Neoplasms of the Thyroid Gland

Classification of Neoplasms of The Thyroid Gland

See Box 28-1 .

General Considerations

• Thyroid cancer is the most common endocrine malignancy but represents 1.4% to 4.6% of all new human cancers diagnosed in the United States.

• Incidence of thyroid carcinoma in United States has increased rapidly since 1980:

  • More refined/sophisticated detection methods including radiologic imaging (ultrasound, CT, MRI) contribute to increase in incidence.

  • Sharpest increase is in diagnosis of papillary thyroid carcinoma, particularly papillary microcarcinoma but also follicular variant of papillary thyroid carcinoma.

• Percentage of cancer deaths (mortality rate) due to thyroid cancer is low (less than 0.4% in women and in men):

  • In contrast to increase in incidence, changes in mortality rates have been much smaller, likely resulting from:

    • –

      Improved treatment

    • –

      Increased incidence primarily in early stage papillary carcinoma

• Clinically apparent thyroid nodules occur in fairly large percentage of the population (up to 10%):

  • Many of these nodules are probably benign.

  • Differential diagnosis of any thyroid nodule includes a malignant thyroid neoplasm.

• Demographics:

  • In general, thyroid tumors are more common in women than in men and occur in all ages ranging from the young (children in the first and second decades of life) to elderly adults.

• Risk factors for development of thyroid cancer include:

  • Radiation exposure:

    • –

      Causes thyroid carcinoma primarily by direct effects on DNA

    • –

      Primarily associated with external radiation

    • –

      Internal ( ¹³¹ iodine) radiation therapy used safely for diagnostic and therapeutic purposes associated with small increase risk of thyroid carcinoma incidence

    • –

      Risk factors associated with radiation-induced thyroid tumors include:

      • ▪

        Amount of radiation exposure

      • ▪

        Young age at exposure to radiation

      • ▪

        High serum thyroglobulin levels

  • Genetic predisposition:

    • –

      Only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome.

    • –

      Familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases classified into two distinct groups:

      • ▪

        Syndromic-associated tumors occur in syndromes in which nonmedullary thyroid carcinomas are predominant tumor encountered, including:

        • □

          Phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome

        • □

          Familial adenomatous polyposis/Gardner syndrome

        • □

          Carney complex type 1, Werner syndrome, Pendred syndrome

        • □

          Other syndromes, such as McCune-Albright syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia syndrome, may be associated with development of follicular cell-derived tumors but link is less established than above syndromes.

      • ▪

        Nonsyndromic tumors occur in tumor syndromes in which thyroid involvement is minor component, including:

        • □

          Familial follicular cell-derived tumor syndromes or nonsyndromic tumors:

          • –

            Non-medullary thyroid carcinomas are major findings, including:

            • Pure familial papillary thyroid carcinoma with or without oncocytic cytoplasmic change; familial papillary thyroid carcinoma with papillary renal cell carcinoma; familial papillary thyroid carcinoma with multinodular goiter; familial nonmedullary (papillary) thyroid carcinoma type 1

    • –

      Familial adenomatous polyposis (FAP) syndrome, including its subtype Gardner syndrome:

      • ▪

        Autosomal dominant inheritance with mutations in APC gene (5q21)

      • ▪

        Characterized by multiple adenomatous polyps of the large intestine, multiple osteomas of the skull and mandible, cutaneous keratinous cysts, and soft tissue tumors (e.g., fibromatosis)

      • ▪

        Associated with an increased risk of papillary thyroid carcinoma (PTC):

        • □

          Thyroid carcinoma occurs in up to 12% of patients

        • □

          Tend to occur at early age

        • □

          Histologically, include PTC, cribriform-morular variant, and solid variant

    • –

      Phosphatase and tensin homolog (PTEN)-hamartoma tumor syndrome, including Cowden disease (multiple hamartoma syndrome):

      • ▪

        Autosomal dominant inheritance

      • ▪

        Germline mutation of PTEN gene (10q23.2)

      • ▪

        Characterized by multiple hamartomas, mucocutaneous lesions, including trichilemmomas, acral keratoses, and oral mucosal papillomas

      • ▪

        Associated with increased risk of follicular epithelial cell lesions/tumors, including:

        • □

          Adenomatoid nodules accounting for 75% of thyroid abnormalities in this setting

        • □

          PTC and follicular carcinomas may also occur.

    • –

      Other familial disorders with specific gene mutations associated with thyroid carcinoma include:

      • ▪

        Carney complex:

        • □

          Germline mutation PRKR1α (17q22-24)

        • □

          Follicular carcinoma and papillary carcinoma

      • ■

        Werner syndrome:

        • □

          Germline mutation WRN (8p11-22)

        • □

          Follicular carcinoma, papillary carcinoma, undifferentiated (anaplastic) thyroid carcinoma

      • ▪

        Pendred syndrome

        • □

          Mutation of Pendred syndrome (PDS) gene ( SLC26A4 gene on chromosome 7q31) encodes amino acid protein pendrin shown to function as iodide/chloride transporter

        • □

          Goitrous thyroid

    • –

      Familial nonmedullary thyroid carcinoma (FNMTC):

      • ▪

        Originate from follicular cells of thyroid gland accounting for more than 90% of all thyroid cancers

      • ▪

        Approximately 3% to 10% of FNMTCs are of familial origin defined as two or more affected first-degree relatives with NMTC in the absence of other known familial syndromes.

      • ▪

        Greater than 85% of thyroid tumors in nonsyndromic FNMTC are papillary thyroid carcinoma followed by follicular thyroid carcinoma (approximately 10%); poorly differentiated and undifferentiated (anaplastic) thyroid carcinomas represent approximately 5%.

      • ▪

        Compared to sporadic NMTC, FNMTC:

        • □

          Presents at younger age

        • □

          Associated with higher incidence of multifocal disease, extrathyroidal extension, and nodal metastasis

    • –

      Multiple endocrine neoplasia syndrome:

      • ▪

        Linked to development of C-cell–related lesions/neoplasms

      • ▪

        See Section 10.

  • Dietary factors:

    • –

      Iodine:

      • ▪

        In iodine-deficient diets (endemic goiter areas), follicular thyroid carcinoma more common

      • ▪

        In iodine-sufficient diets, papillary thyroid carcinoma more common

  • Pre-existing thyroid diseases:

    • –

      Thyroid carcinoma often preceded by other thyroid abnormalities, including:

      • ▪

        Adenomatoid nodules

      • ▪

        Lymphocytic thyroiditis

      • ▪

        Graves disease

    • –

      Remains uncertain whether patients with above abnormalities are at increased risk for developing thyroid carcinoma

  • Hormonal and reproductive factors:

    • –

      Thyroid carcinoma occurs more commonly in women than in men.

      • ▪

        Differences between genders in thyroid cancer incidence declines with age.

    • –

      Increasing parity may increase risk of thyroid carcinoma.

    • –

      Thyroid carcinoma reported to occur more often among women who are older when they first give birth.

    • –

      Small increase in risk of thyroid carcinoma with increasing age at menopause

    • –

      Other suggested risk factors for thyroid carcinoma in women are:

      • ▪

        Exogenous estrogens, including oral con­traceptives

      • ▪

        Lactation-suppressant drugs

      • ▪

        Postmenopausal estrogen therapy

      • ▪

        Fertility drugs (e.g., clomiphene, proges­terone)

• Clinical findings:

  • Most patients with benign thyroid nodules/tumor and carcinomas present with asymptomatic thyroid nodule.

  • Clinical findings related to risk of carcinoma in thyroid nodule include:

    • –

      Age:

      • ▪

        Overall most patients with thyroid carcinoma are middle age.

      • ▪

        Thyroid nodule is more likely to be carcinoma in patients under 20 years and in patients over 65 years of age.

    • –

      Gender:

      • ▪

        Men are more apt to have malignant thyroid tumors than women.

    • –

      Family history of thyroid cancer or syndrome associated with thyroid cancer

    • –

      History of childhood head and neck therapeutic irradiation, total body irradiation, or exposure to ionizing radiation

    • –

      History of other cancer:

      • ▪

        Kidney, breast, lung, and melanoma

    • –

      Sudden or rapid enlargement of thyroid or of long-standing thyroid nodule(s) with or without pain:

      • ▪

        Most likely represents hemorrhage into a cystic nodule:

        • □

          Occurs in benign and malignant nodules

      • ▪

        Hallmark presentation for some thyroid malignant tumors, including undifferent­iated (anaplastic) carcinoma and malignant lymphoma

    • –

      Large nodule with distortion of structures of upper neck and mediastinum and/or tracheal compression with difficulty breathing:

      • ▪

        Can occur in association with benign thyroid nodules but presence of these symptoms raises concern for a malignant thyroid lesion, although most malignant thyroid tumors are asymptomatic

    • –

      Hoarseness and/or vocal cord paralysis:

      • ▪

        Most commonly related to laryngeal-based disease (benign or malignant) but can be associated with infiltration of recurrent laryngeal nerve by thyroid cancer

• Physical examination:

  • Number of nodules:

    • –

      Although not always true, multiple nodules more likely to be benign, whereas solitary nodules more likely to be malignant

  • Hard and fixed thyroid mass:

    • –

      More likely to be malignant

  • Ipsilateral cervical adenopathy:

    • –

      May indicate metastasis from an (ipsilateral) thyroid malignant tumor clinically overt or occult

• Laboratory testing:

  • Most patients with thyroid cancer are euthyroid.

  • Serum thyrogloublin:

    • –

      Often elevated in patients with papillary and follicular carcinoma:

      • ▪

        May be elevated in association with follicular adenoma so does not necessarily allow for distinguishing benign and malignant thyroid follicular neoplasms.

    • –

      Not typically elevated in medullary thyroid carcinoma and undifferentiated (anaplastic) thyroid carcinoma

    • –

      Useful in monitoring patients following treatment (surgery and radioactive iodine) for papillary or follicular carcinoma as elevated levels may indicate recurrence or metastasis.

