Hematology and Oncology

How is the incidence (diagnosis) of cancer estimated?

• National Cancer Institute’s Surveillance

• Epidemiology

• End Results (SEER) database

Common Cancers based on Incidence (diagnosis):

1. Breast

2. Prostate

3. Lung

Common Cancers based on Mortality:

1. Lung

2. Colon

3. Pancreas

What is Carcinogenesis: 

• the process by which normal cells are transferred into cancer cells

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How do tumors evolve?

• tumors go from benign to malignant cells by acquiring a series of genetic mutations over time

ex: development of colon cancer

What is metastasis?

• the process where cancer cells break away, travel, and form new tumors in different organs or tissues

• spreads through the blood, lymphatic system, or through direct extravasation into surrounding tissue

• metastatic tumors are the same type of cancer as the original primary tumor

What can mutations do?

• affect genes that encode proteins functioning in important molecular pathways

What are different carcinogenic mutations?

• driver mutations

• passenger mutations

• oncogenes

• tumor suppressor genes

Driver Mutations: 

• mutations that confer a selective growth advantage to the cell in which they occur (birth rate of cells is higher than cell death in comparison to normal cells)

Passenger mutations:

• genetic mutations in cell that do NOT cause a selective growth advantage

• do not contribute to carcinogenesis

Oncogenes: 

• genes that function to regulate growth and survival of cells

• when mutated, lead to gain of function enhancing cell survival, growth, and/or proliferation

• called a proto-oncogene before it is mutated

Germline/Hereditary Mutations:

• found in germ cells, present in all subsequent cells after embryonal development

• influences risk for developing diseases, such as cancer (BRCA mutations) or other diseases (CTFR mutations

How can we test for germline/hereditary mutations?

• tissue: blood (WBCs), buccal swabs, skin fibroblasts (for patients with hematologic malignances)

What are two common hallmarks of cancer?

• sustaining proliferative signaling

• evading growth suppressors

Common Cancer Symptoms:

• weight loss

• fatigue

• fever

• pain

• lumps or swollen lymph nodes

• others

Weight loss - qualities: 

• 10 lbs or more over a few months

• unintentional

Weight loss - pathophysiologic mechanism in cancer:

• cancer cells are hypermetabolic

Fatigue - qualities: 

• unrelieved by rest

Fatigue - pathophysiologic mechanism in cancer:

• cancer cells are hypermetabolic

Fever - qualities:

• recurrent

• unexplained by other illnesses

• more often at night

• accompanied by night sweats

Fever - pathophysiologic mechanism in cancer: 

• inflammatory response to tumors raise body temperature

Pain - qualities:

• persistent

  • may or may not be localized

Pain - pathophysiologic mechanism in cancer:

• tumor growth and pressure

Lumps or swollen lymph nodes - qualities: 

• firm

• fixed

• non-tender

• progressively enlarging

Lumps or swollen lymph nodes - pathophysiologic mechanism in cancer:

• lymph nodes - cancer of B cells (lymphoma)

Other symptoms:

• persistant hoarseness or cough

• sores/ ulcers lasting longer than 3 weeks

• unexplained bleeding or bruising

• skin changes

• changes in bowels or bladder habits

Somatic Mutations:

• occur in the non-reproductive cells in the body

• are not passed down from parent to child

• may influence risk for developing disease or may be underlying disease driver

How can we test for somatic mutations?

• diseased tissue: 

  • solid tumor tissue, bone marrow tissue, lymphoid tissue

  • blood (for cell-free DNA testing)

Weight loss - other potential causes: 

• medications

Fatigue - other potential causes:

• medications

• nutrient deficiencies

• anemia

• other chronic conditions (hypothyroidism, fibromyalgia)

Fever - other potential causes:

• infection

• vaccines

• certain inflammatory conditions

Pain - other potential causes:

• injury

• other chronic and acute conditions

Lumps or swollen lymph nodes - other potential causes: 

• infection

• benign growths

Common pathway to diagnosis: 

• PCP → specialist tests (Gastroenterologist, pulmonologist) → oncologist

• hospital admission for sever symptoms and expedited work up

Performance staus:

• standardized measure of a patient’s functional ability to perform daily activities and tolerate medical therapies, especially in oncology

