Case Series
| Year :
2025 |
Month :
April
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Volume :
14 |
Issue :
2 |
Page :
PS11 - PS16 |
Full Version
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Clinicopathological Spectrum of Gastroenteropancreatic Neuroendocrine Tumours- A Series of Ten Cases
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Muktanjalee Deka, Neeharika Phukan, Bhabesh Kumar Das, Jagannath Dev Sharma, Barasha Sarma Bharadwaj, Adahra Patricia Beso, Lachit Kalita, Smriti Goswami
1. Professor and Head, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
2. Senior Resident, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
3. Professor and Head, Department of Oncosurgery, State Cancer Institute, Guwahati, Assam, India.
4. Professor, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
5. Assistant Professor, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
6. Assistant Professor, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
7. Assistant Professor, Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India.
8. Director cum Assistant Professor, Department of Radiation Oncology, State Cancer Institute, Guwahati, Assam, India.
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Correspondence
Address :
Dr. Neeharika Phukan,
Flat-5B, House No.-18, East Side Villa, Mahatma Gandhi Path, Christian Basti, Kamrup Metro-781005, Guwahati, Assam, India.
E-mail: n.phukan94@gmail.com
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| | | ABSTRACT |  | | : Neuroendocrine neoplasms are unique, as many of them are associated with secretory properties and specific syndromes of uncontrolled hormone hypersecretion. Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETs) represent the second most common digestive tract malignancy. Epithelial neuroendocrine neoplasms of the gastroenteropancreatic system are divided into Neuroendocrine Tumours (NETs) and Neuroendocrine Carcinomas (NECs). NETs are classified as G1, G2 and G3 based on their proliferative activity. NECs are further classified into Large Cell NEC (LCNEC) and Small Cell NEC (SCNEC) based on the morphology of the tumour cells. The present case series was aimed to present the histopathological spectrum of NETs of the GEP system with respect to clinical and imaging findings, as well as, the associated role of Immunohistochemistry (IHC) as a supplement to histopathological diagnosis. It consists of 10 cases collected over a two-year period from January 2022 to December 2023 at the State Cancer Institute, Gauhati Medical College, Guwahati, Assam, India. All cases of neuroendocrine neoplasms of the GEP system were included. There were seven resection cases and three biopsy cases. A total of (4/10) 40% of the cases belonged to the 40-50 years age group. A total of 5/10 (50%) cases were of the oesophagus, 2/10 (20%) were of the pancreas, and 20% (2/10) were of the rectum, while 1/10 (10%) was of the stomach. A total of 5/10 (50%) cases were SCNEC, 3 (30%) cases were mixed neuroendocrine non neuroendocrine neoplasms, and 2 (20%) cases were NETs (G1 and G3). GEP neuroendocrine neoplasms are sporadic, but they can be multiple and part of a familial syndrome. Assessment of the location and extent of GEP neuroendocrine neoplasms is crucial for management. Treatment consists of surgery, chemotherapy and somatostatin analogues. Challenges for the future include individualisation of treatment based on clinical and/or biological features and the evaluation of innovative therapies, including immunotherapy. |
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| Keywords
: Immunohistochemistry, Histopathology, Neuroendocrine carcinoma, Oesophagus |
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| DOI and Others
: DOI: 10.7860/NJLM/2025/73976.2906
Date of Submission: Jul 05, 2024
Date of Peer Review: Sep 13, 2024
Date of Acceptance: Dec 29, 2024
Date of Publishing: Apr 01, 2025
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval Obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Jul 06, 2024
• Manual Googling: Nov 21, 2024
• iThenticate Software: Dec 28, 2024 (10%)
ETYMOLOGY: Author Origin
EMENDATIONS: 6 |
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INTRODUCTION |
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The Neuroendocrine Tumours (NETs) are unique, as many of them are associated with secretory properties and specific syndromes of uncontrolled hormone hypersecretion. Any organ in the body has the potential to develop this tumour (1),(2). There has been a steady increase in the incidence of NETs. In a series of 64,971 NETs reported to the Surveillance, Epidemiology and End Results (SEER) programme of the National Cancer Institute (NCI), the reported annual age-adjusted incidence rate grew from 1.09 per 100,000 in 1973 to 6.98 per 100,000 in 2012 (3). In the digestive tract, GEP-NETs represent the second most common cancer (4). The most common sites of primary NETs in the digestive tract are the small intestine (30.8%), rectum (26.3%), colon (17.6%), pancreas (12.1%)and appendix (5.7%) (5). Epithelial neuroendocrine neoplasms of the GEP system are divided into NETs and neuroendocrine carcinomas (NECs). NETs are classified as G1, G2, and G3 based on their proliferative activity. The World Health Organisation (WHO) Classification 2022 proposes a three-tiered grading system for Neuroendocrine Neoplasms (NEN) of the gastrointestinal and pancreatobiliary tract. Necrosis has no role in the diagnostic criteria of NENs in the GEP system (4).
