serous cystic neoplasm ( scn ) of the pancreas is a very rare benign lesion , accounting for only 1% to 2% of all pancreatic tumors . in 2010
, several new types of scn were added to the world health organization criteria for pancreatic tumor classification ; this includes the mixed scns and pancreatic neuroendocrine tumors ( pannets ) .
these are termed a mixed serous neuroendocrine neoplasm ( msnn ) , and defined as a tumor containing 2 components with different pathologies .
several cases of msnn have been reported , including distinctly separated and intimately admixed tumors . here ,
a 73-year - old chinese woman was admitted to our hospital in august 2010 , having suffered from an incidental mild epigastric pain for 10 months .
the patient had no complaints involving jaundice , vomiting , or weight loss ; however , she had hypertension , and underwent an oophorotomy in 2006 because of an ovarian physiologic cyst .
examination on admission revealed impaired liver function with increased levels of alt ( 133  u / l ) and ast ( 116  u / l ) .
the level of amylase was normal and all of the tumor markers , including ca199 ( 17.9  u / ml ) , ca242 ( 6.1  u / ml ) , cea ( 2.46  ng / ml ) , afp ( 15.7  ng / ml ) , and ca125 ( 10.2  u / ml ) , were within normal limits .
a cystic tumor with a thin capsule at the pancreatic tail , which measured 3.4    2.5  cm in diameter , was detected using ultrasonography ( fig .
1 ) . enhanced computed tomography ( ct ) revealed an ill - defined hypovascular tumor , approximately 3.3    2.6  cm in diameter , located in the pancreatic tail and adhering to the splenic artery .
preoperative ct and ultrasonography scans of our patient , with an ill - defined cystic lesion located in the pancreatic tail , and the arrow points the mural nodules .
the tumor was 3.3    2.6  cm in ct scans and 3.4    2.5  cm in ultrasonography .
laparoscopic distal pancreatectomy with splenectomy was performed , during which a 3-cm tumor was found encroaching on the pancreatic tail .
the resected pancreatic tissue measured 9.0    6.0    2.5  cm , together with a unilocular cystic tumor measuring 2.5    2.0    1.0  cm .
the cyst was filled with serous fluid while the inner surface was white and smooth . a focal gray , solid ill - defined mass ( approximately 1.2    1.0    0.5  cm in diameter )
hematoxylin and eosin staining of the surgical specimen demonstrated that the cyst was formed by a thin fibrous wall , which was lined with a single layer of cuboidal or flattened epithelial cells exhibiting partial denudation ( fig .
the cell cytoplasm was pale to clear while the nucleus was round to oval and centrally located .
cytological atypia was minimal and there were no invasive or metastatic features present . according to the definition of lee et al and kimura et al , serous oligocystic adenoma was identified .
( b ) lining cuboidal epithelial cells ( arrow ) with a pale or clear cytoplasm and a centrally located round nucleus .
( c ) the collisional growth of 2 components with the pancreatic neuroendocrine tumor ( pannet ) growing into the wall of serous oligocystic adenoma .
( f ) immunohistochemistry staining for chromogranin a. neuroendocrine tumor cells were positive ( 300 ) .
the adherent solid mass was composed of cells arranged in a trabecular or banding pattern .
the size and shape of these cells were uniform with a low karyoplasmic ratio , and there was no mucin inside .
in addition , the nucleolus was not obvious , and small nucleoli could occasionally be seen .
nuclear fission was scarce and appeared in less than 1 in every 10 high power fields of view .
perineural invasion and fat tissue permeation were noted , while the lymph nodes examined were negative . in accordance with these findings ,
a pannet ( g1 ) with uncertain behavior was considered ; it was positive for the expression of chromogranin , synaptophysin , and ki67 ( index < 1% ) ( fig .
intriguingly , we found these 2 components exhibited a collision type of growth , with the pannet component growing into the wall of the scn ( fig . 2c and d ) .
the patient started to suffer from diabetes shortly after surgery . during a 54-month follow - up
, there were no signs of tumor recurrence or metastasis , and the complaints of epigastric pain and abnormal liver function evident before surgery had disappeared .
the patient gave her informed consent for treatment and inclusion in this study , after having been provided with all the necessary information .
