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Page 1: Happy New Yearfrom Forpath, 2019 To you all · 2019. 1. 28. · salivary gland • Adipose ... Non‐invasive encapsulated FVPTC comprises of half to two‐thirds of all ... Unger

Happy New Year from Forpath, 2019To you all !!

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The Story of the Thyroid cellNucleus and more: A survival guide.

H Van Dijck, Forpath: 26/01/2019

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Thyroid follicular epithelial cells:Thyroid follicles consist of rounded structures of variable size lined by a singlelayer of flattened (inactive) to cuboidal or rarely columnar (cylindric) cells and a lumen containing a proteinaceous colloid material representing storage productof secretory activity of follicular cells:Cuboidal cells are most numerous and major function is to secrete colloid.Single follicle may have flattened cells on one side and cuboidal cells on other side. Follicular cells have a central

rounded or ovoid nucleus with delicate chromatin, a single (eccentric) nucleolus, nuclear chromatin is coarse, appearing finely granular or clumped 

and an eosinophilic or amphophilic cytoplasm. Lipofuscin appearing as an intracytoplasmic golden brown pigment may be present.Follicles are separated by loose fibroconnective tissue.Follicles have an average diameter of 200 microns.–Size varies according functional status of gland or patient age.

Bruce Wenig, Atlas of Head and Neck Pathology, third edition, Elsevier, Expert Consult series

First: The benchmark: The Normal Follicular Nucleus

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Benign Nuclear changes in thyroid dueto:

• Inflammation• Regeneration after necrosis• Cystic change• Oncytic/ Hurtle cell change• Squamous Metaplasia• Processing artefact• Medication and Radio active Iodine therapy• Graves disease, Dyshormogenetic Goiter, Hyperplasia• ….• CAVE: Metaplasia in Neoplastic conditions. e.g.:PTCand Squamous metaplasia.

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Solid Cell Nest(s), cystic or not

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Differentiate follicular nucleus fromother nuclei

• Swollen endothelial cells• Macrophages• Solid Cell Nests• Thyro‐glossal duct or Thymic remnants• Intrathyroidal cartilage, skeletal muscle or salivary gland

• Adipose metaplasia: fat between follicles• …

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Atypia due to inflammation

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PTC

Graves

Hashimoto

Histopathology

2006, 49, 107‐120.

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“Other” nuclei in adenoma/ adenomatous nodule(s) due to

metaplasia, production, change,…

• Spindle cell ( Can be TG/ TTF1 neg) • Signet ring cell• Clear cell change• …..

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C‐cells show some atypia

Scognamiglio T, Arch Pathol Lab Med, 2017 Dec;141(12):1646‐1652. 2017 Jun 23.C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid.

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Adenoma with bizarre nuclei: often in clusters

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From benign to malignant

• If you think it is malignant.ALWAYS

• Check if it is not a Medullary Carcinoma• Mimicker of everything in Thyroid

• Medullary or Neuro Endocrine Nucleus

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Neuro‐Endocrine Nucleus in Med Ca

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Med Ca

• Med Ca can be Calcitonine negative but are 100% CEA positive. Not specific but verysensitive.

• Important Heriditary syndromes in 25% of cases. Always Genetic Consultaion.

• Cave: Many histological patterns

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Histological Patterns of Medullary Carcinoma( Uscap Short Courses 2004)

• Epithelial (nested)• Spindled• Mixed spindle and epithelial• Papillary• Follicular• Glandular• Giant cell• Small cell

• Clear cell• Oncocytic• Squamous• HTT like• Carcinoid like• Pseudo angiosarcoma• Pigmented• Neuroblastoma like• Paraganglion like• …

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Other Malignant nucleus in Thyroid

• Poorly differentiated Thyroid Carcinoma (TC)• Undifferentiated TC

• Papillary TC• Follicular TC

• Other ( for ex. Muco Epidermoid Ca) TC

• Other malignancies ( Lymphoma, Angiosarcoma)in Thyroid

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PD Carcinoma

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Poorly Differentiated (PD) TC NucleusConvoluted ("brain‐like") cell nuclei, such as the nuclei seenin T‐cells in T‐cell prolymphocytic leukemia or Sézary's ...

