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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 2  |  Page : 78-85

Neuroendocrine tumors of gastrointestinal tract with special reference to immunohistochemistry markers at a tertiary care hospital


1 Department of Pathology, Government Medical College, Anantnag, India
2 Department of Internal Medicine, Sher-I-Kashmir Institute of Medical College, Srinagar, India
3 Department of Pathology, Government Medical College, Baramulla, Jammu and Kashmir, India

Date of Submission06-Feb-2021
Date of Decision26-Aug-2021
Date of Acceptance20-Nov-2021
Date of Web Publication05-Apr-2022

Correspondence Address:
Dr. Shuaeb Bhat
GMC, Anantnag, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajim.ajim_14_21

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  Abstract 


Background: Neuroendocrine tumors (NETs) are epithelial neoplasms that originate from the endocrine cells, contain cytoplasmic granules, and secrete a variety of biogenic amines, which are responsible for a variety of signs and symptoms produced by these tumors. Endocrine cells are interspersed within the mucosa of the gastrointestinal tract (GIT) and are also present in a variety of other viscera such as pancreas, adrenal gland, lung, and thyroid. The present study included forty cases of NETs of the GIT (excluding pancreas) reported in the Department of Pathology at Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Kashmir. The objectives of this study were to study the histopathological spectrum of NETs of the GIT and to evaluate the immunohistochemical (IHC) expression of chromogranin, synaptophysin (SYP), neuron-specific enolase, and Ki-67 (MIB) in these tumors. Materials and Methods: The study was conducted at the SKIMS, Srinagar, Kashmir, in the Department of Pathology. It was a prospective study for a period of 1½ years starting from July 2015 to December 2016 and retrospective study for 3½ years from January 2012 to June 2015. The study included all cases of NETs of GIT with or without nodal metastasis. Results: Most of the tumors were well-differentiated NETs (45% G1 and 25% G2). Stomach was the most common site (27.5%) followed by duodenum (25%). Regional lymph node involvement was present in 25% of the cases. Liver was the most common site for distant metastasis. There was a slight female predominance (57.3%). On IHC, SYP, chromogranin-A, and neuron-specific enolase were positive in 100%, 77.5%, and 85% of cases, respectively. Ki-67/MIB-1 index was used to grade the neuroendocrine neoplasms and 45% were graded as G1 NETs, 25% as G2 NETs, and 30% as NEC. Conclusion: Lately, there has been a surge in the number of cases being diagnosed as NETs most probably due to advancement in various diagnostic modalities and increasing knowledge about these tumors which have helped in diagnosing more of these tumors early and correctly.

Keywords: MIB, neuroendocrine carcinomas, neuroendocrine tumor, neuron-specific enolase


How to cite this article:
Abdullah H, Wani Z, Nabi Z, Shah P, Bhat S. Neuroendocrine tumors of gastrointestinal tract with special reference to immunohistochemistry markers at a tertiary care hospital. APIK J Int Med 2022;10:78-85

How to cite this URL:
Abdullah H, Wani Z, Nabi Z, Shah P, Bhat S. Neuroendocrine tumors of gastrointestinal tract with special reference to immunohistochemistry markers at a tertiary care hospital. APIK J Int Med [serial online] 2022 [cited 2022 Dec 2];10:78-85. Available from: https://www.ajim.in/text.asp?2022/10/2/78/342536




