Head and Neck

Thyroid Gland

Granulomatous Thyroiditis (De Quervain Thyroiditis)

Clinical Features

  • Also called subacute thyroiditis

  • Presents with clinically marked tenderness of thyroid, fever, sore throat, and malaise most likely related to systemic viral illness

  • Most commonly affects middle-aged women

  • Majority of cases show complete resolution; initial phase often is hyperthyroid (elevated thyroxine [T 4 ] and triiodothyronine [T 3 ] levels); may lead to hypothyroidism, usually euthyroid on resolution

  • Rarely comes to surgery; treated with aspirin, steroids

Gross Pathology

  • Asymmetrically enlarged, firm thyroid

  • Nodular process involving entire gland


  • Nodular process, variable fibrosis

  • Mixed inflammatory infiltrate: lymphoplasmacytic, giant cells, neutrophils with microabscesses (early), and foamy histiocytes

  • Giant cells contain ingested extravasated colloid material ( Figure 3.1 )

    Figure 3.1

    Subacute thyroiditis (de Quervain thyroiditis).

    Section shows foreign-body giant cell granulomas. The giant cells contain ingested colloid material.

  • Centered around follicles, which are lost in later stage

Special Stains and Immunohistochemistry

  • May need acid-fast bacillus (AFB) stain and Gomori methenamine silver (GMS) stain to evaluate for infectious etiology

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Acute Thyroiditis

  • Neutrophilic infiltration within thyroid gland parenchyma

  • Microabscesses and necrosis common, possible vasculitis

  • No granuloma formation

  • Caused by bacterial, fungal, or viral infections

Granulomatous Diseases

  • Sarcoidosis: granulomas (noncaseating) in interstitial location

  • Tuberculosis: caseating granulomas (AFB stain)

  • Fungal: usually acute and necrotizing, less likely granulomatous (GMS stain)

Riedel Thyroiditis

  • Diffuse fibrotic process involving the thyroid obliterating the thyroid architecture

  • Fibrosis extends to soft tissue outside the thyroid

  • Giant cells are absent

Hashimoto Thyroiditis

  • Lymphocytic thyroiditis with germinal center formation and oxyphilic change of the follicular epithelium

  • May have extensive fibrosis with follicular loss and architectural distortion

Palpation Thyroiditis

  • Result of minor trauma to thyroid tissue

  • Usually an incidental finding

  • Scattered small foci of histiocytes, few lymphocytes, and rare giant cells within thyroid follicles (no neutrophils)


  • Associated with systemic viral infection, usually self-limited, ending euthyroid

  • Neutrophilic inflammation only seen in initial or early stage of disease

Selected References

  • Benbassat C.A., Olchovsky D., Tsvetov G., et. al.: Subacute thyroiditis: clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005. J Endocrinol Invest 2007; 30: pp. 631-635.

  • Duininck T.M., van Heerden J.A., Fatourechi V., et. al.: De Quervain’s thyroiditis: surgical experience. Endocrine Pract 2002; 8: pp. 255-258.

  • Kojima M., Nakamura S., Oyama T., et. al.: Cellular composition of subacute thyroiditis: an immunohistochemical study of six cases. Pathol Res Pract 2002; 198: pp. 833-837.

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Clinical Features

  • Immune-mediated inflammatory disease

  • Autoantibodies detected in serum: antithyroglobulin, antithyroid peroxidase, antithyroid microsomal antibodies

  • Marked female predominance (5:1); peak in middle-aged women

  • Higher incidence in high-iodine areas (United States, Japan)

  • Clinically hypothyroid with diffuse, firm, enlarged thyroid

  • Familial cases; associations with human leukocyte antigen (HLA)-DR3 and HLA-DR5

  • Higher incidence in Turner and Down syndromes and familial Alzheimer disease

  • May coexist with other autoimmune diseases (Sjögren syndrome, diabetes, others)

  • Increased risk for primary thyroid lymphoma

  • Immunoglobulin G4 (IgG4) may be related to a subset with fibrosis

Gross Pathology

  • Firm, diffusely enlarged thyroid

  • Cut surface is pale tan-yellow and nodular ( Figure 3.2A )

    Figure 3.2

    Hashimoto thyroiditis.

    A, Gross photograph showing thyroid enlargement with a pale lobulated cut surface. B, Marked lymphocytic infiltration with germinal center formation; inset shows follicular atrophy, marked plasma cell infiltrate, and fibrosis.


  • Marked lymphoplasmacytic infiltration with germinal center formation (see Figure 3.2B )

  • Follicles are small with scant colloid

  • Oncocytic metaplasia (Hürthle cell change) with enlarged, hyperchromatic nuclei of follicles may show proliferation (dominant nodules)

  • Squamous metaplasia is common

  • Fibrosis varies; marked in fibrous variant

  • Nodularity of follicles and inflammation may extend into adjacent soft tissue (do not mistake for metastasis in lymph node)

  • Optically clear and enlarged follicular nuclei often present

Special Stains and Immunohistochemistry

  • Rarely necessary—inflammation is mixed B (CD20) and T (CD3, CD4, CD8) cells, plasma cells polyclonal (κ and λ cells)

Other Techniques for Diagnosis

  • Clinical evaluation for antibodies

Differential Diagnosis

Extranodal Marginal Zone B-Cell Lymphoma (Mucosa-Associated Lymphoid Tissue [Malt] Lymphoma)

  • Rapid enlargement with sheets of lymphocytic infiltrate

  • Increased risk in Hashimoto thyroiditis

Associated Papillary Thyroid Carcinoma

  • Look for architectural distortion, fibrosis, invasive nests

  • Cellular proliferation with strict nuclear criteria of papillary carcinoma

  • Optically clear and enlarged nuclei may accompany lymphocytic thyroiditis

Follicular Neoplasm

  • Well-circumscribed lesion with capsule

  • Define based on capsular breach and lymphovascular invasion

Nonspecific Lymphocytic Thyroiditis

  • Scattered, patchy chronic inflammation, occasional germinal center

  • Lacking oncocytic changes

  • Minimal fibrosis


  • May coexist with other thyroid neoplasms (especially papillary thyroid carcinoma); follicular nuclear changes may overlap

  • Rare malignant transformation into lymphoma (mucosa-associated lymphoid tissue [MALT], diffuse large B-cell lymphoma)

  • Benign follicles and lymphocytes may form nodules separated from the gland (parasitic nodule) in soft tissue

Selected References

  • Deshapande V., Huck A., Ooi E., et. al.: Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease. J Clin Pathol 2012; 65: pp. 725-728.

  • MacDonald L., Yazdi H.M.: Fine needle aspiration biopsy of Hashimoto’s thyroiditis: sources of diagnostic error. Acta Cytol 1999; 43: pp. 400-406.

  • Nguyen G.K., Ginsberg J., Crockford P.M., et. al.: Hashimoto’s thyroiditis: cytodiagnostic accuracy and pitfalls. Diagn Cytopathol 1997; 16: pp. 531-536.

Riedel Thyroiditis

Clinical Features

  • Also called Riedel struma, fibrous thyroiditis

  • Very rare; predilection for women (5:1) with peak in fifth decade

  • Clinically appears as an ill-defined, extremely firm, painless goiter

  • May present with dyspnea as a result of tracheal compression

  • Belongs to the spectrum of IgG4-related disease

  • One third of patients will develop a process in other sites: mediastinal or retroperitoneal fibrosis, sclerosing cholangitis (regarded as a manifestation of the idiopathic inflammatory fibrosclerosis disorders)

Gross Pathology

  • Diffuse enlargement of thyroid gland, hard, stonelike with adherent soft tissue

  • Cut surface white, fibrotic, and “woody”


  • Prominent finding is fibrosis extending into soft tissue and muscle (greater than inflammation)

  • Scattered mixed chronic inflammatory infiltrate (lymphocytes, plasma cells, neutrophils, monocytes, eosinophils) ( Figure 3.3 )

    Figure 3.3

    Riedel thyroiditis.

    Diffuse fibrosis is present with scattered inflammatory cells.

  • “Occlusive phlebitis” with infiltration of veins by lymphocytes and plasma cells; vessels have thickened wall and myxoid change

  • Giant cells or germinal centers are not present

Special Stains and Immunohistochemistry

  • Presence of IgG4 plasma cells with IgG4 to IgG ratio (usually >40%)

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Hashimoto Thyroiditis (Fibrous Variant)

  • Characterized by lobulated, follicular epithelium with oncocytic change, giant cells, lymphocytes with germinal center formation, and plasma cells

  • Eosinophils not identified

Undifferentiated Thyroid Carcinoma

  • Scattered malignant cells (spindle, epithelioid, or pleomorphic) within fibrosis

  • Cytokeratin may assist in identification of tumor cells within fibrosis and outside of the thyroid gland

Granulomatous (Subacute) Thyroiditis

  • Asymmetrical enlargement of the thyroid gland

  • Granulomas with giant cells involving follicles, neutrophils at early stage


  • Clinically may be mistaken for malignancy

  • Treatment with corticosteroid or tamoxifen therapy; surgery for compression

  • Benign: self-limited (almost half develop hypothyroidism)

Selected References

  • Harigopal M., Sahoo S., Recant W.M., et. al.: Fine-needle aspiration of Riedel’s disease: report of a case and review of the literature. Diagn Cytopathol 2004; 30: pp. 193-197.

  • Rotondi M., Carbone A., Coperchini F., et. al.: Diagnosis of endocrine disease: IgG4-related thyroid autoimmune disease. Eur J Endocrinol 2019; 180: pp. R175-R183.

  • Schwaegerle S.W., Bauer T.W., Esselstyn C.B.: Riedel’s thyroiditis. Am J Clin Pathol 1988; 90: pp. 715-722.

  • Yasmeen T., Khan S., Patel S.G., et. al.: Clinical case seminar. Riedel’s thyroiditis: report of a case complicated by spontaneous hypoparathyroidism, recurrent laryngeal nerve injury, and Horner’s syndrome. J Clin Endocrinol Metab 2002; 87: pp. 3543-3547.

Graves Disease (Diffuse Toxic Goiter)

Clinical Features

  • Autoimmune thyroid disease; thyroid-stimulating immunoglobulin (TSI)

  • Peak in third to fourth decade; marked predominance in women at least 5:1

  • Strong association with HLA-DR3 and HLA-B8

  • Clinically presents with thyrotoxicosis: muscle weakness, weight loss, exophthalmos, tachycardia, and goiter

  • Suppressed thyroid-stimulating hormone (TSH), increased T 4 and T 3

Gross Pathology

  • Diffuse enlargement of the thyroid, usually symmetrical ( Figure 3.4A )

    Figure 3.4

    Graves disease.

    A, Gross photograph of a diffusely enlarged pale thyroid. B, Low-power view shows scant colloid in hyperplastic follicles with papillary formations and inflammatory infiltrate; inset shows bland nuclei, papillary growth pattern, and scalloped colloid.

  • Diffusely beefy-red cut surface


  • Hyperplastic thyroid follicles with papillary infoldings (see Figure 3.4B )

  • Follicular nuclei remain round and basally located, may be clear

  • Colloid is typically decreased; when present, shows prominent peripheral scalloping

  • Colloid increases after treatment

  • Lymphocytic inflammation patchy in stroma (varies)

  • Nuclear atypia and stromal fibrosis may be seen after radioactive iodine therapy

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Clinical evaluation for antibodies and thyroid levels

Differential Diagnosis

Adenomatoid Nodule, Nodular Hyperplasia

  • Follicles of varying sizes with occasional Sanderson polsters (groups of small, active follicles at one pole)

  • Nonencapsulated

Papillary Thyroid Carcinoma

  • Complete nuclear features are absent in Graves disease (overlapping, grooving)

  • Invasive pattern when present is helpful


  • Treatment is drug therapy or radioactive iodine; surgery if uncontrolled

  • Morphologic appearance cannot predict the patient’s current functional status

  • Radioactive iodine causes nuclear atypia in follicular cells of no significance

Selected References

  • LiVolsi V.A.: The pathology of autoimmune thyroid disease: a review. Thyroid 1994; 4: pp. 333-339.

