Pathology of Endocrine Glands - II

Thyroid

Jaroslava Dušková Inst. Pathol. 1st Med. Fac. Charles Univ. Prague

Pathology of the thyroid- contents

History, embryology, anatomy, physiology

notes

Regressive changes

Inflammation

Syndromes

Tumours and tumour–like lesions

Thyroid Gland History I.

China (2nd mill.b.C.) description of goitre

(Charvát 1935)

Vitruvius (16.a.C.) goitre in the Alpine region

Warton (1656) „ Adenographia“ the term

glandula thyreoidea

Luschka (1860) mechanical support of the

laryngeal structures

Thyroid Gland History II.

Basedow (1840) hyperthyreosis

Köstl (1855 - Wien):

Der endemische Kretinismus als Gegenstand

der öffentlichen Fürsorge (habilit. thesis)

Gull (1873) hypothyreosis

Murray (1883) Therapy with

bovine thyroid extracts

Arthur Biedl:

Innere Sekretion,

Wien 1913

Arthur Biedl: Innere

Sekretion, Wien 1913

Thyroid Gland History III

Hashimoto (1912) struma lymphomatosa

Kendall (1914): Tyroxine discovery

Aron a Loebe (1929) TSH discovery

Adams a Purves (1952) LATS discovery

Štítná žláza - glandula thyreoidea

historie IV.

Duprez et al. (1994) - mutace v genu TSH R

– neautoimunní hypertyreoza

Ikeda et al. (1995) – TTF1

Giordano (1997) funkce FAS L u HT

Fuhrer et al. (1997) hyperf. adenom- mutace v TSH genu

RET/PTC, BRAF, RAS, PAX8-PPAR gamma …..

Thyroid Gland- embryology and fetal endocrinology

mouth epithelium, end of the 1st iu.

month ductus thyreoglosus

lateral pharynx

ultimobranchial bodies C- cells.

parathyroid glands

fetal secretion starts at 12 weeks

effect on GROWTH

effect on DIFFERENTIATION

Thyroid Gland - anatomy

Weight in adults 15-20g

over 60g (7g in a neonate) struma/goitre

lobus dexter

isthmus et lobus pyramidalis

lobus sinister

aberant, accesory, ectopic gland

(polyclonality should help to tell it from ca)

Hypothalamo - Hypophyso-Thyreoidal Axis

TRH - TSH

TSH receptor- G protein –

c AMP

enzymes - deiodases

autoregulation influenced

by iodine intake

immune system

T3 and T4 - TR

TREs in the nucleus -

transcriptionNegative feedback loops

Thyreopathy worldwide

Iodine-Deficiency-Disorders –IDD

1990 28,9% of the world´s population

were at risk of IDD.

During 1990-1999

– 78% of the 130 countries with IDD risk had an action plan

– 75% hald salt iodination legislation in place.

– Normal range of urinary iodine (100-200 g/l) 41%;

in Chile e.g. 17,5% above the potentially toxic level 1000 g/l

Progress in the control of IDD: a major public health achievement.

EFES News, 2001,issue 6

Iodine-Deficiency-Disorders – IDD

Global iodine nutrition: Where do we stand in 2013?

Pearce EN, Andersson M, Zimmermann MB

Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine , USA.

Approximately 70% of all households worldwide - access to adequately iodized salt.

According to the median urinary iodine concentration of 100-299 μg/L in school-

aged children, 111 countries have sufficient iodine intake.

Thirty countries remain iodine-deficient; 9 are moderately deficient

21 are mildly deficient

none are currently considered severely iodine-deficient.

Ten countries have excessive iodine intake.

Iodine deficiency remains a significant health problem worldwide and affects both

industrialized and developing nations.

Reduced population sodium intake must be coordinated with salt iodization

programs in order to maintain adequate levels of iodine nutrition.

