Homo sapiens diseases - Lymphoproliferative disorders

HOMO SAPIENS DISEASES - LYMPHOPROLIFERATIVE DISORDERS (LPD)

Table of contents :

Hodgkin's disease (HD) or lymphoma / malignant lymphogranuloma / granulomatous lymphoma

non-Hodgkin's lymphomas / leukemias (NHL)

B cells acute lymphoblastic or lymphocytic leukemia (B-ALL)

mature peripheral B-cell neoplasms

diffuse large B-cell lymphoma (DLBL / DLBCL)

follicular center cell lymphoma (FL)

mantle cell lymphoma (MCL)

marginal zone B-cell lymphoma (MZL)

MALT-type lymphomas (MALTomas)

Burkitt's lymphoma (BL) / African lymphoma

hairy cell leukemia (HCL)

primary effusion lymphoma (PEL)

B-cell chronic lymphocytic leukemia (B-CLL)

plasma cell dyscrasias (PCD)

immunocytic amyiloidosis

Waldenström's macroglobulinemia (WM)

monoclonal gammopathy of undertermined significance (MGUS)

smoldering multiple myeloma (SMM)

multiple myeloma (MM)

immunoproliferative small intestine disease (IPSID) / Mediterranean lymphoma

Oligoclonal lymphomas

T-cell leukemias/lymphomas

T-cell acute lymphoblastic leukemia (T-ALL)

T-cell large granular lymphocyte leukemia (T-LGL)

aggressive NK-cell leukemia

adult T-cell lymphoma / leukemia (ATL / ATLL) (HTLV-1⁺)

peripheral T-cell lymphoma (PTCL), unspecified

angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy (AILD)-like)

adult T-cell lymphoma / leukemia (ATL / ATLL) (HTLV-1⁺)

anaplastic large cell lymphoma (T- and null cell) (ALCL)

mycosis fungoides /Sézary's syndrome

primary cutaneous ALCL (pcALCL)

extranodal nasal/nasal type NK/Tcell lymphoma

blastic NK-cell lymphoma

myeloid/NK cell precursor acute leukemia

enteropathy-associated T-cell-lymphoma (EATCL)

subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)

hepatosplenic T-cell lymphoma (HTCL)

mixed lineage leukemias

lymphomas in the immunosuppressed patient

AIDS-related lymphomas (ARL)

post-transplant lymphoproliferative disorder (PTLD)

Web resources

lymphoproliferative disorders (LPD) / lymphomas (i.e.cancers beginning in a lymphoid tissue)

bone marrow => intramedullary accumulation of precursors => uneffective hemopoiesis => normocytic and normochromic anemia, neutropenia, thrombocytopenia.
thymus (thymomas )

lymph nodes

Genetic lesion involves a committed lymphocyte precursor. If in such a leukosis neoplastic lymphocytes are found into blood, neoplasm is named lymphatic, lymphoblastic, lymphocytic, lymphogenous, or lymphoid leukemia, otherwise it is said to be an aleukemic or subleukemic leukosis or "leukemia" / leukopenic or aleukocythemic leukemia (total white blood cell count in the peripheral blood is either normal or below normal). It is classified according to degree of cell differentiation as acute or chronic (terms no longer referring to duration of disease). Leukemias cause hyperviscosity syndrome. Neoplastic lymph nodes are usually wooden and painless : diagnosis is made by lymph node biopsy. Primary lymphoma have not to be confused with metastatic localizations. Average life expectancy after diagnosis varies from some weeks (highly aggressive) to some years (indolent).

pseudoleukemia : an obsolete term for a group of conditions resembling one another in showing enlargement of the lymph glands and in characteristics which resemble the conditions present in leukemia, but without leukemic blood findings. The group included Hodgkin's disease, multiple myeloma, agnogenic myeloid metaplasia, and several other conditions.
pseudolymphoma / lymphocytoma : a group of disorders having a benign course but exhibiting clinical and histologic features suggestive of malignant lymphoma

Spiegler-Fendt pseudolymphoma / lymphocytoma cutis

Pathogenesis : most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)

/T cell receptor (TCR)

gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination

has been proposed to be involved in the translocation process. 2 distinct mechanisms are involved^ref :

translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1)
in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin's lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2).

Tumorigenic cell morphology :

French-American-British (FAB) classification : a classification of acute leukemia produced by a 3-nation joint collaboration; acute lymphocytic leukemia is subdivided into 3 types
Revised European American Lymphoma (REAL) classification : a classification of lymphomas based on histologic criteria, dividing them into 3 main categories: B-cell neoplasms, T- or NK-cell neoplasms, and Hodgkin's disease.
non-Hodgkin's lymphomas / leukemias (NHL) : a heterogeneous group of malignant lymphomas, the only common feature being an absence of the giant Reed-Sternberg cells characteristic of Hodgkin's disease. They arise from the lymphoid components of the immune system, and present a clinical picture broadly similar to that of Hodgkin's disease except the disease is initially more widespread, with the most common manifestation being painless enlargement of one or more peripheral lymph nodes. There have been numerous classifications of the NHLs :

Rappaport classification (1956) : a classification of NHLs based on cytomorphology, grading, and architectural pattern (Rappaport G, Winter & Hicks EB. Follicular lymphomas. A reevaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer 9:792:821 (1956))
Lukes-Collins classification (1974) : a classification of NHLs based on their presumed cells of origin. It stresses the distinction between B-cell, T-cell, and lymphocytic lymphomas, with the B-cell and T-cell types having several subtypes that can be arranged by grade of malignancy^ref
Kiel classification (1975) : city in Germany where the pathologist Lennert developed its classification of NHLs, used primarily in Europe and based on morphologic and cytologic criteria (Lennert KK, Mohrio N, Stein H & Kaiserling E. The histopathology of malignant lymphoma. Brit. J. Hematol. 31:(suppl.1) 193-203 (1975))
French-American-British (FAB) Cooperative Group classification for acute leukemias, 1976^ref
Berlini's diagnosis and classification of the polycythemias, 1975^ref
French-American-British (FAB) Cooperative Group classification for myelodysplastic syndromes, 1982^ref
International Working Formulation (IWF) for Clinical Use (1982)^ref : a classification of NHLs based on histology and clinical parameters

low grade NHLs (30%) :

lymphocytic lymphoma
follicular, predominantly small cleaved cell lymphoma
follicular mixed small cleaved and large cell lymphoma

intermediate grade NHLs (50%) :

follicular, predominantly large cell lymphoma
diffuse small cleaved cell lymphoma
diffuse, mixed small and large cell lymphoma
diffuse large cell lymphoma

high grade NHLs (10%) :

large cell immunoblastic lymphoma
lymphoblastic lymphoma
small non-cleaved cell lymphoma

Treatment and prognosis of NHLs :

high and intermediate grade NHLs :

untreated diseases have fatal prognosis with short survival measured in months
possibility ot cure exists for a sizable portion of patients but the majority of patients develop recurrent disease after initial chemotherapy

low grade NHLs and follicular lymphoma :

natural history less aggressive however there is no curative treatment
there is a pattern of repeated remissions and relapses
median survival of low grade or follicular lymphoma is about 6.2 years
no survival benefits from therapies

transformed NHLs : transformation to more aggressive NHL occurs in 40-50% of patients at 5 years, 90% patients at death

Treatrment modalities of NHLs

chemotherapy with cytotoxic agents alone or in combination (chlorambucil , cyclophosphamide , ifosfamide with or without prednisolone or vincristine , fludarabine , cladribrine , pentostatin , mitoxantrone , paclitaxel , IFN-a or IFN-b)
combination regimens with myeloablation
external beam radiotherapy (EBRT)
immunotherapy /radioimmunotherapy (RIT)

updated Kiel classification (1988)^ref
Polycythemia Vera Study Group (PVSG) with essential thrombocythemia, 1997^ref
Revised European American Lymphoma (REAL) classification (1994) by the International Lymphoma Study Group (ILSG) : a classification of NHLs based on morphology, immunophenotype, genetic features, and clinical features^ref. The relative importance of each of these features varies among diseases, and there is no one 'gold standard'. In some tumors morphology is paramount, in others it is immunophenotype, a specific genetic abnormality, or clinical features. The R.E.A.L. Classification can be used by pathologists, with inter-observer reproducibility better than for other classifications (> 85%). Immunophenotyping is helpful in some diagnoses, but not required for many others. New entities not specifically recognized in the Working Formulation account for 27% of the cases. Diseases that would have been lumped together as 'low grade' or 'intermediate/high grade' in the Working Formulation show marked differences in survival, confirming that they need to be treated as distinct entities^ref.

Staging

I : 1 organ or lymph node (excepted mediastinum and abdomen)
II : 1 organ and locoregional lymph nodes on the same side of diaphragm
III : 2 organs or 2 lymph nodes on different sides of the diaphragm; primary location in mediastinum or abdomen
IV : CNS and/or bone marrow

Onset

lymph nodes (60%)

abdomen (31%)
mediastium (26%)
head & neck (29%)
noncervical lymph nodes (7%)

extranodal (40%)

other sites (7%)

WHO classification (2001) : based on cell type (myeloid, lymphoid T or B (with grade), histiocyte/dendritic, mast cell), this classification unifies large cell lymphomas (immunoblastic or not) and introduces anaplastic large cell lymphomas [Jaffe ES,Harris NL,Stein H,Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001]^ref

Epidemiology

Aetiology

familial susceptibility (5%)
extrinsic aetiology :

toxics :

pesticides , expecially phenoxyacids (4-11%) for CLL and FL
solvents

lifestyle

infectious agents : there are 2 very different pathways to drive malignant lymphoproliferative diseases:

some infectious agents activate extrinsic pathways through lymphocyte antigen receptors

Helicobacter pylori drives the proliferation of B cells in an antigen-specific manner and treatment with anti-infective agents sometimes results in tumor regression
HCV may similarly act through immunoglobulin receptors and may similarly respond to treatment with anti-infective agents^ref.

others activate intrinsic pathways bypassing antigen receptors^ref

HTLV1 drives the proliferation of infected T lymphocytes independent of the specificity of the TcR^ref
in posttransplant lymphoproliferative disease, EBV drives lymphoproliferation independent of the specificity of the immunoglobulin. Several different EBV genes are required to act in concert to bring about this transformation, including 5 of the 6 EBV nuclear antigens.

Pathogenesis

disease	cytogenetic abnormality	oncogene
B1 cells chronic lymphocytic leukemia (B-CLL)	t(14;15)(q32;q13)	-
MALT lymphoma	t(11;18)(q21;q21)	-
precursor B cell acute lymphoid leukemia	t(9;22)(q34;q11) or variant t(4;11)(q21;q23) BCR/ABL AF4, ALLI
precursor acute lymphoid leukemia	t(9;22) t(1;19) t(17;19) t(5;14) BCR, ABL E2A, PBX HLF, E2A IL3, IG
mantle cell lymphoma (MCL)	t(11;14)(q13;q32)	BCL-1, IgH
follicular lymphoma (FL)	t(14;18)(q32;q21)	BCL-2, IgH
diffuse large B-cell lymphoma (DLBCL)	t(3;-)(q27;-) a t(17;-)(p13;-)	BCL-6 p53
Burkitt's lymphoma (BL)	t(8;-)(q24;-) (numerous sites of translocation may be involved with these genes)	C-MYC
CD30⁺ anaplastic large cell lymphoma	t(2;5)(p23;q35)	ALK
lymphoplasmacytoid lymphoma	t(9;14)(p13;q32)	-

Symptoms & signs

disease	median age, years	frequency in children	% male	stage I/II vs III/IV, %	% B symptoms	% bone marrow involvement	% gastrointestinal tract involvement	% surviving 5 years
B1 cells chronic lymphocytic leukemia (B-CLL)	65	rare	53	9 vs 91	33	72	3	51
mantle cell lymphoma (MCL)	63	rare	74	20 vs 80	28	64	9	27
extranodal marginal zone B-cell lymphoma (MZL) of MALT type	60	rare	48	67 vs 33	19	14	50	74
follicular lymphoma (FL)	59	rare	42	33 vs 67	28	42	4	72
diffuse large B-cell lymphoma (DLBCL)	64	25% of childhood NHL	55	54 vs 46	33	16	18	46
Burkitt's lymphoma (BL)	31	30% of childhood NHL	89	62 vs 38	22	33	11	45
precursor T cell lymphoblastic lymphoma	28	40% of childhood NHL	64	11 vs 89	21	50	4	26
anaplastic large T/null cell lymphoma	34	common	69	51 vs 49	53	13	9	77
peripheral T cell non-Hodgkin's lymphoma	61	5% of childhood NHL	55	20 vs 80	50	36	15	25

Laboratory examinations

physical examination
documentation of B symptoms
laboratory evaluation
complete blood counts
liver function tests
uric acid
calcium
serum protein electrophoresis
serum b₂-microglobulin
CXR
CT scan of abdomen, pelvis, and usually chest
bone marrow biopsy
lumbar puncture in lymphoblastic, Burkitt's, and diffuse large B cell lymphoma with positive marrow biopsy
gallium scan (SPECT) or PET scan in large-cell lymphoma

Tumorigenic cell types :

B cell leukemias / B cell lymphoproliferative disorders (BCLD) : c-Myc overrides eIF4E-induced cellular senescence and eIF4E antagonizes c-Myc-dependent apoptosis^ref. Acquired N-glycosylation sites (AGS) within tumor-specific immunoglobulin : 100% of follicular lymphomas (FL) cases present with at least one AGS, whereas the vast majority of other B-cell lymphoma types other than FL (Burkitt's lymphomas (BL), diffuse large B-cell lymphomas (DLBL / DLBCL), mantle cell lymphomas (MCL) and B-cell chronic lymphocytic leukemia (B-CLL)) do not. A second tumorigenic event?^ref. Most IgM-bearing FL cases feature their AGS within CDR2, as opposed to those bearing an IgG, which mostly display the AGS within CDR3. The vast majority of AGS located within either CDR ended with a serine residue, whereas those located within FRs mostly featured threonine as the last amino acid residue^ref. These V regions express a strikingly high incidence of N-glycosylation sequons, NXS/T. These potential glycosylation sites are introduced by somatic mutation and are lymphoma-specific, pointing to their involvement in tumor pathogenesis. Analysis of the V-region sugars from lymphoma-derived IgG/IgM reveals that they are mostly oligomannose and, remarkably, are located in the antigen-binding site possibly precluding conventional antigen binding. The Fc region contains complex glycans, confirming that the normal glycan processing pathway is intact. Binding studies indicate that the oligomannose glycans occupying the V-regions are accessible to mannose-binding lectin. These findings suggest a potential contribution to lymphoma pathogenesis involving antigen-independent interaction of sIg of the BCR with mannose-binding molecules of innate immunity in the germinal center^ref

Hodgkin's disease (HD) or lymphoma / malignant lymphogranuloma / granulomatous lymphoma (10.5 of all BCLD; 25% of all lymphomas; incidence = 3 per 100,000 per year)
B-cell non-Hodgkin's lymphomas/leukemias (NHL) (80% of all NHLs)

B-cell acute lymphoblastic or lymphocytic leukemia (B-ALL) (80% of all ALL; 80% of all leukemias before age 15; prevalence = 4 per 100,000 children)
mature peripheral B-cell neoplasms (85% of all B-NHLs)

diffuse large B-cell lymphoma (DLBL / DLBCL) (30-50% of all B-NHLs)
follicular center cell lymphoma (FL) (35% of all B-NHLs)
mantle cell lymphoma (MCL) / mantle zone lymphoma / centrocytic lymphoma (5-10% of all B-NHLs)
marginal zone B-cell lymphoma (MZL)

nodal MZL (NMZL)
splenic MZL (SMZL) (< 1% of NHL)
mucosa-associated lymphoid tissue (MALT)-type lymphomas

immunoproliferative small intestinal disease (IPSID)

Burkitt's lymphoma (BL) / African lymphoma
hairy cell leukemia (HCL)
primary effusion lymphoma (PEL)
B-cell chronic lymphocytic leukemia (B-CLL) (7% of all B-NHLs; 15 every 100,000)

