<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec><h3>Objectives</h3>
<p>Gastrointestinal neuroendocrine tumours (GI-NETs) are actually malignant tumours, and their most common location of metastasis is the liver. In this study, we define the epidemiologic features of NETs and investigate the demographic factors, clinicopathologic features, survival, and the oncologic results related to GI-NETs.</p>
</sec>
<sec><h3>Materials and Methods</h3>
<p>In this 10-year study (2009–2019), all GI and liver NETs were taken out from the pathology records. When classification based on the WHO classification criteria, patients were categorized based on their location, sex, age, and proliferative index. After studying clinical charts of GI-NET cases, a complete panel of IHC markers such as Chromogranin A, ‘Ki67’ and synaptophysin were used. Results: Based on published data, the liver is not a common primary site for NETs; most liver lesions are most likely to have been metastases. The mean age of patients at diagnosis was 52.72 years. In this research, 27.78% of patients had colon NETs and 27.78 liver. Two (11.11%) patients were classified as stage II, seven (38.89%) as stage III, and one (5.56%) as stage IV. After a 120-month follow-up, 13 (72.22%) patients with colorectal NETs were alive, and 5 (27.78%) of the patients had died.</p>
</sec>
<sec><h3>Conclusion</h3>
<p>Treatment of colon and rectal NETs is difficult because it affects the patient's initial site of involvement, and this often makes treatment difficult for the patient. With suitable management, the prognosis can be positive with long survival, but it is related to the tumour variation grade, the efficiency of the selected treatment, and also to the patient's adherence to the follow-up.</p>
</sec>
</abstract>

Objectives
Gastrointestinal neuroendocrine tumours (GI-NETs) are actually malignant tumours, and their most common location of metastasis is the liver. In this study, we define the epidemiologic features of NETs and investigate the demographic factors, clinicopathologic features, survival, and the oncologic results related to GI-NETs.

Materials and Methods
In this 10-year study (2009–2019), all GI and liver NETs were taken out from the pathology records. When classification based on the WHO classification criteria, patients were categorized based on their location, sex, age, and proliferative index. After studying clinical charts of GI-NET cases, a complete panel of IHC markers such as Chromogranin A, ‘Ki67’ and synaptophysin were used. Results: Based on published data, the liver is not a common primary site for NETs; most liver lesions are most likely to have been metastases. The mean age of patients at diagnosis was 52.72 years. In this research, 27.78% of patients had colon NETs and 27.78 liver. Two (11.11%) patients were classified as stage II, seven (38.89%) as stage III, and one (5.56%) as stage IV. After a 120-month follow-up, 13 (72.22%) patients with colorectal NETs were alive, and 5 (27.78%) of the patients had died.

Conclusion
Treatment of colon and rectal NETs is difficult because it affects the patient's initial site of involvement, and this often makes treatment difficult for the patient. With suitable management, the prognosis can be positive with long survival, but it is related to the tumour variation grade, the efficiency of the selected treatment, and also to the patient's adherence to the follow-up.

