Perforated primary adenocarcinoma of the colon with choriocarcinoma differentiation treated with targeted colorectal cancer chemotherapy: a case report

Introduction

Background

Extragonadal non-gestational choriocarcinoma is an extremely rare condition, particularly when it originates from sites other than the primary reproductive organs. Moreover, diagnosis and treatment are particularly challenging when it arises from non-reproductive sites (1).

Rationale and knowledge gap

Primary choriocarcinoma of the colon is exceedingly uncommon, and no established chemotherapy guidelines are available for treating colorectal choriocarcinoma (2). Our case is notable for harboring a BRAF V600E mutation, which has important therapeutic implications. Owing to this lack of standardization, treatment protocols have involved the use of chemotherapy regimens targeting either choriocarcinoma or colorectal adenocarcinoma, or both (2-4).

Objective

Here, we report a case of colorectal choriocarcinoma treated with cetuximab, encorafenib, and binimetinib, which is typically used for colorectal adenocarcinoma, that resulted in a favorable clinical outcome. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-252/rc).

Case presentation

A 59-year-old woman presented to our hospital with a 1-day history of abdominal pain, frequent diarrhea, and fever. She had no medical or family history of cancer, significant comorbidities, or previous surgeries. On examination, her abdomen was firm and there was rebound tenderness in the umbilical region. Laboratory examination findings indicated the following: white blood cell count, 8.95 ×10⁹/L (normal range, 3.5–9.1 ×10⁹/L); C-reactive protein level, 15.02 mg/dL (normal range, 0–3 mg/dL); lactic acid level, 3.13 mmol/L (normal range, 0.8–1.77 mmol/L); and beta-human chorionic gonadotropin (hCG) level, 8.39 ng/mL (normal range, 0–1.00 ng/mL), suggestive of an inflammatory process with possible malignancy. Contrast-enhanced chest and abdomen computed tomography (CT) scans showed free air, ascites, and edematous thickening of the transverse colon. Enlarged lymph nodes around the transverse colon and para-aortic lymphadenopathy led to a diagnosis of perforated colorectal cancer based on clinical findings and imaging characteristics. No obvious lung or liver metastases were observed (Figure 1). An emergency laparotomy revealed a small amount of purulent ascites. The peritumoral area of the transverse colon was highly hardened, but could be separated. The patient’s vital signs were stable, and a right hemicolectomy with D2 lymph node dissection was performed.

Figure 1 Contrast-enhanced computed tomography findings. (A) Axial image shows extraluminal free air (arrow) and ascites (arrowhead). (B) Axial image demonstrating edematous wall thickening of the transverse colon (arrowhead). (C) Coronal reconstruction reveals enlarged regional lymph nodes adjacent to the transverse colon (arrows).

Macroscopic examination findings showed a 100 mm × 50 mm type 4 lesion in the transverse colon with an associated intestinal perforation (Figure 2). Histopathology results indicated primary colon adenocarcinoma with choriocarcinoma differentiation. The patient was diagnosed with tumor-node-metastasis (TNM) stage pT3, N2b, M1a, and stage IVA [American Joint Committee on Cancer (AJCC) 8^th edition] owing to sub-serosal invasion, multiple tumor deposits in the sub-serosa and mesentery, and extra-regional lymph node metastases involving the pancreas and peritoneum.

Figure 2 Macroscopic findings. The transverse colon shows a type 4 tumor (100 mm × 50 mm) with perforation (arrowheads).

