Case presentation Non diabetic patient with hypoglycemic attacks
• 30 years old • Non diabetic female patient • History of several unexplained hypoglycaemic attacks • CECT- Pancreatic head lesion • Serum insulin level- elevated
• Underwent central pacreatectomy • Macroscopy - The cut surface shows two well demarcated, greyish- white nodules, ranging from 2cm to 0.7cm in maximum diameters.
• Microscopy-
• Multifocal neoplasm • Organoid architecture • Nested, acinar patterns and pseudorosette formation • Monotonous epithelial cells with regular round nuclei with salt and pepper chromatin pattern and finely granular cytoplasm • Mitoses <2/10 HPF • No necrosis or tumour vascular emboli.
Diagnosis • Well differentiated multifocal pancreatic neuroendocrine tumour
Pa Pancr ncreati eatic c Ne Neuroe oendocr ndocrin ine e ne neoplasms lasms
• Accounting for 2-5% of all panceratic tumours. • Commonest age group- 30-60 yrs • No significant sex difference • Potentially malignant neoplasms * Well differentiated types- Pancreatic neuroendocrine tumours (PanNETs) * Poorly differentiated types- Pancreatic neuroendocrine carcinomas (PanNECs)
Etiology Genetic syndromes Sporadic PanNETs -10-20% of cases -due to Germline • Multiple endocrine mutations in DNA neoplasia type 1 repair genes. • von Hipple- Lindau (MUTYH,CHEK2,BRCA2) Syndrome • Neurofibromatosis type1 • Tuberous sclerosis • Glucagon cell hyperplasia and neoplasia PanNEC usually donot show such associations
2017 WHO classification of neoplasms of the neuroendocrine pancreas • Non functioning(non-syndromic) neuroendocrine tumours - not associated with clinical features of hormone hypersecretion -Secrete peptide hormones,biogenic sustances like pancreatic polypeptides and chromogranins * Pancreatic neuroendocrine microadenoma - Diameter of tumour <5mm * Non functioning pancreatic neuroendocrine tumour
• Insulinoma • Glucagonoma • Somatostatinoma • Gastrinoma • VIPoma • Serotonin producing tumours with and without carcinoid tumour • ACTH producing tumour with Cushing syndrome • Pancreatic neuroendocrine carcinoma • Mixed neuroendocrine- non neuroendocrine neoplasms -Non neuroendocrine component is usually ductal adenocarcinoma or acinar cell carcinoma. -Each component should be >30% of the tumour cell population.
Histological grading and classification • WHO classification 2010 -PanNETs were graded according to proliferation index. Mitoses Ki67 G1 <2/10HPF <2% G2 2-20/10HPF 3-20% PanNEC were classified as G3 > 20/10HPF >20% PanNEC were further subclassified into small cell CA or large cell CA
• WHO CLASSIFICATION 2017 The grading of PanNEN depends on - proliferation index -Tumour morphology Ki67 index Mitotic index Well differentiated PanNENs( PanNETs) PanNET G1 <3% <2/10HPF PanNET G2 3-20% 2-20/10HPF PanNET G3 >20(<55% ) >20/10HPF Poorly differentiated PanNENs(PanNECs) PanNEC(G3) >20% >20/10HPF small cell type Large cell type Mixed neuruendocrine- nonneuroendocrine neoplasm -Both components are usually high grade(G3) - Each components should be individually graded , using respective grading systems for each.
Comparison of the WHO classifications of PanNENs WHO 2010 WHO 2017 • NETs G1/G2 • NETs G1/G2/G3(Well differentiated NEN) • NECs G3 • NECs G3(Poorly Large cell type and small cell type differentiated NEN) Large cell type and small cell type • • Mixed adenoneuroendocrine CA Mixed neuroendocrine- non neuroendocrine neoplasm • Hyperplastic and preneoplastic lesions
The difference between NENs in digestive system and NENs in other organs • 2015 WHO classification of lungs and thymus NENs take into account the grade of necrosis in addition to Ki67 proliferation index. Define 3 distinct subgroups -Typical carcinoid(correspond to NET G1) -Atypical carcinoid(NET G2) -Large and small cell NECs
Macroscopy • NETs -Solitary, well demarcated, tan to yellow nodules • NECs – Tan-red or yellowish, solid masses Necrotic and haemorrhagic areas
Microscopy • Well differentiated NET -Organoid architecture including solid nests,trabeculae,acinar and pseudo rosette formation - No necrosis -Monotonous tumour cells with regular nuclei, salt and pepper chromatin pattern -Stromal amyloid deposition, psammomatous calcification, dense stromal fibrosis -Histo- morphological variants Clear cell/ lipid rich, oncocytic, pleomorphic, rhabdoid and glandular
The tumor has a so- called “ organoid structure” including ribbonlike and pseudo- rosette patterns. B
A B C (A). Glandular formation with psammomatous calcification. (B). Clear cell pancreatic NET. (C). Oncocytic pancreatic NET.
Poorly differentiated NECs • No differentiated morphology • Sheets and nests of tumour cells with pleomorphic, hyperchromatic nuclei and abundant mitoses • Salt and pepper chromatin pattern is lost • Necrosis
Histologic features of pancreatic neuroendocrine carcinoma (NEC)(WHO PanNEC G3
Immunohistochemistry • Diagnostic markers Synaptophysin, chromogranin A • Prognostic markers Ki67, CK19, KIT, CD99, CD44, p27 • Markers to subclassified the functioning PanNETs Insulinoma- ISL1,Insulin Glucagonoma-ISL1, Glucagon Somatostatinoma- Somatostatin Gastrinoma- Gastrin VIPoma-VIP, Peptide histidine methionin Serotonin producing tumour- serotonin ACTH producing tumour- ACTH PanNEC- p53
Insulinoma • Most common functioning PanNET. • 20% of all PanNENs • Composed of insulin producing cells and proinsulin producing cells • Secrete uncontrolled insulin causing hypoglycaemic syndrome. • Female > men • Commonest age- 60 yrs rare in young adults and children • 10% of cases of insulinomas are multiple • Associated with MEN type 1 Insulimatosis • Almost insulinomas are found in the head and tail of the pancreas • Diagnosis Whipple triad-1. Hypoglycaemic symptoms 2. Plasma glucose <40mg/dl 3. symptoms relief following glucose administration other Ix- CT/MRI PET Prognostic markers- Size of the tumour <2cm- 10 yr survival rate 100% >2cm-10 yrs survival rate30% proliferation index
MCQ 1. Genetic syndromes associated with PanNETs a. MEN Type 1 b. Von Hipple Lindau syndrome c. neurofibromatosis -1 d. Tuberous sclerosis e. Glucagon cell hyperplsia
2. Features of pancreatic neuroendocrine carcinoma a. poorly differentiated b. Necrosis c. Strongly positive of neuroendocrine markers d.Usually not associated with genetic syndromes e. Good prognosis
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