IUHS Student-2-Student USMLE Step 1 Recall
Hematology
Leukemia
Acute Lymphocytic Leukemia (ALL)
normocytic...normochromic...
in this form of leukemia, an immature (
blastic) lymphoid precursor proliferates at a high rate...fully 80% are of B-cell origin (CD19, CD20, CD21, CD22) (early pre-B, pre-B, or B)...
b/c of the good chance for cure of ALL with specific therapy, it is important to disinguish it from AML...
ALL occurs most often in children, in whom it represents the most common form of leukemia...for patients with B-cell types,
the average age at diagnosis is 4 years; for those with T-cell ALL, the average age is 7 years...adult ALL occurs in the same age group as AML...Young males with mediastinal mass (think thymus)
...60% are alive in 5 years...
translocation of chromosome 8/14 in 100% of cases...
the bone marow shows complete replacemnt by leukemia cells...very high lymphocyte counts above 50,000/uL and a
mediastinal mass are seen more frequently in T-cell ALL (CD2, CD3, CD5, CD7)...T-cell ALL tend to present in adolescent males as lymphomas often with thymic involvement...
immunostaining
for terminal deoxytransferase (TdT) in 95%
translocation of chromosome 8/14 in 100% of cases...
in childhood ALL, the cure rate is greater than 50% and appears to be approaching 75%...
patients are treated aggressively and given drugs that differ from those used for AML...
anemia, neutropenia, and thrombocytopenia...
abrupt stormy onset, symptoms related to depression of normal marrow function...bone pain and tenderness...generalized lymphodenopathy, splenomegaly, and hepatomegaly...CNS manifestations...headache, vomiting, and nerve palsies...
Chronic Lymphocytic Leukemia (CLL)
normocytic normochromic...
CLL is a lesion of the
mature small lymphocyte and has a low proliferative rate...fully 98% of cases are of B-cell intermediate origin; lesions of T-cell origin are more aggressive...smudge cells
...a common form of leukemia, CLL affects the elderly...patients present with splenomegaly and symptoms related to anemia...occasionally, patients are symptomatic...
usually prinicpal complication is due to infection...
peak age
50-60...usually in patients older than 60...most alive in
5 years...50%
of CLL have Trisomy 21...unknown etiology...
T cell lymphomas
occuring in the thoracic cavity in young patients usually arise in the mediastinum and have a particularly aggressive clinical course with rapid growth in the mediastinum impinging upon the trachea or mainstem bronchi and leading to marked respiratory deficiency, which can in turn lead to death in a relatively short period of time if not treated...while most patients have a marked lymphocytosis (above 20,000/uL),
some only a mild absolute lymphocytosis defined as a lymphocyte count above 4000/uL...the marrow shows focal or diffuse lymphocytic infiltration...
the length of survival is most closely related to total tumor burden...
since many cases are diagnosed early, longevity is not necessarily affected by the presence of CLL, and patients often die of other diseases of the elderly...
patients presenting with profound anemia have bulky disease and survive and average of 2 years...
as the disease progresses, infiltrates in organs occur...rarely, patients develop Richter's syndrome, in which transformation to a large cell type signals aggressive preterminal disease with tumor nodules in various sites...
the tumor cells resemble a small subset of circulating B cells that express the surface marker CD19, CD20, CD5
...Acute Myelomonocytic Leukemia
normocytic...
is a marrow derived neoplasm composed of
blasts and cells differentiating into early granulocytes...the marrow is infiltrated by blasts and promyelocytes....AML affect adults mainly and is preceded by a few days to weeks of weaknes, bleeding, and fever...physical examination shows petechiae,
sternal tenderness, and sometimes thickened gums, adenopathy, splenomegaly, and hepatomegaly...infection is evident often...occasionally, the leukemia presents as a mass
lesion composed of blast cells (granuloctyic sarcoma or chloroma) in the head,
neck, and bowel...
Trisomy of chromosome 8.
