title: Pathogenesis of colloid (pure mucinous) carcinoma of exocrine organs: Coupling of gel-forming mucin (MUC2) production with altered cell polarity and abnormal cell-stroma interaction may be the key factor in the morphogenesis and indolent behavior of colloid carcinoma in the breast and pancreas.
abstract: In the exocrine organs, breast and pancreas, colloid carcinoma (CC, pure mucinous carcinoma), characterized by well-circumscribed lakes of mucin that contain scanty, detached malignant cells, has a significantly better prognosis than conventional ductal carcinomas (DCs). It has been speculated by us and others that an inverse polarization of cells may be responsible for the accumulation of extracellular mucin. Another possibility is that this mucin is biochemically and biologically distinct from the mucin secreted by the conventional carcinomas of these organs. This study was undertaken to investigate these two hypotheses: 1) To test whether there is indeed an alteration in cell polarity in CC. Immunohistochemical stains for luminal surface glycoproteins (carcinoembryonic antigen in pancreas and MUC1 in breast) were performed in 18 pancreatic and 30 mammary CCs and compared with the expression pattern in DCs (37 pancreatic and 47 mammary) and normal ducts. The results disclosed that these glycoproteins were expressed predominantly in the stroma-facing surfaces of CC cells, in contrast to the DCs, in which the expression was either on the luminal surface (in well-differentiated areas) or dispersed throughout the cell, intracytoplasmic in the poorly differentiated areas. Ultrastructural examination performed on 10 breast and two pancreatic CCs showed the condensation of mucigen granules (generally underlying an apical-type cell membrane) in the stroma-facing surface in all cases. In contrast, in the DCs (five pancreatic and five mammary), no clustering of mucigen granules was identified in the cytoplasm facing the stroma in any of the cases. Furthermore, no external lamina or basement membrane was detected in any of the CCs, whereas in the DCs, a distinct (in 3 of 10) or discontinuous (4 of 10) external lamina separated the tumor cells from the stroma. 2) To determine the expression frequency of MUC2 in CCs and to compare it with that in DCs and normal tissue, immunohistochemical stains with MUC2 (clone ccp58) were performed. MUC2 expression was detected in 18 of 18 pancreatic and 30 of 30 breast CCs and was exceedingly rare in DCs (1 of 136 pancreatic DC and 3 of 47 mammary, p <0.0001 in both organs). No labeling was detected in normal ducts. In conclusion, it appears that coupling of two factors is important for the distinctive morphologic characteristics and slow growth of CCs: The first one is the alteration in cell orientation as evidenced by the direction of surface glycoproteins and secretory organelles to the stroma-facing surface of the cells and the disruption of cell-stroma interaction as manifested by lack of basal lamina formation. Apparently, this altered polarity allows the CC cells to secrete the mucin toward the stroma. The mucin produced, MUC2 (also called gel-forming mucin), is highly specific for CC and is known to form strong bonds with the stroma, and also was found recently to have tumor suppressor activity. This distinctive mucin, accumulated in the stroma surrounding the CC cells, may act as a containing factor, slackening the spread of the cells.
authors.affiliation: Department of Pathology, Karamanos Cancer Institute and Wayne State University, Detroit, Michigan 48201, USA. adsayv@med.wayne.edu
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.forename: Kambiz
authors.initials: K
authors.lastname: Merati
authors.forename: Hind
authors.initials: H
authors.lastname: Nassar
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Fazlul
authors.initials: F
authors.lastname: Sarkar
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Jeanette D
authors.initials: JD
authors.lastname: Cheng
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016764:Cell Polarity; D003102:Colloids / Q000378:metabolism; D003593:Cytoplasm / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018396:Mucin-1 / Q000378:metabolism; D055262:Mucin-2; D009077:Mucins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D003102:Colloids; C524625:MUC2 protein, human; D018396:Mucin-1; D055262:Mucin-2; D009077:Mucins