Surg Patho: Thyroid Diseases

  |2018
ANATOMY
Normal adult thyroid gland is composed of:
• Two lobes joined by the isthmus, which lies across the trachea
anteriorly, below the level of the cricoid cartilage
• It is endowed with a rich lymphatic network, not always evident
in hematoxylin and eosin (H&E) sections but clearly evident with
the D2-40 immunostain.
• The lymph vessels coalesce in the subcapsular region to give rise
to collecting trunks that drain into the following nodes:
pericapsular;
-­‐
-­‐ internal jugular chain;
-­‐ pretracheal, paratracheal, and prelaryngeal (the
pretracheal node located near the isthmus is sometimes
referred to as the Delphian node);
-­‐ recurrent laryngeal nerve chain;
-­‐ retropharyngeal and retroesophageal
-­‐ The anterosuperior mediastinal nodes are secondary to the
recurrent laryngeal nerve chain and pretracheal groups,
but studies have shown that dye injected into the thyroid
isthmus can also drain directly into them
-­‐ expressed in the normal lung (bronchial cells and
pneumocytes) and in most cases of lung carcinoma
(including the small cell neuroendocrine type)
-­‐ occasionally expressed in other sites, such as the
normal and neoplastic female genital tract, Wilms
tumor, and Merkel cell tumor.
Thyroglobulin – most widely used marker
CONGENITAL ABNORMALITIES
THYROGLOSSAL DUCT ANOMALIES
• Result of a localized persistence of the thyroglossal duct
• In form of a sinus tract connected to foramen cecum,
supersternal notch or in form of blind tubular structure
• May accompany cyst formation due to secretion of lining cells
• THYROGLOSSAL DUCT CYTS – prominent cystic changes
• Most cases – clinically evident in childhood
• Tx: surgical removal – include the middle 3rd of the hyoid bone
and the entire length of the sinus tract

HISTOLOGY MICRO
• Made up of round or oval follicles that vary considerably in Thyroglossal duct cyst
size -­‐ Cyst: lined by pseudostratified ciliated / squamous epithelium
• With an average diameter of 200 m -­‐ IHC: TTf 1 (+), thyroglobulin (-)
• Lined by a single layer of follicular cells whose shape ranges -­‐ Subjacent stroma: mucous glands and thyroid follicles
from flattened to low columnar, depending on their degree of
activity • Secondary inflammation
• Cytoplasm has a pale acidophilic or amphophilic staining -­‐ In cases accompanied by sinus tract
quality; the greater the activity of the cell, the greater its -­‐ Epithelial lining may be absent as a result
amount -­‐ Stroma infiltrated by inflammatory cells
• Follicular cells with abundant granular acidophilic cytoplasm
are referred to as Hürthle cells (a misnomer), Askanazy cells, • Thyroid tissue present can undergo malignant transformation:
oxyphilic cells, or oncocytes. -­‐ Papillary carcinoma
• Divided by CT septae into lobules, each containing 20-40 § Prognosis is excellent after surgical removal. Does
follicles (Functional unit) not need to include thyroid gland.
-­‐ Others: oncocytic (Hurthle cell) carcinoma and
C-cells undifferentiated (anaplastic) carcinoma
• Or parafollicular cells
• At the junction of the upper 3rd and middle 3rd of the lateral
lobes
• The number of C cells varies according to age; they are more HETEROTROPIC THYROID TISSUE
numerous in infancy and old age than in adults.
• Most adult glands contain no more than 10 C cells in a low-
• As a component of thyroglossal duct cyst, anywhere along the
power microscopic field.
course of the thyroglossal duct, or as a sole abnormality
• In old age, they may form nodular aggregates.
• Most frequent: base of the tongue à difficulty in swallowing and
• Ultrastructurally:
respiratory obstruction
-­‐ contain numerous dense-core granules of neurosecretory
• Microscopic lingual (subclinical) thyroid seen in 10% of individuals
type
-­‐ Not different microscopically from the main gland
-­‐ argyrophilic with the Grimelius reaction;
-­‐ Sometimes with capsule or follicles grow between skeletal
-­‐ metachromatic with toluidine blue;
muscle
-­‐ positive for lead hematoxylin;
-­‐ in 70% of patients with grossly evident lingual thyroid there is
-­‐ immunoreactive for calcitonin, katacalcin, calcitonin gene–
absence of the normal thyroid gland
related peptide, neuron-specific enolase (NSE),
• Other sites of heterotrophic thyroid
chromogranins A and B, secretogranin II, and synaptophysin
-­‐ The anterior tongue
-­‐ also immunoreactive for carcinoembryonic antigen (CEA),
-­‐ Submandibular region
although less so than their neoplastic counterparts in
-­‐ Larynx
medullary carcinoma
-­‐ Trachea
-­‐ Mediastinum (usually superior but sometimes posterior)
IMMUNOHISTOCHEMICAL STAIN
-­‐ Heart
• Distant locations
Ttf-1
-­‐ Wall of the duodenum, gallbladder region of the porta
• an extremely useful marker for all types of primary and
hepatis, adrenal gland, fallopian tube, vagina, and the
metastatic thyroid tumors (including medullary carcinoma),
ovary and other sites as a component of teratoma
except for anaplastic carcinoma
-­‐ Is subject to the same diseases that can affect the main
-­‐ not expressed in normal, hyperplastic, or
gland
adenomatous parathyroid tissue
Ø Inflammation, hyperplasia, and tumors

