Pulmonary tumours : cytologic aspects & diagnostic difficulties. Respiratory specimens for cytologic evaluation. evaluation

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1 Pulmonary tumours : cytologic aspects & diagnostic difficulties Myriam Remmelink CUB-ULB Hôpital Erasme Brussels, Belgium Respiratory specimens for cytologic evaluation Sputum, Bronchial brushings & washings, Bronchoalveolar lavages, Fine needle aspiration (transthoracic, transbronchial, transtracheal) Respiratory specimens for cytologic evaluation Sputum, Bronchial brushings & washings, Bronchoalveolar lavages, Fine needle aspiration (transthoracic, transbronchial, transtracheal) Bronchoscopy : visualization of the tracheobronchial mucosae via a flexible fiberoptic bronchoscope. 1

2 Bronchoscopy Bronchoscopy Bronchoscopy 2

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4 Respiratory specimens for cytologic evaluation Sputum, Bronchial brushings & washings, Bronchoalveolar lavages, Fine needle aspiration (transthoracic, transbronchial, transtracheal) Bronchial aspiration Bronchial brushing 4

5 Respiratory specimens for cytologic evaluation Sputum, Bronchial brushings & washings, Bronchoalveolar lavages, Fine needle aspiration (transthoracic, transbronchial, transtracheal) Cytological aspects Common primary carcinomas Non small cell lung carcinoma, NSCLC squamous cell carcinoma adenocarcinoma bronchiolo-alveolar carcinoma large cell carcinoma Small cell lung carcinoma, SCLC 95% of pulmonary carcinoma 5

6 Non small cell lung cancer (NSCLC) Squamous cell carcinoma SCC : clinical features 30-40% of all lung carcinomas Strongly associated with a prolonged history of cigarette smoking 6

7 SCC : histologic findings WHO (2004) : malignant epithelial tumour showing keratinization and/or intercellular bridges that arises from bronchial epithelium SCC : cytopathologic findings Keratinizing Predominant single cell presentation Keratinised malignant cells; cytoplasm refractile & eosinophilic (Pap, H&E); dense, pure blue (MGG) Perinuclear halo Bizarre cell shapes, spindle & caudate cells Irregular angular, densely hyperchromatic nuclei Necrosis Non-keratinising Irregular solid cohesive fragments Elongated or spindleshaped nuclei Variable chromatin density Keratinizing SCC Orangeophilic Cannibalism 7

8 Keratinizing SCC Spindle cell Irregular angular, densely hyperchromatic nuclei Keratinizing SCC Non-keratinising SCC 8

9 Non-keratinising SCC Cells are smaller High N/C ratio Non-keratinising SCC Fibrillary cytoplasm Clumped chromatin Irregular nucleoli Non-keratinising SCC 9

10 SCC : cytopathologic findings Variations in morphologic presentations in differenttypes of specimens Sputum: necrotic & cellular debris may obscure the diagnostic cells. Degenerative changes are also more likely to be encountered. Bronchial brushings; very cellular Bronchial washings &BAL : malignantcells may disperse. FNA : attention : Poorly differentiated carcinomascavitate, malignantcells are generally sparse & obscured by the cellular & necrotic debris, making the identification difficult. Cavitary lesions are frequently the source of false negative diagnosis. SCC : differential diagnoses SCC : differential diagnoses 10

11 !!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia Single cells in sputum; Single cells or in sheets in bronchial brushings/washings; Pleomorphic in size & shape with well-defined cell borders N/C ratio low to moderate increased; Nucleus round, central Smoothnuclear membrane Chromatin fine to coarsely granular No nucleolus Keratinization+/- Background clear to inflammatory Atypia is usually mild to moderate!!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia!!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia 11

12 !!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia!!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia Cavitary lesion of the lung!!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia 12

13 !!!!! Important source of diagnostic error!!!!! Squamous metaplasia with dysplasia Overlying a subepithelial neoplasm Evidence of repair/regenerative changes Hemosiderin- containing macrophages Pulmonary infarct LawtherRE et al, Ann Thorac Surg, 2002 Kaminsky DA et al, Respir care, 2004!!!!! Important pitfall!!!!! Repair/Regeneration Cells mostly in tissue fragments with well-defined borders Single cells rare Low N/C ratios Nuclei central Nuclear border smooth Finely granularchromatin Single/multiple micronucleoli/macronucleoli Nucleoli may be irregular in shape Background variably inflamed!clinical data! 13

14 !!!!! Important pitfall!!!!! Repair/Regeneration!!!!! Important pitfall!!!!! Repair/Regeneration Radiation/Chemotherapy Mostly single cells markedly pleomorphic small to large N/C ratios variable Nuclear membrane smooth Chromatin coarsely granular, clumped, smugdyu Nucleoli large, irregular Cytoplasm variable, generally abundant, delicate to dense, vacuolated!clinical data! 14

15 Radiation/Chemotherapy Mesothelium (transthoracic) Honeycomb sheets of cuboidal cells Well-defined cell borders Nuclei round with sharp nuclear membrane Granular chromatin with prominent nucleoli Cytoplasm dense & eosinophilic Nuclear polarity altered Lack of obvious malignant criteria Non small cell lung cancer (NSCLC) Adenocarcinoma 15

