Abstract

According to the classification of pancreatic carcinoma, rare neoplasms containing numerous multinucleated giant cells are categorized as giant cell carcinoma in anaplastic ductal carcinoma. Osteoclast-like giant cells in the giant cell carcinoma are considered of reactive histiocytic origin, whereas the stroma is considered as a neoplastic component. However, multinucleated giant cells are occasionally found even in usual pancreatic diseases. In 62.5% of usual ductal adenocarcinomas, and in 34.5% of chronic pancreatitis cases, we found giant cells. Various histological and immunohistochemical types of giant cell were found. Epithelial atypical giant cells are positive for epithelial markers and negative for mesenchymal markers; they are bizarre atypical cells in the cancer nest. This type was seen in pleomorphic-type anaplastic carcinoma and in 55% of usual ductal adenocarcinoma. Coexpressed-type atypical giant cells are positive for both epithelial markers and vimentin. Non-expressed-type atypical giant cells are pleomorphic giant cells negative for epithelial markers and CD68. Coexpressed- and non-expressed-type giant cells are considered to be epithelial neoplastic cells with a non-cohesive invasive growth pattern. This type was seen in 10% of usual ductal adenocarcinomas. Mesenchymal-type giant cells are negative for epithelial markers and positive for mesenchymal markers (vimentin and CD68). These giant cells are considered of reactive histiocytic origin. In the giant cell carcinomas and usual ductal carcinomas, they are found in the lumen of the tumor gland or stroma. In chronic pancreatitis, they are accompanied by protein plugs, pancreatic stones, abscesses, and fat necrosis. This type was seen in 15% of usual ductal adenocarcinomas and 34.5% of chronic pancreatitis cases.

Copyright © 2007 S. Karger AG, Basel

Although the majority of pancreatic cancers are ductal carcinomas, rare neoplasms containing numerous multinucleated giant cells have been found. In the Japanese classification of pancreatic carcinomas, giant cell carcinoma is categorized as anaplastic ductal carcinoma. However, multinucleated giant cells were occasionally found even in usual pancreatic lesions. There is a variety of

Fig. 1. Osteoclastoid-type giant cell carcinoma. CD68 is positive in osteoclast-like giant cells and some histiocyte-like mononuclear cells, but negative in pleomorphic large cells and atypical mononuclear cells.

giant cells. On the one hand, bizarre multinucleated giant cells are considered to represent pleomorphic forms of the malignant epithelial cells. On the other, macrophages and foreign-body giant cells may occasionally be drawn into areas of hemorrhage, abscess and necrosis. These giant cells arise from the fusion of macrophages. In these cases, the giant cells represent a reactive infiltration of macrophages.

We present some pancreatic tumors accompanied by numerous multinucleated giant cells and some types of multinucleated giant cells in various pancreatic diseases.

Pancreatic Tumors with Numerous Giant Cells

Extraskeletal osteoclast-like giant cell tumors have been described infrequently in a variety of organs. Among them, the pancreas is relatively frequent. Giant cell carcinoma of the osteoclastoid type is classified as anaplastic carcinoma. Associations with mucinous cystic tumors have also been reported.

Giant Cell Carcinoma (Anaplastic Carcinoma)

Histologically, the giant cell carcinoma is composed of osteoclast-like giant cells, pleomorphic giant cells and mononuclear cells. Some of the mononuclear cells appear to be histiocytic, whereas others are atypical. Typical glandular structures of adenocarcinoma are occasionally present (fig. 1).

The osteoclast-like giant cells and histiocytic mononuclear cells are positive for histiocytic markers and negative for epithelial markers. The pleomor-phic giant cells and atypical mononuclear cells are negative for both epithelial and histiocytic markers. Some atypical mononuclear cells are positive for some cytokeratins and vimentin. Overt adenocarcinoma cells are positive for epithelial markers and negative for histiocytic markers. Although K-ras activation is

Fig. 2. Mucinous cystadenocarcinoma associated with osteoclast-like giant cells. Mucinous epithelium lining cystic spaces and osteoclast-like giant cells in the stroma.

considered as an early event in tumorigenesis of the pancreatic ductal epithelium, according to some reports [1-4], pleomorphic giant cells and some atypical mononuclear cells had K-ras gene mutations; however, the osteoclast-like giant cells lacked this mutation. A ductal neoplastic origin of such sarcomatous elements is suggested. Osteoclast-like giant cells and histiocytic mononuclear cells are considered to be of reactive histiocytic origin.

Osteoclast-Like Giant Cell Tumors Associated with

Mucinous Cystic Tumor

Mucinous cystic tumors usually appear as a unilocular or multilocular encapsulated cystic mass, located in the tail or body of the pancreas, and predominantly occurs in middle-aged woman. Microscopically, the tumor is composed of mucin-producing columnar epithelium and overlying ovarian-type stroma (fig. 2). The ovarian-type stroma is considered as a component of the neoplasm, not a reactive phenomenon. Immunohistochemical features have been demonstrated in the stromal cells, such as overexpression of p53 and relationship to some ovarian hormonal functions [5-8]. Osteoclast-like giant cells associated with ovarian-type stroma of the mucinous cystic tumors have been reported [5, 9]. These giant cells were positive for histiocytic markers.

Osteoclast-like giant cells are hence considered to be reactive inflammatory cells, although stromal cells are neoplastic cells.

