Unusual Neuroendocrine Tumors (NETs) AACE 27 th Annual Congress Meet-the-Expert Session May 17, Karel Pacak

Transcription

1 Unusual Neuroendocrine Tumors (NETs) AACE 27 th Annual Congress Meet-the-Expert Session May 17, 2018 Karel Pacak

2 Talk Outline 1. NETs: Definition and location 2. Clinical presentations of rare NETs, summary, discussion

3 Objectives After this session, participants should be able to: 1. Learn the appropriate diagnostic approach in identifying patients with rare NETs 2. Perform appropriate biochemical tests to identify patients with rare NETs 3. Identify imaging techniques to properly localize rare NETs 4. Learn about ongoing therapeutic options for rare NETs

4 Classification of NETs Carcinoids and gastroenteropancreatic tumors (GEPs) Chromaffin cell tumors Pheochromocytoma Neuroblastoma Ganglioneuroma/ganglioneuroblastoma MEN1-, MEN2-, NF1-related NETs* Medullary thyroid carcinoma (MTC) Poorly differentiated small cell carcinoma NETs of unknown origin *MEN: multiple endocrine neoplasia NF: neurofibromatosis

5 Classification of carcinoids and GEPs Tumor Peptide Incidence per 10 6 persons per year Symptoms/Syndrome Carcinoid Serotonin Tachy-and bradykinins Diarrhea, flushing, heart failure, bowel obstruction Insulinoma Insulin 1-2 Hypoglycemia Gastrinoma Gastrin ZE syndrome, ulcers, diarrhea VIPoma* VIP Verner-Morrison syndrome diarrhea, diabetes, hypokalemia Glucagonoma* Glucagon Diabetes, necrolytic erythema Somatostatinoma* Somatostatin Very rare Diabetes, bile stones, diarrhea *to be discussed Adapted from de Herder Best Pract. Res. Clin. Gastroenterol. 2012; 26:689

6 CASE 1 A 24 y.o. white female presented to her physician with occasional sweating, palpitations, headaches, pain in the RUQ (usually after eating food with a high fat content), more frequent urination, and occasional diarrhea. Past Medical History: Polycythemia from age 7, phlebotomies every 3-6 months. In the last 4 months, she s lost about 4 pounds and had 2 UTIs. In the last 3 years she s had frequent headaches, more tiredness, and needed to change her eyeglasses once due to blurred vision while reading.

7 CASE 1 On physical examination, the patient was found to be anxious, with wet skin, especially on her arms, along with facial sweating. There was noted redness in her face. BP: 139/85, HR: 95; Temp. 36.7; RR:17. A physician decided to prescribe atenolol 25 mg BID and recommended a low fat diet. In a week, the patient presented back to her physician complaining of more frequent headaches, sweating, and diarrhea (BP: 149/89; HR:75). What would the next step be? 1. Measurement of plasma serotonin 2. Lab tests including plasma metanephrines 3. Work-up for polycythemia 4. Start an alpha-adrenoceptor blocker

8 CASE 1 Lab tests: Plasma normetanephrine: 404 pg/ml (URL: 112) Plasma metanephrine: 23 pg/ml (URL: 61) Additional lab tests also performed: Glucose (fasting): 125 mg/dl EPO: 99 miu/ml (URL: 38) Chromogranin A: 85 ng/ml (URL 50) Abdominal ultrasound: cholelithiasis What would the next step be? 1. Measurement of urinary 5-HIAA 2. Anatomic imaging of the abdomen 3. Clonidine suppression test 4. Bone marrow biopsy

9 CASE 1 Axial contrast enhanced CT showed an adrenal mass (2.5 x 1.9 cm) Axial contrast enhanced CT showed a mass in the organ of Zuckerkandl (1.0 x 0.7 cm)

10 CASE 1 Patient s tumors were surgically removed. Polycythemia improved but not normalized; problems with her diarrhea, hyperglycemia, and digestion persisted. Lab tests: plasma metanephrines normalized, but chromogranin A still elevated at 67 ng/ml (URL: 50). Therefore, she was sent back to an endocrinologist for further evaluation.

