Synchronous Rectal Tumours with Different Molecular and Genetic Phenotypes Occurring in a Patient with Lynch Syndrome

Abstract

The increasingly widespread use of immunohistochemistry and next-generation sequencing (NGS) in the detection of microsatellite instability (MSI) and DNA mismatch repair (MMR) status has led to the observation of various unusual tumour types that exhibit MMR protein deficiency in Lynch syndrome (LS). Here, we report a case of two synchronous colorectal cancer (CRC) tumours simultaneously occurring in a 42-year-old woman with a deleterious germline mutation in MSH6, abundant expression of PD-L1 and high tumour mutation burden (TMB). The two CRC tumours (tumours A and B) harboured highly heterogeneous features. One showed loss of MSH6 protein and a microsatellite stable (MSS)/MSI-low (MSI-L) status, while the other presented no loss of MMR protein and MSI-H status. Furthermore, the 9 common mutated genes between the two CRC tumours had no shared mutation sites. Only 4 KEGG pathways were identified as enriched for five of the common mutated genes, while 8 cancer-related pathways were identified as enriched for 9 and 13 unique mutated genes in tumours A and B, respectively. Therefore, we chose immune checkpoint inhibitors (ICIs) as the potential therapy. This case exemplifies the complexity of tumorigenesis and potential ICI treatment in LS patients.

Keywords: colorectal cancer; heterogeneity; immune checkpoint inhibitors; lynch syndrome; microsatellite instability.

Figure 1

Heterogeneous morphology, MMR protein expression and PD-L1 expression patterns of the 2 synchronous rectal tumours (masses A and B) in the LS patient. (A and G) HE staining of masses A and B showing the classic protruding pattern of adenocarcinoma growth. The IHC staining of mass A showed intact expression of MLH1 (B), PMS2 (C), MSH2 (D), and PD-L1 (F) in addition to loss of expression of MSH6 (E). Mass #B showed intact expression of MLH1 (H), PMS2 (I), MSH2 (J), MSH6 (K) and PD-L1 (L). All images were collected at 100× magnification.

Figure 2

The patient’s pedigree. The proband had rectal cancer and carried the MSH6 p.R495* germline mutation. Similarly, the individuals (the patient’s mother and the patient’s brother) without cancers carried the MSH6 p.R495* germline mutation. One of the patient’s uncles had colon cancer but did not undergo NGS assessment.

Figure 3

Assessment of the TIME via multiplex IHC (mIHC). (A and F) The green fluorescence indicates CD8⁺ T cells. (B and G) The pink fluorescence indicates PD-1 expression. (C and H) The yellow fluorescence indicates CD68 expression. (D and I) The Orange fluorescence indicates PD-L1 expression. (E and J) The pictures show all layers merged.