Thyroid. 2013;23(5):523.

http://www.ign.org/news.htm

Morphological Thyroid Investigation

Clinic

scintigraphy

SONOGRAPHY

CT

Pathologybiopsy

FNAB

histopathology

(resecates)

Main Tasks

in the Thyroid Cytology

reduction of the unnecessary surgery

diagnosis of subclinical inflammation

EARLY DIAGNOSIS of NEOPLASMS

Thyroid Cytology- getting sample

needle 0.6-0.8mm

min. 2 punctionsaspiration

nonaspiration

cyst: evacuate and aspirate with the

second punction the periphery

fluid: whole volume for cytology

Thyroid Cytology- processing

Fixation

– air dried

– etanol / spray

(cytospin)

CYTOBLOCK

Staining:

MGG

HE

polychrom

all histo.

imunocyto

TGB,calcitonin,

parathormon

EFCS Tutorial2010

Thyroid Cytology (1986-2014 n>36000)

22,1%

69,7%

4,4%1,7% 1,5% 0,8%

Thyroid FNAB in the Bethesda 2010 SystemOctobre 2010-May 2014

n = 3836

B I B II B III B IV B V B VI

Regressive changes

dystrophy: amyloid deposits, calcification

atrophy: due to the lack of TSH

stimmulation, postinflammatory

necrosis: only in hyperplastic or

neoplastic goitre

Thyreoiditis

NON-SPECIFIC purulent - abscess lymphocytic (Hashimoto)

hypertrophic atrophic focal

invasive sclerosing Riedel

GRANULOMATOUS subacute granulomatous de Quervain´s tbc syphilis sarcoidosis

abscess

(months

following

PTE)

chronic

abscess

repair

Subacute Granulomatous

Thyreoiditis de Quervain´s (1904)

Synonyma: „Giant cell“

„Subacute non-purulent“

Clin.features: Oedema, pain, eufunction,may be also silent

Histopath. features: disperse granulomas

with giant cells

Course: spontaneous healing by 2-4 weeks

de Quervain´s thyreoiditis

Bethesda II

Thyreoiditis lymphoplasmocellularis Hashimoto – HT (1912)

Macro - diffuse parenchymatose goitre firm, elastic, gray-yellow

Micro - diffuse

lymfoplasmocellular

lymph. folicules

ONCOCYTES

recently also disperse, nodular forms accepted

„lympho-histiocytic“ nodules

HT micro

Etiopathogenesis of HT

Etiology: unclear - viri ?

Pathogenesis:• dysregulation of T lymphocytes

IL-1 expression Fas molecules on the surface of thyreocytes (they have FasL)

• apoptosis activation

Activity: CD 44 proteoglycan influencing migration and lymphocyte proliferation, and metastasizing

mainly HLA DR5 profile, anti TPO, anti TGB, anti TSH

Course of HT

a) progressive

oncocytic transformation loss of thyreocytes,

transformation to a lymph-node-with-ca- meta image

hyperfunction folowed by hypofunction

Course of HT

b) regressive loss of parenchyma,

fibrosis (a part only of these predominantly with interfollicular fibrosis represents IgG4 related disease)

hypofunction

Course of HT

c) neoplasia

carcinoma

lymphoma (mostly B - MALT)

WHO 2004 Histol. Classification of Thyroid Tumours

Carcinomas

– papillary

– follicular

– poorly differentiated

– undifferentiated– squamous

– mucoepidermoid

– sclerosing mucoepidermoid

– mucinous

– medullary

– mixed medullary & follicular

– spindle cell tumour with thymus like diff. SETTLE

– ca showing thymus like diff. CASTLE

Adenoma & related tumours

– follicular– hyalinized trabecular tumour

Other thyroid tumours

– teratoma

– primary lymphoma &

plasmacytoma

– ectopic thymoma

– angiosarcoma

– smooth muscle tumours

– peripheral nerve sheet tumours

– paraganglioma

– solitary fibrous tumour

– follicular dendritic cell tu

– Langerhans cell histiocytosis

– SECONDARY

Thyroid Malignant Lymphomas

2% thyroid primary malignancies

mostly women with HT

clinically rapid growth, often hypothyreosis

mostly B (MALT),features of lymphoepithelial lesion

both LG and HG

diff. dg. HT

clinical and cytology suspicion

dg. excision

MALT in HT

CD20

nH ML - HG

Chronic Sclerosing Thyreoiditis

Riedel (1910)

Synonyma: „Invasive Fibrotising“„ Iron hard goitre“ (eisenharte Struma)

Clin.features: slight assym. edema fixation to surrounding structures eu- or hypofunction tracheal stenosis recurrens paresis

Histol. features: tissue destruction fibrotisation fixation to surrounding structures involment of the neck vessels

Course: Stabilisation, possible progression

IgG4 related disease

–

alergic & autoimmune

Riedel´s Thyroiditis

Martínez-de-Alegría A, Baleato-González S, García-Figueiras R et al.:

IgG4-related Disease

from Head to Toe.Radiographics. 2015; 35(7):2007-25.

