The chronic malignant lymphoproliferative disorders originate in the
bone marrow and slowly progress to involve the peripheral blood, lymph
nodes, spleen, and liver. The proliferating lymphocyte appears morphologically
mature, and may be of B, T, or natural killer (NK) origin.
Leukemia: Chronic Lymphocytic Leukemia
Epidemiology: Chronic lymphocytic leukemia (CLL) is
the most common (2.7/100,000 incidence) of the chronic lymphoproliferative
disorders, representing about 30% of all leukemia.
CLL is a disease of adults. Most patients are > 60 years of age
and asymptomatic (essentially normal physical examination) at diagnosis.
Definition: CLL is a proliferation of mature appearing, but
functionally incompetent lymphocytes, in the marrow, peripheral blood,
and various organs. The most characteristic feature of CLL is a peripheral
blood absolute lymphocytosis (>5.0 x109/L, but usually >15.0
x109/L and sometimes > 100.0 x109/L).
Clinical Features: Lymphadenopathy and splenomegaly are common
especially late in the disease because small lymphocytes accumulate in
the marrow, spleen, lymph nodes and liver. Hypogammaglobulinemia is also
common late in the disease course with an associated increased susceptibility
to infection. Ten percent of patients have an IgM monoclonal gammopathy.
Anemia and thrombocytosis may indicate marrow replacement or autoimmune
The clinical course is highly variable with survival ranging
from 1-20 years. The Rai staging system (1975;1987) is used to assess
the leukemic "burden" in CLL and to accurately predict the clinical course.
Morphology: CLL lymphocytes are generally smaller than normal
and appear to be more fragile resulting in characteristic "smudge" cells.
The smudge cell nuclei are smashed against the glass slide.
Immunophenotype: In CLL the malignant lymphocytes are almost always
B cells (98%). Only 2% are of T cells. The CLL-B lymphocytes weakly
express surface immunoglobulin IgM or IgM & IgD. The light chain
is monoclonal. These cells also express the B-cell antigens CD19, CD20,
and CD21 and the T-associated antigen CD5.
The coexpression of CD19 and CD5, (seen on <1% of normal B
cells), is also seen in mantle cell lymphoma, and some prolymphocytic
Chromosomal Abnormalities: The chromosome abnormality trisomy
12 is associated with CLL and the 14q+ chromosome abnormality with prolymphocytic
leukemia (see below). When trisomy 12 is accompanied by other abnormalities
of chromosomes 11 or 14 the prognosis is worsened.
Marrow: The bone marrow is often diffusely replaced by small
lymphocytes. Other patterns include interstitial or nodular infiltration
usually seen earlier in the disease. The diffuse infiltration suggests
a worse prognosis and correlates with a Rai stage III or IV.
Disease Complications: In some instances CLL undergoes change
into a more aggressive disease.
Prolymphocytic transformation occurs when increasing numbers of prolymphocytes
are produced in the course of CLL. At this point the CLL is often refractory
to therapy and the prognosis worsens.
Richter's syndrome" refers to the development of a large cell
lymphoma, usually immunoblastic. This phenomenon happens in about 5%
of the CLL patients and is an ominous occurence.
Leukemia: Chronic Prolymphocytic Leukemia
Morphology: Prolymphocytic leukemia can be thought of
as a morphologic variant of chronic lymphocytic leukemia. The predominate
cell is a prolymphocyte, larger than the lymphocytes of CLL (10-15m),
This cell resembles activated lymphocytes with fine almost blastic chromatin,
a single large nucleolus, and pale blue cytoplasm.
Immunophenotype: The immunophenotype of most prolymphocytic leukemia
cells is similar to CLL (CD19+; CD5+), but surface Ig is strongly expressed.
Clinical Features: The peripheral WBC count is high (usually >100.0
x10 /L). Splenomegaly is common, but lymphadenopathy unusual. Patients
with prolymphocytic leukemia tend to be older (70 years) than patients
with CLL (64 years) and have an aggressive clinical course. The median
survival of prolymphocytic leukemia is 3 years versus the 8 years of CLL.
About 20% of prolymphocytic leukemias are of T cell origin. Again
the prognosis is poor, as the median survival is only 6 months. T cell
prolymphocytic leukemia frequently involves the skin causing a papular
nonpruritic nonscaling rash.
Leukemia: Hairy Cell Leukemia
Definition: Hairy cell leukemia (HCL) is a low grade B cell
leukemia of moderately large mononuclear cells having distinctive "hairy"
cytoplasmic projections (upper right).
Morphology: The abundant cytoplasm creates a "fried egg" appearance
to each cell in tissue sections producing a characteristic "honeycomb"
appearance on biopsy of bone marrow (lower right).
Marrow: Bone marrow aspirates are usually "dry" because of a network
of increased recticulin.
Diagnosis: Cytologic features on a PBS or marrow aspirate,
positive tartrate resistant acid phosphatase stain ( TRAP positive) and
a characteristic phenotypic pattern (CD19+; CD5-; CD11c+; CD25+) are diagnostic
in most cases.
Clinical Features: Splenic involvement is common. Typically it
is the splenic red pulp that is involved. There is a 4:1 male to female
predominance (compared to a 2:1 ratio in CLL).
