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Anaplastic


Minor changes: 11 February 2021

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PubMed Search: Anaplastic carcinoma[TI] thyroid[TI] pathology

Xiaofeng Zhao, M.D., Ph.D.
Shuanzeng (Sam) Wei, M.D., Ph.D.
Page views in 2020: 17,716
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Cite this page: Zhao X, Wei S. Anaplastic. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidUndiff.html. Accessed March 9th, 2021.
Definition / general
  • A highly aggressive thyroid malignancy composed of undifferentiated follicular thyroid cells (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
  • 1 - 1.7% of all thyroid cancers in the United States
  • Rapidly enlarging, bulky neck mass invades adjacent structures causing hoarseness, dysphagia, dyspnea
  • Most thyroid sarcoma-like tumors are probably anaplastic carcinomas; small cell types reported in past were probably lymphoma or variants of medullary or insular carcinoma (Am J Clin Pathol 1985;83:135)
  • Paucicellular variant: uncommon; resembles Riedel thyroiditis; may be due to extensive infarction
  • Rhabdoid variant: very rare; aggressive, often metastasizes; to date, always rapidly fatal
Essential features
  • Highly aggressive thyroid carcinoma composed of undifferentiated follicular cells that demonstrate immunohistochemical or ultrastructural features of epithelial differentiation but devoid of morphologic and immunophenotypic markers of thyroid origin
Terminology
  • Undifferentiated thyroid carcinoma, carcinosarcoma, sarcomatoid carcinoma, metaplastic carcinoma, spindle cell carcinoma, giant cell carcinoma, pleomorphic carcinoma
ICD coding
  • ICD-10: C73 - Malignant neoplasm of thyroid gland
  • ICD-0: 8020/3 - Carcinoma, undifferentiated, NOS
Epidemiology
  • Medium age 60 - 70 years with incidence to rise with age, F:M = 2:1 (Ann Surg Oncol 2007;14:3011)
  • Higher incidence in areas of dietary iodine deficiency
  • Median 1 year survival rate: 10 - 20%
  • Rhabdoid variant: usually women, mean 56 years, range 42 - 67 years
Sites
  • Thyroid gland: rare cases from ectopic thyroid tissue were reported (Int J Gynecol Pathol 2014;33:607, Int J Gynecol Pathol 2016;35:357)
  • Often presents with local invasion and metastatic spread to regional lymph nodes and distant sites
  • All are considered high stage (IV) tumor (J Oncol 2011;2011:542358)
    • Stage IVA and IVB patients have intrathyroidal tumors (IVA) and extrathyroidal tumors (IVB), whereas stage IVC patients have distant metastasis
Pathophysiology
  • May arise as anaplastic transformation of differentiated thyroid carcinoma (papillary, follicular or Hürthle cell carcinoma)
  • Most cases have a core of conserved mutations in well differentiated and anaplastic areas, plus increases in mutation rates in anaplastic areas (Am J Surg Pathol 2003;27:1559)
Etiology
  • Unclear, may be associated with radiation and iodine deficiency
  • Coexisting well differentiated thyroid carcinomas in 22 - 78% of cases
Clinical features
  • 25 - 50% have prior multinodular goiter, 20% have prior differentiated carcinoma, 20% have concurrent differentiated carcinoma
  • Rapidly enlarging, painful, firm, ill defined, lower anterior neck mass usually fixed to the underlying structures
  • Local invasion of the surrounding structures occurs in almost 70% of patients: muscles (65%), trachea (46%), esophagus (44%), laryngeal nerve (27%) and larynx (13%)
  • Hoarseness, dyspnea and dysphagia as compressive symptoms
  • Extrathyroidal extension in majority of cases
  • Regional nodal metastases and vocal cord paralysis present in up to 40% and 30%, respectively (Int J Surg 2014;12:S170)
  • Up to 75% of patients have distant metastases (lung [80%], bone [6 - 15%] and brain [5 - 13%])
Radiology description
  • Ultrasonography:
    • Solid masses, marked hypoechogenicity, irregular margin, internal calcification, wider than tall shape and cervical lymph node involvement (Yonsei Med J 2013;54:1400)
  • Computed tomography scan:
  • Magnetic resonance imaging:
    • Useful to assess tumor extension, particularly in the esophagus musculature, trachea and carotid vessel
  • F-fluorodeoxyglucose positron emission tomography (FDG-PET):
    • Staging assessment due to its enhanced expression of glucose transporter (GLUT1), resulting in increased glucose uptake (AME Case Rep 2018;2:20)
Radiology images

