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Background <p>Cribriform-morular thyroid carcinoma (CMTC) is a rare thyroid malignancy with distinctive morphology that occurs sporadically or in association with familial adenomatous polyposis. Despite known WNT/β-catenin pathway involvement, CMTC’s cellular origin and therapeutic targets remain poorly characterized.</p> Methods <p>Five CMTC cases diagnosed between 2012 and 2022 were retrospectively analyzed using next-generation sequencing and comprehensive immunohistochemical profiling to elucidate molecular characteristics and potential therapeutic targets.</p> Results <p>All patients were young females (mean age 28 years, range 19–47) presenting with small tumors (mean 19.4&#xa0;mm, range 7–28&#xa0;mm) without lymph node metastasis. Histologically, all cases demonstrated characteristic cribriform and morular architecture. Nuclear β-catenin positivity was observed in four cases, while CD56 was expressed in all cases. Low-level HER2 expression was present across all tumors. Next-generation sequencing revealed somatic APC mutations in three cases, concurrent APC/CTNNB1 mutations in one case, and CTNNB1 mutations in both lobes of one case. High tumor mutational burden was detected in two cases.</p> Conclusions <p>The consistent presence of APC or CTNNB1 mutations coupled with CD56 positivity supports CMTC’s origin from thyroid follicular epithelial cells that acquire an intestinal-like phenotype through characteristic genetic alterations. The presence of HER2 expression and high tumor mutational burden in a subset of cases identifies potential therapeutic targets for this rare malignancy.</p>

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Molecular and immunohistochemical characterization of cribriform-morular thyroid carcinoma: insights into its origin and therapeutic targets

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Joo Yeon Koo,
  • Ji Young Lee,
  • Nah Ihm Kim,
  • Yoo-Duk Choi,
  • Tae Mi Yoon,
  • Sung Sun Kim,
  • Kyung-Hwa Lee

摘要

Background

Cribriform-morular thyroid carcinoma (CMTC) is a rare thyroid malignancy with distinctive morphology that occurs sporadically or in association with familial adenomatous polyposis. Despite known WNT/β-catenin pathway involvement, CMTC’s cellular origin and therapeutic targets remain poorly characterized.

Methods

Five CMTC cases diagnosed between 2012 and 2022 were retrospectively analyzed using next-generation sequencing and comprehensive immunohistochemical profiling to elucidate molecular characteristics and potential therapeutic targets.

Results

All patients were young females (mean age 28 years, range 19–47) presenting with small tumors (mean 19.4 mm, range 7–28 mm) without lymph node metastasis. Histologically, all cases demonstrated characteristic cribriform and morular architecture. Nuclear β-catenin positivity was observed in four cases, while CD56 was expressed in all cases. Low-level HER2 expression was present across all tumors. Next-generation sequencing revealed somatic APC mutations in three cases, concurrent APC/CTNNB1 mutations in one case, and CTNNB1 mutations in both lobes of one case. High tumor mutational burden was detected in two cases.

Conclusions

The consistent presence of APC or CTNNB1 mutations coupled with CD56 positivity supports CMTC’s origin from thyroid follicular epithelial cells that acquire an intestinal-like phenotype through characteristic genetic alterations. The presence of HER2 expression and high tumor mutational burden in a subset of cases identifies potential therapeutic targets for this rare malignancy.