Spontaneous colonic transection following pathologic complete response to pembrolizumab in high microsatellite instability colorectal cancer: A case report and review of literature

Abstract

BACKGROUND

High microsatellite instability (MSI-H) colorectal cancer (CRC), caused by deficient mismatch repair, accounts for about 15% of all CRC cases and is more common in right-sided tumors. While early-stage MSI-H CRC has a relatively good prognosis, advanced cases often respond poorly to standard chemotherapy. Immune checkpoint inhibitors, such as pembrolizumab, have shown strong and lasting effects in MSI-H CRC. Pembrolizumab is now approved as a first-line treatment for metastatic MSI-H CRC due to its superior outcomes compared to traditional chemotherapy.

CASE SUMMARY

A 44-year-old male with MSI-H transverse colon cancer presented with hematochezia, abdominal pain, and significant weight loss. Imaging revealed a bulky tumor with invasion of adjacent structures and multiple liver lesions. A diverting ileostomy was performed followed by 36 cycles of pembrolizumab. The patient achieved a clinical and radiologic complete response. One month after completing the treatment, the patient underwent laparoscopic right hemicolectomy. A spontaneous transection of the colon at the original tumor site was unexpectedly identified. Final pathology confirmed pathological complete response (ypT0N0) with fibrosis. The patient recovered well after surgery, and follow-up showed no evidence of recurrence.

CONCLUSION

Immune checkpoint inhibitors may cause delayed structural damage to bowel tissue even after apparent complete tumor regression.

Key Words: Pembrolizumab; Colon cancer; High microsatellite instability; Mismatch repair deficient; Transection; Case report

Core Tip: We report here the first case of spontaneous colonic transection in a patient with high microsatellite instability colon cancer who achieved pathologic complete response after long-term pembrolizumab therapy. Despite no residual tumor on imaging or pathology, intraoperative findings revealed a discontinuity of the bowel at the original tumor site. Immune-mediated remodeling can compromise bowel integrity and may not be apparent on imaging. Clinicians should consider potential anatomic changes when planning surgery in patients treated with immunotherapy, even in the context of a complete response.

INTRODUCTION

The introduction of immune checkpoint inhibitors for the treatment of high microsatellite instability (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC) brought a paradigm shift in the medical field. Pembrolizumab emerged as a key therapeutic option for patients with advanced-stage disease[1-3]. Recently, studies have demonstrated the durable antitumor efficacy of pembrolizumab, with some patients achieving a complete response (CR)[4,5].

Bowel obstruction associated with immune checkpoint inhibitor therapy has been reported in a limited number of cases[6]. It typically occurs during or after treatment. However, spontaneous colonic transection in the setting of complete tumor regression has not been documented in the literature previously.

We report herein a case of a patient with MSI-H transverse colon cancer who achieved a pathologic CR (pCR) following long-term pembrolizumab therapy. During surgical resection an unexpected spontaneous transection of the colon at the site of the original tumor was discovered. To our knowledge this is the first reported case of colonic transection associated with immune checkpoint inhibitor therapy in the setting of complete tumor regression.

CASE PRESENTATION

Chief complaints

A 44-year-old male presented with intermittent hematochezia and right upper quadrant abdominal pain.

History of present illness

The patient reported a 6-month history of intermittent hematochezia and loose stools occurring every 1-2 days. These symptoms were accompanied by anorexia and significant weight loss of approximately 25 kg.

History of past illness

The patient had a history of liver cirrhosis due to chronic HBV infection. Viral suppression was attained by tenofovir therapy.

Personal and family history

The patient’s mother had a history of hepatocellular carcinoma, and his father had been diagnosed with CRC. No other notable personal or familial conditions were reported.

Physical examination

The patient’s vital signs were stable. Abdominal examination revealed a soft, non-tender abdomen without rebound tenderness or palpable mass.

Laboratory examinations

Initial laboratory investigations showed severe anemia with a hemoglobin level of 9.0 g/dL (normal range: 13.0-17.0 g/dL) and carcinoembryonic antigen of 3.5 ng/mL (normal range: 0-6.0 ng/mL). Liver function was classified as Child-Pugh B. HBV DNA level was normalized at 1.9 × 10⁷ IU/mL (normal range: < 10 × 10⁷ IU/mL).

