Abstract
Goblet cell carcinoid (GCC) of the perforated appendix is rare, and its pathological features and prognosis remain poorly described. A 71-year-old woman was admitted to our hospital for right lower abdominal pain, vomiting, and high-grade fever. She was diagnosed with acute appendicitis and underwent emergency laparoscopic appendectomy. Intraoperative examination revealed an enlarged and perforated appendix. Histopathological examination revealed GCC of the appendix with subserosal invasion. She underwent laparoscopic ileocecal resection with lymph node dissection (D3) following appendectomy. Histopathological findings showed no residual tumor or lymph node metastases. To the best of our knowledge, this report is a valuable addition to the GCC literature, describing a case of GCC of the appendix presenting as perforated appendix.
Keywords: Goblet cell carcinoid, Appendix, Acute appendicitis, Perforation
Introduction
Goblet cell carcinoid (GCC) is a rare tumor of the appendix with histological features of both adenocarcinoma (AC) and neuroendocrine tumor [1]. In the 2010 WHO classification, mixed adenoneuroendocrine carcinoma is defined as a tumor with both AC and neuroendocrine carcinoma components, each comprising at least 30% of the lesion. Considered as a subgroup of mixed adenoneuroendocrine carcinoma [2], GCC is rarely diagnosed preoperatively, but usually intraoperatively or on pathological examination after appendectomy for acute appendicitis [3].
GCC is estimated to account for 10% of all appendiceal neuroendocrine tumors [4]; it is found in 0.3–0.9% of post-appendectomy specimens and accounts for 35–58% of all appendiceal tumors and approximately 14% of all appendiceal malignancies [5]. Five-year survival rates for GCC are reported to range between 58 and 84% [6], with peritoneal carcinomatosis being the most common cause of death [5].
Again, GCC of the perforated appendix is rare, and its pathological features and prognosis remain poorly elucidated. We herein report a case of GCC of a perforated appendix.
Case Presentation
A 71-year-old woman was admitted to our hospital for right lower abdominal pain, vomiting, and high-grade fever. Physical examination findings included: height, 145 cm; weight, 48 kg; fully conscious; blood pressure, 165/60 mm Hg; heart rate, 92/min; oxygen saturation of the peripheral artery, 93%; and body temperature, 39.2°C. Laboratory findings included: white blood cell count, 6.3 × 109/L; and C-reactive protein, 2.5 mg/dL. Computed tomography revealed an enlarged appendix, appendiceal wall enhancement, and peri-appendiceal fat stranding (Fig. 1).
Fig. 1.
a, b Computed tomography revealed an enlarged appendix, appendiceal wall enhancement, and peri-appendiceal fat stranding.
The patient was diagnosed with acute appendicitis and underwent emergency laparoscopic appendectomy. Intraoperative examination showed an enlarged and perforated appendix, with turbid ascites found in the Douglas fossa and the right colon fossa. Macroscopically, the resected appendix was a 45 × 25 mm lesion with a negative margin (Fig. 2). Histopathologically, the lumen near the entrance of the appendix was filled with degenerative necrotic material, with the peripheral lumen showing purulent inflammation, the inflammatory cell infiltration exceeding the serosa, and complicated acute appendicitis. In addition, extensive tumor cell infiltration was observed from the mucosal to the subserosal layer, with tumor invasion to the perineural space and lymphatic vessels. The tumor was composed of small, rounded nests of signet ring-like cells resembling normal intestinal goblet cells, except for nuclear compression (Fig. 3a). Immunohistochemically, tumor cells were positive for chromogranin A (Fig. 3b), synaptophysin, CD56 (Fig. 3c), MUC1-014E, CAM5.2, serotonin (Fig. 3d), CEA (Fig. 3e), CK20 (Fig. 3f), and CDX2; however, they were negative for somatostatin (Fig. 3g) and CK7 (Fig. 3h). Ki-67 was positive in 10% of tumor cells (Fig. 3i). The tumor of the appendix was therefore diagnosed as GCC of the appendix with subserosal invasion.
Fig. 2.
a, b Macroscopic view of the resected specimen, which was a 45 × 25 mm lesion with a negative margin.
Fig. 3.
Histopathological examination of the appendix lesion. a H&E staining showed tumor cells containing a large amount of mucin-like signet ring cell carcinoma. ×100. b–h Immunohistochemical staining indicated that tumor cells were positive for chromogranin A (b), CD56 (c), serotonin (d), CEA (e), and CK20 (f); however, they were negative for somatostatin (g) and CK7 (h). ×100. i Ki-67 was positive in 10% of tumor cells. ×200.
