Clinical Case Clinical Case ConferenceConferenceShivan Mehta, MDShivan Mehta, MD

August 11, 2010August 11, 2010

CaseCase

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

HPIHPI Initially diagnosed with Multiple Myeloma 1 Initially diagnosed with Multiple Myeloma 1

year prior to presentation. Disease course year prior to presentation. Disease course c/b acute renal failure requiring short c/b acute renal failure requiring short course of dialysis.course of dialysis.

Presented to outpatient GI with intermittent Presented to outpatient GI with intermittent hematochezia x 2 weeks. Reports bright red hematochezia x 2 weeks. Reports bright red blood up to 4 times a day on toilet paper blood up to 4 times a day on toilet paper and mixed with stool. No melena. Mild and mixed with stool. No melena. Mild abdominal pain.abdominal pain.

ROS significant for 25 lb weight loss, mild ROS significant for 25 lb weight loss, mild abd cramping and pain, no dizziness/lt abd cramping and pain, no dizziness/lt headedness/chest pain/sobheadedness/chest pain/sob

PMHPMH PMH: Multiple Myeloma (IgA monoclonal PMH: Multiple Myeloma (IgA monoclonal

gammopathy) c/b CKD presenting with renal gammopathy) c/b CKD presenting with renal failure requiring HD and plasmapheresis. failure requiring HD and plasmapheresis. Bone marrow biopsy/ fat pad neg for Bone marrow biopsy/ fat pad neg for amyloid.amyloid.

PSH: NonePSH: None Allergies: NKDAAllergies: NKDA Meds: Velcade/Decadron/Cytoxan (1 course Meds: Velcade/Decadron/Cytoxan (1 course

3 months prior), Renagel 800mg tid, 3 months prior), Renagel 800mg tid, Nephrocap 1tab daily, AcyclovirNephrocap 1tab daily, Acyclovir

SH: Works as office manager. Married with SH: Works as office manager. Married with no children. Social Etoh. Denies no children. Social Etoh. Denies tobacco/illicitstobacco/illicits

FH: no malignancy or other GI issuesFH: no malignancy or other GI issues

Physical ExamPhysical Exam VS- T 97.8, BP 102/63, HR 85, RR 16, 99% VS- T 97.8, BP 102/63, HR 85, RR 16, 99%

RA RA Gen- NAD, Ox3, pleasant, comfortableGen- NAD, Ox3, pleasant, comfortable HEENT- anicteric, pale conjunctivaeHEENT- anicteric, pale conjunctivae CV- RRR, no m/r/gCV- RRR, no m/r/g Chest- CTA b/lChest- CTA b/l Abd- soft, ND, + BS, mild diffuse TTPAbd- soft, ND, + BS, mild diffuse TTP Ext- 1+ lower extremity edemaExt- 1+ lower extremity edema Rectal- no masses, brown stool with Rectal- no masses, brown stool with

streaks of red bloodstreaks of red blood

LabsLabs

140| 106| 36140| 106| 36

------------------< 82------------------< 82

4.5 | 25 | 3.44.5 | 25 | 3.4

8.18.1

5.8 >-----< 1865.8 >-----< 186

2424

MCV 88, RDW 16.1MCV 88, RDW 16.1

TP 7.4, Alb 3.0TP 7.4, Alb 3.0

Tbili 1.0, Alk 73Tbili 1.0, Alk 73

ALT 45, AST 38ALT 45, AST 38

PT 13.2, INR 1.1PT 13.2, INR 1.1

PTT 26.4PTT 26.4

LDH 90LDH 90

Differential DiagnosisDifferential Diagnosis

What is your differential diagnosis What is your differential diagnosis for hematochezia in a patient with for hematochezia in a patient with multiple myeloma?multiple myeloma?

Differential DiagnosisDifferential Diagnosis Ischemic colitisIschemic colitis Infectious colitisInfectious colitis

CMV, Salmonella, Shigella, Campylobacter, E. Coli, CMV, Salmonella, Shigella, Campylobacter, E. Coli, EntameobaEntameoba

DiverticulosisDiverticulosis AVMAVM Upper GI bleedUpper GI bleed NeoplasmNeoplasm

Adenocarcinoma, Lymphoma, PlasmacytomaAdenocarcinoma, Lymphoma, Plasmacytoma Colonic ulcersColonic ulcers

Medications, IdiopathicMedications, Idiopathic GI amyloidGI amyloid Inflammatory bowel diseaseInflammatory bowel disease HemorrhoidsHemorrhoids

EGDEGD

Normal esophagusNormal esophagus Mild antritis-> pathology shows mild Mild antritis-> pathology shows mild

lymphocytic infiltrate, otherwise normal.lymphocytic infiltrate, otherwise normal. Normal duodenumNormal duodenum

ColonoscopyColonoscopy

A large 5cm mass lesion with ulceration was seen in the cecum.A large 5cm mass lesion with ulceration was seen in the cecum. Small fragment of colonic mucosa within normal limits.Small fragment of colonic mucosa within normal limits. Fragment of fibrinopurulent exudate consistent with nearby ulcer.Fragment of fibrinopurulent exudate consistent with nearby ulcer.