Lymphoblastic Lymphoma/ leukemia with convoluted nuclei,C. Boucheix et al, Cancer 45: 1569‐1577, 1980 

Pathology outlines.com: Case of the Week #435

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AJSP(31), 8, aug 2007

• Convoluted nuclei: small round hyperchromaticnuclei with convolutions of the nuclear membrane( raisin like contour, occasional grooves)

• Weaker positivity for TG and TTF1, sometimes dot like paranuclear

• If PTC nuclei: PTC with necrosis, PTC with trabeculargrowth pattern, …

• De novo or from PTC or FC

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Undifferentiated (Anaplastic) CaHigh grade

1.Large pleomorphic Giant cells resembling osteoclasts withcellular tissue septae, may have cavernous blood filledsinuses (Osteoclasts are  CD 68 pos)

2.Spindle cells resembling sarcoma (Vim pos)

3.Squamoid

4.Paucicellular variant EMA pos, Ker pos.P53 pos

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Undiff Thyroid Carcinoma

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Follicular carcinomaNuclei are:–Regularly shaped (round to oval), often aligned along basal aspect of cell–Small to medium in size, hyperchromatic with coarse nuclear chromatin–Absent to inconspicuous nucleoliNuclear pleomorphism may be present:▪Endocrine atypia characterized by markedly enlarged and hyperchromatic nuclei may be focally identified.

Bruce Wenig, Atlas of Head and Neck Pathology, third edition, Elsevier, Expert Consult series

See earlier: picture of adenomawith bizare cells

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In general, usually shows single architectural pattern but may show admixture of growth patterns, including:  Follicular and/or microfollicular: NEVER MACRO FOLLICULAR–Uniform‐appearing colloid‐filled folliclesSolidTrabecularInsular:(Presence of increased mitotic activity and necrosis (as well as so‐called cleaved nuclei) required for diagnosis of poorly differentiated thyroid carcinoma (see later in chapter))•Cellularity and cytologic appearance vary from tumor to tumor and even within the same tumor:○Tendency to demonstrate greater cellularity as compared to follicular adenoma○Lesional cells generally uniform with defined cell borders

FC 

Bruce Wenig, Atlas of Head and Neck Pathology, third edition, Elsevier, Expert Consult series

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FA versus FC versus PTC

• Follicular Adenoma with capsular invasion andor vascular invasion is a Follicular carcinoma.

• So nuclei are the same in FA and FC• It is difficult to differentiate FC from PD just on the nuclei

• Vascular invasion and capsular invasion also in PTC.PTC nuclei to differantiate

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PTC NUCLEUS

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NIHMS878541‐supplement‐supp JAMA Oncol; 2016 Aug1; 2(8): 1023‐1029Supplementary online material:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539411/#SD1

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539411/#SD1

JAMA Oncol; 2016 Aug1; 2(8): 1023‐1029

No papillae !

7.No BRAF V600 E mutation and/or TERT mutation

In Red: added criteria since publication

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At that time it had a lot of coverage including the New York TimesSo surgeons, endocrinologists, ... were quicly aware of this new terminology

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Nuclear Score for PTC Nucleus

• Use it also in Cytology.• Score 1 out of tree: NOT PTC Nucleus, seeprevious slides

• Score 2/3 or 3/3 : PTC Nucleus• PTC Nucleus in all variants of PTC AND in NIFT‐P

• Non Invasive Follicular Tumourwith Papillary Nuclear Features.

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How much?

• PTC nuclei are often situated in smaller of largergroups of cells between area’s of normal (withnuclear score 1 out of tree) cells

• How much do we need? No rocket science.• There is no micro or occult NIFT P!• Micro PTC if less than 1 cm( WHO, 2017)• One area: Micro PTC, two separate area’s: NIFT P. • Still in debate. Clinically not important so far.

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The ‘‘Sprinkling’’ Sign in the Follicular Variant of Papillary Thyroid Carcinoma: A Clue to the Recognition of This EntityALICE VANZATI, MD FRANCESCA MERCALLI, MD JUAN ROSAI, MDInternational Center for Oncologic Pathology Consultations Centro Diagnostico Italiano Milan, ItalyArch Pathol Lab Med—Vol 137, December 2013

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Criterium, No1: Encapsulation or Clear Demarcation

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Thick Capsule in NIFT P

Subcapsular some are Irregular Regular

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Other 4 Criteria for NIFT P

• Follicular. Small, Medium or Large follicles or mixed.

• Less than 30% of solid area’s…. Difficult toassess.

