5. Leukemia/Lymphoma Flashcards
Myeloproliferative diseases – Polycythemia vera
• Clonal proliferation of hematopoietic ____ cells
• Erythrocytosis
– May be associated with ____ and ____
• ____ mutations
- I’ll start the discussion today by talking about red blood cell disorders, specifically and most commonly, Polycythemia vera.
- Myeloproliferative disease includes an array of different diseases, all of which affect red blood cells.
- There are some rare forms and some not-so-rare forms. In the grand scheme of things, all cancer is unusual and uncommon, but of the cancers that occur of the red blood cells, this is by far the most ____. (“This” being Polycythemia vera.) This represents a clonal proliferation of a stem cell that is differentiating into RBCs.
stem leukocytosis thrombocytosis somatic JAK2 tyrosine kinase common
Myeloproliferative dx - Polcythemia vera
Conversely, in anemia, there’s fewer RBCs relative to blood volume, and that’s a lower ____
So, Polycythemia is the exact opposite of ____ in regards to hematocrit effects In a blood smear, look at a microliter or a pin prick that you spread on a slide of normal or anemic blood.
You would see far more cells in polycythemia in the same amount of volume in a smear than you would in anemic. Because there are more RBCs, hemoglobin is ____, and then by extension, iron is ____.
One of the treatments for this disease is actually ____ blood from the body to reduce
blood volume and hence reducing the risk for iron overload. This is one of the main
treatments we use apart from medication.
Again, understanding signaling - if EPO is used to activate RBC formation, and too many red blood cells already formed, the EPO should be ____. And that’s exactly what happens.
So, because there’s so many RBCs in the system, there’s less EPO that needs to be released
from kidney to stimulate more synthesis. So, you’re stopping additional synthesis.
ESR (Erythrocyte Sedimentation Rate) will be reduced. Will discuss in a second. Clinically, you will see the effects that occur as a result of too many red blood cells.
They may ____ more frequently (thrombosis)
◦
The body is in overdrive trying to kill off the excess RBCs, so they will have ____ as a result.
Patients are systemically itchy all over (pruritus). As a palliative measure, the patients are
typically prescribed ____ to reduce itchiness.
hematocrit
anemia
elevated
elevated
drawing
decreased
clot
antihistamines
Erythrocyte sedimentation rate
• Rate at which red blood cells sediment in ____ hour (mm / hr)
• Balance between ____-sedimentation factors (eg fibrinogen) vs
factors resisting sedimentation (eg negative charge on RBCs)
• Reduced in ____ and sickle cell anemia
ESR=Erythrocyte Sedimentation Rate
An “intuitive test because the name itself is what it actually is in terms of the test.”
◦ What you do: take a blood draw, put it into tube, and let it sit at room temperature for an hour.
RBCs will drop to bottom of the tube via ____ alone. Will sediment to the bottom of the tube.
◦ You are measuring the total length of the ____ volume in relation to the ____ volume.
That is Erythrocyte Sedimentation Rate It’s measured as a function of ____
◦
◦
one
pro
polcythemia
gravity
RBC
total tube
time
Finding the ESR = measuring the amount of that tube that is ____ of RBCs after 1 hour Measure the difference in millimeters per unit time Very quick and easy test - nothing required beyond taking the blood sample There are different factors that affect how quickly those RBCs drop:
____
◦ ____ WBCs and cytokines in bloodstream ◦ ◦
◦The more “dirt,” the more foreign stuff you have in your bloodstream, the ____ likely the
ESR will be reduced.
The more dirt, the ____ the distance between the initial volume to where the RBCs end
up. Why? Because you have ____.
devoid inflammation excess less shorter interference
Conversely, if you have certain factors in your bloodstream that promote excessive sedimentation, it will ____ ESR.
For example, excessive RBCs in your original blood sample will cause a reduced ESR
Having more RBCs in your sample, the length will be ____
◦ Why Sickle Cell? Because cells are abnormal and tend not to sediment as readily as regular cells. So, the blood distance remains ____ than it would be normally.
◦
So really there is only 2 conditions where the ESR is reduced:
____
____
increase
shorter
polycythemia
sickle cell anemia
Myeloproliferative diseases – Polycythemia vera
• Weekly ____
– To reduce blood thickness and maintain HCT < ____%
• ____
– To limit blood clots
• Cytoreductive therapy with ____ – To reduce RBC production in bone marrow
So to treat this condition, want to do one of two things:
Either reduce ____ activation (done medicinally), OR
◦
Do something that requires ____ intervention - reducing the amount of blood in the
body. Patients go to laboratories every couple of weeks and have blood drawn from their
bodies to reduce their blood volume.)
Palliatively and prophylactically, they are given ____ to prevent blood clots. Cannot ____ this blood because its a cancer of the bloodstream itself
Another option of treatment is Hydroxyurea, which we’ve discussed in the context of Sickle Cell Anemia to destroy any additional red cell formation.
It’s ____; can destroy other elements in the bloodstream
phlebotomy
45
aspirin
hydroxyurea
JAK2 technical aspirin donate nonspecific
Myeloproliferative diseases – Essential thrombocythemia
• Overproduction of platelets due to more ____
• Usually identified on ____ blood test
• ____, leukocytosis, reduced RBCs
– Platelets > ____ / µL for at least two months
• ____, thrombosis, splenomegaly
• ____ or ____ mutations
– Dysregulate ____ pathway
A second myeloproliferative disease is called Essential thrombocythemia This is a cancer of ____. Megakaryocytes give rise to platelets. Therefore, patients have too many platelets in the bloodstream Platelets are not cells; do not have ____. Megakaryocytes are the originating cells of platelets. Megakaryocytes are the malignant cells in this context
So patients with thrombocythemia have a risk for significant, random blood ____ - a potential life-threatening condition. Rarely is this disease strictly ____.
megakaryocytes thrombocytosis 450,000 bleeding JAK2 calreticulin STAT
megakaryocytes
nuclei
clotting
megakaryocytes
Myeloproliferative diseases - essential thrombocythemia
When the stem cells differentiate, and a mutation occurs, it will will dictate which cell types will be affected in that lineage.