Old entities

small or well-differentiated lymphocytic lymphoma : a diffuse form of NHL with a low grade of malignancy; it represents the neoplastic proliferation of well-differentiated B lymphocytes and may present with either focal lymph node enlargement or generalized lymphadenopathy and splenomegaly. The predominant cell type is a compact, small, normal-appearing lymphocyte with a dark-staining round nucleus, scanty cytoplasm, and little size variation. It nearly always involves the bone marrow, and often malignant cells are found in the blood, so that its clinical picture is similar to that of chronic lymphocytic leukemia
mixed lymphocytic-histiocytic lymphoma : NHL characterized by the presence of a mixed population of cells, with the smaller cells resembling lymphocytes and the larger ones histiocytes. When predominantly follicular it is called follicular, mixed small cleaved and large cell lymphoma, and when predominantly diffuse it is called diffuse, mixed small and large cell lymphoma
giant follicular lymphoma / giant follicle lymphoma / Brill-Symmers disease / nodular lymphoma (Brill NE, Baehr G & Rosenthal N. Generalized giant lymph follicle hyperplasia of lymph nodes and spleen. A hitherto undescribed type. JAMA 84:668 (1925); Symmers D. Follicular lymphadenopathy with splenomegaly. A new recognized disease of the lymphoid system. Arch.Pathol.3:816-870 (1927)) : any of several types of NHL in which the lymphomatous cells are clustered into identifiable nodules or follicles. The cells may be either small cleaved or large (cleaved or uncleaved) cells; tumors in which most or all of the cells are small and cleaved have a better prognosis than those with large cells

diffuse, mixed small and large cell lymphoma

diffuse, small cleaved cell lymphoma : small cleaved cell lymphoma with a diffuse infiltrate of small lymphocytes that have round nuclei and clumped chromatin; this type has an intermediate grade of malignancy
provisional entity : high-grade B-cell lymphoma, Burkitt-like (highly aggressive, high grade malignancy) (CD5^-10 / CALLA^-19⁺20⁺22⁺79a⁺, sIg^+/-, cIg^+/-)
histiocytic lymphoma : a rare type of NHL of intermediate to high malignancy, characterized by the presence of large tumor cells that resemble histiocytes morphologically but are considered to be of lymphoid origin. Many tumors formerly placed in this category are now considered to belong in one of the large cell lymphoma groups.
large cell lymphoma : any of several types of lymphoma characterized by the formation of malignant large lymphocytes in a diffuse pattern; some varieties contain exclusively one type of cell, such as lymphoblasts or cleaved or uncleaved follicular center cells, and others have a mixture of cells, sometimes including ones that cannot be characterized as to lineage

large cleaved cell lymphoma : a type of NHL characterized by the formation of malignant large cleaved follicular center cells; there are both follicular and diffuse varieties. Because of the wide variety of prognostic levels and the existence of tumors with several types of cells, these tumors have been divided among several different groups of follicular and diffuse lymphomas.
large noncleaved cell lymphoma : a type of NHL characterized by the formation of malignant large noncleaved follicular center cells. Because of the wide variety of prognostic levels and the existence of tumors with several types of cells, these tumors have been divided among several different groups of follicular and diffuse lymphomas.
large cell, immunoblastic lymphoma : a type of NHL characterized by large lymphoblasts (immunoblasts : few organelles, abundant RER, lack of glycogen granules and membrane specializations) that resemble histiocytes rather than follicular center cells, and have a diffuse pattern of infiltration; the cell population may be exclusively B or T lymphoblasts or a mixture. It has a high degree of malignancy and often grows rapidly. Tumors of predominantly B cells are often associated with a preexisting immunologic disorder such as Sjögren's syndrome , systemic lupus erythematosus , or Hashimoto's thyroiditis or with an immunosuppressed state.

immunoblastic sarcoma of B cells : large cell, immunoblastic lymphoma composed predominantly of B cells

small B-cell lymphoma : the usual type of small lymphocytic lymphoma, having predominantly B lymphocytes

small cleaved cell lymphoma : a group of NHL characterized by the formation of malignant small cleaved follicular center cells; it may have either a follicular or a diffuse pattern. One type, called follicular, predominantly small cleaved cell lymphoma, is particularly common. Because of the wide variety of prognostic levels and the existence of tumors with several types of cells, these tumors have now been divided among several different groups of follicular and diffuse lymphomas.
small noncleaved cell lymphoma : any of several types of lymphoma characterized by the formation of malignant large lymphocytes in a diffuse pattern; some varieties contain exclusively one type of cell, such as lymphoblasts or cleaved or uncleaved follicular center cells, and others have a mixture of cells, sometimes including ones that cannot be characterized as to lineage

Symptoms & signs

lymphoma cutis

Web resources

Immunogenetics in Defining B-Cell Malignancy

Surinder S. Sahota

plasma cell dyscrasias (PCD) / monoclonal gammopathies or immunoglobulinopathies / dysproteinemias / paraproteinemias : a diverse group of neoplastic diseases involving proliferation of a single clone of cells producing a serum M component (a monoclonal immunoglobulin or immunoglobulin fragment); the cells usually have plasma cell morphology, but may have lymphocytic or lymphoplasmacytic morphology

gammopathy : a condition marked by disturbed immunoglobulin synthesis.

immunocytic amyiloidosis (incidence = 8 per 1,000,000 per year)
non-Hodgkin's lymphomas (NHL)

Waldenström's macroglobulinemia (WM) (prevalence = 2% of all hematological malignancies)

smoldering multiple myeloma (SMM) (incidence = 15% of newly diagnosed MM)
telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric-fluid collections, and intrapulmonary shunting (TEMPI) syndrome

Symptoms & signs : pentad of telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting.
Therapy : bortezomib^{ref1,
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monoclonal gammopathy of uncertain (or undertermined) significance (MGUS) (prevalence = 3 per 100)
multiple myeloma (MM) (incidence = 5-10 per 100,000 per year)
heavy chain diseases (HCD) : a group of rare malignant neoplasms of lymphoplasmacytic cells that secrete an M component consisting of monoclonal immunoglobulin heavy chains or heavy chain fragments; they are classified according to heavy chain type

g heavy chain disease (g-HCD) / Franklin disease : a heavy chain disease occurring usually in elderly persons that clinically resembles a malignant lymphoma

Symptoms & signs

lymphadenopathy

hepatosplenomegaly

infections

Laboratory examinations

eosinophilia

a heavy chain disease (a-HCD) / Seligmann disease : the most common heavy chain disease, occurring predominantly in young adults in the Mediterranean area, and characterized by ...

immunoproliferative small intestine disease (IPSID) / Mediterranean lymphoma
pulmonary involvement (exceedingly rare)

m heavy chain disease (m-HCD) : the rarest heavy chain disease, found in patients with chronic lymphocytic leukemia

Symptoms & signs

hepatomegaly

splenomegaly

d heavy chain disease (d-HCD)

germinotropic lymphoproliferative disorder (GLD) :

Aetiology

HHV-8 / KSHV

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HHV-4 / EBV

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Symptoms & signs

Therapy

Pathogenesis

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Laboratory examinations

M component / paraprotein [for myeloma or macroglobulinemia] is an abnormal monoclonal immunoglobulin with a characteristic electrophoretic pattern, occurring in the serum of patients with PCDs and formed by the proliferating concentrations of immunoglobulin-producing cells
autoimmune hemolytic anemias

Summary of lymphomagenesis

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pro-B cell => B1 acute lymphoblastic leukemia

pre-B cell => B3 acute lymphoblastic leukemia

mature naive B-cell =>

mantle zone B-cell => mantle cell lymphoma (MCL) / mantle zone lymphoma / centrocytic lymphoma

germinal centre B cell (Ig mutations) =>

follicular center cell => follicular center cell lymphoma (FL) => secondary ...
de novo germinal center B-cell like (GCB) diffuse large B-cell lymphoma (DLBL / DLBCL)
B1 cells chronic lymphocytic leukemia (B-CLL)
Burkitt's lymphoma
Hodgkin's disease (HD)
germinotropic lymphoproliferative disorder (GLD)
AIDS-related body cavity-based B-cell primary effusion lymphomas (PEL) (?)

memory B cells => Burkitt's lymphoma

post-germinal centre B-cell =>

marginal zone B-cell => marginal zone B-cell lymphoma (MZL)

MALT-type lymphomas (MALTomas)

plasma cell => multiple myeloma
activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBL / DLBCL)
AIDS-related body cavity-based B-cell primary effusion lymphomas (PEL) (?)

B-cell chronic lymphoproliferative disorders (B-CLPDs)

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2 or more morphologically different populations

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mantle cell lymphoma (MCL)

follicular lymphoma (FL)

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follicular lymphoma (FL)

B-cell chronic lymphocytic leukemia (B-CLL)

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mantle cell lymphoma (MCL)

B-cell chronic lymphocytic leukemia (B-CLL)

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B-cell chronic lymphocytic leukemia (B-CLL)

diffuse large B-cell lymphoma (DLBCL)

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B-cell chronic lymphocytic leukemia (B-CLL)

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dependance on BcR (exceptions : cripple mutations in HD) : different types of B-cell lymphoma express different levels of B-cell receptor (BCR), or BCRs with different specificities or levels or activity. Listed below are the details of BCR function in these various cancer types.

lymphomas that express BCR :

lymphomas associated with BCR expression and indication for antigen activation :

follicular lymphomas (FL) arise and grow in the GC and in some patient samples the BCR is autoreactive. The BCR variable domain contains mutations that promote carbohydrate modification^ref
gastric MALTomas are in many cases associated with autoreactive BCR, particularly with rheumatoid factors
B-cell chronic lymphocytic leukemia (B-CLL) has a restricted variable (V)-region gene repertoire and the BCR is often autoreactive.A BCR specific to human T-cell lymphotropic virus 1 has been identified in patients who are infected with this virus.
in hepatitis C virus (HCV)-associated lymphomas, HCV E2-specificity of BCR has been reported in some cases. Disease regression occurs after antiviral therapy.
primary central nervous system lymphomas : about half the cases express the same heavy-chain (V_H) gene segment (V_H4-34), whereas other genes of the BCR are diverse, indicating tumour-cell stimulation by superantigen binding to the BCR.

lymphomas that do not express BCR :

classical Hodgkin’s lymphomas are associated with inactivating Ig V-region gene mutations in at least 25% of cases. Transcription factors that promote BCR expression are downregulated. A transcriptionally inactive chromatin structure is seen in these lymphomas. Rather than nonfunctioning cis-acting elements, a defective transcription machinery was recently identified as a competing mechanism for down-regulation of immunoglobulin expression in classical Hodgkin disease^{ref1,
ref2}
post-transplant lymphoproliferative disorders (PTLD), inactivating V-region gene mutations are observed in at least 10-20% of cases.
primary effusion lymphomas (PELs) are not associated with inactivating Ig V-region gene mutations. However, downregulation of transcription factors that promote BCR expression is seen.
primary mediastinal B-cell lymphomas (PMBL) are not associated with inactivating Ig V-region gene mutations. Expression of transcription factors that regulate BCR expression is seen, but internal Ig enhancer activity is downregulated^ref.

most translocations involve the nonrearranged Ig allele
anti-idiotype therapeutic vaccination never selects for BcR negative tumor clones
somatic hypermutation (SHM), the hallmark of the GC reaction^ref, causes tumors inducing mutations^ref : 10% in nonselecting conditions

B-cell lymphomas showing ongoing SHM => intraclonal diversity :

lymphocytic and histiocytic cells of lymphocyte-predominant Hodgkin’s lymphoma are presumably derived from selected GC B cells and often show ongoing SHM
nodal marginal zone B-cell lymphoma (NMZL) / monocytoid B cell lymphoma (MBCL): SHM does not take place in human rearranged Vk region genes when the Ck gene and the k enhancers have been deleted in cis by rearrangement of the k-deleting element^ref.
Burkitt's lymphoma : the average mutation frequency of rearranged Vk genes from 8 BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in 5 endemic cases (3 biopsy specimens and 2 BL cell lines). The mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for m chain-expressing GC B cells, whereas the mutation frequency found in eBL is significantly higher^ref.
mantle cell lymphoma (MCL) (16%)^ref
B-cell chronic lymphocytic leukemia (B-CLL)^{ref1,
ref2} and splenic marginal zone lymphoma (SMZL)^{ref1,
ref2}. In both conditions, approximately half of the cases bear IgV_H mutations in > 2% of the sequence. This relationship is associated with lower clinical aggressiveness and extended survival.

B-cell lymphomas not showing ongoing SHM :

Hodgkin-Reed/Sternberg (HRS) cells in classical Hodgkin’s lymphomas , derived from preapoptotic GC B cells, carry mutated Ig gene rearrangements that are often "crippled" and lack intraclonal diversity
Hodgkin-Reed/Sternberg (HRS) cells in lymphocyte-rich classical Hodgkin's lymphoma derive from (preapoptotic) GC B cells^ref.
mantle cell lymphoma (MCL) (84%)^ref
in infectious mononucleosis , GC and/or memory B cells are directly infected by EBV and expand without SHM, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence. Most, if not all, EBV-infected cells in GCs exhibited an unusual EBV gene expression pattern in that they were EBNA2⁺ but LMP1^-. Although the 3 main types of EBV-associated B cell lymphomas (Burkitt's, Hodgkin's, and posttransplant lymphomas) presumably are derived from GC B cells, EBV⁺ GC B cells resembling these EBV⁺ GC B cell lymphomas in terms of EBV gene expression and SHM pattern could not be identified^ref.

BCL6 : GC or post-GC B cell lymphomas commonly display multiple somatic mutations clustering in the 5'-regulatory region of BCL-6, a proto-oncogene encoding for a POZ/Zinc finger transcriptional repressor expressed in GC B cells and required for GC formation^ref.
CD95 (Apo-1/Fas) mutations in (post) GC B-cell lymphomas originate from the GC reaction and are introduced most probably as targeting errors of the SHM machinery, which bears--besides its physiological role--an inherent risk of malignant transformation and the persistence of autoreactive B-cell specificities^ref. About 15% of GC and memory, but not naive, B cells carried mutations within the 5'regionR of the CD95 (mutation frequency 2.5 x 10^-4 per basepair). Mutations within the death domain (DD) were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway^ref

in order to determine whether V gene replacement accompanies SHM in the GC reaction in the human, we analyzed V_kJ_k and V_lJ_l joints and the k-deleting element in single l⁺naive and post GC B cells for rearrangements at the k and l loci. Among 265 l⁺ post GC B cells, not a single unequivocal and only 2 potential examples of a cell that switched to l light chain expression after accumulation of (unfavorable) mutations in its productive V_k rearrangement were observed. Taking the PCR efficiency into account, the frequency of such cells is likely < 3%. In addition, H and L chain gene rearrangements were amplified and sequenced from the oligoclonal population of IgD-only peripheral blood post GC B cells which display extensive intraclonal sequence diversity. Among 61 IgD-only B cells belonging to 15 clones with intraclonal diversity, no combination of V gene rearrangements indicating receptor revision during clonal expansion was observed. Moreover, among 124 and 49 V_H genes amplified from IgD-only and class-switched B cells, respectively, not a single example of V_H revision through V_H hybrid generation was detected. These results suggest that in the human GC reaction V gene replacement either does not usually accompany SHM or is mostly counterselected^ref.
angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of EBV-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of 6 patients with frequent EBV⁺ cells and their rearranged Ig genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or GC B cells. EBV⁺ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV^- B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of "forbidden" (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells^ref.
progressively transformed germinal centers (PTGCs) are histologic structures mainly composed of small resting B cells and intermingled proliferating centroblast-like cells. The B-cell differentiation processes within PTGCs and their relation to classical GC and to lymphocyte-predominant Hodgkin disease (LPHD), with which PTGCs are often associated, are largely unknown. To address these issues, single small resting (Ki67^-) and proliferating (Ki67⁺) centroblast-like cells were isolated from 7 PTGCs of 5 lymph nodes, and rearranged immunoglobulin genes were amplified and sequenced. Most small resting B cells were clonally unrelated, and most carried unmutated immunoglobulin gene rearrangements resembling mantle zone B cells. Small resting B cells with mutated Ig gene rearrangements may represent centrocytes, memory B cells, or both. Among the centroblast-like Ki67⁺ cells, expanded B-cell clones were observed in 6 of 7 PTGCs analyzed. Clonally related V region genes showed extensive intraclonal diversity, and the mutation pattern indicated stringent selection of the cells for the expression of functional antigen receptors. Thus, SHM, clonal expansion, and selection occur also in the disorganized PTGC microenvironment, as in classical GCs. In lymph nodes affected by PTGCs, no clonal expansion across the borders of individual PTGCs was observed, distinguishing PTGCs from LPHD^ref.
T lymphocytes in human GCs usually represent a diverse population of cells. Sequence analysis of V region genes did not provide evidence that in the human the process of SHM acts on the TCRb loci^ref.

N-glycosylation sites

79% of follicular lymphoma (FL) (59% in V_k) : in another series novel glycosylation sites were identified in 4 out of 10 FL V_H genes, but none of V_k; there were 2 novel sites in the CDR2 and one each in the FWR1 and FWR2 regions^ref. The fact that clonogenic V_k genes are less frequently mutated indicates that the somatic hypermutation machinery might have ceased to operate in the V_k locus at the time when neoplastic transformation had occurred. Perhaps this is a reflection of the generally smaller potential contribution of V_k genes (compared with V_H genes) in antigen selection of the clonogenic B cells in FL^ref. Similar conclusions regarding the role of Ig L chains in antigen recognition (evidenced by the mutation status of the corresponding V_k region genes) have been reached from single-cell studies in the normal peripheral B-cell repertoire, indicating a more limited mutational load both in the expressed as well as nonfunctional V_k genes compared with their partner V_H genes in IgM⁺/CD5 B cells^ref
41% in DLBCL
13% in the mutated subset of B-cell chronic lymphocytic leukemia (B-CLL)
9% in the normal B-cell population
8% in multiple myeloma : accordingly, in another study novel glycosylation sites were detected in only 11.7% of V_k and V_l; both sites were located in V_k CDR1 region^ref

^ref

^{ref1,
ref2}

^ref

^{ref1,
ref2}

^ref

^ref

antigen selection, as seen by :

preferential SHM in CDRs rather than in FRs : the contrary would suggest rather a superantigen
intraclonal variability :
in-frame vs. out-of-frame ratio > 0.33 : the randomly selected D gene segment of a given VDJ complex can potentially be found in all 3 possible RF :

in B-cell chronic lymphocytic leukemia (B-CLL) : 25% for RF1, 46% for RF2 and 29% for RF3
in B-cell acute lymphoblastic leukemia (B-ALL) : all 3 RFs were used with similar frequencies.
in follicular lymphoma (FL) and multiple myeloma : 10% for RF1, 40% for RF2, and 40% for RF3. The marked under-representation of RF1 in FL and MM clonogenic rearranged D genes suggests selection on the basis of antigenic properties, possibly due to constraints in forming a flexible loop within CDR3. In contrast, the more even distribution of D-RF usage in B-CLL and precursor-B-ALL suggests that, for these disorders, transformation of a immature type B cell repertoire has occurred^ref.

