R0 Resection for Stage IVc Appendiceal Goblet Cell Adenocarcinoma Diagnosed after Left Adnexectomy: A Case Report

Abstract

The role of surgical resection in stage IV appendiceal goblet cell adenocarcinoma remains unclear. We report a case of a 44-year-old woman who underwent left adnexectomy for an ovarian tumor at another hospital. Pathological examination revealed not only an ovarian mature cystic teratoma but also goblet cell adenocarcinoma in the ovarian stroma, later diagnosed as appendiceal goblet cell adenocarcinoma with ovarian metastasis. Further evaluation suggested tumor invasion or metastasis to the rectosigmoid colon. Given the feasibility of curative resection, laparoscopic surgery was performed. Intraoperative findings confirmed rectal metastasis rather than direct invasion from appendiceal goblet cell adenocarcinoma. Peritoneal seeding to the greater omentum was confirmed intraoperatively, leading to total proctocolectomy with Hartmann's procedure, omentectomy, and right adnexectomy. Macroscopically, R0 resection was achieved. Pathological examination confirmed Grade 1 appendiceal goblet cell adenocarcinoma with metastases to the right ovary, rectosigmoid colon, and peritoneum. The patient received adjuvant chemotherapy and remains recurrence-free at 33 months postoperatively. This case highlights the importance of precise pathological assessment in ovarian tumors and suggests that aggressive surgical management may contribute to long-term survival, even in stage IV appendiceal goblet cell adenocarcinoma.

Introduction

Appendiceal goblet cell adenocarcinoma (GCA) is a rare and highly aggressive malignancy. In the 2019 WHO classification, entities previously termed “goblet cell carcinoid” or “goblet cell carcinoma” were redefined as adenocarcinomas, reflecting their biologic behavior more akin to adenocarcinomas than to neuroendocrine tumors[1]. GCA is frequently characterized by extensive peritoneal dissemination and lymph node metastasis, both of which contribute to its poor prognosis[2-4]. While GCA typically originates in the appendix, it has been reported to metastasize to distant organs, including the ovaries, posing a diagnostic challenge[5]. In advanced cases, particularly in stage IV appendiceal GCA, the role of surgical resection remains unclear due to the widespread nature of the disease.

We present a case of stage IVc appendiceal GCA, which was initially diagnosed after resection of a left ovarian tumor. Preoperative and intraoperative findings revealed metastases to the ovaries, rectosigmoid colon, and peritoneum, including the greater omentum and Douglas pouch. Despite the advanced stage, aggressive laparoscopic surgery with R0 resection was successfully performed, achieving macroscopically complete tumor removal. Remarkably, the patient has remained recurrence-free for 33 months postoperatively.

This case underscores the critical importance of accurate pathological diagnosis in ovarian tumors, highlights the potential for aggressive surgical interventions in managing stage IVc appendiceal GCA, and emphasizes the need for early identification, meticulous preoperative planning, and effective intraoperative strategies to achieve optimal surgical outcomes.

Case Report

The patient was a 44-year-old woman who initially underwent laparoscopic adnexectomy for a left ovarian tumor, performed by gynecologists at a previous hospital. At the time, no other lesions, including peritoneal dissemination or an appendiceal tumor, were noted. Histological examination of the left ovarian tumor revealed a cyst composed of stratified squamous epithelium with mixed skin appendage structures and cartilage, confirming a diagnosis of mature cystic teratoma. Additionally, the ovarian stroma exhibited the formation of the corpus albicans, and areas of fibrosis contained solitary or clustered glandular carcinoma. The carcinoma cells exhibited eosinophilic granules in some areas. Immunohistochemical staining revealed synaptophysin and chromogranin A positivity in cells with eosinophilic granules, although most carcinoma cells were negative. Endocrine differentiation was observed in some tumor cells. Staining was positive for CDX2 and CK20 but negative for CK7, suggesting a gastrointestinal origin. Based on these findings, the tumor was diagnosed as Grade 1 GCA with ovarian metastasis from a gastrointestinal source.

Subsequent diagnostic workup was performed at our hospital. Abdominal CT revealed a tumor in the ileocecal region, as well as thickening of the intestinal wall in the rectosigmoid colon (Figure 1a). Colonoscopy identified a tumor in the appendiceal foramen of the cecum with involvement of Bauhin's valve (Figure 1b) and stiffening of the intestinal wall, along with mucosal reddening in the rectosigmoid colon (Figure 1c). A gastrografin enema revealed a filling defect in the rectosigmoid colon (Figure 1d). Biopsies from both the appendiceal foramen and rectosigmoid colon confirmed GCA, indicating invasion or metastasis to the rectosigmoid colon from primary appendiceal GCA.

