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Oncology

Basic principles behind oncogenesis

Haematological and non-haematological malignancies

Oncological emergencies

John McFarlane (He/Him), Doctorials 2021/2022

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Learning Objectives

The nomenclature of oncology
Revise the cell cycle and its relevance to the pathogenesis of cancer
Organize and list known carcinogens
Introduction to haematological malignancies

Leukemia and lymphoma
Hodgkin’s vs Non-Hodgkins
Myeloproliferative disorders
WM vs MM

Introduction to non-haematological malignancies

Adenoma-carcinoma sequence
Polyposis syndromes
Cervical Cancer
Psammoma bodies

Management of cancer: Chemotherapy
Oncological emergencies: febrile neutropenia, spinal cord compression, tumor lysis syndrome

J. McFarlane, Doctorials 2021/2022

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Definitions

Tumour: “Swelling”

Can be any tissue mass – solid, liquid-filled, benign, or malignant

Cancer: A malignant tumour

Has the potential to metastasize
Synonymous with neoplasia, where tissue growth occurs despite the absence of stimulus

Differentiation: The morphology of cells when compared to normal cells of the same tissue

Well differentiated cells will look like and function the same as normal cells of that tissue type
Poorly differentiated cells do not function like normal and appear abnormal under microscopy

J. McFarlane, Doctorials 2021/2022

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Definitions

Features of anaplastic/poorly differentiated cells

Pleomorphic: A continual variety in size and shape
Hyperchromatic: Dark staining cells with a large nuclei
Loss of polarity: Loss of uniform orientation and new disorganized growth
Mitoses: Increased proliferation resulting in an abnormally large number of cells undergoing mitosis

J. McFarlane, Doctorials 2021/2022

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Definitions

Types of tissue growth

J. McFarlane, Doctorials 2021/2022

	Hypertrophy	Hyperplasia	Metaplasia	Dysplasia	Anaplasia	Neoplasia
Definition	Increase in cell size without increase in cell number	Increase in cell number	Reversible replacement of one cell type with another	Altered cell maturation, orientation, and tissue architecture.	“To form backward”. A lack of cell differentiation. A hallmark of malignancy	“New growth”. Unregulated cell proliferation as a result of genetic changes
Example	Skeletal or cardiac muscle cells in response to increased workload	Physiologic: Liver cells after resection Pathologic: Benign prostatic hyperplasia	Acid reflux – esophageal squamous epithelium to glandular columnar epithelium	Cervical intraepithelial neoplasia – a premalignant lesion of the cervix with various grades of epithelial dysplasia.	Colorectal cancer displaying a progressive dedifferentiation of colon epithelial cells	Adenocarcinoma of the lung involves uncontrolled growth as a result of oncogene KRAS expression and loss of TSG p53
Mechanism	Increase in protein production in response to mechanical stress and growth factors	Growth factors stimulate cell proliferation from existing mature cells or stem cells	External stimuli triggering altered gene expression, leading to differentiation of stem cells	Dysregulation of cell maturation and growth as a result of altered gene expression or mutations	A lack of differentiation of the cancer stem cells	We will discuss
Cancer risk	-	+	++	+++	++++	Cancer formed

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Definitions

Benign vs malignant:

J. McFarlane, Doctorials 2021/2022

	Benign	Malignant
Nomenclature	Ends in “-oma”	Ends in –carcinoma (cells of endodermal or ectodermal origin) Ends in –sarcoma (cells of mesenchymal origin)
Growth Rate	Slow	Fast
Local Invasiveness	None. Grows as a cohesive mass covered in dense connective tissue	Yes. Destroys surrounding tissue and has no well-defined capsule
Metastasis	No	Yes. Except for CNS and cutaneous basal cell carcinomas
Differentiation	Well differentiated	Poorly differentiated - anaplastic
Examples	Adenoma Osteoma Squamous cell papilloma	Adenocarcinoma: a glandular epithelial cancer Osteosarcoma: bone cancer Squamous cell carcinoma: skin cancer

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The Cell Cycle

A highly regulated series of steps to govern cell proliferation
G0 - Quiescence: A period of inactivity of dormancy
G1 – Early and late stage. The cell is sensitive to the influence of growth factors
S – Synthesis: DNA replication occurs
G2 – Growth of necessary internal cell structures
M – Mitosis: The equal splitting of one cell into two identical daughter cells

J. McFarlane, Doctorials 2021/2022

The cell cycle is a highly regulated series of steps that every normal cell has to go through in order to divide into two identical daughter cells. Along the way are many checks and restrictions that protect our cells from becoming cancerous.

The G0 stage/Gap 0 stage is the quiescence stage, or a stage of dormancy where the cell is not actively attempting to grow or divide. It is simply carrying out its intended purpose. It can re-enter the cell cycle at any point once exposed to a growth factor or mitogen

During the G1 stage/Gap 1 stage the cell is sensitive to growth factors and mitogens and it is during this stage that a cell will begin preparations for division if stimulated to. This includes making more organelles, synthesizing more proteins and enzymes necessary for cell function, and repairing thymidine dimers which may be present on the cell’s DNA. During this stage the cell is checking over its DNA to look for any obvious errors that it doesn’t want to give to the daughter cells.

This stage is broken up into an early stage, which is mitogen dependent, and a late stage, which is mitogen independent. Separating the two is a restriction point. Once the restriction point has been passed, the cell no longer needs a stimulus to divide and will continue to go through the stages until the division is done

In the S phase the cell replicates its DNA, going from a 2n cell to a 4n cell briefly. This process on average takes 6 hours.

In G2 phase the cell is focused on growing large enough to provide enough supplies to each daughter cell so they can survive and function properly. It creates more cytoplasm, cell membrane structures, and develops any organelles that may be required.

The cell can then enter into M phase and undergo mitosis. The steps of which are not the focus of this lecture, but the end result is two identical daughter cells.

Image: https://www.sciencefacts.net/cell-cycle.html

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J. McFarlane, Doctorials 2021/2022

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G1 Phase - Presynthetic

Early phase

Mitogen dependent

R point

Point of no return
Requires hyperphosphorylation of RB by Cyclin Dependent Kinase (CDK)6,4/Cyclin D

Late phase

Mitogen independent
CDK2/Cyclin E

G1/S checkpoint

Requires CDK2 and Cyclin A
Checks the integrity of the DNA before replication

J. McFarlane, Doctorials 2021/2022

The G1 phase is also known as the presynthetic phase, as it occurs prior to the synthesizing of new DNA for the daughter cells.

