Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase

Ceppi, Paolo; Volante, Marco; Saviozzi, Silvia; Rapa, Ida; Novello, Silvia; Cambieri, Alberto; Iacono, Marco Lo; Cappia, Susanna; Papotti, Mauro; Scagliotti, Giorgio V.

doi:10.1002/cncr.22208

Cited by 349 publications

(258 citation statements)

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“…The data from this study indicate significantly higher thymidylate synthase expression levels in squamous cell carcinomas than adenocarcinomas, consistent with prior studies (using both immunohistochemistry and direct mRNA measurement 15,25 ) regarding histology and thymidylate synthase. This study also identifies high thymidylate synthase expression in Table 3 Summary of EGFR and KRAS mutations in the adenosquamous specimens, including the microdissection cases adenosquamous tumors, showing more similarity to squamous cell specimens than adenocarcinomas.…”

Section: Discussionsupporting

confidence: 91%

“…Finally, a recent pivotal phase III study showed improved overall survival with maintenance pemetrexed therapy following four cycles of platinum-based first-line chemotherapy in patients with advanced non-small cell lung cancer only in the non-squamous as opposed to the squamous subset. 14 Squamous cell carcinomas are known to have higher levels of thymidylate synthase expression than adenocarcinomas, 15 and it is speculated that the efficacy of pemetrexed partially depends upon the level of thymidylate synthase expression. [16][17][18] Accordingly, pemetrexed is approved solely for the treatment of patients with non-squamous tumors for whom it is viewed as a superior drug as compared with taxanes or gemcitabine based on the above data.…”

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confidence: 99%

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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: 91%

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confidence: 99%

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

et al. 2013

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“…The enzyme thymidylate synthase was differently expressed in adenocarcinoma and squamous-cell carcinoma and preliminary data in LCC indicate expression levels more closely related to those detected in squamous-cell carcinoma. 21 Similarly, the DNA repair gene ERCC1 was more highly expressed in squamous carcinomas than adenocarcinomas, but LCCs were not specifically analyzed, 22 although in another study expression levels of this gene were not correlated with specific histotypes. 23 Finally, in this study we demonstrated that the immunoprofile can be tentatively defined in at least part of cytological or biopsy samples obtained during the diagnostic work-up of a lung tumor mass.…”

Section: Discussionmentioning

confidence: 99%

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

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“…Because of evidence that there might be a greater benefit of pemetrexed therapy among nonsquamous NSCLC patients than among squamous cell patients [3][4][5][6][7], a retrospective analysis of a histology effect on efficacy outcomes was performed. That analysis demonstrated that pemetrexed was more effective in patients with adenocarcinoma and large cell lung cancer than in patients with squamous cell carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Approval Summary: Pemetrexed Maintenance Therapy of Advanced/Metastatic Nonsquamous, Non-Small Cell Lung Cancer (NSCLC)

et al. 2010

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After completing this course, the reader will be able to:1. Consider tumor histology when making treatment decisions for patients with NSCLC.2. Identify patients with NSCLC who may be appropriate candidates for maintenance therapy with pemetrexed.This article is available for continuing medical education credit at CME.TheOncologist.com. The Oncologist CME Program is located online at http://cme.theoncologist.com/. To take the CME activity related to this article, you must be a registered user. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash. The Oncologist 2010;15:1352-1358 CME CME ABSTRACT

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Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase

Cited by 349 publications

References 30 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

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Approval Summary: Pemetrexed Maintenance Therapy of Advanced/Metastatic Nonsquamous, Non-Small Cell Lung Cancer (NSCLC)

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