..high WBC count...
peak age 15-20...
fatal quickly...
30% alive in 5 years...
myelodysplastic syndrome can predispose to AML...
the blood picture is characterized by anemia,
thrombocytopenia, and an elvated leukocyte count in which the predominant cell is a blast...the bone marrow shows a myeloblastic infiltrate replacing all marrow...
on a bone marrow aspirate,
abnormal blasts may show the Auer rod, an abnormal granule...untreated, this form of leukemia caused death within 1 to 3 months, usually as a result of infection or hemorrhage...with current therapeutic regimens, about half of the patients achieve complete remission...
high WBC count...
myelodysplastic syndrome can predispose to AML...
is associated with acquired genetic alterations that result in the replacement of normal marrow elements by relatively
undifferentiated blasts exhibiting one or more types of early myeloid differentiation...the replication rate of these blasts is actually lower than that of normal myeloid progenitors...hence the most important net effect of the genetic alterations is likely to be the inhibition of terminal differentiation...
Chronic Myeloproliferative Leukemia (CML)
CML have pathologic cells that appear very similar to normal white cells or
their precursors...
CML is a marrow derived neoplasm composed principally of granulocytic cells in various stages of maturation...
WBCs are usually greater than
50,000/uL...the
Philadelphia chromosome is present in bone marrow cells in 90% of cases...the typical patient is an adult who has peripheral blood and marrow granulocytosis with a shift to the left with myelocytes and
scattered blasts...fever, splenomegaly, and fatigue are common symptoms...leukmoid reactions are frequent and acid fast bacilli such as TB are often present...
peak age 40-50
...
translocation of chromosome 9/22 (created protein tyrosine kinase) in >90% of cases...
myelocytes > metamyeloctye...
the
leukocyte alkaline phosphatase (LAP) test is one way to distinguish a reactive leukocytosis from CML...LAP is low or absent...a blood smear is made and substrate added; if the enzyme is present in a cell, the cell is colorized by the detection system...the number and degree of positive (0-4) cells per 100 cellls are counted...
in reactive leukocytosis, over 25% leukocytes are positive (high score: 100-200)
...by contrast, the cells of CML are defective, and only a small number of positive cells are seen (low score: 10-40)...more patients with CML enter an accelerated phase (
increase in blasts with differentiation) or blast crisis (pure blastic proliferation) in which the predominant cells resemble blast cells of primitive myeloid, monocytic, or lymphoid cells...in many cases, death is the result of a
blast crisis...recently, bone marrow transplantation (BMT) has altered the prognosis - with improved length of survival...
polycythemia vera...
essential thrombocytosis...
myelofibrosis with myeloid metaplasia...
Hodgkin Disease
HD arises in a single node or chain of nodes and spreads characteristically
to the antomically contiguous nodes...
it is characterized morphologically by the presence of distinctive neoplastic giant cells,
RS cells, which induce the accumulation of reactive lymphocytes, histiocytes, and granulocytes...the neoplastic cells of HD typically make up a minor fraction (1-5%) of the total tumor cell mass...the origin of the neoplastic cell in the more common forms of HD has yet to be identified with certainity and has a phenotype unique from that observed in other lymphoid neoplasms...
HD accounts for 0.7% of all new cancers in the US, with approximately 7400 new cases reported per year...
its importance stems from the fact that it is one of the most common forms of malignancy in young adults with an average age at diagnosis of 32 years...
progressive, painless enlargement of neck lymph nodes, marked enlargement of mediastinal nodes
...express surface marker
CD30...RS cell is considered to be the true neoplastic element in HD, and identification of RS cells and their variants is therefore essential for the histologic diagnosis...
classic RS cells are quite large,
binucleate or bilobed, with the two halves often appearing as mirror images of each other...RS cells must be present in an appropriate background of non-neoplastic
inflammatory cells (lymphocytes, plasma cells, eosinophils)...
