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Update on thyroid tumors
- 1. UPDATE ON THYROID TUMOURS Moderator: Prof Uma Nahar Saikia
- 2. DISCLAIMER I shall be discussing the changes that have taken place between the 2WHO blue Books which is spread over a period of 13 years 2004 2017
- 3. OUTLINE OF PRESENTATION Introduction Thyroid tumors with follicular pattern Hyperplastic versus follicular adenoma Encapsulated follicular pattern tumors - FVPTC, NITFP Invasion Role of IHC Role of molecular methods Hurthle cell tumors Poorly differentiated carcinoma TNM classification IgG4 related Hashimoto thyroiditis
- 4. DR PIERRE MASSON (1880-1959) “No classification is more difficult to establish than that of thyroid [carcinomas]…….. ……….Of all cancers, they teach, perhaps, the greatest lessons of humility to histopathologists” Excerpt from book Human Tumors
- 6. J Endocr Soc. 2017 May 1; 1(5): 480–487.
- 7. MOST IMPORTANT ASPECT OF PATHOLOGY “Making a correct and timely diagnosis with provision of sufficient detailed histological information upon which to risk stratify patients for treatment decisions”
- 8. THYROIDTUMOURS WITH FOLLICULAR PATTERN “Bane of the histopathologist”
- 9. FOLLICULAR ADENOMAVS HYPERPLASTIC NODULES Adenoma – clonal vs Hyperplastic nodule – polyclonal How to assess clonality X chromosome inactivation – Only ladies are lucky Cytogenetics- numerical chromosome changes 7, 12, 5; translocations 19p & 2p Somatic mutations : RAS, PAX8/PPRG, BRAFK601E, GNAS,TSHR Is the clonality assessment worth the effort ? NO Completely removed lesion pose no further risk
- 10. FOLLICULAR ADENOMA IN A MULTINODULAR GOITRE “Many pathologists do not make the diagnosis of adenoma in a multinodular gland, preferring to designate all lesions as hyperplastic nodules provided there is no evidence of malignancy” -WHO blue book 2017
- 12. FOLLICULARVARIANT OF PTC Recognized in the mid-1970s Defined as a tumour composed of neoplastic follicles rather than papillae, but with follicular cells showing nuclear features characteristic of PTC Two types Infiltrative (non-encapsulated) Encapsulated Am J Surg Pathol. 1977;1(2):123-130
- 13. Arch Pathol Lab Med—Vol 137, December 2013
- 15. AFIP UNDER J ROSAI RECOMMENDED IN 2014 Capsular invasion Present Questionable Absent Nuclear features of PTC Present Follicular variant of PTC Questionable Well differentiated carcinoma, NOS Well differentiated tumor of uncertain malignant potential Absent Follicular carcinoma Follicular tumor of uncertain malignant potential Follicular adenoma
- 16. EVFPTC – A CONTROVERSIAL AND CONTENTIOUS DIAGNOSIS “..considerable inter-observer and intra-observer variability in the diagnosis of FVPC seems to result from lack of agreement on the minimal criteria needed to diagnose FVPC, even among experts”
- 17. INCREASING PREVALENCE OF EVFPTC
- 18. EVFPTC – FAVOURABLE OUTCOME Am J Surg Pathol. 2010;34(6):868-872
- 21. NON-INVASIVE FOLLICULARTHYROID NEOPLASMWITH PAPILLARY-LIKE NUCLEAR FEATURES Encapsulation or clear demarcation Follicular (micro/nomro/macro) growth pattern with <1% Papillae No psammoma bodies <30% Solid/trabecular/insular growth pattern Nuclear score 2-3 No vascular or capsular invasion No tumour necrosis No high mitotic activity (<3 per 10 hpf)
- 23. Score 1 Score 2 Score 3
- 24. MOST CONTROVERSIAL Classification of well-differentiated follicular tumours Morphologically and behaviorally intermediate between follicular adenoma and follicular carcinoma / the follicular variant of papillary carcinoma Hints towards follicular carcinoma (Unpublished data from Dept.) Thick capsule favors carcinoma >4 mitosis per 10 hpf favors carcinoma
- 25. CAPSULAR INVASION Questionable capsular invasion
- 26. CAPSULAR INVASION While conceptually simple, there is no consensus as to the definition of the tumor capsular invasion - CAP Guidelines Fletcher CDM, ed. Diagnostic Histopathology of Tumours. 3rd ed.
