Difficult Diagnoses and Controversial Entities in Neoplastic Lung
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1 Difficult Diagnoses and Controversial Entities in Neoplastic Lung Lynette M. Sholl, M.D. Associate Pathologist, Brigham and Women s Hospital Chief, Pulmonary Pathology Service Associate Professor, Harvard Medical School
2 Disclosures Consultant for Foghorn Therapeutics, AstraZeneca, LOXO Oncology
3 Objectives Recognize unusual entities and their morphologic mimics in lung Appreciate the genomic underpinnings of aggressive tumors of the lung Recognize the clinical implications of specific lung cancer diagnoses
4 Adenocarcinoma Squamous cell carcinoma Small cell carcinoma ROS1 1.1 ERBB2 2.5 No/unknown driver 29.9 RET 1.0 NRAS 1.0 PIK3CA 2.9 MET BRAF EGFR 19.1 KRAS 33.8 ALK 3.9 Genomic data extracted from BWH/DFCI PROFILE sequencing database.
5 Case 1: A 68-year-old man presents with cough and weight loss. Imaging shows a 5.5 cm mass in the right upper lobe and 4.0 cm mass in the liver. Liver FNA shown here.
6 Case 1: What is your favored diagnosis? 1. Non small cell carcinoma, NOS 2. Squamous cell carcinoma 3. Large cell neuroendocrine carcinoma 4. Small cell carcinoma 5. High grade neuroendocrine carcinoma, NOS
7 Histology/cytomorphology of LCNEC Biopsy/resection: Solid nests with peripheral palisading and central necrosis Cribriform architecture with rosette-like structures May resemble atypical carcinoid tumor Mitoses >10 per 2mm 2 Cytology prep: Overlapping features with adenocarcinoma and neuroendocrine neoplasms Cells may appear small Hyperchromatic nuclei resembling small cell carcinoma Nucleoli should be evident Confirmation of neuroendocrine differentiation (chromogranin, synaptophysin, CD56) using IHC is required for the diagnosis.
8 Genomic subsets of Pulmonary LCNEC Napsin-A negative Napsin-A weak/focal Rekhtman et al. Clin Canc Res and Mod Pathol. 2017
9 Morphologic classification: NSCLC, favor LCNEC 90 year old man, 100 pack year smoker, 4cm pleuralbased mass
10 90 year old man, 100 pack year smoker, 4cm pleuralbased mass Biallelic TP53 and RB1 loss Morphologic classification: NSCLC, favor LCNEC Genomic classification: Small cell lung carcinoma
11 Morphologic classification: Combined LCNEC and SCLC 50 year old, light remote smoking history, large hilar mass
12 50 year old, light remote smoking history, large hilar mass EGFR exon 20 insertion mutation Biallelic TP53 mutation and RB1 loss Morphologic classification: Combined LCNEC and SCLC Genomic classification: Small cell lung carcinoma ex adenocarcinoma?
13 Morphologic classification: LCNEC 55 year old woman with 30 pack year smoking history, 6cm peripheral mass
14 55 year old woman with 30 pack year smoking history, 6cm peripheral mass KRAS, STK11 mutations No TP53, RB1 mutations Morphologic classification: LCNEC Genomic classification: Adenocarcinoma
15 Morphologic classification: LCNEC 65 year old woman with pack year smoking history, with diffuse chest and neck lymph node metastases
16 65 year old woman with pack year smoking history, with diffuse chest and neck lymph node metastases CTNNB1, TP53, NF1 mutations. No RB1 mutations. Morphologic classification: LCNEC Genomic classification:???
17 LCNEC: Outcomes following NSCLC vs. SCLC therapy ASCO 2015 Oncology practice guidelines: SCLC or NSCLC-based regimen ok. Derks et al., 2017: Patients with LCNEC do better with NSCLC platinum combination therapy than with SCLC (etoposide) therapy OS only; no difference in PFS Caveats: Uncontrolled, retrospective comparisons Practitioners biased towards giving SCLC regimens to patients with greater burden of mets Derks et al. Eur Respir J Masters et al. JCO
18 LCNEC: Outcomes following NSCLC vs. SCLC therapy Retained RB1 expression predicts improved benefit with NSCLC platinum doublet therapy. Derks et al. Clin Cancer Res. Oct 2017
19 Case 1: RB1 immunohistochemistry H&E RB1 protein loss
20 Case 2: 64 year old female never smoker with cough, large lung mass, and rapidly growing mass on her shoulder.
21 Pulmonary sarcomatoid carcinoma Pleomorphic carcinoma Rhabdomyoblastic differentiation in a carcinosarcoma An umbrella term that encompasses: Pleomorphic carcinoma Giant cell carcinoma Spindle cell carcinoma Carcinosarcoma Carcinoma + sarcoma with heterologous elements Desmin expression in heterologous elements of pulmonary blastoma Pulmonary blastoma Fetal adenocarcinoma+ mesenchymal stroma CTNNB1 hotspot mutations
22 Pleomorphic, giant cell, spindle cell carcinomas Pleomorphic carcinoma Poorly differentiated NSCLC containing 10% spindle and/or giant cells Spindle cell carcinoma Pure population of epithelial spindle cells lacking differentiated carcinoma Giant cell carcinoma Pure population of tumor giant cells lacking differentiated carcinoma Definitive diagnosis can only be made on resection specimen Giant cell/spindle cell features should be described on biopsy/cytology specimens Differentiated components (adenocarcinoma, squamous cell carcinoma) should be mentioned in the diagnosis.
