Neoplasia (I, V): Intro and Epidemiology

Question 1

Definitions and Classification

Answer 1

Neoplasm: Suffix -oma
_Uncontrolled, *Autonomous *Overgrowth of Cells without protective purpose for the host
_Progressive and Persistent

_________________

Benign Tumors:
_Suffix: -oma
_Prefix: Cell/Tissue of Origin
Example: Adenoma
= Benign Epithelial Neoplasm producing glands or derived from glands

Malignant Tumors:
_Suffix: Carcinoma or Sarcoma
_Prefix: Cell/Tissue of Origin

Carcinoma (karkinos, crab):
= *Epithelial Malignant Neoplasm
Examples: 
_Squamous cell or epidermoid carcinoma
_Basal cell carcinoma
_Adenocarcinoma (adenos = gland)

Sarcoma (sarkos, flesh):
= *Connective Tissue Malignant Neoplasms (stroma)
Examples:
_Liposarcoma
_Fibrosarcoma
_Osteosarcoma

Question 2

Mixed Tumors

Answer 2

Mixed Tumors:
= Neoplasms Composed of More Than One Cell Type Derived from One Germ Cell Layer
Examples: 
_Mixed Tumor of Salivary Gland
_Pleomorphic Adenoma
_Fibroadenoma of the Breast

Teratomas:
= Neoplasms composed of More Than One Cell Type Derived from More Than One Germ Cell Layer:
_Typically Arise from Totipotential Cells in Gonads
_Can be Benign (Mature) or Malignant (Immature).

Question 3

Exceptions: Malignant -Omas

Answer 3

Exceptions: Malignant -Omas

1) Lymphoma, Mesothelioma, Melanoma, Seminoma:
= MALIGNANT
_Lymphomas are ALWAYS Malignant.
_Mesotheliomas are most often Malignant. Frequently occur in Pleura.
_Melanomas are the Most Malignant Tumors that exist.
_Seminomas are Malignant.

2) Blastoma: MALIGNANT
= Primitive or Embryonal Malignant Tumors.
_Occur in Children.
_Highly Malignant
_Childhood cancers have better prognosis, though, and respond well to chemotherapy.
Examples:
_Neuroblastoma
_Retinoblastoma
_Hepatoblastoma

3) Endocrine Tumors: Named by Secretory Product
=> Some behave Benign; Some behave Malignant.  Difficult to Predict.
Examples:
_Insulinoma
_Glucagonoma
_Prolactinoma
4) Hamartoma: NOT CANCER
= NOT A NEOPLASM
= IS A Congenital Malformation

Question 4

Eponyms

Answer 4

Eponyms:

1) Hodgkin’s Disease:
= MALIGNANT Lymphoma with
Diagnostic Reed-Sternberg Cells

2) Burkitt’s Lymphoma:
= MALIGNANT Lymphoma of Small Non-cleaved Lymphocytes,
usually involving Extranodal sites.

3) Kaposi’s Sarcoma:
= Single or Disseminated Vascular-Like Proliferation that Develops Spontaneously or Complicates AIDS.

4) Wilms’ Tumor or Nephroblastoma:
= Embryonal Carcinosarcoma of Kidney

5) Ewing’s Sarcoma:
= Primitive Neuroectodermal Tumor of Bone and Paraskeletal Soft Tissue

Question 5

Secondary Descriptors

Answer 5

Secondary Descriptors:

1) Cystadenoma:
= Hollow Cystic Masses typically seen in Ovaries
_The Malignant form
= Cystadenocarcinoma

2) Polyp:
= Neoplasm that projects above the Mucosal surface, producing an Exophytic Mass:
_Fibroepitihelial Polyps of Skin
_Adenomatous Polyps of colon, aka Tubular Adenoma

Polyps can be Benign or Malignant.

3) Papilloma (papilla, nipple):
= Benign Epithelial Neoplasm that grows exophytically in Finger-like Fronds like a Cauliflower
_Benign or Malignant.

4) Papillary Adenocarcinoma:
= Adenocarcinomas in which Neoplastic Cells grow upon Stromal Finger-like projections.

