Lymphomas

 

Description:

Lymphomas, in contrast to the leukemias, the myeloproliferative and myelodysplastic disorders, originate in lymph nodes or in lymphocytes that reside in other organs or tissues (extranodal lymphomas). The classification of lymphomas is based, to a great extent, on the morphologic appearance of the clonal cells and the pattern of involvement of the lymph node. If the cell is a mature lymphocyte, it is classified as a low grade or indolent lymphoma. If the cell is a more immature cell (e.g. large B or T cell lymphoma cells) it is classified as intermediate grade lymphoma. When the cell is a lymphoblast it is classified as high grade lymphoma. When a high grade lymphoma spreads to involve the bone marrow it usually does so in a diffuse pattern, and is indistinguishable from acute lymphocytic leukemia originating in the bone marrow. When this occurs, it is referred to as "leukemic transformation" of a high grade lymphoma. When intermediate grade lymphomas spread to involve the bone marrow it is usually in a spotty pattern, and is referred to as bone marrow involvement by lymphoma (Stage IV). The pattern of bone marrow involvement in low grade lymphomas is variable. In follicular small cleaved lymphoma, bone marrow involvement is focal and characteristically paratrabecular (adjacent to bone) in location. In well differentiated (small lymphocytic) lymphomas, the pattern may be focal or diffuse and indistinguishable from chronic lymphocytic leukemia. Lymphomas that have spread to involve other organs (e.g. bone marrow, liver, lung) are referred to as Stage IV lymphomas. The term "leukolymphosarcoma" refers to the presence of lymphoma cells in the peripheral blood, usually in small numbers as contrasted to leukemias.

The pattern of involvement of the lymph node is not only important in classification, but also has prognostic significance. The pattern may be diffuse, follicular (nodular), a mixture (mixed), or sinusoidal. Follicular lymphomas tend to be low grade while diffuse lymphomas may be low, intermediate or high grade. High grade lymphomas are always diffuse as are essentially all the low grade, small lymphocytic subtypes. Intermediate grade lymphomas are mostly diffuse but may be follicular.

 

Classification:

Lymphomas are separated into two groups: Non-Hodgkin lymphomas (NHLs) and Hodgkin lymphoma or disease (HL, HD)

 

Non-Hodgkin's lymphomas: 

NHLs are further separated into those that originate in lymph nodes (nodal NHLs) and those that originate in other organs or tissues (extranodal NHLs). And, in addition to the morphologic appearance of the clonal cells (e.g. small mature lymphocytes, lymphoblast) and pattern of involvement of lymph nodes (follicular versus diffuse versus sinusoidal) as determined by light microscopy, other features are used to further subclassify:

  • Immunophenotypic profile, e.g. T cell, B cell, NK cell, dendritic cell, histiocyte
  • Immunohistochemistry, e.g. ALK+ diffuse large B cell lymphoma (DLBCL)
  • Cytogenetic abnormalities, e.g. t(11;14) in mantle cell lymphoma
  • Molecular genetic studies, e.g. lineage determination
  • Gene expression profiling
  • Other clinicopatholotic features such as site of initial presentation (e.g. intravascular large B cell lymphoma, primary effusion large B cell lymphoma)

Based on these various features several distinct subtypes are recognized (adapted from Jaffe ES, et al. In Swerdlow SH, et al, eds. WHO classification of tumours of haematopoietic and lymhpoid tissues. Lyon, France: IARC Press, 2008, p158 and 179)
 

B Cell Lymphomas:

  • Precursor B cell leukemia/lymphoma
    • Precursor B lymphoblastic lymphoma, NOS
    • Precursor B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
  • Mature B cell lymphoma
    • Small lymphocytic B cell lymphoma (SLL)/chronic lymphocytic B cell leukemia (CLL, B-CLL)
    • Lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM)
    • Splenic marginal zone B-cell lymphoma (SMZL)/splenic lymphoma with villous lymphocytes (SLVL)
    • Marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma, maltoma)
    • Nodal marginal zone B cell lymphoma
    • Follicular lymphoma (FL)
    • Primary cutaneous follicle center lymphoma (PCFCL)
    • Mantle cell lymphoma (MCL)
    • Diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS)
    • T cell/histiocyte-rich DLBCL (THRDLBCL)
    • Lymphomatoid granulomatosis (LYG)
    • ALK positive DLBCL
    • Primary mediastinal (thymic) LBCL (PMLBCL)
    • EBV positive DLBCL of the elderly
    • DLBCL associated with chronic inflammation
    • Plasmablastic lymphoma (PBL)
    • LBCL arising in HHV8-associated multicentric Castleman's Disease
    • Primary effusion LBCL
    • Intravascular LBCL
    • Primary CNS DLBCL
    • Primary cutaneous DLBCL, leg type
    • Primary testicular DLBCL
    • Burkitt lymphoma (BL)
    • B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
    • B cell lymphoma, unclassifiable, with features intermediate DLBCL and classical Hodgkin lymphoma

T Cell Lymphomas:

  • Precursor T cell lymphomas
    • Precursor T lymphoblastic lymphoma
  • Mature T cell lymphomas
    • Peripheral T cell lymphoma, NOS (PTCL, NOS)
    • Subcutaneous panniculitis-like T cell lymhpoma (SPTCL)
    • Enteropathy-associated T cell lymphoma (EATL) 
    • Angioimmunoblastic T cell lymphoma (AITL)
    • Anaplastic large cell lymphoma (ALCL), ALK+
    • Anaplastic large cell lymphoma (ALCL), ALK-
    • EBV+ T cell lymphoproliferative disorders of childhood
    • Hepatosplenic gamma-delta T cell lymphoma (HSTL) 
    • Mycosis fungoides (MF) 
    • Sezary syndrome (SS)
    • Primary cutaneous CD30+ T cell lymphoproliferative disorders (CD3+ CTCL)
    • Primary cutaneous peripheral T cell lymphomas, (rare subtypes)
      • Primary cutaneous CD4+ small/medium T cell lymphoma
      • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma
      • Primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL)
    • Extranodal NK/T cell lymphoma, nasal type

The distribution of the various subtypes of NHLs varies depending on age and the geographic location. Precursor B and T cell lymphomas/leukemias are seen mostly in children with some 75% being under the age of 6 years. Mature B cell neoplasms are seen mainly in adults. In an analysis of 1,403 cases of mature NHLs of worldwide distribution, 1,378 were confirmed as NHLs (The Non-Hodgkins Lymphoma Classification Project. Blood 89:3909, 1997). There were 1,178 cases of mature B cell NHL (85%), 163 cases of T cell NHL (12%), and 3% other (not specified). Of the mature B cell NHLs the distribution by subtype was:

  • DLBCL- 37%
  • FL- 29%
  • CLL/SLL- 12%
  • MALT lymphomas- 7%
  • MCL- 7%
  • All other subtypes- 8%

The percentage for CLL/SLL was felt to be low because Stage 0 CLL cases were not included.

In an analysis of 1,314 cases of mature, post-thymic or peripheral T cell and NK-T cell lymphomas, also of worldwide distribution, 1,153 (87.8%) were confirmed as T cell NHLs (International T Cell Lymphoma Project. J Clin Oncol 26:4124, 2008). The breakdown by subtype was:

  • PTCL, NOS-25.9%
  • Angioimmunoblastic T cell lymphoma- 18.5%
  • Anaplastic LCTCL (ALK+ and ALK- cases)- 12.1%
  • Extranodal NK/T Cell L- 10.4%
  • Adult T cell leukemia/lymphoma- 9.6%

The 12.2% designated as other in this report included some with B cell lymphomas, Hodgkin's disease, and diagnoses other than lymphoma.