…identified in the biliary tree, salivary and

lacrimal glands, periorbital tissues, lungs,

lymph nodes, thyroid gland, kidneys,

prostate gland, testicles, breasts, and

pituitary gland.

Stan MN, Sonawane V, Sebo TJ, Thapa P, Bahn RS:

Riedel's thyroiditis association with

IgG4-related disease. Clin Endocrinol (Oxf). 2017 Mar;86(3):425-430.

Jokisch F, Kleinlein I, Haller B, Seehaus T, Fuerst H, Kremer M.

A small subgroup of Hashimoto's

thyroiditis is associated with IgG4-

related disease.Virchows Arch. 2016 Mar;468(3):321-7.

Jokisch F, Kleinlein I, Haller B, Seehaus T, Fuerst H, Kremer M.

A small subgroup of Hashimoto's

thyroiditis is associated with IgG4-

related disease.Virchows Arch. 2016 Mar;468(3):321-7.

Compared to the non-IgG4-related cases, IgG4-related thyroiditis

showed a higher IgG4/IgG ratio (0.6 vs. 0.1, p < 0.0001), a higher

median IgG4 count (45.2 vs. 6.2, p < 0.0001), an association with

younger age (42.1 vs. 48.1 years, p = 0.036), and a lower female-to-

male ratio (11:1 vs. 17.5:1). Fibrous variant of Hashimoto's thyroiditis

was diagnosed in 23 of the 24 IgG4-related cases (96 %) and in 13 of

167 (18 %, p > 0.001) non-IgG4-related cases.

Thyreoidal Syndromes

hypothyreosis

– inborn – cretinism

endemic, sporadic

– acquired – myxedema

hyperthyreosis - thyreotoxicosis

Infancy Hypothyreosis - CRETINISM

disturbances of growth & differentiation

BRAIN

LUNG

BONE

Arthur Biedl: Innere Sekretion, Wien , 1913

Acquired Hypothyreosis - MYXEDEMA

decreased metabolism

– bradycardia, low blood pressure, water

retention, obstipation, hyperprolactinemia

intolerance of cold

lowered lipolysis

– weight increase

– hyperlipemia ATHEROSCLEROSIS

apathy, mental sluggishness

Endemic

CRETINISM(dr. Vomela´s archive)

Endemic cretinism

Hypothyreosis- myxedema

Thyreoidal Syndromes

hypothyreosis

– inborn – cretinism

endemic, sporadic

– acquired – myxedema

hyperthyreosis - thyreotoxicosis

Hyperthyreosis - manifestation

increased metabolism

tachycardia, high blood pressure, fibrilation,

– hypercalciuria, diarrhoe

intolerance of warm

increased lipolysis, glycogenolysis

– weight decrease

– hyperglycemia, diabetes

muscle weekness, insomnia, exophtalmus, pretibial myxedema

Orbitopathia

Struma diffusa toxica

Endocrine orbitopathy

correction after surgery

prior to the surgery

Graves´ – Basedow´s Disease - 1835autoimmune toxic goitre

Thyroid stimulating Ig

Thyroid growth stimulating Ig

TSH-binding inhibitor Ig

mainly HLA-DR 3

overlap with HT

morphology– diffuse (nodular) goitre

– colloid reduced to consumed

– thyrocytes cubic

– focal lympho infiltrates

– exophtalmos

– myxedema

Incidence of neoplasia statistically

increased!

