L.D.R. Thompson

Overall Objectives

 What is the current management of papillary carcinoma? WHOse New in  What are the trends and what can we do Thyroid Pathology differently?  Supporting data  Recommendations Lester D. R. Thompson www.lester-thompson.com

2

Thyroid Neoplasms: General Considerations  Thyroid carcinoma is most common endocrine malignancy (3.8% of all new US cancers; 9th most common cancer type)  Incidence = 62,980 /year  Death rate = 1,890 (annual) (0.3% all deaths)  Age = 45 – 54 years old  Sex = F > M (3:1)  14.7 /100,000 population /year  1.1% will develop thyroid cancer during lifetime

 97.8% 5-year survival for all thyroid cancers 3 4

WHO Histological Classification of Current Management Thyroid Tumours

Thyroid carcinomas Thyroid adenoma  Papillary carcinoma 8260/3  Follicular adenoma 8330/0  Lobectomy or Thyroidectomy  Hyalinizing trabecular tumour 8336/0  Follicular carcinoma 8330/3  Pre-op FNA dependent  Poorly differentiated carcinoma Other thyroid tumours  Undifferentiated (anaplastic) carcinoma  Completion thyroidectomy if any of following: 8020/3  Teratoma 9080/1  Primary lymphoma and plasmacytoma  Squamous cell carcinoma 8070/3  Ectopic thymoma 8580/1  Known distant metastases  Mucoepidermoid carcinoma 8430/3  Angiosarcoma 9120/3  Extrathyroidal extension  Sclerosing mucoepidermoid carcinoma  Smooth muscle tumours with eosinophilia 8430/3  Peripheral nerve sheath tumours  Tumor >4 cm  Mucinous carcinoma 8480/3  Paraganglioma 8693/1  Medullary carcinoma 8345/3  Solitary fibrous tumour 8815/0  Confirmed cervical lymph node metastasis  Mixed medullary and follicular cell  Follicular dendritic cell tumour 9758/3 carcinomas 8346/3  Langerhans cell histiocytosis 9751/1  Positive margins  Spindle cell tumour with thymus-like  Secondary tumours differentiation 8588/3  Macroscopic multifocal disease (not microscopic)  Carcinoma showing thymus-like differentiation 8589/3  Lymphovascular invasion  Poorly differentiated histology

5 Version 1, 2016 (07/2016): NCCN Clinical Practice Guidelines 6

WHOse New in Thyroid Gland Pathology 1 L.D.R. Thompson

Current Management

 NO completion thyroidectomy only if all are present:  Age between 15 – 45 years  No prior radiation  No lymphovascular invasion  No distant metastases  No cervical metastases (suspicious lymph node)  No extrathyroidal extension  Tumor 1-4 cm  Negative resection margins  No contralateral lesion  No aggressive variant  Tall, columnar, diffuse sclerosing, poorly differentiated

Version 1, 2016 (07/2016): NCCN Clinical Practice Guidelines 7

10

Thyroid Papillary Carcinoma: Thyroid Papillary Carcinoma: Classic Histologic Types Clinical Features  Usual or Conventional types  Most common malignant thyroid tumor  Occult, incidental, microcarcinoma, microscopic  Sex: F >> M (4:1) rd th  Follicular  Age: 3 –5 decades (majority)  Macrofollicular  Ethnicity: White > Black  Oncocytic or oxyphilic  Symptoms:  Clear cell  Asymptomatic, palpable mass  “Biologically Aggressive” Variants  Solitary nodule: 28x fold increased risk of tumor  Diffuse sclerosing  Lateral neck mass (mets in up to 30%)  Tall cell  Columnar cell

 Insular or Poorly differentiated 11 12

WHOse New in Thyroid Gland Pathology 2 L.D.R. Thompson

Thyroid Papillary Carcinoma: Thyroid Papillary Carcinoma: Classic Pathology Classic Morphologic Features  Macroscopic Architectural Cytomorphologic/Nuclear  Vascular or capsular  Enlarged cells (compared to  Majority are solid and solitary invasion normal thyroid)  Variable growth patterns  High nuclear to cytoplasmic  May be cystic ratio  Elongated and/or twisted  Nuclear overlapping,  Encapsulated versus overt invasion follicles crowding  Adjacent tissues or extrathyroidal extension  Calcospherites  Irregular placement around (pT3) (psammoma bodies) follicle  Intratumoral fibrosis  Nuclear grooving/folding  Fibrosis and calcification may be present  Tincture of colloid (bright  Intranuclear cytoplasmic  Size varies: and rich) & scalloping inclusions  Crystals or giant cells in  Pale chromatin with the colloid chromatin  Occult, incidental, minute, microscopic margination/condensation  < 1.0 cm by WHO definition and clearing  Orphan Annie Nuclei  Large: > 5 cm

