Magnetic resonance imaging in the detection of pancreatic neoplasms

Recently, with the rapid scanning time and improved image quality, outstanding advances in magnetic resonance (MR) methods have resulted in an increase in the use of MRI for patients with a variety of pancreatic neoplasms. MR multi-imaging protocol, which includes MR cross-sectional imaging, MR cholangiopancreatography and dynamic contrast-enhanced MR angiography, integrates the advantages of various special imaging techniques. The non-invasive all-in-one MR multi-imaging techniques may provide the comprehensive information needed for the preoperative diagnosis and evaluation of pancreatic neoplasms. Pancreatic neoplasms include primary tumors and pancreatic metastases. Primary tumors of the pancreas may be mainly classified as ductal adenocarcinomas, cystic tumors and islet cell tumors (ICT). Pancreatic adenocarcinomas can be diagnosed in a MRI study depending on direct evidence or both direct and indirect evidence. The combined MRI features of a focal pancreatic mass, pancreatic duct dilatation and parenchymal atrophy are highly suggestive of a ductal adenocarcinoma. Most cystic neoplasms of the pancreas are either microcystic adenomas or mucinous cystic neoplasms. Intraductal papillary mucinous tumors are the uncommon low-grade malignancy of the pancreatic duct. ICT are rare neoplasms arising from neuroendocrine cells in the pancreas or the periampullary region. ICT are classified as functioning and non-functioning. The most frequent tumors to metastasize to the pancreas are cancers of the breast, lung, kidney and melanoma. The majority of metastases present as large solitary masses with well-defined margins.     

The pathology of ductal-type pancreatic carcinomas and pancreatic intraepithelial neoplasia: Insights for clinicians

The phenotypic classification of pancreatic neoplasms is based on their cellular lineage. Thus, tumors with a ductal, acinar, and endocrine phenotype can be distinguished. Most pancreatic neoplasms show a ductal phenotype and can be classified as ductal adenocarcinomas. Less common tumors with a ductal phenotype are the variants of ductal adenocarcinoma, intraductal papillary mucinous neoplasm (including colloid carcinoma), mucinous cystic neoplasm, medullary carcinoma, and other rare tumors. Ductal adenocarcinomas most likely develop from ductal proliferative lesions arising in the pancreatic duct system. A recently adopted classification system for these lesions distinguishes between three grades of pancreatic intraepithelial neoplasia (PanIN). Molecular studies have revealed that PanIN-2 and PanIN-3 lesions represent a distinct step toward invasive carcinoma.     

Inhibition of Ankyrin-B Expression Reduces Growth and Invasion of Human Pancreatic Ductal Adenocarcinoma

Background: In spite of the increasing knowledge of the molecular pathology of pancreatic ductal adenocarcinoma (PDAC), treatment of this tumor still remains an unresolved problem. Thus, the identification of ‘novel’ genes involved in pancreatic tumor progression is essential for early diagnosis and new treatment regimens of PDAC. Ankyrin-B (ANK2) was identified as being overexpressed in PDAC in a previous study by our group. ANK2 overexpression has been described in several tumors; however, the function of ANK2 in pancreatic carcinoma has not been elucidated. Materials and Methods: In the present study, we confirmed ANK2 overexpression in PDAC and analyzed the effects of ANK2 knockdown in the pancreatic tumor cell line PANC-1. Results: ANK2 silencing reduced the activity of FAK, ERK1/2 and p38. Decreased ANK2 expression restrained migration and invasive potential of PANC-1 cells. Moreover, silencing of ANK2 decreased the proliferation of the pancreatic tumor cells and reduced their tumorigenicity in vitro and in vivo. Conclusion: Our results demonstrate that silencing of ANK2 expression reduced the malignant phenotype of pancreatic cancer cells, indicating that ANK2 represents a potential target for therapy of pancreatic cancer.     

Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics

Mucinous cystic neoplasm (MCN) of the pancreas is a distinct clinicopathological entity characterized by mucin-producing epithelial and cyst-forming neoplasm with “ovarian-type” stroma beneath the epithelial component. It is clearly distinguished from ductal adenocarcinoma and intraductal papillary mucinous neoplasm (IPMN). However, MCN can progress to infiltrating carcinoma, and frequently shows a similar histological pattern to ductal adenocarcinoma. Several genetic alterations such as K-ras oncogene mutation, and epigenetic alterations such as hypermethylation of p16 in the invasive component of MCN are also common with ductal adenocarcinoma. Furthermore, recent technologies, including a laser-assisted microdissection system for histological slides and global gene expression profilings using DNA microarrays, made possible to identify more information about molecular abnormalities of MCNs. It is important to diagnose the lesions before they progress to an invasive carcinoma. MCN is one of the precursors of invasive pancreatic carcinoma.     

Precursors to pancreatic cancer

Infiltrating ductal adenocarcinoma of the pancreas is believed to arise from morphologically distinct noninvasive precursor lesions. These precursors include the intraductal papillary mucinous neoplasm, the mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia. Intraductal papillary mucinous neoplasms are grossly visible mucin-producing epithelial neoplasms that arise in the main pancreatic duct or one of its branches. The cysts of mucinous cystic neoplasms do not communicate with the major pancreatic ducts, and these neoplasms are characterized by a distinct ovarian-type stroma. Pancreatic intraepithelial neoplasia is a microscopic lesion. This article focuses on the clinical significance of these three important precursor lesions, with emphasis on their clinical manifestations, detection, and treatment.     

Expression of E-cadherin,alpha-and beta-catenins in patients with pancreatic adenocarcinoma

Background/Aims: E-Cadherin and its associated cytoplasmic proteins, catenins, are important mediators of epithelial cell-cell adhesion and intracellular signaling. Much evidence exists suggesting a tumor invasion suppressor role for E-cadherin and catenins and loss of expression, as well as mutations, has been described in a number of epithelial cancers. The aim of this study was to evaluate the expression of E-cadherin and catenins in pancreatic adenocarcinoma tissue, and to examine the relationship between these expression and various clinicopathological parameters. Methods: In this study, we conducted an immunohistochemical investigation of expression of E-cadherin, α- and β-catenins in 30 tissue samples obtained from pancreatic ductal adenocarcino-ma patients undergoing surgical treatment. Results: In the pancreatic mucosa of noncancerous areas, epithelial cells showed equally strong membranous expression of E-cadherin, α- and β-catenin proteins at the cell-cell boundaries. Reduced expression of E-cadherin, α- and β-catenins was demonstrated in 60.0, 40.0, and 56.7% of cancer tissues, respectively. Reduced expression of E-cadherin, α- and β-catenins correlated with tumor dedifferentiation (p = 0.012, 0.013, and 0.033, respectively). Reduced expression of E-cadherin correlated with stage and lymph node involvement (p = 0.031, 0.009, respec-tively). α-Catenin and β-catenin expression did not correlate with the patient's age and sex, with the tumor size, location, stage and depth of invasion, or lymph node involvement and distant metastasis. Conclusion: These results suggest that the E-cadherin and catenins may be a useful marker of differentiation and prognosis in pancreatic adenocarcinoma, although the mechanisms underlying changes in E-cadherin and catenin expression are not fully known.     

Update on the pathology and genetics of exocrine pancreatic tumors with ductal phenotype: precursor lesions and new tumor entities

The majority of pancreatic neoplasms show a ductal phenotype and can be classified as ductal adenocarcinomas. Pancreatic duct lesions have been discussed as tumor precursors. This review presents a recently adopted standard system for these lesions which distinguishes among three grades of pancreatic intraepithelial neoplasia (PanIN). Molecular studies revealed that PanIN-2 and PanIN-3 lesions represent a distinct step towards invasive carcinoma. Another focus of the review is the advances that have been made in the further immunohistochemical and molecular characterization of special pancreatic neoplasms showing a ductal phenotype, such as undifferentiated carcinoma, mucinous noncystic (colloid) carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, medullary carcinoma, and other rare tumors.     

Cystic ductal adenocarcinoma of pancreas: an unusual variant.

