Thyroid & parathyroid

Other uncommon thyroid carcinomas

Cribriform-morular thyroid carcinoma



Last staff update: 18 March 2024 (update in progress)

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PubMed Search: Cribriform-morular thyroid carcinoma

Jonathan K. Lai, M.D.
Marc Pusztaszeri, M.D.
Page views in 2024 to date: 1,953
Cite this page: Lai JK, Pusztaszeri M. Cribriform-morular thyroid carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidcribriformmorular.html. Accessed March 28th, 2024.
Definition / general
  • Uncommon thyroid carcinoma of uncertain histogenesis characterized by a complex architecture, primarily cribriform with squamoid morules and absent / scant colloid formation
  • Cribriform-morular thyroid carcinoma (CMTC) was traditionally considered as a variant of papillary thyroid carcinoma (PTC); recent studies, however, showed that CMTC constitutes a clinicopathologically distinct category of thyroid carcinoma driven by Wnt / beta catenin pathway activation (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Relat Cancer 2017;24:R109)
Essential features
Terminology
  • Previously known as cribriform-morular variant of papillary thyroid carcinoma (not recommended) (Endocr Pathol 2022;33:27)
ICD coding
  • ICD-O: 8201/3 - cribriform carcinoma, NOS
  • ICD-11: 2D10.Y & XH1YZ3 - other specified malignant neoplasms of thyroid gland & cribriform carcinoma, NOS
Epidemiology
Sites
  • Thyroid
Pathophysiology
  • Germline mutation in APC gene is seen in cases of FAP with thyroid tumors
  • Somatic mutations that result in activation of the Wnt / beta catenin signaling pathway can also lead to CMTC (Endocr Pathol 2022;33:27)
  • APC protein is a tumor suppressor that normally promotes degradation of beta catenin; in cases of APC protein mutation, the Wnt / beta catenin signaling pathway is constitutively activated, thus leading to uncontrolled proliferation and loss of cellular differentiation (see Diagrams)
  • Due to distinct clinicopathological, immunohistochemical profile and genetics, CMTC is no longer considered as a subtype of papillary thyroid carcinoma in the 2022 WHO classification of thyroid tumors (Endocr Pathol 2022;33:27)
    • Complete lack of colloid in CMTC; absent PAX8 and thyroglobulin immunoreactivity suggest it is not a follicular cell derived tumor but rather a tumor of uncertain histogenesis (Endocr Pathol 2021;32:327)
    • Squamoid morules typically coexpress CK5 and CD5, which suggests a thymic / ultimobranchial pouch related differentiation (Endocr Pathol 2021;32:327)
Etiology
  • Genetic alterations in the Wnt / beta catenin pathway
  • APC mutations are the most common genetic alteration and can be found in both familial and sporadic forms
  • Some cases may develop after external radiotherapy to the neck (J Clin Lab Anal 2023;37:e24819)
Diagrams / tables

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Molecular alterations associated with pathogenesis

Clinical features
Diagnosis
  • Diagnosis may be done or suggested either preoperatively using thyroid FNA or (more commonly) postoperatively with histologic evaluation and immunohistochemical confirmation
Laboratory
Radiology description
  • Sonography findings are similar to follicular tumor or nodular goiter, rather than papillary thyroid carcinoma (J Med Ultrason (2001) 2015;42:83)
    • Sonographic findings include smooth or focal jagged margin, hypoechoic nodule, lateral shadow, posterior acoustic enhancement, poor marginal and internal vascularity and no microcalcification (J Med Ultrason (2001) 2015;42:83)
    • Most cases do not have features of malignancy on sonography (Thyroid 2013;23:45)
Radiology images

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Heterogeneous, hypoechoic mass without calcifications

Prognostic factors
Case reports
Treatment
  • Lobectomy is recommended for non-FAP associated CMTC and total thyroidectomy for FAP associated CMTC (Endocr J 2011;58:685, Pathol Res Pract 2015;211:712)
  • Extensive lymph node dissection is not necessary because nodal metastases are rare (Endocr J 2011;58:685, Pathol Res Pract 2015;211:712)
  • Lack of follicular cell differentiation raises the possibility that these tumors may not benefit from radioactive iodine (RAI) related adjuvant therapies
  • Cases with recurrences or distant metastases may respond to lenvatinib (Thyroid 2019;29:1511)
  • Clinicians should be alerted to exclude FAP since this diagnosis is the first indicator of FAP syndrome in 25% of cases
Gross description
Gross images

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Multifocal tumors throughout the entire thyroid

Microscopic (histologic) description
  • Lesion is well circumscribed and encapsulated
  • Fibrous septa separating the tumor into multiple lobules
  • Common growth patterns: cribriform, follicular, papillary, trabecular and solid
  • Tubular follicles without colloid
  • Papillary or pseudopapillary structures lined with tall or pseudostratified columnar cells
  • Cribriform architecture with anastomosing bars and arches without intervening fibrous stroma
  • Hyperchromatic nuclei with occasional papillary thyroid carcinoma nuclear features, such as nuclear overlap, grooves, pseudoinclusions and clearing
  • Distinctive squamoid morules composed of whorls of spindle to ovoid cells with nuclear clearing and lacking keratinization
  • These morules may be rare and difficult to find in some cases
  • Psammoma bodies are rare (Endocr Relat Cancer 2017;24:R109)
  • Capsular invasion (30%), angioinvasion (40%) and extrathyroidal extension in a subset of cases (Mod Pathol 2018;31:1168)
  • Aggressive features include neuroendocrine differentiation, necrosis and high mitotic activity (Mod Pathol 2018;31:1168, Am J Clin Pathol 2009;131:134, Pathol Int 2018;68:700)
Microscopic (histologic) images