- 28. VASCULAR INVASION Questionable vascular invasion
- 29. VASCULAR INVASION Questionable vascular invasion
- 30. VASCULAR INVASION True invasion - Penetration through the vessel wall - Reaction to the vascular deposit
- 31. VASCULAR INVASION Fletcher CDM, ed. Diagnostic Histopathology of Tumours. 3rd ed. While there is no standard definition of “deeper levels,” generally, each level is at a certain interval (ie, 3 serial sections deeper or 15-micron intervals) below the original H&E rather than an immediate serial section. - CAP
- 33. Capsular or vascular invasion Present Questionable Absent Nuclear features of PTC Present Invasive encapsulated follicular variant of PTC Well differentiated tumor of uncertain malignant potential Non-invasive follicular thyroid neoplasm with papillary-like nuclear features Questionable Well differentiated carcinoma, NOS Absent Follicular carcinoma Follicular tumor of uncertain malignant potential Follicular adenoma
- 36. FOLLICULAR CARCINOMA –TYPES BASED ON INVASION Minimally invasive follicular carcinoma - Rrestricted to histological proven tumoral capsular invasion only Widely invasive follicular carcinomas Grossly apparent invasion of thyroid and/or soft tissue
- 37. IMMUNOMARKERS USED IN THE DIFFERENTIAL DIAGNOSIS OF FOLLICULAR PATTERNED TUMORS Hector Battifora mesothelial–1 (HBME-1) Galectin-3 (GAL-3) Cytokeratin 19 (CK19) Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain, 1 (CITED1) TPO Trophoblastic cell surface antigen 2 (TROP2) BRAF Mutation-Specific Antibody “No single marker sensitive enough to provide a definitive malignant diagnosis” Arch Pathol Lab Med—Vol 139, January 2015
- 38. HECTOR BATTIFORA MESOTHELIAL–1 (HBME-1) Membrane antigen that exists in the microvilli of mesothelial cells and other epithelial cells Membranous Sensitivity of 77% Specificity of 83% de Matos et al. Diagnostic Pathology 2012, 7:97
- 39. GALECTIN-3 (GAL-3) Beta-galactoside-binding protein family Cytoplasmic Sensitivity of 82% Specificity of 81% de Matos et al. Diagnostic Pathology 2012, 7:97
- 40. GAL-3VARIABLE EXPRESSION IN PTC (Unpublished data from dept)
- 41. GAL-3 EXPRESSION INTILS (Unpublished data from dept) Possible role in immune cycle modification in tumour microenvironment
- 42. CYTOKERATIN 19 (CK19) Nuclear and cytoplasmic Sensitivity of 81% Specificity of 73% de Matos et al. Diagnostic Pathology 2012, 7:97
- 43. COMBINATION OF HBME1, GALECTIN-3 AND CK19 Sensitivity of 85% Specificity of 97% Diagnostic odds ratio of 95.1 Diffuse and intense expression should be taken as positive de Matos et al. Diagnostic Pathology 2012, 7:97
- 44. CBP/P300-INTERACTINGTRANSACTIVATOR WITH GLU/ASP-RICH CARBOXY-TERMINAL DOMAIN, 1 (CITED1) Transcriptional coactivator Nuclear and cytoplasmic Sensitivity 74% Specificity 90%
- 45. INSULIN-LIKE GROWTH FACTOR II MRNA BINDING PROTEIN 3 (IMP3) Ribonucleoprotein Nuclear Sensitivity 82.1% Specificity 33.3%
- 46. UTILITY IN DIAGNOSTICS Immunostain Follicular adenoma Follicular carcimoma Follicular variant of Papillary carcinoma HBME1 Usually - May be + Usually + Galectin 3 Usually - Usually + Usually + CK19 Usually - Usually - Usually + CITED3 - Usually - May be + IMP3 - May be + May be +
- 47. TPO Follicular carcinomaFollicular adenoma Cytoplasmic Negative predictor Sensitivity 80% Specificity 86%
- 48. TROPHOBLASTIC CELL SURFACE ANTIGEN 2 (TROP2) Transmembrane glycoprotein Membranous
- 49. BRAF MUTATION-SPECIFIC ANTIBODY Cytoplasmic Sensitivity 95% Specificity 95%
- 50. ALGORITHMIC APPROACHTO FOLLICULAR PATTERNED NODULE Follicular patterned nodule Benign Malignant Indeterminate Multiple nodules with lack of PTC nuclear features Hyperplastic nodule Solitary nodule, No PTC nuclear features FA PTC nuclear features with invasion FVPTC Capsular /vascular invasion FC Equivocal Capsular /vascular invasion or PTC nuclear features Submit entire capsule & check multiple levels Equivocal capsular invasion with no vascular invasion FTUMP No invasion IHC NIFTPWDTUMP
- 51. MOLECULARTESTS INTHYROIDTUMORS Diagnostic – benefit in FNAC setting only Molecular testing followed by total thyroidectomy : $16 414 Lobectomy followed by completion total thyroidectomy : $19 638 Prognostic Therapeutic
- 52. CURRENT CONCEPTS Endocr Pract. 2017 Aug;23(8):979-988
- 53. CURRENT CONCEPTS BRAFV600E like Classical PTC Tall cell PTC RAS like FVPTC NIFTP FC TERT like Anaplastic Poorly differentiated
