Cystic Neoplasms of the Pancreas

RMS Mitchell, M.D.
Paul S. Jowell, M.D.

Keywords

Cystic neoplasms, EUS, pancreatic tumors

Introduction

Cystic neoplasms of the pancreas are an uncommon, though increasingly reported, entity. They account for approximately 10% of all cystic lesions of the pancreas (1, 2), but only 1% of all pancreatic malignancies (2, 3). A classification of pancreatic cystic neoplasms is shown in Table 1.

Table 1: Classification of cystic neoplasms of the pancreas

Pancreatic cystic neoplasms can be evaluated with endoscopic ultrasound (EUS), abdominal ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). The addition of fine needle aspiration (FNA) during EUS has enabled the endoscopist to biopsy suspicious lymph nodes and to aspirate cyst fluid for subsequent analysis for the presence of epithelial cells, mucin, tumor markers and amylase (Figures 1A and 1B). The impact of EUS on the diagnosis of pancreatic cystic neoplasms will be reviewed.

Figure 1A	Figure 1B

Case/Body

Figure 2A

Figure 2B

Figure 3A

Figure 3B

EUS CHARACTERISTICS OF PANCREATIC CYSTIC NEOPLASMS

Serous (microcystic) cystadenomas
Serous cystadenomas (Figures 2A & 2B) are predominantly benign, though they may grow large and become symptomatic (4, 5), have a female preponderance and occur in patients over the age of 60 years. They are usually microcystic with thin septa, though they may have macrocystic components and a central fibrotic or calcified area visible on ultrasound (6, 7). The main pancreatic duct (PD) is rarely obstructed. The presence of glycogen-staining cells in cyst fluid is diagnostic. However, EUS-FNA is difficult due to the small cyst size, and the yield from fluid analysis is therefore low. The diagnosis is confirmed in only 50% of patients aspirated (8).

Mucinous cystadenomas and cystadenocarcinomas
Mucinous cystadenomas (Figures 3A & 3B) as visualized by EUS are characteristically macrocystic with a thin septum clearly separating it from normal pancreatic tissue (9). They occur mainly in females in the age range 40 years to 60 years. It is usually straightforward to obtain at least 2 ml to 3ml of cyst fluid by EUS-FNA, and the septa may also be aspirated to increase yield. The finding of epithelial cells and mucin in cyst fluid is highly suggestive of the mucinous cystadenoma (10). If there is no communication with the PD there should be low levels of amylase within the cyst fluid, in contrast to inflammatory pseudocysts which have high cyst fluid amylase. Using imaging alone it can be difficult to differentiate cystadenomas from pseudocysts (11). If there is communication with the PD, and the cyst fluid amylase is elevated, the diagnosis may, in fact, be IPMT. High levels of the tumor markers CEA and CA 72-4 within cyst fluid tend only to occur in mucinous cystadenocarcinoma (12), which characteristically have a mixed hypoechoic cystic/solid mass on EUS, often with a dilated main pancreatic duct and a complex cyst (9) (Figures 4A & 4B). The prognosis for benign mucinous cystadenomas is excellent and five-year survival rates may exceed 95% (13). Long term survival for completely resected mucinous cystadenocarcinomas is over 60% (14-16), whereas the survival for invasive disease is very poor and similar to that of pancreatic ductal adenocarcinoma (3). Accurate staging is therefore important to differentiate benign from malignant disease, and to identify potentially resectable tumors, in order to facilitate prompt surgical referral (14).

Figure 4A

Figure 4B

Figure 5

Figure 6

Intraductal papillary mucinous tumors (IPMT)
IPMT lesions are a relatively newly reported lesion, consisting of a dilated PD associated with a cystic or mass lesion (9, 17) (Figure 5). They are often diffuse and associated with copious mucin production. A focal hypoechoic wall lesion, which may represent a focus of malignancy, can often be seen (18), especially with intraductal US (19, 20). Cellier et al. (21) described rupture of the main pancreatic duct wall with intra-pancreatic spread of tumor, an intra-pancreatic mass, tumor invasion of the duodenum or common bile duct, metastatic peripancreatic lymph nodes, and extrapancreatic spread as the EUS criteria for invasive pancreatic intraductal papillary mucinous tumors. Cyst fluid findings are similar to those of mucinous tumors, though high levels of amylase are seen in side branch IPMT lesions (11). EUS has shown to be superior to transabdominal US and ERCP in the diagnosis of cystic tumors and IPMT (22), and may be comparable to CT and ERCP in detecting malignancy arising in IPMT (1, 2).

