Lecture 13/14 - Lymphoproliferative disorders Flashcards
Lymphoproliferative disorders are neoplasms of?
- Lymphocytes
- Plasma cells
Myeloproliferative disorders are neoplasms from?
Bone marrow stem cells
* Neutrophils
* Monocytes
* Erythrocytes
* Rarely: eosinophils, basophils
Lymphoma is a neoplastic process that is
Neoplastic process
confined to solid
tissues
Involves B or T cells –> neoplastic
Lymphocytic leukemia is a neoplastic process that is
Neoplastic process involves either bone marrow and/or blood
B or T cells –> neoplastic
A-Acute Lymphocytic leukemia ALL
B-Chronic lymphocytic leukemia CLL
Multiple myeloma is a specific ____ cell neoplastic process
- _______ cell differentiation
Specific B cell neoplastic process
Plasma cell differentiation
In a case of acute lymphocyte leukemia (ALL)
Undifferentiated/ immature
lymphocytes (lymphoblasts)
* Cats: most were FeLV of FIV
positive
In a case of chronic lymphocytic leukemia (CLL)
Normal-
appearing/mature
lymphocytes
What are the DDx in a case of Lymphocytosis
See below
In a case of Lymphocytosis in a dog, if the CBC >35,000/uL then your Dx is?
Surely: LEUKEMIA
In a case of Lymphocytosis in a dog, if the CBC >15,000/uL
& tick borne dz Neg, then your Dx is?
LEUKEMIA
- 50% of Acute lymphocytic leukemia cases will have?
- 65% of Multicentric lymphoma cases will have?
- What happens when you perform a blood test on both patients?
- How will you determine whether or not your patient has stage 5 lymphoma aka leukemic stage of lymphoma?
- Lymphadenopathy
- Lymphadenopathy
- Both patients will have leukemia.
- The location of the neoplastic cells will help you determine whether the patient has Stage 5 Lymphoma or Leukemia.
- if it is in the bone marrow and organ it is stage 5 lymphoma.
Circulating lymphoblasts in bone marrow and lymphoma in LN = stage 5
Lymphoblasts but NO lymphoblastic cells in an organ = ALL
What can be seen on the slide below?
In this slide, nearly all lymphoid cells are “______” with prominent ______; ______ are not seen, and normal leukocytes are _____.
In this slide, nearly all lymphoid cells are “large” with prominent nucleoli; platelets are not seen, and normal
leukocytes are rare.
(ALL) is a _______ malignancy that affects dogs of ____ ages and of ______ sex; ____-breed dogs may be overrepresented.
ALL primarily involves ____ _____, which is _______ and usually replaced by an overabundance of _________.
* ________ ______ of malignant cells, not cellular morphology, generally differentiates ALL from ?
lymphoid, all, either, large
bone marrow, hypercellular, lymphoblasts
Anatomic distribution, stage V lymphoma..
What are the Clinical presentation of ALL?
- Pale mucous membranes
- Splenomegaly
- Hepatomegaly
- Lethargy
- Weight loss
What are the Lab findings ALL?
- Anemia
- Thrombocytopenia
- Lymphocytosis **
- Neutropenia
- Lymphoblasts in blood
How do we identify lymphoblasts?
- ________
- __________
- ___________ (_____ for most stains), (____ for non-specific esterase)
- Morphology
- Immunophenotyping
- Cytochemistry (negative for most stains)
- positive for non-specific esterase
What is the prognosis of ALL?
- CD34+ extreme ____ prognosis, median survival ___ d
- CD8+ (T-cells) median survival ___ d >30,000 L0 vs _____d <30,000
- B cell median survival ____d (large cells) vs >_____d if ”small cells”
- POOR
- Rapid clinical course, progressive, poorly responsive to therapy
* CD34+ extreme poor prognosis, median survival 16 d
* CD8+ (T-cells) median survival 131 d >30,000 L0 vs 1068d <30,000
* B cell median survival 129d (large cells) vs >100d if ”small cells”
In a case of Chronic lymphocytic leukemia
* Lymphocytes are ?