Most patients present with symptoms pancytopenia (fatigue, infection,
easy bruising) or splenomegaly, but with little lymphadenopathy.
Two hairy cells positive for acid phosphatase despite attempted
tartrate inhibition (TRAP positive).
Natural History of the Disease: Hairy cell leukemia has a variable
clinical course with a median survival of 5 years before current interferon
or adenosine deaminase (ADA) inhibitor therapy. The most common cause
of death is from infection.
Treatment: In the past splenectomy (curing pancytopenia caused
by the hypersplenism) was the only effective form of therapy for HCL.
Today treatment with alpha-2-interferon, deoxycoformycin (Pentostatin)
and 2-chlorodeoxyadenosine may result in most patients approaching a normal
age-matched life expectancy.
Leukemia: T-cell Chronic Lymphoid Proliferations
T-cell chronic lymphoproliferative diseases are heterogeneous in terms
of their phenotype and clinical behavior. Most are post-thymic T cells
expressing either CD4 or CD8. Some cells express natural killer (NK) antigens.
Aberrant pan T antigen expression is frequently seen.
T cell Chronic Lymphoid Proliferations
T cell chronic lymphocytic leukemia
T prolymphocytic leukemia
T g lymphocytosis syndrome
These disorders are relatively rare and some may not even be malignant.
Sezary syndrome and ATLL are post-thymic T cell malignancies that must
be distinguished from the T-cell chronic lymphoproliferative disorders.
Sezary syndrome is a proliferation of malignant cerebriform T
cells that circulate in the peripheral blood but present primarily in
ATLL is an aggressive proliferation of highly atypical T lymphocytes
associated with HTLV-1, involving the peripheral blood, skin, liver, spleen,
Leukemia: T gamma lymphocytosis
True T-cell chronic lymphocytic leukemia is exceptionally
rare and must be distinguished from the various subtypes of the T g lymphocytosis
syndrome and from T prolymphocytic leukemia. The T lymphocytes of T-cell
CLL morphologically resemble the cells of B-cell CLL. Nearly all have
a CD4 T-helper phenotype. Too few definitive cases have been studied to
define the clinical course.
T prolymphocytic leukemia (20% of prolymphocytic leukemias) is
an aggressive malignant proliferation of T cells with a median survival
of only 6 months. Skin involvement (a papular nonpruritic nonscaling rash)
and lymphadenopathy are common. Peripheral blood lymphocyte counts are
exceptionally high (frequently >100.0x109/L).
T g lymphocytosis syndrome is the most
important of the T-cell chronic lymphoproliferative disorders. T g lymphocytosis
is a proliferation of large granular lymphocytes (LGL) in the peripheral
blood and bone marrow often accompanied by neutropenia, less often by
Clinical Features: At presentation people with T g lymphocytosis
are usually 55-65 years of age. Recurrent infections are the most common
presentation. Rheumatoid arthritis is found in one-third of patients.
The spleen is enlarged in 50 to 70 percent. Lymphadenopathy is uncommon.
Natural History of the Disease/Treatment: Although the course
is usually indolent it may be quite variable. About one-quarter slowly
progress to death due to infection secondary to neutropenia. Chemotherapy
is not very effective. Control of the neutropenia by growth factors may
play a significant role in treatment of T g lymphocytosis.
LGL can be subdivided as shown below. Although Second Year
Medical students don't need to know the CD antigen patterns shown below
they should appreciate how a pattern of antigen reactivity is used
to describe and identify the phenotype of cells.
Immunophenotype: Clonal rearrangements of various
T cell receptor genes has been found in some, but not all cases of the
T g lymphocytosis syndrome. While the majority are monoclonal and would
appear to represent a low grade malignancy, others could be reactive proliferations.
It is also possible that we are simply unable to detect the T cell rearrangements.
A 64-year-old man is referred to you from the pulmonary clinic where
he has been seen for a series of upper respiratory infections in the last
There is no lymphadenopathy, but you note splenomegaly, 4 cm below the
LCM. The WBC was 25.0 x109/L with a differential of 75 lymphocytes,
13 monos, 7 segs, 3 eos, 2 basos. These lymphocytes are slightly larger
than the usual small lymphocyte.
The lymphocytes are CD19-, CD5-, CD3+, CD8+ and CD56+.
With the results of this information you suggest the following as the
most likely diagnosis:
A. Chronic lymphocytic leukemia
B. Prolymphocytic leukemia
C. T gamma lymphocytosis
E. Infectious mononucleosis
A 53-year-old man is resting comfortably in the CCU after a mild MI.
You are surprised tosee the lab results showing a WBC of 14.0 x109/L
with a differential of 70 lymphocytes, 3 monos, 25 segs, 2 eos. The lymphocytes
are slightly smaller than the usual small lymphocyte.
There is no lymphadenopathy nor splenomegaly. He has no history of unusual
infections. He had a small squamous cell carcinoma removed from the base
of his tongue about 2 years ago without evidence of metastses.
The lymphocytes are CD19+, CD5+, CD3-, SIg kappa+, lambda-.
With the results of this information you suggest the following as the
most likely diagnosis:
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