THYROID & PARATHYROID GLANDS

HURTHLE CELLS
o Azkanazy cells, oxyphilic cells, oncocytes
o Follicular cells with abundant granular acidophilic cytoplasm
o Granularly due to accumulation of mitochondria

C-CELLS/PARAFOLLICULAR CELLS
o Neuroendcorine cells
o Reach the thyroid via ultimobranchial body
o Middle and upper third of the lateral lobes
o Number varies according to age
o Numerous: infancy and old age
o Adult: no more than 10 C cells/LPF
o Immunoreactive for CEA

SOLID CELL NESTS (RESTS)

o Remnants of ultimobranchial body
o 0.1 mm average
o 90% of neonatal thyroid glands
o Composed of polygonal/oval cells admixed with clear cell
o Positive for high and low MW keratin and for CEA

CONGENITAL ABNORMALITIES

Thyroglossal duct anomalies

o Localized persistence of thyroglossal duct
o 2 forms:
 Sinus tract connect to foramen cecum or suprasternal notch
 Blind tubular structure

Thyroglossal duct cyst

o Cystic change are prominent
o Midline of the neck, region of hyoid bone
o Lined by pseudostratified ciliated/squamous epithelium
o Treatment: surgical removal
o To minimize recurrence: excision of the middle third of the hyoid bone and entire length of sinus tract

Heterotrophic thyroid tissue

o Base of the tongue - MC
o Anterior tongue, submandibular region, larynx, trachea, mediastinum, and heart
o Majority are found in WOLFLER AREA (Isosceles triangle with edge of the mandible at its base and the
concavity of aortic arch at apex)

Branchial pouch anomalies

o Present as patent fistula, simple sinus, blind cyst, island of cartilage
o Location: anterolateral region of the neck
o FIRST POUCH: Preauricular area/ beneath the posterior half of the mandible
o SECOND POUCH: Anterior to SCM in the mid-neck and have an open tract communicating with the
pharynx
o FOURTH POUCH: Lower neck, suprasternal or supraclavicular

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THYROIDITIS

ACUTE THYROIDITIS
o Infectious in nature
o Associated with acute infection of the upper aerodigestive tract, general sepsis, major trauma to the neck
with an open wound
o Malnourished infant, debilitated elderly, immunocompromised patient
o Common cause:
 Streptococcus haemolyticus
 Staphylococcus aureus
 Pneumococcus
o Other causes:
 Gram negative bacteria
 Fungi esp. Candida
 Penumocystis
o Morphologically
 Neutrophilic infiltration
 Tissue necrosis
o Diagnosis: fine needle biopsy with smear cytologic exam and culture
o Treatment: medical, surgical – drainage
o Best treatment: Fistulectomy

GRANULOMATOUS (de Quervain) THYROIDITIS

o AKA Subacute thyroiditis
o Middle-aged women with sore throat, painful deglutition, and marked tenderness on palpation in the
thyroid region
o Associated with fever and malaise
o Majority of cases there is complete resolution
o Unknown etiology
o Follows an infection of the upper aerodigestive tract

Autoimmune (lymphocytic and Hashimoto) thyroiditis

o Production of autoantibodies that alter thyroid function.
o One of the two major forms in which autoimmune thyroid disease may manifest
o Hashitoxicosis
o Immune-mediated insult >> diffuse or nodular hyperactivity of the gland >> exhaustion atrophy,
manifested by diffuse oxyphilia of the follicular epithelium.

Lymphocytic thyroiditis
o more commonly diagnosed in children
o ‘juvenile form’ of lymphocytic/autoimmune thyroiditis
o radioactive iodine uptake is generally low
o Gland is diffusely enlarged and of increased consistency, with a solid, white, vaguely nodular cut surface.

Hashimoto thyroiditis
o AKA struma lymphomatosa,
o Predominantly a disease of women over 40 years of age.
o Diffuse firm thyroid enlargement, accompanied by signs of tracheal or esophageal compression.
o Complications:
 malignant lymphoma and leukemia
 papillary carcinoma

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  Hürthle cell neoplasms

o Treatment: depends on its severity

 Mild cases no therapy is needed.

Multifocal sclerosing thyroiditis

o Characterized by multiple (sometimes innumerable) foci of fibrosis throughout the gland, often having a
radial configuration.
o LPO: the appearance can be indistinguishable from that of papillary microcarcinoma
o HPO: lack of a neoplastic glandular component.
o The pathogenesis of this lesion is obscure

HYPERPLASIA

Table 1.Major types of thyroid hyperplastic disorders

NAME MECHANISM PATHOLOGY FUNCTIONAL STATUS
Dyshormonogenetic Genetically Nodular or (less frequently) Hypothyroid
goiter determined error in diffuse hyperplasia
TH metabolism
Graves disease Autoimmune Diffuse hyperplasia Hyperthyroid
Nodular hyperplasia      
 Endemic goiter Iodine deficiency Nodular hyperplasia (preceded Usually euthyroid; sometimes
by a transient phase of diffuse hypothyroid
hyperplasia)
 Sporadic goiter Unknown Nodular hyperplasia Usually euthyroid; sometimes
hyperthyroid or hypothyroid

Dyshormonogenetic goiter
o Defects in hormone synthesis >> Types of goiter
 Lack of responsiveness to TSH
 Defects in iodide transport
 Defects in organification
 Defects in coupling
 Abnormalities of thyroglobulin synthesis and secretion
 Defects in deiodinase
 Abnormalities in the transport of TH

Graves disease (diffuse toxic goiter)

o AKA Basedow dse, thyrotoxicosis, diffuse toxic goiter, and exophthalmic goiter
o Young adult females with muscle weakness, weight loss, irritability, tachycardia, goiter, and often a great
increase of appetite.
o Exophthalmos (ophthalmopathy) is present in 25–50% of the patients.
o Most common cause of hyperthyroidism.

Nodular hyperplasia
o AKA nodular or multinodular goiter, adenomatoid goiter, adenomatous hyperplasia
o Most common thyroid disease.

