Dilemmas in Cytopathology and Histopathology

Transcription

1 Dilemmas in Cytopathology and Histopathology Yuri E. Nikiforov, MD, PhD Division of Molecular & Genomic Pathology University of Pittsburgh Medical Center, USA

2 Objectives Discuss new WHO classification of thyroid tumors Discuss the effect of introduction of NIFTP on malignancy risk in indeterminate thyroid cytology Discuss challenges in cytological detection of thyroid cancer with low grade morphology

3 2017 WHO Classification NIFTP Hurthle cell carcinoma Hurthle cell adenoma

4 2017 WHO Classification Hurthle cell adenoma Hurthle cell carcinoma Oncocytic cells 75% or more of tumor should be composed of oncocytic cells Carcinomas have capsular or vascular invasion Capsular invasion L/n metastasis

5 2017 WHO Classification

6 2017 WHO Classification

7 2017 WHO Classification

8 2017 WHO Classification

9 2017 WHO Classification

10 2017 WHO Classification

11 Challenges in histopathologic diagnosis of Encapsulated follicular variant of PTC

12 Clinical Behavior on Follow up *352 non invasive EFVPTC reported in the literature, 2/352 (0.6%) recurred Nikiforov et al. JAMA Oncology 2016; 2:

13 79 large size ( 4cm) NIFTP cases Clinical follow up: 56 (71%) at least 2 years, and 49 (62%) 4 years Median size 4.5cm (range cm) 67% total thyroidectomy, 53% receive RAI ablation. No lymph node metastases at diagnosis No recurrence was observed in the entire cohort: 32 patients with 2 years of FU who did not receive RAI therapy (median FU: 6.7 years) 25 individuals with 4 years of FU without RAI therapy (median FU:11.2 years) Patients with a larger tumor size tended to receive postoperative RAI ablation (p=0.001)

14 Molecular profile of NIFTP Gene mutation NIFTP n=27 RAS* 8 NRAS (5) HRAS (2) KRAS (1) BRAF K601E 1 PPARG fusion 6 THADA fusion 6 TOTAL MUTATION POSITIVE 21 (78%) *2 cases with double mutations: RAS & EIF1AX IMPORTANT: No BRAF V600E or other BRAF V600E like mutations No TERT 1 additional tumor THADA fusion + 1 additional tumor MAP2K1 mutation + TOTAL: 23/27 (85%) with mutations all RAS-like mutations Nikiforov et al. JAMA Oncology 2016; 2:1023-9

15 Histopathological diagnosis of NIFTP remains challenging Requires examination of entire tumor capsule No well formed papillae Challenging cases: second opinion, molecular analysis helpful Incorrectly diagnosed cases may metastasize more often!

16 Principles of thyroid FNA cytology Nuclear features of PTC Ratio cell:colloid and architectural pattern The cytologic diagnosis of follicular lesions simplified Zone I Zone II Zone III <3% risk of malignancy 15%-30% risk of malignancy Colloid nodule Cellular nodule Follicular nodule Benign follicular Follicular lesion of (Suspicious for) nodule undetermined significance follicular neoplasm DeMay RM. Art and Science of Cytopathology (2011)

17 Impact of NIFTP diagnosis on thyroid cytology Cytology Study Benign (Bethesda II) AUS/FLUS (Bethesda III) FN/SFN (Bethesda IV) SUSP (Bethesda V) Malignant (Bethesda VI) Maletta F et al, 2016 n=96 Brandler TC et al, 2017 n=56 Zhao L. et al, 2017 n=50 Rosario PW et al, 2017 n=126 15% 56% 27% 2% 10.7% 37.5% 26.8% 17.9% 7.1% 4% 28% 26% 18% 18% 8% 20% 42% 25.4% 4% Mean 6% 26% 40% 19% 7%

18 Diagnostic categories unchanged ROM adjusted accounting for NIFTP Molecular testing recommended for indeterminate categories

19 Principles of histopathologic diagnosis of thyroid tumors Diagnostic question HN FA Microscopic features Architectural pattern, capsule Assumptions These features reflect lesion biology FA FTC Invasion Tumor capsule is fully and thoroughly examined Non PTC PTC Nuclear features of PTC Nuclear features either clearly present or absent

