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LYMPHOID
NEOPLASMS
Definitions and Classification
One confusing aspect concearns the use of the term LEUKEMIA and
LYMPHOMA.
LEUKEMIAS present with widespread involvement of the bone marrow
and peripheral blood.
LYMPHOMA is used for proliferations arising as discrete tissue masses.
Originally, terms LEUKEMIA and LYMPHOMA were consistent distinct
entities, but this division has blurred.
Many lymphomas may have leukemic presentations and evolution to
leukemias is not unusual.
Conversely, leukemias sometimes arise as soft-tissue masses.
Both terms merely reflect the usual tissue distribution of each disease at
presentation.
LYMPHOMAS are known in two categories: Hodgkin´s Lymphoma, treatable
in a unique fashion, and the family of NHL.
The clinical presentation of the various lymphoid neoplasms is most often
determined by the anatomic distribution of the disease.
2/3 of NHLs and virtually all HL present as enlarged non-tender lymph nodes
(› 2 cm).
The remaining 1/3 of NHLs present with symptoms related to involvement of
extranodal sites: stomach, intestine, skin, brain.
In NHL an important group of tumors is represented by the plasma cell
neoplasms.
Leukemias present with symptoms related to the supression of
hematopoesis. Multiple myeloma causes bony destruction or pain due to
pathologic fracture. Certain tumors may cause fever (HL) and secretion of
circulating factors (e.g.amyloid) from plasma cells.
HISTORY
The oldest classification scheme has used only few terms: lymphosarcoma,
reticulosarcoma, lymphogranulatomasis Paltauf-Sternberg, M. Hodgkin.
Rappaport: nodular – difuse involvement of the lymph nodes.
During the years 1960 – 1980 there temporarily existed several national
classifications (German, French, English, American (Florida and California)
and international (REAL) , introducing new basic and research-based and
clinically accepted information. Soon afterwards, at the end of the 20th
century, WHO experts from several medical specialities have developed
a unified, modern and open international classification system (2001)
based on morphological, immunophenotypic, genotypic and clinical
features (interdisciplinary acepted).
Lymphoid tumors are sorted into 5 broad categories
1. Precursor B-cell neoplasms (immature B cells)
2. Peripheral B-cell neoplasms (mature B cells)
3. Precursor T- cell neoplasms (immature T cell)
4. Peripheral T cell ad NK-cell neoplasms (mature T cell and NK cell)
5. Hodgkin Lymphoma
The WHO Classification of Lymphoid Neoplasms (2001)
I Precursor B Cell Neoplasms
B cell acute lymphoblastic leukemia/lymphoma (B - ALL)
II Peripheral B Cell Neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B cell prolymphocytic leukemia
Lymphoplasmocytic lymphoma
Splenic and nodal marginal zone lymphoma
Extranodal marginal zone lymphoma
Follicular lymphoma
Marginal zone lymphoma
Hairy cell leukemia
Plasmacytoma/plasma cell myeloma
Diffuse large B cell lymphoma
Burkitt lymphoma
The WHO Classification of Lymphoid Neoplasms (2001)
III Precursor T cell neoplasms
T cell acute lymphoblastic leukemia/lymphoma (T – ALL)
IV Peripheral T cell and NK cell neoplasms
T cell prolymphocytic leukemia
Large granular lymphocytic leukemia
Mycosis fungoides/Sézary syndrome
Peripheral T cell lymphoma unspecified
Anaplastic large cell lymphoma
Angioimmunoblastic T cell lymphoma
Enteropathy-associated T cell lymphoma
Panniculitic T cell lymphoma
Hepatosplenic gamma-delta T cell lymphoma
Adult T cell leukemia/lymphoma
Extranodal NK/T cell lymphoma
NK cell lymphoma
The WHO Classification of Lymphoid Neoplasms (2001)
V Hodgkin lymphoma
Classical subtypes
• Nodular sclerosis type
• Mixed cellularity type
• Lymphocyte-rich type
• Lymphocyte depletion type
• Lymphocyte predominance type
Important principles of lymphoid neoplasms
1. Lymphoid neoplasms may be clinically suspected, but histologic
examination is required for diagnosis.
2. In most lymphoid neoplasms, antigen receptor gene rearrangement
presents transformation, hence, all of the daughter cells derived from
the malignant progenitor share the same configuration and sequence,
and synthesise identical antigen receptor protein (Ig, T cell receptor).
In contrast to reactive (polyclonal) proliferations the lymphoid
neoplasms are monoclonal lymphoid proliferations.
3. These antigen gene rearrangement produce a unique DNA sequences
that constitute a highly specific clonal marker, detectable by MoAb.
4. The vast majority (85-90%) of lymphoid neoplasms are of B-cell origin.
Important principles of lymphoid neoplasms
NK tumors are rare. B cell and T cell represent some recognizable stage of B or
T cell differentiation, a feature used in their nomenclature/terminology.
Benign counterparts of lymphomas do not exist.