  • Serum calcitonin:

    • –

      Elevated levels represent diagnostic feature that may occur in medullary thyroid carci­noma

  • Germline RET proto-oncogene mutation testing:

    • –

      Indicated in patients with thyroid nodule and family history of medullary thyroid carcinoma or potential diagnosis of multiple endocrine neoplasia (MEN) type II syndrome

• Radiologic imaging:

  • Ultrasonography:

    • –

      Thyroid ultrasound used in patients with palpable nodules (with or without elevated TSH) to:

      • ▪

        Determine presence of single discrete nodule or multiple nodules

      • ▪

        Demonstrate anatomic location of nodule in thyroid (anterior versus posterior) as well as composition (cystic versus solid)

      • ▪

        Assess nodule(s) size

    • –

      Thyroid malignancies tend to:

      • ▪

        Be hypoechogenic (particularly marked hypoechogenicity)

      • ▪

        Be solid

      • ▪

        Have infiltrative or microlobulated margins

      • ▪

        Show presence of microcalcifications

      • ▪

        Be taller than wide shaped when measured in transverse view

      • ▪

        However, no single feature or combination of sonographic features is sufficiently sensitive to be the sole screening test for thyroid cancer.

    • –

      Thyroid nodule may be considered benign when:

      • ▪

        Purely cystic

      • ▪

        Spongiform appearing (>50% of nodule volume occupied by microcystic spaces)

    • –

      On basis of thyroid sonographic imaging features, nodule appearance can be classified as:

      • ▪

        Low risk for malignancy:

        • □

          Tend to be purely cystic or spongiform

        • □

          Noninfiltrative borders

      • ▪

        Intermediate risk for malignancy:

        • □

          Predominantly solid, hypo- or iso- to hyperechoic

        • □

          Noncalcified

        • □

          Regular margins

      • ▪

        High risk for malignancy:

        • □

          Hypoechoic

        • □

          Microcalcifications

        • □

          Infiltrative or microlobulated margins

  • Radionuclide imaging

    • –

      Thyroid scintigraphy using ¹²³ I or ^99m Tc pertech­netate

    • –

      Incidence of carcinoma higher for hypofunctioning “cold” nodules than for hyperfunctioning (“hot”) nodules

      • ▪

        “Hot” nodules are almost always benign

• Fine-needle aspiration biopsy (FNAB)

  • Represents an extremely useful initial approach in diagnosis of thyroid mass

  • Quick and inexpensive with minimal com­plications

  • Thyroid nodules are one of most common indications for neck FNAB.

  • Presurgical diagnosis via FNAB prevents unneeded surgery for benign, nonprogressive lesions and helps to triage patients with a neoplasm for appropriate procedure.

  • Diagnostic sensitivity and specificity reported to be high, greater than 90%

  • Standardization and interpretation of thyroid cytology greatly improved by widespread adoption of Bethesda reporting system ( Table 28-1 ), which classifies biopsies in six-tiered system as well as including implied risk of malignancy and associated usual management ( Table 28-2 )

    TABLE 28-1

    Bethesda System for Reporting of Thyroid Cytopathology: Diagnostic Categories

    From Ali SZ, Cibas EA, editors: The Bethesda system for reporting thyroid cytopathology: definitions, criteria and explanatory notes, New York, 2010, Springer.

    Category	Diagnoses	Findings	Frequency of Diagnosis
    I	Nondiagnostic or unsatisfactory	Cyst fluid only; virtually acellular specimen; other (obscuring blood, clotting artifact, etc.)	<15%
    II	Benign	c/w: Benign follicular nodule (e.g., ANs) CLT Granulomatous (subacute) thyroiditis	30% to 75%
    III	Atypia of undetermined significance or follicular lesion of undetermined significance	Contain cells with architectural and/or nuclear atypia not sufficient to be classified as suspicious for follicular neoplasm, suspicious for malignancy, or malignant but show atypia more marked than benign lesions	<10%
    IV	Follicular neoplasm or suspicious for follicular neoplasm	Specify if oncocytic (Hürthle) cell type	~5%
    V	Suspicious for malignancy	Suspicious for: PTC; MTC; metastatic carcinoma; lymphoma	<5%
    VI	Malignant	PTC; PDTC; MTC; UC; SCC; carcinoma with mixed features; metastatic carcinoma; NHL	~5%

    ~, Approximately; c/w, consistent with; ANs , adenomatoid nodules; CLT , chronic lymphocytic (Hashimoto) thyroiditis; MTC, medullary thyroid carcinoma; NHL, non-Hodgkin lymphoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; SCC, squamous cell carcinoma; UC, undifferentiated (anaplastic) carcinoma.

    TABLE 28-2

    Bethesda System for Reporting of Thyroid Cytopathology: Risk of Malignancy and Recommended Clinical Management

    From Ali SZ, Cibas EA, editors: The Bethesda system for reporting thyroid cytopathology: definitions, criteria and explanatory notes, New York, 2010, Springer.

    Bethesda Classification	Risk of Malignancy	Recommended Management
    Nondiagnostic or unsatisfactory (Bethesda I)	N/A	Repeat FNA with ultrasound guidance
    Benign (Bethesda II)	0 to 3%	Clinical follow-up
    Atypia of undetermined significance, follicular lesion of uncertain significance (Bethesda III)	5% to 15%	Repeat FNA
    Follicular neoplasm, suspicious for follicular neoplasm (Bethesda IV)	15% to 30%	Surgical lobectomy
    Suspicious for malignancy (Bethesda V)	60% to 75%	Near total thyroidectomy or surgical lobectomy
    Malignant (Bethesda VI)	>95%	Near total thyroidectomy

  • Post-FNAB histologic changes may create diagnostic problems in the evaluation of tissue sections, including presence of features raising concern for malignancy, including:

    • –

      Pseudoinvasion, necrosis, papillary architecture, cytologic atypia

    • –

      See Chapter 29 .

• Intraoperative consultation (frozen section diag­nosis):

  • Use of intraoperative frozen sections in diagnosis of thyroid tumors has decreased with increasing use of FNAB.

  • See Chapter 29 .

• Histologic types of thyroid neoplasms:

  • Majority of thyroid tumors are of follicular epithelial cell origin and include:

    • –

      Follicular adenoma and variants thereof

    • –

      Follicular carcinoma and variants thereof

    • –

      Papillary carcinoma and variants thereof

  • Less common are C-cell–derived medullary thyroid carcinoma

  • Nonepithelial neoplasms of thyroid are un­­common:

    • –

      Most common nonepithelial thyroid neoplasm is malignant lymphoma.

    • –

      Rarely, primary mesenchymal tumors as well as metastases to thyroid gland occur.

  • Frequency of malignant thyroid neoplasms include:

    • –

      Papillary carcinoma: approximately 80% to 85%

    • –

      Follicular carcinoma: approximately 10% to 15%

    • –

      Medullary carcinoma: <5%

    • –

      Poorly differentiated thyroid carcinoma: <2%

    • –

      Undifferentiated (anaplastic) thyroid carcinoma: <2%

    • –

      Malignant lymphoma: <5%

• Immunohistochemistry of thyroid neoplasms

  • Majority of thyroid cancers are differentiated carcinomas of follicular epithelial cell origin diagnosed on morphologic grounds.

  • Immunohistochemical staining can be important and at times essential in confirming specific diagnosis.

  • Table 28-3 includes an overview of more common antibodies that may be used in diagnosis of the more common thyroid neoplasms.

    TABLE 28-3

    Antibodies Used in Diagnosis of Thyroid Neoplasia

    Antibody	FA	FTC	PTC	MTC	UTC	PDTC
    Thyroglobulin	+	+	+	−	−	+ *
    TTF-1 (N)	+	+	+	+	−	+
    PAX8 (N)	+	+	+	+	+	+
    Calcitonin	−	−	−	+	−	−
    NE markers	−	−	−	+	−	−
    CD56	+	+	R/A	+	−	−
    CK (AE1/AE3)	+	+	+	+	±	+

    CK, Cytokeratin; FA, follicular adenoma; FTC, follicular thyroid carcinoma; N , nuclear; NE markers, synaptophysin and chromogranin; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; R/A , reduced to absent; TTF-1, thyroid transcription factor 1; UTC, undifferentiated thyroid carcinoma.

    * Typically very focal limited to abortive or small follicles containing colloid or limited to isolated cells as paranuclear globules or vacuoles.

• Molecular genetics of thyroid tumors ( Table 28-4 ):

  • Papillary thyroid carcinomas have activating mutations of genes coding for proteins, which signal along the mitogen-activated protein kinase pathway (MAPK).

    • –

      Papillary thyroid carcinomas commonly have three genetic alterations, including:

      • ▪

        RET/PTC rearrangements

      • ▪

        BRAF point mutations

      • ▪

        RAS point mutations

    • –

      Mutations in RET, BRAF, and RAS genes found in approximately 70% of all papillary thyroid carcinomas but rarely overlap in same tumor

  • RET (rearranged during transfection) protoon­cogene:

    • –

      Rearrangements of RET gene, known as RET/PTC rearrangements, occur in papillary thyroid carcinoma (PTC).

    • –

      RET/PTC rearrangement implicated in early stages of PTC representing early event in development of PTC

    • –

      Several types of RET/PTC identified differing according to 5′ partner gene involved in rearrangement

      • ▪

        Two most common rearrangement types are:

        • □

          RET/PTC1: typically found in classic PTC, papillary microcarcinomas

        • □

          RET/PTC3: more common than the other fusion proteins in solid and radiation-induced PTCs, especially in children exposed to the radiation fallout from the Chernobyl accident

    • –

      Uncommon to rare in follicular variant of PTC

    • –

      Germline mutations present in virtually all patients with familial forms of medullary thyroid carcinoma, including:

      • ▪

        MEN-2A

      • ▪

        MEN-2B

      • ▪

        Familial medullary thyroid carcinoma

    • –

      Somatic mutations of RET codon 918 occur in approximately 50% of sporadic medullary thyroid carcinomas.

  • B-RAF proto-oncogene, serine/threonine kinase (BRAF) mutation:

    • –

      Belongs to RAF family of protein kinases important components of the mitogen-activated protein kinase (MAPK) signaling pathway mediating cell growth, differentiation, and survival

    • –

      Spectrum of mutations include point mutations, small in-frame deletions or insertions, and chromosomal rearrangement.