<div xmlns="http://www.w3.org/1999/xhtml">
<sec id="j_fco-2022-0004_s_001"><label>1.</label><div>Introduction</div>
<p>Neuroendocrine tumours (NETs) originating in the GI tract comprise only 0.5% of all cancerous, malignant tumours<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_001">1</a>]</sup>. Historically, the term ‘carcinoid’ was employed to designate the intestinal epithelial tumours that presented a relatively similar structure and behaviour that was less aggressive than carcinomas<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_002">2</a>]</sup>. Because of the morphological and biological heterogeneity of this disease, in 2000 the World Health Organization (WHO) adopted new classifications for these neoplasms: neuroendocrine tumours and neuroendocrine carcinomas<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_003">3</a>]</sup>. A distinction was made between well-differentiated neuroendocrine tumours and well-differentiated neuroendocrine carcinomas. The neuroendocrine tumours showed (1) benign behaviour with an uncertain malignant potential (WHO classification 1a) or (2) benign behaviour with low malignant potential (WHO classification 1b). Well-differentiated neuroendocrine carcinomas showed low malignant potential (WHO classification 2), whereas poorly differentiated neuroendocrine carcinomas showed high malignant potential (WHO classification 3)<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_003">3</a>]</sup>.</p>
<p>Functional proliferation of these tumours indicates that the endocrine neurons from which they arise can spread up to two-thirds within the gastrointestinal tract, one-fourth within the bronchopulmonary system, and the remaining 10% or more at additional sites<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_001">1</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_004">4</a>].</sup> NETs can appear throughout the gastrointestinal tract. Sites of origin have historically been reported to be the appendix (50%), small intestine (10%), and rectum (10%). More population-based data from the Third National Cancer Survey and the US Surveillance Epidemiology and End Results (SEER) Program, covering 10%–14% of the US population, show a steady increase in the incidence of NETs throughout the 35-year period from 1969 to 2004<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_005">5</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_006">6</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_007">7</a>]</sup>. The general frequency of GI-NETs rose twofold to threefold during this period, with significant changes in anatomic dissemination. Thus, the proportion arising in the appendix fell from 43% to 4%, with corresponding increases in the stomach (from 2% to 9%), small intestine (from 3%1 to 42%), and rectum (from 15% to 27%)<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_008">8</a>]</sup>. Smoking, genetic, and hormonal influences have been implicated in increasing the risk of developing the carcinoma<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_009">9</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_010">10</a>]</sup>. Improved understanding of the epidemiology of these tumours has become particularly important following recent evidence of a possible link between gastric NETs and the increasingly widespread use of powerful drugs to overwhelm gastric acid secretion<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_011">11</a>]</sup>. Despite a perception that GI-NETs carry a favourable prognosis, overall 5-year survival is reported to be around 60%–70%, and it has changed little in recent decades<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_012">12</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_013">13</a>]</sup>.</p>
</sec>
<sec id="j_fco-2022-0004_s_002"><label>2.</label><div>Objectives</div>
<p>Although we are aware of racial differences in the incidence of NETs, data is lacking about the epidemiology of NETs. In the present study, population-based data is used to describe epidemiologic features of NETs from 22 June 2009 through 19 December 2019 in order to evaluate the demographic factors, clinicopathologic features, treatment, prognostic factors, and the oncologic results related to GI-NETs.</p>
</sec>
<sec id="j_fco-2022-0004_s_003"><label>3.</label><div>Materials and Methods</div>
<sec id="j_fco-2022-0004_s_003_s_001"><label>3.1.</label><div>Ethics</div>
<p>This study was approved by the Ethics Committee of Milad General Hospital; informed consent was obtained from all participants or from their parent or legal guardian in the case of minors.</p>
</sec>
<sec id="j_fco-2022-0004_s_003_s_002"><label>3.2.</label><div>Study Population</div>
<p>Cases of NET of the gastrointestinal tract were spontaneous as determined by the Kaplan-Meier method in a ten-year study (2009–2019) and a total of 18 samples were collected from databases. All collected data were reviewed by an oncologist. We retrospectively reviewed the medical records of all GI-NET patients admitted from 22 June 2009 to 19 December 2019, and the follow-up data were collected by telephone or clinical follow-ups. Methods were carried out in agreement with the approved guidelines. Ten years of medical records of patients with a diagnosis of GI-NET determined by pathology were retrieved for the study. Patients who had missing medical records, preoperative and postoperative reports, or survival status reports that could not be used in assessments were excluded. Of these, two patients were excluded because of missing medical records, and two more patients were excluded because their survival status was unavailable. The final study population consisted of 18 patients who fulfilled the criteria for inclusion.</p>
</sec>
<sec id="j_fco-2022-0004_s_003_s_003"><label>3.3.</label><div>Histological Classifications</div>
<p>Pathologic data for immunohistochemical analysis, chromogranin A, synaptophysin, and Ki67 information at the tumour site were obtained from pathology reports. In this study, the effect of different factors, such as sex, age, tumour location, disease stage, treatment type, primary pathologic diagnosis, grade of tumour, origin of disease, lymph node involvement, metastasis to other organs, necrosis, tumour metastasis, and metastases location were evaluated from pathology reports.</p>
</sec>
<sec id="j_fco-2022-0004_s_003_s_004"><label>3.4.</label><div>Statistics</div>
<p>Descriptive statistics were reported in terms of absolute frequencies and percentages for the qualitative data. PFS was calculated from the date of surgery to the date of first relapse at any site, death, or the last follow-up and were spontaneous as determined by the Kaplan-Meier method. OS was measured from the date of tumour resection to the date of final follow-up or death. Differences between groups were assessed using the log-rank test. All tests were two-tailed, and a <italic>P</italic> value of 0.05 was considered to be statistically significant. Analyses were carried out with SPSS software 22.0 (IBM, Armonk, NY, USA).</p>
</sec>
</sec>
<sec id="j_fco-2022-0004_s_004"><label>4.</label><div>Results</div>
<sec id="j_fco-2022-0004_s_004_s_001"><label>4.1.</label><div>Patient and Tumour Features</div>
<p>Between June 2009 to December 2019, 18 patients underwent tumour removal. No patients were lost to follow-up. Ultimately, a total of 18 patients were included in our cohort (Table 1). The mean age at surgery was 52.72 years. Eight patients were women (44.44%) and 10 were men (55.56%). The tumour site stages and grades for patients are shown in Table 1. All 18 pathology slides were reviewed again. Ki67, Synaptophysin and chromogranin A for all patients was determined, and the results of are provided in Table 1. Chromogranin A levels were positive in 88.89% of patients, and a synaptophysin test of 38.89% was considered positive.</p>
</sec>
<sec id="j_fco-2022-0004_s_004_s_002"><label>4.2.</label><div>Survival Analysis</div>
