Transition from Squamous Cell Carcinoma to Adenocarcinoma in Adenosquamous Carcinoma of the Lung

Kanazawa, Hironobu; Ebina, Masahito; Ino-oka, Nozomu; Shimizukawa, Minoru; Takahashi, Toru; Fujimura, Shigefumi; Imai, Tadashi; Nukiwa, Toshihiro

doi:10.1016/s0002-9440(10)64999-1

Cited by 48 publications

(46 citation statements)

References 37 publications

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“…Interestingly, the two components of the adenosquamous tumors appear to be correlated, suggesting that the expression of thymidylate synthase is driven more by other tumor determinants than histological pattern. This is also consistent with the Kanazawa study 26 of 12 adenosquamous tumors, in which they sought to determine polyclonality versus monoclonality of these tumors. With immunohistochemistry, they found higher expression levels of squamous cell carcinoma-related antigen and lower expression of Mucin-1 in the glandular components than usual adenocarcinomas of the lung.…”

Section: Discussionsupporting

confidence: 78%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

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Thymidylate synthase expression is known to be higher in squamous cell carcinoma than in adenocarcinoma of the lung. It is thought that this is the reason for the poor efficacy of pemetrexed in squamous cell carcinoma. However, there is limited data on thymidylate synthase expression in adenosquamous carcinoma, a distinct subtype of lung cancer containing both squamous and glandular differentiation. Furthermore, molecular alterations like epidermal growth factor receptor and Kirsten rat sarcoma 2 viral oncogene homolog mutations, which are seen in adenocarcinomas, are not well understood in mixed histology tumors such as adenosquamous carcinoma. In our study, we sought to better characterize adenosquamous tumors of the lung. Using immunohistochemistry to evaluate thymidylate synthase protein levels, we found that the expression of thymidylate synthase in these mixed tumors roughly parallel that of squamous cell carcinoma, instead of falling in between squamous cell and adenocarcinoma. Of note, in adenosquamous samples, the expression of thymidylate synthase was more closely correlated within the two components than would be expected by random chance alone. Also, we had a relatively high rate of epidermal growth factor receptor (11%) and Kirsten rat sarcoma 2 viral oncogene homolog (33%) mutations in these specimens, with the mutations showing convergence in both the glandular and squamous components upon microdissection. Our results indicate that adenosquamous carcinomas are not simple mixtures of their two histological components; they rather behave as their own entity, and it is important to further understand their behavior. Given the similarity of thymidylate synthase expression between squamous cell and adenosquamous carcinoma, and that thymidylate synthase is the main target of pemetrexed, we extrapolate that pemetrexed may also have inferior clinical activity in adenosquamous carcinoma.

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Section: Discussionsupporting

confidence: 78%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

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“…[10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.…”

Section: Dear Sirmentioning

confidence: 99%

“…3 Information on genetic alterations is also limited; only TP53, K-ras mutation and loss of heterozygosity at several loci have been reported in a limited number of adenosquamous carcinomas. [10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.…”

Section: Dear Sirmentioning

confidence: 99%

“…10,11 Immunohistochemical analyses have indicated that the protein expression characteristics of the adenocarcinomatous and squamous cell carcinomatous components differ. 3,9,11 Taking together these findings, the tumorigenesis in some population of adenosquamous carcinoma is hypothesized; the critical event causing oncogenesis, such as a mutation in K-ras or EGFR, occurs in the progenitor cells of the adenosquamous carcinoma, then, in the process of multistep tumorigenesis, subsequent differences in the protein expression profiles may cause the cells to differentiate into 2 different phenotypes. Second, although adenosquamous carcinoma is believed to arise from pluripotential bronchial reserve cells, little is known about the progenitor cells of adenosquamous carcinoma.…”

