PATHOLOGY

OF
THYROID
GLAND
Dody Novrial
Departmen of Anatomical Pathology
Faculty of Medicine and Health
Sciences
Jenderal Soedirman Universit
y

Congenital
Abnormalities

Heterotopic Thyroid Tissue

Definition Ectopic thyroid tissue

Clinical Features Most frequent location at base of the tongue may

result in:
difficulty in swallowing, respiratory
obstruction In 70% of patients with grossly
evident lingual thyroid:
normal thyroid gland is absent, removal of the
 heterotopic thyroid tissue will therefore lead to
hypothyroidism
Pathogenesis A component of thyroglossal duct cyst
Histopathology •Microscopic (subclinical) lingual thyroid in 10% of
normal individuals •Does not differ microscopically from thyroid in the
main glan
d
 Thyroiditis
Autoimmune Thyroiditis
Lymphocytic Thyroiditis Hashimoto's
Thyroiditis Definition Lymphocytic thyroiditis and Hashimoto's
thyroiditis represent
different manifestations of an organ-specific immune-mediated
inflammatory disorde

rClinical Features •‘Juvenile form’ with

•asymptomatic goiter, often of short hyperth
duration yroidis
•painless or silent m
thyroiditis
•Known as struma lymphomatosa •Initially variable mild
•Women over 40 years of age •Diffuse hyperthyroidism, later
firm thyroid enlargement hypothyroidis

mPathogenesis Circulating autoantibodies against: thyroglobulin other

follicular cell antigens, notably TSH receptors
 Autoimmune Thyroiditis
Lymphocytic Thyroiditis Hashimoto's Thyroiditis
Histopathology •Lymphocytic nodules with

germinal centers are scattered in Two main abnormalities are:

the interstitium
•Follicles:
•generally unremarkable •some
may show atrophy or oncocytic
change
•lymphocytic infiltration of the
stroma with prominent germinal
centers
•oxyphilic change of the follicular
epitheliu

mSpecial try
Stains
and
Immuno
histochemis
•Follicular profile resembles that of
cells: papillary carcinoma cells
immunohist •Oncocytic cells: defects of cytochrome-c oxidase,
ochemical deletions of mitochondrial DN
A
Hashimoto's thyroiditis showing
lymphoid follicles with prominent
germinal centers and
oncocytic follicular epithelium
Hashimoto's thyroiditis with branchial cleftlike cyst
s

Cytologic Features of Hashimoto’s

Thyroiditis
• Cellular aspirate • !bundant mixed
lymphocytes and plasma cells
• Lymphohistiocytic aggregates • Follicular cells with
oncocytic features (Hurthle cells) and variable nuclear
atypi
a
Granulomatous Thyroiditis
(De Quervain, Sub acute
Thyroiditis)
Definition Non bacterial granulomatous inflammation of the thyroid
gland with multinucleated giant cells
Clinical Features Middle-aged woman Usually there is
complete resolution May develop: pressure symptoms, mild
hypothyroidism
Pathogenesis Etiology not known

Histopathology •Marked inflammation •The granulomas surround

follicles and are not very distinct •The multinucleated giant cells (most
are histiocytic) engulf colloid
•Caseation necrosis is consistently absent
•Areas of fibrosis in a patchy distribution •Different stages of the same
process may be seen in the same glan
d
Granulomatous Thyroiditis (De
Quervain, Sub acute Thyroiditis)
Late stage: strong immunoreactivity for CA19-9
Special Stains
and Acute stage: positivity for CEA in the center of the
Immunohistoch granuloma
em Initial phase, typically : elevated serum T4 and T3
complete suppression of 131I uptak
istry
O
ther
Inves
tigati
ons
e

Cytologic Features of Subacute

Thyroiditis
• Hypocellular • Multinucleated giant cells
•Loose clusters of epithelioid histiocytes
• Mixed chronic inflammation
• Scant follicular cells with reactive change
s
Riedel's Thyroiditis
Definition Inflammatory fibrosclerosis of the thyroid gland with
infiltration of dense fibrous tissue into surrounding soft tissues
Clinical Features •Extremely rare •Occurs in adults and the elderly,
slight predilection for females •Presents with ill-defined thyroid
enlargement •Often thought to be carcinoma •Regional lymph nodes
are not involved •May coexist with: mediastinal or retroperitoneal
fibrosis sclerosing cholangitis inflammatory pseudotumor of the orbit
Histopathology Fibrous tissue:
extensively hyalinized, replaces the area of the gland involved
Inflammation: Patchy, may be seen in walls of medium-sized veins
predominance of lymphocytes and plasma cells IgA-producing cells
abundant among plasma cells collections of eosinophils +/-, giant cells
-
Riedel's thyroiditis showing
sclerosis, chronic inflammation,
and parenchymal atrophy