  Introduction Top


Neuroendocrine tumors (NETs) are epithelial neoplasms which originate from the endocrine cells. Endocrine cells are distributed all along the gastrointestinal tract (GIT) and are also present in a variety of other viscera such as pancreas, lung, thyroid, and adrenal gland. They contain cytoplasmic granules and secrete a variety of biogenic amines and polypeptide hormonal substances that regulate the GI motility and secretion. These secretory products are responsible for a variety of signs and symptoms produced by these tumors. A criterion defining the neuroendocrine cells was proposed by Langley,[1] according to that a neuroendocrine cell is characterized by:(1) production of a neurotransmitter, neuromodulator, or neuropeptide hormone; (2) presence of dense core secretory granules from which the hormones are released by exocytosis in response to a stimulus; and (3) absence of axons and synapses. The neuroendocrine cells of GIT are of many different types and are derived from the neural crest, neuroectoderm, and endoderm. Approximately two-thirds of neuroendocrine neoplasms (NENs) arise in the GIT and pancreas.[2] Endocrine cells are interspersed within the mucosa of the GIT and comprise approximately 1% of all mucosal cells.[3] NETs commonly present as polypoidal or nodular circumscribed elevations which are located within the mucosa or submucosa. The overlying mucosa can be intact or ulcerated. Microscopically, the tumor cells are arranged in nests, sheets, islands, trabeculae, strands, and less commonly form rosettes or tubules. Individual cells are uniform polygonal to cuboidal cells having moderate amount of eosinophilic cytoplasm with round to oval nuclei and stippled chromatin. High-grade tumors have a high nuclear-to-cytoplasmic ratio with hyperchromatic or vesicular nuclear chromatin and areas of necrosis can be present. Mixed adenoneuroendocrine tumors (MANEC)/mixed endocrine neuroendocrine carcinoma (MINEN/MENEN) consist of both epithelial nonneuroendocrine and a neuroendocrine component with each representing at least 30% of the tumor mass.[4] NETs show different clinical presentation, behavior, etiology, histopathology, and metastatic potential depending on the primary location.[5] According to the anatomical site/location, NETs are classified into tumors of foregut, midgut, and hindgut. According to the clinical behavior, NETs can be classified as functioning and nonfunctioning tumors. According to the degree of differentiation, NETs are classified as well-differentiated NETs which are further divided on the basis of number of mitosis/Ki-67 index into G1 and G2, poorly differentiated neuroendocrine carcinomas (NECs), and MANECs.[4] According to the architectural pattern, NETs can be subclassified into insular, trabecular, glandular, and diffuse types.[6]

NENs show positivity for chromogranin A (CgA), synaptophysin (SYP), neuron-specific enolase (NSE), protein gene product 9.5 (PGP 9.5), CD56 (NCAM), and CD57 (leu7).[7]

In the World Health Organization (WHO) 2010 classification for gastroenteropancreatic NETs (GEP-NETs), all GEP-NETs are considered malignant and this grading is applied regardless of the primary site of the tumor, as shown in [Table 1].
Table 1: The World Health Organization 2010 classification

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  Tumor-Node-Metastasis Staging for Neuroendocrine Tumors Top


The WHO includes parameters for tumor-node-metastasis (TNM) staging of neuroendocrine tumors (NETs) in its 2010 classification guidelines.[4] Pathologic staging is based on endoscopic biopsy specimens, percutaneous biopsies, fine-needle aspirates, and surgical exploration, as well as on examination of surgically resected primary tumors, lymph nodes, and distant metastases. The parameters differ for each anatomic site, as follows:

  • Stomach[4]


    • Primary tumor (T) a


      • Tx Primary tumor cannot be assessed
      • T0 No evidence of primary tumor
      • Tis Carcinoma in situ/dysplasia (tumor <0.5 mm, confined to mucosa)
      • T1 Tumor confined to mucosa and 0.5 mm or more but no >1 cm in size; or invades submucosa and is no >1 cm in size
      • T2 Tumor invades muscularis propria or is more than 1 cm in size
      • T3 Tumor invades subserosa
      • T4 Tumor perforates visceral peritoneum (serosa) or other organs or adjacent structures.


    • Regional lymph nodes (N)


      • Nx Regional lymph nodes cannot be assessed
      • N0 No regional lymph node metastasis
      • N1 Regional lymph node metastasis.


    • Distant metastasis (M)


      • M0 No distant metastasis
      • M1 Distant metastasis.


  • Small intestine


    • Primary tumor (T) a


      • Tx Primary tumor cannot be assessed
      • T0 No evidence of primary tumor
      • T1 Tumor invades lamina propria or submucosa and is no >1 cm in size (b)
      • T2 Tumor invades muscularis propria or is >1 cm in size
      • T3 Tumor invades subserosa (jejunal or ileal tumors) or invades pancreas or retroperitoneum (ampullary or duodenal tumors)
      • T4 Tumor perforates visceral peritoneum (serosa) or invades other organs or adjacent structures.


    • Regional lymph nodes (N)


      • Nx Regional lymph nodes cannot be assessed
      • N0 No regional lymph node metastasis
      • N1 Regional lymph node metastasis.


    • Distant metastasis (M)


      • M0 No distant metastasis
      • M1 Distant metastasis.