A. Endemic goiter
o Due to low iodine content of the water and soil
o Parencymatous goiter
 Increased TSH secretion

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  hyperactive thyroid with tall follicular epithelium and small amounts of colloid

o Diffuse or nodular colloid

 Follicular atrophy with massive storage of colloid, with or without nodularity

B. Sporadic (nodular) goiter

o Pathogenesis remains unknown.
o Etiologies: Mild dietary deficiency of iodine, slight impairment of hormone synthesis, increased iodide
clearance by the kidneys, presence of thyroid-stimulating immunoglobulins, and increased production of
insulin-like GF I
o Incidence: 3–5% clinically and 50% at autopsy.
o Degree of thyroid nodularity is directly related to the duration of the disease.
o Treatment:
 If mild, no treatment.
 Suppressive therapy with exogenous thyroid hormones is only moderately effective
 Symptomatic: bilateral subtotal thyroidectomy
 Table 2. Differential diagnosis: nodular hyperplasia vs true adenoma

Table 2 Differential diagnosis: nodular hyperplasia vs true adenoma

Adenoma Nodular hyperplasia

Single
Totally surrounded by a capsule
Dissimilar from the remaining parenchyma
Compresses the adjacent tissue
Composed mainly of follicles that are smaller than
those of the normal gland
Lesion is almost always one of many nodules
Encapsulation is incomplete
Follicular size is variable
No compression of the adjacent parenchyma.
Some or all of the follicles are larger than those in the
surrounding gland

TUMORS

The majority of clinically apparent thyroid neoplasms are primary and epithelial.

Three major categories:

1. Tumors exhibiting follicular cell differentiation
2. Tumors exhibiting C-cell differentiation
3. Tumors exhibiting follicular and C-cell differentiation.

Lesions in the first category comprise more than 95% of the cases, the remainder being largely made up by tumors
in the second category.

EPITHELIAL TUMORS – SPECIFIC TYPES

FOLLICULAR ADENOMA
o benign encapsulated tumor that shows evidence of follicular cell differentiation
o lacks:
1. evidence of capsular, vascular or any other type of invasion; and
2. The nuclear features of the papillary family of neoplasms.
o most common thyroid neoplasm
o Most patients are euthyroid adults who initially have a thyroid lump
o The large majority of ‘hot’ nodules are benign

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 o elevated circulating levels of thyroglobulin,
o few are associated with clinical hyperthyroidism: toxic or Plummer adenomas
o The thyroid outside hyperfunctioning nodules: contains intraluminal crystals of calcium oxalate
o Adenomas are almost always solitary
o surrounded by a thin capsule that is grossly and microscopically complete
o may exhibit a variety of patterns
a. normofollicular (simple),
b. macrofollicular (colloid),
c. microfollicular (fetal), and
d. trabecular/solid (embryonal)
o Mitoses are rare or absent
o Secondary degenerative changes:
 Hemorrhage
 Edema
 Fibrosis
 Calcification
 bone formation
 cystic degeneration
o muscular cushions: the vessels in the capsule show prominent focal thickenings of their wall
o microscopic appearance of a follicular adenoma and its activity:
a. hyperfunctioning (hot) adenomas
 more cellular and their cells have more abundant cytoplasm
 decreased nucleocytoplasmic ratio
 have activating mutations of TSHR or of its downstream effector GNAS1
b. Nonfunctioning (cold) tumors
o Chromosomal translocations
 identified in approximately 10% of FA
a. Chromosome 19q13, with the breakpoint at the ZNF331 gene locus,
b. chromosome 2p21, with the breakpoint at the thyroid adenoma associated (THADA) gene
locus

Differential diagnosis:
1. nodular hyperplasia
2. minimally invasive follicular carcinoma,
3. follicular variant of papillary carcinoma

Treatment
o Standard therapy: removal by lobectomy
o Levothyroxine: Suppression of the nodule
o 131I : toxic adenoma

PAPILLARY CARCINOMA

General features:
o most common type of thyroid malignancy.
o Females are more affected than males
o mean age at the time of initial diagnosis: 40 years
o > 90% of thyroid malignancies in children
o 5–10%: (+) history of irradiation exposure to the neck

Gross features
o The size of the primary tumor ranges from microscopic to huge.

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 o A very high proportion of thyroid cancers measuring less than 1 cm in diameter are of papillary type.
o solid, whitish, firm, and clearly invasive;
o <10% are surrounded by a complete capsule

Microscopic features
o contains numerous true papillae
o papillae are usually complex, branching, and randomly oriented,
o with a central fibrovascular core and a single or stratified lining of cuboidal cells
o stroma
 edematous or hyaline
 may contain lymphocytes, foamy macrophages, hemosiderin, adipose tissue
o follicles tend to be irregularly shaped, often tubular and branching
o Nuclear features (which we will herein refer to as PTC-type nuclei) consist of:
1. Ground glass (optically clear) nuclei
 nucleolus is usually inconspicuous and pushed against the nuclear membrane, which appears
thickened
2. Nuclear pseudoinclusions
 invaginations of the cytoplasm
 appear as sharply outlined (nuclear membrane-bound) round acidophilic vacuoles
3. Nuclear grooves.
 occur in oval or spindle nuclei
4. Nuclear microfilaments.
o Mitoses are very scanty or absent
o Over half show extensive fibrosis
o Elastic tissue is usually abundant in the tumor stroma
o Psammoma bodies are seen in approximately half of the cases
o contain a bland-looking spindle cell component;
o Lymphocytic infiltration

Electron microscopic features

o most distinctive feature: highly indented nuclear membrane, with formation of pseudoinclusions and
multilobation.
o cytoplasm is rich in mitochondria, lysosomes, and intermediate filaments.

Histochemical and immunohistochemical features

o reactive for pan-keratin stains
o usual profile: CK7+/CK20
o Potentially greater diagnostic importance: stain for cytokeratin 19 and keratin demonstrated with 34ßE12.
o Reactive for thyroglobulin and TTF-1: Most specific markers
o The luminal surface of the tumor cells is covered by a glycoproteinaceous material that reacts positively
with mucin stains (such as Alcian blue) and EMA

Molecular genetics features

o Activation of the mitogen-activated protein kinase (MAPK) pathway
 consequence of three distinct events:
1. gene rearrangements (RET/PTC or the less common TRK rearrangements)
2. BRAF
3. RAS activating mutations
o Rearrangements
 occur in 20–40% of papillary carcinomas,
 majority involve RET
1. NTRK1

