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: Because of the current controversy on the origin and clinical value of circulating KRAS codon 12 mutations in lung cancer, we screened 180 patients using a combined restriction fragment-length polymorphism and polymerase chain reaction (RFLP-PCR) assay. We detected KRAS mutations in 9% plasma samples and 0% matched lymphocytes. Plasma KRAS mutations correlated significantly with poor prognosis. We validated the positive results in a second laboratory by DNA sequencing and found matching codon 12 sequences in blood and tumor in 78% evaluable cases. These results support the notion that circulating KRAS mutations originate from tumors and are prognostically relevant in lung cancer.Cancer Letters 10/2007; 254(2):265-73. DOI:10.1016/j.canlet.2007.03.008 · 5.02 Impact Factor
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ABSTRACT: Neuroendocrine tumours of lungs represent a subgroup of pulmonary tumours with typical morphofunctional traits. In light microscopy, the four principal types of the tumours (typical and atypical carcinoids, small cell lung cancer, large cell neuroendocrine carcinoma) demonstrate typical arrangement of cells (organoid nesting, palisading, a trabecular pattern, and rosette-like structures), variable number of mitoses, presence or absence of necrosis. In ultrastructure, neuroendocrine tumours manifest groups of cells with cytoplasmic granules (and the so called dense-core neurosecretory granules in particular). Neuroendocrine cells release hormones to circulation or in a paracrine manner. Some pulmonary tumours exhibit no neuroendocrine morphology at the level of light microscopy but demonstrate ultrastructural and/or immunohistochemical traits of neuroendocrine differentiation. Proteins the presence of which confirms neuroendocrine origin of the tumours have been found relatively early to include neuron-specific enolase (NSE), the group of chromogranins and synaptophysin. Present study aimed at summing up results of investigations conducted in, approximately, recent 30 years pertaining expression and/or serum concentrations of four neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin, protein gene product 9.5) and at an attempt to evaluate the role of such studies in extension of diagnostic and prognostic potential as related to neuroendocrine pulmonary tumours. Until now, the most sensitive and specific marker or marker combination for early detection of neuroendocrine subtypes of lung tumours has not been identified. All of the markers examined in present study were detected both in the typical neuroendocrine pulmonary tumours and in a certain proportion of non-endocrine tumours. In the case of chromogranin A improved sensitivity and specificity of immunocytochemical studies was obtained using a panel of antibodies directed to various epitopes of the protein. Both in endocrine and non-endocrine tumours, neuron-specific enolase (NSE) is thought to represent mainly a prognostic index, and only quantitation of serum concentrations of the protein or of the fraction of immunopositive cells may permit to differentiate between subtypes of the tumours. Synaptophysin is regarded to represent one of the most specific markers of neuroendocrine differentiation, manifesting a much higher sensitivity than chromogranin A and NSE. With increasing frequency, PGP 9.5 is regarded to provide a prognostic marker in diagnosis of non-small cell lung carcinomas rather than of typical neuroendocrine tumours.Polish journal of pathology: official journal of the Polish Society of Pathologists 02/2007; 58(1):23-33. · 0.83 Impact Factor
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ABSTRACT: The organizing stage of acute lung injury syndrome is characterized, in part, by a reactive hyperplasia of type II pneumocytes. These cells may be recovered in large numbers and in an excellent state of preservation by bronchoalveolar lavage. It was noted recently that such cells in lavage samples may mimic adenocarcinoma. To examine the dynamics of type II pneumocyte shedding in acute lung injury, we studied 62 bronchoalveolar lavage samples from 38 patients with acute onset of the adult respiratory distress syndrome (median age, 54 years). A single lavage was performed in 25 patients, whereas from two to five studies were performed in 13 individuals. The timing of lavage ranged from 1 to 435 days after the onset of respiratory distress. Type II pneumocytes were present in 12 specimens as follows: 6 of 24 (25%) samples from days 1 to 3, 4 of 9 (44%) samples from days 4 to 10, and 2 of 11 (18%) samples from days 21 to 32. Specimens obtained after day 32 never contained such cells. Cytologically, type II pneumocytes may resemble the cells of acute radiation injury. Alternatively, they may be smaller, with an increased nuclear-cytoplasmic ratio, nuclear membrane irregularities, and prominent nucleoli, thus resembling the cells of adenocarcinoma. They may shed singly or in groups. A spectrum of changes from small cells to large, fully hyperplastic type II cells may be seen. Recognition of the morphologic features of type II pneumocytes and careful clinical correlation usually will suffice to prevent a false diagnosis of malignancy. Sequential lavage provides a means to study pulmonary epithelial changes after lung injury.American Journal of Clinical Pathology 06/1992; 97(5):669-77. · 3.01 Impact Factor