Management of Gastrointestinal LymphomasPresentation Transcript
Gastrointestinal lymphomas are the most common form of primary extra nodal lymphomas.
Primary lymphoma accounts for 1-4% of all gastrointestinal tumors
Most commonly these are Non Hodgkin’s lymphomas.
Hodgkin's disease usually involve the GIT secondarily.
Gastric lymphomas are the most common form of gastrointestinal lymphomas with very interesting etiology and natural history.
Typically account for 15% of all NHL patients.
In our institution GI lymphomas have accounted for approximately 10% of all NHL patients.
In large retrospective series gastric lymphomas occupy the lion’s share of the primary GI lymphomas.
NE Italy has a very high incidence of primary gastric lymphomas e.g. Feltre region 1 where population incidence was 66 /100,000 (13 * times more common than UK /USA incidence).
Most commonly staged by the Ann arbor staging criteria.
Inadequate information regarding spread.
Prognostic information is diluted.
Pattern of spread of GI ENL is different.
Musshoff 1 proposed a modification for the scheme. (1977) which was adopted at the Lugano workshop for GI ENLs in 1993
Blackledge modification of Ann Arbor staging Involvement of distant organs & extralymphatic organs. IV E Involvement of organ and lymph-nodes on both sides of diaphragm III E
IIE 2 N on-contiguous nodes involved.
IIE 1 Involvement of local nodes
Involvement of organ & regional nodes IIE Limited to the intestine or stomach with focal / multifocal spread. IE
Some pathological classification schemes available include:
The Working formulation.(1972)
The REAL classification (1993)
Now a days the REAL classification based upon the cell of origin and immunophenotyping is considered most authentic but for practical purposes the working formulation suffices.
► Burkitt’s (small, non cleaved cells)
► Diffuse large cell lymphoblastic
► Diffuse large
► Diffuse mixed
► Diffuse small
► Follicular large cell
► Follicular mixed
► Follicular small cell
► Small lymphocytic
In 1973 Issacson and Wright 1 gave the concept of MALT lymphomas based upon their findings in 3 patients with FCC type ENLs.
They found that some low grade lymphomas will recapitulate the features of a Peyers patch rather than a node.
This was subsequently incorporated into the REAL classification but failed to find a place in the working classification.
The main features identified by Issacson included:
Long history with evidence of ongoing chronic inflammation in the mucosa.
Propensity to invade and destroy the epithelium characteristic lesions called lymphoepitheliomas .
B-cell phenotype with MONOCLONAL plasma cell differentiation.
Cells retained the homing pattern of the MALT lymphocytes with typical multi focal spread.
MALT lymphoma (contd.)
Now MALT lymphomas are categorized as Extranodal marginal zone B-cell lymphomas .
The term “ marginal ” refers to the distribution of the lymphoma cells around the germinal centers in Peyers patches
MALT lymphomas don’t have a specific immunological marker but they are positive for:
Absence of CD 10 and CD 5 help to differentiate them from Follicle center cell and Mantle cell lymphomas.
PAN B cell Antigens
MALT lymphomas have a well understood etiopathogical pathway.
Predominant association of Gastric MALT with H. Pylori infection exists.
Other bacteria know to be associated include:
Several DNA translocations known:
A gram –ve spiral bacillus that is know to colonize the gastric mucosa of > 50% of the human population.
The bacillus elaborates an enzyme urease which allows it to survive in the acidic environment in the stomach.
Molecular detection of clonal B cells in H. pylori gastritis patients that can give rise to further MALT lymphomas. 1998 4 First clinical trial confirming that anti-Helicobacter therapy leads to regression of gastric MALT lymphomas. 1995 3 First evidence of low-grade gastric MALT lymphoma regression after eradication of H. pylori. 1993 2 > 90% prevalence of H pylori infection in patients with gastric MALT. 1991 1
Pathogenesis H pylori Infection Chronic gastritis due to bacterial products like NH 3 Polyclonal multiplication of B cells in face of antigenic stimulation. Acquisition of EARLY t(11:18 ) Monoclonal proliferation in face of continuous antigenic stimulation Independence from continued H. pylori infection and low risk of other abnormalities. Lymphomatous transformation
Dawsons criteria 1
Originally used to define a primary intestinal lymphoma now modified to define gastric lymphomas also.
