WBC disorder

Question 1

lymphomas

Answer 1

malignant proliferations of cells native to lymphoid tissue- lymphocytes and their precursors and derivations. these tumors usually arise in lymphoid tissue and can spread to involve solid tissue, marrow, and blood.
2 categories of lymphoma- hodgkin and nonhodgkin lymphomas

Question 2

leukemias

Answer 2

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)

Question 3

lymphoma and lymphocytic leukemia

Answer 3

distinction difficult. since in advanced states both can involve lymphoid tissue at any site

Question 4

hodgkin lymphoma

Answer 4

characteristic type of lymphoma defined morphologicallly by the presence of reed-sternberg cells admixed with a variable inflammatory infiltrate
unlike non-hodgkin lymphomas, hodgkin lymphoma 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 it characterized by contiguous spread within lymph node groups (for this reason, staging is particularly important in assessing prognosis).

Question 5

what is the cause of hodgkin lymphoma?

Answer 5

unknown but ebv has been implicated in playing a role

Question 6

what are the clinical characteristics of hodgkin’s lymphoma?

Answer 6

bimodal age distribution
20-30 years old and >50 years old
around 9000 cases in 2015
painless lymphadenopathy (often cervical, supraclavicular, mediastinal)
sphenomegaly detected by MRI

Question 7

what is the cell of origin of hodgkin’s lymphoma?

Answer 7

neoplastic cell is the reed-sternberg cell.
distinctive large cell with mirror image nuclei and prominent nucleoli.
usually only small numbers (2%) of RS cells are present in the involved node
a diagnosis of hodgkin lymphoma 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 and the precise origin of the RS cell remains uncertain- possibly germinal center b lymphocyte origin
in some cases, the epstein barr virus genome (70%) can be identified in the RS cells

Question 8

how is hodgkin’s lymphoma diagnosed?

Answer 8

lymph node biopsy is necessary for diagnosis
diagnosis requires identification of reed-sternberg cells in appropriate background
5 different types are recognized each with their own clinical presentations and histopathologic features
variable numbers of lymphocytes, plasma cells, eosinophils

Question 9

what is the classfication (grading) of hodgkin’s lymphoma

Answer 9

several variant of hodgkin lymphoma are recognized each with their own common clinical presentations, histologic features and to a certain extent- prognosis

Question 10

what is the staging of hodgkin’s lymphoma?

Answer 10

spread of disease is predictable: lymph nodes, spleen, liver, bone marrow- staging is used to determine treatment and prognosis
assessing tumor extent- combination of clinical findings and imaging (MRI)
low stage- localized involvement
high stage- widespread disease with distant or bone marrow involvement

Question 11

what are the specific stages of hodgkin’s lymphoma?

Answer 11

stage 1- tumor in one anatomic region or two contiguous anatomic regions on the same side of the diaphragm
stage 2- tumor in more than 2 anatomic regions or two non-contiguous regions on the same side of the diaphragm
stage 3- tumor on both sides of the diaphragm not extending beyond lymph nodes, spleen or waldeyer’s ring
stage 4- tumor in bone marrow, lung etc- any organ site outside of the lymph nodes, spleen or waldeyer’s ring
b signs/symptoms- fever night sweats and significant unexplained weight loss

Question 12

more on staging and choices of therapy of hodgkin’s lymphoma

Answer 12

staging refers to the assessment of the amt 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, often 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
treatment consists of a combination of chemotherapy and to a less extent today, radio therapy
all stages are further divided on basis of absence or presence of systemic symptoms, including fever, night sweats and significant unexplained weight loss

Question 13

what are the clinical features and course of non-hodgkin’s lymphoma?