the world health organization classified the scns into 5 types in 2010 : serous microcystic adenoma , serous macrocystic / oligocystic adenoma , von hippel  lindau ( vhl)-associated scn , solid serous adenoma / neoplasm , and msnn .
to investigate msnn , the pubmed , embase , and science citation index databases were systematically searched until february 2015 .
  endocrine tumor / neoplasm ,   islet cell tumor / neoplasm ,  and  pancreas . 
the citation lists associated with all of the studies retrieved were used to identify other potentially relevant publications .
the search results were then screened according to the following inclusion criteria : any form of publications focused on msnn , without a third pancreatic tumor ; and presentation of sufficient data , including clinicopathological characteristics and histopathological features .
studies were excluded if they met the following criteria : were not published in english ; and duplicated data from the same sample of patients .
hough et al reported a case of diffuse cystic changes in the pancreas associated with pannets , but detailed data was not available .
baek et al and jung et al reported the same patient in korea , while heresbach et al reported a case of cystadenocarcinoma with msnn in the pancreatic head .
thus , 14 patients remained for analysis in the current study after excluding these 3 studies .
the baseline characteristics of the included studies are summarized in table 1 . as for statistical analysis , we used fisher test , the t - test , and the t-test when comparing different groups .
clinical features of msnn ( 15 cases ) . to the best of our knowledge ,
after reviewing the other cases , we found that our case was the first where the mixed lesion arose in the pancreatic tail ; it was also the first case with an intimately , partially overlapped but mostly separated mixed scn and pannet . among these patients , 13 were female and 2 were male .
the chief complaints were abdominal pain , nausea / vomiting , weight loss , and jaundice , in 46.7% , 26.7% , 20.0% , and 13.3% of patients respectively .
however , no endocrine syndrome was detected in any of the patients ( table 1 ) .
the results of laboratory tests in these cases were mostly within the reference range , except for the case reported by hsieh et al that involved an increased level of ca199 .
all patients underwent preoperative ultrasonography and/or enhanced thin - sliced spiral ct and/or magnetic resonance imaging scans .
the unifocal cystic lesions were often located in the head of the pancreas ( 50% [ 10 cases ] ) with varying sizes , from 1.3  cm to 13  cm in greatest dimension .
most tumors were hypoechoic in ultrasonic images and exhibited low density in ct scans , with or without enhancement after contrast injection .
the medical history in all 15 patients was investigated ; gallbladder stones and diabetes mellitus were most frequently seen with an incidence of 5/15 .
all 15 patients accepted intentional radical surgery ; there were 7 pancreaticoduodenectomies , 6 distal pancreatectomies with splenectomy and 2 total pancreatectomies .
the longest follow - up time was 2 years ( not including our patient ) .
none of these patients had died of tumor recurrence or distant metastasis by the time they were reported .
we analyzed all 15 cases with regard to different clinical , morphological , and histological appearances , and found that msnn could be subdivided into several types ( fig .
the diffuse type : the entire pancreas was involved with numerous serous cysts and pannets , which could be located in any region of the pancreas .
the 2 components grew together and jointly constituted the tumor tissue ; these components could not be distinctly divided .
the solitary type : there were isolated scns and pannets arising in the pancreas without any intermingling area , and the transitional zone was normal , resembling 2 different tumors coinciding in one organ . the collision type : as in the case reported by us , most parts of these 2 components were separated with a partially intermixed or overlapping zone .
there were 5 patients with diffuse scn associated with pannet , 5 with mixed ones , and 4 with solitary ones .
we noted that the diffuse type was mostly associated with vhl disease ( 3 confirmed , 1 suspected , and 1 uncertain ) , and that all of the pannet components were well - differentiated endocrine carcinomas .
all the mixed type of msnn presented as serous microcystic adenoma with larger cysts as compared with those of the solitary type ( mean 9.1:1.9  cm ; p  <  0.05 ) .
serous microcystic adenoma or serous oligocystic adenoma could both be discovered in the solitary type , in which all of the pannets were benign .
there were no significant differences between the mixed and solitary types regarding patient age or the location of the mass .
our case was an unequivocal type of coexistent scn and pannet which was intimately adjacent to a partially intermingling area , and was termed a collision type combination ( fig .
only one case of the collision type has been reported , and it seemed to have the same clinical and histological features as mixed msnn .
