Annexin A2 Expression in Aerogenous Metastasis of Pulmonary Invasive Mucinous Adenocarcinoma: A Case Report including Immunohistochemical Analysis

Abstract

Aerogenous metastasis (AM) is a form of lung cancer that spreads in a unique fashion, but its mechanisms are still unclear. Annexin A2 (ANX A2), a membrane-binding protein, promotes cancer invasion and is involved in cell adhesion and polarity. The relationship between ANX A2 and cancers with poor stromal invasion capacity has not been studied. We immunohistochemically analyzed ANX A2 expression in AM observed in a patient with pulmonary invasive mucinous adenocarcinoma. In the primary site, ANX A2 immunopositivity on the cell-cell borders weakened as tumor cells projected and separated into alveolar spaces. In AM, tumor cell aggregates with ANX A2 immunopositivity near the surface and within the cytoplasm attached to alveolar epithelial cells, then engulfed them and formed a protrusion. As tumor cell aggregates adhered to the alveolar wall and formed a single layer, cytoplasmic ANX A2-positive products accumulated in the lateral sides of the tumor cells and exhibited distinct membranous positivity. These results indicated that ANX A2 near the tumor cell surface was related to alveolar wall attachment. Furthermore, the translocation of cytoplasmic ANX A2 to cell-cell borders changed cell morphology, adhesion, and polarity restoration.

Figure 1

Axial computed tomography (CT) images. (a) A follow-up chest CT image obtained before left lobectomy shows a solid mass accompanied by infiltrative and reticular shadows, and the shadow of a suspected skip lesion (arrow) is also found near the mass. (b) Chest CT image obtained 1 month before partial resection of the right lung shows a widespread infiltrative shadow.

Figure 2

Left lung cancer. (a) Gross view shows an ill-defined gelatinous tumor with a diffuse pneumonia-like consolidation. Bar, 1 cm. (b) Columnar tumor cells with intracytoplasmic vacuoles reveal a papillary growth pattern. H&E stain, ×200. (c) Multiple mucin-producing tumor cells. Alcian blue stain, ×200. (d) Several tumor cells are positive for MUC 5AC. MUC 5AC immunostain, ×200.

Figure 3

Detachment of tumor cells in the primary site of left lung cancer. (a) Villous-shaped tumor cells project and separate into the alveolar space. H&E stain, ×100. (b) Immunopositivity on the cell-cell borders is weakened as tumor cells project or separate. Annexin A2 immunostain, ×400. (c) Tumor cells are negative, whereas the remaining alveolar epithelial cells are positive. TTF-1 immunostain, ×400.

Figure 4

Aerogenous metastasis of left lung cancer I. (a) Many isolated lesions are seen. H&E stain, ×40. (b) Small tumor cell aggregates are attached to alveolar epithelial cells, forming a protrusion. Some of the alveolar epithelial cells have an obscure nucleus and are detached within the alveolar spaces. H&E stain, ×400. (c) Tumor cell aggregates represent the immunopositivity near the cell surface with granular cytoplasmic positivity. Alveolar epithelial cells also show a weak positivity near the cell surface. Annexin A2 immunostain, ×400. (d) Alveolar epithelial cells are positive. The arrangement of these cells is well kept; however, some show weakened immunopositivity. TTF-1 immunostain, ×400.

Figure 5

Aerogenous metastasis of left lung cancer II. (a) Tumor cell aggregates adhere to the alveolar wall, and pseudoluminal gaps are seen inside the aggregates. H&E stain, ×400. (b) Cytoplasmic-positive products accumulate in the lateral sides, especially on the underside, forming membranous positivity. Annexin A2 immunostain, ×400. (c) Many alveolar epithelial cells disappear or are indistinct compared with those observed in Figure 4(d). TTF-1 immunostain, ×400.

Figure 6

Aerogenous metastasis of left lung cancer III. (a) Tumor cells arrange in one layer along the alveolar wall, and intracytoplasmic mucins are localized on the luminal sides. H&E stain, ×400. (b) Distinct membranous positivity on the cell-cell borders is seen. Annexin A2 immunostain, ×400.