Clinicopathologic features and genomic analysis of pulmonary blastomatoid carcinosarcoma

Abstract

Background: This study was designed to investigate the clinicopathologic features of pulmonary blastomatoid carcinosarcoma and explore the genomic profiles of epithelial and mesenchymal components in this tumor.

Methods: Three cases of pulmonary blastomatoid carcinosarcoma were enrolled in this study. Clinicopathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were microdissected to investigate the genomic profiles by performing capture-based targeted next generation sequencing.

Results: The epithelial components in patient one consisted of low-grade and high-grade fetal lung adenocarcinoma. Low-grade epithelial cells showed nuclear expression of β-catenin and missense mutation of CTNNB1. The epithelial components in another two patients consisted of high-grade fetal lung adenocarcinoma/enteric adenocarcinoma. The epithelial cells showed membrane staining of β-catenin and harbored no mutation of CTNNB1. The mesenchymal components in all three tumors were composed of primitive round/spindle cells without definite differentiation and showed cytoplasmic dot positive of β-catenin and no corresponding mutation. Within a tumor, both components exhibited relatively comparable molecular profile. In patient one, 4 mutations: RB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial component had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient two, 12 mutations were shared. The epithelial component had BRCA2 mutation and the mesenchymal had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN and RICTOR. Patient three had 6 shared mutations. The epithelial component had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor.

Conclusions: Blastomatoid carcinosarcoma showed characteristic morphology and immunophenotype. Parallel detection of genetic abnormalities in epithelial and mesenchymal components could provide further evidence for tumor differentiation, molecular targeting and differential diagnosis.

Keywords: Blastomatoid carcinosarcoma; CTNNB1; High-grade fetal adenocarcinoma; Low-grade fetal lung adenocarcinoma; Pulmonary blastoma; β-Catenin.

Fig. 1

Imaging and morphology in patient one. a CT showed a soft tissue tumor in the right lower lobe. b and c The epithelial consisted of H-FLAC with marked pleomorphism and necrosis and mild L-FLAC with typical squamoid morules h and e, × 400). d Primitive mesenchymal in some areas displayed fusiform structure and mucoid stroma (H&E, × 400)

Fig. 2

Imaging, grossing photograph and morphology in patient two. a CT displayed a peripheral mass in right upper lobe. b Gross appearance showed a well-circumscribed tumor with areas of necrosis and glistening homogeneous yellow-white cut surface. c CT revealed no signs of relapse in the primary site 48 months after surgical resection. d The tumor contained pure H-FLAC mixed with primitive stroma (H&E, × 400)

Fig. 3

Imaging, grossing photograph and morphology in patient three. a Mediastinal window of CT indicated that the tumor shrank significantly before (white arrow) and after (arrowhead) chemotherapy. b Gross excision of the specimen showed obvious intratumoral hemorrhage. c The epithelial arranged in papillary structure and resembled the morphology of enteric adenocarcinoma at scanning magnification (H&E, × 100). d-e Higher magnification demonstrated the cytological features of epithelial and mesenchymal cells respectively (H&E, × 400)

Fig. 4

Immunohistochemical features of blastomatoid carcinosarcoma (BCS). a β-catenin was nucleus positive in squamoid morule cells of L-FLAC and membrane positive in columnar epithelial of H-FLAC and dot-positive in mesenchymal cells b (× 400). c Neuroendocrine marker CD56 were expressed in both epithelial and mesenchymal cells. Some epithelial cells were positive for CDX2 d and the mesenchymal cells was positive for S-100 e in the third patient (× 400). f The proliferation index of epithelial components was significantly higher than that of mesenchymal (× 400)

Fig. 5

Gene mutation spectrum of blastomatoid carcinosarcoma (BCS) of three cases