Pathological Complete Response Achieved with Colorectal Cancer-Based Chemotherapy for Locally Recurrent Cecal Neuroendocrine Carcinoma after Surgery: A Case Report

ABSTRACT

INTRODUCTION

Primary neuroendocrine carcinoma (NEC) of the colon is extremely rare, accounting for only 0.2% of all colorectal malignancies, and is associated with a poor prognosis. Early diagnosis is often challenging, as endoscopic biopsies are frequently misinterpreted as adenocarcinoma. Although platinum-based regimens such as etoposide plus cisplatin or irinotecan are commonly used, no standard chemotherapy protocol has been established. We report a case of locally recurrent cecal NEC that responded remarkably to a colorectal cancer–based chemotherapy regimen, achieving a pathological complete response.

CASE PRESENTATION

A 52-year-old man presented with severe anemia. Imaging and colonoscopy revealed a cecal tumor initially diagnosed as adenocarcinoma. He underwent laparoscopic right hemicolectomy with lymph node dissection. Final pathology revealed NEC, staged as pT3N2aM0, Stage IIIB. Adjuvant etoposide–cisplatin chemotherapy was initiated. Three months postoperatively, carcinoembryonic antigen (CEA) rose to 44.4 ng/mL, and CT demonstrated a perianastomotic peritoneal nodule and lymphadenopathy, consistent with recurrence. Considering the adenocarcinoma component in the primary tumor and elevated CEA, chemotherapy was switched to a colorectal cancer–based regimen: FOLFOXIRI plus bevacizumab. After 7 cycles, both radiologic regression and normalization of CEA levels were achieved. Resection of the recurrent lesions confirmed a pathological complete response with no residual tumor cells.

CONCLUSIONS

To the best of our knowledge, this is the first reported case of cecal NEC achieving pathological complete regression with a colorectal cancer–based chemotherapy regimen. Our findings indicate that colorectal NEC may respond not only to platinum-based regimens but also to colorectal cancer–based regimens. Furthermore, CEA levels may serve as a clinically relevant biomarker to guide chemotherapy selection in this setting.

Abbreviations

CEA

carcinoembryonic antigen

EP

etoposide and cisplatin

MANEC

mixed adeno-neuroendocrine carcinoma

NEC

neuroendocrine carcinoma

INTRODUCTION

Primary neuroendocrine carcinoma (NEC) of the colon is a rare entity, representing approximately 0.2% of all colorectal malignancies, and is associated with an extremely poor prognosis.¹⁾ Early and accurate diagnosis remains challenging, as endoscopic biopsy specimens are frequently misinterpreted as adenocarcinoma.^2–4) While no standardized treatment protocol has been established, multidisciplinary approaches combining surgical resection and adjuvant chemotherapy are commonly employed. Platinum-based regimens with etoposide or irinotecan are generally used as first-line chemotherapy, yet a standard regimen has not been established.^5,6) Herein, we report a case of locally recurrent cecal NEC that was successfully treated with a colorectal cancer–based chemotherapy regimen, resulting in a pathological complete response.

CASE PRESENTATION

A 52-year-old man with no significant past medical history was emergently admitted with lightheadedness. Laboratory investigations on admission revealed severe anemia with a hemoglobin level of 6.0 g/dL. Abdominal CT demonstrated irregular wall thickening of the cecum along with increased density of the surrounding adipose tissue (Fig. 1A and 1B). Colonoscopy revealed a tumor in the cecum (Fig. 1C), and biopsy results led to a diagnosis of advanced cecal adenocarcinoma (Fig. 1D). Genetic analysis revealed that both RAS and BRAF were wild-type, and microsatellite instability was negative. The patient subsequently underwent laparoscopic right hemicolectomy with lymph-node dissection.

Fig. 1. Imaging and histological findings. (A, B) Abdominal CT demonstrated irregular wall thickening of the cecum accompanied by regional lymphadenopathy, with no evidence of distant metastasis. (C) Lower gastrointestinal endoscopy revealed a type 2, semicircumferential lesion on the side opposite the ileocecal valve. (D) Histopathological diagnosis revealed moderately differentiated adenocarcinoma (tub2) predominant over well-differentiated adenocarcinoma (tub1).

Histopathological examination of the surgical specimen revealed a diagnosis of NEC, staged as pT3N2aM0 (Stage IIIB, according to UICC TNM classification, 8th edition). Although an adenocarcinoma component was identified, it accounted for less than 30% and did not meet the criteria for mixed adeno-neuroendocrine carcinoma (MANEC) (Fig. 2A–2D). Postoperatively, the patient received 1 course of adjuvant chemotherapy with the etoposide and cisplatin (EP) regimen. However, 3 months after surgery, serum carcinoembryonic antigen (CEA) levels rose to 44.4 ng/mL, whereas the preoperative CEA was 12.3 ng/mL. Subsequent CT revealed a perianastomotic peritoneal nodule and lymphadenopathy, suggestive of local recurrence (Fig. 3A).

Fig. 2. Histological findings of the tumor. (A) H&E staining revealed tumor cells with a higher N/C ratio compared to conventional adenocarcinoma. (B) Immunohistochemical staining for synaptophysin was diffusely positive. (C, D) Both chromogranin A and CD56 were negative on immunohistochemical staining.

