Thyroid & parathyroid

Other common thyroid carcinomas

Anaplastic thyroid carcinoma


Editorial Board Member: Marc Pusztaszeri, M.D.
Deputy Editor-in-Chief: Andrey Bychkov, M.D., Ph.D.
Shipra Agarwal, M.D.

Last author update: 19 January 2024
Last staff update: 19 January 2024

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PubMed Search: Anaplastic thyroid carcinoma

Shipra Agarwal, M.D.
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Cite this page: Agarwal S. Anaplastic thyroid carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidUndiff.html. Accessed February 22nd, 2024.
Definition / general
  • The most aggressive follicular cell derived thyroid malignancy composed of undifferentiated cells
  • Total or near total loss of follicular cell differentiation
  • Concomitant with previous history of differentiated thyroid carcinoma
  • Clinically, a rapidly enlarging neck mass with survival < 6 months in most cases
Essential features
  • Composed of undifferentiated, pleomorphic, mitotically active tumor cells, that may show focal follicular cell differentiation morphologically or immunohistochemically
  • Develops from progression of differentiated thyroid carcinoma (DTC) or de novo
  • Rapidly growing, widely invasive thyroid mass needing multimodal treatment, still with near 100% disease specific mortality
Terminology
ICD coding
  • ICD-O: 8020/3 - carcinoma, undifferentiated, NOS
  • ICD-10: C73 - malignant neoplasm of thyroid gland
  • ICD-11: 2D10.3 - undifferentiated carcinoma of thyroid gland
Epidemiology
Sites
  • Either lobe or isthmus of thyroid gland
  • Anaplastic transformation can be seen in local and distant metastases of DTC
Pathophysiology
  • May arise de novo or from dedifferentiation from DTC, such as papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic carcinoma of the thyroid
  • Accumulation of genetic events, commonly TP53 and TERT promoter
Etiology
  • 2 pathways: develops from pre-existing DTC or de novo (Endocr Pathol 2022;33:27)
  • Radiation exposure and iodine deficiency in 10% of cases
Diagrams / tables

Images hosted on other servers:
Molecular landscape

Molecular landscape

Treatment of stage IVA - B

Treatment of stage IVA - B

Treatment of stage IVC

Treatment of stage IVC

Clinical features
Diagnosis
  • Anaplastic thyroid carcinoma (ATC) is a clinicopathological diagnosis to be corroborated with radiology; confirmation on histopathology or cytopathology supplemented by immunohistochemistry or molecular analysis is essential
  • Diagnostic workup (Thyroid 2021;31:337)
    • Fine needle aspiration cytology (FNAC)
      • Can be supplemented by immunohistochemistry and BRAF evaluation
    • Core biopsy, if FNAC does not have adequate cellularity for diagnosis or for ancillary testing
    • Ultrasonography of neck for evaluation of the thyroid mass and assessment of cervical node involvement
    • Staging of disease using 18F FDG PET / CT (whole body); if unavailable, computed tomography (CT) / magnetic resonance imaging (MRI) of neck, chest, abdomen and pelvis
    • MRI or CT brain with contrast for brain metastases
Laboratory
  • Blood tests and biochemistry: complete blood count with differential, blood chemistry, thyroid function tests, Tg and Tb antibody (Thyroid 2021;31:337)
    • Part of clinical workup but changes are not specific to ATC
  • Optional, liquid biopsy to assess mutational profile or monitor treatment response
Radiology description
  • Sonography
  • Computed tomography scan
Radiology images

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Neck CT, FDG PET scan, sonography

Neck CT, FDG PET scan, sonography

Neck CT Neck CT

Neck CT

Neck CT

Neck CT

CT for staging

CT for staging

FDG PET before / after therapy

FDG PET before / after therapy

Prognostic factors
Case reports
Treatment
  • Based on American Thyroid Association and National Comprehensive Cancer Network guidelines, usually multimodal therapy (Thyroid 2021;31:337, NCCN: NCCN Guidelines - Thyroid Carcinoma [Accessed 14 August 2023])
    • Surgery, if resectable
    • Radiotherapy with or without chemotherapy
    • Targeted therapy
      • Dabrafenib and trametenib, if BRAF V600E mutated
      • Crizotinib, ceritinib, alectinib, in case of ALK fusions
      • Pralsetinib, selpercatinib, in case of RET fusions
      • Larotrectinib, entrectinib, in case of NTRK fusions
    • Checkpoint inhibitor (e.g., pembrolizumab)
      • High PD-L1 expression or ≥ 10 MB mutations/Mb
Clinical images

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Fungating neck mass

Fungating neck mass

Gross description
  • Large mass (often > 5 cm) with ill defined margins that infiltrate adjoining skeletal muscle and trachea
  • Cut surface is tan, fleshy, may be variegated; hemorrhage, necrosis (Endocr Pathol 2022;33:27)
Gross images

Contributed by Shipra Agarwal, M.D., Mark R. Wick, M.D. and AFIP
Variegated, fleshy