V_H and V_L gene segment restrictions (biased usage)

microenvironment

Oligoclonal lymphomas

established by IgH or IgL rearrangement analysis (oligogenotypic)

4.8% of B-CLPD patients

^{ref1,
ref2,
ref3,
ref4}

same disease (based on morphological, immunophenotypical (oligophenotypic) and cytogenetic studies)

detected simultaneously :

true primary biclonality (rare) :

chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)^{ref1,
ref2,
ref3,
ref4}
nodal marginal zone B-cell lymphoma ^ref
secondary VDJ recombination in a patient with indolent lymphoma^ref and in childhood acute lymphoblastic leukemia (ALL)
serum immunoelectrophoresis revealed a biclonal increase of IgAk and IgGk^ref

pseudooligoclonality :

different maturation stages within the original malignant tumor stem cell line^ref

the most common CLs consist of different subsets of follicular lymphoma (FL), usually one with low-grade follicular histologic characteristics and another with diffuse architecture and/or more aggressive cytologic features^ref
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (IgG₁k) and multiple myeloma (MM) (IgAk)^ref

Ig gene rearrangements and idiotope expression are not consistently stable clonal markers for follicular lymphoma (FL) since they are subject to variability as a result of :

ongoing somatic hypermutation (intraclonal heterogeneity)^ref
instability of DNA sequences within or around the m switch region^ref

nonfunctional rearrangement of IgH allele if the assay is performed on DNA (length analysis show the 2 clones differ by values that are not multiplies of 3, i.e. one of the 2 rearranged alleles is out-of-frame)

detected at different time points :

B-cell subclone formation within the original malignant tumor stem cell line^ref resulting from the occurrence of additional genetic abnormalities on the neoplastic cells along the evolution of the disease^{ref1,
ref2}

distinct diseases (based on morphological, immunophenotypical and cytogenetic studies) (most cases) :

at the same anatomical site (composite lymphomas) :

simultaneous (synchronous) diagnosis :

true primary biclonality (rare)

mantle cell lymphoma + follicular lymphoma : 3 cases reported^ref. Both manual and LASER-capture microdissection combined to multiple molecular approaches were used for clonality determination, including detection of IgH and IgL recombination, as well as presence of k/Kde recombination and sequence analysis. By IHC and FISH, the presence of 2 distinct lymphoma types characterized by specific translocations [namely, t(11;14) and t(14;18)] was confirmed, while 2 distinct and not clonally related cell populations were demonstrated by molecular techniques. The light chain approach, and particularly the k and k/Kde recombination detection, proved very useful for solving the clonality issue^ref.
follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)^ref
mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)^ref
IgGk nodular poorly differentiated lymphocytic lymphoma were surrounded by a diffuse growth of IgMl well-differentiated lymphocytic lymphoma^ref
mantle cell lymphoma and plasmacytoma ^ref
a unique case in which there were 3 non-Hodgkin's lymphomas, according to the Rappaport's nomenclature, in the spleen and abdominal lymph nodes^ref
follicular lymphoma and NMZL ^ref (Abou-Elella AA, Nathwani BN, Gascoyne R, Weisenburger DD, Velankar M, Greiner TC, Chan WC: The relationship between monocytoid B-cell (MBC) lymphoma and coexisting follicular lymphoma. Mod Pathol 1998, 11:124A)

pseudooligoclonality :

chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (IgMk) and multiple myeloma (MM) (IgAl)^ref
follicular lymphoma and interfollicular B-cell infiltrate^ref

differite (metachronous) diagnosis :

true primary biclonality (rare)

chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) => primary thyroidal lymphoma of the centroblastic type (stage IE)^ref
In a patient with Richter's syndrome, the chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) expressed l, m, and d IgH chains and the NHL k, m, and d IgH chains. The difference in IgL chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the 2 malignancies were rearranged in a different way^ref

pseudooligoclonality :

Richter's syndrome :

chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (IgMl) and DLBCL (IgMk)^ref
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Igl) and DLBCL (Igk)^ref
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (IgM) and DLBCL (no sIg) due to postrearrangement deletion of the heavy chain mu gene^ref

at different anatomical sites :

simultaneous (synchronous) diagnosis :

hairy cell leukemia (HCL) + chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare^ref
typical mantle cell lymphoma and B-CLL with IGH/BCL-2^ref
B-cell chronic lymphocytic leukemia (B-CLL) and DLBCL ^ref
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and multiple myeloma (MM) : 5 cases^ref

differite (metachronous) diagnosis :

true primary biclonality (rare)

hairy cell leukemia (HCL) + non-Hodgkin's lymphomas is well known^ref
colon MALToma and composite biclonal composed peripheral T-cell unspecified and B-cell lymphomas in the esophagus^ref
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) => multiple myeloma (MM) : 6 cases^ref

pseudooligoclonality :

follicular lymphoma => precursor-B-cell blast crisis^ref
follicular lymphoma => DLBCL ^ref

^ref

^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7}

^{ref1,
ref2}

^{ref1,
ref2,
ref3,
ref4,
ref5}

^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6}

^{ref1,
ref2,
ref3}

⁺

^ref

⁺

^ref

Laboratory examinations

disease\CD

11a

11b

11c

FMC7

45RA

45RO

w75

79a

79b

103

117

138

154

227

other

typical B-CLL

- (1-2% +^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7})

weak

- (rarely +^ref)

weak

bad px

18% (atypical CLL and trisomy 12)^ref; truncated

Ig^low
IgL^dim

atypical B-CLL

-^ref

+ (< 0.5%)^ref

high

+^ref

IgL high

T-CLL

- (rarely +)

- (+ in 5%)

- (+)

+/-

TdT-, sIg- HLA-DR-

B-PLL

30%

Ig high

T-PLL

-/+

+/-

TdT-, sIg-, HLA-DR -/+

ATL

++(-)

+/-

TdT-, sIg-, HLA-DR+

- (rarely +)

TdT-, sIg-, HLA-DR-

81%

100%

38%

33%

61%

71%

48%

100%^ref

85%

cIg⁺, IgM^hi

+/-

5%^ref

72%

18%

HM1.24
SP17
MUC1
sIg^-
cIg^hi

SMZL

- (+ in 20%)

- (+ in SLVL)

-/+

+/-

-/+

high IgM
low IgD
L chain⁺
MIB1^low
cyclin D1^-
p53^-
Bcl-2⁺
Bcl-6^-
Ln3⁺, Kib3^-/+, TRAP^-/+, p27^-/+, CXCR3⁺, IRTA-1⁺, BSAP⁺, IRF4^-, E2F-1^-

HCL

+^ref

B-ly-7⁺, sIg⁺, cIg⁺

MALT

+^ref

IPSID

NMZL

-/+

AlkP⁺ centrocytes;
AlkP^- centroblasts.
Blc-6⁺

MCL

86%^ref (rarely -^ref)

- (rarely +^ref)

- (rarely + ^{ref1,
ref2})

62%^ref

60%^{ref1,
ref2}

BCL-6 (5%), cyclin D1⁺(95%), IgL^bright, IgD (62%), IgM (100%)^ref

DLBCL

-/+

50%

-/+

50%

+/-

75%^ref

50%

HLA-DR 50%

ALBCL

MLBCL

+/-

EATCL

TcR^- cyTcRb^+,HLA-DR^-ßF1^-

/BL-like

+/-

eBL

75%^ref

Ig+/-

B-ALL

+^ref

T-ALL

-^ref

AITL

+ (sometimes - but cyCD3^+ref)

+^ref

TcR⁺

ALTCL

-^ref

PTCL-NOS

-^ref

AML

-^ref

APL

T cell leukemias/lymphomas (usually more aggressive than B cell leukemias) : similar to earlier functional classification systems (Lukes-Collins and Kiel), the Revised European American Lymphoma (REAL) and new World Health Organization (WHO) classifications have divided lymphomas into B and T cell types and whether they are composed of

precursor (thymic or lymphoblastic) lymphocytes
peripheral (mature or post thymic) lymphocytes^ref (Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November, 1997. Histopathology.2000;36:69).

most have a cytotoxic T-cell or NK-cell phenotype with frequent apoptosis and/or necrosis

naive

most T cells express the aß TCR protein and have a helper (CD4⁺) or suppressor/cytotoxic (CD8⁺) phenotype. A small population of T cells expresses the gd TCR and usually has a double negative (CD4^-8^-) phenotype, although some may express CD8 or more rarely, CD4. Normal T cells are preferentially located at extranodal sites such as the splenic red pulp, gastrointestinal tract, and skin
NK-cells arise from a pluripotential stem cell and are related to T-cells, but at some point branch off to form a separate lineage^ref. NK-cells are distinguished immunologically by the absence of TCR gene rearrangements and TCR protein and lack of surface CD3 (Leu 4) and usually CD5. NK-cells and T-cells can express CD2, CD7, and in paraffin sections cytoplasmic CD3e, CD45RO and CD43. NK-cells usually express one or more "NK-associated" antigens (CD16, CD56, CD57), but some populations of NK-cells do not express these antigens and are identified by functional studies. A subset of cytotoxic T-cells also expresses NK associated antigens and have been called "NK-like" T-cells^ref (Kinney MC. The role of mophologic features, phenotype, genotype, and anatomic site in defining extranodal T-cell or NK-cell neoplasms. Am J Clin Pathol.1999;111 (Suppl. 1):S104-S118)

Most extranodal lymphomas arise from cytotoxic cells

parameter	T-cell	NK-like T cell	NK-cell
NK-cell antigens	-	+	+ (some populations lack NK-cell antigens )
cytoplasmic CD3 (e chain)	+	+	+/-
surface CD3	+	+	-
CD4, CD8	CD8⁺>>>CD4⁺	CD8⁺>CD4^-8^->>CD4⁺	CD4^-8^+/-
TCRaß, gd (TCR gene rearrangement and protein expression)	+	+	-
cytotoxic granules	+	+	+
killing mechanism	MHC restricted	non-MHC restricted	non-MHC restricted

Although not specific, most extranodal T-cell and NK-cell neoplasms have a characteristic immunophenotype with a propensity to involve certain cell populations such that one phenotype predominates but is not exclusive :

lymphoma type	T-cell subset	CD56	cytotoxic proteins	CD30	EBV	cell type
hepatosplenic	CD4^-8^->CD8⁺	+	+ (most cases have a non-activated phenotype (TIA-1+, granzyme B-, perforin-))	-/+	-	gd > ab
subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)	CD8⁺>CD4^-8^->CD4⁺	-/+	+	-/+	-	ab > gd
anaplastic large cell lymphoma (ALCL), primary cutaneous	CD4⁺>CD4^-8^->CD8⁺	-/+	+/-	+	- (based on nodal cases)	ab > gd
nasal/nasal type NK/T-cell	CD8⁺>CD4^-8^-	+	+	+/-	+	NK > gd > ab
aggressive NK-cell leukemia	CD8⁺,CD4^-8^-	+	+	NT	-/+	NK,T cell
intestinal	CD4^-8^->CD8⁺>CD4⁺	-/+	+	+/-		ab > gd >>NK
blastic NK-cell lymphoma/leukemia	CD4	+	+	NT	-	NK

T-cell acute lymphoblastic leukemia (T-ALL) / precursor T-lymphoblastic lymphoma / leukemia (highly aggressive, high grade malignancy)
hairy T cells leukemia (HCL) or tricholeukemia (5 % of all HCLs)

Aetiology

HTLV-2

post thymic T-cell and NK-cell neoplasms included in the REAL and WHO classifications :

predominantly leukemic malignancies

T-cell prolymphocytic leukemia (T-PLL) / T-cell chronic lymphocytic leukemia (T-CLL) (5% of all CLLs : 30 % of all PLLs)

small cell variant
pleomorphic variant (knobby cell type)

Symptoms & signs

Laboratory examinations

hyperleukocytosis
immunophenotype : CD1a^-2⁺3⁺4^+/-5⁺7^+/-8^+/-25^-, TdT^-

Prognosis

mildly aggressive

Therapy

anti-CD52 mAbs

peripheral T-cell lymphomas (PTCL) and NK-cell neoplasms

large granular lymphocyte (LGL) leukemia (indolent)^{ref1,
ref2,
ref3} : LGL comprise 10-15% of normal peripheral blood mononuclear cells (Timonen T, Ortaldo JR, Herberman RB. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J Exp Med. 1981;53:569–582). They are characterized morphologically by a size bigger than normal lymphocytes and azurophilic granules in the cytoplasm. LGL can be divided into 2 major lineages: CD3^- and CD3⁺. Most LGL in the peripheral blood of normal individuals represent NK cells. These LGL are CD3^-, therefore lacking the CD3/TCR complex, and mediate non-MHC-restricted killing^ref. In contrast, CD3⁺ LGL are T cells that do express the CD3/TCR complex and rearrange TCR genes^ref. These cells mediate non-MHC-restricted cytotoxicity in vitro and are thought to represent in vivo activated cytotoxic T cells (CTL)^ref. Clonal diseases of LGL can arise from either of their normal counterparts and thus be of NK or T cell lineage^ref. A syndrome of increased numbers of circulating LGL associated with chronic neutropenia was described in 1977^ref. A major question in this disorder was whether the lymphocytosis was reactive or neoplastic in nature. In 1985 we first detected clonal chromosomal abnormalities in such patients^ref. We termed this disease LGL leukemia based on this observation of clonality and demonstration of tissue invasion by LGL of marrow, spleen, and liver. In 1993 we proposed the classification of LGL leukemia into NK- and T-LGL leukemia, for clonal LGL diseases of NK cell and T cell origin, respectively^ref. The REAL classification recommended that LGL leukemia be a distinct entity classified in the peripheral T cell and NK cell neoplasms^ref

T-cell large granular lymphocyte leukemia (T-LGL)
NK-cell large granular lymphocyte leukemia (NK-LGL)

Laboratory examinations

⁺

Therapy

2 prospective phase II studies investigating the role of high-dose sequential chemotherapy, followed by autologous HSCT in 62 patients with advanced stage peripheral T-cell lymphomas (PTCLs) at diagnosis. Conditioning regimen consisted of mitoxantrone (60 mg/m²) and melphalan (180 mg/m²) or carmustine, etoposide, Ara-C and melphalan followed by peripheral blood stem cell autografting. In an intent-to-treat analysis, 46 out of 62 patients (74%) completed the whole programme, whereas 16 patients did not undergo ASCT, mainly because of disease progression. At a median follow-up of 76 months, the estimated 12-year overall (OS), disease-free and event-free survival (EFS) were 34, 55 and 30%, respectively. OS and EFS were significantly better in patients with anaplastic lymphoma-kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), as compared with the remaining PTCL. Multivariate analysis showed that patients attaining complete remission (CR) before ASCT had a statistically significant benefit in terms of OS and EFS (P<0.0001). Overall treatment-related mortality rate was 4.8%. In conclusion, (1) up-front high-dose therapy and ASCT are feasible, but could induce a high rate of long-term CR only in patients with ALK⁺ ALCL and (2) the achievement of CR before autografting is a strong predictor of better survival^ref
autologous HSCT : the results of 24 patients with PTCL who underwent ASCT for relapsed or refractory disease after responding to second-line therapy, excluding patients with indolent histologies and those with ALK⁺ ALCL, were compared with those of 86 consecutive patients with chemosensitive relapsed or primary refractory DLBCL. With a median follow-up time of 6 years for surviving patients with PTCL and DLBCL, the 5-year PFS rates for PTCL and DLBCL patients were 24% and 34% respectively (P = 0.14); the corresponding OS rates were 33% and 39% respectively. There were no significant differences between the 2 groups with respect to time to disease progression or survival after progression. The second-line age-adjusted IPI was the only variable prognostic for PFS and OS in a multivariate analysis. The outcome of ASCT for patients with chemosensitive relapsed or primary refractory PTCL is similar to that for patients with DLBCL^ref

granular lymphocyte proliferative disorders (GLPD)
aggressive NK-cell leukemia
adult T-cell lymphoma / leukemia (ATL / ATLL) (HTLV-1⁺)
hepatosplenic T-cell lymphoma (HTCL) (1.4%)

predominantly nodal (lymphoma) :

peripheral T-cell lymphoma (PTCL), unspecified (23%)
angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy (AILD)-like) (18.4%)
adult T-cell lymphoma / leukemia (ATL / ATLL) (HTLV-1⁺) (9.6%) (adult T-cell leukemia/lymphoma (ATLL) has varied clinical presentations that can be predominantly leukemic or lymphomatous)
anaplastic large cell lymphoma (T- and null cell) (ALCL) (11.9%)