Cystic Islet Cell Tumors
Endocrine tumors of the pancreas undergo cystic transformation in approximately 2-3% of cases (15, 23). They are more common in females, and usually present in the 3rd or 4th decades (23). They tend to be non-functioning (24), though functioning cystic insulinomas (25) and glucagonomas (26) have been reported. They are generally larger than the corresponding solid tumor (27). Preoperative localization of pancreatic neuroendocrine tumors with traditional imaging fails in 40% to 60% of patients. EUS, however, has a sensitivity of over 90% in the detection of these tumors (3).

Other cystic tumors of the pancreas
Very rare cystic neoplasms of the pancreas include acinar cell cystadenocarcinoma (28), invasive ductal adenocarcinoma with cystic change, and cystic metastatic pancreatic tumors, for instance ovarian clear cell carcinoma (23). These rare tumors will not be discussed further in this review.





RELIABILITY OF EUS
Concerns regarding the correlation of EUS findings to histology have been partially addressed in a number of studies. Koito et al. (29) retrospectively correlated EUS findings with cut-surface histology in 52 patients with pancreatic cystic lesions who had undergone surgical resection. The non-neoplastic cysts were all thin walled and could be easily differentiated on EUS from thick walled neoplastic cysts. EUS was also valuable for visualizing small (<2cm) cysts. In a later study, Gress et al (9) retrospectively studied 35 consecutive patients with cystic neoplasms of the pancreas who had an established histological diagnosis in order to determine the relative frequency of EUS findings in each lesion. In their series, mucinous cystadenocarcinomas were characterized by a mixed hypoechoic cystic/solid mass, often with a dilated main pancreatic duct and complex cyst formation. The features of IPMTs were similar to those of mucinous cystadenocarcinoma, but in addition they also had echogenic foci within the mass, a thickened PD wall and occasionally inhomogeneous intraductal hyperechoic material representing either intraductal carcinoma or mucin. Microcystic cystadenomas had a mixed hypoechoic solid/cystic mass or a complex cyst, but no lymph node metastases or dilatation of the PD. The authors concluded that it should be possible to differentiate mucinous tumors (peripheral type), microcystic cystadenoma and IPMT from ductal carcinoma, and to differentiate benign from malignant cystic lesions based on EUS imaging alone. However, both these small retrospective studies only included patients who had an established histological diagnosis, and therefore suffer somewhat from selection bias.

Ahmad et al. (30), using still images from a radial EUS scope, correlated surgical histopathological findings with two blinded reviewers’ independent analysis of EUS images in 48 patients with pancreatic cysts who had previous non-diagnostic cross-sectional imaging, in order to attempt to assess EUS features differentiating benign from malignant cysts. In contrast to the previous studies, the reviewers were unable to differentiate between benign and malignant cysts on the basis of the following EUS features: presence of a cyst wall, a solid component to the cyst, septa, lymphadenopathy, and the number of cysts present. Although this study had the advantage of blinded reviewers, the omission of analysis of real time EUS imaging, exclusion of PD features, lack of utilization of FNA and the blinding of the reviewers to the patient’s clinical presentation may have adversely affected the ability of the reviewers to identify malignancy in these patients.

Brandwein et al. (31) prospectively assessed the accuracy of EUS using FNA of the lesion in staging and identifying malignancy in 26 patients with cystic pancreatic lesions who subsequently underwent surgery. The sensitivity and specificity of EUS morphology for malignancy were 83.3% and 95% respectively in cystic lesions with a mass. EUS-FNA was 100% specific for detecting malignancy in cystic lesions, but the sensitivity was only 50% (36). EUS was 100% accurate in determining resectability of a cystic lesion i.e. no vascular invasion, no ascites and no hepatic involvement.