13 14

Thyroid Papillary Carcinoma: Classic Morphologic Features Architectural  Vascular or capsular invasion  Variable growth patterns  Elongated and/or twisted follicles  Calcospherites (psammoma bodies)  Intratumoral fibrosis  Tincture of colloid (bright and rich) & scalloping  Crystals or giant cells in the colloid

15 16

17 18

WHOse New in Thyroid Gland Pathology 3 L.D.R. Thompson

19 20

21 22

23 24

WHOse New in Thyroid Gland Pathology 4 L.D.R. Thompson

Thyroid Papillary Carcinoma: Thyroid Papillary Carcinoma: Classic Morphologic Features Classic Morphologic Features Architectural Cytomorphologic/Nuclear Cytomorphologic/Nuclear  Vascular or capsular  Enlarged cells (compared to invasion normal thyroid)  Enlarged cells (compared to normal thyroid)  Variable growth patterns  High nuclear to cytoplasmic ratio  High nuclear to cytoplasmic ratio  Elongated and/or twisted  Nuclear overlapping, follicles crowding  Nuclear overlapping, crowding  Calcospherites  Irregular placement around  (psammoma bodies) follicle Irregular placement around follicle  Intratumoral fibrosis  Nuclear grooving/folding  Nuclear grooving/folding/irregular contour  Tincture of colloid (bright  Intranuclear cytoplasmic and rich) & scalloping inclusions  Intranuclear cytoplasmic inclusions  Crystals or giant cells in  Pale chromatin with  Pale chromatin with chromatin the colloid chromatin margination/condensation margination/condensation and clearing and clearing  Orphan Annie Nuclei  Orphan Annie Nuclei

25 26

27 28

29 30

WHOse New in Thyroid Gland Pathology 5 L.D.R. Thompson

31 32

NIFTP: Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclei

Accepted term at March, 2015 The Endocrine Pathology Society Conference for Re-Examination of the Encapsulated Follicular Variant of Thyroid Papillary Carcinoma

33 in Boston

Materials Reviewed

 All thyroid surgeries performed in 2002  A minimum of 10 years of follow-up  721 cases reviewed  All histology slides reviewed  7,977 primary slides  2,022 additional intraoperative, IHC, levels, specials, deepers  Follow-up obtained from EMR or direct communication

35 36

WHOse New in Thyroid Gland Pathology 6 L.D.R. Thompson

Papillary carcinoma: Type/Variant Breakdown % of all # of papillary Diagnosis (= 324) Cases cases Classical 106 32.7 Microscopic 98 29.6 Follicular variant 94 29.0 Tall cell 19 5.9 Diffuse sclerosing 4 1.2

37 38

Study Design Study Materials

 International, multi-disciplinary study of 138  A total of 268 tumors diagnosed as EFVPTC based on current criteria were contributed by working patients with Noninvasive EFVPTC followed for 10- group pathologists from 13 institutions 26 years and 130 patients with invasive EFVPTC  Potential cases for Group 1 included Noninvasive followed for 1-18 years collected at 13 sites in 5 EFVPTC with no radioiodine (RAI) treatment and countries. Review of digitalized histologic slides by at least 10 years of follow-up (n=138). Potential 24 thyroid pathologists from 7 countries. cases for Group 2 included EFVPTC with vascular invasion and/or tumor capsule invasion and ≥1  Two endocrinologists, one surgeon, and one year of follow-up (n=130). psychiatrist. In addition, a molecular pathologist, a  8 week series of weekly teleconferences aimed to biostatistician, and a thyroid cancer survivor/patient refine groups 1 and 2 and to achieve consensus advocate participated in the study.  http://image.upmc.edu:8080/NikiForov%20EFV%2 0Study/view.apml

