Neoplasia and Neoplastic Disease

Uncontrolled, abnormal growth of cells or tissues

Tumor, Nodule, Mass, (nonspecific term)

●Neoplasia (new growth) - a process involving the abnormal proliferation of cells, leading to tumor formation.

Neoplasia

Neoplasm

●Neoplasm - an abnormal mass of tissue that results from neoplasia, which can be benign or malignant.

Does not imply benign or malignant.

I.e. there are benign neoplasms and malignant neoplasms

Disease in which abnormal cells divide uncontrollably and destroy body tissue

Cancer

Branch of medicine that specializes in the diagnosis and treatment of cancer

Oncology

Malignancy

The presence of cancerous cells

Metastasis

A pathogenic agent’s spread from an initial or primary site to a different or secondary site.

Refers to how much cancer cells resemble their cell of origin- both morphologically and functionally.

Differentiation- Well-differentiated refers to tumor cells that closely resemble normal cells, while poorly differentiated indicates significant deviation from original cell types.

Dysplasia

Disorder growth of epithelium.

Does not neceform mass or tumor.

In many cases dysplasia may be a precursor to malignancy however does not always progress.

Carcinoma id Situ

full thickness of the epithelium.

○Again, many times precursor to malignancy

What is the difference between Benign and Malignant?

Benign tumors are non-cancerous, typically grow slowly, and do not invade surrounding tissues or metastasize, while malignant tumors are cancerous, can grow rapidly, invade nearby tissues, and spread to other parts of the body.

A benign neoplasm often ends in?

-oma, indicating a tumor that is generally non-invasive.

A malignant neoplasm often ends in?

-carcinoma or -sarcoma, indicating a tumor that is invasive and cancerous.

Exceptions to the neoplasm nomenclature:

What is the most common type of cancer common in adults?

Carcinoma-

○Derived from ectodermal and endodermal tissue

○Includes epithelial tissue cancers

■Lung, colon, breast, prostate cancer

■Think adenocarcinoma, squamous cell carcinoma,  intraductal carcinoma

○More common in adults

Feature	Carcinoma	Sarcoma
Origin	Epithelial tissue	Connective tissue
Tissues involved	Skin, glands, organ linings	Bone, muscle, fat, cartilage, blood vessels
Frequency	Most common cancers	Much rarer cancers
Examples	Lung carcinoma, breast carcinoma, colon carcinoma	Osteosarcoma, liposarcoma, chondrosarcoma

What is the rarer type of cancer and often aggressive?

Sarcoma-

○Originates from mesodermal tissue

○Arises from mesenchymal cell types in connective tissue (fat, cartilage or bone)

■Rhabdomyosarcoma (skeletal muscle)

■Leiomyosarcoma (smooth muscle)

■Angiosarcoma (Blood vessels)

○More common in children

Often times aggressive :(

Feature	Carcinoma	Sarcoma
Origin	Epithelial tissue	Connective tissue
Tissues involved	Skin, glands, organ linings	Bone, muscle, fat, cartilage, blood vessels
Frequency	Most common cancers	Much rarer cancers
Examples	Lung carcinoma, breast carcinoma, colon carcinoma	Osteosarcoma, liposarcoma, chondrosarcoma

Reliable indicators of malignancy in many organs?

Histologic features

However, in some sites, they do not always distinguish benign from malignant neoplasms

What are microscopic features that make pathologists suspect a tumor is malignant (cancerous)?

1. Pleomorphism- variation in nuclear and cytoplasmic shape between cells. Cancer cells look irregular and different from one another.

2. Abnormal mitotic figures and increased numbers of mitotic figures: They may show abnormal mitotic figures, meaning mistakes occur during chromosome separation.

3. Hyperchromasia- the nucleus stains darker than normal. increase in DNA material in nucleus.

4. Hypercellularity: Increased number of cells (i.e. within the bone marrow) with a loss of normal polarity

(Abnormal mitotic figures- dysregulated and random nuclear material assembly

Increased numbers of mitotic figures- more cells in mitosis, higher turnover

Polarity- asymmetric distribution of cell’s proteins, organelles, cytoplasm etc)

Differentiation

Refers to how closely a tumor resembles the normal tissue from which it originated, Indicating its level of maturity and function.