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 THYROIDITIS LYMPHOCYTIC THYROIDITIS

Lymphoid infiltration with limited evidence of parenchymal

damage
GRANULOMATOUS (DE QUERVAIN) THYROIDITIS
Several clinical entities:
-­‐ Painless (or silent, or subacute lymphocytic) thyroiditis that
• Aka: Quervain thyroiditis, giant cell thyroiditis, subacute thyroiditis,
can be sporadic or postpartum
subacute granulomatous thyroiditis, or painful subactue
-­‐ Hyperthyroid followed by hypothyroid à return to euthyroid
thyroiditis
in majority of cases
• Middle-aged women
-­‐ “juvenile form” – course is variable
-­‐ Drug-induced thyroiditis – amiodarone and lithium
Signs and symptoms:
Morphology:
• Sore throat
-­‐ Germinal centers are few
• Painful deglutition
-­‐ Oncocytic changes are focal
• Tenderness on palpation
-­‐ Follicular atrophy is absent
• Associated with fever and malaise
-­‐ Fibrosis is mild or altogether absent
Labs:
• Focal Lymphocytic thyroiditis (or nonspecific thyroiditis, focal
• Thyrotoxicosis with increased levels of T3 and T4
autoimmune thyroiditis)
• Decreases radioactive iodide uptake – initial
-­‐ Mostly euthyroid, latent subclinical hypothyroidism in
minority
GROSS
-­‐ Collections of lymphocytes are found but removed by the ff.
• Entire gland
reasons:
• Enlargement is often asymmetric – typically 2x the size
o Can be found around thyroid tumors (papillary Ca)
• Advanced stages – involved areas firm
o Irradiated (radioactive iodine ablation or external
• No adherence to the surrounding structures
beam therapy)
o Autopsy
MICRO
§ Autopsy studies found in: females
• Marked inflammation and granulomas (surrounding follicles)
(white females highest in prevalence,
• (+) foreign body giant cells – common to engulf colloid
increases with age)
§ Focal lymphoid infiltration: 55% of white
AUTOIMMUNE (LYMPHOCYTIC AND HASHIMOTO) THYROIDITIS
women aged 80 years or older

• Different manifestations of organ-specific, immune-mediated HASHIMOTO THYROIDITIS

inflammatory disorder
• One of the 2 forms of autoimmune thyroid disease, the other is • 1912 by Hakaru hashimoto as struma lymphomatosa
Grave’s • Extensive damage to the thyroid parenchyma
• Immune-mediated insult à diffuse or nodular hyperactivity à • Women over 40 years of age
exhaustion atrophy (diffuse oxyphilia of follicular epithelium)
Clinical:
Mechanism: humoral and cellular • diffuse firm thyroid enlargement with signs of esophageal /
• Circulating autoantibodies vs. autoantibodies (thyroglobulin, tracheal compression
TSHr) • may be accompanied by mild hyperthyroidism à
• Leading pathogenic event: breakdown of immune tolerance hypothyroidism
(immunologic, genetic, environmental) symptoms:
• Triggered by: events related to infection or injury of cells due to -­‐ thyroid gland easily separated from other structures
toxins -­‐ fascial attachment slightly thickened
-­‐ Thyrocytes exhibit new epitopes/unmask hidden ones à -­‐ no fixation
arrival of MHC II antigen presenting cells (dendritic -­‐ firm (may be confused carcinoma
cells/macrophages)
-­‐ Present to naïve lymphocytes à clonal expansion of CD4, GROSS
CD8, & IgG producing B cells à accumulate in thyroid à • Diffuse and symmetrical enlargement of the gland
thyroiditis • Consistency: firm
-­‐ CD4, CD8, & IgG producing B cells produce cytokines à • No extension of the process outside the gland
altering behavior of follicular cells à express MHC class II • Cut surface:
contributes to autoimmune process -­‐ Friable
-­‐ Vaguely or distinctly nodular or micronodular
Common Morphology:
-­‐ yellowish gray
• Lymphocytic infiltration of the gland associated with germinal -­‐ greatly resembles a hyperplastic lymph node
center formation • colloid (-)
• Appearance of the intervening follicles that determines the • necrosis and calcification (-)
category to which a given case belongs
MICRO
DISEASE MORPHOLOGY • Lymphocytic infiltration of the stroma
Grave’s Disease Diffusely hyperplastic -­‐ Distributed within and around the lobules
Lymphocytic Relatively Normal, limited -­‐ Large follicles with prominent germinal centers
damage -­‐ Lymphocytes: T cells > B cells
Hashimoto’s Damaged cells with oncocytic -­‐ Plasma cells, histiocytes, and scattered intrafollicular
change; marked damage multinucleated giant cells (+)
-­‐ Lymphatic vessels are increased in number and dilated
(Cracking spaces)