Reed-Sternberg cells are multinucleated with large nucleoli
65-70% are Nodular Sclerosis Type
...frequent lacunar cells (Empty areas around RS cells)
and occasional diagnostic RS cells; background infiltrate composed of T lymphocytes, eosinophils, macrophages, and plasma cells; fibrous bands dividing cellular areas into nodules...RS cells CD15+,
CD30+...stage 1 or 2 disease most common...
frequent mediastinal involvement...females affected more than males, most patients young adults...young adult females get...excellent prognosis...
more common in women...
25% of cases are Mixed Cellularity Type...
frequent mononuclear and diagnostic RS cells;
background infiltrate rich in T lymphocytes, eosinophils, macrophages, plasma cells...RS cells CD15+, CD30+...
more than 50% present as stage 3 or 4 disease...males affected more than females...biphasic incidence, peaking in young adults and again in adults > 55...
intermediate prognosis...
Lymphoctye Predominance Type -
accounts for 6% of all cases...frequent L + H (popcorn cell)
variants in a background of follicular dendritic cells and reactive B cells...RS cells negative for CD20+, CD15-, CD30-...
young males with cervial or axillary lymphadenopathy...mediastinal disease uncommon...
many lymphocytes, few RS cells...RS cells hardest to find in lymphocyte predominance type...
prognosis excellent...usually seen in <35 year old male...
HD is a clonal neoplastic disorder and that the RS cells and variants represent the transformed cells...in all likelihood, the characteristic accumulation of reactive cells occurs in response to cytokines secreted by the RS cells...
many cytokines, including
IL-4, 5, TNF-alpha, GM-CSF, and TGF-beta have been detected in HD...of these,
IL-5 synthesis by RS cells correlates with eosinophil accumulation (a feature of mixed cellularity and nodular sclerosis subtypes)...TGF-beta, a fibrogenic cytokine, is found almost exclusively in the nodular sclerosis variant
, where it is produced by eosinophils...thus, the specific pattern of HD may be determined by the unique combination of cytokines secreted by RS cells and non-neoplastic cellular infiltrate...
Multiple Myeloma
plasma cells...
multiple myeloma is a
plasma cell neoplasm that is characterized by involvement of the skeleton at multiple sites...although bony disease dominates the clinical picture, it can also spread to lymph nodes and extranodal sites, such as the skin...
multiple myeloma causes 1% of all cancer deaths in western countries...
its incidence is higher in women, in people of african descent relative to the US population at large, and in older adults as compared to the young...
usually occurs in people greater than 50
years old with a less than 5 year survival...monoclona gammopathy of unknown significance (MGUS) is often seen before MM develops...
M spike: monoclonal immunoglobulin spike
most common IgG (60%)
next most common IgA (20%)
beta-2-microglobulin - excellent prognostic factor.
..plasma cells...derive from B cells...
phenotypic studies imply that the cell of origin is a less differentiated cell...
CD38 and cytoplasmic immunoglobulin
...small lymphoid cells within the peripheral blood have been shown to express Ig identical to that of neoplastic plasma cells, suggesting that they represent a progenitor cell population...
multiple lytic bone lesions due to the
osteoclastic activating factor (OAF)...OAF is IL-6...the proliferation and survival of myeloma cells seem to be dependent on several cytokines, most notably
IL-6...serum levels of this cytokine are increased in patients with active disease, and it appears that high serum IL-6 levels are associated with a poor prognosis...IL-6
is produced by tumorous plasma cells and stromal cells in the marrow...in addition to causing the growth of myeloma cells,
cytokines also mediate bone destruction, the major pathologic feature of multiple myeloma...loss of bone is in large part due to osteoclastic reabsorption induced by the tumor...a variety of cytokines produced by the tumor cells, particularly IL-1beta and IL-6, serve as osteoclast activating factors...
can present as elevated serum creatinine, hypertension, and mild anemia...
plasma cell...
