OUP user menu

Nonmucinous Cystadenomas of the Pancreas With Pancreatobiliary Phenotype and Ovarian-Like Stroma

Jorge Albores-Saavedra MD, Carlos Manivel MD, Rita Dorantes-Heredia MD, Fredy Chablé-Montero MD, César Godoy-Valdés MD, Carlos Chan-Nuñez MD, Donald E. Henson MD
DOI: http://dx.doi.org/10.1309/AJCPHSV7TV2WOJFE 599-604 First published online: 1 May 2013

Abstract

Among 31 benign cystic neoplasms of the pancreas diagnosed as mucinous cystadenomas, we identified 9 (29%) cases of nonmucinous cystadenomas with a pancreatobiliary phenotype and an ovarian-like stroma. Although both cystic tumors belong to the same family, they should be separated because their epithelial lining and cyst fluid are different. The lining cells of the nonmucinous cystadenomas consisted of a single layer of cuboidal cells, similar to the epithelial cells of the normal pancreatic ducts, and were not dysplastic (90%–100% of the lining cells). The cyst fluid was described as serous or clear. The remaining 22 classical mucinous cystadenomas, lined predominantly by mucinous and foveolar epithelium, revealed focal pancreatobiliary epithelium in 86% of the cases, and 6 pancreatic invasive mucinous cystadenocarcinomas failed to show pancreatobiliary differentiation. We believe that these nonmucinous cystadenomas of the pancreas represent a distinctive subset of cystic neoplasms of the pancreas that probably have no malignant potential.

Key Words:
  • Nonmucinous cystadenoma
  • Pancreas
  • Pancreatobiliary phenotype
  • CK7
  • MUC 1
  • CAM5.2
  • CDX2

Although mucinous cystic neoplasms of the pancreas were initially described more than 100 years ago,1 it was not until 1978 that Compagno and Oretel2 defined the morphologic features that allowed separation of mucinous from serous cystic tumors of the pancreas. Their observations were subsequently confirmed by many other studies.38 In addition to the tall columnar mucinous epithelium, the presence of an ovarian-like stroma was emphasized in these tumors.2,4,6,810 The Armed Forces Institute of Pathology (AFIP) fascicle on tumors of the pancreas11 described the microscopic features of mucinous cystic tumors as lined by “tall mucin producing epithelium with gastric foveolar differentiation and in some cases goblet cells scattered among columnar cells. The septa of the cysts at least focally contain a distinctive ovarian like stroma.” The World Health Organization’s classification of tumors of the digestive system12 basically uses the same histologic criteria for these pancreatic cystic neoplasms. Foci of low- or high-grade dysplasia have subsequently been recognized and incorporated into the classification of these tumors.8,11,13,14 However, there is no reference to pancreatobiliary epithelium lining the cysts in any publication on mucinous cystic pancreatic neoplasms.

The purpose of this report is to describe 9 cystic neoplasms of the pancreas that belong to the family of mucinous cystic neoplasms but should be distinguished from them because they display a predominant or exclusive nondysplastic cuboidal epithelial lining similar to the normal ductal epithelium of the pancreas or to the epithelium of biliary-type tubular adenomas of the gallbladder. For this reason, we will refer to this as pancreatobiliary-type epithelium.

Materials and Methods

During a review of 31 tumors that had been interpreted as mucinous cystadenomas of the pancreas filed in the Departments of Pathology from 3 academic hospitals (University Hospital of the University of Minnesota, Minneapolis; Medica Sur Hospital, Mexico City, Mexico; and Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” Mexico City, Mexico), we identified and selected 9 cases (29%) of cystic neoplasms with a predominant or exclusive pancreatobiliary epithelium for this study. Clinical and follow-up information was obtained from the patients’ charts. Gross findings, including tumor size, location, and type of cyst fluid, were obtained from the pathology reports. In addition, a specific search for pancreatobiliary-type epithelium was made among the remaining 22 mucinous cystic tumors lined predominantly by mucinous and foveolar epithelium, as well as 6 invasive mucinous cystadenocarcinomas of the pancreas.

In 7 cases, the entire cystic neoplasms were submitted for microscopic examination. Multiple H&E-stained sections were available for review in all 9 cases. Paraffin blocks were available in 8 cases, and additional slides were prepared for immunohistochemical analysis. Immunostains were performed using the standard avidin-biotin-peroxidase method. The following antibodies were studied Table 1 with appropriate controls.

Results

Clinical Features

All patients were female with a mean age of 45 years (range, 24–64 years). Seven tumors were symptomatic and 2 were incidental findings. A distal pancreatectomy was performed in all patients.

View this table:
Table 1

Gross Features

Eight cystadenomas originated in the tail, and 1 involved the tail and body of the pancreas. Their size ranged from 1.7 to 7 cm (average, 4.8 cm). Five tumors were multilocular and 4 unilocular; the variably sized locules had thin walls and a smooth pink inner surface Image 1. The cyst fluid of 7 cystadenomas was described as serous and as clear in another tumor. The ninth cystadenoma was ruptured during the surgical procedure, and the quality of the fluid was not recorded. The carcinoembryonic antigen (CEA) serous fluid level was measured in 2 cystadenomas and was not elevated. There was no communication between the cystadenomas and the pancreatic ducts.

