Beyond the image: achieving complete pathologic response in MSI-high metastatic colon cancer despite persistent PET activity

Abstract

Background:

Microsatellite instability-high (MSI-H) colorectal cancer, presents high tumor mutational burden and is highly responsive to immune checkpoint inhibitors (ICIs). ICIs have transformed metastatic colorectal cancer (mCRC) treatment. However, the role of partial or discontinued immunotherapy and the interpretation of PET imaging in this setting remain challenging.

Objective:

We aim to report a case of MSI-H mCRC with liver metastasis demonstrating complete pathological response after partial immunotherapy despite persistent PET activity, highlighting integrative approaches of immunotherapy and surgery.

Case presentation:

A 49-year-old female with MSI-H left colon adenocarcinoma and a single liver metastasis underwent laparoscopic subtotal colectomy, followed by chemotherapy (FOLFOX plus bevacizumab) combined with pembrolizumab. Immunotherapy was discontinued after four cycles due to limited resources. PET-CT after chemotherapy showed persistent metabolic activity in liver lesions. She underwent surgical segmentectomy with negative margins. Final pathology showed no residual tumor.

Discussion:

Partial immunotherapy can induce profound pathological response in MSI-H mCRC. Persistent PET positivity may reflect immune-related inflammation rather than viable tumor, complicating response assessment. Combined immunotherapy and surgery improve survival in MSI-H metastatic disease. Emerging evidence supports tailored immunotherapy duration and multidisciplinary management.

Conclusion:

Partial immunotherapy in MSI-H metastatic colon cancer can achieve complete pathological remission despite PET persistence. Surgery remains vital for definitive response assessment and cure. Multimodal strategies integrating systemic immunotherapy and local treatment optimize outcomes for MSI-H mCRC patients.

Introduction

Microsatellite instability-high (MSI-H) colorectal cancer is a unique molecular subgroup, characterized by deficient mismatch repair (dMMR), which leads to a high tumor mutational potential and enhanced tumor genetic instability^[1^]. This feature makes MSI-H tumors particularly responsive to immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, fundamentally transforming the therapeutic approach to metastatic colorectal cancer (mCRC) with MSI-H status since their introduction^[2,3^]. Immunotherapy shows very promising results in patients with mCRC, particularly in transforming unresectable disease to resectable^[2^]. Cases reporting complete pathological response (pCR) after immunotherapy, including in patients with liver metastases, signal new opportunities in treatment where surgeries previously considered palliative now can be curative^[4,5^]. However, although ICIs are approved for unresectable or metastatic cases, their efficacy in partial or as neoadjuvant protocol is still being explored^[5^].

HIGHLIGHTS

• This clinical case highlights the potential for immunotherapy to induce a complete pathological response in metastatic MSI colon cancer even when the full protocol is not completed, highlighting individual variability in response. The optimal duration of immunotherapy is not yet established; discontinuation in selected patients may not compromise survival.

• The case reports the role and limitations of PET imaging in evaluating residual tumor activity after immunotherapy. Persistent metabolic activity on PET scans after immunotherapy does not necessarily indicate residual cancer; it may represent immune-related inflammation (pseudoprogression).

• The case report emphasizes the role for surgical management after partial immunotherapy response, comforting the possibility of cure despite atypical imaging findings. Multimodal approaches blending immunotherapy, surgery, and other local treatments offer the best outcomes in managing MSI-H metastatic disease.

Positron emission tomography (PET) can be used in context of metastatic colorectal cancer assessment following neo-adjuvant therapy. Indeed, it is an imaging modality based on evaluating metabolic activity after therapy and can therefore provide misleading information in the context of immunotherapy due to immune-related inflammation described. Therefore, PET-scan can show persistent metabolic activity despite absence of viable tumor cells in pathology specimens described as “pseudoprogression” (6,7G). Unfortunately, various studies highlight the challenge in assessing true residual disease after immunotherapy^[6–8^].

Surgical resection following immunotherapy is increasingly recognized as a valuable strategy to achieve complete tumor clearance and enhance survival^[9,10^]. Despite the relatively low prevalence of MSI in metastatic colorectal cancer, reports highlight that liver metastasectomy after neoadjuvant immunotherapy in MSI-H mCRC patients is a promising approach to managing MSI metastatic colorectal cancer with notable improvements in survival^[11^]. Such observations support the growing integration of immunotherapy and surgery to improve long-term outcomes in MSI-H m-CRC.