Inclusion criteria : The organ is predominantly involved, and the intra-abdominal lymphadenopathy, if present, corresponds to the expected lymphatic drainage of the organ.
Exclusion criteria :
Palpable subcutaneous nodule.
Abnormal leucocytes on PBS / BM aspirate.
Splenic / Hepatic involvement
Danish criteria 2 : Patients with primary gastric lymphoma have more than 75% of their disease volume in the stomach, based on clinical and radiological staging
Usually common in the age group of 50 – 60 yrs.
Most series report a slight female preponderance.
Most patients have a history of long standing gastritis.
50% are MALT lymphomas and the rest are usually DLBCLs.
Fever & Night sweats are uncommon.
Almost all patients are symptomatic at presentation.
Mean duration of symptoms vary from 4 to 10 months prior to diagnosis.
Approx 20% may present with bleeding and 2% with perforation .
Routine hematological workup:
Barium meal & follow through
CT scan abdomen
Chest X ray
LDH & ß 2 microglobulin
CT scan features :
Clefts & tracks in the mucosa.
Diffuse wall thickening
Has sensitivity & specificity of 89% and 97% for assessing transmural spread.
Specific echogenic patterns reported.
Typical findings are:
Diffuse infiltrative process making the stomach indistensible
Confluent mucosal ulceration
Differences between primary gastric and secondary gastric lymphomas:
Fundic and duodenal involvement uncommon in primary lymphomas
Multifocal growth more common in SECONDARY lymphomas.
BULKY disease commoner in HGPGL while diffuse infiltrative pattern seen in LGPGL.
In contrast polypoidal and ulcerative leisons more common in secondary lymphomas.
The treatment strategy for MALT lymphoma and DLBCL are different because of the different natural history, response to treatment and prognosis.
MALT lymphomas are unlike other nodal indolent lymphomas as they are amenable to CURE .
This is because:
The tumors are very radiosensitive.
They usually have less distant spread.
Often respond to H pylori eradication alone.
H pylori eradication
A triple drug therapy is recommended by the Maastricht 2 -2000 workshop on eradication of H pylori.
First line regimen is:
Clarithromycin 500 mg BD
Amoxicillin 1000 mg BD
In the Indian population the wide spread amoxicillin resistance makes metronidazole 500mg TD the DOC.
2 nd line regimen in case of failure:
Bismuth subsalicylate 120 mg QDS
Metronidazole 500 mg TD
Tetracycline 500 mg QDS
X 7 days X 7 days
H pylori eradication
Guide lines for FU in patients on H pylori eradication therapy are as below.
Further FU should be done for a prolonged period of time ( 2 - 4 years).
In some situations where the initial infection has not been cured a 2 nd course of antibiotics is appropriate before any other measures
Fresh Biopsy at 3 months Lymphoma positive Lymphoma negative Local RT Observation Fresh Biopsy at 6 months
H pylori eradication is proven to result in CR in many patients who have Stage IE gastric MALT lymphomas.
Indicators of response 2 :
Stage IE disease
Negative for t (11:18)
However Neubauer et al 3 have shown the presence of monoclonal B cells during follow-up in 22 of 31 (70%) assessable patients in complete remission by PCR.
71% 21 41 Takeshita et al 4 70% 50 35 Neubauer et al 3 47 15 CR 73% 64 Liu et al 2 57% 26 Roggero et al 1 % Total Study
Radiotherapy forms the most commonly used modality for definitive treatment of gastric MALT lymphomas.