_____ and appear Well ___________
* More common in _____
* Must differentiate from other causes of ___________
small and appear Well Differentiated
* More common in dogs
* Must differentiate from other causes of lymphocytosis
What are the lab findings you would see in a case of Lymphocytosis?
- DDx in cats:
a. Excitement: usually < _______/uL
b. ________ _______ disease (?)
- Dx by _______, ____ for lymphoma, _______
c. ___ stimulation (rare for lymphocytosis in small animals)
- In cats: ?
- DDx in cats:
a. Excitement: usually <20,000/uL
b. Neoplastic lymphoproliferative disease (lymphocytic leukemia) - Dx by morphology, PCR for lymphoma, immunophenotyping
c. Ag stimulation (rare for lymphocytosis in small animals) - In cats: Bartonella henselae -Cat scratch fever-
The cells pictured below are seen in dogs with what condition?
This condition results in _________ and _____ stimulation. This ___ stimulation over the course of a _____ period of time with lymphocytes that are ____ in size and ____ in appearance.
Lymphocyte (L0) count seen = ?
Anything above this is ____.
- Erlichia canis
- Lymphocytosis, Ag, Aglong, large, granulr,
- up to 10,000 uL, rare
Ag stimulation (rare for lymphocytosis in small animals)
Dogs:
* Ehrlichia canis
* Chronic phase
* Large granular L0 up to 10,000 uL but
* L0 count rarely >10,000/uL in other Ag stimulation which is also rare
* Excitement lymphocytosis is rare in dogs
What is the clinical presentation of CLL?
- May be __________
* Dx during ? - If clinical signs are seen?
- Very similar to ____:
- May be asymptomatic
* Dx during wellness exam - If clinical signs are seen:
* Lethargy
* Anorexia
* Pale mucosal membranes
* Lymphadenopathy
* Splenomegaly
* Hepatomegaly
Very similar to ALL:
Pale mucous membranes
Splenomegaly
Hepatomegaly
Lethargy
Weight loss
What are the lab findings you would see in a case of CLL?
- ___________
- Ranging from ______ elevated to highest RI to >_______/uL
- May be _____
- May exhibit ____________
- FOR SURE will have ________ _______ _______ in bone marrow
- ____-____% of the count
- Rarely will we see __________ _______
- Cats are usually ?
- Lymphocytosis
- Ranging from slightly elevated to highest RI to >300,000/uL
- May be anemic
- May exhibit thrombocytopenia
- FOR SURE will have Increased small Lymphocytes (L0) in bone marrow
- 25-100% of the count
- Rarely will we see Monoclonal gammopathy
- Cats are usually FeLV Neg.
What are the arrows pointing to below?
For comparison: see morphology of a smear with LARGE Lymphocytes (arrows) vs
small Lymphocytes (arrowheads)
What diagnostic techniques are used to phenotype lymphocytes?
- Flow cytometry
- Immunophenotyping
How do you immunophenotype by Flow cytometry?
- Flow cytometry detects antigenic proteins expressed on the surface of lymphocytes
- T –cells: CD3,CD4, CD5,CD8
- B-cells: CD21 CD45, CD11
–> For prognosis and targeted treatment:
* CD 34 expression predicts ______ outcome
* CD8+ and lymphocyte conc >30,000/μl _______ survival time than <30,000.
* Similar outcome with CD__, CD__, CD___+ and CD__+ T-cell leukemias
* CD21+ B-cells patients with ______ L0 survive LESS time than patients with _____ cells
* Old dogs with B-cell Leukemia survive ______ than young dogs
* Dogs with T-cell CLL and no anemia survive ______
–> For prognosis and targeted treatment:
* CD 34 expression predicts poor outcome
* CD8+ and lymphocyte conc >30,000/μl shorter survival time than
<30,000.
