Lung/Thoracic Neoplasms. Manish Powari

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1 Lung/Thoracic Neoplasms Manish Powari

2 Biopsy Techniques in Lung cancer diagnosis Decreased cellularity and architecture; thereby influencing subtyping Thoracotomy, resection VATS biopsy/resection L.node excision, mediastinoscopy, liver biopsy, core biosy, bronchial biopsy FNA Fluids, bronchial brushings Sputum

3 Diagnostic Hierarchy

4 Not all lumps are neoplastic or malignant

5 Case 2 (22608/09)

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9 Malakoplakia Malakoplakia is an uncommon condition, considered to be a type of xanthogranulomatous inflammation. In general it is rarely suspected clinically. It is well recognized in the urinary tract (about 75 % of cases). The diagnosis is made histologically often following clinical or radiological suspicion of malignancy.

10 The cornerstone of this diagnosis are Michaelis- Gutmann bodies (MG bodies) Use of special stains like PAS (to stain magenta eosinophilic granules), Alizarin red S (red), Perl s (blue) or von Kossa (black) (to visualize intra- and extracellular round target-like structures incrusted with iron or calcium) is helpful Malakoplakia is thought to result from ineffective phagocytosis of causative bacteria by macrophages in a setting of decreased host immunity, most often acquired.

11 CASE 13 (1647/11)

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15 LCH Smoking associated Multiple small nodules and cysts Also called pulmonary eosinophilic granuloma. Most cases are nonneoplastic, reactive process in smokers. Proliferative phase and fibrotic phase Stellate scar Co-expression of S100 and CD1a

16 Case 10 (3184/10)

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20 Amyloid tumour Broncho-pulmonary amyloidosis Tracheobronchial Nodular or diffuse. Usually confined to respiratory tract Parenchymal- Nodularsolitary or multiple confined to respiratory tract Parenchymal Diffuse septal manifestation of systemic amyloidosis

21 Non-carcinomatous tumours

22 Case 9 (8311/11)

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26 FLI 1 and CD31

27 TTF 1

28 Haemangioendothelioma (CASE /11) Low to intermediate grade vascular tumour 0.3 to 2cm circumscribed gray tan firm tissue, centre may be calcified Round to oval nodules with central sclerosis and a cellular peripheral zone. Spread into adjacent airways in a micropolypoid manner Sharp intracytoplasmic vacuoles D/D- Organised infarcts, granulomatous inflammation, amyloid nodules, sclerosing haemangioma, chondrosarcoma, adenoca.

29 Metastatic tumours Colorectal, RCC, Prostate, Breast, HCC

30 Case 12 (8346/11)

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32 PSA

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40 Case 5 (3974/10)

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43 CD5 and EMA

44 Thymic carcinoma are rare. Most frequent subtype is squamous Epithelial nests and cords with broad zones of thick fibrohyaline stroma. Express CD5, CD117 and CD70. Some B3 thymomas express CD5. Expression of CD5 and CD70 helps confirm thymic origin.

45 Interobserver consistency reported to be excellent (k- 0.86) Diagnostic accuracy is good NSCLC- 98% SCLC- 90%

46 Case 4 (14298/10)

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49 CD56 and CAM 5.2

50 Small cell Ca Granular chromatin Nuclear moulding High mitotic and apoptotic counts Morphology variable depending on sample type Neuro-endocrine markers positive (occasionally all negative) Punctate positivity with MNF116 is helpful. Can be very scantily positive 34BE12 predominantly negative Oat cell morphology Intermediate sized cells Round or fusiform Occasional small nucleoli and some cytoplasm is not against the diagnosis

51 Case 15 (19034/11)

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54 Histology Small cell Large cell NE ca Size Smaller (3 lymphocyte) Larger N:C ratio Higher Lower Chromatin Fine granular, uniform Coarse, vesicular/ less uniform Nucleoli Absent or faint Often seen, prominent moulding characteristic uncharacteristic Fusiform shape common uncommon Polygonal shape uncharacteristic characteristic Nuclear smear frequent uncommon