Localized and are highly radiosensitive.
RT offers the benefits of:
Acceptable local toxicity
Absence of systemic toxicity
Reliable and durable cure
Maintenance of quality of life
Less stringent FU requirements.
Lower treatment cost in 3 rd world countries.
Doses: 30 -35 Gy delivered over 4 – 5 weeks is the usual standard.
Both Co 60 and LINACs can be used with equal efficacy and toxicity profiles.
These lymphomas are know to respond to lower doses of radiation than other indolent lymphomas.
No comparative trials between whole abdomen and IFRT but toxicity of the former significantly more.
Fundus : At the 5 th interspace or the 6 th costal cartilage, a little below the apex of the heart
Cardia : Opposite the 7 th left costal cartilage about 2.5 cm from the side of the sternum;
Corresponds to the level of the D-10 vertebra.
Pylorus : On the transpyloric line about 1 cm. to the right of the middle line.
Corresponds to the level of the L-1 vertebra
The planning process is preceded by delineation of the organs at risk and the site of interest using appropriate oral / IV contrast.
Usually a 2 field technique is used with the field borders as demonstrated.
In order to spare the left kidney separate field arrangements may be used. MC a 3 field technique is used.
However alternate field arrangements lead to unnecessary liver radiation dose.
RT Results ** In 2001 Koch et al treated all patients by WAR. (+ 6 cycles CHOP in stage IIE patients) * In 2005 field borders were shrunk to lower border of L5 in stage I N.B. Little clinical data exists for treatment of stage III /IV gastric MALT lymphoma perhaps owing to the relative rarity of the disease. EFRT ** 52 mo 30 Gy + 10 Gy boost I /II 52 Koch et al 3 (2001) IFRT 27 mo 30 Gy (28.5-43.5) I / II 17 Schechter et al 4 (1998) IFRT 59 mo 25 Gy ( 20–30) I / II 13 Tsang et al 2 (2003) 42 mo FU I / II Stage EFRT * Technique 30 Gy + 10 Gy boost 144 Koch et al 1 (2005) Dose (Gy) N Series
RT Failure * Combined figures for DLBCL & low grade lymphoma Noteworthy point is that 5 out of 6 relapses in the German 02/96 study were seen in stage IIE (Blackledge stage) patient perhaps indicating a need for a combined modality approach in these patients. 0 0 0 Schechter et al (1998) 7 ( 13.4%) * Not specified Not specified Koch et al (2001) 0 0 0 Tsang et al (2003) 6 (4.1%) Not specified Not specified Koch et al (2005) Total Out field failure In field failure Series
In the series reported by Tsang et al toxicity reported included transient anorexia and malaise and occasional nausea or dyspepsia, and were treated conservatively. Late ulceration or hemorrhage was not observed.
Separate toxicity data has not been reported by the German NHL study group but a total of
11 treatment related deaths were observed in the 2005 study (total 759 patients)
11 patients died in the 2002 series (total 185).
In this study whole abdomen radiation was used.
Reported by Maor et al in 1998, who analysed 27 patients who had received > 24 Gy to at least 1/3 rd of the left kidney. ( Mean prescribed dose = 37.9 Gy at 1.5 Gy/ #)
3 patients had persistent, mild elevations of urea and creatinine levels but all had received Cisplatin
Only 2 patients developed hypertension, both at a low level of 150/90; one patient had had 40 Gy to the whole kidney, the other 40 Gy to half the kidney.
Ipsilateral kidney shrinkage was evident in most patients. The degree of atrophy was related to the volume of kidney irradiated.
Surgery has a diminishing role in the management of gastric lymphomas as whole.
A total gastric resection is required as the entire stomach is at risk.
Morbidity of gastrectomy series ranges 8% -16%
Multifocal nature of the disease results in inability to obtain clear resection margins
Survival benefit over conservative management is absent
Risks of RT / CCT feared in past now greatly diminished.