    • –

      V600E is most common mutation (98% to 99%) and involves nucleotide 1799, resulting in valine-to-glutamate substitution at residue 600 (V600E).

    • –

      Mutations of BRAF gene found in 40% to 45% of PTCs

    • –

      Occur early in development of PTC based on presence in papillary microcarcinomas

    • –

      Among thyroid tumors BRAF mutations restricted to:

      • ▪

        Papillary thyroid carcinoma:

        • □

          Classic type

        • □

          Papillary microcarcinomas

        • □

          Tall cell variant

      • ▪

        Poorly differentiated thyroid carcinomas

      • ▪

        Undifferentiated (anaplastic) thyroid carcinoma arising from thyroid papillary carcinoma.

    • –

      Uncommon to rare in follicular variant of PTC

    • –

      Not found in follicular carcinoma and benign thyroid nodules

    • –

      Reported to serve as prognostic marker for PTC associated with more aggressive features including:

      • ▪

        Tumor recurrence

      • ▪

        Extrathyroidal extension

      • ▪

        Metastatic disease (regional, distant)

      • ▪

        Advanced tumor stage (AJCC III/IV)

    • –

      Purported aggressive behavior of BRAF -associated PTCs not universally reported

  • Rat sarcoma (RAS) oncogene mutations:

    • –

      Found in benign and malignant thyroid neoplasms, suggesting RAS activation may be an early step in thyroid tumor development

    • –

      3 RAS genes prominent in cancer pathogenesis, including:

      • ▪

        Neuroblastoma RAS viral oncogene homolog (N-RAS)

      • ▪

        Kirsten rat sarcoma viral oncogene homolog (K-RAS)

      • ▪

        Harvey rat sarcoma viral oncogene homolog (H-RAS)

    • –

      Found in all types of follicular cell-derived tumors:

      • ▪

        Prevalence includes N-RAS > H-RAS > K-RAS

    • –

      RAS mutations found in:

      • ▪

        40% to 50% follicular carcinomas:

        • □

          Lower incidence of oncocytic variant

      • ▪

        20% to 40% follicular adenomas:

        • □

          Lower incidence of oncocytic variant

      • ▪

        10% to 20% PTCs:

        • □

          Virtually all follicular variants of PTC

      • ▪

        Also found in 20% to 50% of poorly differentiated thyroid carcinoma and 10% to 50% of undifferentiated (anaplastic) thyroid carcinoma

  • Other molecular genetic findings in thyroid neoplasms:

    • –

      Peroxisome proliferator-activated receptor γ (PAX8/PPARγ) gene rearrangement:

      • ▪

        Nuclear receptors that bind DNA as heterodimers with retinoid X receptors

      • ▪

        Shown to play important role in regulating genes involved in adipocytic differentiation and lipid metabolism

      • ▪

        Result in recurrent translocation t(2;3)(q13;p25) leading to fusion of thyroid transcription factor PAX8 and PPARγ genes

      • ▪

        PAX8/PPARγ rearrangements involved in thyroid cancer found in:

        • □

          20% to 50% of conventional FTC: ~5% of oncocytic carcinomas

        • □

          5% to 20% of follicular adenoma s

        • □

          1% to 5% follicular variant of PTC

        • □

          0 to 1% of classic PTC

      • ▪

        Thyroid tumors with PAX8/PPARγ rearrangement do not usually carry any RAS mutation, suggesting that the development of FTC involves two independent pathways associated with either PAX8/PPARγ translocation or RAS mutation

      • ▪

        Tend to be present in:

        • □

          Younger-age patients

        • □

          Smaller tumors

        • □

          Tumors more likely to be angioinvasive

    • –

      Telomerase reverse transcriptase (TERT) gene mutations:

      • ▪

        Telomeres are the terminal portion of chromosomes that protect chromosome integrity by preventing their degradation and uncontrolled fusion and breaking cycles with other chromosomes

      • ▪

        Telomerase (telomere terminal trnasferase) is an RNA-dependent reverse transcriptase complex that maintains telomere length allowing for cell replication and extending the life span of the cell

      • ▪

        TERT is the enzyme protein core encoded by the TERT gene and is expressed in thyroid tumors (but is not normally expressed in thyroid tissue).

      • ▪

        Found in 12% of papillary thyroid cancers and 14% of follicular thyroid cancers

      • ▪

        Found to significantly correlate with older age at diagnosis

      • ▪

        Demonstrated in thyroid cancers particularly prevalent in aggressive, less differentiated thyroid cancers, including:

        • □

          Tall cell variant-PTC, poorly differentiated thyroid cancer, undifferentiated (anaplastic) thyroid cancer, and BRAF V600E mutation-positive PTC

      • ▪

        Shown to strongly correlate with poorer outcome in differentiated thyroid tumors

        • □

          Prognostic value of TERT mutations reported to be significantly stronger than that of BRAF (V600E)

      • ▪

        TERT protein by immunohistochemical staining found to be more expressed in neoplastic than in normal tissues and to display different cellular localization, suggesting it could contribute to thyroid cancer pro­gression by mechanisms taking place in cytoplasm

    • –

      Phosphatidylinositol 3-kinase (PI3K)/AKT (AKT) signaling pathway

      • ▪

        Plays important role in regulation of cell survival, proliferation, and migration

      • ▪

        Activating mutations in RAS, PIK3CA, and AKT genes or inactivating mutations in PTEN tumor suppressor gene can inappropriately stimulate signaling pathway.

      • ▪

        Mutations in signaling pathway occurs in:

        • □

          5% to 10% of (differentiated) follicular carcinomas

        • □

          More common in poorly differentiated thyroid carcinoma and undifferentiated (anaplastic) thyroid carcinoma harboring: PIK3CA mutation (10% to 20%) and AKT1 mutation (5% to 10%)

        • □

          PIK3CA and AKT1 mutations frequently present in undifferentiated (anaplastic) thyroid carcinoma coexisting with BRAF and RAS mutations

      • ▪

        Late event in thyroid carcinogenesis:

        • □

          Higher prevalence in advanced thyroid cancer and undifferentiated (anaplastic) thyroid carcinoma

    • –

      β-catenin:

      • ▪

        Ubiquitously expressed cytoplasmic protein

      • ▪

        Inappropriate stabilization followed by nuclear translocation proposed as important step in oncogenesis

      • ▪

        CTNNB1 gene encodes β-catenin

      • ▪

        Somatic mutations in exon 3 reported in:

        • □

          25% of poorly differentiated thyroid carcinoma

        • □

          60% of undifferentiated (anaplastic) thyroid carcinoma

        • □

          Rare in (well) differentiated thyroid cancers

        • □

          Oncogenic signaling through β-catenin occurs in the cribriform morular variant of PTC in the setting of familial adenomatous polyposis with germline APC mutations and in sporadic cases.

    • –

      Tumor protein 53 (TP53) tumor suppressor gene

      • ▪

        Most commonly mutated tumor suppressor gene in human cancer

      • ▪

        Transcriptional activator involved in cell cycle progression:

        • □

          Ability to arrest cell cycle and activate program cell death confers significant to TP53 in determining cell survival

        • □

          Inactivating point mutations of TP53 tum­or suppressor gene highly prevalent in poorly differentiated thyroid carcinoma and undifferentiated (anaplastic) thyroid carcinoma

        • □

          Not present in (well) differentiated thyroid cancers

      • ▪

        Represent late event in progression and dedifferentiation of thyroid cancer

    • –

      Micro-RNAs (miRNAs or miRs):

      • ▪

        Belong to class of small noncoding messenger RNA that have emerged as potent regulators of a variety of biologic processes, including oncogenesis

        • □

          Act as posttranscriptional regulators of gene expression and are constantly deregulated in human cancer; found downregulated in lung, colon, and prostate cancer

      • ▪

        Increasingly implicated in regulating malignant progression of cancer

      • ▪

        Involved in thyroid cell proliferation and migration validating role in downregulation in thyroid carcinogenesis

        • □

          MiR-221 and miR-222 found to be deregulated in human papillary thyroid carcinomas; involved in cell proliferation through inhibition of cell cycle regulator, p27kip1, in human papillary carcinomas

      • ▪

        miRs may regulate fundamental aspects of the PTC phenotype, i.e., signaling, differentiation, invasion and metastasis, by fine tuning gene expression

      • ▪

        Increased role in determining thyroid cancer phenotype serving as important diagnostic tool and useful as class identifiers especially in context of follicular thyroid carcinoma, papillary thyroid carcinoma, and anaplastic thyroid carcinoma

      • ▪

        Cancer-relevant miRs include oncomiRs (miR-21 and miR-146b) and tumor sup­pressor miRs (let-7 family, miR-204, and miR-375).

