Abstract
Background
Typical carcinoid is a subtype of neuroendocrine neoplasia of the lung making up <1% of all lung cancers and 2% of resected lung tumors. This study assessed the impact of demographic features, racial and gender disparities, and tumor characteristics on survival in patients with typical carcinoid tumors.
Methods
Data were extracted from the SEER database from 2000 to 2018. Multivariate Cox regression analyses were used to analyze the survival based on demographic and clinical factors.
Results
We identified 11,713 cases of typical carcinoid tumors of the lungs. The mean age was 61.8 years (standard deviation, 14.7), and the tumors affected predominantly women (70.1%) and White (89.4%) individuals. The overall 5-year survival rate was 84.3% (95% confidence interval [CI] 83.5–85.2). The 5-year survival rate for those treated with systemic therapy was 49.8% (95% CI 43.5–55.9). Those treated with surgery had a 5-year survival rate of 97.2% (95% CI 96.7–97.6), and those treated with radiation had a 5-year survival rate of 71.9% (95% CI 60.3–80.6). Combination therapy provided a survival rate of 86.9% (95% CI 64.6–95.6).
Conclusion
Surgery was the most common treatment modality and offered the best prognosis. On multivariate analysis, age >60, male gender, distant spread, and liver metastases were associated with worse prognosis.
Keywords: Carcinoid, disparity, SEER, survival analysis
Lung neuroendocrine neoplasms (NEN) have four histological subtypes: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma, and small cell lung carcinoma. Carcinoid tumors make up 1% to 5% of lung malignancies, with TCs displaying a mean age of diagnosis of 45 years and no association with smoking.1 TCs are classified as a well-differentiated, low-grade NEN, and they should be evaluated separately from other pulmonary NENs as their unique characteristics impact the therapeutic options available to optimally treat and manage the disease, as well as the overall prognosis.2,3 It is necessary to determine the typical/atypical nature of carcinoid tumors based on necrosis and mitotic activity.4,5 Typical carcinoids have no necrosis and have <2 mitoses in 10 high-powered fields (2 mm2). In contrast, ACs have necrosis and 2 to 10 mitoses in 10 high-powered fields.
Most TCs are diagnosed early, making surgical resection the preferred first-line treatment. Lymph node dissection can also serve as part of routine pulmonary carcinoid management to improve local disease control and guide future management.3 Histologic differentiation between TC and AC can impact treatment plans as well. In TC, a lymph node metastasis of N1 may not require adjuvant therapy, whereas in AC tumors, adjuvant therapy may be added to the treatment regimen even without lymph node metastasis.6,7 While there exists a substantial literature on pulmonary NENs overall, analyses specific to TC tumors are scarcer. A more robust understanding of the demographic and clinical progression of TCs not only impacts how clinicians treat the malignancy but can also allow them to make more personalized treatment plans and accurate prognoses.
In this study, we utilized the Surveillance, Epidemiology and End Results (SEER) database to assess the demographic features and tumor characteristics of patients diagnosed with TC tumors. We conducted a survival analysis further stratified by demographic features such as race and gender. We also analyzed patient and tumor characteristics associated with mortality. To our knowledge, this is one of the largest and most up-to-date analyses of the demographic and clinical tendencies of TC tumors.
METHODS
The SEER database, initiated by the National Cancer Institute in 1973, covers approximately 26.5% of the US population. The SEER*Stat software (Version 8.4.2) was used to collect data from 2000 to 2018 using the International Classification of Diseases version 3 (ICD-O-3) and anatomical code (C75.0). The data (https://seer.cancer.gov/seerstat/, accessed October 25, 2022) were exported to the Statistical Analysis System (SAS) on-demand version 9.4 for analysis.
We included all TC cases reported as positive based on histology, exfoliative cytology, immunophenotyping, genetic studies, and/or positive microscopy methods not specified. The cases excluded from our study were positive laboratory test/marker study, direct visualization without microscopic confirmation, radiography without microscopic confirmation, diagnosis only, and those with unknown status. We also excluded cases with a reporting source type of “autopsy only” or “death certificate only.” Furthermore, in the survival analyses, we excluded patients with no survival time.
