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Clinicopathological features of non-carcinoid malignant epithelial appendix tumors and risk factors for recurrence, single-center experience

1 Department of Medical Oncology, Dr. A. Y. Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara, Turkey
2 Department of General Surgery, Dr. A. Y. Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara, Turkey
3 Department of Medical Oncology, Dr. Zekai Tahir Burak Women Health Education and Research Hospital, Health Sciences University, Ankara, Turkey

Date of Submission27-Apr-2020
Date of Decision05-May-2020
Date of Acceptance04-Feb-2021
Date of Web Publication12-Oct-2022

Correspondence Address:
Ozturk Ates,
Department of Medical Oncology, Dr. A. Y. Ankara Oncology Education and Research Hospital, Health Sciences University, Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_395_20


Background: Non-carcinoid appendix epithelial tumors are rare. These tumors include low-grade and high-grade mucinous neoplasm also adenocarcinomas. We aimed to investigate the clinicopathological features, treatment, and risk factors of recurrence.
Methods: Patients diagnosed between 2008 and 2019 were retrospectively analyzed. Categorical variables were expressed as percentages and compared using the Chi-square test or Fisher's exact tests. Overall survival and Disease-free survival of the groups were calculated by the Kaplan–Meier method, and the log-rank test was used to compare the survival rates.
Results: A total of 35 patients were included in the study. Of the patients, 19 (54%) were women and the median diagnosis age of patients was 50.4 years (19–76). As for pathological types, a total of 14 (40%) patients were mucinous adenocarcinoma and 14 (40%) patients were Low-Grade Mucinous Neoplasm (LGMN). Lymph node excision and lymph node involvement were 23 (65%) and 9 (25%) patients respectively. The majority of patients were stage 4 (27, 79%) and 25 (71%) of these patients had peritoneal metastasis. A total of 48.6% patients had been treated with cytoreductive surgery and hyper-thermic intraperitoneal chemotherapy. Median Peritoneal cancer index value was 12 (2-36). The median follow-up time was 20 (1-142) months. Recurrence developed in 12 (34%) of patients. When risk factors for recurrence are considered, there was a statistically significant difference in appendix tumors with high-grade, adenocarcinoma pathology, ones with peritoneal cancer index ≥12 and not having pseudomyxoma peritonei. Median disease-free survival was 18 (13-22, 95% CI) months. Median overall survival could not be reached while the 3-year survival rate was 79%.
Conclusion: The risk of recurrence is higher in high-grade appendix tumors, having peritoneal cancer index ≥ 12, not having pseudomyxoma peritonei and adenocarcinoma pathology. High-grade appendix adenocarcinoma patients should be followed closely for recurrence.

Keywords: Adenocarcinoma, appendiceal neoplasm, mucinous neoplasm, pseudomyxoma peritonei

How to cite this URL:
Ates O, Aksel B, Karadag I, Karakaya S, Sunar V, Oksuzoglu O B. Clinicopathological features of non-carcinoid malignant epithelial appendix tumors and risk factors for recurrence, single-center experience. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 2]. Available from:

  Background Top

Appendix tumors are very rare and constitute 1% of gastrointestinal cancers.[1],[2] Most appendix tumors are carcinoid (65%) and others include low-grade mucinous neoplasm (LGMN), high-grade mucinous neoplasm (HGMN) and adenocarcinomas (20%) (mucinous, non-mucinous = colonic type, adenocarcinoma with signet ring cells types).[3] Mucinous tumors make up one-third of all epithelial tumors of the appendix. Mucinous adenocarcinomas are the second most common subtype. Goblet cell carcinomas (adenocarcinoid) include adenocarcinoma and carcinoid components.[4] It is classified as appendix carcinoma.[5] Terminology and classification of mucinous tumors of the appendix have been much discussed since even well-differentiated tumors that do not have an invasion in the appendix wall can lead to pseudomyxoma peritonei (PMP).