Struma hyperplastica

diffusa / nodularis

Struma

uninodularis

Struma multinodularis

Struma

colloides

polyploid

thyrocyte

Bethesda II

Bethesda II

colloid goitre -

regressive changes

macrophages

131J

Bethesda II

Neoplasms of the Thyroid Gland –

epidemiology and clinical manifestation

malignancies in thyroid - 1% of all

F : M up to 4x more

including children (!!!) , young adults(differentiated types)

solitary nodules (esp. in children) or in multinodular goitre

microcarcinoma with a large cervical lymph node meta (papillary ca) or even generalisation (medullary ca) possible

rapid large sweling (nHML HG in young patients , non differentiated ca in old patients)

Neoplasms of the Thyroid Gland

– etiology a pathogenesis

environmental factors, hormonal, genetic

– iodine - radioactive 131J and 132J

– in children less than 1 yr acummulation (milk) about

1000times greater than the rest of the body

– iodine defitiency – growth stimmulation TRH-TSH

activation – FOLLICULAR ca

– high intake of iodine regions PAPILLARY ca

– increased incidence of ca (esp. papillary) in HT and

tyreotoxicosis

– mutations of RET (medul. ca), BRAF (papil. ca),

PAX8/PPAR (follic. ca), and TP53 (undiff. ca)

oncogenes

Neoplasms of the Thyroid Gland

primary

– adenomas (follicular, oncofollicular)

– carcinomas differentiated – follicular, papillary, medullary

non-differentiiated

– tumors of other than epithelial histogenesis

(benign & malignant)

metastatic

pseudotumours:

hyperplasia,inflammation

FNAB

WHO 2004 Histol. Classification of Thyroid Tumours

Carcinomas

– papillary

– follicular

– poorly differentiated

– undifferentiated– squamous

– mucoepidermoid

– sclerosing mucoepidermoid

– mucinous

– medullary– mixed medullary & follicular

– spindle cell tumour with thymus like diff. SETTLE

– ca showing thymus like diff. CASTLE

Adenoma & related tumours

– follicular– hyalinized trabecular tumour

Other thyroid tumours

– teratoma

– primary lymphoma &

plasmacytoma

– ectopic thymoma

– angiosarcoma

– smooth muscle tumours

– peripheral nerve sheet tumours

– paraganglioma

– solitary fibrous tumour

– follicular dendritic cell tu

– Langerhans cell histiocytosis

– SECONDARY

Follicular Neoplasia (proliferating microfollicular lesion)

Histological

diagnosis

– microfollicular

adenoma

– follicular

carcinoma

Cytological features

highly cellular smears– few colloid– microfollicular

formations– thyreocytes regular,

small or slightly enlarged

– bare nuclei– regressive changes:

mostly absent

post PTE

hyperplasia

Bethesda III

proliferative microfollicular lesionB IV SFN - histopathology: adenoma

Follicular

adenoma

pressure atrophy

capsule

proliferative microfollicular lesion B IV SFN histopathology: carcinoma

Follicular carcinoma – transcapsular invasion

Minimally invasive follicular carcinoma

Poorly differentiated follicular carcinoma - widely

invasive

Poorly differentiated follicular carcinoma - widely

invasive

Poorly differentiated follicular carcinoma - widely

invasivePoorly differentiated follicular carcinoma - widely

invasive

Ki 67

Oncocytic Tumours

adenoma

– architecture follicular, trabecular

– cellular atypiae without predictive value

for biological behaviour

– more risk in case of solid architecture

EXCLUDE

ANGIOINVASION, CAPSULOINVASION

oncocytes

Adenoma oncofolliculare

Papillary Carcinoma

Histological variants

- WHO

microcarcinoma

encapsulated

follicular

diff. sclerosing

oxyphil cell

Histological variantsadditional

tall cell

columnar cell

macrofollicular

with desmopl.stroma

hyal. trabecular ca

Papillary Carcinoma

Cytological features

general highly cellular smears

few colloid

waxy colloid, may be absent

architecture

phragments of papillae

groups trabecular

microfollicular

syncytial formations

squamous metaplasia

psammomata

NUCLEI

enlarged

non - circular

overlapping

grooves

pseudoinclusions

No invasion evidence needed for the MALIGNANCY diagnosis in papillary ca!!

TGB+

HE

Carcinoma glandulae thyreoideae

ca papillare

BV - SFM

ca papillare

BV - SFM

ca papillare BVI - malignant

ca papillare

BVI – malignant

cytoblock

ca

papillare

macro

follicular

variant

Thyroid tumors

currently

diagnosed as

noninvasive

EFVPTC have a

very low risk of

adverse outcome

and should be

termed

“noninvasive

follicular thyroid

neoplasms with

papillary-like

nuclear features”

(NIFTP).

