Types of Carcinogens

Clinical aspects of neoplasia

Paraneoplastic syndromes

Grading & staging

Carcinogens cause genetic damage and induce neoplastic transformation of cells

1. Chemical carcinogens

2. Radiant energy

3. Microbial – virus, bacteria, parasites

Parasites include • Schistosoma hematobium (Squamous cell carcinoma of the urinary bladder) • Clonorchis sinensis, Opisthorchis viverrini (Cholangiocarcinoma of the bile ducts)

Chemical carcinogenesisINITIATION - permanent DNA damage (mutations)

PROMOTION - can induce tumors in initiated cells, but cannot cause tumors on their own

Direct acting and indirect acting

Tobacco is the agent most responsible for cancer/cancer deaths in the United States.

DIRECT - ACTINGAlkylating Agentsβ-Propiolactone, Dimethyl sulfate, Diepoxybutane, Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, etc.)Acylating Agents1-Acetyl-imidazole, Dimethylcarbamyl chloride

PROCARCINOGENS (REQUIRE ACTIVATION)Polycyclic and Heterocyclic Aromatic HydrocarbonsBenz(a)anthracene, Benzo(a)pyrene (Cigarette Smoke), Dibenz(a,h)anthracene, Methylcholanthrene, 7,12-Dimethylbenz(a)anthracene

Aromatic Amines, Amides, Azo Dyes2-Naphthylamine (β-naphthylamine), Benzedrine, 2-Acetylaminofluorene, Dimethylaminoazobenzene (butter yellow)

Natural Plant and Microbial ProductsAflatoxin B1 , Griseofulvin Cycasin, Safrole, Betel Nuts

OthersNitrosamine and amidesVinyl chloride, nickel, chromiumInsecticides, fungicides, Polychlorinated biphenyls

Carcinogens

Initiation and promotion

Experiments demonstrating the initiation and promotion phases of carcinogenesis in mice.

Events in chemical carcinogenesis

Tumor Progression

RADIATION CARCINOGENESIS

UV light - skin cancers (SCC, BCC, Melanomas)

UV-B, pyrimidine dimers

• X-ray pioneers: skin cancers• Miners of radioactive elements: lung cancers • Atom Bomb survivors: initially leukemias (AML/CML), later

on - solid tumors • Thorotrast (radioactive dye in radiology) - liver sarcoma

Most frequent - acute and chronic myeloid leukemia followed by cancer of the thyroid in the young

MICROBIAL CARCINOGENESIS

RNA virusHuman T-Cell Leukemia Virus Type 1 (HTLV-1): causes T-cell leukemia/lymphoma, endemic in parts of Japan and Caribbean, sporadic elsewhere

‘Tax’ gene product • Stimulates transcription of viral mRNA for its

replication • Activates transcription of genes involved in

proliferation and differentiation of T cells• Inactivates p16/INK4a• Enhances cyclin D activity• Activates NF-κb, a transcription factor • Interferes with DNA-repair functions, inhibits

ATM-mediated cell cycle checkpoints

Oncogenic DNA VirusesHPV, EBV, HBV, KSHV(HHV8)

Human Papillomavirus• Types 1, 2, 4, and 7 (low risk) : benign squamous papillomas (warts)• Types16 and 18 (high risk) : Squamous Cell carcinoma of cervix /

anogenital region

• Two viral genes, E6 and E7• E6 mediates degradation of p53 and BAX• E7 protein binds to the RB protein and displaces the E2F transcription

factors, inactivates CDKIs p21 and p27, activate cyclins E and A

Effect of HPV proteins E6 and E7 on cell cycle

Epstein-Barr Virus• African form of Burkitt lymphoma• B-cell lymphomas in immunosuppressed • Subset of Hodgkin lymphoma• Nasopharyngeal carcinoma• Gastric carcinomas• T cell/NK cell lymphomas

Infects B lymphocytes - latent infection (LMP-1, EBNA-2, vIL-10)

Burkitt lymphoma (most common childhood tumor in central Africa and New Guinea)

EBV is not directly oncogenic, but acts as polyclonal B-cell mitogen

Nasopharyngeal carcinoma is endemic in southern China

Hepatitis B and C Viruses

70 - 85% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV

Maladaptive Immune response promotes tumorigenesis

HBV – Activates NF-κB pathway, HBx gene, viral integration

HCV - Chronic inflammation, HCV core protein

Helicobacter pyloriFirst bacterium classified as a carcinogen

Gastric Adenocarcinoma - increased epithelial cell proliferation in a background of chronic inflammation (cytotoxin-associated gene A - CagA)

Gastric ‘MALT’ lymphoma - infection leads to H. pylori-reactive T cells, which stimulate a polyclonal B-cell proliferation (NF-κB)

Antibiotic therapy can cure lymphoma

HHV-8 causes Kaposi's sarcoma in AIDS(acts via cytokines released from HIV and HSV)

Human Herpes Virus -8

Mechanisms by which tumors evade the immune system

Clinical Aspects of Neoplasia

(1) Location and impingement on adjacent structures

(2) Functional: hormone synthesis / paraneoplastic syndromes

(3) Bleeding and infections when the tumor ulcerates

(4) Fever

(5) Symptoms from rupture or infarction

(6) Cachexia (TNF, Proteolysis-inducing factor, Lipid-mobilizing factor)

Hormone production• Pituitary tumors

– Prolactinoma: prolactin amenorrhea, infertility and galactorrhea

– Somatotropic adenoma Growth hormone gigantism in children and acromegaly in adults

• Adrenal adenoma– Cortisol Cushing’s syndrome– Mineralocorticoids Conn’s syndrome– Sex hormone Adrenogenital syndrome