Well-differentiated NETs are composed of uniform, round to polygonal cells with a low nucleocytoplasmic ratio, abundant cytoplasm and ‘salt-and-pepper’ chromatin with few mitoses arranged in nests, ribbons, acini and trabeculae with delicate vasculature. NECs are further classified as large cell neuroendocrine carcinoma (LCNEC) and small cell neuroendocrine carcinoma (SCNEC) based on the morphology of the tumour cells. SCNECs are composed of sheets or nests of small cells with a high nuclear-to-cytoplasmic ratio, scant cytoplasm, nuclear molding, hyperchromatic nuclei, finely granular chromatin and inconspicuous nucleoli. Large cell NECs are composed of round to polygonal cells with a moderate amount of cytoplasm, round nuclei, vesicular chromatin and prominent nucleoli (6),(7),(8).
Synaptophysin, chromogranin and Insulinoma-associated protein 1 (INSM1) are the immunohistochemical stains used for the accurate characterisation of neuroendocrine neoplasms, with p53 and Retinoblastoma Protein (RB) aiding in the diagnosis when there are overlapping morphological features of G3 NET and NEC. In G3 NETs, there is wild-type p53 and retained RB, while NECs exhibit diffuse positive or null staining for p53 and loss of staining for RB (1). In GEP-NENs, the antigen Kiel 67 (Ki-67) proliferative index has a well-documented and accepted diagnostic and prognostic role, and its evaluation is mandatory in their diagnostic work-up (9). The classification of GEP-NENs, along with the diagnostic criteria, is illustrated in (Table/Fig 1) (1).
Mixed Neuroendocrine Non Neuroendocrine Tumours (MiNEN) are tumours that consist of both a neuroendocrine component and a non neuroendocrine component, which may include squamous cell carcinoma, adenocarcinoma, etc., with each component comprising at least 30% of the resection specimen (10). Both components must be established separately in different groups of cells using IHC. They pose a diagnostic challenge, especially in biopsy. The prognosis of these tumours depends on the grade of the more aggressive component (11).
The present study was aimed to explore the histopathological spectrum of NETs of the GEP system in relation to clinical and imaging findings, as well as, the associated role of IHC as a supplement to histopathological diagnosis. This is a rare series, one of its kind, shedding light on the pathological and immunohistochemical spectrum of NETs of the GEP occurring at the State Cancer Institute, Gauhati Medical College, Guwahati, Assam, India, which is a state-of-the-art tertiary cancer care centre in the northeastern region of India.
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Case Report |
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This case series consists of 10 cases diagnosed over two years, from January 2022 to December 2023, in the Department of Oncopathology, State Cancer Institute, Gauhati Medical College, Guwahati. Ethical clearance was obtained from the Institutional Ethics Committee, No. SCI/GMC/ECR/2020/139.
Inclusion criteria: All cases of NEN of the GEP system.
Exclusion criteria: i) NEN of other systems; ii) Non-NEN of the GEP system.
