Vincent P. Groot

Systematic review on the role of serum tumor markers in the detection of recurrent pancreatic cancer

BACKGROUND Biomarker testing can be helpful to monitor disease progression after resection of pancreatic cancer. This systematic review aims to give an overview of the literature on the diagnostic value of serum tumor markers for the detection of recurrent pancreatic cancer during follow-up. METHODS A systematic search was performed to 2 October 2017. All studies reporting on the diagnostic value of postoperatively measured serum biomarkers for the detection of pancreatic cancer recurrence were included. Data on diagnostic accuracy of tumor markers were extracted. Forest plots and pooled values of sensitivity and specificity were calculated. RESULTS Four articles described test results of CA 19-9. A pooled sensitivity and specificity of respectively 0.73 (95% CI 0.66-0.80) and 0.83 (95% CI 0.73-0.91) were calculated. One article reported on CEA, showing a sensitivity of 50% and specificity of 65%. No other serum tumor markers were discussed for surveillance purposes in the current literature. CONCLUSION Although testing of serum CA 19-9 has considerable limitations, CA 19-9 remains the most used serum tumor marker for surveillance after surgical resection of pancreatic cancer. Further studies are needed to assess the role of serum tumor marker testing in the detection of recurrent pancreatic cancer and to optimize surveillance strategies.

IPMNs with co-occurring invasive cancers: neighbours but not always relatives

Objective Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. Design We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. Results We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. Conclusion This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

Rare Case of an Epithelial Cyst in an Intrapancreatic Accessory Spleen Treated by Robot-Assisted Spleen Preserving Distal Pancreatectomy

Epithelial cyst in an intrapancreatic accessory spleen (ECIPAS) is exceedingly rare with only 57 cases reported since the first publication in 1980. Comprehensive clinical and diagnostic features remain to be clarified. We present a case of ECIPAS in a 21-year-old Philippine woman who was admitted with right upper quadrant abdominal pain. A cystic lesion in the pancreatic tail was discovered and evaluated by computed tomography and magnetic resonance images. Based on clinical and radiological features a solid pseudopapillary neoplasm was suspected. The patient underwent robot-assisted spleen preserving distal pancreatectomy. Pathological evaluation revealed a 26 mm intrapancreatic accessory spleen with a 16 mm cyst, lined by multilayered epithelium in the tail of the pancreas. The postoperative course was uneventful. Differentiating ECIPAS from (pre)malignant cystic pancreatic neoplasms based on clinical and radiological features remains difficult. When typical radiological signs can be combined with scintigraphy using Technetium-99m labelled colloid or Technetium-99m labelled erythrocytes, which can identify the solid component of the lesion as splenic tissue, it should be possible to make the right diagnosis noninvasively. When pancreatectomy is inevitable due to symptoms or patient preference, minimally invasive laparoscopic or robot-assisted spleen preserving distal pancreatectomy should be considered.

Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology

Visualizing pathologies in three dimensions can provide unique insights into the biology of human diseases. A rapid and easy-to-implement dibenzyl ether-based technique was used to clear thick sections of surgically resected human pancreatic parenchyma. Protocols were applicable to both fresh and formalin-fixed, paraffin-embedded tissue. The penetration of antibodies into dense pancreatic parenchyma was optimized using both gradually increasing antibody concentrations and centrifugal flow. Immunolabeling with antibodies against cytokeratin 19 was visualized using both light sheet and confocal laser scanning microscopy. The technique was applied successfully to 26 sections of pancreas, providing three-dimensional (3D) images of normal pancreatic tissue, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, and infiltrating pancreatic ductal adenocarcinomas. 3D visualization highlighted processes that are hard to conceptualize in two dimensions, such as invasive carcinoma growing into what appeared to be pre-existing pancreatic ducts and within venules, and the tracking of long cords of neoplastic cells parallel to blood vessels. Expanding this technique to formalin-fixed, paraffin-embedded tissue opens pathology archives to 3D visualization of unique biosamples and rare diseases. The application of immunolabeling and clearing to human pancreatic parenchyma provides detailed visualization of normal pancreatic anatomy, and can be used to characterize the 3D architecture of diseases including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and pancreatic ductal adenocarcinomas.

Analogous detection of circulating tumor cells using the AccuCyte®-CyteFinder® system and ISET system in patients with locally advanced and metastatic prostate cancer

Circulating tumor cells (CTCs) can provide important information on patients prognosis and treatment efficacy. Currently, a plethora of methods is available for the detection of these rare cells. We compared the outcomes of two of those methods to enumerate and characterize CTCs in patients with locally advanced and metastatic prostate cancer (PCa). First, the selection‐free AccuCyte® − CyteFinder® system (RareCyte®, Inc., Seattle, WA) and second, the ISET system (Rarecells Diagnostics, France), a CTC detection method based on cell size‐exclusion.

Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature

BACKGROUND Lymphoepithelial cysts (LECs) are rare pancreatic cystic lesions. Since LECs are benign, preoperative diagnosis is important to differentiate from a cystic neoplasm and avoid unnecessary surgery. The aim of this study was to identify clinical, radiographic and cytopathologic features associated with LECs. METHODS A retrospective review was performed of patients diagnosed with LEC between 1995 and 2017 at our hospital. Clinicopathologic and radiographic imaging features were documented. RESULTS Of 29 patients with pancreatic LEC, 22 underwent surgical resection. The majority were male (n = 24) with a median age of 55 years (range, 21-74). During the evaluation, all patients underwent a CT, with endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) biopsy (n = 22) and/or MRI/MRCP (n = 11) performed in a smaller number of patients. A combination of exophytic tumor growth on imaging and the presence of specific cytomorphologic features on the EUS-FNA cytology biopsy led to the correct diagnosis of LEC and prevention of unnecessary surgery in 7 patients. DISCUSSION Differentiating LECs from premalignant pancreatic cystic neoplasms remains difficult. Findings of an exophytic growth pattern of the lesion on abdominal imaging and the presence of specific cytomorphologic features in the EUS-FNA biopsy could help clinicians diagnose LEC preoperatively.