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  a gene encoding a transmembrane tyrosine kinase receptor that binds the nerve growth factor
 much less common than RET/PTC rearrangements: 5% of Pca
 The mechanisms responsible for NTRK1 activation are the same as those described for RET: intra- or
interchromosomal recombination of the NTRK1 locus at 1q22, fusion of NTRK1 to heterologous
genes producing chimeric oncogenes, aberrant expression, and ligand independent activation of the
NTRK1 tyrosine kinase.
2. BRAF
 30–70% of Pca
 most common molecular alteration
 a serine–threonine kinase in the MAPK pathway activated by RAS,
 represents the most important isoform in follicular cells
 The vast majority (>90%) of BRAF mutations:
 thymidine to adenine transversions in the nucleotide 1799 (T1799A) of exon 15 that cause a
valine to glutamate substitution at residue 600 (V600E) of the protein activation loop
3. RAS
 In the thyroid, RAS mutations are a marker for follicular-patterned thyroid lesions, being typically
associated with follicular adenomas and carcinomas

Spread and metastases

o Extrathyroidal extension into the soft tissues of the neck
o Involvement of cervical lymph nodes is very common (particularly in young patients), and it may be the
first manifestation of the disease.
o Blood-borne metastases are less frequent
o most common site is the lung

Prognosis
o The overall survival of patients with papillary carcinoma is excellent.

FOLLICULAR CARCINOMA

Generalities and molecular genetic features

o any malignant thyroid tumor exhibiting evidence of follicular cell differentiation.
o Poorly formed follicles, cribriform areas, or trabecular formations may be present,
o Mitotic activity and nuclear atypia are usually seen
o Psammoma bodies are absent,
o Immunohistochemically:
 reactive for thyroglobulin, TTF-1, low molecular weight keratin, EMA, and basement membrane
components such as laminin and type IV collagen.
o At a molecular genetic level, follicular carcinomas share with follicular adenomas a common tumorigenic
pathway, characterized by aneuploidy and by the frequent occurrence of RAS mutations
o The most common oncogenic mutations are those that involve RAS
o almost always solitary and only exceptionally occult.
o Metastases are usually blood-borne
 most common sites are lungs and bone
 can be seen in kidney and skin.

HÜRTHLE CELL (ONCOCYTIC) TUMORS: THE ONCOCYTE

o common denominator for all the tumors

o cytoplasmic granularity is due to the accumulation of mitochondria,
o Secondary clearing is not uncommon, usually due to mitochondrial swelling.
o Immunohistochemically,

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  reactivity for thyroglobulin (although to a lesser degree than non-oncocytic follicular cells), many
mitochondrial antigens, glucose transporter 4 (GLUT-4), and keratin
 CK14 is emerging as a selective marker for these cells
 also immunoreactive to CEA, S-100 protein and HMB-45

o The total amount of mitochondrial DNA (mtDNA) is increased

o Most patients are adults, and there is a predominance of females.
o Grossly, the tumors are:
 solid, tan, and well vascularized
 well encapsulated throughout;
 invasive tumors tend to grow into the parenchyma in a multinodular fashion that can be very
deceptive in that it can be underinterpreted as nodular hyperplasia.
o Microscopically:
 the pattern of growth may be follicular, trabecular/solid, or papillary.
 follicles, when large, are separated by long and thin fibrovascular septa that simulate papillae when
cut tangentially.
o Another diagnostic trap:presence of inspissated intraluminal colloid with concentric laminations
o Nuclei: pleomorphism and prominent nucleoli, with occurrence of isolated bizarre forms
o Immunohistochemically: reactivity for thyroglobulin
o capsular and/or blood vessel invasion should be used as the main criterion for malignancy.
o tendency to undergo massive infarct-type necrosis, often following fine needle aspiration.
o Hürthle cell adenomas are almost always cured by excision.
o carcinomas are rather aggressive neoplasms, with a 5-year mortality rate ranging between 20% and 40%
o Metastases: mainly in lungs and bone and less commonly in cervical node
o Older patient age, large tumor size, extrathyroidal extension, extensive vascular invasion, and metastases
represent unfavorable prognostic factors

CLEAR CELL TUMORS

o consequence of a variety of mechanisms, which include cytoplasmic vesicles (of mitochondrial, reticulum
endoplasmic, or Golgi origin) and accumulation of glycogen, lipid, thyroglobulin, or ‘mucin’
o Hürthle cell tumor
 most prone to undergo secondary clear cell changes,
 result of vesicular swelling of mitochondria
o can also occur in follicular adenomas and carcinomas (usually because of vesicles of either mitochondrial
or granular endoplasmic reticulum derivation), papillary carcinoma (usually because of glycogen
accumulation), undifferentiated carcinoma (also the result of glycogen overload), and – exceptionally –
medullary carcinoma.
o Except for the latter, thyroglobulin stain is usually positive in these neoplasms, although sometimes in a
focal and faint fashion.
o it occurs more frequently in carcinomas than in adenomas
o A peculiar variant: signet ring type
 formation of variously sized cytoplasmic vacuoles results in a configuration reminiscent of signet ring
cells or lipoblasts
 Most are adenomas
 Immunohistochemically,
 Vacuoles: contain intracellular thyroglobulin
 Stroma: heavily hyalinized and with punctate calcification, suggesting that the signet ring
change may be of degenerative nature and the expression of an arrest of folliculogenesis.
 found to react positively with mucin stains
o Differential diagnosis: parathyroid neoplasms and metastatic renal cell carcinoma

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  both of these lesions can be intrathyroidal, whereas thyroid clear cell tumors can occur in ectopic
locations.
o can also occur in non-neoplastic thyroid disorders, including Hashimoto thyroiditis and
dyshormonogenetic goiter.

Squamous Cell, Mucinous, And Related Tumors

Mucoepidermoid carcinoma
o low-grade thyroid neoplasm combining foci of squamous change with mucin production and lacking
immunoreactivity for thyroglobulin
o originate from solid cell nests, which in turn are thought to be of ultimobranchial body derivation. [723,734]
o The clinical features:
 presence of ground glass nuclei and psammoma bodies
 P-cadherin neoexpression and the marked abnormalities of the E-cadherin/catenins complex
o Distinctive variant: sclerosing mucoepidermoid carcinoma with eosinophilia
 arises in thyroid glands affected by Hashimoto thyroiditis, often of the fibrous type
 Microscopically,
 strands and nests of squamous tumor cells with mild to moderate pleomorphism
 infiltrating a dense fibrohyaline stroma.
 constant and often striking infiltration by eosinophils
 Immunohistochemically
 strong reactivity for keratin, but only focally if at all for TTF-1,
 none for thyroglobulin
 The clinical course is generally indolent, but cases with distant metastases and aggressive behavior
have been reported.
 Lymph node metastases may simulate microscopically Hodgkin lymphoma.