This differentiation resembles tissue of origin and are well differentiated:

Benign tumor- closely resembles normal tissue and maintains similar structure.

Poorly differentiated or undifferentiated (anaplastic)

Malignant tumor- that lacks structural and functional features of the tissue of origin, making it difficult to determine its cellular origin.

This refers to poorly differentiated cells that have lost the normal features of the tissue they came from.

Anaplastic

What are examples of microscopic appearance of neoplasms?

Well Differentiated: resembles normal tissue structure. Benign tumor)

Poorly Differentiated: lacks normal architecture. (malignant tumor)

Cells that lose their specialized characteristics and revert to a more primitive - “to form backwards” embryonic state:

Anaplasia

Disordered growth of epithelium where there is loss of cellular uniformity and architectural orientation.

dysplasia

What are the characteristic of Dysplasia?

Doesn’t always form a mass or tumor therefore not always referring to a neoplasm.

•Precursor of malignancy, but dysplasia does not always progress to malignancy.

•Dysplasia can be reversible, if the inciting agent is removed

full thickness dysplasia of the epithelium

carcinoma in situ

Neoplasm that tend to grow slower

benign neoplasm

tend to grow more quickly

malignant neoplasm

Proportion of neoplastic cells in the proliferative phase

Growth fraction

Growth fraction = % of tumor cells that are actively dividing

Infiltration of tumor cells into surrounding organs

Invasion

The spread of tumor cells to distant organs

Metastasis

cancer of epithelial tissues (lining/covering).

Carcinoma- through the lymphatics

cancer of connective tissues (bone, muscle, fat, cartilage

Sarcoma- through the blood

A definite indicator of a malignant neoplasm

Metastasis

Benign vs Malignant neoplasm

Benign neoplasm

Malignant neoplasm

What is pre clinical phase of cancer?

The pre-clinical phase is the period when cancer is already developing, but the patient has no symptoms yet.

The pre-clinical phase of cancer is the stage when cancer or precancerous changes are present but the patient has no symptoms; the disease can often be detected through screening tests such as mammography or colonoscopy.

normal cellular gene that promotes cellular growth and division

Proto-oncogenes

proto-oncogenes that have mutated and are now capable of producing neoplasms.

Oncogenes:

○Always “on”

○Cause unregulated cell growth through promotion of cellular division, which results in further mutations

what is the function of proto-oncogene?

Function of a Proto-Oncogene

A proto-oncogene is a normal gene that helps regulate:

• Cell growth

• Cell division

• Cell survival

• Cell differentiation

Activation of Proto-oncogene?

When a proto-oncogene becomes overactive, it is called an oncogene.

The cell receives constant "grow" signals even when none are needed.

Proto-oncogenes are normal growth-promoting genes that regulate cell proliferation; when activated by mutation, amplification, overexpression, or translocation, they become oncogenes that drive uncontrolled cell growth and cancer.

What are the methods of conversation of Proto-oncogene to Oncogene

1.Overexpression of the gene

2.Amplification of the gene

3.Point mutation in the gene

4.Translocation of the gene to another region with a strong promoter of the gene

Cinical oncologic disorder of RAS

Colon Cancer

Intracellular signaling protein that promotes cell growth and division. Mutations leading to cellular division.

Clinical Oncologic disorder of KRAS

Lung, colon, Pancreatic

Another member of RAS family

Clinical Oncologic Disorders of HER2

Breast cancer

Growth factor receptor

Clinical Oncologic Disorders APC gene

Disruption of this leads to adenomas (non cancerous polyps) which then lead to colon cancer

Unlike RAS and HER2, APC normally prevents excessive cell growth. (Tumor suppressor gene)

Clinical Oncologic Disorders P53

Leukemias

Inactivated in many cancers, cannot repair DNA or lead to apoptosis. (Tumor Suppressor gene)

Clinical Oncologic Disorders: BRCA1 and BRCA 2

Involved in DNA repair

Mutations related to BOTH breast and ovarian cancers

Hepatitis B virus (HBV)

Hepatocellular carcinoma (liver cancer)

Mechanism: Through chronic inflammation; also because HBV protein binds p53(normally a tumor suppressor gene), interfering with its function leading to cancer

Helicobacter pylori

Associated neoplasm: MALTomas of the stomach (neoplasm of mucosa-associated lymphoid tissue)

Human herpesvirus 8 (HHV-8)

Associated neoplasm: Primary effusion lymphoma and Kaposi sarcoma

Role of hormones in Carcinogenes

Hormones can stimulate cell growth and increase the chance of mutations.