Inflammation of a vein
in Riedel's thyroiditi
s

Cytologic Features of Reidel’sThyroiditis

• Hypocellular • Collagenous
fibrous tissue
•Bland spindle cells
• Mild chronic inflammation • !bsent follicular cell
s

Hyperplasia
Dyshormonogenetic
Goiter
Definition Group of several types of goiter with cellular
pleomorphism and mitoses, resulting from enzyme defects in
hormone synthesis
Clinical Features •Thyroid carcinoma has been associated with a very
few cases
•Follicular adenomas have sometimes occurred after
T4 replacement therapy
Pathogenesis Resulting from enzyme defects in hormone synthesis
Histopathology •Hypercellular nodules with a variety of architectural
appearances •a predominance of solid and microfollicular patterns
•Sometimes papillary and insular formations •fibrosis •marked nuclear
atypia in the form of bizarre hyperchromatic nuclei •minimal amounts of
colloid •mitotic figures
 The follicles are hyperplastic
and lined by follicular cells with
marked nuclear pleomorphis
m

Grave’s Disease
Definition An autoimmune disease characterized by elevated T3/T4,
enlarged thyroid and hyperplastic follicular epithelium
Clinical Features Typically: young adult women, muscle weakness,
weight loss, exophthalmos, irritability, tachycardia, goiter, and
increased appetite Late manifestations: localized pretibial
myxedema, ‘thyroid acropachy’(swelling of the extremities, clubbing of
fingers and toes) In children the most common cause of hyperthyroidism
Pathogenesis TSH is not involved Thought to be initiated by IgG
antibodies against specific domains of the TSH receptor: TSI, TBII,
antithyroid peroxidase autoantibodies
Histopathology Follicles: Markedly hyperplastic, prominent papillary
infolding,
 variable number of oxyphilic cells
Colloid: pale, finely vacuolated Stroma: contains
aggregates of lymphoid tissue with germinal center
formation Hyperplastic follicles: may be seen
outside the thyroid gland, should
not be interpreted as evidence of malignanc
y
Lymphoid
follicles with
germinal
centers
and hyperplastic
thyroid follicles in
diffuse hyperplasia
The prominent infoldings of the hyperplastic epitheliu
m

Nodular Hyperplasia
Endemic Goiter Sporadic (Nodular)
Goiter Definition Proliferation of benign follicles forming multiple
nodules
Clinical Features •Most common thyroid disease
•euthyroida •multinodular gland •Occasionally signs of hyperthyroidism
initiall
yPathogenesis Iodine deficiency results secretio
in n
deficient thyroid
hormone
production, which in
turn leads to
increased TSH
Pathogenesis unknown elevate
Usually, blood TSH levels are not
dHistopathology initially a hyperactive thyroid with tall follicular
epithelium and small amounts of colloid (parenchymatous goiter) later
follicular atrophy with massive storage of colloid, with or without
nodularity (diffuse or nodular colloid goiter)
 Tumors

Follicular Adenoma
Benign encapsulated thyroid tumor that shows evidence
of
follicular cell differentiation

Clinical Features :
Most common thyroid neoplasm Usually occurs in
euthyroid adult Scan of lump: usually ‘cold’, rarely ‘hot’
Elevated thyroglobulin levels common
Histopathology
A variety of patterns, singly or in
combination: •normofollicular (simple)
•macrofollicular (colloid)
•microfollicular (fetal)
•trabecular/solid (embryonal)

Morphologic differences between patterns may be

striking, but
no apparent clinical significance
Mitoses: rare or absent, not necessarily indicators of
malignanc
y
Special Stains and
Immunohistochemistry
Thyroglobulin +; TTF+; AE1 dan AE3+

Varian
• Hürthle cell adenoma
• hyalinizing trabecular
adenoma • Atypical adenoma
• Adenoma with bizarre nuclei
• Rare types of follicular adenoma: clear cell changes,
adenolipoma, adenochondroma, black
adenom
a
 Intact fibrous capsule around a follicular adenoma

Microfollicular pattern of growth in a follicular adenoma

follicular adenoma with bizarre nuclei
Follicular carcinoma
Malignant thyroid tumor with follicular
differentiation, other than follicular variants of
papillary, Hürthle cell and poorly differentiated
carcinomas

