| Abstract|| |
Background: Gastric neuroendocrine tumors (G-NETs) are classified into well-differentiated NETs with three grades and poorly differentiated neuroendocrine carcinomas based on morphology and the Ki-67 index. Besides, G-NETs are broadly classified into four types based on clinical and pathophysiological features. Aim: To study clinical and pathological features of different types and grades of G-NET. Materials and Method: All G-NETs, diagnosed from January 2011 to December 2020, were included. Clinical presentation, peritumoral findings, lymph node status, and liver involvement were obtained and correlated with different grades and types of G-NETs. Results: NET was diagnosed in 88 cases. Tumors were graded as I, II, III, and carcinoma in 58, 14, 12, and 4 cases, respectively. Type I NET (49.2%) in the background of chronic atrophic gastritis was the most common type followed by type III (33.3%). Type I tumors were predominantly graded I (91.1%) and limited to the mucosa and submucosa. MEN-1-associated G-NET (type II) was seen in eight cases. All except one type II tumor was associated with ZES syndrome. Remarkably, peritumoral mucosa showed atrophy and intestinal metaplasia in 52.1% and 24.6% cases, respectively. Two cases were associated with adenocarcinoma. Lymph node metastasis was seen in all carcinoma and grade III cases. All carcinoma cases and 58.3% of grade III tumors showed liver metastasis. Conclusion: Biological behavior of G-NET varies with different types and grades of tumor. Typing and grading of G-NET should be done whenever possible to predict the aggressiveness of the tumor.
Keywords: Atrophic gastritis, gastric neuroendocrine tumor, MEN syndrome
|How to cite this article:|
Sekar A, Vaiphei K. Clinical and pathological profile of gastric neuroendocrine tumors. Indian J Pathol Microbiol 2022;65:551-7
| Introduction|| |
Gastric neuroendocrine tumors (G-NETs) are neoplasms, most commonly derived from enterochromaffin-like cells (ECL) and rarely from D cells, G cells, and enterochromaffin cells (EC) present in the stomach. It constitutes 8.7% of all gastrointestinal neuroendocrine tumor and 2% of all gastric cancer. Due to advanced diagnostic strategies and widespread use of upper gastrointestinal endoscopy, the detection of G-NET is steadily increasing in recent years. The incidence of gastric carcinoids has increased 10-fold in the last 35 years as per the Surveillance, Epidemiology, and End Results Program conducted in the United States.
G-NETs have a heterogenous presentation in terms of clinical, histopathological, and functional characteristics. Most gastric tumors, except those associated with Zollinger–Ellison syndrome (ZES), do not cause specific symptoms and are discovered during endoscopic evaluation for dyspepsia or abdominal pain. In 2018, World Health Organization (WHO) proposed the new classification of neuroendocrine neoplasms (NENs) in different sites. NENs in the gastrointestinal tract and pancreas are broadly classified into well-differentiated NETs and poorly differentiated neuroendocrine carcinomas based on morphology. Further, NETs are graded into three tiers (G1, G2, and G3) based on the proliferation assessed by mitotic count and the Ki-67 index. Besides, based on clinical, pathophysiological, and histomorphology characteristics, G-NETs are broadly classified into four types. Type I is the most common and constitutes about 70%-80% of G-NETs. It is associated with hypergastrinemia in the background of hypochloridria due to chronic atrophic gastritis (CAG). CAG may result from either antiparietal cell antibody or H-pylori infection. However, approximately in 50% of CAG cases, there was no underlying etiology identified. Type II is also a gastrin-dependent tumor and is associated with hypergastrinemia due to ZES in the background of MEN-1 syndrome. Type III G-NET is a sporadic solitary tumor and not associated with autoimmune gastritis or MEN syndrome. It is a gastrin-independent high-grade tumor, usually accompanied by angioinvasion with lymph node and liver metastases. Type IV G-NET is a recently added type and is usually a solitary, large, and highly malignant tumor with either small cell or large cell neuroendocrine morphology on histology. Types I to III G-NETs are frequently of ECL origin, while type IV tumor arises from endocrine cells other than ECL. Only a few studies in the literature describe clinical and pathological characteristics of different types of G-NETs., We intend to put forward our last 10 years of institutional experience in different G-NETs diagnosed on biopsy or resected specimens.