Poorly Differentiated Carcinoma: Insular Carcinoma

o occurs in an older group than the well-differentiated tumors
o grossly invasive
o Microscopically
 nesting (‘insular’) pattern of growth,
 solid to microfollicular arrangement,
 small uniform tumor cells,
 variable mitotic activity
 fresh tumor necrosis resulting in a peritheliomatous pattern
o Immunohistochemically
 reactive for thyroglobulin and TTF-1 but not for calcitonin
 focal reactivity for neuroendocrine markers
o Cytologic features
 high cellularity, necrotic background, low grade of atypia, nests, trabeculae and microfollicles, and
cytoplasmic vacuoles.[751,764]
 generally aggressive, with a high incidence of both nodal and blood-borne metastases.
o Complex karyotypic alterations and aneuploidy are frequent with a median number of chromosomal DNA
alterations detectable by CGH
o Inactivating TP53 mutations occur in approximately one-fourth of cases, high enough to link loss of p53
o RAS mutations are frequently detected have been associated with poor prognosis and with the less
differentiated components of the tumor

Undifferentiated Carcinoma: Anaplastic Carcinoma

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 o elderly patients
o rapidly growing mass associated with hoarseness, dysphagia, and dyspnea.
o Extrathyroidal extension is encountered at the time of initial presentation
o Grossly, a highly necrotic and hemorrhagic solid tumor mass is seen replacing large portions of the organ

o Microscopically
1. Squamoid
 it does not make follicles, papillae, or even trabeculae or nests, but the tumor still retains an
unmistakable epithelial appearance on morphologic and immunohistochemical grounds.
2. Sarcomatoid: spindle cell and giant cell
 exhibit a fascicular or storiform pattern of growth, heavy neutrophilic infiltration, prominent
vascularization, and divergent differentiation into bone, cartilage, and skeletal muscle.
 Osteoclast-like multinucleated giant cells may be present

o Common and diagnostically useful features:

 palisading at the necrotic edges
 tendency to invade the wall of veins, replacing the normal smooth muscle

o Immunohistochemically,
 the most useful marker for confirming the epithelial nature is keratin (expressed in 50–100% of
cases)
 Vimentin is consistently present in the spindle cell component
 scattered stromal (basement membrane-related) reactivity for laminin,
 focal EMA and CEA positivity may be found, especially in the squamoid type.
 TTF-1 is generally negative

o Gene mutations
 typically aneuploid, have complex karyotypes by conventional cytogenetics and high rates of
chromosomal DNA alterations detected by CGH
 Inactivating TP53 mutations are found in the majority of cases
 have been correlated with widespread nuclear accumulation of p53 throughout the tumor.
 Stabilizing mutations of the CTNNB1 gene coding for ß-catenin prevent its cytoplasmic degradation
and activate Wnt signaling by allowing ß-catenin to localize to the nucleus.
 RAS mutations are common
 RET/PTC and PAX8/PPAR? are not usually found
 The PI3K/PTEN/AKT pathway is altered by loss of function PTEN mutations or by activating mutations
of the PIK3CA gene
o The evolution of all types of undifferentiated thyroid carcinoma is very rapid, with massive growth in the
neck and infiltration of the ribbon muscles, esophagus, trachea, skin, and even contiguous bones.
o Tracheal extension may simulate a primary tracheal tumor
o Nodal and distant metastases are also common
o Mortality rate is over 95%
o Mean survival is less than 6 months
o Immediate cause of death is usually involvement of vital structures in the neck

MEDULLARY CA

o composed of C (parafollicular) cells

o mostly located in the midporiton or upper half of the gland
o described also as
 solid CA w/ amyloid stroma

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  hyaline CA
 C-cell CA
o medullary microCA - greatest diam of 1cm or less
o gross: solid, firm, nonencapsulated, but relatively well circumscribed

o classic microscopic presentation:

 solid prolif of
 round to polygonal cells of
 granular amphophilic cytoplasm and
 medium sized nucleus
 separated by highly vascular stroma
o gray to yellowish cut surface
o enveloped medullary CA - enveloped by continous fibrous capsule
o patterns of growth
 carcinoid-like
 paraganglioma -like
 trabecular
 glandular (tubular and follicular)
 pseudopapillary
o stroma
 scanty
 hemorrhagic
 ossified
 edematous
o tumor cells
 plasmacytoid - w/ nuclear peripheralization
 spindle-shaped
 oncocytic - resemblance to Hürthle cell neoplasms of follicular cell derivation
 squamoid
 squamous
 bizarre - anaplastic or giant cell-type
o diagnosis - suspected if
 cells are amphophilic
 tumor is divided into nests by sharply outlined fibrous bands
o cytologic features: FNA preps
 eccentric nuclei
 neuroendocrine-type chromatine
 inconspicuous nucleoli
 bi- and multinucleated cells
 ill-defined cell borders
 clean background
 *amyloid mat’l
o histochemical features
 cytoplasmic dense-core secretory granules - argyrophilic w/ Grimelius stain
 (+) w/ mucin stain
o immunohistochemical features
 tumor cells are reactive for calcitonin
 (+) for CEA
 generally (-) for thyroglobulin

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Hereditary medullary CA and C-cell hyperplasia

2 forms of medullary CA
o sporadic
 80%
 adults (mean age, 45)
 almost always solitary
 presents as thyroid mass - cold on thyroid scan
 sometimes accompanied by intractable diarrhea or Cushing syn
o inherited
 AD
 young age (mean age, 35)
 multiple, bilateral
 invariably accompanied by C-cell hyperplasia
 diagnosed at microCA stage
 almost all cases of medullary CA in children
 gene involved is the RET gene on chromosome 10q11.2
 occurs in 3 settings
 multiple endocrine neoplasia (MEN) - medullary CA is usually the first manifestation
 type 2a
 type 2b
 isolated (familial medullary thyroid CA syn, FMTC)

