patoloji-ders-notlari

Title

Serdar Balcı

Clinicopathological Features of Neoplasia and Epidemiology

Serdar BALCI, MD

Clinical problems caused by both benign and malignant tumors

• Location and pressure on/ infiltration of adjacent structures
• Functional activity
  • Hormone synthesis
  • Paraneoplastic syndromes
• Bleeding and infections
  • Tumor ulcerates through adjacent surfaces
• Rupture or infarction
• Cachexia or wasting

Effects of Tumor on Host

• Location
  • 1 cm pituitary adenoma → hypopituitarism
  • 0.5 cm leiomyoma in renal artery → ischemia and hypertension
  • A small tumor on biliary tract → cholestasis, death
• Hormone production
  • Islet cell benign and malignant tumors → hyperinsulinemia → hypoglycemia
  • Adrenocotical neoplasms → hyperaldesteronism
• Ulcer
  • Tumors of GI tract
  • Intussusception
  • Intestinal obstruction
  • Infarct

Cancer Cachexia

Progressive loss of body fat

Progressive loss of lean body mass

Profound weakness

Anorexia

Anemia

Cachexia

• Correlation between

  • Size and extent of spread of the cancer
  • Severity of the cachexia

• In tumors;

  • Despite reduced food intake
    • Normally recognized as starvation
  • Calorie expenditure remains high
  • Basal metabolic rate is increased

• Cachexia is NOT caused by the nutritional demands of the tumor

• Cytokines produced by the tumor and the host, rather than reduced food intake

• TNF

  • Produced by macrophages in response to tumor cells
  • Tumor cells themselves mediates cachexia

• TNF

  • Suppresses appetite
  • Inhibits the action of lipoprotein lipase
  • Inhibiting the release of free fatty acids from lipoproteins

• Proteolysis-inducing factor

  • A protein-mobilizing factor
  • Causes breakdown of skeletal muscle proteins by the ubiquitin-proteosome pathway

• No satisfactory treatment for cancer cachexia other than removal of the tumor

Cancer cachexia: understanding the molecular basis Nature Reviews Cancer, 14, 754–762 (2014)

Cancer cachexia: understanding the molecular basis Nature Reviews Cancer, 14, 754–762 (2014)

Cancer cachexia: understanding the molecular basis Nature Reviews Cancer, 14, 754–762 (2014)

Paraneoplastic Syndromes

• Symptom complexes that cannot be explained by local or distant spread of the tumor
• The secretion of unexpected hormone
• Important to recognize:
  • Earliest manifestation of an occult neoplasm
  • Significant clinical illness and may even be lethal.
  • May mimic metastatic disease, changing treatment

Hypercalcemia due to bone metastasis is not considered as paraneoplastic

If hypercalcemia is due to PTH related protein then it is a paraneoplastic syndrome

Robbins Basic Pathology

Robbins Basic Pathology

• Hypercoagulability
  • Leading to venous thrombosis
  • Nonbacterial thrombotic endocarditis
• Lung carcinomas
  • Clubbing of the fingers
  • Hypertrophic osteoarthropathy

Grade (Derece)

• Attempts to establish
  • Aggressiveness
  • Level of malignancy
• Based on
  • Cytologic differentiation of tumor cells
  • The number of mitoses within the tumor
• Grade I, II, III, or IV –> in order of increasing anaplasia

Different Grades for Different Tumors

Criteria for the individual grades vary with each form of neoplasia

Fuhrman Grade

Gleason Grade and Score

FIGO grade

Cancer Grading Manual

Cancer Grading Manual

Cancer Grading Manual

Cancer Grading Manual

Cancer Grading Manual

Cancer Grading Manual

Stage (Evre)

Based on

The size of the primary lesion or its extend to local tissues

Its extent of spread to regional lymph nodes

The presence or absence of metastases

Stage

• TNM system
• Based on
• T0, T1, T2, T3, T4
  • The size of the primary lesion or its extend to local tissues
• N0, N1, N2
  • Its extent of spread to regional lymph nodes
• M0, M1
  • The presence or absence of metastases
• AJCC/UICC system
• Combines T, N, M
• Groups under 4 stages
  • Stage I, II, III, IV
  • Changes in each organ
• FIGO staging system for gynecologic tumors

Atlas of Staging in Gynecological Cancer

Atlas of Staging in Gynecological Cancer

Arch Pathol Lab Med. 2009 Oct;133(10):1539-51

cancerstaging.org

• Grade
  • Given by pathologist
  • Using microscope
  • Determining atypia, ## of mitosis, …
• Stage
  • Requires a team effort
  • Using histopathologic, radiologic, clinical features
  • Determining T, N, M status

