Review Article
Pancreatic Cysts Preoperative Diagnosis and Clinical Management Martha Bishop Pitman, MD1; Kent Lewandrowski, MD1; Jian Shen, MD1; Dushyant Sahani, MD2; William Brugge, MD3; and Carlos Fernandez-del Castillo, MD4
Preoperative diagnosis of pancreatic cysts benefits from integrating the clinical, radiological, and cytological features. As patient management algorithms evolve to increasingly nonsurgical options, accuracy in distinguishing mucinous from nonmucinous and benign from malignant mucinous cysts is important. This review focuses on pseudocysts, serous cystadenomas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Patients with pseudocysts almost always present with pancreatitis and are usually medically managed. Radiological studies reveal a unilocular cyst mostly in the pancreatic tail. Cyst fluid is thin, with high amylase but low carcinoembryonic antigen (CEA) levels. DNA mutations are absent. Serous cystadenomas are benign and do not require resection. Patients are usually asymptomatic and have microcystic or macrocystic masses anywhere in the pancreas. Cytology is frequently nondiagnostic. CEA and amylase levels are low. DNA analysis may reveal loss of heterozygosity (LOH) at 3p if associated with Von Hippel-Lindau disease. Neoplastic mucinous cysts are highly variable in their presentation. Most are resected. Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. Branch duct IPMNs are more common in the pancreatic head of elderly men. Main duct dilatation correlates with main duct or combined type IPMN. Both types of mucinous cysts produce variable amounts of mucin. Cytologically nonmalignant but atypical epithelial cells, even when scant, are an indication of a high risk for malignancy. High CEA level supports a mucinous cyst, as do KRAS mutation and good quality DNA levels. KRAS mutation and multiple LOH support malignancy. C 2009 American Cancer Society. Cancer (Cancer Cytopathol) 2010;118:1–13. V KEYWORDS: pancreas, endoscopic ultrasound, fine-needle aspiration biopsy, endoscopic ultrasound fine-needle aspiration, intraductal papillary mucinous neoplasm, mucinous cyst, pancreatic cysts, cyst fluid analysis, carcinoembryonic antigen, molecular analysis, KRAS.
Cysts of the pancreas constitute a broad spectrum of entities from non-neoplastic to malignant cysts (Table 1). Until the 1980s, cysts of the pancreas were thought to be relatively rare, but with the routine use of improved cross-sectional imaging, there has been a dramatic increase in the detection of pancreatic cysts in general and asymptomatic cysts in particular.1-8 It is now estimated that approximately 1.2% of general medical patients have a pancreatic cyst requiring follow-up.4,9 Historically, all suspected neoplastic pancreatic cysts have been resected in good surgical candidates because of the uncertainty in the biological behavior of mucinous cysts as well as the uncertainty in preoperative diagnosis. Management algorithms have evolved, however, and nonsurgical treatment options are increasingly available because of our improved understanding of the biological behavior of cystic neoplasms as well as our improved ability to accurately diagnose these cysts preoperatively.8,10-20 Accurate preoperative diagnosis is essential for proper patient management, and the pathologist plays a key role in the preoperative diagnosis. Despite the relatively low sensitivity and specificity of cytology alone in this regard,21-23 when used in a multimodal approach, cytology plays an important role in patient management decisions.11,12,24 We review our current multimodal approach to the preoperative diagnosis of pancreatic cysts at the Massachusetts General Hospital, which includes clinical and radiological evaluation, cytology, cyst fluid chemical analysis for Corresponding authors: Martha Bishop Pitman, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; Fax: (617) 724-6564;
[email protected] 1 Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 2Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; 3Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; 4Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
DOI: 10.1002/cncy.20059, Received: July 27, 2009; Revised: August 28, 2009; Accepted: September 1, 2009, Published online December 30, 2009 in Wiley InterScience (www.interscience.wiley.com)
Cancer Cytopathology
February 25, 2010
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Review Article Table 1. Cysts of the Pancreas
Non-neoplastic cysts Pseudocyst Retention cyst Congenital cyst Foregut cyst Endometriotic cyst
Cystic nonepithelial neoplasms Lymphangioma Hemangioma
Primarily cystic epithelial neoplasms Serous cystadenoma Microcystic Macrocystic
Mucinous cystic neoplasm Mucinous Mucinous Mucinous Mucinous
cystic cystic cystic cystic
neoplasm neoplasm neoplasm neoplasm
with with with with
low-grade dysplasia moderate dysplasia high-grade dysplasia (CIS) invasive carcinoma
Intraductal papillary mucinous neoplasm Intraductal papillary Intraductal papillary Intraductal papillary dysplasia (CIS) Intraductal papillary
mucinous neoplasm with low-grade dysplasia mucinous neoplasm with moderate dysplasia mucinous neoplasm with high-grade mucinous neoplasm with invasive carcinoma
Miscellaneous cysts Lymphoepithelial cyst Epidermoid cyst in intrapancreatic heterotopic spleen
Secondarily cystic solid neoplasms Solid-pseudopapillary neoplasm Ductal adenocarcinoma Endocrine neoplasms Acinar cell neoplasms CIS indicates carcinoma in situ. Modified from Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas. Atlas of Tumor Pathology. 4th Series. Fascicle 6. Washington, DC: American Registry of Pathology, Armed Forces Institutes of Pathology; 2007.