If the mutation occurs early in the stem cell, then all the lineages that derive from that
stem cell will be affected.
So, oftentimes patients will have leukocytosis, erythrocytosis, may have some ____ as well.
Conversely, some patients have ____ RBCs, depending if the mutation occurs later in that stream of events. All depends on which stage of differentiation the mutation occurred in. Will dictate
This disease is often clinically ____. Many patients don’t realize they are experiencing blood clots until it’s too late for them.
Oftentimes, this disease is found in indirectly routine blood tests - manifesting as In addition to thrombotic events, these patients may also experience increased bleeding or spontaneous bleeding. Because sometimes their platelets don’t work properly.
____ bleeding may occur in gums, may be present in urine or feces, etc. which phenotypes the patient manifests with.
◦
excessive platelets. Platelet levels would be higher than normal
____ oftentimes are enlarged
◦ Like polycythemia, there is an attempt by the body to try to destroy some of this excess material.
◦
polycythemia reduced asymptomatic spontaneous spleens
Myeloproliferative diseases – Essential thrombocythemia
Like Polycythemia vera, ____ plays a role in this pathway as well.
So does a 2nd protein called ____
◦
If either of these proteins is mutated, it will trigger the same phenotype
◦ Calreticulin does NOT play a role in polycythemia. But it may play a role in this condition, thrombocythemia
In both cases, both proteins regulate the same downstream cascade (____ signaling)
STAT is a transcription factor that regulates a bunch of downstream genes
◦ Understand that Calreticulin doesn’t play any role in Polycythemia vera, but does play a role in Essential Thrombocythemia. How to treat?
◦
◦
There is a treatment for JAK2, as we alluded to when discussing Polycythemia. No treatment for ____ mutations - must do treatment that is indirect, not direct
Indirect=get ____ drawn to reduce platelet loads. May get ____ therapy
‣
to reduce formation of karyocytes in the bone marrow. So, it’s not a direct
treatment.
JAK2 calreticulin STAT calreticulin blood hydroxyurea
Leukemia • AML – acute myeloid leukemia • CML – chronic myeloid leukemia • CMML – chronic myelomonocytic leukemia • ALL – acute lymphoblastic leukemia • CLL – chronic lymphocytic leukemia
Some literature describes Essential Thrombocythemia as a form of Leukemia, and
technically it sort of is. But from our standpoint, it’s not.
We are specifically talking about cancers of ____ elements (neutrophils, eosinophils, basophils, and monocytes). Leukemias are categorized as acute vs. chronic, myeloid vs. lymphoid
Acute and chronic - not the typical “acute” and “chronic” definitions we are used to. Onset doesn’t dictate this. The nomenclature we use describes cancer that’s exquisitely ____ (as acute leukemias are) versus those that are not as
aggressive as the ____ typically are.
So in this case, Acute and Chronic is not reflective of quick onset vs. late onset vs. ◦
protracted onset. It’s more reflective of ____ vs less aggressivity.
myeloid
aggressive
chronic leukemias
aggressivity
Leukemia
Acute Myeloid Leukemia could be a cancer of ____, a cancer of eosinophils, a cancer of basophils.
They all fall into same category of AML.
v
◦ We have CLL, chronic lymphocytic leukemia - the least ____ cancer of all subtypes. This chart is from 2014, but the numbers hold true even to today, whereby the vast majority of new cancers, new leukemias diagnosed every year are of the AML category.
Of the cancers that are most prevalent in the population - ____
There is a difference between incidence and prevalence
____ = new onset
____ = how many patients in the population have that cancer
Of all ____, AML is most common. In ____, ALL is most common. Of all patients
across all leukemia subtypes, ____ is by far the most common leukemia that is formed.
neutrophils
aggressive
CLL incidence prevalence patients kids AML
Leukemia – Acute myeloid leukemia
• Excessive production of immature ____ (myeloblasts)
• Most common ____
– Highest ____ rate
AML is defined as….reads first bullet point Again, ____, ____, and/or ____
Again, of all subtypes, this is the most common acute adult form of leukemia
In kids, it’s ____. We’ll talk about that in a second.
WBCs
acute adult leukemia
incidence
neutrophils
eosinophils
basophils
ALL
Risk factors • \_\_\_\_ • Prior chemo- or radiotherapy • Exposure to \_\_\_\_ bomb or benzene • Aplastic anemia • Genetic mutations – \_\_\_\_ syndrome – high \_\_\_\_ rates – \_\_\_\_
Signs and symptoms • \_\_\_\_ • Spontaneous bleeding / petechiae • \_\_\_\_ pain • Splenomegaly • Masses – \_\_\_\_
Patients who have ____ are also at a high risk for developing leukemia, AML specifically.
Why? Because patients with Aplastic Anemia have lost the ability to produce normal erythroid and myeloid elements. As a result, their body is trying to
compensate. At some point during the course of their disease, a cell will experience a
____ that will propel it to become malignant.
AML is one of the most common cancers when it gets into the Aplastic Anemia background.
There are a plethora of molecular changes associated with AML. In fact, we categorize leukemia on ____ and molecular ____.