2016

JAMA Oncol.

doi:10.1001/jamaoncol.2016.0386

Published online April 14, 2016.

NIFTP – diagnostická kritéria

JAMA Oncol. 2016 Aug 1;2(8):1023-9.

doi:10.1001/jamaoncol.2016.0386. Publishedonline April 14, 2016.

Major

Features

Minor Features

Exclusion criteria

RAS Mutations in Indeterminate Thyroid

Nodules are Predictive of the Follicular

Variant of Papillary Thyroid Carcinoma.

RAS is mutually exclusive with BRAF mutations.

Among the 65 BRAFV 600E -negative indeterminate thyroid nodules

identified by FNAC, 25 (38.5%) exhibited point mutations in RAS

61 consisting of 18 NRAS 61 (72%), and 7 HRAS 61 (28%)

mutations.

In contrast, only 5 of 90 (5.6%) nodules with benign cytology had

RAS mutations.

An JH, et al.: Clin Endocrinol (Oxf). 2014 Aug 11. doi: 10.1111/cen.12579.

Korea University, Seoul, Korea

Jaderné skóre papilárního karcinomu

1. velikost a tvar1. překrývání

2. natěsnání

3. protažení

2. nepravidelnosti jaderné membrány1. nepravidelný obvod

2. rýhy

3. pseudoinkluze

3. struktura chromatinu1. projasňování

2. marginace (matnicová jádra)V každé kategorii 0 nebo 1

= celkové skóre 0-3

Thyroid Carcinogenesis

Medullary Carcinoma

origin fom C-cells

clinical forms :

(parafollicular)

sporadic

familiar

– MEN 2a

– MEN 2bActivating RET

mutation in all

Medullary Carcinoma familiar forms

MEN 2a

medullary ca

parathyr. adenoma

pheochromocytoma

MEN 2b

MEDULLARY CA

marphanoid habitus

mucous neuromas

pheochromocytoma

parathyr. adenoma -

Medullary carcinoma

C-cells (parafollicular)

sporadic

familiar

MEN 2a

MEN 2b

Medullary Carcinoma

Cytological

types large cell

small cell

fusocellular

plasmocytoid

carcinoma

medullare

B VI - malignant

fusocellular

variant

carcinoma medullare B VI - malignant

cytoblock

calcitonin

carcinoma

medullare

B VI - malignant

Medullary carcinoma

Histological

diagnosis

Calcitonin +

amyloid +-

argyrophilia +

Medullary Carcinoma

Histological

diagnosis

architecture may mimic any other

thyroid ca!!! (WHO)

Calcitonine +

amyloid +-

argyrophilia +

amyloid –

Kongo Red

Ca medullare

WHO 2004 Histol. Classification of Thyroid Tumours

Carcinomas:

- medullary

ICD-O 8345/3

variants

– papillary

– glandular (tubular/follicular)

– giant cell

– spindle cell

– small cell, neuroblastoma like

– paraganglioma-like

– oncocytic

– clear cell

– angiosarcoma like

– squamous cell

– melanin producing

– amphicrine

Carcinoma medullare gl. thyreoideae

Kalcitonin

TGB

kalcitonin

chromogranin

Carcinoma medullare gl. thyeoideae

highly malignant neoplasm of the old age with rapid progression

origin:

non diag. differentiated ca

hyperplastic goitre

chronic inflammation

without preceeding goitre

Undifferentiated Carcinoma(anaplastic)

Undifferentiated CarcinomaICD-O 8020/3

Histological variants (often combined)

fusocellular

small cell (?) exclude lymphoma!

giant cell (monstrous cells)

squamous metaplasia

composed lmsa, rmsa,osa, chsa, hae, MFH,

classify as carcinoma!

TGB neg

Undifferentiated

carcinoma

B VI - malignant

EMA

TGB

Nediferenovaný karcinom

vimentin

Undifferentiated carcinoma

Angiosarcoma

CD34

Other Types

of

PrimaryThyroid Carcinomas

epidermoid

mucoepidermoid

mixed follicular and mucoepidermoid

Metastases into Thyroid

kidney

lung

breast

other

Thank You