  • Lloyd R.V., Douglas B.R., Young W.F.: Endocrine diseases.King D.W.Atlas of Nontumor Pathology.2002.ARP PressWashington, DC:pp. 125-133.

  • Takamatso J., Takeda K., Katayama S., et. al.: Epithelial hyperplasia and decreased colloid content of the thyroid gland in triiodothyronine predominant Graves disease. J Endocrinol Metab 1992; 75: pp. 1145-1150.

Multinodular Goiter

Clinical Features

  • Also known as adenomatoid goiter, adenomatous hyperplasia

  • Incidence of 3% to 5% in general population; endemic in iodine-deficient areas

  • Probably caused by impairment of hormone production

  • Adult females predominate over adult males (8:1)

  • Clinically often asymptomatic; may cause discomfort, compression

  • May grow to massive size in neck or mediastinum

  • Number and size of nodules varies; dominant nodule leads to workup

Gross Pathology

  • Enlarged, nodular thyroid gland, may be asymmetrical ( Figure 3.5A )

    Figure 3.5


    A, Gross photograph of an enlarged thyroid with nodularity, fibrosis, and hemorrhage. B, Thyroid follicles vary in size and are often dilated with colloid accumulation.

  • Cut surface shows various-sized nodules, often with colloid

  • Variegated appearance from hemorrhage to cystic degeneration and calcification


  • Heterogeneous, unencapsulated, medium to large distended follicles (see Figure 3.5B )

  • May have scattered, solid, microfollicular nodules; papillary hyperplasia; or oncocytic changes

  • Surrounding thyroid follicles are usually not compressed by nodules

  • Background of hemorrhage, fibrosis, calcification

  • Parasite nodules (nodules separated from the main gland) are common

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Follicular Adenoma

  • Typically solitary

  • Composed of uniform small follicles or macrofollicles

  • Distinct fibrous capsule surrounds nodular proliferation

  • Compression of adjacent thyroid tissue

Graves Disease

  • Gross examination: diffuse, beefy-red, less nodular than multinodular goiter

  • Hyperplastic thyroid follicles with papillary infoldings

  • Vacuolated cytoplasm of follicular cells, and colloid with scalloped borders

  • Laboratory tests indicate hyperthyroidism

Amyloid Goiter

  • Diffusely enlarged thyroid; waxy, pale cut surface

  • Amyloid deposits around vessels and intercellular between follicles

  • Secondary follicle atrophy and squamous metaplasia

  • Congo red stain with polarization to detect birefringent apple-green amyloid

  • Clinical history, evaluation for cause (e.g., myeloma, rheumatologic diseases)


  • Cellular hyperplastic nodules can be difficult to distinguish from follicular neoplasms by fine-needle aspiration (FNA)

  • Most common cause of sudden increase in size of hyperplastic nodules is hemorrhage and cystic degeneration

  • Extensive nodularity and enlargement may extend to mediastinum and cause detached nodules (parasitic thyroid nodules)

Selected References

  • Kotwal A., Priya R., Qadeer I.: . Arch Med Res 2007; 207: pp. 1-14.

  • Krohn K., Führer D., Bayer Y., et. al.: Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 2005; 26: pp. 504-524.

  • Ríos A., Rodríguez J.M., Canteras M., et. al.: Risk factors for malignancy in multinodular goitres. Eur J Surg Oncol 2004; 30: pp. 58-62.

Dyshormonogenetic Goiter

Clinical Features

  • Rare genetic disorder of defects in thyroid hormone synthesis pathway, most commonly cannot incorporate iodine

  • Patients are usually hypothyroid, frequently with enlarged thyroid

  • May present with congenital hypothyroidism; mean age, 16 years

  • Slight female predominance

  • Rare cases of associated carcinoma; predominantly follicular carcinomas

  • Surgery in children or young adult for dominant nodule or compression

Gross Pathology

  • Enlarged for age, frequently nodular, lacking colloid


  • Nodular arrangement of small follicles with scant colloid separated by fibrous trabeculae; may show papillary areas ( Figure 3.6 )

    Figure 3.6

    Dyshormonogenetic goiter.

    Small thyroid follicles with scant colloid composed of follicular cells with atypical nuclei (inset) and surrounded by dense fibrosis.

  • Often hypercellular with marked cellular pleomorphism (thyroid cancer is not diagnosed by pleomorphism)

  • Follicles may extend to involve adjacent soft tissue; not a sign of malignancy

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Clinical evaluation for underlying genetic defect

Differential Diagnosis

Nodular Hyperplasia

  • Bland follicular cells forming nonencapsulated nodules

  • Frequently follicles enlarged with colloid

Follicular Adenoma, Carcinoma

  • Uniform, small follicles (unlike atypical cytology of background follicles in dyshormonogenetic goiter)

  • Nodule surrounded by fibrous capsule

  • Vascular invasion or capsular invasion must be present to make a diagnosis of follicular carcinoma

Graves Disease

  • Hyperplastic thyroid follicles with papillary infoldings

  • Follicular cells with granular cytoplasm

  • Scant colloid; when present, apical vacuolation leads to scalloping of colloid

  • Laboratory tests indicating hyperthyroidism

Postradioactive Iodine Therapy

  • Cytologic atypia

  • Various degrees of fibrosis

  • Clinical history of prior therapy

  • Frequently an older patient group


  • Histology is diagnostic, although clinical history should also be noted; frequently patient is young

  • Caution in diagnosing cancer in this setting, requires characteristic nuclear features to diagnose papillary carcinoma (presence of papillary architecture is not sufficient); diagnosis of follicular carcinoma requires capsular or vascular invasion

  • Nuclei of the follicular neoplasm are frequently more uniform than the background dyshormonogenetic thyroid

Selected References

  • Deshpande A.H., Bobhate S.K.: Cytological features of dyshormonogenetic goiter: case report and review of the literature. Diagn Cytopathol 2005; 33: pp. 252-254.

  • Ghossein R.A., Rosai J., Heffess C.: Dyshormonogenetic goiter: a clinicopathologic study of 56 cases. Endocr Pathol 1997; 8: pp. 283-292.

  • Kennedy J.S.: The pathology of dyshormonogenetic goitre. J Pathol 1969; 99: pp. 251-264.

Thyroglossal Duct Cyst

Clinical Features

  • Congenital persistence of the thyroid developmental tract

  • Midline, from foramen cecum (tongue) to hyoid bone, to pyramidal lobe or isthmus

  • May fistulize to skin

  • Moves on swallowing

  • Most often detected during childhood or young adulthood

  • Associated thyroid tissue may develop well-differentiated thyroid carcinomas

Gross Pathology

  • Cystic lesion in soft tissue, middle third of hyoid bone, skin if fistula present


  • Cyst is lined by respiratory or squamous epithelium ( Figure 3.7 )

    Figure 3.7

    Thyroglossal duct cyst.

    Respiratory epithelium-lined cyst in the midline, often with thyroid follicles in the wall.

  • Secondary inflammation and granulation tissue if infected; lining may be lost

  • Underlying stroma contains mucous glands and thyroid follicles (50% of cases)

Special Stains and Immunohistochemistry

  • Thyroid epithelium is positive for thyroid transcription factor-1 (TTF-1) and thyroglobulin

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Branchial Cleft Cyst

  • Located in the lateral neck

  • Cyst lined by squamous, columnar, or ciliated epithelium or, if ulcerated, by granulation tissue

  • Prominent lymphoid infiltrate in cyst wall

  • Cyst may contain anucleated squamous cells, histiocytes, or cholesterol clefts

  • Epithelium is thyroglobulin negative (differentiate from metastatic papillary carcinoma)

Adenomatoid, Colloid Nodule

  • May occur in isthmus or pyramidal lobe, leading to midline mass

  • Squamous metaplasia can occur, but squamous debris is rare; colloid is typically abundant

  • Lacks ciliated cells


  • Malignancy may occur in the thyroid tissue (most cases involve papillary carcinoma); medullary carcinoma is not seen (different route of embryologic development)

  • Ciliated cells are occasionally seen on FNA of thyroid gland nodules near the trachea from “tracheal aspirates” if the needle enters the trachea (patient usually coughs when this occurs)

Selected References

  • Allard R.H.: The thyroglossal cyst. Head Neck Surg 1982; 5: pp. 134-146.

  • Mondin V., Ferlito A., Muzzi E., et. al.: Thyroglossal duct cyst: personal experience and literature review. Auris Nasus Larynx 2008; 35: pp. 11-25.

  • Shahin A., Burroughs F.H., Kirby J.P., et. al.: Thyroglossal duct cyst: a cytopathologic study of 26 cases. Diagn Cytopathol 2005; 33: pp. 365-369.

Branchial Cleft Cyst

Clinical Features

  • Anterolateral neck mass, multiple locations based on which pouch is affected

  • Derived from first, second, third, or fourth branchial pouches

  • Congenital, identified in children and young adults (be wary in older adults)

Gross Pathology

  • Mostly unilocular cysts with slightly granular inner surface due to presence of numerous lymphoid follicles

  • May be associated with a fistula tract


  • Cyst and fistula tracts are lined by squamous, columnar, or ciliated epithelium

  • Subepithelial stroma contains abundant lymphoid tissue

  • Lining contains mucinous and serous or even sebaceous glands, particularly when located in lower neck area

  • Cyst may contain anucleated squames, histiocytes, and cholesterol clefts ( Figure 3.8 )

    Figure 3.8

    Branchial cleft cyst.

    Epithelium-lined cystic space has associated lymphoid stroma; the cyst is often lined by respiratory epithelium but may be squamous, as in this case.

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Squamous Cell Carcinoma Metastatic to Lymph Node With Secondary Cystic Change

  • Must be considered in all adult patients with neck mass

  • Aggregates of malignant squamous cells forming cyst in lymph node

  • May at times appear cytologically bland

  • Squamous pearl formation may be seen

  • Sites of primary tumor are frequently in Waldeyer ring (tonsils, base of tongue) and are not apparent at time of presentation (image and biopsy for primary)

Cystic Papillary Thyroid Carcinoma Metastatic to Lymph Node

  • Cystic lining may be flattened without overt nuclear changes

  • Adequate sections usually show papillary architecture and nuclear features

  • Thyroglobulin level on FNA fluid diagnostic

  • Lateral neck location of thyroid tissue equals metastasis

  • TTF-1 and thyroglobulin will be positive


  • FNA is a valuable tool in evaluating neck lesions

  • Keep cystic papillary thyroid carcinoma in mind for patients of all ages with neck mass

  • Use caution in diagnosing branchial cleft cyst in adult patients when metastatic cystic squamous cell carcinoma (SCC) is the overwhelming cause of neck masses

Selected References

  • Al-Khateeb T.H., Al Zoubi F.: Congenital neck masses: a descriptive retrospective study of 252 cases. J Oral Maxillofac Surg 2007; 65: pp. 2242-2247.

  • Burgess K.L., Hartwick R.W.J., Bedard Y.C.: Metastatic squamous cell carcinoma presenting as a neck cyst: differential diagnosis from inflamed branchial cleft cyst in fine-needle aspirates. Acta Cytol 1993; 37: pp. 494-498.

  • Firat P., Ersoz C., Uguz A., et. al.: Cystic lesions of the head and neck: cytohistological correlation in 63 cases. Cytopathology 2007; 18: pp. 184-190.


Clinical Features

  • Very rare primary thyroid neoplasm with trilineage differentiation

  • Reported in newborn patients to those in their 50s; same incidence in males and females

  • Teratomas are classified as benign (mature), immature, and malignant

  • Teratomas of infants: greater than 90% benign, often contain immature components

  • Teratomas in adolescents and adults: 50% malignant

Gross Pathology

  • Variable with multiloculated cysts, soft glial tissue, gritty bone or cartilage ( Figure 3.9 )

    Figure 3.9

    Thyroid teratoma.

    Trilineage cellular components are present—mature cartilage, glial tissue, and a malignant epithelial component.


