Clinical Case Conference

1. Clinical Case Conference Shivan Mehta, MD August 11, 2010

2. Case • 43M h/o Mulitiple Myeloma, chronic kidney disease presents with 2 weeks of hematochezia.

3. HPI • Initially diagnosed with Multiple Myeloma 1 year prior to presentation. Disease course c/b acute renal failure requiring short course of dialysis. • Presented to outpatient GI with intermittent hematochezia x 2 weeks. Reports bright red blood up to 4 times a day on toilet paper and mixed with stool. No melena. Mild abdominal pain. • ROS significant for 25 lb weight loss, mild abd cramping and pain, no dizziness/lt headedness/chest pain/sob

4. PMH • PMH: Multiple Myeloma (IgA monoclonal gammopathy) c/b CKD presenting with renal failure requiring HD and plasmapheresis. Bone marrow biopsy/ fat pad neg for amyloid. • PSH: None • Allergies: NKDA • Meds: Velcade/Decadron/Cytoxan (1 course 3 months prior), Renagel 800mg tid, Nephrocap 1tab daily, Acyclovir • SH: Works as office manager. Married with no children. Social Etoh. Denies tobacco/illicits • FH: no malignancy or other GI issues

5. Physical Exam • VS- T 97.8, BP 102/63, HR 85, RR 16, 99% RA • Gen- NAD, Ox3, pleasant, comfortable • HEENT- anicteric, pale conjunctivae • CV- RRR, no m/r/g • Chest- CTA b/l • Abd- soft, ND, + BS, mild diffuse TTP • Ext- 1+ lower extremity edema • Rectal- no masses, brown stool with streaks of red blood

6. Labs 140| 106| 36 ------------------< 82 4.5 | 25 | 3.4 8.1 5.8 >-----< 186 24 MCV 88, RDW 16.1 TP 7.4, Alb 3.0 Tbili 1.0, Alk 73 ALT 45, AST 38 PT 13.2, INR 1.1 PTT 26.4 LDH 90

7. Differential Diagnosis • What is your differential diagnosis for hematochezia in a patient with multiple myeloma?

8. Differential Diagnosis • Ischemic colitis • Infectious colitis • CMV, Salmonella, Shigella, Campylobacter, E. Coli, Entameoba • Diverticulosis • AVM • Upper GI bleed • Neoplasm • Adenocarcinoma, Lymphoma, Plasmacytoma • Colonic ulcers • Medications, Idiopathic • GI amyloid • Inflammatory bowel disease • Hemorrhoids

9. EGD • Normal esophagus • Mild antritis-> pathology shows mild lymphocytic infiltrate, otherwise normal. • Normal duodenum

10. Colonoscopy • A large 5cm mass lesion with ulceration was seen in the cecum. • Small fragment of colonic mucosa within normal limits. • Fragment of fibrinopurulent exudate consistent with nearby ulcer. • Additional areas of ulceration were seen in the left colon. • Colonic mucosal biopsies with areas of acute inflammation and ulceration, granulation tissue formation and reactive atypia. • Underlying homogeneous material favor negative for Congo without typical polarization properties

11. Repeat Colonoscopy (1 month) • Resolution of large cecal mass with improvement in ulceration throughout colon. Only areas of mild erythema. • Colonic mucosal biopsies with focal acute inflammation and granulation tissue formation. Submucosal pink amorphous material present which stains with Congo red but does not show characteristic apple-green birefringence. • Addendum: A PAS stain was performed and showed no definitive staining in the amorphous material. A Congo Red stain was repeated and also was negative for apple-green birefringence. Electon microscopy was performed as an aid to evaluate the amorphous material and electron microscopy photographs did not support the presence of amyloid deposition.

12. Clinical Course • 1 month later, patient admitted with multiple episodes of hematochezia. Hemoglobin down to 5.3. Stool studies negative. • CT scan shows: • Transmural wall thickening with pericolonic fat stranding involving the rectum and sigmoid . There is also thickening of the cecum. In addition, this could also represent hemorrhage into the bowel wall in the setting of thrombocytopenia.

13. Repeat Colonoscopy (#3) • There were innumerable medium-sized punched-out ulcers in the rectum, rectosigmoid junction, and sigmoid colon. Appeared to have progressed since prior endoscopy. • Extensive blood, fibrin, and inflammatory cells, with extremely scant epithelial cells. Inadequate tissue to evaluate for amyloid or plasmacytoma.

14. Repeat EGD/Colonoscopy (#4) • EGD normal. • Colonoscopy showed similar ulceration throughout colon with multiple biopsies taken. • Ischemic changes with ulceration, colonic epithelium. Congo red stain negative for amyloid.

15. Differential • With multiple unrevealing biopsies, what do you think is still on the differential for colonic ulcers? • Medication-associated ulcers (Velcade, Acyclovir) • Ischemic ulcers • Infectious ulcers • Amyloid • Plasmacytoma

16. Medication-associated colitis “Acylovir- induced colitis” • 3 cases of hematochezia within 24 hours of starting oral acyclovir (guanosine analog that inhibits viral DNA synthesis) • No other causes was found, and symptoms resolved with cessation • Colonoscopy showed friable mucosa with biopsy revealing ulcerated large bowel • Thought to be caused by local irritation to mucosal surfaces. Wardle TD et al.

