Respiratory cytology in the era of molecular diagnostics: A review
ABSTRACT Carcinoma of the lungs remains one of the primary causes of cancer mortality in the United States and represents a significant diagnostic challenge. Current diagnostic protocols depend substantially on cytology as an initial diagnostic modality. Pulmonary cytology can be diagnostically challenging with false positive and false negative diagnoses being relatively frequent. False positive diagnoses remain a significant problem for the cytologist with benign conditions including reactive atypia of type II pneumocytes, reactive bronchial respiratory epithelium, basal cell hyperplasia, and reactive metaplastic squamous cells being potentially misinterpreted as carcinoma. False negative diagnoses also occur usually attributable to sampling. Traditionally, cytopathologists were expected to recognize carcinoma when present and subdivide it into small cell or nonsmall cell varieties. With the advent of targeted therapy, expectations now include separation of adenocarcinoma from squamous cell carcinoma. Additionally, molecular testing for EGFR mutations and ALK rearrangements is now required as an accompaniment to morphologic diagnosis. This review summarizes the morphologic appearances of the common and diagnostically important carcinomas of the lung and discusses diagnostic pitfalls responsible for false positive and false negative diagnoses. Molecular testing for selection of targeted therapy is also reviewed.
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ABSTRACT: The traditional distinction between small cell lung cancer and non-small cell lung cancer (NSCLC) is no longer sufficient for treatment planning. It is advised to handle small diagnostic specimens prudently because they are often the only specimen available for molecular analysis. Pathologists are experiencing pressure to subclassify lung carcinoma based on extremely small tumor samples, because NSCLC tumor subtyping is now essential to determine molecular testing strategies. Evaluation for EGFR mutations and ALK rearrangements are now considered to be the standard of care in advanced-stage pulmonary adenocarcinomas. Immunohistochemical stains can aid in subclassifying NSCLC, but performing these ancillary studies can significantly reduce the quantity of tissue available for molecular tests, requiring careful balancing of these 2 needs. The pathologist plays a pivotal role in facilitating clear and timely communication between the clinical oncology care team and the molecular laboratory to ensure that the appropriate tests are ordered and optimal material is submitted for testing.American Journal of Clinical Pathology 09/2012; 138(3):332-46. DOI:10.1309/AJCPFR12WJKCEEZZ · 2.51 Impact Factor
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ABSTRACT: BACKGROUND Minimally invasive sampling by cytology or core needle biopsy often provides an initial diagnosis for treatment in patients with lung nodules. From these limited specimens, multiple molecular studies are frequently requested. Current guidelines from the US Food and Drug Administration recommend using formalin-fixed paraffin-embedded tissue sections for the detection of anaplastic lymphoma kinase (ALK) gene rearrangement by fluorescence in situ hybridization (FISH). The authors compared alcohol-fixed and formalin-fixed cytology specimens using a novel automated detection for ALK rearrangements by FISH and immunohistochemistry (IHC).METHODSALK FISH testing was performed on 129 lung adenocarcinomas from 71 cytology cases and 58 biopsy/resection specimens using Papanicolaou staining with integrated cytomorphology. IHC with the ALK D5F3 antibody was performed on cases with residual material (88 of 129 cases).RESULTSThe mean age of the patients was 66 years; there were 62 women and 67 men. ALK gene rearrangement was present in 4% of cytology specimens (3 of 71 specimens) and 7% of surgical specimens (4 of 58 specimens). FISH in 13 cases was technically unsuccessful. Of the 7 FISH-positive cases, only 2 cytology cases (4%) and 2 surgical cases (6%) were found to be positive with the ALK antibody, demonstrating 80% concordance. The one case found to be negative for ALK by IHC demonstrated a variant rearrangement of the ALK 2p23 gene locus by FISH.CONCLUSIONS The results of the current study validate the usefulness of alcohol-fixed and/or formalin-fixed cytology specimens for ALK rearrangement by a novel automated FISH method. IHC using the D5F3 antibody for ALK is specific in this limited cohort. The authors also demonstrated that alcohol-fixed cytology specimens can be used for ALK rearrangement by automated FISH, alone or in conjunction with IHC. Cancer (Cancer Cytopathol) 2014. © 2014 American Cancer Society.Cancer Cytopathology 11/2014; 122(11). DOI:10.1002/cncy.21467 · 3.35 Impact Factor