If intraductal ultrasound (IDUS) is combined with luminal EUS, it may be possible to further differentiate benign from malignant cysts (32, 33). Inui et al. (19), in 23 patients with a mucin-producing tumor, found that a mural nodule, irregular wall thickness, mucus echoes, and solid tumor with a mixed pattern were predictive of malignancy. The presence of a solid tumor indicated invasive carcinoma exclusively.

IS EUS SUPERIOR TO OTHER PANCREATIC IMAGING MODALITIES?
Other imaging modalities also have significant limitations when assessing pancreatic cystic lesions. For instance, ERCP is not capable of detecting cystic lesions and masses within the pancreatic parenchyma (34-36). It can be difficult to differentiate a cystic tumor from a pseudocyst by transabdominal US (37, 38). CT can readily detect cystic lesions of the pancreas, however in IPMT, the cyst morphology may not be diagnostic unless excrescent nodules in the cystic component were present (39). CT is good at diagnosing serous cystadenomas (when they have the classical microcystic features) but has difficulty in distinguishing mucinous cystadenomas and pseudocysts (40). Indicators of a cystic malignancy on CT are the presence of solid masses, or of other high attenuation content within the cyst cavity, local invasion of surrounding structures and multilocularity (Figure 6). Displacement of, or occlusion of, the pancreatic duct is suggestive of tumor rather than a pseudocyst (15), as is calcification of the cyst wall which, if present, is usually well seen (38, 41), though septations within the cyst may be missed (42). MRI of pancreatic tissue is no better than CT (42), though it may be useful for imaging the ductal system, and magnetic resonance angiography (MRA) may help to differentiate vascular tumors from pseudocysts (43-45).

Discussion/Summary Statement

EUS is a useful tool in the diagnosis of cystic neoplasms of the pancreas, though it has limitations when used alone. An approach that combines EUS, FNA of cyst fluid for cytology and tumor markers analysis, and cross-sectional scanning may improve pre-operative diagnosis and staging of these potentially curable lesions.

References

1. Sachs JR, Deren JJ, Sohn M, Nusbaum M. Mucinous cystadenoma: pitfalls of differential diagnosis. Am J Gastroenterol 1989; 84: 811-6.

2. Hoover E, Natesha R, Dao A, Adams CZ, Jr., Barnwell S. Proliferative pancreatic cysts: pathogenesis and treatment options. Am J Surg 1991; 162: 274-7.

3. Fernandez-del Castillo C, Warshaw AL. Cystic tumors of the pancreas. Surg Clin North Am 1995; 75: 1001-16.

4. Compagno J, Oertel JE. Microcystic adenomas of the pancreas (glycogen-rich cystadenomas): a clinicopathologic study of 34 cases. Am J Clin Pathol 1978; 69: 289-98.

5. Siech M, Tripp K, Schmidt-Rohlfing B, Mattfeldt T, Widmaier U, Gansauge F, et al. Cystic tumors of the pancreas: diagnostic accuracy, pathologic observations and surgical consequences. Langenbecks Arch Surg 1998; 383: 56-61.

6. Torresan F, Casadei R, Solmi L, Marrano D, Gandolfi L. The role of ultrasound in the differential diagnosis of serous and mucinous cystic tumours of the pancreas. Eur J Gastroenterol Hepatol 1997; 9: 169-72.

7. Gouhiri M, Soyer P, Barbagelatta M, Rymer R. Macrocystic serous cystadenoma of the pancreas: CT and endosonographic features. Abdom Imaging 1999; 24: 72-4.

8. Carlson SK, Johnson CD, Brandt KR, Batts KP, Salomao DR. Pancreatic cystic neoplasms: the role and sensitivity of needle aspiration and biopsy. Abdom Imaging 1998; 23: 387-93.

9. Gress F, Gottlieb K, Cummings O, Sherman S, Lehman G. Endoscopic ultrasound characteristics of mucinous cystic neoplasms of the pancreas. Am J Gastroenterol 2000; 95: 961-5.

10. Sperti C, Pasquali C, Guolo P, Polverosi R, Liessi G, Pedrazzoli S. Serum tumor markers and cyst fluid analysis are useful for the diagnosis of pancreatic cystic tumors. Cancer 1996; 78: 237-43.