  • Mixture of mature or immature tissues (ectoderm, endoderm, and mesoderm)

  • Thyroid parenchyma should be identified

  • Maturation of neural tissue determines grade

  • Frank malignant component may be present (i.e., embryonal carcinoma)

Special Stains and Immunohistochemistry

  • Various stains to highlight lineages

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Thyroglossal Duct Cyst

  • Cyst lined by respiratory or squamous epithelium

  • May be associated with chronic inflammation

  • Clinically correlate with anatomic region (anterior, midline)


  • Single population of atypical small cells

  • Other tissue types are not identified

  • Immunohistochemistry (IHC) to identify cell type


  • Single population of tumor cells without other lineages

  • Rhabdomyoblasts may be found in teratomas


  • Grading based on percentage of immature component

  • Prognosis based on age, size, and proportion of immature component

Selected References

  • Nishihara E., Miyauchi A., Hirokawa M., et. al.: Benign thyroid teratomas manifest painful cystic and solid composite nodules: three case reports and a review of the literature. Endocrine 2006; 30: pp. 231-236.

  • Thompson L.D., Rosai J., Heffess C.S.: Primary thyroid teratomas: a clinicopathologic study of 30 cases. Cancer 2000; 88: pp. 1149-1158.

Hyalinizing Trabecular Tumor

Clinical Features

  • Follicular neoplasm of debated classification

  • Females affected more than males; patients are usually in their 50s and 60s

Gross Pathology

  • Solitary, well-circumscribed nodule


  • Trabecular and insular growth patterns ( Figure 3.10 )

    Figure 3.10

    Hyalinizing trabecular tumor.

    Trabeculae and nests of elongated cells with prominent grooves and pseudonuclear inclusions (inset) .

  • Large elongated cells with oval nuclei

  • Nuclear grooves and intranuclear cytoplasmic inclusions

  • Intracytoplasmic bodies and perinuclear halos are common

Special Stains and Immunohistochemistry

  • TTF-1 and thyroglobulin positive

Other Techniques for Diagnosis

  • Paired Box 8 -GLIS Family Zinc Finger 3 ( PAX8-GLIS3 ) gene rearrangements

Differential Diagnosis

Papillary Thyroid Carcinoma

  • Shares overlapping nuclear features, including clearing and grooves

  • Invasive growth pattern is helpful

  • Lymphovascular invasion is often identified

Follicular Adenoma

  • Nuclei in general are bland and round, lacking clearing and grooving

  • Lacks intracytoplasmic bodies


  • Rare tumor in thyroid; cells forming nests

  • Nuclear features are bland and round, lacking clearing and grooves

  • Positive for chromogranin, synaptophysin

  • Negative for TTF-1 and thyroglobulin

Medullary Thyroid Carcinoma

  • Overlapping nuclear features of grooving and elongation

  • Overlapping growth patterns (trabecular)

  • Amyloid helpful when present

  • Thyroglobulin negative

  • Both express TTF-1


  • Unclear if biologically capable of metastasis

  • Suggested relationship to papillary thyroid carcinoma

  • Conservative treatment recommended

Selected References

  • Baloch Z.W., LiVolsi V.A.: Cytologic and architectural mimics of papillary thyroid carcinoma: diagnostic challenges in fine-needle aspiration and surgical pathology specimens. Am J Clin Pathol 2006; 125: pp. S135-S144.

  • Casey M.B., Sebo T.J., Carney J.A.: Hyalinizing trabecular adenoma of the thyroid gland: cytologic features in 29 cases. Am J Surg Pathol 2004; 28: pp. 859-867.

  • Galgano M.T., Mills S.E., Stelow E.B.: Hyalinizing trabecular adenoma of the thyroid revisited: a histologic and immunohistochemical study of thyroid lesions with prominent trabecular architecture and sclerosis. Am J Surg Pathol 2006; 30: pp. 1269-1273.

  • Nikiforova MN, Nikitski AV, Panebianco F, et al. GLIS Rearrangement is a Genomic Hallmark of Hyalinizing Trabecular Tumor of the Thyroid Gland. Thyroid. 29(2):161–173.

Follicular Adenoma

Clinical Features

  • Benign tumor more common (about 5:1) than follicular carcinoma

  • Usually solitary lesion; mainly affects lobes of thyroid, rare in isthmus

  • Predilection for middle-aged women; clinically euthyroid

  • Associated with iodine deficiency and Cowden disease (hamartomas, PTEN gene)

Gross Pathology

  • Solitary, well-circumscribed, round to oval nodule, thin capsule ( Figure 3.11A )

    Figure 3.11

    Follicular adenoma.

    A, Gross photograph of a thyroid lobe with a well-defined nodule without a prominent capsule. B, The cellular proliferation is well circumscribed with a thin capsule.


  • Encapsulated follicular proliferation; variable amount of colloid (see Figure 3.11B )

  • Thin fibrous capsule may contain small blood vessels; thinner than in follicular carcinoma

  • Various architectural patterns: trabecular or solid, microfollicular, and macrofollicular, which have no clinical significance

  • Central area may be hypocellular with loose and edematous stroma

  • Uniform polygonal follicle cells with round or oval nuclei

  • Absent or minimal mitotic activity

  • Occasionally bizarre nuclei do not indicate malignancy

  • Papillary or pseudopapillary structures without nuclear changes

  • Follicular adenoma variants

    • Adenoma with oncocytic (Hürthle) cells

      • Follicular cells with ample eosinophilic cytoplasm with round nuclei and prominent nucleoli

      • More susceptible to infarction, especially after FNA

      • May show necrosis, infarction, mitoses

    • Atypical adenoma, follicular lesion of uncertain malignant potential

      • Thickened capsule with irregularity and partial capsule invasion

      • Lacks lymphovascular invasion

      • Worrisome features without meeting criteria for carcinoma

    • Toxic adenoma (rare)

      • Also called Plummer adenoma

      • Solitary, hyperfunctioning nodule causing hyperthyroidism

      • Cytologic features within nodule mimics Graves disease

Special Stains and Immunohistochemistry

  • Thyroglobulin and TTF-1 positive

  • Cytokeratin positive

  • Chromogranin and calcitonin negative

Other Techniques for Diagnosis

  • One fourth of cases are aneuploid; however, this does not correlate clinically with malignant behavior or recurrence

  • Some reports of Ras mutations and PAX/PPARgamma rearrangements (see “Follicular Carcinoma”)

Differential Diagnosis

Hyperplastic Nodule

  • Typically multiple; mixture of microfollicles and macrofollicular, marked colloid

  • Incomplete fibrous capsule; does not compress surrounding thyroid tissue

Non-Invasive Follicular Neoplasm With Papillary-Like Nuclear Features (NIFTP)

  • Encapsuled or well demarcated nodule with follicular architecture without capsular or lymphovascular invasion

  • Cytologic features with nuclear enlargement, clearing, and nuclear membrane irregularity; intranuclear pseudoinclusions are typically not found

  • No well-formed papillae; no psammoma bodies

Follicular Carcinoma

  • Follicular proliferation with thick capsule and evidence of vascular invasion or full-thickness capsular invasion by neoplastic follicles

Encapsulated Follicular Variant of Papillary Carcinoma

  • Characterized by follicular architecture with capsular or lymphovascular invasion with cytologic features of classic papillary carcinoma, including enlarged, cleared nuclei, and intranuclear cytoplasmic pseudoinclusions

  • May have microfollicles or macrofollicles

Medullary Thyroid Carcinoma or Nodular C-Cell Hyperplasia

  • Not encapsulated

  • Isochromatic cytoplasm versus eosinophilic cytoplasm in follicular cells

  • Calcitonin positive; also frequently expresses TTF-1

Intrathyroidal Parathyroid (Normal) or Parathyroid Adenoma

  • Well circumscribed, may or may not have intercellular fat

  • Small, hyperchromatic nuclei in nests, which may have cytoplasmic clearing

  • Parathyroid hormone (PTH) positive

  • Calcitonin and TTF-1 negative


  • FNA shows follicular lesion or follicular neoplasm; treatment is lobectomy or subtotal thyroidectomy

  • Frozen sections are of little value and are discouraged

  • Thorough examination of the follicular capsule is warranted

Selected References

  • Baloch ZW, LiVolsi VA. Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol . 117:143–150.

  • Baloch Z.W., LiVolsi V.A.: Our approach to follicular-patterned lesions of the thyroid. J Clin Pathol 2007; 60: pp. 244-250.

  • Nikiforov Y.E., Baloch Z.W., Hodak S.P., et. al.: Change in diagnostic criteria for noninvasive follicular thyroid neoplasm with papillary like nuclear features. JAMA Oncol 2018; 4: pp. 1125-1126.

  • Suster S.: Thyroid tumors with a follicular growth pattern: problems in differential diagnosis. Arch Pathol Lab Med 2006; 130: pp. 984-988.

Follicular Carcinoma

Clinical Features

  • Malignant epithelial tumor with follicular cell differentiation and no features of the other distinctive types of thyroid malignancy

  • Constitutes about 5% of thyroid cancers

  • In iodine-deficient areas, it comprises between 25% and 40% of thyroid cancers

  • Not associated with prior radiation therapy

  • Predilection for women

  • Patients present with a solitary nodule that is typically “cold” on isotopic scan

  • Patients are usually euthyroid

Gross Pathology

  • Solid, round tumor with fibrous capsule that is thicker and more irregular than in adenomas, usually larger than 1 cm ( Figure 3.12A )

    Figure 3.12

    Follicular carcinoma.

    A, Gross photograph of a circumscribed thyroid mass with thickened capsule and gross invasion of the capsule at the superior left aspect of the image. B, Lymphovascular invasion is present within the markedly thickened capsule. C, Widely invasive follicular carcinoma with nodules extending into the adjacent thyroid parenchyma.

  • Cut surface is light-tan and solid; secondary changes such as cystic degeneration, hemorrhage, and fibrosis

  • Mahogany-colored nodule corresponds to Hürthle cell morphology

Histopathology (see Figure 3.12B and C )

  • Frequently divided into (1) minimally invasive and (2) widely invasive, although these definitions are variably used

  • Cells similar to those of follicular adenoma: round or oval nuclei in follicular cells

  • Various architectural patterns: solid, trabecular, microfollicular, macrofollicular (not clinically significant)

  • Diagnosis depends on demonstration of full-thickness capsular or vascular invasion

    • Capsular invasion

      • Penetration of entire thickness of capsule is required (mere presence of follicular cell clusters within capsule is not regarded as capsular invasion)

      • Caution of FNA defects in capsule with associated hemorrhage and reactive changes

    • Vascular invasion (also termed angioinvasive follicular carcinoma )

      • Vessel should be located within or outside the capsule; frequently of large caliber

      • Tumor cells should be within the vascular lumen and must be at least focally attached to the vessel wall (not pushing beneath the vessel)

    • Some require endothelial growth over a portion of the tumor or fibrin deposition

Special Stains and Immunohistochemistry

  • TTF-1, PAX8, and thyroglobulin positive

  • No currently available marker to distinguish adenoma from carcinoma

Other Techniques for Diagnosis

  • Translocation of PAX8/PPARgamma t(2;3) seen in approximately 35% of follicular carcinomas

  • Identification of Ras mutations ( K-ras, N-ras , or H-ras in 40% to 50%) (also seen in adenomas, noninvasive follicular neoplasms with papillary-like nuclear features, and follicular variants of papillary carcinoma)

Differential Diagnosis

Follicular Adenoma

  • Thin fibrous capsule without evidence of vascular invasion

Atypical Adenoma or Follicular Lesion of Uncertain Malignant Potential

  • Cellular follicular lesion with thickened capsule

  • Cells may partially invade capsule

  • Lymphovascular invasion is not identified

Dominant Nodule of Nodular Hyperplasia

  • Background of multiple, variably sized nodules

  • No fibrous capsule

Follicular Variant of Papillary Carcinoma

  • Nuclear features of papillary carcinoma present: overlapping and clearing of nuclei, pseudoinclusions, and nuclear grooves in most of the lesion (not just focally)

Follicular Variant of Medullary Carcinoma

  • Calcitonin positive and thyroglobulin negative

  • Polygonal cells with abundant eosinophilic to clear cytoplasm and coarsely clumped chromatin with inconspicuous nucleoli; may have plasmacytoid appearance


  • Vascular invasion is a more reliable sign of malignancy than capsular invasion

  • FNA cannot distinguish between follicular lesions (i.e., adenoma from carcinoma), requiring surgical excision for diagnosis

  • FNA can produce WHAFFT (“worrisome histologic alterations following FNA of the thyroid”) (including artifactual capsular invasion)

  • Typically metastasize via hematogenous route, most commonly to lung and bone

Selected References

  • D’Avanzo A., Treseler P., Ituarte P.H., et. al.: Follicular thyroid carcinoma: histology and prognosis. Cancer 2004; 100: pp. 1123-1129.