Question 6

Benign vs. Malignant

Answer 6

Benign Neoplasm:

1) Composed of Well-Differentiated Cells
2) Well Circumscribed
3) Remains Localized
4) Lacks Capacity to Invade or Spread Distantly (Metastasis)

Malignant Neoplasm:
1) Characterized by a Wide Range of Cell Differentiation, from Well-Differentiated to Completely Undifferentiated (Anaplastic) Cells.

2) Poorly Circumscribed
3) Invades Surrounding Tissues
4) Capable of Spreading Distantly or Metastasizing

_____________________

Differentiation:
= Resemblance to Parental Mature Cell and Tissue of Origin
_Morphologically, Phenotypically, Functionally

Dedifferentiation:
= Process of Progressive Loss of Resemblance
=> Dedifferentiated Cells Display:
(1) Marked Nuclear Pleomorphism
(2) Hyperchromatic Nuclei (Dark)
(3) Enlarged Nuclei 
(Increased N/C Ratio)
(4) Increased Mitosis
(5) Loss of Polarity

Anaplasia:
= Complete LOSS of Resemblance to Parental Mature Cell and Tissue of Origin
___________________

1) Differentiation:

Benign: Very Well Differentiated;
_Closely Resemble Cell of Origin.
_Closely Express Function and Phenotypic Markers of Cell of Origin.

Malignant:
_Differentiation Varies by GRADE.

2) Rate of Growth:

Benign: Slow;
_May Plateau or Regress.

Malignant: Varies; Slow to Rapid; _Usually Progressive;
_Rarely Regress.

3) Mitosis:

Benign:
_Few Mitosis;
_Usually Normal or Bipolar.

Malignant: 
_Frequent Mitosis, 
especially in Grade IV;
_Often Abnormal: 
Tripolar, Quadripolar.

4) Karyotype:

Benign: Usually Diploid.

Malignant: Near Diploid;
_Often Aneuploid and Polyploid

5) Local Growth:

Benign: Expansive (Centrifugal)

Malignant: Infiltrative (Crab-Like)

6) Capsule:

Benign: Often Encapsulated

Malignant: Seldom Encapsulated

7) Metastasis:

Benign: Absent

Malignant:
_Potential for Metastasis in Early Stages;
_Often Present in Late Stage

8) Mortality:

Benign: Low Mortality

Malignant: High Mortality

Question 7

Nuclear Characteristics of Malignant Cells

Answer 7

The Most Significant Microscopic Features of Malignancy Occur
@ Cell Nuclei:

1) Nuclear Enlargement with Increased Nuclear/Cytoplasmic Ratio.
2) Nuclear Hyperchromasia
3) Irregular Nuclear Contour
4) Prominent Nucleoli
5) Abnormal Mitosis

Question 8

Premalignant / Precancerous Lesions

Answer 8

= Lesions that have a Statistically Significant Potential to Transform or Evolve into a Malignant Neoplasm:

1) Tubular/Villous *Adenomas of Colon

2) *Dysplastic Nevi
(Atypical Melanocytic Hyperplasia)
(Atypical Mole)

3) *Epithelial Dysplasia
4) Actinic Keratosis of Sun-Damaged Skin

Question 9

Dysplasia

Answer 9

= Disordered Cell Proliferation:
_Loss of Uniformity
_Loss of Architectural Orientation

Dysplastic Cells Have
_Hyperchromatic Nuclei
_Nuclear Pleomorphism
_Increased Mitosis

Dysplasias May Regress, Remain, or Progress into Carcinoma In Situ, which May Remain Localized or Become Invasive.
_Thus, this is a Continuum of Cytological Changes.

Dysplasia applies to squamous epithelia but can also be extended to glandular epithelia.

Question 10

Carcinoma In Situ and

Intraepithelial Neoplasia

Answer 10

Carcinoma In Situ (CIS):
= Marked Dysplastic Changes involving the Entire Thickness of the Epithelium,
But still Confined Within the Epithelium

= Is a Preinvasive Neoplasm.