The phase is broken up into two sections – an early phase, and a late phase. Between them is a restriction point (R point).

In the early phase, mitogens are required to initiate growth and provide a stimulus for the cell to initiate the cell cycle, ultimately ending up in the culmination of two daughter cells. Mitogens are growth factors that bind tyrosine kinase receptors and tell the cell to start this process. They are soluble factors (either peptide or small proteins) that influence the growth of the neighboring cells or of the cells themselves. Once they bind to their receptors, they initiate a cascade of signaling that ends up with the cell entering into the cell cycle. Some examples of mitogens are PDGF, TGF-a, EGF (epidermal growth factor), EPO, and insulin.

The R point is the restriction point. Once the conditions within the cell have been met for it to enter into the cell cycle and begin the process of growth and division, a signal is required to fully commit to the process. This process is the hyperphosphorylation of RB – a process we will talk about on the next slide.

The late phase is mitogen Independent, so the cell is now committed to either growing and dividing into two ideally healthy and normal daughter cells, or it will end up undergoing apoptosis due to error. It cannot go back to a G0 stage at this point.

The G1/S checkpoint is the last point in the G1 phase. It is during this phase that the cell checks over the integrity of the DNA, looking for obvious errors like thymidine dimers that it can fix before replication occurs.

Thymine dimers are the result of UV radiation and it is the process of two thymine bases on the same strand of DNA linking to one another, rather than to their complementary adenine bases on the other strand.

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RB Phosphorylation

Retinoblastoma gene

First tumor suppressor gene discovered
Gene product is a DNA-binding protein expressed in every cell type
Exists in a hypophosphorylated state, bound to E2F (family of transcription factors), preventing transcription of Cyclin E
Growth factor signaling leads to Cyclin D expression and the activation of CDK4,6/Cyclin D complexes
RB becomes hyperphosphorylated by these complexes
E2F is released
Gene transcription of Cyclin E is allowed to continue

J. McFarlane, Doctorials 2021/2022

The retinoblastoma gene was the first tumour suppressor gene discovered. A tumour suppressor gene being anything that prevents a cell from continuing through the cell cycle. These are important to have as they prevent uncontrolled cell division. They are not permanent suppressors of cell division, but exist to be overcome by proto-oncogenes which drive the cells through the cell cycle. More on these later.

The retinoblastoma gene is present in every cell type and is found bound to E2F. E2F is a transcription factor that wants to bind to its receptor site on a DNA strand, allowing for transcription of associated genes, but it cannot bind to its intended site whilst RB is attached to it.

The presence of growth factors/mitogens allows for the creation of Cyclin D/CDK4,6 complexes to form, which then serve to HYPERphosphorylated the previously HYPOphosphorylated RB. With RB HYPERphosphorylated, E2F is free to bind to its DNA receptor, and the production of late G1 phase genes and S phase genes can begin (including Cyclin E and A).

Image: Robbins Pathology, 9^th Edition

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CDK-Cyclin Complexes

Cyclins D, E, A, B

David Eats A Brownie

CDK 6, 4, 2, 1

6-4 = 2
2-1 = 1

CDK-Cyclin Complexes

Cyclin D/CDK6
Cyclin D/CDK4
Cyclin E/CDK2
Cyclin A/CDK2
Cyclin A/CDK1
Cyclin B/CDK1

J. McFarlane, Doctorials 2021/2022

The pattern seen in G1 phase is similar to what happens in the other stages of the cell cycle. Certain cyclins are produced in response to the production of previous cyclins, and they bind to specific CDK (Cyclin Dependent Kinases) present in the cytoplasm of the cell to create their desired effects for each stage. You can see that the Cyclins get expressed at certain parts of the cell cycle, become very high in concentration, and then fade out after their work is done.

In S phase the DNA is replicated

In G2 phase the cell grows larger and prepares for division

CyclinB/CDK1 is required for the final restriction point before entering into M phase, where mitosis happens and two identical daughter cells are created.

Images:

Robbins Pathology, 9^th Edition

https://opened.cuny.edu/courseware/lesson/655/student/?task=4

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TP-53

The “Guardian of the Genome”
Encodes p53 – a tumour suppressor gene
One of the most commonly mutated genes in human cancers
Prevents neoplasm by 3 processes:

1. Activation of temporary cell cycle arrest (quiescence)
2. Induction of permanent cell cycle arrest (senescence)
3. Triggering of programmed cell death (apoptosis)

Senses internal stress

Anoxia, inappropriate oncoprotein activity (MYC or RAS), damage to DNA integrity.

J. McFarlane, Doctorials 2021/2022

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TP-53 Continued

Normal function:

Short half life – 20 minutes

Targeted by MDM2

Internal cell stressors activate “sensors” like protein kinases to catalyze post-translational modifications in p53 to release it from MDM2 and increase its half-life and give it opportunity to transcribe target genes.

CDKI gene – CDKN1A AKA p21: Inhibits cyclin-CDK complexes and thus prevents the phosphorylation of RB, arresting the cell in the G1 phase
Gives the cell time to complete necessary repairs

Once damage is repaired, p53 upregulates transcription of MDM2, leading to its own destruction and allowing the cell cycle to continue
If damage cannot be repaired, the cell may enter senescence or undergo apoptosis

J. McFarlane, Doctorials 2021/2022

P53 has a very short half life, so it is not intended to hang around and stop the cell from dividing all the time. It is broken down by a molecule called MDM2. P53 is produced in response to various internal stressors. These internal stressors lead to the release of p53 from MDM2, giving it time to complete its function within the cell.

One of the more important roles of p53 is the creation of p21

P21 inhibits cyclin-CDK complexes and prevents the phosphorylation of RB, which prevents the cell from getting over the restriction point.

This freedom is short lived however. The half-life of p53 may be extended, but it does come to an end after a period of time. At this point, if the damage has been repaired, p53 upregulates the transcription of MDM2 and causes its own destruction. If the cell damage cannot be repaired in time, p53 will trigger other genes that initiate the process of senescence or apoptosis.