Patients with appendix neoplasms are diagnosed with bloating abdominal mass and ascites. They are usually diagnosed by mucin and tumor-containing primary tumors that are perforated and spread to the peritoneal cavity. Abdominal distention due to mucinous acid is called PMP.[6] Acute appendicitis is common in patients with appendix adenocarcinoma. They are rarely diagnosed incidentally by appendix surgery. Appendiceal malignant neoplasm has indolent course and distal metastasis is rare. If appendiceal neoplasm ruptures, cytoreductive surgery (CRS) and hyper-thermic intraperitoneal chemotherapy (HIPEC) are recommended but if not ruptured; en-bloc excision and appendectomy are sufficient. Peritoneal cancer index (PCI), defined by Sugarbaker et al. is the parameter showing peritoneal spread of the tumor during surgery. It is divided into 13 regions each scored 0-3 points and is evaluated as a maximum score of 39 points. According to the residue left after cytoreduction (completeness of cytoreduction), it is evaluated as 0-3. Goblet cell carcinomas are staged and treated like appendix adenocarcinomas. The risk of non-carcinoid appendix tumors for recurrence is not fully known and it is a matter of curiosity how these patients should be followed.

In this study, we aimed to investigate the frequency, clinicopathological features, treatment and risk factors of recurrence of non-carcinoid epithelial tumors of the appendix.

  Methods Top

Patients diagnosed with non-carcinoid malignant epithelial appendix tumors between 2008 and 2019 were retrospectively analyzed. Ethics committee approval was obtained from the Dr. Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital (serial number; 2019-03/240). Demographic data, histopathological features, treatment (surgery and chemotherapy) and the existence of recurrence were recorded. American Joint Committee on Cancer (AJCC) TNM staging system classification for appendix cancer eighth edition, 2017 was used for staging.[7] All Mucinous epithelial tumors were classified into LGMN and HGMN groups, according to the World Health Organization classification of appendiceal tumors. The patients were operated only by a single surgeon who performed oncological gastrointestinal surgery and is experienced in the field of HIPEC. The Closed abdominal perfusion technique was applied to all patients. With this technique, after cytoreduction was completed, 4 catheters (26 F) and 2 temperature measurement probes were placed in the abdomen before closing the abdomen. After the abdomen was closed, patients were applied HIPEC at 42-42.5 °C for 60 minutes using a Thermo solutions HT 2000 hyperthermic perfusion device. During the procedure, cisplatin 100 mg/m[2] and mitomycin C 15 mg/m[2] were used as chemotherapeutic agents in all patients. Isotonic sodium chloride was used as the chemotherapeutic carrier solution in all patients. The procedure was monitored with temperature measurement probes placed in the abdomen, and the intraabdominal temperature was kept constant at 42-42.5 °C. After 60 minutes of HIPEC, the operation was completed by draining all the fluid in the abdomen. PCI was used perioperatively for CRS. CRS was performed for those with a PCI score of 13 or less for HGMN and adeno cancers. For LGMN, it was applied to all patients regardless of the PCI score. Data on normal distribution were expressed as mean ± standard deviation (SD) and compared by T-test. Disease-free survival (DFS) is defined as the time from randomization to recurrence of tumor or death. Categorical variables were expressed as percentages and compared using the Chi-square test or Fisher's exact tests where appropriate. Non-parametric variables were analyzed using the Mann-Whitney U test. Overall survival (OS) and DFS of the groups were calculated by the Kaplan–Meier method, and the log- rank test was used to compare the survival rates.