ALK+ (6.4%)
ALK- (5.5%)

⁺

^ref

predominantly extranodal/cutaneous malignancies :

indolent :

mycosis fungoides /Sézary's syndrome
primary cutaneous ALCL (pcALCL) (1.7%)

aggressive :

extranodal nasal/nasal type NK/Tcell lymphoma (7%)
immature NK cell neoplasms^{ref1,
ref2} :

blastic NK-cell lymphoma (0.2%)
myeloid/NK cell precursor acute leukemia

enteropathy-associated T-cell-lymphoma (EATCL) (4.7%)
subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) (0.9%)
mucocutaneous gdT-cell lymphoma (0.1%) (provisional WHO/EORTC 200547)

unclassifiable T-cell lymphoma (2.9%)

^{ref1,
ref2}

immature^{ref1,
ref2}:

mature :

leukemia:

indolent LGL leukemia
aggressive NK-cell leukemia

extranodal nasal/nasal type NK/Tcell lymphoma

immature

blastic morphology
azurophilic granules inconspicuous or absent
TIA-1 usually negative
lacks killer activity in vitro

mature

small, medium or large lymphocytes
azurophilic granules present
TIA-1⁺
has killer activity in vitro
EBV- EBV+ (true NK LGL leukemia is not associated with EBV

Laboratory examinations

^ref

^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8,
ref9}

⁺

^{ref1,
ref2}

^ref

^{ref1,
ref2}

CD20

CD79a

^ref

⁺

^ref

⁺

^{ref1,
ref2}

^ref

⁺

^ref

⁺

^ref

small population of CD20⁺ T cells in healthy donors

^{ref1,
ref2}

⁺

in vitro

^ref

⁺

^ref

feature	blastic NK-cell lymphoma	aggressive NK-cell leukemia (tumor cells vary from mature-appearing large granular lymphocytes (LGLs) to cells with a more blastic appearance)	myeloid/NK-cell precursor leukemia
marrow involvement	++	++ (the number of blasts may be small and involvement patchy compared to other leukemias)	++ (13-41% of AML overall are CD56⁺)
skin disease	++	-	< 10%
lymph node involvement	+	++	++
hepatosplenomegaly	15%	+	< 10%
EBV	-	+/-	-
cytoplasmic granules	+/-	+	-

^ref

there is no immunophenotypic marker of clonality
there is morphologic heterogeneity
there is poor correlation between cytomorphology and prognosis^{ref1,
ref2}

Prognosis

^{ref1,
ref2,
ref3}

diffuse large B-cell lymphoma (DLBCL)

^ref

^{ref1,
ref2,
ref3}

⁺

^{ref1,
ref2}

^ref

^ref

^{ref1,
ref2,
ref3}

In the Western hemisphere, the nodal diseases tend to predominate with PTCL, not otherwise specified, and ALCL representing the largest groups, while in the East, there are increased numbers of patients with extranodal disease, particularly of the nasal type

^ref

site		no. pts	PCTL NOS (%)	ALCL (%)	AILD (%)	angiocentric (%)	rare subtypes (%)	comments
Spain^ref		174	95 (55)	30 (17)	22 (13)	4 (8)	13 (7)	ALCL had the best survival (65 mo median); the others were in 20-25 mo range with the in testinal as the predominant rare subtype at only 4 mos.
France^ref		288	160 (55)	60 (21)	68 (24)	-	-	5 yr OS for T-ALCL was 64% compared to 53% for DLBCL and 35% for other PTCL
Italy^ref		167	78 (47)	62 (37)	19 (11)	2 (1)	6 (4)	ALCL had a better DFS (66% vs 38%, p=0.0001) than the remaining PTCL
USA^ref (Arrowsmith ER, Greer JP, Stein RS, et al. Peripheral t-cell lymphomas: A clinicopathological study of 94 unselected patients using the Revised European American Lymphoma (REAL) classification. J Clin Oncol. 1998;17:50a)		78	53 (68)	8 (10)	7 (9)	9 (12)	1 (1)	IPI correlated with 5 yr OS: 76% low, 32% low- intermediate, 28% high-intermediate, 9% high risk
		92	28 (30)	40 (43)	13 (14)	-	11 (12)	OS was 49% and PFS was 22% at 5 yr. ALCL had best prognosis (58% OS, 40% PFS) compared to other subtypes
Korea^ref		125	53 (42)	5 (4)	5 (4)	59 (47)	3 (2)	Angiocentric were primarily nasal/nasopharyngeal origin. PTCL, NOS, had a worse survival compared to DLBCL.
Japan (Lymphoma Study Group of Japanese Pathologists. The World Health Organization classification of malignant lymphomas in Japan: incidence of recently recognized entities. Pathol Internat. 2000:50:696:702)	Kyushu	265	83 (27)	22 (6)	38 (10)	28 (8)	3 (1)	ATLL accounted for 181 (52%) in Kyushu and 47 (15%) in other areas, for a combined 238 cases in Japan
	Other	315	130 (41)	27 (9)	39 (12)	55 (17)	17 (5)

^ref

clinical factors : the International Prognostic Index (IPI) provides a prognostic score based on clinical and laboratory factors which has been validated for DLBCL and shown to predict survival accurately^ref. However, insufficient immunophenotypic data were available when the IPI was designed to assess the influence of the T-cell phenotype on prognosis. Interpretation of older studies evaluating the usefulness of the IPI in PTCL are complicated by the use of outdated lymphoma classification systems and frequent "lumping" of histologic subtypes, obscuring the impact of the IPI in specific disease entities^{ref1,
ref2,
ref3}. However, several reports have confirmed the IPI’s usefulness in some of the specific PTCL subtypes including ALCL (ALK-positive and -negative) and PTCL US^{ref1,
ref2,
ref3,
ref4}. Recently, the IPI has been applied to PTCLUS according to the WHO classification and found to be predictive of survival^{ref1,
ref2}. A large study also evaluated a new prognostic model for PTCLUS which incorporates many of the current IPI factors (age, PS, LDH) in addition to bone marrow involvement^ref. In this model, survival ranged from 18% (3 or 4 factors) to 62% (0 factors). Unfortunately, many patients with PTCLUS fall into the high-risk categories with poor survival, emphasizing the urgent need for better therapies.

^{ref1,
ref2}

biological and molecular prognostic factors

PTCLUS: Attempts have been made to identify biologically distinct subgroups within the morphologically and clinically heterogeneous PTCLUS subtype. Although morphologic variants have been recognized, their prognostic significance is unknown. Most nodal cases of PTCLUS are CD4⁺CD8^-, prompting speculation that within the CD4⁺, T-helper (T_h) phenotype some of the biological heterogeneity may be explained by variable expression of T_h1 and/or T_h2 surface chemokine receptors^ref. In one study, two distinct subgroups with PTCLUS were identified; group 1, positive for any of ST2(L) (T_h2 marker, interleukin [IL]-1R family member), CCR5 (Th1), CXCR3 (T_h1); group 2, negative for all these markers^ref. Group 1 cases, considered "functional" based on the receptor expression, had a more favorable prognosis compared to group 2 cases; however, adjustment for known clinical prognostic factors was not incorporated into this analysis^ref. In a separate study the prognostic significance of CXCR3 was confirmed, and CCR4 (T_h2) expression was found to be associated with a poor outcome and remained significant after adjustment for other clinical factors, including the IPI^ref. Interestingly, CCR4 expression correlated with CD25 expression. The functional significance of these chemokine receptor profiles remains unknown, and confirmation of their prognostic value awaits further study. It is hoped that they may provide rational targets for novel therapies in this poor-risk population^{ref1,
ref2}.
ALCL: Other biological markers beyond the ALK phenotype have been determined to have prognostic significance in ALCL. Both ALK-positive and -negative cases that express CD56 have a worse prognosis, independent of the IPI^ref. Further, expression of survivin, a member of the inhibitor of apoptosis family, also confers a worse prognosis, irrespective of ALK expression^ref. In ALK-negative ALCL several other biological prognostic factors have been determined to affect clinical outcome. High numbers of activated (granzyme B⁺) cytotoxic T-lymphocytes indicate a poor prognosis^ref. Recent studies also suggest that high BCL2 protein expression in ALK-negative ALCL, a known prognostic factor in DLBCL, is associated with poor outcome^ref. Conversely, expression of caspase 3, a critical component in the pro-death pathways, is associated with a favorable outcome, suggesting that alterations in apoptotic pathways may in part explain the prognostic differences between ALK-positive and -negative ALCL subtypes^ref

gene expression profiling of PTCLs : gene expression studies have been much less extensive in the T-cell lymphomas than in B-cell lymphomas. Using the CNIO Oncochip, a recent study evaluated the gene signature of 42 newly diagnosed T-cell lymphomas that included 34 PTCLs of various histologic subtypes (including 19 PTCLUS) and compared the gene expression pattern signature to normal cellular counterparts and to lymphoblastic lymphoma^ref. Within the PTCL tumors, upstream and downstream targets of the NF-kB pathway were featured in the molecular signature; however, evidence of NF-B activation and of its effect on tumor biology await further study. This analysis was limited because it grouped all PTCL cases together, and because it mixed nodal and extranodal tumor samples; however, it is the first microarray analysis of PTCLs and will be useful for comparison in future studies. 2 further groups have since attempted to utilize gene expression to subclassify PTCLs. The GELA investigators evaluated 59 primary nodal specimens of a variety of T-cell lymphomas using a cDNA array and specifically applied a multiclass predictor to separate PTCLUS into the three subgroups: U1, characterized by the expression of cyclin D2 and few reactive cells; U2, with some overlap with U1 but also associated with overexpression of genes involved in T-cell activation and apoptosis including NF-B1 and BCL2; and U3, which included the previously defined "Lennert's lymphoma" and was characterized by overexpression of histiocytic markers in addition to genes involved in the interferon /JAK/STAT pathway^ref. Whether these subgroups correlate with clinical outcome awaits further study. Another group compared the gene expression profile of 17 PTCLUS nodal primary tumor specimens to normal T-cell subsets using the Affymetrix 133 A/B microarray and found that PTCLUS cells were more related to activated T cells, both CD4⁺ and CD8⁺ (Piccaluga PP, Agostinelli C, Zupo S, et al. Gene expression analysis of peripheral T-cell lymphoma not otherwise specified reveals the existance of two subgroups related to two cellular counterparts [abstract]. Ann Oncol 2005;16(Supp 5):125a). Of interest was overexpression of PDGFRA, confirmed by immunohistochemistry, which may be a potential therapeutic target.

Therapy

primary treatment approaches in PTCLs : CHOP-type chemotherapy has been the mainstay of therapy for PTCLs, but with the notable exception of ALK-positive ALCL, outcome has been uniformly disappointing. The large intergroup trial comparing CHOP to second and third generation regimens in diffuse large-cell lymphoma failed to reveal any survival differences among the regimens but unfortunately, as immunophenotyping was not widely available at the time of the study analysis, the impact of the specific treatment regimens in the subgroup of patients with T-cell lymphomas was not assessable^ref. Some groups have specifically evaluated more dose-intensive regimens in PTCL^{ref1,
ref2,
ref3,
ref4} with no firm conclusions demonstrating superiority to CHOP chemotherapy. Generally, treatment approaches to date have been similar among the PTCL subtypes. One exception is extranodal NK/T cell lymphoma, where radiotherapy appears to be the key treatment modality, with more favorable outcomes observed in treatment regimens that incorporate radiotherapy^{ref1,
ref2,
ref3}. Frequent progression during anthracycline-based chemotherapy has been observed in several studies of NK/T nasal type lymphoma, suggesting an inherent resistance of these tumors to conventional systemic therapy that may be related to expression of P-glycoprotein resulting in multi-drug resistance^ref. Because of this some groups have advocated the use of front-line radiotherapy in localized NK/T-cell lymphoma^ref. Collectively, these results suggest that radiation should be the primary therapy in localized NK/T-cell lymphoma. However, both local and systemic relapse remain problematic, suggesting that new approaches are needed, perhaps combining radiotherapy with alternate, radiosensitizing chemotherapy. Further, survival in patients with more widespread disease at presentation is extremely poor, underscoring the need for improved chemotherapy. Cutaneous ALCL should also be treated differently as it has an indolent course, and although relapses are frequent, the 5-year OS is approximately 90%. The majority of patients can be treated with localized excision with or without radiotherapy. Patients with disseminated skin disease may be at greater risk of developing extracutaneous involvement and may benefit from systemic therapy (Banks PM, Warnke RA. Mature T-cell and NK-cell neoplasms. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Hematopoetic and lymphoid Tissues. IARC Press: Lyon; 2001:189-230)
the role of high-dose chemotherapy and stem cell transplant in PTCL : several small, uncontrolled trials have attempted to evaluate the role of high-dose chemotherapy (HDC) and stem cell transplant (SCT) in PTCL. However, these studies are difficult to interpret because they are heterogeneous with respect to usage of different lymphoma classification systems; inclusion of multiple disease entities in outcome analyses; transplant type (allogeneic vs autologous); timing (primary vs relapsed/refractory); salvage and conditioning regimens used; and inclusion of pediatric cases.
primary HDC and SCT in PTCL : with poor outcomes in most patients with PTCL using CHOP-type treatment, several investigators have attempted to add consolidation treatment for patients with PTCL, including ALCL, in first complete remission (CR1) with HDC and SCT^{ref1,
ref2}. In one study, 37 patients were transplanted in first CR with an encouraging 5-year OS of 80%.38 However, the population evaluated was young (median age 31) and included some patients with ALCL, a group with a more favorable prognosis when transplanted in CR1^ref. Further, ALK protein status was unavailable^ref. In ALCL, similar excellent results have been observed in other studies of up-front transplant; however, CHOP alone also results in high cure rates^ref. Another prospective study evaluated 24 patients with PTCL (PTCLUS n = 12; AILT n = 12), transplanted in first remission. With a median follow-up of 15 months, 16 of the 21 patients who were successfully transplanted patients remained in remission^ref. In the absence of randomized trials proving superiority to conventional chemotherapy, the use of HDC and SCT in the primary treatment remains experimental in any histological subtype. Selected studies in the last 5 years evaluating the outcome of peripheral T-cell lymphoma (PTCL) patients who have received high dose chemotherapy and autologous (auto) or allogeneic (allo) stem cell transplant in first remission or with relapsed refractory disease.

study	total no. pts	PTCL subtype (n)	first remission or relapsed/refractory (n)	EFS/PFS	OS	comments
Rodriguez^ref	115	PTCLUS (80)	first remission (37)	79% (5 y)	80 % (5 y)	ALK status unknown; median age 31 for primary transplant
		ALCL (25)	auto
		AILT (6)
		other (2)	relapsed/refractory (78)	79% (5 y)	80% (5 y)	No patient salvaged with refractory disease
			auto	39% (5 y)	45% (5 y)
Jagasia^ref	28	PTCLUS (6)	relapsed/refractory	50% (3 y)	43% (6 y)	Outcome analyses combined auto and allo transplants superior outcome to other PTCLs and DLBCL
		ALCL (11)	auto (23)
			allo (5)	Non-ALCL 38% (3 y)	Non-ALCL 47% (3 y)
			ALK positive (7)
			ALK negative (4)
		CUTALCL (5)
		AILT (3)	ALK ALCL	ALK⁺ ALCL 100% (3 y)	ALK⁺ ALCL 100% (3 y)
		NK/T (3)		ALK^- ALCL 0% (3 y)	ALK^- ALCL 50% (3 y)
Blystad^ref	40	PTCLUS(20)	first remission (17)	48% (3 y)	58% (3 y)	Outcome analyses combined first remission and relapsed groups ALK status unknown
		ALCL (14)	auto
		AILT (2)			non-ALCL 44% (3 y)
		ETTL (2)	relapsed (23)		ALCL 79% (3 y)
		NK/T (2)	auto
Song^ref	36	PTCLUS (20)	relapsed/refractory	37% (3 y)	48% (3 y)	ALCL (ALK status unknown) xxx to improve outcome compared with PTCLUS and DLBCL
		ALCL (9)	auto
		AILT (2)		PTCLUS 23% (3 y)	PTCLUS 35% (3 y)
		NK/T (4)
		ETTL (1)		ALCL 67% (3 y)	ALCL 78% (3 y)
Corradini^ref	17	PTCLUS (9)	relapsed/refractory	64% (3 y)	81% (3 y)	Many had late relapses
		ALK^- ALCL (4)	RIC allo
		AILT (4)				Unknown whether primary CUTALCL were included