Contributed by Mark R. Wick, M.D.

CT scan

Prognostic factors
Case reports
Treatment
  • Radiation therapy, surgery when feasible or chemoradiation either concurrently or sequentially (J Oncol 2011;2011:542358)
  • EGFR, VEGFR and ALK alteration may be used for targeted therapy
  • Some cases may express PD-L1 (Oncologist 2017;22:1149)
Gross description
  • Bulky solid mass (mean: 6 cm) with zones of homogeneous and necrosis or variegated appearance (Crit Rev Oncol Hematol 2013;86:290)
  • On cut section, light tan and fleshy with zones of necrosis and hemorrhage
  • Infiltrating, often into adjacent soft tissues and organs
  • Paucicellular variant: hard fibrotic mass
Gross images

Contributed by Mark R. Wick, M.D. and AFIP

Scant residual thyroid

Metastases to stomach with ulcerated center



Images hosted on other servers:

Encapsulated tumor with focal necrosis

Large necrotic tumor

Nodular tumor

Solid and cystic tumor

Microscopic (histologic) description
  • Common features include widely invasive growth, extensive tumor necrosis, marked nuclear pleomorphism and high mitotic activity
  • Three patterns (can be singly or in any combination):
    1. Sarcomatoid (about 50%): malignant spindle cells resembling high grade pleomorphic sarcoma
    2. Giant cell (30 - 40%): highly pleomorphic tumor cells with marked nuclear hyperchromasia and some tumor giant cells, may have cavernous blood filled sinuses resembling aneurysmal bone cyst and angiosarcoma (Am J Surg Pathol 1991;15:160)
      • Multiple small intracytoplasmic hyaline globules have been described
    3. Epithelial (< 20%): squamoid / squamous tumor nests with abundant dense eosinophilic cytoplasm resembling nonkeratinizing squamous cell carcinoma of the lung or upper aerodigestive tract and occasional focal keratinization
  • Necrosis
  • Vascular invasion with obliteration of the lumen
  • Increased mitotic figures
  • Heterologous differentiation: neoplastic bone and cartilage
  • Secondary change: acute inflammation, macrophages, osteoclast-like multinucleated giant cells (PLoS One 2011;6:e22567, Endocr Relat Cancer 2008;15:1069)
  • Microscopic variants:
    • Paucicellular (< 1%): infiltrative, composed of acellular or necrotic fibrous tissue with hypocellular foci of mildly atypical spindle cells obliterating large blood vessels, mixed with collagen and small lymphocytes (Am J Clin Pathol 1996;105:388)
    • Rhabdoid: more prevalent in patients who had received chemotherapy (Endocr J 2016;63:441)
      • Highly cellular, solid infiltrative growth with extracapsular invasion
      • Tumor cells are large and pleomorphic with abundant cytoplasm, eosinophilic inclusions, eccentric nuclei with distinct nucleoli (Am J Surg Pathol 2007;31:729)
      • Typically strongly positive for vimentin and low molecular weight cytokeratin but are negative for thyroglobulin
    • Small cell: extremely rare, behaves differently than other anaplastic carcinomas and most may be able to be reclassified as lymphoma, medullary carcinoma or poorly differentiated thyroid carcinomas (Am J Clin Pathol 1985;83:135, Virchows Arch A Pathol Anat Histopathol 1984;404:117)
Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D.

Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma with necrosis and inflammation




Contributed by Stephen J. Schultenover, M.D.

