In December 2013, a 64-year-old man was hospitalized because of worsening asthenia and abdominal pain. Past medical history included a surgically treated pT1 pN0 cM0 left clear cell renal carcinoma in 2005 and a recto-sigmoid resection for colonic low-grade tubular adenoma in 2008. Family history was positive for brain and haematologic tumours not otherwise specified in 2nd degree relatives. During admission as an inpatient to a Unit of General Medicine of a community hospital, blood tests revealed grade 2 microcytic anaemia, and abdominal radiography showed signs of sub-occlusion. Colonoscopy revealed a right-sided neoplastic lesion. A biopsy documented an adenocarcinoma with a mucinous component. Pre-operative staging total body computed tomography (CT) including the neck, chest, abdomen and pelvis showed thickening of the right bowel wall and diffuse peritoneal nodules with maximum diameter of up to 6 cm. On December 2013, the patient underwent a palliative right hemicolectomy and diagnostic resection of a peritoneal nodule, the latter only with a diagnostic and confirmatory intent. Figure summarizes the complete clinical course over time. Gross pathology examination described a 9 cm mass completely obstructing the colonic lumen. Pathological reports confirmed the diagnosis of an adenocarcinoma with the presence of heterogeneous phenotypic areas of mucinous (40% of the neoplastic area) and signet ring differentiation (pT4 pN2b [7 metastatic lymph nodes out of 10 examined], pM1c; stage IVC). Routine molecular testing showed a G12D KRAS mutation, whereas NRAS, BRAF, and PIK3CA genes showed a wild-type status (Myriapod Colon status kit; Diatech Pharmacogenetics, Jesi, Italy). Post-operative total body CT re-evaluation confirmed the presence of large peritoneal nodules (in the right inferior, left upper and inferior abdomen), while no other lesions were detected. CEA and CA19.9 levels were within their normal range values. In February 2014, the patient was started on FOLFIRI plus bevacizumab. Tolerance was good, and partial response was documented at first re-evaluation after 4 cycles. A total of 12 cycles of therapy were delivered with regular radiologic re-evaluation every 8 weeks, confirming an initial response. In September of the same year, a CT scan showed a clear peritoneal progression of disease with the enlargement of known lesions and the appearance of new lesions. Second-line FOLFOX was then started in November 2014. Despite a good tolerance and no treatment reductions or delays, on January 2015, a CT scan re-evaluation revealed progressive disease with dimensional increases in nodules located at the anterior abdominal wall and appearance of retroperitoneal lymph nodes. After extensive discussion of additional treatment options, the treating physicians recommended best supportive care only. The patient was referred to our Cancer Centre in May 2015. To complete the molecular evaluation of the tumour, MMR status was examined. MMR protein immunohistochemical analysis (i.e., MLH1, PMS2, MSH2, and MSH6; Dako, Glostrup, Denmark) [] of the right-sided colonic tumour showed an unusual pattern of large areas (almost 50% of the tumour) of dMMR characterized by the complete loss of the coupled MLH1/PMS2 coexistence with areas with retained MLH1/PMS2 immunoreactivity. Based on the exceptionality of the finding, the different areas were macrodissected and tested separately for MSI (Titano kit, Diatech Pharmacogenetics, Jesi Italy), confirming previous immunohistochemistry (IHC) results. To give a clear and comprehensive description of the case, IHC and molecular analyses were also performed on the first endoscopic biopsy and in the peritoneal metastatic nodule. The endoscopic biopsy showed a homogeneous pattern of proficiency in MMR (pMMR), whereas the peritoneal lesion showed the complete loss of MLH1/PMS2. Again, MSI testing confirmed the microsatellite stability (MSS) status of the biopsy and the MSI high status of the peritoneal nodule. We further characterized the molecular landscape of this MMR heterogeneity by performing an integrated WGS and RNA-seq analysis (GPS Cancer, Nantomics, Culver City, CA) on microdissected areas of the tumour according to their different MMR/MSI statuses. Both components showed the p.G12D KRAS mutation and a CMS2 status according to the classification proposed by Guinney and colleagues []. The dMMR component presented a high tumour exonic mutational burden (TMB) with 11.0 mutations per megabase, 0.78% unstable loci (which correspond to a microsatellite instable status), and a high expression of IDO, CTLA-4 and PD-1 (Additional file ). The pMMR component presented a low tumour exonic mutational burden (TMB) with 5.2 mutations per megabase, 5.4% unstable loci (which correspond to an MSS status), and a high expression of IDO and TIM-3 (Additional file ). No MMR gene mutations (tumoural or germline) were identified, leading to the consideration of protein loss due to MLH1 promoter methylation. Considering the MSI-high status of the metastatic sample, the multidisciplinary tumour board decided to start treatment with an ICI, ipilimumab 1 mg/kg plus nivolumab 3 mg/kg every 3 weeks in June 2015. After 4 cycles, chest-abdomen CT scan revealed a 32% reduction in the diameters of target lesions. i.e., partial response according to RECIST criteria 1.1. Since then, the patient was continued on nivolumab monotherapy every 2 weeks. No adverse events occurred. In November 2018, after 84 cycles and 41 months of disease control, CT showed a dimensional increase in the left antero-inferior peritoneal nodule (85 vs 69 mm), which was re-biopsied and displayed a dMMR/MSI-high status. After disease progression during treatment with ICI, the patient was started on regorafenib. He had a good subjective tolerance, reporting no side effects, no alterations in laboratory tests and an improvement in ECOG PS (from 1 to 0). On the chest-abdomen CT re-evaluation after 8 weeks of treatment, the two bilateral inferior nodules of the peritoneum were reduced in maximum diameters (42 vs. 50 mm and 40 vs. 85 mm, respectively), and the nodules attached to the recto-sigmoid junction had signs of excavation that were compatible with the necrotic process. At the time of writing the present report, treatment with regorafenib is still ongoing.