A rather unique epidemiologic aspect of the NHLs is the steady increase in incidence observed since 1973 (Fisher SG, Fisher RI. Oncogene 23:6524, 2004). Even if the AIDS-related cases are not included, the incidence is still increasing, and this increase is also not felt to be accounted for by better reporting, more accurate diagnosis and the ever-increasing subtyping.

 NK Cell Lymphomas:

  • Extranodal NK/T cell lymphoma, nasal type

 

 

Hodgkin Lymphoma (HL), Hodgkin's disease (HD):

  • Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
  • Classical Hodgkin lymphoma (CHL)
    • Nodular sclerosing classical Hodgkin lymphoma (NSCHL)
    • Mixed cellularity classical Hodgkin lymphoma (MCCHL)
    • Lymphocyte-rich classical Hodgkin lymphoma (LRCHL)
    • Lymphocyte-depleted classical Hodgkin lymphoma (LDCHL)

Several features of HLs, which makes up about 1/3 of all lymphomas, serve to separate them from NHLs

  • It is usually a unicentric disease presenting in lymph nodes with rare presentations in only an extranodal site
  • Even though the age incidence curve is a bimodal one most patients are young adults, under the age of 35 years
  • The clonal cells, (Reed-Sternberg cells) usually comprise <1% of cellular composition of an involved lymph node, the overwhelming majority being reactive cells
  • The incidence does not appear to be increasing

Immunodeficiency-Associated Lymphoproliferative Disorders:

  • Lymphoproliferative diseases associated with primary immunodeficiency disorders (PIDs)
  • Lymphomas associated with HIV infection
  • Post-transplant lymphoproliferative disorders (PTLDs)
    • Plasmacytic hyperplasia and infectious mononucleosis-like PTLD
    • Polymorphic PTLD
    • Monomorphic PTLD
    • CHL type PTLD
  • Lymphoproliferative disorders associated with iatrogenic immunosuppression in a non-transplant setting

Included in this broad category is a spectrum of lymphoproliferative disorders ranging from polyclonal to oligoclonal reactive processes to clonal lymphomas. A progression from polyclonal to clonal lymphomas occurs, particularly in those situations in which the immunodeficiency persists (e.g. continued use of T cell suppressive agents). Loss of host immune surveillance against the EBV is a critical factor. When lymphomas evolve, they tend to be of the more aggressive ones (e.g. Burkitt) and often present in extranodal sites (e.g. CNS).

Histiocytic and Dendritic Cell Neoplasms:

  • Histiocytic sarcoma
  • Langerhans cell histiocytosis (LCH)
  • Langerhans cell sarcoma (LCS)
  • Interdigitating dendritic cell (IDC) sarcoma
  • Follicular dendritic cell (FDC) sarcoma
  • Blastic plasmacytoid dendritic cell neoplasm (BPDC)
  • Disseminated juvenile zanthogranuloma (JXG)

General References:

  1. Jaffe ES, Harris NL, Stein H, et al. In Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of tumours and haematopoietic and lymphoid tissues. Lyon, France, IARC Press, 2008, p158, 179, and 269
  2. Good DJ, Gascoyne RD. Classification of non-Hodgkins lymphoma. Hematol Oncol Clin N Am 22(5):781, 2008
  3. The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin's Lymphoma. Blood 89:3909, 1997
  4. International T Cell Lymphoma Project. International peripheral T cell and natural killer/T cell lymphoma study: pathologic findings and clinical outcomes. J Clin Oncol 25:4124, 2008
  5. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin's lymphoma. Oncogene 23:6524, 2004
  6. Stein H. Hodgkin lymphoma: Introduction. In Swerdlow SH, Campo E, Harris NL, et al, eds. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press, 2008, p321
Charles  E.  Hess,  M.D.,FACP    [more information]
Professor of Internal Medicine
Department: Medicine
Division: Hematology/Oncology