1. AMR Seminar Symposium Split, Croatia Case #63
Vania Nosé, MD, PhD Professor of Pathology Associate Chief and
Director, Anatomic and Molecular Pathology

2. Case #63 - Clinical History
The patient is a 23 year old female, senior in college with a self-palpated thyroid nodule
Right thyroid: 3.0 cm, heterogeneous, mostly solid nodule, isoechoic, replacing right thyroid lobe extending from hyoid to clavicle

3. Pathological Findings
Right thyroid lobe: 22 g, 5.2 x 2.4 x 2.2 cm enlarged lobe
The thyroid surface displays focal nodularity
3.1 x 2.5 x 2.0 cm tan-white to tan-pink, soft, well delineated lesion with a slightly lobulated cut surface and focal cystic areas
Pathological Findings

9. Immunohistochemistry
POSITIVE: p53 & HBME1
NEGATIVE: BRAF
Ki67 proliferative index is 5%

10. Non-invasive follicular thyroid tumor with papillary-like nuclear features (NIFTP), well-circumscribed, non-invasive, 3.1 cm
No capsular invasion identified
No lymphovascular and perineural invasion identified
The tumor has follicular pattern
Mitosis up to 2/10 HPF
Final Diagnosis

11. Definition of NIFTP WHO 2017
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is noninvasive neoplasm of thyroid follicular cells with follicular growth pattern, and nuclear features of PTC that has extremely low malignant potential (WHO 2017)

12. Non-invasive Follicular Thyroid Tumor with Papillary-like Nuclear Features (NIFTP)
New proposed terminology, NIFTP, reflects key histopathologic features of this lesion, i.e.:
Lack of invasion
Follicular growth pattern
Nuclear features of PTC

13. Diagnostic Criteria for NIFTP
Encapsulation or clear demarcation
Follicular growth pattern
Nuclear features of PTC, score 2-3
No vascular or capsular invasion
No tumor necrosis
Absence of high mitotic activity

14. Exclusion Criteria for NIFTP
"True" Papillae
Psammoma bodies
Infiltrative border
Tumor necrosis
High mitotic activity
Cell morphology characteristic of other variants of PTC

15. Based on available data, great majority of NIFTPs are of low risk and conservative surgical excision is adequate treatment
Evidence so far published indicates that those lesions that are adequately examined microscopically do not recur or metastasize
Prognosis

16. Histologic Features (1) Encapsulation or circumscription
Thick, thin, or partial capsule or well circumscribed with clear demarcation from adjacent thyroid tissue
(2) Absence of vascular or capsular invasion
Requires adequate microscopic examination of tumor capsule interface
Histologic Features

17. The gross characteristic features of NIFTP is a well-circumscribed or encapsulated nodule, which is lighter than the adjacent thyroid parenchyma, and compresses the red-brown adjacent thyroid parenchyma (white solid arrow).

18. NIFTP Characteristics
Well-circumscription, well-demarcation, or encapsulated follicular-patterned neoplasm, with no capsular invasion are some of the criteria for the diagnosis of NIFTP. Nuclear features of papillary thyroid carcinoma (inset) must be present. No papillae should be seen

19. Histologic Features (3) Follicular growth pattern with
No papillae
No psammoma bodies
< 30% solid/trabecular/insular growth pattern
Including microfollicular, normofollicular, or macrofollicular architecture with abundant colloid
(3) Follicular growth pattern with
Diagnostic nuclear score: 3-point scoring scheme
Simplified and reproducible criteria for nuclear features for diagnosis of NIFTP in routine pathology practice, 6 main consensus nuclear features were grouped into 3 categories
(1) Size and shape (nuclear enlargement/overlapping/crowding, elongation)
(2) Nuclear membrane irregularities (irregular contours, grooves, pseudoinclusions)
(3) Chromatin characteristics (clearing with margination/glassy nuclei)
(4) Nuclear features of PTC: Score 2-3
Histologic Features

20. As with invasive encapsulated tumors and infiltrative tumors, the nuclei show most of the features of those in classic papillary carcinoma except that intranuclear inclusions are rare, and the nuclei often are more rounded than oval.

21. Nuclear Score 0-3
Nikiforov et al JAMA Oncology, Aug 2016

22. This diagnostic algorithm for the evaluation of encapsulated follicular-patterned neoplasms uses the evaluation of the capsular invasion and papillary carcinoma-type nuclear features differentiating NIFTP from follicular adenoma and carcinoma.

23. Multifocal Membranous HBME1 Staining
In areas of a microfollicular pattern, the HBME1 immunostain shows focal and patchy membranous staining and focal luminal-pattern staining
This staining pattern is characteristic of these tumors

24. Clinical Correlation Classification is molecular driven
EFVPTC – RAS-like (not local metastasis)
Infiltrative non-encapsulated FVPTC – BRAFV600E-like (local metastasis to lymph nodes)
Integrated genomic characterization of papillary thyroid carcinoma.
Cancer Genome Atlas Research Network
Cell Oct 23;159(3):676-90

25. Molecular Findings in
Follicular-Patterned Neoplasms
This scheme demonstrates that NIFTP does not demonstrate molecular alterations associated with classic papillary thyroid carcinoma, as BRAF alterations, but shows RAS mutations which have been associated with follicular-patterned neoplasms

26. Does FVPTC still exist? Answer: YES!!!
FVPTC is an architectural entity
Two types FVPTC:
1. Infiltrative FVPTC
-Tumor not well-circumscribed with marked infiltration of the surrounding thyroid tissue
Generally associated with BRAFV600E
2. FVPTC with capsular/vascular invasion
-Consider like follicular thyroid carcinoma
Does FVPTC still exist?

27. Invasion
FVPTC with capsular invasion
FVPTC, infiltrative

28. Follicular Variant – Two Species
RAF-like (typically have BRAFV600E mutations)
Spread is lymphatic, local
Bad behavior shows local metastasis to lymph nodes and potentially distant metastases
IFVPTC
RAS family of mutations
Spread is hematogenous
Bad behavior shows metastasis to distant sites
Lung, Bone, Brain, etc
EFVPTC (invasive, same pattern as follicular thyroid carcinoma)
Follicular Variant – Two Species

29. Reduced diagnosis of follicular variant of papillary thyroid carcinoma
Reduced over-treatment of indolent thyroid tumors
Reduced need for consultation due to increased reproducibility of morphological features – and reduced use of immunohistochemistry
Update to Bethesda FNA criteria
Implications of NIFTP

30. AMR Seminar Symposium Split, Croatia Case #63
Vania Nosé, MD, PhD Professor of Pathology Associate Chief and
Director, Anatomic and Molecular Pathology

31. Questions? Vania Nosé, MD, PhD
Thank you!
Questions?
Vania Nosé, MD, PhD