- 55. TESTS AVAILABLE “Rule-in tests” BRAF V600E mutation: high specificity and positive predictive value (PPV) 7-gene panel: BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8-PPARG ”Rule-out tests” Afirma test: 142 genes : NPV of near 100% Thyroseq v2: NGS panel, point mutations and small insertions/deletions in 14 genes, 42 types of gene fusions, and expression levels of 16 genes
- 58. THERAPY
- 59. HURTHLE (ONCOCYTIC) CELLTUMORS Criteria >75% cells Mahogony cut surface Large cells with loss of polarity and centrally placed nuclei Abundant granular cytoplasm – increased mitochondria
- 60. WHY IT DESERVED A SEPARATE CHAPTER? Can spread to lymph nodes unlike follicular carcinoma Also displays hematogenous spread Higher frequency of mitochondrial mutations Defect in assembly of multimetric protein – defective oxidative phosphorylation Increased mitochondria Activation of Beta-catenin and PI3K/AKT/MOR pathway Association with PTEN (Cowden syndrome) Radio-iodine resistant
- 61. POORLY DIFFERENTIATED CARCINOMA ANDTURIN CONSENSUS Well differentiated Poorly differentiated Anaplastic
- 62. TURIN CONSENSUS Pattern – Insular, Alveolar & Solid Nuclei – Small, irregular dark chromatin Mitosis and necrosis
- 63. TURIN ALGORITHM “Immunohistochemistry is usually not necessary to place a lesion within this group, except for the confirmation of follicular-cell derivation if needed”
- 64. MEDULLARY MICROCARCINOMA In the setting of prophylactic thyroidectomy in germline RET mutation Differentiate C cell hyperplasia Medullary Microcarcinoma (<1 cm ) Microcarcinoma – potential for metastasis
- 65. CRITERIA Complex architecture Stromal fibrosis C cells infiltrating the stroma outside of the basement membrane of thyroid follicle Presence of amyloid
- 66. TNM – 8TH AJCC
- 67. UPTO 55YEARS IS CONSIDEREDYOUNG
- 68. T3 – REDESIGNED WITH GROSS INVASION TAKING PRECEDENCE Minor extrathyroidal extension detected only on histological examination was removed from the definition ofT3 disease and therefore has no impact on eitherT category or overall stage
- 69. NO CAN BE STATED WITHOUT NODAL DISSECTION Pathologic confirmation of lymph node status is not required, and patients can be classified as having N Zero disease, as long as there is no evidence of lymph node metastasis on routine preoperative and intraoperative evaluations
- 70. REGIONAL NODAL METASTASIS HAS BEEN DOWNSTAGED N1 disease no longer upstages a patient to stage III If <55 years of age - N1 disease is stage I If >55 years of age - N1 disease is stage II Level VII lymph nodes : previously classified as lateral neck lymph nodes (N1b) reclassified as central neck lymph nodes (N1a) to be more anatomically consistent and because level VII presented significant coding difficulties for tumor registrars, clinicians, and researchers
- 71. ANAPLASTIC CARCINOMA IS SHOWN ITS PLACE ! Previous editions where all anaplastic thyroid cancers were classified as T4 disease Anaplastic cancers will now use the same T definitions as differentiated thyroid cancer
- 72. RiedelThyroiditis Fibrosing variant of Hashimoto thyroiditis (FVHT) IgG4-related Hashimoto thyroiditis (IgG4-RHT) Graves disease with elevated IgG4 level
- 73. Finding FVHT Riedels thyroiditis Fibrosing variant of Hashimotos thyroiditis Thyroid antibodies Moderate titre High titre Normal thyroid tissue Sharply demarcated Diffuse involvement Venulitis Yes No Extrathyroidal invasion Yes No Hurthle cells No Yes Lymphocyte light chains λ-dominant κ-dominant Plasma cell production Increased IgA (47%) IgG-dominant, IgA (<15%) Associated autoimmune disease Yes Yes Associated de Quervain syndrome Yes No Ultrasound appearance Hypoechoic Hypoechoic Doppler flow Diminished Enhanced
- 74. IGG4 RELATED HASHIMOTOTHYROIDITIS Emerging entity More progressive course Female predilection Higher levels of circulating autoantibodies Thyroid limited disease may benefit from thyroidectomy and replacement therapy
- 75. IGG4 RELATED HASHIMOTOTHYROIDITIS No obliterative phlebitis Lack of extrathyroidal extension >20 cells / hpf
- 76. SUMMARY Morphology is of paramount importance in thyroid lesions Diagnosis can be achieved with application of objective criteria Immunohistochemistry are best supportive Molecular diagnostics – RQ PCR, Sanger, NGS Role in pre-operative planning following FNAC TNM has changed Awareness about medullary microcarcinoma & IgG4 Hashimoto thyroiditis
- 77. Technically, the name "Hurthle cell" is incorrect, because the cells described by Hurthle were not what we now term Hurthle cells; however, the name is now too engrained in the literature to be changed -WHO Blue book