Cystic lesions of the pancreas are usually pseudocysts (90%); only 10% of them are cystic tumors. These cystic tumors constitute less than 10% of all pancreatic neoplasms, making them an extremely uncommon type of pancreatic malignancy. What is more important is that these tumors are very easily misdiagnosed as pseudocysts because their characteristics are very similar to those of the benign pseudocysts. This gains importance as the cystic tumors have a high cure rate and good prognosis if diagnosed and treated on time. Of all the cystic tumors, the most common are the benign serous cystadenomas, mucinous cystic tumors, intraductal papillary mucinous neoplasms etc. Ductal adenocarcinoma of pancreas presenting in cystic form is an uncommon type of cystic tumor, making it extremely rare among all pancreatic malignancies (solid or cystic). We present the following case report. The review of literature concerning the diagnosis and management has also been discussed.     

Less common neoplasms of the pancreas

Recently, there has been an increased recognition of neoplasms of the pancreas other than ductal adenocarcinoma. Although not as well studied or characterized as pancreatic adenocarcinoma there are many distinct lesions which exhibit diverse biological behaviors and varying degrees of malignancy. These lesions include: endocrine neoplasms, cystic tumors, solid pseudopapillary tumors, acinar cell carcinoma, squamous cell carcinoma, primary lymphoma of the pancreas, and metastatic lesions to the pancreas. These less common neoplasms are being diagnosed more frequently as the number and sensitivity of diagnostic imaging studies increase. This review article discusses the clinical course, diagnosis, and treatment of these less common, but quite relevant, neoplasms of the pancreas.     

Patient- and Cyst-Related Factors for Improved Prediction of Malignancy within Cystic Lesions of the Pancreas

Background and Aims: Early diagnosis of cancer in pancreatic cysts is important for timely referral to surgery. The aim of this study was to develop a predictive model for pancreatic cyst malignancy to improve patient selection for surgical resection. Methods: We performed retrospective analyses of endoscopic ultrasound (EUS) and pathology databases identifying pancreatic cysts with available final pathological diagnoses. Main-duct intraductal papillary mucinous neoplasms (IPMNs) were excluded due to the clear indication for surgery. Patient demographics and symptoms, cyst morphology, and cyst fluid characteristics were studied as candidate riskfactors for malignancy. Results: 270 patients with pancreatic cysts were identified and analyzed (41% men, mean age 61.8 years). Final pathological diagnoses were branch-duct IPMN (n = 118, 50% malignant), serous cystadenoma (n = 71), pseudocyst (n = 37), mucinous cyst adenoma/adenocarcinoma (n = 36), islet cell tumor (n = 4), simple cyst (n = 3), and ductal adenocarcinoma with cystic degeneration (n = 1). Optimal cut-off points for surgical resection were cyst fluid carcinoembryonic antigen (CEA) ≥3,594 ng/ml, age >50, and cyst size >1.5 cm. Cyst malignancy was independently associated with white race (OR = 4.1, p = 0.002), weight loss (OR = 3.9, p = 0.001), cyst size >1.5 cm (OR = 2.4, p = 0.012), and high CEA >3,594 (OR = 5.3, p = 0.04). In white patients >50 years old presenting with weight loss and cyst size >1.5 cm, the likelihood of malignancy was nearly sixfold greater than in those patients who had none of these factors (OR = 5.8,95% CI = 2.1-16.1, p = 0.004). Conclusions: Riskfactors other than cyst size are important for determination of malignancy in pancreatic cysts. Exceptionally high cyst fluid CEA levels and certain patient-related factors may help to better predict cyst malignancy and the need for surgical treatment.     