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• Oxyphylic change of the follicular epithelium
-­‐ Atrophic
-­‐ Others show features consistent with regenerative
hyperplasia
-­‐ Most lined by variably sized oncocytic (Hurthle) cells
-­‐ Nuclei: enlargement and hyperchromasia / atypically clear
-­‐ Squamous nests and duct-like structures – metaplasia of
follicular cells as a response to the chronic inflammatory
injury
-­‐ Rarely, large cysts lined by squamous epithelium and
bordered by a row of lymphoid follicles are seen
• Connective tissue is scarce, with slight or moderate thickening
of the interlobular septa
VARIANTS:
• Fibrous (or fibrosing) variant of the disease
-­‐ Comprising approximately 10% of all cases; fibrosis is more
extensive
-­‐ Fibrosis is of dense hyaline type; does not extend beyond
the capsule
-­‐ Older women, with hypothyroidism requiring prompt
hormone replacement
• IgG4-related form
-­‐ éIgG4-positive plasma cells, high titers of thyroid
autoantibodies, more aggressive course, shows greater
ultrasound alterations with pronounce hypoechogenicity
-­‐ Lower female-to-male ratio
-­‐ The lympho-plasmacytic infiltration is extensive and there is
predominantly interfollicular pattern
• Nodular Hashimoto thyroiditis
-­‐ Distinct nodularity is evident, the epithelial component of
the nodules having a hyperplastic quality
REIDEL THYROIDITIS
• AKA: reidel struma, fibrous thyroiditis, and invasive thyroiditis
• Adult and elderly patients, slight predilection on females
Clinical:
• ill-defined enlargement
• with profound dyspnea
• extremely firm
• binds the soft tissues of the neck in an iron collar (eisenharte)
• may compress the trachea to a slit like state
• not preceded by an acute inflammatory process or by
tenderness of the thyroid gland. LN not involved
GROSS
• Asymmetric
• Involves localized areas
• Stony hard and cuts with great resistance
• Tissue planes are obliterated – dense fibrous tracts extends from
the thyroid capsule in to the adjacent muscle
• On cross section, areas with complete obliteration of the
architecture alternate with others having a nearly normal
appearance
MICRO
• Fibrous tissue completely replaces area of gland involved
• Fibroblasts and myofibroblasts showing areas of storiform growth
and dense hyalinization in late stages
• Hyalinization is frequently extensive
• Skeletal muscle cells are infiltrated by fibrous tissue
HYPERPLASIA
DYSHORMONOGENETIC GOITER

• May be associated with lymphocytic inflammation of the other • Enlargement of the thyroid gland is due to defects in the
organs synthesis of thyroid hormones
-­‐ As parts of autoimmune polyendocrine syndromes: • Thyroid dyshormonogenesis – accounts 20% of cases of primary
Ø Addison’s disease (the combination being known as congenital hypothyroidism, 80% of thyroid dysgenesis
Schmidt syndrome) and • Mutations: steps of thyroid hormone synthesis
Ø Diabetes mellitus -­‐ Defective iodide transport
-­‐ Distinctive features of autoimmune polyendocrine -­‐ Defective iodide organification
syndrome type II: -­‐ Defects of thyroglobulin synthesis
Ø Chronic autoimmune thyroiditis -­‐ Dehalogenation
Ø Addison’s disease,
Ø and type 1A diabetes MICRO
Ø Type I characterized by: -­‐ Solid and microfollicular patterns
Ø Hypoparathyroidism -­‐ In some cases, there are papillary and insular formations
Ø Addison’s disease is not typically associated with thyroid -­‐ Fibrosis is a common finding
disease)

