Differential Diagnosis for Follicular Lymphoma

Loretta J. Nastoupil, MD:The symptoms associated with follicular lymphoma can be vast or heterogenous, but oftentimes, there are no symptoms associated with follicular lymphoma. So, what do we mean by that? Oftentimes, patients will have an incidental finding of an enlarged lymph node, either they’re having an imaging study done for another health reason or as this patient presents to her primary care physician with a palpable lymph node that’s often painless and can be stable in size or maybe growing. It can be quite heterogenous in presentation. The symptoms we often will ask about when we’re trying to discern whether or not there’s an aggressive feature to the follicular lymphoma are the traditional B symptoms associated with lymphoma, such as weight loss. We generally will use a cutoff of 10% of their dry weight or more. For night sweats, we generally look to see if those are drenching or occurring more than 3 times per week. Fatigue is oftentimes subjective, but if it’s often impacting their quality of life or daily routine, or even their functional status, we find that to be very valuable and associated with their lymphoma. And fever, in the absence of an infection, might otherwise explain it. Patients will feel frustrated when we routinely ask about these symptoms and they oftentimes do not have them. But I still think it’s valuable to at least address these questions during each visit or each treatment assessment.

Follicular lymphomas are most common low-grade B cell lymphomas, and oftentimes, patients will come into our clinic and know they have a diagnosis of non-Hodgkin lymphoma. But they do not further differentiate or understand that there are various subtypes of lymphoma that are probably very important to discern because it has implications for how we treat and what their outcomes are. The most common phenotype of follicular lymphoma is based on their flow cytometry or immunohistochemistry, and that it’s A or B cell lineage, so it’s often traditionally CD20-positive, CD10-positive. It is hard to distinguish follicular lymphoma from a large cell that’s a germinal center derivation just based on flow cytometry or immunohistochemistry. So, oftentimes, I will advocate that an FNA is an inadequate diagnostic approach for these patients, but that’s their first diagnostic approach, meaning they’ll have an FNA that’s ordered by a primary care physician or an ENT physician to discern what type of cancer it is.

For instance, this patient presenting with axillary adenopathy breast cancer would have been on the list of differentials. And so, it’s not uncommon for us to see a patient come in with an FNA and we know that there’s a B cell clone, but we can’t distinguish between, say, a large-cell lymphoma or even a Burkitt, which may have a similar phenotype. So, I do advocate that an incisional biopsy, particularly at diagnosis, is incredibly important so you can have the morphology to help distinguish between which type of B cell lymphoma you’re dealing with and also look at the grading of the follicular lymphoma—which, even though this is quite controversial and oftentimes pathologists will disagree, is still pertinent information.

I would say in the United States, we tend to put more emphasis on grades than European countries. Meaning, we still are giving more anthracyclines to grade 3 follicular lymphoma based on the retrospective data that suggest they do well. And we’re waiting on prospective data to tell us whether or not bendamustine and rituximab or bendamustine and a CD20 antibody is appropriate therapy for patients with grade 3 follicular lymphoma. Those prospective studies have completed enrollment, but we don’t know the results yet. The morphology is still very important in this disease, and it’s helpful in distinguishing the type of lymphoma that will have treatment implications.

The other things that you have to consider when you’re looking at a new diagnosis is whether or not there’s an underlying concomitant or concordant lymphoma, meaning 2 lymphomas at the same time. About 10% of the time—and we’re an institution that sees quite a bit of follicular lymphoma—it’s not that infrequent for us to see both a diagnosis of follicular and large-cell lymphoma as their initial diagnosis. We do know that about 30% of patients with follicular lymphoma will ultimately transform at some point in their disease course, meaning they develop more aggressive features and, histologically, it’s more consistent with large-cell lymphoma. There’s also about 10% of patients at diagnosis who will have both follicular and large-cell lymphoma. And again, this is where an incisional biopsy is very meaningful to help distinguish out those patients.

We’re not currently clear as to whether or not those patients do as poorly as the traditional patients who transform, meaning they have a preexisting diagnosis of follicular lymphoma and then later develop the histologic transformation that’s been historically associated with poor outcomes. There’s still something that’s important to tease out. There’s a growing trend to pursue more needle biopsies for patients with a new diagnosis or initial presentation with lymphadenopathy. I know this is more convenient for patients and oftentimes for physicians. I feel that this is a growing trend that may have implications for how confident we are in the diagnosis and, secondly, how we manage these patients. Are we confident about the grading? Are we confident that there is only 1 lymphoma present at the initial presentation?

An FNA will clearly determine whether or not there is a malignant clone present and decide that T or B cell lineage, but it will not render a complete diagnosis. You may get as far as knowing whether it’s a germinal center or follicle center lymphoma, but, again, it’s not a definitive diagnosis. And there leaves some ambiguity whether or not this is a large-cell or follicular, which, again, the treatment management may be vastly different. So, that is valuable information to know.

Corneal biopsies can give more information than an FNA because generally you will have some morphology to examine. But our pathologists oftentimes remind us that those are often very limited samples that are impacted by crush or processing artifacts that make their jobs very challenging. However, there are situations where corneal biopsy is the only appropriate approach for a patient, meaning if you have a retroperitoneal lymph node or a mesenteric node that is not easily obtained with outside of a large surgical exploration. So, in these situations, we’re oftentimes relying on a core needle biopsy as our original or initial diagnosis. Again, there are limitations for this, and our pathologists will often describe those limitations in the pathologic diagnosis, but this may be our only option.

Transcript edited for clarity.

January 2014

• A 71-year-old female reports having symptoms of bilateral axillary swelling of 1.5 years’ duration and presents with diffuse inguinal and cervical adenopathy.
• Past medical History: 15-year history of treatment for rheumatoid arthritis with methotrexate
• Physical examination:
  • The patient is generally well-appearing; temperature, pulse, blood pressure, and HEENT are all WNL; extremities show no edema.
  • Cardiac exam is normal; chest is clear
  • Abdomen shows no abnormal hepatosplenomegaly
  • Lymph nodes: left axillary 1.5 cm, right axillary 2 cm; cervical and inguinal nodes <1 cm bilaterally; non-tender
• Notable laboratory findings:
  • CBC with diff, WNL
  • LDH, 148
• Right groin excisional node biopsy shows small lymphocytes with nuclear indentations (centrocytes) and large lymphocytes without indentations (centroblasts).
  • Pathology: t(14;18); co-expression of Bcl2, CD10, CD20.
• CT shows scattered adenopathy in the cervical, axillary, mesenteric, and pelvic regions. The largest lymph node measures 4.5 cm. The remaining lymph nodes are smaller than 3 cm.