50 – 70% of all tumors are resectable.
Subtotal resection has resulted in poorer control rates in many series (German NHL studies found both EFS and OS significantly poorer in patients with subtotal resections).
Results 75% 80% OS 52% 52% 10 yr EFS 78 80 N Aviles et al (2005) 1 RT Surgery Series 87.2% 90.6% 5 yr OS 82.2% 87.6% 5 yr EFS 32 52 N RT Koch et al (2001) Surgery Series RT Surgery Series 92% 90% 5 yr OS 88% 83% 5 yr EFS 23 34 N Sonnen et al (1994) RT Surgery Series 87% 88% 5 yr OS 56 27 N Norman et al (2000)
Modern day indications for surgery in gastric MALT lymphomas include:
Salvage after RT / CCT failure
Institutional practice plays an important role in defining the optimal practice in the absence of prospective randomized trials comparing stomach preservation vs resection.
Primary chemotherapy has not been successful in limited stage MALT lymphomas owing to the indolent nature of the disease.
CCT is usually reserved for a symptomatic patient with bulky abdominal disease who is not suited for RT.
The regimen of choice is CHOP in the doses administered in DLBCL.
In the patient with poorer GC COP or single agent may be used.
H pylori eradication is usually recommended concurrently.
Fisher et al comment that from the SWOG experience it is seen that the pattern of relapse in MZL is similar to that observed in follicular lymphomas implying CCT alone may not be curative.
Main concern for patients undergoing CCT is the risk of gastric perforation as it carries a 100% mortality rate in the immunosuppressed.
The incidence of chemotherapy-induced complications is variable and has been reported to be as high as 13% to 25%
In a review of the literature involving 188 patients, Gobbi et al reported an incidence of 3.2% and 2.7% for perforation and bleeding, respectively.
Now a days it appears that risk is inherent and is not increased by medical treatment
Gastric MALT: Approach 1 * NCCN advocates observation in patients who have advanced stage IV but asymptomatic disease. Gastric MALT Stage IE Others H pylori positive H pylori (-)ve or t (11:18) +ve H pylori eradication Recurrence / Failure Local Radiotherapy Complications e.g. Bleeding/ perforation/ Bulky disease Uncomplicated * Surgery ? Radiation + CCT *
High Grade Lymphomas 1
Higher frequency of weight loss at presentation
Palpable abdominal mass
Elevated serum LDH
Higher incidence of stage III-IV disease
Significantly larger primary tumors
Deeper invasion of the gastric wall,
Infiltration of the abdominal lymph nodes
Approach Stage I & II Non Bulky Disease Bulky Disease CCT with CHOP x 6 cycles ± Rituximab (CD 20 +ve) IFRT 30 – 35 Gy in 4 – 5 weeks ≥ 2 risk factors No risk factors CCT with CHOP x 3-4 cycles ± Rituximab (CD 20 +ve)
CCT forms the mainstay of treatment of high grade localized lymphomas of stomach.
Multiple centers report survival rates between 70 – 80%
Therapy should be initiated with CHOP in the following doses:
Cyclophosphamide (750 mg /m 2 )
Adriamycin (50 mg /m 2 )
Vincristine (1.5 mg / m 2 )
Prednisone (100 mg D 1 – D 5 )
Number of cycles required?
6 cycles are required in most instances but in limited stage disease 3-4 cycles combined with IFRT has shown better result.
Raderer et al 1 found that 24 / 25 patients had CR after CHOP and 22 were alive after 2 yrs. They concluded that primary CCT with CHOP was a effective treatment modality in patients with stage I / II gastric DLBCL.
In another series 2 by the same author 36 /37 patients attained CR after CHOP. Out of these 34 had attained CR after only 3 cycles.
Aviles et al 1 reported the following results in PRT comparing 4 different therapeutic strategies in stage I / II gastric DLBCL.