Neoplastic B and T cells recapitulate the behaviour of their normal
counterparts. Examples: follicular lymphomas home to germinal centers,
cutaneous lymphomas home to the skin. This is governed by particular
adhesion molecules and chemokine receptors.
Variable numer of B or T cells recirculate through the lymphatics and blood
vessels, so that at time of diagnosis most tumors are widely disseminated.
Exceptions: Hodgkin lymphoma and Marginal zone B cell lymphoma. This
feature reminds of the physiological daily repeating multiple recirculation of
lymphocytes between the central and peripheral lymphatic organs.
Hodgkin lymphoma spreads in an orderly fashion. In contrast, most forms of
NHL spread widely early in their course in a less predictable fashion.
Therefore, staging is of most utility in HL.
PRECURSOR B cell and T cell neoplasms
are composed of immature B and T cells (lymphoblasts). About 85%
are B-ALL and it is the most common cancer of children up to 15
years. Adults are affected less frequently. Individual cases may be
more or less immature or mature, so that various CD markers: B: CD
10, 19, 20 and T: CD 1,2,3, 4, 5, 7 and 8 may be expressed in tumor
cells.
Approximately 90% of ALLs have various numerical or structural
chromosomal changes.
Pediatric ALL is one of the great success stories of oncology with
complete remission in 95% of children and 30-40% of adults.
Clinical features: abrupt
onset, depression of bone marrow
functions, mass effect, CNS manifestations.
Peripheral B-cell Neoplasms
Chronic lymphocytic Leukemia (CLL)/Small lymphocytic Lymphoma (SLL)
Represents the most common adult leukemia with median age at
diagnosis being 60 years, 2:1 male preponderance in Western countries
comparing with Asian countries and Japan.
Microscopically: diffuse infiltration with small lymphocytes with
proliferation centers in the lymph nodes, bone marrow, spleen and
liver.
Expression of CD 19, 20, 23 and 5, surface IgM.
Clinically, fatigability, anorexia, weight loss, lymphadenopathy,
hepatosplenomegaly, hypogammaglobulinemia, relatively slow course ,
tendency to transformation to more aggressive forms (Richter
syndrome). Possible use of immunotherapy, chemotherapy and
transplantation.
Follicular Lymphoma
• An indolent ,most common NHL in middle age
frequency in the Word.
with uneven
• Typical cell is a small lymphocyte with irregular/cleaved nuclei
(centrocyte) in predominant follicular arrangement.
• Immunophenotype:CD 10, 19, 20, surface Ig, BCL 6.
• Clinically: generalized, painless lymphoadenopathy, and relatively
uncommon involvement of extranodal sites. Median survival: 7-9
years, with possible transformation to diffuse large B cell lymphoma
(duration less than 1 year).
Diffuse large B-cell Lymphoma
• The most common NHL with median age of 60 years, may affect even
children.
• Microscopically these tumors grow diffusely and contain relatively
large cells.
• Immunophenotype: CD 19, 20, sometimes also CD10 and BCL-6.
• Cytogenetic gene expression is heterogenous.
• Special forms: Immunodeficiency-associated large B cell Lymphoma
and Primary effusion lymphoma in AIDS and elderly.
• If untreated, is an aggressive tumor affecting many sites and rapidly
fatal.
• Immunotherapy improves responses and outcome/prognosis.
Burkitt Lymphoma (BL)
1. African (endemic) BL
2. Sporadic (non-endemic) BL
3. Aggressive lymphoma in AIDS
• Microscopically: a starry-sky appearance, high mitotic index
• Immunophenotype: CD 10, 19, 20, BCL-6, sIgM
• Molecular pathogenesis: Translocations of the C MYC gene on
chromosome 8
• Endemic and sporadic BLs are formed mainly in children and
young adults mostly in extranodal sites (mandible, kidneys,
ovaries, adrenals) Tumors are aggresive but treatable
Plasma Cell Neoplasms and Related Disorders (dyscrasias)
Contain plasma cells secreting monoclonal Ig or a Ig fragment. The worst
type is Multiple myeloma (plasma cell myeloma). Special terms are used
for these neoplasms: monoclonal gammopathy, dysproteinemia,
paraproteinemia, primary amyloidosis or immunocyte-associated
amyloidosis.
Plasmocytoma (solitary myeloma) is an infrequent variant that represents
as a single (isolated) mass in bone or in soft tissue. Smoldering myeloma
with lack of symptoms and high plasma M. component.
Waldenström macroglobulinemia is a syndrome: monoclonal
gammopathy, blood hyperviscosity and incurable lympho-plasmocytic
lymphoma .
Heavy chain disease and Monoclonal gammopathy of undetermined
significance (MGUS), common in elderly, with a constant rate of
transformation to myeloma.
Mantle Cell Lymphoma
Is a rare, prognostically poor form of lymphoma with painless
generalized lymphadenopathy in elderly with male predominance.
Small cells resemble the normal mantle zone B cells surrounding
germinal centers.
Immunophenotype: CD 5, 19, 20, cyclin D1.
