Introduction

Appendiceal carcinomas (AC) are extremely rare, accounting for approximately 0.5 % of all intestinal tumors [1]. Our knowledge about appendiceal tumors is based mainly on anecdotal reports with a small number of cases. The majority of appendiceal cancers are discovered incidentally in appendectomy specimens, and further surgical management is subject to debate. However, evidence from literature and consensus-based guidelines advocate complete right colectomy for patients with tumors greater than 2 cm and for tumors <2 cm and presence of meso-appendiceal invasion or adverse histological features [2, 3].

Currently, there are no evidence-based guidelines for follow up after resection for appendiceal cancer. Generally, no follow up is advised for tumors <2 cm and treated by simple appendectomy [4]. Although some histological variants such as signet ring cell carcinoma are associated with poor prognosis, the overall survival of patients with appendiceal cancer is excellent. For instance, 5-year survival rate of appendiceal carcinoid <3 cm without regional nodal or distant metastases is reported to be 100 % [5].

It is well established that cancer survivors are prone to developing additional subsequent cancers [6]. However, despite growing knowledge on the occurrence of additional cancers in patients with other malignancies [7, 8], data is insufficient for appendiceal cancer. There is limited evidence from small retrospective series suggesting an elevated risk of additional malignancies in patients successfully treated for carcinoid tumors of the appendix [9]. However, except for carcinoid tumors, the risk of additional malignancies in other histological subtypes has not been explored. Considering a high 5-year survival rate after surgical resection, there exists a need to report occurrence of additional subsequent cancers among survivors of appendiceal cancer.

In this work, we aim to investigate the risk of subsequent malignancies in patients with appendicular carcinoma compared to the general population, including an analysis on whether several demographic and clinical characteristics are associated with having a higher or a lower risk of these subsequent cancers.

Methods

National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database was utilized for data mining. SEER database is a set of 18 cancer registries that covers approximately 28 % of the US population. We used SEER 13 Regs Research Data, Nov 2013 Sub (1992–2011) database [10] and identified cases with histologically confirmed appendiceal carcinoma from 1992 to 2011 using site code for appendix (C18.1). We only included patients who were surgically treated for AC. Patients with unknown or missing variable status on demographics, tumor characteristics, and treatment were excluded. In addition, subsequent malignant neoplasms (SMNs) diagnosed during the 2-month period after the primary diagnosis of AC were excluded due to potential misclassification of synchronous cancers and metastases. Patient selection algorithm is shown in Fig. 1.

Fig. 1
figure 1

Patient selection algorithm

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Statistical analysis

We used the multiple primary standardized incidence ratio session of SEER stat software. Standardized incidence ratio (SIRs) were used to estimate the risk of additional neoplasms after AC. SIRs is defined as the number of observed cases divided by the number of expected cases of additional cancer. The 2000 US Standard Population was used as the reference population in the determination of the expected incidence. Confidence intervals were calculated using the Poisson distribution assumption [8, 11].

Subgroups analysis for expected incidence rates were stratified by gender, race (white, black, others), latency period (2–11 months, 12–59 months, >60 months), primary tumor stage (localized, regional, distant), and primary tumor histology. Tumor histology was consolidated into five groups using International Classification of Disease (ICD) oncology codes and based on similar histopathological and clinical features as defined previously [12]. The groups consisted of malignant carcinoid, goblet cell carcinoid, adenocarcinoma, mucinous adenocarcinoma, and signet ring cell adenocarcinoma. Disease stage was derived from SEER Historic Stage variable and included three categories. Tumors limited to the site of origin were coded as “Localized” disease; extension beyond the primary organ into the surrounding structure, lymph nodes, or combination was categorized as “Regional” malignancies. Distant metastasis was coded as “Distant.”

Differences between groups were assessed using χ 2 tests for categorical variables and Student’s t test for continuous variables. A multivariate analysis using the Cox-proportional hazards model was used to evaluate the association between various factors and the development of subsequent malignant cancers. Analysis was conducted using SEER stat software version 8.2.1 (available at: http://seer.cancer.gov/seerstat/; release April 8, 2015) and Statistical Package for the Social Sciences (SPSS v.22) Software. A p-value of ≤0.05 was considered as statistically significant.