<p>The Kaplan-Meier survival approach for estimating NET patients’ 10-year survival shows that the survival curves of the patients were significantly different (log-rank test; <italic>P</italic> = 0.02) (Figure 1). The 10-year survival rates by age group were 80% for under 50 years and 57% for over 50 years. After a follow-up of 120 months, recurrence or progression was observed in 18 patients, and 13 patients were still alive. The survival time of patients in years is shown in (Table 2).</p>
</sec>
<sec id="j_fco-2022-0004_s_004_s_003"><label>4.3.</label><div>Treatment Outcome and Prognostic Factor of Survival of NET Patients</div>
<p>On the basis on the results, the recurrence and mortality rates for patients in the survival study along with the causes of death are shown in Table 3. The Cox Model to determine the prognostic factor of survival for NET patients is shown in (Table 3).</p>
<p>The survival of female patients under 50 years as well as of those with localized or regional tumours has gradually improved over time: hazard ratio (HR), 40.8, with 94.5% confidence intervals (CI) (see Table 2). The mean age at diagnosis was 52.72 years. In this research, 27.78% of patients had colon NETs and 27.78 had liver NETs. Two (11.11%) patients were classified as stage II, seven (38.89%) as stage III, and one (5.56%) as stage IV. After a 120-month follow-up, 13 (72.22%) patients with colorectal NETs were alive, and 5 (27.78%) patients had died.</p>
</sec>
</sec>
<sec id="j_fco-2022-0004_s_005"><label>5.</label><div>Discussion</div>
<p>Neuroendocrine tumours commonly develop in the gastrointestinal system<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_014">14</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_015">15</a>]</sup>. Characteristics such as age at diagnosis, an almost equal distribution between both sexes, the head of the pancreas as most usual location for the tumours, symptoms and signs, stage at presentation, overall survival, and prognosis for our patients are comparable with previous reports<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_016">16</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_017">17</a>]</sup>. We could not report the frequency of occurrence of gastroenteropancreatic neuroendocrine tumours, because of the lack of epidemiologic studies. Maggard et al.<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_018">18</a>]</sup> reported that the most common localisation (by 44.7%) was in the small intestine in a series of 11,427 cases, followed by rectum (19.6%), appendix (16.7%), colon (10.6%), and stomach (7.2%). The most frequent localisation was the stomach (24.4%) in the gastrointestinal system. In 2003, Modlin et al.<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_019">19</a>]</sup> examined 13,715 NETs collected between 1973 and 1999; the highest frequency of NETs occurred in the gastrointestinal tract (67.5%) followed by the bronchopulmonary NETs. When only the gastrointestinal tract NETs were analysed, most of them occurred in the small intestine, followed by the rectum (27.4%) and stomach. Localized disease was more common in gastric and appendix tumours than in pancreatic, colon, and rectal tumours (66.6% and 75% versus 44%, 47%, and 45%). In small intestine tumours, however, the rate of recurrence of local and metastatic disease was equal. Percentage and size, regardless of the size and number of rectal tumours, are similar to those reported by Quaedvlieg et al.,<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_020">20</a>]</sup> in a series of 2,391 cases. Many studies have been performed in cell proliferation markers, Ki-67, mitotic rate, and tumour suppressor protein (p53) as predictors of malignant behaviour in NETs. The basic immunohistochemistry in the evaluation and histological classification include Ki-67, chromogranin, and synaptophysin. Of these, the Ki-67, chromogranin A, and synaptophysin were used in this study and were demonstrated to be adequate prognosis markers Although serum chromogranin A is not a specific marker, it is very useful in the follow-up, that is, in the evaluation of response after treatment and disease progression<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_021">21</a>]</sup>. High serum concentrations are found in patients with advanced disease, and is, therefore, considered a prognostic marker<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_022">22</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_023">23</a>]</sup>. The prostatic acid phosphatase is present in 80%–100% of rectal NETs<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_022">22</a>]</sup>; this marker should always be requested when the diagnosis is made for purposes of evaluating the reaction to the treatment and follow-up after surgery. Surgical intervention was carried out in 100% of our patients, and surgical margin negativity was achieved in 50%; these findings were similar with those in other studies<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_024">24</a>,<a ref-type="bibr" href="#j_fco-2022-0004_ref_025">25</a>]</sup>. Likewise, multifocal disease was diagnosed in 17.9% of cases as reported in the literature; Habal et al.<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_026">26</a>]</sup> reported multifocal disease in 17% of their cases. Although tumour size, lymph node, and liver metastasis were independent factors that affected 5-year survival, univariate analysis showed that only the number of lymph nodes removed, multifocal disease, and metastasis correlated with survival; however, multivariate analysis did not reveal any independent risk factors. This may be ascribed to the small number of patients and the dissimilarities of the group. A positive rate of synaptophysin (38.89%) and chromogranin A and Ki67 (88.89%) was found; only 11.11% were negative for Ki67. In our samples, exhibited a somewhat different rate as compared with the positive rates in China (chromogranin A and synaptophysin were 81.1% and 87.7%, respectively) <sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_017">17</a>]</sup>. This difference might be partially because of the different pathological sources, surgical specimens, and organs. In the previously mentioned study in China, the authors reported the results for all gastroenteropancreatic neuroendocrine neoplasms. Gastric NETs are broadly differentiated into three types, and each type has a different therapeutic and surveillance strategy. Although rare, it is essential to keep GC in the differential diagnosis of gastric malignancies<sup>[<a ref-type="bibr" href="#j_fco-2022-0004_ref_027">27</a>]</sup>. This article also emphasizes the need for having evidence-based surveillance strategies for gastric NETs, which is still lacking at this point, given the rarity of this disease. So, our research and data are similar to other reported research. It is hoped that more complete research in this category of cancers will be performed for faster identification and ultimately timely treatment of patients with a higher and more extensive sample range.</p>
</sec>
<sec id="j_fco-2022-0004_s_006"><label>6.</label><div>Conclusion</div>
<p>Treatment of colon and rectal NETs is difficult because it affects the patient's initial site of involvement, and this can sometimes make treatment difficult for the patient. With suitable management, the prognosis can be positive with long survival, but it is related to the degree of tumour differentiation, the efficiency of the selected treatment, and the patient's compliance with follow-up visits after treatment. Although surgery is highly effective in the treatment of smaller tumours, procedures for the treatment of larger tumours and metastatic disease remain unstandardized. Regular surgical techniques may still be a good choice for therapy but must be considered carefully for each patient. Further descriptions of treatments and larger studies are needed in order to calculate the real rate of treatment development and discover improvements in prognosis for patients with NETs to help plan future protective strategies.</p>
</sec>
</div>