11 CASE 1 New lab tests: pancreatic polypeptide,vip, somatostatin, chromogranin A, and gastrin. All normal, except somatostatin: 29 pg/ml (URL: 20) and chromogranin A: 78 ng/ml (URL: 50). What would the next step be? 1. Repeat somatostatin measurement 2. Regular follow-up 3. CT with negative enteric contrast 4. Repeat plasma metanephrine measurement

12 CASE 1 Due to frequent abdominal pain, recurrent diarrhea, some weight loss, and tiredness, abdominal CT with negative enteric contrast was ordered: CT showed a periampullar mass (1 x 1 cm) HIF2A-related new neuroendocrine tumor syndrome In all patients, polycythemia presents at birth or early childhood, EPO levels are always elevated, multiple PHEOs/PGLs, and somatostatinoma always in the 2 nd portion of duodenum. Zhuang et al. NEJM 2012; 367:922

13 Somatostatinoma (SOM): Basic Facts Secretes somatostatin but only in 10% of patients Through somatostatin receptors: Decreases intestinal/gallbladder motility and absorption of nutrients from small intestine, inhibits gastric/pancreatic secretion Duodenal SOMs: 68% in the ampulla of Vater Pancreatic SOMs: 36% in the head, 14% in the body, and 32% in the tail 47% are hereditary (NF1, MEN1, VHL); somatic HIF2A mutation Ganda et al. NEJM 1977; 296:963 Garbrecht et al. Endocr. Relat. Cancer 2008; 15: 229 WHO: Classification of Tumours of Endocrine Organs, 2017 Levy-Bohbot et al. Gastroenterol. Clin. Biol. 2004; 28:1075 Zhuang et al. NEJM 2012; 367:922

14 Somatostatinoma: Clinical features Most common symptoms: abdominal pain, GI bleed, jaundice; but incidentally found in 35% (especially pancreatic ones) Classic SOM syndrome (almost non-existing): Diabetes mellitus, diarrhea, and gallstones May also present with weight loss, hypochlorhydria Diarrhea (usually more than 3 stools a day); steatorrhea (usually more than 7-12 g of fat a day) Metastatic SOM found in tumors larger than 2 cm (often also in those larger than 1 cm) Fisher et al. Gastroenterology 1987; 92:885 Axelrod et al. JCEM 1981; 52:886 Bloom et al. Lancet 1974; 2:1106 Tanaka et al. Pathol. Int. 2000; 50:146 Mullen et al. Surgery 2005; 138:971 Fendrich et al. Surg. Clin. North. Am. 2001; 81:527

15 CASE 2 A 64 y.o. old male initially presented with severe painful, nonpruritic erythematous superficially necrotic and crusted skin lesions, particularly involving the groin, perineum, genital area and spreading to perioral regions, face, and lower extremities. Lesions occurred within the last several years, usually in cycles, starting as erythematous, pustular, then turned black, then necroses with resolution over 1-2 weeks healing with pigmented scars. Lesions did not respond to topical/systemic treatment using corticosteroids, antibiotics, and antifungal medications. He also lost about 15 kg over a period of 6 months.

16 CASE 2 Past medical history: depressive symptoms for last year, frequent urination, especially during night, occasional palpitations and shortness of breath, frequent loose/greasy stool during last few months, irritability, a very low energy level and some muscle weakness (walking, standing up, rising arms). Ataxia. Physical Examination: Multiple lesions found as shown previously, looks tired, depressed; edema on lower extremities. Tongue redness, some hair loss. Malnourished. Weight: 56 kg; height: 180 cm (BMI: 17.3), BP: 105/73, HR: 92.

17 CASE 2 Lab tests: Blood Hb: 9.3 (URL: 11.2); Hct: 30 (URL: 34.1); MCV: 83.1 (URL 79.4); MCH 25.9 (URL: 25.6). Glucose: 135 mg/dl, HbA1c: 7.2% Albumin 2.5 g/dl (URL: 3.5); total protein 4 g/dl (URL: 6.4) Mg 0.7 mmol/l (URL: 0.8) Stool Presence of fat (around 12 g/24 hours) What would the next step be? 1. Referral to a dermatologist 2. Anatomic imaging of the abdomen 3. Anatomic imaging of the abdomen and measurement of specific tumor-related biomarkers 4. First treat anemia and hypoproteinemia

18 CASE 2 Additional laboratory blood tests Glucagon: 380 pmol/l (URL: 23) Pancreatic polypeptide: 182 pg/ml (URL: 114) Chromogranin A: 134 ng/ml (URL: 50) Imaging CT showed a mass in the tail of pancreas (4.5 cm) What would the next step be?