Multinucleated Giant Cells in the Ductal Carcinoma and

Chronic Pancreatitis

Multinucleated giant cells are occasionally found even in the usual pancreatic lesions. According to our previous report [10], multinucleated giant cells were found in 62.5% of tubular adenocarcinomas, and 34.5% of chronic pancreatitis cases (table 1). However, multinucleated giant cells varied from

Table 1. Multinucleated giant cells in various pancreatic diseases

n

Epithelial

Coexpressed

Mesenchymal

fype

type

type

I. Chronic pancreatitis

29

0

0

10 (34.5%)

II. Pancreatic carcinomas

Mucinous cystic tumor

Mucinous cystadenocarcinoma

1

0

0

1

Invasive ductal carcinomas

Tubular adenocarcinoma

[40

22 (55%)

4 (10%)

6 (25%)]

WeIl differentiated type

3

1

0

1

Moderately differentiated type

30

16

2

4

Poorly differentiated type

7

5

2

1

Mucinous carcinoma

2

1

0

0

Anaplastic carcinoma

Pleomorphic type

1

1

0

0

Osteoclastoid type

4

0

0

4

Epithelial type: Keratin (+); EMA (+); Vimentin (-); CD68 (-). Coexpressed type: Keratin (+); EMA (+); Vimentin (+); CD68 (-). Mesenchymal type: Keratin (-); EMA (-); Vimentin (+); CD68 (+).

Epithelial type: Keratin (+); EMA (+); Vimentin (-); CD68 (-). Coexpressed type: Keratin (+); EMA (+); Vimentin (+); CD68 (-). Mesenchymal type: Keratin (-); EMA (-); Vimentin (+); CD68 (+).

benign-looking histiocytic to bizarre neoplastic giant cells. They were classified histologically and immunohistochemically into several types.

Epithelial Atypical Giant Cell (fig. 3 a)

We classified the giant cell as the epithelial type if it was positive for epithelial markers (keratin or EMA) and negative for mesenchymal markers (vimentin and CD68). Histologically, these giant cells showed marked cellular pleomorphism with sometimes irregular bizarre nuclei and abundant mitotic figures. These were found in the cancer nest and a transitional form from glandular structure was seen. This type was seen in pleomorphic-type anaplastic carcinomas and even in 55% of usual ductal adenocarcinomas.

Coexpressed Atypical Giant Cell and Non-Expressed

Atypical Giant Cell (fig. 3b)

We classified the giant cell as the coexpressed type if it was positive for both epithelial markers (keratin or EMA) and vimentin. These giant cells were also pleomorphic atypical cells. These were found in the invasive area which showed a non-cohesive growth pattern, and these cells were individually detached from one another. This type was recognized in 10% of usual ductal

Fig. 3. Multinucleated giant cells in various pancreatic diseases. a Epithelial atypical giant cells in a moderately differentiated tubular adenocarcinoma. This type expressed keratin and EMA. b Coexpressed atypical giant cells in a poorly differentiated tubular adenocarcinoma. This type reacted with both epithelial and vimentin antibodies. c Mesenchymal giant cells in a moderately differentiated tubular adenocarcinoma. d Mesenchymal giant cell in chronic pancreatitis. This type (c, d) reacted with CD68.

Fig. 3. Multinucleated giant cells in various pancreatic diseases. a Epithelial atypical giant cells in a moderately differentiated tubular adenocarcinoma. This type expressed keratin and EMA. b Coexpressed atypical giant cells in a poorly differentiated tubular adenocarcinoma. This type reacted with both epithelial and vimentin antibodies. c Mesenchymal giant cells in a moderately differentiated tubular adenocarcinoma. d Mesenchymal giant cell in chronic pancreatitis. This type (c, d) reacted with CD68.

adenocarcinomas. All were far advanced autopsy cases. We considered this type as epithelial neoplastic origin. Epithelial neoplastic giant cells are common in ductal carcinomas with poor differentiation. These cells are usually positive for epithelial markers; however, coexpression of vimentin and cyto-keratin is occasionally seen. Coexpression of vimentin and cytokeratin was reported in some conditions [11-13]. In cultured epithelial cells, when extensive cell-cell contact was achieved, the cells synthesized high levels of cyto-keratins and low levels of vimentin. In contrast, when cell-cell contact was minimal, the cells synthesized very low levels of cytokeratins and high levels of vimentin. The results suggest that vimentin synthesis responds to alterations of cell spreading [12]. In clinicopathological study of gastric carcinoma, vimentin expression was related to infiltrative growth, lymph node involvement and vascular invasion [13].

In the anaplastic carcinoma, there were pleomorphic atypical giant cells which were negative for epithelial markers and CD68, and some of which were positive for vimentin. These giant cells were considered to be of similar type as the coexpressed type.

Mesenchymal Giant Cell (fig. 3c)

We classified the giant cell as the mesenchymal type if it was negative for epithelial markers (keratin and EMA) and positive for mesenchymal markers (vimentin and CD68). These giant cells had multiple uniformly oval nuclei and abundant cytoplasm without atypical features. Osteoclast-like giant cells and foreign-body giant cells were included in this type. It was seen in 15% of usual ductal adenocarcinomas and 34.5% of chronic pancreatitis cases. In the tubular adenocarcinomas, these giant cells were found in the lumen of tumor the gland or stroma. In the giant cell carcinomas of osteoclastoid type, these giant cells were scattered between the stromal cells. In the mucinous cystadenocarcinoma, they were scattered in the ovarian-like stroma. In chronic pancreatitis, they were foreign-body giant cells associated with protein plugs, pancreatic stones, abscesses and fat necrosis. We considered this type of reactive histiocytic origin.

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