Role of Cytology in the Management of Non–Small-Cell Lung Cancer
Authors: Andrew H. Fischer, Edmund S. Cibas, Lydia P. Howell, Elizabeth M. Kurian, Rodolfo Laucirica, Ann T. Moriarty, Andrew A. Renshaw, Maureen F. Zakowski, Nancy A. Young
Journal: Journal of Clinical Oncology (2011)

Role of Histology in the Management of Advanced Non-Small-Cell Lung Cancer," Langer et al 1 raised the rhetorical question: "Can we use cytologic diagnosis?"Their one-sentence answer is disparaging toward cytology: "Fine-needle aspiration [FNA] does not provide optimal specimens to enable histologic diagnosis based on architectural patterns."In fact, there are many advantages of using cytology for diagnosis as well as molecular testing of lung tumors, and these are not widely appreciated.The morphologic features that distinguish squamous cell carcinoma (predominantly keratinized cytoplasm and intercellular bridges) from adenocarcinoma (mucin vacuoles and gland formation) span less than the 250-m inner diameter of a 25-gauge fine needle.These features are apparent in cytology samples without histologic sectioning, and they can certainly be identified in cell block sections (Fig 1).Internationalconsensuscriteriaforlungcancerdiagnosis have been developed by a multidisciplinary group that included pathologists, and these criteria encompass cytology samples. 2 As noted by Langer et al, 1 immunohistochemical markers may be required for subclassification of non-small-cell carcinoma in biopsies, and these immunohistochemical markers have been widely applied to cytologic samples.The quantity of procured material can be comparable between FNA and core biopsies of most lung cancers.In one study, 18-gauge core biopsies of non-small-cell lung cancers yielded an average of 10.15 mg of tissue that was dedicated for molecular analysis. 3 One FNA pass with one drop of material (50 L) that consists of 50% blood and 50% tumor cells would contain about 25 mg of cells.Fragments that are 250 m in size allow approximately 60 sections, 4 m in size, to be cut from a paraffin-embedded cell block.Core biopsy may not be superior to FNA for obtaining a representative sample of a heterogeneous tumor.An FNA needle can be directed to different areas of a neoplasm with one pass, whereas one core biopsy acquires tissue from one contiguous area of a tumor.If the fragments of one FNA pass are laid out in a paraffin cell block at one plane, relatively larger numbers of tumor cells are displayed in each section compared with a core biopsy of comparable weight.FNA has outperformed core biopsy for definitive diagnosis of lung cancers in studies that have evaluated both procedures 4,5 ; this suggests better sampling can be obtained by FNA.It is also not obvious whether cytologic samples or formalinfixed, paraffin-embedded histologic biopsies provide a better platform for molecular studies.Cytology can use formalin fixation and paraffin embedding, but typical alcohol-based cytology fixatives are well known to preserve nucleic acids better than formalin. 6Furthermore, direct smears from FNAs display the entire nucleus of cells and therefore provide a better platform for fluorescent in situ hybridization studies than tissue sections.Molecular assays on cytology samples of lung cancers are well established, 7-10 including assays performed on sparse circulating tumor cells. 11It will be important to include a cytology arm in future clinical trials of molecularly targeted therapies.Although core biopsy is relatively safe, there is evidence that FNA has fewer risks with respect to pneumothorax, pulmonary hemorrhage, and seeding of tumor cells, 12 and there are circumstances in which core biopsy may not be feasible.For example, only FNA is available for endoscopic bronchial ultrasound-guided biopsies.Proper FNA technique is essential for procuring a good sample.FNA has the benefit of ensuring that diagnostic material is obtained with an intraprocedural assessment of adequacy. 13Inthisneweraofmolecularlyguidedtreatmentoflungcancers,it is in the best interest of patients that we answer the question, "Can we use cytologic diagnosis?"with a resounding "Yes."