Possible Oncogenesis of Mucinous Cystic Tumors of the Pancreas Lacking Ovarian-Like Stroma

Background/Aims: Clinicopathological features and postoperative results from mucinous cystic tumors of the pancreas (MCTs) were reviewed. MCTs with ovarianlike stroma (MCTs-OLS+; n = 6) and those lacking ovarianlike stroma (MCTs-OLS–; n = 4) were compared to elucidate the oncogenesis of MCT without OLS. Patients and Methods: Ten patients with MCT were studied. Results: The 6 MCTs-OLS+ cases occurred in females and were located in the body and tail of the pancreas. The mean tumor size was 6.5 cm (range 2–11 cm). The majority (5/6) of MCTs-OLS+ were multilocular and exhibited tiny loculi on the cyst wall and septum characteristic of MCTs-OLS+. Pathological classifications were adenoma in 4 patients and noninvasive adenocarcinoma in 2 patients. All 6 patients were alive without tumor recurrence 6–124 months after tumor resection. Of the 4 MCTs-OLS– cases, 2 were males and 2 females; MCTsOLS– were located in the tail of the pancreas. The mean tumor size was 6.9 cm (range 4–8.4 cm). Invasive cancer in the pancreatic parenchyma or extrapancreatic tissue was recognized in all 4 patients, and the pathological classification of epithelia of the cyst wall were adenocarcinomas. These findings were also compatible with common invasive ductal carcinomas of the pancreas with secondary retention cyst on pseudocyst. All patients died of the disease (15, 27, 31 and 80 months after resection, respectively). Whether or not OLS is specific for MCTs of the pancreas should be clarified in future studies. Conclusion: The results of our study led to three hypotheses regarding the oncogenesis of MCTs-OLS–: (1) MCTs in which OLS disappears during the development of invasive carcinoma; (2) advanced cancer derived from intraductal papillary mucinous tumor of the pancreas, and (3) invasive ductal carcinoma of the pancreas with secondary cyst.     

Pancreatoblastoma in Adults: A Review of the Literature

Background: Pancreatoblastoma is a very uncommon neoplasm in adults and its management represents a great challenge with regards to different treatment options. Given the rarity of the disease, the aim of this study was to review our personal experience with adult pancreatoblastoma as well as the cases reported in the literature in order to support clinicians observing this entity. Methods: Adult patients with histologically proven pancreatoblastoma were identified from our prospective database of pancreatic resections. After a search on the Medline database, a review of all cases was performed as well, focusing on clinical, radiological and hystopathological features and treatment options. Results: At our Institution, 2 adult males, 26 and 69 years old, underwent successful pancreatic resection for pancreatoblastoma. The diagnosis of pancreatoblastoma mainly depends on the pathological findings characterized by squamoid corpuscles at histopathology. Only 21 cases of adult pancreatoblastoma have been identified in the literature. In general, despite aggressive treatment, pancreatoblastoma in adults is associated with poorer outcome than in children, with a median survival time of 18.5 months. Both our patients are disease free after 15 months (case 2) and 51 months (case 1). The latter represents the most successful result in long-term disease-free survival. Conclusion: Pancreatoblastoma is a rare neoplasm in adults. The differential diagnosis includes nonfunctional pancreatic endocrine tumor, acinar cell carcinoma, solid pseudopapillary tumor and adenocarcinoma. Surgical resection is the only treatment associated with long-term survival. Chemotherapy may play a role as palliative treatment in advanced disease.     

Serine protease inhibitor Kazal type 1 and epidermal growth factor receptor are expressed in pancreatic tubular adenocarcinoma, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia

Background

Serine protease inhibitor Kazal type 1 (SPINK1) is expressed in normal human pancreatic acinar cells and in a variety of tumors, and binds to the epidermal growth factor receptor (EGFR), mediating cell proliferation through the mitogen-activated protein kinase cascade in pancreatic cancer cell lines. Here, we aimed to assess SPINK1 and EGFR expression in various neoplastic lesions, including tissues demonstrating precancerous changes.

Methods

Surgical specimens of pancreatic ductal adenocarcinoma (n = 23), intraductal papillary mucinous neoplasm (IPMN; n = 21), pancreatic neoplasms other than ductal adenocarcinoma (n = 8), chronic pancreatitis (n = 11), and pancreatic intraepithelial neoplasia (PanIN) lesions within the resected specimens were analyzed immunohistochemically for SPINK1 and EGFR expression.