The patient underwent laparoscopic ileocecal resection with lymph node dissection (D3) 1 month after appendectomy. Histopathological findings showed no evidence of residual tumor or lymph node metastases. Tegafur/uracil was administered as adjuvant chemotherapy for 1 year. She was diagnosed with early gastric cancer 5 years after appendectomy and underwent laparoscopic cardiac gastrectomy for pathologically confirmed AC, type 0-IIb, measuring 20 × 15 mm, por+tub2, pT1b (SM). Regular follow-up computed tomography examinations revealed no recurrence or metastasis of GCC for 6 years after appendectomy.
Discussion and Conclusion
Our case has two important clinical implications.
The first implication of our case is that GCC may present as acute perforated appendicitis. GCC of the appendix with perforation is rare, and its pathological features and prognosis remain poorly described in the literature. GCC is a rare tumor involving the appendix almost exclusively [5]. Tang et al. [6] classified GCC into three groups: (A) typical GCC, (B) AC ex GCC, signet ring cell type, and (<c) AC ex GCC, poorly differentiated carcinoma type. Of these, the present lesion fulfilled the definition of group B (i.e., AC ex GCC, signet ring cell type). In addition, GCC is reported to share the immunohistochemical features with classical well-differentiated neuroendocrine tumor (WDNET) and conventional AC of the appendix [5]. To date, the frequency of the epithelial marker CEA/CK20/CK7 expression in GCC, WDNET, and conventional AC is reported to be 100/100/33–75%, 0–26/0–32/0–11%, and 100/100/14–53%, respectively. In addition, the frequency of the endocrine marker chromogranin A/synaptophysin expression in GCC, WDNET, and conventional AC is reported to be 85–100/88–100%, 100/100%, and 0/0–29%, respectively. The tumor in the present case was shown to be positive for CEA, CK20, chromogranin A, and synaptophysin and was therefore diagnosed as GCC.
The second implication of our case is that the patient had no recurrence or metastasis for 6 years postoperatively despite having a high-risk tumor. To date, only 19 cases of perforated GCC of the appendix have been reported (Table 1) [3, 7, 8, 9, 10, 11, 12]. Of the 10 patients whose prognosis was reported, 3 had recurrence, 3 died of recurrence, and 4 had no recurrence, with the follow-up of the 4 patients with no recurrence being 5 months [12], 9 months [7], 1.3 years [8], and 4.5 years [7]. Pham et al. [13] reported that stage is the most important prognostic factor, with 5-year survival rates in stage I–IV being 100, 76, 22, and 14%, respectively. In addition, they proposed as criteria for additional resection (1) T3/4 disease, (2) direct cecum extension, and (3) clinically positive mesenteric nodes [13]. Thus, diagnosed as having stage II disease, our patient underwent an additional resection according to their criteria. Furthermore, Tang et al. [6] recommend chemotherapy in patients with high-stage GCC and localized perforation. While the role of chemotherapy remains controversial in GCC, consensus guidelines recommend 5-FU-based chemotherapy in GCC in reference to that in colorectal cancer [4]. Thus, tegafur/uracil was administered in the present case.
Table 1.
Cases reported to date of perforated goblet cell carcinoid of the appendix
| No. | Ref. No. | Year | Age, years | Sex | Surgical procedure | Adjuvant CTx | Prognosis |
|---|---|---|---|---|---|---|---|
| 1 | 57 | M | appendectomy followed by right hemicolectomy | (−) | no recurrence for 4.5 years | ||
| [7] | 1974 | ||||||
| 2 | 45 | M | appendectomy followed by right hemicolectomy | (−) | no recurrence for 9 months | ||
| 3 | 82 | F | appendectomy followed by right hemicolectomy | NA | no recurrence for 1.3 years | ||
| 4 | [8] | 2001 | 61 | M | appendectomy followed by right hemicolectomy | NA | DOD after 19.2 years |
| 5 | 68 | F | appendectomy followed by right hemicolectomy | NA | DOD after 5.4 years | ||
| 6 | 41 | M | appendectomy followed by right hemicolectomy | (−) | recurrence after 32 months | ||
| 7 | 56 | M | appendectomy | (−) | NA | ||
| 8 | 74 | M | appendectomy | (−) | NA | ||
| 9 | 49 | F | appendectomy | (−) | NA | ||
| [9] | 2003 | ||||||
| 10 | 40 | M | appendectomy and regional LND | (−) | NA | ||
| 11 | 38 | M | appendectomy | (−) | recurrence after 22 months | ||
| 12 | 23 | F | appendectomy | (−) | recurrence after 36 months | ||
| 13 | [10] | 2005 | 39 | F | appendectomy followed by right hemicolectomy | NA | NA |
| 14 | NA | NA | appendectomy followed by right hemicolectomy | (−) | NA | ||
| 15 | [3] | 2007 | NA | NA | appendectomy followed by right hemicolectomy | (+) | DOD after 14 months |
| 16 | NA | NA | appendectomy followed by right hemicolectomy | (−) | NA | ||
| 17 | NA | NA | NA | NA | NA | ||
| [11] | 2013 | ||||||
| 18 | NA | NA | NA | NA | NA | ||
| 19 | [12] | 2018 | 68 | F | ileocecectomy | NA | no recurrence for 5 months |
| 20 | our case | 2020 | 71 | F | appendectomy followed by ileocecectomy | (+) | no recurrence for 6 years |
CTx, chemotherapy; DOD, death of disease; LND, lymph node dissection; NA, not available.