* Similar outcome with CD4, CD8, CD5+ and CD8+ T-cell leukemias
* CD21+ B-cells patients with large L0 survive LESS time than
patients with small cells
* Old dogs with B-cell Leukemia survive longer than young dogs
* Dogs with T-cell CLL and no anemia survive longer
- Lymphoma is a diverse, _________ disease that results from the ________ ______ expansion of malignant _________
- Generally considered a ______ disease
- Broad range of potential outcomes
- From ______ clinical decline to a long _______ dz lasting for years
heterogeneous, uncontrolled clonal, lymphocytes, systemic, rapid, indolent
How is lymphoma classified?
- __________ distribution in body
- ___________ distribution in organ
- ____________
- Immunophenotype (?)
- __-cell
- ___-cell
- Aberrant (________) cell
- Cell _____-
- Grade (by ________ index)
- Class ____ Major Histocompatability (MHC) expression
- _______ at presentation
- _________ characteristics
- BIOLOGIC BEHAVIOR (?)
- Anatomic distribution in body
- Histologic distribution in organ
- Cytomorphology
- Immunophenotype (Flow cytometry, Immunohistochemistry, PCR for
antigen receptor rearrangement (PARR)- B-cell
- T-cell
- Aberrant (Atypical) cell
- Cell Size
- Grade (by mitotic index)
- Class II Major Histocompatability (MHC) expression
- Stage at presentation
- Molecular characteristics
- BIOLOGIC BEHAVIOR (indolent, aggressive, response to Rx)
Anatomic distribution: dermal lymphoma, intestinal lymphoma, splenic lymphoma,
etc
Histologic distribution: epitheliotropic, etc
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How do you classify Lymphoma?
How would you describe the prognosis of Lymphoma?
What is the difference between cytology and histopathology for Lymphoma?
- Cytology Dx of lymphoma not for classification
- Histopathology Dx of lymphoma and classification
- Most Lymphomas are Dx by cytology and histopath is not performed
What can be seen in the image below?
Aspirates from lymph nodes with high grade B cell lymphoma
STUDENTS notes: atypical medium to large lymphoid cells with dispersed chromatin
and multiple prominent nucleoli (red arrows).
Large lymphoid cells relative to small lymphocytes (black arrows)
neutrophils (yellow arrow).
The green arrow identifies a mitotic figure.
(Diff-Quik, 600x magnification)
Your patient presents to you for parotid lymphadenopathy. You aspirate each lymph node and analyze your sample under the microscope and see this.
1. What is your preliminary diagnosis, solely based on this aspirate alone?
2. What do you notice about the cells in this aspirate?
- >85% of cells are morphologically distinct ______-sized lymphocytes with round ______, loosely clumped _______ and increased amounts of _____ _____ cytoplasm which often extends from one pole of the cell in a _____ ______ configuration (yellow arrows).
- Dx: High grade B cell lymphoma
- > 85% of cells are morphologically distinct small-sized lymphocytes with round nuclei, loosely clumped chromatin and increased amounts of pale blue cytoplasm which often extends from one pole of the cell in a hand mirror configuration (yellow arrows).
(Diff-Quik, 500x magnification)
Multiple myeloma
Proliferation of _______ cells at various sites in the ______ _____, and eventually other _______.
* Release into the __________ blood occurs occasionally, but usually in very _____ numbers
* survival time is _____ if leukemia present
- Proliferation of plasma cells at various sites in the bone marrow, and
eventually other tissues. - Release into the peripheral blood occurs occasionally, but usually in
very small numbers - survival time is less if leukemia present
Describe the Clinical presentation of Multiple Myeloma
- Non Specific
- Related to the presence of neoplastic plasma cells in the marrow and
other tissues - Lethargy,
- anorexia,
- lameness,
- polyuria and polydipsia
Lameness, paresis or paralysis, and pain occur secondary to osteolysis or spinal cord
compression.
- What occurs in 1/3 of dogs and cats with Multiple myeloma?