Clinical Features
• Relatively rare •
Predilection for
females
• Mean age at diagnosis approximately 50 years
• Almost always: –solitary –not occul
t
Histopathology
• Variable, ranging from well-formed follicles to a
predominantly solid growth pattern
• May be: poorly formed follicles,
cribriform areas and
trabecular formations
focal or extensive cytoplasmic
clear changes • Usually mitotic activity
and nuclear atypia • No psammoma
bodies
• Squamous metaplasia is rare
• Ultrastructurally, not significantly different from
follicular adenom
a
Minimally Invasive Follicular
Carcinoma
Terminology for well-differentiated follicular
neoplasm in which capsular interruption is
‘incomplete’

• follicular carcinoma - definite capsular invasion •

follicular tumor of uncertain malignant potential
(FT-UMP) -
questionable capsular invasion if papillary
carcinoma-type
 nuclear changes are absent) • well-differentiated
tumor of uncertain malignant potential
(WDT-UMP) - questionable capsular invasion if
papillary
carcinoma-type nuclear changes are questionable
Widely Invasive Follicular
Carcinom
a
Vascular invasion in minimally
invasive follicular carcinoma
Capsular invasion in minimally invasive follicular carcinoma
Hürthle Cell Tumors (Oncocytic
Tumors)
Follicular neoplasms composed of oncocytes
which are characterized by deeply
eosinophilic cytoplasm

Clinical Features
• Usually adult •
Predominance of
females
Histopathology
• Cytoplasmic granularity: deeply eosinophilic quality •
Growth pattern may be: follicular (most common),
trabecular/solid,
papillary
• Nuclei may show: pleomorphism, prominent nucleoli,
isolated
bizarre form
s
Special Stains and
Immunohistochemistry
Reactivity for: • thyroglobulin (less reactive than
nononcocytic follicular cells)
• keratin (CK14 is emerging as a selective marker for
oncocytes)
• CEA •
S-100
protein
• HMB-
45
Hürthle Cell Carcinoma
• Older age group •
Less female
predominance
• Larger, tends to have a solid/trabecular rather than a
follicular
growthpattern • Cells: often smaller, higher
nucleocytoplasmic rati
o
Hürthle cell adenoma
showing follicular pattern
of growth and intact thin
capsule
Hürthle cell carcinoma with a predominantly solid pattern of growt
h
Hyalinizing Trabecular
Adenoma and Related Lesions
A type of adenoma with trabecular pattern
and hyaline appearance
Pathogenesis
Controversial, may be a morphologic variant of
papillary carcinoma (the hyalinizing trabecular
variant, though almost always benign)
Histopathology
• prominent trabecular
arrangement • equally
prominent hyaline appearance •
nuclear grooves and
psammoma bodies
• round, pale yellow cytoplasmic inclusion bodies in a
paranuclea
r

Special Stains and

Immunohistochemistry
• Consistent positivity for thyroglobulin • Focal and
inconstant reactivity for neuroendocrine markers
such as: neuron-specific enolase (NSE), neurotensin
• Heavy deposition of type IV collage
nLow-power view of Psammoma body formation in
hyalinizing trabecular adenoma hyalinizing trabecular adenoma
Medullary Carcinoma (MTC)
Thyroid malignancy with C (parafollicular) cell
differentiation

Clinical Features
Sporadic Medullary Carcinoma
• Occurs in adults (mean age 45 years) • Almost always
solitary • Presents as a thyroid mass that is cold on thyroid
scan • Sometimes accompanied by intractable diarrhea or
Cushing's
syndrome • Rarely
clinically occult
Familial Medullary Carcinoma
• Autosomal dominant inheritance with virtually complete
penetrance. • Becomes clinically apparent at mean age 35
years • Most cases in children are familial medullary
carcinoma • Often multiple and bilatera
l

Gross Pathology
•solid
•firm
•nonencapsulated
•relatively well
circumscribed
•in the midportion or upper half of the gland,
corresponding to a greater concentration of C cells
in this regio
n
Histopathology
Classically: • solid proliferation of round to polygonal
cells with:
–granular amphophilic cytoplasm –
medium-sized nuclei
• highly vascular stroma
• hyalinized collagen •
amyloid • coarse
calcification
Pattern of growth can be:
• carcinoid-like, •
paraganglioma-like •
trabecular
• glandular (tubular and follicular)
• pseudopapillar
y
FNAB
• eccentric nuclei • ‘neuroendocrine-type’ chromatin
• inconspicuous nucleoli
• binucleated and multinucleated cells
• ill-defined cell borders • a clean background •
amyloid sometimes identifiable