  • Colon or rectum[4]


    • Primary tumor (T)


      • Tx Primary tumor cannot be assessed
      • T0 No evidence of primary tumor
      • T1 Tumor invades lamina propria or submucosa and is no >2 cm in size
      • T1a Tumor <1 cm in size
      • T1b Tumor 1–2 cm in size
      • T2 Tumor invades muscularis propria or is >2 cm in size
      • T3 Tumor invades subserosa or nonperitonealized pericolic or perirectal tissues
      • T4 Tumor perforates peritoneum or invades other organs.


      • Regional lymph nodes (N)


        • Nx Regional lymph nodes cannot be assessed
        • N0 No regional lymph node metastasis
        • N1 Regional lymph node metastasis.


      • Distant metastasis (M)


        • M0 No distant metastasis
        • M1 Distant metastasis


    • Appendiceal NETs


      • Primary tumor (T)


        • TX Primary tumor cannot be assessed
        • T0 No evidence of primary tumor
        • T1 Tumor 2 cm or less in greatest dimension
        • T1a Tumor 1 cm or less in greatest dimension
        • T1b Tumor more than 1 cm but not more than 2 cm
        • T2 Tumor more than 2 cm but not more than 4 cm or with extension to the cecum
        • T3 Tumor more than 4 cm or with extension to the ileum
        • T4 Tumor perforates peritoneum or invades other adjacent organs or structures, for example, abdominal wall and skeletal muscle.


    • Regional lymph nodes (N)


      • Nx Regional lymph nodes cannot be assessed
      • N0 No regional lymph node metastasis
      • N1 Regional lymph node metastasis.


    • Distant metastasis (M)


      • M0 No distant metastasis
      • M1 Distant metastasis.


    • Stage grouping


      • Stage 0 Tis N0 M0
      • Stage I T1 N0 M0
      • Stage II A T2 N0 M0
      • Stage II B T3 N0 M0
      • Stage III A Any T N0 M0
      • Stage IV Any T Any N M1.


    • Note:


      • a For any T, add (m) for multiple tumors
      • b Tumor limited to ampulla of Vater for ampullary gangliocytic paraganglioma
      • Tis applies only to stomach.



  Materials and Methods Top


The study was conducted at the Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Kashmir, in the Department of Pathology. It was a prospective study for a period of 1½ years starting from July 2015 to December 2016 and retrospective study for 3½ years from January 2012 to June 2015. The present study included forty cases of NETs of the GIT (excluding pancreas) reported at our center. All cases of NETs of GIT (excluding pancreas) with or without nodal metastasis were selected and all other primary epithelial GI neoplasms were excluded from the study. Relevant information was taken from the records. Histopathological data were collected and relevant details were noted. In each case, a brief clinical history was taken, along with other relevant investigations.

The clinical data of the patient were recorded and samples were collected in 10% formalin for routine histopathological examination. After overnight fixation, the specimen was grossed with 3–4 sections taken from the tumor. Gross photographs of the specimen were taken. Sections from all resection margins were taken. The tissue was processed and 4–5 micron thick sections were cut on microtome and stained by routine hematoxylin and eosin stain. Immunohistochemistry (IHC) was done in all NENs. Expression of Ki-67 was assessed by staining with MIB-1 antibody which binds to the Ki-67 antigen. It shows nuclear positivity. The Ki-67 index has to be assessed in areas where the highest nuclear labeling is observed (hot spot areas) and 500–2000 cells are to be counted. Manual cell counting method was used in this study.


  Results and Observations Top


The present study included forty cases of NETs of the GIT (excluding pancreas) reported in the Department of Pathology at SKIMS, Srinagar, Kashmir. The observations made were as follows:

Age of the patients ranged from 12 years to 77 years with a mean age of 48.22 years, as shown in [Figure 1].
Figure 1: Age range of the patients

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Majority of the patients were female (23/40 [57.5%]) with a male-to-female ratio of 0.74:1. In our study, 34 cases were symptomatic and 6 were asymptomatic. The most frequent symptom was pain abdomen which was present in 22 cases (55%). The most common site was stomach (11 cases – 27.5%) followed by duodenum (10 cases – 25%) and colon (8 cases – 20%). Most of the cases were seen in foregut 26 cases (72.22%), as shown in [Table 2].
Table 2: Distribution according to site

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Size of the tumors ranged from <1 cm to 10 cm with most of the tumors were in the size range of 3–4 cm (25% of cases). Most of the tumors were polypoidal lesions –18 cases (45%).