        • □

          Increased expression of miR-21 associated with known aggressive form of PTC (tall cell variant) and may be a critical event in pathogenesis

        • □

          OncomiRs miR-221 and miR-222 reported to play role in PTC aggressiveness; associated with less differentiated tumors

      • ▪

        miRNAs and their target genes could be targeted for novel therapeutics

  TABLE 28-4

  Common Genetic Alterations in Thyroid Neoplasia

  Tumor Type	Affected Genes	Prevalence
  Follicular adenoma	RAS	20% to 40%
  	PAX8/PPARγ translocation	5% to 20%
  Follicular carcinoma	RAS	30% to 50%
  	PAX8/PPARγ translocation	20% to 50%
  	PIK3CA mutation	5% to 10%
  	PTEN	5% to 10%
  Papillary carcinoma, classical	BRAF	30% to 70%
  	RET/PTC translocation	20% to 40%
  	RAS	0 to 10%
  	TRK	0 to 10%
  Papillary carcinoma, follicular variant	RAS	25% to 45%
  	PAX8/PPARγ translocation	0 to 30%
  	RET/PTC translocation	5% to 10%
  	BRAF	5% to 10%
  Poorly differentiated carcinoma	RAS	20% to 50%
  	TP53	15% to 40%
  	B-catenin (CTNNB1)	0 to 25%
  	BRAF	5% to 15%
  	PIK3CA mutation	10% to 20%
  	AKT1 mutation	5% to 10%
  Undifferentiated (anaplastic) carcinoma	TP53	50% to 80%
  	B-catenin (CTNNB1)	5% to 65%
  	RAS	10% to 50%
  	BRAF	10% to 40%
  	PIK3CA mutation	5% to 25%
  	PTEN mutation	5% to 20%
  Medullary carcinoma Sporadic Familial	RET, somatic	50%
  	RET, germline mutation	>95%

• Molecular classification

  • The Cancer Genome Atlas (TCGA) project:

    • –

      Comprehensive multiplatform analysis of nearly 500 PTCs (excluding clinically aggressive thyroid cancers including poorly and undifferentiated carcinomas)

    • –

      Integrated genomic characterization of papillary thyroid carcinoma (PTC)

    • –

      Refine classification of PTC into molecular subtypes and associate them with clinically relevant parameters

      • ▪

        PTC is MAPK-driven cancer that has two mutually exclusive drivers with distinct signaling consequences, including:

        • □

          BRAF V600E–like tumors include classic PTC with papillary architecture and characteristic nuclear features (whether invasive or noninvasive); gene expression profile shows relatively less evidence of thyroid differentiation with lower expression levels of thyroid differentiation scores (TDS) genes; used for all infiltrative lesions despite follicular architecture that may predominate

        • □

          RAS- like tumors include encapsulated or circumscribed (noninvasive) tumors with follicular architecture and nuclear atypia (hallmarks characteristic of follicular variant of PTC); gene expression profile that resembles normal thyroid (high TDS scores); genetics similar to follicular adenoma and follicular carcinoma (not part of the TCGA project analysis).

    • –

      Reclassification of follicular variant (FV) of PTC is inevitable with recent recommended by panel of expert thyroid pathologists to replace FVPTC with alternative nomenclature such as “Noninvasive follicular tumor [NIFT] with papillary-like features.” See later under FVPTC.

• Treatment for thyroid cancer:

  • Surgery is preferred treatment for vast majority of thyroid tumors:

    • –

      Extent of surgery varies to include:

      • ▪

        Lumpectomy:

        • □

          Removal of a nodule/mass alone with minimal surrounding thyroid tissue

        • □

          Generally not recommended for removal of thyroid tumors

      • ▪

        Partial thyroidectomy:

        • □

          Removal of nodule/mass with larger margin of surrounding thyroid tissue

        • □

          Unacceptable in management of thyroid cancer

      • ▪

        Isthmusectomy:

        • □

          Removal of tumor within isthmus to include a margin of surrounding thyroid tissue

      • ▪

        Lobectomy or hemithyroidectomy:

        • □

          Removal of thyroid lobe with or without isthmus

      • ▪

        Subtotal thyroidectomy:

        • □

          Complete resection of one lobe and isthmus and partial removal of contralateral lobe

      • ▪

        Bilateral subtotal thyroidectomy:

        • □

          Significant portion of both lobes removed

      • ▪

        Near total thyroidectomy:

        • □

          Removal of all thyroid tissue except for 1 gram remnant on one side typically preserved to protect adjacent parathyroid tissue or to avoid distal recurrent laryngeal nerve dissection; such a remnant must be anodular and away from cancer focus

      • ▪

        Total thyroidectomy:

        • □

          Removal of entire thyroid gland; advantages of total thyroidectomy include association with higher survival rate for larger lesions (greater than 1.5 cm); association with lowest recurrence rate; improved sensitivity of serum thyroglobulin as marker for persistent or recurrent disease; allows for utilization of radioactive iodine to treat persistent or recurrent disease; reduction in (unlikely) possibility of residual tumor in contralateral lobe transforming to an anaplastic carcinoma

    • –

      Surgical complications may include:

      • ▪

        Recurrent laryngeal nerve paralysis

        • □

          In hands of expert thyroid surgeon risk is low (e.g., 1% to 2%)

        • □

          Risk increases (e.g., 6% to 8%) in nonexpert thyroid surgeons

      • ▪

        Hypoparathyroidism:

        • □

          May be a significant problem in patients following bilateral or total thyroidectomy

        • □

          Rates of temporary hypoparathyroidism (calcium levels <8.0 mg/dl within 6 months after thyroidectomy) reported to be 17% to 40%

        • □

          Rates of permanent hypoparathyroidism range from 1.2% to 6.5%.

        • □

          Risk of hypoparathyroidism increases with invasive cancers; when lymph node dissection is performed with thyroidectomy; linked to experience of surgeon

  • Lymph node dissection:

    • –

      Cervical lymph nodes divided into levels I through VI and grouped into central and lateral compartments

    • –

      See Section 4 for more detailed discussion of anatomy of cervical neck lymph nodes.

    • –

      Surgical treatment of cervical lymph nodes in thyroid carcinoma remains subject of debate:

      • ▪

        Node dissection indicated when there are palpable nodes and/or radiographically suspicious or positive lymph nodes

    • –

      Selective neck dissection designed to remove regional lymph nodes involved by tumor or at risk for metastasis

    • –

      Central compartment neck dissection includes tissue from hyoid bone to mediastinum and from one jugular vein to the other jugular vein:

      • ▪

        Lateral deep jugular area is carefully examined (palpated) for disease.

      • ▪

        In presence of palpable lymph nodes laterally lymphadenectomy to include levels II, III, IV is performed.

      • ▪

        Further, evaluation of the lymph nodes accompanying the inferior thyroid artery into the posterior triangle of the neck is indicated in the presence of palpable nodes, dissection of level V nodes is performed.

      • ▪

        Submandibular triangle usually is not included in the dissection because thyroid cancer rarely metastasizes to the submandibular triangle.

      • ▪

        In presence of cervical nodal metastasis and in patients with aggressive disease, imaging to include the parapharyngeal space and base of skull is indicated; because standard neck dissections do not allow for dissection of lymph nodes in these areas, if significant adenopathy of these regions is visualized, then appropriate techniques for nodal dissection of these sites should be planned and performed in addition to the standard cervical node dissection.

  • Radioactive iodine therapy ( ¹³¹ I):

    • –

      Thyroid ablation with ¹³¹ I used in treatment of differentiated thyroid carcinoma:

      • ▪

        ¹³¹ I destroys residual microscopic (metastatic) thyroid cancer.

      • ▪

        Facilitates identification of metastatic foci by radioactive iodine scanning

      • ▪

        Used in treatment of distant metastasis with best results seen in patients who are under 40 years of age at time of their metastasis and whose metastatic foci con­centrate ¹³¹ I

      • ▪

        Poorer outcomes seen in patients over 40 years of age at time of their metastasis, have extensive metastatic disease, poorly differentiated tumors, and/or tumors that do not take up ¹³¹ I

      • ▪

        Utility of radioactive iodine therapy is negated in presence of a normally situated thyroid gland proper because the latter would concentrate radioactive iodine rather than the planned intent for this therapy to destroy residual cancer outside the confines of thyroid gland proper.

      • ▪

        Reasonably safe procedure

      • ▪

        Potential complications may include:

        • □

          Usually involve organs known to concentrate iodine, including salivary glands causing sialadenitis, loss or change in taste, xerostomia; eyes causing xerophthalmia, epiphora; gonads causing transient reductions in fertility; serious life-threatening complications are rare but may include acute bone marrow failure, reduced pulmonary function, second primary malignancy (e.g., leukemia, solid tumors)

  • External irradiation:

    • –

      May be used postoperatively in patients with differentiated thyroid carcinoma with or without metastasis

  • Chemotherapy:

    • –

      Generally has limited role in treatment of thyroid cancers; most often used in conjunction with other modes of therapy (surgery and radiation) in treatment of poorly differentiated or undifferentiated (anaplastic) carcinomas

  • Thyroid hormone therapy:

    • –

      Differentiated thyroid carcinomas contain functional thyroid stimulating hormone (TSH) receptors that are more abundant in follicular carcinoma than papillary carcinoma.

    • –

      TSH stimulates growth of differentiated thyroid carcinoma.

    • –

      In theory, suppression of TSH receptors with suppressive doses of thyroxine may result in tumor regression.

  • Prognosis:

    • –

      Prognosis with more common types of thyroid cancers is good with best overall survival rates associated with papillary carcinoma.

    • –

      Important prognostic factors include:

      • ▪

        Presence or absence of extrathyroidal extension

      • ▪

        Presence or absence of metastatic disease: in lymph nodes, presence or absence of extranodal extension

      • ▪

        Age and gender of patient

      • ▪

        Pathologic features including histology, tumor size, presence or absence of encap­sulation

  • Follow-up:

    • –

      There is no standard protocol in follow-up of patients with thyroid cancer.

    • –

      In general, scintiscan should be done within 3 months following initial therapy with reexamination at 1 year.

    • –

      Disease-free patients then have whole-body radioactive iodine scans at 3 and 5 years.

    • –

      Recurrent tumor is treated with radioactive iodine.

    • –

      Serum thyroglobulin measurement

      • ▪

        Reliable biomarker for well-differentiated thyroid follicular epithelial cell–derived cancer recurrence

      • ▪

        Specific and sensitive marker

      • ▪

        Shown to have poor accuracy for predicting malignancy in follicular neoplasms with oncocytic cells

    • –

      Serum calcitonin measurement:

      • ▪

        Used to follow patients with residual or metastatic medullary thyroid carcinoma

Clinical Staging of Thyroid Carcinoma

• Clinical staging of thyroid tumors is determined by physical examination, thyroid imaging, or endoscopic examination:

  • Inspection and palpation of thyroid gland and cervical neck

  • Imaging studies include radioisotope thyroid scans, ultrasonography, CT scan, MRI scan.

  • Endoscopic evaluation includes indirect laryngoscopy to evaluate vocal cord motion.

• TNM classification of thyroid gland cancers ( Table 28-5 ) must include all information obtained in clinical staging plus patient demographics (i.e., age and gender) and information gathered on pathologic evaluation (i.e., fine-needle aspira­­tion biopsy, gross and microscopic evaluation) including:

  • Cancer type (e.g., papillary or follicular carcinoma versus medullary carcinoma versus undifferentiated [anaplastic] carcinoma)

  • Primary tumor size (T)

  • Regional lymph node involvement (N)

  • Distant metastasis (M)

  TABLE 28-5

  TNM Classification of Thyroid Carcinomas

  From Edge SB, et al: AJCC cancer staging manual, ed 7, New York, 2010, Springer, p 89.