^ref

transplant in relapsed/refractory PTCL : patients with relapsed PTCL who demonstrate chemosensitivity respond favorably to HDC and SCT, with long-term survival rates of approximately 35-45%^{ref1,
ref2,
ref3}. The results in patients with refractory PTCL are less favorable with some studies reporting no long-term survivors^ref. Another report by the same authors reported a 5-year OS of 37% in a group of patients who were deemed induction failures^ref. However, most of the patients had achieved a PR and in the absence of functional imaging, some of these cases may have represented true CRs^ref. Success rate varies with pre-transplant IPI^ref and, not surprisingly, by histologic subtype, with ALCL demonstrating consistently superior salvage rates than PTCLUS^{ref1,
ref2,
ref3}. These favorable results in ALCL may not extend to ALK-negative ALCL, with one small study suggesting poor outcome with HDC SCT in this population^ref. Patients with relapsed or refractory PTCL and documented chemosensitive disease should be offered HDC and SCT, similar to the practice in DLBCL. Experience with allogeneic SCT in PTCL is limited to small series with highly selected patients. Treatment mortality is high in patients receiving full myeloablative allogeneic transplant^ref. Reduced-intensity conditioning (RIC) has recently emerged as an attractive strategy for patients at increased risk of treatment-related toxicity, although it has not been extensively evaluated in aggressive lymphomas. A small pilot study (n = 17) was recently performed evaluating RIC in patients with PTCL^ref. The majority of cases were PTCLUS and many had relapsed after autologous HDC SCT. Although this was a highly selected population including many with a history of late relapse and almost all having a sibling donor and demonstrating chemosensitive disease, the 3-year overall and progression-free survival rates were encouraging at 81% and 64%, respectively. Further, responses were observed after donor leukocyte infusion (DLI), providing further evidence that a graft-versus-T-cell lymphoma effect may exist in PTCLs^ref
novel treatment approaches : for many PTCL patients current treatment strategies are largely ineffective and new therapies are being explored

agents	target	PTCL (n)	clinical studies
nucleoside analogs
gemcitabine	nucleoside analog; non-specific DNA synthesis inhibition	PTCL (10)	60% ORR^ref
araG
506U78 (nelarabine)-pro-drug	nucleoside analog; selective toxicity for T cells	PTCL (8)	Phase II ORR 14% (Czuczman MS, Porcu P, Johnson J, Niedzwiecki D, Canellos G, Cheson BD. CALGB 59901: Results of a phase II study of 506U78 in CTCL and PTCL [abstract]. Blood 2004;104(11):2486a) Toxicity: 2 early deaths
immunotoxin
denileukin difitox	IL-2 receptor	PTCL (14)	Phase II ORR 50% (Dang NH, Pro B, Hagemeister FB, et al. Interim analysis of a phase II study of denileukin diftitox (Ontak) for relapsed/refractory T-cell non-Hodkin’s lympoma [abstract]. Blood. 2004;104(11):2641a)
histone deaceylase Inhibitors
depsipeptide	Histone de-acetylation	PTCL (19)	Phase II ORR 26% (Piekarz RL, Frye R, Turner M, et al. Responses and molecular markers in patients with peripheral t-cell lymphoma treated on a phase II trial of depsipeptide, FK228. Proc ASCO. 2005;24:3061a)
immunotherapy
anti-CD25 mAbs , yttrium-90 labeled	CD25	ATLL (18)	Phase I/II ORR 56%^ref
alemtuzumab	CD52	PTCL (14)	Pilot ORR 36%^ref Toxicity: CMV reactivation 43%; 36% TRM-study closed early
alemtuzumab + fludarabine , cyclophosphamide + doxorubicin	CD52	PTCL except ALK⁺ ALCL (23) included untreated patients	Pilot ORR 61% (Weidmann E, Hess G, Krause SW, et al. Combination chemo-immunotherapy using alemtuzumab, fludarabine, cyclophosphamide and doxorubicin is an effective first-line regimen in peripheral T-cell lymphoma [abstract]. Blood. 2004;104(11):2640a) Toxicity: 81% grade III/IV leukopenia; 56% CMV reactivation
SGN30	CD30	ALCL (5)	SGN30 phase II OR 33% (Forero-Torres A, Bernstein S, Gopal A, et al. SGN-30 (anti-CD30 monoclonal antibody) is active and well tolerated in patients with refractory or recurrent systemic anaplastic large cell lymphoma [abstract]. Blood. 2004;104(11):2637a) Toxicity: well tolerated
MDX-060	CD30	ALCL (6)	MDX-060 ORR 33% Toxicity: no MTD^ref
5F11	CD30	CD30⁺ ALCL	5F11 phase I study ongoing in CD30⁺ lymphomas
KM2760	CCR4	ATLL CCR4⁺ PTCLs	preclinical studies ongoing^ref

anthracycline-containing regimens have demonstrated limited success in PTCLs, with most series documenting few long-term survivors. Nucleoside analogs have recently been gaining interest in this disease. Gemcitabine has shown activity in relapsed PTCLs as a single agent^ref, but has not yet been explored in combination with other agents. Compound 506U78, a pro-drug of AraG, a deoxyguanosine analog, has been evaluated as a single agent in PTCL. The drug is rapidly converted in the blood to Ara-G and has toxic effects on T-cells. Unfortunately, grade 3/4 neurotoxicity is problematic, and early treatment related deaths have limited further development (Czuczman MS, Porcu P, Johnson J, Niedzwiecki D, Canellos G, Cheson BD. CALGB 59901: Results of a phase II study of 506U78 in CTCL and PTCL [abstract]. Blood 2004;104(11):2486a).
IL2-receptor (IL-2R) is a marker of T-cell differentiation, and the CD25 subunit of this receptor is expressed in a subset of patients with PTCLUS and CD30+ ALCL. Denileukin diftitox (ONTAK) is a fusion molecule of IL-2 to diphtheria toxin that targets tumor cells expressing the IL-2R and has been shown to have efficacy in patients with cutaneous T-cell lymphoma. Limited reports have also demonstrated tumor responses in relapsed PTCLs (Dang NH, Pro B, Hagemeister FB, et al. Interim analysis of a phase II study of denileukin diftitox (Ontak) for relapsed/refractory T-cell non-Hodkin’s lympoma [abstract]. Blood. 2004;104(11):2641a), but toxicity remains significant. Flu-like symptoms and hypersensitivity reactions have limited its usage and combination with other therapies.
antibodies directed at the CD25 subunit (human anti-TAC antibody, daclizumab) and an anti-CD25 recombinant immunotoxin in addition to a radioconjugate of anti-Tac with 90-yttrium are also currently being evaluated as potential therapeutic agents^ref
histone deacetylase inhibitors (HDIs) are a new class of anti-neoplastic agents currently being evaluated in cancer clinical trials. Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deaceylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. Depsipeptide, an inhibitor of histone deacetylation, has demonstrated activity in relapsed PTCL patients with a overall response rate of 26% (Piekarz RL, Frye R, Turner M, et al. Responses and molecular markers in patients with peripheral t-cell lymphoma treated on a phase II trial of depsipeptide, FK228. Proc ASCO. 2005;24:3061a)
recently, immunotherapy has emerged as an important adjunct to traditional cytotoxic chemotherapy in B-cell lymphomas. Alemtuzumab, a humanized monoclonal antibody directed against the CD52 antigen, is present on most malignant T-cells, making it an attractive target for PTCL. Additional widespread CD52 expression on normal T/B-cells, monocytes, and macrophages results in profound immunosuppression and has restricted combination with chemotherapy. As a single agent in heavily pretreated patients with PTCL the overall response rate with alemtuzumab was 36% in one report^ref. Several studies are evaluating the addition of alemtuzumab with chemotherapy. Combination of alemtuzumab with fludarabine, cyclophosphamide, and doxorubicin in untreated and relapsed patients was evaluated in a variety of PTCLs (Weidmann E, Hess G, Krause SW, et al. Combination chemo-immunotherapy using alemtuzumab, fludarabine, cyclophosphamide and doxorubicin is an effective first-line regimen in peripheral T-cell lymphoma [abstract]. Blood. 2004;104(11):2640a). Of 18 evaluable patients, the majority had PTCLUS (n = 10), with an overall response rate of 61%, and those patients treated primarily with this regimen had a CR rate of 78%; however, assessment of survival awaits longer follow-up. Of concern, over half of the patients developed cytomegalovirus (CMV) reactivation. These encouraging results suggest that the combination of alemtuzumab with chemotherapy is feasible; however, toxicity remains a major limitation.
CD30 is uniformly expressed in ALCL and a subset of patients with PTCLUS. With minimal expression on normal cells, it is the ideal therapeutic target. Phase I/II studies have been initiated with chimeric (SGN30) and fully humanized antibodies directed against CD30 (MDX-060, 5F11) in ALCL^ref (Forero-Torres A, Bernstein S, Gopal A, et al. SGN-30 (anti-CD30 monoclonal antibody) is active and well tolerated in patients with refractory or recurrent systemic anaplastic large cell lymphoma [abstract]. Blood. 2004;104(11):2637a). Several objective responses have been reported in phase II reports, and ongoing studies with these agents suggest that an additive benefit is seen in combination with chemotherapy. Unfortunately, the majority of PTCLs do not express this antigen and better targets, with limited expression on normal tissue, are needed. With recent studies demonstrating that a subset of patients with PTCLUS and ATLL express CCR4, investigators are evaluating the efficacy of anti-CCR4 monoclonal in these diseases^ref. Finally, studies are also underway testing the effect of tumor vaccines directed against the idiotypic TCR, particularly in cutaneous TCLs, and targeting the ALK protein in ALK⁺ ALCL^ref

dose intensive therapy including transplantation : the Intergroup trial comparing CHOP to newer regimens did not address the role of dose intensity since the doses of cyclophosphamide and doxorubicin were either equivalent or smaller in the newer regimens when compared to CHOP. Phase II trials have developed regimens with higher doses of drugs than CHOP, but the numbers of patients with T/NK neoplasms are too small to assess the impact of dose intensity^{ref1,
ref2}. Small series have reported that new regimens with higher doses of Adriamycin than are in CHOP along with the addition of etoposide have equivalent responses and survivals between PTCL and aggressive B cell lymphomas. However, the numbers of PTCL are small; the PTCL group includes chemosensitive ALCL patients, and the studies are not randomized^{ref1,
ref2}. Despite the chemosensitivity of ALCL, pediatric studies have indicated a role for more intensive regimens in ALCL patients with poor prognostic factors^ref (Bruegieres L, Deley MC, Pacquement H, et al. CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in 2 consecutive studies of the French Society of Pediatric Oncology. Blood. 1998;92:35921-3598). The role of HSCT in first relapse is accepted as standard of care after the findings of the phase III PARMA study which favored autologous HSCT over additional platinum-based chemotherapy^ref; however, its use in first remission is an area of controversy because randomized trials have yielded mixed results^ref. European investigators have advocated a role of ASCT in first CR for ALCL and report > 90% DFS in first CR^ref. They justify early transplantation on the hypothesis that the IPI in ALCL does not correlate with prognosis. Because subsequent studies of ALCL have had prognosis correlate with the IPI and systemic ALCL has the best prognosis of PTCL with chemotherapy alone, a policy of transplantation in first CR for ALCL cannot be supported. Until randomized trials prove differently, transplantation for NK/T cell neoplasms should be utilized similar to DLBCL as a part of salvage therapy in relapsed patients who are chemosensitive. The M. D. Anderson group reported a 3 year OS of 36% and PFS of 28% in a series of 36 relapsed patients with PTCL who underwent transplantation (29 autologous, 7 allogeneic)^ref. In a Vanderbilt series of 26 relapsed patients (ALCL-15, PTCL-9, NK-1, T-cell -1) who underwent transplant (18 autologous, 8 allogeneic) the 3 year EFS was 48% (+ 11%), which was similar to 38% (+ 6%) EFS in 84 patients with DLBCL (Jagasia M, Stein R, Kinney M, et al. High dose chemotherapy and hematopoietic stem cell transplant in peripheral T cell, NK cell and Ki-1 anaplastic large cell lymphoma. J Clin Oncol. 2001;20:294a). Of note, all 7 patients with ALK+ ALCL remained free of disease while 5 patients with primary cutaneous ALCL relapsed but remained alive. Small numbers of patients with extranodal NK/T lymphoma, including hepatosplenic, SCPTCL, and nasal-type NK cell lymphomas, have undergone transplantation, usually as salvage therapy^{ref1,
ref2}. Because the latter diseases have a worse prognosis than ALCL, they are more likely candidates for early transplantation, particularly in patients with a high IPI. The role of transplantation, primarily allogeneic, in ATLL has been performed in a few patients with mixed results due in part to the additional problem of eradicating HTLV-1 ^{ref1,
ref2}. In summary, the T/NK neoplasms, other than ALK⁺ ALCL, have been more chemoresistant than the DLBCL. Mechanisms of drug resistance in T/NK lymphomas have included increased expression of the multidrug resistance proteins and p53 (Drenou B, Amiot L, Lamy T, LePrise PY, Fauchet R. Multidrug resistance in aggressive lymphoproliferative disorders of T and natural-killer origin. Leuk Lymphoma. 1988;30:381-387; Pescarmona E, Pignoloni P, Santangelo C, et al. Expression of p53 and retinoblastoma gene in high-grade nodal peripheral T-cell lymphomas immunohistochemical and molecular findings suggesting different pathogenic pathways and possible clinical implications. J Pathol. 999;1188:400-406). Available chemotherapy agents, including paclitaxel and topotecan , and new agents, such as flavopiridol and UCN-1, modulators of cyclin-dependent kinases, have activity in relapsed hematologic malignancies^ref (King K, Younes A. Ifosfamide- and paclitaxel-based treatment of relapsed and refractory lymphoma. Semin Oncol. 2000;27(Suppl1):14-22). However, there is little data regarding their efficacy in T/NK neoplasms. Additionally, monoclonal antibodies are likely to be effective when directed toward specific markers on a T/NK tumor, such as anti-CD30 Abs or the anti-IL-2R mAbs . Because of the rarity of these diseases, only cooperative groups or a few large centers will be able to adequately evaluate the role of new drugs, monoclonal antibodies, and transplantation.

Old entities

immunoblastic sarcoma of T cells : large cell, immunoblastic lymphoma made up predominantly of T cells.
small lymphocytic T-cell lymphoma : small lymphocytic lymphoma that has predominantly T lymphocytes.
lymphoblastic lymphoma : a highly malignant type of NHL composed of a diffuse, relatively uniform proliferation of cells with round or convoluted nuclei and scanty cytoplasm, which are cytologically similar to the lymphoblasts seen in acute lymphocytic leukemia

convoluted T-cell lymphoma : lymphoblastic lymphoma with markedly convoluted nuclei

diffuse lymphoma / lymphatic sarcoma / lymphosarcoma : malignant lymphoma in which the neoplastic cells diffusely infiltrate the entire lymph node, without any definite organized pattern. This category from the Rappaport Classification was replaced by some of the cleaved-cell lymphomas in the Lukes-Collins Classification, by the 3 subtypes of diffuse lymphomas in the Working Formulation of Non-Hodgkin's Lymphomas, and by a variety of specific B- and T-cell neoplasms in the Revised European American Lymphoma (REAL) Classification
reticulosarcoma / reticulum cell sarcoma : a rare type of non-Hodgkin's lymphoma of intermediate to high malignancy, characterized by the presence of large tumor cells that resemble histiocytes morphologically but are considered to be of lymphoid origin. Many tumors formerly placed in this category are now considered to belong in one of the large cell lymphoma groups
U-cell lymphoma / undefined lymphoma : a category of NHLs comprising those tumors that cannot be classified into a definite type by either morphologic or currently available immunocytochemical markers.

mixed lineage leukemias

Localizations :

lymphomas in the immunosuppressed patient

AIDS-related lymphomas (ARL)

Aetiology

HIV-1

NHL (80-85%)

Epidemiology

Histology

brain (31%)
liver (26%)
gastrointestinal tract (24%)
bone marrow (24%)
spleen (21%)
kidney (10%)
skin (7%)
lung (7%)
pancreas (5%)
adrenal glands (4%)
myocardium (3%)
pleura (3%)
bone (1%)

Therapy

HAART

^ref

Prognosis

⁺

Hodgkin's disease (HD) (15-20%)

Epidemiology

Histology

Prognosis

⁺

Prevention

HAART

posttransplant lymphoproliferative disorder (PTLD) is a relatively infrequent but devastating complication that occurs in 1-10% of transplanted patients (2-5% of solid organ recipients on immunosuppression) :

allogeneic HSCT : rapidly progressive, often-fatal complication occurring relatively early after transplant
solid organ transplantation (SOT)

Aetiology

heavy immunosuppressive regimen : patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine ) have a lower risk of PTLD than those without^ref
young age at the time of transplant
type of transplant that the recipient receives (5-10% of lung transplants)
recipient HLA-A26, B38 haplotype was strongly correlated with a higher incidence of EBV-positive PTLD (OR 3.99; p = 0.001). The common ancestral haplotype HLA-A1, B8, DR3, when carried by the donor, was protective against PTLD (OR 0.41; p = 0.05)^ref

Histology

B-cell PTLDs (most) : 44% are EBV^+ref

early lesions :

reactive plasmacytic hyperplasia
infectious-mononucleosis-like PTLD

polymorphic PTLD
monomorphic PTLD

B-cell PTLD

monomorphic B cell / plasmacytic hyperplasia : 31% are EBV⁺
polymorphic or polymorphous B-cell hyperplasia (PBCH) or lymphoma

precursor B cell lymphoblastic lymphoma : EBV^-ref

immunoblastic lymphoma and multiple myeloma : even if most described cases of PTLD-myeloma type are aggressive, some patients are very young, have a clear association with EBV, and an indolent clinical course^ref

T-cell PTLD

Hodgkin lymphoma (HL) and HL-like PTLD : there are important immunophenotypic, molecular genetic, and clinical differences between HL PTLD and HL-like PTLD, suggesting that HL-like PTLD is in fact most often a form of B-cell PTLD^{ref1,
ref2}

Aetiology

primary HHV-4 / EBV infection following in chronically immunosuppressed (IS) transplantation recipients occurs in as many as 90% of cases of PTLD in children : pretransplant EBV seronegativity is a recognized risk factor for developing PTLD owing to the lack of anti-EBV memory T lymphocytes to control subsequent EBV challenges and suppression of CTLs function => outgrowth of latently infected EBV⁺ B-cells (58% have positive EBER-ISH)

a 45-year-old man was admitted with fever and elevated pancreas enzymes 6 months after simultaneous pancreas-kidney transplantation (SPKT). Function of the allografts was normal. Bacterial and fungal infections were excluded, while EBV-PCR was positive. However, screening for EBV-associated lymphoma was negative. EBV infection did not respond to antiviral therapy. After an ¹⁸F-FDG PET positive signal and an abnormal CT scan of the pancreas transplant, a biopsy revealed a diffuse large monomorphic B-cell lymphoma, which was confined to the grafted organ. Its origin was assigned to the donor by microsatellite analysis. Reduction of immunosuppression and immunotherapy with rituximab was unsuccessful. After 10 weeks, the patient developed an acute hemolytic uremic syndrome which required explantation of the allografts. Subsequent to the intervention, fever disappeared, EBV DNA became undetectable and lymphoma screening remained negative. In posttransplant lymphoproliferative disorder of donor origin after SPKT, transplantectomy may be a curative therapy^ref.