  • Kroll TG. Molecular events in follicular thyroid tumors. Cancer Treat Res . 204;122:85–105.

  • Leteurtre E., Leroy X., Pattou F., et. al.: Why do frozen sections have limited value in encapsulated or minimally invasive follicular carcinoma of the thyroid?. Am J Clin Pathol 2001; 115: pp. 370-374.

  • LiVolsi VA, Baloch ZW. Follicular neoplasms of the thyroid: view, biases, and experiences. Adv Anat Pathol . 11:279–287.

  • Rosai J., Kuhn E., Carcangiu M.L.: Pitfalls in thyroid tumour pathology. Histopathology 2006; 49: pp. 107-120.

  • Thompson L.D., Wieneke J.A., Paal E., et. al.: A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature. Cancer 2001; 91: pp. 505-524.

Papillary Thyroid Carcinoma

Clinical Features

  • Most common type of thyroid cancer (80%) in the United States

  • More common in women (4:1)

  • Well-documented association with radiation exposure (after Chernobyl and Hiroshima)

  • Relative incidence is higher in areas of high iodine intake compared with follicular carcinoma

  • Prognostic features include age and gender (worse when >55 years of age and male)

  • Regional lymph node metastasis is common (50% of cases at presentation); does not adversely affect long-term prognosis

Gross Pathology

  • Variable, from well circumscribed to diffusely involving lobe or multifocal

  • White-gray, firm, granular cut surface; may have small papillary structures ( Figure 3.13A )

    Figure 3.13

    Papillary thyroid carcinoma.

    A, Gross photograph of a thyroid with a partially calcified tumor. B, Papillary thyroid carcinoma growing in microfollicles consistent with the follicular variant. C, Papillary architecture with fibrovascular cores. The nuclei are clear, elongated, and grooved.

  • Calcifications may be present

Histopathology (See Figure 3.13B and C )

  • Complex branching true papillae (contain fibrovascular stalks)

  • Papillae lined by neoplastic epithelial cells with characteristic enlarged optically clear, empty “Orphan Annie eye” nuclei (formalin fixation only), nuclear grooves (usually parallel to long axis), cytoplasmic pseudoinclusions, and overlapping nuclei

  • Psammoma bodies seen in up to 50% of cases

  • Cystic growth pattern is commonly present in lymph nodes with flattened nuclei

  • Solid areas, squamous metaplasia, are not infrequently seen

  • Colloid is thick and dark eosinophilic with bubblegum-like quality

  • Stroma is often abundant, and fibrous lymphatic invasion is common

  • Multicentricity is common compared with follicular neoplasms

  • Histologic variants

    • Microcarcinoma

      • Microscopic tumor less than 1 cm in diameter

      • Subcapsular region and scar growth pattern is common

    • Follicular variant of papillary carcinoma

      • Microfollicular or macrofollicular

      • Nuclear features must show enlargement, clearing, and grooves throughout most of the lesion

      • Focal papillae may be found if multiple sections are taken

      • Prognosis is similar to that for classic papillary carcinoma

    • Diffuse sclerosing variant

      • Often, diffusely involves both lobes

      • Extensive fibrosis, squamous metaplasia, lymphocytic infiltrate, and psammoma bodies

      • Solid or papillary growth with extensive lymphovascular spread

      • Higher incidence of cervical lymph node and pulmonary metastases

    • Oncocytic variant

      • Distinct Hürthle cell features (abundant eosinophilic cytoplasm) with classic papillary thyroid carcinoma nuclei often with papillary architecture

      • Nuclei frequently do not overlap secondary to ample cytoplasm

      • May be associated with lymphoid stroma in chronic lymphocytic thyroiditis

      • Degenerative changes after FNA are common

    • Tall or columnar cell variant

      • More common in older patients

      • Often greater than 5 cm, extrathyroidal extension and vascular invasion are more frequent

      • Tall cell nuclei at base with cells that are three times as tall as wide and have abundant eosinophilic cytoplasm

      • Columnar nuclei are pseudostratified and luminal with basal cytoplasmic vacuoles and squamous metaplasia

Special Stains and Immunohistochemistry

  • Noncontributory—although high-molecular-weight cytokeratins (CK19), galectin-3, and HBME-1 are noted to be expressed in papillary thyroid carcinoma; lack of sensitivity and specificity limits their use

Other Techniques for Diagnosis

  • Oncogene alterations

    • Point mutation BRAF V600E, exon 15 (up to 60%)

    • Translocations of RET proto-oncogene with multiple different genes ( RET/PTC gene rearrangements), 30%, more often in children and those with radiation exposure

    • N-ras mutations particularly follicular variant (10%)

    • TRK gene rearrangements with multiple genes (10%)

  • New tyrosine kinase inhibitors affect the BRAF and RET pathways and may provide targeted therapy for patients with aggressive disease or distant metastases

Differential Diagnosis

Papillary Hyperplasia in Graves Disease and Adenomatous Goiter

  • Classic nuclear features of papillary carcinoma are absent

Non-Invasive Follicular Neoplasm With Papillary-Like Nuclear Features

  • Well demarcated or encapsulated, non-invasive with follicular pattern

  • True papillae are absent

  • Nuclear features of clearing, enlargement, and nuclear membrane irregularity

Follicular Adenoma and Carcinoma

  • Most commonly exhibits a microfollicular pattern with fibrous capsule

  • Large-vessel vascular invasion frequently seen in follicular carcinoma

  • Lack characteristic nuclear features such as enlargement and overlapping of cleared-out nuclei

Medullary Carcinoma

  • Spindle and plasmacytoid features; may be follicular or papillary growth pattern

  • Amyloid frequently present in stroma (Congo red positive)

  • Calcitonin positive and thyroglobulin negative


  • All variants of papillary carcinoma, irrespective of architecture, must have characteristic nuclear features (hypochromasia, elongated nucleus with grooves, and intranuclear pseudoinclusions)

  • Prognosis correlates with clinical factors (age, sex, stage)

  • Clear “Orphan Annie eye” nuclei are an artefact of formalin fixation and are not seen in frozen sections and cytologic preparations

  • Psammoma bodies are not pathognomonic

Selected References

  • Akslen L.A., LiVolsi V.A.: Prognostic significance of histologic grading compared with subclassification of papillary thyroid carcinoma. Cancer 2000; 88: pp. 1902-1908.

  • Al-Brahim N., Asa S.L.: Papillary thyroid carcinoma: an overview. Arch Pathol Lab Med 2006; 130: pp. 1057-1062.

  • DeLellis R.A.: Pathology and genetics of thyroid carcinoma. J Surg Oncol 2006; 94: pp. 662-669.

  • Ghossein R., Livolsi V.A.: Papillary thyroid carcinoma tall cell variant. Thyroid 2018; 18: pp. 1179-1181.

  • Michels J.J., Jacques M., Henry-Amar M., et. al.: Prevalence and prognostic significance of tall cell variant of papillary thyroid carcinoma. Hum Pathol 2007; 38: pp. 212-219.

  • Sanders E.M., LiVolsi V.A., Brierley J., et. al.: An evidence-based review of poorly differentiated thyroid cancer. World J Surg 2007; 31: pp. 934-945.

  • Seethala R.R., Baloch Z.W., Barletta J.A., et. al.: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists. Mod Pathol 2018; 31: pp. 39-55.

  • Trovisco V., Soares P., Sobrinho-Simoes M.: BRAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas. Hum Pathol 2006; 37: pp. 781-786.

Medullary Thyroid Carcinoma

Clinical Features

  • Malignant tumor composed of neural crest–derived C cells

  • Accounts for up to 5% of thyroid malignancies

  • Can be sporadic (80%) or hereditary (20%); more common in women

  • Lymph nodes common at presentation (about 50%)

  • Elevated serum calcitonin; can be used to monitor residual, recurrent, or metastatic disease postoperatively; carcinoembryonic antigen (CEA) elevation is usually a late finding in progressive disease

  • Hereditary types include familial medullary thyroid carcinoma and multiple endocrine neoplasia (MEN) IIA and IIB and are caused by different germline mutations in RET proto-oncogene

    • Sporadic type

      • Occurs in middle-aged adults, some show RET mutations in the tumors

      • Solitary tumor mass

  • Hereditary syndromes are often multicentric and involve both lobes

    • Familial medullary thyroid carcinoma

      • Medullary carcinoma without other endocrine abnormalities, onset in adults

    • MEN IIA

      • Medullary carcinoma, pheochromocytoma, parathyroid adenoma or hyperplasia

      • Mean age at diagnosis in MEN IIA cases is in the third decade

    • MEN IIB

      • All patients develop medullary thyroid carcinoma typically with onset in childhood or young adulthood

      • Same possible endocrinopathies as MEN IIA, plus gastrointestinal and ocular ganglioneuromas and skeletal abnormalities

Gross Pathology

  • Often circumscribed

  • Cut section is tan-yellow with soft to firm consistency ( Figure 3.14A )

    Figure 3.14

    Medullary thyroid carcinoma.

    A, Gross photograph of a pale-tan tumor replacing the thyroid parenchyma. B, Nests of neuroendocrine cells are associated with dense amorphous stroma (amyloid). Higher-power magnification (inset) of tumor cells shows the amphophilic cytoplasm and the round nuclei with salt-and-pepper chromatin. C, Immunohistochemical stain for calcitonin is positive in a medullary thyroid carcinoma with spindled morphology.

  • Tumors arise in upper and middle third of lobe, corresponding to the area in which C-cells predominate

  • May have multifocal nodules in hereditary types


  • Wide spectrum of histologic patterns, including solid, lobular, trabecular, insular, and sheetlike

  • Tumor cells are round, polygonal, or spindle shaped; frequently mixed cell types

  • Polygonal cells have abundant amphophilic to clear cytoplasm, and nuclei often have a plasmacytoid appearance (see Figure 3.14B )

  • Cytoplasmic pseudoinclusions and grooves can be seen

  • Nuclear chromatin is coarsely clumped (i.e., salt-and-pepper like) with inconspicuous nucleoli

  • Binucleated cells are commonly seen

  • Necrosis, hemorrhage, and mitoses are rare features

  • Bizarre nuclear atypia can occur

  • Variants (have no clinical significance)

    • Follicular or trabecular, papillary, paraganglioma-like, amphicrine, small cell, giant cell, clear cell, encapsulated, oncocytic, and melanotic (melanin pigment present), have been described

  • Stromal amyloid is present in up to 80% of cases; amyloid can induce foreign-body giant cell reaction

  • Stroma may contain calcifications or rarely psammoma bodies

  • Can be diagnosed preoperatively by FNA but should be supported by immunocytochemistry; use caution because nuclear changes include grooving and pseudonuclear inclusions

Special Stains and Immunohistochemistry

  • Calcitonin positive (see Figure 3.14C ); clinical serum biomarker

  • Chromogranin and synaptophysin positive

  • CEA positive in tumor cells and serum; may have prognostic value

  • Congo red positive in amyloid material (polarizes: birefringence apple-green)

  • TTF-1 usually positive

  • Thyroglobulin negative

Other Techniques for Diagnosis

  • Germline mutations in RET proto-oncogene are present in all hereditary forms

  • RET mutations are identified in some sporadic cases (20% to 80%)