carcinoembryonic antigen (CEA) and amylase, and in select cases, molecular analysis. Although there are many benign and malignant cysts in the pancreas to be aware of, we focus on pseudocysts, serous cystadenomas (SCA), and mucinous cysts (mucinous cystic neoplasms [MCN] and intraductal papillary mucinous neoplasms [IPMNs]), as these cysts represent the most commonly encountered cysts in the pancreas. Clinical Management Patients with known pseudocysts are generally treated medically with drainage.25 A history of acute or chronic pancreatitis, or trauma, is almost always present.26 Serous cystadenomas are benign neoplasms that can be monitored when small but are resected when large (>4 cm),
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growing rapidly, or symptomatic.27 For patients with suspected mucinous cysts, treatment decisions may be based on the presence or absence of symptoms, size of the cyst, radiological features of the cyst, cytological and other parameters of cyst fluid analysis, patient age, and surgical risk factors.14-16,20 Although both MCNs and IPMNs are known to have malignant potential, and therefore have historically all been resected, recent studies highlighting slow growth and indolence of many of these neoplastic mucinous cysts15,17 have led to increased use of nonsurgical alternatives, from close clinical follow-up to in situ ablation.13,20,28-33 Main duct IPMNs, regardless of symptoms, cytology, or the presence of a mural nodule, are considered high risk for malignancy, and are therefore all resected in surgically fit candidates.8,34 For patients with suspected branch duct IPMNs or MCNs, recent international consensus guidelines recommend surgical resection for patients with mucinous cysts either >3 cm or smaller cysts with high-risk features such as symptoms, positive cytology, or a mural nodule.14 We and others have shown, however, that not all asymptomatic cysts 10 mm, thick septations, and biliary obstruction are recognized features of malignancy (Fig. 2).20,37 Both multidetector row CT and MRCP are helpful in characterizing cystic pancreatic neoplasms and, if performed appropriately, demonstrate comparable performance.39,41 In patients with small cysts (10 mm, 2) focal cystic lesion >3 cm, and 3) nodule >5 mm.45,46 EUS-FNA is performed with a linear echoendoscope passed into the duodenum through the stomach. Pancreatic cystic lesions are readily seen as hypoechoic (dark) lesions within the pancreatic parenchyma on EUS (Fig. 3). FNA is usually performed with a 22-gauge needle containing an occluding stylet. With the echoendoscope transducer in close proximity to the cystic lesion, the needle is guided in a perpendicular path to the wall of the cyst. With 1 passage of the needle into the lumen of the cyst, aspiration of cyst fluid is initiated with suction. The cyst fluid is aspirated until the cyst collapses. Highly viscous fluid may require a considerable amount of time for evacuation of the cyst contents, and this is the first clue that the cyst is likely mucinous. Focal nodules, thick septations, and adjacent masses should be targeted for aspiration and cytologic examination.
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Figure 3. A mucinous cystic neoplasm with low-grade dysplasia is shown. This endoscopic ultrasound image depicts a large cyst with thin septations in the pancreatic tail of a middle-aged woman. The aspiration needle is seen reflected diagonally across the cyst cavity.
Allocation of cyst fluid should be based on the dominant clinical question (Fig. 4). When the clinical question is whether the cyst is mucinous, cyst fluid CEA should receive the highest priority for testing. Consideration of molecular testing of the cyst fluid for KRAS or other mutations is entertained when the clinical and radiological features strongly support a mucinous cyst without obvious malignant features such as a mural nodule or invasion of adjacent structures, and the clinical question is benign versus malignant. Molecular testing should also be considered if the cyst fluid is too scant for CEA and likely nondiagnostic cytology (800 ng/mL is 98% specific for a mucinous cyst using a meta-analysis of pooled data from 12 studies at different institutions.47 Increasing the cutoff value of CEA for support of a mucinous cyst will have a negative effect on sensitivity. In this same meta-analysis, levels
