L30 - Molecular Basis of Cancer: Malignancy & Host Interactions

What are the 3 Major Tumor Categories?

1. Mesenchymal tumors

2. Epithelial tumors

3. Hematopoietic/round cell tumors

What is the main identifying feature of a Mesenchymal tumors?

Mesenchymal tumors arise from connective/supporting tissues and often make and secrete extracellular stroma/matrix

Examples of origin include:

• Fibroblasts

• Muscle

• Adipose tissue

• Bone/cartilage

• Endothelial cells

What do Mesenchymal tumor cells typically look like histologically?

• Elongated/spindle-shaped cells

• Arranged in streams, fascicles, or bundles

• Often accompanied by stroma/matrix

• Usually have a higher nuclear:cytoplasm ratio

What question should you ask when trying to identify a Mesenchymal tumor?

“What are these cells making?”

• The matrix/stroma produced helps identify the tumor's cell/tissue of origin

What types of matrix can Mesenchymal tumors produce?

• Collagen

• Osteoid (bone)

• Cartilage

How could you distinguish a fibrosarcoma from an osteosarcoma?

Look at what the malignant mesenchymal cells are producing:

• Fibrosarcoma → collagen/fibrous stroma

• Osteosarcoma → osteoid (bone matrix)

How are Benign Mesenchymal tumors generally named?

Cell/tissue of origin + “-oma”

Examples:

• Fibroblast → fibroma

• Fat → lipoma

• Bone → osteoma

• Cartilage → chondroma

How are Malignant Mesenchymal tumor generally named?

Cell/tissue of origin + “-sarcoma”

Examples:

• Fibrosarcoma

• Liposarcoma

• Hemangiosarcoma

• Osteosarcoma

• Chondrosarcoma

How does a fibroma differ from a fibrosarcoma?

• Fibroma: benign, makes collagen, does not invade

• Fibrosarcoma: malignant, neoplastic cells invade surrounding tissue

What is the key difference between Round Cell Tumors and Mesenchymal tumors?

Round cell tumors do NOT make stroma/matrix → they primarily consist of cell proliferation

What are the major Histologic features of Round Cell Tumors?

• Individualized cells with clear spaces around them

• Lack an orderly arrangement

• Round to polygonal cells

• Variable N:C ratio

• Often infiltrate adjacent tissue

What are two Benign Examples of Round Cell Tumors from the lecture?

• Histiocytoma — skin

• Plasmacytoma — mucosal surfaces

What is the major identifying feature of Epithelial Tumors?

Epithelial cells like to form structures, including:

• Glands

• Tubules

• Acini

• Sheets

What do Epithelial Tumor cells typically look like histologically?

• Large, polygonal cells

• Defined cell borders

• Cells remain grouped together

• Arranged in sheets, tubules, acini, or glands

How are Benign Glandular Epithelial Tumors generally named?

• Glandular: ______ adenoma

• Lining epithelium: ______ papilloma

• Mucosal: ______ polyp

How are Malignant Epithelial Tumors generally named?

Cell/tissue of origin + “-carcinoma”

• If gland-forming: _____adenocarcinoma

What are 2 common gross features of Malignant Carcinomas?

1. Scirrhous response → reactive fibrous stroma → tumor feels firm

2. Necrosis → can cause ulceration and/or umbilication

Why can Malignant Epithelial Tumors develop a necrotic center?

They may grow faster than their blood supply, causing central cells to become deprived of oxygen and undergo necrosis

What are 3 major general histologic hallmarks that help distinguish benign from malignant tumors?

Feature	Benign	Malignant
Growth	Expansion/local	Invasion/infiltration ± metastasis
Differentiation	Well differentiated	Poorly differentiated/anaplastic
Mitotic activity	Low mitotic index	Increased mitotic index

How does a benign tumor generally grow?

By local expansion, sometimes with pedunculation; it is usually well circumscribed and often encapsulated

How does a malignant tumor generally grow?

By expansion AND invasion/infiltration into surrounding tissues, with the potential for metastasis

How does cellular differentiation differ between benign and malignant tumors?

• Benign: well differentiated → resembles tissue of origin

• Malignant: poorly differentiated → may show anaplasia

How does mitotic activity differ between benign and malignant tumors?

• Benign → low mitotic index

• Malignant → increased mitotic index

What does normal glandular epithelium look like?

• Orderly arrangement

• Uniform cell morphology

• No cellular atypia

What does a Benign Epithelial Adenoma look like histologically?

• Glandular arrangement still present

• Less orderly; some cell jumbling/piling

• Well circumscribed

• Encapsulated

• Mild cellular atypia

What does a Malignant Epithelial Carcinoma look like histologically?

• Loss of glandular arrangement

• Solid areas

• Unencapsulated

• Invades adjacent stroma

• May invade lymphatic/blood vessels

• Increased pleomorphism and atypia

Why is Vascularization critical for tumor growth?

Tumors require a blood supply to continue growing and spreading

Tumors require a blood supply to continue growing and spreading.

Tumors induce the formation of their own blood supply/vessels

How is cancer-associated vasculature different from normal vasculature?

Neoplastic vasculature has:

• Abnormal structure

• ↑ Leakage

• ↑ Fragility

• Abnormal paracrine and autocrine signaling

• Continued vascular growth

This can contribute to edema and vascular fragility

What are the 4 Major Steps of Tissue Invasion?

1. Break cell-cell junctions

2. Bind extracellular matrix

3. Use type IV collagenase

4. Invade

   
   

Why is type IV collagenase important for tumor invasion?

It helps tumor cells degrade the extracellular/basement membrane barrier, allowing invasion

What are the 3 Major Routes of Metastasis?

