THYROID TUMOR WITH
FOLLICULAR GROWTH PATTERN,
PROBLEM IN DIFFERNTIAL
DIAGNOSIS
Dr. Vikram Prabhakar (DCP,DNB Pathology)

Anatomy
• 2 lateral lobes;
• 1 isthmus
• 15 to 25 grams
• Blood supply

Normal Histology

Major patterns of thyroid carcinoma
• Follicular
- Well formed colloid containing follicles
- Solid
- Trabecular
- Cribriform( poorly formed)
• Papillary
• Medullary
• Undifferentiated ( Anaplastic )

D/D in Follicular growth pattern
1) Adenomatous (Hyperplastic , adenomatoid)
nodules
2) Follicular adenoma
3) Follicular carcinoma
4) Follicular variant of Papillary carcinoma
5) Follicular variant of Medullary carcinoma
6) Poorly differentiated carcinoma
7) Undifferentialed ( Anaplastic) carcinoma

Hyperplasia – Neoplasia sequence
Follicular
cell Hyperplasia
Adenoma
Carcinoma

Adenomatous nodules
• Also called hyperplastic or adenomatoid
• Unilateral painless mass
• Arises in a background of nodular goiter
• Can show complete or partial encapsulation

• Usually contain a mixture of macrofollicules
and microfollicules or indl single pattern.
• Asymptomatic & accidentally discovered.
• Pressure symptoms
• Toxic adenomas
• Investigations : USG, FNAC, excision biopsy
Adenomatous nodules

• Nodules are not showing any specific growth pattern
even if they are solitary.
• It occurs in a normal thyroid showing only
microscopic evidence of nodular goiter( so called
dominant hyperplastic nodule)
• Some nodules may be hyperfunctional and
morphologically represent hyperplastic nodule or
adenoma
• If multiple nodules are hyperfunctioning than it
called Toxic nodular goiter.
Adenomatous nodules

Points to remember
• Solitary nodules
• Nodules in younger pts
• Nodules in males
• H/O radiation therapy to head
& neck region
• Hot nodules are more likely to be benign
More likely
to be
neoplastic

FOLLICULAR Adenomas
• Discrete solitary masses (follicular adenomas)
Simple colloid adenomas [macrofollicular]
Fetal/microfollicular, embryonal, trabecular
Mixed patterns
• Nonfunctional, most of the times
• Hormone production in functional adenomas is
independent of TSH stimulation( Toxic Adenomas)

CYTOLOGY
• Cellular smear with numerous follicular cells and
little or no colloid.
• Most of the follicular cells arranged in syncytial
fragments and exhibit a microfollicular pattern.
• Microfollicules consists of 6-12 nuclei in a small
ring with central dot of colloid
•In macrofollicular adenoma cells are arranged in
monolayer sheets with abundant colloid.

Follicular adenoma showing
microfollicular pattern

Gross
• Solitary, spherical, encapsulated
• Average 3cm, upto 10cm
• C/S gray-white to red-brown, bulges
• Hemorrhage, calcification, fibrosis, cystic
change

Microscopy
• Uniform follicles containing scant colloid
• Follicles distinct from surrounding thyroid
• Hurthle cell adenoma, clear cell, signet ring cell
• Endocrine atypia : focal nuclear pleomorphism, atypia,
prominent nucleoli
• Atypical adenoma : ↑↑ anisonucleosis, mitotic activity

TRABECULAR PATTERN
TUMOR CELLS HAVE DEEPLY EOSINOPHILIC WITH
GRANULAR CYTOPLASM

IHC
• FA are immunoreactive for Cytokeratins,
Thyroglobuline and TTF-1.
• But non reactive for CK-19, Calcitonin or pan-
neuroendocrine markers

Variants of FA
- Oncocytic Adenoma
- FA with papillary hyperplasia
- Fetal Adenoma
- Singnet ring cell FA
- Mucinous FA
- Lipoadenoma
- Clear cell FA
- Toxic Adenoma
- Atypical Adenoma
- FA with bizarre nuclei

FOLLICULAR CARCINOMA
• Malignant epithelial tumor showing evidence
of follicular cell differentiation and lacking of
diagnostic nuclear features of papillary
carcinoma.
• 10-15% of thyroid malignancy.
• More common in female and peak age 50 yrs.
• Rarely occur in children

• Incidence is dramatically decreased due to
adequate dietary supplementation of iodine
and exclusion of FVPTC from this category.
• Iodine deficiency and irradiation is the most
common etiological factor.
• Most common site is normally situated thyroid
and ectopic thyroid tissue( struma ovarii)

Clinical features
• Most common presentation asymptomatic
intrathyroidal mass lesions.
• Ipsilateral lymphadenopathy is less common
than PC ( less than 5%)
• Cold on scintigraphic scan.
• Hoarseness, dysphegia and dyspnea rare but
may occur in widely invasive FC.