• No papillae and No Psammoma bodies whichare calcified papillae

• No Necrosis• No more mitosis than 3 per 10 HPF. See criteria for PDC

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Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland Version: Thyroid 4.0.0.0. College of American Pathologists

Original concept for schematic from Fletcher CDM, ed. Diagnostic Histopathology of Tumours. 3rd ed. Edinburgh; Churchill Livingstone Elsevier; 2007. Modified with permission. © Elsevier. 

Vascular Invasion

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VI or not?

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VI

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Vascular markers?

They can become Negative in presence of follicles but you can easier identify a vesselAnd follow it.

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Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland Version: Thyroid 4.0.0.0. College of American Pathologists

Original concept for schematic from Fletcher CDM, ed. Diagnostic Histopathology of Tumours. 3rd ed. Edinburgh; Churchill Livingstone Elsevier; 2007. Modified with permission. © Elsevier. 

Capsular Invasion

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Seethala RR, Modern Pathology, 2018, 31(1), 39‐55

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Half of a mandarine shell in twosections

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How many Blocks

• For the examination of the capsule and to excludepresence of  true papillae?

• Cfr. Follicular carcinoma???• FOR FOLLICULAR Ca ,Guideline to number of sections

required for adequate histologic evaluation.• SAME FOR NIFT P ???????????? Debate

• Less than 6 cm: entire nodule, 6 cm: 10 blocks, more than 6 cm: add 1 bloc per centimeter of tumour.

Page 1334 of Atlas of Head and Neck pathology by Bruce Wenig, third edition, Elsevier, 2016

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NIFT P

• Diameter. More than 1 cm otherwise Micro PTC

• No upper limit. Most are resected at 3 cm.• Indolent tumour• Hemithyreodectomie• Follow‐up

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Not NIFT P

• If One of the 7 criteria is not met. • So BRAF V600E necessary,TERT:?,Other?• Follicular variant of Papillary Thyroid carcinoma: with, …

• Angio invasion ( mention how many vessels)• Capsular Invasion• Encapsulated FV PTC• Infiltrative FV PTC• FV PTC with a solid component of more than 30%• …

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3 mitosis

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NIFT P Incidence: 10 to 15 % of Previous PTC became an indolent 

tumour

The incidence of follicular variant of papillary thyroid carcinoma (FVPTC) has increased to 20% to 30% of all papillary thyroid carcinomas (PTC) over the last three decades in the USA. Non‐invasive encapsulated FVPTC comprises of half to two‐thirds of all FVPTCs, and is now reclassified as non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP). Asian populations were found to have a lower incidence of NIFTP than the Western populations.

Jung CK and Kim C Impact of diagnostic threshold on cancer prevalenceJBCM 2017; 6(1):26‐28

Written by Gary Clayman, DMD, MD, FACS https://www.endocrineweb.com/conditions/thyroid‐cancer/papillary‐cancer

Papillary thyroid carcinoma is the most common thyroid cancer. About 80% of all thyroid cancers cases are papillary thyroid cancer.

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Modern Pathology volume31, pages39–55 (2018)

Review Article, Raja R Seethala et alNoninvasive follicular thyroid neoplasm with papillary‐like nuclear features: a review for pathologists, 

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Seethala RR, Modern Pathology,  2018 Jan;31(1):39‐55. 

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And More

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ETE

Histopathology 2018 72 12‐19, ReviewCrucial parameters in thyroid carcinoma reporting‐ challanges, controversies andclinical implications, Bin Xu, R. Ghossein

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Why is “degree” of ETE so important?

• AJCC 8th edition (Amin: AJCC Cancer Staging Manual, 8th Edition, 2017) is effective from January 1, 2018

• T2: Tumor > 2 cm but ≤ 4 cm in greatest dimension limited to the thyroid • T3*: Tumor > 4 cm limited to the thyroid or gross extrathyroidal extension invading 

only strap muscles 

• T2 recommendation is: total thyreodectomie• T3: consider I* Therapy

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WHO Classification of Tumours of Endocrine Organs, 2017

Encapsulated Follicular PatternedTumours and WD T UMP, FT UMP

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WHO Classification of Tumours of Endocrine Organs, 2017

Follicular thyroid carcinoma

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HBME 1 and CK  19. Yes if it is black and white.Strong positive in entity and negative in normal thyroid.Especially good for smaller PTC.

