Malignant Lymphocyte Disorders Flashcards
What are the important chronic lymphoid leukemias?
- Chronic lymphocytic leukemia (CLL)
- Prolymphocytic leukemia (PLL)
- Hairy cell leukemia (HCL)
- Large granular lymphocytic leukemia (LGLL)
- Adult T cell leukemia/lymphoma (ATLL)
Who tends to get chronic lymphoid leukemias and what are the most typical clinical features?
Older adults, diseases have indolent course (except ATLL)
Lymphadenopathy, hepatosplenomegaly (like ALL)
Constitutional symptoms - fever, night sweats, weight loss, fatigue
Abnormal CBC with bone marrow infiltration
What is the cell morphology of chronic lymphocytic leukemia (CLL)?
- Small, mature-looking lymphocytes indistinguishable from normal
- Smudge cells present - ruptured lymphocytes (cells are fragile in CLL) CLL = crushed little lymphocytes
What is the most common leukemia? Who gets it? What are the flow cytometry markers?
CLL - always older adults
Phenotype by flow cytometry:
CD19+,CD20+ (B-cell), CD5+ (T cell marker)
-> these are naive B cells which co-express B and T cell markers
What other B cell malignancy also co-expresses B and T cell markers and how do you tell it apart from CLL?
Mantle cell lymphoma (MCL)
CD23: + in CLL, - in MCL
FMC7-: - in CLL, + in MCL
What are good and poor prognostic factors to have by FISH for CLL? By flow cytometry?
FISH:
Good: del13 - miRNA
Bad: del17 - p53
Flow cytometry:
High or positive = bad: CD38 or Zap70
What is the most common cause of death in CLL? What does this do to blood counts as well?
Infections due to hypogammaglobulinemia - neoplastic B cells do not want to produce useful antibody
If they do, often causes autoimmune hemolytic anemia (leads to thrombocytopenia (Evan’s syndrome) and anemia)
What is Richter’s syndrome / transformation?
Transformation of SLL / CLL into an aggressive lymphoma, most commonly a diffuse large B-cell lymphoma
What is the sister disease of CLL? How exactly are they related?
SLL = small lymphocytic lymphoma - involvement of lymph nodes leading to generalized lymphadenopathy. Absolute leukocyte count <5k
CLL = bone marrow and blood presentation, absolute lymphocyte count >5k
Both features present = phenotypically the same = treat the same
How is CLL staged?
Via the Rai Staging
0 - monoclonal lymphocytosis >5k
I - >5k + any lymphadenopathy
II - >5k +/- lymphadenopathy + hepatomegaly or splenomegaly
III - >5k + Anemia (<11 gm/dL) +/- lymphadenopathy or organomegaly
IV - >5k + Thrombocytopenia (platelets <100K/ul) +/- lymphadenopathy or organomegaly
When do we treat CLL and what with?
Generally we treat in stages III & IV only (once anemia / thrombocytopenia have developed), though we may treat earlier if constitutional symptoms arose or lymphs are doubling faster than 6 months
Treatment is best with Rituximab (anti-CD20) + chemotherapy
What are common infections in late CLL?
Neutropenia can also occur due to marrow failure and treatment, as well as B cell dysfunction, so:
Pneumonia, cellulitis, herpes zoster
What type of AIHA does CLL cause and what will be seen on peripheral smear?
Warm antibody Coomb’s positive
Microspherocytes - small with no central pallor
Polychromatophilic RBCs - large, pale RBCs
How do the cells appear in prolymphocytic leukemia (PLL)?
They appear halfway in maturity between blast cells and mature lymphocytes of CLL
Immature: Large cells with large nucleolus
Mature: Clumped nuclear chromatin
What are the distinctive clinical features of PLL?
Massive splenomegaly WITHOUT lymphadenopathy (except for T-cell PLL)
High lymphocyte count
More aggressive than CLL with poorer prognosis -> treat more aggressively
What are the two types of PLL?
About 75% are B-cell PLL (CD20+, CD5-)
25% are T-cell PLL (CD2+, CD3+)
How do patients present with hairy cell leukemia (HCL) and why?
Usually an older male presenting with infection or fatigue
HCL causes pancytopenias which leave you susceptible to infection or anemia / fatigue
What will physical exam and CBC show with HCL? Why do these things happen?
Massive splenomegaly due to accumulation of hairy cells in red pulp
NO lymphadenopathy (similar to PLL)
Pancytopenia will be the rule
-> due to massive fibrosis of bone marrow
What are the lab staining features of hairy cell leukemia? How do they look on peripheral smear? What is the mnemonic?
