Blood Cancers and Lymphoma Flashcards
Peripheral blood smear
PelgerHuët cells - dysplastic change which are abnormal appearing neutrophils having only two nuclear lobes
Dysplasia associated with myelodysplastic syndromes
PelgerHuet cells
Hypersegmented PMNs
Hypo/hypergranular cells
RBCs - presence of ringed sideroblasts (seen w/ prussian blue), megaloblastoid erythroid precursors, and mishapen erythroid precursors w/ nuclear budding
Megakarycytes may be abnormal and only have a single nuclear lobe or multiple separate nuclei (prawn ball megakaryocytes)
How are myelodysplastic syndromes classified?
Based on # of blasts present w/i marrow
WHO classification:
<5% blasts - MDS is either refractory anemia (RA) or RA w/ ring sideroblasts (RARS)
5-20% blasts in marrow - RA w/ excess blasts (RAEB)
> 20% blasts in marrow = acute leukemia
5q- syndrome
myelodysplastic syndrome which is characterized by megakaryocytes that are uniformly small and monolobated
Sxs of acute leukemia
Fever (secondary to infection), easy fatigability (due to anemia), and bleeding (due to thrombocytopenia)
Both ALL and AML are characterized by a decrease in mature forms of cells and increase in immature forms (blasts which have immature chromatin with multiple nucleoli)
Acute myelogenous leukemia
Epidemiology
Typically adults between ages of 15-39
Risk Factors:
-Akylating chemo
-Radiation
-Myelodysplastic syndromes
-Myeloproliferative neoplasms
-Down syndrome
CD markers for Pt w/ acute myelogenous leukemia
Myeloid markers:
CD13
CD33
Blast markers:
CD34
CD117
Myeloperoxidase (MPO) = stain to differentiate AML from ALL
Auer rods in AML
Abnormal lysosomal structures (primary granules) considered pathognomonic of myeloblasts
Stain red with MPO
Acute promyelocytic leukemia (APL)
APL is also characterized by the
translocation t(15;17), which results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 to the PML unit on chromosome 15
produces an abnormal retinoic acid receptor such that physiologic levels of retinoic acid no longer activate it.
Treatment for APL is with large doses of vitamin A derivatives, such as all-trans-retinoic acid, which inhibits the proliferation of cells of acute myeloid leukemia.
What subtype of acute myelogenous leukemia is associated with gingival infiltrates?
Acute monocytic leukemia
What subtype of acute myelogenous leukemia is associated with marked fibrosis of the bone marrow
Acute megakaryocytic leukemia is associated with acute myelofiborisis
Acute megakaryocytic leukemia is
associated in children younger than 5 years of age with Down syndrome.
Special stains for megakaryocytes include stains for von Willebrand factor and stains for GpIb/IIIa (on platelets).
Acute lymphoblastic leukemia (ALL)
Primarily disease of children and young adults
Lymphoblasts stain positively for TdT (nuclear enzyme)
ALL is associated with CNS infiltration (distinguishes from AML) where malignant lymphoblasts are protected from chemotherapy by the BBB
Pt’s with ALL may be given prophylactic radiation to head
Also, acute lymphoblastic leukemia is associated with Down syndrome after the age of 5
Immunologic classification of acute lymphocytic leukemia
Most of ALL are B-cell origin:
Lymphoblasts express CD19
Few cases are T-cell origin:
Lymphoblasts lack CD19 but instead express T-cell Ags (CD3 and CD7)
CD markers for T cells are CDs less than 10
Many cases of T-ALL involve a mediastinal mass (which may press on the esophagus causing dysphagia) and are clinically similar to cases of T-cell lymphoblastic lymphoma.
