Serous cystadenoma (SCA) of the pancreas is a benign nonmucinous cystic pancreatic neoplasm and the second most common type of pancreatic cystic neoplasm. Conservative management is advocated in asymptomatic cases as they have indolent clinical behavior and risk for postoperative morbidity, making an exact diagnosis essential. Morphologically, serous cystadenoma has a prominent subepithelial capillary meshwork causing the aspirate to be paucicellular and nondiagnostic. Therefore, cytologic diagnosis can be challenging, resulting in repeat aspirations or even unnecessary surgical resections. Since this is a diagnosis that is often overlooked, herein we offer a concise review of SCA along with characteristic radiology findings, diagnostic criteria including ancillary studies and possible differential considerations.

Fine-needle aspiration (FNA) diagnosis of pancreatic serous cystadenoma (SCA) remains challenging. This retrospective study aimed to evaluate the roles of cyst fluid ancillary testing and combined fine-needle biopsy (FNB) in improving the diagnostic yield.

The authors retrospectively reviewed cytology cases that were histologically confirmed SCAs. Clinical features and FNA cyst fluid biochemical and molecular analysis results along FNB findings were reviewed.

The study cohort included 31 cases from 13 male and 18 female patients with a mean age of 65. The original cytologic diagnoses were nondiagnostic (n = 6, 19%), negative for malignant cells/cyst contents (n = 7, 23%), atypical cells (n = 3, 10%), nonmucinous cyst (n = 11, 35%), and serous cystadenoma (n = 4, 13%). Cyst fluid carcinoembryonic antigen (CEA) analysis was performed in 17 cases, all of which showed a low CEA level (<192 ng/mL). All 14 cases with molecular testing showed a wild-type KRAS. Inhibin immunohistochemistry was retrospectively performed on the FNA cell blocks, inhibin was positive in six of seven cases tested. In 15 cases with concurrent FNA and FNB biopsies, the diagnosis of SCA was seen in only one FNA case (7%) but 13 FNB cases (87%).

This study suggests that FNA diagnosis of SCA remains challenging even with ancillary testing including cyst fluid CEA level and KRAS mutation analysis. Adjunct inhibin immunostaining may help improve the cytologic diagnosis of selective SCA cases. FNB appears superior to FNA for a definite diagnosis of SCA.

Serous (cystic) neoplasm (SCN) of the pancreas is generally benign, and surgical treatment is recommended in only a limited number of cases. To avoid unnecessary surgery, an accurate diagnosis of SCN is essential. In the present study, we aimed to identify new immunohistochemical markers with which to distinguish SCN from other tumours.

We compared the comprehensive gene expression profiles of SCN with those of normal pancreas and pancreatic ductal adenocarcinoma (PDAC). We selected the candidate molecules that were up-regulated in SCN, were minimally expressed or unexpressed in PDAC, and had specific and available antibodies suitable for immunohistochemistry, and then analysed their immunohistochemical expression in various tumours. We selected aquaporin 1 (AQP1), stereocilin (STRC), fibroblast growth factor receptor 3 (FGFR3), and transmembrane protein 255B (TMEM255B), which were diffusely expressed in SCN cells in 79%, 100%, 100% and 100% of SCN cases. AQP1 was not expressed in other tumours, except in 20% of mucinous cystic neoplasms (MCNs) and 19% of PDACs. STRC was rarely expressed in MCNs, neuroendocrine neoplasms (NENs), and PDACs. FGFR3 was expressed in 31% of intraductal papillary mucinous neoplasms (IPMNs), 50% of intraductal oncocytic papillary neoplasms, 40% of NENs, 30% of acinar cell carcinomas, 40% of solid pseudopapillary neoplasms, and 52% of PDACs. TMEM255B was not expressed in the other tumours, except in 50% of MCNs, 80% of gastric-subtype IPMNs, and 29% of PDACs. All antigens were usually expressed in a small proportion of cells when they were positive in tumours other than SCN.

These findings indicate that AQP1 and STRC, and potentially TMEM255B, may act as SCN markers.

Because serous cystadenoma (SCA) does not usually require excision, it is critical to distinguish it from differential diagnoses which do, especially neuroendocrine tumour (NET). The gold standard for diagnosing SCA is assessment of endoscopic ultrasound-guided fine needle aspiration/biopsy (EUS-FNAB) material. Inhibin immunohistochemistry aids this assessment, but such positivity is not absolutely sensitive or specific to SCA. The following is the largest known study of SCA EUS-FNAB specimens and the first to compare four potential SCA immunomarkers between themselves and inhibin, compared against NET.

