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Neuroendocrine Tumor(carcinoid) of stomach : A case report and update Dr. Md. Rashedul Islam MD(Thesis Part Student) Department of Medical Oncology National Institute of Cancer Research & Hospital

Chief complains: 1.Upper abdominal pain for 0ne and half year. 2.Anorexia and nausea for one year 3.Weight loss for 6 months On examination Mildly anemic (Hb%-9 gm/dl) Epigastric tenderness without clinically palpable mass USG of whole abdomen-normal(10/7/2017) Endoscopy report-Peptic ulcer disease (17/7 /2017).

She was treated conservatively by local physician She was treated conservatively by local physician. symptomatic improvement lasted for 6 months, then she again visited with same complains and evaluated properly. Upper GI endoscopy- Gastropathy (07/9/2018) 2nd endoscopy revealed -Polypoid,ulcerated& mobile growth seen at the lower end of oesophagus involving the cardiac part of stomach (24/10/2018) and biopsy was taken

Digital barium swallow of esophagus: no organic lesion Digital barium swallow of esophagus: no organic lesion. (out side the NICRH) Spiral CT scan of whole abdomen-Thickening of the wall of lower end of esophagus .post contrast scan revealed enhancement of the thickened wall. (16/10/2018) HPR: -suggestive of poorly differentiated adenocarcinoma(27/10/2018)

After proper investigations and evaluation she was diagnosed as a case of Ca- esophagus involving the cardiac part of stomach and admitted at NIDCH for surgical management. Oesophagogastostomy with feeding jejunostomy was done 13/12/2018. HPR :- CARCINOID TUMOR with lymphnode metastasis (pT3N3Mx) (15/12/2018)

Patient was advised for IHC but due to financial issues, patient denied, so we advised for slide review. Slide Review:- Small cell neuroendocrine carcinoma (17/02/19)

Patient admitted at medical Oncology department of NICRH for further management. We evaluated the patient properly and advised for palliative systemic chemotherapy with Cisplatin and Etoposide.

Neuroendocrine Tumor Neuroendocrine tumors (NET) of the gastrointestinal tract (carcinoid tumors) are uncommon The incidence of gastrointestinal (GI) NETs is 6.2 per 100,000 Small bowel NETs (midgut carcinoids) are more common than both foregut and hindgut & also can remain small (<1 cm) and still metastasize to regional lymph nodes and liver Risk factors for the development of midgut carcinoid tumors include age , male sex, increased body mass index, and menopausal hormone therapy

These tumors are indolent and patients survive a long time The prevalence is quite high, making them the second most prevalent GI tract tumor, second only to colon cancer Some are clinically silent and have been detected only at autopsy (incidence 8%) In 1907, Oberndorfer first used the term carcinoid, meaning “cancer-like,” to describe a rare ileal tumor with less malignant behavior than the large bowel carcinomas

They are derived from the diffuse neuroendocrine system that is composed of peptide- and amine-producing cells that may secrete different hormones depending on the site of origin There is currently no single system for staging for NETs at all anatomic site Critical factors in NET pathology include key features are Embryologic site of origin (foregut, midgut, hindgut), Functional status (defined as hormone secretion associated with symptoms of hormone excess), and Grade

The recent 2010 World Health Organization pathology classification relies mainly on proliferation rates as measured by Ki67 antibody staining or mitotic index. Low-grade tumors (grade 1) are the most common and have a mitotic index of fewer than two mitoses/10 high power field (hpf) and a Ki67 <3% Intermediate-grade tumors (grade 2) have a mitotic index of 2 to 20 mitoses/10 hpf and a Ki67 3% to 20% High-grade tumors (grade 3) have a mitotic index >20 mitoses/10 hpf and a Ki67 >20%.

General Diagnostic Principle Diagnosis of GI and pulmonary NET is often incidental Patient with functional tumor can present with symptoms of hormone excess Elevated serum hormone markers can be a surrogate marker of symptoms of hormone excess or tumor growth Chromogranin A levels are elevated in approximately 80% of patients with GI NETs Urine 5-hydroxyindoleacetic acid (5-HIAA), the primary metabolite of serotonin, is elevated in carcinoid syndrome.

