Discussion

In 1959, Frantz [1] first designated this tumor as 'papillary tumor of the pancreas-benign or malignant?'. In 1981, Klöppel et al. [2] described it as solid cystic acinar cell tumor because of its pathological features, and it had become

Fig. 3. Case 2. a A metastatic tumor is seen in the parapancreatic lymph node. HE. X 1.25. b The metastatic tumor cells have the same histology as those in the primary tumor, but have a few mitotic figures. HE. X10

Fig. 4. Case 3. a The tumor reveals prominent cystic formation with low papillary lesions on the inner surface. b The tumor displays a pseudopapillary structure with fibrovas-cular cores. HE. X10.

Fig. 3. Case 2. a A metastatic tumor is seen in the parapancreatic lymph node. HE. X 1.25. b The metastatic tumor cells have the same histology as those in the primary tumor, but have a few mitotic figures. HE. X10

Fig. 4. Case 3. a The tumor reveals prominent cystic formation with low papillary lesions on the inner surface. b The tumor displays a pseudopapillary structure with fibrovas-cular cores. HE. X10.

a well-known tumor. Since then, the same tumor has been given a variety of names, including solid and cystic tumor, papillary-cystic tumor, and solid and papillary epithelial neoplasm. In 1996, the World Health Organization (WHO) reclassified pancreatic tumors, and named this tumor solid-psuedopapillary tumor [3].

SPTP is a relatively rare tumor that has been reported to account for approximately 1-2% of all exocrine pancreatic tumors [4], but recently the rate has increased. To date, more than 700 cases have been reported in English-language medical literature [5], whereas almost 300 cases have been reviewed in Japanese literature. Kosmahl et al. [6] reported that of 1454 pancreatic

a i i i i i i i r r i i i i r
Fig. 5. Case 4. a Cut surface shows grayish-white solid tumor with hemorrhage. b The tumor is composed of ovoid cells with mild nuclear pleomorphism. HE. X10.

tumorous lesions they examined, 418 cases (29%) showed cystic formation, and the most numerous tumors among these cases were SPTPs (89 cases; 21.9%). The mean age of the patients was 30 years (range 11-73) and 87% were females. According to Yoshioka et al. [7], a series of 302 cases of SPTP reported during a 21-year period from 1979 to 1999 in Japan included 262 females (87%) and 40 males (13%) with a median age of 30 years (range 7-79). Based on 292 cases in a cumulative review of the world literature, Mao et al. [8] reported that 90% of patients were females with a mean age of 23.9 years. As mentioned above, most patients are young females, and development of this tumor thus suggests that hormonal [9] and genetic factors may play an important role.

Fig. 6. Case 2. Immunohistochemical findings are positive for (a) AAT, (b) NSE, (c) vimentin, and (d) PgR. X10.
Fig. 7. Ultrastructurally, the tumor cells contain zymogen-like secretory granules and annulate lamellae (X20,000).

In general, the gross appearance of this tumor shows cystic change with a solid component. However, of 173 cases of classic SPTPs reported in Japan, 22 cases were noncystic tumors, and reports of this type of tumor have been recently increasing [10]. Histologically, SPTP is characterized by solid and pseudopapillary patterns which are composed of relatively small uniform tumor cells with clear cytoplasm. The tumor cells have little or no nuclear pleomor-phism and mitotic figures are usually rare. Immunohistochemically, this tumor has a wide spectrum, showing different findings for epithelial, mesenchymal and endocrine markers [4]. According to a detailed Immunohistochemical study of 59 SPTPs by Kosmahl et al. [11], immunoreactivity for vimentin, AAT, NSE, and the progesterone receptor is each found in more than 90% of the tumors, whereas cytokeratin is found in almost 70%, and synaptophysin in 22%. Ultrastructural characteristic findings in SPTP are the presence of zymogen-like granules of various diameters or resembling endocrine granules, and annulate lamellae in the cytoplasm [2, 4]. As shown above, SPTP has immunohistochemical and ultrastructural features of both acinar-ductal and endocrine cells. These distinctive findings may be useful for the diagnosis of SPTP.

Despite many studies with immunohistochemistry and electron microscopy, the origin of tumor cells in SPTP is still undetermined. In the general rules for surgical and pathological studies on cancer of the pancreas in Japan [12], this tumor is categorized as an epithelial tumor of uncertain differentiation. Formerly, the origin of SPTP was considered to be acinar cells, because of positivity for AAT in immunohistochemistry and zymogen-like granules in electron microscopy [2]. Moreover, a neuroendocrine cell origin has been suggested by positivity for NSE and synaptophysin. Notohara et al. [13] reported that the tumor cells indicate, at least focally, neuroendocrine differentiation by CD10 and CD56 expression. However, it has now been suggested that SPTP derive from a totipotential stem cell which might be able to develop into all types of ductal, acinar or neuroendocrine cells, because results of immunohis-tochemical studies are not uniform. In addition, annulate lamellae, which are often ultrastructurally observed in this tumor, are considered to be a marker of immature cells because of their common appearance in germ cells. Therefore, some investigators support this hypothesis [8, 14]. As another unique hypothesis, Kosmahl et al. [11] recently proposed that this tumor might derive from ridge/ovarian anlage-related cells which were incorporated into the pancreas during early embryogenesis.

In general, patients with SPTP show a good prognosis after complete resection. However, approximately 10% of tumors are clinically malignant [6] and metastases have been reported in a few cases; tumor extension into surrounding organs, vessel invasion, local recurrence, and distant metastases have been documented [5-7, 13, 14]. The most common sites of distant metastasis are the liver, lymph nodes and peritoneum. According to Papavramidis et al. [5], of 497 PSTPs reported in the English-language literature, there were 97 cases of metastatic or invasive diseases, including liver (27 cases), portal vein (26 cases), spleen (17 cases) and other organs (duodenum, omentum, colon, etc.). Cappellari et al. [15] noted that the metastatic tumor cells showed bizarre giant cells and more increased nuclear pleomorphism and mitotic rate, although the primary tumor had the typical histology of SPTP. Moreover, Nishihara et al. [16] reported that venous invasion, nuclear grade, and prominent necrobiotic nests were important parameters of the malignancy potential of this tumor. However, in our case 2, there was histologically no difference between the primary tumor and the metastatic tumor in lymph node. Therefore, in many cases, it may be difficult to evaluate the malignancy potential of this tumor. According to several studies differentiating benign from malignant tumors by using DNA flow cytometry [15, 16], a few cases of PSTP with metastases revealed patterns of aneudiploidy. In addition, the proliferative fraction determined by Ki-67 immunostaining usually shows low indexes in both benign and malignant cases. However, Tang et al. [17] recently reported that in two rapidly fatal cases of SPTP with marked nuclear atypia and high mitotic rate, the Ki-67 labeling indexes were 30 and 40%, although the mean Ki-67 labeling in 34 conventional cases was <1%.

To the surgical pathologist, SPTPs might be still considered as an enigma. Further studies will be required to elucidate their nature and biological behavior.

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