Image: https://www.nature.com/articles/s41420-020-0251-x

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TP-53 Continued

Homozygous loss of function:

DNA damage goes unrepaired
Previous mutations become fixed in the genome and are passed to daughter cells
Increased risk of malignancy

More than 70% of human cancers have mutations in this gene

Li-Faumeni Syndrome:

Inheritance of a mutated TP-53 allele
Only one further mutation to the normal TP-53 allele required to create a homozygous lack of function
25x more likely to develop a malignant tumour before age 50

J. McFarlane, Doctorials 2021/2022

Loss of function of TP-53 can be devastating to the cell. As TP-53 is a gene on our DNA, there are two copies of it that exist in every cell, one on the paternal strand, and one on the maternal strand. If one is mutated, the other can compensate, but if both are mutated and non-functional, then DNA damage that occurs goes unrepaired, and previous mutations become fixed into the genome and are passed onto daughter cells.

An estimated 70% of human cancers will have a direct homozygous mutation to TP-53, while the rest of them will have mutations either upstream or downstream of this – stressing the importance of this gene.

Some people are born with one already mutated copy of TP-53 in a condition called Li-Fraumeni Syndrome. As these people already have one non-functional copy of TP-53 in their genome, it only takes one more mutation to trigger a complete loss of function. It is because of this reason that people who have Li-Fraumeni Syndrome are 25x more likely to develop a malignant tumour before the age of 50.

Image: Robbins Pathology, 9^th Edition

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Knudson Two-Hit Hypothesis

Initially investigated for retinoblastoma

A neoplasm of the retina
Two copies of the same gene need to be mutated (loss of function) for neoplasia to occur
Approximately 60% are sporadic mutations, and the rest are familial
Essentially there needs to be “two-hits” to the RB gene to create a retinoblastoma.
In familial acquired, one of the hits comes from an inherited mutated allele.

Common feature of many neoplasms – breast, lung, bladder cancers

J. McFarlane, Doctorials 2021/2022

It was the study of the rare childhood retinoblastoma neoplasm that led to the creation of the two-hit hypothesis. While the original thought was that this must be the inheritance of an autosomal dominant trait, Knudson in 1974 proposed that there was a requirement of two mutations that had to occur for this tumour to happen. The theory goes that in the sporadic form of the neoplasm, both the maternal and the paternal copy of the RB gene need to be mutated after conception for the neoplasm to occur, while in the familial form the first mutation has already occurred from the inheritance of a single mutated form of RB.

Li-Fraumeni syndrome is the condition whereby one of the mutated copes of RB has been inherited and a greater risk of neoplasm is possible.

The loss of this gene is not only for retinoblastoma neoplasms, but is a common feature of several tumours, including breast cancer, small cell lung cancer, and bladder cancer. There is also an increased risk for development of osteosarcomas and some soft tissue sarcomas.

Image: Robbins Pathology, 9^th Edition

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A very detailed picture from http://www.pathophys.org/introneoplasia/ that can summarize a lot of what we just talked about.

Oncogenes are mutated copies of proto-oncogenes that code for proteins that want to push the cell cycle forward. A proto-oncogene is something like Cyclins, CDKs, E2F, MYC, and MDM2, because they all move the cycle forward. If one of these becomes mutated such that it continuously tries to push the cell forward and is unresponsive to stimulus trying to shut it down, then it becomes an oncogene.

A tumour suppressor gene is a product that is designed to slow down or stop the cell cycle from progressing forward. These are things like RB, p53, p21, BRCA1 & BRCA2. A mutation of these leads to a loss of the normal brakes on the cell cycle.

Typically a neoplasm will have mutations in oncogenes and in tumour suppressor genes in order to become successful and proliferate uncontrollably.

All gas, no brakes.

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Hallmarks Of Cancer

Six keys to success for a cancer cell

Create your own stimulus to grow
Don’t let anything slow you down
Continue to divide infinitely
Don’t let anything trigger cell death
Establish a strong source of nutrients
Invade into other areas and spread

J. McFarlane, Doctorials 2021/2022

In order for a cancer to be successful in growing and spreading, there are six things that it needs to do. This is true of all cancers.

Mutations in proto-oncogenes into oncogenes to push the cell cycle forward without the need for an external stimulus. This is creating your own growth signals. Gain of function mutations to Cyclins, CDK, MDM2 for example will help to provide internal stimulus for the cell to continue growing and dividing.

Become insensitive to anti-growth signals. This happens when there are loss of function mutations to the tumour suppressor genes like RB, p53, and p21 for example. With reduced capability to slow down the cell cycle and fix errors, division continues at an alarmingly fast rate and becomes full of errors.

Continue to divide infinitely. Cells typically have a programmed set number of times that they can divide before they end up dying, and there is theory that this is tied into telomeres on the ends of our chromosomes getting shorter with each division. As a cancer cell, there is no concern for the shortening telomers, and so they will continue to divide uncontrollably.

Don’t let anything trigger your death. Whether this is internal or external stimulus, shutting down the apoptosis mechanism will allow for more cells to divide and grow larger. One of the ways that cells do this is though overexpression of Bcl-2 – a molecule that stabilizes the mitochondrial membrane and inhibits apoptosis.

By continually secreting molecules like VEGF (vascular derived growth factor), angiogenesis occurs and more blood vessels are created in the area of the tumour. This provides a steady stream of nutrients to the cancerous cells, providing them with the fuel they need to grow and divide.

And finally the cells need to be able to grow into other tissues and/or break off and spread to other parts of the body to metastasize. This can be accomplished with downregulation of E-Cadherin, production of metalloproteinases to break down basement membranes.

Image: Robbins Pathology, 9^th Edition

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Why Is Cancer So Hard To Beat?

J. McFarlane, Doctorials 2021/2022

Cancer is such a difficult thing to treat for one simple reason – a malignancy is made of cells that are exceptionally talented at surviving.

As a tumour is in it’s early stages of development, it only has a couple of mutations that make it divide uncontrollably, but as we get to further generations that each develop their own mutations, some of them will help the cell survive, and some may reduce the likelihood of survivability. The cells that develop mutations that increase survivability will survive and give their newly mutated genes to their offspring, while the mutations that did not increase survivability may be targeted by our immune system and destroyed.

After a few generations of this we end up with a group of cells that has a plethora of mutations specifically designed to allow the mass of cells to survive and thrive.

