patoloji-ders-notlari

Title

Serdar Balcı

Characteristics of Benign and Malignant Neoplasms

Serdar BALCI, MD

Benign vs Malignant

Benign

Malignant

Good news

Genetically simple

Few mutations

Curable

• Bad news, generally
• Genetically complex
• Accumulating mutations
• Mostly Fatal

Robbins and Cotran’s Pathological Basis of Diseases

Robbins Basic Pathology

DIFFERENTIATION

Differentiation

• The differentiation of parenchymal tumor cells
  • How much they resemble their normal counterparts
  • Morphologically and functionally
• Benign neoplasms
  • Well-differentiated cells
  • Closely resemble their normal counterparts
    • Morphologically and Functionally
• Lipoma: mature fat cells filled with cytoplasmic lipid vacuoles
• Chondroma: mature cartilage cells that synthesize their usual cartilaginous matrix

MUIR’S TEXTBOOK OF PATHOLOGY

Leiomyoma of the uterus

Robbins and Cotran’s Pathological Basis of Diseases

Malignant Neoplasms

Well Differentiated

Moderately Differentiated

Poorly Differentiated

Undifferentiated

Anaplastic

Differentiation is defined as “grade” in certain classification shemes.

Grade is determined microscopically

Adenocarcinoma of Colon

Robbins and Cotran’s Pathological Basis of Diseases

Urologic Surgical Pathology, 3 rd __ Ed__

Urologic Surgical Pathology, 3 rd __ Ed__

Urologic Surgical Pathology, 3 rd __ Ed__

Well-differentiated squamous cell carcinoma of the skin

Robbins Basic Pathology

Well-differentiated squamous cell carcinoma of the skin

Similar to normal squamous cells

Robbins Basic Pathology

Rubin’s Pathology 7th Ed

Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma)

Robbins Basic Pathology

Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma)

Prominent nucleoli

Does not resemble any cell

Hyperchromatic nuclei

Fragmanted nuclei

Increased nuclear size

Increased N/C ratio

Irregular nuclear contours

Robbins Basic Pathology

Anaplasia: backward formation

Lack of differentiation is a hallmark of cancer

Dedifferentiation

Loss of the structural and functional differentiation of normal cells

Dedifferentiation or failure/ arrest in differentiation (stem cell origin)

Robbins Basic Pathology

Pleomorphism: variation in size and shape of nuclei

Atypical mitosis

Tripolar

chromatin is coarse and clumped

increased N/C ratio 1:1 (normal: 1:4-1:6)

Robbins Basic Pathology

Rubin’s Pathology 7th Ed

Rubin’s Pathology 7th Ed

Malignant tumor features:increase as tumor approaches anaplasia

• Marked pleomorphism

  • variation in size and shape

• Nuclei are extremely hyperchromatic (dark-staining)

• Nuclei are large

• Increased nuclear-to-cytoplasmic ratio that may approach 1:1 (normal 1:4-1:6)

• Giant cells with one enormous nucleus or several nuclei

• Nuclei are variable and bizarre in size and shape

• Chromatin is coarse and clumped

• Nucleoli may be of astounding size

• Mitoses often are numerous and distinctly atypical

  • Anarchic multiple spindles, tripolar or quadripolar mitotic figures

• Fail to develop recognizable patterns of orientation to one another

  • lose normal polarity

• Grow in sheets, with total loss of communal structures

  • no gland or stratified squamous architecture

Well differentiated tumorsretain normal function and morphology

Cancers of endocrine organs secrete hormones

Squamous cell carcinoma produce keratin

Hepatocellular carcinoma secrete bile

Some cancers function unexpectedly

• Secrete fetal proteins
• Secrete ectopic hormones
  • ACTH, parathyroid-like hormone secreted in lung carcinomas

Stromal Changes

• Capillaries increase in number
  • Angiogenesis
• Dense abundant fibrous stroma is seen
  • Desmoplasia
  • Schirrous tumors