because of the coexistence of 2 types of tumor , we should consider them together when discussing the surgical indication and prognosis .
nevertheless , there is a challenge in accurately distinguishing scn from mucinous cystic neoplasms , which are highly suspected of being malignant .
pannets are usually regarded as being potentially malignant because their behavior is difficult to predict from their histopathological features and cellular products .
surgery is considered to be the first - line therapy for patients with pannets when the lesion is resectable .
as suggested by slukvin et al , msnn may have a higher malignant potential than scn alone . among these patients ,
including our case , malignant biological behavior such as perineural , lymphatic , and duodenal invasion appeared in 33.3% ( 5/15 ) of all the cases , which is much higher than that of scn or pannet alone . as a result ,
once a diagnosis of msnn is made , we are more inclined to surgical treatment ; in the cases that have been followed up , this lesion seemed to have a better prognosis after curative surgery .
however , the robustness of our treatment recommendation is diminished by the small number of cases . evaluation of the malignant potential and prognostic outcomes of mixed tumors requires a long - term follow - up and data from additional reports of such cases .
high potential for malignancy has been reported in vhl - associated pannets . among the patients , including our case , 3 vhl - scns were described ; all these cases had diffuse lesions and invasion .
despite the fact that no metastasis was seen , these 3 cases should be attributed to neuroendocrine carcinoma .
therefore , close attention should be paid to the presentation of diffuse msnn regarding vhl disease .
the world health organization classified the scns into 5 types in 2010 : serous microcystic adenoma , serous macrocystic / oligocystic adenoma , von hippel  lindau ( vhl)-associated scn , solid serous adenoma / neoplasm , and msnn .
to investigate msnn , the pubmed , embase , and science citation index databases were systematically searched until february 2015 .
  endocrine tumor / neoplasm ,   islet cell tumor / neoplasm ,  and  pancreas . 
the citation lists associated with all of the studies retrieved were used to identify other potentially relevant publications .
the search results were then screened according to the following inclusion criteria : any form of publications focused on msnn , without a third pancreatic tumor ; and presentation of sufficient data , including clinicopathological characteristics and histopathological features .
studies were excluded if they met the following criteria : were not published in english ; and duplicated data from the same sample of patients .
hough et al reported a case of diffuse cystic changes in the pancreas associated with pannets , but detailed data was not available .
baek et al and jung et al reported the same patient in korea , while heresbach et al reported a case of cystadenocarcinoma with msnn in the pancreatic head .
thus , 14 patients remained for analysis in the current study after excluding these 3 studies .
the baseline characteristics of the included studies are summarized in table 1 . as for statistical analysis , we used fisher test , the t - test , and the t-test when comparing different groups .
clinical features of msnn ( 15 cases ) . to the best of our knowledge ,
after reviewing the other cases , we found that our case was the first where the mixed lesion arose in the pancreatic tail ; it was also the first case with an intimately , partially overlapped but mostly separated mixed scn and pannet . among these patients , 13 were female and 2 were male .
the chief complaints were abdominal pain , nausea / vomiting , weight loss , and jaundice , in 46.7% , 26.7% , 20.0% , and 13.3% of patients respectively .
however , no endocrine syndrome was detected in any of the patients ( table 1 ) .
the results of laboratory tests in these cases were mostly within the reference range , except for the case reported by hsieh et al that involved an increased level of ca199 .
all patients underwent preoperative ultrasonography and/or enhanced thin - sliced spiral ct and/or magnetic resonance imaging scans .
the unifocal cystic lesions were often located in the head of the pancreas ( 50% [ 10 cases ] ) with varying sizes , from 1.3  cm to 13  cm in greatest dimension .
most tumors were hypoechoic in ultrasonic images and exhibited low density in ct scans , with or without enhancement after contrast injection .
the medical history in all 15 patients was investigated ; gallbladder stones and diabetes mellitus were most frequently seen with an incidence of 5/15 .
all 15 patients accepted intentional radical surgery ; there were 7 pancreaticoduodenectomies , 6 distal pancreatectomies with splenectomy and 2 total pancreatectomies .
the longest follow - up time was 2 years ( not including our patient ) .
none of these patients had died of tumor recurrence or distant metastasis by the time they were reported .
we analyzed all 15 cases with regard to different clinical , morphological , and histological appearances , and found that msnn could be subdivided into several types ( fig .