• Hashimoto thyroiditis (and other autoimmune thyroid diseases) GRAVES DISEASE (DIFFUSE TOXIC GOITER)
can also be associated with non-endocrine autoimmune
disorders like vitiligo, pernicious anemia, myasthenia gravis, • Graves ophthalmopathy (or orbitopathy) develops in 25%-30%
autoimmune gastritis, celiac disease, and hepatitis • Dermatopathy (pretibial myxedema) and so-called thyroid
acropathy – late manifestation
Complications: • Elevation of bound T4, free T4, or bound T3 levels
• Thyroid lymphoma, oncocytic (Hurthle cell) neoplasms, and • Increased radioactive iodine uptake in the presence of low TSH
papillary carcinomans levels
• Can have loss of heterozygosity (LOH) at tumor suppressor
ggene loci GROSS
• RET/PTC may provide a link between Hashimoto thyroiditis and • Mild to moderate symmetric diffuse enlargement
papillary carcinoma • Succulent and reddish
• Cut surface:
Treatment: -­‐ Uniformly gray or red
• No treatment -­‐ Long standing
• Hormone therapy -­‐ Friable and dull yellow
• Subtotal thyroidectomy: size, pressure symptoms MICRO
• Markedly hyperplastic, with prominent papillary infoldings
• Columnar
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• Aggregates of lymphoid tissue with germinal center formation -­‐hemorrhage, edema, necrosis, calcification, bone
• T-cell type formation, and cystic degeneration (LARGER TUMORS)
• MICRO:
NODULAR HYPERPLASIA -­‐ Patterns: singly or in combination
o Normofollicular (simple)
• AKA: multinodular hyperplasia, nodular or multinodular goiter, o Macrofollicular (colloid)
adenomatoid goiter, adenomatous hyperplasia o Microfollicular (fetal)
• Euthyroid o Solid / trabecular (embryonal)
• Large, cause tracheal obstruction and produce considerable -­‐ Mitoses are rare or absent
disfigurement -­‐ Muscular cushions - vessels in the capsule of adenomas
show thickening of the wall
GROSS -­‐ May exhibit papillary or pseudopapillary structures-
• Enlarged, and its shape is distorted follicular adenomas with papillary hyperplasia
• One lobe being frequently larger than the other -­‐ Hyperfunctioning (hot) adenomas- cellular, more
• Multiple nodules cytoplasm (Inc. N:C ratio)
• Hemorrhage, calcification, and cystic degeneration are o Activating mutations in gene TSH receptor
common (TSHR)/ Gsa subunit protein (GNAS)
o EIH1 gene mutations (20-30%)
MICRO -­‐ Chromosomal abnormalities activating RAS mutations,
• Huge follicles lined by flattened epithelium and PAXS/PPARG rearrangement (same as follicular Ca)
• Conglomerate of small active follicles at one pole (so-called
Sanderson pollsters) SEVERAL VARIANTS: FOLLICULAR ADENOMA
• Benign papillary formations protruding toward the center of a
cystically dilated follicle 1. Oncocytic (Hurthle cell) Adenoma and Hyalinizing Trabecular
Adenoma
2. Atypical adenoma
-­‐ pronounced cellular proliferation and less regular
cytoarchitectural patterns
3. Adenoma with bizarre nuclei
-­‐ presence of huge hyperchromatic nuclei, usually in
clusters
4. Rare types:
-­‐ clear cell changes (including the signet ring, mucin-
producing and lipid- rich types)
-­‐ lipoadenomas or adenolipomas (adipose metaplasia of
the stroma)
-­‐ adenochondromas (with cartilaginous metaplasia)
-­‐ spindle cell and black adenomas (cytoplasmic pigment
ff minocycline therapy)

