Follicular Derived Thyroid Tumors Jennifer L. Hunt, MD, MEd Aubrey J. Hough Jr, MD, Endowed Professor of Pathology Chair of Pathology and Laboratory Medicine University of Arkansas for Medical Sciences jhunt2@uams.edu 1
Dissecting Indeterminate Benign vs. Malignant Follicular variant of PTC NIFT-P Follicular carcinoma In pursuit of the low grade malignancy 2
Follicular Variant of Papillary 1980 1985 1990 1995 2000 2005 Chen KTK, Rosai J. Follicular variant of thyroid papillary carcinoma: A clinicopathologic study of six cases. American Journal of Surgical Pathology, 1(2):123, 1977. Juan Rosai 4
Follicular Variant Histology: Definition Pure follicular architecture Papillary carcinoma nuclei Growth Pattern Invasive and infiltrative Encapsulated 5
Invasive follicular variant PTC
Encapsulated follicular variant PTC
Encapsulated Follicular Variant Low power clues Nuclear atypia at 4X Clustered nuclear atypia Nuclear features better under capsule Peri-follicular fibrosis Dense colloid 8
Follicular variant PTC
Follicular variant PTC
Encapsulated Follicular Variant High power clues: Nuclear atypia Flattened, pushed in, irregular nuclear contours Peripheral condensed chromatin Small peripheral nucleoli 11
Follicular variant PTC
Encapsulated Follicular Variant Borderline nuclear atypia: not perfect FVPTC Patchy nuclear atypia: Good nuclei, but very non-uniform distribution 13
Follicular variant PTC
Patchy features
Patchy features
The Problem Most of these tumors behave well.but Some have nodal metastases Rare cases have distant metastases In pursuit of the low grade malignancy 17
Attempts to Resolve Ancillary tests to refine diagnosis Special stains Molecular markers Changing terminology Changing practice patterns 18
Immunohistochemistry Stains might be useful, when. Nuclear features are incomplete Nuclear features are only patchy Stains are not diagnostic, they are only supportive 19
Immunohistochemical Stains 100% 90% 80% 70% 60% 50% 40% 30% CK19 HBME 1 Galectin 3 CD 56 20% 10% 0% Follicular adenoma Follicular carcinoma Hurthle cell carcinoma Papillary carcinoma Dunderovic, Diagnositc Pathology 10:196; 2015 20
Immunohistochemical Stains 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Classic PTC FVPTC Follicular adenoma CK19 HBME1 Galectin 3 HBME/CK19 Scognamiglio T, AJCP, 126:700,2006 21
Incomplete and patchy nuclear features
CK19 HBME 23
Molecular Mutations in Thyroid Cancer Papillary carcinoma BRAF gene mutations RET/PTC translocations RAS mutations Follicular carcinomas RAS mutations PPARγ/PAX8 translocations 24
BRAF Mutations in Thyroid Lesions 25
RAS Gene Mutations 100% 80% 60% 40% 20% 0% FVPTC Conv PTC FA FCC 26
Reported Molecular Profiles Category Name RAS BRAF RET/ PTC PAX8/ PPAR Conventional Papillary Ca 10-20% 50-75% ~30% 0 Follicular carcinoma ~30-50% 0 0 ~30-35% Follicular Adenoma ~30% 0 0 ~5-10% Follicular Variant PTC ~25% ~5% ~5% ~35% 27
Commercial Assays Gene expression array testing Mutation panel approach 28
<1% risk 5-10% risk 20-30% risk 50-75% risk Thyroid Fine Needle Aspiration Benign Molecular Result Suspicious Molecular Result 7% risk 47% risk
The Real Question Will the results of the molecular test change treatment? Will some patients be spared unnecessary surgery? Will some patients be given more extensive (appropriate) surgery? Will there be overall cost savings? 30
Attempts to Resolve Improving diagnosis Special stains Molecular markers Changing terminology Changing practice patterns 31