Section: Dear Sirmentioning

confidence: 99%

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Mutations of epidermal growth factor receptor andK-rasgenes in adenosquamous carcinoma of the lung

et al. 2005

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Dear Sir,Lung cancer is one of the most common malignant diseases in developed countries and is classified into nonsmall cell lung cancer (NSCLC) and small cell lung cancer.1 Adenocarcinoma and squamous cell carcinoma are the 2 major subtypes of NSCLC. However, significant differences in etiology and genetic and epigenetic alterations exist between these 2 subtypes.2-4 For example, squamous cell carcinoma generally arises in smokers and rarely occurs in never-smokers; mutations in the K-ras and EGFR genes are also infrequent. In contrast, adenocarcinoma is the dominant histological subtype in female never-smokers, and K-ras or EGFR mutations are frequently present in this subtype. 5,6 Adenosquamous carcinoma of the lung is a rather rare subtype of NSCLC, comprising 0.4-4% of pulmonary carcinomas.3 According to the World Health Organization's classification, adenosquamous carcinoma is defined as a carcinoma showing components of both adenocarcinoma and squamous cell carcinoma, with each component comprising at least 10% of the tumor. 3 The etiology of adenosquamous carcinoma, including age, smoking status and race, is similar to that of other types of lung cancers.7 A clinicopathological analysis has demonstrated that adenosquamous carcinoma is more aggressive and results in a poorer prognosis than does adenocarcinoma or squamous cell carcinoma, 7 indicating that its biological features are different from these major types of NSCLCs. Regarding the histogenesis of adenosquamous carcinoma, monoclonal or polyclonal pathways have been proposed. Monoclonality is considered to be a fundamental feature of neoplasms and consists of the transformation of 1 component to the other, whereas the polyclonal pathway may result from a collision of 2 types of independent tumors. 8,9 However, little is known about the progenitor cells and the process of tumorigenesis in adenosquamous carcinoma of the lung.3 Information on genetic alterations is also limited; only TP53, K-ras mutation and loss of heterozygosity at several loci have been reported in a limited number of adenosquamous carcinomas. [10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.In our previous analysis for EGFR mutation in 397 cases of NSCLCs, we found somatic mutations in 2 cases for EGFR and 1 for K-ras out of 6 adenosquamous carcinomas by direct sequence of exon 18-21 for EGFR and codon 12 and 13 for K-ras genes.13,14 The rates of EGFR mutation in each histology of lung cancer are shown in Table I. In our study, we added 5 new cases of adenosquamous carcinomas of the lung for EGFR and K-ras analysis, and EGFR mutation was present in 1 case and K-ras mutation was absent in 5 cases. Thus, 4 of 11 cases showed either EGFR or K-ras mutations (27% for EGFR and 9% for K-ras). The characteristics of 11 cases are exhibited in Table II. These results provoked considerable interest, because mutations in these genes were assumed to be usually present in adenocarcinoma and rarely present in ...

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“…Thus, dierent animals or dierent breasts in the same animal developed independently invasive tumors with a predominating solid, nodular form that possibly evolved into a few variants, including a pattern of adenoacanthomatous metaplasia. Although adenosquamous carcinomas developing in the breast or in other organs are rarely observed in humans (see, for example, Denley et al, 2000), it is interesting to note that independent molecular analyses of lung tumors have suggested that the squamous and adenocarcinomatous components had originated from the same cell (Niho et al, 1999;Kanazawa et al, 2000).…”

Section: Tumor Pathogenesis In the Absence Of Brca2mentioning

confidence: 99%

Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice

et al. 2001

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Cre-mediated deletion of exons 3 and 4 of the mouse Brca2 gene occurring speci®cally in mammary epithelial cells of conditional female mutants carrying a combination of loxP-modi®ed and null Brca2 alleles resulted in a high incidence (77%) of breast tumors that were often palpable and developed in one or more glands after long latency (time for median tumor-free survival of *1.4 years; total of 40 tumors in 20 animals). These invasive adenocarcinomas were histologically quite uniform, exhibiting predominantly a solid, nodular tumor pattern with very few variants, in striking contrast to the morphological heterogeneity of analogous Brca1-associated tumors. The karyotypes of tumor cells lacking Brca2 had various chromosomal aberrations and ranged from diploid to hypertetraploid, but this wide variability was incongruous with the histological appearance of carcinomas that was comparable between specimens. The implications of these observations in the context of models positing that Brca2 is involved in the maintenance of genomic stability are discussed. Oncogene (2001) 20, 3937 ± 3948.

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Transition from Squamous Cell Carcinoma to Adenocarcinoma in Adenosquamous Carcinoma of the Lung

Cited by 48 publications

References 37 publications

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

Mutations of epidermal growth factor receptor andK-rasgenes in adenosquamous carcinoma of the lung

Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice

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