Rare GI Malignancies

Transcription

1 Rare GI Malignancies Jordan Karlitz, MD Associate Professor of Medicine, Division of Gastroenterology Director, Hereditary GI Cancer and Genetics Program Tulane University School of Medicine

2 Outline Gastrointestinal Stromal Tumors (GISTs) Mucosal Associated Lymphoid Tissue Tumors (MALT). Neuroendocrine Tumors (NETs) and Pancreatic Neuroendocrine Tumors (PNETs)

3 Outline Clinical Presentation Diagnosis Treatment Prognosis/Survival tumors relatively rare so epidemiology not as robust as more common tumors.

4 GIST Gastrointestinal Stromal Tumors 2 categories of stromal/mesenchymal tumors (tumors arising from stromal/mesenchymal components of GI tract) 1) GIST any portion GI tract but usually stomach >> proximal small bowel. 2) Others lipoma, leiomyoma (benign smooth muscle tumor), schwannomas etc. Mesenchymal=diffuse network of cells forming the embryonic mesoderm and giving rise to connective tissue, muscle, blood and blood vessels and lymphatic system.

5 GISTs and other mesenchymal tumors are submucosal

6 GIST continued 6,000 new cases per year in USA likely underestimate as we may be missing smaller lesions. GISTs initially thought to arise from smooth muscle and were confused with leiomyomas. With advances in molecular biology, GISTs became better defined. Main distinguishing characteristic is the almost universal expression of CD117 antigen (leiomyomas and other submucosal lesions do not express this).

7 CD117 part of the KIT transmembrane receptor tyrosine kinase, which is a product of the c KIT protooncogene. Mutation leads to activation (gain of function) of tyrosine kinase protein (sporadic>hereditary). Those GISTs that are not CD117 positive have mutations in other proteins that play a similar role in oncogenic stimulation. Gleevac (Imatinib) is a tyrosine kinase inhibitor and targets GISTs but not other submucosal lesions (i.e. leiomyomas).

8 GISTs are thought to arise from stem cells within the gut wall whose future differentiation would be towards the interstitial cells of Cajal (ICC). ICC have both smooth muscle and neuronal differentiation and serve as the GI pacemaker cells, regulating peristalsis.

9 Histology Spindle cell (elongated nuclei) 70% Epitheliod (oval/round nuclei) 20% Mixed 10% Molecular studies (i.e. CD117) are more important.

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11 Behavior Depends on size, mitotic rate and location (SI more aggressive than stomach). Not defined simply as benign or malignant, but more of a spectrum of aggressive behavior (metastases, risk of recurrence post resection) based on above. Even small GISTs (i.e. 1 cm) can behave in a malignant fashion. Clinical manifestations range from no symptoms to bleeding, abdominal mass, abdominal pain.

12 Risk of aggression size Mitotic count Very low risk < 2cm <5 per 50 HPF Low risk 2-5 cm <5 per 50 HPF Intermediate High risk <5 cm 5-10 cm >5 cm >10 cm Any size 6-10 per 50HPF <5 per 50 HPF >5 per 50 HPF Any mitotic rate >10 per 50 HPF

13 Diagnosis Various imaging tests including CT and PET scan. EGD/EUS EUS can help to distinguish GISTs from other submucosal lesions. GISTs arise from the muscularis propria.

14 epithelium Lamina propria Muscularis mucosa submucosa Muscularis propria Mucosa=epithelium + lamina propria

15 GI tract wall layers Mucosa (carcinoid) Muscularis mucosa/lamina propria (carcinoid) Submucosa (lipoma, cysts, varices, carcinoid) Muscularis propria (GIST) Carinoids, GISTS Hypoechoic (dark) Lipoma Hyperechoic (bright) Muscle dark

16 Lipoma in submucosahyperechoic lesion In hyperechoic layer Muscularis propria hypoechoic layer

17 Hypoechoic lesion from muscularis propria=gist

18 Management All gastric GISTS >2 cm surgical removal. (****some say resect all sizes, even < 1 cm) < 2 cm controversial as growth rate and metastatic potential is unclear. < 2 cm? Follow endoscopically,? remove endoscopically,? Remove surgically. Endoscopic removal also controversial due to risk of + margin and tumor spillage.

19 Larger GISTs can be quite aggressive and even after surgery with negative margins the recurrence rate can be high (55% at 5 years for larger lesions).