Molecular cytogenetics may play a role in ____
Patients with Neurofibromatosis Type 1 also have an increased risk for AML but with a very ____ prognosis. We don’t know exactly why. How do leukemias manifest? Nothing specifically. reads the bullets under “Signs and Symptoms” but he adds “increased infection”
There’s nothing about the way that these patients present clinically that is indicative
◦
of leukemia ____
smoking nuclear down cure NF1
anemia
bone
myeloid sarcoma
aplastic anemia mutation morphology cytogenetics prognosis poor specifically
Clinically, they may look like ____ The small nodule on the nose was initially thought to be basal cell carcinoma. Upon biopsy, turned out to be leukemia. Rash on hand - upon biopsy, turned out to be leukemia Leukemia of the orbit - not systemic (can get leukemia in ____ sites as opposed to systemically)
anything
soft tissue
Baby developed leukemia in utero. The baby’s physical response was one of ____ - the attempt on the baby’s part to form blood outside of the blood marrow. These babies are born with bluish papules on the skin - called “____ baby” because the papules kind of look like blueberries.
extramedullary hematopoeisis
blueberry muffin
Myelocytic and myelomonocytic most common leukemic variants in mouth
So these are what we would call Extramedullary Lesions. If they have solitary lesions, we tend to call them \_\_\_\_. (Goes back to the previous slide and points out 2nd photo from the right - this young girl has Myeloid Sarcoma of the Orbit.) These two patients (the two photos show different cases) - limited to the oral cavity. There are several different subtypes of AML. Two of them most commonly occur in the oral cavity: \_\_\_\_ version of AML ◦ \_\_\_\_ version of AML ◦
It’s important to differentiate AML Myelomonocytic from CMML. They are two very different cancers. In this picture, we’re talking only about AML Myelocytic and Myelomonocytic variant occurring within the oral cavity
myeloid sarcomas
myelocytic
myelomonocytic
Myelocytic and myelomonocytic most common leukemic variants in mouth
Photo on the left
Patient had green gums, green fibrotic enlarged gums of both maxillary and mandibular ◦
◦
gingiva. It turned out to be leukemia.
Leukemia may result in a ____ discoloration of the tissue. Why? Because
myeloperoxidase (an enzyme found within neutrophils) may oxidize ____ to
give off a green coloration.
‣
These are called a “____” because of the green color.
Clinically, they may be mass-forming, they may be diffuse, they may be localized. Nothing about the clinical presentation is ____ to these cancers. These versions are strictly morphologic variants, which may dictate how they are treated therapeutically. (Therapy is based on ____ and ____.)
greenish free radicals chloroma unique morphology molecular genetics
Leukemia – Acute myeloid leukemia
• Categorized based on ____ levels and ____
• Chemotherapy / stem cell transplant
• Curable in up to 40% of patients < 60 years
Treatments are based on ____ findings now. In fact, these are one of the cancers that are routinely analyzed at the molecular level in all cases.
Why? Because certain molecular changes impart or correlate with prognosis. And certain molecular changes can be treated specifically and directly against that molecular change.
What does that mean? Well, there are some ____ that produce, for example, hybrid proteins - for which there are now treatments specifically against those hybrid
proteins.
In other cases, some of these mutations don’t have treatments for them. So, they are treated indirectly (routine ____)
maturation cytogenetics molecular translocations chemotherapy
Leukemia - acute myeloid leukemia
Chemotherapy is ____-line therapy in all cases. If chemotherapy doesn’t work, oftentimes the patient will undergo ____ transplantation to clear the body of all their damaged and malignant stem cells.
Sometimes, even after chemotherapy, they may still undergo ____ transplantation to ensure there’s no further risk.
Stem cell transplantation is ____ a cure-all for all patients
AML used to be a death sentence.
It’s still not a good prognosis - only 40% of all patients under age 60 will survive their disease with treatment. But this is across all AMLs. Some versions of AML with very
distinct molecular changes are much more ____, and these have a better prognosis
than those that don’t have targetable forms of the disease.
first stem cell stem cell not treatable
Leukemia – Chronic myeloid leukemia • Rarely affects \_\_\_\_ • 50% patients \_\_\_\_ • t(\_\_\_\_) – Philadelphia chromosome – \_\_\_\_ fusion
CML=Chronic Myeloid Leukemia - almost always occurs in ____ patients.
AML can occur in kids - then, very ____
◦
But, kids rarely get CML
◦ At least half of all patients are ____ and don’t know they have the disease. Instead, they present with a longstanding history of ____ findings (ex: tired, bruising, bleeding, gums bleeding, etc.)
◦
So most patients do have symptoms, but they’re low-grade non-aggressive symptoms. These patients don’t seek treatment until they become bothersome.
CML is almost always characterized by a unique molecular change that was discovered here at Penn back in the 60’s - that’s why it’s called the Philadelphia Chromosome.
The translocation is Chromosomes 9 to 22, resulting in a fusion protein between the
◦
BCR gene and the ABL1 gene
The BCR-ALB1 fusion protein is a ____
◦
children asymptomatic 9;22 adult aggressive asymptomatic non-specific
tyrosine kinase
Leukemia – Chronic myeloid leukemia
• BCR-ABL1 constitutively active ____
In patients that have CML, this tyrosine kinase is constitutively activated (as it is in ____). Therefore, it’s constantly producing new ____. That’s how leukemia develops. This was the first ____ protein for which a treatment was developed specifically for this leukemia. This was the first targetable cancer for which a drug was created specifically for this one protein and only in this context.
Context=CML; drug=____
◦
tyrosine kinase polcythemia vera neutrophils/WBCs targetable gleevac
Leukemia – Chronic myeloid leukemia
• Targeted therapies improved 10 year survival from 20% to 80-90% - ____
Gleevec prevents the binding site of ____ to trigger the kinase reaction. All tyrosine kinases need energy to perpeturate the functionality.
