p53 and K-ras Mutational Genotyping in Pulmonary Carcinosarcoma, Spindle Cell Carcinoma, and Pulmonary Blastoma: Implications for Histogenesis

Abstract

In an attempt to understand the molecular pathogenesis of biphasic pulmonary neoplasms, the authors studied 25 cases of carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma using a combined immunohistochemical and topographic genotyping approach for the presence of p53 abnormalities within the different epithelial and mesenchymal components of these tumors. Genotyping involved a search for point mutational damage in p53 exons 5-8, which was correlated with p53 immunoreactivity. This analytical approach demonstrated p53 missense point mutations in four of nine cases of spindle cell carcinoma with a 100% concordance rate between p53 immunopositivity and the presence of DNA mutational damage. One of six carcinosarcomas, heterologous in type, exhibited a p53 mutation. The concordance rate among carcinosarcomas was also 100%. However, the concordance rate among classic biphasic pulmonary blastomas was only 43%, with one of seven cases demonstrating a p53 mutation by DNA genotyping. The lack of concordance in pulmonary blastomas was possibly due to the existence of genotypically distinct subsets of tumor cells likely bearing mutations among largely nonmutated cells. In a similar fashion, among three well-differentiated fetal type adenocarcinomas, no p53 mutations were detected despite the presence of focal p53 immunopositivity in one of the cases. No K-ras mutations were detected in any of the 25 tumors examined. Monoclonal histogenesis from a single totipotential cell in a subset of these neoplasms (six of 22 cases) was supported by the finding of p53 overexpression and identical p53 mutational genotype in both the epithelial and spindle elements of the tumors. Furthermore, the finding of a small percentage of p53-positive tumor cells within one or both components suggests late acquisition of p53 mutational change in a subset of pulmonary blastomas.

K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung

“…28 In the present investigation, we found K-ras point mutations in 6/27 (22%) tumors. The occurrence of the same point mutation in both the epithelial and the sarcomatoid component within individual tumors supports a monoclonal origin for most of these biphasic pleomorphic carcinomas, with a statistical odds of only one in 32 for the two distinct neoplastic populations of undergoing the same allele inactivation by random chance alone.…”

“…28,32,33 The different proportion of K-ras mutations among these three series, however, most likely depends on the type of the epithelial component of pleomorphic carcinomas. In fact, in one series, K-ras mutations were absent in 12 biphasic neoplasms predominantly composed of squamous cell carcinoma associated with spindle cells, 28 and in the second published series, a 12% prevalence of mutations was reported among 25 pure pleomorphic carcinomas, including exclusively spindle-and giant-cell tumors. 32,33 At variance with these two series, the epithelial component of our biphasic pleomorphic carcinomas was largely represented of adenocarcinoma and large-cell carcinoma.…”

“…3,7,[13][14][15]17,19,22 In different anatomical sites, most, but not all, of these tumors composed of carcinoma and sarcoma or sarcoma-like components are considered monoclonal growths (the so-called divergent hypothesis) rather than true collision tumors (convergent hypothesis). 20,[23][24][25][26][27][28][29][30][31] In turn, these monoclonal growths may originate from a single ancestor undergoing divergent epithelial and mesenchymal differentiation early during the neoplastic transformation (combination theory), or the full-blown carcinoma cells undergo sarcomatoid changes during tumor progression (conversion theory). 21,[23][24][25] In the lung, a monoclonal origin has been suggested for carcinosarcoma and blastoma using diverse molecular strategies, such as X chromosome inactivation, 24 microsatellite analysis, 29 and mutational genotyping of p53 gene, 28 whereas little is known about clonality of pulmonary pleomorphic carcinomas.…”

“…20,[23][24][25][26][27][28][29][30][31] In turn, these monoclonal growths may originate from a single ancestor undergoing divergent epithelial and mesenchymal differentiation early during the neoplastic transformation (combination theory), or the full-blown carcinoma cells undergo sarcomatoid changes during tumor progression (conversion theory). 21,[23][24][25] In the lung, a monoclonal origin has been suggested for carcinosarcoma and blastoma using diverse molecular strategies, such as X chromosome inactivation, 24 microsatellite analysis, 29 and mutational genotyping of p53 gene, 28 whereas little is known about clonality of pulmonary pleomorphic carcinomas. 28 Using laser-assisted microdissection of formalinfixed and paraffin-embedded sections, we have investigated the prevalence of K-ras codon 12 mutations in 27 biphasic pleomorphic carcinomas, in both the epithelial and sarcomatoid components.…”

“…21,[23][24][25] In the lung, a monoclonal origin has been suggested for carcinosarcoma and blastoma using diverse molecular strategies, such as X chromosome inactivation, 24 microsatellite analysis, 29 and mutational genotyping of p53 gene, 28 whereas little is known about clonality of pulmonary pleomorphic carcinomas. 28 Using laser-assisted microdissection of formalinfixed and paraffin-embedded sections, we have investigated the prevalence of K-ras codon 12 mutations in 27 biphasic pleomorphic carcinomas, in both the epithelial and sarcomatoid components.…”