Additional areas of ulceration were seen in the left colon.Additional areas of ulceration were seen in the left colon. Colonic mucosal biopsies with areas of acute inflammation and Colonic mucosal biopsies with areas of acute inflammation and

ulceration, granulation tissue formation and reactive atypia.ulceration, granulation tissue formation and reactive atypia. Underlying homogeneous material favor negative for Congo Underlying homogeneous material favor negative for Congo

without typical polarization propertieswithout typical polarization properties

Repeat Colonoscopy (1 Repeat Colonoscopy (1 month)month)

•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.

Resolution of large cecal mass with improvement in ulceration throughout colon. Only areas of mild erythema.

Clinical CourseClinical Course

1 month later, patient admitted with 1 month later, patient admitted with multiple episodes of hematochezia. multiple episodes of hematochezia. Hemoglobin down to 5.3. Stool studies Hemoglobin down to 5.3. Stool studies negative.negative.

CT scan shows:CT scan shows: Transmural wall thickening with pericolonic Transmural wall thickening with pericolonic

fat stranding involving the rectum and fat stranding involving the rectum and sigmoid . There is also thickening of the sigmoid . There is also thickening of the cecum. In addition, this could also represent cecum. In addition, this could also represent hemorrhage into the bowel wall in the setting hemorrhage into the bowel wall in the setting of thrombocytopenia.of thrombocytopenia.

Repeat Colonoscopy (#3)Repeat Colonoscopy (#3)

There were innumerable medium-sized punched-There were innumerable medium-sized punched-out ulcers in the rectum, rectosigmoid junction, out ulcers in the rectum, rectosigmoid junction, and sigmoid colon. Appeared to have progressed and sigmoid colon. Appeared to have progressed since prior endoscopy.since prior endoscopy. Extensive blood, fibrin, and inflammatory cells, with Extensive blood, fibrin, and inflammatory cells, with

extremely scant epithelial cells. Inadequate tissue to extremely scant epithelial cells. Inadequate tissue to evaluate for amyloid or plasmacytoma.evaluate for amyloid or plasmacytoma.

Repeat EGD/Colonoscopy Repeat EGD/Colonoscopy (#4)(#4)

EGD normal.EGD normal. Colonoscopy showed similar ulceration Colonoscopy showed similar ulceration

throughout colon with multiple biopsies taken. throughout colon with multiple biopsies taken.

Ischemic changes with ulceration, colonic epithelium. Ischemic changes with ulceration, colonic epithelium. Congo red stain negative for amyloid.Congo red stain negative for amyloid.

DifferentialDifferential

With multiple unrevealing biopsies, With multiple unrevealing biopsies, what do you think is still on the what do you think is still on the differential for colonic ulcers?differential for colonic ulcers? Medication-associated ulcers (Velcade, Medication-associated ulcers (Velcade,

Acyclovir)Acyclovir) Ischemic ulcersIschemic ulcers Infectious ulcersInfectious ulcers AmyloidAmyloid PlasmacytomaPlasmacytoma

Medication-associated Medication-associated colitiscolitis

““Acylovir- induced colitis”Acylovir- induced colitis” 3 cases of hematochezia within 24 3 cases of hematochezia within 24

hours of starting oral acyclovir hours of starting oral acyclovir (guanosine analog that inhibits viral (guanosine analog that inhibits viral DNA synthesis)DNA synthesis)

No other causes was found, and No other causes was found, and symptoms resolved with cessationsymptoms resolved with cessation

Colonoscopy showed friable mucosa Colonoscopy showed friable mucosa with biopsy revealing ulcerated with biopsy revealing ulcerated large bowellarge bowel

Thought to be caused by local Thought to be caused by local irritation to mucosal surfaces.irritation to mucosal surfaces.

Wardle TD et al.

Medication-associated Medication-associated colitiscolitis

Case report of MM patient treated with Velcade Case report of MM patient treated with Velcade (26S proteosome inhibitor) presenting with (26S proteosome inhibitor) presenting with abdominal pain, hematochezia.abdominal pain, hematochezia.

Colonoscopy showed multiple colonic ulcers, with Colonoscopy showed multiple colonic ulcers, with pathology c/w severe interstitial inflammation.pathology c/w severe interstitial inflammation.

Thought to be iatrogenic colitis 2/2 mucositis.Thought to be iatrogenic colitis 2/2 mucositis.