  • Genetic testing for germline mutations should be offered to all patients diagnosed with medullary thyroid carcinoma regardless of age at diagnosis

Differential Diagnosis

C-Cell Hyperplasia, Reactive

  • Lacks fibrosis

  • Proliferations of C cells often surround follicles

  • Scattered cells are often appreciated only by immunostaining

C-Cell Hyperplasia, Nodular (Preneoplastic)

  • Greater than 50 cells per cluster

  • Identified on hematoxylin and eosin stain, confirmed by immunostaining

  • Lacks fibrosis, infiltration

  • Nodular proliferation considered preneoplastic

  • Difficult to separate from or define microscopic medullary thyroid carcinoma

Hürthle Cell Carcinoma

  • Stroma does not contain amyloid

  • Thyroglobulin positive and calcitonin negative

Papillary Carcinoma

  • Characteristic nuclear features of papillary thyroid carcinoma

  • Thyroglobulin positive and calcitonin negative

  • Pseudoinclusions and grooving may be seen in both papillary and medullary carcinoma

Poorly Differentiated Thyroid Carcinoma

  • Islands of tumor cells that typically grow in a solid fashion but may form small follicles

  • Stroma does not contain amyloid (negative for Congo red)

  • Thyroglobulin positive and calcitonin negative

Plasmacytoma (Extramedullary)

  • Plasmacytoid form of medullary carcinoma can resemble a plasmacytoma

  • Immunoglobulin light-chain restriction can be demonstrated by kappa and lambda staining, negative for calcitonin


  • Lobular, nested growth pattern (Zellenballen)

  • Nuclei are round with fine granular chromatin

  • Rare in this location

  • Negative for calcitonin and TTF-1

Hyalinizing Trabecular Tumor

  • Well circumscribed

  • Lacks amyloid

  • Thyroglobulin positive and calcitonin negative

Spindle Epithelial Tumor With Thymus-Like Differentiation (SETTLE)

  • Occurs in young patients (teens to 20s)

  • Well circumscribed

  • Biphasic tumor of spindled and epithelial cells in glands, tubules, and sheets

  • TTF-1, thyroglobulin, and calcitonin negative


  • Medullary carcinoma can mimic a variety of benign and malignant thyroid neoplasms

  • TTF-1 is positive in most medullary thyroid carcinomas

  • Presence of C-cell hyperplasia suggests hereditary or germline mutation, as does bilateral and associated endocrine abnormalities (i.e., parathyroid, pheochromocytoma)

  • Incidental finding of C-cell hyperplasia (>50 cells in aggregate, often seen bilaterally) should be reported

  • Survival correlates with stage

  • Radioactive iodine plays no role in treatment

Selected References

  • Guyetant S., Josselin N., Savagner F., et. al.: C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. Mod Pathol 2003; 16: pp. 756-763.

  • Leboulleux S., Baudin E., Travagli J.P., et. al.: Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 2004; 61: pp. 299-310.

  • Massoll N., Mazzaferri E.L.: Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 2004; 24: pp. 49-83.

  • Simpson N.E., Kidd K.K., Goodfellow P.J., et. al.: Assignment of multiple endocrine neoplasia type IIA to chromosome 10 by linkage. Nature 1987; 328: pp. 528-529.

Poorly Differentiated Thyroid Carcinoma

Clinical Features

  • Poorly differentiated carcinoma arising from follicular cells (insular or trabecular pattern)

  • May arise from follicular carcinoma or papillary carcinoma or de novo

  • Rare in the United States (2% to 3% of thyroid carcinomas)

  • Mean age at diagnosis is in the fifth and sixth decades

  • Slightly more common in women

  • Viewed by the World Health Organization (WHO) classification as a morphologic variant of follicular carcinoma

  • Intermediate behavior between well-differentiated and anaplastic thyroid carcinomas

Gross Pathology

  • Typically greater than 5 cm

  • Cut surface is gray-white and solid with areas of necrosis

  • Usually extrathyroidal extension with gross invasion into adjacent soft tissue


  • Tumor cells with round to oval hyperchromatic nuclei and scant cytoplasm forming a nested pattern (insulae) ( Figure 3.15 )

    Figure 3.15

    Poorly differentiated thyroid carcinoma. Solid nests of follicular cells with scant cytoplasm lacking the nuclear features of papillary thyroid carcinoma.

  • May be defined by the presence of convoluted nuclei; mitotic activity greater than 3/10 high-power fields (hpff); or tumor necrosis

  • Infiltrative growth pattern with invasion into surrounding tissue

Special Stains and Immunohistochemistry

  • Pax8 positive in the majority of tumors

  • Thyroglobulin and TTF-1 often focally or weakly positive

  • Cytokeratin positive

  • Calcitonin negative (if positive, classify as medullary)

Other Techniques for Diagnosis

  • See “Papillary Thyroid Carcinoma” and “Follicular Carcinoma” for current expression patterns

Differential Diagnosis

Medullary Carcinoma

  • Round to oval, spindled, or plasmacytoid

  • Amyloid in stroma (Congo red positive)

  • Calcitonin positive and thyroglobulin negative

Undifferentiated (Anaplastic) Carcinoma

  • Pleomorphic cellular features may also show giant, spindled, or squamous cells

  • Lacks architectural growth pattern (insulae)

Carcinoma Showing Thymus-Like Differentiation (CASTLE)

  • Occurs in adults, fifth decade

  • One third develops metastatic disease

  • Invasive growth in sheets and nests with dense fibrosis; moderately pleomorphic cells

  • TTF-1, thyroglobulin, and calcitonin negative

  • Tumor positive for CD5

  • Likely this entity represents ectopic thymic carcinoma


  • May originate from papillary or follicular carcinoma, clinically aggressive

  • Not viewed as a distinct tumor but in the spectrum from well-differentiated to anaplastic thyroid carcinoma

  • If calcitonin is positive, classify as medullary thyroid carcinoma

Selected References

  • Hiltzik D., Carlson D.L., Tuttle R.M., et. al.: Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer 2006; 106: pp. 1286-1295.

  • Sanders E.M., LiVolsi V.A., Brierley J., et. al.: An evidence-based review of poorly differentiated thyroid cancer. World J Surg 2007; 31: pp. 934-945.

  • Volante M., Collini P., Nikiforov Y.E., et. al.: Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol 2007; 31: pp. 1256-1264.

  • Volante M., Landolfi S., Chiusa L., et. al.: Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients. Cancer 2004; 100: pp. 950-957.

Anaplastic (Undifferentiated) Carcinoma

Clinical Features

  • Less than 5% of thyroid neoplasms

  • Highly malignant tumor, totally or partially undifferentiated by microscopy

  • Mean age at diagnosis is sixth to seventh decades; slightly more common in women

  • Presents as a rapidly enlarging neck mass in the thyroid region associated often with compression signs, including dyspnea, dysphagia, and hoarseness

  • High likelihood of cervical lymph node metastases at presentation

  • Fatal in most cases within 6 months regardless of treatment

  • Most of the anaplastic carcinomas arise from a preexisting tumor, usually a papillary carcinoma

Gross Pathology

  • Widely invasive tumor, often with spread beyond the thyroid ( Figure 3.16A )

    Figure 3.16

    Undifferentiated (anaplastic) carcinoma.

    A, Gross photograph of the tumor invading trachea and soft tissue. B, Anaplastic spindled and giant cells are present. C, Papillary thyroid carcinoma (left side) merging with an anaplastic thyroid carcinoma with spindled morphology.

  • Variegated appearance with necrotic and hemorrhagic areas


  • Most common phenotypes: squamoid, spindle cell, and giant cell (often more than one pattern within a tumor) (see Figure 3.16B )

    • Squamoid pattern (if exclusively squamous morphology WHO classifies as SCC)

      • Resembles nonkeratinizing SCC; rarely, squamous pearls may be present

      • Must exclude direct extension from aerodigestive tract primary

      • Squamous metaplasia in papillary thyroid carcinoma lacks atypia

    • Spindle cell pattern (may mimic sarcomas which are rare arising outside of the thyroid)

      • Resembles a sarcoma (fibrosarcoma, malignant fibrous histiocytoma [MFH], or angiosarcoma)

      • May have sharply demarcated foci of necrosis, myxoid change, or prominent vascularity

    • Giant cell pattern

      • Markedly pleomorphic cellular features, including many tumor giant cells with bizarre nuclei, usually solid growth pattern

  • Scattered inflammatory cells, high mitotic activity, necrosis, and infiltrative growth pattern are typically seen in all three patterns

  • Rarely heterologous elements are seen, such as neoplastic cartilage and bone (most common in spindle cell type)

  • Metastases resemble primary morphology

  • Background well-differentiated component (most often papillary) may be identified, confirming thyroid origin of anaplastic carcinoma (see Figure 3.16C )

Special Stains and Immunohistochemistry

  • Cytokeratin (particularly low molecular weight) and epithelial membrane antigen (EMA) patchy positive (75%)

  • PAX8 positive (66% to 75%)

  • Frequently thyroglobulin and TTF-1 negative

Other Techniques for Diagnosis

  • BRAF V600E present in 40%; clinically targeted for therapy

  • Frequent TP53 and TERT mutations

Differential Diagnosis

Poorly Differentiated Carcinoma

  • Nests of uniform, small, round tumor cells

  • Aggressive, but prognosis better than for anaplastic

Medullary Carcinoma

  • Round to oval, spindled, or plasmacytoid features

  • Amyloid stroma (Congo red positive)

  • Calcitonin positive

Papillary Carcinoma, Solid Variant

  • Characteristic nuclear features such as cleared-out nuclei, nuclear pseudoinclusions, grooves, and overlapping of nuclei

  • Thyroglobulin positive (stronger and more uniform than anaplastic)

True Sarcoma of the Thyroid

  • Rare, typically arise outside and invade into thyroid

  • Negative for pax8 and cytokeratins

Metastatic Carcinoma to the Thyroid

  • Well-circumscribed, usually multiple nodules, or diffuse intralymphatic

  • Does not show as much cytologic pleomorphism

  • Clinical history important to rule out metastasis

Malignant Lymphoma

  • Critical to exclude; both present with rapid growth

  • Leukocyte common antigen (LCA) positive; cytokeratin negative


  • Highly aggressive tumor, usually with extrathyroidal extension at the time of diagnosis

  • Coexisting papillary thyroid carcinoma when present aids in confirming thyroid origin

  • BRAF mutational status is utilized for clinical treatment planning

Selected References

  • Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma: treatment outcome and prognostic factors. Cancer . 103:1330–1335.

  • Venkatesh Y.S., Ordonez N.G., Schultz P.N., et. al.: Anaplastic carcinoma of the thyroid: a clinicopathologic study of 121 cases. Cancer 1990; 66: pp. 321-330.

  • Wiseman S.M., Loree T.R., Rigual N.R., et. al.: Anaplastic transformation of thyroid cancer: review of clinical, pathologic, and molecular evidence provides new insights into disease biology and future therapy. Head Neck 2003; 25: pp. 662-670.


Clinical Features

  • Up to 5% of thyroid tumors; malignant tumor is composed of lymphoid cells

  • More common in women; peak incidence is in the seventh decade

  • Rapidly enlarging, firm, hard thyroid; compression symptoms are common

  • Considered primary when the thyroid gland is the predominant or exclusive site of involvement

  • The thyroid is involved in 5% of systemic lymphoma or leukemia

  • Primary thyroid lymphoma is rare (about 2% of all thyroid malignancies)

  • Primary thyroid lymphoma is often associated with autoimmune thyroiditis (Hashimoto or lymphocytic thyroiditis); causal relationship is widely accepted

Gross Pathology

  • Solid, homogeneous, tan mass with a fish-flesh appearance

  • Unencapsulated tumor with a poorly defined tumor-gland interface

  • No necrosis or hemorrhage


Non-Hodgkin Lymphoma

  • Most common

  • Thyroid is considered to be a MALT site, and low-grade and high-grade lymphomas can occur

  • Most are of B-cell origin, large cell type

  • Diffuse pattern of growth with entrapped thyroid follicles ( Figure 3.17 )

    Figure 3.17

    Lymphoma, follicular grade 3.