Immunostaining was negative for cytokeratin 7 and positive for cytokeratin 20, indicating intestinal epithelial characteristics. Additionally, prognostic biomarkers for colonic adenocarcinoma, namely, CDX2 and SATB2, were negative, whereas hCG was positive in approximately 20–30% of the cancer cells. The germ cell marker SALL4 was negative, indicating non-pregnant, non-gestational choriocarcinoma, while acknowledging the intestinal epithelial nature of colorectal cancer (Figure 3). Histologically, a tubular adenocarcinoma that had abruptly migrated from the normal intestinal epithelium was observed in the mucosa. In addition, this tubular adenocarcinoma had transitioned to a choriocarcinoma at a deeper level (Figure 4). Based on these findings, a diagnosis of primary colonic adenocarcinoma and choriocarcinoma was made. Following the presumptive diagnosis, we performed additional genetic testing for RAS, BRAF V600E mutation, and microsatellite instability (MSI). Genetic testing was negative for RAS and MSI, and positive for BRAF V600E mutation. On postoperative day (POD) 5, the hCG levels had decreased to 0.57 ng/mL. Given this reduction, chemotherapy targeting colorectal cancer instead of choriocarcinoma was selected, and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy and bevacizumab were initiated on POD 22. Six cycles of chemotherapy were administered because hCG on POD 66 was undetectable (<0.1 ng/mL), and a reduction in lymph node size was noted on contrast-enhanced CT scans of the chest and abdomen. Three months following the start of chemotherapy, chest and abdomen CT scans showed enlarged lymph nodes and increased peritoneal dissemination, and the patient was switched to cetuximab, encorafenib, and binimetinib. The serial CT scans (chest and abdomen) were performed every 3 months following the switch to cetuximab, encorafenib, and binimetinib. These periodic scans consistently demonstrated no evidence of metastasis or recurrence and showed a continued reduction in the size of the lymph nodes and peritoneal lesions. The combination chemotherapy has been administered for 83 courses to date. The CT scan after the 83^rd course showed similar findings and, according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1, the patient has achieved partial response (PR). The patient has shown good overall tolerability to the treatment regimen. The main adverse event has been hand-foot syndrome (HFS), which has been predominantly grade 2. The patient experienced grade 3 HFS on two occasions, which required temporary dose reduction and discontinuation of cetuximab. The condition has been managed with 0.12% betamethasone valerate ointment and lotion, allowing continued treatment. No hospitalization or additional surveillance testing has been required beyond routine monitoring. The patient remained alive at 34 months postoperatively and continued to receive anticancer therapy.

Figure 3 Immunohistochemical findings (magnification ×100) showing: (A) negative staining for cytokeratin 7; (B) positive staining for cytokeratin 20; (C) negative staining for CDX2; (D) negative staining for SATB2; (E) focal positive staining for hCG in 20–30% of tumor cells; (F) negative staining for SALL4. hCG, human chorionic gonadotropin.

Figure 4 Histological findings: (A) coexistence of colonic adenocarcinoma and choriocarcinoma (hematoxylin and eosin stain, magnification ×40). The white rectangle indicates the area shown in (B), and the red rectangle indicates the area shown in (C). (B) Abrupt transition from normal intestinal epithelium to tubular adenocarcinoma in the mucosa (hematoxylin and eosin stain, magnification ×100). The arrowhead indicates the site of the abrupt transition from normal epithelium to tubular adenocarcinoma. (C) Transition from tubular adenocarcinoma to choriocarcinoma in the deeper layers (hematoxylin and eosin stain, magnification ×100).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Patient perspective

In terms of the patient’s perspective, the patient stated: “When chemotherapy began, I was told to prepare for a poor prognosis. However, seeing the treatment work has given me hope, and I’m determined to keep fighting”.

Discussion

Key findings

In this case report, a 59-year-old woman diagnosed with primary colorectal adenocarcinoma with choriocarcinoma differentiation presented with intestinal perforation of the transverse colon. The initial treatment involved right hemicolectomy to address the perforation and remove the tumor. Adjuvant chemotherapy with FOLFOX and bevacizumab was subsequently administered. Despite an initial positive response, disease progression with lymph node enlargement and increased peritoneal dissemination was observed 3 months following chemotherapy initiation. The patient was switched to a cetuximab, encorafenib, and binimetinib regimen, which resulted in sustained disease control for 34 months postoperatively.

Strengths and limitations

This case report had some limitations in relation to the methods used to treat this patient. The patient has been under observation for 34 months. The short-term effects of treatment have been confirmed; however, the long-term effects of treatment and recurrence rates remain unknown. Despite these limitations, chemotherapy for colorectal adenocarcinoma may be effective in improving the survival rates of patients with perforated colorectal choriocarcinoma.

Comparison with similar research

Choriocarcinomas usually result from the abnormal proliferation of trophoblastic cells. Extragonadal non-gestational choriocarcinoma is rare and can occur in the mediastinum, retroperitoneum, intracranial tract, or in the gastrointestinal tract (5). In the gastrointestinal tract, choriocarcinoma most commonly occurs in the stomach, with only 30 cases of choriocarcinoma in the colon having been reported (2,3). No similar cases of perforation have been reported. The average age at onset of colorectal choriocarcinoma is 52 years, with a male-to-female ratio of 1:1.3 (2,3). At the time of diagnosis, 86.3–93.5% of patients already have extensive hematogenous metastases in the liver, lungs, and other organs, and the prognosis is poor (mean survival time, 108 days) (6).