Gleevac binds in the place of ATP to prevent activation of that Tyrosine Kinase. It only works on this one specific ____ of Tyrosine Kinase that is unusual and only forms in this context. Upon binding of ATP, the Tyrosine Kinase doesn’t activate sufficiently, therefore the cell can’t grow. Name of drug: Gleevec (Imatinib)
CML also at one time was a death sentence. Now, it’s one of the most treatable forms of leukemia. Patients respond very well to this drug. This is first generation; there are now ~4 generations of drugs since then that specifically target BCR-ABL1
imatinib
ATP
type
Leukemia – Chronic myelomonocytic leukemia
• Monocyte count > \_\_\_\_ per cubic millimeter blood – May also see \_\_\_\_ in blood • Disease of \_\_\_\_ – Male : female \_\_\_\_ • Prior \_\_\_\_ increases risk • May progress to \_\_\_\_
CMML - this is different than what I described before. In the context of oral leukemias, it’s typically AML of the myelomonocytic lineage or the myelocytic lineage. CMML is a wholly different cancer altogether. CMML is a cancer of ____
Patients get ____ - have far many more monocytes in the bloodstream than they normally should have.
Precursor to Monocytes is ____. The defect is occurring in an early precursor that is in the lineage toward monocyte development.
1000 monoblasts elderly 2:1 chemotherapy AML
monocytes
monocytosis
monoblast
Leukemia – Chronic myelomonocytic leukemia
This cancer may may develop on its own, but patients have distinct risk for this cancer if they’ve had a previous cancer that was treated with chemotherapy
Chemotherapy is not a targeted treatment; it’s very ____ and is aimed at killing a whole bunch of rapidly proliferating cells.
Chemotherapy for any type of cancer increases the risk for ____
◦ CMML patients may progress on to ____. (Going from a chronic, slow-forming disease to a more acutely aggressive disease) CMML is actually quite a difficult cancer to treat. ____ don’t respond well to treatment, therefore, typically these patients are treated with whole-body nonspecific chemotherapy.
◦ There is no ____ forms of treatment for this version of the disease.
non-specific CMML AML monocytes targetable
Leukemia – Acute lymphoblastic leukemia
• Most common \_\_\_\_ cancer • 75% of childhood leukemias are ALL – \_\_\_\_ lineage or \_\_\_\_ lineage • Cytogenetics have prognostic value – Subset harbor \_\_\_\_ chromosome • \_\_\_\_ association – \_\_\_\_ outcome • \_\_\_\_ >>> adult 5 year survival
ALL - most common form of pediatric cancer. This is a treatable form of pediatric cancer Only those cancers that have distinct molecular changes that are targetable by treatment
Some patients don’t have distinct changes, which makes it harder to treat them and
worse prognosis
Of all childhood leukemias, they are most commonly ALL. The rest are typically AML.
The chronic versions are less likely….CML vs CLL
If it’s ALL, then it’s either B or T lineage ____ lineage may also occur in some patients. That’s the exquisitely aggressive cancer - often very difficult to treat.
B ALL and T ALL are actually treatable forms of cancer depending on the changes.
pediatric B T philadelphia down syndrome poor childhood
NK
Leukemia - ALL
As with all leukemias, cytogenetics have an important prognostic role here
They are prognosticators
◦ If Leukemia has molecular change X, versus molecular change Y, whatever X and Y represent, X may have a better prognosis and be much more treatable than the Y version of that same cancer if it’s the same cell type. So, molecular ____ are evaluated on each and every patient with leukemia irrespective of subtype. Some of these same patients may also have the same 9:22 chromosomal translocation (the Philadelphia Chromosome)
Yet, may not be CML - may be ALL If they have ____ onset mutation, may develop ALL instead of CML with exact same cytogenetics
Down Syndrome patients are at risk for leukemias. AML in that context is a treatable
cancer; very high response rates.
Why don’t know why - research group at CHOP studying why Down Syndrome is only
risk for ____ and not solid cancers (liver cancer, head/neck cancer, etc.).
AML is treatable and much more ____. ALL is a very ____ cancer in these patients.
If these same patients were to develop ALL, it is a very poor prognosis ◦ ◦
cytogenetics early leukemia curable deadly
ALL
Don’t memorize this chart - it’s meant to illustrate some of the different kinds of changes that ALLs manifest with at the micro level, including BCR:ABL1
BCR:ABL1 only forms a very small portion of all ALLs in ____
◦
BCR:ABL1 forms a much larger portion in ____
◦ Of all these molecular changes, there’s about six on the list here that have targetable treatments. The rest don’t. Those that dont have targetable treatment have worse prognosis
pediatrics
adults
Leukemia – Chronic lymphocytic leukemia
• \_\_\_\_-lineage CLL most prevalent adult leukemia – \_\_\_\_ has higher incidence • \_\_\_\_ patients, 2:1 male • Often asymptomatic with \_\_\_\_ course – \_\_\_\_ most common complaint – Cervical lymphadenopathy • CLL in lymph node = \_\_\_\_ lymphoma • B cells express \_\_\_\_ – targeted by \_\_\_\_
CLL is most prevalent cancer of all in terms of leukemia
Low grade indolent cancer. Means that patients may eventually die of their disease, but not in the next couple of years May go on to live 15-20 years without any complications
◦ Typically B cell cancer Manifests primarily in older people, and typically in male patients. “Higher tendency for leukemia across all forms of leukemia”
As with leukemias occurring in soft tissues in extramedullary sites, you get can also get CLL occurring in ____ sites.
When it occurs as a solitary mass, which it might, we call that a ____
B AML elderly indolent fatigue small lymphocytic rituximab
extramedullary
small lymphocytic lymphoma
Leukemia - CLL
This disease is a targetable disease because all B cells, including these malignant B cells, express a cell surface marker called ____.
◦ You learned CD20 in a different context last year when we discussed treatments for ____ and other autoimmune diseases in which B cells are causative. CD20 is targeted by a drug called ____ (an antibody drug)
◦
◦
Upon binding CD20 by the Rituximab, that alone is enough to trigger the killing of the B cell. So this drug is used to kill the malignant B cells by exploiting the fact that these cells express CD20 on the surface
So, first-line therapy for CLL is Rituximab therapy.