Mature B cells with hairy cytoplasmic processes (appear fuzzy on LM with indistinct borders)
Lab features - TRAP + (tartrate resistant acid phosphatase)
Remember these hairy cells are TRAPPED in the bone marrow (causing fibrosis) and TRAPPED in the red pulp causing splenomegaly
What will happen on bone marrow aspiration of HCL?
Dry tap -> due to marrow fibrosis
-fibrosis caused by B cell overexpression of FGF
What is the prognosis / treatment of hairy cell leukemia?
Excellent response to cladribine (2-CDA) + rituximab, and splenomegaly
90% complete remission with once cycle of 2-CDA
What will the CBC show for Large Granular Lymphocytic Leukemia (LGLL) and what does the peripheral smear show?
CBC shows cytopenias (neutropenia, anemia) with lymphocytosis
Peripheral smear shows GRANULES in lymphocytes (vs CLL) -> shows they are NK or CD8 T cells
What disorder is associated with LGLL and what lab testing is done to show it?
Rheumatoid arthritis - autoimmune phenomenon
Lab testing shows T-cell markers or NK markers (CD56, CD57)
What is the treatment for LGLL?
Not routinely needed. Give G-CSF for neutropenia, and steroids, cyclophosphamide, and MTX if needed
How is PLL told apart from CLL?
PLL will be associated with massive splenomegaly while CLL is less so
PLL is CD23- and FMC7+
CLL is CD23+ and FMC7-, and CD5+ (T cell marker)
What important marker is co-expressed with CD19 in HCL?
CD103+
What are lymphomas and the two broad types?
Large group of disorders characterized by malignant transformation of lymphocytes - usually leading to lymphadenopathy, but may be in extranodal tissue
Broad categories:
- Hodgkin Lymphoma
- Non-Hodgkin lymphoma
What are the “B” symptoms of lymphomas and how do they relate to prognosis?
Patients are “B”othered by constitutional “B” symptoms. At least one of:
- Fever
- Night sweats
- Weight loss
Indicates poorer prognosis
How does the lymph node spread pattern differ between NHL and HL? Extranodal involvement?
BOth are painless, non-tender lymphadenopathy
HL - usually contiguous lymph nodes and localized
NHL - usually skips lymph nodes (noncontiguous) with more extranodal involvement common
Which type (NHL or HL) is more dependent on staging? What is its treatment?
HL is much more dependent on staging
-> radiation is mainstay of therapy
How is diagnosis of lymphoma made? What’s the golden rule?
Need a biopsy, and usually a tissue biopsy (excisional is best, fine needle aspiration won’t work)
- > golden rule is always check CBC for lymphocytosis first in patients presenting with lymphadenopathy
- > may be able to diagnose CLL/SLL without need for biopsy based on presence of lymphocytosis / peripheral smear
When is staging done and how is it done?
AFTER diagnosis is established
-> do via history, blood work (CBC, chemistry, titers), Imaging (PET/CT), bone marrow biopsy may be warranted in some
cases
What are stages I-IV of the Ann Arbor staging system for lymphomas?
I - involvement of one group of LN
II - involvement of 2 or more groups of LN on same side of diaphragm (above or below)
III - 2 or more groups of LN on BOTH above and below diaphragm
IV - involvement of any organs or tissues outside of lymphatic system (extranodal sites), including bone marrow
How do you determine stage IA or IB?
IB = worse prognosis, presence of “B” symptoms!!!
What is PET/CT?
An imaging procedure used for staging of lymphoma
PET - functional glucose utilization to visualize tumor activity
CT - anatomical enlargement
PET/CT = fused image
What would be the stage of lymphoma if patient had involvement of hilar lymph nodes alone and disease extends into adjacent lung tissue?
IE, not IV
Because E = extension into tissue directly adjacent to a lymph node
Note, if you had lung involvement but the lymph nodes involved were the mesenteric nodes for instance, it would be Stage IV
What are the most common extranodal sites of spread for lymphoma?
Liver and bone marrow (peritrabecular area, around the little bone spindles will be hypercellular)
What is the presentation of Adult T-cell leukemia/lymphoma?
Most common in Caribbean and Japan (endemic areas)
A diffuse erythematous rash due to skin infiltration, generalized lymphadenopathy with hepatosplenomegaly
What cells are present in peripheral smear of Adult T-cell leukemia/lymphoma? What causes it?