TUMORS DIFFERENTIAL DIAGNOSIS

• Dominant nodule of nodular hyperplasia
• Noninvasive follicular thyroid neoplasm with papillary-like
• Majority – primary and epithelial nuclear features (NIFTP)
• Adenomas and carcinomas • Minimally invasive carcinomas (follicular carcinoma or follicular
• Composed of follicular cells variant papillary carcinoma)
• Medullary carcinoma of intrathyroidal
THREE MAJOR CATEGORIES: • Parathyroid adenoma
1. Tumors exhibiting follicular cell differentiation – 95% • Vascular human- high vascularization
2. Tumors exhibiting C- cell differentiation
3. Tumors exhibiting follicular and C-cell differentiation IHC
• Mirrors that of the normal follicle:
FOLLICULAR ADENOMA • LMWK, TPO, and thyroglobulin (cytoplasm) for TTF-1 and PAX8
(nuclei) and for laminin and other BM components around the
follicles
• Benign encapsulated
• LACKS: DIFFERENTIAL DX IHC
-­‐ Evidence of capsular, vascular, or any other type of NIFTP and Follicular- variant (-) for galectin – 3, HBME1 and
invasion papillary carcinoma CITED1 and the retention of
-­‐ Nuclear features of the papillary family of neoplasms CD56
• CLINICAL:
Solid/ trabecular growth from (+) Thryroglobulinand lack of
-­‐ euthyroid with a thyroid lump
medullary carcinoma calcitonin and CEA
-­‐ Thyroid scan usually “cold”, sometimes cool/ warm”,
Intrathyroidal parathyroid (+) thyroglobulin, TTF-1 (-)
rarely hot
adenomas chromogranin , parathyroid
• Associated with clinical hyperthyroidism (toxic/ Plummer
adenomas)
• ULTRASOUND: PROGNOSIS and TREATMENT:
-­‐ Well circumscribed • Removal by lobectomy
-­‐ Solid, isoechoic or hypoechoic with peripheral halo • Enucleation not recommended
(similar to follicular CAs) • Suppression of the nodules with levothyroxine and treatment of
• GROSS: the toxic adenoma with radioactive iodine- less than
-­‐ Solitary (except with genetically determined syndromes) satisfactory
-­‐ (+) capsule (complete)
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HYALINIZING TRABECULAR TUMOR & RELATED LESIONS

• Unclear relationship with malignancy

• Rare cases: May show invasion (capsule, vascular) and
metastasis
• Prominent trabecular arrangement and an equally prominent
hyaline appearance
• Hyaline: cytoplasm (accumulation of intermediate filaments),
extracellular space (deposition of hyalinized collagen fibers and
basement membrane material)
• may simulate that of paraganglioma and medullary carcinoma PAPILLARY MICROCARCINOMA
• (+) perinuclear clearing, nuclear grooves, and psammoma
bodies may suggest papillary carcinoma • common incidental finding
• cytoplasmic yellow body- 2-5um, pale yellow cytoplasmic • 1cm or less in diameter
inclusion body (paranuclear represents giant secondary • stellate configuration (formerly known as occult sclerosing
lysosomes) carcinoma or nonencapsulated sclerosing tumor) or partial or
• (+)Thyroglobulin and TTF-1 but (-) for calcitonin (+/-) HBME, near total encapsulation
galectin-3 and cytokeratin 19, focal (+) NSE, chromogranin • mutations in BRAF p,V600E and RET/PTC

PAPILLARY CARCINOMA FOLLICULAR VARIANT

• most common type of thyroid carcinoma and the most • composed of entirely or almost entirely of follicles
common endocrine malignancy • a.k.a. “Lindsay tumor”
• Females > males • Dx: PTC like nuclei
• Initial Dx approximately 40-50 years • Infiltrative follicular variant Papillary Carcinoma
• History of irradiation exposure in 5% • Devoid of a fibrous capsule
• Increase in incidence of Hashimoto’s • Partial remnants of capsule identified
• With infiltrative growth margins
GROSS:
-­‐ Microscopic to very large ENCAPSULATED FOLLICULAR VARIANT AND
-­‐ High proportion <1cm NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH
-­‐ Solid, whitish, firm and clearly invasive
PAPILLARY-LIKE NUCLEAR FEATURES
-­‐ 10-20% encapsulated
-­‐ marked cystic changes in 10%
-­‐ Sometimes papillary formations seen by naked eye • Surrounded by a capsule, follicular growth pattern (no
papillae),
NUCLEAR FEATURES (PTC- TYPE NUCLEI) nuclear alterations of papillary carcinoma
• Ground glass (optically clear) nuclei • “well- differentiated tumor of uncertain malignant potential
• Nuclear pseudoinclusions- invaginations of the cytoplasm (WDT- UMP)
sharply outlined (nuclear membrane bound) round • cytoarhitectureal alterations “incomplete/ focal” (+) galectin-3
acidophilic vacuoles and HBME-1 with questionable/ incomplete nuclear changes
• Nuclear grooves- infoldings of a redundant nuclear membrane that fall short of a diagnosis of papillary carcinoma
• Nuclear microfilaments- nuclear clearing due to accumulation • well- differentiated carcinoma, not otherwise specified (WDC-
of thread like fibrils NOS) – similar cases with invasion
• Mitoses- very scanty or absent • “noninvasive follicular thyroid neoplasm with papillary-like
nuclear features” (NIFTP)- to avoid overdiagnosis of CA
OTHER FEATURES: • Based on a 0-3 point scoring system conventional morphologic
• Extensive fibrosis- sharply outlined bands traversing the tumor features
• Psammoma bodies – ½ of cases, strongly suggests the diagnosis • If criteria met, the likelihood of the tumor recurring or
of papillary carcinoma, if found in non- neoplastic thryroid, metastasizing is less than 1%
chances are high (+) papillary CA near the vicinity • Encapsulated follicular variant of papillary carcinoma with
• Solid/ trabecular pattern in 20%, foci of squamous metaplasia in capsular and/or vascular invasion – when invasive
similar number
• Bland- looking spindle cell component