Abnormal levels (>5 mg/24 hours) of 5-HIAA are diagnostic of carcinoid syndrome Less common NETs may also be identified by the specific hormone and syndrome that is produced Imaging play an important role in diagnostic evaluation of GI and pulmonary NET like CT scan, MRI, SRS Ga-68 DOTATATE is a newer somatostatin-based scintrigraphy that is thought to be more sensitive than octreoscan

PET-CT with FDG has poor sensitivity for well differentiated NETs ¹³¹I-meta-iodobenzylguanidine scan in patients with small intestine is useful in patients whose tumors secrete catecholamines CT-enteroclysis is a newer imaging modality designed to image tumors of the small bowel

Staging and Grading

Management

Oncological principles of management in patients with NETs depend on many factors and require a multidisciplinary approach Treatment often requires individualization Surgery is the only definitive cure but is rarely possible in patients with metastatic disease, and other approaches are therefore necessary Anti-proliferative treatment decisions depend on: Origin of the primary tumour Histological differentiation Tumour grade (or proliferative capacity)

Evaluation and treatment of Local gastric NETs

Resect primary Gastrinoma Primary gastrinoma not resected Metastatic disease Endoscopic resection of prominent tumor EGD Gastric biopsy Serum Gastrin level Consider gastric Pᴴ Hypergastrinemic/type 1 (atropic gastritis, or High gastric Pᴴ Hypergastrinemic/type2 Zollinger-Ellison syndrome,no atropic gastritis,low gastric Pᴴ Vit B12 level EUS as clinically indicated Abdominal multiphasic CT/MRI Somatostatin receptor based imaging(68 Ga-dotatate or SRS EUS as clinically indicated Other biochemical evaluation as clinically indicaed Consider testing for inherited genetic syndromes Normal gastrin/ type 3 EUS Somatostatin receptor based Imaging Radical resection with lymphadenectomy Or Endoscopic surgical wedge resection

Consider endoscopic Surveillence and endoscopic resection of prominent tumor and/or Consider Octreotide or Lanreotide And Manage gastric hypersecretion with high dose PPI Primary gastrinoma not resected

Management of Locoregional advance disease And/or distant metastasis of GI tract NETs

Multiphasic CT/MRI of abdomen and pelvis Chest CT as clinically indicated Somatostatin based Imaging or Somatostatin receptor scintigraphy Biochemical evaluation as clinically indicated If complete resection possible Resect primary+ metastasis Refer for surveillance Asymptomatic low tumor burden Observe with imaging or Octreotide/Lanreotide Locally symptomatic primary tumor Consider resection of primary tumor Clinically significant tumor burden Or Alternative frontline therapy Every 3-12 mo

Multiphasic CT/MRI of abdomen and pelvis Every 3-12 mo Chest CT as clinically indicated Clinically significant tumor burden If disease progression on Octreotide or Lanreotide If disease progression Everolimus(10mg/d) or PRRT with 177 lu-dotatate(if somatostatin receptor positive and progression on octreotide) Or Hepatic directed therapy for hepatic predominant disease Arterial embolization or Hepatic chemoembolization or Radioembolization or Cytoreductive therapy Interferon alpha-2B Cytotoxic chemotherapy If no other option is feasible

Systemic therapy for well differentiated NETs Streptozocin based Combination chemotherapy with either 5 FU or Doxorubicin Molecular targeted therapy Either with Everolimus Or Sunitinib Temozolamide based Oxaliplatin based Combination chemotherapy with capcetabine Combination chemotherapy with FOLFOX/ CapOx

Systemic therapy for poorly differentiated NETs Cisplatin based Combination chemotherapy with Etoposide Irinotecan based Combination with leucovorin and 5 FU(FOLFIRI) Temozolamide based Oxaliplatin based Combination chemotherapy with capcetabine Combination chemotherapy with FOLFOX/ CapOx