  Primary Tumor (T)
  Note : all categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).
  TX	Primary tumor cannot be assessed
  T0	No evidence of primary tumor
  T1	Tumor 2 cm or less in greatest dimension limited to thyroid
  T1a	Tumor 1 cm or less, limited to the thyroid
  T1b	Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid
  T2	Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid
  T3	Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
  T4a	Moderately advanced disease Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
  T4b	Very advanced disease Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
  All anaplastic carcinomas are considered T4 tumors.
  T4a	Intrathyroidal anaplastic carcinoma
  T4b	Extrathyroidal anaplastic carcinoma with gross extrathyroid extension
  Regional Lymph Nodes (N)
  Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.
  NX	Regional lymph nodes cannot be assessed
  N0	No regional lymph node metastasis
  N1	Regional lymph node metastasis
  N1a	Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
  N1b	Metastasis to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph node (Level VII)
  Distant Metastasis (M)
  M0	No distant metastasis
  M1	Distant metastasis

  Pathologic staging (p): Correspond to the T (pT), N (pN), and M (pM) categories.

  Residual tumor is designated as R: RX, Residual tumor cannot be assessed; R0, no residual tumor, R1, microscopic residual tumor, R2, macroscopic residual tumor.

  Additional descriptors: “m” suffix indicates the presence of multiple primary tumors in a single site [pT(m)NM]; “r” prefix indicates recurrent tumor when staged after a disease-free interval [rTNM]; “a” prefix indicates stage determined at autopsy [aTNM].

NOTE: Pathologic staging (p): correspond to the T (pT), N (pN), and M (pM) categories

• Clinical staging of thyroid gland cancers, including papillary or follicular carcinoma, medullary carcinoma, and undifferentiated (anaplastic) carcinoma is detailed in Table 28-6 .

  TABLE 28-6

  Clinical Staging

  From Edge SB, et al: AJCC cancer staging manual, ed 7, New York, 2010, Springer, pp 87-88.

  Separate stage groupings are recommended for papillary or follicular (differentiated), medullary, and undifferentiated (anaplastic) carcinoma.
  Papillary or Follicular (Differentiated)
  Under 45 years
  Stage I	Any T	Any N	M0
  Stage II	Any T	Any N	M1
  45 Years and Older
  Stage I	T1	N0	M0
  Stage II	T2	N0	M0
  Stage III	T3	N0	M0
  	T1	N1a	M0
  	T2	N1a	M0
  	T3	N1a	M0
  Stage IVA	T4a	N0	M0
  	T4a	N1a	M0
  	T1	N1b	M0
  	T2	N1b	M0
  	T3	N1b	M0
  	T4a	N1b	M0
  Stage IVB	T4b	Any N	M0
  Stage IVC	Any T	Any N	M1
  Medullary Carcinoma (All Age Groups)
  Stage I	T1	N0	M0
  Stage II	T2	N0	M0
  	T3	N0	M0
  Stage III	T1	N1a	M0
  	T2	N1a	M0
  	T3	N1a	M0
  Stage IVA	T4a	N0	M0
  	T4a	N1a	M0
  	T1	N1b	M0
  	T2	N1b	M0
  	T3	N1b	M0
  	T4a	N1b	M0
  Stage IVB	T4b	Any N	M0
  Stage IVC	Any T	Any N	M1
  Anaplastic Carcinoma
  All anaplastic carcinomas are considered Stage IV.
  Stage IVA	T4a	Any N	M0
  Stage IVB	T4b	Any N	M0
  Stage IVC	Any T	Any N	M1

Follicular Adenoma (FA) ( Figs. 28-1 through 28-6 )

Definition: Benign encapsulated tumor with evidence of follicular cell differentiation showing growth pattern and cytomorphology different from surrounding thyroid parenchyma, but lacking features of papillary thyroid carcinoma.

• • Whether clonality is a part of definition of an ade­noma in contrast to adenomatoid nodules is controversial because clonality has been shown to be present in a large percentage (70%) of dominant adenomatoid nodules in setting of nodular goiter.

Histologic Types of Follicular AdenomaS ( Box 28-2 )

• Generally, histologic variants of follicular adenoma do not confer on a given neoplasm any difference in clinical parameters or biologic behavior as compared to conventional types of follicular adenomas.

Follicular Adenoma, Oncocytic Type ( Figs. 28-7 through 28-9 )

Definition: Follicular epithelial cell-derived neoplasm dominated by presence of mitochondria-rich cells (i.e., oncocytes, oxyphilic cells) without evidence of invasion or metastasis.

• • Terminology derived from the Greek word meaning “swollen”

  • Results from increase in mitochondrial content of a cell

    • –

      By light microscopy, an oncocytic cell is one that has a prominent granular eosinophilic-appearing cytoplasm.

    • –

      Should be distinguished from cells with cytoplasmic eosinophilia, which:

      • ▪

        Has eosinophilic appearance of cytoplasm in hematoxylin and eosin stain (H&E)-stained sections but lacks granularity and bright pink appearance of oncocytic cells

  • Oncocytic change in thyroid gland not restricted to follicular cells as it can also occur in:

    • –

      Neoplastic C-cells (i.e., oncocytic medullary thyroid carcinoma [MTC])

Synonyms: Hürthle cell adenoma; oncocytic ade­noma; oxyphilic cell adenoma; Askanazy cell adenoma

• Hürthle originally described the cell that is now felt to represent parafollicular cell or C-cell of ultimobranchial derivation and not the oncocyte; description of oncocyte attributed to Askanazy

• Use of designation oncocytic (Hürthle, oxyphilic) is purely descriptive, indicative of a type of change in a cell and NOT indicative of any specified biologic behavior in a thyroid tumor

• Too often, assumption made that diagnosis of “Hürthle cell neoplasm” qualifies tumor as malignant, essentially being synonymous with a follicular carcinoma:

  • Erroneous assumption as oncocytic cell changes can be seen in non-neoplastic and neoplas­tic (benign and malignant) thyroid lesions ( Box 28-3 ).

    Box 28-3

    Thyroid Lesions with Oncocytic Cells

    Non-Neoplastic Lesions

    • Nodular goiter (adenomatoid nodules)

    • Chronic lymphocytic (Hashimoto) thyroiditis

    • Graves disease

    • Postradiation

    • Aging

    Neoplasms

    • Follicular adenoma variants

    • Follicular carcinoma variants

    • Papillary carcinoma variants

    • Medullary carcinoma

    • Undifferentiated (anaplastic) thyroid carcinoma

Clinical

• Similar demographics, clinical presentation, treatment, and biology to “conventional” follicular adenoma

• Serum thyroglobulin measurement reliable biomarker for thyroid cancer recurrence but shown to have poor accuracy for predicting malignancy in follicular neoplasms with oncocytic cells

Pathologic Features

Fine-Needle Aspiration Biopsy

• FNAB diagnosis is “follicular neoplasm or suspicious for a follicular neoplasm, oncocytic (Hürthle) cell type (Bethesda IV),” which informs treating physician that a neoplasm is present requiring surgical removal (e.g., lobectomy)

• Smears or aspirates dominated by enlarged oval to polygonal cells, often in sheets, that have abundant, granular-appearing cytoplasm:

• Nuclei tend to be enlarged, round to oval, eccentrically located with prominent eosinophilic nucleoli.

  • Binucleated cells can be seen.

  • Nuclear chromatin tends to be course.

• Colloid is minimal to absent.

Gross

• Similar to “conventional” follicular adenoma except that oncocytic cell change imparts distinct bright orange to brown coloration

• Vary in size and may be quite large (>4 cm):

  • Large size may correlate to presence of malignant neoplasm (follicular carcinoma, oncocytic type) but does not uniformly correlate to malignancy.

Histology

• Similar histologic features as “conventional” follicular adenoma:

  • Encapsulated tumors

    • –

      Capsule may vary in thickness.

  • No capsular and/or vascular invasion

• Growth patterns may include:

  • Follicular

  • Microfollicular

  • Solid

  • Trabecular

  • Organoid

  • Papillary architecture

    • –

      May be focal or extensive

      • ▪

        Prominent/extensive papillary growth may be seen as a retrogressive phenomenon occurring spontaneously or following fine-needle aspiration biopsy

    • –

      Nuclear characteristics diagnostic for papillary carcinoma absent

• Characterized by presence of cells with abundant eosinophilic granular-appearing cytoplasm

  • Cytoplasmic margins often distinctly seen

• Presence of oncocytic cytoplasm often causes nuclear enlargement but in spite of nuclear enlargement nuclei tend to remain rather uniform-appearing round to oval with coarse to granular to vesicular-appearing chromatin and presence of distinct (centrally located) eosinophilic nucleoli

  • Nuclear grooves and nuclear (pseudo)inclusion may be identified.

  • Presence of such features not diagnostic for papillary thyroid carcinoma and can be seen in benign thyroid lesions/neoplasms

• Clear cell change may be seen:

  • May be juxtaposed or intermixed with oncocytic cells

  • Caused by swelling of mitochondria

• Colloid:

  • May be readily apparent or limited in extent

  • May calcify including concentric laminations, suggesting presence of psammoma bodies and a possible diagnosis of papillary thyroid carcinoma:

  • Typically located within lumens, not usual location in papillary thyroid carcinomas

  • Cytomorphologic (i.e., nuclear) features not those of papillary thyroid carcinoma

• Oncocytic cells owing to oxygen-sensitive nature of mitochondria more readily undergo retrogressive changes either spontaneously or following traumatic event such as post-fine-needle aspiration biopsy; such alterations may include:

  • Infarction

  • Necrosis

  • Hemorrhage (recent and remote in form of hemosiderin-laden macrophages)

  • Papillary architecture

  • Cyst formation

  • Fibrosis

  • Calcifications

• Term Hürthle cell neoplasm of uncertain malignant potential has been ascribed to those tumors showing worrisome but inconclusive features of malignancy, including:

  • Smaller cells with high nuclear-to-cytoplasmic ratio

  • Increased mitotic activity

  • Because these tumors have uniformly followed a benign clinical course this terminology is not advocated and designation of follicular adenoma, oncocytic type is preferred.