| Materials and Methods|| |
All cases with a diagnosis of G-NETs, diagnosed from January 2011 to December 2020 in the Department of Histopathology, were retrieved. Hematoxylin and eosin and immunohistochemistry (IHC)-stained sections of all these cases were reviewed. Cases with a suspicious diagnosis of the NET due to lack of material for immunochemistry were excluded from the study. Clinical details and endoscopic findings were recorded from the request forms and records in the Medical registry Department. Histological findings such as the predominant pattern of tumor, extent of invasion, mitotic activity, the Ki-67 index, the status of immunoreactivity to chromogranin, synaptophysin, and gastrin in available cases were noted. Grading of tumors was done as per WHO 2018 criteria with the help of the Ki-67 index. If peritumoral mucosal fragment also available in the biopsy, the presence or absence of findings such as atrophy, intestinal metaplasia, enterochromaffin hyperplasia activity, and H. pylori were recorded and graded as per the updated Sydney classification system. In resected specimens, additional parameters such as location, size, number, the extent of invasion, lymph node, and liver involvement were also recorded. In cases of a specimen with only biopsies, lymph node and liver involvement status were noted from clinical records.
Based on clinical features and histopathological findings observed in tumor and peritumoral fragments, G-NET tumors were subtyped into four categories, as shown in [Figure 1]. Continuous data were expressed as mean, and category data were expressed as number (percentage) for analysis.
|Figure 1: Algorithmic approach used in classifying gastric neuroendocrine tumors|
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| Results|| |
From 2011 to 2020, NET in the stomach was diagnosed in 88 cases. It includes biopsies (n = 53, 60.2%), resected specimen without prior biopsies (n = 19, 21.7%), block submitted from elsewhere for review (n = 16, 18.1%).
The age ranged from 16 to 102 years with M:F ratio of 2.1:1. Most cases presented with nonspecific symptoms such as dyspepsia (79.5%), abdominal pain (18.1%), followed by melena (4.5%), and diarrhea (2.3%). In three cases, NET was diagnosed on evaluation for anemia (3.4%). ZES due to gastrinoma was seen in seven out of eight cases of G-NET associated with MEN-1 syndrome. In all cases, gastrinoma was seen in the duodenum, and in three cases, it was seen in both pancreas and duodenum. The diagnosis of the second NET in the gastric body was made during endoscopic evaluation for gastric manifestation.
Location and nature of the tumor
Commonest location observed was body (n = 70, 79.6%) followed by fundus (n = 13, 14.8%), and antrum (n = 5, 5.6%). Of the five antral located tumors, four showed immunoreactivity to gastrin. In 19 resected specimens, lesions were of multiple and nodular in 11 cases (57.8%). Solitary nodule with size ranged 1–6 cm was seen in eight cases (42.1%). [Figure 2]
|Figure 2: (Gross photograph): (a) Total gastrectomy specimen of MEN-1 associated G-NET case showing multiple nodules of variable size in the body. (b) Gastrectomy specimen of case categorized as type III tumor showing large solitary nodule measuring 8 cm in maximum dimension and firm cut surface with areas of hemorrhage|
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The pattern of tumor
Most cases showed mixed pattern. The predominant pattern observed was nests admixed with cords and trabeculae (n = 79, 89.7%), acini (n = 3, 3.4%), papillae (n = 2, 2.3%), and solid pattern (n = 4, 4.5%). [Figure 3]
|Figure 3: Histopathology of neuroendocrine tumors depicting different patterns such as nests (a), cords and trabeculae (b), acinar (c), papillae (d), rosettes (e) and diffuse pattern (f). (H and E, 200×)|
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Grades of tumor
Based on morphology and the Ki-67 index, tumors were classified. Grade I, grade II, grade III, and neuroendocrine carcinoma were seen in 58 (65.9%), 14 (15.9%), 12 (13.6%), and 4 (4.5%) cases, respectively. Large cell neuroendocrine morphology was observed in all carcinoma cases.
The extent of invasion
Tumor was limited to muscularis mucosa in four cases (21%) and extended to the submucosa, muscularis propria, and serosa in six (31.5%), three (15.7%), six (31.5%) cases, respectively.