11. Sand JA, Hyoty MK, Mattila J, Dagorn JC, Nordback IH. Clinical assessment compared with cyst fluid analysis in the differential diagnosis of cystic lesions in the pancreas. Surgery 1996; 119: 275-80.

12. Hammel P, Voitot H, Vilgrain V, Levy P, Ruszniewski P, Bernades P. Diagnostic value of CA 72-4 and carcinoembryonic antigen determination in the fluid of pancreatic cystic lesions. Eur J Gastroenterol Hepatol 1998; 10: 345-8.

13. Albores-Saavedra J, Gould EW, Angeles-Angeles A, Henson DE. Cystic tumors of the pancreas. Pathol Annu 1990; 25 Pt 2: 19-50.

14. Le Borgne J, de Calan L, Partensky C. Cystadenomas and cystadenocarcinomas of the pancreas: a multi-institutional retrospective study of 398 cases. French Surgical Association. Ann Surg 1999; 230: 152-61.

15. Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990; 212: 432-43; discussion 444-5.

16. Whang EE, Danial T, Dunn JC, Ashley SW, Reber HA, Lewin TJ, et al. The spectrum of mucin-producing adenocarcinoma of the pancreas. Pancreas 2000; 21: 147-51.

17. Fukushima N, Mukai K, Kanai Y, Hasebe T, Shimada K, Ozaki H, et al. Intraductal papillary tumors and mucinous cystic tumors of the pancreas: clinicopathologic study of 38 cases. Hum Pathol 1997; 28: 1010-7.

18. Maeshiro K, Nakayama Y, Yasunami Y, Furuta K, Ikeda S. Diagnosis of mucin-producing tumor of the pancreas by balloon-catheter endoscopic retrograde pancreatography--compression study. Hepatogastroenterology 1998; 45: 1986-95.

19. Inui K, Nakazawa S, Yoshino J, Yamachika H, Kanemaki N, Wakabayashi T, et al. Mucin-producing tumor of the pancreas--intraluminal ultrasonography. Hepatogastroenterology 1998; 45: 1996-2000.

20. Ariyama J, Suyama M, Satoh K, Wakabayashi K. Endoscopic ultrasound and intraductal ultrasound in the diagnosis of small pancreatic tumors. Abdom Imaging 1998; 23: 380-6.

21. Cellier C, Cuillerier E, Palazzo L, Rickaert F, Flejou JF, Napoleon B, et al. Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series. Gastrointest Endosc 1998; 47: 42-9.

22. Sugiyama M, Atomi Y, Saito M. Intraductal papillary tumors of the pancreas: evaluation with endoscopic ultrasonography. Gastrointest Endosc 1998; 48: 164-71.

23. Adsay NV, Klimstra DS. Cystic forms of typically solid pancreatic tumors. Semin Diagn Pathol 2000; 17: 81-8.

24. Schwartz RW, Munfakh NA, Zweng TN, Strodel WE, Lee E, Thompson NW. Nonfunctioning cystic neuroendocrine neoplasms of the pancreas. Surgery 1994; 115: 645-9.

25. Marrano D, Campione O, Santini D, Piva P, Alberghini M, Casadei R. Cystic insulinoma: a rare islet cell tumour of the pancreas. Eur J Surg 1994; 160: 519-22.

26. Brown K, Kristopaitis T, Yong S, Chejfec G, Pickleman J. Cystic glucagonoma: A rare variant of an uncommon neuroendocrine pancreas tumor. J Gastrointest Surg 1998; 2: 533-6.

27. Kotoulas C, Panayiotides J, Antiochos C, Sambaziotis D, Papadopoulos G, Karameris A. Huge non-functioning pancreatic cystic neuroendocrine tumour: a case report. Eur J Surg Oncol 1998; 24: 74-6.

28. Joubert M, Fiche M, Hamy A, Heymann MF, Sagan C, Valette PJ, et al. [Extension of an acinar cell pancreatic carcinoma with cystic changes invading the Wirsung canal]. Gastroenterol Clin Biol 1998; 22: 465-8.

29. Koito K, Namieno T, Nagakawa T, Shyonai T, Hirokawa N, Morita K. Solitary cystic tumor of the pancreas: EUS-pathologic correlation. Gastrointest Endosc 1997; 45: 268-76.

