HEMATOLOGY- Neoplastic White Blood Cell Disorders

Amy S. Gewirtz, M.D.

2008
Learning Objectives:
1. Compare and contrast the clinical and pathologic features of Hodgkin's and non-Hodgkin's
lymphomas.
2. Define the features of a Reed-Sternberg cell.
3. Compare and contrast the clinical and pathologic features of acute and chronic leukemias.
4. Discuss how a diagnosis of leukemia is established.
5. Differentiate features of acute myelogenous and acute lymphocytic leukemias.
Reference: Kumar, Cotran, Robbins: Basic Pathology, 7th edition, Chapter 12, pages 358-383, 8th
edition, pages 441-68.
Introduction
This discussion will focus on malignant disorders of white blood cells. Lymphomas are malignant
proliferations of cells native to lymphoid tissue lymphocytes and their precursors and derivatives. These
tumors arise in lymphoid tissue, and can spread to involve solid tissue, marrow, and blood. Lymphomas are
categorized into two main types Hodgkin's disease and non-Hodgkin's lymphomas (everything else).
Leukemias are malignant proliferations of cells native to the bone marrow, which often spillover into the
blood. Leukemias can spread to involve solid organs (usually liver and spleen). Try to compare and contrast
types of leukemia and lymphoma with respect to clinical symptoms, complications, and pattern of disease
involvement.
The distinction between lymphoma and the lymphocytic leukemias can be difficult in some instances,
since in advanced states both can involve lymphoid tissue at any site.
MALIGNANT LYMPHOMA
Hodgkin's Disease
This is a characteristic type of lymphoma defined morphologically by the presence of Reed-Sternberg cells
admixed with a variable inflammatory infiltrate. Unlike non-Hodgkin's lymphomas, Hodgkin's disease is often
accompanied by fever, arises in a single lymph node or chain of nodes, is more common in young adults
(average age 30 years), and is characterized by contiguous spread within lymph node groups (for this reason,
staging is particularly important in assessing prognosis). The cause of Hodgkin's disease is unknown.
Cell of Origin: The neoplastic cell is considered to be the Reed-Sternberg (RS) cell, a distinctive large cell
with mirror image nuclei and prominent nucleoli. Usually only small numbers of RS cells are present in the
involved node. A diagnosis of Hodgkin's disease requires the presence of RS cells in the appropriate
histologic background: RS-like cells alone are not specific, and may be seen in non-neoplastic disorders like
infectious mononucleosis. RS cells may arise from specialized antigen-presenting cells in lymph nodes; the
precise origin of the RS cell remains uncertain. In some cases the Epstein-Barr virus genome can be identified
in the RS cells.
Classification (Grading): Several variants of Hodgkin's disease are recognized each with their own common
clinical presentations, histologic features, and prognosis.
Staging: This term refers to the assessment of the amount of tumor burden and its distribution in the body.
Low stage disease denotes localized lymph node involvement, without systemic signs (fever, weight loss), and
has a better prognosis. High stage disease indicates widespread disease with bone marrow involvement, and
has a worse prognosis. Choice of therapy (chemotherapy, radiotherapy, or both) and prognosis are based on
stage. More aggressive forms of disease typically present in higher stages. Higher stages receive combination

