Evolving research improves lymphoma diagnosis, treatment

As researchers uncover biomarkers for cancer subtypes, collaboration between researchers, pathologists and physicians will improve accurate diagnosis of lymphoma subtypes.

Lymphoma diagnosis, patient risk stratification and treatment planning are increasingly informed by a growing list of molecular insights and tests, requiring closer teamwork between researchers, pathologists and clinicians, experts reported December 5 during the 57th American Society of Hematology (ASH) Annual Meeting in Orlando.

Dr. Hsi

As researchers identify immunophenotypes and genetic subtypes of cancers like the large-cell lymphomas, closer interdisciplinary collaboration is necessary, said Eric D. Hsi, MD, chair of clinical pathology at the Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, in Cleveland, of Ohio.

“Accurate diagnosis requires clinical context,” Hsi said. “It’s best done in collaboration with clinical teams.”

For example, there might be morphologic “clues” suggesting a diagnosis of primary mediastinal large cell lymphoma (PMBL) to the pathologist, he noted, “but definite diagnosis with current tools can be difficult for a pathologist in isolation.”

Researchers’ efforts to assess newer molecular markers might improve the ability to make definitive diagnoses with molecular data, he said. Newer molecular tests like those for the programmed-death ligand protein 2 (PD-L2) or PD-LI and PD-L2 gene abnormalities will increase the accuracy of pathology reports for large b-cell lymphomas, for example.

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A particular case of PMBL might harbor specific genetic rearrangements-deletion mutations, translocations or duplications-that might affect how a tumor interacts with the patient’s immune system or treatment. Or two gene mutations might work together synergistically to make a malignancy more aggressive, as happens with “double-hit” lymphomas. These are diffuse large B-cell lymphomas (DLBCLs) that harbor mutations in the MYC and BCL2 (or sometimes, BCL6) genes, Hsi said.


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Studies have shown that double-hit lymphomas are very aggressive. That makes sense: The overexpression of BCL2 protein makes the malignant cells resistant to apoptosis, or programmed cell death - and therefore drug-resistant - while the MYC mutation hastens their proliferation.

Retrospective studies have suggested that patients with double-hit DLBCL do worse when treated with standard “R-CHOP” chemotherapy regimen than other, more intensive treatments. (But patients with double-hit DLBCL still have worse survival than other patients with DLBCL, even when they receive dose-intensified therapy.)

Dr. Friedberg

“Treating all DLBCL with R-CHOP is no longer appropriate,” noted Jonathan Friedberg, MD, of the Wilmot Cancer Institute, University of Rochester, in Rochester, New York. “We are moving quickly to ‘precision medicine’ approaches to the treatment of DLBCL.”

Several experimental targeted therapies that inhibit MYC and BCL2 are under investigation, Friedberg noted. “An active treatment for double-hit DLBCL would have a profound impact on the natural history of the majority of treatment failures in DLBCL.”

Like PD-L1 and PD-L2 expression, the MYC+BCL2 “double hit” is a prognostic biomarker - a molecular detail that can help clinicians understand a patient’s disease and likely response to treatment. Many other candidate biomarkers are under development, though sometimes their availability has outpaced the evidence base for clinical usefulness.

In many cases, gene profiling is just not yet “ready for prime-time in the clinic,” Hsi cautioned. Other techniques, like immunohistochemical (IHC) testing, remain more widely used, even though there sometimes can be issues with standardization and subjective interpretation, he said.

“IHC is widely available on routine, automated platforms in clinical laboratories,” he explained. Some IHC tests will likely be replaced by gene tests in the future, but others will remain useful alongside, or as alternatives to, newer tests.

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