IHC
• (+) S- 100 protein- positive dendritic/ Langerhans cells and
macrophages
• (+) Thyroglobulin
• (+) pan- keratin, CAM 5.2, AE1/3 antibodies, with a CK 7
positive/ CK 20 negative profile, Low molecular weight CK19
• Vimentin (+)
• TTF-1 (+) PAX 8 (+) vs Lung adenocarcinoma PAX8 (-)
• Benign and malignant thyroid lesions
• (-) HBME-1, galectin -3, CK 19, CITED1, (-) CD 56

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SOLID VARIANT
• Particularly common in children
• Proliferation predominates over secretion
• Solid nests generally round shape that can be viewed as filled-
up follicles
• Nuclear features remain those of papillary carcinoma
SPREAD and METASTASES
• Extrathyroid extension – ¼ of cases
• Occasional spread into the parathyroid glands
• Cervical lymph nodes is very common (particularly in yound
patients), may be 1st manifestation
• Blood- borne metastases are less frequent most common sire is
the lung, they can also develop in bones, soft tissues, central
nervous system, pancreas, breast and many other organs

MACROFOLLICULAR VARIANT PROGNOSIS

• Excellent
• The opposite of the solid variant • Age- deaths occur if > 40 years; children and adolescents
• The secretory activity predominates over proliferation, resulting (good)
in large dilated follicles • Sex- female better prognosis
• Extrathyroidal extension- adverse incorporated to staging
system
DIFFUSE SCLEROSING VARIANT • Microscopic variants
• History of previous irradiation- not seem to differ significantly
• Diffuse involvement of one or both thyroid lobes from the others
• Sclerosis, abundant psammoma bodies, extensive solid foci, • Tumor size- inverse correlation to prognosis
squamous metaplasia, heavy lymphocytic infiltration and • Capsule and pushing margins- better outcome
extensive lymph vessel permeation • Multicentricity- metastasis
• Misdiagnosed as Hashimoto’s • Lymph node metastases- limited, extranodal tumor extension –
• (+) Nodal metastases, lung metastases poor
• Distant metastases
ONCOCYTIC (OXYPHILIC, WARTHIN –LIKE) VARIANT • Poorly differentiated- squamous or anaplastic foci detrimental
Effect
• TERT promoter- poor
• cytoplasm is abundant and has a granular oxyphilic quality
• papillary or follicular growth
• encapsulated or invasive HURTHLE CELL (oncocytic) Tumors
• may harbor the BRAF p.V600E mutation
• prognosis is poor? (accdg to Ackermann- generally very good)
• 3%- 4% of all thyroid carcinomas
• (over 75%) of follicular cells exhibiting oncocytic features
TALL CELL CARCINOMA • Females; adults
GROSS:
• Papillae lined by a single layer of “tall” cells (2-3x) width- - solid, tan and well vascularized can be ecapsulated
cordlike, running side to side MICROSCOPIC:
• abundant acidophilic (oncocytoid) cytoplasm - follicular, trabecular/ solid, or papillary, multinodular fashion thun
• older patients fibrovascular septa that simulate papillae when cut tangentially;
• more aggressive little stroma
• BRAF p.V600E mutation TERT promoter mutations in 30%
FOLLICULAR CARCINOMA
COLUMNAR CELL CARCINOMA

• rare variant • A malignant epithelial tumor showing evidence of follicular cell