Intraepithelial Neoplasia:
= Includes Various grades of Dysplasia and Carcinoma In Situ (Full Thickness Dysplasia)

_Once the Neoplasm spreads beyond the epithelium, it is no longer intraepithelial.

Question 11

Poor Morphological Correlation

Answer 11

Histologically MALIGNANT,
BUT Rarely Metastasize:

1) **Basal Cell Carcinoma
2) Fibrosarcoma protuberans

Histologically BENIGN or BORDERLINE,
BUT Sometimes MALIGNANT:

1) **Smooth Muscle Tumors
2) Carcinoid Tumors

Question 12

Grade of Malignancy

Answer 12

= Degree of Cell Differentiation of a Neoplasm.

The Less Differentiation
=> The More Aggressive
=> More Likely to Metastasize

Grade I: Well Differentiated
Grade II: Moderately Differentiated
Grade III: Poorly Differentiated
Grade IV: Anaplastic (Undifferentiated)

Question 13

Determination of Cell of Origin in Undifferentiated Neoplasms

Answer 13

(Nuclear Cell Morphology provides the diagnosis of Malignancy.)

*Characteristics of the *Cytoplasm Determines the Cell of Origin:

1) **Immunohistochemistry
2) Electron Microscopy

Question 14

Invasion and Metastasis

Answer 14

Invasiveness and Metastasis are the 2 Most Reliable Features of Malignancy.

_Nearly All Benign Tumors grow cohesively as expandable masses that Remain Localized.

_Malignant Tumors First Invade Locally, then Spread Distantly (Metastasis).
_________________

Growth of Cancer is Accompanied by *Progressive Invasion and *Destruction of Surrounding Tissues

Metastasis is the Single Most Important Criterion of Malignancy.

_Benign tumors do not metastasize.
___________________

Metastasis Occurs 3 Ways:

1) Seeding of Body Cavity Surfaces:
_Examples: Peritoneal, Pleural, or Pericardial Cavities
_Characteristic of Ovarian Cancer

2) Lymphatic Spread:
= The Initial Way of Dissemination for CARCINOMAS
=> The pattern that follows the routes of lymphatic drainage.
(Will eventually reach blood b/c lymph returns to bloodstream)

3) Hematogenous Spread:
=> Typical of SARCOMAS
_Can also be seen in Carcinomas.

Question 15

Stage of Malignancy

Answer 15

= Refers to

1) *Size,
2) *Local Invasiveness,
3) *Distant Spread (Metastasis)

T: Local topography and Size of Primary Lesion; T1-T4

N: # Lymph Node Involvement;
N0-N4

M: Metastasis to Distant Tissues/Organs; M0-M1

Clinically and Therapy-wise, Stage is often More Important than Grade.

Note: Stage and Grade apply only to Malignant cancers.

Question 16

Cancer Epidemiology: Gender

Answer 16

** 1/5 Chancer of Dying from Cancer in U.S.

• *More than 50% of USA Cancers:
  1) **Lung
  2) **Breast
  3) **Prostate
  4) **Colorectal

Most Common:

• *Men:
  1) **Prostate
  2) **Lung
  3) **Colorectal
• *Women:
  1) **Breast
  2) **Lung
  3) **Colorectal

_______________

Death Rate has Increased over Last 50 Years (males and females).

Alarming Increase in Death Rates of Lung Cancer (males and females).

Most Recently, Overall Adjusted Cancer Death Rates have Decreased (males and females).

_________________

Question 17

Cancer Epidemiology: Disparities

Answer 17

Disparities:
1) Higher Mortality:
==> African Americans

2) Latinos: 
_Lower Frequency of Most Common Cancers
_Higher Incidence of Other Cancers:
=> Stomach (estómago)
=> Liver (hídago)
=> Cervix (cuello uterino)
=> Gallbladder (vesícula)

Question 18

Cancer Epidemiology: Age

Answer 18

Age has a Profound Effect on Cancer Incidence.