Imaging examinations

Abdominal CT demonstrated a mass in the proximal transverse colon invading the second portion of the duodenum, pancreatic head, and superior mesenteric vein. There were multiple low-attenuation lesions in the liver and ascites. Positron emission tomography-CT showed intense fluorodeoxyglucose uptake in the hepatic flexure and suggested possible peritoneal involvement (Figure 1A).

Figure 1 Serial fluorodeoxyglucose positron emission tomography-computed tomography. A: Baseline imaging showed intense fluorodeoxyglucose uptake in the hepatic flexure of the colon, multiple hypermetabolic liver lesions, and suspected peritoneal involvement; B: After 7 months of pembrolizumab treatment, a marked reduction in fluorodeoxyglucose uptake at the primary site and metastatic lesions was observed, indicating a significant treatment response; C: After completion of pembrolizumab treatment, complete resolution of prior hypermetabolic activity at the primary tumor site was observed. A new focal uptake was seen near the stoma and gallbladder bed, suggestive of either post-treatment inflammation or possible recurrence. The primary tumor site is marked with a yellow circle, and the stoma location is indicated by a orange arrow.

FINAL DIAGNOSIS

The patient was diagnosed with MSI-H CRC, specifically a poorly differentiated adenocarcinoma of the transverse colon. Molecular testing revealed dMMR with loss of MLH1 and PMS2 and KRAS G13D mutation.

TREATMENT

Due to a high risk of obstruction, a laparoscopic loop ileostomy was performed 1 month after diagnosis. Immunotherapy with pembrolizumab (200 mg every 3 weeks) was initiated shortly thereafter and continued for approximately 2 years (36 cycles in total). The patient initially showed a partial response to treatment. Seventeen months after initiation of immunotherapy, a colonoscopy was attempted but could not be advanced beyond the lesion due to persistent obstruction (Figure 2). No additional endoscopic evaluations were performed thereafter.

Figure 2 Colonoscopy performed after receiving immunotherapy for 17 months. The scope was inserted through the anus and advanced to the transverse colon, but further passage was not possible due to luminal obstruction at the tumor site.

During the treatment course interval CT demonstrated a marked reduction in tumor burden, including near-complete resolution of the primary lesion (Figure 3). Positron emission tomography-CT performed at the same time confirmed the disappearance of the initial mass but revealed new hypermetabolic foci near the stoma site and gallbladder bed, suspicion for inflammatory changes (Figure 1).

Figure 3 Axial Abdominopelvic computed tomography during the treatment course. A: Baseline imaging revealed a large soft tissue mass in the proximal transverse colon with invasion into adjacent structures; B: After 6 months of pembrolizumab treatment, a marked reduction in tumor size was revealed; C: After 20 months of pembrolizumab treatment, radiologic complete response of the primary lesion was observed. The yellow circles indicate the location of the primary tumor across the treatment timeline. The orange arrow indicates the primary tumor in the colon with suspected invasion into the pancreas.

OUTCOME AND FOLLOW-UP

After completion of immunotherapy, the patient showed a clinical CR. Surgery was scheduled approximately 1 month later, considering both the imaging findings and coordination of the surgical schedule between the patient and the hospital (Figure 4). Intraoperatively, a spontaneous transection of the colon was identified at the hepatic flexure. Postoperatively, the patient experienced colitis due to Clostridium difficile infection that was successfully treated with oral vancomycin. The remainder of the patient’s recovery was uneventful, and he was discharged in stable condition on postoperative day 14.

Figure 4 Clinical timeline of diagnosis, treatment, and surgery in a patient. Clinical timeline showing key events from diagnosis to surgery. Pembrolizumab treatment began after loop ileostomy and continued for 36 cycles over approximately 2 years. Colonoscopy (Month 17), computed tomography (Month 21), and positron emission tomography/computed tomography (Month 25) were performed during follow-up, culminating in a laparoscopic right hemicolectomy at Month 26.

A follow-up CT and laboratory tests were performed 1 month after surgery and showed no evidence of recurrence and no remarkable findings. Final pathology confirmed a pCR (ypT0N0, 0/45 Lymph nodes). Histopathologic examination of the hepatic flexure revealed transmural fibrosis and calcification, accompanied by mild microvascular damage and chronic inflammatory response, suggesting ongoing tissue remodeling. Additionally, a granulomatous abscess with actinomycosis was identified near the stoma site. Although these findings support the hypothesis of immune-related structural changes, additional histologic characterization such as immunohistochemical staining was not performed.