Image: Robbins Pathology, 9^th Edition

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Common Carcinogens - Chemicals

Robbins Pathology, 9^th Edition

Found in smoked foods

Stomach carcinoma

Nitrosamines

Occupational exposure in plumbing

Associated with angiosarcoma of liver

Vinyl Chloride

Exposure can lead to lung carcinoma or mesothelioma

Insulation in walls

Asbestos

Overuse assoc w/ squamous cell carcinoma of oropharynx , upper esophagus and HCC

EtOH

Carcinoma of oropharynx, esophagus, lung, kidney, bladder, pancreas

Most common carcinogen world wide

Cigarette smoke

Derived from Aspergillus

Associated with HCC

Aflatoxin

Carcinogen: An agent that damages DNA and increases the risk for cancer formation

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Common Carcinogens – Viruses and Radiation

Robbins Pathology, 9^th Edition

Kaposi sarcoma

HHV-8

Adult T cell leukemia/lymphoma

HTLV-1

Sq cell carcinoma of vulva, vagina, anus and cervix; adenocarcinoma of cervix

High risk HPV

Subtypes 16, 18, 31, 32

Nasopharyngeal carcinoma Chinese/African male

Burkitt lymphoma, CNS lymphoma in AIDS

EBV

Hepatocellular carcinoma

HBV and HCV

Pyrimidine dimer formation in DNA

Basal cell carcinoma, sq cell carcinoma, melanoma

Non ionizing (UVB sunlight)

Generation of hydroxyl free radicals

AML, CML, Papillary carcinoma of thyroid

Ionizing

(Nuclear reactor accidents, radiotherapy)

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5 Minute Break!

J. McFarlane, Doctorials 2021/2022

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Hematological Malignancies – Leukemia and MPD

J. McFarlane, Doctorials 2021/2022

Pathoma

Hematopoeitic CD34+ stem cell

Myeloid stem cell

Erythroblast

RBC

PV

Myeloblast

AML

Granulocytes : neutrophils, basophils, eosinophils

CML

Monoblast

Ac. Monoblastic leuk

Monocytes

Megakaryoblasts

Ac. Megakaryoblastic leukemia

Megakaryocytes (platelet)

Myelofibrosis, ET

Lymphoid stem cell

B lymphoblast

B-ALL

Naïve B cells

CLL, Hairy cell leukemia

Plasma cell

MM, WM,

T lymphoblast

T-ALL

Naïve T cells

CD8 T cells CD4 T cells

MF, ATLL

Acute myeloid leukemia

Myeloproliferative disorders

Acute lymphoblastic leukemia

Chronic lymphoblastic leukemia

This chart show the names of the various leukemias created by over production of different types of cells in the hematopoietic CD34+ stem cell lineage.

In acute leukemia, over 20% of the cells will be blast cells that cannot differentiate into their later forms. This proliferation crowds out normal hematopoeisis within the bone marrow and suppresses the ability of the non-mutated cells to proliferate.

Signs and symptoms indicating marrow failure?

Pancytopenia

Anemia
Neutropenia
Thrombocytopenia

Present with increased WBC because the blast cells leave the bone marrow and enter the blood stream in large quantities.
What test would you need to determine if the high WBC is just an infection or a specific form of leukemia? An FBC with differential.
Leukemic cell infiltration of liver, spleen, lymph nodes and skin (leukemia cutis) is also possible

PV – Polycythemia vera

AML – Acute myelogenous leukemia

CML – Chronic myelogenous leukemia

ET – Essential thrombocythemia

B – ALL – B-cell acute lymphoblastic leukmia

CLL – Chronic lymphocytic leukemia

MM – Multiple Myeloma

WM – Waldenstrom Macroglobulinemia

T – ALL – T-cell acute lymphoblastic leukemia

MF – Mycosis fungoides

ATLL – Adult T-cell leukemia/lymphoma

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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Acute Lymphoblastic Leukemia – tDt+

J. McFarlane, Doctorials 2021/2022

Pathoma

	B-ALL	T-ALL
Epidemiology	Children, associated with Down syndrome (after age 5) B – Cell ALL – 80-85% of cases T – Cell ALL – 15-20% of cases
Other key info	t(12;21): good prognosis (more common in children) t(9;22): poor prognosis (more common in adults)	Present as Thymic masses in Teenagers (lymphoblastic lymphoma)
Cell markers	CD10, 19 and CD20	CD3, CD4, CD7

The most common childhood malignancy

How might a thymic mass present?

Acute lymphoblastic leukemia is the most common childhood malignancy. It can be difficult on initial inspection of WBC proliferation to tell if you’re dealing with an AML or a CML or ALL, one of the ways to do so is that ALL will test positive to tDt. tDt is a DNA polyermase that is present in the nucleus of lymphoblasts. It’s not found in myeloid cells, nor is it found in mature lymphocytes. So a tDt+ means that you’re dealing with immature lymphoblasts.

Cell surface markers >10 = B cells

Cell surface markers <10 = T cells

In T-cell ALL, you can think of the T’s as clues – it presents as a Thymic mass commonly in Teenagers. Because of this, we call it a lymphoblastic lymphoma rather than a leukemia. It’s a lymphoma because it is a mass (-oma) present in the lymph system (thymus), rather than a leukemia, which would be in the blood.

Thymic mass 🡪 superior vena cava syndrome

Raised JVP, facial plethora, upper extremity edema, cough, dyspnea

What is the name of t(9;22) translocation? Philadelphia + ALL

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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Acute Myelogenous Leukemia

Accumulation of immature myeloid cells
Older adults

J. McFarlane, Doctorials 2021/2022

Pathoma

	Myeloblasts*	Monoblasts	Megakaryoblasts
Epidemiology	Older adults (average 50-60 years old)		Associated with Down syndrome (before age 5)
Characteristics	Presence of Auer rods (MPO) t(15;17) 🡪 translocation of retinoic acid receptor to chromosome 17 🡪 disruption blocks maturation 🡪 accumulation of promyelocytes Increased risk of DIC	Blasts infiltrate gums
Treatment	All trans retinoic acid (ATRA)

In acute forms of leukemia, the cell loses the ability to mature, and so there is a pile up of these immature cells that don’t have the same function as their mature counterparts.

Auer rods are crystallized forms of myeloperoxidase – an enzyme present in the cytoplasm of the cell

The t(15;17) translocation is a specific type of AML called Acute promyelocytic leukemia and is due to the retinoic acid receptor being disrupted, leading to an accumulation of promyelocytes. These promyelocytes will contain a number of Auer rods within them, and if the cells lyse and the auer rods leak into the serum it triggers the clotting cascade that ends up using a lot of your body’s platelet stores, putting the patient at increased risk of DIC.