19 CASE 2 Treatment Surgery: refused Octreotide 50 mcg TID and then switched to Sandostatin LAR 100 mg q4 weeks. Nutritional support provided. Disease Course One month later, skin lesions improved and were no longer painful, some disappeared, patient regained weight, no frequent urination, mood improvement. In the years that followed, the primary tumor and metastases progressed. What would the next step be? 1. Chemotherapy using TKIs 2. Radiotherapy using 131 I-MIBG 3. Radiofrequency ablation 4. Radiotherapy using 177 Lu-DOTATATE

20 CASE 2 Treatment Offered peptide receptor radiotherapy (PRRT) using 177 Lu-DOTATATE (Lutathera; total dose: 818 mci). Stable for next 3 years. Disease course Progression of metastatic lesions. Refusing additional treatments, taking zinc and B supplements, and his diabetes is controlled by metformin.

21 Glucagonoma: Clinical Features Classic glucagonoma syndrome represents: Necrolytic migratory erythema (82% of patients), usually starts as an erythematous lesion, progresses to form bullous lesions and ulcerates, skin hyperpigmentation Glossitis, cheilitis, stomatitis, anemia (61%), weight loss (90%) Mild diabetes (80%), hypoaminoacidemia Deep vein thrombosis (50%), depression (50%), anemia (90%) This syndrome also goes by the acronym 4D syndrome: Dermatosis, diabetes, deep vein thrombosis, depression Several metabolic disorders are associated: Zinc, essential fatty acid, and niacin deficiency Protein calorie malnutrition, steatorrhea Wilkinson Proc. R. Soc. Med. 1971; 64:1197 Vinik et al. Endotext 2000 Bloom et al. Am. J. Med. 1987; 82:25 Ito et al. Best Pract. Res. Clin. Gastroenterol. 2012; 26:737 Sweet Br. J. Dermatol. 1974; 90:301

22 Glucagonoma: Behavior Metastatic glucagonomas found in tumors larger than 3 cm; more than 50% of patients have metastasis at initial dx (liver, LN) A high rate of thromboembolic complications; death due to pulmonary embolism A 5- and 10-year survival rate is about 50% and 40%, respectively Wermers et al. Mayo Clin. Proc. 1996; 71:1030 Soga et al. J. Hepatobiliary Pancreat. Surg. 1998; 5;312 Bloom et al. Clin. Endocrinol. 1980; 9;285

23 Glucagonoma: Localization and Treatment NETs cell specific characteristics currently used for their localization 18 F fluorodopa ( 18 F DOPA) 18 F DA 11 C HED 123/131 I MIBG Norepinephrine transporter (NET) L type amino acid transporter L amino acid* decarboxylase Octeotride 68 Ga DOTA analogs (SSTR2) Somatostatin receptors (SSTRs) 18 F DOPA 18 F fluoronorepinephrine Dopamineβ hydroxilase Vesicular monoacid transporter 18 F DA *Inhibited by carbidopa both peripherally and intracellularly Neuroendocrine Cell Vesicle Adapted from Ilias et al. Trends Endocrinol. Metab. 2005; 16:66 and Pacak et al. Endocr. Rev. 2004; 25: FDG Glucose transporters 68 Ga-DOTATATE PET/CT (glucagonomas express high numbers of somatostatin receptors) Somatostatin receptor analogs Radiotherapy using 177 Lu-DOTATATE (Lutathera) Interferon alpha, tyrosine kinase inhibitors Strosberg et al. NEJM 2017; 376:125 Vinik et al. Ther. Adv. Gatroenterol. 2013; 6:396 Sahoo et al. Asia Pac. J. Clin. Oncol. 2014; 10:190 Makis et al. Clin. Nucl. Med. 2015; 40:877

24 CASE 3 A 13 y.o. male presented initially with severe diarrhea, dehydration, fainting, and facial flushing (especially during attacks of diarrhea). Diarrhea: lasting for several months, usually 4-6 times/day; no relation to food intake, odorless, watery, no association with any recent infection, no response to antibiotics, lost about 6 kg. No typical abdominal pain. Occasional nausea and vomiting. Initially no anorexia, at present some days. Often tired, very low energy level, episodes of dizziness. Last month or so more frequent urination and some muscle cramps, paresthesia, and palpitations.