Immunohistochemistry for calponin, mucin 6 (MUC6), glucose transporter 1 (GLUT1) and vascular endothelial growth factor A (VEGFA) was performed on 30 EUS-FNAB and three resection specimens of SCA and 32 EUS-FNAB specimens of NET. GLUT1 and VEGFA were suboptimal as diagnostic immunomarkers of SCA, being expressed by 10 and 44% of NETs, respectively. Further, their expression by cellular constituents of blood which often contaminate EUS-FNAB specimens hampered identification of neoplastic cells, especially in hypocellular samples. While 19% of NETs showed nuclear MUC6 positivity, cytoplasmic expression of the protein showed 100% specificity and sensitivity as an SCA marker. However, assessing MUC6 in EUS-FNAB specimens must also consider the protein's focal expression in physiological pancreatic, gastric or duodenal tissues, which can contaminate these specimens. Calponin was less sensitive (71% versus 100%) but more specific (100% versus 91%) than inhibin, although easier to assess in EUS-FNAB specimens than MUC6.

Of the four potential immunomarkers of SCA suggested by the existing literature, calponin and MUC6 are useful complementary studies to inhibin for application to EUS-FNAB specimens.

Chylous ascites represents a relatively uncommon condition. In this paper, we present a case of chyloperitoneum associated with pancreatic ductal adenocarcinoma (PDAC) and a review of literature regarding chylous ascites. A 76-year-old male patient was admitted in emergency department with acute abdomen. A pancreatic cancer was suspected. Subtotal spleno-pancreatectomy, for a nodular mass infiltrating the mild and distal portion of the pancreas, was necessary. During surgical intervention in the peritoneal cavity, a moderate quantity of whitish and thick consistency fluid with milk-like appearance was observed to be accumulated. After examination of the fluid, chyloperitoneum was diagnosed. The histologic examination showed a PDAC, with multiple emboli in lymph vessels, with tumor cells with plasmacytoid morphology, diagnosed as lymphangiosis carcinomatosa. The patient died at 3 weeks after surgical intervention. In patients with pancreatic cancer and chylous ascites, suspicion of tumor-related blockage of the lymphatic flow should be suspected. Prognosis of PDAC should be evaluated not only based on the number of lymph node metastases, but also considering the number of lymph vessels with tumor emboli and the architecture of tumor cells. This is the first reported case of a PDAC with plasmacytoid morphology of lymphangiosis carcinomatosa.

Serous cystadenoma (SCA) is an uncommon benign pancreatic neoplasm that is most often managed conservatively with follow-up rather than surgical excision. Therefore, to avoid the serious complications of pancreatic surgery, SCA should be diagnosed accurately at the preoperative level. Preoperative SCA diagnosis requires a multimodal diagnostic approach that includes imaging, cystic fluid biochemical analysis and/or endoscopic ultrasound fine-needle aspiration (EUS-FNA). In this brief report, we describe six EUS-FNA cases from five patients that were reported as "benign, consistent with serous cystadenoma". Samples were hypocellular, composed of loose clusters and single cuboidal, bland-looking cells among epithelial sheets representing gastrointestinal contamination. Cell blocks were prepared and all six FNA cases revealed cuboidal cells with a positive α-inhibin immunophenotype, consistent with a diagnosis of SCA. As EUS-FNAs of SCA commonly result in non-diagnostic interpretations, cell block preparations with subsequent immunochemistry can increase their diagnostic accuracy and guide patient management.

Pancreatic serous cystadenoma (SCA) is a benign neoplastic lesion with a distinctive gross and microscopic appearance consisting of numerous thin-walled cysts lined by uniform epithelial cells with clear cytoplasm and small nuclei. The vast majority of serous cystadenomas are benign. Pancreatic SCA has rarely been reported in association with other pancreatic lesions. We present a challenging case in which a cystic and solid pancreatic mass was identified on imaging studies. FNA was performed and showed clusters of atypical cells with significant nuclear pleomorphism (>4:1), disorganized, overlapping nuclei, and prominent nucleoli. The FNA diagnosis was positive for malignancy, consistent with adenocarcinoma. The patient underwent neoadjuvant therapy and pancreaticoduodenectomy. Final pathology showed a serous cystadenoma associated with small foci of high-grade PanIN. The lack of invasive adenocarcinoma in the resection specimen was most likely due to complete response of the tumor to neoadjuvant chemoradiation therapy, but it is also possible that only high-grade PanIN was present initially. To our knowledge, this is the first reported case of SCA and high grade PanIN/PDAC that was assessed by FNA. We discuss the cytologic differential diagnosis and how to avoid potential pitfalls highlighted by this case.

