Abstract
Solid pseudopapillary tumor of the pancreas was studied in a 20-year-old woman and a 54-year-old woman. In the younger patient, the tumor had metastasized to the liver 8 years after distal pancreatectomy. In both neoplasms, the distinct histologic pattern of solid, pseudopapillary, and degenerative cystic areas was present. Analysis by means of immunohistochemistry revealed a diffuse expression for vimentin, neuron-specific enolase, and a focal positivity for α1-antitrypsin, whereas epithelial markers were negative in the tumor of the older patient and only focally expressed in the tumor of the younger patient. Immunohistochemical analysis of cell cycle–associated proteins provided an overexpression of cyclin D1 and cyclin D3 in both tumors, although to varying degrees. In addition, the cyclin-dependent kinase inhibitors p21, and to a lesser extent p27, were up-regulated just as mdm2. There was no accumulation of p53 protein, and Ki67-positive cells were extremely scarce. Analysis of the liver metastases showed an immunoreactive profile similar to that of the primary tumor. The results show a deregulation of the cell cycle with overexpression of cell cycle–activating proteins D1 and D3 and a probably counterbalancing up-regulation of the cyclin-dependent kinase inhibitors p21 and p27. The findings may explain the low pool of Ki67-reactive tumor cells and the generally good clinical outcome of these tumors. Whether a more profound dysbalance of the cell cycle regulation is responsible for the development of metastatic disease remains to be clarified.
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INTRODUCTION
Solid pseudopapillary tumor is an uncommon neoplasm of the pancreas accounting for approximately 1 to 2% of all exocrine tumors of the pancreas (1). It occurs predominantly in girls (not before the age of 9 yr) and in younger women (mean age, 35 yr). Follow-up has shown that most tumors are clinically indolent. After complete tumor resection, more than 95% of the patients are cured (1). In malignant behavior, metastases occur most often in the liver (2, 3, 4, 5, 6, 7). Only a few patients have died of metastatic disease (reviewed in Solcia et al. (1)). The histogenesis and etiology of the tumor is still unknown. Analysis of ultrastructural studies performed in other investigations favors an origin from a totipotential stem cell with the capacity for endocrine-exocrine differentiation (8, 9, 10, 11). An occasional tumor may even be indistinguishable from mitochondria-rich oncocytic carcinoma (12).
In tumor genesis, the study of regulatory, cell cycle–associated cyclins, of cyclin-dependent kinase inhibitors p21, p27, of p53, and others are of special interest in various neoplasms. The cyclins D1 and D3 are important for the transition of cells from the G0/1 phase to the S phase (13, 14), and they activate cycle-dependent kinases. The complex of cyclin D1 and its cycle-dependent kinases phosphorylate retinoblastoma protein and thereby dissociate E2F-1 in its unbound active form (15). E2F-1, a member of the E2F transcription factor family, is the ultimate mediator of G1/S progression (16). E2F-1 may also be directly activated by the mdm2 oncoprotein (17), which additionally has an inhibitory effect on tumor suppressor gene p53 on G1 transition (18, 19).
Dysregulation or activation of D cyclins is documented in a wide variety of human malignancies. Cyclin D1 has especially been shown to be overexpressed in mantle cell lymphomas (20, 21) and a variety of carcinomas (22, 23, 24, 25, 26, 27, 28, 29, 30, 31). To date, accumulation of cyclin D3 has been studied less often; its accumulation has also been shown to be associated with an increase in breast tumors and pulmonary carcinomas (32, 33).
The cyclin-dependent kinase inhibitors p21 and p27 are reversible inhibitors of cell cycle progression at the G1 and G2 checkpoints (34, 35, 36, 37, 38, 39, 40). Along with p57/kip2, they interfere with kinase activities of cyclin–cycle-dependent kinases complexes. Functional p21 is essential for p53-mediated G1 arrest (36).
A marked decrease of p27 has been found in endocrine and nonendocrine tumors (37). An inverse correlation between p27 expression and cell proliferation was demonstrated in both normal and neoplastic human tissue; p27 expression was increased in quiescent cells and was expressed to a lesser degree in proliferative cells. In addition, mutations of the p53 suppressor gene have been established in various types of cancers (41).
In the present study, we analyzed the role of these cell cycle–regulatory proteins in two primary solid pseudopapillary tumors of the pancreas and in liver metastases to analyze their role in tumor initiation and progression.
CASE REPORT
Patient A, a 54-year-old woman, was healthy until nonspecific complaints led to the localization of a circumscribed, nodular, cystic mass in the head of the pancreas by means of nuclear magnetic resonance imaging. Clinical chemistry revealed normal values of GTP (12 U/L). γ-GT was slightly elevated (19 U/L), as was C-reactive protein (1.6 mg/dL) and blood glucose (127 mg/dL). Normal serum levels were obtained for CEA (<1.0 ng/mL), Ca 72-4 (1.7 U/mL), and Ca 19-9 (7.8 U/mL). Red blood cell counts were 4.62 106/μL, white blood cell counts were 7500/μL, and platelets were 435,000/μL. A gastro-pancreatico-duodenectomy (Whipple resection) was performed. The postoperative course and 1 year of follow-up were uneventful.
Patient B, a 12-year-old girl, was found via ultrasonography and magnetic resonance imaging to have a well-circumscribed mass in the tail of the pancreas; she underwent tests because she had accident-related epigastrial pain. A left hemipancreatectomy and splenectomy were performed. The postoperative course was uneventful. The girl developed normally. Normal levels were obtained for red and white blood cells (7000/μL and 4.44 106/μL, respectively) and platelets (495,000/μL). Liver enzymes (γ-GT and GPT) were in the normal range (7 and 14 U/L, respectively), as was blood glucose (72 mg/dL) during the next few years.
At the age of 22.5 years, the patient complained of unexplained fatigue. Laboratory investigations of samples found them to be within normal ranges. However, magnetic resonance imaging and ultrasonography revealed six nodular masses (up to 4 cm) in both hepatic lobes. A diagnostic liver biopsy and resection of the tumor masses were performed.
MATERIAL AND METHODS
Formalin-fixed, paraffin-embedded tissue was studied in routine diagnostics (hematoxylin and eosin, EVG, and periodic acid–Schiff). Immunohistochemistry was performed for the detection of epithelial and endocrine differentiation as well as for vimentin and α1-antitrypsin. Furthermore, cell cycle–associated proteins cyclin D1 and cyclin D3, and cell cycle inhibitors (cyclin-dependent kinase inhibitors) p21, p27, and bcl2, mdm2, p53, Ki67 and HER-2/neu were studied immunohistochemically with varying detection methods and antigen retrieval (Table 1). For evaluation of the immunocytochemical results, the amount of reactive cells and the intensity of the reaction (weak, moderate, and strong) were taken into account.
RESULTS
Gross Findings
In both patients, a well-circumscribed, partially solid, cystic mass with a gray, focally hemorrhagic cut surface was resected from the pancreas. The diameter was 5 cm in Patient A and 7.5 cm in Patient B. On the cut surface, a fibrous pseudocapsule existed that allowed demarcation from the surrounding tissue (Fig. 1A).
Microscopic Findings
Histology revealed a monomorphous epithelial differentiation of the tumor cells forming solid and pseudopapillary areas with a fibrovascular stalk (Fig. 1B). The cells showed round, nonhyperchromatic nuclei with finely dispersed chromatin and a weakly eosinophilic or clear cytoplasm. Mitosis was not seen. In the cystic areas, hemorrhage and cholesterol clefts, as well as resorptive giant cells, were present. Occasionally islets and ductal structures were included between the tumor tissue. A fibrous capsule separated the tumor tissue from the neighboring regular pancreatic parenchyma, especially at the periphery. In Patient B, the fibrous capsule was invaded by tumor tissue, but an infiltration of the fibrofatty peripancreatic tissue was not seen. The liver metastases had a histologic architecture identical to the primary tumor, with a solid tumor growth pattern and a well-developed fibrovascular stroma.
Immunohistochemistry
A panel of antibodies was used (Tables 1 and 2). In both tumors, a homogeneous intensive reaction for vimentin, neuron-specific enolase, and a focal intensive reaction for α1-antitrypsin was found. In Patient A, progesterone receptor protein could be localized in the nuclei in more than 50% of tumor cells with moderate staining intensity. In both patients, estrogen receptor protein was not demonstrated.
Ki67 could not be demonstrated in Patient A and was present in less than 1% of tumor cells in Patient B in both the primary tumor and the metastasis. Cyclin D1 was expressed in about 50% of tumor cell nuclei of both tumors (Fig. 2A), with reaction intensity found to be strong in Patient A and moderate in Patient B. In the adjacent regular pancreatic parenchyma, scattered nuclei were also present, but weakly stained. Cyclin D3 was expressed to a lesser degree in both tumors, being present in about 30% of tumor cell nuclei in Patient A with moderate reaction intensity, whereas in Patient B, less than 5% of cells reacted positively. The exocrine pancreas remained unstained, and islet cells showed a regular and intensive staining.
p21 protein was intensively expressed in nearly 100% of tumor cell nuclei in Patient A (Fig. 2B) and about in 10% of tumor cell nuclei of Patient B. In normal exocrine parenchyma, less than 1% of cell nuclei were moderately stained. p27 showed a moderate staining intensity in 50 to 100% of cells with an inhomogeneous reaction pattern in both tumors (Fig. 2C). The immunoreactivity for cyclin D3 and p21 in tumor tissue in the liver was at a similarly low level as in the primary tumor, whereas a slightly lower immunoreactivity was found for p27 and cyclin D1 (Fig. 3). No expression of p53 protein could be detected in the primary tumors and in the metastatic tumor tissue.
Negative immunohistochemical staining reactions were obtained in both patients for bcl2, HER-2/neu, chromogranin, and synaptophysin, as well as for keratin in Patient A; Patient B showed focal reactivity for keratin in about 30% of tumor cells.
DISCUSSION
The solid pseudopapillary tumor of the pancreas is still an enigma (42); it is a rare tumor of uncertain histogenesis and undetermined differentiation (8) and with low malignant potential. The tumor is likely derived from a pluripotent indifferent stem cell capable of both endocrine and exocrine differentiation.
A recent review reports 174 cases in the literature (7). Twenty-two of these patients' tumors had metastasized (7). Metastases most often occurred in the liver (15 of 22 patients). Multiple metastases, as in the patient we studied, are not uncommon (2, 3, 4, 5, 10, 43). As in the patient we studied, patients younger than 20 years of age at tumor diagnosis may have metastatic disease 8 to 10 years later (7), whereas patients diagnosed when they are older experience a shorter tumor-free interval. The morphology of the metastases in most cases does not differ from that of the primary tumor, as shown in the patient we studied. Both the primary tumor and the liver metastases had an extremely low staining for MIB-1 in our study. In one patient with peritoneal spread, a high mitotic index has been described (2). Death as a result of tumor metastases has been reported in four patients (7) 4 to 11 years after diagnosis. In two of these patients, aged 47 and 60 years, the tumor had been undiagnosed for 9 and 25 years, respectively (2).
Surgical resection in most cases has proven to be sufficient for cure. Tamoxifen therapy was administered to two patients who experienced metastases. The success of this type of treatment has not been documented, however (5). In one patient with multiple metastases of the liver, chemoembolization proved useful as a palliative measure for tumor regression (43). Liver metastases developed in one patient despite gamma irradiation and chemotherapy of the primary tumor (2).
The criteria determining malignant behavior of solid pseudopapillary tumor of the pancreas are still difficult to define. Mitotic activity, perineural angioinvasion, and infiltration of peripancreatic tissue have been proposed as discriminating factors (1). In one study (3), venous invasion, a higher nuclear grade, and prominent necrobiotic changes were associated with hepatic, peritoneal, and nodal metastasis (3). However, only three cases could be analyzed.
Flow cytometric analyses have shown that most tumors are diploid (3, 8, 44), although focal aneuploidy may be found after extensive sampling (44). Two tumors with metastatic disease were DNA aneuploid (3, 4). However, the small number of patients does not allow a definitive conclusion on the prognostic validity of DNA cytometry.
To our knowledge, the present study reports for the first time on the expression of cell cycle proteins in two cases of solid pseudopapillary tumor of the pancreas. Our study emphasizes that solid pseudopapillary tumors are extremely low proliferative neoplasms that lack evidence for dysregulation of the p53 gene. Instead, there was evidence of dysregulation of activating cyclins and inhibitory proteins, although to a varying extent in both patients.
We found an increased protein expression of cyclin D1 and of p21 and p27 protein. Interestingly, p21 was highly expressed in nearly 100% of tumor cells in one of the two patients. However, in the patient with liver metastasis, p21 expression was found only in about 10% of cells both in the primary tumor and in the liver metastases. Cyclin D1 was expressed at similar rates in both primary tumors, and the expression of cyclin D1 was not enhanced in the metastatic liver tissue. D cyclins are deregulated in a wide range of human malignancies. Cyclin D1 in particular has been shown to be overexpressed in mantle cell lymphoma and in a variety of carcinomas (19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31). In transitional carcinoma of the bladder (27) and ductal carcinoma in situ of the breast (45), cyclin D1 expression correlates inversely with the degree of differentiation.
Accumulation of p21 has been found to correlate with increased rate of proliferation and aggressive clinical course—for example, in head and neck squamous carcinoma (46) or in multiple myeloma (47)—indicating that the antiproliferative effect of p21 on the cell cycle progression may be overridden by other mechanisms. However, in low-malignancy solid pseudopapillary tumor of the pancreas, p21 and p27 cyclin-dependent kinase inhibitor up-regulation appears to continue to function, as judged from the extremely low pool of Ki67-positive cells in both the primary tumor and the liver metastases.
How p27 protein accumulates in solid pseudopapillary tumor remains to be clarified. It is known that p21 accumulation may occur through a p53-independent mechanism (48), which would seem to be the case in the patients we report. In vitro studies have shown that cyclin D1 induces transcriptional activation of p21 (49). It may therefore be assumed that in the case of solid pseudopapillary tumor, overexpression of cyclin D1 may be involved in the overexpression of p21. Although p21 protein was expressed to a lesser degree in Patient B than in Patient A, and although p27 protein was somewhat reduced in the metastatic tumor tissue of patient B compared with the primary tumor, our results give no definitive explanation for the metastatic potential of this tumor.
In summary, there is evidence of deregulation of cell cycle proteins in solid pseudopapillary tumor of the pancreas with varying overexpression of cell cycle–activating and cell cycle–inhibiting proteins. These features may help to explain the generally good clinical outcome of these rare tumors. However, it remains to be clarified how these alterations are involved in the initiation and progression of this type of tumor. The lack of expression of c-erbB-2 (HER-2/neu) and of p53 emphasizes that the pathogenesis of solid pseudopapillary tumor differs from that of usual carcinoma of the pancreas (50, 51, 52). However, the role of cyclins and cyclin-dependent kinase inhibitors has not yet been fully investigated in pancreatic adenocarcinoma (53, 54). At least it is known that inactivation of the p16 pathway may occur (53, 54) and that loss of p27 is associated with a poor prognosis (55).
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Acknowledgements
The authors are indebted to S. Nikolarakis and M. Wittmaier for their careful preparation of the manuscript and to Prof. W. Nathrath, Institute of Pathology, Städt, Krankenhaus Hanlaching, for providing tissue from the primary tumor of Patient B.
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Müller-Höcker, J., Zietz, C. & Sendelhofert, A. Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas. Mod Pathol 14, 47–53 (2001). https://doi.org/10.1038/modpathol.3880255
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DOI: https://doi.org/10.1038/modpathol.3880255
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