Microscopic Features

Microscopically, the thin-walled locules were lined predominantly or exclusively by a single layer of cuboidal cells with uniform round or ovoid nuclei and eosinophilic cytoplasm (90%–100% of the lining cells). These cells were similar to those of normal pancreatic ducts and biliary-type tubular gallbladder adenomas Image 2 and Image 3. In some areas, the cuboidal cells became flat. In 3 cystadenomas, 2% to 5% of the epithelial lining of the locules consisted of mature goblet cells mixed with cuboidal cells, reflecting intestinal differentiation Image 4. No low- or high-grade dysplasia was in any of the cystic neoplasms. Likewise, no mitotic figures were identified. Beneath the cuboidal epithelium was a layer of variable thickness composed of spindle cells resembling ovarian stroma. In 2 cystic neoplasms, the wall of the locules was extensively fibrotic, and the ovarian-like stroma was focal. There were no luteinized cells in any of the tumors. Beneath the ovarian-like stroma, a variable amount of hyalinized fibrous tissue was present. Nineteen of 22 (86%) classical mucinous cystadenomas lined by mucinous and foveolar epithelium showed a focal nondysplastic pancreatobiliary phenotype (5%–50% of the epithelial lining) Image 5. There was no pancreatobiliary differentiation in any of the 6 invasive mucinous cystadenocarcinomas of the pancreas.

Immunohistochemistry

The cuboidal epithelial lining of 8 cystadenomas showed strong and diffuse immunoreactivity for CK7 and CAM5.2, as well as focal reactivity for MUC1 Image 6. Focal expression of MUC5AC was noted in 8 tumors. CDX2 and MUC2 were focally positive in 2 cystadenomas that contained goblet cells Image 7, whereas CK20 and MUC6 were negative in all cystadenomas. The ovarian-like stroma showed immunoreactivity for estrogen and progesterone receptors in 7 of the 8 tumors Image 8 and Image 9, whereas the cuboidal pancreatobiliary epithelium was unreactive. Focal expression of inhibin was noted in the ovarian-like stroma of 5 cystadenomas.

Image 1

A multiloculated cystic neoplasm involved the tail of the pancreas, which appears compressed.

Image 2

Whole-mount section of a multiloculated cystic pancreatic neoplasm. Different-sized locules are seen (H&E stain, ×5).

Image 3

The wall of a locule is lined by a single layer of cuboidal pancreatobiliary cells. A cellular ovarian-like stroma is present beneath the epithelium (H&E stain, ×100).

Image 4

Two mature goblet cells are seen among the cuboidal pancreatobiliary epithelial cells. A cellular ovarian-like stroma is visible beneath the epithelium (H&E stain, ×100).

Discussion

Our findings indicate that nonmucinous and mucinous cystadenomas of the pancreas share a number of clinicopathologic features. Similarities include middle-age female predominance, location in the tail of the pancreas, multiloculation, and ovarian-like stroma. Among the most important differences are the lack of mucinous or foveolar epithelium, the nonmucinous quality of the fluid, and the lack of dysplastic changes in the cuboidal pancreatobiliary epithelium. Surprisingly, nonmucinous cystadenomas are not uncommon. In our material, they represented 29% of classical mucinous cystadenomas with ovarian-like stroma, and more than 86% of these latter neoplasms showed the focal (5%–50%) pancreatobiliary phenotype. We believe pancreatic cystadenomas that show more than 50% of lining cells with the pancreatobiliary phenotype should be included in the nonmucinous cystadenoma category. Surprisingly, in the chapter on mucinous cystic neoplasms in the AFIP fascicle on tumors of the pancreas, Figures 5–23 and 5–24 illustrate pancreatobiliary differentiation, not mucinous epithelium, as indicated by the figure legends.11 The pancreatobiliary differentiation, as reported in biliary-type tubular gallbladder adenomas, is supported by the diffuse immunoreactivity for CK7, CAM5.2, and MUC1, which are markers of pancreatobiliary differentiation.11,15 The immunoprofile of the ovarian-like stroma was similar to that reported in classical mucinous cystadenomas of the pancreas. The spindle cells expressed estrogen and progesterone receptors in all 8 tumors, whereas inhibin was focally positive in 5 of 8 cases.11,16 The pancreatobiliary phenotype is not unique to nonmucinous cystic tumors of the pancreas. It has long been recognized in intraductal papillary mucinous neoplasms (IPMNs), although the pancreatobiliary cells are dysplastic and the ovarian-like stroma is lacking in these tumors. In addition, these IPMNs arise in the main pancreatic duct or its branches.11 Cystic neoplasms of the extrahepatic biliary system may also show pancreatobiliary differentiation, and some may lack a mucinous epithelial component and contain serous fluid. Among 6 cystadenomas of the extrahepatic bile ducts we examined, 4 had a predominant or exclusive pancreatobiliary phenotype and contained serous or clear fluid (J. Albores-Saavedra, unpublished observations).

Image 5

On one side, a connective tissue septum is lined by columnar mucinous epithelium, whereas the opposite side is lined by 3at pancreatobiliary epithelium (H&E stain, ×100).

Image 6

The cuboidal pancreatobiliary epithelium shows diffuse immunoreactivity for CK7 (×100).

Image 7

The cuboidal cells adjacent to goblet cells show immunoreactivity for CDX2 (×100).

Image 8

Nuclear expression of estrogen receptors in the cells of the ovarian-like stroma (×100).

Our findings also indicate that mucinous cystadenomas of the pancreas display a broader morphologic spectrum than previously reported. The identification of nondysplastic cuboidal epithelium similar to the epithelium of normal pancreatic ducts or the epithelium of tubular-type biliary gallbladder adenomas, as the predominant or exclusive lining found in the locules of the 9 cystadenomas described here, expands on the cytologic features of cystic pancreatic neoplasms. Moreover, the content of the locules was not described as mucinous but rather as clear or serous. In fact, the CEA cyst fluid level determined in 2 cases was not elevated, as has been reported in serous cystadenomas of the pancreas.17 Nonetheless, we believe these 9 benign nonmucinous cystic neoplasms belong to the family of mucinous cystic neoplasms of the pancreas because they are found predominantly in the tail of the pancreas of middle-aged women and contain the characteristic ovarian-like stroma, which is the hallmark of these tumors.18,19 However, in our opinion, they should not be classified as mucinous because they contain serous or clear fluid, and their epithelial lining consists of a single layer of cuboidal epithelium. Moreover, it seems reasonable to assume that these pancreatic cystic neoplasms with the pancreatobiliary phenotype have no malignant potential because they lack dysplastic changes. The absence of pancreatobiliary epithelium in 6 invasive mucinous cystadenocarcinomas of the pancreas further supports this hypothesis, although the number of cystadenocarcinomas we examined is too small to be conclusive, and a larger series is needed to confirm this hypothesis. Mucinous cystadenomas with low-grade dysplasia probably follow the same benign clinical course as the nonmucinous cystadenomas described in this report. In contrast, some of the classical mucinous cystadenomas show high-grade dysplasia and may progress to cystadenocarcinomas.11 The pancreatobiliary phenotype has not been described in invasive mucinous cystadenocarcinomas of the pancreas.11,12

Image 9

Stronger nuclear expression of progesterone receptors in the cells of the ovarian-like stroma (×100).

Nonmucinous pancreatic cystic tumors with the pancreatobiliary phenotype and ovarian-like stroma should be distinguished from all other cystic lesions of the pancreas, especially those lined by pancreatic ductal cuboidal epithelium.11 Although retention cysts are lined by cuboidal pancreatic ductal epithelium, they result from ductal obstruction commonly caused by chronic pancreatitis or a neoplasm located in the head of the pancreas or ampulla of Vater. They are usually single and unilocular, and they lack the ovarian-like stroma. Serous cystadenomas, which are usually microcystic and less frequently macrocystic, are lined by cuboidal glycogen-rich clear cells. The ovarian-like stroma is not present in these tumors. Congenital cysts usually occur in children and are lined by cuboidal nondysplastic epithelium but lack the ovarian-like stroma. Although pseudocysts lack an epithelial lining clinically, they can be confused with the nonmucinous pancreatic cystic tumors that are the subject of this report. Pseudocysts, however, are often seen in patients with a history of acute pancreatitis. They are unilocular, and their fibrotic wall contains inflammatory cells.

On the basis of the presence of an ovarian-like stroma, some authors may contend that cystic pancreatic tumors should be classified as mucinous cystic neoplasms, an opinion we do not share for the following reasons: the 9 cystic pancreatic tumors we have described were not lined by mucinous or foveolar epithelium, they did not produce a mucinous fluid, and their nondysplastic epithelial lining was similar to the epithelium of normal pancreatic ducts. Moreover, their cuboidal epithelium did not show dysplastic changes, a sine qua non for the diagnosis of mucinous pancreatic cystadenomas. Furthermore, these pancreatic cystic neoplasms with a pancreatic biliary phenotype probably did not have malignant potential. The ovarian-like stroma was similar to that of mucinous cystic pancreatic neoplasms, and it has been recognized in other cystic neoplasms such as cystic nephromas and, of course, ovarian cystic neoplasms, which are classified according to their epithelial lining.2022 Finally, we emphasize that cystic pancreatic tumors are epithelial in origin, not mesenchymal neoplasms.

CME/SAM

Upon completion of this activity you will be able to:

  • distinguish 2 types of pancreatic cystic neoplasms with ovarian-like stroma: mucinous and nonmucinous.

  • discuss and compare the biological potential and risk for malignant transformation of nonmucinous and mucinous pancreatic cystic neoplasms with ovarian-type stroma.

  • outline immunohistochemical stains that may assist in differentiation of mucinous vs nonmucinous cystic neoplasms of the pancreas with ovarian-like stroma.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Questions appear on p 691. Exam is located at www.ascp.org/ajcpcme.

Footnotes

  • This study was supported by Medica Sur Clinic and Foundation, Mexico City, Mexico.

References

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.
  11. 11.
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. 16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
View Abstract