Laboratory Diagnosis of Cancer

Morphologic Methods

Tumor Markers

Molecular Diagnosis

Morphologic Methods

• Done by pathologist
  • Macroscopic and microscopic features
• It is easy to diagnose normal and malignant cases
• Problematic cases are the borderline ones

Clinical information is necessary in all casesBut absolutely necessary in some cases

Radiation-induced changes in the skin or mucosa can be similar to cancer

Sections taken from a healing fracture can mimic an osteosarcoma

Giant cell tumor of bone vs bone cysts vs hyperparathyroidism

Specimen

• Must be adequate
• Representative
• Properly preserved
  • Formaldehyde

Types of Specimens

Radical Surgery

Excisional biopsy

Tru-cut (needle) biopsy

Int J Surg Case Rep. 2014; 5(1): 30–33

Frozen Section

http://www.ihcworld.com/

Fine Needle Aspiration

• Aspiration of cells from a mass
• Followed by cytologic examination of the smear
• Palpable lesions
  • Breast
  • Thyroid
  • Lymph nodes
  • Salivary glands

Exfoliative Cytology

Cytologic (Papanicolaou) smears

Robbins Basic Pathology

Immunohistochemistry

Bancroft’s Theory and Practice of Histological Techniques

Flow cytometry

Tumor Markers

Tumor-associated enzymes, hormones, and other tumor markers in the blood

NOT for definitive diagnosis of cancer

Useful screening tests

Quantitating the response to therapy

Detecting disease recurrence

PSA

CEA

AFP

CA-125

CA19-9

Molecular Diagnosis

• Diagnosis of malignancy
• PCR
  • Lymphoid neoplasms
  • T cell receptor, Ig gene monoclonality
• FISH
  • Translocation
  • Ewing Sarcoma, Lymphomas, Leukemias

Bancroft’s Theory and Practice of Histological Techniques

• Prognosis and behavior
• FISH
  • Her2/Neu
  • N-Myc
• Detection of minimal residual disease
  • Detection of BCR-ABL transcripts by PCR
  • Residual disease in chronic myeloid leukemia
• Diagnosis of hereditary predisposition to cancer
  • BRCA1
  • Microsatellite Instability
• Therapeutic decision-making
• Targeted Therapy
• Lung Carcinomas
  • Mutations of the ALK kinase
• Melanomas
  • BRAF V600E mutation
• Colon Cancers
  • RAS mutation

Robbins Basic Pathology

Molecular Profiling of Tumors

Expression Profiling

Robbins Basic Pathology

Molecular Profiling of Tumors

• Whole Genome Sequencing
• Tumors can contain from a handful of somatic mutations
  • Certain childhood leukemias
• Tens of thousands of mutations
  • Exposed to mutagens, skin, lung cancer

Two types of mutations

• **Driver mutations **
  • change normal control of cell proliferation, differentiation, and homeostasis
  • drive the neoplastic process
  • could be therapeutic targets
• Passenger mutations:
  • no effect on cell phenotype
  • more numerous than driver mutations
  • noncoding regions of the genome
  • have a neutral effect on growth, not conferring any advantage or disadvantage

Driver mutations

• Recurrent
  • Present in a substantial percentage of patients with a particular cancer
  • BCR-ABL fusion genes
• Driver mutations may be present in only a subset of tumors of a particular type
  • 4% of non–small cell lung cancers harbor an EML4-ALK tyrosine kinase fusion
  • Respond well to ALK inhibitors

A new classification

BRAF-omas???

Robbins Basic Pathology

Factors effecting clinical outcome

Factors effecting survival

Histologic Type of Tumor

Grade

Presence of preinvasive component

Tumor size

Perineural invasion

Lympatic invasion

Venous invasion

Stage T, N, M

Clues for hereditary syndromes

Markers used in pathology

Diagnostic

Predictive

Prognostic

Therapeutic

Product of a pathologist is a report

What do we expect to see in a report?