Adjacent peritumoral mucosa for evaluation was available in 69 cases (78.4%). Observed findings were atrophy (n = 36, 52.1%), intestinal metaplasia (n = 17, 24.6%), enterochromaffin hyperplasia (n = 25, 36.2%), Helicobacter pylori (n = 9, 13.1%), and activity (n = 5, 7.2%). [Figure 4]
|Figure 4: Histopathology of adjacent nontumorous fragment depicting marked atrophy of glands (a, H and E, 200×), intestinal metaplasia (b, H and E, 200×), linear and nodular endocrine cell hyperplasia highlighted by IHC for chromogranin (c, immunoperoxidase, 200×). Adjacent fragment in one case showing adenomatous polyp with low-grade dysplasia. (d, H and E, 200×)|
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Other tumors of epithelial origin
Adenocarcinoma was seen in two cases, of which one also showed mucinous component. A single case was associated with adenomatous polyp with low-grade dysplasia.
Regional lymph node metastasis
Status of lymph node involvement was available in 80 cases. Lymph node metastasis was seen in all carcinoma and grade III cases, whereas 3.7% and 40% of grade I and grade II tumors showed regional lymph node involvement.
Status of liver metastasis was available in 80 cases. All carcinoma cases, 3.7%, 10%, and 58.3% of grade I, grade II, and grade III tumors, respectively, showed liver metastasis.
Immunoreactivity for chromogranin, synaptophysin, and gastrin was observed in 76 out of 88 cases (86.3%), 30 out of 43 (69.7%), 4 out of 63 cases (63.4%), respectively.
Types of NET
Based on the clinical features and histological findings in the tumorous and peritumoral fragment, we could categorize the tumor into four types in 69 cases (78.4%). Most common type of tumor observed was type 1 (n = 34, 49.2%), followed by type III (n = 23, 33.3%), type II (n = 8, 11.5%) and type IV (n = 4, 5.7%) tumors.
Serum gastrin was available in all eight cases of MEN syndrome-associated NET. Of the eight cases, seven cases showed a marked rise in serum gastrin levels (>10000 pg/ml) and a single case with normal gastrin levels.
Clinical and histological findings of different types of NETs
The mean age of type I, II, III, and IV tumors were 51.8, 44.8, 47.4, and 56, respectively. Males were frequently affected of all types except in type II, in which there was no sex predilection observed. Lesions were predominantly multiple in all types. The distribution of different grades of the tumor, various peritumoral findings, the extent of invasion of the tumor, IHC findings, lymph node, and liver involvement in each type are shown in [Table 1].
Clinical and histological findings of different grades of NETs
The mean age of grade I, II, III, and carcinoma cases was 51.4, 47.3, 46.6, and 56.8, respectively. The distribution of various peritumoral findings, IHC findings, lymph node, and liver involvement in different grades, and carcinoma are shown in [Table 2].
| Discussion|| |
In the stomach, 88 cases were diagnosed as a NET based on morphology and with the help of IHC. It constitutes 4.6% of all gastric tumors reported in our institute. Comparable to other studies, tumors were commonly seen in the body (79.6%) and fundus (14.8%), followed by antrum (5.6%). Type I NET (49.2%) in the background of CAG was the most common type in our study. The mean age of type I NET in this study was 51.8 years. Contrary to the other studies, male predilection (70.6%) was observed for type I G-NET.
CAG can be due to autoimmune etiology with antibody formation against H+/K+-ATPase antigen in the parietal cells or due to chronic H-pylori infection., In autoimmune etiology, atrophy is restricted to the body and fundus, whereas H-pylori-mediated CAG is multifocal and involves both body and antrum. The underlying pathophysiological mechanism leading to the development of type I NET in atrophic gastritis is hypersecretion of gastrin by G cell in the antrum in response to achlorhydria developed due to loss of parietal cells. Besides hypergastrinemia, multiple factors such as age >50 years, pangastritis, the severity of intestinal metaplasia, and enterochromaffin hyperplasia were documented as risk factors for the progression of atrophic gastritis to NETs. In a Swedish cohort study, during the 20-year follow-up period of atrophic gastritis cases, there was a 13-fold increase in the occurrence of gastric carcinoid.
Multifocal atrophic gastritis, enterochromaffin hyperplasia, and intestinal metaplasia were present in 58.8%, 64.7%, and 41.2%, respectively, of type I G-NET cases. H-pylori organism was observed in 17.6% of cases. The possibility of prior anti-H-pylori treatment administration in the remaining cases was not excluded in this study. In a study by Asaka et al., the overall prevalence of atrophic gastritis and intestinal metaplasia in H-pylori infection was 82.9% and 43.1%, respectively. Though H. pylori eradication may modify the natural history of atrophy, the lesion may persist in the tissue even after many years following treatment.