the diffuse type : the entire pancreas was involved with numerous serous cysts and pannets , which could be located in any region of the pancreas .
the 2 components grew together and jointly constituted the tumor tissue ; these components could not be distinctly divided .
the solitary type : there were isolated scns and pannets arising in the pancreas without any intermingling area , and the transitional zone was normal , resembling 2 different tumors coinciding in one organ .
the collision type : as in the case reported by us , most parts of these 2 components were separated with a partially intermixed or overlapping zone .
there were 5 patients with diffuse scn associated with pannet , 5 with mixed ones , and 4 with solitary ones .
we noted that the diffuse type was mostly associated with vhl disease ( 3 confirmed , 1 suspected , and 1 uncertain ) , and that all of the pannet components were well - differentiated endocrine carcinomas .
all the mixed type of msnn presented as serous microcystic adenoma with larger cysts as compared with those of the solitary type ( mean 9.1:1.9  cm ; p  <  0.05 ) .
serous microcystic adenoma or serous oligocystic adenoma could both be discovered in the solitary type , in which all of the pannets were benign .
there were no significant differences between the mixed and solitary types regarding patient age or the location of the mass .
our case was an unequivocal type of coexistent scn and pannet which was intimately adjacent to a partially intermingling area , and was termed a collision type combination ( fig .
only one case of the collision type has been reported , and it seemed to have the same clinical and histological features as mixed msnn .
because of the coexistence of 2 types of tumor , we should consider them together when discussing the surgical indication and prognosis .
nevertheless , there is a challenge in accurately distinguishing scn from mucinous cystic neoplasms , which are highly suspected of being malignant .
pannets are usually regarded as being potentially malignant because their behavior is difficult to predict from their histopathological features and cellular products .
surgery is considered to be the first - line therapy for patients with pannets when the lesion is resectable .
generally speaking , the prognosis of msnn depends on the malignant component . as suggested by slukvin et al
, msnn may have a higher malignant potential than scn alone . among these patients , including our case , malignant biological behavior such as perineural , lymphatic , and duodenal invasion appeared in 33.3% ( 5/15 ) of all the cases , which is much higher than that of scn or pannet alone . as a result ,
once a diagnosis of msnn is made , we are more inclined to surgical treatment ; in the cases that have been followed up , this lesion seemed to have a better prognosis after curative surgery . however , the robustness of our treatment recommendation is diminished by the small number of cases .
evaluation of the malignant potential and prognostic outcomes of mixed tumors requires a long - term follow - up and data from additional reports of such cases .
high potential for malignancy has been reported in vhl - associated pannets . among the patients , including our case , 3 vhl - scns were described ; all these cases had diffuse lesions and invasion .
despite the fact that no metastasis was seen , these 3 cases should be attributed to neuroendocrine carcinoma .
therefore , close attention should be paid to the presentation of diffuse msnn regarding vhl disease .
msnn is a distinct clinicopathological entity rather than an incidental concurrence of 2 separate tumors . to the best of our knowledge , we are the first to report a collisional case of msnn , followed by a literature review and analysis based on its morphological and clinicopathological appearance
. different types of msnn exhibit various features that could be helpful in indicating the prognosis .
 abstractintroduction : the aim of this study was to report a new case of mixed serous neuroendocrine neoplasm ( msnn ) and review the literature concerning this type of lesion , which was added to the world health organization classification of pancreatic tumors in 2010.results:a 73-year - old woman presented with a pancreatic mass . 
 the lesion was an intriguing combination of serous cystic neoplasm ( scn ) and pancreatic neuroendocrine tumor ( pannet ) , in which the pannet component grew into the wall of the serous oligocystic adenoma . 
 we searched different databases for studies that had investigated msnn . 
 a total of 15 patients ( age , 2878 ) , including the patient in the present study , were evaluated . 
 we discuss these cases in detail especially regarding morphology and pathology ; our case was the only one involving a collision type combination.conclusion:although msnn is recognized as a variant of scn , it is quite different from scn or pannet . a new morphological analysis of msnn may help in elucidating its histogenesis and prognosis . 
Introduction
Case report
Discussion
Review of literature
Morphological and clinicopathological analysis of MSNN
Surgical indication and prognosis of MSNN
Conclusion