We analyzed patient and tumor characteristics that may be associated with mortality. We further conducted survival analyses using the Cox regression method to calculate the hazard ratio (HR) and identified the independent factors that affect survival. Unidentified and missing data were removed from multivariate analyses. Univariate analysis was used to identify significant factors for the multivariate model with an accepted P value of <0.25. Multivariate Cox regression analyses were used to analyze the data. Statistical significance was defined as P < 0.05.
RESULTS
Demographic and tumor characteristics
We identified 11,713 cases of TC tumors of the lungs. The mean age was 61.8 years (standard deviation 14.7). Most of the cases were female (70.1%) and White (89.4%). The staging was known among 88.9% of cases, of which 67.7% were localized, 18.0% had regional spread, and 12.2% had distant spread. About 81.5% of the cases had sizes between 0 and 3 cm, and most of the patients (59.1%) presented with a right-sided origin of primary tumor, followed by a left origin of primary, 38.8% (Table 1).
Table 1.
Demographic profiles and tumor characteristics of patients with a typical carcinoid tumor of the lungs from the Surveillance, Epidemiology, and End Results (SEER) database, 2000 to 2018 (n = 11,713)
| Variables | Frequency (%) |
|---|---|
| Female gender | 8210 (70.1%) |
| Age | |
| 0–69 years | 4210 (65.9) |
| >69 years | 4000 (34.1) |
| Race | |
| White | 10,472 (89.4%) |
| Black | 859 (7.3%) |
| Asian or Pacific Islander | 291 (2.5%) |
| American Indian or Alaska Native | 41 (0.4%) |
| Unknown | 50 (0.4%) |
| Stage of tumor: n (%)* | |
| Unknown | 1299 (11.1%) |
| Localized | 7263 (67.7%) |
| Regional | 1877 (18.0%) |
| Distant | 1274 (12.2%) |
| Size of tumor: n (%)* | |
| Unknown | 5218 (44.5%) |
| 0–3 cm | 5292 (81.5%) |
| 3.1–5 cm | 857 (13.1%) |
| 5.1–7 cm | 183 (2.8%) |
| ≥7.1 cm | 163 (2.5%) |
| Laterality of tumor: n (%)* | |
| Right-sided primary tumor | 6925 (59.1%) |
| Left-sided primary tumor | 4547 (38.8%) |
| Unpaired | 14 (0.1%) |
| Paired site – but no information concerning laterality | 102 (0.9%) |
| Only one side – side unspecified | 18 (0.2%) |
| Bilateral – single primary | 107 (0.9%) |
Frequency and percentage among known cases only.
Regional and distant metastases
Of 61.4% of cases with known lymph node status, only 12.8% of cases were positive for spread to the lymph nodes. Distant metastasis status was known only in 55.3% of the cases. No metastases existed in 96.3% of the known cases. The Supplemental Material summarizes the nodal status, distant metastases, and treatment modalities used for patients with TC tumors (Figure 1).
Figure 1.
Distribution of patients with typical carcinoid tumors by distant metastasis and by treatment modality used.
Treatment modalities used
Overall, 258 (2.2%) of the cases had systemic treatment only, 29 (0.2%) had systemic plus radiation therapy, and 116 (1.0%) received systemic treatment plus surgery. Furthermore, 50 (0.4%) cases underwent combination therapy (Figure 1, Supplemental Table 1).
Outcomes and survival analysis
The overall observed 1- and 5-year survival rates were 95.0% (95% confidence interval [CI] 94.5–95.5) and 84.3% (95% CI 83.5–85.2), respectively. Cause-specific 1- and 5-year survival rates were 97.3% (95% CI 96.9–97.6) and 92.3% (95% CI 91.6–92.9), respectively. For those treated medically (systemic therapy), the 1- and 5-year survival rates were 84.7% (95% CI 80.0–88.4) and 49.8% (95% CI 43.5–55.9). For those treated with surgery, the 1- and 5-year survival rates were 99.3% (95% CI 99.1–99.5) and 97.2% (95% CI 96.7–97.6), respectively (Figure 2, Supplemental Table 2). Kaplan–Meier curves were generated to visualize the survival rate by treatment modality (Figure 2).