Though the status of antiparietal cell antibody was not known in all type I G-NET cases, the observations such as male predominance, relatively a more significant number of cases with multifocal atrophy and presence of H-pylori organisms favor atrophic gastritis of nonautoimmune etiology were common in the present study. Comparable to studies done by Chung et al., type I NETs followed an indolent course in most cases. In the present study, type I tumors were predominantly graded I (91.2%) followed by grade II (8.8%) and limited to the mucosa and submucosa. Though rare, lymph node and liver metastasis were seen in 8.5% and 5.8% cases, respectively.
MEN 1-associated type II NET occurred in a relatively younger age group (mean age = 44.8 years), with no sex predilection and tumors were predominantly limited to the mucosa and submucosa (71.4%). Type II NET is also gastrin dependent and occurs mainly in ZES due to gastrinoma in the background of MEN-1 syndrome. Interestingly, in our study, a single case of MEN-1-associated NET was not associated with ZES and hypergastrinemia. This similar rare observation was also observed by Hosoya et al. and Bordi et al. In a study by Berna et al., on long-term follow-up of sporadic ZES, NETs were developed only in less than 2% of cases. So, loss of heterozygosity in the MEN-1 gene is also required for the pathogenesis of G-NETs in addition to hypergastrinemia. Remarkably, in MEN-associated NET, multifocal atrophy was seen in two cases, with the presence of H-pylori in one of them. Though the eradication of H-pylori does not affect the degree of ECL hyperplasia in MEN-1 syndrome, the presence of concomitant H-pylori infection may accelerate the development of type I NET in MEN-1 syndrome. In this study, MEN-associated NETs showed lymph node and liver metastasis in 75% and 25% cases, respectively. In all except one case, metastasis was from gastrinoma rather than type II NET arising from EC. IHC for gastrin in the metastatic site is necessary to determine the type of tumor that get metastasized in MEN-1 cases. The metastatic rate of type II NET reported in the literature was from 3 to 12%.
Type III NETs are sporadic tumors, and their occurrence is not related to atrophic gastritis or MEN-1 syndrome. It was seen in 33.3% of cases with a mean age of 47.4 years and male predominance (69.5%). Though resected specimens were less for the type III category, the serosa involvement, the lymph node, and the liver metastasis were seen in 75%, 39.1%, and 26.1% cases, respectively. These findings highlight the aggressive behavior of type III tumors as documented in other studies.,
Newly described type IV neuroendocrine cancers are poorly differentiated with the solid pattern on histology. It was seen in four cases with male predominance, and all were solitary with infiltration up to serosa and showed metastasis to regional lymph node and liver. Notably, three cases failed to show expression for CG in immunostaining. IHC for other neuroendocrine markers such as synaptophysin may be required for diagnosis. Of the four carcinoma cases, two were seen in the antrum and showed immunoreactivity to gastrin, indicating its origin from G cells. La Rosa et al. observed that vacuolated parietal cells in peritumoral mucosa of type IV tumor. However, in this study, vacuoles in the parietal cells were not specific for type IV as it was also observed in type III and type II tumors. Though the aggressive nature of the tumor is related to the Ki-67 index and high-grade morphology, a small proportion of grade I tumors (3.7%) with a size more than 1 cm also showed regional lymph node and liver metastasis. Though the size of tumors was not available in all cases in the present study, none of the tumors with a size less than 1 cm in resected specimens showed nodal or distant metastasis. A similar observation was also made by Chung et al. and suggested that endoscopic resection can be used as a curative treatment for grade I and grade II G-NETs with a size less than 1 cm.
Due to the retrospective plan, there are some limitations in this study. It includes nonavailability of diagnostic workup such as antiparietal cell antibody, serum gastrin in all cases, and intragastric pH. In spite of limitations, we attempted to classify gastric NETs with clinical and histological findings in a relatively good number of cases (78.4%). As prognosis differs with types and grades, one should also attempt to categorize the tumor in addition to grade based on clinical information and histological findings observed in the tumorous and peri-tumorous fragment.
This study was in accordance with the ethical standards of the institutional and national research committee.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]