Thyroid gland
Bethesda system

Topic Completed: 1 July 2014

Minor changes: 13 October 2020

Copyright: 2014-2020,, Inc.

PubMed Search: Bethesda guidelines

Phillip A. Williams, M.D., M.Sc.
Shahid Islam, M.D., Ph.D.
Page views in 2019: 4,481
Page views in 2020 to date: 3,672
Cite this page: Williams, P, Islam S. Malignant. website. Accessed October 20th, 2020.
Definition / general
  • Use when diagnostic features of malignancy are seen (e.g., papillary carcinoma, medullary carcinoma, lymphoma, metastatic carcinoma)
  • Risk for actual malignancy is 97 - 99%
  • Malignant includes:
    • Papillary thyroid carcinoma
    • Poorly differentiated carcinoma
    • Medullary thyroid carcinoma
    • Undifferentiated (anaplastic) carcinoma
    • Squamous cell carcinoma
    • Metastatic carcinoma
    • Non-Hodgkin lymphoma
    • Other
  • Papillary thyroid carcinoma accounts for ~80% of thyroid malignancies, with female preponderance (4:1 over males), most often ages 25 - 50 years
Papillary thyroid carcinoma
  • Defined by nuclear features, or true papilla (rarely seen on cytology)
  • Papillary / syncytial-like follicle cells, sometimes with "cartwheel" pattern
  • Nuclear features: large oval, molded or irregular nuclei with crowding / overlapping, nuclear clearing (so called "Orphan Annie" eyes) with powdery chromatin, nuclear grooves or nuclear pseudoinclusions
  • Psammoma bodies are characteristic but not pathognomonic
  • May see multinucleated giant cells
  • Variants
    • Follicular variant:
      • Hypercellular sample with virtually no papilla but with microfollicles, isolated neoplastic follicles (e.g., sheets, branched)
      • Nuclear features of papillary thyroid carcinoma (as mentioned above) required for diagnosis and may be more subtle
    • Macrofollicular variant:
      • Flat / monolayered sheets of epithelial cells with atypia, follicles of variable sizes, abundant colloid (thick or thin fragments)
      • Nuclear features of papillary thyroid carcinoma required for diagnosis and may be more subtle
    • Oncocytic variant:
      • Papillary configuration, sheets or single oncocytic cells (polygonal, abundant blue cytoplasm on Diff-Quick, green on Pap or pink on H&E), lymphocytes are absent or scant
      • Nuclear features of papillary thyroid carcinoma required for diagnosis
    • Tall cell variant (more aggressive):
      • Tall cells (height / width > 3:1) are 50% or more of tumor cells, usually in papillary clusters
      • Have abundant granular dense cytoplasm, nuclear features of papillary thyroid carcinoma required for diagnosis
      • Often with multiple intranuclear pseudoinclusions ("soap bubbles")
      • Nuclei may have less powdery chromatin and more granular chromatin
    • Columnar cell variant (more aggressive):
      • Papillary configuration, clusters, sheets or follicles, consisting of cells with oval, stratified, dark, elongated nuclei with less prominent nuclear features of papillary thyroid carcinoma, cytoplasm has supra or subnuclear vacuolization
      • Resembles respiratory epithelium or metastatic colon carcinoma
    • Warthin-like: associated with Hasimoto thyroiditis, abundant lymphocytic infiltrate
    • Other: clear cell, diffuse sclerosing, cribiform variants
Follicular carcinoma
Medullary thyroid carcinoma
  • Moderately or markedly cellular, single cells and clusters (syncytial-like)
  • Plasmacytoid, spindled, round or polygonal cells with mild to moderately pleomorphic nuclei, eccentrically located (Pathologica 1998;90:5)
  • Cytoplasm is granular, variable in amount, sometimes with red granules (70%) on Diff-Quck and rarely melanin pigment
  • Nuclei are round or elongated with "salt and pepper" chromatin, pseudoinclusions (50%) and prominent nucleoli
  • Multinucleated or binucleated cells are common, occasionally bizarre giant cells
  • Amyloid, an amorphous dense material reminiscent of colloid (Congo red positive), is often seen
Poorly differentiated thyroid carcinoma
  • Highly cellular material with solid, nested (insular) or trabecular patterns and many isolated cells
  • Uniform population of follicular cells with scant cytoplasm with some plasmacytoid forms
  • Follicular cells have high N/C ratio and nuclear atypia
  • Mitoses and apoptotic forms are present; often necrosis
Undifferentiated (anaplastic) carcinoma
  • Moderate to increased cellularity, with single cells or groups of various sizes
  • Cells are epithelioid (round or polygonal) or spindled, small to giant; plasmacytoid or rhabdoid forms are seen (Acta Cytol 1996;40:953)
  • Nuclei are large and pleomorphic with irregular membranes, clumped chromatin, prominent nucleoli, nuclear inclusions; often eccentrically located and multinucleated
  • Necrosis and inflammatory infiltrates are common
  • Nonneoplastic osteoclast-like giant cells are scattered in some cases
  • Many mitoses are present
Squamous cell carcinoma of thyroid
  • Large pleomorphic keratinized cells with necrosis
Metastatic tumors
  • Metastatic renal cell carcinoma:
    • Moderate to marked cellularity, with single cells and clusters, fragments of papillary structures, sheets
    • Cytoplasm is pale, vacuolated, granular or clear
    • Nuclei are round or oval, with prominent large nucleoli
    • Often prominent vascularity
  • Metastatic melanoma:
    • Moderate to marked cellularity with noncohesive pleomorphic cells, some plasmacytoid, spindled or anaplastic
    • Cytoplasm is finely granular, but melanin pigment is not commonly seen
    • Nuclei are large, eccentric with intranuclear inclusions
    • Histiocytes with coarse granules are common
    • Tumor cells are immunoreactive for S100, Melan-A (MART1), HMB45
  • Metastatic breast carcinoma:
    • Moderate to marked cellularity with oval or polygonal cells isolated or in clusters
    • Intracytoplasmic magenta inclusions (due to mucin) are common
    • The single cells retain cytoplasm
    • Tumor cells are usually immunoreactive for ER and PR, GATA3; negative for TTF1, thyroglobulin and calcitonin
  • Metastatic lung carcinoma:
    • Adenocarcinoma has round balls or sheets of medium to large cells with prominent nucleoli and intracytoplasmic mucin; nuclei are more pleomorphic than thyroid follicular neoplasms
    • Small cell carcinoma has neuroendocrine features, friable nuclei, crush artifact
Non-Hodgkin lymphoma
  • Cellular sample with noncohesive cells with oval or round nuclei
  • Lymphoglandular bodies are common (better seen on Diff-Quick)
  • Marginal zone (MALT) lymphoma has cells 2× size of small lymphocytes, with vesicular open nuclei
  • Diffuse large B cell lymphoma has cells with moderate bluish cytoplasm, course chromatin, conspicuous nucleoli, necrotic debris
  • Papillary thyroid carcinoma:
    • Initial management is surgical; for unifocal tumors < 1.0 cm (microcarcinoma) confined to one lobe, lobectomy and isthmusectomy is recommended, tumors larger than this require total thyroidectomy
    • Central (Level VI) neck dissection in addition to total thyroidectomy should be reserved for patients with clinical nodal involvement or tumors > 4 cm or with extrathyroid extension
    • Radioiodine can be considered in the post thyroidectomy treatment stage (Thyroid 2009;19:1167)
  • Medullary carcinoma: total thyroidectomy (since frequently bilateral) with central node dissection (due to high risk of lymph node metastases) (Ann Surg 1999;230:697)
  • Poorly differentiated thyroid carcinoma: more aggressive than well differentiated carcinoma; requires surgery plus postoperative radioactive iodine therapy; use radiation therapy in T3 or T4 tumors
  • Undifferentiated (anaplastic) thyroid carcinoma:
    • All are considered T4 tumors
    • For tumors localized to the thyroid or locally advanced operable disease: total thyroidectomy / complete resection followed by combined radiotherapy and chemotherapy (Thyroid 2012;22:1104)
Cytology images