Dysplasia

• Disordered
• But not neoplastic proliferation
• In epithelium
  • Pleomorphism, hyperchromasia, increased mitosis … start
• When these changes reach the full thickness of epithelium: carcinoma in situ

Urologic Surgical Pathology, 3 rd __ Ed__

Urologic Surgical Pathology, 3 rd __ Ed__

Robbins Basic Pathology

Carcinoma in situ

Hypechromasia

Mitosis in upper layers

Polarity is not preserved

No maturation

No normal stratified layer

Basal layer is intact

Robbins Basic Pathology

Carcinoma in situ

Robbins Basic Pathology

RATE OF GROWTH

How long does it take to produce a clinically overt tumor mass?

• Original transformed cell
• 30 population doublings
• 10 9 __ cells (1 gm)__
  • smallest clinically detectable mass
• 10 additional doubling cycles
• 10 12 __ cells (∼1 kg)__
  • maximal size compatible with life.

Until we detect it, tumor completed most of its lifespan

Rate of Growth

• Most benign tumors grow slowly

  • months to years

• Mitoses are usually rare and have normal configuration.

• Most cancers grow much faster, eventually spreading locally and to distant sites (metastasizing) and causing death

• Some benign tumors grow more rapidly than some cancers

• Leiomyoma growth rate depend on circulating estrogen levels

  • Increase rapidly in size during pregnancy, then stop growing, become largely fibrocalcific, after menopause

• Blood supply or pressure affect growth of benign tumors

  • Adenomas of the pituitary gland locked into the sella turcica may shrink suddenly. A wave of necrosis as progressive enlargement compresses their blood supply

• In malignant tumors growth rate correlates inversely with differentiation

  • Poorly differentiated tumors grow more rapidly

• Wide variation in the rate of growth

  • Grow slowly for years, enter a phase of rapid growth
  • Emergence of an aggressive subclone

• Some grow relatively slowly and steadily

  • More G1 cells than S or M phase cells

• Growth may come almost to a standstill

  • almost all G1

• Some primary tumors (choriocarcinomas) become totally necrotic, leaving only secondary metastatic implants

Robbins and Cotran’s Pathological Basis of Diseases

Rate of Growth depends on

the doubling time of tumor cells

the fraction of tumor cells that are in the replicative pool

the rate at which cells are shed or die

Rate of Growth is determined by

• Counting mitosis under microscope
• Detecting tumor cells preparing to divide
  • Ki-67 labelling index
  • PCNA stains

Rate of Growth and Necrosis

Rapidly growing malignant tumors contain central areas of ischemic necrosis

Tumor blood supply fails to keep pace with the oxygen demand

In benign tumors necrosis may occur, degenerative type necrosis

In malignant tumor necrosis is abrupt, tumor necrosis

LOCAL INVASION

Local invasion is not seen in benign tumors

• Benign neoplasm remains localized at its site of origin
• Does not have the capacity to infiltrate, invade, or metastasize to distant sites
• Separated from normal tissue with well defined border
• Adenomas slowly expand
• Develop an enclosing fibrous capsule
  • Separates them from the host tissue

Robbins Basic Pathology

Robbins Basic Pathology

Tumor Capsule

• Derived from
  • the stroma of the host tissue
    • via pressure atrophy
  • the stroma of the tumor
• Not all benign neoplasms are encapsulated
  • Leiomyoma
    • **demarcated from the surrounding smooth muscle by a zone of compressed and attenuated normal myometrium, no well-developed capsule. **
• Few benign tumors are neither encapsulated nor discretely defined
  • some benign vascular neoplasms of the dermis
• Lack of a capsule does not mean that a tumor is malignant