Whereas, Rituximab therapy is typically ____ line therapy for patients with autoimmune
disease
◦
Patients with autoimmune disease are usually treated with ____ first ◦
If they aren’t resolving, at that point they add Rituximab therapy.
Rituximab does have complications that are quite significant. But in the context of cancer, you weigh benefits vs. the risks. This drug’s ____ are much greater than its complications
CD20
pemphigus vulgaris
rituximab
third or fourth
immunosuppressants
benefits
Post-transplant lymphoproliferative disorder
- Due to chronic ____-induced immunosuppression
- Proliferation of ____ cells latently infected with ____
- May ____ regress after drug cessation
- Or may progress to ____
- Lymphoproliferative disorder→ it is a cancer, but it is the direct result of severe and chronic immunosuppression
- this disease is always a B cell disease, associated with EBV infection (Epstein-Barr virus)
- Patients have EBV in their bodies, and the virus stays dormant within B cells
- If any of us would ever become severely immunosuppressed, you run the risk of the virus becoming activated and a propagation of B cells resulting is disorder called post- transplant lymphoproliferative disease or disorder
- In HIV pts, they have the same mechanism, same cancer, just different name
- This is in cancer in pts who have had stem cell transplantation or organ transplantation
- This is a B cell malignant proliferation→ if you remove the immunosuppres stated, this cancer can regress spontaneously. If the pt restores their immune system→ this disease can regress. Similar to ____ cancer (MALT lymphoma)
- Don’t have to treat w/ traditional chemotherapy
- OR, some pts may progress to B-cell non-Hodgkin lymphoma, a true lymphoma
drug B EBV spontaneously B-cell non-Hodgkin lymphoma
h pylori stomach
Post-transplant lymphoproliferative disorder
• You can txt these pt/s w/ ____, same treatment used for CLL, because these B cells also express ____→ these pts have a much better survival rate
rituximab
CD20
• If those pts do progress to TRUE B-cell lymphoma, they are categorized has a ____ or Non-Hodgkins B cell lymphoma→ same things
• There are 3 types of lymphoid cancers:
◦ ____ lymphoma
◦ ____ lymphoma→ which is a much broader category
◦ cancers of plasma cells→ if it’s diffuse, we call that ____
▪ But, if it’s solitary cancer of plasma cells → its called the ____
▪ Do not memorize the chart→ you should know the patterns
▪ Of all lymphoma type cancers→ ____ is the most commonly occurring
▪ Second most common are the myelomas -> deadly disease, very poor prognosis
▪ Least common (but most treatable)–> ____→
▪ Hodkin lymphoma is a disease that is known to be a ____ age predilection→ rarely do kids get this, rarely to do mid-age adults gets this. This is typically an ____ disease or more commonly a ____disease.
▪ Survival rates are much higher in ____ patients than they are in non-hodgkin and certainly much more than myeloma
B cell non-hodgkin’s lymphoma
hodgkin
non-hodgkin
multiple myeloma
plasmacytoma
non-hodgkins hodgkin lymphoma bimodal eldery young adult
hodgkin
▪ Again don’t memorize this chart
▪ This illustrates that the peak incidence is for Hodgkin’s is ____ age range
▪ Overall, 15 yrs and then after the age of ____ is when these cancers primarily develop
▪ Non-Hodgkin’s → typically patients are much ____
▪ Same with myeloma
▪ The younger the onset for both NH and Myeloma→ the much worse the ____
20-35
55-60
older
prognosis
Hodgkin lymphoma
• Primarily within ____ system
• ____ age of onset – usually ____
• ____ virus is risk factor
▪ These cancers can occur in ____ sites, as well. He has seen it in the oral
cavity, very rare tho
▪ Most commonly in the ____ lymph nodes
▪ Most common S&S: a patient has nonspecific signs & symptoms, they have night sweats, excessive fatigue, dizzy, nauseous, vomiting and then some point during the course of those symptoms and signs, they develop bumps along their neck or ____ (armpit area), or groin area. Most commonly in the ____ area
lymphatic bimodal male epstein-barr extranodal cervical (neck area) axilla head and neck
Hodgkin lymphoma
- Painless ____
- Night sweats
- Unexplained ____ loss
- Hepatosplenomegaly
▪ ____ is the most common risk factor for several lymphoid cancers.
▪ READ SLIDE
▪ ____ swelling in the neck area
▪ If a swelling is unilateral, typically a worse sign than bilateral swelling
▪ Night sweats is non ____, but very characteristic of Hodgkin
lymphadenopathy weight EBV firm specific
Histopathology
• Classical
– ____ variant most common
– ____ cells
• Nodular lymphocyte predominant
– More common in ____ patients
– ____ cells
– ____ Reed-Sternberg cells
▪ Microscopically, there are different variations of Hodgkin’s that may have some prognostic importance→ dont worry about prognosis.
