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2010—December Case of the Month

Posted January 14, 2011

CLINICAL SUMMARY: PANCREAS  

CAP Foundation December 2010 Online Case of the Month

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A 55-year-old woman underwent abdominal ultrasonography for evaluation of possible gallstones. Cholelithiasis could not be demonstrated, but there was a 7.5 cm multiloculated cyst involving the distal pancreas. Subsequent distal pancreatectomy revealed a multiloculated cyst (7.5 x 7.0 x 6.0 cm) filled with cloudy, amber-colored, thin fluid. The cyst wall ranged from 1mm to 3.0 mm in thickness. No communication with the pancreatic ductal system was seen. No papillary excrescences were seen.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 24 and is a mucinous cystic neoplasm (mucinous cystadenoma).

Criteria for Diagnosis and Comments: This neoplasm is lined by a single layer of cuboidal cells with round nuclei and clear cytoplasm and it represents a mucinous cystic neoplasm of the pancreas (mucinous cystadenoma). In general, neoplastic cysts of the pancreas can be categorized as true cysts (serous cystadenoma and mucinous cystic neoplasm), dilations of the pancreatic duct system (intraductal papillary mucinous neoplasm), and cystic degeneration of solid tumors (solid pseudopapillary tumor, cystic islet cell tumor). The most common cystic lesion of the pancreas is the pseudocyst. Primary cystic neoplasms of the pancreas comprise mostly serous cystadenomas (SCA), mucinous cystic neoplasms (MCN), and intraductal papillary mucinous neoplasms (IPMN). Solid pseudopapillary neoplasms of the pancreas and cystic islet cell neoplasms are much less common. Cystic pancreatic neoplasms often can be distinguished by their imaging morphology; however, in some patients, accurate differentiation may be difficult, and cyst aspiration and biopsy may be necessary to determine appropriate treatment. The importance of identifying mucinous neoplasms is because of their overt or latent malignant potential.

Patients with SCA or MCN have a mean age at presentation of 50 years with a distinct female predominance. Some authors even suggest that MCN do not occur in men. Patients with SCA or MCN are often asymptomatic with the cystic mass identified incidentally during diagnostic investigation of an unrelated abdominal complaint. Occasionally, symptoms are secondary to the mass effect of the neoplasm. In contrast, patients with IPMN usually present at an older age (mean 65 years), show a slight male predominance, and frequently have abdominal pain and chronic pancreatitis.

SCA characteristically are composed of multiple small (<2 cm) and occasionally microscopic cysts. These benign neoplasms occur most commonly in the body and tail of the pancreas, but occasionally are seen to arise in the head of the gland. SCA have three morphologic patterns: polycystic (70%), oligocystic (10%), and honeycomb (20%). A central fibrous scar with a characteristic stellate pattern of calcification occurs in up to 30% of these neoplasms and, when present, is considered to be virtually pathognomonic. The cysts in SCA are lined by a single layer of cuboidal cells with round nuclei and clear cytoplasm. Serous cystadenocarcinomas are extremely rare, and SCA should be managed as benign neoplasms.

Gross and microscopic pathologic features usually allow one to distinguish between MCN and IPMN. Tumor site is one helpful feature, in that more than 90% of MCN occur in the body or tail, while IPMN can involve any part of the pancreatic ductal system. MCN predominantly are macrocystic, but they can be multilocular in 20% of cases, or have several adjacent cysts. MCN usually range in size from 4 to 5 cm in diameter, but may reach very large sizes of up to 20 cm in diameter. Calcifications are uncommon but when present (<20%) tend to be located in an eggshell distribution within the peripheral cyst walls. MCN have a round contour formed by a thick fibrous capsule that encircles cystic spaces that do not communicate with the pancreatic ductal system. In contrast, the characteristic feature of IPMN is a poorly demarcated cystic dilatation of either the main pancreatic duct or a primary segmental side branch of the main duct. Mucus can be seen “oozing” from a normal or patulous papilla during endoscopy, since cystic areas communicate with the pancreatic ductal system. IPMN often show polypoid excrescences or solid areas in the duct wall. Histologic examination of the cyst lining does not necessarily help distinguish between IPMN and MCN, as both lesions can feature papillary architecture and columnar cells with mucin production. The lining of MCN is usually a single layer of tall, mucin-producing columnar cells, but papillae and complex architectural patterns may be seen. The epithelium in IPMN is classified as intestinal, pancreaticobiliary, gastric or oncocytic. Pseudopyloric, squamous, and osseous metaplasia can be seen in MCN and IPMN. Examination of subepithelial stroma is very useful, since in IPMN the involved ducts are surrounded by loose fibrous stroma. In contrast, MCN features ovarian-type spindle cell stroma, which may contain single epithelioid cells resembling luteinized ovarian hilar cells. The spindled stromal cells are often positive for estrogen and progesterone receptors, and the epithelioid cells are positive for inhibin. Extensive hyalinization of the cyst wall can obscure this characteristic stroma. Tissue adjacent to both IPMN and MCN can show chronic pancreatitis, and changes in duct epithelium can be reactive with the columnar epithelium becoming taller and mucin rich. In IPMN, nearby ducts often show dysplastic changes, with nuclear crowding, stratification, and hyperchromasia. These changes represent spread of the intraductal neoplasm along small duct branches or multifocal involvement of the duct system.