DISCUSSION

Immune checkpoint inhibitors, particularly those targeting programmed death-1 (PD-1), have become the primary treatment for patients with MSI-H or dMMR CRC[7-10]. The most well-known PD-1 inhibitors include pembrolizumab, nivolumab, and dostarlimab. These agents restore the function of exhausted T cells and enhance antitumor immune responses[11-13].

Among these, pembrolizumab is the most widely used PD-1 inhibitor. It has been approved as a first-line treatment for MSI-H/dMMR metastatic CRC based on the KEYNOTE-177 trial. Pembrolizumab showed superior outcomes compared with conventional chemotherapy with a progression-free survival of 16.5 months vs 8.2 months (hazard ratio: 0.60). The incidence of grade 3 or higher adverse events was only 22%[14,15].

Although PD-1 blockade was initially introduced for use in patients with metastatic or treatment-refractory disease[16], its application has rapidly expanded into the neoadjuvant setting, particularly for patients with locally advanced MSI-H/dMMR tumors[11,17,18]. Recent trials demonstrated high rates of pCR, paving the way for organ-preserving strategies and reduced treatment intensity in selected patients[19]. These findings reflect a broader shift in CRC treatment toward personalized, biomarker-driven approaches to optimize therapy according to individual tumor biology and treatment response[19-22].

Recent reports have shown an increasing number of cases achieving pCR[23,24]. The first report of a patient achieving a pCR with pembrolizumab monotherapy was initially diagnosed with metastatic ascending colon cancer[5]. Several other cases have since demonstrated CR even in high-risk patients with liver or peritoneal metastases[4,25-27]. However, PD-1 inhibitors are not effective in all patients. Approximately 20%-30% of patients exhibit primary resistance, showing no initial response, while others develop acquired resistance during treatment. These resistance mechanisms may involve mutations in B2M or JAK1/2, reduced antigen presentation, activation of alternative immune checkpoints such as LAG-3 and TIM-3, or an immunosuppressive tumor microenvironment enriched with regulatory T cells or myeloid-derived suppressor cells[11,28-30].

Recently, gastrointestinal complications related to immune-related adverse events have been identified during PD-1 inhibitor therapy. A multicenter case series reported 9 cases of bowel obstruction that occurred during pembrolizumab treatment[6]. Notably, most of these patients had achieved pCR. However, obstruction developed due to fibrosis or strictures induced by immune-mediated reactions.

However, the present case was differs significantly from previously reported cases. Our patient was diagnosed with MSI-H transverse colon cancer. He achieved radiologic CR after long-term pembrolizumab treatment, and a spontaneous colonic transection was identified intraoperatively. To our knowledge this highly unusual finding has not been previously reported in the literature. While prior reports have described findings such as mucin pools, necrotic tissue, or fibrosis, none have documented structural disruption severe enough to cause a loss of anatomical continuity.

Immune checkpoint inhibitor-related tissue remodeling has been observed across various organs, including the lung and heart, where structural damage may persist even after cessation of therapy[31,32]. Similar to pneumonitis or myocarditis, where chronic inflammation and fibrosis can remain despite clinical resolution, our case suggests that bowel wall fragility may reflect a parallel mechanism of immune-mediated injury[33].

Immune-mediated tissue remodeling processes are complex biological phenomena that involve a range of pathological alterations, including but not limited to fibrosis and microvascular damage[34,35]. These processes can lead to significant and lasting changes in the architecture of the bowel wall. Even in cases where tumor regression has been achieved, the effects of these immune-mediated alterations may persist, continuing to compromise the structural integrity of the bowel. Furthermore, although clinical CR may be observed, the actual mechanical integrity of the bowel may remain compromised. This case represents the first surgical confirmation of such a risk. Therefore, in patients with MSI-H CRC receiving immune checkpoint inhibitors, surgical planning should carefully consider the risk of bowel obstruction or perforation. In select cases the need for prophylactic stoma formation may warrant consideration.

CONCLUSION

This study presented a rare case of MSI-H CRC in which a spontaneous colonic transection was identified during surgery following pembrolizumab treatment. It suggested that immune checkpoint inhibitors may exert structural effects beyond the tumor itself and provided important clinical insight for surgical planning in patients undergoing immunotherapy.