39 40

Mutations in Papillary Carcinoma and Phenotypical Associations

41 42

WHOse New in Thyroid Gland Pathology 7 L.D.R. Thompson

Gene Profiles and Molecular Alterations Histologic Variants  Point mutations involving RAS genes about Histology Molecular 10% of papillary carcinomas  Almost exclusively the follicular variant  Seen in NRAS, HRAS, and KRAS genes  Strong correlation with  More frequent tumor encapsulation  Lower rate of lymph node  BRAF K601E mutation usually in follicular variant of papillary carcinoma  PAX8/PPARγ  Usually follicular carcinoma  5% of follicular variant papillary carcinomas

4343 44

https://en.wikipedia.org/wiki/N oninvasive_follicular_thyroid_ neoplasm_with_papillary‐ like_nuclear_features

45 46

Fine Needle Aspiration Fine Needle Aspiration

 Most NIFTP were classified as Bethesda  V. Suspicious for Malignancy System for Reporting Thyroid  Suspicious for papillary carcinoma Cytopathology:  VI. Malignant  III. Atypia of Undetermined Significance or  Papillary thyroid carcinoma Follicular Lesion of Undetermined Significance  But – now these categories can only be  IV. Follicular Neoplasm or Suspicious for a used if you have 3-dimensional papillary Follicular Neoplasm structures and/or psammoma bodies –  Most will have molecular findings in RAS otherwise a NIFTP could be the diagnosis genes (KRAS, NRAS, HRAS)  But, not BRAF, PPARγ, RET/PTC

47 48

WHOse New in Thyroid Gland Pathology 8 L.D.R. Thompson

ALGORITHM FOR DIAGNOSIS OF NIFTP

Criteria Encapsulated or Well-demarcated Infiltrative FVPTC No Yes N Major Features Minor Features Features not seen/ Capsular and/or Lymphovascular invasion EFVPTC or FC with invasion Yes O Exclusion criteria No 1. Encapsulation or clear 1. Dark colloid 1. “True” papillae >1% >30% solid/insular/trabecular and/or T Solid PTC and/or demarcation >1% true papillary pattern and/or 2. Irregularly-shaped 2. Psammoma bodies Classical PTC and/or 2. Follicular growth Psammoma bodies identified and/or Yes follicles 3. Infiltrative border Tall cell or columnar cell variants pattern (<1% papillae) Tall cell or columnar cell variants 3. Intratumoral fibrosis (capsular or 3. Nuclear Features of No 4. “Sprinkling” sign lymphovascular PTC (Score 2 or 3): Classical PTC encapsulated 5. Follicles cleft from invasion) Predominantly follicular pattern and/or Follicular adenoma  Enlargement/crowding/ No N stroma 4. Tumor necrosis Yes overlapping 6. Multinucleated giant 5. High mitotic activity Poorly differentiated tumor  Elongation Tumor necrosis and/or >3 mitoses/10 HPFs I cells within follicles (>3/10 HPFs) Yes No  Irregular contours 6. Cell/morphologic F Follicular adenoma and/or  Grooves characteristics of other Nuclear features of papillary thyroid carcinoma (score 2 or 3) No adenomatoid nodule  Pseudoinclusions variants of PTC T Yes  Chromatin clearing P NIFTP 49

Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclei Surrounded by thick, well formed capsule Capsule may be thinned and attenuated Partially encapsulated and incompletely encapsulated are equivalent Smooth muscle-walled vessels within the fibrosis

51 52

Partially encapsulated—circumscribed

53 54

WHOse New in Thyroid Gland Pathology 9 L.D.R. Thompson

Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclei Absent invasion By definition this must be “noninvasive” No capsular invasion No vascular invasion Must be adequately (completely) sampled Tumor to capsule to parenchyma 3 sections (not blocks) per cm of tumor

55 56

Capsular invasion

57 58

Vascular Invasion Frozen section

 Unreliable and not meaningful  You have to have the whole periphery sampled to be included in NIFTP category  Cannot be done during intraoperative assessment  If a frozen is called “follicular variant of papillary carcinoma,” then it may be NIFTP at the time of permanents (if there is no invasion)

59 60

WHOse New in Thyroid Gland Pathology 10 L.D.R. Thompson

Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclei Predominantly follicular pattern of growth Small to medium, round, twisted and elongated follicles Follicles are often a monotonous size and shape (helpful feature) Isolated or rare papillae may be seen  Must be ≤ 1% of overall tumor volume  If >1%, then it is NOT follicular variant

