Neoplasm Full PDF

NEOPLASM By Prof. A.K. Srivastava Department of Pathology Sanskaram college of Veterinary Science, Jhajjar  DEFINITION By Vegad- Neoplasm is a growth of new cells that proliferates without control, serves no useful funct...

NEOPLASM By Prof. A.K. Srivastava Department of Pathology Sanskaram college of Veterinary Science, Jhajjar  DEFINITION By Vegad- Neoplasm is a growth of new cells that proliferates without control, serves no useful function and has no orderly arrangements. By Mallory- A neoplasm is a growth of new cell which- 1) Proliferates continuously without control 2) Bears considerable resemblance to the healthy cell from which they arise 3) Has no orderly arrangement 4) Serve no useful purpose 5) Has no clearly understood cause  Terminology Oncology- Study of tumor (benign or malignant) is called oncology. Tumor- It is used to designate especially benign neoplasm. Benign tumor- A benign tumor that does not grow in aggressive manner, does not invade surrounding tissue and has no feature of metastasis. Malignant tumor- A malignant tumor multiplies very rapidly that bearing high degree of pleomorphic cells showing mitotic figures without orderly arrangement and has characteristic feature of metastasis. Cancer- Malignant tumors are called as cancer. Incomplete carcinogen- The chemical carcinogen which acts as initiator of tumour formation is called incomplete carcinogen. This usually produce benign tumor. Tumour marker- A chemical substance which either secreted by the cancerous cell or produced by the body in response to developing cancer is called Tumour marker. Metastasis- Spread of cancerous cells from primary site to secondary areas of the body this may be regional or distant is called metastasis. Carcinogen- Any agent that causes tumor formation is called carcinogen. Ultimate carcinogen- Indirect chemical carcinogen such as poly cyclic aromatic hydrocarbons requires metabolic conversion to transform into potent active form of carcinogen that develops full blown cancer is called as Ultimate carcinogen. Complete carcinogen- The chemical carcinogen having properties of both initiation and promotion of neoplasm is called complete carcinogen. They are said to be weak carcinogen. Incomplete carcinogen- The chemical carcinogen which acts as initiator of tumor formation is called incomplete\ carcinogen. This usually produce benign tumor. Tumor marker- A chemical substance which either secreted by the cancerous cell or produced by the body in response to developing cancer is called Tumor Marker. Metastasis- Spread of cancerous cells from primary site to secondary areas may be regional or distant is called metastasis. Initiator- The chemical carcinogen having potential to initiates the irreversible process of tumor formation is called initiator. Promoter- Promotor is a chemical substance that is not carcinogenic but has the potential to accelerate the process of tumor formation once it is initiated. Proto-oncogene- Normal gene present in the body responsible for physiological replication of cells. It is precursor of tumor producing gene (oncogene). Oncogene- It is the abnormal gene (mutated version of a proto- oncogene) responsible for generation & replication of even those cells that are destined for apoptosis in normal condition. The affected cells survive and proliferate continuously to form cancerous cell. Onco-supressor gene- Normal gene present in the body restricting replication of the cells beyond physiological limits. P 53gene- Identified as one of the onco-supressor gene. It produces 53 KD nuclear phospho-protein. Its role is in controlling cell cycle, repair and synthesis of DNA, differentiation of cell and to induce apoptosis. In normal cell this protein has a very short life and does not accumulate to detectable level. P53 gene has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. PATHOGENESIS OF CANCER Differences between Benign and Malignant tumor Benign tumor Malignant tumor 1- Occurs singly 1-Single or multiple 2 Shape rounded, elliptical, wart 2-Shape is irregular like, pedunculated. 