C-cell hyperplasia
o precursor lesion
o typically in the central part of the lateral lobes
o indicator: >6 cells per per thyroid follicle
o nodular form - only definite precursor for the hereditary type of medullary CA
o hyperplastic C cells - greater immunoreactivity with
 CEA than N cells
 calcitonin than medullary CA
 elevated serum calcitonin and CEA; (+ chromogranin A for those w/ medullary CA)
o DDx
 early medullary CA (microCA)
 nesting expansile pattern
 destruction fo follicular BM
 diminished calcitonin immunostaining intensity
 reactive or physiologic C-cell hyperplasia
 immediate periphery of thyroid neoplasms
 in assoc w/ lymphocytic thyroiditis
 2ndary hyperPTH
o spread and metastasis
 local: cervical and mediastinal LNs
 distal: lung, liver & skeletal sys
 more common in sporadic and MEN2b than 2a
o tx and prognosis
 primary: surgical
 total thyroidectomy - impt for the familial form
 cervical lymphadenectomy
 persistent or recurrent elevation of serum calcitonin after surgery indicates tumor
persistence or relapse
 good prognostic fxs:

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  young age
 female
 familial setting
 tumor size
 tumor confinement to the gland
 poor prognostic fxs
 of sporadic cases
 older age at detection
 more advance tumor stage at dx
 as to immunoreactivity
 poor calcitonin reactivity
 esp if w/ increased CEA reactivity
 excellent prognosis: small medullary CA in phrophylactic thyroidectomies
 greater deg of aggressiveness expected in those w/
 high mitotic activity
 necrosis
 squamous patern
 w/ desmoplastic rxn
 small cell type

Other Neuroendocrine Tumors

o Medullary (C-cell) adenoma - encapsulated variants of medullary CA
o Mixed medullary-follicular CA - morphologic immunoreactivity features of medullary (calcitonin) and
follicular neoplasm (thyroglobulin) coexist
o Mixed medullary-papillary CA
o Paraganglioma
 reacts for panendocrine markers
 (-) for calcitonin and thyroglobulin
 useful feature: presence of S-100 protein-(+) sustentacular cells at the periphery of the ‘Zellballen’
o Small cell (neuroendocrine) CA
 morphologically identical to the homonymous lung tumor in the thyroid
 small cell variants of medullary CA

Epithelial Tumors

o geographical features
 correlation bet iodine def and increased incidence of thyroid CA of both follicular and
undifferentiated types
 iodine def - suggested modulating agent for RAS oncogene mutations
 papillary CA
 predominant type in areas w/o iodine def
 freq increased in regions w/ high iodine uptake

o thyroid neoplasia in childhood

 most are benign
 either follicular adenoma or nodular hyperplasia
 rank
 papillary CA
 majority of cases
 extensive solid and/or squamous areas
 assoc w/ high freq of cervical node metastases
 overall prognosis is excellent

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  hereditary form of medullary CA
 Hürthle cell neoplasms

o thyroid neoplasia and radiation exposure

 MC result of low-dose therapeutic radiation of the thyroid gland
 benign nature
 nodular hyperplasia
 lymphocytic thyroiditis
 fibrosis
 inc incidence of CA, majority of the papillary type
 high-dose radiation exposure
 thyroid CA, particularly the papillary type and with RET/PTC rearrangement
 differentiation pattern among children
 follicular - exposed at a young age
 papillary - exposed at a later age
 RET/PTC3 - assoc w/ papillary CAs that are more aggressive
 larger tumor size
 higher stage
 solid architecture

o familial incidence
 5% of thyroid CAs
 of nonmedullary type
 2 groups
 predominance of nonthyroid tumors
 familial adenomatous polyposis including Gardner syn (colonic polyposis)
 Cowden/PTEN hamartoma tumor syn
 Carney complex type I
 McCune-Albright syn
 Werner syn (adult progeria)
 MEN1
 predominance of non-thyroid tumors - pure familial papillary thyroid CA (fPTC)
 w/ or w/o oncocytic features
 w/ renal cell CA
 w/ nodular hyperplasia

o solitary solid nodule, evaluation of

 4x more common in females
 majority are benign, most are not even neoplastic
 fxs to consider
 age - malignancy higher in children and the elderly
 sex - malignancy higher in males
 Hashimoto thyroiditis
 neck irradiation - likelihood of malignancy higher if w/ hx of irradiation to the neck in infancy
 number - solitary are more likely to be malignant than multiple ones
 rate of growth - rapid enlargement of a long-standing nodule may signify either
 an undifferentiated (anaplastic) transformation or
 development of hemorrhage w/in the nodule
 assoc ipsilateral adenopathy - strongest clinical indicator of malignancy
 function - hyperfunctioning (‘toxic’) and/or hot on thyroid scan are much less likely to be malignant
 ultrasonography - cystic nodules are less likely to be malignant than solid ones
 CT and MRI - MRI is superior to CT for evaluation of metastatic, retrotracheal, or mediastinal lesions

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  serum thyroglobulin levels
 elevated w/ papillary and esp follicular CA - for monitoring after removal of
 N w/ medullary or undifferentiated CA

o core needle biopsy and FNA

 CNB
 helpful in diffuse dses and confirming the dx of an advanced malignant neoplasm
 DDx bet a benign and malignant is usually impossible
 but is able to demonstrate 2 main histologic criteria of malignancycapsular and vascular
invasion

 FNA
 popular
 quick and inxexpensive
 minimal risk of complications
 partial or complete infarction of the tumor particularly w/ Hürthle cell tumors, and
may result in transient elevation of serum thyroglobulin
 hemorrhage & thrombosis w/c may lead to pseudoangiosarcomatous papillary
endothelial hyperplastic changes
 dev’t of thyrotoxicosis when carried out in cystic lesions
 suitable for immunohistochemical eval
 sensitivity and specificity over 90%
 initial test in the eval of any thyroid nodule
 main difficulty - identification of well-differentiated follicular CA

o frozen section
 specimen either from
 an area of extrathyroidal invasion or
 metastatic cervical node
 MC specimen received is a lobectomy - in majority of the cases, the DDx will be between
 a dominant nodule of nodular hyperplasia
 adenoma, and
 CA
 difficulty in the distinction bet a
 dominant nodule of nodular hyperplasia
 follicular adenoma
 minimally invasive follicular CA
 variant of papillary carcinoma that is both follicular and encapsulated
 ground glass nuclear feature of papillary carcinoma may not show
 most useful in lesions interpreted by FNA as ‘suspicious for papillary carcinoma’
 diagnostic adjunct

o presence of thyroid tissue outside gland

 normal or abnormal
 ectopic thyroid tissue resulting from faulty embryogenesis - MC are
 thyroglossal duct cyst and
 lingual thyroid
 hyperplastic thyroid tissue in Graves disease
 mechanical implantation
 sequestered thyroid nodule
 aka parasitic or accessory nodule