Sinischalchi et al.

Intestinal PlasmacytomaIntestinal Plasmacytoma Case reports of plasmacytoma in GI Case reports of plasmacytoma in GI

tract causing bleeding.tract causing bleeding. Extramedullary plasmacytoma account Extramedullary plasmacytoma account

for 4% of plasma cell tumors.for 4% of plasma cell tumors. Most occur in stomach and 20-30% in Most occur in stomach and 20-30% in

small intestine.small intestine. Biopsy shows plasma cell infiltrate, Biopsy shows plasma cell infiltrate,

reactive for CD138 (plasma cell reactive for CD138 (plasma cell marker).marker).

Hypothesis that extramedullary Hypothesis that extramedullary plasmacytomas represent low-grade plasmacytomas represent low-grade lymphoma of mucosal lymphoid tissues lymphoma of mucosal lymphoid tissues (MALT) with extensive plasmacytic (MALT) with extensive plasmacytic differentiation. differentiation.

Ammar et al. , Carneiro et al

Clinical courseClinical course

Patient’s bleeding stabilized and he was Patient’s bleeding stabilized and he was discharged to home with stable discharged to home with stable hemoglobin.hemoglobin.

Patient received Revlamid, Patient received Revlamid, Dexamethasone, but Velcade was stopped Dexamethasone, but Velcade was stopped due to possible association with ischemic due to possible association with ischemic colitis.colitis.

Re-admitted 1 month later with abdominal Re-admitted 1 month later with abdominal pain, diarrhea, hematochezia. Stool studies pain, diarrhea, hematochezia. Stool studies negative. EGD/ Flex sig was performed.negative. EGD/ Flex sig was performed.

EGD/Flex Sig (#5)EGD/Flex Sig (#5) EGDEGD

Multiple small patchy Multiple small patchy areas of irregular areas of irregular erosion in the incisura erosion in the incisura and antrum and on the and antrum and on the lesser curvature of the lesser curvature of the stomach body.stomach body.

Normal duodenum.Normal duodenum.

Flex sigFlex sig Multiple small ulcers in Multiple small ulcers in

rectum and rectum and circumferential ulcers in circumferential ulcers in sigmoid. Biopsies taken.sigmoid. Biopsies taken.

PathologyPathology

DiagnosisDiagnosis

Amyloidosis of the ColonAmyloidosis of the Colon

AmyloidosisAmyloidosis Extracellular deposition of protein Extracellular deposition of protein

fibrils with a fibrils with a ββ-sheet fibrillar -sheet fibrillar structure.structure.

Deposits appear homogeneous and Deposits appear homogeneous and amorphous under light microscope, amorphous under light microscope, but produce a green birefringence but produce a green birefringence when stained with Congo red and when stained with Congo red and viewed in polarizing microscope.viewed in polarizing microscope.

Ebert EC et al.

Types of Amyloid:Types of Amyloid:•Primary or light-chain associated (AL)- 15% Primary or light-chain associated (AL)- 15% have MMhave MM•Secondary or reactive (AA)- chronic Secondary or reactive (AA)- chronic inflammatory disordersinflammatory disorders•Hemodialysis associated (AHemodialysis associated (Aββ2M)2M)•Familial amyloid polyneuropathy (ATTR)Familial amyloid polyneuropathy (ATTR)•Senile amyloidosisSenile amyloidosis

Gastrointestinal AmyloidGastrointestinal Amyloid Amyloid may cause GI symptoms extending Amyloid may cause GI symptoms extending

from mouth to anusfrom mouth to anus Amyloid deposition in the GI tract is near Amyloid deposition in the GI tract is near

universal in systemic AL amyloidosis, but universal in systemic AL amyloidosis, but only 30-60% develop GI symptoms.only 30-60% develop GI symptoms.

When GI tract is involved, frequency of When GI tract is involved, frequency of amyloid in biopsy specimens area 100% in amyloid in biopsy specimens area 100% in the duodenum, 95% in the stomach, 91% in the duodenum, 95% in the stomach, 91% in the colorectum, and 72% in the esophagus. the colorectum, and 72% in the esophagus. Best in blood vessel wall.Best in blood vessel wall.

Endoscopically, AL typically forms polypoid Endoscopically, AL typically forms polypoid protrusions, while AA amyloidosis is protrusions, while AA amyloidosis is characterized by a fine granular appearancecharacterized by a fine granular appearance

Sleisinger and Fordtran., Menke DM et al., Tada S et al., James et al.

GI manifestationsGI manifestations

UlcersUlcers Erosions Erosions Polypoid lesionsPolypoid lesions Submucosal Submucosal

hemorrhagehemorrhage

DysphagiaDysphagia GastroparesisGastroparesis Constipation, Constipation, Pseudo-obstructionPseudo-obstruction Nausea/vomitingNausea/vomiting

Weight lossWeight loss DiarrheaDiarrhea SteatorrheaSteatorrhea Protein-losing Protein-losing

enteropathyenteropathy

Ebert et al.