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.

Serous neoplasms are uncommon, usually cystic tumors that account for less than 1% of all primary pancreatic lesions. They consist predominantly of a monomorphic epithelial cell population with a glycogen-rich, clear cytoplasm, reminiscent of clear cell renal cell carcinoma, with which serous neoplasms share an association with underlying VHL loss-of-function mutations. Serous neoplasms have no metastatic potential. Accurate recognition of this entity, including its various architectural subtypes, is critical to appropriate prognostication and treatment. Immunohistochemical detection of inhibin and calponin expression, along with the absence of both estrogen and progesterone receptors and nuclear β-catenin, can help to distinguish serous neoplasms from mimics. With the advent of minimally invasive and molecularly driven diagnostic techniques, the pathologist's role in the assessment and management of serous neoplasms has become increasingly complex and important. We provide an update on the histologic, immunohistochemical, and molecular features of pancreatic serous neoplasms for the practicing pathologist.

Minimally invasive techniques used to evaluate canine peripheral lymphadenopathy (PLN), including fine needle aspiration biopsy with cytological evaluation (FNAB-C) and flow cytometry (FC), have benefits and limitations. The cell block (CB) method is an alternate processing technique in which fine needle aspirate biopsy samples are concentrated, fixed, and embedded in paraffin for routine histological processing/staining. Utilizing three observers, we determined the diagnostic value of the CB in evaluating canine PLN across six categories (non-diagnostic, reactive, inflammatory/infectious, probable lymphoma and lymphoma, metastatic neoplasia) and correlated findings to immunophenotypic and clonal antigen receptor rearrangement results in canine nodal lymphoma. Eighty-five paired FNAB-C and CB samples were evaluated from canine patients presenting to the University of Minnesota Veterinary Oncology or Internal Medicine services. Diagnostic quality samples were obtained in 55/85 (65%) CB and 81/85 (95%) FNAB-C samples, respectively, and nodal pathology impacted CB diagnostic yield. Overall percent agreement between diagnostic-quality FNAB-C and CB samples was 86%, but increased to 95% if the categories of lymphoma and probable lymphoma were combined. There was 100% agreement for both the diagnoses of metastatic neoplasia and reactive lymph nodes and 92% agreement for the diagnosis of lymphoma/probable lymphoma. Using immunohistochemistry (IHC), CB samples correctly immunophenotyped 22/23 (96%) cases of B-cell lymphoma, but only 1/6 (17%) cases of T-cell lymphoma. IHC was not completed on nine cases of lymphoproliferative disease because of insufficient cellularity. When the CB method (CBM) yielded diagnostic quality samples there was good to excellent agreement with FNAB-C samples and CB samples were suitable for some IHC tests.

Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.

Despite diagnostic refinements, pancreatic resection (PR) is eventually performed in some patients with asymptomatic serous cystadenoma (A-SCA). The aim of this study was to define incidence and reasons of PR in A-SCA.

A retrospective analysis of a prospectively maintained database was performed for all the patients referred for pancreatic cystic lesions (PCL) between January 2005 and March 2016.

Overall, there were 1488 patients with PCL, including 1271 (85.4%) with incidental PCL (I-PCL). During the study period referral of I-PCL increased 8.5-fold. Surgery was immediately advised in 94 I-PCL (7.3%) and became necessary later on in 11 additional patients (0.9%), because of the development of symptoms. Overall, PR was performed in 105/1271 patients presenting with I-PCL (8.2%), including 27 with A-SCA (2.1%). All patients with A-SCA underwent ultrasonography and contrast-enhanced computed tomography. Magnetic resonance imaging was performed in 21 patients (77.8%), 18 F-FDG positron emission tomography in 8 (29.6%), endoscopic ultrasonography (EUS) in 2 (7.4%), and EUS-guided fine needle aspiration (EUS-FNA) in 1 (3.7%). These studies demonstrated a combination of atypical features such as solid tumor (3; 11.1%), oligo-/macrocystic tumor (24; 88.8%), mural nodules (14; 51.8%), enhancing cyst walls (17; 62.9%), dilation of the main pancreatic duct (3; 11.1%), and upstream pancreatic atrophy (1; 3.7%). Additionally, 14/27 patients (51.8%) were females with oligo-/macrocystic tumors located in the body-tail of the pancreas.

Management of patients with A-SCA entails a small risk of PR especially when these tumors demonstrate atypical radiologic features associated with confounding anatomic and demographic characteristics.