    Atypical lymphoid infiltrate surrounds and replaces thyroid follicles. At high power (inset) , the nuclear atypia and discohesive nature of the lymphoma cells are noted.

  • Extends into skeletal muscle and fat

  • Lymphoma cells may accumulate within follicular lumens

T-Cell Lymphoma

  • Extranodal involvement by mycosis fungoides can affect the thyroid

Hodgkin Disease

  • Rarely involves the thyroid gland

  • Usually nodular sclerosing type

Special Stains and Immunohistochemistry

  • LCA positive

  • Cytokeratin and thyroglobulin highlight entrapped follicular structures

  • For subtyping, refer to Chapter 14

Other Techniques for Diagnosis

Differential Diagnosis

Hashimoto Thyroiditis, Chronic Lymphocytic Thyroiditis

  • Infiltrate of mature small lymphocytes without atypia

  • Lymphoid follicles with germinal centers common

  • Expansion and effacing of germinal centers are not seen


  • Although patients with chronic lymphocytic thyroiditis are at increased risk, primary lymphomas of the thyroid are still rare

  • Accumulation of lymphoid cells is seen within follicular lumens (a histologic feature usually not seen in thyroiditis and Graves disease)

  • Prognosis depends on the classification and stage of the tumor

  • Plasmacytomas of the thyroid are believed to represent a variant of MALT with plasma cell differentiation

Selected References

  • Belal A.A., Allam A., Kandil A., et. al.: Primary thyroid lymphoma: a retrospective analysis of prognostic factors and treatment outcome for localized intermediate and high grade lymphoma. Am J Clin Oncol 2001; 24: pp. 299-305.

  • Derringer G.A., Thompson L.D., Frommelt R.A., et. al.: Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol 2000; 24: pp. 623-639.

  • Thieblemont C., Mayer A., Dumontet C., et. al.: Primary thyroid lymphoma is a heterogeneous disease. J Clin Endocrinol Metab 2002; 87: pp. 105-111.

  • Widder S., Pasieka J.L.: Primary thyroid lymphomas. Curr Treat Options Oncol 2004; 5: pp. 307-313.

Tumors Metastasizing To The Thyroid Gland

Clinical Features

  • Direct extension from carcinomas of the head and neck area (pharynx, larynx, trachea, esophagus); occurs most frequently with SCCs

  • Hematogenous metastasis to the thyroid occurs in patients with widespread disease

  • Common tumors metastasizing to the thyroid are malignant melanoma and carcinomas of the lung, gastrointestinal tract, breast, kidney, and head and neck area

  • Clinically present as thyroid enlargement

Gross Pathology

  • Often multiple nodules

  • Appearance varies with primary lesion; may be very vascular in the case of renal cell carcinoma


  • Varies with the histology of the primary tumor ( Figure 3.18 )

    Figure 3.18

    Metastasis to thyroid.

    High-grade adenocarcinoma with comedo necrosis. Tumor nests are present in lymphatic spaces.

  • Metastatic renal cell carcinoma is markedly vascular with clear cytoplasm

  • Nuclear atypia may favor metastasis because thyroid carcinomas (well differentiated) have bland nuclear features

Special Stains and Immunohistochemistry

  • Thyroglobulin negative in all metastatic tumors

  • See “Differential Diagnosis”

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Malignant Melanoma

  • Variable cytology, often large polygonal cells with prominent nucleoli

  • S-100 protein, HMB-45, Melan-A, tyrosinase positive

Renal Cell Carcinoma

  • Cells with abundant clear cytoplasm and surrounding delicate vascularity

  • Cytokeratin and vimentin positive (also seen in papillary thyroid carcinomas)

Carcinoid Tumor

  • Typically has a nested architecture

  • Uniform cells with round nuclei and neuroendocrine-type chromatin

  • Chromogranin, synaptophysin, and cytokeratin positive; rarely expresses calcitonin

  • Clinical history required to differentiate from primary medullary carcinoma

Breast Carcinoma

  • Glandular or solid growth pattern typically with marked cytologic atypia and desmoplastic stroma

  • Mucin stains may be positive (mucin may be seen in papillary thyroid carcinomas)


  • Always obtain a good clinical history so that any previous malignancy is revealed

  • If something does not fit into a known primary thyroid tumor, use select immunohistochemical stains and obtain clinical correlation

Selected References

  • Chen H., Nicol T.L., Udelsman R.: Clinically significant, isolated metastatic disease to the thyroid gland. World J Surg 1999; 23: pp. 177-180.

  • Heffess C.S., Wenig B.M., Thompson L.D.: Metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study of 36 cases. Cancer 2002; 95: pp. 1869-1878.

  • Wood K., Vini L., Harmer C.: Metastases to the thyroid gland: the Royal Marsden experience. Eur J Surg Oncol 2004; 30: pp. 583-588.

Parathyroid Glands

Parathyroid Cyst

Clinical Features

  • Rare lesions, more common in the neck than mediastinum

  • Clinically often mistaken for cystic thyroid nodule, may be palpable

  • Can result from degeneration of an adenomatous or hyperplastic parathyroid gland

  • Usually nonfunctioning; minority are functioning and associated with hyperparathyroidism

  • More common in women than men

  • Peak incidence in fourth to sixth decades

Gross Pathology

  • Can measure up to 10 cm

  • Thin-walled, unilocular cyst

  • Cyst fluid is thin and watery, occasionally hemorrhagic

  • May appear to distend from the surface of the thyroid gland but is loosely attached


  • Cyst is lined by flattened to cuboidal epithelium with small, basally located nuclei and clear cytoplasm

  • Cyst wall consists of fibrous connective tissue

  • Entrapped parathyroid chief cells can be seen in wall in cases resulting from degeneration of adenoma, hyperplasia

Special Stains and Immunohistochemistry

  • PTH and cytokeratin positive

  • Thyroglobulin and TTF-1 negative

  • FNA of cyst fluid may be sent for PTH and thyroglobulin levels to confirm diagnosis

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Thyroid Cyst

  • Fluid on FNA positive for thyroglobulin, negative for PTH

  • Lining cells positive for TTF-1 and thyroglobulin

Degenerated Parathyroid Adenoma or Hyperplasia

  • Cystic degeneration may occur in either adenoma or hyperplasia

  • Background cells are those of adenomatous or hyperplastic parathyroid tissue

  • Entrapped parathyroid chief cells can be seen in wall in cases resulting from degeneration of adenoma or hyperplasia

Cystic Parathyroid Adenoma

  • May be associated with hyperparathyroidism–jaw tumor (HPT-JT) syndrome

  • Higher risk for parathyroid carcinoma

Third Pharyngeal Pouch Cysts

  • Mediastinal cysts that contain both parathyroid and thymic tissue

Branchial Cleft Cyst

  • Located in the lateral neck

  • Cyst lined by squamous, columnar, or ciliated epithelial lining

  • Abundant lymphoid stroma in cyst wall


  • FNA is the best “first” test to evaluate neck nodules

  • When FNA of a neck nodule yields clear fluid, a parathyroid cyst should be in the differential diagnosis, and the fluid should be sent for PTH assay because microscopic examination is nonspecific (histiocytes and a few epithelial cells that may be mistaken for follicular thyroid epithelium)

Selected References

  • Ippolito G., Palazzo F.F., Sebag F., et. al.: A single-institution 25-year review of true parathyroid cysts. Langenbecks Arch Surg 2006; 391: pp. 13-18.

  • Layfield L.J.: Fine needle aspiration cytology of cystic parathyroid lesions: a cytomorphologic overlap with cystic lesion of the thyroid. Acta Cytol 1991; 35: pp. 447-450.

  • Ujiki M.B., Nayar R., Sturgeon C., et. al.: Parathyroid cyst: often mistaken for a thyroid cyst. World J Surg 2007; 31: pp. 60-64.

Parathyroid Hyperplasia

Clinical Features

  • Hyperplasia of parathyroid tissue that involves more than one gland, usually all four

  • Primary hyperparathyroidism (result of parathyroid hyperplasia in about 15% of cases)

    • Patients have increased PTH, hypercalcemia, and hypophosphatemia

  • Secondary hyperparathyroidism

    • Typically secondary to chronic renal failure, which causes hypocalcemia and hyperphosphatemia leading to increased PTH levels

  • Hyperplasia of chief cells may be associated with multiple MEN syndromes (I, IIA, and IIB)

Gross Pathology

  • Typically all glands are enlarged, but they may be unequally enlarged (normal glands weigh up to 40 mg)

  • Cut section appears homogeneous but may be nodular or have cystic changes


  • Proliferation of chief cells, oncocytic cells, transitional cells, or clear cells, which are frequently mixed ( Figure 3.19A )

    Figure 3.19

    A, Normal parathyroid. Note the cellularity of the gland showing nests of chief cells with intercellular adipose tissue. B, Hyperplastic parathyroid. Multiple lobulated nests of parathyroid cells show loss of intercellular adipose tissue. C, Parathyroid adenoma. Gross photograph shows a smooth, well-circumscribed, enlarged gland. D, Parathyroid adenoma. Low-power view shows an expansile nodule (adenoma); note a small, compressed rim of normal parathyroid at top of nodule. E, Parathyroid carcinoma. Gross photograph of a parathyroid carcinoma with necrosis. F, Parathyroid carcinoma. Low-power view shows infiltrating uniform tumor cells in a dense stromal reaction.

  • Nodular pattern of cellular growth within the gland

  • Cellular growth pattern may be solid, follicular (glandlike), or in cords

  • Occasionally mitotic figures may be identified

  • Involved glands have decreased intracytoplasmic fat content and decreased intercellular fat (see Figure 3.19B )

Special Stains and Immunohistochemistry

  • Oil red O on frozen section will demonstrate decreased intracytoplasmic fat (also seen in adenomas)

Other Techniques for Diagnosis

  • MEN menin gene on chromosome 11q

  • MEN II Ret proto-oncogene on chromosome 10q

Differential Diagnosis

Parathyroid Adenoma

  • Typically only one enlarged gland; two adenomas are rare

  • Rim of compressed parathyroid tissue, but otherwise normal parathyroidal tissue is often present


  • Intraparenchymal fat will be reduced in both hyperplasia and adenomas

  • Treatment is subtotal parathyroidectomy (i.e., removal of 31⁄2 glands)

Selected References

  • Elliott D.D., Monroe D.P., Perrier N.D.: Parathyroid histopathology: is it of any value today?. J Am Coll Surg 2006; 203: pp. 758-765.

  • Johnson S.J., Sheffield E.A., McNicol A.M.: Best practice no. 183: examination of parathyroid gland specimens. J Clin Pathol 2005; 58: pp. 338-342.