Marginal Zone Lymphoma
Encompasses a heterogenous group of B cell tumors arising within
lymph nodes, spleen or extranodally (e.g. mucous membranes,
„maltoma“). They often arise within tissues involved by chronic
inflammatory disorders of autoimmune (Sjögren, Hashimoto) or
infectious etiology (H. pylori) with possible regression following
successful treatment of H. pylori.
Hairy Cell leukemia
Is a rare, distinctive B cell NHL (2%) with massive splenomegaly and
frequent infections. Males are affected more frequently (5:1), median
age is 55 years. Overall prognosis is excellent.
Immunophenotype: CD 11c, CD 19, 20, 25 and 103.
Peripheral T cell and NK cell Lymphomas
Because of problems with categorization, many forms are classified as
Peripheral T cell Lymphomas, unspecified. These tumors efface lymph
nodes diffusely and are composed of pleomorphic mixture of variously
sized malignant T cells and intensve angiogenesis.
Immunophenotype: CD 2, 3, 4, 5, 8, and alpha/beta or gamma/delta
T cell receptors.
These tumors present with generalized lymphadenopathy, weight loss,
fever, and eosinophilia.
Anaplastic Large cell Lymphoma (ALK positive)
Is composed of anaplastic large cells with horseshoe-shaped nuclei,
so-called „HALLMARK CELLS“, mimicking metastatic carcinoma.
Immunophenotype: ALK cytoplasmic fusion protein expression,
a reliable indicator of an ALK gene rearrangement.
These tumors occur in children and young adults, involve soft
tissues and carry a very good prognosis.
Adult T cell Leukemia/Lymphoma
This adult tumor is a rapidly progressive disease despite aggressive
therapy. It develops after infection with HTLV-1 (retrovirus) in
specific geographic areas. In some instances, this infection may give
rise to a progressive demyelinizating disease of the CNS and spinal
cord.
Mycosis Fungoides/Sézary Syndrome
Are different manifestations of a CD4+ helper T cell disease affecting skin (MF) with
three stages: premycotic inflammatory stage, plaque phase, and a tumor stage
with simultaneous involvement of lymph nodes and bone marrow. In Sézary
syndrome the skin manifestations represent generalized exfoliative erythroderma
and leukemia with cerebriform nuclei in peripheral blood.
These are indolent tumors (up to 9 years) with immunophenotype: adhesion
molecule CLA, chemokine receptor CC4, CCR 10, and CD4 T cell.
Large granule Lymphocytic Leukemia
Rare in two variants (T cell, CD3, indolent) and (NK, CD56, more aggressive) of an
adult disease. Despite the relative paucity of marrow infiltration, neutropenia and
anemia dominate the clinical picture.
Extranodal NK/T cell Lymphoma
Is rare in Europe and USA and more frequent in Asia. Presents as a destructive
nasopharyngeal mass in association with EBV infection, also affecting testis and
skin. Surrounding and infiltrating small vessels, it leads to extensive ischemic
necroses. This tumor is highly aggressive and with poor prognosis.
HODGKIN LYMPHOMA
Is a group of lymphoid neoplasms differing from NHL in several respects.
The main differences are tabularized:
HL
NHL
More often localized to a single node or
group of nodes
Involvement of multiple peripheral nodes
Orderly spread by contiguity
Non-contiguous spread
Mesenteric nodes and Waldayer ring rarely
involved
These sites ( ←left) are commonly involved
Extra-nodal presentation rare
Common
Identification of Reed-Sternberg cells (and their variants and
„mumification“) in a prominent background of a group of inflammatory
cells is principal for the diagnosis.
HODGKIN LYMPHOMA
Immunophenotype for 1-4: CD 15, 30, PAX5, excellent or less
favorable prognosis, for 5: CD 20, BCL6.
RS cells produce signals (cytokines IL-5, 10,13, TGF-beta) and
chemokines (ARC, MDC, IP-10, CCL-28), that attract reactive cells.
Once attracted, the reactive cells produce factors that support the
growth and survival of RS cells, further modifying the reactive cell
response.
Clinical features of HL
Painless lymphadenopathy, fever, night sweats, weight loss,
immune dysregulation, dyspnoe, etc. The spread is remarkably
stereotyped: nodes, spleen, liver, other tissues. The staging not
only determines the prognosis, but also guides therapy. Radiation
therapy may be curative in many patients.
HODGKIN LYMPHOMA
Staging of HL
I Involvement of a single node or a single extranodal organ site
II Involvement of 2 or more lymph node regions on the same side of diaphragm
III Involvement of lymph node regions on both sides of diaphragm without
localized involvement of an extralymphatic organ/site
IV Diffuse involvement of 1 or more extranodal organs/sites without/with
lymphatic involvement
Additional features included into staging procedure: fever, kachexia, night sweats
With current protocols, tumor stage (better than biopsy) is the most important
prognostic variable.
Survival of stage I-II – 90%, III-IV – 60-70%.
Increased risk of survivors by second cancers, especially because of applied
irradiation together with fibrosis and atherosclerosis, which can be avoided by
modern therapy.