Figure 2.
Overall 5-year survival based on treatment modality used.
Survival analysis by race and gender
The cumulative White race 1- and 5-year survival rates were 97.4% (95% CI 97.0–97.7) and 92.7% (95% CI 92.0–93.3), respectively. The male gender 1- and 5-year survival rates were 96.3% (95% CI 95.5–96.9) and 90.0% (95% CI 88.6–91.2), respectively (Figure 3, Supplemental Table 3). Kaplan–Meier curves were generated to visualize survival rate by gender and race (Figure 3).
Figure 3.
Overall 5-year survival by (a) gender and (b) race.
Multivariable analysis
Multivariable analyses by Cox survival regression analysis identified age >69 years (HR 1.954; P = 0.001), male gender (HR 1.509; P = 0.001), localized stage (HR 1.00; P = 0.001), regional stage (HR 1.259; P = 0.004), distant stage (HR 1.316; P = 0.001), and tumor size > 7 cm (HR 1.438; P = 0.009) as associated with decreased survival. Surgery as a treatment modality (HR 0.457; P = 0.001) and systemic therapy (HR 0.622; P = 0.001) were associated with improved survival (Table 2).
Table 2.
Multivariable Cox regression analyses for independent predictors of mortality in patients with typical carcinoid tumor of the lungs from the Surveillance, Epidemiology, and End Results (SEER) database, 2000 to 2018
| Variables | Hazard ratio | P value |
|---|---|---|
| Age >69 years | 1.954 | 0.001 |
| White (reference) | 1.000 | 0.547 |
| Black | 1.131 | 0.271 |
| Asian or Pacific Islander | 1.219 | 0.329 |
| American Indian or Alaskan Native | 0.890 | 0.841 |
| Localized spread (reference) | 1.000 | 0.001 |
| Regional spread | 1.259 | 0.004 |
| Distant spread | 1.316 | 0.001 |
| Male gender | 1.509 | 0.001 |
| Chemotherapy | 0.622 | 0.001 |
| Radiation | 1.237 | 0.297 |
| Surgery | 0.457 | 0.001 |
| Tumor size > 7 cm | 1.438 | 0.009 |
DISCUSSION
With the large SEER database, our study serves as a concentrated analysis of pulmonary TC, distinguishing it from previous studies that analyzed pulmonary carcinoid tumors as a whole (typical and atypical) or pulmonary NENs as a whole. This allows us to gain insight into the clinicopathologic tendencies of this pulmonary TC specifically. In this large-sample epidemiological study, we found that old age, male gender, regional and distant spread, tumor size, and liver metastasis were associated with worse overall prognoses in patients with this disease. We also found that surgery and systemic therapy as a treatment modality were associated with improved overall prognoses.
Demographically, our mean age of diagnosis was 61.8 years, higher than the average found by Metovic et al in their analysis of NENs as a whole. This could convey that, of all NENs, TCs may tend to present at an older age than other NENs. Further, although men had worse outcomes, we found White women to be affected primarily, consistent with previous epidemiological studies.1
Our findings of old age, male gender, localized, regional, and distant metastases, and tumor size as negative prognostic indicators in patients with TC tumors are consistent with the findings of La Salvia et al, who found age to be an independent negative prognostic factor, and Georgakopoulou et al, who found the advanced stage to be associated with shorter survival.8,9 Compared to these studies, however, the larger dataset in our analysis and emphasis on TC rather than both TC and AC allows for more specific results regarding TC.