Answer 13

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 less common at presentation, except in lymphocyte-depleted type. involvement of the spleen and liver increase the stage and are assessed by MRI. complications with infections (decreased cell-mediated immunity), anemia and thrombocytopenia can occur in advanced disease. combination chemotherapy and to a lesser extent, 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

Question 14

what is the treatment of hodgkin’s lymphoma

Answer 14

based primarily on stage
low stage- localized disease- chemotherapy and radiotherapy
high stage- widespread disease- chemotherapy
low risk for development of secondary treatment- related acute leukemia

Question 15

what is the prognosis of hodgkin’s lymphoma

Answer 15

patients without B signs/symptoms have better prognosis
stage 3 and 4 disease more likely to have b symptoms
5- year survival- stage 1 and 2 a- almost 100%
5 year survival rate in stage 4 is 50%

Question 16

non-hodgkin lymphoma

Answer 16

nhl 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 two dozen subtypes of nhl are recognized for purposes of determining prognosis and selecting therapy
only 8 of these subtypes comprise over 90% of nhl in the us
in contrast to hd, nhls tend to have multiple node involvement, more frequent extranodal spread and peripheral blood involvement and affect all ages.
like hd, histologic examination of involved tissue is required for diagnosis
over 2 dozen types are currently recognized- most (85%) are of b cell origin
most of remainder are of t cell origin
incidence rises steadily after age 40, roughly 71000 cases in 2015

Question 17

what are the clinical symptoms of nhl?

Answer 17

painless lymph node enlargement
systemic symptoms in 30% of patients
frequent immune abnormalities
splenomegaly
may involve GI tract, bones, central nervous system

Question 18

what are the cell of origin of nhl?

Answer 18

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%). b lymphocytes normally have the capacity to differentiate into plasma cells (the 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 that 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 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)

Question 19

what is the classification of nhl?

Answer 19

recognizes distinct clinicopathologic entities
numerous subtypes (over 2 dozen) with great morphologic divrersity
based on morphologic, clinical, immunophenotypic and molecular features
growth pattern- nodular vs diffuse
cell size- small vs large
nodular disease better than diffuse
small cell disease better than large
classification of nhl is moderately complicated. 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. nhls are classified on the basis of their morphology (microscopic appearance), cell of origin (immunophenotype), clinical features and genotype. the world health organization convenes panels of lymphoma experts to examine the accuracy and utility of the classification system and the most recent system published in 2008 is based on the revised european american lymphoma classification that was first proposed in the mid 1990s

Question 20

staging of nhl

Answer 20

localized disease- low stage
numerous sites of involvement or bone marrow involvement- high stage
prognosis often based more on the subtype of lymphoma than stage (exception to the general rule- grading or subtyping is critical with nhl)
staging is similar to hodgkin lymphoma. there is less correlation between stage and prognosis in nhl than in hd. cell type and tumor proliferative index are better correlated with prognosis

Question 21

specific stages of nhl

Answer 21

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

Question 22

clinical features and course of nhl

Answer 22

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 peripheral blod represent a leukemic phase of the disease in distinction to the group of diseases classified as leukemia. the disease can spread to 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

Question 23

leukemias

Answer 23

malignant neoplasms of hematopoeitic 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

Question 24

classification of leukemia

Answer 24

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. basic classification would thus include acute lymphoblastic leukemia (ALL) crhonic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML)
the classificatiion becomes increasinly complex as greater number of tests become available to evaluate specific morphologic, enzymatic, immunologic and genetic aspects of malignant cells

Question 25

acute vs chronic leukemia

Answer 25

acute- rapid onset with blasts in the blood
myeloid and lymphoid cells affected
course- rapidly fatal, survival in months- mostly blasts
blood- mostly blasts, white cell count typically increased. bone marrow- more than 20% blasts
chronic- indolent onset and tends to involve more mature cells
myeloid and lymphoid cells affected
course- indolent- survival in years
blood mostly mature cells, white cell count typically increased and bone marrow- blasts no usually increased

Question 26

acute lymphoblastic leukemia

Answer 26

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 50 chromosomes per leukemic cell) being the subtype with best prognosis (most are children)
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 2-19 with pre b cell type.

• Clonal growth of primitive lymphoid cell
• Both B and T cell types exist
• Increased white blood cell count often accompanied by thrombocytopenia
• Most common in children, most frequent cancer in those < 15 yrs of age
• May have lymphadenopathy, splenomegaly
• Prognosis related to cytogenetics
• Children have good prognosis
• Adults often have bad prognosis
• Chemotherapy is mainstay of treatment with bone marrow transplantation considered at relapse