23 Resection: Pleomorphic carcinoma with giant cell features Resection: Pleomorphic carcinoma with giant cell and spindle cell features Pleural fluid: Adenocarcinoma with giant cell features Thin prep, 60X Diffuse TTF-1 expression consistent with derivation from adenocarcinoma Arising in association with adenocarcinoma, solid and lepidic patterns. Cell block, 40X Cytology images courtesy of M. Vivero
24 Genotype-phenotype correlations Lui et al. J Clin Oncol. 2015: Whole exome and targeted sequencing of 36 pulmonary sarcomatoid carcinomas identified 8 (22%) with MET exon 14 splice mutations Awad et al. J Clin Oncol. 2016: Targeted next generation sequencing of 15 pleomorphic carcinomas identified 4 (27%) with MET exon 14 splice Other alterations include: KRAS (13%) NRAS (7%) no known driver (53%). Awad et al. J Clin Oncol. 2016
25 64 year old female never Case smoker 2: with cough and MET rapidly exon growing 14 splice mass on her shoulder. variant identified by NGS. Patient responds to crizotinib therapy. Awad et al. J Clin Oncol. 2016
26 Outcomes in patients with metastatic MET splice-mutated lung cancers No MET targeted tx: mos = 8.3 months With MET targeted tx: mos = 24.6 months Awad et al. ASCO 2017 (abstract)
27 Clinicopathologic correlates of pleomorphic carcinoma 2-3% of lung cancer diagnoses Pure forms of giant cell or spindle cell carcinoma are vanishingly rare May represent evolution from a better differentiated carcinoma Smokers > nonsmokers Aggressive clinical course 20+% of cases have MET splice mutations, conferring sensitivity to MET targeted inhibitors
28 Case 3: 34 year old nonsmoking man with cough, chest pain.
29 TTF-1 p63 Adenosquamous carcinoma? Squamous cell carcinoma?
30 Nut [midline] Carcinoma Nut protein 9q34 BRD3 15q13 NUT
31 Nut Carcinoma Thought to represent a variant of squamous cell carcinoma- abrupt keratinization may be seen Most cases harbor t(15;19) BRD4-NUT fusion but several other NUT fusion partners known Largest series to date report on predominance of tumors at head and neck and mediastinal locations
32 NUT Carcinoma in the lung Nested to diffuse growth of monomorphic, primitive appearing cells Granular chromatic Prominent nucleoli Abrupt keratinization may be seen Morphologic variation seen Bair et al. Cardiopulm Imaging. 2014
33 Nut Carcinoma in the lungclinicopathologic features Uniformly lethal (2 month overall survival) NUT translocations drive aberrant chromatin modulation May predict efficacy of BET inhibitors (in clinical trials) This represents <1% of lung tumors, but one has probably crossed your scope. Think of Nut when: The patient is young You are about to diagnose squamous cell carcinoma in a non smoker The immunohistochemistry pattern is confusing/unusual Your morphologic diagnosis includes lymphoma, germ cell tumor, and carcinoma Sholl et al. J Thor Oncol
34 Case 4: 72 year old former 50 pack year smoker, presents with a dry cough.
35 Undifferentiated carcinoma? Undifferentiated malignant neoplasm with focal rhabdoid features Primitive -appearing nuclei Abundant mitoses Positive for synaptophysin Negative for keratin, TTF-1, P63, LCA, SOX10, desmin, ERG, OCT3/4
36 Undifferentiated carcinoma? Undifferentiated malignant neoplasm with focal rhabdoid features Primitive -appearing nuclei Abundant mitoses Positive for synaptophysin Negative for keratin, TTF-1, P63, LCA, SOX10, desmin, ERG, OCT3/4 DDX: Large cell carcinoma (why no keratin?) Nut carcinoma (check a Nut stain) Metastasis (check clinical history) Other?
37 SMARCA4-deficient undifferentiated thoracic malignancies RNA sequencing of unclassified sarcomas identified a family of mediastinal and lung tumors transcriptionally related to SMARCA4-deficient small cell carcinomas of the ovary and SMARCB1-deficient malignant rhabdoid tumors Identified in adults aged M>F Majority smokers Median overall survival of 7 months. All show SMARCA4 loss by IHC All show SMARCA4 loss of function mutations by sequencing LeLoarer et al. Nature Genetics 2015
38 Our patient s SMARCA4 IHC: Differential diagnosis: Newly described SMARCA4-deficient thoracic malignancy No evidence of lung-specific differentiation SOX2 amplification and overexpression is common No other oncogenic mutations observed Undifferentiated large cell carcinoma with SMARCA4 loss SMARCA4 mutations in 5-10% of lung adenocarcinomas Expect keratin expression May have TTF-1 expression Typical oncogenic mutations observed (especially KRAS)
39 SMARCA4-deficient thoracic malignancy: managing a newly described entity Reports of these tumors suggest an aggressive clinical course Most cases arise in the mediastinum and pleura, but rarely may present as a lung primary Outcomes for patients with optimal surgical management are unclear Our patient has no evidence of disease at 18 months f/u Sauter et al. Mod Pathol 2017: Of 40 undifferentiated thoracic tumors with rhabdoid morphology, 12 (30%) were SMARCA4 deficient; all tested cases were also SMARCA2 deficient Does combined SMARCA4+SMARCA2 separate these from lung carcinomas?
40 Take home points: Genomics are increasingly (re)defining the classification of poorly/un- differentiated lung tumors Many of these defining genomic alterations have some IHC correlate
41 Thanks and questions?
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