EBV-negative PTLDs (median onset time around 50-60 months post-transplant)

Pathogenesis

⁺

BCL6⁺/MUM1^+/-/CD138^- : B-cells actively experiencing the GC reaction and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma .
BCL6^-/MUM1⁺/CD138^- : B-cells that have concluded the GC reaction and comprise the majority of polymorphic PTLD and a fraction of DLBCL .
BCL6^-/MUM1⁺/CD138⁺ : post-GC and pre- terminally differentiated B-cells, morphologically represented by either polymorphic PTLD or DLBCL immunoblastic.

^ref

T-cell PTLDs : 40 cases in solid organ transplant recipients have been reported

HHV-4 / EBV -associated T-cell PTLDs (16 cases in : gastrointestinal tract, lungs, bone marrow, skin, liver and spleen) : it is speculated that the EBV may infect a subset of T-cells that express the CD21 receptor.

Therapy

bexarotene

^ref

Prognosis

non-EBV-associated T-cell PTLD (first described in a renal allograft recipient in 1987)

primary cutaneous T-cell lymphoma (CTCL)^ref

anaplastic T cell

Symptoms & signs

Laboratory examinations

Differential diagnosis

cat scratch disease (CSD)

Therapy

reduction of immunosuppression :

chemotherapy is associated with higher survival rates (100% versus 18% at 3 years)

low-dose chemotherapy in children who fail reduction of immune suppression : cyclophosphamide (600 mg/m²) and prednisone (2 mg/kg per day for 5 days) given every 3 weeks for 6 cycles. The complete remission rate was 82%. Graft survival was 90%. Relapse rate was 22%, with late-onset PTLD (> or =2 years from transplant) more likely to relapse. Of the 7 patients with relapsed PTLD, 4 were salvaged with "conventional" non-Hodgkin's lymphoma chemotherapy. The overall 1-year survival for patients treated with low-dose chemotherapy was 86%. The estimated 2-year survival is 73%
the lack of viral TK expression in EBV⁺ tumor cells, due to viral latency, makes anti-viral therapy alone ineffective as an anti-neoplastic therapy. Pharmacologic induction of the latent viral TK gene and enzyme by arginine butyrate in latently EBV-infected human lymphoid cells and tumor cells, followed by treatment with ganciclovir in a 3-week course^ref

rituximab every 6 months for 2 years (ORR = 64%, CR = 55%, PR = 9%)^{ref1,
ref2}. 2 of 6 patients developed PTLD during the first year after lung transplantation, while 4 developed late-onset PTLD. One patient presented with PTLD localized to the graft, one had unilateral cervical lymph nodes, and the others presented with multi-organ involvement. All patients had DLBCL. Immunosuppressive therapy was reduced and rituximab was administered at a dose of 375 mg/m²/wk for 4 wk. 1 patient did not respond to the first 2 courses of rituximab, received conventional chemotherapy, and achieved CR; 4 patients achieved CR after 4 courses with a median relapse-free survival of 34 months (range: 14-55); and 1 patient did not respond and died. The diagnosis of complete remission was established by conventional imaging techniques combined to whole-body positron emission tomography scan^ref.

Prognosis

^ref

most methotrexate -related lymphoproliferative disorders (LPDs), which undergo spontaneous remission after discontinuation of therapy, LPDs secondary to purine analogs often fails to resolve after discontinuation of therapy and requires additional therapy^ref

primary cardiac lymphoma (0.5% of the extranodal lymphomas) occurs more commonly in immunocompromised patients, frequently involves the pericardium with no or minimal evidence of extracardiac involvement, and, unlike other primary cardiac malignancies, may respond to chemotherapy. About 80% of cases of the primary cardiac lymphoma in immunocompetent hosts are of diffuse B-cell lymphoma, and in patients with immunodeficiency states, small noncleaved or immunoblastic lymphomas are more frequent. The right atrium and right ventricle are the 2 most frequently involved sites. Clinical presentation is heterogeneous and is generally related to the site of involvement in the heart. The diagnosis is suspected when patients present with a cardiac mass or an unexplained refractory pericardial effusion. A thorough workup should include transthoracic and TEE, CT, and MRI. Diagnosis is confirmed by cytology of the serous fluid from pericardial or pleural effusion or transvenous intracardiac tumor biopsy of the pericardial mass or endomyocardial tissue (under fluoroscopic or transesophageal echocardiographic guidance). The exploratory thoracotomy should not be delayed if indicated. Chemotherapy has been used alone or combined with radiotherapy. Similarly, palliative cardiac surgery has been performed, mainly for tumor debulking. Combination of chemotherapy and radiation therapy is considered as the treatment of choice. The survival is generally less than a month without treatment but has been prolonged up to 5 years with palliative treatments in selected cases.
primary non-Hodgkin lymphoma of the lacrimal sac
primary ovarian lymphoma can be a cause of, and can manifest solely as, a severe and symptomatic increase in the serum calcium level, which is mediated by an increased serum concentration of 1,25-dihydroxy-vitamin D.
primary breast lymphoma (PBL) is a rare form of localized extranodal lymphoma.
primary NK/T cell lymphoma of the testis
primary central nervous system lymphoma (PCNSL)

primary leptomeningeal lymphoma (PLML) of the spine

MALT-type lymphomas (MALTomas)

Epidemiology : expected rate of 4.2 cases of leukaemia for every 100,000 kids over a 5-year period
Aetiology :

extrinsic :

chemicals :

tungsten (assessed in tree rings) has been linked to clusters in Fallon, Nevada, Sierra Vista, Arizona, and Florin, California
benzene , a chemical found in vehicle emissions, could damage sperm in a way that would promote leukemia in the father's children. High levels of benzene in the workplace have been tied a higher risk of leukemia among workers.
cigarette smoking was not associated with the risk of non-Hodgkin's lymphoma overall (OR = 0.97) nor with the major subgroups such as diffuse large B-cell lymphoma (DLBCL) (OR = 0.94), B-cell chronic lymphocytic leukemia (B-CLL) (OR = 0.86), or follicular lymphomas (OR = 1.03). Female smokers were at a marginally increased risk of follicular lymphomas (OR = 1.41). Men who had ever smoked had a significantly increased risk of T-cell lymphoma (OR = 1.67). No dose-response association with cigarette smoking could be established for any lymphoma subgroup^ref. Similarly no association was found for most leukemia subtypes, and in particular for acute myeloid leukemia. But in contrast, the risk for B-CLL was clearly associated with ETS exposure, with an adjusted OR = 2.3 for > 83 smoker-years of residential exposure and 2.4 for > 72 smoker-years of occupational exposure. There was a dose-response relationship for chronic lymphocytic leukemia with both indices of exposure. Risk was not higher with recent exposure, using time-window-exposure analyses^ref. Cigarette smoking was associated with the development of acute myeloid leukemia in men only (RR = 2.8). Chronic myeloid leukemia showed an association with smoking of borderline significance in men only. B-CLL and MM were not related to cigarette smoking. In the men with AML there was a suggestion of a dose-response relation but it was not statistically significant^ref. Among women there was a suggestion of a positive association between smoking and the risk of NHL + B-CLL. A slight increased risk of leukemias was observed among women using permanent hair dye. Housewives were at increased risk for leukemia and multiple myeloma. The risk of NHL + B-CLL, leukemias, multiple myeloma, and Hodgkin's disease increased among women employed as hairdressers and textile workers. Teachers were at increased risk for NHL + B-CLL, leukemias, and Hodgkin's disease^ref.
herbicide use on the lawn or garden was similar among NHL cases and controls. Estimated risk did not increase with greater duration, frequency, or total number of applications of herbicides to the lawn, the garden, or to both combined. Risk was not elevated for respondents who applied the herbicides themselves and not for those exposed during the 1970s, 1980s, or 1990s. 2,4-dichlorophenoxy-acetic acid was detected equally often in homes of cases and controls (78%). Dicamba was found in homes of 15% of cases and 20% of controls. No elevation in risk was found among the respondents who had the highest dust levels and highest self-reported exposures. No consistent patterns were found for specific histologies^ref. Previous studies have suggested an association between exposure to pesticides and different types of childhood cancer. This paper presents results from a population-based case-control interview study of parents of children less than 15 years of age, which was conducted in the states of West Germany from 1993 to 1997. Cases were 1,184 children with leukemia, 234 with NHL, and 940 with a solid tumor; 2,588 controls were also included. Parental occupational exposures were found to be related to childhood cancer regardless of the time period of exposure and the type of cancer. This finding might partially be explained by different recall of past exposures by the parents of cases and controls. Residential use of insecticides was associated with childhood lymphoma: both extermination of insects by professional pest controllers (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.2, 5.7) and frequency of parental use of household insecticides (p for trend = 0.02) were significant risk factors for this diagnosis. The use of pesticides on farms was weakly related to childhood leukemia (OR = 1.5, 95% CI: 1.0, 2.2), while their use in gardens was not associated with childhood leukemia (OR = 1.0, 95% CI: 0.8, 1.2). The major strengths of this study were the population base and the large number of cases and controls included; a drawback was assessment of exposure on the basis of parental interviews. The data provide some evidence for an increased leukemia risk for children living on farms and for an association between use of household pesticides and risk of childhood leukemia or lymphoma^ref
ethylene oxide : positive trends for haematopoietic cancers which were limited to males (15 year lag). The trend in haematopoietic cancer was driven by lymphoid tumours (NHL, myeloma, lymphocytic leukaemia), which also have a positive trend with cumulative exposure for males with a 15 year lag. Haematopoietic cancer trends were somewhat weaker in this analysis than trends in the earlier follow up, and analyses restricted to the post-1987 data did not show any significant positive trends (exposure levels dropped sharply in the early 1980s)^ref.
polychlorinated biphenyls (PCB) have been suspected as possible contributors to increasing NHL incidence during the latter half of the 20th century based on their toxicologic properties and provocative epidemiologic reports. Congeners of PCBs (including coplanar congeners), dioxins, furans and pesticides or pesticide metabolites were measured in plasma of 100 untreated cases and 100 control subjects in USA. A multiple imputation procedure was used to fill in missing values of levels determined to be below the detection limits. Risks of NHL associated with each analyte were estimated using conditional logistic regression for the continuous measure, exposure quartiles, trend across quartile categories, and exposures above the 95th percentile. Certain PCB congeners were associated with increased risk of NHL, including coplanar PCBs 156, 180, and 194, with odds ratios for the highest versus lowest quartile ranging from 2.7 to 3.5, and significant trends. Each of the furan congeners was associated with risk of NHL, as were total furans, with 3.5-fold increased risk for the highest versus lowest quartile and a significant trend across quartiles. The toxic equivalency quotient (TEQ), a summed metric that weights congeners by their dioxin-like potency, was associated with NHL, with 35% increased risk per 10 TEQ pg/g lipid^ref

low-frequency electromagnetic fields (EMF) : on the basis of the job held longest during the 10-year period before diagnosis, we found an association between the average, daily, mean level of EMF and B-cell chronic lymphocytic leukemia (B-CLL). The risk increased with increasing level of exposure. The odds ratios (OR) and the 95 percent confidence interval (CI) for 3 consecutive levels of exposure were: 1.1 (CI = 0.5-2.3); 2.2 (CI = 1.1-4.3); 3.0 (CI = 1.6-5.8), respectively. No association was observed for acute myeloid leukemia (OR = 1.0, CI = 0.5-1.8; OR = 0.8, CI = 0.4-1.6; OR = 1.0, CI = 0.6-1.9)^ref
hormone replacement therapy (HRT) : there are few data regarding HRT and NHL. A case-control study reported a positive association of estrogen replacement therapy and NHL^ref, whereas another case-control study of intermediate and high grade NHL found a weak inverse association that was not statistically significant^ref. The early results (7-year follow-up) from the Iowa Women’s Health Study cohort found no association with HRT use^ref. Another work showed HRT is a risk factor for follicular lymphomas (RR = 2.6-3.9) but not for diffuse or small lymphocyte NHL or CLL^ref. There are data showing that s.c. estrogen can also induce lymphoma^ref. Bernstein and Ross^ref published preliminary results from a population-based case-control study (n = 337 female cases and matched controls) conducted from 1979 to 1982 in Los Angeles. Compared with women who had never used estrogen replacement therapy, women who had ever used it were at a slightly increased risk of NHL (OR, 1.29; 95% CI, 0.94-1.79), mainly attributable to women who had used it 13 or more months (OR, 1.58; 95% CI, 1.09-2.29). These estimates were not adjusted for other risk factors, and the distribution of cases by subtypes (or a subtype analysis) was not reported. In a case-control study of intermediate- and high-grade B-cell NHL, conducted in Los Angeles from 1989 to 1992^ref, ever use of HRT was inversely associated with risk (OR, 0.60) among HIV^- women, although this estimate was not statistically significant (95% CI, 0.31-1.18). Additional adjustment for age at menopause did not alter this association. The proportion of intermediate to high-grade cases was not reported; therefore, we cannot directly compare these results with our data. The use of HRT for >5 years among both former and current users was associated with RRs of <1 for diffuse NHL (all intermediate grade), although the estimates were based on small numbers and lacked precision. Thus, the association of HRT with intermediate- and high-grade NHL remains unresolved at this time. No prior study has evaluated HRT use and the risk of follicular or small lymphocytic NHL or CLL. Correlates of endogenous estrogen, including reproductive^{ref1,
ref2,
ref3,
ref4,
ref5}and menstrual history^ref factors, have not shown a consistent association with NHL in the few studies to evaluate these associations. No data are currently published evaluating these factors with specific subtypes of NHL. Although we cannot rule out the possibility that the specific association of HRT use with follicular NHL may be a chance finding, this association is supported by several lines of evidence. Overall, the incidence rate of NHL is about 50% higher in men than women (in both Iowa and in the USA), and this is true for nearly all subtypes except follicular NHL, for which the rates are approximately equal (Ries L. A. G., Kosary C. L., Hankey B. F., Miller B. A., Clegg L. X. SEER Cancer Statistics Review, 1973-1996, NIH Pub. 99-2789 National Cancer Institute Bethesda, MD 1999) . In Iowa from 1978 to 1997, the age-incidence curve for follicular NHL among women is similar to that seen for female breast cancer, in contrast to the age-incidence curves for diffuse, small lymphocytic leukemia and CLL (which continue to increase rapidly with age) or high-grade NHL (which shows neither pattern). These patterns are similar for all SEER data for white females for 1993-1997. The age-incidence pattern for female breast cancer (which follicular NHL follows) has been widely interpreted as suggesting a role for ovarian hormones in this malignancy (Henderson B. E., Pike M. C., Bernstein L., Ross R. K. Breast cancer Schottenfeld D. Fraumeni J. F., Jr. eds. Cancer Epidemiology and Prevention, 1022-1039, Oxford University Press New York 1996) . Evaluation of ovarian hormones (particularly estrogen) in the etiology of NHL generally, or follicular NHL specifically, is limited. However, estrogen clearly plays a role in immunological function^{ref1,
ref2,
ref3,
ref4,
ref5}, and immunological function is thought to be important in lymphomagenesis^ref. For example, estrogen is known to influence lymphopoiesis, T_h1/T_h2 balance, antigen presentation, lymphocyte homing, and cytokine production^{ref1,
ref2}. Estrogen at physiological levels is considered to be immunostimulatory, in part by increasing T_h1 cytokine production (e.g., secretion of IL-2, IFN-g, and TNF-ß), which is associated with an augmentation of the cellular immune system and the suppression of the humoral immune system. At higher concentrations (e.g., in pregnancy), there is a shift toward T_h2 cytokine production (e.g., secretion of IL-4, IL-5, IL-6, and IL-10), which is associated with the suppression of the cellular immune system and stimulation of humoral immunity^{ref1,
ref2,
ref3} . However, the exact roles and mechanisms of estrogen in the immune system are not completely understood^ref, in part because estrogen effects vary between sexes and across species^ref, and even across strains of mice^ref. Even less is known about the role of estrogen in lymphomagenesis. Both estrogen-receptor-mediated and non-receptor-mediated mechanisms may be relevant^{ref1,
ref2}.
drugs : use of antibiotics > 10 times during adulthood is positively associated with risk of NHL and most major NHL subtypes; when users were compared with nonusers, the odds ratio for NHL is 1.8 (IC₉₅: 1.4, 2.3); p(trend) for total antibiotic use <0.001. In addition, high cumulative use of nonsteroidal anti-inflammatory drugs was marginally associated with elevated NHL risk. Other medications evaluated were not associated with risk of NHL or its most common subtypes. Inflammation, infections, susceptibility to infections, and/or use of antibiotics or nonsteroidal anti-inflammatory drugs to treat these conditions may increase the risk of NHL^ref.
infections :

