MALT Lymphoma

Question 1

What does MALT stand for? Where is MALT generally located?

Answer 1

MALT stands for mucosa-associated lymphoid tissue. It consists of small concentrations of lymphoid tissue found in the mucosa of various sites of the
body, such as the GI tract.

Question 2

What is the etiology of MALT lymphomas?

Answer 2

Chronic inflammation from infection or autoimmune disorder predisposes to the development of MALT lymphomas.

Question 3

What are the most common locations of MALT lymphoma in the body?

Answer 3

The most common locations of MALT lymphoma are the GI tract (stomach > small intestine > colon), lung, thyroid, salivary gland, tonsil, breast, and orbit.

Question 4

What types of infectious or autoimmune conditions are associated with MALT lymphoma in the stomach? Ocular adnexa? Salivary gland? Skin? Thyroid?

Answer 4

Infections or autoimmune conditions associated with MALT:
Stomach: Helicobacter pylori
Ocular adnexa: Chlamydia psittaci
Salivary gland: Sjögren syndrome, hepatitis C
Skin: Borrelia burgdorferi
Thyroid: Hashimoto thyroiditis

Question 5

What is the natural Hx of MALT lymphoma?

Answer 5

The natural Hx follows an indolent clinical course, as a low-grade lymphoma. MALT lymphomas typically remain localized to the tissue of origin.

Question 6

From where do MALT lymphomas typically arise in the lymphoid follicle?

Answer 6

MALT lymphomas typically arise from the marginal zone of the lymphoid follicle (and therefore are also termed as extranodal marginal zone lymphoma).

Question 7

What are some important cytogenetic abnormalities in MALT lymphomas?

Answer 7

Important cytogenetic abnormalities include t(11;18)(q21:q21) and trisomy 3.

Question 8

What is the immunophenotype of MALT lymphoma?

Answer 8

MALT lymphoma is a low-grade B-cell lymphoma that is CD20+, CD35+, CD5–, and CD10–.

Question 9

What is the typical stage of MALT lymphomas?

Answer 9

Because MALT lymphomas remained localized to a particular tissue, most are usually Ann Arbor stage IAE (80%).

Question 10

What is the typical presentation of a pt with gastric MALT?

Answer 10

The typical presentation of gastric MALT is dyspepsia (#1), epigastric pain or discomfort, n/v, GI bleed, and B Sx (rare).

Question 11

What workup should be included in a pt with suspected MALT lymphoma of the stomach?

Answer 11

Suspected MALT lymphoma of the stomach workup: Complete H&P (with emphasis on B Sx and evaluation of all LNs, including the Waldeyer ring [15% association; check hepatosplenomegaly]), CBC/CMP, LDH, CXR, CT
abdomen/pelvis, esophagogastroduodenoscopy (EGD) with Bx, and EUS if available (to assess DOI). Test for H. pylori infection with a rapid urease test (RUT) on the Bx specimen and test for t(11;18) with FISH or PCR. Consider
BM Bx in pts with suspected systemic Dz. Routine PET/CT is not considered necessary but may be useful in some cases.

Question 12

What is the sensitivity and specificity of the RUT for H. pylori? What are other alternatives if the RUT is negative?

Answer 12

The sensitivity and specificity of RUT are >90%. However, if the test on the tissue sample is negative and the clinical suspicion is high, preferred noninvasive tests are (1) H. pylori serum serology (antibody), (2) urea breath test, or (3) stool antigen test.

Question 13

How is the Ann Arbor system used for staging MALT lymphoma of the GI tract?

Answer 13

Ann Arbor staging for MALT lymphoma of the GI tract if no B Sx:
Stage IAE: confined to GI tract
Stage IIAE: GI + nodal involvement below diaphragm
Stage IIIAE: GI + nodes above diaphragm +/– nodes below diaphragm
Stage IVAE: GI + other extranodal involvement (BM, liver, etc.) +/– nodes above or below diaphragm

Question 14

What is the 1st-line therapy used for the Tx of gastric MALT lymphoma?

Answer 14

If there is documented H. pylori infection, the initial therapy is H. pylori eradication (triple therapy of clarithromycin/metronidazole/proton pump inhibitor (PPI) or clarithromycin/amoxicillin/PPI). If there is lymphoma but
the pt is H. pylori–, consider RT as a primary therapeutic approach,especially if there are chromosomal abnormalities.

Question 15

How is the eradication of H. pylori determined?

Answer 15

A urea breath test should be done 1 mo after antibiotic use. If there is persistence of tumor and H. pylori infection, switch to a different antibiotic regimen.

Question 16

What response rate is expected from 1st-line Tx of gastric MALT lymphoma?

Answer 16

75%–80% of pts have a CR (Wündisch T et al., JCO 2005), with an extremely low rate of relapse.

Question 17

What is the typical response period to antibiotics in MALT lymphoma?