Gastrointestinal Neuroendocrine Tumours: A Single-Centre Experience

Forum of Clinical Oncology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

{"article-title":"Gastrointestinal Neuroendocrine Tumours: A Single-Centre Experience"}

Objectives
Gastrointestinal neuroendocrine tumours (GI-NETs) are actually malignant tumours, and their most common location of metastasis is the liver. In this...

Gastrointestinal Neuroendocrine Tumours: A Single-Centre Experience

Article Category: Research Article

Online veröffentlicht: 15. Okt. 2022

Seitenbereich: 3 - 8

Eingereicht: 31. Okt. 2021

Akzeptiert: 30. März 2022

DOI: https://doi.org/10.2478/fco-2022-0004

Schlüsselwörter
Neuroendocrine tumours, Gastrointestinal, Immunohistochemistry, Survival, Chemotherapy

© 2022 Hossein Yahyazadeh et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Gastrointestinal Neuroendocrine Tumours: A Single-Centre Experience

Article Category: Research Article

Online veröffentlicht: 15. Okt. 2022

Seitenbereich: 3 - 8

Eingereicht: 31. Okt. 2021

Akzeptiert: 30. März 2022

DOI: https://doi.org/10.2478/fco-2022-0004

SchlüsselwörterNeuroendocrine tumours, Gastrointestinal, Immunohistochemistry, Survival, Chemotherapy

© 2022 Hossein Yahyazadeh et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Schlüsselwörter
Neuroendocrine tumours, Gastrointestinal, Immunohistochemistry, Survival, Chemotherapy