Histologically, most colorectal choriocarcinomas are characterized with the presence of both adenocarcinomas and choriocarcinomas (7). A histological transition zone is typically observed between the two tumors (2), and a transition zone was also observed in this case. This suggests that colorectal choriocarcinoma may develop as a result of dedifferentiation from adenocarcinoma. It has been reported that mature tumors may undergo dedifferentiation, resulting in cells with different morphological characteristics (4,8). Previous reports have shown a lack of specific genomic patterns and a weakened genetic contribution to tumorigenesis (2).

Explanations of findings

The treatment of colorectal choriocarcinomas involves both surgery and chemotherapy (2,6). In one case report, a patient with no distant metastases underwent curative resection and had no recurrence for 1 year. However, many cases have already metastasized at the time of diagnosis, resulting in non-curative resection (6,9). Previous reports suggest that achieving a radical cure through surgery may be associated with better outcomes (10). Our patient did not have distant metastasis at the time of diagnosis, and the ability to operate on the primary tumor may have influenced the prognosis in her case.

There is no established consensus or standard chemotherapeutic regimen for colorectal choriocarcinoma (2). Therefore, standard chemotherapy has been used to treat choriocarcinoma (e.g., EMA-CO: etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) (4), colorectal adenocarcinoma (e.g., FOLFOX) (3,11), or both (2,6). Colorectal choriocarcinoma is often associated with high hCG levels and several reports have indicated that hCG trends can help determine the choice of chemotherapy (2,12). Colorectal choriocarcinoma is a dedifferentiated adenocarcinoma, not a primary gonadal choriocarcinoma. It has been reported that systemic chemotherapy regimens, such as FOLFOX or folinic acid, fluorouracil, and irinotecan (FOLFIRI), are effective (11). In our case, treatment decisions were guided by a multifaceted evaluation incorporating hCG trends and genetic testing.

Our patient’s hCG level decreased postoperatively, and chemotherapy was administered for colorectal adenocarcinoma instead of choriocarcinoma; however, this was unsuccessful. A notable aspect of our case was the presence of BRAF V600E mutation in colorectal choriocarcinoma. While this mutation is well-documented in colorectal adenocarcinoma, occurring in approximately 10–15% of cases (13), its identification in our patient provided a rational basis for using targeted therapy with encorafenib and binimetinib, combined with cetuximab. The combination of encorafenib, cetuximab, and binimetinib significantly prolonged her overall survival.

The combination of encorafenib (BRAF inhibitor), binimetinib (MEK inhibitor), and cetuximab (EGFR inhibitor) has demonstrated significant efficacy in the treatment of BRAF V600E-mutated metastatic colorectal cancer (mCRC). Evidence from the BEACON CRC trial showed that this triplet therapy significantly prolonged overall survival and increased the treatment response rate compared to standard therapies, such as cetuximab combined with irinotecan or FOLFIRI (14). Specifically, the trial reported a median overall survival of 9.0 months in the triplet-therapy group versus 5.4 months in the control group, with a confirmed response rate of 26%, far surpassing the 2% observed in the control group. The ANCHOR CRC study further supports its efficacy, demonstrating a confirmed objective response rate of 47.4%, a median progression-free survival of 5.8 months, and a median overall survival of 18.3 months in previously untreated patients (13). Both studies highlighted the manageable safety profile of this regimen, establishing its potential as a valuable treatment option for BRAF V600E-mutated mCRC.

Implications and actions needed

In our patient’s case, despite initial chemotherapy for colorectal adenocarcinoma, which was unsuccessful, the combination of encorafenib, binimetinib, and cetuximab led to significant improvement. Her survival was prolonged for 34 months, which is consistent with the promising results from both the BEACON CRC and ANCHOR CRC studies. This response suggests that this regimen could be a valuable option for patients with BRAF V600E-mutated genes, even in second-line settings, and further supports the potential influence of this treatment strategy on future clinical practices. This is the first reported case using this combination therapy for primary colorectal adenocarcinoma with choriocarcinomatous differentiation.

Conclusions

In conclusion, colorectal choriocarcinoma is an exceedingly rare condition with a poor prognosis. A combination therapy with encorafenib, cetuximab, and binimetinib may be useful for colorectal choriocarcinoma patients with a BRAF V600E mutation. This case report provides valuable insights that may assist clinicians in developing effective treatment strategies for treating this challenging malignancy.

Acknowledgments

We wish to thank pathologist Koji Asano for advice in relation to the histological images from pathology.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-252/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-252/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-252/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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