Variegated, fleshy

Large, tan, fleshy mass with hemorrhage

Large, tan, fleshy mass with hemorrhage

Metastases to stomach with ulcerated center

Metastases to stomach with ulcerated center



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Diffusely infiltrative, fleshy

Diffusely infiltrative, fleshy

Gray-white, fleshy

Gray-white, fleshy

Frozen section description
  • Rarely used
  • Sometimes may be helpful to assess adequacy of diagnostic tissue, besides margins and tumor extent (Thyroid 2021;31:337)
  • May not be diagnostic if only necrotic or inflammatory areas are sampled
Microscopic (histologic) description
  • Marked cellular pleomorphism
    • Bizarre, hyperchromatic nuclei
  • Prominent mitotic activity
    • Atypical mitoses
  • Necrosis, usually extensive
    • Accompanied by acute inflammatory infiltrate, tumor associated macrophages
  • Invasion
    • Deep infiltration of adjacent structures such as trachea / larynx and esophagus, fibroadipose tissue and skin
    • Vascular invasion
    • Very rarely encapsulated (Thyroid 2020;30:1505)
  • Coexistent DTC (papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic carcinoma of thyroid) or poorly differentiated thyroid carcinoma (PDTC) (Thyroid 2020;30:1505, Ann Surg 2000;231:329)
  • Heterologous differentiation: bone, with or without cartilage
  • Common patterns: epithelioid / squamoid, spindle / sarcomatoid, giant cell and pleomorphic; occur singly or in combination (Endocr Pathol 2022;33:27)
    • Epithelioid / squamoid: tumor nests with abundant eosinophilic cytoplasm, appear squamoid, may show keratinization
    • Spindle / sarcomatoid: malignant spindle cells simulating pleomorphic sarcoma
    • Pleomorphic: highly pleomorphic tumor cells, having bizarre nuclei and prominent nucleoli, some with multiple nuclei
    • Giant cell: numerous multinucleated giant cells, which can be cancer cells or macrophages
  • Rare patterns (Endocr Pathol 2022;33:27)
    • Squamous cell carcinoma pattern
      • Focal or diffuse squamous phenotype (previously primary squamous cell carcinoma of thyroid) (Endocr Pathol 2022;33:27)
    • Paucicellular
      • Mimics Riedel thyroiditis
      • Abundant fibrotic stroma, chronic inflammatory cell infiltrate
      • Few atypical spindle cells
    • Angiomatoid
      • Irregular channels within tumor cell islands mimicking blood vessels
      • May contain red blood cells
      • Mimics angiosarcoma
    • Rhabdoid
      • Rhabdoid cells
      • Eccentric nucleus, paranuclear inclusion, prominent nucleoli
    • Lymphoepithelioma-like
Microscopic (histologic) images

Contributed by Shipra Agarwal, M.D., Shuanzeng Wei, M.D., Ph.D., Stephen J. Schultenover, M.D. and AFIP
Malignant spindle cells

Malignant spindle cells

Nuclear hyperchromasia and pleomorphism

Nuclear hyperchromasia and pleomorphism

Squamoid cells

Squamoid cells

Tumor giant cells

Tumor giant cells

Angiomatoid pattern

Angiomatoid pattern

Neck muscle infiltration

Neck muscle infiltration


Angioinvasion

Angioinvasion

Associated papillary thyroid carcinoma

Associated papillary thyroid carcinoma

Anaplastic carcinoma and adjacent papillary thyroid carcinoma Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma with necrosis and inflammation Anaplastic carcinoma with necrosis and inflammation

Anaplastic carcinoma with necrosis and inflammation


Malignant spindle cells Malignant spindle cells

Malignant spindle cells

AE1 / AE3 AE1 / AE3

AE1 / AE3

CK903 CK903

CK903


Keratin stains many mesenchymal-like tumor cells

Keratin stains many mesenchymal-like tumor cells

Thyroglobulin stain

Thyroglobulin stain

Virtual slides

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Epithelioid pattern, ATC

Epithelioid pattern, ATC

Sarcomatoid pattern, ATC

Sarcomatoid pattern, ATC

Cytology description
  • Cellular or less commonly, sparse aspirate (Endocr Pathol 2022;33:27)
  • Marked nuclear pleomorphism
  • Epithelioid and spindle cells, osteoclast-like tumor giant cells
  • Necrosis
  • Mixed with acute inflammatory cells
  • DTC component may be present
  • Usually classified as Bethesda VI
Cytology images

Contributed by Shipra Agarwal, M.D. and Ayana Suzuki, C.T.
Necroinflammatory background

Necroinflammatory
background

Atypical mitoses

Atypical mitoses

Epithelioid pattern

Epithelioid pattern

Sarcomatoid variant

Sarcomatoid variant

Differentiated thyroid carcinoma component

Differentiated thyroid carcinoma component

Pleomorphism

Pleomorphism

Positive stains
Negative stains
Molecular / cytogenetics description
Molecular / cytogenetics images