Chernobyl Classification FVPTC Category Name Atypical Nuclei Invasion Follicular Adenoma X X Follicular carcinoma X Yes Well differentiated carcinoma, NOS Questionable Yes Well differentiated tumor of UMP Questionable X Follicular tumor of UMP X Questionable For consensus classification, not for diagnostic and clinical utility Williams ED, Int J Surg Pathol 2000;8:181. 32
New Proposed Terminology Non-invasive follicular thyroid neoplasm with papillary-like nuclear features 24 pathologists 109 thyroids Retrospective analysis with 10-26 years followup NIkiforov, JAMA Oncology 2(8):1023, 2016 33
NIFT-P Criteria Follicular growth pattern (<1% papillae) No psammoma bodies Encapsulation or clear demarcation Nuclear score 2-3 No vascular or capsular invasion No tumor necrosis <30% solid, trabecular, insular growth Low mitotic activity (<3 /10 HPF) 34
Abortive papillae
Implications of NIFT-P A very low risk of adverse outcome when the tumor is non-invasive 36
My 2 Cents I infrequently use NIFT-P, because Some lesions have papillae Some lesions have some invasion or are suspicious for invasion Some lesions have increased mitoses or nuclear atypia My most common use: lesions I used to call adenoma, after worrying about atypia 37
Dissecting Indeterminate Benign vs. Malignant Follicular variant of PTC NIFT-P Follicular carcinoma In pursuit of the low grade malignancy 38
39 Thin capsule Intermediate capsule Thick capsule
Follicular carcinoma, NOS Minimally Invasive Widely Invasive Minimally Invasive Encapsulated Angio-invasive
Follicular carcinoma Widely invasive Multifocal invasion throughout thyroid Invasion outside of the thyroid 41
Mortality in Follicular Tumors Capsular invasion Vascular invasion Widely invasive Measured Van Heerden (1992) D Avanzo (2004) 0% 28% N/A Disease specific mortality 2% 20% 62% 5-year mortality Van Heerden, Surgery 112:1130, 1992 D Avanzo, Cancer 100:1123, 2004 42
Minimally Invasive Follicular carcinoma By definition: Capsular invasion Invasion through the capsule Usually with a mushroom type appearance 43
Capsular Invasion
Capsular Invasion
Avoid FNA track areas
Angio-Invasive Follicular carcinoma By definition: Vascular invasion At or beyond level of tumor capsule Medium to large sized vessels Usually tumor is attached to vessel wall Tumor has reaction around it Endothelialization Fibrin deposition Capsular invasion may be present 48
Vascular Invasion Vascular Invasion
Vascular Invasion 50
Vascular Invasion
Capsular Vessels make right angle turns
Vascular invasion
Vascular invasion
Vascular invasion
ATA Risk Stratification Low Risk Intermediate Risk High Risk Papillary carcinoma & FVPTC No metastases No vascular invasion No extrathyroidal extension No aggressive variants Papillary carcinoma N1 disease Vascular invasion Extrathyroidal spread Variants: tall, columnar, hobnail Multifocal microscopic Distant mets Large lymph node mets Grossly identified extrathyroidal extension Minimally invasive follicular and angioinvasive follicular carcinoma (with <4 foci vascular invasion Follicular carcinoma with >4 foci vascular invasion 57
Changing Practice Patterns Very Low Risk Low Risk Intermediate Risk Papillary carcinoma Unifocal microscopic papillary carcinoma Encapsulated FVPTC (NIFT-P) Papillary carcinoma No metastases No vascular invasion No extrathyroidal extension No aggressive variants Papillary carcinoma N1 disease Vascular invasion Extrathyroidal spread Variants: tall, columnar, hobnail Multifocal microscopic Minimally invasive follicular carcinoma (capsular invasion alone) Angio-invasive follicular carcinoma (with <4 foci vascular invasion 58
Summary Follicular variant Non-invasive follicular neoplasm with papillary like nuclear features (NIFT-P) Follicular carcinoma 59