All morphologic, phenotypic, molecular features that are effecting the clinical outcome

Checklists, CAP

cap.org/cancerprotocols

Epidemiology

Epidemiologic data is used to find factors that are associated with cancer

Smoking → Lung cancer

Dietary fat and fiber → Colon cancer

Environmental, racial (hereditary), cultural influences

Cancer Incidence

• ## of new cancer patients per population
• USA
  • 1.5 million new cancer cases occurred in 2011
  • 569,000 people died of cancer
• Turkey

http://globocan.iarc.fr/Pages/fact_sheets_population.aspx

Cancer Rates changes over time

• Significant increase in the overall cancer death rate among men
  • Lung cancer, begun to drop
• The overall death rate among women has fallen slightly
  • Decline in death rates for cancers of the uterine cervix, stomach, and large bowel
  • Striking climb in the rate of lung cancer in women

Geographic and Environmental Variables

• Environmental factors are the predominant cause of the most common sporadic cancers
• Geographic differences in death rates from specific forms of cancer
  • Breast cancer
    • 4-5x higher in the United States and Europe than in Japan
  • Stomach carcinoma
    • 7x higher in Japan than in the United States
  • Liver cell carcinoma
    • Relatively infrequent in the United States
    • Most lethal cancer among African populations
• Environmental factors are the predominant cause of the most common sporadic cancers
• These geographic differences are environmental rather than genetic in origin
  • Nisei (second-generation Japanese living in the United States)
  • Have mortality rates for certain forms of cancer that are intermediate between those in natives of Japan and in Americans who have lived in the United States for many generations
  • The two rates come closer with each passing generation

Environmental carcinogens are everywhere

In the workplace, in food, and in personal practices

Sunlight

Asbestos

Certain occupation

Certain features of diet

Cigarette smoking

Chronic alcohol consumption

Age at first intercourse

Number of sex partners

• There is no escape
  • Everything people do to earn a livelihood, to subsist, or to enjoy life turns out to be illegal, immoral, or fattening, or—most disturbing—possibly carcinogenic.

?questions to think?

Why do we see cancer in older people?

Why do we see cancer in newborns?

Why certain cancers have peaks at certain ages?

Age

• Most cancer deaths occur between ages 55 and 75
• The rate declines, along with the population base, after age 75
• The rising incidence with age
  • Accumulation of somatic mutations
  • The decline in immune competence
• Cancer causes slightly more than 10% of all deaths among children younger than 15 years
• The major lethal cancers in children
  • Leukemias
  • CNS tumors
  • Lymphomas
  • Soft tissue and bone sarcomas

Heredity

• Inheritance of a single mutant gene greatly increases the risk of developing a tumor
• Carriers of mutant Rb have a 10,000-fold increased risk of developing retinoblastoma
• Often are associated with a specific marker phenotype
  • Polyps in APC
  • Lisch nodules and café-au-lait spots in neurofibromatosis type 1

characterized by chromosomal or DNA instability and high rates of certain cancers

• Features that characterize familial cancers
  • Early age at onset
  • Tumors arising in two or more close relatives of the index case
  • Multiple or bilateral tumors
• Familial cancers
  • Not associated with specific marker phenotypes
  • In contrast to APC, familial colonic cancers do not arise in preexisting benign polyps
• Incomplete penetrance or multifactorial inheritance

Why all smokers do not get cancer?

Polymorphisms in drug-metabolizing enzymes

Genome-wide association studies (GWAS) in lung cancer

Identified variants in a nicotinic acid receptor

Associated with the number of cigarettes smoked

Indirectly increase lung cancer risk by enhancing the addictiveness of cigarettes

?My uncle used to smoke 3 packages per day, he did not get cancer?

Acquired Preneoplastic Lesions

• Preneoplastic lesions, precancers
• Precursor lesions arise in the setting of chronic tissue injury or inflammation
• Squamous metaplasia and dysplasia of the bronchial mucosa
  • Habitual smokers
  • A risk factor for lung cancer
• Endometrial hyperplasia and dysplasia
  • Women with unopposed estrogenic stimulation
  • A risk factor for endometrial carcinoma
• Leukoplakia of the oral cavity, vulva, or penis
  • May progress to squamous cell carcinoma
• Villous adenomas of the colon
  • Associated with a high risk of transformation to colorectal carcinoma

What is the risk of malignant change in a benign neoplasm?

• Are benign tumors precancerous?
  • Adenomas of the colon as they enlarge can undergo malignant transformation in 50% of cases
  • Malignant change is extremely rare in leiomyomas of the uterus

Early Detection of Cancer

• Screening Tests
  • Hormone Markers
• PAP Test
• HPV Test
• KETEM
• kanser.gov.tr

N Engl J Med 373;18 October 29, 2015

How can you find cancer statistics?

SEER: seer.cancer.gov/

Globocan: globocan.iarc.fr/

http://www.cancerindex.org/Turkey