**Most Carciniomas: Over Age 55

**Cancer is FIRST Cause of Death:
=> **Women: Ages 40 - 79
=> **Men: Ages 60 - 79

____________________

Children:

Death Rate 10% Under Age 15

**Acute Leukemias and **CNS Tumors = ** 60% of Deaths

Most Common Cancers of
Infancy and Childhood:

1) Neuroblastoma,
Wilms Tumor / Nephroblastoma,
Retinoblastoma

2) Acute Leukemia
3) Rhabdomyosarcoma

Question 19

Occupational Cancers

Answer 19

• Asbestos => *Mesothelioma

* Benzene => *Leukemia

Question 20

Genetic Predisposition to Cancer

Answer 20

*Environmental and *Hereditary Factors Predispose to Most Cancers

**Lung Cancer: Clearly Associated with **Tobacco Smoking

• *Mortality from Lung Cancer is
• • 4x Higher Among *Non-Smoking Relatives of Lung Cancer Patients.

____________

*Genes Associated with *Familial Forms of Cancer are very *Often Also Involved in *Sporadic Cancers.

3 Types of Genetic Predisposition:

1) Autosomal Dominant:
=> Inherited Cancer Syndromes

2) Autosomal Recessive:
=> Defective DNA Repair Syndromes

3) Familial Cancers

Question 21

Autosomal Dominant Cancer Syndromes

Answer 21

Autosomal Dominant Cancer Syndromes:
=> Inherited Cancer Syndromes

1) *Rb => Retinoblastoma
2) *p53 => Li Fraumeni Syndrome
3) *APC => Familial Adenomatous Polyposis / Colon Cancer

4) *BRCA1, *BRCA2
=> Breast and Ovarian Tumors

5) *MSH2, *MLH1, *MSH6
=> Hereditary Non-Poliposis Colon Cancer

Question 22

Autosomal Recessive Cancer Syndromes

Answer 22

Autosomal Recessive Cancer Syndromes:
=> Defective DNA Repair Syndromes

(none are in red)

1) Xeroderma Pigmentosum
2) Ataxia-Telangiectasia
3) Bloom Syndrome
4) Fanconi Anemia

Question 23

Familial Cancer Syndromes

Answer 23

Familial Clustering; Role of Inherited Predisposition is not always clear.

**Onset @ Early Age in 2 or More Close Relatives.

**Multiple or Bilateral Tumors.

Examples: Colon, Breast, Ovary, Brain, Melanoma.

Question 24

Non-Hereditary Predisposing Conditions

Answer 24

**Regenerative, **Hyperplastic, and **Dysplastic Cell Proliferations

=> Are high risk for malignant transformation.

Examples: endometrial hyperplasia, bronchial metaplasia, cervical dysplasia, etc.
__________________

**Chronic Inflammation:
=> Ulcerative Colitis, Crohn’s Disease, Helicobacter Pylori Gastritis, Viral Hepatitis, Chronic Pancreatitis, etc.

=> **ROS
=> Cytokines
=> COX-2 is overexpressed in colon cancer.

**Precancerous Conditions:
=> Chronic Atrophic Gastritis, Solar Keratosis, Leukoplakia, etc.

Question 25

Clinical Features

Answer 25

All tumors, including Benign, may cause morbidity and mortality.

**Each Tumor Requires careful evaluation to rule out malignancy.

**Mass or **Lump:
=> Most Common Presenting Symptom of Benign or Malignant Tumors.

**All Masses Require Cytological or Histopathological Evaluation
(with some exceptions).
_

**Local Effects due to Impingement on Adjacent Structures

• *Tumor Functional Activity,
  e. g. hormone production

**Paraneoplastic Syndromes

**Bleeding or Secondary *Infection, which may result in **Acute Symptoms.

*Symptoms from Metastasis

**Cachexia

Question 26

Clinical Features:

Local Effect

Answer 26

Pituitary Adenoma:
= Benign Tumor that can Destroy the Pituitary, Leading to Endocrinopathy that can be Lethal.

Meningioma:
= Benign Tumor that can Lead to Intracranial Hypertension and Death.

Gut Tumors:
=> Can Cause Intestinal Obstruction, whether benign or malignant.