Out of total 40 cases of NENs, on histopathology, 28 cases (70%) were diagnosed as well-differentiated NETs out of which, G1 comprised 18 cases (45%) and G2 comprised 10 cases (25%) and 10 cases (25%) were NEC. There were two cases of MANEC/MINEN-MENEN, as shown in [Table 3].
Table 3: Histopathological diagnosis

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All 40 cases (100%) of the cases on IHC showed cytoplasmic positivity for SYP. NSE was positive in 34 (85%) of the cases. CgA was positive in 31 cases (77.5%). According to the IHC staining done for MIB-1 (Ki-67), NENs were graded into NET-G1 (MIB index <2%) which constituted 18 cases (45%), NET G2 (MIB index 3-20%) which comprised 10 cases (25%), and NEC (neuroendocrine carcinoma) as shown in [Figure 2]. MIB-1 (Ki-67) showed nuclear positivity.
Figure 2: Bar chart showing distribution of the tumors according to gender

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Out of the total forty cases of NETs, regional lymph nodal involvement was present in ten cases (25%) and three cases (7.5%) showed evidence of distant metastasis to liver and one case showed evidence of metastasis to the left supraclavicular lymph node. On TNM staging, 14 cases (14/31 cases – 45%) were in T2 stage, 10 cases (32.2%) were in T3 stage, as shown in [Figure 3].
Figure 3: Distribution of tumors at different sites

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  Discussion Top


According to Sippel et al., the estimated prevalence of NETs is 1–2 cases per 100,000 people, of which GI tract is the most common site.[8] The NETs of GIT are rare neoplasms, but their incidence has been increasing probably because of advancement in various diagnostic modalities. The main aim of the study was focused on these rare tumors.

The most common age group in our study was 51–60 years and comprised 42.5% cases, followed by 41–50 (15%) and 21–30 (15%) years' age group, with a mean age of 48.22 years and an age range of 12 years–77 years as shown in [Figure 1]. This is comparable to a study done by Amarapurkar et al.[9] who reported the mean age as 53.01 years (range 16–82 years) and majority of the patients were between 41 and 60 years. Similar results were reported by Zeng et al.[10] who conducted a study comprising 122 patients in Japan between 2000 and 2011, reported the mean age as 49.13 ± 16.21 years.

Out of the total of 40 cases of NENs, 23 were from females (57.3%) and 17 were from males (42.5%) [Figure 2]. Zeng et al.[10] also reported a slight female predominance, with 67 (54.9%) being females and 55 (45.1%) being males. In a study done by Estrozi et al.[11] which included 773 patients, females constituted 57.7% of the cases. Yucel et al.[12] noted similar findings with females comprising 58% of the cases. They did not find any statistically significant difference between females and males in terms of median age which was similar to our study.

Pain abdomen was the main symptom in our study and was present in 55% (22/40 patients) and 6 patients (15%) were asymptomatic, in whom the neoplasm was detected microscopically. In a study by Zeng et al.,[10] abdominal pain was the most common symptom which was present in 99 patients out of a total of 122 patients (77.9%). In a study by Niederle et al.,[13] the most common presenting symptom was abdominal pain (29.5%) followed by diarrhea (8.7%) and weight loss (7.5%).

In the present study, the most common site was stomach [Figure 4] and [Figure 5], comprising 11 cases out of a total of 40 cases (27.5%), followed by duodenum (25%), colon (20%), esophagus (12.5%), and appendix (10%). Both ileum and rectum comprised 2.5% of the cases as depicted in [Figure 2] and [Figure 5]. This is comparable to a study conducted by Estrozi et al.[11] who also found stomach as the most commonly involved site (24.5% or 190/773 cases) followed by small intestine (161 cases or 20.8%). In a study by Niederle et al.,[13] the most common site of the primary was stomach 22.8% (65/277) followed by appendix 20.7% and small intestine (15.4%). Li et al.[14] in their study analyzed the pathologic characteristics of mixed colorectal glandular-neuroendocrine tumors and a total of 87 cases were included in their study. None of these tumors was found in the rectum, with the majority of them located in the right colon (56%) and the left colon (41%), which was comparable to our study and both the cases of mixed endocrine- NETs were present primarily in the colon.
Figure 4: Distribution according to gross appearance