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Hierarchical clustering

Hierarchical clustering

Genetic alterations

Genetic alterations

Involved molecular pathways

Involved molecular pathways

Recurrent MSK-IMPACT derived copy number alterations

Recurrent MSK-IMPACT derived copy number alterations

Increased mutation burden

Increased mutation burden

Videos

Cytology of ATC

Management of ATC

Sample pathology report
  • Thyroid, total thyroidectomy:
    • Anaplastic thyroid carcinoma, epithelioid pattern, 12 cm, replacing the entire specimen (see synoptic report)
    • It is dedifferentiating from papillary thyroid carcinoma, classical subtype
    • Gross extrathyroidal extension into adjoining skeletal muscles
    • Multiple lymphovascular emboli and perineural invasion are present
    • 4 of the 5 lymph nodes dissected from the specimen are involved by tumor
    • AJCC stage IVB (pT3bN1Mx)
    • Immunohistochemically, the tumor cells are positive for pan-CK, PAX8, VE1 and p53 but are negative for TTF1 and TG; the Ki67 labeling index is 35%

  • Thyroid, needle biopsy:
    • Anaplastic thyroid carcinoma, spindle cell pattern
    • Immunohistochemically, the tumor cells are positive for pan-CK, vimentin and p53 but are negative for PAX8, p40 and VE1; the Ki67 labeling index is 55%
    • Findings corroborate with but are not specific for the above diagnosis; a clinicoradiological correlation is advised

  • Thyroid, fine needle cytology:
    • Malignant (Bethesda diagnostic category VI): anaplastic thyroid carcinoma, pleomorphic pattern
    • Immunohistochemistry performed on cell block shows that the tumor cells are positive for pan-CK and PAX8 but are negative for VE1
    • The findings corroborate with but are not specific for the above diagnosis; a clinicoradiological correlation is advised
Differential diagnosis
Board review style question #1

    A 72 year old woman presented with a hoarse voice and rapid enlargement of neck mass of 3 months' duration. Radiology revealed lumbar vertebral metastases. Cytological examination from the low anterior neck mass showed a tumor composed of mitotically active pleomorphic polygonal and spindle cells in a necrotic and inflammatory background. Incisional biopsy revealed a malignant spindle cell tumor. What is the most likely diagnosis?

  1. Anaplastic thyroid carcinoma
  2. Follicular thyroid carcinoma
  3. Metastatic carcinoma to thyroid gland
  4. Papillary thyroid carcinoma
  5. Spindle epithelial tumor with thymus-like differentiation
Board review style answer #1
A. Anaplastic thyroid carcinoma. Anaplastic thyroid carcinoma typically presents with a short duration history of a rapidly enlarging neck mass, with symptoms secondary to compression of adjacent structures, such as pain, dysphonia, dysphagia, dyspnea and cough. Lymph node and distant metastases are common. Cytological examination reveals a pleomorphic tumor cell population, including bizarre forms, dispersed in a necrotic and inflammatory background. Mitotic activity is frequent and atypical mitotic forms common. Answer B is incorrect because follicular thyroid carcinoma, on cytology, shows a microfollicular architecture and lacks marked cellular pleomorphism and extensive necrosis. Answer C is incorrect because the clinical presentation of hoarseness of voice, a rapidly enlarging neck mass and radiology revealing distant metastases are indicative of a thyroid primary. Answer D is incorrect because papillary thyroid carcinoma, on cytological evaluation, lacks cellular pleomorphism and extensive necrosis. Instead, classic papillary thyroid carcinoma shows follicular cells arranged as papillae, sheets and fragments showing typical nuclear features. Answer E is incorrect because spindle epithelial tumor with thymus-like elements is characterized by low grade spindle cells and an amyloid-like material with or without an epithelial component.

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Reference: Anaplastic thyroid carcinoma
Board review style question #2
    Which of the following immunohistochemical profiles best defines anaplastic thyroid carcinoma?

  1. TTF1 negative, thyroglobulin negative, CD5 positive, CD117 positive
  2. TTF1 negative, thyroglobulin negative, PAX8 positive, cytokeratin positive
  3. TTF1 negative, thyroglobulin negative, S100 positive, HMB45 positive
  4. TTF1 positive, thyroglobulin negative, PAX8 negative, calcitonin positive
  5. TTF1 positive, thyroglobulin positive, PAX8 positive, vimentin negative
Board review style answer #2
B. TTF1 negative, thyroglobulin negative, PAX8 positive, cytokeratin positive. Anaplastic thyroid carcinoma (ATC) is usually immunonegative for TTF1 and thyroglobulin but expresses PAX8; cytokeratin is variably positive. Answer E is incorrect because vimentin can also be variably positive in ATC but in this case thyroglobulin is positive as well. Answer D is incorrect because calcitonin is immunopositive in medullary thyroid carcinoma. Answer A is incorrect because CD5 and CD117 are positive in intrathyroidal thymic carcinoma. Answer C is incorrect because S100 and HMB45 are positive in malignant melanoma.

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Reference: Anaplastic thyroid carcinoma
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