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Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis

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Abstract

Tumors with papillary cribriform and morular architecture were initially considered to be variants of papillary thyroid carcinoma; however, recent observations have challenged this view. In this study, we reviewed the demographical, histopathological, and immunohistochemical features of the largest case series, consisting of 33 tumors. The age at time of pathological diagnosis ranged from 18 to 59 (mean 33) years, and all patients except one were female. Sixteen patients had multifocal and fifteen had unifocal disease. The status of focality was unavailable in two patients. Tumors were well-circumscribed, ranging in size from 0.1 to 8.0 cm. The cribriform component was admixed with morulae in the majority, except seven had a cribriform-predominant architecture and two had predominantly solid growth. Variable degrees of nuclear enlargement, elongation, overlapping, and grooves were seen but florid nuclear convolution, intranuclear pseudoinclusions, and optically clear nuclei due to chromatin margination were not appreciated. There was no or little colloid material within the cribriform spaces. Two solid tumors had high-grade features. Immunohistochemical studies showed beta-catenin nuclear and cytoplasmic positivity in all cases. The cribriform component was positive for TTF1 and negative for thyroglobulin. PAX8 was absent in half of these tumors and focal in the remainder. Morulae were positive for keratin 5 and CD5 and negative for p63, p40, TTF1, and PAX8. Molecular studies revealed germline APC mutations in 12 tumors and were negative in 5 sporadic tumors in a subset of tested tumors. Irrespective of the antibody used in this cohort, all cribriform-morular carcinomas express TTF1; however, PAX8 immunoreactivity is weak, focal or negative, and all tumors lack thyroglobulin reactivity; these findings raise questions about tumor cell origin and may indicate that these are not of thyroid follicular epithelial differentiation. We postulate that morulae may represent divergent thymic/ultimobranchial pouch-related differentiation. Given their unique cytomorphology, immunohistochemical profiles, and genetic features that have little overlap with traditional follicular cell-derived thyroid carcinomas, we propose that these tumors represent a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells.

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Acknowledgements

The preliminary results of various components of this series were also presented at the USCAP annual meeting in 2009, 2012, and 2014 and at the ECP/IAP meetings in 2020.

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Author notes

  1. Vania Nosé and Ozgur Mete contributed equally, senior co-authors

Authors and Affiliations

  1. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Baris Boyraz, Peter M. Sadow, Dora Dias-Santagata & Vania Nosé

  2. Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA

    Sylvia L. Asa

  3. Department of Pathology, University Health Network, Toronto, ON, Canada

    Ozgur Mete

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Ozgur Mete

  5. Endocrine Oncology Site, The Princess Margaret Cancer Centre, Toronto, Canada

    Ozgur Mete

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  1. Baris Boyraz
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Contributions

Concept: OM; design: OM, VN, PMS, SLA; data collection and/or processing: BB, DDS, VN, PMS, SLA, OM; analysis and/or interpretation: BB, OM, DDS, VN; literature search and writing: BB, OM, VN; critical reviews: OM, VN, SLA, PMS, DDS; approval of the final version of the manuscript: OM, VN, SLA, PMS, DDS, BB.

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Correspondence to Ozgur Mete.

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Dr. Ozgur Mete is the Editor-in-Chief of Endocrine Pathology. This article was handled by an independent senior editor and peer-reviewed as per the journal standards. The remaining authors declare no competing interests.

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Boyraz, B., Sadow, P.M., Asa, S.L. et al. Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis. Endocr Pathol 32, 327–335 (2021). https://doi.org/10.1007/s12022-021-09683-0

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  • DOI: https://doi.org/10.1007/s12022-021-09683-0

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