Pro B-cell ALL
+TdT (marker for immature cells)
Lacks CD10/cytoplasmic μ/surface Ig
Common B-ALL
+TdT and +CD10
CD10 is called CALLA - common ALL antigen
Pre-B-ALL
Characteristic translocation t(1;19)
+cytoplasmic μ chains
-TdT and -surface Ig
May be + for CD10
Mature B-ALL
Cells have surface Ig
Lack TdT/CD10/ and cytoplasmic μ
Mature B-ALL is the leukemic form of Burkitt’s lymphoma
-Similarly malignant cells have cytoplasmic vacuoles that stain positively with the oil red O lipid stain
Prognosis with ALL
The presence of CALLA (CD10) is a marker of a favorable prognosis, as is the presence of t(12;21), which is the most common chromosomal rearrangement in childhood B-ALL.
t(9;22) is associated with a poor prognosis. Most children with ALL achieve complete remission with
chemotherapy.
____ is the most common leukemia and is similar in may aspects to small lymphocytic lymphoma (SLL)
Chronic lymphocytic leukemia (CLL)
If Pt presents w/ blood findings first = CLL
If they present w/ lymph node findings first = SLL
What sxs are associated w/ chronic lymphocytic leukemia?
CLL has an indolent course - disease is associated w/ long survivial in many cases
Sxs that may develop are related to anemia or infections - malignant cells are non-functional
Lymphadenopathy or splenomegaly may be noted
Minority of Pt - disease may transform into prolymphocytic leukemia or a large cell immunoblastic lymphome (Richters syndrome)
Richter’s syndrome (transformation)
CLL transformation into immunoblastic lymphoma
Prolymphocytic leukemia
Can be transformation from CLL
Characterized by massive splenomegaly and a markedly increased leukocyte count consisting of enlarged lymphocytes having nuclei with mature chromatin and nucleoli
What leukemia is associated with warm AIHA?
CLL - warm autoimmune hemolytic anemia is characterized by finding spherocytes in the peripheral blood
Tx of B-CLL
Rituximab - mAb against CD20 (B cell marker)
Drug is associated w/ increased risk of progressive multifocal leukoencephalopathy (demyelinating disease of CNS caused destruction of oligodendrocytes secondary to reactivation of JC virus)
Hairy cell leukemia
(HCL) - indolent type of mature B-cell leukemia found most often in older males
Signs:
Pancytopenia (due to leukemic infiltration of marrow)
Splenomegaly (most common sign) - leukemic cells infiltrating red pulp (unusual because leukemias preferentially infiltrate white pulp)
These neoplastic cells proliferate in spleen = splenectomy
Peripheral smear of HCL Pt blood
Numerous lymphocytes w/ cytoplasmic projections
Cells stain for acid phosphatase and rx’n is refractory to Tx w/ tartaric acid (tartrate-resistant acid phosphatase [TRAP])
Hairy cells also express pan-B-cell markers (CD19 and CD20) and monocyte marker CD11c
Hairy cells are negative for CD5 and CD10
What does aspiration of marrow in Pt w/ HCL show?
Dry tap
But biopsy shows proliferation of malignant cells w/ fried-egg appearance
Tx of HCL
Purine analogs like cladribine (2-CDA = first-line Tx)
Also pentostatin (also purine analog)
These drugs are resistant to breakdown by adenosine deaminase (enzyme that is deficient in the AR form of SCIDs) - inhibits nucelotide metabolism and leads to the accumulation of toxic amounts of dexyadenosine
Adenosine deaminase (ADA) is an enzyme that converts adenosine to inosine. ADA inhibition results
in the metabolism of deoxyadenosine through an alternate pathway, which is toxic to lymphocytes.
What stain differentiates AML from ALL?
Myeloperoxidase
Myeloblast stain +
Lymoblasts are -
What translocation is associated with acute promyelocytic leukemia?
t(15;17)
17 - retinoic acid receptor alpha (RARA) gene
15 - promyelocytic leukemia (PML) gene
What increases risk for disseminated intravascular coagulation (DIC) in Pt’s w/ acut promyelocytic leukemia (APL)?