  Results Top

A total of 35 patients were included in the study. Of the patients, 19 (54.3%) patients were women. Clinicopathologic features of patients were seen in [Table 1]. The median age at diagnosis was 50.4 years (19-76). As for pathological types, a total of 14 (40%) patients were mucinous adenocarcinoma and 14 (40%) patients were LGMN. Most of the cases with appendix tumors were grade 1 (23, 65%) and T4 (25, 71%) tumors. Median tumor size was 6.5 (1-19) cm. Lymph node excision was performed in 23 (65.7%) patients and lymph node involvement was detected in 9 (25%) of patients. The number of excised median lymph nodes is 15 (3–36). Majority of patients with lymph node involvement had colonic adenocarcinoma 5 (50%) followed by mucinous adenocarcinoma 3 (35%) and LGMN 1 (7%), respectively. A total of 17 (48.6%) patients had been treated with CRS and HIPEC. Median PCI value was 12 (2-36). The majority of patients were stage 4 (27, 79%), and 25 (71%) of these patients had peritoneal metastasis followed by liver 2 (5.7%) and lung metastases 1 (2.9%). PMP and acute appendicitis were detected in 16 (45.7%) and 8 (22.9%) patients respectively. Right hemicolectomy was performed in 25 (71%) of patients. When LGMN and appendix adenocarcinoma (mucinous-colonic adenocarcinoma type) were compared, grade 1 versus grade 2-3 tumors were statistically significantly higher than in the LGMN group [Table 2]. Also, PMP was significantly higher in the LGMN group. Lymph node excision, right hemicolectomy, recurrence rates and administration of chemotherapy were also significantly higher in the appendix adenocarcinoma group. Tumor markers (CEA, CA-125 and Ca 19-9, one or all) were examined in 18 (51.4%) patients and serum levels were high in 10 (28%). Fifty percent of the LGMN, 40% of the appendix adenocarcinoma, and 10% of colonic adenocarcinoma groups had a high level of plasma tumor marker respectively. A total of 19 (55.5%) patients received chemotherapy after the surgery. The majority of patients receiving chemotherapy had adenocarcinoma histology (n = 18). While most of patients receiving chemotherapy were stage 4 (n = 15), followed by stage 2 (n = 2) and stage 3 (n = 1). KRAS was evaluated in 9 patients with appendix adenocarcinoma; Kirsten rat sarcoma viral oncogene homolog (KRAS) mutants and wilds were 3 and 6 patients, respectively. In addition, 6 patients with appendix adenocarcinoma were Neuroblastoma RAS (NRAS) and B-Raf murine sarcoma viral oncogene homolog B1 (BRAF) wild type. Microsatellite instability (MSI) was examined in 3 patients in the entire group and it was Microsatellite stabile (MSS). Chemotherapy regimens consisted of FOLFOX (oxaliplatin, leucovorin plus infusion fluorouracil), Capecitabine plus oxaliplatin (Capeox), capecitabine, FOLFIRI (irinotecan, leucovorin plus infusion fluorouracil)-bevacizumab, Capeox-bevacizumab, and fluorouracil (5 FU)-interferon respectively. Median follow-up time was 20 (1-142) months. Recurrence occurred in 12 (34%) patients. Of the 12 patients, 11 had peritoneal recurrence. Recurrence occurred only in patients with appendix adenocarcinoma. When the risk factors for recurrences were considered; there was a statistically significant difference in tumor grade (1 versus 2-3), pathology (LGMN versus adenocarcinoma), PCI (<12 versus >12) and having PMP versus not. There was no correlation with sex, lymph node excision, number of lymph nodes excised, right hemicolectomy, HIPEC, chemotherapy, and splenectomy [Table 3]. Median DFS was 18 months. Also, when clinicopathological features were evaluated in terms of DFS, there was no statistically significant difference in tumor pathology, lymph node excision, chemotherapy, right hemicolectomy, getting chemotherapy, and application of HIPEC. The median DFS was 18 months in patients with colonic adeno cancer and 16 months in patients with mucinous type neoplasms (P = 0.46). Median OS could not be reached (6 patients died) and 3-year survival rate was 79% [Figure 1].
Figure 1: Kaplan-meier curve of overall survival of patients

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Table 1: Clinicopathologic Features of Patients

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Table 2: Clinical and Pathological variables according LGMN versus appendix adenocancer

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Table 3: Risk factors of recurrent non-carcinoid appendix tumors

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  Discussion Top

In this study, we evaluated clinicopathological features, treatment, and risk factors of recurrence of non-carcinoid epithelial tumors of the appendix. Approximately 3000 new cancer cases per year are seen in Dr. Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital. Roughly 350 of these cases are colon and rectal cancers. Based on the data of last 10 years, approximately 1% of colorectal cancers are appendix epithelial tumors which seem rather compatible with this literature. A slight female predominance has been documented in the literature of non-carcinoid epithelial primary appendix tumors which is similar to this study results.[8] The mean age of presentation has been published as the 5th or 6th decade similar to this study results.

According to the SEER data in which 1404 patients were evaluated between 2004 and 2013, T4 and lymph node positivity rates were 44% and 25%.[9] In this study, T4 and node positivity rates were 70% and 25%, respectively. In general, lymph node metastasis occurs in appendix tumors with adenocarcinoma subtype.[10] Colonic type nodal metastasis is higher than mucinous type adenocarcinoma, whereas some studies did not reach the level of statistical significance.[11] LGMN type nodal metastasis is low, similar to this study findings. In addition, the grade 1 ratio is 65% in this study which is higher than the data of the SEER (28.8%).