Figure 1.

Preoperative examination findings.

(a) Enhanced abdominal CT revealed a swollen appendix (arrow), as well as focal wall thickening and strong enhancement of the rectosigmoid colon wall (arrowhead).

(b) Colonoscopy identified a tumor in the appendiceal orifice of the cecum, with involvement of Bauhin’s valve.

(c) Colonoscopy showed that the rectosigmoid colon wall was hardened, making scope insertion difficult in this region.

(d) A gastrografin enema revealed a filling defect in the rectosigmoid colon.

Upon determining the feasibility of curative resection, laparoscopic surgery was performed 30 days after the first surgery at the previous hospital. Intraoperative findings revealed seeding-like lesions in the omentum (Figure 2a), small intestinal mesentery in the ileocecal area (Figure 2b), and Douglas pouch. With regard to the mesenteric lesions, multiple peritoneal metastases were observed on the lower ileum (corresponding to Region 12 of the Peritoneal Cancer Index). In contrast, no peritoneal seeding was identified in the upper jejunum (Region 9), the upper lower abdomen (Region 10), or the upper ileum (Region 11). Intraoperative frozen section of the greater omentum confirmed peritoneal metastasis. The appendiceal tumor was a white mass involving the cecum and terminal ileum (Figure 2c). The rectosigmoid region was not in contact with the appendix (Figure 2d). Therefore, the lesion in the rectosigmoid colon was diagnosed as rectal metastasis rather than direct invasion. Pale yellow ascitic fluid approximately 50 mL in volume was observed (Figure 2d), and cytological analysis of the ascites revealed class IV findings. Peritoneal dissemination was also observed in the Douglas pouch (Figure 2e). Subsequently, total proctocolectomy with Hartmann's procedure, omentectomy, and right adnexectomy were performed, achieving macroscopically complete resection was achieved (Figure 3, Figure 4a-4c). In order to achieve en bloc resection of the tumor involving the Douglas pouch, the rectum was transected 2 cm distal to the peritoneal reflection, corresponding to a level 6 cm from the anal verge (Figure 4d).

Figure 2.

Surgical findings.

(a) Peritoneal disseminated lesions were found in the greater omentum (dotted circle).

(b) Peritoneal disseminated lesions were also found in the small intestinal mesentery near the ileocecal area.

(c) The appendiceal tumor appeared as a white mass involving the cecum and terminal ileum (arrow).

(d) Pelvic view. The rectosigmoid region was not in contact with the appendix, suggesting that the lesion in the rectosigmoid colon was a distant metastasis rather than direct invasion. Approximately 50 mL of pale yellow ascitic fluid was observed, and cytological analysis of the ascites revealed class IV findings.

(e) Intraoperative photograph demonstrating the peritoneal seeding in the Douglas pouch.

Figure 3.

Excised specimen.

The surgical procedure involved total proctocolectomy with Hartmann’s procedure, omentectomy, and resection of multiple peritoneal lesions, including those in the small intestinal mesentery and Douglas pouch, as well as right oophorectomy. This figure shows the entire resected colon and rectum, as well as the right ovary.

Figure 4.

Excised specimen.

(a) A white appendiceal tumor (arrows) observed from the serosal surface of the ileocecal region.

(b) The appendiceal tumor extending over Bauhin’s valve, observed from the mucosal surface of the ileocecal region.

(c) A metastatic lesion in the rectosigmoid colon (dashed circle), characterized by redness and thickened walls.

(d) The resected rectal specimen shows the transection line made 2 cm distal to the peritoneal reflection (indicated by two arrows), performed to achieve en bloc resection of the Douglas pouch lesion. The solid circle indicates peritoneal metastasis in the Douglas pouch.

Pathological examination revealed an appendiceal GCA, measuring 5 cm in size, with metastases to the right ovary (in addition to the previously involved left ovary) and rectosigmoid colon, and peritoneal seeding to the greater omentum and Douglas pouch (Figure 5a-5d). The tumor exhibited >75% low-grade features and was thus classified as Grade 1 GCA according to the WHO classification[1] (Figure 5b). All surgical margins were negative. The tumor perforated the visceral peritoneum but did not directly invade other organs or structures (T4a). Metastases were observed in 14 of 86 dissected lymph nodes, including two lymph nodes at station 201 (pericolic lymph nodes around the cecum) and 12 at station 205 (pericolic lymph nodes around the rectum) (N2). This case was classified as stage IVc (distant metastases to the peritoneum, rectosigmoid colon, and bilateral ovaries) according to the UICC classification. The tumor was found to be wild-type for RAS, negative for the BRAF V600E mutation, and exhibited microsatellite instability-low (MSI-low) status.