• ECOG (Eastern Cooperative Oncology Group)

• Karnofsky Performance Status (KPS)

ECOG: 

• simpler and widely used in clinical trials

KPS:

• more granular, used in prognosis and research

Tumor markers:

• substances produced by cancer cells or by the body in response to cancer that can be measured in blood, urine, or tissues

• not diagnostic on their own since levels can rise in non-cancerous condition

Biopsies:

• a medical procedure in which a small sample of tissue or cells is extracted from the body for analysis

• allows for pathologist review of tissue leading to definitive diagnosis of cancer

Types of biopsies: 

• bone marrow biopsy

• excisional biopsy

• needle biopsy

• sentinel node biopsy

How is cancer definitively diagnosed?

• biopsies, actually looking at the cells to determine what is happening under the skin

Tumor Suppressor Genes:

• genes that function to prevent the development of malignant cells

• when mutated, they lead to the loss of function enhancing cell survival, growth, and/or proliferation

Driver mutations vs. passenger mutations - anaology: 

• driver mutations are driving the car in cancer development

• passenger mutations are just there for the ride, don’t actually contribute anything

Oncogenes vs. tumor suppressor genes - analogy:

• oncogenes are the fire

• tumor suppressor genes are the fire extinguisher

How many liters of Blood to adults have?

• 4-5 L of blood

What are the components of blood? 

• formed elements - blood cells

  • Red blood cells (erythrocytes)

  • White blood cells
    (leukocytes)

  • Platelets (thrombocytes)

• Plasma - fluid phase

Where does hematopoiesis occur?

• in the Bone marrow

What is hematopoiesis?

• formation of new blood cells in the bone marrow

Lymphoid lineage cell types:

• B lymphocytes (B cells)

• plamsa cells

• T lymphocytes (T cells)

• Natural Killer (NK) cells

• Dendritic cells (lymphoid)

How can you analyze abnormal amounts of blood cells for a patient? 

• CBC - complete blood count

What does a CBC (complete blood count) measure?

• fishbone outline

• RBCs

• Platelets

• WBCs

• Hemoglobin (Hgb)

• Hematocrit (Hct)

Acute myloid leukemia:

• rapidly growing cancer of the immature myeloid progenitor cells

Acute lymphoblasic leukemia: 

• rapidly growing cancer of the immature lymphoid progenitor cells

Chronic myeloid leukemia:

• slow glowing cancer of the mature myeloid progenitor cells

Chronic lymphocytic leukemia: 

• slow growing cancer of the mature B cells

What is anemia?

• a disorder characterized by low oxygen carrying capacity of red blood cells (RBCs, erythrocytes) due to low OR dysfunctional RBCs

What are the symptoms of anemia?

• fatigue

• shortness of breath

• inc. workload on the heart (tachycardia, pallor, dizziness, syncope

• dec. mental acuity

• dec. vibratory sense or unsteady gait

• chewing ice (iron deficiency)

What is the WHO’s definition of anemia? 

• Male: Hgb < 13 g/dL

  • Female: Hgb < 12 g/dL

What is hemoglobin?

• RBCs transport oxygen from the lungs to the tissues; CO2 from Tissues to the lungs

  • enucleated cells in concave disc form to max. SA of gas exchange and allows fexibility to travel through capillaries

• lifespan = 120 days

HEMOGLOBIN IS: iron-containing oxygen transport metalloprotein in RBCs

• iron converts to heme used to make Hgb

How does the body make and use red blood cells?

1. bone marrow

2. gastrointestinal tract (GI)

3. liver

4. Kidney

Making and using RBC - liver: 

• regulated iron balance

• transferring brings iron into tissues for storage

• hepatocytes produce hepcidinn in response to iron, controlling iron levels by limiting intestinal absorbtion of iron, iron recycling by macrophages, and release from stores

  • low iron: liver reduces hepcidin production

  • high iron: liver inc. hepcidin production

Lab Values for anemia: 

• CBC

• Reticulocyte count (RBC precursor)

• RBC indices (MCV, MCH)

• WBC with differential

• Anemia labs

  • iron panels

  • B12 and folate levels

• occult blood stool samples

What are the different types of anemia labs?