• thin papillae or glandular-like spaces lined by an epithelium with differentiation but NO diagnostic nuclear features of papillary
carcinoma
prominent nuclear stratification
• cytoplasm is clear
EPIDEMIOLOGY
• nuclei- lack the optically clear appearance, grooves
• 10-15% if thyroid malignancy
• Ki-67/ MIB1 proliferative index may be very high
• more common in female and 5th decade
• rarely occurs in children
CRIBRIFORM- MORULAR VARIANT • incidence is higher in iodine- deficient areas
ETIOLOGY
• Rare • Iodine deficiency
• Cribriform pattern of growth and morular formations • Irradiation
• Round squamoid morular structures are characteristic finding GROSS
• Intraluminal colloid- scant/ absent • Single nodule that may be well circumscribed or widely
• Invasion of the tumor capsule or of vessels infiltrative
• Essentially similar to follicular adenoma
PAPILLARY CARCINOMA with EXUBERANT MICRO
• Composed of fairly uniform cells forming small follicles
FIBROMATOSIS/ FASCITIS- LIKE STROMA containing colloid
• Psammoma bodies are absent
• Stromal reaction may obscure the neoplastic component CLINICAL COURSE
• Misinterpratated as nodular fasciitis, fibromatosis, or some other • Slowly enlarging painless nodules
proliferative stromal condition • Cold nodules on scintigrams
• Mutations in beta- catenin and (+) B- catenin by IHC- biphasic • Vascular* *hematoegnous) dissemination is common with
nature spread to lungs, liver , bone, etc
FNAC – limited
SURVIVAL RATE

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• Minimally invasive follicular CA- 10 year survival rate > 90%
• Widely invasive follicular CA- 10 year survival rate is 50%
THE TNM SYSTEM
Classification according to Tumor, nods and metastases
MANAGEMENT of PAPILLARY & FOLLICULAR THYROID CANCER
1st Stage of Management
• Total thyroidectomy with central node dissection
• Radioactive iodine - 4 weeks after surgery
• Thyroid hormone supplementation

Primary tumor (p1) The most common causes of death are local recurrence and
pulmonary metastases
P1X cannot be assessed
P10 no evidence of primary tumor UNDIFFERENTIATED (ANAPLASTIC)
P11 Tumor size 2cm or less, limited to thyroid
P11a Tumor < 1cm in greatest dimension CARCINOMA
P11b Tumor 1-2 cm in greatest dimension
P12 Tumor >2cm to 4cm, limited to thyroid
P13 Tumor >4cm, limited to thyroid or any tumor • Undifferentiated (high grade) carcinoma of thyroid gland
extension • Also called carcinosarcoma, sarcomatoid carcinoma
P14a moderately advanced disease, tumor of any • Aggressive
size extending beyond they thyroid capsule to • Mortality rate approaches 100%
invade subcutaneous soft tissues, larynx, • Mean age of 65 years
trachea, laryngeal nerve • 20% have prior undifferentiated carcinoma
P14b very advanced disease , tumor invades • 20% have concurrent differentiated carcinoma (probably arises
prevertebral fasca or encases carotid artery or as anaplastic transformation)
mediastinal vessels • presents as a rapidly enlarging, bulky neck mass
• invades adjacent structures causing hoarseness, dysphagia,
Note: there is no category of carcinoma in situ to carcinoma of dyspnea
thyroid gland • highly necrotic and hemorrhagic solid tumor mass

All anaplastic carcinomas are considered T4 tumors PATTERNS OF ANAPLASTIC CARCINOMA

CRIBRIFORM- MORULAR VARIANT
T4a intrathyroidal anaplastic carcinoma: surgically resectable
• solid carcinoma, hyaline carcinoma, C-cell carcinoma
Regional Lymph Nodes
• neuroendocrine tumor derived from C cells (parafollicular
pNX cannot be assessed
cells)
pN0 No regional lymph node metastasis
• Either sporadic (nonhereditary) or hereditary (familial)
pN1a nodal metastases to level V1 (pretracheal ,
paratracheal and prelaryngeal/ delphian)
pN1b metastases to unilateral, bilateral or
SPORADIC 70% FAMILIAL 20-25%
contralateral cervical (Levels I,II,III,IV,V) or
retropharyngeal or superior mediastinal lymph - age 40-60 years - younger patients (mean
nodes (Level VII) - solitary - usually multiple and bilateral
- some have paraneoplastic - associated with C cell
Distant metastasis (pM) syndromes (diarrhea from VIP, hyperplasia
pM0 No distant metastasis Cushing’s syndrome) - MEN 2A or 2B (more
pM1 Distant metastasis - (-) hypercalcemia aggressive) syndromes, familial
medullary thyroid carcinoma
Papillary or follicular carcinoma staging syndrome, von Hippel-Lindau
Under 45 years 45 years and older disease or neurofibromatosis
- usually discovered by
Stage I Any T, any N, M0 pT1, N0, M0 screening test for serum
Stage II Any T, any N, M1 pT2, N0, M0 calcitonin or peripheral blood
Stage III pT3, N0, M0 Any pT, N1, M0 RET oncogene mutation
Stage IV pT4, N0, M0 Any pT, any N, M1 analysis