55 Case 14 (21685/10)

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58 CD56 and TTF 1

59 MIB 1

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61 Subclassification of NSCLC Interobserver consistency poor (k to 0.39) Reported diagnostic accuracy is variable

62 Non- small cell lung carcinoma Large cell Not on small biopsy Squamous Keratin Prickles/intercellular bridges Adenocarcinoma Gland formation Mucin production (PASAB)

63 Case 7 (9634/11)

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68 Case 1 (7480/10)

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73 Case 1 (7480/10)

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75 Case 11 (842/11)

76 Case 8 (11431/11)

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78 Case 3 (23049/10)

79 (keratinization)

80 CASE 6 (19397/09)

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82 Intra bronchial component

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84 Epithelial-myoepithelial carcinoma Salivary gland tumours occur in the tracheo-bronchial tree. These include: pleomorphic adenoma, adenoid cystic carcinoma, muco-epidermoid carcinoma and epithelial myoepithelial carcinoma. Epithelial-myoepithelial carcinoma predominantly are endobronchial, although occasional intra-pulmonary type have been reported. No chondromyxoid stroma is seen. The luminal cells are EMA and CK7 positive. The abluminal cells and cells in solid areas show patchy S100 and p63 positivity. Overall percentage of tumour staining with MIB1 is low

85 Case 19 (9378/11)

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88 EMA and MNF116

89 Case 18 (21263/12 frozen)

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92 Case 16 (20383/12 frozen)

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96 Case 17 (26907/12)

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101 Differential Histology Differential Therapy SCLC NSCLC Definite SCLC Non SCLC High grade NE ca Adenoca Squamous Not squamous probably Pl/Etoposide Possibly the same Pl/Gem/Tax/Vin Pemetrexate EGFR TKIs Bevacizumab Pl/Gem/Tax/Vin Not Pemetrexate Not Bevacizumab Pl/Gem/Tax/Vin Pemetrexed?EGFR TKIs Bevacizumab

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103 Molecular studies in Lung adenocarcinoma Most therapeutic successes seen in low mutations settings (smoking Vs non smoking) Most successes have been in adenocarcinoma or large cell carcinoma where genetic mutations are mutually exclusive. EGFR, ALK, B-RAF

104 EGFR Tyrokinase receptor of the HER family 28 exons on chromosome 7p21 Approx 90% mutations involve in-frame deletion of exon 19 or point mutation in exon21 EGFR mutated adenoca are typically low stage where a prominent lepidic pattern is associated with acinar or papillary growth

105 These adenoca express CK7, TTF 1, Napsin A and surfactant apoprotein Adenoca with extensive mucinous or goblet cell differentiation rarely EGFR positive. More commonly they express K-Ras Currently, detected by DNA sequencing analysis or real time PCR Mutations in exon 18 and 20 confer resistance to anti- EGFR treatment

106 EML4-ALK ALK gene on chromosome 2p23 Most often occur as inversion with EML4 4-8% of lung ca Predisposition in year-old particularly men with light or no smoking High stage, poorly differentiated with solid or acinar growth pattern with broad areas of necrosis and prominent host reaction

107 EML4-ALK FISH is a better technique and the gold standard Commercially available antibody

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109 B-RAF 3-8% of lung adenocarcinoma Over 50% of mutations involve V600E Exclusive of EGFR, ALK and K-Ras Often in smokers, elderly with equal sex distribution High stage disease Poorly differentiated with solid and acinar growth

110 With the availability of targeted therapy for some lung cancers, accurate subtyping has become essential. Sample size are small. Efficient use of tissue is paramount. Judicious use of IHC to conserve tissue for molecular studies.