Contributed by Jonathan K. Lai, M.D., Drs. Safa Alshaikh and Aalaa Mohammed (Case #470) and Dr. Bin Xu (Case #528)

Encapsulated thyroid nodule

Complex architecture

Cribriform-morular architecture

Trabecular pattern

Sieve-like spaces and morules

Squamoid morules


Squamoid morules

Hallmark feature

19 year old woman with right sided neck swelling

Papillary and cribriform architecture

Papillary and cribriform architecture


Scattered squamous morules

Scattered squamous morules

Scattered mitotic figures

Scattered mitotic figures

Multifocal tumor necrosis

Multifocal tumor necrosis

CK5/6

TTF1


TTF1

TTF1

PAX8

PAX8

Thyroglobulin

Thyroglobulin

Beta catenin


Beta catenin

Beta catenin

Estrogen receptor

Estrogen receptor

CD10

CD10

CDX2

CDX2

Virtual slides

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Cribriform-morular thyroid carcinoma

Cytology description
Cytology images

Contributed by Drs. Safa Alshaikh and Aalaa Mohammed (Case #470)

May-Grünwald-Giemsa

Pap stain



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Hypercellular, morular or papillary fragments

Electron microscopy description
Molecular / cytogenetics description
Sample pathology report
  • Left thyroid lobe, resection:
    • Cribriform-morular thyroid carcinoma, pathologic stage: pT2, N0 (see comment)
      • Tumor size: 2.0 cm
      • Microscopic extrathyroidal extension: not identified
      • Margins: < 1 mm
      • Lymphovascular invasion: identified
      • Perineural invasion: not identified
      • Ancillary studies: BRAF V600E immunostain is negative; beta catenin immunostain is positive (cytoplasmic and nuclear)
      • Lymph nodes:
        • Number identified: 1
        • Number involved: 0
      • Intrathyroidal parathyroid identified
    • Comment: Cribriform-morular thyroid carcinoma is frequently associated (up to 53%) with FAP or Gardner syndrome. Genetic testing is recommended.
Differential diagnosis
Board review style question #1

A 26 year old woman presented with multiple thyroid lesions. After a thyroidectomy, the histological features were consistent with the diagnosis of cribriform-morular thyroid carcinoma. Further clinical surveillance includes monitoring for which of the following associated neoplasms?

  1. Cardiac myxoma
  2. Colorectal carcinoma
  3. Pheochromocytoma
  4. Pleuropulmonary blastoma
  5. Trichilemmomas
Board review style answer #1
B. Colorectal carcinoma. Familial adenomatous polyposis (FAP) is a related to germline mutation of APC tumor suppressor gene, which strongly predisposes to colorectal carcinoma. Cribriform-morular thyroid carcinoma is associated with FAP as well. Other syndromes associated with thyroid pathologies include DICER1 syndrome (pleuropulmonary blastoma and multinodular goiter), Carney complex (cardiac myxoma and thyroid follicular adenoma / carcinoma), Cowden disease (trichilemmomas and follicular adenoma / carcinoma), MEN 2A / B (pheochromocytoma and C cell hyperplasia / medullary thyroid carcinoma).

Comment Here

Reference: Cribriform-morular thyroid carcinoma
Board review style question #2
What is the beta catenin immunohistochemical staining pattern in cribriform-morular thyroid carcinoma (CMTC)?

  1. Diffuse cytoplasmic and nuclear positivity
  2. Loss of nuclear staining
  3. Membranous, cytoplasmic and Golgi staining
  4. Stippled nuclear staining
  5. Strong membranous staining
Board review style answer #2
A. Diffuse cytoplasmic and nuclear positivity. CMTC is associated with FAP and driven by Wnt / beta catenin pathway activation. The hallmark immunoreactivity of CMTC is diffuse nuclear and cytoplasmic positivity for beta catenin due to decreased proteasomal degradation of beta catenin following mutation of the APC tumor suppressor gene.

Comment Here

Reference: Cribriform-morular thyroid carcinoma
Board review style question #3
Which of the following statements about cribriform-morular thyroid carcinoma is true?

  1. It does not occur in a familial setting
  2. It is a subtype (variant) of papillary thyroid carcinoma
  3. It typically is negative for thyroglobulin and PAX8
  4. No distinct mutations are commonly identified
Board review style answer #3
C. It typically is negative for thyroglobulin and PAX8. Answer A is incorrect because they may be familial. Answer B is incorrect because the tumors are no longer considered a variant of papillary thyroid carcinoma. Answer D is incorrect because up to 53% of cases occur in the setting of germline APC mutation (familial adenomatous polyposis) and sporadic cases often harbor molecular alterations of the WNT / beta catenin pathway.

Comment Here

Reference: Cribriform-morular thyroid carcinoma
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