Amyloid deposition

Signs/ symptoms

Blood vessel wall

Muscle layers

Mucosa

GI bleeding

Dysmotility

Malabsorption

Prognosis/ TreatmentPrognosis/ Treatment

Median survival for AL amyloidosis Median survival for AL amyloidosis less than 2 years, if treated with less than 2 years, if treated with melphalan and prednisonemelphalan and prednisone 5-year survival improved to 60% with 5-year survival improved to 60% with

hematopoietic stem cell transplantationhematopoietic stem cell transplantation Treatment of AL involves Treatment of AL involves

chemotherapy, while AA involved chemotherapy, while AA involved treatment of underlying disease.treatment of underlying disease.

Follow-up CourseFollow-up Course After amyloid diagnosis, pt given Etoposide, After amyloid diagnosis, pt given Etoposide,

Cyclophosphamide, Dexamethasone.Cyclophosphamide, Dexamethasone. 2 weeks after EGD/Colonoscopy, pt with 2 weeks after EGD/Colonoscopy, pt with

fevers, abdominal pain, hypotension. KUB fevers, abdominal pain, hypotension. KUB showed no perforation.showed no perforation.

Patient went to the OR. Ex-lap, lysis of Patient went to the OR. Ex-lap, lysis of adhesions, diverting ileostomy, and blow-adhesions, diverting ileostomy, and blow-hole colostomy was performed, but hole colostomy was performed, but colectomy deferred due to patient instability.colectomy deferred due to patient instability.

Pt with prolonged post-operative hospital Pt with prolonged post-operative hospital course. Re-started on Revlamid. On HD. Just course. Re-started on Revlamid. On HD. Just discharged to home.discharged to home.

ReferencesReferences Ammar T et al. “Primary Antral Duodenal Extramedullary Plasmacytoma Ammar T et al. “Primary Antral Duodenal Extramedullary Plasmacytoma

Presenting With Melena” Clinical Gastroenterology and Hepatology. Presenting With Melena” Clinical Gastroenterology and Hepatology. 2010;8:xxxii2010;8:xxxii

Carneiro FP et al. “Extramedullary plasmocytoma associated with a massive Carneiro FP et al. “Extramedullary plasmocytoma associated with a massive deposit of amyloid in the duodenum.” World J Gastroenterol 2009 July 28; deposit of amyloid in the duodenum.” World J Gastroenterol 2009 July 28; 15(28): 3565-356815(28): 3565-3568

Ebert EC et al. “Gastrointestinal Manifestations of Amyloidosis.” Am J Ebert EC et al. “Gastrointestinal Manifestations of Amyloidosis.” Am J Gastroenterol 2008;103:776–787Gastroenterol 2008;103:776–787

James DG et al. “Clinical Recognition of AL Type Amyloidosis of the Luminal James DG et al. “Clinical Recognition of AL Type Amyloidosis of the Luminal Gastrointestinal Tract” Clinical Gastroenterology and Hepatology. 2007; Gastrointestinal Tract” Clinical Gastroenterology and Hepatology. 2007; 5:582–588.5:582–588.

Maza I et al. “Rectal bleeding as a presenting symptom of AL amyloidosis 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): and multiple myeloma” World J Gastrointest Endosc 2010 January 16; 2(1): 44-46.44-46.

Menke DM et al. “Symptomatic gastric amyloidosis in patients with primary Menke DM et al. “Symptomatic gastric amyloidosis in patients with primary systemic amyloidosis.” systemic amyloidosis.” Mayo Clin Proc 1993 Aug; 68(8):763-7.Mayo Clin Proc 1993 Aug; 68(8):763-7.

Sinischalchi A et al. “Bortezomib-related colon mucositis in a multiple Sinischalchi A et al. “Bortezomib-related colon mucositis in a multiple myeloma patient” Support Care Cancer (2009) 17:325–327.myeloma patient” Support Care Cancer (2009) 17:325–327.

Sleisenger and Fordtran’s “Gastrointestinal and Liver Disease” Ninth ed, Sleisenger and Fordtran’s “Gastrointestinal and Liver Disease” Ninth ed, 2010.2010.

Tada S et al. “Endoscopic and biopsy findings of the upper digestive tract in 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.patients with amyloidosis.” Gastrointest Endosc 1990 Jan-Feb;36(1):10-4.

Wardle TD et al. “Acyclovir-induced colitis” Aliment Pharmacol Ther. 1997 Wardle TD et al. “Acyclovir-induced colitis” Aliment Pharmacol Ther. 1997 (11): 415-417(11): 415-417