Examples

• Estrogen → promotes breast cell proliferation

• Androgens (testosterone) → promote prostate cell growth

Role of growth factors in carcinogenesis

Growth factors are proteins that tell cells to grow, divide, and survive.

Example: PDGF

Some tumors (such as glioblastomas) produce their own platelet-derived growth factor (PDGF), creating a continuous growth signal.

Role of growth factor receptors

Growth Factor Receptors

Cancer cells may make too many receptors.

Example: HER2 and EGFR

• HER2 amplification → breast cancer

• EGFR (ERBB1) overexpression → lung cancer

More receptors = stronger growth signals

Synthesize nuclear transcription factors

Nuclear Transcription Factors

These proteins turn genes on inside the nucleus.

Example: MYC

MYC activates genes involved in cell growth and the cell cycle.

When MYC is overexpressed:

➡ Increased transcription

➡ Increased cell division

➡ Cancer development

Associated with Burkitt lymphoma and several solid tumors.

Loss of regulation of cyclins and cyclin-dependent kinases

Cell Cycle Genes Cyclins and Cyclin-Dependent Kinases (CDKs)

These regulate progression through the cell cycle.

If cyclins/CDKs become overactive:

➡ Cell-cycle checkpoints are bypassed

➡ Cells divide uncontrollably

➡ Tumors develop

Early changes in progression of neoplasia:

Early Changes: Dysplasia

Dysplasia is the earliest recognizable precancerous change.

Dysplasia = "abnormal cells but not cancer yet."

○Disordered growth of epithelium

○Does not necessarily form a mass or a tumor

○In many cases dysplasia may be a precursor to malignancy however does not always progress.

middle changes in the progression of neoplasia?

Changes: Carcinoma in situ

Carcinoma in situ refers to a localized tumor that has not invaded surrounding tissues.

late changes in the progression of neoplasia?

malignant neoplasm

The malignant cells break through the basement membrane and invade surrounding tissues.

Malignant neoplasm that originates from mesodermal tissue

Sarcoma

○Originates from mesodermal tissue

○Arises from mesenchymal cell types in connective tissue (fat, cartilage or bone)

■Rhabdomyosarcoma (skeletal muscle)

■Leiomyosarcoma (smooth muscle)

■Angiosarcoma (Blood vessels)

○More common in children

Often times aggressive

Malignant neoplasm that is derived from ectodermal and endodermal tissue:

Carcinoma

○Most common type of cancer

○Derived from ectodermal and endodermal tissue

○Includes epithelial tissue cancers

■Lung, colon, breast, prostate cancer

■Think adenocarcinoma, squamous cell carcinoma,  intraductal carcinoma

○More common in adults

Phenotypic changes in the progression of neoplasia:

Phenotypic Changes of Dysplasia

Dysplasia means disordered growth of epithelial cells.

Phenotypic changes:

• Increased cellularity

• Hyperchromatic (dark) nuclei

• Increased mitotic figures

• Loss of normal cell organization (polarity)

• Increased nuclear-to-cytoplasmic ratio

At this stage:

• Cells look abnormal

• Basement membrane remains intact

• May be reversible if the cause is removed

📌 Not yet cancer, but often a precursor to cancer.

Describe the phenotypic changes in the progression of neoplasia?

The phenotypic progression of neoplasia involves dysplasia (abnormal growth), carcinoma in situ (full-thickness dysplasia without invasion), invasive carcinoma (penetration through the basement membrane), and metastatic carcinoma (spread to distant sites).