The diagnostic performance of CT versus FDG PET-CT for the detection of recurrent pancreatic cancer: a systematic review and meta-analysis

OBJECTIVES Radiologic surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) can provide information on the extent and location of disease recurrence. This systematic review and meta-analysis aims to give an overview of the literature on the diagnostic performance of different imaging modalities for the detection of recurrent disease after surgery for PDAC. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library up to 20 December 2017. All studies reporting on the diagnostic value of imaging modalities for the detection of local and/or distant disease recurrence during follow-up after resection of PDAC were eligible. Both histologic confirmation of recurrent PDAC and clinical confirmation by disease progression on follow-up imaging were considered as suitable reference standard. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used for critical appraisal of methodological quality. Diagnostic accuracy data were extracted or calculated and presented in forest plots. A bivariate random-effects model was used to calculate pooled estimates of sensitivity and specificity. RESULTS A total of seven retrospective studies with 333 relevant patients were ultimately eligible for data extraction. Overall, the methodological quality of the included studies was acceptable. All seven articles described test results of contrast-enhanced CT, whilst five and three articles reported outcomes on diagnostic accuracy of FDG PET-CT and FDG PET-CT combined with contrast-enhanced CT, respectively. For CT, pooled estimates for sensitivity were 0.70 (95% CI 0.61-0.78) and for specificity 0.80 (95% CI 0.69-0.88). For FDG PET-CT, pooled estimates for sensitivity and specificity were 0.88 (95% CI 0.81-0.93) and 0.89 (95% CI 0.80-0.94), respectively. For FDG PET-CT in combination with contrast-enhanced CT, pooled estimates for sensitivity were 0.95 (95% CI 0.88-0.98) and for specificity 0.81 (95% CI 0.63-0.92). CONCLUSIONS According to the current literature, post-operative CT has a moderate diagnostic accuracy in the detection of recurrent disease. FDG PET-CT imaging could be of additional value when disease recurrence is suspected despite negative or equivocal CT findings. Nevertheless, evidence supporting radiologic surveillance after resection of PDAC is limited. Future prospective studies are needed to optimize surveillance strategies after resection of pancreatic cancer.

ASO Author Reflections: Do Distinct Patterns of Recurrence Impact the Prognosis of Patients With Resected Pancreatic Ductal Adenocarcinoma?

For patients with localized pancreatic ductal adenocarcinoma (PDAC), a combination of resection and systemic therapy offers the best chance for long-term survival. However, even after completion of multimodality therapy, disease recurrence is common and is the foremost cause of disease-specific mortality. Recent evidence suggests that not all PDAC recurrences exhibit the same biological behavior. For instance, a recent study from our institution showed that post-recurrence survival differs based on the timing of recurrence. Furthermore, a different study found that the time to recurrence varies for distinct recurrence locations. However, the relationship of these specific PDAC recurrence patterns with survival after recurrence and overall survival from surgery remains poorly described. Knowledge on the prognostic impact of distinct recurrence sites could aid clinicians with prognostic stratification, and might potentially provide a basis for a more individualized approach to the treatment of PDAC recurrence. Therefore, the aim of our study was twofold: (1) to characterize the association of specific patterns of disease recurrence with survival after recurrence; and (2) to investigate the predictive value of specific recurrence locations on overall survival while adjusting for known prognostic clinicopathologic variables.

AB015. S015. Circulating tumor cells dynamics in pancreatic adenocarcinoma correlate with disease status: data from a prospective trial

Background: Previous retrospective studies demonstrated that circulating tumor cells (CTCs) subtypes in patients with pancreatic ductal adenocarcinoma (PDAC) correlate with disease-specific survival. Herein, we report results of a prospective observational trial on CTC dynamics to assess their clinical significance. Methods: The CLUSTER trial is a prospective longitudinal study on PDAC CTC dynamics (NCT02974764). Multiple peripheral blood samples are collected from 160 consecutively enrolled patients with PDAC diagnosis. CTCs are enriched using an isolation-by-size assay, and their phenotype is characterized by immunofluorescence. Results: Two major CTC subtypes are identified in all patients: epithelial CTCs (eCTCs) and mesenchymal CTCs (mCTCs). Patients who previously received neoadjuvant chemotherapy have significantly lower total CTCs (tCTCs) and mCTCs, compared to untreated patients eligible for upfront resection (P<0.001). In multivariable logistic regression analysis, preoperative numbers of tCTCs and mCTCs are the only predictors of early recurrence and disease-associated mortality, within 12 months from surgery (P=0.03). Surgical resection of the primary tumor results in significant reduction in CTC burden across all cell subtypes (P<0.001). Longitudinal monitoring of CTCs postoperatively shows an increase in CTC numbers within a median time of 2 months, prior to radiological evidence of disease recurrence. Conclusions: We report novel findings regarding CTCs from a large prospective trial in patients undergoing PDAC resection. CTC dynamics reflect response to treatment and progression of disease, providing important information on clinical outcomes, not available by current tumor markers and imaging.