CHOP was used in standard doses and RT was given to a tune of 40 Gy.
96% 91% 53% 54% 10 yr OS 92% 150 CCT alone 82% 153 Surgery + CT 23% 138 Surgery + RT 28% 148 Surgery 10 yr EFS N ARM
Results: CMT Early stage NA 94% 2 yr OS NA 88% 2 yr EFS NA 52 N Satoshi et al (2005) 77.9% 86.0% 5 yr EFS 77.8% 21 91.6% 91.1% 44 CCT + Sx 72.6% 5 yr OS 38 N Liu et al (2000) 85.9% 5 yr EFS 90.5% 5 yr OS 40 N Binn et al (2003) CCT ± RT Series 76.6% 69.6% 2 yr EFS 78.9% 77.9% 2 yr OS 47 54 N Koch et al (2001) 85.4% 88.4% 5 yr EFS 87.5% 49 62% 67% 13 CCT + Sx 88.5% 5 yr OS 188 N Koch et al (2005) 85% 5 yr EFS 60% 5 yr OS 24 N Popescu et al (2003) CCT ± RT Series
Sparse evidence is available for advanced stage high grade gastric lymphomas but consensus is systemic chemotherapy with or without IFRT.
It is unclear as to how much surgery is useful in these patients.
Role of radiotherapy has remained undefined as it has not shown to add to the overall survival. However most studies reveal a better local control.
Account for 50% - 20% all primary GI lymphomas.
These account for 19-38% of all small intestinal malignancies
Like gastric lymphomas males are more commonly affected.
C. Jejuni infection
Gluten sensitive enteropathy ( T cell )
33.8% 34.2% 8.4% 9% Multiple sites 12.6%
Histology Intestinal Lymphomas B Cell Lymphoma (60% - 70%) T cell lymphoma ( 20% - 30%) High Grade B cell (70% -80%) Low – intermediate grade (20% - 30%) MALT Others (mainly MCL) Mediterranean lymphoma Or Immunoproliferative small intestinal disease
Most common modes of presentation include:
Obstruction / perforation more commonly reported than for gastric lymphomas (30% -40%).
T cell lymphomas are notorious for association with:
Obstruction & perforation (50% -30%)
Protein loosing enteropathy ( hypoalbuminemia)
Anemia and thrombocytosis
Management : B cell
DLBCL of the intestines are managed similar to DLBCL of the stomach with anthracycline based chemotherapy being the mainstay of treatment.
However primary surgery is more commonly needed to
Establish the diagnosis
Stage the disease
Relieve obstruction & prevent perforation
Reduce tumor bulk
Treat peritonitis resulting from perforation
RT results in better local control.
Addition of RT justified when there is:
Bulky residual disease
Partial resections / debulking
Techniques : WAR / IFRT.
Dose is limited to 30 Gy due to the intrinsic radiosensitivity of the tumor as well as the surrounding organs.
Dose per fraction should be 1.5 -18 Gy
Whole abdomen radiation associated with greater toxicity and has not been proven better as compared to IFRT.
Chul et al report that in 31 patients who received WAR ± CCT 3 patients had recurrence in abdomen/ pelvis and 5 patients had recurrence outside.
CCT reduced recurrences outside the field ( 6.7% vs 33%).
However rates of infield recurrences did not differ (11% vs 9%).
Other series report incidence of recurrence outside RT field ranges from 50 - 60% if CCT is not added.
Guidelines for addiction of CCT for Small intestinal lymphomas are non existent.
CHOP x 6 cycles delivered 3 weekly is the standard of care.
Other CCT regimens have been used for aggressive B cell lymphomas but results are equivocal.
In low grade lymphomas esp. MALT lymphomas addition of CCT remains debatable in view of the indolent nature of the disease and prolonged expected survival.