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Figure 5: Histopathological diagnosis at different sites

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However, according to a study conducted by Maggard et al.,[15] the small intestine was found to be the most common site (44.7%), followed by rectum (19.6%), appendix (16.7%), colon (10.6%), and stomach (7.2%). Godwin et al.[16] conducted a study and found that the most common site of carcinoid tumors was appendix followed by the rectum, ileum, lung and bronchi, and stomach. In contrast in our study, stomach was the most common site followed by duodenum. This could be explained as the number of cases in our study was limited and the study group did not represent the exact incidence maybe because of selection bias.

Most of the tumors were in the size range of 3–5 cm (25%) and the size ranged from a maximum of 10 cm to a minimum of 0.1 cm, with the mean size being 3.1 cm. Ten cases (25%) were more than 5 cm read as [Figure 3]. Our findings were consistent with most studies. In a study done by Zeng et al.,[10] majority of the tumors ranged in size from 1 to 5 cm (62.7%) and 24.6% of the tumors were larger than 5 cm. The tumor size has been correlated with metastatic potential and prognosis. This is comparable to a study by Lee et al.[17] In their study, the mean tumor size for well-differentiated NET was 0.7 cm and 7.3 cm for high-grade neuroendocrine carcinoma. In a study consisting of 125 patients, Chul-Hyun et al.[18] reported that the median primary size was smaller for G1 and G2 tumors than for G3 tumors (5.7 mm vs. 53.3 mm).

The syndromic association was seen in only one case in our study who was a 30-year-old female with a primary lesion in duodenum and was associated with neurofibromatosis type 1 (NF-1). Hyun et al.[18] did not find any association with multiple endocrine neoplasia type 1 or any other syndrome in their study.

Out of the 40 cases in our study, 18 cases (45%) were polypoid read as [Figure 4]. This is comparable to a study conducted by Estrozi et al.[11] consisting of 773 patients who also reported that most tumors were polypoid. A study conducted by Chang et al.[19] also found similar results.

NETs in the present study were analyzed immunohistochemically for expression of CgA, SYP, NSE, and Ki-67/MIB-1 [Figure 5]. All 40 cases (100%) showed positivity for SYP [Figure 6], 34 cases (85%) showed positivity for NSE, and 31 cases (77.5%) cases showed positivity for CgA. These three markers showed cytoplasmic positivity. Positive staining of both CgA and SYP was seen in 77.5% of cases, both SYP and NSE were positive in 85% of cases. All of the three markers were positive in 67.5% of cases. Our findings were comparable with a study done by Zeng et al.[10] in their study, 81.1% of cases were positive for CgA, 87.7% for SYP, and 57.4% for NSE. In a study by Lee et al.,[17] 96% of the tumors showed positive reaction for SYP and 44% of the tumors showed positive reaction for CgA. Yucel et al.[12] conducted a study comprising 52 patients and found that the most frequently used IHC stains were CgA, SYP, and NSE stains. Thirty-six (92%) patients were positively stained with CgA, 38 (95%) patients were positively stained with SYP, and 21 (71%) patients were positively stained with NSE. Positive staining with both CgA and SYP was seen in 33 (87%) patients, positive staining with CgA and NSE was observed in 13 patients (65%), positive staining with SYP and NSE was seen in 13 (65%) patients, and positive staining with all three stains was seen in 12 (63%) patients. Combined staining characteristics were seen most frequently in CgA and SYP stains with a frequency of 87%. When the relationship between the staining characteristics and the grade of tumor is considered, no correlation was found between CgA, SYP, and NSE.
Figure 6: Photomicrograph showing high-power view of cytoplasmic positivity for synaptophysin in a well-differentiated neuroendocrine tumor (×40, anti-synaptophysin antibody)

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According to a few other studies conducted by Shayanfar and Shahzadi[20] and Korse et al.,[21] they reported that there was a correlation between the staining characteristics of the tumor and the grade of the tumor and CgA positive staining was seen mostly in well-differentiated NETs whereas NSE-positive staining was seen in poorly differentiated NETs. However, in our study, we did not find any significant association between the grade of the NENs and the IHC staining pattern of these markers.