The demographic data, clinical profiles and radiological findings were retrieved from patient records. The selected cases were routinely processed using the automated tissue processor Thermo Fisher Scientific, STP120, and stained with haematoxylin and eosin using the automated stainer Thermo Fisher Scientific, Gemini AS model and examined, while IHC was performed in the automated IHC stainer Leica Bond Max, as required. The various antibodies used were obtained from BioGenex: Pancytokeratin (panCK) (AMA46), synaptophysin (AM363), chromogranin (AM126), and Ki67 (AM410). The slides were examined, data were entered into an Excel sheet, a master chart was prepared, and statistical analysis was conducted.
Results are presented in the form of demographic analysis (age, gender, organ-related), clinical analysis (symptoms presented and imaging findings), pathological analysis (tumour size, lymphovascular invasion, morphological subtypes, perineural invasion, tumour regression grade, immunohistochemical profile), and finally, the follow-up management, including details of cases lost to follow-up. A detailed evaluation of all 10 cases is provided in (Table/Fig 2),(Table/Fig 3), respectively.
Demographic analysis: The prevalence of GEP-NEN in the study Institute for the two-year period from 2022 to 2023 was 0.17% (10/5747), with MiNEN constituting 3/10 (30%) cases. The series consisted of 10 patients, 7 (70%) males and 3 (30%) females; there were seven resection cases and three biopsy cases. The highest number of cases, i.e., 4/10 (40%), belonged to the 40-50 years age group. (Table/Fig 4) is a bar diagram showing the age-wise frequency distribution of all the cases. (Table/Fig 5) is a pie-chart showing the organ-wise percentage distribution of cases. Out of 10, 5 (50%) cases were of the oesophagus, 2 (20%) each were of the pancreas and rectum, and 1 (10%) was of the stomach, as illustrated in the pie-chart labelled (Table/Fig 6). (Table/Fig 7) is a pie-chart showing that 5 (50%) cases were SCNEC, 3 (30%) cases were MiNEN, and 2 (20%) cases were NET (G1 and G3).
Clinical analysis: Three cases of oesophageal tumours presented with dysphagia and haematemesis, while two presented with only difficulty in swallowing. The single case of a stomach tumour presented with abdominal distention; both cases of rectal tumours presented with bleeding per rectum, and one pancreatic tumour presented with jaundice, vomiting and abdominal distention, while the other presented with only jaundice. Imaging findings in cases of oesophageal, stomach and rectal tumours showed circumferential wall thickening; the pancreatic tumour showed a well-defined mass lesion. Functional imaging was not performed in any of the cases due to the non availability of facilities during the study period.
Pathological analysis: The average size of the NET was 4.31 cm, with sizes ranging from 2-10 cm. Lymphovascular invasion was seen in a single case of mixed squamous cell carcinoma NEC (oesophagus), and perineural invasion was observed in a residual SCNEC case (rectum). Two out of the 10 cases received Neoadjuvant Chemoradiotherapy (NACRT) to reduce tumour burden followed by surgery. Residual tumours were present in two cases of SCNEC: one in the rectum with a tumour regression grade of 3 and the other in the oesophagus with a tumour regression grade of 2. Regional lymph nodal metastases were found in three of the 10 cases: Mixed Adenocarcinoma Neuroendocrine Carcinoma (MANEC) in the stomach (9 out of 16), residual SCNEC in the oesophagus (4 out of 13), and Mixed Squamous Cell Carcinoma NEC in the oesophagus (1 out of 30). Omental metastasis was found in a single case of MANEC in the stomach. (Table/Fig 8) shows a case of NET grade 3 in pancreas, (Table/Fig 9) shows a case of mixed squamous cell carcinoma neuroendocrine carcinoma with lymphovascular invasion in esophagus, (Table/Fig 10) shows a case of SCNEC in rectum with perineural invasion, (Table/Fig 11) shows a case of SCNEC in oesophagus and (Table/Fig 12) shows a case of MANEC in stomach.