Results

Patient characteristics

Among 3445 patients with surgically treated primary appendiceal cancer, 313 (9.1 %) developed 359 subsequent malignancies. Mean age at diagnosis of primary appendiceal cancer was 60 years with a male predominance (57 %). Adenocarcinoma (32.4 %) was the most prevalent subtype of primary appendiceal cancer, followed by mucinous adenocarcinoma (30 %) and goblet cell carcinoid (23 %). The stage of primary appendiceal cancer was localized (56.2 %) in the majority of patients. Primary tumor characteristics for patients who developed additional malignancies and patients with no subsequent cancers are summarized in Table 1.

Table 1 Characteristics of patients with surgically treated primary appendiceal cancer (n=3445)
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Overall risk by cancer site, gender, and race

The overall risk for a subsequent malignancy at all sites was elevated by 20 % compared with the general population (SIR, 1.20; 95 % CI, 1.08–1.33, p < 0.05). A significant excess risk of subsequent cancers was observed in the small intestine (SIR, 10.59; 95 % CI, 5.64–18.11) followed by the colon/rectum (SIR, 1.40; 95 % CI, 1.03–1.86) (Fig. 2). Malignant carcinoid and adenocarcinoma were the dominant histological subtypes of subsequent cancers at these sites, respectively. A large numbers of additional malignancies were observed in the prostate (n = 59), the breast (n = 49), and the lung (n = 44), but the risk was not significantly increased as compared to the general population.

Fig. 2
figure 2

The standardized incidence ratios for the risk of additional cancers in patients with appendiceal cancer

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Notable differences were observed between various demographic and clinical characteristics and the probability of developing additional malignancies. When stratified by gender and race, the risk of additional malignancies at all sites was significant in men (SIR, 1.24; 95 % CI, 1.08–1.42) with white (SIR, 1.17; 95 % CI, 1.04–1.31) or other (American Indian/Asian/Pacific Islander) races (SIR, 1.66; 95 % CI, 1.04–2.52). No significant elevated risk was observed in females and in the black race. Overall SIRs by site and gender are summarized in Tables 2 and 3.

Table 2 Standardized incidence ratios of second cancer risk in patients with appendiceal cancer, overall, and by sex
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Table 3 Standardized incidence ratios of selected second cancers by race
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SIRs according to follow up time after appendiceal cancer diagnosis

SIRs according to latency period were calculated for selected cancer sites with statistically significant elevated cancer risk. We found that the risk of additional tumors was most evident within the first 5 years after the diagnosis of primary appendiceal cancer. The greatest risk was seen within 1 year (SIR, 1.91; 95 % CI, 1.43–2.53). The increased risk of subsequent cancers normalized after 5 years of follow up (Table 4).

Table 4 Standardized incidence ratios of selected second cancers by latency period
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SIRs according to primary tumor stage and histology

SIRs according to primary tumor stage and histology were calculated for all tumor sites. Increased risk of subsequent malignancies was observed for localized (SIR, 1.16; 95 % CI, 1.00–1.33) and regional disease (SIR, 1.34; 95 % CI, 1.10–1.61). No statistically significant risk was seen with distant disease (Fig. 3) possibly reinforcing the lower survival rates of advanced disease. Based on histological subtypes of appendiceal cancer, the greatest risk of additional cancer was observed with goblet cell carcinoid (SIR, 1.55; 95 % CI, 1.23–1.92) and adenocarcinoma (SIR, 1.42; 95 % CI, 1.18–1.69. The risk was significantly reduced in patients with malignant carcinoid tumor (Fig. 4).