Figure 5.

Pathological findings.

(a) Hematoxylin and eosin (HE) staining (×4): Proliferation of fibrous connective tissue and mucus production in the appendiceal wall, with infiltration into the large intestine.

(b) HE staining (×40): Clusters of poorly differentiated adenocarcinoma and signet ring cell carcinoma observed in the appendiceal wall. Tumors exhibiting >75% low-grade features, thus classified as Grade 1.

(c) Chromogranin A staining (×20): Positive staining in tumor cells, indicating neuroendocrine differentiation. Strong granular cytoplasmic staining is observed in the majority of tumor cells.

(d) Ki-67 staining (×20): The Ki-67 proliferation index shows nuclear staining in approximately 20% of tumor cells, indicating the tumor’s proliferative activity.

The patient began systemic chemotherapy with a 5-fluorouracil and oxaliplatin regimen (CAPOX therapy, comprising oral capecitabine and intravenous oxaliplatin) on postoperative day 11 and was discharged on day 15. This chemotherapy regimen was continued for six months, followed by oral 5-fluorouracil therapy. The patient remains recurrence-free 33 months postoperatively.

Discussion

GCA displays mixed glandular and neuroendocrine differentiation and is often incidentally diagnosed during appendectomy. Histologically, it is characterized by clusters of goblet-like cells, sometimes with signet-ring features, infiltrating the appendiceal wall. Despite its neuroendocrine elements, GCA typically exhibits more aggressive behavior and frequently presents at an advanced stage with peritoneal, ovarian, and lymph node metastases. The exceptional long-term survival of our patient, despite the diagnosis of stage IVc GCA with peritoneal dissemination and metastases to bilateral ovaries, the rectosigmoid colon, and multiple lymph nodes, is noteworthy. While peritoneal and lymph node metastases are well-established poor prognostic factors in appendiceal GCA[3], survival data for stage IVc cases remain limited. A limited number of reports have described surgical resection for stage IVc GCA with peritoneal dissemination. Ihemelandu et al. reported 53 patients with appendiceal GCA (formerly termed adenocarcinoid) treated with cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy, among whom 21 patients (44.7%) had distant metastases[4]. Complete cytoreduction (CC0/1) was achieved in 41.6% of stage IVc cases, with a median survival of 26.8 months. Hristov et al. described 21 patients with ovarian metastases from stage IVc GCA, though the rate of R0 resection was not specified[5]. One patient survived for 43 months before succumbing to disease progression. Additionally, Randle et al. reviewed 31 cases of stage IVc GCA undergoing CRS and HIPEC, achieving macroscopic complete cytoreduction (R0/R1) in 36% of cases[6]. To our knowledge, no previous report has clearly documented an R0 resection in stage IVc GCA with long-term disease-free survival, highlighting the novelty of our case. This case provides rare evidence that prolonged survival can be achieved in selected patients through a multimodal therapeutic strategy.

Several key factors contributed to this favorable outcome. First, the precise pathological diagnosis of the ovarian tumor was crucial. The patient initially underwent adnexectomy under the assumption that the ovarian tumor was a mature cystic teratoma. However, detailed histopathological examination unexpectedly revealed GCA components within the teratoma, ultimately leading to the correct diagnosis of metastatic appendiceal GCA. This phenomenon aligns with previous reports of coexistence of ovarian mature teratoma and appendiceal adenocarcinoma[7], underscoring the necessity of meticulous pathological assessment, particularly in cases of complex ovarian tumors with unusual histological findings.

Second, the decision to pursue aggressive radical surgery was pivotal. Despite the presence of peritoneal dissemination, bilateral ovarian metastases, and rectosigmoid colon involvement, we opted for a curative-intent laparoscopic approach aimed at achieving complete macroscopic R0 resection. The surgical procedure involved total proctocolectomy with Hartmann's procedure, omentectomy, and resection of multiple peritoneal lesions, including those in the small intestinal mesentery and Douglas pouch. This comprehensive surgical approach resulted in macroscopically complete tumor removal, with pathologically negative surgical margins. Notably, this strategy is in line with recent Japanese guidelines for the treatment of colorectal cancer[8] advocating for R0 resection in cases of peritoneal metastasis rather than conventional cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, which lacks robust support in the current literature[9]. Unlike the more common palliative or non-resective approaches typically considered for stage IV appendiceal GCA, our case highlights the potential benefit of an aggressive surgical strategy in selected patients.