In the presented study, the rate of mucinous neoplasm was 80% (40% of patients LGMN, 40% of patients HGMN) and 25 (71%) of patients underwent right hemicolectomy. However, according to SEER data, 47.8% of the patients were of mucinous type and 70% of patients underwent extended colectomy (total or right colectomy), and 30% of patients had distal metastasis. In the current study, the rate of distal metastasis is 5.7%. Most of our patients had peritoneal metastasis (71%). In some studies, plasma tumor marker level, which is high in colonic and mucinous type appendix adenocarcinoma types, also correlates with the disease course.[12],[13] In this study, tumor markers were examined in 18 (51%) of the patients and were higher in 10 (28%).

Management of primary appendix cancer depends on histological features and the extent of the disease. Low-grade appendix mucinous neoplasm is a slowly progressive disease. Simple appendectomy is sufficient for well-differentiated unruptured appendix tumors that are not invaded from submucosa to the skin[14] since lymph node metastasis occurs in less than 2% of these patients.

Right hemicolectomy is especially important for complete staging with lymph node excision. Especially it is recommended if tumors are greater than 2 cm and high-grade, muscularis propria invasion is existent, and in case of peri-appendiceal area invasion.[9] In a study, 5-year survival was only 20% in appendectomy and 63% in right hemicolectomy.[2] Most of the literature data deals with intestinal type appendix cancers.[2] Mucinous type adenocarcinoma and PMP type were previously treated with CRS with intravenous chemotherapy. However, the success rate was low, cases recurred and 5-year survival was 30-50%. Recently, Sugarbaker has developed a definitive CRS with HIPEC yielding good results and the five-year survival rate can be improved up to 52%-96%. In another study, the 5-year survival was reported as 53% at the end of CRS with HIPEC with mitomycin. 5-year survival with CRS and HIPEC is better in patients with LGMN (with peritoneal involvement) compared to HGMN or non-mucinous appendiceal cancer. CRS and HIPEC have demonstrated the benefit of both DFS and OS in patients with especially LGMN perforated and peritoneal involvement (PMP). CRS and HIPEC were applied to 6 patients with LGMN in this study. For the HIPEC several chemotherapeutic agents such as mitomycin, oxaliplatin, cisplatin, and 5FU have been used in combination or as single agents. Mitomycin and cisplatin were used in this study patient group.

The application of adjuvant chemotherapy in appendix mucinous neoplasm is controversial and has not been evaluated in a prospective study. Adjuvant chemotherapy (fluorouracil-based) is recommended for poorly differentiated histology, with lymph node involvement and perforated appendix mucinous neoplasm. Adjuvant chemotherapy is not recommended in low-grade mucinous neoplasms. However, in cases of perforation, lymph node involvement and Lymphovascular invasion (LVI), it can be given. According to the National Cancer Database, in which 11,871 appendix adeno cancer patients were evaluated between 1985 and 2006, the survival benefit of adjuvant chemotherapy was demonstrated in mucinous and non-mucinous stage 2-3 tumors.[15] Six-month adjuvant chemotherapy is recommended for node-positive appendiceal adenocancer. In our study, 19 (55%) patients received chemotherapy. The majority of chemotherapy consisted of FOLFOX (31%). In our study, the contribution of adjuvant chemotherapy after HIPEC in terms of relapse and DFS could not be demonstrated.

Systemic treatment of patients with appendix adeno cancer is controversial. These agents are FOLFOX, FOLFIRI, Capeox-bevacizumab, or single-agent 5FU-based treatments. There is no comparative data on the efficacy of these chemotherapy agents. Low-grade and well-differentiated tumors respond well to CRS and HIPEC. In a retrospective study, the clinical response rate of unresectable appendix tumors with 2 cycles of chemotherapy was 55%, the partial response rate was 24%, and the median PFS was reported to be 7.6 months.[16]

Despite complete cytoreduction of mucinous appendix carcinoma, recurrence is not uncommon. Different rates of recurrence have been reported in relatively limited studies. Approximately 25% of the patients with PMP developed recurrence after CRS and HIPEC.[17] Recurrence is associated with high-grade, high PCI, not having systemic chemotherapy, and no HIPEC after CRS.[18] In our study, recurrence occurred in 12 (34%) patients with appendix adenocarcinoma. Recurrence rate is higher than the literature and can be associated with all patients with adenocarcinoma. The risk of recurrence is higher in high-grade appendix tumors, not having PMP, PCI >12 and adenocarcinoma pathology. There was no association of recurrence with HIPEC and chemotherapy, which may be attributed to the low patient number. In a study, DFS was 38 months in LGMN, 21 months in HGMN, and 22 months in non-mucinous adenocarcinoma. In the presented study, median DFS was 18 months. In the literature, median OS at 5 years has been reported as 75% to 81% and 45% to 65% for low-grade and high-grade tumors.[2] In this study, the 3-year survival rate was 79%.