Fig. 3
figure 3

SIR of additional cancer by stage of primary appendiceal cancer

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Fig. 4
figure 4

Standardized incidence ratio of additional cancer by histology of primary appendiceal cancer

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In a multivariate Cox-proportional hazards model, increased age at diagnosis (p<0.001), male sex (p<0.001), and tumor histology (goblet cell carcinoid, adenocarcinoma, mucinous adenocarcinoma, and signet ring cell carcinoma [p<0.001]) was associated with increased hazards of developing an additional malignancy, while race and disease stage had no significant effect on development of a subsequent cancer (Table 5).

Table 5 Multivariate Cox-regression model for the risk of additional subsequent malignancies in patients with primary appendiceal cancer
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Discussion

We conducted a population-based analysis including patients with surgically treated primary appendicular cancer and observed that 9.1 % developed additional subsequent malignancies, representing a 20 % excess risk compared to the general population. Small intestine and colorectal cancers accounted for the greatest significant cancer burden. Additional malignancies were primarily seen in males with white/Asian/Pacific Islander race. In patients with goblet cell carcinoids and adenocarcinomas of the appendix, the risk of developing an additional subsequent malignancy was elevated as compared to other histological subtypes. A multivariate Cox-regression model reinforced that increasing age at primary cancer diagnosis, male sex, and tumor histology was associated with increased hazards of developing an additional cancer.

With the increasing survival rates among cancer survivors, improved understanding and identification of long-term complications are important to guide surveillance, prevention and treatment. There is a scarcity of data on additional cancers after appendiceal carcinoma. Fernandez et al. [9] evaluated clinical course and follow up of 28 pediatric patients with an appendiceal carcinoid tumor. In a median follow up of 84 months, they observed no second malignancies. In contrast, Habal et al. [13] reviewed over 5000 cases of adult gastrointestinal carcinoids and reported a 13 % to 32 % rate of additional cancers in patients with appendiceal carcinoids. Similar to what we found in our analysis, adenocarcinoma of the colon was the most common subsequent malignancy observed in their review. Interestingly, all previous reports have investigated the risk in appendiceal carcinoids only which were previously believed to be the most common histological subtype at this site. However, recent literature [12] reports mucinous adenocarcinoma to be the most appendiceal tumor followed by intestinal-type adenocarcinoma, with carcinoid tumors comprising only 11 % of all appendiceal tumors.

To the best of our knowledge, this is the first population-based study with the largest number of patients that reports the occurrence of additional malignancies after primary appendiceal cancer. We highlight the possibility of additional malignancies specific to anatomic sites, latency, and various demographic and primary tumor characteristics. The main strengths of our study were its large sample size, an inclusion of all appendiceal cancer histologies, and long-term follow up. The larger sample size of our study was important for increasing the precision of results for studying associations. Additionally, utilization of a population-based database provided us with a high level of quality control and reflects national patterns with increasing generalizability of our results. Furthermore, we quantified our results based on several patient and clinical characteristics with the risk of developing additional cancer and identified the population at risk. Moreover, we only included cases with a primary diagnosis of appendiceal cancer, thus, eliminating the potential confounding of other malignancies on the development of additional cancers.

There are limitations to consider with the present study. SEER database lacks information on comorbidities, risk factors, family history of cancer, occupation, genetic mutations, and the use of chemotherapy. In addition, the inherent limitations of its retrospective nature and using a population-based database including reporting errors, misdiagnosis, and miscoding, exist in this study. Another potential limitation is the lack of classification of subsequent cancer as recurrence vs. a new primary. It is possible that some tumor recurrences may be misclassified as a new primary tumor. We cannot deny the effect of detection bias which might reflect a higher incidence of subsequent digestive tract malignancies in our sample. Despite all these limitations, this is the largest group of cohort reported to date and the first study that investigated additional cancer risk after appendiceal cancer.

Our study reports a 20 % increased risk of subsequent cancers in patients with appendicular carcinoma compared to the general population. The risk of additional tumors was most evident within the first 5 years of follow up in males with adenocarcinoma or goblet cell carcinoid of the appendix. This warrants for increased early surveillance in patients who are considered to be cured after resection for primary appendiceal cancer.