• No definit precursor lesions but may arise
from FA
• Multifocality is uncommon.
• Recurrence rate is high in residual tumor after
partial thyoidectomy.
• Lymph node metastases uncommon.
• Most common site for distant metastases are
lung and bone.

Cytology: Follicular carcinoma
• Hypercellular with a dispersed microfollicular
arrangement of tumor cells and scant colloid.
• Microfollicules consists of 6-12 nuclei forming
a small ring like structure.
• Presence of nuclear atypia does not correlate
with malignancy since FC may shows bland
cytological characteristic and FA may shows
considerable nuclear atypia.

Cellular smear single cell & microfollicles pattern, diagnosed by
histopath as follicular carcinoma with vascular invasion.

Microfollicular cell cluster/rosette with nuclear
hyperchromesia and coarseness

Histopathology
• Depending on degree
of invasiveness FC has
two major category
- minimally invasive
- widely invasive

• FC shows variable morphological pattern
ranging from well formed colloid containing
follicles, solid, trabecular to poorly form
follicles to atypical pattern ( cribriform).
• Neither architectural pattern nor cytological
features are reliable for its diagnosis

• FC diagnosed on the basis of invasiveness.
• Minimally invasive FC have limited capsular
and vascular invasion.
• Widely invasive FC have widespread
infiltration of adjacent thyroid tissue or
blood vessels.

• Capsular invasion- Defined by tumor
penetrating through the tumor capsule
unassociated with the site of previous FNAC.
• Vascular invasion- Defined by presence of
intravascular tumor cells either covered by
endothelium or associated with thrombus.
Criteria
- Involved vessels must be within or
beyond the tumor capsule.
- Foci of vascular invasion should be
distinguish from sub endothelial collection of
tumor cells and retraction artifacts.

FOLLICULAR CARCINOMA MINIMALLY INVASIVE TYPE: (A) TUMOR DEMONESTRATE
COMPLETE PENETRATION OF THE CAPSULE AND HAS MUSHROOM LIKE
CONFIGURATION. (B) MINIMAL CAPSULAR AND VASCULAR INVASION. (C) FOCAL
INVASION OF A CAPSULAR VESSELS.

FOLLICULAR CARCINOMA WIDELY INVASIVE TYPE (A) MULTIFOCAL AREAS OF INVASION
OF CAPSULAR VESSELS. (B) TUMOR HAS EXTENDED BEYOUND THE CAPSULE AND IS
PRESENTS WITHIN VASCULAR SPACE. (C) MULTIPLE FOCI OF VASCULAR INVASION ARE
SEEN.

Variants of FC
• Oncocytic variant
- 3-4% thyroid malignancy.
- other name oxyphil and hurthle cell
carcinoma.
- Median age 61yrs
- 30% cases associated with nodal
metastases. Distant metastases is rare

• Clear cell variant
- Composed predominantly of clear cells.
- Contain glycogen, mucin, lipid or dilated
mitochondria.
- Signet ring follicular cell may sometime
major component of this variant.

IHC-FC
• Immunoreactive to Thyroglobulin, TTF-1 and
LMW CK
• CK-19 and lewis blood antigen are focally
positive but rare in FA and NG. But strong
positivity in PC
• Galectin-3, HBME-1, CD-15 & CD44v6 positive.

• E-cdherin and beta catenin shows
membranous positivity but also positive in
case of normal thyroid, benign follicular
lesions and FVPTC.
• Bcl-2 positive, TP53 negative, display low level
of cyclin D1 and high levels of P27 with low
proliferation rate.
• Telomerase expression is higher than FA and
PC
IHC-FC

Follicular variant of PC
• Tumors resemble encapsulated follicular
neoplasm composed of small to medium sized
irregularly shaped follicles with virtually no
papillary structures.
• Variable amount of colloid may appear
hypereosinophilic and scalloped.
• Majority of the cells lining in the follicles
contain large clear nuclei with grooves and
nuclear pseudoinclusion.

• Intrafollicular multinucleated giant cells are
frequent but stromal sclerosis and psammoma
bodies are occasional.
• Despite complete encapsulation, lymph node
and rarely distant metastases can occur.

Cytology -FVPTC
• Cytology smear shows non-cohesive cells
arranged in follicles found in a background of
little colloid. Nuclear crowding with powdery
chromatin and grooves are seen. Intranuclear
inclusions are less as compared to
conventional PTC.

