Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy

Warth, Arne; Macher-Goeppinger, Stephan; Muley, Thomas; Thomas, Michael; Hoffmann, Hans; Schnabel, Philipp A.; Penzel, Roland; Schirmacher, Peter; Aulmann, Sebastian

doi:10.1183/09031936.00105911

Cited by 92 publications

(58 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to previously published studies, in our study histo-molecular characterization correlated with Martini-Melamed criteria in about 50% of the cases, including both adenocarcinoma and squamous cell carcinoma. 4,5,9,16,17 This is not surprising as morphological subtying of lung adenocarcinoma has changed in the past decade, and the proposed detailed approach has been implemented in the 2015 World Health Organization classification of lung tumors. 18 Adenocarcinoma of the lung is morphologically heterogenous and careful comparison of morphological subtypes between two tumors is potentially useful in staging of synchronous tumors.…”

Section: Discussionmentioning

confidence: 99%

“…It is striking that many studies, including ours, failed to demonstrate correlation between clonality defined by genotype and outcomes. 9,10 Therefore, it is uncertain whether different mutations identify separate primary cancers or just a different clone within single tumor. Large prospective studies with precisely defined treatment management could potentially provide the answer.…”

Section: Discussionmentioning

confidence: 99%

“…2,[4][5][6][7][8][9][10] The data from published reports indicate a highly variable percentage of multifocal tumors identified as clonally related (up to 70%) and all reports agree that multifocal tumors may arise either as metastases from a single tumor or as independent tumors. Discrepancy between clinical and molecular classification of originally presumed cases of multiple primary lung cancers ranged in different series from 18 to 30%.…”

mentioning

confidence: 92%

See 2 more Smart Citations

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

et al. 2016

View full text Add to dashboard Cite

Distinction between multiple primary cancers and intrapulmonary metastases in patients with synchronous multifocal lung cancer can be challenging. Histological and genotypic assessment of multifocal lung tumors have been suggested to influence the staging. The aim of this study was to determine the role of morphology and genotype in staging of surgically treated multifocal non-small cell lung carcinoma. Synchronous lung cancers from 60 patients (42 with adenocarcinoma and 18 with squamous cell carcinoma), clinically considered to represent intrapulmonary metastases, were histologically subtyped according to the 2015 World Health Organization classification of lung tumors and subjected to genotypic analysis (KRAS, EGFR, BRAF, PIK3CA, ALK, MET and ROS1 in adenocarcinoma and PIK3CA and p16 in squamous cell carcinoma). Concordance between clinical criteria and histological subtyping was identified in about 50% of cases (Po 0.0001). Genotypically, 44% of adenocarcinomas and 60% of squamous cell carcinomas with identified molecular alterations were considered to be intrapulmonary metastases. Concordance between histological and molecular staging was observed in 89% of adenocarcinomas and 56% of squamous cell carcinomas. Univariate survival analyses failed to demonstrate significant differences in overall or cancer-specific survival in patients with adenocarcinoma and squamous cell carcinomas restaged according to histology and/or molecular profile. Lymph node metastases (N1/N2 vs N0) (P = 0.03) and age 465 years (P = 0.05) were associated with shorter overall survival. In addition, squamous cell carcinomas with p16 deletion showed shorter overall survival when compared with squamous cell carcinomas without p16 deletion (P = 0.05). No correlation between other molecular alterations, clinico-pathological characteristics and prognosis was found. Our study demonstrates that a comprehensive genotypic and morphological assessment of surgically treated multifocal lung cancers is feasible but not sufficient to establish their clonal relationship and prognosis. Modern Pathology (2016) 29, 735-742; doi:10.1038/modpathol.2016 published online 15 April 2016 The reported incidence of multiple synchronous tumors of the lung in recent series is up to 20%. 1,2 Staging of such tumors as independent primary tumors or intrapulmonary metastases is often challenging. Morphological criteria, especially those proposed by Martini and Melamed, 3 have been used as the main tool with the idea that morphology of metastases should match the primary tumor, while different morphology supports classification of tumors as unrelated separate primaries. However, clinico-pathological distinction between the two possibilities is not always possible and may not be prognostic.Over the past decade, multiple studies using different molecular approaches to analysis of synchronous lung tumor nodules have emerged, including DNA microsatellite analysis, CGH/aCHG and most recently next-generation sequencing. 2,[4][5][6][7][8][9][10] The data from published rep...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