Nuclear pseudoinclusions and multinucleated

cells can be seen in MTC. (Smear, Papanicolaou.
)

Special Stains and

Immunohistochemistry
Calcitonin, CEA, Chromogranin, Keratin AE 1/3,
TTF-1
 Medullary carcinoma with
pseudopapillary pattern of
growth resulting from lack of
cohesiveness of tumor
cells

Medullary carcinoma.
Low-power microscopic view
showing solid pattern
of growth and deposition of amyloi
d
Papillary Carcinoma (PTC)
• Most common thyroid malignancy; with distinctive
nuclear features. Papillae may be a minor component
or absent
• Thyroid mass which is typically COLD in radio-iodine
scan or
lymphadenopathy

Gross Pathology
• PTC show variety of Gross pattern
• Grey white firm masses (mostly)
• Irregular border, infiltration of surrounding thyroid
parenchym • Some show dystrophic calcification/ bone
formation • Size range from minute 1 mm to several cm
• Cystic change (rarely most entire cystic
)
Histopathology
Typically contains numerous easily recognizable true
papillae Nuclear Features: • Ground glass (optically
clear) nuclei • Nuclear pseudoinclusions
• Nuclear grooves
• Nuclear microfilaments •
Mitoses are scanty or
absent Other Changes:
• Extensive fibrosis
• Psammoma
bodies • chewing
gum colloid • giant
cell
Special Stains and
Immunohistochemistry
CK7, TTF-1, CK1
9
Diagnosis
Depends on characteristic nuclear features Tumors
with papillary and follicular structures should be
classified as papillary carcinoma
Thyroglobulin and TTF-1
Morphologic variants:
• papillary
microcarcinoma •
encapsulated variant
• follicular variant
• diffuse sclerosing variant • oncocytic (oxyphilic)
variant • tall cell and columnar cell carcinoma •
cribriform-morular variant • papillary carcinoma with
exuberant nodular fasciitis-like
strom
a
 with fibrovascular cores are
FNAB uncommon in fine needle
aspiration (FNA) samples.
(Smear, Diff-Quik.)

PTC. Large, intact papillae

PTC. Classic nuclear features of extensive nuclear grooves and
PTC, including enlarged, oval fine pale chromatin. (Smear,
nuclei with Papanicolaou.
)

PTC. Papillary Microcarcinoma

• have a stellate configuration • correspond to lesions
formerly known as occult sclerosing
carcinoma or nonencapsulated sclerosing tumor •
Prognosis generally excellen
t
PTC. Encapsulated Variant
• A papillary carcinoma totally surrounded by a capsule
• Cytoarchitectural (and particularly nuclear) features are the
same as for the conventional invasive type
• Distinguish from the hyperplastic nodule with central
cystic
degeneration and papillary or pseudopapillary fronds in
the wall
• Papillary areas are largely limited to the area facing the
cystic cavity
PTC. Follicular Variant
Papillary carcinoma composed entirely or almost
entirely of
follicles
Diagnosis is largely
associated with based
papillary on the nuclear features
carcinoma
diagnosis are:features
Supportive forgrowth
• invasive the
pattern
• fibrous trabeculation (particularly at the tumor
periphery)
• psammoma bodies • strongly eosinophilic colloid with
scalloped edges • abortive papilla
e
PTC. Solid Variant
Particularly common in children
Proliferation predominates over secretion
Characterized by solid nests of generally round shape
that can
be viewed as filled-up follicles
Distinguish from poorly differentiated carcinoma:
• the nuclear features are those of papillary carcinoma
• behavior is that of papillary carcinoma (or a little
worse), but
notably different from that of poorly differentiated
neoplasm
s
PTC. Macrofollicular Variant
Rarest form •(>50%
•macrofollicles Microscopy, composed of predominantly
area)
• Many of macrofollicles are lined by cells with
hyperchromatic
nuclei and the
vacuolization colloid
• Some oftenare
follicles show peripheral
lined by cells with
LARGE CLEAR NUCLEI
with GROOVE and PSEUDOINCLUSION • Low incidence
of lymphnode metastasi
s
PTC. Diffuse Sclerosing Variant
Characterized by: • diffuse involvement of one or both
thyroid lobes • dense sclerosis • abundant psammoma
bodies • extensive solid foci • squamous metaplasia •
heavy lymphocytic infiltration • extensive lymph vessel
permeatio
n
PTC. Oncocytic (Oxyphilic) Variant
• Grossly characterized by mahogany brown
appearance • Microscopy, papillary tumor are
characterized by complex
branching papillae in which oncocytic cells cover
thin
fibrovascular stromal core
• The oncocytic cells are usually polygonal (may be
columnair), have abundant granular eosinophilic
cytoplas
m
PTC. Tall Cell and Columnar Cell Variant
Thebytall
lined cell variant
a single is characterized
layer of ‘tall’ cells (theby: • papillae
height being at
least twice
acidophilic, the width) • ancytoplasm
quasi-oncocytic abundant
• Growth pattern is usually highly papillary
Nuclei usually
•grooves, lack the optically
and pseudoinclusions of clear appearance,
papillary carcinoma
and its other variants
• May be an extensive lymphocytic infiltration of
the stroma The columnar cell variant:
• there is prominent stratification • the cytoplasm is
clear (sometimes with subnuclear vacuolization,
reminiscent of early secretory endometrium)
rather than acidophilic
• Mitotic figures can be found • MIB-1 is relatively hig
h
Tall cell variant of papillary
carcinoma. Note the abundant
granular acidophilic
cytoplasm with
oncocyte-like features
Columnar cell variant of papillary
carcinoma.
The papillae are lined by a
pseudostratified layer of spindle
tumor cell
s