We report a case of discontinued immunotherapy in MSI-H metastatic colon cancer with complete pathological responses despite lingering PET activity. This case report has been reported in line with the SCARE checklist^[12^]

Case report

A 49-year-old female patient with no previous medical history was diagnosed with a moderately differentiated adenocarcinoma of the left colon with liver metastasis. She had never smoked cigarettes or consumed alcohol. The patient reported chronic diarrhea for less than 1 month, no hematochezia or melena. Family history was unremarkable for cancer. Laboratory studies showed no elevation in serum CEA and CA19-9. Initial computed tomography (CT)-SCAN showed a left-sided colon cancer with a single liver lesion at segment VIII, which was confirmed on hepatic MRI measuring 7.5 × 8.8 mm. Total colonoscopy showed colon cancer difficult to pass, confirming diagnosis on histology of biopsy with no associated lesions in the rest of the colon. Upon multidisciplinary panel discussion under guidelines of our institution, primary tumor resection followed by secondary metastasis resection was decided for this case considering various factors including imminent risk of obstruction patient’s resources.

The patient initially underwent a laparoscopic subtotal left colectomy. Immunohistochemical analysis of the operative specimen (pT4bN1bM1 Stage IVa) showed loss of MSH2 and MSH6 expression in tumor cells with retained low expression 10–20% of MLH1 and 40–50% of PMS2, thus MSI-High. She was started on FOLFOX (Oxaliplatin with 5-Fluorouracyl and Leucovorin) regimen with pembrolizumab. Due to limited resources, the immunotherapy was discontinued in the fourth cycle, and chemotherapy was maintained conforming to standard protocol of FOLFIRI and Avastin (Bevacizumab). The patient underwent computed tomography after chemotherapy showing a regression of the liver metastasis of 31%. However, PET-CT scan was performed after her last cycle of chemotherapy and revealed a persistent activity of the liver lesions (Fig. 1). Assessment of treatment response using cfDNA or MRD to assess was not performed due to limited availability. She was referred to surgery for discussion of either surgical resection or stereotaxic radiotherapy. The patient underwent hepatic resection of segments VIII and IV-a for achieving no residual tumor and clear margins R0 with open laparotomy. Surgical follow-up was uneventful. Final pathology was negative for residual carcinoma, with areas of necrosis and negative margins on surgical pathology (Fig. 2). Formal consent was obtained from the patient for clinical report. Clinical case reports were exempted from board or ethical committee approval at our institution with patient’s consent. Our clinical case has not been previously reported or presented at a conference or regional meeting.

Figure 1.

A positron emission tomography (PET) scan demonstrated persistent metabolic activity within the hepatic lesion with increased uptake value (SUV) significantly above background hepatic parenchyma, indicative of residual viable tumor tissue.

Figure 2.

Representative micrograph of the lesion showing ischemic, eosinophilic necrosis, without residual cancer cells. Lesion is circumscribed by fibrous capsule and macrophage infiltration. (Hematoxylin-eosin; a: x10, b: x20, c: x100, d: x300).

Discussion

Targeted therapies, especially immunotherapy, have improved treatment responses, surgical outcomes, and survival in mCRC^[2^]. MSI-H mCRC results from mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) causing dMMR tumors^[2,13^]. These tumor cells express PD-L1, which binds PD-1 on T-cells, suppressing immune attack and allowing cancer to persist. Blocking PD-L1 with antibodies like pembrolizumab has shown promise against dMMR tumors^[2,14^].

The presented case embodies critical aspects regarding the benefits of immunotherapy in MSI m-CRC. We report a case of MSI-H colon cancer patient with metastatic liver lesions who underwent discontinued immunotherapy showing persistent PET-positive lesions, yet post-surgical pathology after liver resection revealed no tumor cells. This aligns with reports showing that even incomplete immunotherapy cycles can trigger profound pathological responses, possibly reflecting tumor heterogeneity and differential immune sensitivity^[5^]. Similar case report by Kinney et al reported a case involving a 52-year-old male with right-sided colon cancer who achieved a complete pathological response after receiving three cycles of combined immunotherapy^[15^]. An experimental study called NICHE trial investigated 20 patients with resectable dMMR/MSI-H colorectal cancer treated with a combination of immune checkpoint blockade. Their results demonstrated a major pathological response (defined as 10% or less viable tumor remaining) in 19 out of 20 participants, while 12 patients achieved a complete pathological response. These findings highlight the strong efficacy of immunotherapy as a neoadjuvant regimen^[7^]. All these findings emphasize the potential positive effect of immunotherapy as neoadjuvant therapy for m-CRC.