There are some limitations in the current study; mainly low number of patients and partial heterogeneity of patients. In addition, we could not evaluate the post cytoreduction residue. However, due to low incidence of the disease and limited literature data, our results are still important.

In conclusion, recurrence-progression developed in 34% of patients. Median DFS was 18 months. The risk of recurrence is higher in appendix tumors with high-grade, not having PMP, PCI >12, and adenocarcinoma pathology. Patients with high-grade appendix adenocarcinoma should be followed closely for recurrence.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Connor SJ, Hanna GB, Frizelle FA. Retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies. Dis Colon Rectum 1998;41:75–80.  Back to cited text no. 1
Hesketh KT. The management of primary adenocarcinoma of the vermiform appendix. Gut 1963;4:158–68.  Back to cited text no. 2
Carr NJ, Cecil TD, Mohamed F, Sobin LH, Sugarbaker PH, González-Moreno S, et al. A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal neoplasia. Am J Surg Pathol 2016;40:14–26.  Back to cited text no. 3
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;32:1429–43.  Back to cited text no. 4
Edge SB, Compton CC. The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471–4.  Back to cited text no. 5
Sugarbaker PH, Ronnett BM, Archer A, Averbach AM, Bland R, Chang D, et al. Pseudomyxoma peritonei syndrome. Adv Surg [Internet] 1996;30:233–80.  Back to cited text no. 6
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93–9.  Back to cited text no. 7
Shaib WL, Goodman M, Chen Z, Kim S, Brutcher E, Bekaii-Saab T, et al. Incidence and survival of appendiceal mucinous neoplasms. Am J Clin Oncol 2017;40:569–73.  Back to cited text no. 8
Xie X, Zhou Z, Song Y, Li W, Diao D, Dang C, et al. The management and prognostic prediction of adenocarcinoma of appendix. Sci Rep 2016;6:39027.  Back to cited text no. 9
González-Moreno S, Sugarbaker PH. Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding. Br J Surg 2004;91:304–11.  Back to cited text no. 10
McCusker ME, Coté TR, Clegg LX, Sobin LH. Primary malignant neoplasms of the appendix: A population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer 2002;94:3307–12.  Back to cited text no. 11
van Ruth S, Hart AAM, Bonfrer JMG, Verwaal VJ, Zoetmulder FAN. Prognostic value of baseline and serial carcinoembryonic antigen and carbohydrate antigen 19.9 measurements in patients with pseudomyxoma peritonei treated with cytoreduction and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2002;9:961–7.  Back to cited text no. 12
Wagner PL, Austin F, Sathaiah M, Magge D, Maduekwe U, Ramalingam L, et al. Significance of serum tumor marker levels in peritoneal carcinomatosis of appendiceal origin. Ann Surg Oncol 2013;20:506–14.  Back to cited text no. 13
Hata K, Tanaka N, Nomura Y, Wada I, Nagawa H. Early appendiceal adenocarcinoma. A review of the literature with special reference to optimal surgical procedures. J Gastroenterol 2002;37:210–4.  Back to cited text no. 14
Asare EA, Compton CC, Hanna NN, Kosinski LA, Washington MK, Kakar S, et al. The impact of stage, grade, and mucinous histology on the efficacy of systemic chemotherapy in adenocarcinomas of the appendix: Analysis of the National Cancer Data Base. Cancer 2016;122:213–21.  Back to cited text no. 15
Shapiro JF, Chase JL, Wolff RA, Lambert LA, Mansfield PF, Overman MJ, et al. Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: A single-institution experience. Cancer 2010;116:316–22.  Back to cited text no. 16
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Chua TC, Moran BJ, Sugarbaker PH, Levine EA, Glehen O, Gilly FN, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012;30:2449–56.  Back to cited text no. 18


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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