Parathyroid Adenoma

Clinical Features

  • Benign neoplasm composed of chief cells

  • Most commonly occurs in the fifth and sixth decades, female predominance (3:1)

  • Most are single adenomas involving one gland

  • May occur in various sites such as within the thyroid, mediastinum, or retroesophageal area

  • Single most common cause of primary hyperparathyroidism (about 80% of cases)

  • Patients may present with signs of hypercalcemia (“stones, moans, psychiatric overtones”), or elevated serum calcium is incidentally found during routine blood tests

  • Evaluate by ultrasound, sestamibi scan, or computed tomography

  • May be associated with MEN I and II or HPT-JT syndrome (also associated with parathyroid carcinoma)

Gross Pathology

  • Single enlarged gland; two adenomas are rare

  • Round to oval with thin capsule (see Figure 3.19C )

  • Reddish brown on cut sectioning, usually homogeneous, may on occasion show cystic changes and hemorrhage

  • Typically weigh more than 300 mg and up to several grams


  • Well circumscribed; cellular proliferation of chief cells that may have clear or oncocytic changes

  • Adjacent rim of compressed normal parathyroid tissue is seen in about half of cases and is not required for diagnosis (see Figure 3.19D )

  • Stromal fat content, although minimal to absent in adenoma, is not reliable in separating adenoma from hyperplasia

  • Cells with bizarre nuclei may be seen (endocrine atypia), not a sign of malignancy

  • Mitoses are usually absent; high mitotic rate should raise suspicion for malignancy

  • Growth pattern is solid, nested, follicular, or pseudopapillary; follicular cystic structures may contain colloid-like periodic acid–Schiff (PAS)–positive material

  • Variants

    • Atypical adenoma

    • HPT-JT

      • Lacks unequivocal evidence of malignancy

      • May show thickened capsule, dense fibrotic bands without lymphovascular invasion, or invasion into adjacent structures (i.e., thyroid, esophagus, larynx)

      • Familial, autosomal dominant, involving CDC73 gene, which encodes parafibromin

      • Cystic change common

      • Associated with parathyroid carcinoma in 10% to 15%

Special Stains and Immunohistochemistry

  • Cytokeratin, chromogranin, and PTH positive

  • Thyroglobulin and TTF-1 negative

  • Follicle or cyst contents are PAS positive and thyroglobulin negative

Other Techniques for Diagnosis

  • Frequent loss of chromosome 11q (location of MEN I) not seen in carcinomas

  • Cyclin D1/PRAD1 oncogene activated by clonal rearrangement (40%)

  • Sestamibi scan can localize most parathyroid adenomas preoperatively, and rapid intraoperative PTH assay allows for a minimally invasive parathyroidectomy (MIP), which is a small incision with removal of only the affected gland, avoiding neck exploration and identification of all four glands

Differential Diagnosis

Parathyroid Hyperplasia

  • May be primary or secondary, frequently as a result of renal failure

  • If primary, may be associated with MEN I and II

  • All glands are enlarged, often asymmetrically

Parathyroid Carcinoma

  • Ill-defined, infiltrative mass with extension into adjacent structures

Thyroid Nodules

  • Follicular nodules: thyroglobulin and TTF-1 positive and PTH negative

  • Medullary thyroid carcinoma: calcitonin and CEA positive; negative for PTH

Oncocytic Nodules in Parathyroids of Elderly Patients

  • Oncocytic cells within the parathyroid gland increase with age and may form small nodules


  • Most parathyroid adenomas are functionally active

  • Treatment is surgical resection of adenoma—preoperative localization and use of intraoperative PTH assay allows for limited surgical exploration with identification and resection of only the affected gland, resulting in less morbidity

  • Thyroid lesions may coexist

Selected References

  • Absher K.J., Truong L.D., Khurana K.K., et. al.: Parathyroid cytology: avoiding diagnostic pitfalls. Head Neck 2002; 24: pp. 157-164.

  • Carling T.: Molecular pathology of parathyroid tumors. Trends Endocrinol Metab 2001; 12: pp. 53-58.

  • Grimelius L., Johansson H.: Pathology of parathyroid tumors. Semin Surg Oncol 1997; 13: pp. 142-154.

Parathyroid Carcinoma

Clinical Features

  • Malignant tumor derived from the chief cells of the parathyroid gland

  • Rare cause of hyperparathyroidism (accounts for <1% of cases)

  • High probability of local recurrence and late metastasis to lymph nodes, distant sites

  • Age range is 45 to 55 years, 10 years younger than adenomas; no sex predilection

  • Usually marked hypercalcemia (higher than in patients with adenomas) at presentation, leading to increased renal and bone disease

  • May be associated with HPT-JT syndrome

Gross Pathology

  • Ill-defined, infiltrative mass with extension into muscle, thyroid, esophagus, or trachea (see Figure 3.19E )

  • Cut section firm and gray-white

  • Mean size, 3 cm; mean weight, 6 g

  • Lymph nodes usually not involved at time of surgery

  • Surgeons report adherent and difficult-to-remove mass


  • Histology is frequently mild to moderate variation in chief cells resembling adenomas; rarer cases have marked pleomorphism and macronucleoli

  • Various architectural patterns include solid (most often), glandular, and trabecular (see Figure 3.19F )

  • Thick acellular fibrous bands and thick capsule (60% of cases) are common

  • For diagnosing carcinoma, invasion should extend into adjacent structures (esophagus, larynx, muscle)

  • Necrosis is worrisome for carcinoma

  • Vascular invasion (10% to 15% of cases) is defined as attachment to the wall within a vessel located outside the tumor (diagnostic of carcinoma)

  • Capsule in carcinoma is generally thicker than in adenoma

  • Mitoses are seen in about 50% of cases but can also be seen in adenoma or hyperplasia

Special Stains and Immunohistochemistry

  • Cytokeratin and chromogranin positive

  • TTF-1 and thyroglobulin negative

  • Parafibromin loss may be secondary to sporadic or germline alterations in CDC73 gene (formerly HRPT2)

Other Techniques for Diagnosis

  • Recurrent loss of chromosome 13q (region of retinoblastomas and BRCA2 tumor suppressor genes)

  • HPT-JT syndrome involving CDC73 gene (1q25), which encodes parafibromin (germ-line alteration)

Differential Diagnosis

Parathyroid Hyperplasia

  • Well-defined growth pattern without extension into adjacent structures

  • Multiple parathyroid glands enlarged

Parathyroid Adenoma

  • Well-defined mass with a distinct, thin fibrous capsule; lacks infiltrative growth pattern

  • Lacks capsular and vascular invasion

Atypical Adenoma

  • May have some features associated with parathyroid carcinoma, such as adherence to soft tissue, broad fibrous bands, and capsular invasion

  • The term atypical adenoma is used if some of these features are present, but the tumor lacks unequivocal evidence of malignancy, including vascular invasion or invasion into muscle or adjacent structures

Primary Neoplasms of the Thyroid

  • Lack clinical hyperparathyroidism (hypercalcemia)

  • Papillary and follicular tumors are positive for thyroglobulin and negative for chromogranin; medullary carcinoma is positive for calcitonin and frequently positive for TTF-1


  • Treatment is surgical en bloc resection; if local recurrence happens, it is usually during first 3 years after surgery

  • Most common sites of metastases are cervical lymph nodes, lung, and liver; metastases typically occur late

  • No scientific basis for progression from hyperplasia to adenoma to carcinoma

Selected References

  • Clayman G.L., Gonzalez H.E., El-Naggar A., et. al.: Parathyroid carcinoma: evaluation and interdisciplinary management. Cancer 2004; 100: pp. 900-905.

  • DeLellis R.A.: Parathyroid carcinoma: an overview. Adv Anat Pathol 2005; 12: pp. 53-61.

  • Evans H.L.: Criteria for the diagnosis of parathyroid carcinoma: a critical study. Surg Pathol 1991; 4: pp. 244-265.

Tumors Metastasizing to the Parathyroid Glands

Clinical Features

  • Metastases to the parathyroid glands are relatively rare

  • Most common sites of origin are breast, skin, lung, soft tissue, and involvement by leukemia

  • Rarely the destruction of parathyroid tissue by the metastases may lead to clinical presentation of hypoparathyroidism

Gross Pathology and Histopathology

  • Depends on the primary site of malignancy ( Figure 3.20 )

    Figure 3.20

    Metastasis to parathyroid gland.

    Prostatic adenocarcinoma with large nuclei infiltrating fibrous tissue between parathyroid follicles as seen on frozen section.

Special Stains and Immunohistochemistry

  • Staining for PTH and other epithelial markers may be helpful

Other Techniques for Diagnosis

  • Depends on primary tumor

Differential Diagnosis

  • Depends on cell type and pattern

  • Clinical history is essential


  • Parathyroids may be involved by direct extension of tumors from adjacent structures (thyroid, larynx) or from distant sites (metastatic spread)

Selected References

  • De la Monte S.M., Hutchins G.M., Moore G.W.: Endocrine organ metastases from breast carcinoma. Am J Pathol 1984; 114: pp. 131-136.

  • Venkatraman L., Kalangutkar A., Russell C.F.: Primary hyperparathyroidism and metastatic carcinoma within parathyroid gland. J Clin Pathol 2007; 60: pp. 1058-1060.

Salivary Glands


Clinical Features

  • May present as acute, chronic, and granulomatous forms

  • Causative agents include viral (paramyxovirus, Epstein-Barr virus [EBV], coxsackievirus, influenza A, parainfluenza virus) and bacterial ( Staphylococcus aureus, Streptococcus species, gram-negative bacteria) organisms

  • Chronic sialadenitis may be associated with rheumatoid arthritis

  • Predisposing conditions include dehydration, malnutrition, immunosuppression, and sialolithiasis

  • Etiology of granulomatous subtype is tuberculosis, mycosis, sarcoidosis, duct obstruction

  • Male predilection; mean age, 40 years

Gross Pathology

  • Sialolith (stone) may be present (more common in extraglandular secretory ducts than in gland)

  • Firm to hard; gland consistency depends on the extent of fibrosis


  • Varies depending on the causative agent (viral vs. bacterial), underlying condition (sialolithiasis, obstruction), and age of lesion (acute or chronic)

  • Variable atrophic changes, fibrosis, and acute and chronic inflammatory features ( Figure 3.21 )

    Figure 3.21

    Chronic sialadenitis, sialometaplasia.

    Retained lobular architecture with fibrosis and marked squamous metaplasia of the ducts.

  • Interlobular variation of the extent of inflammatory and fibrotic changes

  • Chronic sclerosing sialadenitis of the submandibular gland is unilateral and characterized by lymphocytic and plasmacytic inflammation encasing ducts

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Benign Lymphoepithelial Lesion

  • Epimyoepithelial islands within lymphoid stroma

  • Parenchymal atrophy

Benign Lymphoepithelial Cyst Almost Always in Parotid Gland

  • Often bilateral

  • Irregular luminal surface with lymphoid infiltrate in wall of cyst

  • Often associated with HIV infection

Necrotizing Sialometaplasia

  • Reactive inflammatory condition with lobular coagulative necrosis of acini

  • Squamous metaplasia and pseudoepitheliomatous hyperplasia of overlying mucosal epithelium

  • May resemble neoplasia if unilateral

  • Can affect any site (palate is common), probably related to ischemia

  • FNA yields mostly ductal elements and some chronic inflammatory cells


  • Clinically, sialadenitis can be confused with malignancy

Selected References

  • Brook I.: Diagnosis and management of parotitis. Arch Otolaryngol Head Neck Surg 1992; 118: pp. 469-471.

  • O’Brien C.J., Murrant B.J.: Surgical management of chronic parotitis. Head Neck 1993; 15: pp. 445-449.

  • Richardson M.S.: Non-neoplastic lesions of the salivary glands.Thompson L.D.R.Goldblum J.R.Head and Neck Pathology.2006.ElsevierPhiladelphia:pp. 283-286.

  • Van der Walt J.D., Leake J.: Granulomatous sialadenitis of the major salivary glands: a clinicopathological study of 57 cases. Histopathology 1987; 11: pp. 131-144.

Benign Lymphoepithelial Lesion (Mikulicz Disease)

Clinical Features

  • Most common cause of diffuse bilateral enlargement of salivary and lacrimal glands

  • Clinically, slowly increasing bilateral and symmetrical swelling of salivary glands

  • One manifestation of Sjögren syndrome

  • Systemic autoimmune disease; develop small clonal expansions; can evolve into lymphoma

Gross Pathology

  • Multiple small, tan nodules may diffusely replace gland


  • Epimyoepithelial islands are solid nests of mainly basal epithelial cells and myoepithelial cells; typically permeated by monocytoid B-cells of MALT; they can also be seen in low-grade MALT lymphoma ( Figure 3.22 )

    Figure 3.22

    Benign lymphoepithelial lesion.

    High-power view shows a vaguely defined epimyoepithelial island surrounded by small lymphoid cells.