the
peak incidence of multiple myeloma is between 50-60 years of age...the clinical features of myeloma stem from the effects of (1) infiltration of organs, particularly bones, by the neoplastic plasma cells; (2) the production of excessive Ig, which often has abnormal physiochemical properties; and (3) the suppression of normal humoral immunity...infiltration of bones is mainfested by pain and pathologic fractures...
hypercalcemia resulting from bone resorption may give rise to neurologic mainfestations, such as confusion, weakness, lethargy, constipation, and polyuria, and also contribures to renal disease...elevated alkaline phosphatase...
decreased production of normal Ig sets the stage for recurrent infection with bacteria such as streptococcus pneumoniae, staphylococcus aureus, and escherichia coli...
cellular immunity is relatively unaffected...of great significance is renal insufficiency, which is second only to infections as a cause of death...
the pathogenesis is renal failure, which may occur in up to 50% of patients...Amyloid Light chain is present...
increased total serum Protein...
most important is Bence Jones Proteinuria
, since the excreted light chains are toxic to the tubular epithelial cells...in 99% of patients with multiple myeloma, electrophoretic analysis reveals increased levels of Ig in the blood or
kappa light chains (Bence Jones proteins) in the urine, or both...80% = monoclonal spike (M-protein) in serum
80% = Bence-Jones Protein (M-protein) in urine
60% = M-Protein in both serum and urine
20% = M-Protein only in serum
20% = M-Protein only in urine
2/3 IgG... 1/3 IgA...
Waldenstrom's Macroglobinemia
WM is associated with a
monoclonal production of IgM, is clinically distinct from multiple myeloma...it is somewhat like a cross between multiple myeloma (MM) and small lymphocytic lymphoma (SLL)...as with myeloma, there is a
monoclonal production of immunoglobulin (IgM) that produces anM spike
...unlike the case with myeloma, however, there are no lytic bone lesions and nohypercalcemia, and the bone marrow shows proliferation of plasma cells, lymphocytes, and plasmacytoid lymphocytes....like SLL, WM is associated with infiltration of organs outside of the bone marrow by neoplastic cells....these include the lymph nodes and the spleen...
(involvement of these organs is unusual in patients with MM)...
b/c IgM is a large molecule (a pentamer), patients with WM are prone to developing the hyperviscosity syndrome, which consists of visual abnormalities, neurologic signs (headaches and confusion), bleeding, and cryoglobulinemia...Myelofibrosis
the finding of immature white cells and immature red cells in the peripheral blood (leukoerythroblastosis) is suggestive of a
space occupying lesion in the marrow..this may be the result of multiple granulomas, metastatic carcinoma, or myelofibrosis...
the latter disorder is associated with a
spleen that is massively enlarged secondary to extramedullary hematopoiesis
...this splenic change is also associated with the presence of
tear-drop erythrocytes in the peripheral smear...this abnormality, called myelofibrosis with myeloid metaplasia, is one of the four myeloproliferative syndromes, the other three being CML, polycythemia rubra vera, and essential thrombocytopenia...all four of the myeloproliferative syndromes are characterized at some point during their pathogenesis by a
hypercellular (proliferative) bone marrow that involves hyperplasia of all cell lines in the marrow..Tear drop cells
are classic for myelofibrosis (as though the cells had to "squeeze through" the fibrosis. A myelophthisic process that "fills up" the marrow tends to produce a leukoerythroblastic picture with immature red and white cells peripherallymegakaryocytic series predominates in myelofibrosis...
Diffuse Large B-Cell Lymphoma
the diagnostic category of
diffuse large B-cell lymphoma encompasses a heterogeneous group of tumors that together constitute about 20% of all NHL and 60-70% of aggressive lymphoid neoplasms...20% are Large T cell lymphomas...
there is a slight male predominance, with a
median age of about 60 years...the age range is wide, however, and diffuse large B-cell lymphoma constitute about 5% of childhood lymphoma...