Undifferentiated or anaplastic carcinomas: all are stage IV GROSS

• Single or multiple
• Typically nonencapsulated
• Solid, gray-tan-yellow- firm, may be infiltrative
PROGNOSIS of PAPILLARY & FOLLICULAR THYROID CANCER
• Tumor usually in mid- or upper portion of gland
Poor prognosis
MICRO
• Male sex
• Round, polygonal or spindle cells in trabecular, follicular or
• Age > 40 years
pseudopapillary patterns
• Familu History
• Stroma has amyloid deposits from calcitonin
• Large size (> 4cm)
• Extrathyroidal extension
• Extensive vascular invasion
• Lymph node or distant metastases
• Poorly differentiated or widely invasive tumors

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 FAVORABLE PROGNOSTIC POOR PROGNOSTIC FACTORS
FACTOR
• Young age • Older age
• Female • Male
• Familial forms • Sporadic forms
• Microcarcinoma • Advanced tumor stage
• Poor reactivity to
calcitonin
• Cervical nodal metastases
• Small cell type

CLINICAL
• Invades locally
• Metastases to cervical and mediastinal nodes, lung, liver and
bone
• Metastases may be the initial presentation of disease and usually
contain amyloid

LABORATORY
• High serum calcitonin and chromogranin A levels
• Calcitonin – monitors recurrence

• 5-year survival: 70-80%

Positive stains:
• Ttf-1
• Low molecular weight keratin
• Chromogranin A and b
• Synaptophysin
• Neuron specific enolase
• Calcitonin
• Congo red for amyloid
• CEA
• Progesterone receptors
EPITHELIAL TUMORS

Negative for thyroglobulin

General Features:
• Geographic: Papillary carcinoma is the predominant type in
areas without iodine deficiency and its frequency is said to be
Management of Medullary thyroid cancer:
increased in regions with high iodine uptake
• Thyroid neoplasia in Childhood
1. Pre-operative investigation should include:
-­‐ benign follicular adenoma or nodular hyperplasia
-­‐ A baseline value for calcitonin
-­‐ the proportion of carcinomas is much higher than that
-­‐ At least one 24-hour urine sample assayed for
seen in adults
catecholamines and metanephrines, and a serum
• Thyroid Neoplasia and radiation exposure
calcium
-­‐ Nodular hyperplasia, lymphocytic thyroiditis and fibrosis
-­‐ RET mutation analysis
-­‐ Carcinoma à papillary type
-­‐ A stimulation test with calcium/pentagastrin – to confirm
a diagnosis of MTC pre-operatively in relatives of patients
• Core Needle Biopsy and Fine Needle Aspiration – quick and
with familial MTC
inexpensive initial test in the evaluation of any thyroid nodule
-­‐ Bethesda System for Reporting Thyroid Cytopathology
2. Treatment of MTC
• Frozen Section
-­‐ Total thyroidectomy and central compartment node
-­‐ Capsular and/or blood vessel invasion is typically not
dissection
evident in the samples choses for frozen sections
-­‐ Patients with pT2-4 tumors, or palpable lymph nodes in
the central or lateral compartment should in addition
undergo bilateral selective neck dissection of levels IIa-Vb
-­‐ In the absence of direct invasion, the sternomastoid PPT – based
muscle/internal jugular vein/accessory nerve should be
conserved *** special thanks to Doc Paulo for the ppt photos***
-­‐ Even in the presence of disseminated dissection surgery
(total thyroidectomy and central compartment node
dissection) should be considered of the trachea,
esophagus and recurrent laryngeal nerves
-­‐ Prophylactic surgery should be offered to disease-free
carriers of germ line RET mutations, identified by genetic
screening programs
-­‐ Children with MEN2B should undergo prophylactic
thyroidectomy within the first year of life

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