary in a small number of cases . 
 it is important to consider the possibility of a metastatic lesion in the pancreas because this may require a different management than a primary pancreatic tumor .