Small Bowel LymphomaSeptember 15, 2011

UB Department of Surgery

Grand Rounds

Craig Collins MD

Anatomy/PhysiologyPathogenesisBackgroundIncidenceRisk FactorsDiagnosisManagementPrognosisTake Home PointsFuture

Outline

Anatomy/Physiology

Small Bowel ~3mDuodenum ~20-30cmJejunum ~100-110cmIleum ~ 150cm

Blood supply based upon celiac axis and superior mesenteric artery (SMA). Venous return via superior mesenteric vein (SMV).

Anatomy/Physiology

Layers of Small BowelMucosaSubmucosaMuscularisSerosa

Anatomy/Physiology

Spiral folds of mucosa and submucosa (plicae circularis) are more prominent proximally.

Jejunum is larger in diameter, is generally thicker, and has more prominent mucosal folds.

Peyer’s Patches (lymphoid tissue) found in submucosal layer and become more prominent distally in the Ileum.

Anatomy/Physiology

Primary functions are digestion, absorption, and motility.

Endocrine function (CCK, secretin, other peptides)

Immune function via secretion of IgA from Peyer's patches.

Anatomy/Physiology

Small bowel accounts for 75% of GI tract length and 90% of mucosal surface.

Accounts for 3-6% of GI tract tumors and 1-3% of all malignant GI tumors.

2/3 of symptomatic GI tract tumors are malignant.

Majority of benign lesions are asymptomatic and are discovered at autopsy.

Anatomy/Physiology

Several factors thought to account for rarity of small bowel neoplasms.

Rapid transit timeLiquid contentsNeutral pH and high levels of benzopyrene

hydroxylaseBacterial flora/load Increased lymphoid tissue and IgA-

Immunoprotective role.

Pathogenesis

Hodgkin’s Lymphoma first described in 1832 by Dr. Thomas Hodgkin.

Orderly spread of disease from one lymph node group to another, pathologically characterized by presence of Reed Sternberg cells.

One of the first cancers to be cured by XRT and subsequently by combination chemotherapy. ~93% cure rate.

Background

Classified into 4 pathologic subtypes based upon Reed-Sternberg cell morphology.

Nodular SclerosingMixed CellularityLymphocyte richLymphocyte depleted

Background

Non-Hodgkin’s LymphomaB-Cell*

diffuse large cell*Small cell (Mantle cell and follicular)mixed small and large cellMALT Lymphoma

Burkitt’sEATL (Enteropathy Associated T-Cell Lymphoma) Immunoproliferative small intestinal disease

(IPSID)

Background

* Most common (2/3), 70-80% High grade, 20-30% low grade

Lymphomas can affect any lymph node station and nearly every organ.

Primary GI (extra-nodal) lymphomas represent ~30% of all lymphomas.

Gastric- 75%Small Bowel (including duodenum)- 9%Ileo-cecal region- 7%>1 GI site- 6%Rectum- 2%Colon- 1%

Background

All sub-types of nodal lymphomas may also arise in GI tract but NHL are most common.

Ulcerating or infiltrating.

Background

Colon cancer 50-60x more common than small bowel cancers.

Primary small bowel cancer:Adenocarcinoma (40%) > NET (30%) > Lymphoma

(20%) > Sarcoma/other (~10%)

~ 50% of small bowel neoplasms are secondary (metastasis)*.

Colon, stomach, pancreas, melanoma, breast, & lung.

Incidence

*Direct extension, intraperitoneal seeding, hematogenous/lymphatic spread

1.6 cases/million/year

Steep rise in the 1980’s in correlation to AIDS

Bimodal age distribution, 20’s-30’s and >50.

Incidence

Celiac diseaseIBDRAChronic infection, poor sanitationHIV/AIDS with low CD4 count Post transplant

Risk factors

Inflammation

Immunosuppression

Data taken as a whole do not support the hypothesis that IBD alone is a risk factor for lymphoma.

Suggests IBD pts. Treated with AZA and 6-MP are at greater risk of lymphoma than general population.

? Regarding risk of severe or prolonged IBD compared with less severe disease.

Small but real increase in the risk of lymphoma in IBD patients receiving anti-TNF-α therapy, but risk yet to be clearly quantified.

Undoubtedly an increased risk of malignancy in celiac disease with regard to small bowel lymphoma and adenocarcinoma.

Risk of NHL may be increased 3-9 fold, but the overall risk to celiac population is < 1 %.

Risk diminishes over time if compliant with gluten free diet and is equal to general population 15 years after diagnosis.

Prospective cohort study of 637 pts with treated celiac disease in the UK from 1978-2001. Malignancy rates recorded.

Risk to general population was estimated from cancer registries.

Median follow up was 6.6 years (2.2-14.5 yrs).

Cancer diagnosis within 2 years of celiac disease excluded.

No increase in overall malignancy rate in diagnosed celiac disease in the post-diagnosis period when compared with the general population.

5x greater rate of NHL and 40x greater rate of small bowel lymphoma compared with general population in the post-diagnosis period.

Abdominal pain, weight loss, nausea, emesis, GIB, chronic anemia.

Median duration of symptoms- 6 months.

Normal PE in 24%, abdominal mass in 46%.