Normal Epithelium → Dysplasia → Carcinoma in Situ → Invasive Carcinoma → Metastatic Carcinoma.

Describe the two principal lines of evidence that support the model of stepwise genetic alterations in colon cancer.

The two principal lines of evidence are:

1. Histologic observation of progressive lesions from normal mucosa to adenoma to carcinoma.

2. Identification of sequential genetic alterations (APC → KRAS → TP53 and others) that accumulate as the tumor progresses.

•Model of stepwise genetic alterations in cancer is best illustrated by observation of colonic lesions at different stages of progression to malignancy.

•Schematic illustrates the sequential phases of cellular abnormalities and polyp formation in the colon as shown on a timeline that also depicts the corresponding genetic events associated with each cellular landmark.

•APC tumor suppressor gene mutation —> abnormal cell proliferation —> polyps

•Polyp formation—>oncogenes —> activation of growth factor receptor signaling pathways —> polyps grow bigger

•Mutations in specific genes (DCC) or inactivation of TP53 disrupts cell cycle checkpoints and apoptosis → invasive cancer phenotype develops

•Mismatch repair genes (if mutation in gene, then cannot proofread, and thus errors are propagated)

•As adenomas develop and enlarge, an early feature prior to invasion that occurs, is the development of new vessels or destruction of existing vessels —> microscopic bleeding that can be detected on fecal occult blood tests

What are epithelial based carcinoma?

Colon Cancer and Breast Cancer

Carcinoma = Coverings (epithelium)
Sarcoma = Support tissues (connective tissue)
Lymphoma = Lymphocytes
Leukemia = Bone marrow/blood
Germ Cell = Reproductive cells
Neuroendocrine = Hormone-secreting cells.

Colon Carcinoma

A carcinoma arising from epithelial cells of the colon.

Colon Carcinoma

• A carcinoma arising from epithelial cells of the colon.

• Develops through a series of genetic alterations:

  • APC mutation → adenomatous polyp formation

  • KRAS activation → polyp growth

  • TP53 loss and other mutations → invasive carcinoma

• Most colon cancers are adenocarcinomas

Breast Carcinoma

Ductal/Lobular tissue

• Malignant epithelial tumor of the breast.

• Histologic types:

  • Ductal carcinoma

  • Lobular carcinoma

• Clinical classification is based on:

  • Estrogen receptor (ER)

  • Progesterone receptor (PR)

  • Human epidermal growth factor receptor 2 (HER2)

• HER2-positive tumors may respond to HER2-targeted therapy

Breast cancers are frequently classified using different classification systems. Three are shown here—histologic subtypes (top left), intrinsic subtypes (top right), and clinical subtypes (bottom)—with their proportional incidences shown via pie chart. The clinical subtypes, widely used in clinical management, do not divide breast cancers into exclusive categories, such that a cancer can be both ER/PR positive and HER2 positive (ie, HER2 amplified), as shown by the overlapping area in the bottom pie chart.

Mesenchymal, Neuroendocrine, and Germ Cell Neoplasms

Carcinoid Tumors (Neuroendocrine), Testicular Germ Cell Cancer, Sarcomas (Mesenchymal)

Carcinoid Tumors (Neuroendocrine)

• Low-grade neuroendocrine tumors (NETs).

• Arise from cells with endocrine and nervous system features.

• Can secrete hormones such as serotonin.

Neuroendocrine tumors (NET) arise from neural crest tissue. Cells migrate to submucosal layer of intestines and pulmonary bronchi thus they can at times express enzymes to produce peptide hormones.

Testicular Germ Cell Cancer

Arises from germ cells that normally produce sperm.

Sarcomas (Mesenchymal)

• Arise from mesoderm-derived connective tissues.

• More common in children than adults.

• Spread primarily through the bloodstream.

Examples:

• Osteosarcoma (bone)

• Rhabdomyosarcoma (skeletal muscle)

• Leiomyosarcoma (smooth muscle)

• Liposarcoma (fat)

Hematologic Neoplasms

Lymphomas, Acute Myelogenous Leukemia (AML)

Lymphomas

• Malignancies of mature lymphocytes.