20 Gleevac/Imatinib Tyrosine kinase inhibitors. Decreases post operative recurrence as adjuvant therapy. Neoadjuvant therapy to shrink GISTs prior to surgery also used in some cases. Used in metatstatic disease with success but can get Gleevac resistance eventually. Following the introduction of imatinib, the median survival of advanced GIST was 60 months.

21 MALT Lymphoma Mucosa Associated Lymphoid Tissue=MALT= lymphoid tissue of the gut MALT tissue is organized in a similar fashion to lymphoid tissue elsewhere in the body. Lymphoma in MALT tissue usually arises from B cells in the marginal zone. The term MALT lymphoma is often used interchangeably with marginal zone B cell lymphoma.

22 Diffuse large B cell lymphomas of the stomach may evolve from MALT lymphomas, however others have no relation to the marginal zone of MALT tissue.

23 Normal Lymphoid Tissue Structure Marginal zone Follicle center Marginal zone magnified

24 Gastric tissue does not normally contain MALT but may acquire it in response to H. Pylori infection. MALT tissue that is induced by H. Pylori transforms to a lymphoma in a small percentage of patients. MALT lymphomas are usually low grade and can regress after H. Pylori treatment. Occasionally they can be quite aggressive and won t respond to antibiotics.

25 Epidemiology MALT lymphoma accounts for 40% of all gastric lymphomas (45 50% are Large B cell lymphoma). Incidence in H. Pylori infected patients is 1:30,000 to 1:80,000. Median age 60 Male=female H. pylori present in biopsy of 90% of MALT lymphoma cases and serology is + in 98%

26 Pathogenesis/pathology H. pylori induces gastritis and development of MALT tissue. H. Pylori specific T cells promote growth and recruitment of abnormal B cell clones that can grow autonomously, even after H. Pylori is eradicated in some cases. 41% in antrum Multifocal in 33% Ulcers 47% Erythema 30%

27 See lymphoid lesions that invade and destroy gastric glands and crypts. Lymphocytes tend to have cytologic atypia. Express pan B cell antigens including CD19,20,79.

28 MALT Lymphoma

29 lymphoma

30 Magnified view

31 Diagnosis/Staging EGD with biopsy and H. Pylori testing. Other tests include CT, bone marrow biopsy, LDH=staging. EUS to assess extent of stomach wall involvement. 90% are stage 1= gastric wall (can range from mucosa alone or extend all the way to serosa). Stage 2=LNs Stage 3=Adjacent organs Stage 4=Disseminated

32 Stage 1: survival is 80 95% at 5 years. Stage 1: Prognosis worsens in stage 1 if disease extends deeper to serosa.

33 Treatment H. Pylori treatment is mainstay in early stage disease with 50 80% remission. XRT/Chemo/Surgery is reserved for more advanced disease or for early stage disease that doesn t regress with antibiotics or if H. pylori negative or certain chromosomal translocations.

34 Neuroendocrine Tumors (NETs) and Pancreatic Neuroendocrine Tumors (PNETs) NET/PNET arise from neuroendocrine cells. Neuroendocrine cell cells that receive neuronal input and in turn, release hormones to the blood. Can be functional (hormone based syndromesi.e. carcinoid syndrome) or non functional. NET= carcinoid (most common NET/PNET). PNET= gastrinoma, insulinoma, somatostatinoma, VIPoma, glucogonoma.

35 NETs/PNETs can be part of hereditary syndromes Multiple endocrine neoplasia syndrome (MEN) pancreas, pituitary, parathyroid. I.e. Gastrinoma. Neurofibromatosis somatostatinomas Tuberous Sclerosis PNETs Von Hippel Lindau PNETs

36 NETs/PNETS diagnosis Seen on EGD and colonoscopy (carcinoids). Picked up on body imaging incidentally (PNETs) or for symptoms. Neuroendocrine markers Chromogranin A (tumor diagnosis NETs/PNETs and response to treatment). Carcinoid syndrome serum serotonin, urine 5 HIAA (5 hydroxyindoleacetic Acid).

37 NETs/PNETs diagnosis continued PNETs gastrin, insulin etc. (see later) NET/PNET specific imaging=octreoscan NETs and PNETS often have somatostatin receptors (hormone that decreases release of many GI hormones). Octreoscan Octreotide (similar to somatostatin) is radiolabelled, injected into vein and binds NETs/PNETs.

38 Small Carcinoid Octreoscan

39 Rectal Carcinoid

40 Carcinoids (NET) Incidence about 5/100,000 per year, but increasing over time. 45% in small bowel 31% in colorectal (10% colon, 21% rectum). 16% appendix 7% in stomach Non functional (no symptoms due to hormones) > functional (carcinoid syndrome diarrhea, flushing, wheezing). Location important factor for prognosis.