The proportion of TCs that were grade I, well-differentiated was consistent with existing literature, as low-grade characteristics are diagnostic of TC and aid in delineation from AC.2,8 Carcinoid tumors are known to be smaller, as reported by a published case series on 108 cases of pulmonary carcinoid tumors, where the majority were smaller than 3.7 cm. We had the same finding, with most patients having tumors <3 cm in size. This can be attributed to the paracrine nature of these tumors, as carcinoid tumors secrete large amounts of cytokines, bradykinins, and other hormones. These substances produce several systemic and pulmonary symptoms, including flushing, palpitations, wheezing, shortness of breath, and diarrhea, which force the patients to seek early care. This ultimately helps in earlier diagnosis of carcinoid tumors with a small size.8
While distant metastasis was rare, the high rate of no lymph node involvement is consistent with previous studies.8 When present, bone and liver were the most common sites of metastasis, consistent with other studies on the metastatic potential of pulmonary carcinoids.10 This might be attributed to molecular characteristics of the tumor cells, which help them to adhere to and grow in these distant organs. Knowledge of the commonly involved organs in disease is helpful in a more specific diagnostic search and early organ-specific treatment in these patients. Disease patterns are known to change over time and even in different populations. This is particularly seen with cancers, as the concept of cancer is based on abnormal growth. While we provide current and updated information, we advocate for regular studies on the metastatic patterns of these diseases.
When analyzing treatment modalities, we found that surgery was overwhelmingly preferred over systemic therapy. This is consistent with the current preferred guidelines in TC treatment, as it is most frequently localized, low-grade, and well-differentiated, allowing it to be an optimal candidate for surgical resection. We also found improved 5-year survival with surgery as the treatment option, and it serves as an independent positive prognostic indicator, which is also consistent with previous studies.3,11 This finding can be attributed to a few factors, including surgical treatment of the disease while the tumor is small. Chemotherapy has shown no role in the treatment of carcinoid tumors.12 While radiotherapy might be effective, it is required in patients with advanced disease. This will naturally show a worse survival in patients receiving these treatments compared to others. Another factor can be the widespread systemic side effects of chemotherapy and radiotherapy compared to surgery, which will mostly produce localized adverse effects if any.12
Genetic profiling and targeted treatment landscape
While TCs are commonly managed surgically due to their localized nature and good postsurgical prognosis, effective treatment strategies for late-stage TCs are still developing.13 With the advent of targeted molecular therapy, there is increasing effort to better understand the genetic landscape of pulmonary TCs to gain insight into the exact molecular mechanisms leading to its pathogenesis. Currently, there are promising options for targeted therapeutics, such as epidermal growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, bevacizumab, and tyrosine kinase inhibitors.13,14 By uncovering specific gene mutations that lead to pulmonary TC pathogenesis, new therapeutic entry points can be uncovered, opening windows for effective, targeted treatments for later-stage TCs.
Limitations
This large sample study provides detailed and up-to-date information on the epidemiology and survival characteristics of TC tumors, but it is not without limitations. Large database studies are directly affected by the completeness (or lack of completeness) of information in the database used. There were missing data on race, demographics, grading, staging, sizing, metastasis, and treatment modalities. Genomic information, family history, environmental exposures, radiological data, and specifics of chemotherapy were not available in SEER. Further, SEER may not capture all radiotherapy or systemic therapies, and when such therapy is not shown, it is impossible to discern if it is because the patient never received the treatment or if it was missed by the registry. Additionally, the SEER database cannot account for various factors that determine the course of treatment, such as patient preferences, proximity to providers, or comorbidities. This limited the quality of our analysis.
CONCLUSIONS
This large-sample epidemiologic study highlights the current status of disease burden and survival of patients with TC tumors. For TC tumors, surgery was the most commonly used treatment modality and offered the best prognosis. Advanced age, male gender, regional and distant spread, tumor size, and liver metastases were associated with poor prognosis. This study also effectively points out areas for improvement in the SEER database, including the histopathological and genetic findings of such diseases.
Supplementary Material
Disclosure statement/Funding
The authors report no funding or conflicts of interest.
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