Cyst Fluid Markers

Cyst Fluid Markers

A cystic lesion of the pancreas is a radiographic finding that has a broad histologic differential that non-neoplastic pseudocysts, benign neoplastic cysts, premalignant cysts, and cystic lesions with invasive carcinoma. The widespread use of high-quality CT scanning in recent years has led to an increasing number of patients in whom identification of small asymptomatic cysts is made. The management of these patients is controversial, as there is a limited ability to determine the histologic diagnosis without resection.

The potential benefit of resecting any given cyst must be weighed against the potential substantial morbidity and the measurable mortality associated with resection, particularly in those cases where more complex surgical procedures are required. Researchers from Memorial Sloan Kettering Cancer Center (MSK) and other institutions have reported results of studies using a selective approach to resection in these patients. All patients evaluated by our surgeons and gastroenterologists for a cystic lesion of the pancreas are enrolled in our pancreatic cyst registry. This registry currently contains data on more than 3,000 patients. Results of our review of this registry, published in the Journal of the American College of Surgeons, support the use of this selective approach.1 Most studies that have advocated a selective approach to resection for pancreatic cystic lesions have reported the radiographic characteristics of a solid component, cyst size, and symptoms to be associated with treatment recommendations. At MSK, we think that radiographic follow-up is warranted in any patient where the presumed risk of malignancy is less than the risk of mortality from resection (no solid component, smaller than 3 cm, asymptomatic, no main pancreatic duct dilation). Specifically, the majority of patients with incidentally discovered cysts smaller than 3 cm in diameter and without a solid component can be safely followed radiographically.

One of the very interesting areas of current research is into the identification of markers that will allow us to differentiate histopathologic subtypes of cysts and to identify dysplasia in patients who present with intraductal papillary mucinous neoplasms (IPMNs). IPMNs are cystic lesions produced when abnormal cells lining the pancreatic ductal system secrete a thick fluid called mucin leading to the formation of a cyst detectable on CT scan. IPMN lesions have the ability to progress to invasive cancer; however, the pace and frequency of progression among patients is not yet fully understood.

Histopathologic analysis of resected IPMN specimens has revealed that these cysts contain a spectrum of dysplasia, ranging from low-grade dysplasia to high-grade dysplasia to invasive pancreatic cancer. Also, most IPMNs show variable amounts of dysplasia throughout the same cyst. Because of the latter characteristic, preoperative sampling of IPMN cyst fluid with fine-needle aspiration (FNA) cytology has not accurately reflected the degree of dysplasia in the cyst as a whole. We have performed multiple studies on the cyst fluid of patients with pancreatic cysts and have identified several interesting markers that we believe will be able to improve our ability to select patients for resection.

In a 2011 study performed by our group, we hypothesized that dysplasia in IPMN invokes an immunogenic/proinflammatory microenvironment that could be quantified in the cyst fluid and allow for the identification of high-grade dysplasia or carcinoma prior to operation.2 Between 2005 and 2009, 147 patients underwent pancreatic resection for IPMN at MSK. Pancreatic cyst fluid aspirates were collected at resection from 40 of these patients. Cytokine expression was determined for the samples collected at resection, and correlative studies on preoperative cyst fluid carcinoembryonic antigen (CEA) and FNA cytology were performed on a subset of these patients. We found levels of interleukin-1β (IL-1β) to be significantly elevated in the cyst fluid of patients with high-grade dysplasia and absent in the fluid of patients with low-grade dysplasia. (Figure 1) Cyst fluid CEA levels alone, or in combination with IL-1β, did not identify high-risk lesions in the subset, whereas IL-1β levels alone did confidently identify high-risk lesions (p = 0.0007).

Figure 1 – Levels of IL1β, IL5, and IL8 were higher in high-risk cysts [high-grade dysplasia (HGD) or invasive cancer (Ca), n = 19] than in low-risk cysts [low-grade dysplasia (low) or moderate dysplasia (mod), n = 21]. *, P < 0.05. In a multivariate predictive analysis model, only IL1β remained a significant predictor of dysplasia (P = 0.0003).
A more recent study investigated the association between cyst fluid inflammatory markers (CFIMs) expression, levels of tumor-associated neutrophils (TANs), and malignant progression in IPMNs.3 A total of 78 patients were included in the study, and 87 different cyst fluid proteins were measured in the cyst fluid specimens. CFIMs were found to be significantly associated with TANs which were themselves found to be correlated with grade of dysplasia. (Figure 2)

Figure 2 – TANs and representative CFIMs stratified by the low-risk and high-risk groups. Representative CFIMs with significant differential expression between the low-risk and high-risk groups were selected. Each CFIM was standardized (z-score), by subtracting the mean and dividing by the standard deviation, because of the vast difference in the scale of measurements. Average levels of standardized CFIMs are presented. TAN high presented as the percentage of patients with high TAN levels in each group.

Validation studies are ongoing, and we hope in the future that cyst fluid markers will allow us to more appropriately identify patients who need resection and prevent surgery in those who can be safely monitored radiographically.

  1. Gaujoux S, Brennan MF, Gonen M, et al. Cystic lesions of the pancreas: changes in the presentation and management of 1,424 patients at a single institution over a 15-year time period. J Am Coll Surg 2011; 212(4):590-600; discussion 600-603.
  2. Maker AV, Katabi N, Qin LX, et al. Cyst fluid interleukin-1beta (IL1beta) levels predict the risk of carcinoma in intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res 2011; 17(6):1502-1508.
  3. Sadot E, Basturk O, Klimstra DS, et al. Tumor-associated Neutrophils and Malignant Progression in Intraductal Papillary Mucinous Neoplasms: An Opportunity for Identification of High-risk Disease. Ann Surg 2015; 262(6):1102-1107.