1. Hematogenous → vascular spread

2. Lymphatic → lymphatic/vascular dissemination

3. Direct invasion or implantation → carcinomatosis

Which tumors commonly undergo Hematogenous metastasis?

• Sarcomas

• (Neuro)endocrine carcinomas

Venous spread is more common than arterial spread.

Which tumors are especially associated with Lymphatic metastasis?

Carcinomas > sarcomas

What is the general sequence for hematogenous metastasis to the lung?

1. Primary malignant tumor

2. Local tissue invasion

3. Tumor enters blood vessel (intravasation)

4. Travels through venous circulation

5. Reaches pulmonary capillary bed

6. Tumor cells lodge/adhere

7. Exit vessel (extravasation)

8. Establish metastatic focus

9. Angiogenesis + growth → pulmonary metastasis

   
   

Why is the lung a common site of hematogenous metastasis?

Tumor cells entering the venous circulation encounter the pulmonary capillary bed, making the lung an important site where circulating tumor cells can lodge

• Venous blood → right heart → lungs → pulmonary capillaries → tumor cells lodge

What lymph node is most likely to receive metastatic cells first?

The draining (sentinel) lymph node

How does a metastatic carcinoma enter and grow within a lymph node?

1. Primary carcinoma

2. Invades lymphatic vessel

3. Travels through afferent/draining lymphatics

4. Enters draining/sentinel lymph node

5. Reaches subcapsular sinus

6. Tumor cells establish metastatic aggregates

7. Metastatic tumor expands within lymph node

Where can metastatic tumor cells initially aggregate within a draining lymph node?

In the subcapsular region/sinus

What is carcinomatosis?

Direct spread/implantation of carcinoma throughout a body cavity

• It does not require a blood vessel for spread

How is carcinomatosis different from hematogenous metastasis?

• Hematogenous: tumor spreads through blood vessels

• Carcinomatosis: tumor cells directly seed a body cavity

Tumor Classification SUMMARY

Mesenchymal = MATRIX | Epithelial = STRUCTURES | Round cell = INDIVIDUAL CELLS

Feature	Mesenchymal	Epithelial	Round Cell
Main clue	Makes matrix/stroma	Makes structures	Cell proliferation; no matrix
Cell shape	Elongate, spindle-shaped	Large, polygonal	Round → polygonal
Arrangement	Streams, fascicles, bundles	Sheets, tubules, acini, glands	Individualized cells
Matrix/stroma	Often present	Cells grouped into structures	Does not make stroma/matrix
N:C ratio	Usually higher	—	Variable
Malignant name	Sarcoma	Carcinoma	Nomenclature varies
Recognition trick	What are they making?	What are they making?	Individual cells

Identifying Mesenchymal Tumors SUMMARY

MESENCHYMAL TUMOR? → “What are the cells making?” → Identify the matrix → Identify tissue of origin

Tumor origin	What is produced?	Benign	Malignant
Fibroblast clue	Collagen/fibrous matrix	Fibroma	Fibrosarcoma
Fat	Adipose tissue	Lipoma	Liposarcoma
Endothelium	Vascular tissue	Hemangioma	Hemangiosarcoma
Bone	Osteoid	Osteoma	Osteosarcoma
Cartilage	Cartilage	Chondroma	Chondrosarcoma

Benign vs. Malignant SUMMARY

Feature	Benign	Malignant
Spread	Local only	Metastasis possible
Growth	Expansion/pedunculation	Expansion + invasion/infiltration
Borders	Well circumscribed	Poorly circumscribed
Capsule	Often encapsulated	Usually unencapsulated
Differentiation	Well differentiated	Poorly differentiated / anaplastic
Mitotic index	Low	Increased
Angiogenesis	—	Often increased
Necrosis	Less characteristic	Areas of necrosis
Recurrence	Excision often curative	Local recurrence frequent

Routes of Metastasis SUMMARY

Sarcoma → BLOOD → LUNG

Carcinoma → LYMPH → LYMPH NODE

Carcinomatosis → BODY CAVITY

Route	How?	Tumor association	Important destination/concept
Hematogenous	Blood vessels	Sarcomas, (neuro)endocrine carcinomas	Lung
Lymphatic	Lymphatics	Carcinomas > sarcomas	Draining/sentinel LN
Direct implantation	Seeds body cavity	Carcinoma	Carcinomatosis

Normal vs. Cancer Vasculature SUMMARY

Normal vessels	Neoplastic vasculature
Organized structure	Abnormal structure
Controlled permeability	↑ Leakage
Relatively stable	↑ Fragility
Normal signaling	Abnormal paracrine/autocrine signaling
Regulated growth	Continued vascular growth

Epithelial Malignancy Progression SUMMARY

Normal epithelium	Benign adenoma	Malignant carcinoma
Orderly cells	Glandular pattern remains	Loss of glandular pattern
Uniform morphology	Some jumbling/piling	Solid areas
No atypia	Mild atypia	↑ Pleomorphism + atypia
—	Well circumscribed	Invasion
—	Encapsulated	Unencapsulated

Hematogenous spread → Lung SUMMARY

1. Primary tumor

2. Local invasion

3. Intravasation

4. Venous circulation

5. Right heart

6. Pulmonary capillary bed

7. Tumor cells lodge

8. Extravasation

9. Metastatic focus → angiogenesis → growth

Carcinoma → Lymph node SUMMARY

1. Primary carcinoma

2. Invades lymphatic

3. Afferent lymphatic

4. Draining/sentinel lymph node

5. Subcapsular sinus

6. Metastatic aggregates

7. Growth within LN