Enteroblastic and Hepatoid Colorectal Carcinomas are Aggressive Cancers With a Distinctive Immunophenotype, While Clear Cell Carcinoma Appears to Represent Clear Cell Change in Conventional Colorectal Cancer

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC (P<0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P=0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8), APC (n=3), FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

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Journal
The American Journal of Surgical Pathology
Published
2026-04-21
DOI
https://doi.org/10.1097/pas.0000000000002555
Primary Topic
Multiple and Secondary Primary Cancers
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article
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article

Enteroblastic and Hepatoid Colorectal Carcinomas are Aggressive Cancers With a Distinctive Immunophenotype, While Clear Cell Carcinoma Appears to Represent Clear Cell Change in Conventional Colorectal Cancer

Karen Matsukuma, Maria Westerhoff, Won‐Tak Choi, Elias Makhoul et al.
The American Journal of Surgical Pathology
Multiple and Secondary Primary Cancers
article

Enteroblastic and Hepatoid Colorectal Carcinomas are Aggressive Cancers With a Distinctive Immunophenotype, While Clear Cell Carcinoma Appears to Represent Clear Cell Change in Conventional Colorectal Cancer

Karen Matsukuma, Maria Westerhoff, Won‐Tak Choi, Elias Makhoul, Jennifer Vazzano, Nima Sharifai, Zu‐Hua Gao, Aaron Huber, Stefano Serra, W Chen, Jinru Shia, Ignacio Ruz‐Caracuel, Kristen Stashek, Teri A. Longacre, Raul S. González, Thomas M. Ulbright, Daniela Allende, David Papke, Sanjay Kakar, Michael J. Lee, Klaudia Nowak, Alexandros D. Polydorides, Runjan Chetty, John D. Paulsen, Xuchen Zhang, Fahad Khan, M. Lisa Zhang, Deepti Dhall, Kelsey McHugh, Katrina Collins
article en

Abstract

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC (P<0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P=0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8), APC (n=3), FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

The American Journal of Surgical Pathology
University of Maryland, Baltimore (US), Brigham and Women's Hospital (US), Lehigh Valley Hospital-Pocono (US), Cleveland Clinic (US), Memorial Sloan Kettering Cancer Center (US), University of British Columbia (CA), Emory University (US), Duke University (US), University of California, San Francisco (US), University of Toronto (CA), University of Michigan (US), University of Rochester Medical Center (US), University of Alabama at Birmingham (US), Yale University (US), Massachusetts General Hospital (US), Lehigh Valley Health Network (US), Mayo Clinic in Arizona (US), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Diageo (Ireland) (IE), Centro de Investigación Biomédica en Red de Cáncer (ES), Hospital Universitario Ramón y Cajal (ES), The Ohio State University (US), Indiana University – Purdue University Indianapolis (US), Columbia University (US), University of Pennsylvania (US), University of California, Davis (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 16%
Multiple and Secondary Primary Cancers
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