Malignant spindle cells


Malignant spindle cells


AE1 / AE3

CK903



AFIP images

Direct invasion of trachea

Metastasis in wall of colon

Keratin stains many mesenchymal-like tumor cells

Focal CEA staining

Thyroglobulin stains

Cytology description
  • High grade pleomorphic tumor cells, neoplastic giant cells, spindle cells or squamoid cells in a background of tumor diathesis and inflammation
Cytology images

Contributed by Ayana Suzuki, C.T. and Shuanzeng Wei, M.D., Ph.D.

Pleomorphism

Diff-Quik and Pap stains

Corresponding histology shows tumor with neutrophils

Positive stains
Negative stains
Electron microscopy description
  • No junctional complexes or obvious epithelial elements in osteoclast-like giant cells (Am J Surg Pathol 1978;2:401)
  • Rhabdoid variant: whorled cytoplasmic filaments
Electron microscopy images

AFIP images

Tumor cells appear extremely primitive

Retention of microvilli

Molecular / cytogenetics description
  • Highest mutation burden among all thyroid malignancy
  • Ninefold higher median number of nonsynonymous somatic mutations than well differentiated papillary carcinoma (Endocr Relat Cancer 2008;15:1069)
  • TP53 mutation in 30 - 70% cases
  • BRAF V600E: 20%
  • RAS family mutation (NRAS, HRAS and KRAS)
  • Others alterations: TERT (70%) PIK3CA (10 - 20%), PTEN (10 - 15%) and ALK
  • Mutations commonly found in well differentiated papillary and follicular carcinomas, such as RET / PTC and PAX8 / PPARG fusions, are rare
Sample pathology report
  • Thyroid, total thyroidectomy:
    • Anaplastic thyroid carcinoma, spindle cell pattern, 8.4 cm, with extensive extrathyroid extension involving skeletal muscle and nerves (see comment)
    • Extensive lymphovascular invasion identified
    • Metastatic carcinoma in 2 out of 4 lymph nodes (2/4)
    • Comment: Immunohistochemistry performed on block 1A with adequate controls show that the tumor cells are positive for PAX8 and CK7 and the tumor cells are negative for thyroglobulin and TTF1. The morphologic and immunochemical findings support the above diagnosis.
Differential diagnosis
Board review style question #1

    Which of the following features are not found in anaplastic thyroid carcinoma?

  1. All are considered high stage (IV) tumor
  2. Can have squamoid / squamous differentiation

  3. Necrosis and increased mitotic figures
  4. PAX8+, thyroglobulin+, TTF1+
  5. Vascular invasion and pleomorphic nucleus
Board review style answer #1
D. PAX8+, thyroglobulin+, TTF1+. 

Anaplastic thyroid carcinoma can be PAX8+ in more than 50% cases; however, this tumor is generally negative for thyroglobulin and TTF1.

Reference: Anaplastic carcinoma

Comment Here
Board review style question #2
    Which of the following immunohistochemical markers is most useful to differentiate anaplastic thyroid carcinoma from metastasis?

  1. Cytokeratin
  2. PAX8
  3. p63
  4. Thyroglobulin
  5. TTF1
Board review style answer #2
B. PAX8+. Common thyroid lineage markers such as TTF1 and thyroglobulin are usually absent in anaplastic thyroid carcinoma, whereas PAX8+ is retained in more than 50% cases and may be utilized to differentiate from metastasis.

Reference: Anaplastic carcinoma

Comment Here
Board review style question #3
    Which of the following gene mutations / alterations are not usually identified in anaplastic thyroid carcinoma?

  1. BRAF V600E
  2. PAX8 / PPAR
  3. PIK3CA
  4. RAS
  5. TP53
Board review style answer #3
B. PAX8 / PPAR. Mutations commonly found in well differentiated papillary and follicular carcinomas, such as RET / PTC and PAX8 / PPARG fusions, are rare in anaplastic thyroid carcinoma.

Reference: Anaplastic carcinoma

Comment Here
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