Uma Nahar Saikia presented an update on thyroid tumors based on changes between the 2004 and 2017 WHO classification books. Key points included refined definitions for follicular variant papillary carcinoma and non-invasive follicular thyroid neoplasm with papillary-like nuclear features. New immunohistochemistry markers and molecular testing provide additional diagnostic information. The 8th AJCC TNM staging system features changes to N and T categories as well as separate staging for those under 55 years old. IgG4-related Hashimoto's thyroiditis was also discussed as an emerging entity.
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
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”
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
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”
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
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.
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
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
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 +
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
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
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
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
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
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