Question 27

Clinical Features:

Hormonal Effect

Answer 27

Tumors @ Endocrine Glands:
=> May Overproduce Hormones, resulting in Endocrinopathy.

Non-Endocrine Tumors:
=> May produce Hormones and Hormone-Like Products,
=> Leading to
**Paraneoplastic Syndromes

Question 28

Clinical Features:

Paraneoplastic Syndromes

Answer 28

Complex symptoms associated with cancer that
**Cannot be Explained by Local or Distant Spread.

Seen in **10% of Cancer Patients.

May represent the earliest manifestation of an occult tumor.

Symptoms may be a significant clinical problem or even lethal.

May mimic Metastatic Disease.

__________________

Endocrinopathies:

1) *Cushing Syndrome:
_Small Cell Lung Cancer
_Pancreatic Cancer
_ACTH, ACTH-like peptides

2) *Hypercalcemia:
_SCLC, Breast, Renal, Adult T cell Leukemia
_PTH related peptide, TGF-alpha

3) *Hypoglycemia:
_Fibrosarcoma, HCC
_Insulin, Insulin-like hormones

4) *Polycythemia:
_RCC, HCC, Cerebellar Hemangioma
_Erythropoietin

____________________

Nerve and Muscle Syndromes:

1) *Myasthenia:
_Bronchogenic Carcinoma
_Immunologic

____________________

Dermatologic Disorders:

1) *Acanthosis Nigricans:
_Gastric, Lung, Uterine Cancers
_Immunologic, EGF

2) *Dermatomyositis:
_Bronchogenic, Breast
_Immunologic

____________________

Vascular and Hematologic Changes:

1) *Venous Thrombosis
(Trousseau Phenomenon)
_Pancreatic, Bronchogenic
_Tumor products (Mucins)

2) *Anemia:
_Thymic Tumors
_Unknown

____________________

Others:

1) *Nephrotic Syndrome:
_Various cancers
_Tumor Antigens, Immune Complexes

Question 29

Cachexia

Answer 29

= Wasting Syndrome Associated with Cancer

Characterized By:

1) *Progressive LOSS of Body FAT and MUSCLE Mass
2) *Weakness
3) *Anorexia
4) *Anemia

____________________

*NOT Caused by increased tumor nutritional demands.

Factors released by tumor or the immune response, such as **Cytokines, may be related to the cause.

*Abnormalities in *Taste an *Appetite are often seen in Cancer patients;
_However, reduced food intake is not enough to explain cancer cachexia.

____________________

**Basal Metabolism is Increased,
Despite *Reduced Food Intake.

There is **Equal Loss of Muscle and Fat.

Whereas in Starvation, muscle mass is better preserved.

____________________

Many of these changes, including loss of Appetite and changes in Fat Metabolism,
=> Mimic the Effects of Exogenous **TNF-Alpha Administration.

Releas of TNF-alpha by Macrophages or even Tumor cells may play a major role in cancer cachexia.

____________________

IL-1 and IFN-gamma synergize TNF-alpha and may play a role.

Other soluble factors, such as the
**Proteolysis Inducing Factor (PIF), may play a role.

Administration of PIF causes Rapid Weight Loss in healthy mice without reduction in food intake, increasing Catabolism of muscle and adipose tissue.

Neutralization of Non-cytokine factors, such as PIF, may help to ameliorate cancer cachexia.

Question 30

Cancer Lab Diagnosis

Answer 30

Histologic Diagnosis
Cytologic Diagnosis
Immunohistochemistry
Flow Cytometry
Molecular Pathology

Cancer Biomarkers:

_Hormones:
1) *HCG: Trophoblastic and Germ Cell Tumors

_Oncofetal Antigens:

2) *AFP: Germ Cell Tumors
3) *CEA: Colonic, Pancreatic, Gastric

_Isoenzymes:
4)*NSE: Small Cell Lung Cancer

_Specific Proteins:

5) *PSA: Prostate
6) *Ig: Multiple Myeloma

_Mucins/Glycoproteins:

7) *CA-125: Ovarian
8) *CA-19-9: Colonic, Pancreatic