  • Lymphoid infiltrate can contain well-formed germinal centers; polyclonal and composed predominantly of T-cells

  • Intercellular hyaline material resembling basal lamina is deposited

Special Stains and Immunohistochemistry

  • B- and T-cell markers and kappa and lambda stains on paraffin or frozen tissues

Other Techniques for Diagnosis

  • Flow cytometry to evaluate clonality

  • Gene rearrangement studies to exclude lymphoma, if indicated

Differential Diagnosis

Malignant Lymphoepithelial Carcinoma

  • Undifferentiated carcinoma with lymphoid stroma

  • Most in salivary location, EBV associated


  • Increased risk for developing malignant lymphoma in both salivary and extrasalivary locations

  • Lymphomas are mostly B-cell phenotype; large cell lymphoma or MALT type

  • Features that indicate development of lymphoma include prominent aggregations of monomorphic medium-sized lymphoid cells with abundant pale cytoplasm and uniform nuclei (monocytoid B-cells); involvement of adjacent fat and connective tissue, immunohistochemical evidence of monoclonality

Selected References

  • Batsakis J.G.: Pathology consultation: carcinoma ex lymphoepithelial lesion. Ann Otol Rhinol Laryngol 1983; 92: pp. 657-658.

  • MacLean H., Ironside J.W., Cullen J.F., et. al.: Mikulicz syndrome and disease: 2 case reports highlighting the difference. Acta Ophthalmol 1993; 71: pp. 136-141.

  • McCurley T.L., Collins R.D., Ball E., et. al.: Nodal and extranodal lymphoproliferative disorders in Sjögren syndrome: a clinical and immunopathologic study. Hum Pathol 1990; 21: pp. 482-492.

  • Peel R.L.: Diseases of the salivary glands.Barnes L.Surgical Pathology of the Head and Neck.2001.Marcel DekkerNew York:pp. 635-642.

Lymphoepithelial Cyst

Clinical Features

  • Present in the parotid or upper cervical lymph nodes

  • Similar to a salivary duct cyst

  • Etiology

    • Originates from remnant of branchial apparatus and is similar to a branchial cleft cyst

    • Cystic formation of salivary gland nests in intraparotid or periparotid lymph node

  • Some cases associated with HIV infection, often bilateral

Gross Pathology

  • Multiloculated cysts on cut surface ( Figure 3.23A )

    Figure 3.23

    Lymphoepithelial cyst.

    A, Gross photograph of multiple lymphoepithelial cysts within the parotid gland. B, Low-power view shows a cyst lined by epithelium and a prominent lymphoid infiltrate in the cyst wall.

  • Solid, tan homogeneous areas in the cyst wall represent lymphoid tissue


  • Multilocular cysts covered by glandular or squamous epithelium surrounded by hyperplastic lymphoid follicles with germinal center formation (see Figure 3.23B )

  • HIV-associated cases

    • Multifocal

    • Occur early and associated with florid lymphoid hyperplasia

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Cystic Warthin Tumor

  • Lymphoid follicle formation with oncocytic epithelium

Branchial Cleft Cyst

  • Lateral location is in neck near sternocleidomastoid muscle

  • Cyst is lined by squamous, columnar, or ciliated epithelium

  • Cyst wall has prominent lymphoid stroma

  • Cyst may contain anucleated keratinized epithelium, histiocytes, or cholesterol clefts


  • HIV infections show marked increase in dendritic reticular cells and intrafollicular CD8-positive lymphocytes

  • FNA can be diagnostic and therapeutic; can be the first indication that the patient should be tested for HIV

Selected References

  • Cleary K.R., Batsakis J.G.: Lymphoepithelial cysts of the parotid region: a new face on an old lesion. Ann Otol Rhinol Laryngol 1990; 99: pp. 162-164.

  • Mandel L., Reich R.: HIV parotid gland lymphoepithelial cysts: review and case reports. Oral Surg Oral Med Oral Pathol 1992; 74: pp. 273-278.

  • Richardson M.S.: Non-neoplastic lesions of the salivary glands.Thompson L.D.R.Goldblum J.R.Head and Neck Pathology.2006.ElsevierPhiladelphia:pp. 288-290.

  • Terry J.H., Loree T.R., Thomas M.D., et. al.: Major salivary gland lymphoepithelial lesions and the acquired immunodeficiency syndrome. Am J Surg 1991; 162: pp. 324-329.

Salivary Duct Cyst

Clinical Features

  • Cystic dilatation of a salivary duct due to ductal obstruction

  • Majority occur in parotid

Gross Pathology

  • Well-circumscribed, unilocular cyst with smooth lining

  • Cyst contains thin, watery to viscous fluid


  • Cyst wall consists of dense fibroconnective tissue with mild to moderate infiltrate of chronic inflammatory cells and lined by stratified squamous epithelium ( Figure 3.24 )

    Figure 3.24

    Salivary duct cyst.

    Low-power view shows a cyst lined by a single layer of epithelium. Notice the adjacent salivary gland tissue and marked fibrosis of the wall.

  • Goblet-type mucinous or oncocytic cells may be present in the epithelium

  • Surrounding parenchyma of parotid is atrophic as a result of compression

  • Mild sialadenitis and duct ectasia may be seen

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Mucus Retention Cyst (Ranula)

  • More common in minor salivary glands, lower lip

  • Lack of cystic wall

  • Pools of mucin in fibrous tissue

Cystic Warthin Tumor

  • Cyst wall lined by oncocytic cuboids or columnar epithelium with underlying dense lymphoid stroma


  • Surgical excision is curative

Selected References

  • Cohen M.N., Rao U., Shedd D.P.: Benign cysts of the parotid gland. J Surg Oncol 1984; 27: pp. 85-88.

  • Peel R.L.: Diseases of the salivary glands.Barnes L.Surgical Pathology of the Head and Neck.2001.Marcel DekkerNew York:pp. 651-653.

Mucocele (Ranula)

Clinical Features

  • Most common non-neoplastic lesion of the salivary glands (4% to 9%)

  • Two types of mucoceles: extravasation type and retention type

    • Extravasation-type mucocele

      • Results from extravasation of secreted salivary fluid into surrounding tissue; peak incidence in third decade

      • Lip most common location

    • Retention-type mucocele (plunging ranula)

      • Mucus pools within epithelium-lined cysts (partially obstructed excretory ducts with cystic dilatation or congenital or acquired weakness of duct wall)

      • Occurs in all ages; peak incidence in seventh decade

      • Clinically may fluctuate in size; can develop within hours to days

Gross Pathology

  • Small, dome-shaped swelling of mucosa ranging in size from 0.2 to 1 cm

  • Consistency is soft and fluctuant


  • Extravasation type

    • Pool of mucin often with scattered inflammation surrounded by granulation tissue ( Figure 3.25 )

      Figure 3.25

      Mucocele (extravasation type).

      Low-power view shows pools of mucoid material surrounded by inflammation and minor salivary glands.

  • Retention type

    • Mucin pool surrounded by cuboidal to stratified squamous epithelial lining and fibrotic cyst wall

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Noncontributory

Differential Diagnosis

Salivary Duct Cyst

  • True epithelium-lined cyst with chronic inflammation in wall

  • Compression of surrounding parenchyma, which has atrophic changes

Lymphoepithelial Cyst

  • Multilocular cyst with marked lymphoid tissue in wall


  • Sublingual mucocele (floor of mouth) is called plunging ranula; can become larger (several centimeters) and dissect through muscles and connective tissue of the neck

  • Treatment is local excision

Selected References

  • Das S., Das A.K.: A review of pediatric oral biopsies from a surgical service in a dental school. Pediatr Dent 1993; 15: pp. 208-211.

  • Richardson M.S.: Non-neoplastic lesions of the salivary glands.Thompson L.D.R.Goldblum J.R.Head and Neck Pathology.2006.ElsevierPhiladelphia:pp. 279-283.

Mixed Tumor (Pleomorphic Adenoma)

Clinical Features

  • Benign tumor that manifests both epithelial and mesenchymal elements

  • Most common neoplasm of salivary gland origin; constitutes about 30% of all parotid neoplasms and 60% of benign tumors from all salivary gland sites

  • Most common salivary gland tumor in children and adolescents; higher incidence in women

  • Most common intraoral site is the palate, followed by the upper lip and buccal mucosa

  • Usually solitary, most common associated tumor is Warthin tumor

  • Peak incidence is in fourth decade

  • Typically presents as a slow-growing, asymptomatic, discrete, mobile, often multinodular, firm mass; may become large if untreated

  • Often occurs in the lower pole of the superficial lobe; facial paralysis may occur only as result of extrinsic compression of facial nerve, not invasion

Gross Pathology

  • Round to ovoid mass with smooth surface

  • Most tumors are encapsulated (incomplete fibrous capsule); tumors that originate from minor salivary glands are often unencapsulated

  • Cut surface is homogeneous or variegated, tan to white, with shiny, translucent zones that represent myxochondroid or cartilaginous areas; often lobulated, especially when larger than 1 cm ( Figure 3.26A )

    Figure 3.26

    Benign mixed tumor (pleomorphic adenoma).

    A, Gross photograph shows a well-circumscribed, gray-white nodule. B, A cellular tumor composed of ducts and myoepithelial cells (right) is adjacent to the hypocellular cartilaginous areas (left) .

  • Occasionally, hemorrhage and infarction occur secondary to surgical or FNA biopsy


  • Shows both epithelial and mesenchymal differentiation; proportions are variable and heterogeneous cellular composition

    • Epithelial component

      • Well-formed ductal structures formed of inner epithelial and outer myoepithelial cells associated with features of spindle, squamous, basaloid, cuboidal, oncocytoid, mucous, sebaceous, round, plasmacytoid, polygonal, or clear cells (see Figure 3.26B )

      • Squamous differentiation with keratin pearls can occur

      • Cytologic features of epithelial cells are bland; rare, if any, mitotic activity

      • Myxoid, hyaline, cartilaginous, or osseous differentiation

  • Several variants

    • Cellular type: epithelial component predominates most commonly myoepithelial predominant; constitutes more than 80% of tumor in only 12% to 15% of cases

    • Myxoid type: myxochondromatous mesenchymal element predominates (most tumors have a myxoid component that makes up about 30% of tumor)

  • Thickness of fibrous capsule varies; often absent in predominantly myxoid tumors and in tumors arising in minor salivary glands

Special Stains and Immunohistochemistry

  • Noncontributory

Other Techniques for Diagnosis

  • Cytogenetic studies often show clonal chromosomal rearrangements, 8q12 and 12q13–15 involving PLAG1 and HMGA2 genes

  • No correlation between cytogenetic findings and prognosis

Differential Diagnosis

Polymorphous Low-Grade Adenocarcinoma (Particularly in Minor Salivary Gland)

  • Frequently shows perineural growth and is infiltrative into periglandular tissue

  • Forms small tubular structures or single-file cords of cells at the periphery

Carcinoma Ex Pleomorphic Adenoma

  • Malignant tumor arising in a background of a mixed tumor

Selected References

  • Bullerdiek J., Wobst G., Meyer-Bolte K., et. al.: Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet 1993; 65: pp. 27-31.

  • Das D.K., Anim J.T.: Pleomorphic adenoma of salivary gland: to what extent does fine needle aspiration cytology reflect histopathological features?. Cytopathology 2005; 16: pp. 65-70.

  • Lee P.S., Sabbath-Solitare M., Redondo T.C., et. al.: Molecular evidence that the stromal and epithelial cells in pleomorphic adenomas of salivary gland arise from the same origin: clonal analysis using human androgen receptor gene (HUMARA) assay. Hum Pathol 2000; 31: pp. 498-503.

  • Wasserman J.K., Dickson B.C., Smith A., et. al.: Metastasizing pleomorphic adenoma: recurrent PLAG1/HMGA2 rearrangements and identification of a novel HMGA2-TMTC2 fusion. Am J Surg Pathol 2019; 43: pp. 1145-1151.


Clinical Features

  • Benign tumor composed entirely of myoepithelial cells

  • May represent the end of the pleomorphic adenoma spectrum

  • About 2% to 5% of benign salivary gland tumors

  • Sites: parotid (50%) and minor salivary glands (40%)

  • Men and women affected equally

  • Peak incidence in third decade

  • Typically presents as an asymptomatic mass

Gross Pathology

  • Well circumscribed and may be encapsulated

  • Cut surface is solid, tan, or yellow-tan and glistening

Histopathology ( Figure 3.27 )

Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Head and Neck

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