DIC – Disseminated Intravascular Coagulopathy. A consumptive coagulopathy that leaves your platelet stores depleted. Can be seen clinically with bleeding around the catheter site and various mucosal surfaces

How does ATRA work ? Able to bind altered receptor 🡪 promyelocytes can fully mature and eventually die

A proliferation of monoblasts, the precursors to monocytes, gives a person acute monocytic leukemia, and one of the defining characteristics of this is that they tend to proliferate in the gums, leading to gum swelling.

A proliferation of megakaryoblasts, which is the precursor to megakaryocytes, where we get our platelets from, gives a person acute megakaryoblastic leukemia. This is associated with Down syndrome, but before the age of 5. So our general principle is that those with down syndrome are more likely to get leukemia, and they are more likely to get acute megakaryoblastic leukemia before the age of 5, and to be a form of ALL after the age of 5.

Image: https://www.UpToDate.com

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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Chronic Lymphocytic Leukemia

J. McFarlane, Doctorials 2021/2022

Pathoma

	B cell origin		T cell origin
Type	Chronic lymphocytic leukemia	Hairy Cell leukemia	Adult T cell leukemia/lymphoma (ATLL)	Mycosis Fungoides
Findings	Naïve B cells	Mature B cells	Mature CD 4+
Cell markers/ histology/cause	CD5+ and CD20 + Smudge cells	TRAP +, hairy cells	Caused by HTLV-1 (Human T-Cell Leukemia Virus – 1)	Cerebriform nuclei (Sezary cells)
Lymphadenopathy	Yes	No	Yes	Cerebriform nuclei (Sezary cells)
Other unique features	Assoc. w/ complications: Hypogammaglobulinemia, autoimmune hemolytic anemia, Richter transformation	Splenomegaly Dry tap on bone marrow aspiration	Common in Japanese and Caribbean, Rash, hepatosplenomegaly, lytic bone lesions, hypercalcemia Caused by HTLV	Skin involvement: rash, plaques, nodules), Pautrier abscesses

A chronic lymphocytic leukemia is a neoplastic proliferation of naïve B cells that co-express CD5 and CD20, which is interesting because CD5 would typically be on a T cell, not a B cell.On a blood smear you can visualize “smudge” cells and increased lymphocytes. This type of neoplasm does end up with a generalized lymphadenopathy, which we call small lymphocytic lymphoma.

Because these lymphocytic cells are neoplastic and do not function properly, they don’t make immunoglobulins, which leads to a hypogammaglobulinemia and puts the patient at risk for infections. These infections become the most common cause of death for patients with chronic lymphocytic leukemia. Another thing they do incorrectly is they can produce antibodies against the patient’s own red blood cells, leading to an autoimmune hemolytic anaemia.

They also have the potential for a Richter transformation, where the neoplasm transitions into a diffuse large B cell lymphoma, which can be seen clinically as an enlarging lymph node/spleen.

Hairy Cell leukemia is a neoplasm of mature B cells which is characterized by hairy cytoplasmic processes and are positive for TRAP (Tartrate Resistant Acid Phosphatase). A common clinical features of this leukemia is splenomegaly with enlargement of the red pulp, rather than the white pulp, which is interesting because the white pulp is where the white blood cells would be found in the spleen. With this type of neoplasm you may find a “dry tap” on bone marrow aspiration due to fibrosis of the bone marrow, so very few cells being produced in the marrow, and there will likely not be any lymphoadenopathy.

Adult T cell leukemia is a neoplastic proliferation of mature CD4+ T cells and is associated with HTLV-1 and seen more often in patients of Japanese or Caribbean origin. Clinically, these patients will present with a rash, hepatosplenomegaly with generalized lymphadenopathy, and lytic bone lesions with hypercalcemia.

Finally mycosis fungoides is another type of CD4+ T cell proliferation that leads to these T cells infiltrating the skin producing rash, plaques, nodules or Pautrier microabscesses (an accumulation of these CD4+ cells within the epidermis). These cells can also spread to the blood in a condition called Sezary syndrome, and under a microscope there will be the appearance of lymphocytes with cerebriform nuclei, as seen in the picture.

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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Myeloproliferative Disorders (MPD)

J. McFarlane, Doctorials 2021/2022

Pathoma

	Chronic Myeloid Leukemia	Polycythemia Vera	Essential Thrombocythemia	Myelofibrosis
Dominant cell type	Granulocytes	RBCs	Platelets	Megakaryocytes
Associated mutation	t(9;22)	JAK2 kinase mutation
Clinical features	Splenomegaly ++ basophils (-) LAP	Hyperviscosity symptoms	++ risk of bleeding (lack of function) and/or thrombosis (gain of function)	Splenomegaly (extramedullary hematopoeisis) Leukoerythroblastic smear ++ risk of infection
Tx	imatinib	1^st line: phlebotomy 2^nd line: hydroxyurea
Complications	Transformation into AML (2/3) or ALL (1/3)	No treatment 🡪 death in 1 yr

Myeloproliferative disorders are a neoplastic proliferation of mature cells of the myeloid lineage. It is typically a disease of late adulthood, and results in a high white blood cell count of all types but the name classification is for the dominant type present.

Chronic myeloid leukemia is a proliferation of all the myeloid cells, but predominantly the granulocyte neutrophils, eosinophils, and especially the basophils. The mutation is driven by a t(9;22) translocation that codes for a BCR-ABL fusion that increases tyrosine kinase activity, leading to uncontrolled cell signaling.

Where did we see a t(9;22) before? Seen in B-ALL with poor prognosis. The first line of treatment is thus imatinib, which is designed to block the increased tyrosine kinase and halt the excessive proliferation.

So how do we know if the overproduction of granulocytes is due to an acute infection or a CML? There are three key ways. First is to look for Leukocyte Alkaline Phosphatase (LAP), which will be positive in granulocytes that are produced correctly with the goal of fighting an infection. LAP will be negative in CML because they are not being produced with the goal of treating infection, they just continue to multiple and divide without a goal. The second way to tell is that there is an overabundance of basophils in CML, and the third is to identify the t(9;22) translocation within the mutated cells.

Hyperviscosity symptoms

Blurry vision and headache
Increased risk of venous thrombosis
Flushed face (plethora)
Itching esp after bathing due to increase from mast cell production and release of histamine

How do you differentiate PV from reactive polycythemia?