See 1 more Smart Citation

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

et al. 2016

View full text Add to dashboard Cite

show abstract

“…4 After heat inactivation of the enzyme, the lysate was directly used for PCR under standard conditions using previously published primer combinations for NRAS (exons 2 and 3, 5 ), BRAF (exon 15, 5 ), KIT (exons 11, 13, 17, and 18, 6 ) and EGFR (exons 18, 19, 20, and 21, 4 ). PCR products were directly sequenced on an ABI Prism 377 sequencer (Applied Biosystems, Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

Comparison of molecular abnormalities in vulvar and vaginal melanomas

et al. 2014

Self Cite

View full text Add to dashboard Cite

Malignant melanoma of the vulva and vagina is relatively uncommon and accounts for o5% of all melanomas in women. The aim of our study was to establish the biological properties and evaluate potential therapeutic targets in these tumors. We collected a series of 65 cases from three centers and re-evaluated the tumor tissue for predominant growth pattern (superficial spreading, nodular, and mucosal lentiginous) and tumor thickness. KIT (CD117) expression was detected immunohistochemically. In addition, tumors were screened for BRAF, NRAS, and KIT mutations by PCR and DNA sequencing as well as for KIT amplifications by fluorescence in situ hybridization. None of the cases contained BRAF mutations. NRAS mutations and KIT amplifications were detected in similar frequency (B12%) in tumors of the vulva and vagina. In contrast, KIT mutations were present in 18% of primary melanomas of the vulva, but in none of the tumors arising in the vagina. Moderate or strong KIT protein expression was detected in 30 cases, including all tumors with KIT mutations and 6 of the 7 with KIT amplifications. In conclusion, BRAF mutations are virtually absent in melanomas originating from the vulva or vagina, whereas NRAS mutations and KIT amplifications occur in both locations. KIT mutations appear to be specific for melanomas of the vulva, suggesting that in spite of the anatomic proximity, the development of vulvar and vaginal melanomas involves different molecular alterations which may be targeted by novel treatment approaches.

show abstract

“…3). Bei der parallelen morphologischen und molekularen Analyse von NSCLC konnte bereits aufgezeigt werden, wie im Grenzbereich der Morphologie ergänzende molekulare Analysen hilfreich sind, um eine klinisch relevante Tumortypisierung zu erreichen [25].…”

Section: Perspektiveintegrierte Analysenunclassified

Diagnose, Prognose und Prädiktion nicht-kleinzelliger Lungenkarzinome

Warth

2015

Pathologe

View full text Add to dashboard Cite

Tumor diagnostics are based on histomorphology, immunohistochemistry and molecular pathological analysis of mutations, translocations and amplifications which are of diagnostic, prognostic and/or predictive value. In recent decades only histomorphology was used to classify lung cancer as either small (SCLC) or non-small cell lung cancer (NSCLC), although NSCLC was further subdivided in different entities; however, as no specific therapy options were available classification of specific subtypes was not clinically meaningful. This fundamentally changed with the discovery of specific molecular alterations in adenocarcinoma (ADC), e.g. mutations in KRAS, EGFR and BRAF or translocations of the ALK and ROS1 gene loci, which now form the basis of targeted therapies and have led to a significantly improved patient outcome. The diagnostic, prognostic and predictive value of imaging, morphological, immunohistochemical and molecular characteristics as well as their interaction were systematically assessed in a large cohort with available clinical data including patient survival. Specific and sensitive diagnostic markers and marker panels were defined and diagnostic test algorithms for predictive biomarker assessment were optimized. It was demonstrated that the semi-quantitative assessment of ADC growth patterns is a stage-independent predictor of survival and is reproducibly applicable in the routine setting. Specific histomorphological characteristics correlated with computed tomography (CT) imaging features and thus allowed an improved interdisciplinary classification, especially in the preoperative or palliative setting. Moreover, specific molecular characteristics, for example BRAF mutations and the proliferation index (Ki-67) were identified as clinically relevant prognosticators. Comprehensive clinical, morphological, immunohistochemical and molecular assessment of NSCLCs allow an optimized patient stratification. Respective algorithms now form the backbone of the 2015 lung cancer World Health Organization (WHO) classification.

show abstract

Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy

Cited by 92 publications

References 29 publications

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

Comparison of molecular abnormalities in vulvar and vaginal melanomas

Diagnose, Prognose und Prädiktion nicht-kleinzelliger Lungenkarzinome

Contact Info

Product

Resources

About