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  peripherally located thyroid nodule in w/c either the anatomic connection with the main gland
is lost or missed by the surgeon
 usually an expression of nodular
 hyperplasia or
 Hashimoto thyroiditis
 dx criteria
 reside in the same fascial plane as the thyroid gland
 unassociated with LNs
 same or similar histologic appearance as the main gland
 thyroid tissue within cervical lymph nodes
 may be the result of two unrelated processes
 most cases represent metastases of clinically undetected thyroid carcinomas, nearly
always papillary
 normal follicles within nodes
© typically presents as a small conglomerate of follicles lacking all the attributes
of papillary carcinoma and limited to the periphery of one or two nodes
© thyroid tissue replacing most of the node and/or involving several nodes is
likely to be metastatic CA
 as a component of teratoma
 may appear normal or hyperplastic
 struma ovarii - ovarian teratomas composed predominantly or exclusively of thyroid
tissue

o treatment
 mostly surgical
 nodule limited to one lobe: lobectomy (with or without isthmusectomy)
 initial approach
 adeq for follicular adenoma, including Hürthle cell adenoma
 subtotal thyroidectomy - for most minimally invasive follicular CAs and papillary CAs
 total thyroidectomy
 followed by radioactive iodine admin - MC therapy for differentiated thyroid CA
 for the high-risk group of
 papillary CAs
 widely invasive follicular CAs
 poorly differentiated CAs, and
 medullary CAs (particularly familial)
 radical neck dissection - recommended for medullary CA
 external radiation therapy - for incompletely excised tumors

o prognosis
 most impt clinical and pathologic factors
 age
 sex
 tumor microscopic type
 tumor microscopic grade
 tumor stage
 survival rates:
 low risk
 men under 40
 women under 50
 high risk - others

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 o majority of deaths from thyroid CAs result from
 undifferentiated
 poorly differentiated
 Hürthle cell, and
 medullary tumors

Lymphoid Tumors and Tumor-like conditions

Primary malignant lymphoma of the thyroid

o MC seen in adult or elderly females
o thyroid enlargement
 rapid
 can lead to tracheal or laryngeal compression
o euthyroid
o one or more cold nodules on thyroid scan
o gross: solid white cut surface with a fish-flesh appearance
o microscopic
 majority of the diffuse large B-cell type
 low-grade lymphomas composed of small or ‘intermediate’ lymphocytes, having either a diffuse or a
nodular (follicular) growth
 belong to the MALT-type category (‘marginal zone B-cell lymphomas’) - result of colonization of the
follicles by the tumor cells
 lymphoepithelial lesions
 important diagnostic finding
 packing of follicular lumina by lymphoid cells
 high proportion arise in a background of lymphocytic or Hashimoto thyroiditis
 localization
 restricted to the thyroid
 spread to the soft tissues by direct extension, or
 involve the regional nodes.
 prognosis is better for marginal zone B-cell lymphomas than for diffuse large BCL
 tx
 thyroidectomy followed by adjuvant therapy
 treatment failures result from distant recurrences MC in the GIT

Plasmacytoma of thyroid
o component of widespread myeloma
o entirely composed of plasma cells of various degrees of maturity
o tumors with a lymphoid component - malignant lymphoma
o distinguished from plasma cell granuloma
 non-neoplastic condition
 mature plasma cells seen admixed with other inflammatory cells
 in a fibrotic background

Langerhans cell histiocytosis

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 o histiocytosis X / eosinophilic granuloma
o occurs w/ lymphocytic/Hashimoto thyroiditis

Extramedullary hematopoiesis - in pxs with myelofibrosis

Mesenchymal Tumors

Benign mesenchymal tumors - severe hypothyroidism can accompany infantile hemangioma of liver and other
sites as a result of degradation of thyroid hormone in the tumor tissue by type 3 iodothyronine deiodinase activity

Sarcomas
o leiomyosarcomas - in a setting of immunodeficiency in association with EBV
o most sarcoma-like thyroid tumors are of the spindle or giant cell types of undifferentiated CA
o thyroid angiosarcoma
 exhibit attributes of angiosarcoma
 anastomosing vascular channels
 Weibel–Palade bodies
 immunoreactivity for endothelial cell markers, and
 tendency to produce hemorrhagic pleuropulmonary metastases
 keratin-positive epithelioid angiosarcomas - with
 epithelioid morphology and
 immunoreactivity for keratin

Other Primary Tumors and Tumor-like Conditions

Teratomas of thyroid
o usually in neonates, infants or children
o majority: cystic and benign
o neural tissue - predominant component
o can lead to obstruction of the airway

Neuroblastomas - distinguished from the much more common teratomas with immature neural elements

Amyloid tumor (‘amyloid goiter’)

o unilateral or bilateral
o commonly foreign body-type reaction.
o amyloid deposits often accompanied by mature adipose tissue

Metastatic Tumors
o occur in
 carcinomas of pharynx, larynx, trachea, or esophagus
 metastatic lesions from adjacent cervical LNs

o majority: squamous cell type

o metastases in the thyroid

 MC sites for the primary tumor: skin (melanoma), breast, kidney and lung
 MC solitary

o metastatic renal cell CA

 rare for metastases to the thyroid to simulate clinically a primary thyroid neoplasm
 can present as a thyroid mass in the absence of renal symptoms

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  features of diagnosis
 multiplicity of the nodules
 optically clear (as opposed to finely granular) cytoplasm
 sinusoidal-type blood vessels
 intraluminal fresh hemorrhage (‘bloody glands’), and a
 large amount of cytoplasmic glycogen and fat

Parathyroid Glands

Normal Anatomy
o Composed of 4 small oval resilient glands
o Located behind the thyroid gland, one at each end of the upper and lower poles, usually in the capsule that
covers the lobes of the thyroid.
o Sometimes they are embedded in the thyroid gland
o Average of 4x 3x 1.5 each gland
o Total weight of about 0.4g
o Any individual gland with an excess of 50mg represents an enlargement
o Color: varies from reddish brown to light tan to yellow, depending on fat content, which in turn depends
on age, nutrition, and activity of the individual.

Embryology
The 2 pairs of the parathyroid glands are derived from the branchial (pharyngeal) pouches:
a. Superior glands
 fourth branchial cleft and descends into the neck with the thyroid gland during embryonic life.
b. Inferior glands
 third branchial cleft and descends into the neck with the thymus.