• Ovarian tumors:– Granulosa theca cell tumor hyperestrinism– Sertoli – leydig cell tumor excess androgen-

Hirsuitism • Trophoblastic tissue

– Hydatidiform mole and choriocarcinoma beta hCGAmmenorrhea & vomiting

Hematological associations with cancer

• Anemia of chronic disease: – Most common type

• Iron deficiency anemia : – right sided colorectal Cancer

• Macrocytic anemia: – due to folate deficiency from rapid

tumor growth– As in Leukemia and lymphomas

• Autoimmune hemolytic anemia: Jaundice, anemia,free Hb in urine– Chronic lymphocytic leukemia

Bone marrow metastasis

• Myelophthisic anemia:– Anemia related to metastasis to bone

marrow• Leukoerythroblastic blood picture:

– Metastasis to bone marrow pushes immature hematopoietic cells ( e.g. nucleated RBC, myeloblasts) into the peripheral blood

Paraneoplastic Syndromes

• 10% of cancers

• earliest manifestation of hidden tumor

• significant clinical issues / lethal

• mimic metastasis, complicate treatment

Clinical Underlying Cancer Mechanism

ENDOCRINOPATHIESCushing syndrome

 Small-cell carcinoma of lungPancreatic ca, Neural tumors

ACTH or ACTH-like substance

 SIADH Small-cell carcinoma of lung;

intracranial neoplasmsADH or atrial natriuretic

hormonesHypercalcemia

  

Squamous cell carcinoma of lungBreast carcinoma, Renal carcinoma

Adult T-cell leukemia/lymphoma

PTH related protein (PTHRP),

TGF-α, TNF, IL-1  

Hypoglycemia 

Ovarian carcinoma, FibrosarcomaOther mesenchymal sarcomas

Insulin or insulin-like substance

 

Carcinoid syndrome Hepatocellular carcinoma, Bronchial adenoma, Pancreatic Ca

Serotonin, Bradykinin 

Polycythemia  

Gastric carcinomaRenal carcinoma

Cerebellar hemangioma, Hepatocellular carcinoma

 Erythropoietin

 

Paraneoplastic Syndromes

Clinical Underlying Cancer Mechanism

NERVE AND MUSCLE SYNDROMESMyasthenia Bronchogenic carcinoma Immunological

Disorders of CNS/PNS Breast carcinoma  

DERMATOLOGIC DISORDERSAcanthosis nigricans Gastric carcinoma, lung,

uterine carcinomaImmunological;

secretion of EGFDermatomyositis Lung, breast carcinoma Immunological

OSSEO-ARTICULARHypertrophic osteoarthropathy

and clubbing of the fingersBronchogenic carcinoma Unknown

VASCULAR AND HEMATOLOGICVenous thrombosis (Trousseau phenomenon)

 

Pancreatic carcinomaLung carcinoma. others

Tumor products (mucins activate

clotting) 

Nonbacterial thrombotic endocarditis Advanced cancers Hypercoagulability

Red cell aplasia Thymic neoplasms Unknown

OTHERSNephrotic syndrome Various cancers Tumor antigens, immune

complexes

Paraneoplastic Syndromes

HypercalcemiaMost common paraneoplastic syndrome

PTH related peptide

Squamous cell bronchogenic carcinomacarcinomas of the breast, lung, kidney, and ovary

IL-1, TGF-α, TNF, and dihydroxyvitamin D

Investigations may show low PTH, high calcium, high PTHrP with normal/low levels of 1,25-dihydroxyvitamin D

Hypercalcemia due to skeletal metastases as in breast cancer is not a paraneoplastic syndrome

Hypertrophic osteoarthropathy 1% to 10% of patients with bronchogenic carcinomas.

• periosteal new bone formation, primarily at the distal ends of long bones, metatarsals, metacarpals, and proximal phalanges;

• arthritis of the adjacent joints; and • clubbing of the digits.

GRADING AND STAGING OF TUMORS

Grading - based on degree of differentiation of tumor cells

(in some cancers on number of mitoses or architectural features)

Staging - based on size of primary lesion, extent of spread to regional lymph nodes, and presence or absence of blood-borne metastases

- TNM system (American Joint Committee on Cancer Staging)

T:primary tumor, N:lymph node involvement, M:metastases

With increasing size, the primary lesion is characterized as T1 to T4

(T0 - in situ lesion)

N0 - no nodal involvement, N1 to N3 - increasing number of nodes

M0 - no distant metastases, M1 indicates metastases

35 year old woman with breast lump in left upper outer quadrant. It is 7x5cms with irregular margins, and puckering of the overlying skin with retraction of nipple. Nodes are palpable in the right axilla and CT abdomen shows multiple hypoechoic nodules in liver. Microscopy of tumor is provided. • What is your diagnosis? • Grade? stage? • Would you suggest surgical resection of the breast lump? • Will Herceptin be useful?

T0 N0 MO

T2 N1 M0

T4 N1 M1

Which of the following genes may be involved in this lesion?TaxE6E7LMP-1HbxCagA

Lung biopsies from two chronic smokers - immunohistochemical staining of the tumor cells is positive for different substances which would also explain different associated clinical manifestations. One of them had presented with neurologic dysfunction, muscle weakness, nausea , vomiting and polyuria. Which patient and what is the IHC likely to be positive for ? What could the other patient have presented with if there were no respiratory symptoms?A Parathormone related peptideB ErythropoietinC ACTHD ADHE Insulin like substance

A B

Required reading: Robbins Basic Pathology 9E, p198-207

Recommended reading: Robbins and Cotran Pathologic Basis of Disease 8E, p309-322