- Renal insufficiency (excessive ______ chain production or _________)
- Proteins interfere with _____ and _______ function
- Also may be secondary to ________ and subsequent ________ of kidneys
Renal disease
* 1/3 of dogs and cats
* Renal insufficiency (excessive light chain production or hypercalcemia)
* Proteins interfere with tubular and glomerular function
* Also may be secondary to hypercalcemia and subsequent mineralization of kidneys
Blood hyper-viscosity occurs in cases of Multiple Myeloma are related to the ____________ that the tumor cells produce.
- Fundoscopic changes (________ hemorrhages and venous ________ with tortuous retinal blood vessels
* –> ______
Blood hyperviscosity
* Related to the immunoglobulins that the tumor cells produce
* Fundoscopic changes (retinal hemorrhages and venous dilatation
with tortuous retinal blood vessels
* àCNS
What are your lab findings in cases of Multiple Myeloma?
- > 20% _______ cells in bone marrow (usually in _________)
- Must be differentiated from _______ ________ _________
- ________ or ______ gammopathy
- Usually Ig__ or Ig___
- Occasionally Ig__
- _______-_____ proteins in urine
*_________ immunoglobulin light chains
- > 20% plasma cells in bone marrow (usually in aggregates)
- Must be differentiated from chronic antigenic stimulation
- Monoclonal or biclonal gammopathy
- Usually IgG or IgA
- Occasionally IgM
- Bence-Jones proteins in urine
- monoclonal immunoglobulin light chains
What can be seen in the image below?
Bence-Jones proteins in urine
In UA, we will look at the urine sediment and see an accumulation of “yarn.” This accumulation is called B-J. If we stain the sediment, or even better if we do immunochemical staining with antiserum to the L-chain.
- monoclonal immunoglobulin light chains
- What samples should you collect when doing Electrophoresis?
- What is the purpose of this process? What is it used for?
- Sample: Serum *, Urine, Body fluids
- Separates the PROTEINS –> Albumin & globulins. Use to determine the elevated globulins (hyperglobulinemia) or if Multiple myeloma is suspected
What are the differences between each of the following graphs:
This is an X-ray image taken of a patient with Multiple Myeloma. What can be seen below?
1. Is this a common occurrence in patients with Multiple Myeloma?
2. What is the % of commonality in dogs? Cats?
- Foci of lytic bone is common
- ~50% dogs
- ~8-67% cats
the true incidence of lytic lesions in cats is unknown
What can be seen in the image below?
This Xray is from A lateral stifle of a dog with multiple myeloma. A lytic punched-out
bone lesion (white arrow) is present in the proximal tibia.
In cases of Multiple Myeloma in cats, what do you see?
- _______ _______ cell morphology
- _______
- Bone ______
- ______ involvement – very common in cats
- Atypical plasma cell morphology
- Anemia
- Bone lesions
- Organ involvement – very common in cats
How do you Dx Multiple Myeloma?
Requires demonstration of at least 2 of the following criteria:
* bone marrow plasmacytosis,
* presence of osteolytic bone lesions,
* monoclonal hyperglobulinemia,
* Bence-Jones proteinuria
Multiple Myeloma prognosis is worse if the patient is ________ or have severe _______, ___________ or _____________.
Other factors associated with shorter survival time are?
- Worse if azotemic or have severe anemia, neutropenia or
thrombocytopenia.
Associated with shorter survival time:
1. Hypercalcemia
2. Bence-Jones proteinuria
3. Plasma cell leukemia
4. Extensive bone lesions
The CBC was unremarkable apart from a mild non-regenerative anemia, which was
thought to be a nonspecific finding and secondary to the underlying problem.
What can be seen in the bloodwork below:
The CBC was unremarkable apart from a mild non-regenerative anemia, which was
thought to be a nonspecific finding and secondary to the underlying problem.
What can be seen in the bloodwork below:
The chemistry profile revealed a marked hyperglobulinemia
- Hyperglobulinaemia could be monoclonal or polyclonal.
