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Related Concept Videos

Tumor Progression02:07

Tumor Progression

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Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
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High-Grade Colorectal Adenocarcinomas With SMAD4 Deficiency.

Yasamin Mirzabeigi1, Nikunj Shah1, Kayla R Schwartz2

  • 1Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|January 8, 2026
PubMed
Summary
This summary is machine-generated.

Patients with SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs) with high-grade morphology have a poor prognosis. These tumors rapidly metastasize, but CDX2 or SATB2 immunolabeling aids diagnosis.

Keywords:
DPC4SMAD4colonmetastasisrectum

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Area of Science:

  • Oncology
  • Gastroenterology
  • Pathology

Background:

  • SMAD4 deficient (dSMAD4) colorectal adenocarcinomas (CRCs) are associated with poor prognosis.
  • Unique tumor morphologies or advanced disease signatures may stratify dSMAD4 CRC patient outcomes.
  • Reappraisal of dSMAD4 CRCs in advanced-stage disease is needed.

Purpose of the Study:

  • To investigate whether unique tumor morphologies stratify prognosis in a homogenous cohort of advanced-stage dSMAD4 CRCs.
  • To compare clinicopathologic features and outcomes between dSMAD4 and SMAD4 proficient (pSMAD4) CRCs.

Main Methods:

  • Leveraged next-generation sequencing (NGS) to identify 50 dSMAD4 CRCs and 50 pSMAD4 CRCs.
  • Compared demographics, clinicopathologic parameters, and genetic drivers between groups.
  • Analyzed histomorphology, metastatic patterns, overall survival (OS), and progression-free survival (PFS).
  • Utilized immunohistochemistry (CDX2, SATB2) for diagnostic utility.

Main Results:

  • Both dSMAD4 and pSMAD4 CRCs progressed to AJCC stage IV metastatic disease at high rates (90% vs. 86%).
  • dSMAD4 CRCs showed enrichment of high-grade (HG) mucinous and non-mucinous histomorphologies (44% vs. 12%; p=0.0007).
  • The HG subset of dSMAD4 CRCs exhibited widely metastatic disease (p=0.0048) and significantly shorter OS and PFS (p≤0.0001).
  • Metastasis of unknown primary was noted for HG dSMAD4 CRCs.
  • All dSMAD4 CRCs retained CDX2 or SATB2 immunolabeling, aiding diagnosis.

Conclusions:

  • Identified an underappreciated class of HG dSMAD4 CRCs with rapid progression to widely metastatic disease and dismal prognosis.
  • HG morphologies in dSMAD4 CRCs drive poor outcomes.
  • Immunohistochemistry for CDX2/SATB2 remains diagnostically useful for dSMAD4 CRCs, even in HG variants, distinguishing them from other HG CRCs.