• Usually involve lymph nodes and lymphatic tissues.

• Types:

  • Hodgkin lymphoma

  • Non-Hodgkin lymphoma

Acute Myelogenous Leukemia (AML)

• Malignancy of immature myeloid (blasts).

• Rapid onset and aggressive course.

• Causes bone marrow failure leading to:

  • Anemia

  • Infection

  • Bleeding.

Chronic Myelogenous Leukemia (CML)

• Myeloproliferative neoplasm with a more indolent course.

• Associated with the Philadelphia chromosome t(9;22) producing the BCR-ABL fusion gene.

• Can progress to an acute "blast crisis."

• Carcinoma = Epithelial

  • Colon cancer

  • Breast cancer

• Sarcoma = Mesenchymal

  • Bone, muscle, fat, connective tissue cancers

• Neuroendocrine Tumors

  • Carcinoid tumors

• Germ Cell Tumors

  • Testicular germ cell cancer

• Hematologic Tumors

  • Lymphomas

  • Leukemias (AML, CML)

How Grading and Staging Predict the Clinical Behavior of a Malignant Tumor

1. Grading = What the Tumor Cells Look Like

Grade describes the microscopic appearance and behavior of tumor cells.

Pathologists evaluate:

• Degree of differentiation

• Nuclear appearance (chromatin)

• Number of mitotic figures (cell division rate)

2. Staging = How Far the Cancer Has Spread

Stage describes the anatomic extent of the cancer.

TNM System

• T = Tumor size and local extent

• N = Lymph node involvement

• M = Presence of distant metastasis

Grading predicts tumor aggressiveness by evaluating how differentiated the tumor cells are microscopically. Staging predicts prognosis by determining the extent of tumor spread using systems such as TNM and stages I–IV. In general, higher grade and higher stage tumors have a worse prognosis and require more aggressive treatment.

Grading tumor

●Grade

●Describes the appearance and behavior of the tumor cells

●Determined by pathologist based on well-defined criteria developed for the tissue analysis of each type of cancer

●Criteria involved:

○Differentiation of a tumor

○Quality of nuclear chromatin

○Quantitative assessment of proliferative rate (mitoses)

Staging

Different systems used to describe the extent and spread

1. Numerical Staging System (I-IV)

a.Describes the anatomic extent of the cancer at and beyond its site of origin

b.Used for solid tumors

2.TNM Staging System

a.T- tumor size and extent

b.N - number of lymph nodes involved

c.M – metastasis stage ( 0 if no distant metastases, or, 1 if distant metastases present)

•The numbering system for TNM staging is different for each type of cancer

What are the direct effects of of Malignancies

Location/Effect	Clinical Manifestation
Bone marrow involvement	Pancytopenia, infection, bleeding
Brain mass	Headache, weakness, numbness, gait abnormalities, visual changes, personality changes
Nerve invasion	Pain, weakness, numbness
Blood vessel invasion	Hemorrhage (hemoptysis, hematuria, bleeding into body cavities)
Compression of blood vessels	Ischemia or infarction
Bowel obstruction	Constipation, bowel obstruction
Lung obstruction	Pneumonia
Bile duct obstruction	Jaundice
Bone destruction	Pain and pathologic fractures

Direct effects = problems caused by the physical presence, growth, invasion, or obstruction of the tumor.

Caused by the physical growth and invasion of the tumor, leading to:

• Obstruction

• Compression

• Hemorrhage

• Neurologic deficits

• Bone destruction

• Organ dysfunction

Indirect Effects (Paraneoplastic Syndromes)

A paraneoplastic syndrome is a symptom or disease caused by a tumor at a distant site, usually through hormone production or immune-mediated mechanisms, rather than by direct tumor invasion.

Caused by hormone secretion or immune responses from the tumor and include:

• Cachexia

• Hypercalcemia (PTH)

• Cushing syndrome (ACTH)

• SIADH

• Polycythemia (EPO)

• Lambert-Eaton syndrome.

Cachexia ("Cancer Wasting")

• Loss of body fat and muscle

• Weakness

• Anorexia (loss of appetite)