Answer 17

In MALT lymphoma, regression can be slow. In 1 study of 120 pts, the 1st CR after antibiotic therapy was diagnosed between 1 mo and 28 mos after the
start of the H. pylori eradication Tx. The majority of pts (61%) achieved a CR within the 1st 3 mos after Tx. However, in some pts, it took up to 28 mos for
all histologic evidence of lymphoma to resolve. (Wundisch T et al., JCO 2005)

Question 18

How should response be assessed when using antibiotics for gastric MALT lymphoma?

Answer 18

Response to antibiotics in MALT lymphoma is assessed by EGD with visual inspection and Bx q3mos. Dz should be stable or regressing. If Dz if progressing, consider RT. If it is stable or regressing and the pt is asymptomatic, repeat the EGD in 3 mos as pts may enter a delayed CR. If CR is attained, monitor for relapse with EGD every 6 mos for 2 yrs and then as clinically indicated.

Question 19

What should be done with minimal histologic residual Dz in the setting of otherwise normalized endoscopy and H. pylori eradication?

Answer 19

The vast majority of these pts will either remain with localized Dz or eventually enter into a CR with observation alone without further oncologic
therapy. Hence, such pts should be observed with regular endoscopy and Bx. (Fischbach W et al., Gut 2007)

Question 20

What are 3 tumor characteristics that portend a poor response to the use of antibiotics for the Tx of gastric MALT lymphoma?

Answer 20

Tumor characteristics that portend a poor response with antibiotics for MALT lymphoma include t(11;18), trisomy 3, and DOI beyond the submucosa (muscularis/serosa/adjacent organs). In 1 study of 22 pts, there was an 86% CR rate with DOI < submucosa and 0% if invasion was beyond the submucosa. (Sackmann M et al., Gastroenterology 1997)

Question 21

What are the options for antibiotic-resistant MALT lymphomas?

Answer 21

Given the indolent nature of the Dz, there are many options. ISRT should be considered. In an early study of 17 pts treated with RT for gastric MALT, all 17 obtained a Bx-confirmed CR. At a median f/u of 27 mos after RT, EFS was 100%. Tx was well tolerated, with no significant acute side effects. (Schechter et al., JCO 1998) Systemic therapy, such as rituximab (Rituxan), can be considered after RT failure or in advanced Dz.

Question 22

When should RT be considered for the Tx of gastric MALT lymphoma?

Answer 22

RT for MALT lymphoma should be considered in the following situations:
1. H. pylori– with stage IAE lymphoma, with or without initial use of
antibiotics
2. t(11;18)
3. Invasion beyond submucosa muscularis/serosa/adjacent organs)
4. Documented progression after initial use of antibiotics
5. Documented failure of 2nd course of antibiotics
6. Rapid symptomatic progression of Dz

Question 23

What are some important prognostic factors for MALT lymphomas?

Answer 23

Important prognostic factors for MALT lymphomas:

1. Cytogenetics
2. Histology/grade
3. DOI
4. Stage/LN involvement
5. Tumor size

Question 24

What are the factors in the MALT International Prognostic Index (MALTIPI) that predict prognosis in MALT?

Answer 24

1. Age greater than or equal to 70
2. Stage III–IV Dz
3. LDH abnl
   (Thieblemont et al., Blood 2017)

Question 25

Is there a benefit of adding chemo in low-risk MALT?

Answer 25

No. Outcomes are excellent with ISRT alone, which remains the standard 1st line modality. (Schechter et al., JCO 1998) Consideration may be given to the addition of rituximab in high-risk cases.

Question 26

What is the 3rd-line therapy for Tx of gastric MALT lymphoma?

Answer 26

The 3rd-line therapy for MALT lymphoma is chemo (e.g., rituximab +/– bendamustine, R-CHOP, R-CVP, single-agent cyclosphosphamide).

Question 27

What is the Tx paradigm for DLBCL of the stomach?

Answer 27

DLBCL of the stomach Tx paradigm: | rituximab/cyclophosphamide/hydroxydaunomycin (Adriamycin)/vincristine (Oncovin)/prednisone (R-CHOP) + ISRT

Question 28

What are the simulation procedures for RT planning for Tx of MALT lymphoma of the stomach?

Answer 28

Pt in a fasting state, supine, arms up and consider a small volume of oral contrast. Use methods to determine respiratory excursion or consider breath hold. IV contrast can be considered if nodal Dz is suspected. Field should encompass the entire stomach. Include regional LNs if they were suspicious for Dz. 4-field 3D-CRT may reduce kidney dose. IMRT may improve kidney and liver dose. (Della Biancia C et al., IJROBP 2005; Goda JS, Cancer 2010) Consider daily CT-guidance to allow for the use of small margins. (Wang et al., PRO 2017)

Question 29

What are common RT Rx for MALT lymphoma of the stomach?