The abnormal promyelocytes seen in APL contain numerous primary granules - increases risk of DIC
Staining of lymphoblasts from Pt w/ acute lymphoblastic leukemia (ALL)
Stain positive for terminal deoxynucleotidyl transferase (TdT)
Negative for myeloperoxidase
What translocation is associated w/ a poor prognosis for Pt’s w/ acute lymphoblastic leukemia (ALL)?
t(9;22)
What factor(s) are associated w/ a favorable prognosis for Pt’s w/ acute lymphoblastic leukemia?
Translocation t(12;21) and presence of CD10 (CALLA)
Why do Pt’s w/ acute lymphoblastic leukemia sometimes receive prophylactic radiation to their head?
ALL is associated w/ CNS infiltration, where malignant lymphoblasts are protected from chemotherapy by the BBB
Peak incidence of acute lymphoblastic leukemia
Between ages 2-5
Also is associated in Pt’s with Down syndrome after age 5
Down syndrome before age 5 is associated with acute megakaryocytic leukemia
What subtype are most cases of acute lymphoblastic leukemia?
B-cell origin (B-ALL)
Express CD10 and CD19
Signs of hairy cell leukemia
Pancytopenia
Dry tap of marrow
Massive splenomegaly
Splenomegaly is most common sign w/ infiltration of red pulp
Strongest evidence of lymphoma malignancy
Monoclonal lymphocytic proliferation
Benign lymph node enlargement is associated w/ a polyclonal proliferation of lymphocytes
What is the most common indolent non-Hodgkin lymphoma?
Follicular lymphoma - B-Cell origin and charcterized by painless waxing and waning lymphadenopathy in an older adult
Histological characterization of follicular lymphoma
Neoplastic nodule that obscure (efface) the normal lymph node arhitecture
Follicle in follicular lymphoma do not contain tingible-body macrophages and are not surrounded by mantle zones
What translocation is associated w/ follciular lymphoma?
t(14;18) - causes BCL2 overexpression and inhibition of apoptosis
Most common type of non-Hodgkin lymphoma in adults
Diffuse large B-cell lymphoma
Agressive (high-grade) type of lymphoma w/ a poor prognosis
Tumor cells have a high proliferative index and stain positively for CD20
Also associated w/ alteration in Bcl-2 proteins
Primary CNS lymphoma
Associated w/ advanced HIV infection (secondary EBV infection)
Primary effusion lymphoma
Associated w/ advanced HIV infection (secondary HHV-8 infection)
Burkitt lymphoma
High-grade B-cell lymphoma associated with t(8;14) resulting in MYC overexpression - produces a nuclear protein whose Fx is to activate transcription
Histopathology of Brukitt lymphoma
Sheets of malignant small, non-cleaved lymphocytes forming a starry-sky appearance due to macrophages unglusing apoptotic cells
African type of Burkitt lymphoma
Endemic form and typically involves the maxilla or madible - especially of the young child
Associated w/ EBV
American type of Brukitt lymphoma
Nonendemic and commonly involvees the abdomen, such as bowel, ovaries, or retroperitoneum
Associated w/ EBV if Pt is immunosuppressed (i.e. HIV)
Gastric MALT lymphoma
Type of marginal zone lymphoma associated w/ H. pylori infection and t(11;18)
Marginal cells
Normally located in marginal zone of the spleen (area where T and B cells first enter spleen)
Mantle cell lymphoma
Characteristically associated w/ t(11;14) - involves the cyclind D1 gene (on 11) and Ig heavy chain locus (on 14) - results in overexpression of cyclin D1 (CCND1 or bcl-1)
Non-Hodgkin B cell lymphoma that originates from B-cells normally found in the mantle zones (normally located immediately outside of the follicle)
Small cleaved cells that stain + for CD5. CD19, and CD20
In contrast to CLL/SLL that are negative for CD23