...
adenoviruses ^{ref1,
ref2,
ref3} :

Burkitt's lymphoma cell lines (Raji and Jijoye) that poorly replicate human adenovirus 5^ref
dogs bearing malignant lymphoma or squamous cell carcinoma tumours had higher levels of antibody against adenovirus type 5 antigens. Human adenovirus type 5 was neutralised by sera from four tumour-bearing and two normal dogs, while sera from two normal and five tumour-bearing dogs were positive in immunodiffusion tests with human adenovirus antigens^ref
type 5 adenovirus isolated from urine of patient with Hodgkin's disease^ref.
superinfection with adenovirus of lymphoblastoid cell lines^ref.
superinfection with adenovirus of Burkitt's lymphoma cell lines^ref
the oncogenicity of human adenoviruses in hamsters^ref

^ref

intrinsic : SNPs in critical genes, IL-4 , IL-5 , IL-6 , and IL-10 , were associated with risk for NHL and in some instances with a specific histologic subtype. Analysis of 4 SNPs in the IL10 promoter (–3575T>A, –1082A>G, –819C>T, and –592C>A) revealed that both the AGCC haplotype (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.21-1.96, P < .001) and the TATA haplotype (OR = 1.37, 95% CI = 1.05-1.79, P = .02) were associated with increased risk for B-cell lymphomas. In contrast, the IL4-1098G allele was associated with increased risk of T-cell lymphomas (OR = 3.84; 95% CI = 1.79-8.22; P < .001). Further, the IL10 and IL4 SNP associations remained significant after adjusting for multiple comparisons. These results suggest that SNPs in T_h2 cytokine genes may be associated with risk of NHL^ref. A large-scale evaluation of common genetic variants in immune genes and their role in lymphoma genotyped 57 SNPs from 36 candidate immune genes in 1,172 non-Hodgkin lymphoma cases and 982 population-based controls from a US multicenter study. A haplotype comprising SNPs in 2 proinflammatory cytokines, TNF-a and LT-a (rs1800629, rs361525, rs1799724, rs909253, and rs2239704), increased NHL risk overall (OR, 1.31; 95% CI, 1.06-1.63; P = 0.01) and notably for DLBCL (OR, 1.64; 95% CI, 1.23-2.19; P = 0.0007). A functional nonsynonymous SNP in the innate immune gene FcgRIIA (FCGR2A; rs1801274) was also associated with NHL; AG and AA genotypes were associated with a 1.26-fold (95% CI, 1.01-1.56) and 1.41-fold (95% CI, 1.10-1.81) increased risk, respectively (P(trend) = 0.006). Among NHL subtypes, the association with FCGR2A was pronounced for FL and SLLs. In conclusion, common variants in genes influencing proinflammatory and innate immune responses were associated with NHL risk overall and their effects could vary by subtype^ref.

Laboratory examinations :

CBC
ESR
LDH
tumor markers : b₂-microglobulin , TK . A raised GGT in HL and NHL is generally associated with active and widespread disease^ref. The expression of AP was enhanced in several samples with a high proportion of mature B cells, particularly in centroblastic-centrocytic lymphoma, whereas tissues mainly composed of T cells always showed low levels of this enzyme. GGT levels were high in thymus, as well as in centroblastic-centrocytic lymphoma and other NHL, thus demonstrating no restriction to a particular cell lineage. Some B-cell neoplasms with cellular origin different from that of centroblastic-centrocytic lymphoma, such as chronic lymphocytic leukemia and centrocytic lymphoma, had low levels of both enzymes^ref.
fibrinogen
creatinine, uricemia
sideremia, transferrin, ferritin
total serum proteins, serum protein electrophoresis with dosage of IgG, IgA, and IgM
immunophenotype of lymphocytes (CD3, CD4, CD8, CD5, CD5/CD19, CD19, CD22, CD23, CD25)
cytochemistry :

acid phosphatase (AP) has a definitive role in the diagnosis of acute and chronic T-cell leukaemias, where a strong positive reaction helps to distinguish them from most B-cell lymphoproliferative disorders
alpha-naphthyl acetate esterase (ANAE) is of value in distinguishing T-lymphocytes (positive localized reaction) from B lymphocytes (negative reaction) and the T micron from the T gamma subpopulation of T-lymphocytes, a positive reaction demonstrable only in the T micron cells.

Auer bodies or rods : finely granular lamellar small azurophil (bluish-red) rods having acid phosphatase activity composed of fused lysosomal granules; they are found in the cytoplasm of myeloblasts, promyelocytes, monoblasts, granular histiocytes, and occasionally plasma cells and mature neutrophils, but never lymphoblasts or lymphocytes; their presence is virtually pathognomonic of acute myeloblastic leukemia and myelodysplastic syndromes

echography of abdomen and soft tissues (neck, armpits, groin)
total-body CT

Therapy :

as for other cancers : myeloablative high-dose chemotherapy with stem cell transplantation produces higher 5-year survival rates than standard salvage chemotherapy in relapsed aggressive lymphoma, but its role as initial therapy is not yet clear. Nonmyeloablative dose-escalated chemotherapy is feasible with G-CSF support, but this approach does not improve outcomes. Dose-dense (14-day) CHOP with G-CSF support produces better results than 21-day CHOP in patients with previously untreated aggressive lymphoma, without additional toxicity. The addition of etoposide to dose-dense CHOP may provide further benefits in younger patients. The addition of rituximab to G-CSF-supported dose-dense CHOP is feasible. Preliminary data suggest the feasibility of dose-dense chemotherapy for NHL with the once-per-cycle G-CSF, pegfilgrastim ^ref

relapse of non-Hodgkin's lymphoma (NHL) remains a problem after autologous HSCT (ASCT). Soon after ASCT, the immune system is not very active, and this immune incompetence could thus result in decreased ability for immune-mediated tumor eradication. The early addition of immunotherapy after ASCT might decrease the incidence of relapse and prolong survival. In an initial phase I/II trial, the immune modulator IL-2 increased over baseline natural killer and LAK activity in vitro. Because rituximab can lyse CD20-bearing cells by ADCC, adding IL-2 to rituximab might boost its effectiveness. It thus seemed reasonable to study this combination after ASCT. In a phase II trial, 20 patients with CD20⁺ NHL who had ASCT were treated. The median time to starting therapy was 79 days (range, 49-100 days) after transplantation. The majority of patients reported grade </= 2 erythema, induration and pain at IL-2 injection sites, flu-like symptoms, and worsening fatigue. Neutropenia that responded to granulocyte colony-stimulating factor was the most common grade 3/4 toxicity, seen in 45% of patients. There were no treatment-related deaths. Eighteen of 20 patients remain alive in complete remission, with a median follow-up of 55.5 months (range, 17-64 months). IL-2/rituximab can be administered after ASCT with manageable toxicity. A randomized trial is under way to address whether this combination therapy is beneficial to patients with NHL who have had ASCT^ref

graft-versus-leukemia (GVL)after allogeneic bone marrow transplantation
NHL after kidney transplantation : after the end of chemotherapy, re-introduction of therapeutic immune suppression was not necessary since, with a significant follow-up (median follow-up of 26 months, range 12-36), 0/6 patients had severe renal function deterioration. These preliminary data suggest that, after lymphoma treatment, immune suppression can be withhold at least for 2 years. Restoration of a functional immune system may contribute to decrease the rate of lymphoma recurrence^ref

Prognosis : ILSG classification

highly aggressive

aggressive

diffuse large B-cell lymphoma (DLBCL)

moderately aggressive

T-CLL/T-PLL
chronic ATL
angioimmunoblastic T-cell lymphoma
angiocentric lymphoma (nasal T-cell / pulminary B-cell)

indolent lymphomas have a relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages. Early-stage (I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with combination chemotherapy regimens. In general, with modern treatment of patients with NHL, the overall survival rate at 5 years is approximately 50-60%. Thirty percent of patients with aggressive NHL can be cured. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients with a divergent histology of both indolent and aggressive disease (Cabanillas, 1992). A subset of aggressive lymphomas, Burkitt lymphoma and lymphoblastic lymphoma, are designated as high grade by the International Working Formulation (IWF) to reflect the rapidly progressive behavior of these subtypes. While indolent NHL is responsive to radiation therapy and chemotherapy, a continuous rate of relapse is usually observed in advanced stages. However, patients can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may achieve complete remission (CR) with combination chemotherapy regimens with or without aggressive high-dose consolidation therapy with marrow or stem cell support. Aggressive lymphomas are increasingly observed in patients who are HIV⁺, and treatment of these patients requires special consideration.

The International Prognostic Index (IPI) is based on

age (favorable if < 60 years)
Ann Arbor stage (favorable if I or II)
serum LDH level (favorable if normal)
performance status (PST) (favorable if ECOG 0 or 1)
number of extranodal disease sites (favorable if 0 or 1)

...., and renders it possible to identify 4 risk groups corresponding to the number of adverse parameters :

0-1 : low IPI score
2 : low-intermediate IPI score
3 : high-intermediate IPI score
4-5 : high risk IPI score

In young patients an age-adjusted IPI based on tumour stage, serum LDH level, and performance status also identified 4 risk groups. In both models, the increased risk of death was the result of both a lower rate of complete responses and a higher rate of relapses. The IPI may also be effectively applied to patients presenting with lymphoma subtypes other than DLCL [3, 6]. The IPI and the age-adjusted IPI have proven significantly more accurate than the Ann Arbor classification in predicting long-term survival. Since the serum b₂-microglobulin level was measured inonly a few centres for patients included in the IPI project, the IPI could not incorporate this important prognostic indicator. However, the MD Anderson Cancer Center team has developed models that included b₂-microglobulin level and other important parameters, and proposed an index based on LDH and b₂-microglobulin level that has proven helpful indistinguishing between good-risk and poor-risk patients, regardless of their lymphoma subtype^ref. The IPI incorporates in its definition only surrogate markers of profound alterations of the cellular biology of tumour cells, particularly the mechanisms involved in the control of mitosis or of the host response machinery to the cancer. Since the time of its description, and in the future, biological or genetic alterations have been, and will be, described that may replace all or some of the classical parameters^ref. These putative parameters include gene alterationsof cell-cycle regulator proteins (Bcl-2, p53, Rb, p16, p21), cytokines (TNF, IL-6), adhesion molecules (CD44, ICAM-1), angiogenic peptides (VEGF), and transmission factor expression.

Complications : late non-neoplastic events were found in 46% of the 757 NHL patients. At 15 years, the cumulative incidences of cardiac disease and infertility were 20% and 29%, respectively. Renal insufficiency (11%), acquired hypertension (8%), and disabling neuropathy (13%) were also frequent. Salvage treatment was a risk factor in most cases. Smoking, age > 50 years during treatment, and preexistent hypertension were the main risk factors for cardiovascular disease. In-field radiation therapy (RT) was related to hypothyroidism, lung fibrosis, hypertension, gastrointestinal toxicity, and renal insufficiency but not to cardiovascular events. Autologous stem cell transplantation and cisplatin- and MOPP-containing therapies were associated with infertility and renal insufficiency^ref
Standardized response criteria : in 1987, Dixon et al^ref emphasized the need for uniform reporting of end points in clinical trials of patients with non-Hodgkin's lymphomas (NHL); of particular importance were the complete remission rate, survival, time to treatment failure, and time to relapse of complete responders. Their recommendations were met with controversy that remained unresolved^ref. Several USA lymphoma investigators from National Cancer Institute (NCI)-sponsored cooperative groups, the NCI, and the pharmaceutical industry collaborated in an effort to resolve the issues regarding response assessment in NHL. The result was a preliminary document that was subsequently reviewed and approved by European lymphoma experts (Horning S, Cheson B, Peterson B, et al: Response criteria (RC) and quality assurance (QA) of responses in the evaluation of new therapies for patients with low-grade lymphoma (LGNHL). Proc Am Soc Clin Oncol 16:18a, 1997 (abstr 61); Grillo-López AJ, Horning S, Cheson B, et al: Development of response criteria (RC) for low-grade or follicular lymphomas (LG/FNHL) and application in a 166 patient study. Exper Hematol 25:732, 1997 (abstr 17)). Eventually, a workshop was held at the NCI on February 25 to 26, 1998, with a subsequent meeting on May 16, 1998, to come to consensus on a standardized set of guidelines for response assessment in adult patients with indolent and aggressive NHL. Response criteria for NHL used by International Cooperative Groups :

group	CR	PR	PD
NCI of Canada Clinical Trials Group	Disappearance of all disease No symptoms Must last 4 weeks or "unconfirmed CR"	>= 50% decrease in SPD No increase or new lesion Assessable disease stable or decreased Must last 4 weeks or "unconfirmed"	Increase by 25% in longest diameter New lesion Assessable disease progression
Cancer and Leukemia Group B	Disappearance of all disease No symptoms Biopsy suspicious residual nodes Must last 4 weeks by physical examination With residual abnormality:Mediastinal or abdominal mass persists for two cycles after > 50% decrease	> 50% decrease in SPD of all lesions No new lesions Disappearance of symptoms > 30% decrease in liver below right costal margin Normal liver function tests	> 25% increase in sum of the products of the greatest diameters (SPD) of any lesion compared with study baseline New lesion
Eastern Cooperative Oncology Group	If Ga scan was positive, now must be negative Disappearance of all disease (normal nodes <= 1 x 1 cm; nodes > 1 x 1 biopsied or observed x 3 months) Normal liver/spleen; biopsy if was positive Negative unilateral bone marrow Must last >= 4 weeks	>= 50% decrease in SPD Liver decrease by 50% (PE) Spleen <= 5 cm below left costal margin must become normal Spleen > 5 cm decrease by 50% Must last >= 4 weeks	Increase by > 25% in sum of the products of the greatest diameters (SPD) or new lesion (relapse: new disease after CR or PD after PR)
European Organization for Research and Treatment of Cancer/Dutch Hemato-Oncology Group	Disappearance of all disease Normal labs, x-rays, bone marrow Persistent nodes biopsied or considered CR Must last 4 weeks	>= 50% decrease in SPD of all lesions, no new lesions No symptoms No increase >= 25% in any lesion (a) with positive bone marrow (> or < 20%), (b) with negative bone marrow Must last 4 weeks	>= 25% increase in sum of the products of the greatest diameters (SPD) of >= one lesion New lesion
Group d'Etude des Lymphomes de l'Adulte	Disappearance of all lesions (No palpable nodes, no mass > 1 cm in diameter on CT, no bone marrow involvement) Normal performance status (PS) Disappearance of initial biologic abnormalities	Regression of initial tumor mass (nodal, extranodal) by > 50% or Disappearance of all lesions but persistent bone marrow involvement with normal PS and disappearance of initial biologic abnormalities	ND
	Uncertain CR: Persistence for 4 months of palpable node or mass on CT that has regressed >= 75% but not disappeared. Biopsy of accessible masses recommended. CT-guided needle biopsy if > 5 cm in thoracic of mediastinum Normal bone marrow, normal PS, no symptoms Disappearance of initial biologic abnormalities	ND	ND
Southwest Oncology Group	Disappearance of all disease No new lesions Normal markers, laboratory values If restaging is required, separate path response is defined Lasts >= 6 weeks	>= 50% decrease in SPD of all lesions No new lesions No progression of assessable disease Lasts >= 6 weeks	50% increase or 10 cm² (whichever is smaller) in sum of the products of the greatest diameters (SPD) over baseline, worse assessable disease New lesion Failure to return, death/worsening Not worse assessable

studies for diagnosis, staging, and restaging :

lymph node biopsies : whenever possible, an excisional-node biopsy of a suspicious lymph node should be performed for the initial diagnosis of lymphoma. A core-needle biopsy may suffice to document relapse or transformation in a patient with a previous indolent NHL. Pappa et al^ref performed needle biopsies on 106 patients, 51 with low-grade lymphoma, 24 with high-grade NHL, 16 with diagnosed HD, and 15 with no diagnosis. The disease was infradiaphragmatic in 92 patients and supradiaphragmatic in 14. A biopsy was diagnostic and yielded information that guided initial treatment in 88 of 106 patients (83%). When the biopsy was performed at the time of a suspected recurrence, a different histology was diagnosed in 33 of 80 patients, leading to a change in treatment plans for 31 patients. This procedure was accurate in making the diagnosis of histologic transformation in 16 of 18 cases. Investigators from Israel^ref reported the results of 1,500 CT-guided core-needle biopsies with which the diagnosis of lymphoma was made in 100 patients, 71 with NHL and 29 with HD. Previous diagnoses of NHL and HD were known in 24% and 31% of patients, respectively. The results of the needle biopsy were adequate to direct therapy in 86% of cases. Although core biopsies are probably more accurate than fine-needle aspirations, the role of both procedures remains controversial; precise classification of the lymphoma may be difficult, and the procedure requires an appropriate level of skill. For example, the sample was inadequate in 15 of 51 (29.4%) indolent lymphomas in the Pappa series^ref. Other problems with this procedure can be anticipated in distinguishing nodular versus diffuse histologies, in lesions with substantial fibrosis or sclerosis, in cases of T-cell NHL, T-cell-rich B-cell NHL, or in lymph nodes only partially involved with lymphoma, particularly in patients with HD.
bone marrow evaluation : assessment of the bone marrow is important both for staging and for an evaluation of the normal bone marrow elements before therapy. Several groups have recommended the use of bilateral bone marrow biopsies to stage and assess response of patients with NHL. The yield of identifying bone marrow involvement is increased by 10% to 20% with multiple sampling; however, even with negative bilateral biopsies, patients may subsequently be proven to have bone marrow involvement^{ref1,
ref2}. Bitran et al^ref compared the yield of a single bone marrow biopsy with bilateral bone marrow biopsies. In patients who underwent a single biopsy, the frequency of detection of bone marrow involvement was 49% compared with 65% with multiple biopsies. In the latter group, both samples were positive in 45% of cases, and a single sample was positive in 20%. In a report by Coller et al^ref, of 52 pretreatment bilateral bone marrow biopsies, only 5 biopsies had one side positive with the other side negative. The yield may correlate with the size of the sample as well as the number of samples. A minimal total length of biopsy in aggregate should be 2.0 cm. Lack of uniformity in the interpretation of bone marrow aspirates and biopsies represents a major problem. Among patients with a low-grade lymphoma, the differential diagnosis between bone marrow involvement and benign lymphoid aggregates can be difficult. Bone marrow biopsies should be scored as positive (unequivocal cytologic or architectural evidence of malignancy), negative (no aggregates or only a few well-circumscribed lymphoid aggregates), or indeterminate (increased number or size of aggregates without cytologic or architectural atypia). The bone marrow report should be reported not only as positive or negative for lymphoma, but the percentage of invasion and the lymphoma subtype should be indicated, the latter to describe any discordance with the nodal disease. Patients whose bone marrow is histologically normal but with a small clonal B-cell population detected by flow cytometry should be considered to have a normal bone marrow until there are clinical studies that demonstrate a different outcome for this group.