Normal Histology

A. Chief Cells
o Secrete PTH
 measures 6–8 µm in diameter
 Polyhedral cells
 has a centrally located nuclei
 a moderate amount of pale granular cytoplasm.
 variable amounts of glycogen particles and secretory droplets

B. Oxyphil Cell
o appear after puberty
o larger than chief cells
o has a more abundant cytoplasm, which is deeply granular and acidophilic.
o there are many mitochondria but few secretory granules
o These oxyphilic cells are often present in the form of nodular collections.

C. Transitional oxyphil cells

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 o intermediate between chief cells and oxyphil cells

D. Water-clear cells
o rarely if ever seen in the normal gland
o characterized by abundant optically clear cytoplasm and sharply defined
o cell membranes
o cytoplasm is packed with glycogen

E. Transitional water-clear cells

o intermediate between chief cells and water-clear cells

 Both types of transitional cell are more common in hyperfunctioning than in normal glands.

Normal Physiology
o The parathyroid glands mediate their endocrine function through the production of PTH.
o The most important physiologic actions of PTH are:
a. increased renal excretion of phosphate
b. increased renal tubular reabsorption of calcium
c. increased intestinal absorption of calcium
d. direct effects in bone ( increase in the number of osteoclasts and an apparent increase in their
phagocytic activity, with a resulting resorption of bone tissue)

Adenoma

Generalities
o Accounts for most cases of hyperparathyroidism
o Occur more in women than men 3:1
o They can develop at almost any age, but most occur in patients in the fourth decade

Pathology
o Circumscribed, grayish brown, solitary mass
o Their size and weight vary greatly, with the majority being too small to allow detection on palpation of the
neck.
o Some may be recognizable only microscopically (‘microadenomas’).
o usually oval, may show slight lobulation, and are surrounded by a thin connective tissue capsule.
o Foci of hemorrhage, calcification, and cystic change may occur.

Microscopic features

o the tumor is encapsulated and very cellular

o chief cells usually predominate with a rich capillary network
o Combinations of chief cells, oxyphil cells, water-clear cells, and transitional elements are common.
o Mitoses are usually absent
o pattern of growth is generally diffuse, but it may be nesting, follicular, or pseudopapillary
o the other parathyroid glands have a normal or atrophic appearance.
o Adenomas have the presence of a microscopically normal second gland which is not seen in chief cell
hyperplasia.
o In contrast to normal chief cells, large quantities of glycogen and secretory vacuoles can be seen
simultaneously.

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Histochemical and immunohistochemical features
o Immunohistochemically
a. (+) reactivity for PTH
b. (+) various types of keratin
c. (+) neuroendocrine markers (such as chromogranin and neuron-specific enolase

o Histochemically
 The intensity of the PTH staining tends to be weaker in the adenoma than in the peripheral rim of
residual normal gland.
 The adenoma cells express neurofilament, an intermediate filament not found in normal
parathyroid cells

Adenoma variants

a. Oxyphil adenoma
o parathyroid adenomas composed entirely or almost entirely of oxyphil cells
o most oxyphil adenomas are non-functioning
o The main ultrastructural feature of these cells is the packing of the cytoplasm by mitochondria.

b. Lipoadenoma
o glandular elements are associated with abundant mature adipose tissue, the latter sometimes
exhibiting myxoid changes
o parathyroid lipohyperplasia, parathyroid hamartoma, parathyroid adenoma with myxoid stroma, and
parathyroid myxoadenoma.
o Most cases are functioning.

Chief cell hyperplasia

o a condition accompanied by increased production of PTH, can be primary or secondary to impairment of
renal function or chronic malabsorption.

a. Primary chief cell hyperplasia

o all glands are enlarged (sometimes weighing 10 g or more)
o tan to reddish color.
o The upper glands tend to be larger than the lower ones
o nodularity, fibrous septation, acinar formation, and giant nuclei are more prominent

Pseudoadenoma
o only one gland is visibly enlarged and nodular, whereas the others are nearly normal in size.
o can be confused grossly with an adenoma

Occult Hyperplasia
o all four glands appear normal in size but are hyperplastic on histologic examination.

Microscopically:

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 o the predominant element is the chief cell
o pattern of growth may be diffuse or nodular
o Diffuse: more common among young patients
o Nodular: more common in the elderly
o Glands with nodular chief cell hyperplasia tend to be asymmetric, with a variable cellular arrangement
and a high proportion of oxyphil cells.
o The ultrastructural features are qualitatively similar to those seen in adenoma and are indicative of a
hyperfunctioning state.

Parathyromatosis
o innumerable microscopic foci of hyperplastic parathyroid tissue found in the neck in association with
primary chief cell hyperplasia of the four glands, in the absence of previous surgery.
o responsible for some cases of recurrent hyperparathyroidism after technically successful surgical therapy.

b. Secondary chief cell hyperplasia

o At one end is the normal-sized gland that is recognized as hyperplastic only because of its tan to reddish
color and the microscopic hypercellularity and at the other, there is the gland measuring up to 2 cm and
weighing up to 6 g.
o there is an inverse correlation between the size of the gland and the mean serum calcium level
o chief cells predominate, but there may also be increased numbers of oxyphil and transitional oxyphil cells
that form nodular collections.
o the number of oxyphil cells is higher than in the primary form

c. Water-clear cell hyperplasia

o In contrast to chief cell hyperplasia, water-clear cell hyperplasia shows no familial incidence and is not
associated with multiple endocrine neoplasia.
o characterized by extreme enlargement of all parathyroid tissue so that the total weight of the glands may
exceed 100 g.
o the superior glands are distinctly larger than the inferior.
o glands may coalesce so that two glands appear as one.
o soft and have a typical chocolate brown color
o Cysts and hemorrhages have been observed.
o There is formation of pseudopods that may extend a considerable distance from the main mass of the
gland.
o A close correlation exists between the weight of the parathyroid tissue and the severity of the symptoms.
o Microscopically, the most characteristic feature is the presence of cells with optically clear cytoplasm
throughout the lesion.
o combination of hyperplasia and hypertrophy.