3- Encapsulation is present 3- Encapsulation is not present 4- Rate of growth is slow 4- Rate of growth is fast 5- Degenerative and necrotic 5- Degenerative and necrotic changes minimal changes minimal 6- Removal is not difficult 6- Removal is difficult 7- Not toxic 7- Always toxic 8- No recurrence after removal 8- Recurrence after removal Differences between Benign and Malignant tumor Benign tumor Malignant tumor 9- No metastasis 9- Metastasis is present 10-Death does not occur 10-Death usually occur 11-Cells appear normal 11- Cells are abnormal 12- Minimal anaplasia 12- High degree of anaplasia 13-Growth not below basement 13- Growth mostly below membrane basement membrane 14- Growth confined in the CT 14- Growth not confined in the CT Capsule Capsule 15-Growth not beyond the blood 15-Growth beyond the blood supply supply 16- Slight degenerative changes 16- High degenerative changes  MMMMMMMMMMM a. Nucleus and nucleus not a. Both are enlarged enlarged. b. Shape of nucleus not altered b. Variation of shape seen. c. Nucleus normlchromic. c.Hyperchromasia of nucleus. d. Nucleolar: nuclear ratio not d. Ratio increased. altered. e. Sometimes multi nucleated. e. Number of nuclei in the cell normal. f. Ratio decreased. f. Cytopasmic: nuclear ratio unaltered. Four types of the gene that control cancer 1-Proto oncogene- a growth promoting gene 2-Tumour suppressing gene- a growth inhibiting gene 3-Gene that regulates Programmed cell death (apoptosis) 4-Gene involved in DNA repair  Immune Surveillance Paul Ehrich stated that the cancer cells are frequently arise in the normal body but are recognized as foreign and efficiently eliminated by the immune system. Later, Lewis Thomas suggested that the cell mediated immune (CMI) system had evolved to petrol the body and eliminates the cancer cells. Therefore, any impairment of immune response results the cancer in the body.  TUMOR ANTIGENS Any protein produced by a tumor cell or by the host cell in response to tumor that usually foreign to the host is called tumor antigen. Tumor antigen is an antigenic substance produced by tumor cells/ host cell that triggers an immune response in the host. Broadly, there are two types of tumor antigens- 1. Tumor-specific antigens- The proteins (antigen) that are only produced by tumor cells are called tumor-specific antigens 2. Tumor associated antigen-The proteins (antigen) produced by tumor cell as well as host cells are called tumor associated antigen.  TUMOUR SPECIFIC ANTIGEN This antigen is produced/expressed only by the tumor cell due to mutation of proto-oncogene and tumor suppressors gene which lead to abnormal protein production are called tumor-specific antigens. This protein is present only on tumor cells that can be recognized by cytotoxic T-lymphocytes. Such type of TSA is usually generated by the chemical carcinogens. Examples of tumor-specific antigens include the abnormal products of ras and p53 genes.  Since these antigens induce resistant to tumor transplant, they are referred to as tumor specific transplantation antigens (TSTAs). TSA are mutant protein antigens that are likely to be much more specific to cancer cells because normal cells should not contain these proteins. TSTS produced due to physical, chemical or viral mutagens. This tumor antigen induces CMI response by tumor specific cytotoxic T cell. The immune system detects and eliminates these tumor cells by recognizing the antigen expressed on cell surface.  Certain proteins that are produced by normal cell during fetal life when the immune system is immature and unable to respond but that normally expressed in the adults due to reactivation of embryonic gene that encode onco-fetal proteins. In tumorous condition in tumor cells result in their expression on the fully differentiated cell. TAA may also be proteins that are normally expressed at extremely low level on normal cells but are expressed at much higher levels on tumor cells. ❖ TSTA which are unique to tumor cells and not expressed on normal cells. They are responsible for rejection of the tumor.  TUMOUR ASSOCIATED ANTIGENS In contrast to tumor specific antigen (TSA), mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins that are called tumor- associated antigens, TSA are present on some tumor cells and also some normal cells. Some of these antigens may be secreted while others are membrane-associated molecules.  