• hemoglobin

• mean corpuscular volume (MCV)

• ferritin

• transferrin

• transferrin saturation (TSAT)

• B12 folic acid

What is iron deficiency anemia?

• a type of anemia in which hemoglobin synthesis is impaired due to insufficient iron

What is Vit. B12/Folate Deficiency Anemias? 

• a group of macrocytic (megaloblastic) anemias caused by deficiency of vit B12 or folate, resulting in impaired DNA synthesis in red blood cell precursors, leading to ineffective erythropoiesis, large immature RBCs, and anemia

What is anemia of chronic inflammation?

• a type of anemia that develops in the setting of chronic infection, inflammation, or malignancy, caused by impaired iron utilization, suppressed erythropoiesis, and reduced red blood cell survival, despite adequate iron stores

Somatic vs. germline mutations:

Somatic:

• occur in non-germline tissues

• cannot be inherited

• mutation in tumor only

Germline:

• present in egg or sperm

• can be inherited

• cause cancer family syndrome

• if there is a mutation in the egg or sperm, all of the cells are affected in the offspring

What history and physical exams are important for solid tumors?

• medical exams

• family history

• social history

• performance status

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What lab evaluations are important for solid tumors?

• tumor markers (CA125, CA19-9)

• organ function (Scr)

• CBC with differential

What imaging is important for solid tumor diagnosis?

• CT scans

• PET scans

• MRI

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What pathology assessments can be done for diagnosis of sold tumors?

• surgery

• biopsy

What is imaging used for in relation to cancer?

• aid in diagnosis

• staging

• planning treatment

• assessing response to treatment

What are the different Imaging devices used?

• ultrasound

• CT scan

• PET scan

• MRI

Ultrasound - technology:

• ultrasound

Ultrasound - how it works:

• uses high-frequency sound waves reflected from tissues to create real-time images

ultrasound - visualizes: 

• real time images of soft tissues and fluid

CT Scan - technology:

• computed tomography

CT scan - how it works:

• uses X-rays taken from multiple angles to create cross-sectional images via computer processing

CT Scan - visualizes: 

• structural detail of bones, organs, blood vessels, and soft tissues

PET Scan - technology:

• Positron Emission Tomography

PET scan - how it works:

• detects metabolic activity using radiotracers and overlays functional data on CT

PET scan - visualizes: 

• displays metabolic activity of cells

MRI - technology:

• Magnetic Resonance Imaging

MRI - how it works:

• uses magnetic fields and radio waves to align hydrogen atoms and generate detailed soft-tissue images

MRI - visualizes: 

• soft-tissue contrast in high detail

what is red bone marrow?

• produces blood cells

what is yellow bone marrow? 

• it is mostly fat

Where does hematopoiesis occur in pediatrics?

• hips

• spine

• breastbone

Where does hematopoiesis occur in adults?

• long bones

How many total blood cells are produced per day? 

• 330 billion

What is the main origin cell of the hematopoietic stem cell lineage?

• multipotential hematopoietic stem cell (Hemocytoblast)

What two types of cells come from a Hemocytoblast ?

• myeloid cells

• lymphoid cells

Myeloid Cell lineage: 

• cells of the innate immune system 

  • neutrophils

  • eosinophils

  • basophils

  • monocytes

  • macrophages

  • dendritic cell (myeloid)

• red blood cells 

• platelets

Erythrocyte (RBC) - main function: 

• transports oxygen and carbon dioxide via hemoglobin

Platelet (thrombocyte) - main function:

• fragments of megakaryocytes that initiate clot formation and help stop bleeding

Neutrophil - main function:

• innate immune cell

• engulfs and destroys bacteria and fungi

• first responders in acute inflammation

Eosinophil - main function; 

• innate immune cell

• defends against parasitic infections

• participates in allergic responses

Basophil - main function:

• innate immune cell

• releases histamine and other mediators in allergic and inflammatory reactions

Monocyte:

• innate immune cell

• circulating precursor of macrophages and dendritic cells

• phagocytoses pathogens and debris

Macrophage: 

• innate immune cell

• engulfs microbes and dead cells

• presents antigens to T cells

• secretes cytokines