PV: EPO are decreased and there is normal SaO2
Reactive polycythemia: occurs d/t high altitude or lung disease so SaO2 is low and EPO is high
Reactive polycythemia d/t ectopic EPO (RCC) 🡪 EPO is high and SaO2 is normal

In myelofibrosis, there is a neoplastic proliferation of mature myeloid cells, especially megakaryocytes. These megakaryocytes produce an excess of PDGF which results in fibrosis of the bone marrow.

Leukoerythroblastic peripheral blood smear showing the presence of nucleated (immature) red cells and immature white cells.

There is an increased risk of infection, thrombosis, and bleeding in these patients. When the bone marrow becomes fibrosed, the site of primary myeloid cell production gets shifted to the spleen, which cannot keep up and so there are a decrease in WBCs and platelets with proper function.

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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Lymphoma: Hodgkin vs Non-Hodgkin

Neoplastic proliferation of lymphoid cells that forms a mass in a lymph node or extranodal tissue

J. McFarlane, Doctorials 2021/2022

Pathoma

Lymphoma

Hodgkin (40%)

Nodular sclerosis

Lymphocyte rich

Mixed cellularity

Lymphocyte sclerosis

Non Hodgkin (60%)

Follicular

Mantle cell

Marginal Zone

Burkitt Lymphoma

Diffuse Large B Cell lymphoma

B Symptoms

Localized, single group of nodes with contiguous spread

Better prognosis

Reed Sternberg Cells

Bimodal : young adulthood and >55YO

M>F except nodular sclerosing

B Symptoms

Multiple lymph nodes, extranodal involvement common, non contiguous spread

Worse prognosis

Majority involve B cells

May be associated with autoimmune disease and viral infections (HIV, EBV, HTLV), late adulthood

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Hodgkin Lymphoma

Reed-Sternberg cells “Owl eye” cells
CD15 + and CD30+ that are B-cell origin
2 Owl eyes x 15 = 30

J. McFarlane, Doctorials 2021/2022

Pathoma

Subtype	Notes
Nodular sclerosis	Most common (70%) Lymph node divided by bands of fibrosis, RS cells in lacunar spaces, Young female, enlarging cervical or mediastinal lymph node
Lymphocyte rich	Best prognosis
Mixed cellularity	Eosinophilia (RS cells produce IL-5), seen in immunocompromised pt
Lymphocyte depleted	Seen in immunocompromised (HIV, elderly), most aggressive, worst prognosis

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Non Hodgkin Lymphoma: Small B cell (CD20+)

J. McFarlane, Doctorials 2021/2022

Pathoma

Marginal zone

Mantle zone

Follicle

	Follicular	Mantle cell	Marginal Zone
Epidemiology	Late adulthood	Late adulthood, M>>F	Chronic inflammatory states
Etiology	t(14;18) Heavy chain Ig and BCL-2	t(11;14) Cyclin D1 and heavy chain Ig	t(11;18)
Location within follicle/ markers	Found in germinal center which is lacking tingible body macrophages	Expand in mantle zone CD5+	Expands in marginal zone
Presentation	Painless lymphadenopathy	Painless lymphadenopathy
Complications	Progression to large B cell lymphoma

Non-Hodgkin lymphoma is the more common of the two types of lymphomas (60%). In this slide we look at the small B cell types of lymphoma, which have small, well differentiated B cells that proliferate within the lymph nodes.

Follicular lymphoma is a neoplastic proliferation of small CD20+ B cells that form follicle-like nodules that clinically present in late adulthood and are a painless lymphadenopathy. One of the main causes for this proliferation of follicles is driven by a t(14;18) translocation that moves the BCL2 gene from chromosome 18 and adds it on to the Ig heavy chain locus on chromosome 14. This results in an overexpression of BCL2 and thus an inhibition of apoptosis.

When B cells are undergoing somatic hypermutation during periods of infection they constantly are undergoing apoptosis if their created immunoglobulin is not a match for the antigen. Because of this we will see macrophages within the germinal center cleaning up the debris from apoptosis. In a follicular lymphoma there will be an absence of these macrophages cleaning up the dead B cells (because they aren’t dying), and so we say there is a lack of tingible body macrophages.

Mantle cell lymphoma is a neoplastic proliferation of small B cells that expand the mantle zone/the region right next to the follicle. It is driven by a t(11;14) that translocates Cyclin D1 from chromosome 11 to the Ig heavy chain locus on chromosome 14 again. This overproduction of Cyclin D leads to an increase in the G1/S transition within the cell cycle.

The marginal zone can be found outside of the mantle, so a marginal zone lymphoma is created when the lymphoma created by neoplastic B cells stretches out pas the mantle. This is often associated with chronic inflammatory states such as Hashimoto’s thyroiditis, Sjogren syndrome, and H. Pylori gastritis which creates a Mucosa associated lymphoid tissue – oma/MALToma.

Slide from Jackie Yang’s Doctorials presentation in 2020/2021

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NHL: Intermediate and Large B cell (CD 20+)

J. McFarlane, Doctorials 2021/2022

Pathoma

	Burkitt Lymphoma	Diffuse Large B Cell Lymphoma
Cell type & growth	Intermediate sized B cells	Large B cells growing in sheets
Presentation	Extranodal mass in child or young adult African: jaw Sporadic: abdomen	Most common NHL Late adulthood, enlarging lymph node or extranodal mass
Associations	EBV Translocation of c-myc: t(8;14) 🡪 overexpression 🡪 +++cell growth	May transform from follicular lymphoma
Histology	“Starry sky”, sheets of lymphocytes, tingible body macrophages, high mitotic index

Burkitt Lymphoma is a neoplastic tumour of intermediate sized CD-20+ B-cells. Associated with Epistein Barr virus. Two different types, and both are extranodal. The African form is found in the jaw, and the sporadic form is found in the abdomen. These tumours are driven by a translocation of c-myc from chromosome 8 to chromosome 14, where it is expressed along with the Ig heavy chain again. This leads to an over expression of c-myc, which is a nuclear regulator of genes for growth, so an overexpression here leads to uncontrolled cell growth. This tumour has a very high mitotic rate and grow so fast that they actually end up dying, so it creates a starry sky appearance on histology where the growing and dividing cells create a sky of blue, and the tingible body macrophages create little pockets within it to make the “stars”.