▪ But overall, prognosis for Hodgkin’s is pretty good→ 86% of 5 years
▪ Classical Hodgkin→ has the best ____ rate
▪ Classical Hodgkin is characterized by pathognomonic cells known as ____ cells → B cells, as in the picture here, look like 2 big eyeballs= ____ eyes
nodular sclerosing
reed-sternberg
older
popcorn
few
survival
reed-sternberg
owl
Histopathology
▪ Nodular lymphocyte predominant subtype–> is a difference of type of Hodgkin’s→ is characterized by cells that look like popcorn → ____ cell
▪ These cells are pathognomonic for this version of Hodgkin’s disease
▪ The difference being → ____ cells are much more prevalent in the classical subtype. And in the nodular subtype, the ____ cells are more prevalent
popcorn
reed-sternberg
popcorn
▪ big dark spots represents a distinct area that’s afflicted by Hodgkin’s lymphoma→ this may be a systemic disease
▪ This is a cancer that can kill people, can be aggressive
▪ But it is a treatable disease
▪ BUT IT IS NOT TREATABLE W/ ____ THERAPY→ there is no one drug that can be used, unlike Rituximab for Post transplant lymphoproliferative disorder or CLL
▪ These pts are given ____ therapy
Don’t worry about staging→ just know that all cancers have staging
targeted
non-specific
Non-Hodgkin lymphoma
- Heterogeneous group of diseases
- Differentiated based on ____, immunophenotype and cytogenetics
• Indolent
– ____ lymphoma
– MALT lymphoma
– ____ lymphoma (Mycosis fungoides)
• Aggressive – \_\_\_\_ lymphoma – Burkitt lymphoma – \_\_\_\_ lymphoma – Adult T cell leukemia/lymphoma
▪ Hodgkin’s disease is a primarily a ____-cell driven process → most pts w/ disease have a B cell phenotype
▪ In contrast, Non-Hodgkin’s (NH) disease maybe ____ cell or ____-cell, with relative equal frequency —> within those categories are several subcategories→ that are sub categorized based on whether they’re small cells morphologically or large cells morphologically
▪ there are treatments that we now have to treat this–> either directly or based on a handful of genetic changes
▪ There are NH that are not as aggressive
▪ MALT are NH lymphoma that are typically not overly aggressive
▪ Follicular lymphoma-> most common NH and not aggressive
▪ Both MALT and follicular are B cell lymphomas
▪ Mycosis fungoides→ T cell lymphoma
morphology
follicular
cutaneous
diffuse
anaplastic large cell
B
B
T
Follicular lymphoma • \_\_\_\_ lymphoma • Neoplasm of \_\_\_\_ center B cells • t(\_\_\_\_) – Chromosome 14 has \_\_\_\_ chain locus – \_\_\_\_ overexpression
• Richter syndrome
– ____ cell transformation
Follicular lymphoma is a morphologically small B-cell lymphoma small
READ SLIDE
▪
shape → these are the germinal centers → this is the area where the premature B cells mature further and eventually going to be released into circulation
Histo slide→ this is a lymph node,. The areas that are clear and nice circular/ovoid
▪ a follicular lymphomas→ develop from ____ B cells within the germinal center
▪ characterized by very distinct and recurrent translocation chromosome 14 & 18
▪ The translocation takes the promoter gene or genes and links it to BCL-2 found on chromosome 18
▪ Bcl-2 is an anti-apoptotic protein
small b-cell germinal 14;18 Ig heavy BCL-2 large
premature
Follicular lymphoma
▪ overexpression bcl-2 which is occurring in these tumor cells→ but because BCL-2 is anti-apoptotic, these cells are NOT programmed to ____
▪ Some pts may go on to develop Richter syndrome–> where they go from a small follicular cell lymphoma to a large cell lymphoma → so if those tumor cells take on additional mutations, that may result in changing of the morphology of the small cells to become a large cells→ becomes more ____ cancer
▪ Richard syndrome–> is large cell transmission of a follicular cell lymphoma
die
aggressive
Follicular lymphoma
▪ How do we test this? You do a blood test
▪ you’ll have ____→ you will see increased lymphocytes in the bloodstream
▪ Biopsy→ normal lymph node, the germinal center should NOT stain w/ BCL-2 antibody because those cells should not be expressing BCL-2
▪ In the cancer→ these same cells in the germinal center will be OVER EXPRESSING ____ → germinal centers are reactive w/ this antibody
▪ This is a treatable cancer→ but NOT with ____ treatment. Txt w/ ____
lymphocytosis
BCL-2
targeted
chemotherapy
Mucosa-associated lymphoid tissue (MALT) lymphoma
- ____ lymphoma
- Develops within lymphoid tissue found in ____ and glandular sites
- ____ marginal zone lymphoma
- t(____) or t(____)
▪ Mucosa-associated lymphoid tissue (MALT) lymphoma —> also called, when it occurs outside the lymph nodes, extranodal marginal Zone lymphoma→ these two terms are synonymous
▪ READ SLIDE
▪ Except, the cell of origin is NOT the germinal center—> it is ____ the germinal
center
(around the periphery of the germinal center - in the marginal zone)
▪ These are almost mature B cells that left the germinal center, and now rimming the
germinal center around it
▪ the same 2 chromosomes that are associated with the previous lymphoma come back here but in 2 different ways→ 1;14 translocation or 11;18 translocation
▪ Know the translocations for these lymphomas
▪ ____ translocation has a better prognosis than t11;18 → treatable
▪ These lymphomas occur more commonly in areas where there is glandular tissue→ in the ____, intestine, ____ glands, kidney and the skin around sweat glands
small b-cell mucosal extranodal 11;18 1;14 outside 1;14 stomach salivary
Mucosa-associated lymphoid tissue (MALT) lymphoma
• ____ infection major risk factor for gastric MALT lymphoma
• ____ associated with high risk for salivary gland MALT lymphoma
helicobacter pylori
sjogren syndrome
Diffuse large B-cell lymphoma
• Most common \_\_\_\_ – Heterogeneous group of lymphomas • \_\_\_\_-growing, painless mass • Usually diagnosed in \_\_\_\_ stages • \_\_\_\_ profiling used to classify and to guide therapeutics
▪ Now, let’s talk about LARGE cell lymphomas→ much more ____ and not as easy treatable compared to small type, except for one type…
Diffusible large B-cell lymphoma→ is by far the largest category of Non-Hodgkin’s
Subcategorized based on molecular genetics
This is one of the first cancers that we learned of that has distinct molecular genotypes
▪
▪
▪ These cancers may occur in lymph nodes or ____ lymph nodes
NHL fast advanced gene expression aggressive outside
Diffuse large B-cell lymphoma
▪ These tumor cells are much ____ than normal lymphocytes
larger
Burkitt lymphoma • Highly \_\_\_\_ B-cell lymphoma ▪ in both cases, this cancer occurs very \_\_\_\_ • Common under age of \_\_\_\_ • Rapidly expansile mass
▪ ▪ ▪
in Africa ▪
▪
Burkitt lymphoma→ very ____ but can be very aggressive
2 subtypes
1→ driven always by ____> occurs in ____, primarily in ____, exclusively
2→ exact same cancer, but no driven by EBV, in ____ ppl, and in the ____
Both caused by the same translocation in both cases→ in chromosomes t____
aggressive
20
treatable
EBV
H+N
kids
older
abdomen
8;14
Burkitt lymphoma – three clinical variants
• Endemic
– Young ____ in equatorial Africa
– Associated with ____
• Sporadic
– Usually ____
• ____-related
kids
EBV
abdominal
immunodeficiency
Burkitt lymphoma
• t(____)
– Overexpression of ____
• ____ histopathology
– ____ macrophages
▪ High levels of MYC= poor prognosis
▪ A very distinctive appearance under the microscope → Starry Sky
▪ The large clear structures are macrophages→ these macrophages are recruited to the area to phagocytose apoptotic lymphocytes
▪ B/c these cells are growing at a rapid rate, some cells are dying at the same time→ these macrophages are brought in to digest the dead cell remnants.