Moreover, our case highlights the synergy of systemic immunotherapy and surgical intervention in managing metastatic disease. Over recent years, survival rates for patients with colorectal liver metastases (CRLM) have improved significantly, particularly in those with oligometastatic disease, for which combining modern systemic treatments with localized approaches, such as advanced liver surgery and ablative therapies, can offer a potentially curative option^[11^]. The 5-year Overall Survival (OS) rate for patients with CRLM is approximately 11% when treated with palliative chemotherapy alone and improves dramatically to 50%–60% when systemic therapy is combined with local treatments such as surgery or ablative procedures^[10^]. Pollini et al reported a large retrospective study that analyzed 9943 patients who underwent curative-intent liver resection for stage IV colon cancer with liver metastases, comparing outcomes between patients receiving adjuvant chemotherapy (CT) alone versus combined CT and immunotherapy (IT). The study found that adjuvant CT + IT was associated with significantly improved 3-year OS compared to CT alone^[9^].

In fact, an increasing number of recent studies advocate for combined approaches to optimize survival in MSI-H mCRC patients, shifting treatment paradigms towards multimodal personalized care^[9–11,16^]. A recent largest cohort study evaluating 18 932 patients with mCRC treated in routine clinical practice, demonstrated that patients with MSI-H tumors who received ICIs early in their treatment had significantly better OS and longer treatment duration compared to chemotherapy alone^[16^]. Moreover, Bari et al illustrated that stopping or partially completing immunotherapy did not negatively affect survival outcomes. In fact, the optimal duration of immune checkpoint inhibitor therapy is not firmly established^[16^]. Considering the context of real-world clinical practice including various circumstances and individualized care, more supporting evidence is reported emphasizing the possibility to discontinue immunotherapy in selected patients without compromising long-term outcomes^[17,18^].

A recent case report of Feng et al confirmed the contributive potential of immunotherapy. Indeed, they provided valuable insight via their case report regarding managing complex cases using modern immunotherapy^[4^]. The case describes a rare patient with bifocal colon cancer associated with both Lynch syndrome (a hereditary colorectal cancer syndrome characterized by MSI-H/dMMR status) and situs inversus totalis, a congenital condition causing mirror-image organ arrangement. The patient received monotherapy with the immune checkpoint inhibitor sintilimab for about 2 years after initially declining surgery. Follow-up imaging 7 months after completing immunotherapy showed no abnormal enhancement of the tumor site, and surgical pathology after colectomy confirmed a pCR with no residual tumor cells (tumor regression grade 0). However, the patient presented a gastrointestinal perforation during therapy, documenting the delayed therapeutic effects of immunotherapy. This case consequently illustrates both the opportunities and challenges in this evolving field^[4^].

Finally, the discrepancy observed between PET results and histopathology underscores PET’s limitations in the immunotherapy setting. In fact, evaluating tumor response to immunotherapy using traditional imaging criteria may be challenging, with atypical patterns of response such as pseudoprogression^[5,7^]. Increased metabolic activity may correspond to immune cell infiltration rather than residual malignancy, a phenomenon documented in various studies and case reports emphasizing the necessity for histological confirmation to guide therapeutic decisions^[8,19^]. Such phenomenon has been reported in 10% of patients during the first trimester of immunotherapy using Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) and immune RECIST (iRECIST) in a study including 123 patients with dMMR/MSI-H mCRC^[19^]. Various studies have shed light toward this challenge, demonstrating that the PET/CT indeed can show variable metabolic changes post-immunotherapy that do not always correlate with conventional imaging or clinical outcomes. Hence similarly to our case, Jin et al report a clinical case with persistent hypermetabolic activity in liver metastases of colorectal cancer following immunotherapy, yet pathology after resection showed no viable tumor cells^[8^]. In summary, our case aligns with recent data underscoring the limited use of PET/CT in distinguishing active cancer from treatment-related changes in the context of immunotherapy, therefore requiring caution in interpretation and a multidisciplinary approach when managing m-CRC MSI undergoing immunotherapy.

Conclusion

In conclusion, partial immunotherapy in MSI-H mCRC can lead to complete pathological responses despite lingering PET activity. The limited reliability of PET-CT underlines surgery’s essential role in confirming remission and achieving cure. Our findings substantiate the multidisciplinary strategy of integrating immunotherapy and surgical resection tailored to tumor biology and patient response patterns.

Best outcomes for patients with CRLM, both in survival and quality of life, are achieved through a multimodal treatment approach within a multidisciplinary team. When managed by experts, combining systemic therapies with loco-regional treatments should be considered whenever feasible to maximize benefits.

Ethical approval

Case report is exempt from ethical approval in our institute.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

None.

Author contributions

S.B. participated in the patient’s care, data collection, writing, analysis, and correction, Y.A., M.Y., S.K., and I.M. participated in patient’s care, data collection, and revision. A.B. participated in writing process, correction, and final review and validation.

Conflicts of interest disclosure

None to declare.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Sarah Benammi.

Provenance and peer review

This article was written by the authors and has undergone internal review within the team. It has not been sent to external peer reviewers.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon request.