chemotherapy/radiotherapy, while lower stages may and usually do receive only radiotherapy. All stages are
further divided on the basis of absence (A) or presence (B) of systemic symptoms, including fever, night
sweats, and weight loss (terminology example: stage IIIA).
Clinical Features and Course: Most patients have enlarged, painless, superficial lymph node involvement as
the initial manifestation of disease. Involvement of other lymph nodes in the chest and abdomen can occur, but
is less common at presentation, except in lymphocyte-depleted type. Involvement of the spleen and liver
increase the stage, and are assessed at surgery. Complications with infections (decreased cell-mediated
immunity), anemia, and thrombocytopenia can occur in advanced disease. Combination chemotherapy and
radiotherapy have dramatically improved the survival in HD. There is a low, but definite risk for developing
acute leukemia after treatment with chemotherapy and radiotherapy because of the bone marrow toxicities of
the chemotherapeutic drugs used.
NON-HODGKIN'S LYMPHOMA
Non-Hodgkin's lymphomas arise in lymphoid tissue either in lymph nodes or lymphoid tissue of solid
organs- and have the capacity to spread into other nodes, solid organs, bone marrow, and blood. There is more
morphologic diversity in NHL than in HD, and more than a dozen subtypes of NHL are recognized for
purposes of determining prognosis and selecting therapy. In contrast to HD, NHL have multiple node
involvement, more frequent extranodal spread and peripheral blood involvement, and affect all ages. Like in
HD, histologic examination of involved tissue is required for diagnosis.
Cell of Origin: The majority (85%) of NHL are clonal neoplasms of B lymphocytes. B lymphocytes are
those lymphocytes specialized for antibody production. The remainder of NHL are of T cell origin (15%). Blymphocytes normally have the capacity to transform to plasma cells (most mature B cell) as part of the
immune response, just as T-lymphocytes become activated as part of the normal immune response. A
lymphoma develops when there is a monoclonal expansion of lymphocytes that have been "arrested" (or have
acquired a genetic rearrangement which alters growth regulation) at a particular stage in transformation. The
clonal cells proliferate without normal regulatory mechanisms. Thus, all lymphoid neoplasms are considered to
arise from a single transformed cell. Daughter cells synthesize antigen receptor proteins identical to the
original cell that reflect a "frozen" state of B cell maturation. As tumors of the immune system, it is not
surprising that immune abnormalities occur frequently (hypogammaglobulinemia, increased risk of infection).
Classification: The classification of NHL is moderately complicated; a few concepts will put the system
into perspective. The principal reason for the classification system is to facilitate communication and to obtain
information on response to treatment and prognosis in similar histologic types. There are two easily
recognizable patterns of growth: nodular (follicular) and diffuse; two cell sizes: small and large; and two
nuclear features: cleaved and non-cleaved that form the basis of classification. In general, nodular lymphomas
occur in older individuals, are commonly disseminated at diagnosis, and have a better prognosis than diffuse
types. Small cell types usually have a better prognosis than large cell types, although the latter may initially
respond well to chemotherapy. Revisions to the classification occur often, most recently in 1994 with the
REAL classification.
Staging: Similar to Hodgkin's disease. There is less correlation between stage and prognosis in NHL than
in HD. Cell type and tumor proliferative index are better correlated with prognosis.
Stage

Distribution of Disease

I
II

Involves single lymph node region or extralymphatic organ or site

Involves two or more lymph node regions on same side of diaphragm
alone or with involvement of contiguous extralymphatic organ or tissue
Involves lymph node regions on both sides of diaphragm which may
include spleen.
Multiple or disseminated foci of involvement of one or more extralymphatic
organs or tissues with or without lymphatic involvement

III
IV

Clinical Features and Course: Presentation is usually with painless enlarged lymph nodes, or evidence of
extranodal spread- enlarged liver or spleen. Bone marrow involvement is more common than in HD, and
lymphoma cells may circulate in peripheral blood. Circulating lymphoma cells in the peripheral blood
represent a 'leukemic phase' of the disease, in distinction to the group of diseases classified as leukemias. The
disease can spread to involve solid organs, GI tract, bones, and nervous system. Enlargement of lymph node
groups can produce vascular and lymphatic obstruction. Complications with infections, anemia, and
thrombocytopenia occur. Treatment involves chemotherapy, and less often, radiotherapy. Bone marrow
transplant may be used for highly resistant disease, allowing higher doses of chemotherapy to be delivered with
the hope of a cure.
ACUTE AND CHRONIC LEUKEMIAS
Leukemias are malignant neoplasms of hematopoietic tissue that arise in the bone marrow. The malignant
cells proliferate in the bone marrow, commonly producing a pattern of diffuse infiltration. There is often "spill
over" of the proliferating cells into the blood and other organs.
Classification: This group of diseases can be roughly conceptualized both in terms of onset and of cell type
involved. Disease onset can be acute (rapid) or chronic (indolent), and cell types include myelogenous
(myeloid and monocytic) and lymphoid. A basic classification would thus include acute lymphocytic leukemia
(ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous
leukemia (CML). The classification becomes increasingly complex as a greater number of tests become
available to evaluate specific morphologic, enzymatic, immunologic, and genetic aspects of the malignant
cells.
Feature
Course

Acute leukemias
Rapid, usually fatal
Survival in months

Chronic leukemias
Indolent, often long survival
Survival in years

Peripheral blood

Mostly blasts
(immature cells)

Mostly mature cells

White cell count

Often increased;
decreased in 30%

Often increased

Bone marrow

>20% blasts

Blasts usually not increased

Acute lymphocytic leukemia (ALL): The proliferating cell is a primitive lymphoid cell. This type of
leukemia accounts for about 40% of the acute leukemias, and is the most frequent type in children <15 years
old. It is the principal cause of cancer deaths in childhood, with a peak incidence at age 4, but ALL can affect
persons of all ages. Five subtypes (early B precursor, pre-B, mature B, and T cell) are recognized
immunologically. Cytogenetic analysis has prognostic significance, with >50 chromosomes identifying the
subtype with best prognosis. Enlargement of lymph nodes, liver and spleen is more common in ALL than
AML. ALL often involves the central nervous system. The best prognosis group is children aged 2-10 with
pre-B cell type.
Acute myelogenous leukemia (AML): The proliferating cell is a primitive myeloid cell. Cytoplasmic
evidence of myeloid differentiation includes the presence of several types of granules (myeloperoxidase) found
in more mature myeloid cells. Cytoplasmic inclusions called Auer rods, when present, are diagnostic. Many
subtypes of AML can be recognized based on morphology, cytochemistry, and immunophenotype. AML
accounts for about 60% of acute leukemias, predominates in adults under 60 years old, and is most common in
the 15-39 year age range. Although many patients can obtain remission of disease after chemotherapy, the
duration of remission is often transient. Bone marrow transplant is the current therapy undergoing
evaluation/trial for treatment of refractory patients as well as those in first remission from standard
chemotherapy, and is a potentially curative procedure.

