Lymphadenopathy

Jorge E. Romaguera, MD

M.D. Anderson Cancer Center, University of Texas, Houston, TX

Copyright of the American Society of Hematology, 2006. ISSN: 1931-6860.

This case was reviewed and updated in January 2011 by Dr. Peter Marks and members of the Teaching Cases Subcommittee.

V. PATHOPHYSIOLOGY

The following information will help you understand lymphoma and decide the proper treatment for this patient.

Polyclonal (reactive) vs. Monoclonal (neoplastic) Lymphomas
Lymphomas are neoplasms arising from the lymphoid hematopoietic tissue. They are fundamentally characterized by their clonal derivation, in contrast to any reactive lymphoproliferation which will be comprised of a diverse lymphocyte population. Lymphocytes have the unique property of undergoing physiologic gene rearrangements of their immunoglobulin (B-cells) or T-cell receptor (T-cell) gene loci. Gene rearrangement studies can be used to assay whether a tumor population is derived from a single clone (only one band for each allele of a single clone), or multiple clones (many bands).

Lymphoma Classification
Reflecting the complexities of lymphocyte development, there are a bewildering assortment of lymphoma sub-types that can broadly be divided into 1) B-cell neoplasms, 2) T- and NK- cell neoplasms, and 3) Hodgkin disease. In the past, there have been many competing lymphoma classification systems, but the World Health Organization (WHO) classification has become the accepted standard as of 2008. The key insights underlying this classification are that 1) there is no single test that is the “gold standard” for sub-type classification, and 2) a broad, international consensus, as opposed to single groups of investigators, is required to form a reproducible classification system. Diffuse large B-cell lymphoma (DBLCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Undoubtedly, there will be further updates to the WHO 2008 classification scheme based upon an evolving molecular understanding of the lymphomas.

Hodgkin Disease (HD) vs. Non-Hodgkin Lymphoma (NHL)
The B-cell and T- and NK- cell lymphomas are called NHL. Recently, it has been determined that Hodgkin disease, also called Hodgkin lymphoma, is most commonly a form of B-cell neoplasm, but for historical and clinical reasons, HD is kept as a separate entity. HD is characterized by tumors that are predominantly comprised of reactive lymphoproliferation and a small population of malignant "Reed-Sternberg cells." HD is also highly curable.

Differential Diagnosis Based Upon Histopathology According to WHO [2008]

The mature B-cell neoplasms.
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma
Hairy cell leukemia
Splenic lymphoma/leukemia, unclassifiable
 Splenic diffuse red pulp small B-cell lymphoma*
 Hairy cell leukemia-variant*
Lymphoplasmacytic lymphoma
 Waldenström macroglobulinemia
Heavy chain diseases
 Alpha heavy chain diseaase
 Gamma heavy chain disease
 Mu heavy chain disease
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
Nodal marginal zone B-cell lymphoma (MZL)
 Pediatric type nodal MZL
Follicular lymphoma
Pediatric type follicular lymphoma
 Primary cutaneous follicle center lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
 T-cell/histiocyte rich large B-cell lymphoma
 DLBCL associated with chronic inflammation
 Epstein-Barr virus (EBV)+ DLBCL of the elderly
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary cutaneous DLBCL, leg type
ALK+ large B-cell lymphoma
Plasmablastic lymphoma
Primary effusion lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
Burkitt lymphoma
B-cell lymphoma, unclassifable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma
 
Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
 Nodular sclerosis classical Hodgkin lymphoma
 Lymphocyte-rich classical Hodgkin lymphoma
 Mixed cellularity classical Hodgkin lymphoma
 Lymphocyte-depleted classical Hodgkin lymphoma
 