Results Survival Relapse 65% (5 yr) 35 (87) 71.3% Sx + CCT ± RT All Cortelazzo et al 5 45% (4 yr) NA NA Sx + CCT All Otter et al 4 (population based registry study) 47% (10 yr) 13 (52) 85.2% Sx + CCT ± RT (WAR) All 94% (2yr) 8 (19) Chul et al 3 95% Sx + CCT (CHOP) I & II 59% (5yr) 1 (2) Duam et al 2 4 (22) 20% 100% CR CCT (MACOP - B) only III & IV SX + CCT (CHOP / MACOP B) I & II Zinzani et al 1 Modality Stage
T cell lymphomas
Special features are:
Occurs in 7% -12 % patients with celiac disease or dermatitis herpetiformis.
Has 3 types (Chott et al)
Enteropathy associated T cell lymphoma (EATCL)
EATCL like lymphoma without enteropathy
A gluten free diet can prevent the occurrence of T cell lymphomas in patients of celiac disease.
In cases in which large immunoblast-like cells predominate, CD30 expression is characteristic.
T cell lymphomas
Major differences from B cell lymphomas are:
Frequent need for emergency operations.
Poorer response to CCT
Tumor progression and death commoner during CCT
Poorer GC at presentation preclude any therapy in many
More frequent and earlier relapses.
Owing to the rarity the ideal treatment remains controversial.
Primary surgery followed by CCT is best.
A higher frequency of intestinal perforation and bleeding noted by some if Sx is omitted.
In the largest series by Daum et al 1 (n = 35)
2yr OS was 28% only
In another large series by Gale et al 2 (n = 31)
5-year OS was 19.7%,,
5-year failure-free survival rate was only 3.2%
Stage of disease:
80.8% of 5yr survival for tumors smaller than 5 cm vs. 44.4% for larger lesions, (p < 0.05).
68.6% in stage II 1E to 44.4% in stage II 2E
DFS falls from 57.1% in stage II 1E to 16.7% in stage II 2E
Depth of invasion and serosal penetration:
5 yr survival rate decreases for the stages I to III from 82% to 24%.
Grade of disease :
The five-year survival rate for low-grade and high-grade tumors was 91% and 56%, respectively.
Older age > 60
Elevated serum LDH
T cell type lymphoma
Higher cell proliferation index
Genetic markers like t (11:18)
Multiple lymphomatous polyposis
Considered to represent Mantle cell lymphoma of the intestine but can represent other types too
Characterized by multiple polyps involving long segments of the gastrointestinal (GI) tract
Best diagnosed by barium studies.
CCT is the basis for treatment
Immunoproliferative small intestinal disease
IPSID is associated predominantly with poor socioeconomic conditions
Affecting young adults with almost equal sex incidence
Involves predominantly the proximal small intestine
Associated with multiple pathogens
Patients present with progressive malabsorption in the 2 nd and 3 rd decades.
Diagnosis is established by small bowel biopsy, with or without high serum levels of the alpha heavy chain protein
Spontaneous remissions in early stages
Tetracycline and metronidazole recommended in the initial treatment.
HIV associated lymphoma
HIV infection leads to a 100 times greater risk of lymphomas.
MC Large B cell type lymphomas are seen.
Extranodal involvement and advanced stage at presentation are common.
Anal and rectal lymphomas are seen frequently.
Patients have B symptoms more frequently.
Therapy is complicated by ongoing immunosupression.
HAART + CHOP x 6 cycles forms the current standard of care.
Rituximab is dangerous – greater chance of fatal infection due to aggravation of CD4+ cell loss.
Gastrointestinal lymphomas are an important subgroup of extranodal lymphomas.
Among them MALT lymphomas are unique as they are very much curable by conservative measures.
Combined modality stomach sparing therapy with CCT and RT is feasible in majority of the localized gastric lymphomas.
Surgery forms the mainstay of treatment for intestinal lymphomas
Elucidation of the important role of gut flora in the pathogenesis of these diseases can act as a model for all lymphomas.