• Histochemistry:

  • Stains for mitochondria may be positive and include:

    • –

      Phosphotungstic acid hematoxylin (PTAH): red staining

    • –

      Novelli stain: dark purple staining

• Immunohistochemistry:

  • Cytokeratins, thyroglobulin, and TTF-1 positive:

    • –

      Thyroglobulin reactivity less intense than in nononcocytic follicular cells

  • Chromogranin, synaptophysin, and calcitonin negative

  • Low proliferation indices (less than 5%) by KI67 (MIB-1) staining

• Electron microscopy:

  • Oncocytic cells are packed with mitochondria.

    • –

      Mitochondrial abnormalities can be seen, including quantitative and qualitative (size, shape, content) changes.

• Cytogenetics and molecular genetics:

  • RET/PTC rearrangements may be present:

    • –

      Questionable relevance relative to diagnosis and classification

    • –

      May reflect very low rearrangement level using highly sensitive detection method or tumor heterogeneity

  • Additional findings reported include:

    • –

      Large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins, and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins

    • –

      Such mitochondrial alterations lead to energy production defects in Hürthle cell tumors:

      • ▪

        Increased proliferation of mitochondria may reflect compensatory mechanism for such defects and is associated with overexpres­sion of factors involved in mitochondrial biogenesis

      • ▪

        Mitochondrial abnormalities also thought to play a major role in predisposition for necrosis instead of apoptosis, which seems to be blocked in most Hürthle cell tumors

Differential Diagnosis

• Follicular carcinoma, oncocytic type:

  • Diagnosis of follicular carcinoma, oncocytic type made in presence of capsular or vascular invasion

  • In absence of invasive growth, features found in an encapsulated follicular neoplasm (including the oncocytic follicular adenoma) that may increase concern for malignancy include:

    • –

      Increased cellularity in particular at the tumor-to-capsule-to-stromal interface

    • –

      Smaller cells with increased nuclear-to-cytoplasmic ratio

    • –

      Increased mitotic activity

    • –

      Necrosis either individual cell or confluent foci

• Papillary thyroid carcinoma (PTC):

  • Usual type:

    • –

      Does not have oncocytic cytoplasm but nuclear enlargement and to some degree nuclear clearing seen in follicular adenoma, oncocytic type may be mistaken for PTC

  • Tall cell type:

    • –

      Some authorities consider tall cells to be variant of oncocyte.

• Medullary thyroid carcinoma, oncocytic type:

  • Oncocytic change in thyroid gland not restricted to follicular cells because it can also occur in neoplastic C-cells (i.e., oncocytic medullary thyroid carcinoma [MTC]):

    • –

      Immunohistochemical staining for calcitonin, neuroendocrine markers present in MTC and absent in follicular epithelial cell tumors

    • –

      Immunohistochemical staining for thyroglobulin and TTF1 present in oncocytic follicular adenoma and absent in MTC

Treatment and Prognosis

• Conservative surgery (lobectomy) is preferred treatment and considered curative.

Hyalinizing Trabecular Adenoma/Tumor ( Figs. 28-10 and 28-11 )

Definition: Encapsulated follicular epithelial-derived tumor with trabecular growth pattern and presence of prominent intratrabecular hyalinization located in cytoplasm of lesional cells and in extracellular space.

Synonym: Paraganglioma-like adenoma of thyroid (PLAT)

Terminology

• Controversy among authorities whether hyalinizing trabecular adenoma should be considered variant of papillary thyroid carcinoma (PTC) based on:

  • Occurrence of hyalinizing trabecular adenoma in the setting of lymphocytic thyroiditis or in patients with a history of radiation therapy, two settings more typically seen in association with papillary thyroid carcinoma

  • Co-existence with typical thyroid papillary carcinoma

  • Presence of HTA-like foci in typical thyroid papillary carcinoma

  • Overlapping nuclear features shared with PTC

  • Demonstration of RET/PTC translocation in percentage of cases

  • Occasional presence of nodal metastasis showing pattern of growth similar to hyalinizing trabecular adenoma

• Weighing in favor for categorization as adenoma includes:

  • Overwhelming majority of solitary encapsu­lated thyroid lesions showing feature of hyalinizing trabecular adenoma behave as benign neoplasms

  • BRAF mutations a finding present in PTCs not reported in hyalinizing trabecular adenoma

  • Micro (mi)-RNAs known to be upregulated in PTC were downregulated in hyalinizing trabecular adenoma

• At present, most authorities view hyalinizing trabecular adenoma as a benign neoplasm but given similarities to papillary carcinoma designation hyalinizing trabecular tumor recommended

Clinical

• Affects women more than men; occurs over a wide age range from the third through eighth decades of life

• Clinical presentation is that of an asymptomatic neck mass.

• May occur in any portion of the thyroid gland

• Radiology:

  • Thyroid imaging ( ¹²³ I or ^99m technetium): “cold” nodule; may appear as a “hot” nodule

• Etiology unknown:

  • Several cases reported following radiation exposure

Pathologic Features

Fine-Needle Aspiration Biopsy

• Cohesive aggregates radially oriented around hyaline material

• Cells with abundant cytoplasm and low nuclear-to-cytoplasmic ratio

• Intranuclear cytoplasmic inclusions, nuclear grooves, and nuclear overlapping are common (best seen with the Papanicolaou method):

  • Cytoplasmic yellow bodies useful cytomorphologic indicator of hyalinizing trabecular ade­noma; see details under microscopic description below

    • –

      May be present but uncommon in papillary thyroid carcinoma and in follicular adenomas (including oncocytic variant)

• Diff-Quik–stained smears highlighted the hyaline material (metachromatic), perinucleolar clearing, and cytoplasmic bodies.

• Overall features may suggest papillary thyroid carcinoma or even medullary thyroid carcinoma but combination of a bloody background, radially oriented cohesive cells, cells with abundant cytoplasm, nuclei with very frequent cytoplasmic inclusions and grooves, and presence of hyalin should suggest hyalinizing trabecular adenoma.

Gross

• Well-circumscribed, single, solid, encapsulated or circumscribed tumor measuring from 1 to 5 cm in diameter but usually less than 2.5 cm

• Cut surface shows tendency to appear lobulated.

Histology

• Circumscribed to encapsulated tumor characterized by trabecular to organoid growth with fibrovascular stroma:

  • Trabeculae may appear coiled.

  • Lobulated growth can be seen.

• Presence of prominent extracellular and intracellular hyalinization

• Follicle formation is minimal or absent:

  • Tumor has little colloid formation.

• Characteristically, microcysts and larger cystic spaces are seen:

  • Possibly represent abortive follicle formation

• Cells are elongated and sharply outlined oriented perpendicular to fibrovascular stroma.

• Nuclei are round, oval, or elongated with

  • Nuclear grooves

  • Eosinophilic nuclear (pseudo)inclusions

  • Perinucleolar halos:

    • –

      Represent giant lysosomes as seen by electron microscopy

• Cytoplasm is finely granular with acidophilic, amphophilic, or clear appearance.

• Cytoplasmic yellow bodies common and frequent finding representing very useful finding in FNAB or in surgical pathology material in diagnosis:

  • On H&E staining, appear as solid, round, pale yellow cytoplasmic inclusions surrounded by clear halo

  • Are refractile with a microvacuolated or granular substructure

  • Located close to the nucleus (paranuclear) sometimes indenting the nucleus resulting in semilunar deformity of nucleus (nuclear molding); rarely, may be intranuclear

  • Positive staining with PAS, GMS, alcian blue-PAS, Sudan black B

  • Ultrastructurally, cytoplasmic intermediate filaments, myelinosomes with parallel whorled and stacked membranes (“fingerprint” bodies), swollen mitochondria and huge membrane-limited organelles composed of disrupted membranes and microtubules, vesicles, and myelinosomes with “fingerprint” bodies; the organelles may occupy a semilunar depression in the nucleus.

  • Yellow bodies are consistent with giant lysosomes.

  • Yellow bodies are uncommon but may be identified in other thyroid neoplasms, including papillary carcinoma, follicular carcinoma, follicular adenoma or carcinoma with oncocytic cells

• Calcifications including calcified colloid and/or psammoma body-like formations can be seen.

• Chronic lymphocytic thyroiditis is often found in surrounding thyroid gland.

• Occasional mitotic figure may be identified

• Histochemistry:

  • Hyalinized foci may suggest presence of amyloid but staining for amyloid including Congo red is negative.

• Immunohistochemistry:

  • Thyroglobulin and TTF-1:

    • –

      Thyroglobulin may be limited to follicles and microcysts.

    • –

      TTF-1 (nuclear staining) present in lesional cells

  • Unique cell membrane and cytoplasmic granular immunoreactivity for MIB-1 (Ki67):

    • –

      Present with some monoclonal antibodies but not polyclonal antibodies suggesting this staining is artifactual

  • Calcitonin, chromogranin, synaptophysin negative

  • Galectin-3 expression may be present:

    • –

      Variable expression; seen in some but not all cases and when present is never as intense as might be present in papillary thyroid carcinoma

  • Until recently HBME-1 negative but immunoreactivity reported with staining of lesional cells and intratrabecular hyaline matrix material identified

  • CD56 reactivity (membranous) may be present.

  • Discrepant results reported for high-molecular-weight cytokeratins and CK19

• Cytogenetics and molecular genetics:

  • Presence of RET/PTC somatic translocations with similar (or greater) frequency to that of thyroid papillary carcinoma.

  • Absence of BRAF mutation

  • Micro (mi)-RNAs known to be upregulated in PTC not found in hyalinizing trabecular adenoma

Differential Diagnosis

• Other thyroid lesions/neoplasms with trabecular growth and hyalinization:

  • Adenomatoid nodules

  • Lymphocytic thyroiditis

• Papillary thyroid carcinoma

• Medullary thyroid carcinoma

• Paraganglioma

Treatment and Prognosis

• Conservative surgery (lobectomy or subtotal thyroidectomy)

• Excellent prognosis following surgical removal

Additional Notes

• Hyalinizing trabecular neoplasms with minimally invasive growth have been identified and termed.