41 Gastric Carcinoids not all the same 75% type 1 associated with pernicious anemia (atrophic gastritis). high PH with secondary increased gastrin. Metastases rare. Generally EMR if small. Indolent behavior. Current status of gastrointestinal carcinoids. Gastroenterology May;128(6):

42 Gastric Carcinoids not all the same 5 10% type 2 associated with gastrinoma with increased gastrin and low PH. Metastases rare. Generally EMR if small. Indolent behavior.

43 Gastric Carcinoids not all the same 15 25% type 3 normal gastrin and PH. More aggressive. Often require surgery. 65% metastases at time of surgery. Overall 5 year survival type 3 < 35%.

44 Mid gut carcinoids Ileum > jejenum 25% have more than one SB lesion. Frequently associated with carcinoid syndrome if liver metastases (functional tumor). Metastases common, especially if > 1 cm in size (70% metastases if > 1 cm). Median survival with metastases is 103 months. Treatment resection of SB and mesentery.

45 Appendiceal Carcinoids Most common tumor of appendix. Not as frequently associated with metastases c/w small bowel. Appendectomy if < 2 cm, right hemicolectomy if > 2 cm. 5 year survival overall of 98%.

46 Colonic Carcinoids Frequently seen in rectum during colonoscopy If rectal and < 1 cm and confined to mucosa/submucosa, metastases infrequent. EMR (Endoscopic mucosal resection). Rectal 1 2 cm, metastases in 6%. Possible EMR. Rectal > 2 cm, metastases 24%. Surgery. Rest of colon frequently surgery. Overall 5 year survival 62% for colon, 87% for rectum.

47 Gastrinoma/Zollinger Ellison Syndrome cases per 1 million people per year. Tumor releasing gastrin despite already low gastric PH (inappropriate gastrin release). Tumor in pancreas or duodenum. High gastric output with gastric and small bowel ulcerations and diarrhea. 25% associated with multiple endocrine neoplasia syndrome. < 1/1000 duodenal ulcers associated with ZES (consider if no NSAIDS, no H. pylori).

48 Gastrinoma Diagnosis High gastrin level in setting of low gastric (acidic) PH. Secretin stimulation test secretin stimulates gastric G cells to secrete gastrin (see very high levels of gastrin). Octreoscan EUS Rule out MEN syndrome

49 Gastrinoma treatment/prognosis High dose PPI Surgery Patients with liver metastases have a 10 year survival of 30 percent compared with a 15 year survival of 83 percent in those without liver metastases.

50 Insulinoma Most common PNET 4 cases per 1 million people per year Always in pancreas Secrete insulin inappropriately with resultant hypoglycemia with typical associated symptoms. Associated with MEN 1

51 Insulinoma Diagnosis and treatment Octreoscan often negative compared to other PNETS because few somatostatin receptors. EUS helpful Treat with surgery NIH cases series some patients with insulinoma, even if metastatic, can live up to 25 years.

52 Other PNETS, very rare Glucogonoma 1 in 1 10 million people per year Increased glucagon associated with hyperglycemia and migratory necrolytic erythema (rash). Somatostatin analogues (octreotide) inhibit hormone release and are used for treatment (mainly for symptoms). Surgery Most metastatic at time of diagnosis however these patients can live 4 5 years or longer after diagnosis per case series reports.

53 Migratory necrolytic erythema

54 Somatostatinoma 1 in 40 million people per year. Can occur outside pancreas. High somatostatin levels impede release of multiple hormones with resultant malabsorption, weight loss. Associated with MEN 1 and neurofibromatosis I (von Recklinghausen disease). Somatostatin analogues (octreotide) inhibit VIP release and are used for treatment (symptom control). Surgery 70 92% present with metastatic disease with 15%, 5 year survival in stage 4 disease.

55 VIPoma 1 in 10 million people per year. Increased vasoactive intestinal polypeptide. Large volume, watery diarrhea. Hypokalemia MEN type 1 in 5%. Somatostatin analogues (octreotide) inhibit VIP release and are used for treatment (symptom control). Surgery Median survival is 96 months

56 Conclusions GIST, MALT lymphoma, carcinoids relatively rare but picked up more frequently with increased endoscopy, imaging. PNETs rare. Epidemiologic data regarding incidence and prognosis not as robust as more common conditions. Size (i.e. GISTs), location (i.e. carcinoids), histology (i.e. GISTs) play important role in aggressivity. Association with hereditary syndromes rule these out.