In our study, we had 18 cases (45%) of well-differentiated NETs G1 followed by 10 cases (25%) of well-differentiated NETs G2 [Figure 7], [Figure 8], [Figure 9]. Together well-differentiated NETs comprised 70%. There were 10 cases (25%) of NEC (G3) and two cases of MANEC (5%). The tumors were graded according to the WHO 2010 guidelines which are based on the number of mitotic figures and/or the Ki-67/MIB-1 index. The higher of the two was considered. In our study, 18 cases (45%) had a Ki-67 index of <2%, 10 cases (25%) had a Ki-67 index of 3–20%, and 12 cases (30%) had a Ki-67 index of >20% [Figure 10] and [Figure 11]. The Ki-67 index has been associated with prognosis. Ki-67 is highly expressed during the cell cycle in dividing and proliferating cells. Our findings were comparable with a study done by Zeng et al.,[10] they found that G1 tumors comprised 55.7% of cases (68/122), G2 comprised 26.2% of cases (32/122), and 18.1% of cases (22/122) were G3 tumors. The most common tumor type was NET (81.9%) followed by NEC (15.6%) and MANEC/MENEN (2.5%). In a study conducted by Lim et al.,[18] the most common histological grade was G1 (74.5%) followed by G2 (13.7%) and G3 (11.8%). In our study, 10 cases (25%) showed evidence of regional nodal metastasis. This is comparable to a study conducted by Amarapurkar et al.[9] in which the regional spread was seen in 14/74 cases (18.9%).
Figure 7: Photomicrograph showing normal lining epithelium with underlying tumor arranged in nests (H and E, ×20)

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Figure 8: Photomicrograph showing infiltration of the muscularis propria by nests of tumor cells (H and E, ×10)

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Figure 9: Photomicrograph showing well-differentiated neuroendocrine tumor arising near gastroesophageal junction (H and E, ×10)

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Figure 10: MIB (Ki-67)

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Figure 11: Photomicrograph showing high Ki-67 labeling index in a small cell carcinoma (×40, MIB-1)

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In our study, distant metastasis was present in 4 cases (10%), out of which majority were present in liver (three cases) and one case showed metastasis to the left supraclavicular lymph node. Our was in accordance with a study done by Zeng et al.[10] who reported that distant metastasis at diagnosis was present in 19.7% (32/122) and liver was the most frequently involved organ followed by lung. In a study done by Amarapurkar et al.,[9] distant spread was seen in 14/74 cases (18.9%). In a study by Lee et al.,[17] 4 cases (6%) showed evidence of metastasis.

Considering the importance and at the same time situations of diagnostic dilemma of NENs, we undertook this retroprospective study at our center both to study histopathologic spectrum and the relevance of the conventional markers such as SYP, CgA, NSE, and Ki-67 which are a marker for mitotic activity in these cases. Broadly our histopathological features are in agreement with most other studies. The IHC markers used also showed comparable results with most other studies. However, our study suggests that at least two of the IHC markers, one of them preferably being SYP should be used in the work up of suspected cases of NENs, which helps in resolving dilemma about diagnosis. Furthermore, Ki-67 proved to be helpful in grading these neoplasms and it has prognostic implications as well, which is a subject of research.

Limitations of our study

There are a few limitations in our study most prominently the limited size of patient population and nonavailability of other modalities and markers for being an adjunct for our results.


  Conclusion Top


The study was focused on NETs of the GIT. Lately, there has been a surge in the number of cases being diagnosed as NETs most probably due to the improvement and advancement in the diagnostic modalities and the knowledge about these tumors has helped in diagnosing more of these tumors early and correctly. The main conclusions of our study are as follows: the mean age in our study was 48.22 years and male-to-female ratio was 0.74:1. Stomach was the most common site (27.5%) followed by duodenum (25%). Most of the tumors were well-differentiated NETs (45% G1 and 25% G2). On IHC, SYP, CgA, and NSE were positive in 100%, 77.5%, and 85% of cases, respectively. Ki-67/MIB-1 index was used to grade the NENs and 45% were graded as G1 NETs, 25% as G2 NETs, and 30% as NEC. It has been shown in many studies that Ki-67 index correlated with the grade of the tumor and prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
 
 
    Tables

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Abstract
Introduction
Tumor-Node-Metas...
Materials and Me...
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