In conclusion, GCC may present as acute perforated appendicitis and call for careful follow-up, given its risk of recurrence.
Statement of Ethics
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Conflict of Interest Statement
The authors have no conflicts of interest to disclose in association with this study.
Funding Sources
No funding was obtained for this study.
Author Contributions
K. Kubo, N. Kimura, M. Suzuoki, S. Matsuda, M. Tsuda, M. Ohara, and M. Kato carried out and confirmed the diagnosis, provided the details of the case, and contributed to the design of the report. K. Kubo, N. Kimura, and M. Kato drafted the manuscript. All authors read and approved the final version of the manuscript.
References
- 1.Roy P, Chetty R. Goblet cell carcinoid tumors of the appendix: an overview. World J Gastrointest Oncol. 2010 Jun;2((6)):251–8. doi: 10.4251/wjgo.v2.i6.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC; 2010. pp. pp. 64–8. [Google Scholar]
- 3.Toumpanakis C, Standish RA, Baishnab E, Winslet MC, Caplin ME. Goblet cell carcinoid tumors (adenocarcinoid) of the appendix. Dis Colon Rectum. 2007 Mar;50((3)):315–22. doi: 10.1007/s10350-006-0762-4. [DOI] [PubMed] [Google Scholar]
- 4.Plöckinger U, Couvelard A, Falconi M, Sundin A, Salazar R, Christ E, et al. Frascati Consensus Conference participants Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology. 2008;87((1)):20–30. doi: 10.1159/000109876. [DOI] [PubMed] [Google Scholar]
- 5.Zhang K, Meyerson C, Kassardjian A, Westbrook LM, Zheng W, Wang HL. Goblet cell carcinoid/carcinoma: an update. Adv Anat Pathol. 2019 Mar;26((2)):75–83. doi: 10.1097/PAP.0000000000000222. [DOI] [PubMed] [Google Scholar]
- 6.Tang LH, Shia J, Soslow RA, Dhall D, Wong WD, O'Reilly E, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008 Oct;32((10)):1429–43. doi: 10.1097/PAS.0b013e31817f1816. [DOI] [PubMed] [Google Scholar]
- 7.Klein HZ. Mucinous carcinoid tumor of the vermiform appendix. Cancer. 1974 Mar;33((3)):770–7. doi: 10.1002/1097-0142(197403)33:3<770::aid-cncr2820330324>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- 8.Kanthan R, Saxena A, Kanthan SC. Goblet cell carcinoids of the appendix: immunophenotype and ultrastructural study. Arch Pathol Lab Med. 2001 Mar;125((3)):386–90. doi: 10.5858/2001-125-0386-GCCOTA. [DOI] [PubMed] [Google Scholar]
- 9.Stancu M, Wu TT, Wallace C, Houlihan PS, Hamilton SR, Rashid A. Genetic alterations in goblet cell carcinoids of the vermiform appendix and comparison with gastrointestinal carcinoid tumors. Mod Pathol. 2003 Dec;16((12)):1189–98. doi: 10.1097/01.MP.0000097362.10330.B1. [DOI] [PubMed] [Google Scholar]
- 10.Gordon R, Burns K, Friedlich M, Gordon G. Goblet cell carcinoid of the appendix. Can J Surg. 2005 Jun;48((3)):251–2. [PMC free article] [PubMed] [Google Scholar]
- 11.Lee KS, Tang LH, Shia J, Paty PB, Weiser MR, Guillem JG, et al. Goblet cell carcinoid neoplasm of the appendix: clinical and CT features. Eur J Radiol. 2013 Jan;82((1)):85–9. doi: 10.1016/j.ejrad.2012.05.038. [DOI] [PubMed] [Google Scholar]
- 12.Abramyan S, Almadani MW, Sirsi S, Xiao PQ, Asarian AP. Perforation of appendiceal adenocarcinoma ex goblet cell carcinoid: a rare case. J Surg Case Rep. 2018 Sep;2018((9)):rjy242. doi: 10.1093/jscr/rjy242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Pham TH, Wolff B, Abraham SC, Drelichman E. Surgical and chemotherapy treatment outcomes of goblet cell carcinoid: a tertiary cancer center experience. Ann Surg Oncol. 2006 Mar;13((3)):370–6. doi: 10.1245/ASO.2006.02.016. [DOI] [PubMed] [Google Scholar]