Scroll to see all images:

Contributed by Ayana Suzuki, C.T.

Papillary carcinoma

Medullary carcinoma

Insular carcinoma

Anaplastic carcinoma


Contributed by Andrey Bychkov, M.D., Ph.D.

Pink intranuclear cytoplasmic inclusion vs. intranuclear bubbles

Microfollicle, enlarged nuclei and single intranuclear inclusion

Images hosted on other servers:

Medullary thyroid carcinoma:

Spindle shaped cells

Epithelioid and spindle shaped cells

Spindle shaped and plasmacytoid cells

Isolated plasmacytoid cells with karyomegaly

Epithelioid and fusiform

Amyloid surrounded by fusiform cells

Monomorphic fusiform cells

Epithelioid cells with anisonucleosis

Large epithelioid cells

Metastatic carcinoma:

Colon carcinoma

Esophageal adenocarcinoma

Gastric carcinoma - Signet ring

MALT (metastatic)

Merkel cell

Renal cell carcinoma

Mucoepidermoid carcinoma of the thyroid:

Squamous differentiation

Prominent nucleoli

Intermediate-type cells

Small pearl

Intermediate-type cells

Glandular-type cells

Non-Hodgkin lymphoma:

Diffuse large B cell lymphoma

Papillary thyroid carcinoma:

Intranuclear pseudo inclusions

Grooves and nucleoli

Nuclear grooves

Nuclear crowding

Intranuclear pseudoinclusions

Cellular crowding

Branching papillae

Monolayered sheet

Intact papilla

Poorly differentiated carcinoma:

Isolated malignant cells

Malignant cells and clusters

Overlapping cells with granular chromatin

Acinar or microfollicular arrays

Insular carcinoma

Squamous cell carcinoma of the thyroid:

Keratinizing malignant cells

Undifferentiated (anaplastic) carcinoma:

Anaplastic carcinoma of thyroid

Pap stained

Extreme pleomorphism

Malignant cells admixed with macrophages

Rhabdoid appearance

Spindle cells

  • Papillary thyroid carcinoma: cytokeratin, thyroglobulin, TTF1, PAX8, negative for calcitonin (Mod Pathol 2008;21:192)
  • Medullary carcinoma: calcitonin, TTF1, CEA, chromogranin and synaptophysin, negative for thyroglobulin
  • Poorly differentiated (anaplastic) carcinoma: cytokeratin and PAX8, with high (> 30%) Ki67, negative for thyroglobulin and usually negative for TTF1
Molecular / cytogenetics description
Additional references
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