25 CASE 3 Physical examination: Looks sick, tired/lethargic, some facial flushing, more comfortable when sitting, otherwise dizzy. Oral mucosa and skin dry. Weight: 53 kg; height: 178 cm (BMI: 16.7); Lying: BP: 100/60, HR: 98; standing: BP: 89/51, HR: 120. Past medical history: non contributory, no meds, no fever, no travel to tropical areas, laxative abuse, or herbal medicine. What would the next step be? 1. Specific blood and stool laboratory tests 2. Anatomic imaging of the abdomen 3. Octreoscan or 68 Ga-DOTATATE PET 4. Specific blood/stool tests followed by proper hydration

26 CASE 3 Lab tests Blood CBC with diff.: Normal Glucose: 125 mg/dl K: 2.6 mmol/l (URL: 3.4), Ca: 2.58 mmol/l (URL: 2.55) Mg: 0.70 mmol/l (URL: 0.8), HCO 3 : 12 mmol/l (URL: 22) Creatinine: 1.4 mg/dl. Blood ph: 7.23 Stool Appearance: dilute tea, 6 l/day (normal: less than 0.3 l) K: 95 mmol/l (URL: 75), Na: 40 mmol/l (URL: 30) HCO3: 80 mmol/l (URL: 30) Osmolality: 240 (URL: 300 mosm/kg) Osmotic gap: 30 mosm/kg (normal around 50) No fat, blood, mucus, leukocytes, C diff. negative and stool cultivation - negative Any additional tests needed?

27 CASE 3 Imaging MRI w/ and w/o contrast showed 12 mm density in the tail of pancreas as well as small nodules in liver and a 4 cm lesion in hepatic dome Additional blood lab tests: Serotonin: 79 (URL: 300 ng/ml) Histamine: 1.28 (URL: <1 ng/ml) Gastrin: 138 (URL: 115 pg/ml) VIP: (URL: 75 pg/ml) Pancreatic polypeptide: (URL: 200 pg/ml) Substance P: 123 (URL: 1780 pg/ml) Pancreastatin: 106 (URL: 90 pg/ml) Chromogranin A: 145 (URL 50 ng/ml) What would the next step be? 1. Continue with hydration and add octreotide p.o. 2. Octreotide infusion followed by specific imaging/biopsy 3. Loperamide (Imodium), specific imaging/biopsy

28 CASE 3 Treatment Octreotide infusion: 30 mcg/hour, fluid, and K + replacement Imaging Octreoscan: negative Biopsy Liver bx showed neuroendocrine tumor positive for VIP Operation Distal pancreatectomy, histopathology: 1.5 x 1 x 0.8 cm tumor

29 CASE 3 However, after operation, diarrhea persisted. How would you treat diarrhea now? Due to persistent diarrhea the patient was started on octreotide 150 mcg/hr (diarrhea stopped) What would the next step be? 1. Long-term treatment with octreotide (Sandostatin LAR) 2. Offer liver transplant or chemotherapy and octreotide 3. Radiofrequency ablation of a liver lesion

30 CASE 2 Liver transplant as a potential cure option, denied Sunitinib: 37.5 mg/day 4 weeks, 2 weeks off (started) Largest 4 cm lesion 1.8 cm lesion Somatuline (Lanreotide): 120 mg twice/month (started)

31 VIPoma: Facts and clinical features First found in 1958 by Verner and Morrison in a pancreatic tumor: watery diarrhea (first sign), hypokalemia, achlorhydria, and acidosis (acronym: WDHA; also termed pancreatic cholera: resembling Vibrio cholera disease) Other problems: flushing, hypercalcemia, tetany (magnesium depletion), abnormal glucose tolerance Diarrhea: secretory (odorless); 6-8 liters a day, high potassium/sodium, persists with fasting, HCO 3 loss, usually no abdominal pain Localization: pancreas, rarely stomach or duodenum, liver, lung, adrenal, esophagus, colon: usually typical NETs Verner & Morison Am. J. Med. 1958; 25:374 Murray et al. NEJM 1961; 264:436 Vinik Endotext 2000

32 VIP: Action Increases bowel motility Inhibition of gastric acid secretion, increases pancreatic secretion, inhibits sodium, chloride, potassium, and water absorption in the small intestine/colon Stimulation of glycogenolysis Hypercalcemia due to increased bone resorption (50%) Gallbladder relaxation VIP levels: high in diarrhea, dehydration, bowel ischemia, lung ca, PHEO, carcinoids Matsumoto et al. Gastroenterology 1967; 52:965 Verner et al. Arch. Intern. Med. 1974; 133:492 Berbazat et al. Science 1971; 174:422

33 Acknowledgements This presentation was prepared with important contributions from: Prof. A. Vinik, MD, PhD, Eastern Virginia Med. School, Norfolk, USA Prof. Romana Netea-Maier, MD, PhD, Nijmegen, The Netherlands Many thanks to all collaborators for their dedication, passion, and long hours of effort towards those who suffer.