Heterogeneity of Large Cell Carcinoma of the Lung An Immunophenotypic and miRNA-Based Analysis

Unit of Surgical Pathology, Laboratory of Molecular Pathology, S. Chiara Hospital, Largo Medaglie Oro 9, Trento, Italy.
American Journal of Clinical Pathology (Impact Factor: 2.51). 11/2011; 136(5):773-82. DOI: 10.1309/AJCPYY79XAGRAYCJ
Source: PubMed


Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]-specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation.

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    • "Discussion: Massive sequencing of lung cancer is providing relevant profiles of single tumor subtypes with important information for prognostic and predictive purposes [66] [67]. Data on LCC are currently scant, but it is reasonable to expect that many if not all LCC will display a genetic profile (including microRNAs) [68] [69] aligned to either ADC or SQC. The same holds true for known predictive markers of response to specific therapies, as thymidylate synthase in LCC [70]. "
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    ABSTRACT: Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question-answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time).
    Lung Cancer 01/2015; 87(3). DOI:10.1016/j.lungcan.2015.01.008 · 3.96 Impact Factor
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    ABSTRACT: Pulmonary large-cell carcinoma-a diagnostically and clinically controversial entity-is defined as a non-small-cell carcinoma lacking morphologic differentiation of either adenocarcinoma or squamous cell carcinoma, but suspected to represent an end stage of poor differentiation of these tumor types. Given the recent advances in immunohistochemistry to distinguish adenocarcinoma and squamous cell carcinoma, and the recent insights that several therapeutically relevant genetic alterations are distributed differentially in these tumors, we hypothesized that immunophenotyping may stratify large-cell carcinomas into subsets with distinct profiles of targetable driver mutations. We therefore analyzed 102 large-cell carcinomas by immunohistochemistry for TTF-1 and ΔNp63/p40 as classifiers for adenocarcinoma and squamous cell carcinoma, respectively, and correlated the resulting subtypes with nine therapeutically relevant genetic alterations characteristic of adenocarcinoma (EGFR, KRAS, BRAF, MAP2K1/MEK1, NRAS, ERBB2/HER2 mutations and ALK rearrangements) or more common in squamous cell carcinoma (PIK3CA and AKT1 mutations). The immunomarkers classified large-cell carcinomas as variants of adenocarcinoma (n=62; 60%), squamous cell carcinoma (n=20; 20%) or marker-null (n=20; 20%). Genetic alterations were found in 38 cases (37%), including EGFR (n=1), KRAS (n=30), BRAF (n=2), MAP2K1 (n=1), ALK (n=3) and PIK3CA (n=1). All molecular alterations characteristic of adenocarcinoma occurred in tumors with immunoprofiles of adenocarcinoma or marker-null, but not in tumors with squamous immunoprofiles (combined mutation rate 50% vs 30% vs 0%, respectively; P<0.001), whereas the sole PIK3CA mutation occurred in a tumor with squamous profile (5%). Furthermore, marker-null large-cell carcinomas were associated with significantly inferior disease-free (P<0.001) and overall (P=0.001) survival. In conclusion, the majority (80%) of large-cell carcinomas can be classified by immunomarkers as variants of adenocarcinoma or squamous cell carcinoma, which stratifies these tumors into subsets with a distinct distribution of driver mutations and distinct prognoses. These findings have practical implications for diagnosis, predictive molecular testing and therapy selection.Modern Pathology advance online publication, 30 November 2012; doi:10.1038/modpathol.2012.195.
    Modern Pathology 11/2012; 27(1). DOI:10.1038/modpathol.2012.195 · 6.19 Impact Factor
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    ABSTRACT: Introduction Napsin-A is a diagnostic marker for pulmonary adenocarcinoma (PA) and a useful alternative to thyroid transcription factor-1 (TTF-1). TTF-1 also stains small cell carcinoma of the lung (SCCA). Napsin-A expression in SCCAs is not as well documented as it is in non-small cell carcinomas. We examined and compared Napsin-A and TTF-1 expression in 36 previously confirmed cytologic cases of small cell carcinoma of lung. To date, ours is the largest cytologic series of such cases examined for Napsin-A expression. Materials and Methods Thirty-six patients, including 20 males and 16 females (age 43-87 years, mean 57 years), presented with lung masses. Primary or metastatic SCCA was diagnosed following examination of; fine needle aspiration biopsies of mediastinum (n=5), liver (n=3), subcutaneous nodule (n=1), lung (n=6) and axillary, cervical and mediastinal lymph nodes (n=20), as well as a pleural effusion (n=1). Napsin-A and TTF-1 expression was tested. In addition previous expression (or lack thereof) with immunocytochemical stains pancytokeratin and neuroendocrine markers (synaptophysin, chromogranin, CD56) were noted. Results All cases with cytomorphologic features of SCCA were positive for pancytokeratin. TTF-1 was positive in 35/36 (97%) and Napsin-A was negative in all 36 cases (100%). All 36 cases expressed at least one neuroendocrine marker, including the TTF-1 negative case. Conclusions In this study, Napsin-A was shown to be negative in all SCCAs of lung. This stain may prove to be a useful exclusionary marker in distinguishing SCCA from other poorly differentiated lung carcinomas with similar morphologic features, especially those with concomitant TTF-1 expression.
    01/2013; 3(2). DOI:10.1016/j.jasc.2013.11.005
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