Review Article: A Reevaluation of the Clinical Significance of Histological Subtyping of Non--Small-Cell Lung Carcinoma: Diagnostic Algorithms in the Era of Personalized Treatments

Division of Pathologic Anatomy, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.
International Journal of Surgical Pathology (Impact Factor: 0.95). 08/2009; 17(3):206-18. DOI: 10.1177/1066896909336178
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The classification of lung cancer has always been primarily based on the morphologic assessment of routinely stained histological sections, but this approach may be difficult or even unfeasible in cytological preparations or small biopsies. Moreover, the simplistic dichotomization between small-cell carcinoma and non-small cell carcinoma (NSCLC) should be overcome, as new drugs have been discovered that are effective in specific subtypes of lung cancer. A more accurate characterization of NSCLC, however, may be hard in carcinomas lacking clear-cut signs of differentiation. The incorporation into the diagnostic algorithm of poorly differentiated carcinomas of an immunohistochemical panel including markers of squamous (high-molecular-weight cytokeratins, p63) and glandular (TTF-1, cytokeratin 7) cell differentiation seems the most promising approach. The evaluation of lung cancer for gene mutations, gene amplification, tumor-related angiogenesis, expression levels of DNA repair genes and genomic or proteomic profiles represents an exciting challenge for the pathologist in the near future.

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Available from: Giulio Rossi, Sep 30, 2015
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    • "Each laboratory may establish different protocols and prefer one marker to another, mainly based on its own specific experience. Mucin stain [8] [39], TTF-1 clone 8G7G3/1 over clones SPT24 and SP141 [49] [50] [51], p40 [52] [53], napsin-A [54] [55] [56], cytokeratins 5/6 [57], desmocollin-3 and other desmosomal markers [58] [59] [60] [61] [62] are the most useful markers. Immunophenotyping highlights a cell differentiation lineage, based on the recapitulation of normal cell products involved in lung development, such as TTF-1 in pneumocytes and respiratory bronchiolar cells (terminal respiratory unit) or p40 in the basal layer cells of non-terminal bronchioles and bronchi. "
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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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    • "Staining was positive for TTF-1 and was negative for CK-19 and CK-20. The negative staining for CK-19 and CK-20 ruled out malignancy of the pancreaticobiliary and colon, respectively, whereas expression of TFF-1 suggested a malignancy of the lung [4]. The patient began palliative chemotherapy with carboplatin and pemetrexed. "
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    ABSTRACT: Esthesioneuroblastomas are rare, soft-tissue tumors that can often extend from the sinonasal cavity into the intracranial and orbital space. Prognosis depends upon the histological grade and location/extent of the tumor. Treatment often consists of maximum surgical resection followed by adjuvant chemoradiation therapy. We present a case of a patient with esthesioneuroblastoma accompanied by an extensive osteoblastic reaction leading to a significant hyperostosis along the skull base. His presenting symptoms included diplopia, and imaging revealed invasion of the orbital and intracranial spaces. Although a gross total resection of the soft tissue component of the tumor was achieved, a complete removal of the involved hyperostotic skull base could not be performed despite endoscopic endonasal and bifrontal craniotomy approaches in the same operative setting. Symptomatically, the patient improved and went on to receive chemoradiation therapy; he remained clinically and radiographically stable at 12 months. Investigation into the genetics and immunohistochemistry of this rare, hyperostotic variant of esthesioneuroblastoma may provide details regarding its aggressive nature.
    07/2013; 3. DOI:10.4303/jcrm/235673
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    • "The histological subtyping of non-small cell lung carcinoma (NSCLC) has recently been recognized for its clinical and therapeutic importance [18]. Relevant distinctions that determine treatment choice have been made between adenocarcinoma (AD) and squamous cell carcinoma (SQ) in NSCLC [18, 28]. The emergence of treatments with differential activities or limited indications in the subtypes of NSCLC has placed further emphasis on the importance of accurate subtyping [3, 4, 8, 18, 22, 28, 35, 36], and immunohistochemical panels have been reported to be useful for subtyping [5, 22, 35]. "
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    ABSTRACT: In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P<0.05) in adenocarcinoma (AD) than in squamous cell carcinoma (SQ), while CK6 and CK14 mRNA expression was significantly higher (P<0.05) in SQ than in AD. Each histology-specific CK, particularly CK18 in AD and CK6 in SQ, were shown to be correlated with a poor prognosis (P=0.02, 0.02, respectively). Our results demonstrated that a quantitative CK subtype mRNA analysis from lung biopsy samples can be useful for predicting the histology subtype and prognosis of advanced NSCLC.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 04/2013; 46(2):85-96. DOI:10.1267/ahc.12024 · 1.39 Impact Factor
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