The immunohistochemical study of the cases for synaptophysin, chromogranin and Ki67 showed that 9 (90%) were positive for Synaptophysin and 6 (60%) were positive for chromogranin. The highest Ki67 was found to be 90%. Pancytokeratin and CK7 were found to be membranous positive in the adenocarcinoma component of mixed adenocarcinoma NEC in the stomach. (Table/Fig 2),(Table/Fig 3) provides an elaborative pathological evaluation and follow-up of the seven resection and three biopsy cases, respectively.
Follow-up of patients: The patients were followed-up until June 2024 (4-23 months). Seven of the ten patients are doing well, one patient was lost to follow-up, one expired after one week of surgery due to postoperative complications, and another after four months of surgery. Two patients underwent NACRT followed by surgery, two received adjuvant chemotherapy and radiotherapy following surgery, three were operated only, one received only chemotherapy and radiotherapy as treatment, and one received palliative treatment. Additionally, one patient was lost to follow-up after diagnosis via biopsy.
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Discussion |
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The present case series is an attempt to achieve a detailed understanding of the pathological spectrum of GEP epithelial NENs with the available resources. IHC for Ki67 is essential in the work-up of pancreatic NETs, as tumour grade represents the cornerstone for the prognostic evaluation of patients (9). In the study conducted by Xie J et al., over a 12-year period across 11 hospitals in China, 405 cases of gastric NETs were collected, with 53.83% (218/405) NEC cases and 46.17% (187/405) being mixed adenoneuroendocrine carcinoma (MANEC) cases. Lymphovascular invasion was noted in 41.48% (168/405) of cases, perineural invasion in 31.36% (127/405) of cases, and Ki67 ≥60% in 61.97% (251/405) of cases (12).
The results of the present series are similar to those of Xie J et al., with 50% (5/10) of cases being small cell neuroendocrine carcinoma (SCNEC) and 3 (30%) being mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN) (12). However, there is a striking difference in the rates of lymphovascular and perineural invasion, which were only 10%, and only 20% of the cases showed Ki67 >60%. Various studies with Ki67 percentages has been presented in (Table/Fig 13) (13),(14),(15),(16),(17),(18),(19),(20),(21),(22),(23),(24). The present series showed that the highest number of cases, specifically 90%, demonstrated proliferative activity >20%, which sharply contrasts with the studies presented in (Table/Fig 13) (13),(14),(15),(16),(17),(18),(19),(20),(21),(22),(23),(24). This could indicate a greater incidence of higher-grade tumours in this particular geographical area, emphasising the need to conduct an in-depth and elaborative study of GEP-NENs with a considerable follow-up period.
Management of NETs consists of appropriate surgery with adequate negative margins, even in metastatic disease, to prevent obstruction in bowel tumours (25),(26). There is hardly any role for chemotherapy. Somatostatin analogues, like octreotide, are recommended with precautionary measures of their associated adverse effects, like nausea, vomiting, diarrhoea and cholelithiasis (27),(28). In peptide receptor radionuclide therapy, administered intravenously every eight weeks for four doses, a therapeutic radio label of 177 Lutetium is attached to a somatostatin analogue, which concentrates in neuroendocrine tissue. This label delivers local cytotoxic radiation to the NET (29). Molecular biologic therapies, like sunitinib and everolimus, have also been utilised, showing good progression-free survival in some trials (30),(31). Currently, there are no guidelines for adjuvant or neoadjuvant treatment for MiNEN. Tumours driven by NEC are typically treated with etoposide and cisplatin-based regimens, while adenocarcinoma-driven tumours are treated with a 5-fluorouracil backbone. However, treatment options vary depending on the tumour’s site, and therapies align with those for adenocarcinoma of that specific site (32),(33),(34),(35).
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Conclusion |
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The GEP-NENs are sporadic, but they can be multiple and may be a component of a familial syndrome. Assessment of the location and extent of GEP-NENs is crucial for management. Treatment consists of surgery, chemotherapy and somatostatin analogues, although alternative options are emerging in this scenario. Hence, a better understanding of this unique group of tumours would facilitate a multidisciplinary approach and improve the quality of life. Challenges for the future include the individualisation of treatment based on clinical and/or biological features and the evaluation of innovative therapies, including immunotherapy.
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