James Saller1, Dahui Qin1, Seth Felder2, Domenico Coppola3. 1. Department of Pathology, H. Lee Moffitt Cancer Center and Research Institution, Tampa, FL. 2. Department of Gastrointestinal Surgery, H. Lee Moffitt Cancer Center and Research Institution, Tampa, FL. 3. Department of Pathology, H. Lee Moffitt Cancer Center and Research Institution, Tampa, FL; Florida Digestive Health Specialists, Brandenton, FL. Electronic address: domenico.coppola@fdhs.com.
Abstract
BACKGROUND: Patients with deficient microsatellite mismatch repair (dMMR) colorectal cancer (CRC) may respond to immune checkpoint inhibition (ICI), whereas patients with microsatellite-stable (MSS) CRC have not demonstrated response. However, a proportion of MSS tumors display histomorphologic features characteristic of dMMR tumors consistent with an increased antigenicity. Therefore, a subset of patients with CRC not currently receiving ICI treatment may derive benefit from ICI therapy. We review tumors in which the histologic features suggestive of dMMR were in disagreement with the DNA mismatch repair proteins obtained by immunohistochemistry (IHC). Possible causes of such disagreement are discussed. MATERIALS AND METHODS: Three patients with CRC suggestive of histomorphologic immunogenicity underwent evaluation by IHC staining for mismatch repair (MMR) status, next-generation sequencing assays, and/or polymerase chain reaction. RESULTS: Findings compatible with an immunogenic response were similarly observed in all patients. Case 1 highlighted the limiting factors inherent to IHC staining for MMR status: a biopsy initially interpreted as MSS was subsequently interpreted as being dMMR. Case 2 examined the challenges in reconciling histologic characteristics traditionally associated with dMMR CRCs but ultimately determined to be MSS. Case 3 examined the microsatellite instability of CRC resulting from MLH1-methylation and/or MSH6 mutation. CONCLUSIONS: We demonstrated the challenges in establishing MMR status when confronted with conflicting results from histology, IHC, polymerase chain reaction, and next-generation sequencing. Given that dMMR status has been shown to be a biomarker for ICI responsiveness, the importance of accurate identification is critical.
BACKGROUND:Patients with deficient microsatellite mismatch repair (dMMR) colorectal cancer (CRC) may respond to immune checkpoint inhibition (ICI), whereas patients with microsatellite-stable (MSS) CRC have not demonstrated response. However, a proportion of MSS tumors display histomorphologic features characteristic of dMMRtumors consistent with an increased antigenicity. Therefore, a subset of patients with CRC not currently receiving ICI treatment may derive benefit from ICI therapy. We review tumors in which the histologic features suggestive of dMMR were in disagreement with the DNA mismatch repair proteins obtained by immunohistochemistry (IHC). Possible causes of such disagreement are discussed. MATERIALS AND METHODS: Three patients with CRC suggestive of histomorphologic immunogenicity underwent evaluation by IHC staining for mismatch repair (MMR) status, next-generation sequencing assays, and/or polymerase chain reaction. RESULTS: Findings compatible with an immunogenic response were similarly observed in all patients. Case 1 highlighted the limiting factors inherent to IHC staining for MMR status: a biopsy initially interpreted as MSS was subsequently interpreted as being dMMR. Case 2 examined the challenges in reconciling histologic characteristics traditionally associated with dMMR CRCs but ultimately determined to be MSS. Case 3 examined the microsatellite instability of CRC resulting from MLH1-methylation and/or MSH6 mutation. CONCLUSIONS: We demonstrated the challenges in establishing MMR status when confronted with conflicting results from histology, IHC, polymerase chain reaction, and next-generation sequencing. Given that dMMR status has been shown to be a biomarker for ICI responsiveness, the importance of accurate identification is critical.
Authors: Mohsin Bilal; Shan E Ahmed Raza; Ayesha Azam; Simon Graham; Mohammad Ilyas; Ian A Cree; David Snead; Fayyaz Minhas; Nasir M Rajpoot Journal: Lancet Digit Health Date: 2021-10-19