Associated with HTLV-1
Bizzare clover-leaf nuclei of T-cells with CD4+ phenotype
What are the X-ray and serum manifstations of ATLL? What could you confuse this with?
Lytic bone lesions, hypercalcemia
-> Easily confused with multiple myeloma, but note the presence of the rash
Because B symptoms can be present in NHL and HL, what are some more specific history / exam findings for HL?
- Intense pruritis
2. Alcohol-induced pain at site of disease
What is the malignant cell in Hodgkin lymphoma? What do they look like? What is this disease associated with?
Reed-Sternberg cells
- > They look like “owl-eyed nuclei” - large B cells with bilobed nuclei and prominent nucleoli
- > associated with EBV
How is the RS cell of HL identified and why? What markers are used?
Identified by immunohistochemistry (not flow cytometry) because majority of cells are reactive to the cancerous RS cells -> lymphocytes, plasma cells, macrophages, eosinophils
15 * 2 owl eyes = 30
Identified by CD15,CD30, they are actually CD20- despite being B cells
What are the four types of classic HL? Which is most common?
- Nodular sclerosis - most common
- Lymphocyte-rich
- Mixed cellularity
- Lymphocyte depleted
Give the salient features of each type of HL in terms of what makes them unique.
- Nodular sclerosis - most common, especially females
- Lymphocyte-rich - best prognosis
- Mixed cellularity - high eosinophils due to RS cells producing IL-5
- Lymphocyte depleted - seen in immunocompromised, worst prognosis (elderly and HIV positive)
What is the treatment for HL?
Aggressive radiation in early stages, with ABVD regimen in all four stages
What are the CBC findings in HL?
Normocytic anemia
Leukocytosis (reactive)
Lymphopenia (in advanced stage)
Platelets (increased early, decreased reactive)
Elevated ESR due to cytokine production
What is the prognosis for HL and the late effects of treatment?
Prognosis is very good for cure
Unfortunately, high risk of later diagnosis of solid tumors from chemo / radiation
What are the general treatment paradigms with NHL?
Early stage (I/II): Radiation, or chemotherapy 3 cycles + radiation if aggressive
Late stage (III/IV): Waiting, Rituximab, or chemotherapy 6 cycles +/- radiation if aggressive
Chemotherapy is R-CHOP (vs AVBD with HL)
What marker tells you generally how aggressive a lymphoma is?
Ki-67 - % of cells expressing this = % of cells in S phase
~30% = low ~50% = intermediate ~80% = high aggression
What are the indolent (low grade) lymphomas?
Follicular lymphoma
Small lymphocytic lymphoma (sister of CLL)
Marginal zone lymphoma (MZL)
Waldenstrom’s macroglobulinemia
Who tends to get indolent lymphomas and what is the treatment goal?
Older adults
- > will be advanced stage at presentation due to slow course
- > often painless lymphadenopathy
- > general intent is palliation
What is the most common indolent lymphoma and what causes it?
Follicular lymphoma
- > caused by t(14;18) -> BCL-2 gene on chromosome 18 is translocated to heavy chain locus on chromosome 14
- > indolent because Bcl-2 inhibits apoptosis and cells slowly proliferate
How is follicular lymphoma differentiated from follicular hyperplasia (reactive)?
No tingible body macrophages due to slow growth, Bcl-2 will be expressed, cells will be monoclonal, and normal lymph node architecture will be disrupted
What are the three stages of follicular lymphoma?
Grade 1 - small cleaved cells
Grade 2 - mixture
Grade 3 - Large cells (getting closer to diffuse B cell lymphoma)
What is marginal zone lymphoma? What is the most common type?
Neoplastic proliferation of small B cells that expands the marginal zone (post-germinal center B cells)
Most common type is MALT (mucosal associated lymphoid tissue) lymphoma
What conditions is marginal zone lymphoma associated with? What is the treatment of a commonly tested subtype?
Associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, H. pylori gastritis
Treatment for gastric MALToma often involves treatment of H. pylori infection
What are examples of intermediate aggressiveness lymphomas?
Diffuse large B cell lymphoma (DLBCL)
Mantle cell lymphoma
What are the germinal center markers expressed by follicular lymphoma?
CD10 and Bcl-6
What is the most common NHL overall? What does it usually arise from?
Diffuse large B cell lymphoma - with poorly differentiated cells
Arises from follicular lymphoma progression, or Richter transformation of CLL
What causes mantle cell lymphoma? What chromosomal abnormality is associated?