111 Squamous markers- p63, CK5/6, p40 Adenocarcinoma- TTF 1, mucin, Napsin A Additional stains depending on morphology and clinical history Use of serials S1 to S9 keeping S 2-7 for IHC. H&E on S1 and S9. Try not to go back to the block

112 Diagnostic accuracy in NSCLC Cytology (43%) Small Biopsy samples (63%) Squamous Adenocarcinoma

113 Lineage Markers for NSCLC, NOS Adenoca ABPAS TTF 1 Sensitivity Specificty PPV NPV 23 54/(80) /(89) /(89) 76 88/(81) ABPAS/TTF1 CK7 Napsin A 69 (100) (58) 97 (37) (100) 90 (61) (100) 83 (100) (70) Squamous CK5/6 34b12 p63 84/(73) 88/(100) 92/(100) 79/(100) 74/(50) 74/(92) 84/(100) 81/(56) 82/(88)

114 Cytology specimens are ideal for this era of personalized medicine and molecular diagnostics: Specimen acquired in minimal invasive way Specimen enriched in tumour cells Utilized for diagnosis and staging

115 Maximizing tissue for molecular testing Specimen acquisition Specimen processing Educating the aspirator Establish lab protocols for processing Optimal diagnostic modality Triage (image guidance) ROSE Cut extra blank slides upfront Additional dedicated passes Use of alternative material

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118 WHO 2004 CLASSIFICATION IASLC/ERS/ATS Small biopsy/cytology Small cell Small cell LCNEC Large cell with neuroendocrine morphology Adenocarcinoma (mixed, papillary, solid, acinar) Squamous (papillary, small, clear, basaloid) Non small cell with neuroendocrine morphology and positive IHC possible LCNEC Non small cell with neuroendocrine morphology (LCNEC suspected but IHC negative) Adenocarcinoma (state the patterns- lepidic, acinar, papillary, micropapillary, solid) Squamous ca Adenosquamous ca No counterpart in 2004 classification BAC (non mucinous) BAC (mucinous) NSCLC ; Morphological glandular and squamous components present (could represent adenosquamous ca) NSCLC; morphological adeno or squamous differentiation not seen but state IHC NSCLC favour adeno, NSCLC favour squamous, NSCLC NOS Adenocarcinoma lepidic pattern (if pure, comment invasion cannot be excluded) Mucinous adenocarcinoma (describe patterns) Sarcomatoid Ca Poorly differentiated NSCLC with spindle+/- giant cell (state if adeno or squamous component present)

119 IASLC/ATS/ERS CLASSIFICATION OF LUNG ADENOCARCINOMA IN RESECTION SPECIMENS PREINVASIVE LESIONS Atypical adenomatous hyperplasia Adenocarcinoma in situ ( 3 cm formerly BAC) - nonmucinous - mucinous - mixed mucinous/non-mucinous MINIMALLY INVASIVE ADENOCARCINOMA ( 3 cm lepidic predominant tumour with 5 mm invasion) -nonmucinous -mucinous - mixed mucinous/non-mucinous INVASIVE ADENOCARCINOMA Lepidic predominant (formerly non-mucinous BAC pattern, with >5 mm invasion) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production VARIANTS OF INVASIVE ADENOCARCINOMA Invasive mucinous adenocarcinoma (formerly mucinous BAC) Colloid Fetal (low and high grade) Enteric

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121 Summary Pathological data are now key determinants of treatment choices for patients with lung cancer, especially in advanced stage disease. The acquisition of diagnostic tissue is vital to support the ever increasing portfolio of molecular tests. Maximizing tissue yield from every sampling procedure in the safest possible way, is a priority.

122 Simple predictive immunohistochemistry can reduce the NSCLC-NOS rate in small diagnostic samples to under 10% of cases. It is impossible to reduce this figure to zero. The pre-analytical steps involved in handling, fixing and processing tissue samples are critical to obtaining accurate and meaningful biomarker tests. Pathological assessment of any material submitted for non-morphological testing (DNA or RNA based) is vital to ensure adequacy and appropriateness of test materials.

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124 Specimen handling

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128 Thank you