Follicular Adenoma with Atypical Features ( Fig. 28-12 )

Definition: Any encapsulated follicular neoplasm that lacks features for papillary thyroid carcinoma but shows histologic features suspicious for a more aggressive neoplasm (i.e., carcinoma) without definitive evidence of either capsular or vascular space invasion .

Synonyms: Atypical follicular adenoma; follicular tumor/neoplasm of uncertain malignant potential; well-differentiated (follicular) tumor of uncertain malignant potential

Clinical

• Demographics and clinical presentation similar to those of (typical) follicular adenoma

Pathology

• Macroscopic and FNAB features similar to those of (typical) follicular adenoma

• Histologic features that raise possibility of a potentially more aggressive follicular neoplasm (i.e., carcinoma) and that may be considered as “atypical” include:

  • Increased mitotic activity in absence of necrosis:

    • –

      Benign endocrine organ neoplasms generally are amitotic, and presence of mitoses raises concern for possibility of a malignant tumor.

    • –

      However, as an isolated finding increased mitotic activity is not indicative of malignancy.

    • –

      In presence of necrosis consideration for a possible diagnosis of poorly differentiated thyroid carcinoma should be entertained (see under Malignant Neoplasms)

  • Necrosis (in absence of previous FNAB):

    • –

      Presence of coagulative type necrosis considered potentially worrisome features for carcinoma (even more so than mitotic activity)

  • Pronounced cellular proliferation with diffuse nuclear atypia

  • Categorization of a tumor as being atypical or of uncertain biologic behavior may include encapsulated follicular tumors in which tumor extends only to inner half of its capsule but falling short for definitive evidence of capsular invasion, which would allow diagnosis of follicular carcinoma

• Classification of an encapsulated follicular tumor showing equivocal cytomorphologic features for papillary thyroid carcinoma or limited foci diagnostic for papillary thyroid carcinoma remains controversial:

  • If extent of change is significant/widespread (to date there is no clear definition of what constitutes “significant” or “widespread”) then diagnosis of encapsulated (noninvasive) papillary thyroid carcinoma, follicular variant, can be made although recent recommendation is to replace the term “follicular variant of PTC” with “noninvasive follicular tumor with papillary-like features.” (See under PTC in malignant neoplasms.)

  • If nuclear features are equivocal and there is no invasion, then such a tumor can be termed as an atypical adenoma.

  • If features are equivocal but there is definitive evidence of invasion, then tumor can be diagnosed as carcinoma:

    • –

      In such circumstances specific designation of type of carcinoma (i.e., papillary versus follicular) is academic because treatment should be similar.

    • –

      Depending on one's level of confidence following designations can be used for a neoplasm with invasive growth but equivocal cytomorphologic features:

      • ▪

        Carcinoma, favor papillary thyroid carcinoma, follicular variant

      • ▪

        Carcinoma, favor follicular carcinoma, minimally invasive

      • ▪

        Well-differentiated carcinoma, not otherwise specified

• In follicular neoplasm considered to be atypical (or in any encapsulated thyroid neoplasm with questionable features for malignancy) most critical issue is adequate and appropriate sectioning to evaluate tumor-capsule-thyroid parenchymal interface for evidence of invasive growth:

  • Guideline to number of sections considered adequate to exclude the presence of invasion include:

    • –

      For a tumor measuring <6 cm = submit entire tumor

    • –

      For a tumor measuring 6 cm = submit at least 10 blocks

    • –

      For a tumor measuring >6 cm = submit one additional block per centimeter of tumor

• Cytogenetics and molecular genetics:

  • Telomerase reverse transcriptase (TERT) promoter mutations (C228T and C250T) found in many malignancies, including in thyroid car­cinomas, may be present in atypical follicular adenoma (and less commonly in “usual” follicular adenoma).

    • –

      May occur as early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathologic workup

Differential Diagnosis

• Follicular carcinoma, minimally invasive

• Adenomatoid nodules

• Papillary thyroid carcinoma, follicular variant

Treatment and Prognosis

• Treatment is surgical removal (similar to usual types of follicular adenomas):

  • Surgery is conservative in extent limited to the affected portion(s) of the thyroid gland (lobectomy or subtotal thyroidectomy).

  • Prognosis is excellent.

  • Long-term follow-up shows atypical follicular adenomas to behave in a benign course.

Follicular Adenomas Classified by Cell Type or Growth Pattern

• All have similar demographics, clinical presentation, treatment, and biology as “conventional” follicular adenomas.

Follicular Adenoma with Clear Cells ( Figs. 28-13 and 28-14 )

• Predominantly or exclusively composed of cells with clear (empty) to finely granular-appearing cytoplasm:

  • Clear-appearing cytoplasm may be due to:

    • –

      Massively dilated mitochondria appearing as intracytoplasmic vesicles on electron microscopy

    • –

      Intracytoplasmic glycogen, lipid, or mucin accumulation

    • –

      Intracytoplasmic thyroglobulin deposition:

      • ▪

        Intracellular thyroglobulin accumulation may be related to effects of thyroid stimulating hormone (TSH) causing increased thyroglobulin deposition within cell cytoplasm due to inability of cell to release or excrete it.

  • Clear cell change may be closely linked to oncocytic cell change representing “end-stage” cytoplasmic changes of a tumor that once was predominantly oncocytic.

• Nuclei are centrally situated, are small, round, and regular with hyperchromasia with or without sharp cell outlines.

• Growth pattern is usually follicular but may include trabecular or solid growth.

• Colloid-containing follicles may be absent or only focally identified; periodic acid Schiff (PAS) is helpful in identifying the presence of colloid.

• Histochemistry:

  • Diastase-sensitive, PAS-positive intracytoplasmic material

• Immunohistochemistry:

  • Thyroglobulin, TTF-1 (nuclear), and PAX8 (nuclear) positive but may be focal and of limited intensity

  • Calcitonin and neuroendocrine cell markers (chromogranin and synaptophysin) negative

  • CD10, renal cell carcinoma (RCC) antibody, carbonic anhydrase IX (CAIX), PAX2, PAX8 negative

Differential Diagnosis

• Metastatic renal cell carcinoma ( Table 28-8 )

  TABLE 28-8

  Follicular Tumors with Clear Cells versus Metastatic Renal Cell Carcinoma

  Features	Follicular Adenoma/Carcinoma with Clear Cells	Metastatic Renal Cell Carcinoma
  Luminal secretion	Colloid; will be PAS positive	No colloid; red blood cells; pseudofollicles
  Nested growth with fibrovascular stroma	Present	Present
  Cytoplasm	Foamy appearing	Clear with distinct cell borders
  Nuclear	Round; dispersed or coarse chromatin	Small, round, hyperchromatic
  Glycogen (diastase-sensitive, PAS-positive)	Yes, but colloid will be diastase resistant	Yes; intensely positive
  IHC findings	Thyroglobulin, TTF-1, PAX8 positive; CD10, RCC, CAIX, PAX2 negative	Thyroglobulin, TTF-1 negative CD10, RCC, CAIX, PAX2, PAX8 positive

  CAIX, Carbonic anhydrase IX; IHC, immunohistochemistry; RCC, renal cell carcinoma antibody; TTF-1, thyroid transcription factor 1.

• Follicular carcinoma with clear cells

• Papillary thyroid carcinoma

• Parathyroid lesions

• Medullary thyroid carcinoma with clear cells

Follicular Adenoma with Signet Ring Cells ( Fig. 28-15 )

Synonym: Signet ring cell adenoma

Pathology

Fine-Needle Aspiration

• Signet ring cells are round to oval, with large cytoplasmic vacuoles and hyperchromatic, eccentric nuclei.

• Colloid in the background may be scanty.

Histology

• Characterized by cells that have large intracytoplasmic vacuoles that result in eccentric displacement of cell nucleus creating a signet ring appearance:

  • Cytoplasm appears clear to acidophilic to finely granular.

  • Nuclei are hyperchromatic and flattened or semilunar in appearance but may retain a rounder appearance.

• Growth pattern is microfollicular and nested; colloid is readily apparent.

• Histochemistry:

  • Diastase-resistant, PAS-positive intracytoplasmic material

  • Mucicarmine and alcian blue may be positive.

    • –

      Thyroglobulin is a sialic acid–containing glycoprotein, and therefore thyroglobulin will stain with periodic acid Schiff (PAS) and acid mucin stains (e.g., alcian blue at pH 2.5, sulfomucin).

    • –

      Mucicarmine, a stain for neutral mucins, is positive but usually weakly positive:

      • ▪

        Mucicarminophilia seen in the signet ring cells is attributed to intracytoplasmic thyroglobulin accumulation.

• Immunohistochemistry:

  • Strong thyroglobulin reactivity is present:

    • –

      Intense thyroglobulin immunoreactivity correlates to intracytoplasmic thyroglobulin deposition that, in turn, gives cell its signet ring appearance.

    • –

      Intracellular thyroglobulin accumulation may be related to effects of thyroid-stimulating hormone (TSH), causing increased thyroglobulin deposition within cell cytoplasm due to inability of cell to release or excrete it.

    • –

      Weak thyroglobulin staining may be present in a given example.

  • TTF-1 and PAX8 (nuclear) immunoreactive

  • Calcitonin and neuroendocrine cell markers (chromogranin and synaptophysin) are negative.

Differential Diagnosis

• Metastatic adenocarcinoma (lung, gastrointestinal tract)

Follicular Adenoma with Intracellular Fat Droplets ( Fig. 28-16 )

Synonym: Lipid-rich adenoma

• Follicular adenoma with fat is extremely rare.

• Fat in follicular epithelial cells may occur as a result of aging.

• Characterized by cells that have small to medium-sized intracytoplasmic vesicles that result in indentation of centrally situated nucleus.

• Histochemistry:

  • Oil red O or other fat stains will be positive.