Proliferation of small B cells that expands the mantle zone
Associated with t(11;14) - cyclin D1 from chromosome 11 is put at heavy chain locus
-> aggressive movement through growth cycle
What are the flow cytometry markers of importance for mantle cell lymphoma?
Remember this is the one to differentiate from CLL because it also expresses T cell markers
CD19+, CD5+, CD23-, FMC7+
What causes Burkitt lymphoma and what is it associated with?
Neoplastic proliferation of intermediate-sized B cell, associated with EBV infection
t(8;14) - movement of c-myc to heavy chain locus
Very high aggression
What are the two forms of Burkitt lymphoma?
- Endemic form - Africa = jaw presentation in children
2. Sporadic - more loosely associated with EBV, lesion in pelvis (especially kidneys) or abdomen
How does Burkitt lymphoma appear under the microscope?
Starry sky appearance from high mitotic rate background with stars of tingible body macrophages eating necrotic cells
You find someone with cutaneous plaques made of CD4+ T cells. They are very itchy and look like psoriasis, and you find out it’s a lymphoma, but you are not in the Caribbean or Japan. What are these skin patches called?
Pautrier microabscesses
What is the name of the disease causing Pautrier microabscesses, and what do the cells inside look like?
Mycosis fungoides
- > cells are called Sezary cells
- > CD4+ T cells with folded, cerebriform nucleoli
What is Sezary syndrome? Prognosis?
Progression of mycosis fungoides to T cell leukemia -> sezary cells in blood.
Prognosis = indolent but incurable course
What T-cell lymphoma is not caused by HTLV-1 and causes a nodular rash rather than psoriasis-like? How do the cells look?
Anaplastic Large Cell Lymphoma (ALCL)
-> cells look anaplastic and bizarre, but prognosis is actually good
What mutation is associated with ALCL, and what markers do the cells express?
t(2;5)
Cells express CD30 (like R-S) cells, but do NOT express CD15
Which Rai stages of CLL are low, medium, and high risk?
Low - 0 and I
Intermediate - II
High - III&IV
Can you treat Burkitt lymphoma?
Yes - it is highly aggressive but a curable disease with chemotherapy
What is Serum Protein Electrophoresis (SPEP)? How do you tell if something is monoclonal or polyclonal?
A way to analyze proteins in the serum
Polyclonal gamma globin peaks will be broad
Monoclonal peaks will be narrow-based (usually about the width of the albumin peak)
What are immunoproliferative diseases and what are the usually associated with on SPEP?
Malignant proliferations of Ig-secreting plasma cells
Usually associated with paraproteinemia -> monoclonal band on SPEP which reflects synthesis of Ig from a single clone
What are the classic symptoms of symptomatic myeloma? Give why all these symptoms happen
CRAB
Calcemia - hypercalcemia due to plasma cells activating RANK on osteoclasts, increasing bone resorption
Renal impairment - Free light chain excreted in urine damages kidney tubules, renal failure
Anemia - normo-cytic or macrocytic - Rouleaux formation
Bone disease - lytic lesions due to increased bone resportion
What is smouldering myeloma vs symptomatic myeloma?
Symptomatic:
- Monoclonal protein in serum or urine
- > 10% plasma cells in bone marrow
- CRAB symptoms
Smouldering:
Asymptomatic - still >10% plasma cells and monoclonal protein, but no CRAB
What is MGUS? Why is it relevant?
Monoclonal gammopathy of undetermined significance
-> M spike - monoclonal spike on SPEP, but plasma cells are <10% on bone marrow and no CRAB symptoms
- MGUS is common in older patients, and progresses to multiple myeloma at a rate of 1% per year (precursor to MM)
What is the definition of multiple myeloma?
Most common primary malignancy of bone - expansion of malignant plasma cells in bone marrow, characterized by lytic bone lesions, manifestations of marrow failure, and consequences of secreted proteins
How do plasma cells appear in MM? What markers do they express?
Deep blue cytoplasm with perinuclear halo where the Golgi is
Plasma cells nuclei are eccentric with clock-face chromatin
Express CD38 and CD138
Why does bone marrow failure happen in MM?
Myeloma (plasma) cells are post-germinal center B cells which hone in on the bone marrow and crowd out normal hematopoiesis as they expand
-> anemia, neutropenia, thrombocytopenia
What happens to the ESR in multiple myeloma and why?
