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
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.
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
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
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
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
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
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
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
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
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
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!
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
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
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!!
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. 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
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
Histological
diagnosis
architecture may mimic any other
thyroid ca!!! (WHO)
Calcitonine +
amyloid +-
argyrophilia +
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
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!
Other Types
of
PrimaryThyroid Carcinomas
epidermoid
mucoepidermoid
mixed follicular and mucoepidermoid
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