Appropriately Diagnosing and Classifying MZL

John N. Allan, MD:Nodal marginal zone lymphoma is a relatively rare subtype of a non-Hodgkin lymphoma. Marginal zone lymphoma, in general, is a relatively rare subtype representing somewhere around 10% of non-Hodgkin lymphomas. There are basically 3 types of marginal zone lymphomas. There are extranodal marginal zone lymphomas, which are called MALT lymphomas, or mucosa-associated lymphoid tissue lymphomas. There is an entity described and known as splenic marginal zone lymphoma. Then, the third entity is a nodal marginal zone lymphoma.

Essentially, this is a diagnosis of exclusion. When you believe you’re dealing with a marginal zone lymphoma, you essentially have to exclude extranodal sites. If there is any involvement of the gut, ocular adnexa, skin, or any other area that would be extranodal, outside of the lymph nodes, the diagnosis typically gets lumped into the category as an extranodal marginal zone lymphoma. Essentially, you have to rule out an extranodal source. Again, splenic marginal zone lymphoma is a relatively straightforward diagnosis. It literally just involves the spleen and the bone marrow. If you have a patient presenting without extranodal sites, without an isolated enlarged spleen and predominantly enlarged lymph nodes, you then get diagnosed with what’s called a nodal marginal zone lymphoma.

When we talk about nodal marginal zone lymphoma, a lot of our data that we extrapolate from is from our patients with follicular lymphoma. These 2 disease entities are similar in their outcomes. Because nodal marginal zone lymphomas are relatively rare, they are less represented in clinical trials—typically, at smaller numbers to where the power isn’t there to really know how these subgroups do long term, respectively, with treatments.

In general, we do believe that they respond well to rituximab-based therapies. Overall, several different studies have shown 5-year overall survival rates that range from 60% to upward of 80% to 90%. It is a mixture. There is some evidence that nodal marginal zone lymphomas may have a slightly worse prognosis than other marginal zone lymphomas, such as extranodal—MALTs—and splenic marginal zone lymphomas.

Marginal zone lymphoma is a diagnosis that is relatively difficult to come to an agreement on. It lacks many features of other B-cell malignancies, such as specific immunophenotypes, and differs from follicular lymphoma in that it is predominately a CD10-negative disease. It differs from CLL, SLL, and mantle cell lymphoma in that it’s typically a CD5-negative disease. Really, it comes down to a histopathologic diagnosis.

The frustrating part, for physicians and pathologists alike, is that the histology can vary dramatically. It can have lymphoplasmacytoid differentiation, plasmacytic differentiation, and can sometimes mimic lymphoplasmacytic lymphoma or Waldenström macroglobulinemia, which are typically CD5 and CD10 negative.

It really comes down to experience—for an experienced pathologist to really hone in on the subtleties for making the diagnosis. We are now using more molecular features to try to understand and differentiate these entities—marginal zone lymphomas from other ones such as follicular lymphoma, Waldenström macroglobulinemia, CLL, mantle cell lymphoma, and such.

Marginal zone lymphomas are noted to involve some type of antigen stimulation or some type of chronic inflammation. The most common marginal zone lymphomas, which are extranodal marginal zone lymphomas, are typically found in settings of infections such hasH.pylori. Certain bacteria are involved with skin and nodal marginal zone lymphomas, as well as ocular extranodal marginal zone lymphomas.

What we have found is that these nodal marginal zone lymphomas also have a relatively common background of patients with chronic antigen stimulation. Sometimes they’re involved with hepatitis, such as in splenic marginal zone lymphomas. In nodal marginal zone lymphomas, although no specific infection has necessarily been associated with them, they do note relatively common associations with autoimmune disorders such as lupus, Sjögren syndrome, and other kinds of chronic inflammatory conditions.

Transcript edited for clarity.

A 65-Year-Old Man With Advanced Nodal MZL

November 2014

History & Physical:

• A 65-year-old man presented with multiple lumps in groin, no pain
• PMH: negative for HCV, HBV, HIV
• PE: marked swelling in right axillary and bilateral inguinal lymph nodes
  • ECOG performance status: 0
  • Otherwise healthy, no history of CV disease or diabetes, weight within normal range
• CT revealed lymphadenopathy at multiple nodal sites with multiple involved nodes (each <2 cm) involved at each site; no extranodal involvement or bulky disease
• Biopsies confirmed presence of B cell infiltrate
• IHC: B cell phenotype CD20, CD19

Treatment History:

• He was started on active monitoring with CT, histology, and pathology every 6 mo.

November 2015

• At 12 months following diagnosis, disease progression was shown on imaging, with additional involved axillary nodes
• The patient was started on treatment with bendamustine/rituximab (BR)

November 2017

• Follow-up imaging at 2 years following initiation of BR revealed disease progression in multiple lymph nodes at several sites
  • 2 nodes measuring >3.0 cm
• The patient was started on R-CHOP; he achieved a partial response

June 2018

• 7 months later, the patient developed relapsed disease
• He was started on treatment with ibrutinib 560 mg/day orally
  • He developed mild diarrhea (managed with OTC anti-diarrheal) and bruising on legs from minor bumps
  • Follow-up CBC showed grade 3 neutropenia without fever
• Ibrutinib was discontinued until neutrophils recovered and restarted at same dose without incident