Chronic Lymphocytic Leukemia (CLL): The proliferating cell is a mature-appearing, but immunologically
incompetent, lymphocyte. Immunologically these cells can be proven to be monoclonal (derived from the same
precursor cell) and within a given patient all have identical cell surface phenotype. More than 95% are of B
cell type, and most commonly express IgM kappa surface immunoglobulin. This type of leukemia accounts for
about 2/3 of chronic leukemias, and is most common in adults over 60, with a male:female ratio of 2:1. The
course of the disease is indolent, and patients may not require treatment during the early stages. As the
monoclonal lymphocytes proliferate and migrate to other lymphoid sites there can be involvement of spleen,
liver, and lymph nodes. Peripheral leukocytosis is common, and can be 5-10x normal. Eventually cytopenias
may develop (anemia and thrombocytopenia) as the marrow is overrun by leukemic cells. Because the
lymphocytes do not respond to antigenic stimuli, hypogammaglobulinemia develops in most patients. Median
survival is 4-6 years.
Chronic Myelogenous Leukemia (CML): The proliferating cell is an immature hematopoietic cell, a stem
cell from which all other hematopoietic cells arise. The stem cell pool is increased 10-20x normal, and
although the cells can mature, there is failure to respond to normal regulators of growth. Typically there is a
marked increase in peripheral white cell count, with all myeloid cell types present (especially myelocytes,
eosinophils, and basophils). A specific chromosomal abnormality, the Philadelphia chromosome [t(9;22)],
occurs in all the proliferating cells. The chromosomal abnormality is critical to the cause of CML, but is not
unique to this disorder. This type of leukemia accounts for about 1/3 of chronic leukemias, and occurs in both
young adults (10-20) and in middle age (50-60). Enlargement of the spleen due to proliferation of abnormal
cells is almost always present. A terminal phase of the disease marked by a relative increase in immature cells
in peripheral blood and bone marrow, and decreased response to treatment, is known as blast crisis. This stage
is equivalent to an acute leukemia, and is of myeloid lineage in 2/3 and of lymphoid lineage in 1/3. Bone
marrow transplant is often performed during the chronic phase of the disease when a suitable donor is
available.
Clinical Features of Leukemia: Clinical features result from: (1) impairment of marrow function as abnormal
cells suppress growth of normal cells, and (2) infiltration of body organs due to proliferation of the abnormal
cells. Anemia is manifest as pallor, weakness, and fatigue. Thrombocytopenia (decreased platelets) produces
bleeding and bruises. Infections result from decreased production of mature granulocytes and production of
non-functional granulocytes and/or lymphocytes. Fever can be due to infection or increased metabolism of
proliferating cells. Organ enlargement (lymph nodes, spleen, liver) occurs as the abnormal cells proliferate in
these sites. Abdominal pain or obstruction of vascular and lymphatic channels can result. Infiltration of the
gums is a feature commonly associated with acute monocytic leukemias.
PLASMA CELL DISORDERS
Plasma cell disorders result from clonal expansion of immunoglobulin-secreting cells. The secreted
immunoglobulin (or portion of immunoglobulin) results in increases in serum monoclonal protein (M
component) which may have adverse effects on renal and neurologic function.
Multiple Myeloma: The proliferating cell is a plasma cell which produces immunoglobulin. Because this is a
clonal disorder, only one immunoglobulin type is produced by the neoplastic cells. In 60% this is IgG; in 2025%, IgA; in the remainder it is only kappa or lambda light chain; rarely it is IgM, IgD, or IgE. When only
light chains are produced, patients can excrete the low molecular weight light chains in the urine (Bence Jones
proteinuria). In some patients, complete monoclonal immunoglobulin is present as well as excess light chains.
Multifocal destructive bone lesions characterize myeloma. Bone resorption results from secretion of osteoclast
activating factors by the myeloma cells. Proteinaceous casts may form in the kidneys (myeloma kidney).
Hypercalcemia is often present, and amyloid may form from the monoclonal protein. Most patients are 50-60
years old, and present with bone pain, hypercalcemia, and renal disease. As the clone expands, complications
with recurrent infections, anemia, and thrombocytopenia develop. Documenting monoclonal protein and
skeletal lesions makes the diagnosis.