- Monoclonal hyperglobulinaemia could be caused by multiple myeloma, lymphoma, lymphatic leukaemia, or less commonly by infectious disease (e.g. leishmaniasis, ehrlichiosis).
- Polyclonal hyperglobulinaemia could be the result of chronic inflammatory and infectious diseases, neoplasia, or immune-mediated diseases.
What can be seen in the bloodwork below:
The chemistry profile also revealed hypercalcaemia based on total calcium.
Hypercalcaemia was confirmed by measurement of ionized calcium. We will talk
more about Calcium and globulins later in the semester.
What can be seen below:
Urine specific gravity was 1.008 and sediment was inactive. The low urine specific
gravity could be secondary to hypercalcaemia.
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Based on these Diganostic tests, what do you see is going on with Sydney?
- X-rays of the caudal vertebrae were unremarkable
- Due to finding
1. hyperglobulinemia
2. hypercalcaemia - DDx: Multiple myeloma or lymphoma
What about Proprioceptive ataxia ? It could be related (e.g. spinal involvement),
however, concurrent disease (e.g. disc protrusion) unrelated to the clinicopathologic
findings cannot be ruled out.
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You determine your patient suffers from hyperglobulinemia. What is the next step?
- Order ______ _______ ________ in order to evaluate the ________ of the hyperglobulinemia.
- Order _______ _____ _______ in order to identify ________-________ _______.
- Order Serum protein electrophoresis
- Urine protein electrophoresis
Order 1-Serum protein electrophoresis to evaluate the nature of hyperglobulinaemia,
2-urine protein electrophoresis to identify Bence-Jones proteinuria.
How would you interpret these Electrophoresis results?
Serum protein electrophoresis:
Narrow spike-like peak in gamma region indicating monoclonal hyperglobulinemia
Hyperglobulinemia was identified as monoclonal with a narrow spike in the gamma
region. Monoclonal hyperglobulinemia supported the assumption of a neoplastic
disease and made an infectious disease less likely. On urine protein electrophoresis
revealed no evidence of Bence-Jones proteins.
What can be seen in the Xray below?
Radiograph of right humerus: extensive bony lysis
Density of the bone has changed, especially on distal portion of humerus.
What can be seen in the histological sample below?
Cytology from bone marrow aspirate
Classic neoplastic plasma cells
- They are very characteristic to have a large amount of cytoplasm, to be more bluish/basophilic and then have mostly peripheralized nucleus.
NORMAL plasma cells:
- Have a round, eccentrically placed nucleus with coarse chromatin arranged in a clock face (art wheel) pattern.
Aspirate confirms, together with lytic changes, that the patient has multiple myeloma.
What can be seen in the diagnostic image below?
Ultrasound image of the spleen showing hypoechoic nodules.
- Also neoplastic cells in visceral tissues
Hypoechoic means: This term means “not many echoes.” These areas appear dark gray/darker on US because they don’t send back a lot of sound waves. Solid masses of dense tissue are hypoechoic.
Based on these findings, what diagnosis would you give Sydney?
Multiple myeloma based on:
1. Hyperglobulinemia,
2. osteolytic lesions in multiple bones
3. plasma cell infiltration into spleen and bone marrow
Monoclonal hyperglobulinaemia could be caused by?
Or less commonly by ?
multiple myeloma, lymphoma, lymphatic leukaemia,
infectious disease (e.g. leishmaniasis, ehrlichiosis).
Polyclonal hyperglobulinaemia could be the result of ?
chronic inflammatory and infectious diseases, neoplasia, or immune-mediated diseases.
Hypercalcaemia could have been malignancy associated (e.g. ?), due to ?
LAMP:
lymphoma
multiple myeloma
apocrine gland carcinoma of anal sac
primary or metastatic bone neoplasia
GHHRP:
hypoadrenocorticism
primary hyperparathyroidism
granulomatous diseases
hypervitaminosis D
renal failure.