• Immunohistochemistry:

  • Thyroglobulin and TTF-1 positive

Differential Diagnosis

• Thyrolipoma

Mucinous Follicular Adenoma or Follicular Adenoma with Mucinous Stroma ( Fig. 28-17 )

• Characterized by presence of abundant extracellular basophilic-appearing mucin

• Growth patterns include microcystic, reticular, or multicystic

• Mucinous pools may be present.

• Signet ring cells may be identified.

• Extracellular mucin stains with alcian blue and colloidal iron but not with mucicarmine and DPAS

• Tumor cells positive for thyroglobulin and negative for calcitonin, CEA, galectin-3, HBME-1, and CK19

• Considered a degenerative phenomenon

Follicular Carcinoma (FC) ( Figs. 28-22 through 28-31 )

Definition: Malignant follicular epithelial cell, not belonging to papillary carcinoma, characterized by invasive growth (i.e., capsular and/or vascular invasion) and/or metastatic disease.

Follicular Carcinoma, Oncocytic Type ( Figs. 28-32 and 28-33 )

Definition: Follicular epithelial cell-derived neoplasm exclusively or predominantly (at least 75%) composed of cells with prominent granular eosinophilic cytoplasm (rich in mitochondria) with evidence of invasion but without diagnostic features for papillary thyroid carcinoma:

• • Similar to nononcocytic follicular carcinomas; classification includes low-grade (minimally invasive) and widely invasive depending on extent of invasion

  • Simply because a tumor has oncocytic cells does not correlate to an aggressive neoplasm; however, higher proportion of solitary encapsulated oncocytic follicular tumors are invasive and therefore malignant as compared to solitary encapsulated nononcocytic follicular tumors.

  • Whether follicular carcinoma, oncocytic type is a histologic variant of conventional follicular carcinoma or a distinct type of follicular carcinoma remains debatable:

    • –

      Similar pathologic features, aside for presence of oncocytes, support inclusion as variant of conventional follicular carcinoma

    • –

      Differences in biologic behavior and natural history support distinct tumor type

Synonyms: Hürthle cell carcinoma, oncocytic follicular carcinoma, oxyphilic cell carcinoma

Clinical

• More common in women than in men; tends to occur in patients approximately 10 years older than those with follicular adenoma, oncocytic type

  • As a group follicular carcinomas with oncocytic cells tend to:

    • –

      Occur in older patients than adenomas (approximately 1 decade older)

    • –

      Be larger tumors (approximately 2.0 cm larger)

      • ▪

        Such features often associated with higher frequency of malignancy as compared to nononcocytic follicular neoplasms.

• Clinical and radiographic features are similar to other follicular carcinomas:

  • Painless thyroid nodule

  • Most are solitary; rarely may be multifocal or bilateral

Pathology

Fine-Needle Aspiration Biopsy

• Cytology essentially similar to follicular adenoma with oncocytic cells

• Smears or aspirates are dominated by enlarged oval to polygonal cells, often in sheets, that have abundant, granular-appearing cytoplasm.

• Due to the oncocytic cytoplasm, there is nuclear enlargement:

  • Nuclei are round to oval and eccentrically located

  • Binucleated cells can be seen.

  • In contrast to its benign counterpart, in follicular carcinoma with oncocytic cells there may be greater nuclear enlargement and increased nuclear pleomorphism, but these findings are not diagnostic for a malignancy.

  • Prominent round, eosinophilic nucleoli are seen.

• Colloid is minimal to absent.

Gross

• Macroscopic appearance is similar to their benign counterparts, although carcinomas tend to be larger than adenomas.

Histology

• Findings similar to follicular adenoma, oncocytic type except that invasion is present:

  • Criteria identical to those described in conventional follicular carcinoma including capsular and/or vascular invasion (see previous)

  • Classification includes minimally and widely invasive categories.

• Histologic features that may be different from follicular adenomas with oncocytic cells include:

  • Thicker capsule

  • Greater degree of solid or trabecular growth

  • Increased nuclear-to-cytoplasmic ratio

  • Presence of increased mitotic activity

  • Presence of necrosis (individual cell or confluent areas)

• Colloid:

  • May be readily apparent or limited in extent

  • May calcify including concentric laminations, suggesting presence of psammoma bodies and a possible diagnosis of papillary thyroid carcinoma:

    • –

      Typically located within lumens, not usual location in papillary thyroid carcinomas

    • –

      Cytomorphologic (i.e., nuclear) features not those of papillary thyroid carcinoma

• Oncocytic cells owing to oxygen-sensitive nature of mitochondria more readily undergo retrogressive changes either spontaneously or following traumatic event such as post-fine-needle aspiration biopsy; such alterations may include:

  • Infarction

  • Necrosis

  • Hemorrhage (recent and remote in form of hemosiderin-laden macrophages)

  • Papillary architecture

  • Cyst formation

  • Fibrosis

  • Calcifications

• Histochemistry:

  • Stains for mitochondria may be positive and include:

    • –

      Phosphotungstic acid hematoxylin (PTAH): red staining

    • –

      Novelli stain: dark purple staining

• Immunohistochemistry:

  • Cytokeratin, thyroglobulin, and TTF-1 positive:

    • –

      Thyroglobulin reactivity less intense than in nononcocytic follicular cells

    • –

      CK14 reported as selective marker for thyroid oncocytic cells

  • Chromogranin, synaptophysin, and calcitonin negative

• Electron microscopy:

  • Oncocytic cells are packed with mitochondria.

    • –

      Mitochondrial abnormalities can be seen including quantitative and qualitative (size, shape, content) changes.

• Cytogenetics and molecular genetics:

  • RAS mutation in 12% to 25%

  • PAX8/PPARγ rearrangement in 27%:

    • –

      Most with follicular architecture

  • RET/PTC rearrangement in 38%:

    • –

      All with solid pattern of growth

    • –

      Identification of RET/PTC using highly sensitive methods possibly reflecting very low rearrangement level disputes this finding

    • –

      Other studies failed to identify RET/PTC in oncocytic follicular tumors.

  • GRIM-19 mutation

  • TERT C228T promoter mutation detected (in widely and minimally invasive tumors)

  • Identification of aneuploidy in an oncocytic follicular neoplasm does not differentiate an oncocytic follicular adenoma from an oncocytic follicular carcinoma because both tumor types may show aneuploid cell populations.

  • PIK3CA-Akt-mTOR and Wnt/β-catenin pathways reported to differentiate follicular carcinoma, oncocytic type from follicular adenoma, oncocytic type

Differential Diagnosis

• Follicular adenoma, oncocytic type:

  • Term Hürthle cell neoplasm of uncertain malignant potential ascribed to those tumors showing worrisome but inconclusive features of malignancy, including:

    • –

      Smaller cells with high nuclear-to-cytoplasmic ratio

    • –

      Increased mitotic activity

    • –

      Because these tumors have uniformly followed a benign clinical course this terminology is not advocated, and designation of follicular adenoma, oncocytic type is preferred.

• Papillary thyroid carcinoma, oncocytic type

• Medullary thyroid carcinoma, oncocytic type

• Oncocytic tumor of parathyroid gland origin

Treatment and Prognosis

• Treatment often includes total thyroidectomy and postoperative radioactive iodine therapy

  • Generally less avidity for uptake of radioactive iodine as compared to nononcocytic follicular carcinomas

• 5-year mortality rates of 20% to 40%

• Metastases occur to:

  • Lungs and bone

  • Less commonly to regional lymph nodes:

    • –

      Reported 5% to 10% of cases

    • –

      Tends to occur in association with locally advanced disease or distant metastases

    • –

      In presence of nodal metastasis strict criteria must be applied as to exclude diagnosis of papillary thyroid carcinoma, oncocytic type

    • –

      When spreads to neck occurs usually does so as soft tissue implants rather than to lymph nodes:

      • ▪

        Likely resulting from spread within venous channels

• Overall mortality rate of 30% to 70%:

  • Worse prognosis as compared to nononcocytic follicular carcinomas may correlate to:

    • –

      Tend to occur in an older population, which carries a greater risk of aggressive behavior

    • –

      Higher percentage show presence of extrathyroidal extension

    • –

      Higher percentage of tumors recur more often and metastasize more frequently.

    • –

      Less avidity to take up radioactive iodine

  • Unfavorable prognosis factors may include:

    • –

      Occurrence in men

    • –

      Older age

    • –

      Larger tumor size (≥4 cm in greatest dimension)

    • –

      Aneuploidy tumors behave more aggressively than diploid tumors.

  • Recent literature reports improvement in survival for follicular carcinoma, oncocytic type such that survival rates now similar to those of conventional follicular carcinoma

    • –

      Improvement in survival reported for both genders, in patients ≥45 years of age, in local and regional disease, and for tumors >4 cm

Papillary Thyroid Carcinoma (PTC), Usual or Conventional Type ( Figs. 28-34 through 28-44 )

Definition: Malignant epithelial cell-derived neoplasm with evidence of follicular cell differentiation defined or diagnosed on basis of characteristic nuclear features:

• • Papillary architecture is not a requisite feature for diagnosis.

  • Invasive growth is not a requisite feature for diagnosis.

Variants of Papillary Thyroid Carcinoma

Papillary Microcarcinoma ( Figs. 28-45 through 28-48 )

Definition: Represents an incidentally identified focus of papillary carcinoma that measures 1.0 cm or less in greatest dimension ( Box 28-6 ).

Box 28-6

Histologic Types of Papillary Thyroid Carcinomas

Variants

• Papillary microcarcinoma

• Encapsulated variant

• Follicular variant

• Macrofollicular variant

• Oncocytic variant

• Clear cell variant

• Solid variant or radiation-induced pediatric variant

• Cribriform-morular variant

• Warthin-like variant

• Diffuse follicular variant

Biologically Aggressive Variants

• Diffuse sclerosing variant

• Tall cell variant

• Columnar cell variant

• Hobnail variant

• Poorly differentiated thyroid carcinoma

• Undifferentiated (anaplastic) thyroid carcinoma

Synonyms: Papillary microtumor; occult thyroid papillary carcinoma; occult sclerosing thyroid papillary carcinoma; microscopic papillary thyroid carcinoma; latent thyroid papillary carcinoma

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