61 62

63 64

Sandison pseudopapillary structure OK Single papillary structure is OK

65 66

WHOse New in Thyroid Gland Pathology 11 L.D.R. Thompson

Too many papillary structures Too many papillary structures

67 68

Non-invasive Follicular Thyroid Hypereosinophilic Colloid Neoplasm with Papillary-like Nuclei Hypereosinophilic colloid Scalloped colloid frequently present Internal, acellular, eosinophilic fibrosis between follicles Dropping substage condenser often creates a “bright” signal

69 70

Colloid scalloping Internal fibrosis

71 72

WHOse New in Thyroid Gland Pathology 12 L.D.R. Thompson

Noninvasive Follicular Thyroid Excluded: Tumor Necrosis Neoplasm with Papillary-like Nuclei Absent psammoma bodies Absent necrosis No increased mitoses ≤ 3 mitoses/10 High Power Fields No other patterns or specific tumor types present Solid, insular, trabecular, morular Oncocytic, tall, columnar

73 74

Excluded: >3 mitoses/10 HPFs Excluded: Solid Pattern

75 76

Excluded: Cribriform-morula Excluded: Tall cell papillary

77 78

WHOse New in Thyroid Gland Pathology 13 L.D.R. Thompson

Excluded: Columnar papillary Thyroid Papillary Carcinoma: Encapsulated Follicular variant  Must have nuclear features of papillary carcinoma  1 point each = 3; 2 or more is diagnostic  Size and shape (1 point)  Nuclear enlargement, overlapping, crowding, elongation  Nuclear membrane irregularities (1 point)  Irregular contours, grooves, pseudoinclusions  Chromatin characteristics (1 point)  Clearing with margination, glassy nuclei

79 80

Noninvasive Follicular Thyroid Nuclear score: Sum of three nuclear features (each 0 or 1) Neoplasm with Papillary-like Nuclei Thus, total score will vary between 0 and 3

Diagnosis rests on cytology Nuclear features: Absent/insufficiently expressed (0) Present/Sufficient (1)

1) Size and Shape  Size and shape = 1 point • Enlargement  Enlargement, elongation, • Elongation overlapping/crowding • Overlapping  Membrane irregularities = 1 point  Irregular contours, grooves/folds, intranuclear cytoplasmic inclusions  Chromatin distribution = 1 point  Chromatin clearing, margination to membrane, “glassy” nuclei

81

83 84

WHOse New in Thyroid Gland Pathology 14 L.D.R. Thompson

Nuclear score: Sum of three nuclear features (each 0 or 1) Thus, total score will vary between 0 and 3

Nuclear features: Absent/insufficiently expressed (0) Present/Sufficient (1)

1) Size and Shape • Enlargement • Elongation • Overlapping

2) Membrane Irregularities • Irregular contours • Grooves • Intranuclear cytoplasmic inclusions

86

Nuclear score: Sum of three nuclear features (each 0 or 1) Thus, total score will vary between 0 and 3

Nuclear features: Absent/insufficiently expressed (0) Present/Sufficient (1)

1) Size and Shape • Enlargement • Elongation • Overlapping

2) Membrane Irregularities • Irregular contours • Grooves • Intranuclear cytoplasmic inclusions

3) Chromatin Features • Chromatin clearing • Margination to nuclear membrane • Glassy nuclei

Slight changes not sufficient to call “present”! 87

89 90

WHOse New in Thyroid Gland Pathology 15 L.D.R. Thompson

Thyroid Papillary Carcinoma: Encapsulated Follicular Variant How much of the tumor must have nuclear feature? 3 foci per cm of tumor gross measurement This is not well defined or agreed upon May be multifocal within same nodule

91 92

93 94

Papillary carcinoma: Follicular Variant Overall Lymphovascular invasion # of Diagnosis (= 324) Absent Present Cases 71 cases 25 cases Classical 106 6 100 Surgery only Thyroidectomy Microscopic 98 63 35 FV: Encap/Inv. 94 80 14 NO RAI RAI Tall 19 0 19 NED NED Diffuse sclerosing 4 0 4 11.1 years 10.6 years Number with disease, p<0.0001 (chi 0/149 20/175 %, average follow-up square 0% 11.4% for diseased patients

(11.1) (9.3) 95 96

WHOse New in Thyroid Gland Pathology 16 L.D.R. Thompson

97 98

NIFTP Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features

WHOse New in Thyroid Gland Pathology 17