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04/09/2018
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Follicular Thyroid Tumors
Updates in Classification &
Practical Tips
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
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Dissecting “Indeterminants”
• “Indeterminates”: Benign vs. Malignant
• Follicular variant of PTC
• Follicular carcinoma
• Molecular testing
“In pursuit of the low grade malignancy”
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Benign
Indeterminant
Malignant
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Case 1
• 37 year old male with a thyroid mass
• Fine needle aspiration
• “Follicular lesion”
• Molecular testing done on FNA
• RAS mutation
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Case 1
• Diagnosis: Follicular variant of papillary
carcinoma
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Follicular Variant of Papillary
Juan Rosai
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.
1980 1985 1990 1995 2000 2005
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Follicular Variant
• Histology: Definition
• Pure follicular architecture
• Papillary carcinoma nuclei
• Growth Pattern
• Invasive and infiltrative
• Encapsulated
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Invasive follicular variant PTC
Conventional papillary carcinoma
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Old Challenge
• Is this follicular variant or is this follicular
adenoma?
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Immunohistochemistry
• Stains might be useful, when….
• Nuclear features are incomplete
• Nuclear features are only patchy
• Stains are not diagnostic, they are only
supportive
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Immunohistochemistry
0
10
20
30
40
50
60
70
80
90
100
FA FVPTC
HBME-1
Galectin
CK19
Nakamura et al, Endo Path, 17:213, 2006
Incomplete and patchy nuclear features
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19 CK19 HBME
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New Challenge
• Is this follicular variant or is this non-
invasive follicular tumor with papillary like
nuclear features (NIFT-P)?
• Second new challenge: Can you remember
what NIFT-P stands for?
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NIFT-P: Inclusion Criteria
• A complete capsule or clear demarcation of
tumor from adjacent thyroid
• A pure follicular growth pattern
• Nuclear features of papillary carcinoma
• Not defined
• Tumors < 1 cm
• Multifocal tumors
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NIFT-P: Exclusion Criteria
• No papillary architecture (change)
• No psammoma bodies
• No capsular or vascular invasion
• Mitotic activity >3 per 10 HPF
• No tumor necrosis
• No vascular or capsular invasion
• No more than 30% solid, trabecular, insular
growth
• BRAF gene: negative for mutation (change)
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Implications of NIFT-P
• “A very low risk of adverse outcome when
the tumor is non-invasive”
• Based on original study of 109 cases
• But, not everyone agrees…
• In a study of 102 NIFT-P (very strict criteria),
6% had adverse outcome
Parente, World J Surg, 2018, 42:321-326.
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Using NIFT-P in Practice
• Adhere to absolutely strict criteria
• Entire capsule must be embedded
• There can be no hint of invasion
• There can be no true papillary growth
• Mitoses and atypia should be minimal
• There can be no high grade features
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Implications of NIFT-P
• How does this diagnosis affect the
Bethesda system for FNA diagnosis?
• Malignancy rate will change
Category Pre-NIFT-P
malignancy rate
Post-NIFT-P
malignancy rate
Benign 5.5% 2.5%
AUS/FLUS 42.3% 22.3%
Follicular
neoplasm
48.7% 17.9%
Suspicious 93.6% 61.7%
Malignant 100% 97%
Based on 750 thyroid FNAs with surgical follow-up
Lau, Am J clin Pathol, 2017 149(1):50-54.
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Issues with NIFT-P
• What will happen with retrospective
review?
• Reclassification?
• New treatment recommendations?
• Legal implications?
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NIFT-P in my Practice
• Occasionally for lesions I used to call
adenomas
• After struggling with mild nuclear atypia)
• Rarely for something I would have called
follicular variant of papillary carcinoma
• After applying strict criteria
“Change in terminology is not a substitute for meaningful patient
education and multidisciplinary discussion to highlight the low-risk
nature of these cancers.” Parente, World J Surg.
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Case 2
• 54 year old male with 5 cm thyroid mass
• Fine needle aspiration
• “Follicular lesion”
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Dissecting “Indeterminate”
• Thyroid nodule management
• “Indeterminate”: Benign vs. Malignant
• Follicular variant of PTC
• Follicular carcinoma
• Molecular testing
“In pursuit of the low grade malignancy”
36 Thin capsule Intermediate capsule Thick capsule
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Follicular carcinoma, NOS
Minimally
Invasive
Encapsulated
Angio-invasive
Minimally
Invasive
Widely
Invasive
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Mortality in Follicular Tumors
Capsular
invasion
Vascular
invasion
Widely
invasive
Measured
Van
Heerden
(1992)
0% 28% N/A Disease specific
mortality
D’Avanzo
(2004)
2% 20% 62% 5-year mortality
Van Heerden, Surgery 112:1130, 1992
D’Avanzo, Cancer 100:1123, 2004
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2017 WHO Classification
Traditional AFIP 2014 WHO 2017
Minimally
invasive
Minimally
invasive
With capsular
invasion
Minimally
invasive
With limited
vascular invasion
(<4 foci) Encapsulated
angio-invasive With extensive
vascular invasion
(>4 foci)
Widely invasive Widely invasive Widely invasive
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Follicular carcinoma
• Minimally Invasive, encapsulated
• By definition: Capsular invasion alone
• What is capsular invasion?