MUIR’S TEXTBOOK OF PATHOLOGY

MUIR’S TEXTBOOK OF PATHOLOGY

Local Invasion in Malignant Tumors

• Malignant tumor growth pattern:
  • Progressive infiltration
  • Invasion
  • Destruction
  • Penetration of the surrounding tissue
  • Do not develop well-defined capsules
    • Slowly growing malignant tumors have stroma around them
    • There are tiny penetrating foci into adjacent structures

Malignant tumors should be removed with a wide margin of surrounding normal tissue because of this growth pattern

Surgical pathologists examine the margins of resected tumors to ensure that they are devoid of cancer cells (clean margins)

Like metastases, local invasiveness is the most reliable feature that distinguishes malignant from benign tumors

Robbins Basic Pathology

Robbins Basic Pathology

MUIR’S TEXTBOOK OF PATHOLOGY

Rubin’s Pathology 7th Ed

Adenocarcinoma of Colon, invading pericolonic adipose tissue

Robbins and Cotran’s Pathological Basis of Diseases

METASTASIS

Metastasis

Secondary implants of a tumor

Discontinuous with the primary tumor

Located in remote tissues

Robbins Basic Pathology

• Property of metastasis identifies a neoplasm as malignant
• Not all cancers have equivalent ability to metastasize
  • Basal cell carcinomas of the skin and most primary tumors of the central nervous system, which are highly invasive locally but rarely metastasize
  • Osteogenic (bone) sarcomas, usually have metastasized to the lungs at the time of initial discovery

30% of patients with newly diagnosed solid tumors present with clinically evident metastases

20% have occult (hidden) metastases at the time of diagnosis

The more anaplastic and the larger the primary neoplasm, the more likely is metastatic spread

Invasion and Spread

• Malignant tumors invade normal structures and spread
• Lymphatic
• Capillary, Vein
• Spaces
  • Peritoneum, Pleura
  • Cerebrospinal Fluid
• Perineural space (cause local invasion)

Spread on body cavities

• Ovarian tumors
  • Spread on peritoneum
  • Reimplant on other structures
    • This feature is different than local invasion
• Tumors of CNS (Medulloclastoma, Ependymoma)
  • Spread via CSF
  • Implant on meningeal surfaces or spinal cord

Lymphatic spread

• Epithelial tumors
• Metastasis develop in lymph nodes
  • Drainage sites
  • Local lymph nodes
• Not all enlarged lymph nodes are metastatic
  • hyperplasia of the follicles (lymphadenitis)
  • Proliferation of macrophages in the subcapsular sinuses (sinus histiocytosis)

Pathology - The Big Picture

• Lung carcinoma
  • Regional bronchial lymph nodes and then to the tracheobronchial and hilar nodes
• Breast carcinoma
  • Upper outer quadrant→ axillary lymph nodes
  • Lower inner quadrant → chest wall, internal mammarian
• Both of them then go to infraclavicular and supraclavicular lymph nodes

Skip Metastasis

Do not follow usual route

Miss one lymph node and develop metastasis in the next one

Sentinel lymph node

The first lymph node the tumor goes to

May be detected with certain dyes and radioactive methods

Hematogenous spread

• Mesenchymal and Epithelial tumors
• Mostly veins
• Follow the venous route
  • Abdomen → Liver
  • All veins → Lung
  • Throid, prostate → paravertebral plexus → vertebra

Rubin’s Pathology 7th Ed

• Some tumors grow in veins:
  • Renal Cell Carcinoma
    • Via inferior vena cava grow into heart
  • Hepatocellular Carcinoma

Not all metastasis can be explained anatomically

Prostate carcinoma goes to bone

Bronchogenic carcinoma goes to adrenals, brain

Neuroblastoma goes to liver, bone

Skeletal muscle have abundant vascular structures but not a place for metastasis

Homing of tumor cells

Robbins Basic Pathology

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What we talk in this lecture are generic statements.

Some “benign” tumors may cause death, so they are clinically not benign at all.

Some “very malignant” tumors respond to therapy more quickly.

Some well-differentiated tumors do not respond to therapy.