Follicular Lymphoma (Non-Hodgkin Lymphoma) Staging

The World Health Organization (WHO)/Revised European-American Lymphoma (REAL) classification and the Cotswolds modified Ann Arbor staging system for follicular lymphoma (non-Hodgkin lymphoma [NHL]) are provided below, ^{[1, 2]} as well as the Follicular Lymphoma International Prognostic Index (FLIPI) score. ^[3]

WHO classification

The 2016 WHO classification of mature B-cell neoplasms includes the following subtypes of follicular lymphoma (FL) ^[1] : 

• In situ follicular neoplasia – Renamed from in situ FL because of the low risk of progression to lymphoma
• Duodenal-type FL –  Localized process with low risk for dissemination
• Pediatric-type FL –  Localized clonal proliferation with excellent prognosis; a conservative therapeutic approach (with no treatment beyond excision) may be sufficient; occurs in children and young adults, rarely in older individuals; this is a nodal disease characterized by large, expansile, highly proliferative follicles that often have prominent blastoid follicular center cells rather than classic centroblasts (or centrocytes);  BCL2 rearrangements must not be present, but there may be some BCL2 protein expression;  BCL6 and MYC rearrangements are lacking
• Predominantly diffuse FL with 1p36 deletion – Accounts for some cases of diffuse FL, lacks BCL2 rearrangement; presents as localized mass, often inguinal

The WHO classification also includes follicular T-cell lymphoma as a provisional entity. To qualify for this designation, the neoplastic cells should express at least 2 or 3 T-follicular helper–related antigens, including CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP, and CCR5. ^[1]

WHO/REAL classification

FL is classified into the following 3 histologic grades ^{[1, 2]} :

• Grade 1: 0-5 centroblasts/high-power field (HPF)
• Grade 2: 6-15 centroblasts/HPF
• Grade 3: > 15 centroblasts/HPF

The WHO classification consolidates cases with few centroblasts as FL grade 1-2 (low-grade). FL grade 3 is divided into 3A and 3B (absence of centrocytes). Diffuse areas in any grade 3 classification should be treated according to diffuse large B-cell lymphoma (DLBCL) criteria. ^[1]

Cotswolds modification of Ann Arbor staging system

The Cotswolds modification maintains the original 4-stage clinical and pathologic staging framework of the Ann Arbor staging system but also adds information regarding the prognostic significance of bulky disease (denoted by an X designation) and regions of lymph node involvement (denoted by an E designation). ^[4]

The A and B designations denote the absence or presence of symptoms, respectively; the presence of symptoms correlates with treatment response. The importance of imaging modalities, such as computed tomography (CT) scanning, is also underscored. ^[4]

Table. Cotswolds modification of Ann Arbor staging system (Open Table in a new window)

FLIPI score

The development and validation of an accurate and easily available prognostic index for FL has facilitated the development of treatment algorithm plans, enabled the cross-talk between investigators, and improved understanding of the results of clinical studies.

Briefly, the FL International Prognostic Index (FLIPI) score was designed by studying clinical characteristics of 1795 newly diagnosed cases of FL between 1985 and 1992 across 27 different cancer centers. Several clinical parameters known to affect the outcome of FL patients were tested in the patient population using a univariate and multivariate analysis. The statistical analysis identified 5 variables that strongly and independently were associated with a poor clinical outcome, as provided below. ^[3]

Factors (1 point for each variable present) ^[3] :

• Age > 60y
• Ann Arbor Stage III-IV
• Hemoglobin level < 12 g/dL
• Lactate dehydrogenase (LDH) level > upper limit of normal (ULN)
• ≥ 4 nodal sites of disease

Risk category (number of factors) ^[3] :

• Low risk (0 or 1)
• Intermediate risk (2)
• High risk (> 3)