Diffuse Large B Cell lymphomas often present in AIDS patients...and EBV...
patients with diffuse large B-cell lymphoma typically present with a rapidly enlarging, often symptomatic masss at a single nodal or extranodal site...
involvement of the GI tract, skin, bone, or
brain may be the presenting symptom...
waldeyer ring, the oropharyngeal lymphoid tissues that include the tonsils and adenoids, is also commonly involved...
there may be large destructive masses in the liver and spleen...bone marrow involvement occurs late in the disease, and rarely a leukemic picture may emerge...
diffuse large B-cell lymphomas are aggressive tumors that are rapidly fatal if untreated
...with intensive combination chemotherapy, however, complete remission can be achieved in 60-80% of patients, and approximately 50% remain free from disease for several years and may be considered cured....Diffuse Large B Cell lymphomas often present in AIDS patients...
BurkittLymphoma
B cell
lymphoma...
within the category of Burkitt Lympohoma fall (1) african (endemic) burkitt lymphoma, (2) sporadic (nonendemic) Burkitt lymphoma, and (3) a subset of aggressive lymphomas occurring in patients infected with HIV...
translocation of chromosome 8/14 in 100% of cases...
extraordinarily rapid, cells can double in 24 hours...mostly affects kids...
"starry skies"
is the characteristic histologic appearance...the cytoplasmic vacuoles of the lymphoma cells contain lipid, and this would be reflected by a positive oil red O reaction...primitive, round lymphoblastic tumor cells are found in tissue taken from patients...
the translocation places the myc oncogene on chromosome 8 downstream of the very active heavy chain locus on chromosome 14, activating myc gene expression in B cells and their derivatives...the translocation is likely an aberrant form of the normal DNA rearrangements that generate unique heavy chain genes in each B cell...
most tumors mainfest at extranodal sites...
c-myc is altered
...chromosome translocation that brings together an Ig heavy chain with an oncogene...endemic african burkitt lymphoma (can be caused by EBV) often presents as a mass involving the mandible and shows an unusual prediliction for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal...
in contrast, nonendemic burkitt lymphoma most often presents as an abdominal mass involving the ileocecum and peritoneum...
both the african and the sporadic cases are found largely in children or young adults, accounting for approximately 30% of childhod NHLs in the US...
evolution to a leukemic picture is uncommon
, especially in african cases...burkitt lymphoma is aggressive but responds well to short-term chemotherapy, with many patients appearing to be cured...P. falciparum is also likely co-factor...
translocation of chromosome 8/14 in 100% of cases...
primitive, round lymphoblastic tumor cells are found in tissue taken from patients...
FollicularLymphoma
most common form of NHL in the US
...comprising about 45% of adult lymphomas...it usually
presents in middle age and afflicts men and women equally...it is less common in europe and rare in asian populations...
the neoplastic cells closely resemble normal germinal center B cells...
all follicular lymphomas are derived from B-lymphocytes
...in most follicular lymphomas, small cleaved cells compose the majority of the cellularity...
peripheral blood involvement sufficient to produce lymphocytosis (usually <20,000/mm3) is seen in about 10% of patients...
bone marrow involvemnt occurs in 85% of patients and characteristically
takes the form of paratrabecular lymphoid aggregates...splenic white pulp and hepatic portal triads are also frequently involved...
the hallmark of follicular lymphoma is a 14;18 translocation
, which leads to the juxtaposition of the IgH locus on chromosome 14 and the bcl-2 locus on chromosome 18...this tanslocation is seen in most but not all follicular lymphomas and leads to overexpression of
bcl-2 protein...bcl-2 is involved with apoptosis
...bcl-2 inhibits apoptosis...leading to immortal cell...tend to present with
painless lymphadenopathy, which is frequently generalized...involvement in extranodal sites, such as the gastrointestinal tract, CNS, or testis, is relatively uncommon
...although follicular lymphoma is incurable, it often follows an
indolent waxing and waning course...