Hodgkin lymphoma
Bimodal age group distribution: young adults and adults older than 50
sxs: fever, night sweats, and weight loss
Characterized by the proliferation of Reed-Sternberg cells - usually present w/ focal, nontender lymphadenopathy in a young adult
Reed-Sternberg cells
Malignant cells in Hodgkin lymphoma
Stain positively for CD15 and CD30
Appear as large binucleated cells w/ an owl-eye appearance in a background of reactive lymphocytes in a biopsy of lymphoid tissue
What is the most common subtype of Hodgkin lymphoma
Nodular sclerosis Hodgkin lymphoma
Characterized morphologically by the presence of lacunar cells (a variant of RS cells w/ a clear space surrounding the nucleus)
Hypercalcemia in individuals w/ Hodgkin lymphoma
May result from paraneoplastic secretion of gamma-interferon by activated T-cells - activates Vit D by increasing the expression of 1alphahydroxylase in malignant lymphocytes and macrophages
This same mechanism causing hypercalcemia can be seen with sarcoidosis
Sézary syndrome
The leukemic form of mycosis fungoides
characterized by finding CD4+ cells with cerebriform nuclei (Sezary cells) in the peripheral blood.
May be associated w/ a generalized pruritic erythematous rash - red-man syndrome
Mycosis fungoides is not associated w/ hypercalcemia
Mycosis fungoides
Malignancy of CD4+ T-cells
Skin biopsy shows atypical lymphocytes w/ markedly convoluted nuclei infiltrating the epidermis
May form characteristic intraepidermal clusters known as Pautrier microabscesses
Sezary syndrome
What malignancy of CD4+ T-cells is endemic in Southern Japan and parts of the Caribbean?
Adult T-cell leukemia/lymphoma - mostly affects CD4+ T-cell subset which have a predilection for the skin (cutaneous T-cell lymphomas)
Characterized by hypercalcemia and poor prognosis
The cause of ATLL is infection with HTLV-1, a virus that infects CD4-positive T-cells. Examination of the peripheral smear will show abnormal hyperlobated lymphocytes, called flower cells. The prognosis of ATLL is poor.
Langerhans cells
APCs found in the skin - possess characteristic racquet-shaped intracytoplasmic graunules known as Birbeck granules (pentilaminar bodies)
Histological markers:
CD1a (mediates Ag presentation)
S-100 (tumor marker for cells derived from the neural crest)
Hand-Schüller-Christian disease
Langherhans cell histiocytosis (multifocal LCH) that is characterized by the clinic triad:
Bone lesions (particularly the calvarium and base of skull)
DM I
Exophthalmos
Lesions are result of proliferations of LC’s - lesions around hypothalamus lead to decreased ADH production and signs of DM insipidus
Poor prognosis
Usually begins between the second and sixth years of life
Letterer-Siwe disease
Acute disseminated LCH
Affects young children (<3 y/o)
Cutaneous lesions that resemble seborrhea, hepatosplenomegaly, and lymphadenopathy
LC’s infiltrate the marrow which leads to anemia, throbocytopenia, and recurrent infections
Usually rapidly fatal, intensive chemotherapy 50% of Pt’s may survive 5 years
Eosinophilic granuloma
Unifocal LCH
Seen in older patients
Usually unifocal - most often affecting the skeletal sytem (usually ribs)
Lesions are granulomas that contain mix of lipid-laden Langerhans cells, macrophages, lymphocytes, and eosinophils
Excellent prognosis
What lymphoma is defined by finding hallmark cells upon histological exam?
Anaplastic large cell lymphoma (ALCL)
T-cell lymphoma
Hallmark cells may have nuclei w/ a horsehoe-like or embryo-like appearance
Malignant cells are strongly + for CD30
Anaplastic large cell lymphoma is associated with what gene mutation?
