Non-Hodgkin lymphoma, with an estimated 77,000 annual new cases in the United States, is the most common hematological malignancy, and diffuse large B-cell lymphoma (DLBCL) is its most common subtype. 

DLBCL accounts for about 30% to 40% of non-Hodgkin lymphoma and is an aggressive form of the disease. It results in the clonal proliferation of malignant B cells, both germinal and postgerminal. DLBCL is a heterogeneous group of entities that remain biologically distinct, even if they share the same core characteristic (malignant B cell growth). 

The diagnosis of DLBCL is usually made from collected biopsy specimens. The best way to obtain specimens for pathological evaluation is an excisional biopsy. For this purpose, biopsies obtained via fine-needle aspiration are inadequate. Core biopsies are also often inadequate for a complete assessment. 

“The diagnosis is commonly made by biopsy of a suspicious lymph node or an extranodal tumor where the normal architecture is replaced by sheets of large cells that stain positive for pan-B cell antigens, such as CD20 and CD79a,” Susanibar-Adaniya and Barts wrote in the American Journal of Hematology. 

Read more about DLBCL etiology 

Our collective understanding of DLBCL is constantly evolving, which is reflected by publications by leading scientists evaluating what we understand about risk stratification and management of the disease.

Staging the Disease 

DLBCL staging is conducted according to the Ann Arbor staging criteria. The Ann Arbor staging system is constructed in a similar way to the classical TNM (tumor, node, metastasis) staging system used in most cancers. 

The Ann Arbor staging criteria are named after the town of Ann Arbor, Michigan. They were agreed upon by the Committee on Hodgkin’s Disease Staging Classification when it met in 1971, replacing the previous Rye staging system. 

The Ann Arbor criteria have 4 stages, indicating increasing dissemination of the disease. In stage IV, the disease involves one or more extralymphatic organs; alternatively, it may include isolated extralymphatic organ involvement without the involvement of adjacent regional lymph nodes, but with disease in distant sites. It may also involve the cerebrospinal fluid, pleura, liver, or bone marrow. 

The Ann Arbor criteria also include 5 substaging variables: A means patients are asymptomatic. B includes the presence of B symptoms (fever, night sweats, and weight loss). E involves a single, extranodal site that is either proximal or contiguous to a known nodal site, while S involves the spleen. X refers to bulky nodal disease, defined as a nodal mass 10 cm in dimension or greater than a third of the intrathoracic diameter. 

Recent studies have found 18F-fluorodeoxyglucose positron-emission tomography with computed tomography (PET-CT) to be superior to normal CT imaging. Its superiority lies in its high sensitivity. It is no longer mandatory for patients who have undergone PET-CT staging to undergo bone marrow biopsy. However, foregoing bone marrow biopsy may cause pathologists to occasionally miss out on low-volume disease or discordant indolent lymphoma, but these do not alter outcomes. 

Read more about DLBCL treatment

“Staging bone marrow biopsy is positive in 15 to 20% of cases and, when concordant large B cells are present, is associated with a poor prognosis,” Sehn and Salles wrote in The New England Journal of Medicine. 

In addition, the total metabolic tumor volume is also measured upon diagnosis because it can yield important prognostic data. Studies have indicated that high total metabolic tumor volume has prognostic utility across various treatment groups. 

Measuring Treatment Response 

Treatment response can also be measured using PET-CT; however, its merits have been the subject of academic debate. While there is general consensus that PET-CT is a highly useful tool for baseline staging of the lymphoma, its use in assessing therapy response is limited because it can yield false positive results when concomitant infection or inflammation is present. It can also yield false negative results because it is unable to detect microscopic disease. 

“PET-CT after two to four cycles of treatment appears to be prognostic, particularly when the response is assessed with the use of quantitative methods,” Sehn and Salles wrote. “However, treatment modification based solely on interim PET-CT findings has not been shown to alter the outcome and thus is not recommended outside of clinical trials.” 

Another useful method for measuring treatment response is to monitor circulating tumor DNA. Circulating tumor DNA is continuously released into the bloodstream by tumors undergoing cell death. Studies indicate it is a promising interim response assessment tool. 

“Advantages of monitoring [circulating tumor DNA] are its non-invasive nature with the potential to track clonal evolution and detect new mutations that arise during treatment, which could be potentially exploited using targeted agents,” Susanibar-Adaniya and Barta wrote. 

A study using circulating tumor DNA to measure treatment progress demonstrates it is overwhelmingly effective at predicting relapse—the positive predictive value was 88.2%, while the negative predictive value was 97.8% over a median of 11 years. 

While the monitoring of treatment response and the risk of relapse can yield clinical benefits, there is less consensus on the usefulness of post-treatment surveillance imaging. Instead, physicians should monitor patients for comorbidities that can increase the risk of mortality. 


Sehn LH, Salles G. Diffuse large B-Cell lymphomaN Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612

Susanibar-Adaniya S, Barta SK. 2021 2021 update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and managementAm J Hematol. 2021;96(5):617-629. doi:10.1002/ajh.26151

Bell DJ. Ann Arbor staging system. Published online November 19, 2021. Accessed August 12, 2022.