Examples Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response. An example of such a protein is the enzyme tyrosinase, which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells. Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonic development and disappear by the time the immune system is fully developed.  Bence Jones protein Bence Jones protein is a monoclonal globulin protein or immunoglobulin light chain found in the urine, with a molecular weight of 22-24 kDa that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple myeloma. Detection of Bence Jones protein in urine may be suggestive of multiple myeloma. About 50% to 80% of people with multiple myeloma have Bence-Jones proteins in their urine. The first biochemical Tumor Marker to be discovered was the Bence Jones proteins in urine.  Anti tumor mechanism The immune system comprises of cell mediated and humoral immune response play an important role in anti tumor mechanism. The various cells participates in anti tumor activity are – 1-Cytotoxic T cell (CTL) 2-Natural Killer (NK / CD 16) cell 3-Macrophage 4-Humoral mechanism  1-Cytotoxic T cell (CTL) CTLs are the major immune defense mechanism against tumors. Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen. CTLs recognize peptide derived from cytoplasmic proteins that are displayed on to MHC-1 molecules. CTLs play a protective role against virus associated neoplasm. CTL that are sensitized to tumour specific antigen (TSA) and perhaps other tumor antigens kills the tumor cells.  2-Natural Killer (NK / CD 16) cell The cell is capable of destroying tumour cells without prior sensitization. It forms first line of defense against tumour cells. It recognizes neo-antigens that are expressed on tumour cells and the cells that have undergone DNA damage. It attacks tumor cells directly without antibody coating or by antibody dependent cell cytotoxicity (ADCC) utilizing the Fc receptor on the NK cells.  3-Macrophage The cytokines like interferon ƴ secreted by T cells and NK cells is a potent activator of macrophages against tumor cells. Macrophages surround the tumor cell identifying presence of foreign antigens. Macrophages may kill the tumor cells by ADCC. Macrophage produces cytokines like TNF alfa inducing hemorrhages and necrosis of the tumor cells.  METASTASIS Development of secondary growth in remote tissue that is discontinuous to the primary tumour Hematogenous spread: ❖Seen in mesenchymal tumour (Sarcoma) ❖Arteries are much more resistant to invasion than veins and lymphatics not because of thickness but also presence of elastin. Lymphatic spread: ❖Seen in epithelial and glandular tumour (Carcinoma) ❖ This spread involves the regional lymph nodes. Spread by nerves: Cancer cell may sometime travel along the perineural lymphatics.  Infiltration &Expansion: ❖Infiltrating cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding (or expand in to the surrounding), healthy tissues. Also called Invasive cancer. Seeding of body cavities and surfaces: Transfer of tumour cell from one serous /mucous surface to another. ❖Implantation: Implantation the cancer cells may occur by; ✓ Coitus: Transmissible Venereal granuloma in dog is transmitted by coitus. ✓By inoculation: While operating on a tumor, the surgeon may implant some neoplastic cells on the edges of the wound where new tumor may develop. ✓By natural passages: Cells of Cancer growing on the lining surface of hollow organs may cast into the lumen & may be implanted in other areas. eg. Carcinoma of the renal pelvis may be washed down to the bladder. Metastasis by infiltration, blood vessels and lymphatics  ETIOLOGY Intrinsic Factors ❖ Heredity ❖ Age ❖ Pigmentation ❖ Sex ❖ Tumour Immunity  Extrinsic Factors ❖ Chemical Carcinogens ❖ Radiant Energy ❖ Chronic Irritation ❖ Hormones ❖ Parasites ❖ Oncogenic Viruses Chemical Carcinogens Direct Acting Agents – - Alkylating Agents - Anticancer Drugs- eg. Cyclophosphamide Indirect Acting Agents – - Polycyclic, Heterocyclic aromatic compounds - Aromatic Amines - Natural Plant & Microbial Product - Miscellaneous Agents AMES TEST Radiation Carcinogens - UV Rays, X-Rays, Nuclear fission THEORIES OF RADIATION CARCINOGENESIS 1- Direct theory- Chromosomal break down 2- Indirect