Mutations involving the ALK gene
What is the most common cutaneous T-cell lymphoma
Mycosis fungoides (MF)
Primarily affects the skin - but extracutaneous spread to lymph nodes, spleen, liver, and lungs is common
Stages in the involvement of skin w/ mycosis fungoides
- Generalized puritic erythematous rash
- Formation of plaques
- Formation of large tumore nodules
Early in the disease a skin biopsy will reveal a bandlike infiltrate in the upper dermis composed of atypical lymphocytes with markedly convoluted nuclei. These PAS-positive cells will infiltrate the epidermis (epidermotropism) and may form characteristic intraepidermal clusters known as Pautrier’s microabscesses.
Type of lymphoma that histologically shows popcorn-cells
Popcorn-cells = varian Reed-Sternberg cells called the lymphohistiocytic cells (L&H) - only seen in the lymphocyte predominant subtype
What class of lymphoma presents with contigous spread to adjacent node groups
Hodgkin lymphoma - therefore early Tx w/ radiation therapy is possible
How is the classification of Hodgkin lymphoma defined?
Based on the inflammatory response
Classic Hodgkin Lymphoma
- Nodular sclerosis HL
- Mixed cellularity HL
- Lymphocyte-rish HL
- Lymphocyte depletion HL (worst prognosis)
Nodular sclerosis is most common subtype of HL
Nodular slerosis is most common in females
Which forms of Hodgkins Lymphoma are associated w/ EBV?
- Mixed cellularity HL
- Lymphocyte-rich HL
- Lymphocyte depleted HL
Types of B-cells in normal germinal centers
- Centroblasts - large non-cleaved lymphocyte that have a nucleolus and usually lack a nuclear cleft
- Centrocytes - lack a nucleolus and have irregular or cleaved nuclei (small cleaved lymphocytes)
Buttock-cells
Malignant centrocytes (small cleaved cells) that are found within the peripheral blood
Associated w/ non-Hodgkin’s lymphomas
Is BCL2 expressed in reactive germinal centers?
No -
the product of BCL2 is located on the outer mitochondrial membrane, ER, and nuclear envelope - it inhibits apoptosis by blocking bax channels and by binding and sequestering apoptosis activating factor 1 (Apaf-1)
Interfers w/ apoptosis mechanism that involves cyt c being released from mitochondria via bax channels (cyt c binds and activates Apaf-1 which stimulates caspase cascade and promotes apoptosis)
Follicular form of non-Hodgkin’s lymphoma
Nodular (follicular) nHL results from neoplastic proliferation of B-cells dervided from germinal centers
Express CD19, CD20, and CD10 (CALLA), and surface Ig
How do nodules seen w/ follicular lymphoma histologically differ from germinal centers?
- Increased numbers (crowding) of nodules
- Location in both cortex an dmedulla
- Uniform size
- Composition (a monotonous proliferation of cells that lack tingible-body macrophages
Follicles are not surrounded by mantle zones (unlike normal reactive germinal centers)
Lymphoblastic lymphoma
high-grade lymphoma that frequently involves the bond marrow and peripheral blood
Malignant cells in most cases are T-cells - clinical picture similar to that of T-cell acute lymphoblastic leukemia
T-cell lymphoblastic lymphomas occurring in the thoracic vacity of young Pt’s usually arise in the mediastinum and have a particularly aggressive clinical course w/ rapid growth
Treatment for acute promyelocytic leukemia is with large doses of what?
All-trans-retinoic acid
Treatment for acute promyelocytic leukemia is with large doses of all-trans-retinoic acid (a vitamin A derivative).
What cells stain positive for terminal deoxynucleotidyl transferase (TdT) and negative for myeloperoxidase?
Lympoblasts
Testing for acute lymphoblastic leukemia vs acute myeloblastic leukemia
Malignant cells of chronic lymphocytic leukemia have what markers?
- The malignant cells of CLL are most often of B-cell origin and express CD19, 20, 21, and 23, along with the T-cell marker CD5.