30. Ahmad NA, Kochman ML, Lewis JD, Ginsberg GG. Can EUS alone differentiate between malignant and benign cystic lesions of the pancreas? Am J Gastroenterol 2001; 96: 3295-300.

31. Brandwein SL, Farrell JJ, Centeno BA, Brugge WR. Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS. Gastrointest Endosc 2001; 53: 722-7.

32. Furukawa T, Oohashi K, Yamao K, Naitoh Y, Hirooka Y, Taki T, et al. Intraductal ultrasonography of the pancreas: development and clinical potential. Endoscopy 1997; 29: 561-9.

33. Mukai H, Yasuda K, Nakajima M. Differential diagnosis of mucin-producing tumors of the pancreas by intraductal ultrasonography and peroral pancreatoscopy. Endoscopy 1998; 30 Suppl 1: A99-102.

34. Sugiyama M, Atomi Y, Hachiya J. Intraductal papillary tumors of the pancreas: evaluation with magnetic resonance cholangiopancreatography. Am J Gastroenterol 1998; 93: 156-9.

35. Koito K, Namieno T, Ichimura T, Yama N, Hareyama M, Morita K, et al. Mucin producing pancreatic tumors: comparison of MR cholangiopancreatography with endoscopic retrograde cholangiopancreatography. Radiology 1998; 208: 231-7.

36. Mera K, Tajiri H, Muto M, Ohtsu A, Furuse J, Maru Y, et al. Clinical significance of magnetic resonance cholangiopancreatography for the diagnosis of cystic tumor of the pancreas compared with endoscopic retrograde cholangiopancreatography and computed tomography. Jpn J Clin Oncol 1999; 29: 294-8.

37. Busilacchi P, Rizzatto G, Bazzocchi M, Boltro E, Candiani F, Ferrari F, et al. Pancreatic cystadenocarcinoma: diagnostic problems. Br J Radiol 1982; 55: 558-61.

38. Scott J, Martin I, Redhead D, Hammond P, Garden OJ. Mucinous cystic neoplasms of the pancreas: imaging features and diagnostic difficulties. Clin Radiol 2000; 55: 187-92.

39. Kyokane T, Furukawa H, Takayasu K, Mukai K, Shimada K, Kosuge T, et al. CT diagnosis of intraductal papillary neoplasm of the pancreas in comparison with histopathologic findings. Int J Pancreatol 1996; 20: 163-7.

40. Procacci C, Biasiutti C, Carbognin G, Accordini S, Bicego E, Guarise A, et al. Characterization of cystic tumors of the pancreas: CT accuracy. J Comput Assist Tomogr 1999; 23: 906-12.

41. Soyer P, Rabenandrasana A, Van Beers B, Barge J, Sibert A, Laissy JP, et al. Cystic tumors of the pancreas: dynamic CT studies. J Comput Assist Tomogr 1994; 18: 420-6.

42. Buetow PC, Rao P, Thompson LD. From the Archives of the AFIP. Mucinous cystic neoplasms of the pancreas: radiologic-pathologic correlation. Radiographics 1998; 18: 433-49.

43. Hawes RH, Xiong Q, Waxman I, Chang KJ, Evans DB, Abbruzzese JL. A multispecialty approach to the diagnosis and management of pancreatic cancer. Am J Gastroenterol 2000; 95: 17-31.

44. Albert J, Schilling D, Breer H, Jungius KP, Riemann JF, Adamek HE. Mucinous cystadenomas and intraductal papillary mucinous tumors of the pancreas in magnetic resonance cholangiopancreatography. Endoscopy 2000; 32: 472-6.

45. Dani R, Cundari AM, Nogueira CE, Reis GM, Silva LD. Magnetic resonance cholangiopancreatography in cystic lesions of the pancreas. Pancreas 2000; 20: 313-8.

Editor:
John C. Deutsch, M.D.
Duluth, MN

Editorial Board:
Manoop S. Bhutani, M.D.
Galveston, TX
William R. Brugge, M.D.
Boston, MA
Peter R. McNally, D.O.
Denver, CO
Iqbal S. Sandhu, M.D.
Salt Lake City, UT
Thomas J. Savides, M.D.
San Diego, CA