▪ This is a treatable disease but clinically acutely ____
8;14 MYC starry-sky tingible-body aggressive
Cutaneous T-cell lymphoma - mycosis fungoides
- ____, protracted disease
- Patch > ____ > Tumor
• ____ syndrome
– Malignant ____ cells in blood
▪ From the standpoint of B-cell lymphoma→ KNOW diffuse large cell and Burkitt lymphoma
▪ You also have small and large T-CELL lymphoma
▪ Mycosis fungoides→ is a ____ lymphoma→ morphologically T cells look small
▪ this cancer is a slow-growing, slowly evolving cancer → but it can cause death or
morbid disease phenotypes
▪ This pt (pics)–> starts as an area of ____/ erythema, over time can develop a
patch, later can develop into plaque, eventually develop into multiple mass of tissue
▪ Pts w/ diffuse erythema→ the disease has spread to bloodstream→ now the entire body is potentially at risk→ Sezary syndrome
▪ Sezary syndrome is mycosis fungoides that spread to bloodstream
slow
plaque
sezary
T
small t-cell
redness
Cutaneous T-cell lymphoma - Mycosis fungoides
Tumor cells with \_\_\_\_ nuclei Tumor cells show \_\_\_\_ – Early MF may resemble \_\_\_\_ \_\_\_\_ microabscesses Clonal \_\_\_\_ of T-cell receptor
▪ characterized by T-cells w/ irregularly shaped nucleus → call this nucleos “cerebriform
nuclei” because almost looks like the morphology of the brain
▪ These tumor cells have very high affinity to ____ epithelium→ they’re found in very close proximity to the epithelium→ sometimes mistaken microscopically for lichen planus
▪ These tumor cells/lymphocytes are found below or IN the epithelium→ ____→ they love the epi cells!
▪ Within the epithelium→ these malignant cells MAY form small collections→ Pautrier microabscesses (he then shows off his french accent…)
▪ T cell receptors are internally rearranged→ results in a clonal proliferation of these cells
cerebriform epidermotropism lichen planus pautrier rearrangement
squamous cell
epidermotropism
Mycosis fungoides
▪ This is a biopsy of an oral lesion, primarily skin
▪ Dark cells are lymphocytes→ which are congregating within the epithelium forming these small micro abscesses due to internal T-cell receptor rearrangement→ thus, this is Mycosis fungoides
▪ No direct ____ txt
target
Anaplastic large cell lymphoma
• Most common ____ in young patients
• t(____)
– Induces expression of ____
• ____ positive
▪ This is the most common peripheral T-cell lymphoma that occurs in ____ pts (younger than 35)–> but it is possible to get it at a older age
▪ T(2;5)–> due to overexpression a protein called ALK1
▪ ALK1→ is a targetable protein
▪ This disease has a targetable therapy targeting ALK1→ thus reducing its functionality and reducing the proliferation of these lesions
▪ These cancers also express a protein on the cell surface of the tumor cells called CD30→ this is also targetable for drug therapy
▪ These cancers have a better prognosis now
young 2;5 ALK1 CD30 younger
Adult T-cell leukemia / lymphoma
• Highly \_\_\_\_ • Caused by \_\_\_\_ – Endemic in parts of world – Expresses \_\_\_\_ protein • Tumor-induced osteolysis – \_\_\_\_ • \_\_\_\_ / flower-shaped nuclei
▪ Adults T-cell Leukemia/ Lymphoma→ this is actually a extremely aggressive cancer
▪ that will cause death almost invariably
▪ It’s a leukemia / lymphoma→ b/c it may occur in the bloodstream or may occur in
____ tissue
▪ This is different than lymphoblastic T cell lymphoma→ very different mechanism of
action/pathogenesis
▪ This MOA→ direct result of the ____ (even tho it sounds like he says thryus?)→
HTLV-1 (Human T-lymphotropic virus)
▪ This virus only affects T cells
▪ Very ____-> including Iran
▪ If it occurs in solid tissue/bones–>it will cause Hypercalcemia→ b/c it will cause massive osteolysis→ this calcium is being released in the serum
▪ First sign of this disease→ ____
aggressive human t-lymphotropic virus (HTLV)-1 TAX hypercalcemia 4-leaf clover
soft/solid
virus
endemic
hypercalcemia
Adult t-cell leukemia/lymphoma
May start off as a ____ on the skin before progressing to something much more significant → doesn’t take time to go from a rash to a full blown cancer
rash
Adult t-cell leukemia/lymphoma
▪ This virus expresses a viral protein called ____→ TAX interferes at several points within the normal human cell cycle → end result is that during the interference, it will lead to ____ of other proteins that usually don’t get expressed→ leading to ____ and cell ____
TAX
expression
hyperproliferation
transformation
Adult T-cell leukemia/lymphoma
▪ This is a blood smear from a patient who had to HTLV- Associated cancer→ these cancer cells are characterized by a ____ or a flower-shaped nuclear morphology–> which is highly characteristic of this cancer cell type
▪ Will not ask what this looks like under the microscope, but DO KNOW THE CAUSE OF T cell leukemia
4-leaf clover
Multiple myeloma • \_\_\_\_ cell malignancy – 2nd most prevalent B-cell lymphoproliferative cancer • Two distinct subtypes • \_\_\_\_ • Chromosomal translocation – t(\_\_\_\_), t(\_\_\_\_), t(\_\_\_\_), t(\_\_\_\_) and t(\_\_\_\_) – Ig heavy chain at \_\_\_\_
▪ This is a systemic diffuse plasma cell cancer
(if only one cancer (solitary) is found -> called a ____)
▪ 1 type→ distinct translocations, any one pt has 1 translocation→ all of these include chromosome ____
▪ don’t memorize all them→ but know at least 14 is found in all these translocations
▪ 2nd type→ caused by a hyperdiploid chromosomal content number–> whatever reason, these plasma cells accumulate ____
(WITHOUT ____!)