Mature T-cell and NK-cell neoplasms.
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of NK-cells*
Aggressive NK-cell leukemia
Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection)
Hydroa vacciniforme-like lymphoma
Adult T-cell leukemia/ lymphoma
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-associated T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Primary cutaneous CD30+ T-cell lymphoproliferative disorder
 Lymphomatoid papulosis
 Primary cutaneous anaplastic large-cell lymphoma
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma*
Primary cutaneous gamma-delta T-cell lymphoma
Primary cutaneous small/medium CD4+ T-cell lymphoma
Peripheral T-cell lymphoma, not otherwise specified
Angioimmunoblastic T-cell lymphoma
Anaplastic large-cell lymphoma (ALCL), ALK+
Anaplastic large-cell lymphoma (ALCL), ALK-*
 
* These represent provisional entities or provisional subtypes of other neoplasms. Diseases shown in italics are newly included in the 2008 WHO classification.

Source: Adapted from: Jaffe ES. Hematology Am Soc Hematol Educ Program.. 2009: 523-531.

Another method of categorizing lymphomas is by their clinical acuity. This method is favored by clinicians because of the large number of different pathologic entities. In general, non-Hodgkin lymphomas are classified as 1) indolent (low grade) or 2) aggressive (high grade), based on features of the lymph node biopsy.

  1. Indolent lymphomas include:
    • Follicular lymphomas - Grade I (mainly small cells, the most common type of indolent NHL) and Grade II (mixed small and large cells),
    • Small lymphocytic lymphoma (the tissue counterpart of chronic lymphocytic leukemia (CLL)),
    • Lymphoplasmacytoid lymphoma (Waldenström's macroglobulinemia), associated with a monoclonal IgM paraprotein),
    • Mycosis fungoides (a cutaneous T-cell lymphoma), and
    • Marginal zone lymphoma (called mucousal-associated lymphoid tissue (MALT) when it involves extranodal tissues).
    Indolent lymphomas tend to progress slowly but are usually not curable with standard treatment approaches. A small percentage of patients with indolent lymphoma present with localized disease and may have long-term disease-free survival after local radiation therapy. However, most patients with indolent lymphoma present with Stage III or Stage IV disease. Many patients live 7 to 10 years after the diagnosis of indolent lymphoma. The treatment approach must be individualized and depends in part on the specific type of indolent lymphoma.

    The most common indolent lymphoma is follicular lymphoma.
    • If the patient with follicular lymphoma is asymptomatic, a "watchful waiting" approach is reasonable, deferring treatment until s/he develops symptoms or marked progression of disease.
    • If the patient has "B" symptoms (fever, drenching night sweats, or significant weight loss), pancytopenia due to marrow replacement with lymphoma, or bulky, obstructing adenopathy, it is reasonable to proceed with treatment. Patients who develop an elevated serum LDH level or who develop "B" symptoms should be investigated for the possibility of transformation of an indolent lymphoma into an aggressive lymphoma, which ultimately can occur in 20-40% of cases. Initial therapeutic options, depending on clinical presentation, include:
      • Oral chemotherapy with chlorambucil or cyclophosphamide
      • Intravenous chemotherapy with cyclophosphamide/vincristine/prednisone (CVP), cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP), or fludarabine
      • Intravenous immunotherapy with the anti-CD20 antibody rituximab
      • Combinations of these approaches
    • Most patients will obtain a remission, which may last many years. Eventually, patients again develop symptoms and require treatment. A second remission is achieved in a smaller proportion of patients and lasts a shorter period of time. Treatment approaches for patients with relapsed low-grade lymphoma include autologous stem cell transplantation or radiation treatment delivered by infusion of an I131- or Y90-conjugated monoclonal antibody that recognizes an antigen present on the malignant cells.
  2. Aggressive lymphomas include:
    • Diffuse large B-cell lymphoma (the most common type of aggressive non-Hodgkin lymphoma),
    • Anaplastic large cell lymphoma (often T-cell, express CD30 antigen),
    • Follicular lymphomas – Grade III (predominately large cells),
    • Mantle cell lymphoma,
    • Lymphoblastic lymphoma and
    • Burkitt lymphoma


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