normal lymph node size : response in patients with lymphomas is most often defined on the basis of a regression in the size of enlarged lymph nodes or confluent lymph node masses; therefore, it is critical to determine how small an involved node must become after treatment to be considered "normal." A number of studies have attempted to determine the normal range of node size in patients without lymphoid malignancies. The size of lymph nodes in normal individuals as determined by CT scanning or at autopsy varies to a minor degree with the location of the node. In general, however, the upper limit has been considered to be approximately 1 cm in measurement of the short axis^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7}. In an autopsy series^ref, there was a difference among mediastinal regions, with upper limits ranging from 8 to 12 mm in the short axis, with greater variation in the long axis. In another autopsy series^ref, lymph nodes ranged in size from 5 mm in one region to 8 to 10 mm in others. Several studies have also looked at the size of abdominal nodes on CT scan in patients with either blunt trauma or benign or malignant diseases other than lymphoma^{ref1,
ref2}. Values varied by region from 8 to 11 mm, but with some normal pelvic nodes as large as 15 mm. Based on these data, at the time of diagnosis, a lymph node that is greater than 1 cm in its longest transverse diameter should be considered compatible with involvement by NHL. The question of lymph node size criteria becomes more problematic when assessing response in patients with NHL. The tumor mass in lymphoma patients is usually located within a normal structure, a lymph node, which it may replace either partially or completely. After effective treatment, this mass may decrease in size, and what remains may have the size and appearance of a normal lymph node, but it does not disappear. Unfortunately, it is common that as tumor-involved nodes shrink in size after treatment, fibrosis, necrosis, or inflammation results in a persistent enlargement of that node, although it may be histologically uninvolved by tumor^ref. It may also be difficult to interpret response in a group of nodes that were initially enlarged and matted together and appeared as a mass, but that broke up into several smaller nodal masses after treatment. We elected to be consistent with the criteria of 1.5 cm for the cross-sectional diameter of nodes established for HD at the Cotswolds meeting^ref. However, nodes that are <= 1.5 cm but are considered to be abnormal should decrease to < 1.0 cm to be considered normal in size. Using the longest transverse diameter seems to provide a more accurate assessment of response than the short axis in patients with NHL (Grillo-López AJ, McLaughlin P, Cheson BD, et al: First report on the application of the new response criteria (RC) proposed for NHL: The Rituximab pivotal trial. Proc Am Soc Clin Oncol ). If the bidimensional requirement for normal node size is decreased from 2.0 cm x 2.0 to 1.5 cm x 1.5 cm, to 1.0 cm x 1.0 cm, then the overall response rate does not change, but there is a significant decrease in the complete remission (CR) rate (Grillo-López AJ, Cheson B, Horning S, et al: Response criteria (RC) for NHL: Importance of "normal" lymph node (LN) size and correlations with response. Blood 92:412a, 1998 (abstr 1701) (suppl 1)). Whether the progression-free survival correlates with normal node size in this context is under evaluation. It is important that the same indicator lesions be used to minimize interobserver variability, because the same radiologist may not be reviewing CT scans^ref. Another major problem in the interpretation of response to treatment has been that persistence of residual masses after chemotherapy does not necessarily indicate residual disease^{ref1,
ref2,
ref3,
ref4}. Residual intra-abdominal masses are particularly problematic because of their common occurrence in patients with NHL. As many as 30-50% of patients with a large intra-abdominal mass at presentation and for whom the physical examination is normal after therapy will have a residual mass. Residual radiographic abnormalities tend to be more common in patients with large-cell NHL than in patients with a follicular low-grade histology. Fuks et al^ref reported 100 patients with advanced NHL of various histologies who were treated with either CVP or CHOP. After treatment there were 33 CRs and 38 partial remissions (PRs). In 20 of the PRs, all physical and chemical evidence of disease had returned to normal; however, a lymphangiogram, gallium scan, sonogram, or CT suggested residual disease. When those patients were subjected to restaging laparotomy, disease was detected in only four patients (20%). Surbone et al^ref reviewed 241 patients with aggressive NHL treated at the NCI between 1977 and 1986. Of the 72 patients (33%) with an abdominal mass at diagnosis, 29 (40%) were left with a radiologically detectable, stable residual mass that had decreased when compared with the initial diagnostic evaluation, but with no other clinical or laboratory evidence of disease. Patients with bulky masses (> 10 cm) before treatment were more likely to experience this circumstance. Residual masses were evaluated by laparotomy (n = 10), needle aspiration (n = 6), autopsy (n = 6), or clinical and radiographic evaluation only (n = 7). All needle aspirations and autopsies were negative. One laparotomy was positive in a patient in whom a preceding needle aspiration had been inadequate. Therefore, there was no evidence of disease detected in 21 of 22 (95%) cases on pathologic examination of the residual mass, and none of these patients subsequently relapsed. Of 7 patients who were observed clinically, 5 were alive and free of disease from 2 to 9 years, but the other 2 patients relapsed. In a comparison of ProMACE/MOPP with ProMACE/CytaBOM with leucovorin conducted at the NCI, restaging laparotomy was abandoned because 95% of residual abdominal masses did not contain lymphoma^ref. The manner in which patients with residual masses are assigned into response categories has varied widely among studies. In some series, responses in patients with residual masses were reclassified at a future time, depending on the subsequent behavior of the mass^ref. In a trial conducted by the NCI of Canada Clinical Trials Group, a CR required a return of all nodes to < 1 cm, unless larger nodes were negative by histologic examination^ref. Some investigators have used terms such as "probable CR"^{ref1,
ref2}. Coiffier et al^ref reported that 553 of 737 (75%) patients with aggressive NHL experienced disappearance of clinical and laboratory evidence of disease, although 150 (27%) had a persistent mediastinal or abdominal mass on CT scan. There was no difference in time to relapse or survival between those with or without a residual mass (relapse rates 24% and 26%, respectively); as a result, they retroactively included such cases within the CR category if morphologic evidence of NHL was not available or if the size of the mass did not change after 2 courses of treatment. Several investigators recommend that a large abdominal or mediastinal mass that undergoes > 50% reduction in size and remains stable for 2 to 4 months should not prevent classification as a CR given the absence of all other measurable disease^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6}, whereas a cut-off of 75% is used by others^ref.
International Working Group recommendations : the following criteria are considered anatomic definitions. In the future, as additional radiographic, laboratory, and functional studies become more widely available and clearly demonstrate predictive value, they may be recommended as well. Response criteria for non-Hodgkin's lymphoma :

response category	physical examination	lymph node	lymph node masses	bone marrow
CR	normal	normal	normal	normal
CRu	normal	normal	normal	indeterminate
CRu	normal	normal	> 75% decrease	normal or indeterminate
PR	normal	normal	normal	positive
	normal	>= 50% decrease	>= 50% decrease	irrelevant
	decrease in liver/spleen	>= 50% decrease	>= 50% decrease	irrelevant
relapse/progression	enlarging liver/spleen; new sites	new or increased	new or increased	reappearance

CR requires the following:

complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (eg, LDH) definitely assignable to NHL.
all lymph nodes and nodal masses must have regressed to normal size (< 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to <= 1 cm in their greatest transverse diameter after treatment, or by > 75% in the sum of the products of the greatest diameters (SPD).
the spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. However, no normal size can be specified because of the difficulties in accurately evaluating splenic and hepatic size. For instance, spleens thought to be of normal size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of lymphoma but variations in anatomy, blood volume, the use of hematopoietic growth factors, or other causes. The determination of splenic volume or splenic index by CT scan are cumbersome and not widely used^{ref1,
ref2}. Any macroscopic nodules in any organs detectable on imaging techniques should no longer be present. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size.
if the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site. The sample on which this determination is made must be adequate (>= 20 mm biopsy core). Flow cytometric, molecular, or cytogenetic studies are not considered part of routine assessment to document persistent disease at the present time. These studies should only be incorporated into trials examining important research questions.

CR/unconfirmed (CRu) includes those patients who fulfill criteria 1 and 3 above, but with one or more of the following features:

a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by > 75% in the SPD. Individual nodes that were previously confluent must have regressed by > 75% in their SPD compared with the size of the original mass.
indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia).

PR requires the following :

>= 50% decrease in SPD of the six largest dominant nodes or nodal masses. These nodes or masses should be selected according to the following features: (a) they should be clearly measurable in at least 2 perpendicular dimensions, (b) they should be from as disparate regions of the body as possible, and (c) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
no increase in the size of the other nodes, liver, or spleen.
splenic and hepatic nodules must regress by at least 50% in the SPD.
with the exception of splenic and hepatic nodules, involvement of other organs is considered assessable and not measurable disease.
bone marrow assessment is irrelevant for determination of a PR because it is assessable and not measurable disease; however, if positive, the cell type should be specified in the report, eg, large-cell lymphoma or low-grade lymphoma (ie, small, lymphocytic small cleaved, or mixed small and large cells).
no new sites of disease.

stable disease is defined as less than a PR (see above) but is not progressive disease (see below).
relapsed disease (CR, CRu) requires the following:

appearance of any new lesion or increase by 50% in the size of previously involved sites.
50% increase in greatest diameter of any previously identified node > 1 cm in its short axis or in the SPD of more than one node.

progressive disease (PR, nonresponders) requires the following:

>= 50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders.
appearance of any new lesion during or at the end of therapy.

CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, and pelvic CT scans are recommended even if those areas were not initially involved because of the unpredictable pattern of recurrence in NHL. Studies should be performed < 2 months after treatment has been completed to assess response. This interval may vary with the type of treatment, eg, a longer period may be more appropriate for biologic agents where the anticipated time to response may be greater.
a bone marrow aspirate and biopsy should only be performed to confirm a CR if they were initially positive or if it is clinically indicated by new abnormalities in the peripheral blood counts or blood smear.

End points

^ref

end point	response category	definition	point of measurement
overall survival (OS)	all patients	death from any cause	entry onto trial
event-free survival (EFS)	all patients (under circumstances where presentation of EFS is more appropriate for responders only, this point should be clearly stated)	failure or death from any cause	entry onto trial
progression-free survival (PFS)	all patients	disease progression or death from NHL	entry onto trial
disease-free survival (DFS)	CR, CRu	time to relapse (TTR)	first documentation of response
response duration	CR, CRu, PR	time to relapse or progression	first documentation of response
time to next treatment	all patients	time when new treatment is needed	entry onto trial
cause-specific death	all patients	death related to NHL	death

Follow-up

^ref

Patients on clinical trials should be reassessed after completion of treatment at a minimum of every 3 months for 2 years, then every 6 months for 3 years, and then annually for at least 5 years

additional studies for evaluation : a number of additional diagnostic studies have been proposed to evaluate response or disease progression but are not currently required.

gallium scanning : the precise role for gallium (Ga) scans in monitoring disease status in patients with NHL is under evaluation. This procedure seems to have limited utility in patients with low-grade NHL, and, therefore, most of the data are in patients with a large-cell histology^ref. Early studies suggested that this test was not cost-effective or better than other imaging studies^{ref1,
ref2}. However, more recent data with improved technology demonstrate the usefulness of this procedure compared with CT scans, radiographs, and physical examination^{ref1,
ref2,
ref3}. Kaplan et al^ref prospectively evaluated 37 patients with ⁶⁷Ga imaging and identified a correlation between residual disease identified with imaging and eventual likelihood of recurrence. 3 of 4 patients in clinical CR but with a positive scan relapsed and died from their disease. The most impressive results have been reported from groups that have used single-photon emission computed tomography (SPECT) with gallium scanning^{ref1,
ref2} to successfully differentiate lymphoma and benign uptake. In one series in which 107 scans were performed on 101 patients^ref, the concentration of gallium in 29 sites of documented NHL was significantly greater than in 75 benign lesions; this study demonstrated a sensitivity of 90%, a specificity of 93%, and positive and negative predictive values of 84% and 96%, respectively. Vose et al^reffound that the 1-year FFS for patients with a positive SPECT gallium scan after high-dose chemotherapy with autologous transplantation for diffuse aggressive NHL was 15% compared with a 3-year failure-free survival of 47% for patients with a negative scan. Although the predictability of gallium studies was rather modest, they were more accurate than CT scanning. However, the procedure was not predictive of outcome for patients with a follicular NHL. Janicek et al^ref found that early restaging with ⁶⁷Ga scans was useful in predicting those patients who were most likely to experience prolonged disease-free survival after treatment with an augmented CHOP regimen. Further prospective study of SPECT gallium scanning is highly desirable. Unfortunately, until this procedure becomes more universally available and uniformly reproducible, it cannot be required as part of routine response assessment for all clinical trials. SPECT gallium scans should be considered part of standard practice at centers with expertise in performing the study in clinically relevant situations (eg, to distinguish masses with viable tumor from fibrosis). Functional studies such as SPECT gallium scans would not be considered as part of the anatomic assessment of response using the guidelines previously discussed, but they should be reported in the results of the clinical trial. Several recent studies have suggested a potential role for PET scanning in monitoring response to therapy^ref. However, other studies suggest that the cost-benefit ratio of gallium + CT is more favorable than MRI^ref. An interesting research question would involve a prospective comparison of SPECT gallium scanning with PET scans in the assessment of residual masses.
additional measures of bone marrow assessment : MRI or immunoscintography has been suggested as a means to improve the accuracy of detection of bone marrow involvement^{ref1,
ref2,
ref3}. Concordance of the 2 imaging studies is almost 90%^ref. In a recent study^ref, results with whole-body PET were found to be concordant with unilateral bone marrow biopsies in 78% of cases; PET was positive in 8 cases in which the bone marrow was negative, and the converse was true in 3 cases. These authors suggested that PET scanning may reduce the need for staging biopsies. Unfortunately, this procedure does not provide important information on the status of normal bone marrow precursors or the histology of the marrow involvement. The latter is important in patients with nodal large-cell NHL who may have a discordant histology in the bone marrow. Immunoperoxidase studies of the bone marrow may also be useful to clarify the residual "nodules" as benign or malignant.

In conclusion, the most important end points of clinical trials in NHL should be overall survival and failure-free survival (time to treatment failure and event-free survival). In phase II trials, particularly in the setting of relapsed and refractory disease where the activity of a new agent may be the most important objective, response rates are important and may provide support for approval by regulatory agencies. On the other hand, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. Response rates will continue to be ambiguous and subject to considerable controversy as long as we are required to base guidelines on consensus opinion of clinical data rather than on more precise and reliable measures of minimal residual disease. Moreover, particularly in the follicular NHL, incremental increases in response rates have not uniformly translated into prolonged time to treatment failure or survival. A residual mass in a patient with a large-cell lymphoma, in whom the disease may have been cured, has different implications from a patient with a follicular lymphoma, in whom the mass may remain stable for months but will inevitably progress. To improve response assessment, we strongly encourage the use of SPECT gallium scanning in patients with large cell-lymphoma
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