Results

Sixty-five PanIN-1A, 32 PanIN-1B, 17 PanIN-2, and 6 PanIN-3 were identified. Both SPINK1 and EGFR were expressed in almost all PanIN lesions. All tubular ductal adenocarcinoma, IPMN, and mucinous cystadenocarcinoma samples (neoplasms of ductal origin) expressed SPINK1, whereas acinar cell carcinoma, anaplastic carcinoma, adenosquamous carcinoma, insulinoma, and islet cell carcinoma did not. EGFR was expressed in 87 % of tubular adenocarcinoma and 48 % of IPMN lesions. Among IPMN lesions, malignant lesions (IPMC) expressed EGFR more often than benign lesions (IPMA) did. Scattered expression of EGFR was observed in normal pancreatic ducts and within the tubular complex within chronic pancreatitis lesions.

Conclusions

These results indicate that SPINK1 plays a role as a growth factor, signaling through the EGFR pathway in pancreatic ductal adenocarcinoma and neoplasms, and that the EGFR is involved in the malignant transformation of IPMN.     

Two cases of pancreatic ductal adenocarcinoma, manifested as solid pseudopapillary tumor and intraductal papillary mucinous neoplasm]

Compared with other types of cancers, pancreatic cancer is one of the most dreadful malignancies and is fifth leading cause of cancer-related death in Korea. It is difficult to expect early diagnosis or improvement in prognosis due to lack of specific early symptoms and effective diagnostic methods. Whereas cystic neoplasm of the pancreas is a rare type of pancreatic tumor, surgical resection provides good prognosis because of its low possibility of local invasion or distant metastasis. In case of pancreatic cystic tumor, radiologic differentiation between benign and malignant lesions is crucial for the selection of appropriate treatment and the prediction of prognosis. And ductal adenocarcinoma of pancreas presenting in cystic form is an uncommon type of cystic tumor, making it extremely rare among all pancreatic malignancies. We report two cases of atypical pancreatic ductal adenocarcinoma presenting as solid pseudopapillary tumor and intraductal papillary mucinous neoplasm, respectively.     

Proteomic Analysis of Pancreatic Ductal Adenocarcinoma Compared with Normal Adjacent Pancreatic Tissue and Pancreatic Benign Cystadenoma

Background: Dual expression of potential biomarkers in both benign and malignant pancreatic tumors was a major obstacle in the development of diagnostic biomarkers of early pancreatic cancer. Methods: To better understand the limitations of potential protein biomarkers in pancreatic cancer, we employed two-dimensional difference gel electrophoresis technology and tandem mass spectrometry to study protein expression profiles in pancreatic cancer tissues, benign pancreatic adenoma and normal adjacent pancreas. Seven differently expressed proteins were selected for validation by Western blot and/or immunohistochemistry. Results: 21 spots were overexpressed and 24 spots were downexpressed in pancreatic cancer compared with benign and normal adjacent tissues. Our study demonstrated that three candidate pancreatic ductal adenocarcinoma biomarkers identified in previous studies, fructose-bisphosphate aldolase A, α-smooth muscle actin and vimentin, were also overexpressed in pancreatic cystadenoma, which might lower their further utility as biomarkers for pancreatic cancer. Aflatoxin B₁ aldehyde reductase (AKR7A2) was confirmed to be only highly expressed in pancreatic cancer, not in normal adjacent pancreas and benign tumors. Conclusions: The protein profile pattern of pancreatic cystadenoma was more similar to normal adjacent pancreas than pancreatic cancer. We identified panels of the upregulated proteins in pancreatic cancer, which have not been reported in prior proteomic studies. AKR7A2 may be a novel potential biomarker for pancreatic cancer.     

Pancreatic Cysts and Guidelines

Pancreatic cysts, especially incidental asymptomatic ones seen on noninvasive imaging such as CT or MR imaging, remain a clinical challenge. The etiology of such cysts may range from benign cysts without any malignant potential such as pancreatic pseudocysts and serous cystadenomas to premalignant or frankly malignant cysts such as mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, cystic degeneration associated with solid tumors such as pancreatic ductal adenocarcinoma or pancreatic endocrine neoplasms, and solid pseudopapillary neoplasms. The clinical challenge in 2017 is to accurately preoperatively diagnose them and their malignant potential before deciding about surgery, surveillance or doing nothing. This review will focus on the currently available clinical guidelines for doing so.     