Often present with perforation, bleeding, or obstruction necessitating emergent surgery (~25-50%)

Clinical Presentation

Criteria:Lack of peripheral or mediastinal

lymphadenopathy.Normal WBC count and differential on peripheral

smear.Tumor involvement primarily in GI tract.No involvement of liver or spleen. No history of previously treated nodal lymphoma.

Diagnosis

SBFT/EnteroclysisBarium Enema EGD/ColonoscopyPush Enteroscopy, Double Balloon EndoscopyCapsule endoscopyCTMRIPET/ PET CTExploratory Laparotomy/Laparoscopy*

Diagnosis- Modalities

* Diagnosis in ~50% of patients

Wide variety of radiologic manifestations- ulceration, stricture, polypoid mass, mechanical obstruction, intussusception, fistulas, aneurysmal bowel dilatation, thick mucosal folds, separation of adjacent loops, mesenteric adenopathy and mesenteric thickening.

Clinical and radiographic challenge due to vague symptoms, rarity of disease, and relative inaccessibility of the small bowel.

Diagnosis

Physical Exam with performance statusCBC with differential, plateletsLDHHep B testing if Rituximab contemplatedCT Chest/Abdomen/Pelvis for stagingPregnancy testing in women of childbearing age if

chemo planned.Select cases- Bone marrow biopsy with aspirate for

multifocal disease. PET-CT, MRI, Hep C testing

Diagnosis/Work up- NCCN

Diagnosis- CT Enteroclysis

Diagnosis- CT Enteroclysis

Diagnosis- CT

Diagnosis- CT

Diagnosis- CT

Diagnosis- CT

Diagnosis- CT

Diagnosis- MRI

Endoscope introduced, balloon inflated, scope advanced. Performed via oral and anal routes. Depth range from 1-8.8m.

Allows for visualization

and tissue diagnosis.

Diagnosis- Double Balloon Endoscopy

Retrospective review of 29 pts with GI lymphoma, further examined by double balloon endoscopy.

Sought to determine prevalence of additional GI lymphomas.

50% of their pts had additional GI lymphomas.

Recommends complete evaluation of the small bowel in any patient with GI lymphoma.

Double Balloon Endoscopy

Diagnosis- Capsule Endoscopy

Low yield but superior test for small bowel

Diagnostic impact in 57%, exclusive therapeutic decisions in 12%

Overall diagnostic yield for obscure GIB 58-80%

6% were SB tumors

PET-CT

Staging- Ann ArborStage I- limited to intestine

Stage II- Extension into regional nodes or infiltration of surrounding organ

Stage III- Involvement of lymph nodes on both sides of diaphragm

Stage IV- Involvement of distant organs or extra abdominal lymph nodes

Optimal treatment remains poorly defined but remains surgical as a primary therapy followed by adjuvant chemotherapy.

Rarity of tumors, paucity of data on mgmt and prognosis…info usually from small case series and extrapolated from nodal lymphomas.

Two most important factors regarding management

HistologyStaging

Management

For localized, early stage disease, surgical resection with wide margins including node bearing mesentery is the standard.

For advanced, disseminated tumors which are not resectable, surgical treatment is limited to obtaining tissue for diagnosis and palliating complications.

Radiation and chemotherapy.

Management

Stage I/II- Resection +/- chemotherapy Negative margins- clinical f/u Q3-6mos for 5 years then

annually thereafter Positive margins- chemotherapy, possible reoperation Multiple lymphomatous polyposis- chemo only

Stage III/IV- Resection + Chemotherapy Observation Close clinical follow up Re-staging- which imaging to use? Neoadjuvant therapy?

Management-NCCN

The best chemotherapy regimen depends on the histology of the tumor. diffuse large B-cell lymphoma-CHOP is still the

gold standard. +/- Rituximab- primary therapy, combination,

maintenence

Low-grade lymphomas- indolent course- Fludarabine alone or in combination with cyclophosphamide. Rituximab as monotherapy.

Management-NCCN

First Line- R+CHOP, RCVP x 6 cycles

First line for elderly or Infirm- Rituximab + single agent alkylator (cyclophosphamide, chlorambucil)

Extended therapy- Rituximab maintenance x 2 years

Fludarabine, cyclo, mitoxantrone

Chemotherapy regimens

Extent of therapy based upon age, performance status, previous therapies, and extent of relapse.

No role for radiation of the small bowel.

Management

Bovine and shark cartilageEchinaceaGarlicGinsengGinger

Alternative/Complementary Therapy

Perforation- median survival of 8 months

AIDS related lymphomasMedian survival 5-11 months

B cellstage I/II- ~60-75% 5 year survivalStage III/IV- ~ 20-40% 5 year survival

EATL5 year survival 10-20%

Prognosis

Small bowel lymphoma is a rare disease with vague symptoms initially, making timely diagnosis difficult.

Risk factors include RA, CD, ?IBD, & immunosuppression.

Imaging plays an integral role in diagnosis but studies remain difficult to obtain/interpret.

Majority of cases diagnosed at laparotomy, many present emergently

Take Home Points

>50% of patients have nodal/distant mets at presentation.

Primary therapy is surgery followed by adjuvant chemotherapy depending on the stage and histology.

Minimal progress in overall survival over the last 2 decades.

Take Home Points

Significant improvement in diagnostic modalities and surgical care over the past 20 years but no significant change in survival.

Need better medical therapyImmunotherapyGene therapyChemotherapyNeoadjuvant therapy?

Future

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