The pancreas is a complex organ that may give rise to large number of neoplasms and non-neoplastic lesions. This article focuses on benign neoplasms, such as serous neoplasms, and tumorlike (pseudotumoral) lesions that may be mistaken for neoplasm not only by clinicians and radiologists, but also by pathologists. The family of pancreatic pseudotumors, by a loosely defined conception of that term, includes a variety of lesions including heterotopia, hamartoma, and lipomatous pseudohypertrophy. Autoimmune pancreatitis and paraduodenal ("groove") pancreatitis may also lead to pseudotumor formation. Knowledge of these entities will help in making an accurate diagnosis.

In this review, we will focus on rare pancreatic tumors. Most of these tumors do not have distinct characteristic appearances so the key to diagnosis requires a combination of imaging appearance, laboratory data, patient demographics, and associated medical syndromes in order to narrow the differential diagnosis. Nonetheless, imaging plays a vital role in narrowing the differential and guiding management. While there are many variant pathologic entities that cannot be encompassed by a single review, we aim to illustrate the imaging appearance of less common pancreatic tumors highlighting key distinctive diagnostic characteristics and discuss the implications for management. While there is overlap in the imaging appearances of many of these entities, for educational purposes, lesions will be categorized into solid (hypoenhancing and hyperenhancing), cystic lesions, mesenchymal neoplasms, and neoplasms seen in younger patients (< 40 years).

To describe the imaging features of serous neoplasms of the pancreas using ultrasound, endoscopic ultrasound, computed tomography and magnetic resonance imaging.

This multicenter international collaboration enhances a literature review to date, reporting features of 287 histologically confirmed cases of serous pancreatic cystic neoplasms (SPNs).

Female predominance is seen with most SPNs presenting asymptomatically in the 5th through 7th decade. Mean lesion size was 38.7 mm, 98% were single, 44.2% cystic, 46% mixed cystic and solid, and 94% hypoechoic on B-mode ultrasound. Vascular patterns and contrast-enhancement profiles are described as hypervascular and hyperenhancing.

The described ultrasound features can aid differentiation of SPN from other neoplastic lesions under most circumstances.

Accurate differentiation of pancreatic cystic lesions is important for early detection and prevention of pancreatic cancer, as well as avoidance of unnecessary surgical intervention. Serous cystic neoplasms (SCNs) have no malignant potential, but can mimic the following premalignant mucinous cystic lesions: mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN). We recently identified vascular endothelial growth factor (VEGF)-A as a novel pancreatic fluid biomarker for SCN. We hypothesize that combining cyst fluid CEA with VEGF-A will improve the diagnostic accuracy of VEGF-A. Pancreatic cyst/duct fluid was collected from consenting patients undergoing surgical cyst resection with corresponding pathologic diagnoses. Pancreatic fluid VEGF-A and CEA levels were detected by ELISA. One hundred and forty-nine patients with pancreatic cystic lesions met inclusion criteria. Pathologic diagnoses included pseudocyst (n = 14), SCN (n = 26), mucinous cystic neoplasm (n = 40), low-/moderate-grade IPMN (n = 34), high-grade IPMN (n = 20), invasive IPMN (n = 10), and solid pseudopapillary neoplasm (n = 5). Vascular endothelial growth factor A was significantly elevated in SCN cyst fluid compared with all other diagnoses (p < 0.001). With a threshold of >5,000 pg/mL, VEGF-A alone has 100% sensitivity and 83.7% specificity to distinguish SCNs from other cystic lesions. With a threshold of ≤10 ng/mL, CEA alone identifies SCN with 95.5% sensitivity and 81.5% specificity. Sensitivity and specificity of the VEGF-A/CEA combination are 95.5% and 100%, respectively. The c-statistic increased from 0.98 to 0.99 in the receiver operating characteristic analysis when CEA was added to VEGF-A alone. Although VEGF-A alone is a highly accurate test for SCN, the combination of VEGF-A with CEA approaches the gold standard for pathologic diagnosis, importantly avoiding false positives. Patients with a positive test indicating benign SCN can be spared a high-risk surgical pancreatic resection.

To study non-diagnostic CT-guided musculoskeletal biopsies and take steps to minimize them. Specifically we asked: (1) What malignant diagnoses have a higher non-diagnostic rate? (2) What factors of a non-diagnostic biopsy may warrant more aggressive pursuit? (3) Do intra-procedural frozen pathology (FP) or point-of-care (POC) cytology reduce the non-diagnostic biopsy rate?