Analysis of pancreatic enzymes, cytologic findings, and tumor markers within intracystic fluid obtained by percutaneous or, more recently, endoscopic ultrasound-guided aspiration may help with the preoperative diagnosis in challenging cases. In a patient with a history of acute pancreatitis and a well-demarcated, unicystic lesion without septae, increased amylase or lipase activity is virtually pathognomonic of a pancreatic pseudocyst. Conversely, absence of increased amylase activity excludes a pancreatic pseudocyst. Cyst fluid cytology will not reliably differentiate pseudocysts from neoplasms, but the presence of cuboidal cells or mucinous epithelium, when present, has a very high specificity for the diagnosis of serous or mucinous cystic neoplasms, respectively. A positive stain for mucin or an increased viscosity is highly sensitive for a MCN, but will not reliably differentiate invasive from noninvasive neoplasms. The most discriminating ancillary markers are a positive stain for mucin and an increase in CEA in mucinous neoplasms.

In SCA, complete resection is curative, and postoperative surveillance imaging is probably neither cost-effective nor necessary. In contrast, all MCN should be considered premalignant or overtly malignant and, whenever safe, resected. The most robust predictor of prognosis for MCN and IPMN is the presence or absence of invasive adenocarcinoma. In MCN, invasive carcinoma has been described in 8% to 36% of patients. The prevalence of invasive carcinoma in IPMN appears to be higher, ranging from 36% to 53% of patients. Crucial to the identification of invasive carcinoma is adequate tissue sampling, because the invasive component may be a small part of the lesion. MCN should be completely embedded for histologic review. The noninvasive epithelium of MCN and IPMN is dysplastic, and the WHO recognizes three levels of dysplasia: low grade, moderate and high high grade. Thus, MCN should be subclassified as (1) mucinous cystadenoma, (2) borderline mucinous cystic neoplasm, (3) non-invasive mucinous cystadenocarcinoma, and (4) invasive mucinous cystadenocarcinoma. Many lesions contain all three grades of dysplasia; grading should be based on the worst type of epithelium present. Complete excision of a noninvasive MCN appears to be curative regardless of the degree of atypia in the lining epithelium. The appropriate surgical treatment of IPMN remains unclear, because the basic and as yet unanswered question is whether or not IPMN represents a localized process or a field defect with the potential to affect all of the pancreatic ductal epithelium. Currently, most experts have gravitated toward an image-guided localized resection with frozen-section guided analysis of the pancreatic margin. Overall, 5-year survival rates in IPMN average about 60% to 70%. For branch duct IPMN, local anatomic resection is essentially curative.

Supplementary Questions:

Question Diagnostic Set
1. Which of the above entities is not a neoplasm? A. Cystic islet cell neoplasm
B. Intraductal papillary mucinous neoplasm
C. Mucinous cystic neoplasm (mucinous cystadenoma)
D. Pancreatic pseudocyst
E. Serous cystadenoma
F. Solid pseudopapillary neoplasm of the pancreas
2. Which entity features ovarian-type spindle cell stroma, which is often positive for estrogen and progesterone receptors? A. Cystic islet cell neoplasm
B. Intraductal papillary mucinous neoplasm
C. Mucinous cystic neoplasm (mucinous cystadenoma)
D. Pancreatic pseudocyst
E. Serous cystadenoma
F. Solid pseudopapillary neoplasm of the pancreas
3. Frozen section analysis of the pancreatic duct margin is most important for which entity? A. Cystic islet cell neoplasm
B. Intraductal papillary mucinous neoplasm
C. Mucinous cystic neoplasm (mucinous cystadenoma)
D. Pancreatic pseudocyst
E. Serous cystadenoma
F. Solid pseudopapillary neoplasm of the pancreas

References

  1. Goldsmith JD. Cystic neoplasms of the pancreas. Am J Clin Pathol. 2003;119:S3-16.
  2. Hamilton SR and Aaltonen LA, Editors, World Health Organization Classification of tumours. Tumours of the digestive system, IARC Press, Washington, DC; 2000:231–240.
  3. Pyke CM, van Heerden JA, Colby TV, et al. The spectrum of serous cystadenoma of the pancreas: Clinical, pathological, and surgical aspects. Ann Surg. 1992;215:132-139.
  4. Sarr MG. Primary cystic neoplasms of the pancreas. Neoplastic disorders of emerging importance-current state-of-the-art and unanswered questions. J Gastrointest Surg. 2003;7:417-428.

Author:
2007
Hagen Blaszyk, MD, FCAP
Surgical Pathology Committee
Spectrum Medical Group
Portland, ME