16 ADC : clinical features More frequent NSCLC Generally peripheral tumoral masse In smokers & non smokers (woman) ADC : histologic findings WHO (2004) : a malignant epithelial tumour with glandular differentiation or mucin production. Adenocarcinoma Medium-sized to large cells with abundant delicate cytoplasm Flat sheets Rosettes, acinar structures or cell clusters/balls Columnar cells Round to oval eccentric nuclei with large solitary nucleoli. 16

17 Adenocarcinoma Medium-sized to large cells with abundant delicate cytoplasm Flat sheets Rosettes, acinar structures or cell clusters/balls Columnar cells Round to oval eccentric nuclei with large solitary nucleoli. Adenocarcinoma 17

18 ADC : differential diagnoses 18

19 Reactive Adenocarcinoma Tumoral diathesis 0 + Number of cells Sheets Aggregats, Aggregats, isolated cells, syncitial groups Nuclei Uniform round, oval, Anisonucleosis, thick fine nuclear membrane nuclear membrane Nucleoli + +, irregular Intranuclear inclusion 0 + Chromatine Uniform Irregular, hyperchromatic Cilia + 0 Mitosis + +, abnormal Cilia Hyperplasia of respiratory epithelium 19

20 Hyperplastic respiratory epithélium Cilia Hyperplastic respiratory epithelium Hyperplastic respiratory epithelium 20

21 Hyperplastic bronchial epithelium Reactive columnar cells : macronucleoli Reactive/hyperplastic type II pneumocytes 21

22 Reactive/hyperplastic type II pneumocytes Inflammatory background Reactive/hyperplastic type II pneumocytes Reactive/hyperplastic type II pneumocytes 22

23 !CLINICAL DATA! Features that favor a reactive process are : Inflammatory background Considerable variations in the morphology of the abnormal cells, Degenerative nuclear changes, Windows between cells, 23

24 Metastasis Non small cell lung cancer (NSCLC) Bronchioloalveolar carcinoma 24

25 BAC : clinical features BAC : histologic findings WHO (2004) : subtype of ADC : growth of the neoplastic cells along pre-existing alveolar structures without evidence of stromal, vascular, or pleural invasion. Non- mucinous Mucinous BAC : cytopathologic findings Profuse amounts of material Large, cohesive, monolayered sheets; variable dispersal Papillaryprocesses, cell balls & clusters Variability in amount of pleomorphism & nuclear atypia Intranuclear cytoplasmic inclusions Psammoma bodies Because the tumors are usuallyperipheral, bronchial brushings are often non diagnostic. Bronchial washing & LBA : BAC s exfoliate malignant cells in large number FNA : excellent 25

26 Non- mucinous Mucinous Non- mucinous Mucinous 26

27 Non-Mucinous Mucinous Non small cell lung cancer (NSCLC) Large cell carcinoma 27

28 Large cell carcinoma 10-20% older age group, median age 60 years strongly associated smoking LCC : histologic findings WHO (2004) : undifferentiated NSCLC that lacksthe cytologic& architectural features of SCLC & glandular or squamous differentiation Classification OMS, 2004 LCC : cytopathologic findings Modern Cytopathology. Geisinger KR et al, Churchill Livingstone,

29 Large cell carcinoma LCC : differential diagnoses Small cell lung cancer (SCLC) 29

30 SCLC : clinical features 20-25% of all lung cancers Most patient have distant metastasis at the time of diagnosis Male preponderance Strong association with smoking SCLC : histologic findings WHO 2004 : a malignant epithelialtumour consisting of small cells with scant cytoplasm, ill defined borders, finely granular chromatin & absent or inconspicuous nucleoli. Nuclear molding is prominent. Necrosis is typically extensive & the mitotic count is high. SCLC : cytopathologic findings Small or medium-sized cells (2-2 ½ times the lymphocytes) with little or no cytoplasm (larger than in sputum) Dispersed cell presentation; some clusters, including some small tight groups Nuclear molding & engulfment; nuclei round, oval to fusiform Uniform finely or coarsely granular nuclear chromatin; nucleoli inconspicuous to absent Indiscernible cytoplasm Tear-drop cells, smeared cells & streaks of nuclear material Engulfment of apoptotic bodies Numerous mitotic figures Necrosis in the background 30

31 Small Cell Carcinoma Nuclear molding, karyorrhexis Small Cell Carcinoma Sputum : nuclear molding Small Cell Carcinoma Sputum : Nuclear molding, necrotic debris 31

32 Small Cell Carcinoma Small Cell Carcinoma Bronchial washing : nuclear molding & crush artifacts are not consistent features in liquid medium SCLC : differential diagnoses 32

33 SCLC : differential diagnoses Mature lymphocytes, no nuclear molding, no karyorrhxis or necrosis, SCLC : differential diagnoses Only in tissue fragment; single cells are difficult to iddentify; often attached to columnar cells; compactly arranged, poorly defined cell border; indicernible cytoplasm with high N/C ratio; minimal nuclear molding; dense staining compact chromatin; nucleoli -; no mitosis; no karrhyorrhexis; no strech artifact SCLC : differential diagnoses Coarsely granular chromatin, no molding; no stretch artifact; immunoprofile Coarsely granular chromatin, nucleoli often conspicuous; immunoprofile 33

34 SCLC : differential diagnoses Finely granular chromatin with micronucleoli/macronucleoli, no nuclear molding, immunoprofile Thank you 34