This study was IRB-approved and HIPAA-compliant. We retrospectively reviewed 963 consecutive CT-guided musculoskeletal biopsies. We categorized pathology results as malignant, benign, or non-diagnostic and recorded use of FP or POC cytology. Initial biopsy indication, final diagnosis, method of obtaining the final diagnosis of non-diagnostic biopsies, age of the patient, and years of biopsy attending experience were recorded. Groups were compared using Pearson's χ(2) test or Fisher's exact test.

In all, 140 of 963 (15%) biopsies were non-diagnostic. Lymphoma resulted in more non-diagnostic biopsies (P < 0.0001). While 67% of non-diagnostic biopsies yielded benign diagnoses, 33% yielded malignant diagnoses. Patients whose percutaneous biopsy was indicated due to the clinical context without malignancy history almost always generated benign results (96%). Whereas 56% of biopsies whose indication was an imaging finding of a treatable lesion were malignant, 20% of biopsies whose indication was a history of malignancy were malignant. There was no statistically significant difference in the nondiagnostic biopsy rates of pediatric versus adult patients (P = 0.8) and of biopsy attendings with fewer versus more years of experience (P = 0.5). The non-diagnostic rates of biopsies with FP (8%), POC cytology (25%), or neither (24%) were significantly different (P < 0.0001).

Lymphoma is the malignant diagnosis most likely to result in a non-diagnostic biopsy. If the clinical and radiologic suspicion for malignancy is high, repeat biopsy is warranted. If the clinical context suggests a benign lesion, a non-diagnostic biopsy may be considered reassuring. Frozen pathology may decrease the non-diagnostic biopsy rate.

Pancreatic serous cystadenomas are uncommon benign tumours that are often found incidentally on routine imaging examinations. Radiological imaging techniques alone have proven to be suboptimal to fully characterize cystic pancreatic lesions. Endoscopic ultrasound, with the addition of fine-needle aspiration in difficult cases, has showed greater diagnostic accuracy than conventional imaging techniques. The best management strategy of these neoplasms is still debated. Surgery should be limited only to symptomatic and highly selected cases and most of the patients should only be strictly monitored. In the current paper, we provide an updated overview on pancreatic serous cystadenomas, focusing our attention on epidemiology, clinical characteristics and diagnostic evaluation; finally, we also discuss different management strategies and areas for future research.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as the diagnostic modality of choice for mass lesions in the pancreas. The objective of the current study was to determine the accuracy and pitfalls of EUS-FNA in the diagnosis of pancreatic lesions in cases that involved follow-up surgical resection.

Cases of EUS-FNA of pancreatic lesions performed from 2007 to mid-2012 for which subsequent surgical resection was performed were retrieved from the department's database. The accuracy of the cytologic diagnosis was assessed using the histological diagnosis as the gold standard. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. "Neoplastic," "suspicious," and "malignant" were classified as a positive cytologic diagnosis. In one calculation method, "atypical" was also included as a positive cytologic diagnosis whereas in another it was not considered to be a positive cytological result. The cases with a cytologic-histological discrepancy were reviewed to identify sources of errors.

A total of 1212 cases from 1104 patients (518 women and 586 men; age range, 18-94 years [average age, 63.5 years]) were identified. Cytologic diagnoses included 52 unsatisfactory, 224 benign, 129 atypical, 140 neoplasm, 35 suspicious, and 632 malignant diagnoses. Of these cases, 397 patients had histological follow-up information available. The sensitivity, specificity, positive predictive value, and negative predictive value were 83.2%, 85.9%, 95.9%, and 56.1%, respectively, with atypical cases excluded from the analysis. When atypical cases were included as a positive cytologic diagnosis, the sensitivity, specificity, positive predictive value, and negative predictive value were 86.7%, 67.9%, 90.7%, and 58.5%, respectively, and were 73.7%, 87.7%, 95.6%, and 48.0%, respectively, when atypical cases were included as a negative cytologic diagnosis. The major difficulty in EUS-FNA cytology was to differentiate pancreatic mucinous neoplasms from contaminants of gastric mucosa. Other pitfalls included differentiating mucinous neoplasm from extensive pancreatic intraepithelial neoplasia, and endocrine tumor from nesidioblastosis versus acinar cell carcinoma or intrapancreatic spleen.

EUS-FNA is a valuable tool for the diagnosis of pancreatic lesions, especially solid malignant tumors. Cytologic-radiological correlation is essential in differentiating pancreatic mucinous neoplasms from gastric mucosa, because the former usually are found to have characteristic features on imaging. Pathologists should be aware of the pitfalls in the cytologic diagnosis of pancreatic lesions that may significantly change the clinical management of the patients.

We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as "serous." Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to "clear cell neoplasms" seen in various other organs that are associated with the von Hippel-Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets.