The Clear Cell Variant of Solid Pseudopapillary Tumor of the Pancreas: A Previously Unrecognized Pancreatic Neoplasm
Jorge Albores-Saavedra, MD, Karen W. Simpson, MD, and Seth J. Bilello, MD
Abstract: Solid pseudopapillary tumor is a rare but distinctive pancreatic neoplasm whose cell phenotype remains a mystery. We report 3 cases of a previously undescribed variant of solid pseudopapillary tumor of the pancreas composed almost entirely of multivacuolated clear cells ( > 90%). The cytoplasmic vacuoles did not contain glycogen, mucin, or lipid but seemed to be formed by dilatation of the endoplasmic reticulum and mitochondria. The tumors displayed prominent trabeculae and a solid growth pattern but lacked the characteristic pseudo- papillary pattern of the classical solid pseudopapillary tumor. In contrast, the clinical features, gross characteristics, and immunoprofile were similar to those of classical solid pseudo- papillary tumor. Two of the patients were young adult females with well-demarcated tumors involving the body and tail of the pancreas. Tumor cells showed immunoreactivity for vimentin, CD10, CD56, synaptophysin, and nuclear accumulation of ß catenin. In 2 patients, 1 male and 1 female, the tumors were discovered incidentally. Despite vascular invasion in one of the tumors all 3 patients are disease free after distal pancreatectomy. Clues to distinguish the clear cell variant of solid pseudopapil- lary tumor from endocrine pancreatic tumor composed of clear cells, clear and foamy cell variants of ductal carcinoma, metastatic renal cell carcinoma, serous cystadenoma and ectopic adrenocortical nodules are provided.
Key Words: pancreas, solid pseudopapillary tumor, clear cell variant
(Am J Surg Pathol 2006;30:1237-1242)
S olid pseudopapillary tumor is a rare but distinctive pancreatic neoplasm with low metastatic poten- tial.2,13,19,23 It accounts for 1% to 2% of all pancreatic malignancies2 and the overall mortality rate of the tumor has been estimated to be low (around 1.5%).2 Despite numerous studies using immunohistochemical markers, electron microscopy and molecular pathology, its cell phenotype remains a mystery.1,5,16-18,22,25,26 Likewise, it
is difficult or impossible to predict the biologic behavior of the tumor based on histologic features alone.23 Recently, however, 2 cases (one with sarcomatoid features) showing diffuse growth patterns, considerable nuclear pleomorphism, tumor necrosis, and high mitotic rate that followed a malignant clinical course have been described.23
The purpose of this investigation is to describe the clinicopathologic, immunohistochemical, and electron microscopic features of 3 examples of the clear cell variant of solid pseudopapillary tumor of the pancreas which to our knowledge has not been previously reported.
MATERIALS AND METHODS
Two cases used in this investigation were obtained from the personal consultation files of one of the authors (J.A.S.) and the third case from the pathology files of the Department of Pathology of Louisiana State University Health Sciences Center in Shreveport, Louisiana. Clinical information was obtained from the pathology reports, clinical charts, and by communication with the referring pathologists. Multiple sections of the 3 tumors and adjacent normal pancreas were fixed in 10% buffered formalin and embedded in paraffin. Hematoxylin and eosin, periodic acid Schiff with and without diastase digestion and mucicarmine stains were available for review. Frozen sections were obtained from fresh tumor tissue and stained with oil red O. Additional sections were obtained from selected paraffin blocks for immunohisto- chemical studies, which were performed on a Ventana Nexus automated immunostainer (Tucson, AZ) using the standard avidin-biotin peroxidase technique. The follow- ing antibodies were used: cytokeratin AE1/AE3 (pre- diluted Ventana, Tucson, AZ), CAM5.2 (prediluted Ventana, Tucson, AZ), synaptophysin (prediluted Cell Marque, Hot Springs, Arkansas), chromogranin (pre- diluted Ventana), CD10 (predulited Ventana), CD56 (prediluted Ventana), vimentin (prediluted Ventana), and ß-catenin (dilution 1:150 B D Biosciences, San Jose, CA.). Known positive and negative controls were used throughout.
Small fragments (1 to 2 mm) of neoplastic formalin- fixed tissue from case 3 were postfixed in Carson fixative (Fisher Scientific Co, Middletown, VA) and embedded in araldite 5% resin. Sections were obtained with the ultramicrotome stained with uranyl acetate and lead
Reprints: Jorge Albores-Saavedra, MD, Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 (e-mail: jalbor@lsuhsc.edu).
Copyright @ 2006 by Lippincott Williams & Wilkins
citrate, and examined with a Phillips transmission electron microscope (CM10 model).
RESULTS
The main clinicopathologic features of the 3 tumors are included in the Table 1. The 3 patients, 2 women and 1 man, were young adults whose ages range from 26 to 32 years. The tumor was discovered incidentally in 2 patients by imaging techniques after trauma in one and during segmental resection of the transverse colon for a large tubulovillous adenoma in another. The diagnosis of solid pseudopapillary tumor of the pancreas was suggested by the radiologist in 2 patients. Serum carcinoembroyonic antigen and CA19.9 levels were within normal range.
Gross Pathology
All 3 tumors were well demarcated and unencapsu- lated. They measured from 4.5 to 8 cm and were gray- white and firm. Two of the tumors had areas of cystic degeneration, and one also displayed hemorrhagic foci (Fig. 1).
Microscopic Pathology
The tumors were well demarcated but unencapsu- lated. Focal neoplastic infiltration into adjacent normal pancreas was seen in 2 tumors, whereas entrapped islets were noted in the third one. A trabecular pattern predominated in all 3 tumors, but a sheetlike pattern was also present (Fig. 2). The trabeculae were separated by bands of hyalinized fibrous tissue of variable thicknesses (Fig. 3). The hyalinized stroma showed prominent myxoid areas in 2 tumors. There were no pseudopapillary structures, but collections of hyaline globules were identified. Formation of pseudotubules due to loss of cohesion of the cells from the central portion of the trabeculae occurred in 1 tumor. The most characteristic and striking feature of all 3 tumors was the presence of numerous small and large cytoplasmic empty vacuoles in nearly all neoplastic cells ( > 90%) (Figs. 4, 5). These vacuoles were periodic acid-Schiff, mucicarmine,
and oil red O negative. The round or ovoid, centrally placed, or eccentric nuclei contained inconspicuous nucleoli and finely stippled or granular chromatin. There were very few or no mitotic figures, but vascular invasion was identified in 1 tumor (Fig. 6).
Immunohistochemistry
The neoplastic cells of the 3 tumors were diffusely positive for vimentin and focally positive for cytokeratin (AE1/AE3), CD10, CD56, and synaptophysin (Figs. 7-9). Immunoreactivity for ß-catenin revealed nuclear accumulation in all 3 tumors. Chromogranin and
| TABLE 1. | ||||||||
|---|---|---|---|---|---|---|---|---|
| Case Number | Age | Sex | Clinical Presentation | Location | Size | Original Diagnosis | Treatment | Follow-up |
| 1 | 32 | Female | During segmental resection of the transverse colon for a tubulovillous adenoma, a pancreatic tumor was palpated. | Body and tail | 6 cm | Well-differentiated endocrine neoplasm | Distal pancreatectomy | Disease free 6 y after surgery |
| 2 | 32 | Female | Abdominal pain of several months duration. CT scan revealed a well-demarcated solid pancreatic mass with a cystic component | Body and tail | 8 cm | Well-differentiated endocrine neoplasm | Distal pancreatectomy | Disease free 4 y after surgery |
| 3 | 26 | Male | CT scan performed for motor vehicle accident revealed a well-circumscribed pancreatic mass | Body and tail | 4.5cm | Solid pseudopapillary tumor, clear cell type | Distal pancreatectomy | Recent case |
cytokeratin CAM5.2 immunostains were negative in all 3 tumors.
Electron Microscopy
The most striking feature of the neoplastic cells was the presence of cytoplasmic vacuoles of different sizes. Most of the smaller vacuoles or vesicles seem to be dilated or distended mitochondria, whereas others seemed to arise from the smooth endoplasmic reticulum (Fig. 10). In some of the small vacuoles, a few cristae could still be identified. There was gradual transition from normal mitochondria with cristae to distended mitochondria with attenuation of cristae and loss of matrix. The large vacuoles contained amorphous granular material and had a limiting membrane but were not connected to the smooth endoplasmic reticulum or mitochondria (Fig. 11).
Some of the large vacuoles seemed to coalesce and displace the nuclei, which were round or ovoid and had small nucleoli and granular chromatin. The cytoplasm contained a moderate amount of smooth and rough endoplasmic reticulum but no glycogen particles, lipid droplets, or neurosecretory granules. The cells were joined by poorly developed cell junctions or small desmosomes.
DISCUSSION
The clinical features of the 3 patients that form the basis of this report were similar to those with classical solid pseudopapillary tumor of the pancreas.14,15 Two patients were young adult females with asymptomatic
tumors discovered incidentally, which may explain their relatively small size. The radiologic findings in 2 patients were considered so characteristic that the diagnosis was suspected preoperatively by the radiologist.6 The gross characteristics and immunohistochemical profile of the clear cell and the classic solid pseudopapillary tumor did not differ and therefore, provide additional support to the idea that the former is a variant of the latter. Micro- scopically, however, the clear cell variant of solid pseudopapillary tumor was characterized by prominent trabecular and diffuse growth patterns and lack of pseudopapillary architecture. The most striking feature, however, was the presence of multiple cytoplasmic vacuoles of different sizes in nearly all neoplastic cells. The vacuoles did not contain glycogen, lipid, or mucin. They seemed to be formed by dilatation of the smooth endoplasmic reticulum and mitochondria. There was
gradual transition from slightly distended endoplasmic reticulum and distended mitochondria to formation of microvesicles and vacuoles having a limiting membrane in many cells. Clear cells with cytoplasmic vacuoles have been described as a focal change in the classical form of solid pseudopapillary tumor of the pancreas. However, the mechanism by which the cytoplasm becomes clear has not been elucidated.15 Another source of clear cells in this tumor are foamy macrophages.15 Unusual cell types that have been described in solid pseudopapillary tumor of the pancreas include oncocytic cells, which may predominate and simulate oncocytoma,10 and pleomorphic spindle cells, which are responsible for the sarcomatoid fea- tures.23 Moreover, cells with melanocytic differentiation have recently been added to the list of unusual cell types.7 Neoplastic cells with multiple cytoplasmic vacuoles, which seem to be the result of distended mitochondria
B
5.20K 0. 1.5.2.
or endoplasmic reticulum, have been reported in a variety of neoplasms including clear cell carcinoma of the thyroid and balloon cell melanoma.8,9,12 In other tumors such as
6.6 1 K 0. 1.5.3.
chromophobe renal cell carcinoma, the origin of the vacuoles has not been clarified.24
Because the clear cell variant of solid pseudopapillary tumor of the pancreas is composed almost entirely of clear cells, the differential diagnosis is broad and includes a variety of clear cell tumors and tumorlike lesions of the pancreas. Endocrine tumors of the pancreas with clear cell morphology can be confused with the clear cell variant of solid pseudopapillary tumor, especially because both tumors express synaptophysin and CD56. Patients with von Hipple- Lindau syndrome may develop clear cell endocrine pan- creatic neoplasms due to a germ line mutation in the VHL tumor-suppressor gene in chromosome 3p25.11 The clear cytoplasm of the tumor cells in these tumors, however, is due to the presence of small lipid droplets. These cells also contain neurosecretory granules that are chromogranin positive and do not label for ß-catenin. Several pancreatic hormones have also been demonstrated by immunohisto- chemistry.11 Furthermore, a component of conventional endocrine tumor of the pancreas is usually present in these tumors. Sporadic endocrine tumors of the pancreas may consist almost exclusively of clear cells loaded with small lipid droplets that provide a microvesicular appearance to the cytoplasm. These tumors contain chromogranin-positive granules and sometimes pancreatic hormones but do not label with ß-catenin.21 The clear cell variant of solid pseudopapillary tumor of the pancreas should be distin- guished from the clear cell variant of ductal carcinoma of the pancreas. The latter is a highly malignant neoplasm occurring in older individuals and is associated with marked stromal desmoplasia, greater cytologic atypia, increased mitotic activity and more importantly, areas of conventional mucin-producing ductal carcinoma.20 The immunohistochemical profile of the clear cell variant of ductal carcinoma is different from that of solid pseudopapillary tumor of the pancreas. The foamy gland pattern of ductal adenocarcinoma of the pancreas consists of cells with a foamy appearance due to the presence of small mucin droplets.3 Although serous cystadenoma is composed entirely of clear cells, these cells contain glycogen and line small or large cystic spaces.15 Metastatic renal cell carcinoma may present as a solitary mass in the pancreas and simulate a primary neoplasm. As metastatic renal cell carcinoma is usually composed of clear cells which are CD10 positive, it may be confused with the clear cell variant of solid pseudopapillary tumor of the pancreas. However, metastatic renal cell carcinoma occurs in older individuals, the neoplastic cells contain lipid and are synaptophysin and ß-catenin negative. Ectopic adreno- cortical nodules in the pancreas are smaller than solid pseudopapillary tumor. Although composed entirely of clear cells, these nodules contain lipid rich cells arranged in thin cords identical to those of the zona fasciculata of the adrenal cortex.4
In conclusion, we have described 3 examples of a variant of solid pseudopapillary tumor of the pancreas composed almost exclusively of clear cells. The clear cytoplasm does not contain glycogen, lipid, or mucin and seems to be the result of distended endoplasmic
reticulum and mitochondria. The clinical features, gross characteristics, and immunoprofile of this clear cell variant are similar to those of the classical solid pseudopapillary tumor. The broad differential diagnosis is discussed.
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