PTC. Cribriform-morular Variant

Characterized by: • cribriform pattern of growth •
morular formations • Strong nuclear-cytoplasmic
staining for ß-catenin (in contrast
to cell membrane staining of normal thyroid
)
Papillary Carcinoma with
Exuberant Nodular Fasciitis-Like
Stroma
• Prominent stromal reaction of the tumor: may
obscure the neoplastic epithelial component
• may lead to misinterpretation of biopsy as nodular
fasciitis,
fibromatosis, or other proliferative stromal condition
• in some foci, the interplay of this stromal component
with the
tumor results in a fibroadenoma-like appearanc
e
Poorly Differentiated
Carcinoma (Insular
Carcinoma)
Thyroid tumor that is, in differentiation and
behavior, intermediate between well-
differentiated (papillary and
follicular carcinoma) and anaplastic thyroid
carcinomas

Histopathology
Distinguishing features: •
nesting (‘insular’) pattern of
growth
• solid-to-microfollicular arrangement
• small uniform tumor cells • variable mitotic activity •
fresh tumor necrosis resulting in a peritheliomatous
patter
n
poorly differentiated
thyroid carcinoma
showing a well-developed
insular pattern

Poorly
differentiated
(insular)
 carcinoma. The
peritheliomatous
pattern of growth
results from necrosis
associated with
preservation
of the tumor cells that are closer to
nutrient vessel
s
Undifferentiated Carcinoma
Usually a result of anaplastic transformation of a pre-
existing well-differentiated tumor (or a metastatic
focus)

Histopathology
Two major categories that sometimes coexist:
• squamoid: –does not make follicles, papillae,
trabeculae, or nests –an unmistakable epithelial
appearance morphologically
and immunohistochemically –may blend
 with clearcut foci of keratinization –an
unusual subset has a lymphoepithelioma-
like
appearance, but does not seem to be related to
EpsteinBarr virus
• sarcomatoid: spindle cell and giant cell:
–composed of two patterns, often seen togethe
r
Anaplastic carcinoma of the
spindle cell type
Anaplastic carcinoma of giant cell typ
e

SETTLE

•Spindle cell tumor with thymus-like

differentiation •Characterized by a
lobulated architecture
and biphasic cellular composition
featuring spindleshaped epithelial cells
that merge
into glandular structure
s

SETTLE
• Biphasic growth pattern, spindle cells (left) merging
into well formed tubulopapillary structure (right
)

SETTLE
• Monophasic appearance dominated by epithelial cells
forming gladular structures
 SETTLE
• Bundles of spindle cells • Tumor cells nuclei show
mild variation in shape and size
 CASTLE
•Carcinoma showing thymus-like
differentiation (CASTLE)
•Ca thyroid with architecture resemble
in thymic epithelial tumor
•Histopa: invade broadband fronts,
variably
in size smooth contour island and cords,
moderate cellular desmoplastic strom
a

CASTLE
• Carcinoma showing thymus-like differentiation
(CASTLE)
• Broadband anastomosing islands of tumor cells,
separated by
desmoplastic strom
a

CASTLE

•Carcinoma showing thymus-like differentiation

(CASTLE)
•Spindle cells appearance
•Moderate atypical
nucle
i