FVPTC, tumor is encapsulated and
grossly resemble a follicular
adenoma
FNAC shows nuclear crowding with
powdery chromatin and grooves.

Follicular variant of medullary
carcinoma
• Extremely rare and also called mixed
medullary-follicular carcinoma.
• Presence of follicular or glandular structures in
a medullary carcinoma can result true
follicular pattern growth or entrapment of
neighboring follicles by invasive tumor.
• Immunoreactivity to calcitonin and
thyroglobulin

Poorly differentiated carcinoma
• Morphologically and behaviorally an intermediate
position between differentiated ( FC, PC) and
undifferentiated carcinoma (anaplastic).
• Etiology is unknown but most likely arise de novo
or preexisting Papillary and follicular carcinoma.
• Large solitary thyroid masses, cold by scintigraphy
and with or without concurrent enlargement of
regional lymph node.

Cytology
-Highly cellular with numerous
dyscohesive small to medium sized
cells, microfollicules and scant
colloid.
- Nuclei are bland with fine
chromatin and small nucleoli.
- Necrosis and mitosis are common.
- Definitive diagnosis is made out in
histopathology.

Syncytial clusters of crowded small cells with
hyperchromatic nuclei and high NC ratio

Gross
-More than 3 cm in diameter at the
time of diagnosis
- Solid gray white with frequent
foci of necrosis.
- Most tumor have pushing borders
and rarely thick capsule.
-Invasive peritumoral growth leads
to satellite nodules within the
thyroid parenchyma

Histopathology
• Three different growth pattern Insular, trabecular
and solid.
• Diagnosis relies on the identification of these
pattern.
• Infiltrative growth pattern, necrosis and vascular
invasion.
• Well defined nest surrounded by fibrovascular
septae. Tumor cells are small, uniform, round
hyperchromatic to vesicular nuclei with indistinct
nucleoli. Mitotic figures are common.

IHC
• Immunoreactive for thyroglobuline and TTF-1.
• Focal TP53 nuclear positivity.
• Increased Ki-67 (MIB-1) index.
• Absence of E-cadherin membranous expresion

Undifferentiated (anaplstic)
carcinoma
• Highly malignant tumors that histologically
appear wholly or partially composed of
undifferentiated cells.
• Occurs mainly in the elderly, only 25%
patients are younger than 60yrs.
• Female are affected more M:F = 1: 1.5

• Presented as rapidly expanded neck mass.
• Most important sign and symptoms are
- Hoarseness (80%)
- dysphagia (60%)
- Vocal cord paralysis (50%)
-Cervical pain (30%)
- Dyspnea (20%)

• Tumor may fixed and hard(75%), single(60%),
multiple nodules(40%) and B/L (25%) cases
• Surrounding structures are frequently
involved, muscles(65%), trachea(50%),
esophagus(45%), laryngeal nerve(30%) and
larynx(15%) cases.
• 40% patients have cervical lymphadenopathy
and distant metastases.
• 50% involved lungs, 15% bone and 10% brain.

Cytology
• Highly cellular, cells are singly or clusters and
marked nuclear pleomorphism.
• The cells types are squamoid, giant and
spindle with bizarre single and multiple nuclei.
• Coarsely clumped chromatin, single and
multiple prominent nucleoli.
• Mitotic figures are numerous.
• Background shows necrotic debris,
inflammatory cells and occasional osteoclast
like giant cells.

Gross
-Tumors are
large, fleshy
and white-tan
in color.
- Infiltrative,
areas,
hemorrhage
and necrosis
are common.

Histopathology
• Majority of UTC are widely invasive tumor
composed of an admixture of spindle cell,
pleomorphic giant cells and epithelioid cells.
• Percentage of cells component varies.
• Extensive coagulative necrosis with irregular
borders and palisading is often seen.
• Infiltration of vascular walls accompanied by
obliteration of the vascular lamina is common.

(A) Anaplastic carcinoma undermining laryngeal mucosa. Note the large atypical cells.
(B) High-power view of anaplastic carcinoma showing large atypical cells with mitoses.
(C) Anaplastic carcinoma with sheets of intermediate cells associated with focal
osteoclast-like giant cells and extensive hemorrhage. (D) A focus of well-differentiated
thyroid carcinoma identified adjacent to an anaplastic carcinoma
A B
C D

IHC
• Cytokeratin - most frequently expressed about
40-100% of cases.
• EMA (30-50%) and CEA(< 10%) less commonly
expressed.
• TTF-1 rarely expressed and thyroglobulin is
invariably negative.
• TP-53 strongly positive.

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