17. Medication-associated colitis • Case report of MM patient treated with Velcade (26S proteosome inhibitor) presenting with abdominal pain, hematochezia. • Colonoscopy showed multiple colonic ulcers, with pathology c/w severe interstitial inflammation. • Thought to be iatrogenic colitis 2/2 mucositis. Sinischalchi et al.

18. Intestinal Plasmacytoma • Case reports of plasmacytoma in GI tract causing bleeding. • Extramedullary plasmacytoma account for 4% of plasma cell tumors. • Most occur in stomach and 20-30% in small intestine. • Biopsy shows plasma cell infiltrate, reactive for CD138 (plasma cell marker). • Hypothesis that extramedullary plasmacytomas represent low-grade lymphoma of mucosal lymphoid tissues (MALT) with extensive plasmacytic differentiation. Ammar et al. , Carneiro et al

19. Clinical course • Patient’s bleeding stabilized and he was discharged to home with stable hemoglobin. • Patient received Revlamid, Dexamethasone, but Velcade was stopped due to possible association with ischemic colitis. • Re-admitted 1 month later with abdominal pain, diarrhea, hematochezia. Stool studies negative. EGD/ Flex sig was performed.

20. EGD/Flex Sig (#5) • EGD • Multiple small patchy areas of irregular erosion in the incisura and antrum and on the lesser curvature of the stomach body. • Normal duodenum. • Flex sig • Multiple small ulcers in rectum and circumferential ulcers in sigmoid. Biopsies taken.

21. Pathology

22. Diagnosis • Amyloidosis of the Colon

23. Amyloidosis • Extracellular deposition of protein fibrils with a β-sheet fibrillar structure. • Deposits appear homogeneous and amorphous under light microscope, but produce a green birefringence when stained with Congo red and viewed in polarizing microscope. • Types of Amyloid: • Primary or light-chain associated (AL)- 15% have MM • Secondary or reactive (AA)- chronic inflammatory disorders • Hemodialysis associated (Aβ2M) • Familial amyloid polyneuropathy (ATTR) • Senile amyloidosis Ebert EC et al.

24. Gastrointestinal Amyloid • Amyloid may cause GI symptoms extending from mouth to anus • Amyloid deposition in the GI tract is near universal in systemic AL amyloidosis, but only 30-60% develop GI symptoms. • When GI tract is involved, frequency of amyloid in biopsy specimens area 100% in the duodenum, 95% in the stomach, 91% in the colorectum, and 72% in the esophagus. Best in blood vessel wall. • Endoscopically, AL typically forms polypoid protrusions, while AA amyloidosis is characterized by a fine granular appearance Sleisinger and Fordtran., Menke DM et al., Tada S et al., James et al.

25. GI manifestations Signs/ symptoms Amyloid deposition • Ulcers • Erosions • Polypoid lesions • Submucosal hemorrhage • Dysphagia • Gastroparesis • Constipation, • Pseudo-obstruction • Nausea/vomiting • Weight loss • Diarrhea • Steatorrhea • Protein-losing enteropathy GI bleeding Blood vessel wall Dysmotility Muscle layers Malabsorption Mucosa Ebert et al.

26. Prognosis/ Treatment • Median survival for AL amyloidosis less than 2 years, if treated with melphalan and prednisone • 5-year survival improved to 60% with hematopoietic stem cell transplantation • Treatment of AL involves chemotherapy, while AA involved treatment of underlying disease.

27. Follow-up Course • After amyloid diagnosis, pt given Etoposide, Cyclophosphamide, Dexamethasone. • 2 weeks after EGD/Colonoscopy, pt with fevers, abdominal pain, hypotension. KUB showed no perforation. • Patient went to the OR. Ex-lap, lysis of adhesions, diverting ileostomy, and blow-hole colostomy was performed, but colectomy deferred due to patient instability. • Pt with prolonged post-operative hospital course. Re-started on Revlamid. On HD. Just discharged to home.

28. References • Ammar T et al. “Primary Antral Duodenal Extramedullary Plasmacytoma Presenting With Melena” Clinical Gastroenterology and Hepatology. 2010;8:xxxii • Carneiro FP et al. “Extramedullary plasmocytoma associated with a massive deposit of amyloid in the duodenum.” World J Gastroenterol 2009 July 28; 15(28): 3565-3568 • Ebert EC et al. “Gastrointestinal Manifestations of Amyloidosis.” Am J Gastroenterol 2008;103:776–787 • James DG et al. “Clinical Recognition of AL Type Amyloidosis of the Luminal Gastrointestinal Tract” Clinical Gastroenterology and Hepatology. 2007; 5:582–588. • Maza I et al. “Rectal bleeding as a presenting symptom of AL amyloidosis and multiple myeloma” World J Gastrointest Endosc 2010 January 16; 2(1): 44-46. • Menke DM et al. “Symptomatic gastric amyloidosis in patients with primary systemic amyloidosis.” Mayo Clin Proc 1993 Aug; 68(8):763-7. • Sinischalchi A et al. “Bortezomib-related colon mucositis in a multiple myeloma patient” Support Care Cancer (2009) 17:325–327. • Sleisenger and Fordtran’s “Gastrointestinal and Liver Disease” Ninth ed, 2010. • Tada S et al. “Endoscopic and biopsy findings of the upper digestive tract in patients with amyloidosis.” Gastrointest Endosc 1990 Jan-Feb;36(1):10-4. • Wardle TD et al. “Acyclovir-induced colitis” Aliment Pharmacol Ther. 1997 (11): 415-417