Third, removal of the macroscopically normal right ovary was a decisive factor. We performed right adnexectomy, despite the absence of gross abnormalities, in accordance with the American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Colon Cancer[10], which recommend bilateral adnexectomy in cases of ovarian metastasis. Pathological examination confirmed metastatic GCA in the right ovary, further justifying the surgical decision. This case reinforces the importance of considering bilateral adnexectomy even when only unilateral ovarian metastasis is initially suspected.

Fourth, postoperative adjuvant chemotherapy likely played a significant role in achieving long-term survival. The optimal chemotherapy regimen for GCA remains undetermined, but protocols similar to those used for colorectal adenocarcinoma have been reported to improve outcomes[11,12]. The 2012 ENETS Consensus Guidelines recommend 5-fluorouracil (5-FU)-based combination chemotherapy regimens for advanced GCA, aligning with colorectal cancer treatment approaches[13]. In line with previous studies suggesting that adjuvant chemotherapy improves survival in stage III GCA, our patient received a 5-fluorouracil and oxaliplatin regimen for six months postoperatively, followed by long-term oral 5-fluorouracil therapy. After completing 6 months of CAPOX, we discussed the patient's case in a multidisciplinary tumor board and decided to continue long-term oral 5-fluorouracil therapy. This approach was based on the rationale that continued suppression may help prevent recurrence, despite limited evidence. This multimodal approach may have contributed to sustained tumor suppression and prolonged disease-free survival.

Finally, histopathological characteristics of the tumor itself may have influenced prognosis. Recent studies have classified appendiceal GCA into low-grade and high-grade subtypes and proposed a grading system (Grades 1-3) based on histological composition[1,14]. Tumors with >75% low-grade features (Grade 1) have been associated with significantly better survival outcomes, with a reported median survival of 204 months and a 5-year survival rate of 82%. In contrast, Grade 3 tumors (<50% low-grade features) exhibit a median survival of only 29 months, with a 5-year survival rate of 22%[14]. In our case, the tumor was classified as Grade 1, which may have contributed to the patient's prolonged survival.

From a surgical perspective, two major considerations informed our operative approach: the rationale for uterine preservation and the choice to perform a total colorectal resection. Intraoperatively, peritoneal dissemination was observed in the Douglas pouch (Figure 2e), yet there was no macroscopic evidence of tumor invasion or surface involvement elsewhere on the uterus. According to the American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Treatment of Colon Cancer, bilateral adnexectomy is recommended in such cases, but no specific guidance is offered regarding hysterectomy[10]. In the absence of gross peritoneal involvement on the uterine surface, we concluded that uterine preservation would not compromise oncologic radicality. To ensure en bloc R0 resection, we performed a partial resection of the posterior uterine wall together with the rectum and involved peritoneum of the Douglas pouch, while sparing the uninvolved uterine tissue (Figure 4d). Regarding the extent of colorectal resection, we considered a more limited procedure involving ileocolic and rectal resections with omentectomy. However, this would have required ligation of both the ileocolic and inferior mesenteric arteries, leaving only the middle colic artery to perfuse a short segment of residual colon. Such a remnant was deemed to offer limited functional benefit and posed a potential risk for ischemic complications. Additionally, a large peritoneal deposit was noted in the greater omentum adjacent to the transverse colon, raising concern for microscopic tumor spread in this region. These considerations collectively supported our decision to pursue total colorectal resection as the most oncologically sound and technically appropriate approach in this case.

In conclusion, we present a rare case of stage IVc appendiceal GCA diagnosed after resection of an ovarian tumor, successfully treated with radical surgery and adjuvant chemotherapy. This case underscores the importance of early and accurate pathological diagnosis, aggressive surgical resection aimed at R0 status, and appropriate adjuvant therapy in achieving favorable outcomes. The patient's recurrence-free survival at 33 months postoperatively provides an encouraging perspective on the potential for long-term survival in selected cases of advanced appendiceal GCA.

Conflicts of Interest

There are no conflicts of interest.

Author Contributions

NS designed the report, analyzed the data, and prepared the first draft of the manuscript; YO collected pathological data; SA, SM, and JM collected clinical data, and coordinated and assisted in drafting of the manuscript; and DS designed the report, finalized and was responsible for writing the manuscript. All authors reviewed and approved the final manuscript.

Approval by Institutional Review Board (IRB)

Ethics approval was obtained from the Institutional Review Board (IRB) of the Institute of Medical Science, The University of Tokyo (IRB code: 2022-9-0524).

Consent for Publication

Consent to publish was obtained from the patient.

Availability of Data and Materials

The data sets supporting the conclusions of this article are included within the article.