Diffuse large B cell is aptly named. It is diffuse because it doesn’t produce follicles, or a mantle or marginal zone, but it grows diffusely. It is large B-cells that are CD-20+ and it is a lymphoma. This is the most common form of Non-Hodgins lymphoma and it is very aggressive. Usually presents in late adulthood as an enlarging lymph node or an extranodal mass.

Slide adapted from Jackie Yang’s Doctorials presentation in 2020/2021

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Plasma Cell Disorders: Monoclonal Plasma Cells

J. McFarlane, Doctorials 2021/2022

Pathoma

	Multiple myeloma	Waldenstrom Macroglobulinemia
Overproduce	IgG (55%), IgA (25%) or Light chains	IgM
SPEP	M spike in gamma region	M spike in gamma region
Presentation	CRABBI Calcium +++ Renal insufficiency (Bence Jones proteinuria), Rouleaux Anemia, amyloidosis Bone lytic lesions (esp. vertebrae and skull) Bone pain Infection	Generalized lymphadenopathy No lytic bone lesions Hyperviscosity Visual and neurologic deficits defective platelet aggregation 🡪 bleeding

Why is there an increased risk of infection if there are more antibodies around?

Multiple myeloma is a malignant proliferation of plasma cells in the bone marrow and is the most common primary malignancy of bone. IL-6 is often elevated in this patients as it drives the production of these plasma cells as a growth factor. These neoplastic cells have the capability to produce RANK receptors on osteoclasts to increase their activity, which will drive up the serum calcium concentration and lead to symptoms of hypercalcemia – CRABBI. This increases the risk of fracture, so pathological fractures where the injury does not match the mechanism can be seen.

SPEP – Serum Protein ElectroPhoresis. A way to measure the concentration of various proteins in serum. The gamma region is used to measure the concentrations of immunoglobulins in serum, and this will show a sharp spike in cases of monoclonal immunoglobulin proliferation. In MM it is typically a proliferation of monoclonal IgG or IgA.

The increased production of light chains seen in MM is a risk for deposition within the tissues as amyloid and within the kidneys causing an obstruction and risk of renal failure.

The increased risk of infection is due to the monoclonal nature of the antibodies – loss of diversity. As such, infection is the most common cause of death in these patients.

Waldenstrom macroglobulinemia is a B-cell lymphoma that has increased monoclonal IgM production. It presents with a generalized lymphadenopathy but without lytic bone lesions. This too will have an M spike on SPEP, but it is due to an overproduction of monoclonal IgM, instead of IgG or IgA found in MM. The main problem with WM is hyperviscosity, which leads to problems like visual and neurological deficits or increased risk of bleeding due to impaired platelet aggregation.

Treatment for WM is plasmapheresis, where the blood is removed from the patient, IgM is removed from the serum, and the blood is replaced back into the patient. It essentially cleans the blood of excess IgM.

Images: Pathoma

https://twitter.com/guptaarjun90/status/1042614480503545856/photo/2

Slide adapted from Jackie Yang’s Doctorials presentation in 2020/2021

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What’s The Neoplasm?

J. McFarlane, Doctorials 2021/2022

Acute Promyelocytic Leukemia

Auer Rods

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What’s The Neoplasm?

J. McFarlane, Doctorials 2021/2022

Hodgkin’s Lymphoma

Reed-Sternberg Cells

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What’s The Neoplasm?

J. McFarlane, Doctorials 2021/2022

Chronic Lymphocytic Leukemia

Smudge Cells

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Non-Haematological Malignancies: Colon Cancer

J. McFarlane, Doctorials 2021/2022

Signs and Symptoms

Iron def Anemia
Hematochezia
Colicky pain
Fecal Occult Blood (FOB)
Weight loss

Screen

Low risk: at age 50, begin colonoscopy
Alternatives: FOBT, FIT, FIT-fecal DNA, CT colonography
1^st deg relative with CRC : colonoscopy at 40 y/o or 10 years prior to age of presentation in relative
Pts with IBD

Imaging and tumor markers

Apple core lesion on barium enema X ray
CEA: only for monitoring, not for screening

Risk factors

Adenomatous and serrated polyps
Familial cancer syndrome
IBD
Tobacco use
Processed meats with low fiber

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Adenoma-Carcinoma Sequence

Stepwise mutations leading to cancer of the colon
Three potential pathways:

Chromosomal instability via the adenoma-carcinoma sequence

Seen in FAP and sporadic types

Microsatellite instability pathway

Seen in lynch syndrome and some sporadic types

Overexpression of COX-2

J. McFarlane, Doctorials 2021/2022

Loss of APC

KRAS Mutation

P53 Mutation

The loss of APC leads to decreased intracellular adhesions, which puts the colon at risk for increased proliferation and polyp formation. This loss of APC can often be sporadic and comes with increased age, or it can be part of Familial Adenomatous Polyposis – an autosomal dominant disorder characterized by an inherited APC mutation that leads to hundreds of thousands of adenomatous colonic polyps forming, often at a young age. They are guaranteed to get colon cancer at one point in their lifetime, so many of these patients with have a preventative colectomy. The associated image here shows a stretch of colon with these polyps present.

The second mutation is a KRAS mutation, which leads to unregulated intracellular signaling and the creation of a polyp and adenoma.

The final mutation is a loss of tumour suppressor genes like p53 or DDC, and this begins tumorigenesis and the formation of a carcinoma.

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Polyposis Syndromes

J. McFarlane, Doctorials 2021/2022

First Aid 2021

Familial adenomatous polyposis

Autosomal dominant mutation of APC

Thousands of polyps arising after puberty

Pancolonic. Always involving the rectum

Prophylactic colectomy or 100% rate of CRC

Puetz-Jeghers Syndrome

Autosomal dominant

Numerous hamartomas throughout GI tract

Hyperpigmented macules on mouth, lips, hands, genitalia

Increased risk of breast and GI cancers

Gardner Syndrome

FAP + osseous and soft tissue tumours

Congenital hypertrophy of retinal pigment epithelium

Impacted/supernumary teeth

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Polyposis Syndromes Continued

J. McFarlane, Doctorials 2021/2022

First Aid 2021

Juvenile Polyposis Syndrome

Autosomal dominant syndrome in children typically <5

Numerous hamartomatous polyps in the colon, stomach, small bowel

Increased risk of CRC

Lynch Syndrome

Autosomal dominant mutation of mismatch repair genes with microsatillite instability

