PATHOLOGY OF

THYROID GLAND
Dody Novrial
Departmen of Anatomical Pathology
Faculty of Medicine and Health Sciences
Jenderal Soedirman University
 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 gland
 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 disorder

Clinical Features •‘Juvenile form’ •Known as struma lymphomatosa

•asymptomatic goiter, often of
short duration
•painless or silent thyroiditis
with hyperthyroidism
•Women over 40 years of age
•Diffuse firm thyroid enlargement
•Initially variable mild
hyperthyroidism, later
hypothyroidism

Pathogenesis Circulating autoantibodies against: thyroglobulin

other follicular cell antigens, notably TSH receptors
 Autoimmune Thyroiditis
Lymphocytic Thyroiditis Hashimoto's Thyroiditis
Histopathology •Lymphocytic nodules with Two main abnormalities are:
germinal centers are scattered in •lymphocytic infiltration of the
the interstitium stroma with prominent germinal
•Follicles: centers
•generally unremarkable •oxyphilic change of the follicular
•some may show atrophy or epithelium
oncocytic change
Special Stains •Follicular cells: immunohistochemical profile resembles that of
and Immuno papillary carcinoma cells
histochemistry •Oncocytic cells: defects of cytochrome-c oxidase, deletions of
mitochondrial DNA
 Hashimoto's thyroiditis showing lymphoid
follicles with prominent germinal centers and
oncocytic follicular epithelium

Hashimoto's thyroiditis with branchial cleft-

like cysts
Cytologic Features of Hashimoto’s Thyroiditis
• Cellular aspirate
• Abundant mixed lymphocytes and plasma cells
• Lymphohistiocytic aggregates
• Follicular cells with oncocytic features (Hurthle cells) and
variable nuclear atypia
 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 gland
 Granulomatous Thyroiditis
(De Quervain, Sub acute Thyroiditis)
Special Stains and Late stage: strong immunoreactivity for CA19-9
Immunohistochem Acute stage: positivity for CEA in the center of the granuloma
istry
Other Initial phase, typically :
Investigations elevated serum T4 and T3
complete suppression of 131I uptake
Cytologic Features of Subacute Thyroiditis
• Hypocellular
• Multinucleated giant cells
• Loose clusters of epithelioid histiocytes
• Mixed chronic inflammation
• Scant follicular cells with reactive changes
 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 thyroiditis
Cytologic Features of Reidel’s Thyroiditis
• Hypocellular
• Collagenous fibrous tissue
• Bland spindle cells
• Mild chronic inflammation
• Absent follicular cells
 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 pleomorphism
 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 malignancy
 Lymphoid follicles with
germinal centers
and hyperplastic thyroid follicles
in diffuse hyperplasia

The prominent infoldings of the

hyperplastic epithelium
 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 initially
Pathogenesis Iodine deficiency results in Pathogenesis unknown
deficient thyroid hormone Usually, blood TSH levels are not
production, which in turn leads to elevated
increased TSH secretion
Histopathology 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

malignancy
 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
adenoma
 Intact fibrous capsule around a
follicular adenoma

follicular adenoma with bizarre nuclei

Microfollicular pattern of growth in

a follicular adenoma
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 occult
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
adenoma
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 Carcinoma

Vascular invasion in minimally Capsular invasion in minimally
invasive follicular carcinoma 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 forms
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 ratio
 Hürthle cell adenoma showing follicular
pattern of growth and intact thin capsule

Hürthle cell carcinoma with a predominantly

solid pattern of growth
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 paranuclear
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 collagen

Low-power view of hyalinizing Psammoma body formation in

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 bilateral
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
region
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)
• pseudopapillary
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 amyloid
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, CK19
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
stroma
FNAB

PTC. Large, intact papillae with PTC. Classic nuclear features of PTC,
fibrovascular cores are uncommon in including enlarged, oval nuclei with
fine needle aspiration (FNA) samples. extensive nuclear grooves and fine pale
(Smear, Diff-Quik.) chromatin. (Smear, Papanicolaou.)
PTC. Papillary Microcarcinoma
• have a stellate configuration
• correspond to lesions formerly known as occult sclerosing
carcinoma or nonencapsulated sclerosing tumor
• Prognosis generally excellent
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 based on the nuclear features associated
with papillary carcinoma
 Supportive features for the diagnosis are:
• invasive growth pattern
• fibrous trabeculation (particularly at the tumor periphery)
• psammoma bodies
• strongly eosinophilic colloid with scalloped edges
• abortive papillae
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 neoplasms
PTC. Macrofollicular Variant
• Rarest form
• Microscopy, composed of predominantly macrofollicles (>50%
area)
• Many of macrofollicles are lined by cells with hyperchromatic
nuclei and the colloid often show peripheral vacuolization
• Some follicles are lined by cells with LARGE CLEAR NUCLEI
with GROOVE and PSEUDOINCLUSION
• Low incidence of lymphnode metastasis
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 permeation
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 cytoplasm
PTC. Tall Cell and Columnar Cell Variant
The tall cell variant is characterized by:
• papillae lined by a single layer of ‘tall’ cells (the height being at
least twice the width)
• an abundant acidophilic, quasi-oncocytic cytoplasm
• Growth pattern is usually highly papillary
• Nuclei usually lack the optically clear appearance, grooves, and
pseudoinclusions of 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 high
Tall cell variant of papillary carcinoma. Columnar cell variant of papillary
Note the abundant granular acidophilic carcinoma.
cytoplasm with oncocyte-like features The papillae are lined by a
pseudostratified layer of spindle tumor cells
PTC. Cribriform-morular Variant
Characterized by:
• cribriform pattern of growth
• morular formations
• Strong nuclear-cytoplasmic staining for β-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 appearance
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 pattern
 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 vessels
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 Epstein-
Barr virus
• sarcomatoid: spindle cell and giant cell:
– composed of two patterns, often seen together
 Anaplastic carcinoma of the spindle cell type

Anaplastic carcinoma of giant cell type

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

• Carcinoma showing
thymus-like
differentiation
(CASTLE)
• Spindle cells
appearance
• Moderate atypical
nuclei