Pancreatic Cystic Neoplasms: Predictors of Malignant Behavior and Management

Background/Aim:

Pancreatic cystic neoplasms are being increasingly identified with the widespread use of advanced imaging techniques. In the absence of a good radiologic or pathologic test to preoperatively determine the dianosis, clinical characteristics might be helpful. The objectives of this analysis were to define the incidence and predictors of malignancy in pancreatic cysts.

Patients and Methods:

Patients with true pancreatic cysts who were treated at our institution were included. Patients with documented pseudocysts were excluded. Demographic data, clinical manifestations, radiological, surgical, and pathological records of those patients were reviewed.

Results:

Eighty-one patients had true pancreatic cyst. The mean age was 47 ± 15.5 years. There were 28.4% serous cystadenoma, 21% mucinous cystadenoma, 6.2% intraductal papillary tumors, 8.6% solid pseudopapillary tumors, 1.2% neuroendocrinal tumor, 3.7% ductal adenocarcinoma, and 30.9% mucinous cystadenocarcinoma. Malignancy was significantly associated with men (P = 0.04), older age (0.0001), cysts larger than 3 cm in diameter (P = 0.001), presence of solid component (P = 0.0001), and cyst wall thickening (P = 0.0001). The majority of patients with malignancy were symptomatic (26/28, 92.9%). The symptoms that correlated with malignancy included abdominal pain (P = 0.04) and weight loss (P = 0.0001). Surgical procedures were based on the location and extension of the lesion.

Conclusion:

The most common pancreatic cysts were serous and mucinous cysts. These tumors were more common in females. Old age, male gender, large tumor, presence of solid component, wall thickness, and presence of symptoms may predict malignancy in the cyst.     

Intraductal Spread of Pancreatic Cancer: Clinicopathologic Study of 54 Pancreatectomized Patients

Background: Invasive ductal adenocarcinoma of the pancreas (IDAP) also spreads through the pancreatic ductal tree. The aim of this study was to clarify the clinicopathologic features of IDAP with intraductal spread. Methods: We studied the intraductal spread of IDAP and its correlation with clinicopathologic parameters in a surgical series of 54 patients. The pancreatic ducts were analyzed by confirmation of mural elastic fibers with elastica van Gieson stain. Results: Intraductal spread of carcinoma was identified in 37 patients (69%). Such spread was frequent in well-differentiated IDAP (93%), and the number of intraductal carcinoma foci was correlated with the grade of tumor differentiation (p < 0.001). The large branch ducts were the main route of intraductal spread (64.1%). The proliferation index, evaluated using Ki67, was lower in the intraductal carcinoma components than in the associated infiltrating carcinoma components (p < 0.001). The presence or absence of intraductal spread was not correlated with age, sex, tumor location, tumor size, or stage. IDAP with intraductal spread showed a tendency, although it was not significant (p = 0.092), to be associated with longer survival compared with IDAP without intraductal spread. Conclusion: IDAP, especially of the well-differentiated type, has a tendency to spread intraductally. The difference between the Ki67 labeling indexes in the intraductal and associated infiltrating carcinoma components suggests that these components show different biological behaviors.     

Intraductal papillary mucinous tumors of the pancreas

Cystic neoplasms of the exocrine pancreas are a small fraction of pancreatic tumors. Within that group of cystic neoplasms, intraductal papillary mucinous tumors (IPMTs) can be distinguished from mucinous cystic neoplasms, serous cystic neoplasms, and pseudopapillary cystic tumors. Awareness of IPMTs has increased since the World Health Organization classified these tumors as its own group in 1996. Because of their favorable prognosis, an extensive diagnostic workup for IPMTs should be performed in patients presenting with cystic lesions of the pancreas. This workup often leads to the diagnosis and the predominant tumor location and size, although the extent of the ductal changes can only be established by histopathology. Surgical resection is the therapy of choice for IPMTs. The type of resection depends upon the extent of the quantitative and qualitative ductal involvement. Total pancreatectomy is currently the treatment for an IPMT that comprises the entire main duct.