H&E, Hematoxylin and eosin; N/C, nuclear-to-cytoplasmic

Fig. 3. Imaging findings before and after chemotherapy. Yellow arrows shows a disseminated nodule and a swelling lymph node. (A) Follow-up CT after initiation of EP therapy revealed peritoneal dissemination nodules adjacent to the anastomosis site and enlargement of the surrounding lymph nodes. (B) CT after 6 courses of Bmab/FOLFOXIRI revealed a marked reduction in both the peritoneal dissemination nodules and lymph node enlargement.

Bmab, bevacizumab; EP, etoposide and cisplatin

Given the adenocarcinoma component in the primary specimen and the elevated CEA level, chemotherapy was switched from EP to a colorectal cancer–based regimen consisting of bevacizumab plus FOLFOXIRI. After 7 cycles, marked regression of both the peritoneal nodule and lymphadenopathy was observed (Fig. 3B), along with normalization of CEA levels. There was no evidence of other distant metastasis. Curative resection of the recurrent lesions was performed (Fig. 4A), and histopathological analysis confirmed a pathological complete response with no residual tumor cells (grade 3 therapeutic effect) (Fig. 4B–4D). At 6 months postoperatively, the patient remains recurrence-free.

Fig. 4. Macroscopic and histopathological findings of the resected specimen after surgery for anastomotic recurrence. (A) Gross appearance of the resected specimen. No obvious mass-forming lesion is identified. (B) The submucosal layer shows extensive fibrosis. No residual tumor is observed, findings consistent with treatment-related changes. (C) Edema and fibrosis are present in the submucosal layer, with scattered lymphoid follicles. (D) Numerous foreign-body–type multinucleated giant cells and foamy macrophages are observed. These findings are compatible with reactive changes induced by treatment.

DISCUSSION

We encountered a case of locally recurrent NEC of the colon, detected during adjuvant chemotherapy, in which a colon cancer–based chemotherapy regimen achieved a pathological complete response. This case provides 2 key insights. First, colorectal NEC may respond not only to the generally recommended platinum-based chemotherapy regimens^7–9) but also to colon cancer–based chemotherapy in selected cases. Second, CEA elevation may reflect adenocarcinoma-like biological behavior in a subset of colorectal NEC, which could potentially aid in therapeutic decision-making.¹⁰⁾

According to the National Comprehensive Cancer Network guidelines, EP regimens, based on protocols for small cell lung carcinoma, are recommended for NEC.¹¹⁾ However, bevacizumab combined with FOLFOX6, based on treatment protocols for colorectal carcinoma, has also been applied in clinical practice, and several reports, in addition to the present case, have documented favorable outcomes with colon cancer–based regimens in colorectal NEC.^12,13)

The histogenesis of colorectal NEC has been proposed to involve 4 possible origins: (i) pre-existing adenocarcinoma, (ii) pre-existing carcinoid tumor, (iii) non-neoplastic multipotent stem cells, and (iv) non-neoplastic immature neuroendocrine cells. Among these, adenocarcinoma-derived NEC is reported to be the most common.¹⁴⁾ This provides a rationale for the potential effectiveness of colon cancer–based chemotherapy in NEC of adenocarcinoma origin.

Furthermore, colorectal NEC has been reported to exhibit elevated expression of vascular endothelial growth factor (VEGF) compared with conventional advanced colorectal carcinoma.¹⁵⁾ Preclinical studies have demonstrated that VEGF inhibition can suppress tumor growth and angiogenesis in NEC models, suggesting a possible therapeutic role for anti-VEGF agents such as bevacizumab. However, clinical evidence supporting this strategy remains limited, and its efficacy should be interpreted with caution.

In the present case, although the adenocarcinoma component was <30% and thus insufficient for a diagnosis of MANEC, the elevated CEA level during recurrence strongly suggested an adenocarcinoma origin. This may explain the profound therapeutic effect of colon cancer–based chemotherapy despite the minimal histological adenocarcinoma component.

CONCLUSIONS

Although platinum-based regimens following protocols for small cell lung carcinoma are currently recommended for colorectal NEC, our case demonstrated marked efficacy of colon cancer–based chemotherapy. These findings suggest that consideration of the biological characteristics and possible cellular origin of colorectal NEC may be important for treatment selection. Serum CEA levels may provide supportive information reflecting adenocarcinoma-like features in a subset of cases; however, their role as a biomarker remains exploratory. Further accumulation of clinical data is required to establish optimal treatment strategies for colorectal NEC.

DECLARATIONS

Funding

This report was prepared without financial support.

Authors’ contributions

KKa, TT, NN, SO, and KKo managed the patient and conceived the idea for the report.

KKa wrote the initial version of the manuscript.

TT revised the manuscript for important intellectual content.

HI, NY, KS, HT, and TH coordinated and helped draft the manuscript.

All authors read and approved the final version of the manuscript.

Availability of data and materials

All data on which the conclusions of this case report are based are included in the present publication.

Ethics approval and consent to participate

Ethical approval was waived by the institutional review board because this report describes a single clinical case without identifiable personal information. Written informed consent for participation and publication of this case was obtained from the patient.

Consent for publication

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

Competing interests

The authors declare they have no competing interests.