It increases, because increased immunoglobulins affect the electrical surface charge of RBCs and cause them to form Rouleaux formations. Rouleaux formation settle faster in the test tube.
What is the most common cause of death in multiple myeloma?
Infection -> decrease in normal serum immunoglobulins because they are suppressed by malignant clone
What causes renal injury in MM?
- Bence Jones protein - kappa or lamda light chains deposit in renal tubules
- Amyloid deposition - in glomeruli and blood vessels
- Calcium deposition - nephrocalcinosis due to hypercalcemia
- Pyelonephritis - from inflammatory cells
- Uric acid crystal deposition (hyperuricemia from cell turnover)
What imaging test must be avoided in patients with multiple myeloma?
IV contrast dye - can precipitate renal failure in patients already with renal problems
What is the most common presenting symptom of MM? Why? How does this relate to standard workup?
Backache - due to bone pain -> loss of bone from osteoclast activation leads to punched out lytic lesions, especially affecting weight bearing bones
- > compression of vertebral bodies and weight bearing bones leads to fractures
- > Standard workup is an X-ray of all bones
What types of antibody are normally produced in multiple myeloma?
IgG - 60% of cases
IgA - 20-25% of cases
Others produce only light chain
Rest are rare
What test has replaced Bence-Jones protein detection in urine for multiple myeloma?
Serum free light chain (FLC)
Normal ratio is 0.6 kappa:lamda. Will be very skewed in multiple myeloma
What protein is produced by plasma cells and has prognostic value in MM? Give the staging scheme.
B2-microglobulin - a part of MHC1
<3.5 mg/L is favorable (Stage I), along with albumin >3.5 g/dL
Middle: Stage II
>5.5 mg/L is poor (Stage III)
What is the best new treatment for multiple myeloma, and what is the most common symptomatic treatment? What can you do if MM is located only at one site?
Only at one site - radiation may be effective
Common symptomatic treatment - bisphosphonates (for hypercalcemia and bone disease, stops osteoclasts)
Best new - Anti-CD38 (plasma cell marker) called Daratumumab
What treatment is initially curative but often results in relapse of MM?
Autologous bone marrow transplant
What condition sometimes follows multiple myeloma but is rarely a primary condition? What is the clinical definition?
Plasma Cell Leukemia (PCL)
>20% plasma cells in blood, with absolute plasma cell count >2k
Clinical features of pancytopenia with CRAB
What are clinical features of amyloidosis?
- Macroglossia
- Cardiomegaly, CHF, arrhythmia - pressure atrophy and conduction disturbances
- Peripheral neuropathy
- Renal failure
- Carpal tunnel syndrome (from beta-2 accumulation)
What is the definition of Waldenstrom macroglobulinemia?
Malignant proliferation of IgM-secreting plasmacytoid B lymphocytes in bone marrow
-> M spike = IgM accumulations
How does Waldenstrom macroglobulinemia differ from MM?
It is associated with soft tissue disease rather than bone disease
- > generalized lymphadenopathy, no lytic bone lesions
- > defects are due to high IgM levels and tissue invasion of neoplastic cells
What are the symptoms of Waldenstrom macroglobulinemia?
-> hepatosplenomegaly
-> cytopenias
-> generalized lymphadenopathy
Hyperviscosity syndrome w/polyneuropathy
What is hyperviscosity syndrome and is it related to MM and/or Waldenstrom?
Increased blood viscosity from increased blood components (could be RBCs / WBCs)
Associated with Waldenstrom much more than MM because IgM is much larger than IgG or IgA
What are the clinical features of hyperviscosity syndrome?
All due to engorgement of small vessels with impaired platelet aggregation
Visual disturbances and retinal changes due to retinal hemorrhages / occlusion
Lethargy, confusion, weakness - stroke symptoms due to poor blood flow
Epistaxis - bleeding due to small vessels in nose and poor platelet function
CHF due to increased afterload
How is hyperviscosity syndrome treated acutely and definitively if due to Waldenstrom?
If due to Waldenstrom: Plasmapheresis - remove IgM
Definitively: treat underlying disease
How do cells appear in peripheral smear in Waldenstrom?
Lymphoplasmacytoid -
Features in between small lymphocytes and plasma cells
What is the mnemonic for translocations in Burkitt lymphoma, follicular lymphoma, and mantle cell lymphoma?
Baby, Mother, Father
8, 11, 18 (ascending size)
t(8;14) = Burkitt t(11;14) = Mantle cell t(14;18) = Follicular
