Pathophysiology, Diagnosis, and Classification of B-Cell NHL: Implications for Personalized Prognosis and Treatment

Editor-in-Chief: Stephanie A. Gregory, MD
Medical Writer: Annette Skorupa, PhD

Diagnosis, Staging, and Risk Classification

Diagnosis starts with obtaining incisional or excisional lymph node biopsy tissue^2,19; additional steps involved in diagnosis and workup are included in Table 2.

Table 2. Diagnosis and Workup for Patients with B-Cell NHL

Biopsy tissue malignant cells2,19 Morphology/histology (cell size and anaplastic features), clinical features (age and lymph node location), and immunophenotype.

Clinical characteristics2,19 Patient age Lymph node location

Immunophenotype Initial assessment using antibodies to Pan-B and Pan-T antigens Further phenotyping using antibody subsets according to morphology and clinical features2

Workup2 Bone marrow biopsy Contrast-enhanced CT scan of chest/abdomen/pelvis regions Hepatitis B testing

Additional workup (depending on type and site)2 Measurement of beta-2-microglobulin Endoscopic ultrasound Integrated PET-CT Lumbar puncture Head CT/brain MRI

Staging2 Ann Arbor staging Other systems for specific subtypes

Two basic prognostic groups of B-cell NHL are recognized¹

• Indolent
  • Not considered curable
  • Overall median survival up to 10 years
• Aggressive
  • Potentially curable with intensive chemotherapy in early stages
  • Otherwise, associated with much shorter survival than indolent forms

The 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, issued in 2008, constitutes the most up-to-date classification system for NHL.²⁰

The 2008 edition includes some notable changes from the 2001 version, with inclusion of new classes and subclasses, for example, based on patient age, clinical setting, and relevant location and/or microenvironment (Table 3).^15,21,22

The major histologic subtypes of B-cell NHL include DLBCL (comprising approximately 31% of NHL cases),² follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma (MALT type), and small B-lymphocytic lymphoma.²³

Table 3. New Classes and Subclasses—2008 WHO Classification
Diffuse large B-cell lymphoma (DLBCL), subtypes22    Primary DLBCL of central nervous system (CNS) Distinctive characteristics related to immune-privileged location, including IL-4 modulation, modulation by IL-4, absence of HLA I and II, extreme Ig hypermutation with accompanying retention of an open reading frame; excludes lymphomas found in the dura, intravascular large B-cell lymphoma, secondary localization to CNS, and lymphomas in immunocompromised patients22  Primary cutaneous DLBCL, leg type  Typically shows activated B-cell gene expression profile20 Epstein-Barr virus (EBV)-positive DLBCL of the elderly (provisional entity) Clinical setting of concomitant viral infection and immunodeficiency (enabling escape from cytotoxic T-cells), often found at extranodal sites, typically aggressive20,21 DLBCL associated with chronic inflammation  Clinical setting with inflammatory process of >10 years duration, generally extranodal with pleural cavity location22; tumor site may occur in areas of localized immunodeficiency due to chronic inflammation24 Large B-cell lymphoma arising in human herpes virus-8–associated with multicentric Castleman disease Similar to EBV-positive DLBCL of the elderly in that it occurs in a clinical setting of comcomitant viral infection and immunodeficiency (enabling escape from cytotoxic T-cells) with immunophenotype resembling plasma cells, and poor prognosis regardless of other indicators20,21
Borderline cases B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features between DLBCL and classical Hodgkin lymphoma	Tumors with immunophenotypic and/or molecular characteristics of both types; not a single type but multiple biologic entities20,25
Follicular lymphoma Pediatric type follicular lymphoma	Usually localized, frequently occur in cervical lymph nodes and Waldeyer's ring, but can also appear in extranodal sites, such as the testis15,20
Nodal marginal zone B-cell lymphoma (MZL) Pediatric type nodal MZL	Commonly found in head and neck lymph nodes, often in outer borders of progressively transformed germinal centers15,20

Some variants of DLBCL not otherwise specified were not formally included in the 2008 WHO classification (Table 4). The molecular variants were excluded because gene expression profiling is not routinely performed in clinical settings and because currently available immunophenotyping does not correlate well with molecular profiles. These variants may have future clinical significance.²⁰ For example, early data indicate that activated B-cell–like disease does not respond as well to the current standard of therapy as to other DLBCL types.²⁶

Table 4. DLBCL Not Otherwise Specified—Variants in the Literature Not Formally Included in the 2008 WHO Classification20,22
Variants	Comments
Rare morphologic variants22	 Morphologically distinct entities for which no distinguishing biologic differences are currently known
Molecular subgroups20 Germinal center B-cell like Activated B-cell like Immunohistochemical subtypes22 CD-5–positive DLBCL Germinal center B-cell like Nongerminal center B-cell like	 The germinal center B-cell–like and activated B-cell–like lymphomas were differentiated using gene expression profiling; these subgroups differ in terms of prognosis

The unique characteristics of B-cell NHL types necessitate tumor-specific prognostic indices (Table 5). Some indices have undergone revision as new prognostic factors have been discovered and asrituximab became available.

Table 5. Prognostic Indices
Abbreviation	Full Name	Important Features
IPI27	 International Prognostic Index	Designed to differentiate between patients with aggressive NHL at high and low risk for death in the setting of intensive combination chemotherapy27 Factors27 Tumor stage, serum lactate dehydrogenase (LDH), and number of extranodal sites—indicative of tumor growth and invasive potential Performance status—patient's response to tumor and ability to withstand therapy Age—patient's ability to withstand therapy Identifies 4 risk groups according to 5-year survival rates
R-IPI28	 Rituximab-IPI	Redistributes factors from the IPI to improve prognostication for patients with DLBCL receiving rituximab along with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) Distinguishes 3 risk groups according to survival rates: very good, good, poor
FLIPI29	 Follicular lymphoma IPI	Developed because of the need for a prognostic index for patients with follicular lymphoma as the IPI is not relevant in this setting Factors: age, Ann Arbor stage, hemoglobin level, serum LDH level, number of nodal areas Distinguishes 3 risk groups based on survival rates: low, intermediate, and poor
FLIPI230	 Follicular IPI 2	Developed to improve prognostication for patients with follicular lymphoma as FLIPI does not take into account rituximab therapy and disease features, such as beta2-microglobulin
CLIPI31	 Cutaneous lymphoma IPI	Factors consist of serum LDH, morphology of the lesion (nodule versus other), and >2 lesions 3 risk groups were defined according to progression-free survival rates: low risk, intermediate risk, and high risk
MIPI32	 Mantle cell IPI	Developed because IPI and FLIPI were not predictive for patients with mantle cell lymphoma Factors: age, performance status, serum LDH, and leukocyte count Distinguishes 3 groups based on overall survival: low risk, intermediate risk, and high risk