▪ Some of these tumors just have more chromosomes w/o translocations
▪ The ____ version of this cancer has a better txt/prognosis
plasma 4;14 14;16 14;20 6;14 11;14 14q32
plasmocytoma
14
chromosomes
translocation
Clinical findings • \_\_\_\_ (C) • \_\_\_\_ insufficiency (R) • \_\_\_\_ (A) • Lytic \_\_\_\_ lesions (B) / Osteopenia / Pathologic fractures • \_\_\_\_
▪ In all cases→ they have these…. READ SLIDE
▪ Radiolucencies in multiple bone, including the oral facial region
▪ Multifocal jaw lesions due to several bones being affected
▪ Renal insufficiency→ b/c these pts are producing lots and lots of immunoglobulins→ which gets stuck in the ____
▪ anemia → because the ____ cells are crowding out the bone marrow elements
▪ bone fractures/lesions–> because they’re producing plasma cells that produce
immunoglobulin → and immunoglobulin that congregate and form ____
▪ “CRAB A”→ KNOW THIS ACRONYM
▪ This is a highly characteristic→ of a lateral ceph→ pt has several radiolucent lesions in the skull, representing distinct foci of the disease
hypercalcemia renal anemia bone amyloidosis
kidneys
plasma
amyloid
Laboratory findings
• \_\_\_\_ • elevated serum \_\_\_\_ • Bence Jones protein – Ig \_\_\_\_ or \_\_\_\_ protein – Excreted in \_\_\_\_
• Monoclonal spike (M spike)
– ____ produced in excess
– ____ heavy chain > ____»_space;> IgD, IgE, IgM
– Measured via serum ____ (SPEP)
▪ How do you diagnose myeloma?
▪ If you do suspect myeloma directly→ take a serum sample→ look for an M spike on electrophoresis → by running it against the current to get seperation of the elements in that sample
▪ In this case, we see here a very bright protein band that represents immunoglobulin=
M spike→ which is most commonly IgG
▪ ____ cells produce excessive IgG→ can get clogged up in the kidneys and excreted in the ____→ this is called Bence Jones protein→ pathognomonic for myeloma !
▪ This is serum protein electrophoresis
hypercalcemia creatinine light chain monoclonal globulin urine
Ig
IgG
IgA
protein electrophoresis
plasma
urine
▪ This disease used to be a “killer”
▪ Txt→ ____ transplantation
▪ Since the 1970s, higher survival rate now at 45-50%→ still not good but better than 25% in the early 70s
▪ This pic of the pt, who has myeloma and systemic bone disease→ are txt with ____ and ____ therapy→ commonly experience Bisphosphonate- related ____
▪ No targeted txt for myeloma→ go thru 6 rounds of ____ to wipe out as much blood as possible, then go thru ____ transplantation
stem cell
chemotherapy
bisphosphonate
osteonecrosis
chemo
bone marrow
L-chain-type amyloidosis
Idiopathic or associated with ____
Secreted monoclonal ____ insoluble deposits
Identified via ____ and/or urine protein ____
• Positive serum or urine in 80-90% patients
▪ Plasma cells produce HELLA immunoglobulin (Ig), said this again
▪ Ig after congregation forms ____→ amyloid as a disease is called amyloidosis
▪ You can get amyloidosis w/o any ____ cells varency
▪ Plasma cells can produce amyloid and for whatever reason the amyloid start aggregating in abnormal ways → you get amyloidosis→ this disease could be found in multiple myeloma or ____
▪ That disease is result of Ig light chains aggregating into insoluble deposits in the tissues
multiple myeloma
Ig light chain
serum
electrophoresis
amyloid
plasma
not
Clinical manifestations
• ____
• Skin papules and ____
▪ ____ is a common site for amyloid deposition
▪ Amyloidosis tends to occur in the ____→ droopy eyelids due to congregating around the eyes
macroglossia
periorbital purpura
tongue
head/neck
Clinical manifestations
▪ Pt has a massive tongue secondary to ____
▪ He did NOT have ____ **
amyloidosis
myeloma
Clinical manifestations
Amyloid microscopically looks acellular and pink → you see aggregates of ____
▪ Also stain using ____
Congo red stains amyloid ____ and under polarized lights stains it ____
pink
congo red
orange
green
L-chain-type amyloidosis
• Prolonged ____ and ____ due to binding of clotting factor
• Survival related to concentration of free ____ monoclonal light-chain
– Independent ____ factor
▪ It may cause bleeding because amyloid may deposit in ____→ inability of clotting factors to form
PT aPTT serum prognostic bone marrow