~80% progress to CRC

Proximal colon is always involved. Associated with endometrial, ovarian, and skin cancers

Turcot syndrome

FAP or Lynch Syndrome + malignant CNS tumour

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Cervical Carcinoma

Cervical Intraepithelial Neoplasia (CIN)

Often associated with persistent HPV infection

Human Papilloma Virus

Sexually transmitted DNA virus that infects the lower genital tract, especially the cervix at the transformation zone
90% of time cleared away by immune system, but persistent infections increase risk for neoplasia
High risk HPV – 16, 18, 31, 33
Low risk HPV – 6, 11

Characterized by koilocytic change, nuclear atypia, and increased mitotic activity
Typically seen in a middle-aged woman (40-50 y/o) with vaginal bleeding

J. McFarlane, Doctorials 2021/2022

Pathoma

Koilocytes

Larger, darker nuclei
Irregular nuclear membrane – raisinoid
Perinuclear halo

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Cervical Carcinoma Continued

CIN progresses stepwise

CIN I -> II -> III -> CIS (carcinoma in situ) -> invasive carcinoma/cervical carcinoma
Possibility to regress

Key risk factors:

HPV infections HPV-16, 18, 31, 33
Smoking
Immunodeficiency

Subtypes

Squamous cell (80%) and adenocarcinoma (20%)

Common cause of death

Post renal failure. Invades into the bladder -> obstructs ureters -> hydronephrosis

Screening to detect CIN before CIS

Pap smears starting at age 21
Abnormal pap smears -> colposcopy and biopsy

J. McFarlane, Doctorials 2021/2022

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Psammoma bodies

Laminated, concentric spherules with dystrophic calcification
Associated with malignant cancer
Function: halt growth of cancer, serve as barrier against spread of malignant cancer cells

Thickening of bottom most layer of cells (basal lamina)
Followed by thrombosis, calcification and tumor necrosis
Mechanism unclear

Associated cancers : PSaMMOMa

J. McFarlane, Doctorials 2021/2022

Papillary carcinoma of thyroid
Somatostatinoma
Meningioma
Malignant mesothelioma
Ovarian serous papillary cystadenocarcinoma
Prolactinoma (Milk)

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Chemotherapy

Target specific steps within the cell cycle and halt its progression

J. McFarlane, Doctorials 2021/2022

First Aid 2021

Nucleotide synthesis	Decrease Thymidine synthesis	MTX, 5-FU
	Decrease de-novo purine synthesis	6-MP
	Inhibit ribonucleotide reductase	Hydroxyurea
Disrupt DNA stability	Cross link DNA	Alkylating agents , Platinum agents
	DNA breakage	Bleomycin
	DNA intercalation	Dactinomycin, doxorubicin
	Inhibit topoisomerase I	Irinotecan/topotecan
	Inhibit topoisomerase II	Etoposide/teniposide

Cellular division	Vinca alkaloids	Inhibit microtubule formation
Cellular division	Paclitaxel	Inhibit microtubule disassembly

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Chemotherapy: Monoclonal Antibodies

J. McFarlane, Doctorials 2021/2022

First Aid 2020

CD20

Rituximab

Tyrosine kinase (bcr-abl and c-kit)

Imatinib, dasatinib, nilotinib

Proteosome (induce arrest at G2-M)

Bortezomib, carfilzomib

VEGF

Bevacizumab

EGFR tyrosine kinase

Erlotinib

EGFR

Cetuximab, panitumumab

Her-2

Trastuzumab

Estrogen receptor

Tamoxifen, raloxifen

BRAF

Dabrafenib, vemurafenib

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Oncological Emergencies

Presentation: Middle aged, male pt

Flank pain, reduced urine output, dysuria, shortness of breath
Recently started chemotherapy for Non - Hodgkin’s lymphoma
Labs: hypocalcemia, hyperphosphatemia, hyperkalemia, hyperuricemia, increased creatinine
ECG: peaked T waves

J. McFarlane, Doctorials 2021/2022

TLS: triggered by massive tumor cell lysis

most often in lymphomas/leukemias

Release of K+ 🡪 muscle weakeness, arrhythmias

Release of PO4^3- 🡪 hyperphosphatemia, hypocalcemia 🡪 seizure, tetany, arrhythmias

Increased nucleic acid breakdown 🡪 hyperuricemia 🡪 acute kidney injury

Dx: Tumor lysis syndrome

Tx and Mx:

- Aggressive hydration, allopurinol, rasburicase

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Oncological Emergencies

J. McFarlane, Doctorials 2021/2022

Presentation: Middle aged F

Rigors, cough and yellow sputum and increased SOBOE
Currently on cycle 3 of adjuvant chemotherapy for breast cancer
Hx : mild COPD, salbutamol inhaler PRN
O/e: fever (38.8), tachycardia, hypotension, low Ox sat on RA,
Labs: low Hb, low WBC, low neutrophils, low platelets, raised CRP, negative urine dip

Dx: Febrile Neutropenia

Dx : oral temperature >38 over 1 hr or any single episode of T >38.2 and absolute neutrophil count <1500 cells/uL

Experienced by up to 80% of pt undergoing chemo

Tx and Mx:

- Early IV broad spec Antibiotic therapy, do not wait for culture

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Oncological Emergencies

J. McFarlane, Doctorials 2021/2022

Presentation: Middle aged, male pt

No known illness, 6 weeks of increasing lumbar back pain. Pain is increasingly unmanageable, worse when supine or coughing
Associated with discomfort in left leg, feels funny when wiping after going to bathroom
Quit smoking 20 years ago
Ex: bilateral leg weakness, decreased pinprick sensation, bilateral stocking distribution, plantar is upgoing bilaterally, hyperreflexic

Dx: Spinal cord compression

Local and neuropathic pain typically preceding motor weakness
Saddle paresthesia
Caused by mechanical compression or infiltration
Mets from lung, prostate, breast; myeloma, lymphoma, melanoma, neuroblastoma and sarcoma

Tx: dexamethasone (taper off)
Mx: urgent MRI, consult radiation oncology on same day as dx, consult neurosurgery

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J. McFarlane, Doctorials 2021/2022

You Did It!

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References

Pathoma
Robbins Pathology 9^th edition
http://www.pathophys.org/introneoplasia/
Jackie Yang’s Doctorials 2020/2021 Presentation used with permission

J. McFarlane, Doctorials 2021/2022