Parathyroid Carcinoma
o typically presents with hyperparathyroidism
o skeletal diseas present in 73% of the patients and renal disease in 26%.
o are said to be more aggressive.
o absence of function may be caused by the lack of conversion of the preparathormone to the biologically
active compound.
o may coexist with chief cell hyperplasia and with adenoma

Clinical features suggestive of parathyroid carcinoma in a hyperparathyroid patient include:

a. very high values of serum calcium or PTH
b. a palpable cervical mass
c. vocal cord paralysis
d. recurrence of hyperparathyroidism a short time after surgery

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A parathyroid tumor should be suspected of being carcinoma if:
a. it is hard
b. surrounded by a dense fibrous reaction
c. adherent to or infiltrating adjacent structures

o Microscopically, carcinomas differ from adenomas:

a. trabecular arrangement
b. dense fibrous bands (present in 90% of the cases)
c. spindle shape of the tumor cells
d. presence of mitotic figures (in 81%)
e. capsular invasion (in 67%)
f. blood vessel invasion (in 12%)

Other lesions

Parathyroid cysts
o usually arise from the lower glands but can be located in the upper region of the neck or in the
mediastinum
o no symptoms other than those related to pressure.
o mean diameter is 4 cm.
o lined by cuboidal or low columnar epithelial cells and contain parathyroid tissue in their wall.
o Heterotopic salivary gland tissue can be found around the cyst.

Amyloidosis
o often involves the parathyroid gland, in both primary and ‘reactive’ forms of the disease

Langerhans cell histiocytosis

o involving simultaneously the parathyroid and thyroid glands

Metastatic carcinoma
o very rare, but papillary thyroid carcinoma can invade them in continuity with the main tumor.

Hyperparathyroidism
o any condition associated with the persistent production of parathyroid hormone

a. Primary hyperparathyroidism
o there is no evidence of previous parathyroid stimulation by chronic renal or intestinal disease.
o The pathologic changes in the gland may be those of adenoma, chief cell hyperplasia, carcinoma, or
water-clear cell hyperplasia.
o Carcinoma: < 4% of cases
o large majority of cases are caused by either adenoma or chief cell hyperplasia
o It is usually seen in adults but can also be found in children
o Familial setting, the abnormality is usually chief cell hyperplasia

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The typical case of primary hyperparathyroidism is biochemically characterized by:
a. hypercalcemia
b. hypophosphatemia
c. lowering of the renal phosphate threshold
d. hypercalciuria
e. elevated levels of immunoreactive PTH
f. elevated concentrations of 1,25-dihydroxyvitamin D
g. enhanced excretion of nephrogenous cyclic AMP

According to the clinical presentation, patients with primary hyperparathyroidism have been traditionally classified
into:
1. those with osseous manifestations
2. those with renal manifestations
3. those with neither of the foregoing

Skeletal changes:
o always generalized
o Initial lesions: decrease in bone density
o In time, they may become very extensive and lead to deformities and fractures.
o Osteitis fibrosa cystica or Recklinghausen disease- full-blown osseous manifestations of
hyperparathyroidism
o They present radiographically as expansile, multilocular masses.
o The jaw is the preferred location, and this may be the first clinical manifestation of the disease.
o Grossly, there is an alternation of solid and cystic areas; the latter often have a brown color because of
the accumulation of abundant hemosiderin, hence the term brown tumor sometimes used for them.
Microscopically, there is a combination of osteoblastic and osteoclastic activity, often associated with cyst
formation and clusters of hemosiderin-laden macrophages.

Renal changes
o include renal stones, nephrocalcinosis, polyuria, polydipsia, and impairment of renal function.
o renal stones are the most common clinical manifestation of hyperparathyroidism.
o renal lesions are frequently associated with hypertension.

Other manifestations:
o Hypertension
o peptic ulcer (mostly in duodenum and more common in males)
o acute and chronic pancreatitis
o mental disturbances

Secondary hyperparathyroidism
o consequence of chronic renal disease or intestinal malabsorption
o The renal insufficiency leads to elevation of the serum phosphorus level and reciprocal decrease of serum
calcium concentrations, with the resulting stimulation of the parathyroid glands.
o Vitamin D resistance is a characteristic feature of advanced renal disease and also may play a role by
contributing to reduced serum calcium concentrations.
o The bone changes are qualitatively similar to those seen in primary hyperparathyroidism. They are
usually milder, but sometimes extensive changes with cyst formation occur.
o The parathyroid abnormality in secondary hyperparathyroidism is chief cell hyperplasia of a generally
diffuse but sometimes nodular pattern of growth.
o C-cell hyperplasia in the thyroid gland has been found in patients with secondary hyperparathyroidism,
supposedly as a compensatory mechanism.

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‘Tertiary’ hyperparathyroidism
o is applied to cases of hyperparathyroidism secondary to chronic renal disease or intestinal malabsorption,
in which one or more of the stimulated parathyroid glands seem to become autonomous.
o also referred to as nonsuppressible, autonomous, or refractory hyperparathyroidism
o usually detected after correction of the renal disease by hemodialysis or homotransplantation.
o Changes include: chief cell hyperplasia, the main difference with the ordinary case of suppressible
secondary hyperparathyroidism being a greater tendency to nodularity and heterogeneity.

Differential diagnosis
Conditions associated with hypercalcemia:
a. sarcoidosis
b. hyperthyroidism
c. multiple myeloma
d. milk–alkali syndrome
e. vitamin D intoxication
f. vitamin A intoxication
g. familial hypercalcemic hypocalciuria
h. humoral hypercalcemia of malignancy.

Forms of Hyperparathyroidism

Feature Primary Secondary Tertiary Hyperparathyroidism

Hyperparathyroidism Hyperparathyroidism
Causes Adenoma, hyperplasia Renal failure, vitamin D Autonomous transformation of
deficiency Secondary Hyperparathyroidism
PTH level Increased Increased Increased
Calcium level Increased Decreased Normal or Increased

Treatment
o Surgical identification of all four parathyroid glands
 remains a widely used approach
o Adenomas are adequately treated by local excision of the tumor. It is highly desirable to excise or biopsy
at least one other parathyroid gland to rule out the alternative possibility of chief cell hyperplasia.
o Primary chief cell hyperplasia and the exceptionally rare water-clear cell hyperplasia are conventionally
treated by subtotal parathyroidectomy, as defined by total excision of three glands and partial excision of
the fourth, leaving 30–50 mg of viable tissue.
o Parathyroid carcinoma is best treated by excision of the tumor and surrounding soft tissues and removal
of the ipsilateral lateral thyroid lobe.
o The large majority of patients with secondary and ‘tertiary’ hyperparathyroidism respond well to medical
treatment. However, if bone lesions are severe and if the hypercalcemia is excessive, subtotal
parathyroidectomy may become necessary.

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