20 Principles of histopathologic diagnosis of thyroid tumors Diagnostic question HN FA Microscopic features Architectural pattern, capsule Assumptions These features reflect lesion biology Tumors of the Thyroid Gland AFIP 1968 Atlas of Nontumor Pathology AFIP 2002

21 Not all benign thyroid nodules are created equal: Variability in malignant potential Benign hyperplastic nodule No Non clonal mutations Benign follicular adenoma Atypical FA FTC Mutation Clonal + (eg. RAS) NIFTP PTC Nikiforov YE. Endocr Pract (2017)

22 Molecular changes precede histological changes C A B NRAS c.181c>a NRAS c.181c>a NRAS c.181c>a Gupta M et al. JCEM (2013)

23 Principles of histopathologic diagnosis of thyroid tumors Diagnostic question FA FTC Microscopic features Invasion Assumptions Tumor capsule is fully and thoroughly examined Wang N, et al. Cancer. 2014;120:

24 Principles of histopathologic diagnosis of thyroid tumors Diagnostic question Microscopic features Nuclear features Non PTC PTC of PTC Assumptions Nuclear features either clearly present or absent Nuclear features of Papillary Carcinoma Clearly absent Clearly present

25 Multistep Cancer Progression and Existence of Borderline Tumors Colon cancer Normal epithelium APC Adenoma RAS BRAF SMAD4 Carcinoma in situ TP53 TGFB BAX Invasive carcinoma Craene B. & Berx G. (2013); Brisken C. (2013)

26 Multistep Cancer Progression and Existence of Borderline Tumors Nikiforov et al. JAMA Oncology 2016; 2:

27 ATA cancer risk stratification Risk of Structural Disease Recurrence (In patients without structurally identifiable disease after initial therapy) High Risk Gross extrathyroidal extension, incomplete tumor resection, distant metastases, or lymph node >3cm Intermediate Risk Aggressive histology, minor extrathyroidal extension, vascular invasion, or > 5 involved lymph nodes (0.2-3 cm) Low Risk Intrathyroidal DTC 5 LN micrometastases (< 0.2 cm) FTC, extensive vascular invasion ( 30-55%) pt4a gross ETE ( 30-40%) pn1 with extranodal extension, >3 LN involved ( 40%) PTC, >1 cm, TERT mutated ± BRAF mutated* (>40%) pn1, any LN > 3 cm ( 30%) PTC, extrathyroidal, BRAF mutated* ( 10-40%) PTC, vascular invasion ( 15-30%) Clinical N1 ( 20%) pn1, > 5 LN involved ( 20%) Intrathyroidal PTC, < 4 cm, BRAF mutated* ( 10%) pt3 minor ETE ( 3-8%) pn1, all LN < 0.2 cm ( 5%) pn1, 5 LN involved ( 5%) Intrathyroidal PTC, 2-4 cm ( 5%) Multifocal PMC ( 4-6%) pn1 without extranodal extension, 3 LN involved (2%) Minimally invasive FTC ( 2-3%) Intrathyroidal, < 4 cm, BRAF wild type* ( 1-2%) Intrathyroidal unifocal PTMC, BRAF mutated*, ( 1-2%) Intrathyroidal, encapsulated, FV-PTC ( 1-2%) Unifocal PMC ( 1-2%) NIFTP (<1%) Haugen BR et al. Thyroid. 2016, 26:1-133

28 DTC with low risk histology and distant metastasis 123 patients with DTC and distant metastasis from MSKCC 15 patients without high risk features at initial surgery Most 2 cm pt1 (n=10) No lymphovascular invasion No extrathyroidal extension Analyzed using multi gene IMPACT panel Mutation profile of tumors with low risk histology and distant metastases Pt RAS BRAF V600E TERT Other mutations 1 Mutated PIK3CA,ARID2, ATM, FAT1 2 NRAS Mutated RBM10 3 NRAS Mutated EIF1AX 4 HRAS Wild type BAP1 5 NRAS Wild type 9 NRAS Mutated PTPRT, NTRK1, INHA, PTPRS, BCL6 12 BRAF Mutated 14 Mutated CDKN1A, ARID2 Xu B et al. Thyroid (2017)