Question 27

acute myelogenous leukemia

Answer 27

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, immunophenotype and karyotype. The karyotype is most predictive of prognosis. AML usually affects an older adult population, with a median age of 50 years. Sometimes the lesional cells will proliferate in soft tissue (including the gingivae), producing what is termed granulocytic sarcoma. 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.
•Clonal proliferation of primitive myeloid cell
•Several subtypes exist based on morphology, cytochemistry, immunophenotype and cytogenetics
•Increased WBC count often accompanied by anemia and thrombocytopenia
•More common in adults
•Myeloperoxidase is present in the cytoplasm
•Chemotherapy is the mainstay of treatment
•While 70% of patients may have a remission, many relapse
•Prognosis influenced by cytogenetics

Question 28

chronic lymphocytic leukemia

Answer 28

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 neoplastic lymphocytes do not respond to antigenic stimuli, hypogammaglobulinemia develops in most patients. Median survival is 4-6 years.
•Clonal proliferation of mature lymphocyte, typically a B lymphocyte
•The B cells are immunologically incompetent
•Monoclonal expression of surface immunoglobulin - either kappa or lambda
•Most common in adults over 60
•Increased white cell count with lymphocytosis
•Often presents with splenomegaly and lymphadenopathy
•Anemia and thrombocytopenia eventually develop as disease progresses
•All cases eventually terminate into a higher grade process - either acute leukemia or high grade lymphoma
•Chemotherapy is the basis of treatment

Question 29

chronic myelogenous leukemia

Answer 29

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 results in fusion of the BCR-ABL genes, which mimic the effects of growth factor activation, driving the proliferation of CML. While this fusion gene is always present in CML, it is not unique to this disorder. CML accounts for about 1/3 of chronic leukemias, and usually occurs in adults from 25-60 years of age. Enlargement of the spleen due to proliferation of abnormal cells is almost always present. The 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. Initial therapy is with targeted inhibitors of the BCR-ABL tyrosine kinase, which induce complete remission in a high percentage of patients. With relapsed or resistant disease, bone marrow transplant may be performed, although this is risky in older patients.
•Clonal proliferation of immature granulocytes - a stem cell disorder
•Marked increase in white blood cell count with eosinophilia and or basophilia, left-shifted granulocytes
•May have thrombocytosis and anemia
•Splenomegaly is typically present•
Cytogenetic abnormality; t(9;22), philadelphia chromosome
•Molecular fusion of bcr and abl genes
•Targeted chemotherapy blocks the bcr-abl tyrosine kinase, inducing remissions in most patients
•Bone marrow transplant for relapsed or resistant disease

Question 30

clinical features of leukemia

Answer 30

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 gingivae is a feature commonly associated with acute myelo-monocytic leukemias.

• Abnormal cells suppress growth, maturation and function of normal cells
• Infiltration of body organs by abnormal cells
• Immune dysfunction

Question 31

plasma cell disorder

Answer 31

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.
A clonal proliferation of monoclonal plasma cells
Monoclonal heavy and or light chain production
IgG is most common
A disease of late middle age to elderly

Question 32

multiple myeloma

Answer 32

The proliferating cell is a plasma cell that produces immunoglobulin. Because this is a clonal disorder, only one immunoglobulin type is produced by the neoplastic cells. In 60% this is IgG; in 20-25%, 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. 24,000 cases are projected to be diagnosed in 2015 in the US, with an average patient being 70 years old. Patients often present with bone pain, hypercalcemia, and renal disease. As the tumor cells proliferate, complications with recurrent infections, anemia, and thrombocytopenia develop due to destruction of normal marrow by the tumor. Documenting monoclonal protein and skeletal lesions makes the diagnosis.

Question 33

multiple myeloma clinical

Answer 33

Multiple lytic bone lesions, hypercalcemia
Bone marrow infiltration by plasma cells
↑↑ serum monoclonal protein, but normal immunoglobulins are suppressed
Bence-Jones proteinuria (light chains)
Renal failure
Infections

Blood and marrow-
Circulating plasma cells in blood are uncommon
RBC show rouleaux formation
Marrow plasma cell infiltrates in single cells and sheets

Question 34

prognosis and treatment of multiple myeloma

Answer 34

Prognosis is variable, but generally poor
Indolent form: survival for years
Typical form: median survival – 4-6 years
Chemotherapy – recent success with thalidomide analogs, anti-resorptive tx
Radiotherapy (palliation – for bone pain)
Bone marrow transplant