• Invasion through the capsule (into the
surrounding thyroid parenchyma)
• Often has a mushroom type appearance
• Not associated with an FNA track
42 Not Capsular Invasion
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Capsular Invasion
Capsular Invasion
Capsular Invasion
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Diagnostic Clues: FNA track
Diagnostic Clues: FNA track
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Follicular carcinoma
• Angio-invasive, encapsulated
• By definition: Vascular invasion
• What is vascular invasion
• Tumor in medium to large sized vessels
• Reaction around tumor thrombus
• Endothelialization or fibrin deposition
• Fibrin deposition
• At or beyond level of tumor capsule
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Not Vascular Invasion
Vascular Invasion Vascular Invasion
51 Vascular Invasion
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Vascular Invasion Vascular Invasion
Diagnostic Clues: Capsular Vessel
Right angle turns
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Diagnostic Clues: Vascular Invasion
Tumor with right angle turns
Diagnostic Clues: Vascular Invasion
Tumor with right angle turns
57 Diagnostic Clues: Vascular Invasion
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Follicular carcinoma
• Widely invasive
• Extensive invasion throughout the thyroid
• Invasion into perithyroidal soft tissues
• Often with extensive vascular invasion
• Important: Differentiate from poorly
differentiated thyroid carcinoma
60 Widely invasive carcinoma
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61 Widely invasive carcinoma
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Dissecting “Indeterminates”
• Thyroid nodule management
• “Indeterminates”: Benign vs. Malignant
• Follicular variant of PTC
• Follicular carcinoma
• Molecular testing
“In pursuit of the low grade malignancy”
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Using Molecular in Practice
• Identifying malignancy pre-operatively (on
FNA)
• Diagnosing difficult tumors
• FA vs. FVPTC
• FVPTC vs. NIFT-P
• Variants or challenging cases
• Prognostic setting
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Molecular Mutations in Thyroid Cancer
• Papillary carcinoma
• BRAF gene mutations
• RET/PTC translocations
• RAS mutations
• Follicular carcinomas
• RAS mutations
• PPARγ/PAX8 translocations
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BRAF Gene Mutations
• Oncogene
• Activating mutation in exon 15
• Thyroid cancer • T1799A (Nucleotide: T > A)
• V600E (Codon: Valine > glutamate)
• Also seen in other tumors
• Colon cancer (nonhereditary MSI cancers)
• Melanomas
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BRAF Mutations in Thyroid Lesions
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Translocations
• RET/PTC Translocations
• Up to 15 different partner genes
• ELE1 and H4 most common
• More common in radiation papillary carcinoma
• Difficult to detect (intra-chromosomal
rearrangement)
• PAX8-PPARγ Translocation
• Relatively specific to follicular carcinoma
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Using Molecular Diagnostically
0%
10%
20%
30%
40%
50%
60%
70%
Metastases BRAF RET/PTC RAS PPAR/PAX8
Conventional
Invasive FV
Encapsulated FV
FA/FCC
Rivera M, Mod Path; 23:1191, 2012
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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%
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Molecular Mutations in PTC
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BRAF Mutation and Sensitivity
0.00%
20.00%
40.00%
60.00%
80.00%
100.00%
Marchetti Zatelli Kim SW Pellizzo
FNA (s)
FNA+BRAF (s)
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Commercial Assays
• Gene expression array testing
• Mutation panel approach
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Expression Array Assay
• Proprietary assay: 142 gene expression
markers are not published
• Most published studies are industry
sponsored
• Performance characteristics are difficult to
assess
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Panel Based Testing
• Commercial assay
• Laboratory Developed Tests can also be
obtained
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The Real Question…
• Will the results of the molecular test
change the treatment algorithm?
• Will some patients be spared unnecessary
surgery?
• Will some patients be given more extensive
(appropriate) surgery?
• Will there be overall cost savings?
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<1% risk 20-30% risk 50-75% risk 5-10% risk
<1% risk 20-30% risk 50-75% risk 5-10% risk
7% risk 47% risk
Benign Molecular
Result
Suspicious Molecular
Result
Thyroid Fine Needle
Aspiration
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Summary
• “Indeterminate”: Benign vs. Malignant
• Follicular variant of PTC
• Follicular carcinoma
• Molecular testing
“In pursuit of the low grade malignancy”