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1, Human pathology2003 Aug;34(8):764‐9.Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: a pathobiologic link?Unger P1, Ewart M, Wang BY, Gan L, Kohtz DS, Burstein DE

The results showed that p63 expression was negative in normal thyroid tissue, nodular goiters, and oncocytic follicular adenomas. Positivity was rare and weak in follicular adenomas. p63‐positive foci were commonly found in Hashimoto's thyroiditis (1 or more foci in 78.8% of cases), but rare in Graves' disease. Twenty‐seven of 33 papillary thyroid carcinomas (81.8%) displayed p63‐positive foci. Staining was uncommon in follicular carcinomas and rare in medullary carcinomas. One case of insular carcinoma was p63‐positive. All squamoid structures were p63‐positive; p63‐positive structures morphologically consistent with solid cell nests were also identified.

2,WHO, 2017 Muco Epidermoid carcinoma

Epidermoid cells and ductal cells are positive for P63.Polyclonal CEA is positive in mucocytes andductal like elements

P63

3,Diagnostic pathology and Molecular Genetics of the thyroidSecond editionY. Nikiforov et al, Wolters Kluwer

P63 pos in 50% of cases of PDC

4, ….

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Modern Pathology, Review Article | Published: 21 May 2018Cribriform‐morular variant of thyroid carcinoma: a neoplasm with distinctive phenotype associated with theactivation of the WNT/β‐catenin pathwayJosé Manuel Cameselle‐Teijeiro1,2, […]Manuel Sobrinho‐Simões4,5,6,9Modern Pathology Volume 31, pages1168–1179 (2018) 

Cribriform‐morular variant of thyroid carcinoma is classically associated with familial adenomatous polyposis but, it can also occur as a sporadic neoplasm. This neoplasm is much more frequently observed in women than in men (ratio of 61:1). In familial adenomatous polyposis patients, tumors are generally multifocal and/or bilateral (multinodular appearance), whereas in the sporadic cases tumors tend to occur as single nodules. The tumors are well delimited, and characteristically show a blending of follicular, cribriform, papillary, trabecular, solid, and morular patterns. Neoplastic cells are tall or cuboidal with the occasional nuclear features of classic papillary thyroid carcinoma. The morules include cells with peculiar nuclear clearing and show positivity for CDX2 and CD10.…/…Tumor cells can be focally positive or negative for thyroglobulin, but are always positive for TTF‐1, estrogen and progesterone receptors, and negative for calcitonin and cytokeratin 20. Nuclear and cytoplasmic staining for β‐catenin is the hallmark of this tumor type…/…

β‐catenin

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B Catenin in  classic PTC is not Nuclear neither cytoplasmic

Case of the Week #470Pathology outlines.com

Cribriform Morular variantof PTC

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Mod Pathol, 2011 Apr;24 Suppl 2:S19‐33. Familial thyroid cancer: areview, V Nosé

Although, the majority of papillary and follicular thyroid carcinomas are sporadic, the familial forms are rare and can be divided into two groups. The first includes familial syndromes characterized by a predominance of non‐thyroidal tumors, such as familial adenomatous polyposis and PTEN‐hamartoma tumor syndrome, within others. The second group includes familial syndromes characterized by predominance of papillary thyroid carcinoma (PTC), such as pure familial PTC (fPTC), fPTC associated with papillary renal cell carcinoma, and fPTC with multinodular goiter. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetics evaluation.

Familial Thyroid Cancer

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The diagnosis of FNMTC is characterised by the presence of NMTCs in three or more first‐degree relatives, in the absence of other known associated syndromes. Statistical analysis suggests that a grouping of two family members with NMTCs could represent the concurrence of sporadic tumours. However, the occurrence of thyroid malignancies in three or more family members, or the diagnosis of PTC in men and children, is more suggestive of a familial predisposition syndrome.5,12,13,115,123 In addition, the age at diagnosis of FNMTC varies, but tumours generally occur in younger patients than their sporadic counterparts. From a morphological standpoint, most thyroid carcinomas arising in FNMTC are PTCs, and have no specific histological findings to distinguish them from sporadic PTCs. 

Guilmette J & Nosé (2018) Histopathology 72, 70 –81. Hereditary and familial thyroid tumours

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Familial thyroid cancer: a reviewVania Nose ´Modern Pathology (2011) 24, S19–S33

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Conclusion• First the Nucleus,• Capsule,• Vessels in and near capsule, Very Important: look formore if just one vessel with VI

• Architecture,• Criteria for NIFT P,• Criteria not met, …..• NIFT P is not a waste basket• More blocks and sections more important than IHC• Genetic: BRAF V600 E ,RAS, TERT,….• WHO 2017

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Thyroid pathology: Love it or leave itAntwerp, 1/1/2019, Midnight