Answer 29

Rx dose: 30 Gy in 1.5 Gy/fx for 20 fx. Consider boosting the area of Dz to 36 Gy. Another option is 24 Gy in 2 Gy/fx for 12 fx, since this is an accepted dose for definitive RT to treat indolent NHL. (Lowry et al., Radiother and Oncol 2011)

Question 30

What are the long-term outcomes with the use of ISRT for Tx of gastric MALT lymphoma?

Answer 30

Appx a 90% recurrence-free rate at 10 yrs. | Goda JS, Cancer 2010; Wirth A, Ann Oncol 2013

Question 31

What is the most common site for non-gastric MALT?

Answer 31

Orbital MALT is the most common nongastric MALT.

Question 32

Which organism is often associated with orbital MALT?

Answer 32

C. psittaci is often associated with orbital MALT, and eradication of the organism with antibiotics (doxycycline) can result in a CR.

Question 33

What volume is treated and what are common RT Rx for orbital MALT?

Answer 33

Typically, the whole bony orbit is treated with care taken to include extraorbital extension. Partial orbital RT may be considered if the site of disease can be visualized and delineated. Dose: 24–30 Gy in 10–20 fx has been used, with >95% LC but with high incidence of late toxicity, arguing for using the lower doses. (Goda JS, IJROBP 2011) ILROG recommendations currently are for 24–25 Gy in 1.5–2.0 Gy daily fx. (Yahalom J, IJROBP 2015) However, excellent results have been observed after Tx with just 4 Gy in 2 fx. (Fasola et al., IJROBP 2013; Pinnix et al., Head & Neck 2017) This ultra-low dose is effective and well tolerated, with the option of re-irradiation in the case of locoregional refractoriness/relapse.

Question 34

What is the typical natural Hx of orbital MALT?

Answer 34

Pts experience excellent overall and CSS. The 10-yr recurrence-free rate is 67% after RT for orbital MALT. Recurrences typically involve the contralat, untreated orbit or distant sites. (Goda JS, Cancer 2010)

Question 35

What is typically associated with MALT of the salivary gland?

Answer 35

MALT of the salivary gland is associated with Sjögren syndrome.

Question 36

What are the fields, volumes, and doses used for MALT of salivary gland?

Answer 36

The ILROG guidelines suggest treatment of the whole gland involved (e.g., superficial and deep lobe of the parotid) with IMRT or 3D-CRT. However, treatment of a portion of the gland may be considered if the site of disease can be delineated. For pts with stage IIE Dz (cervical nodal involvement), encompass the ipsi cervical LN stations. Treat the bilat parotid if there is bilat involvement. The standard definitive dose has been 24–30 Gy. To minimize risk of xerostomia, consideration may be given to initial Tx with 4 Gy in 2 fx, f/b dose escalation if inadequate response.

Question 37

What are the long-term outcomes for MALT of the salivary gland treated with RT?

Answer 37

A 10-yr recurrence-free rate of 68% has been reported with the contralat parotid gland as the predominant site of failure. (Goda JS et al., Cancer 2010) Overall and CSS rates are excellent.

Question 38

What is typically offered for MALT of the lung?

Answer 38

ISRT should be offered, given the high response rate. Observation is a reasonable strategy in the setting of completely excised Dz.

Question 39

How is MALT of the skin managed?

Answer 39

MALT of the skin may be managed by surgical excision for small lesions. ISRT using electrons with bolus is another effective strategy. High rates of Dz response are seen after localized RT, even with low doses such as 4 Gy. (Akhtari M et al., Leuk Lymphoma 2016)

Question 40

What is the regimen used for management of advanced low-grade lymphoma?

Answer 40

For advanced low-grade lymphoma, use systemic agents such as rituximab +/– bendamustine; however, cure is rare. Palliative RT is very effective. A high overall response rate (80%–90%) is seen with the use of 4 Gy (2 Gy × 2).

Question 41

Which systemic options are available for relapsed/refractory indolent lymphomas?

Answer 41

Multiple systemic options exist to treat indolent NHL, including bendamustine + rituximab, R-CVP, R-CHOP, single-agent rituximab, lenalidomide + rituximab, and single-agent cyclophosphamide.

Question 42

To what RT doses should the kidneys and liver be limited in MALT of the stomach?

Answer 42

Pts experience excellent long-term survival, so minimizing the toxicity of therapy is of critical importance. Keep the mean dose to both kidneys to <10–15 Gy (or 20% of left kidney to <20 Gy). The dose to the liver should be V25 <50%. Patient shifts may be necessary during treatment with daily volumetric image guidance, so consider using a kidney PRV (planning risk volume) avoidance structure.

Question 43

What are expected toxicities for using ISRT for Tx of MALT lymphoma of the stomach?

Answer 43

Anorexia and n/v are toxicities associated with ISRT for MALT lymphoma of the stomach and can be lessened with prophylactic daily antiemetics prior to Tx. More significant side effects, such as ulceration, are rare.