theory- Ionization of water 3- Miscellaneous theory- Activation of Suppressor gene IONIZING RADIATION  Chronic Irritation ❑ Clay pipe smoker ❑ Kangari basket ❑ Chutta smoker ❑ Sharpe teeth ❑ Gall stone/Kidney stone ❑ Yoke  Hormones Hormonal imbalance Estrogen, Progesterone, Testosterone & Corticosteroid Increases production of growth factors Chemical structure resembling polycyclic Hydrocarbon (Carcinogen) High estrogen level leads to mammary tumors in mice. Lynoral (Sythetic), Premarin (Natural)  Parasites Spirocera lupi -Fibrosarcoma in oesophagus of dogs Cysticercus fasciolaris – fibrosarcoma in rat liver Eimeria stiedae – bile duct tumour in rabbits Schistosoma haematobium –Carcinoma of Urinary bladder in man Gongylonema neoplasticum- Carcinoma of Gastric mucosa in rats.  Oncogenic Viruses  In 1876 Novinsky successfully transplanted venereal granuloma from one dog to another.  Ellermann and Bang in 1908 identified oncogenic virus of Avian Leucosis  In 1910 found virus in fowl sarcoma  In 1933 discovered papilloma virus in rabbits. GRADING OF TUMOUR & CLINICAL EFFECTS & DIAGNOSIS  GRADING OF TUMOUR Grading of cancer based on – (1) Size of growth (2) Pleomorphism of cell (3) Hyperchromatism of nuclei (3) Number of mitoses within the cell. (4) Orientation of cell (5) Nodal spread (6) Metastasis of tumor cell  Grading of Tumour 1- TNM Method- T – Tumour mass T0, T1, T2, T3, T4 N- Nodal spread N0, N1, N2, N3, N4 M- Metastasis M0, M1, M2, M3, M4 ❖T1, N0,M0 – Prognosis fair ❖T3, N4, M2- Prognosis grave 2- Grading Method- May be classified as Grade I, II, III, IV  EFFECTS OF NEOPLASM 1- CANCER CACHEXIA (WASTING)  Many cancer patient suffer from loss of body fat & lean body mass, anemia.  Due to Production of TNF and IL-1 released by activated macrophages causing anorexia.  Inhibits the action of Lipoprotein lipase preventing release of fatty acid from lipoproteins. CLINICAL EFFECTS OF NEOPLASM 1-CANCER CACHEXIA (WASTING). ❖Many cancer patient suffer from loss of body fat & lean body mass, anemia. ❖Due to Production of TNF and IL-1 released by activated macrophages causing anorexia. ❖Inhibits the action of Lipoprotein lipase preventing release of fatty acid from lipoproteins.  2-Paraneoplastic syndrome (Due to secondary effect of neoplasm) Due to secondary effect of ❑ Hormonal effects neoplasm o Tumour of Anterior pituitary  Pressure atrophy involving causes Gigantism.  Obstruction: o Tumour of Paratyphoid  Destruction of tissue, blood results in Osteoporosis & vessels & nerves ‘Big Head’  Infection o Tumour of Sertoli-cells cause  Anemia: feminization in male. o Tumour of adrenal gland  Death causes Cushing’s syndrome.  Types of Benign tumours Papilloma- Stratified squamous epith. cells Chondroma- Cartilage Adenoma- Glandular epithelium Osteoma- Bone Fibroma – Connective tissue- Nasal Leiomyoma- Smooth muscles Polyps Rhabdomyoma- Skeletal or cardiac a) Fibroma Durum- Firm and hard muscle b) Firoma Molle – Soft –Gingival Melanoma- Melanocyte fibroma (epulus) Hemangioma- Blood vessels Myxoma- Embryonal connective tissue Lipoma – Adipose tissue  Types of Malignant tumours Squamous cell carcinoma Osteosarcoma ❖ Ethemoid carcinoma Leiomyosarcoma ❖ Basal cell carcinoma Rhabdomyosarcoma Adenocarcinoma Melanosarcoma Fibrosarcoma Hemangiosarcoma Myxosarcoma Histeosarcoma – Canine venereal Liposarcoma granuloma Chondrosarcoma PAPILLOMA Papilloma- Tree man SQUAMOUS CELL CARCINOMA LIPOMA FIBROMA FIBROMA MOLLE FIBROSARCOMA OSTEOMA ADENOMA CHONDROMA HEMANGIOMA  Canine Venereal Granuloma (Histiosarcoma) Synonyms- Canine transmissible venereal tumour, Canine condyloma, Sticker tumour, transmissible sarcoma, transmissible lymphosarcoma. Novinsky successfully transmitted Grossly- Single or multiple small to large, soft or friable, sessile or pedunculated, nodular or papillary mass, grey or red in colour, ulcerate and protrude from genitalia Microscopically- Large ,round oval, polyhedral with indistinct boundary, poorly stained, Nucleus large round or oval MALE DOG FEMALE DOG VENEREAL GRANULOMA VENEREAL GRANULOMA MIXED MAMMARY GLAND TUMOUR Mixed mammary gland tumour Mixed salivary gland tumour  Dermoid cyst Dermoid cyst is composed only of dermal and epidermal elements (which are both ectodermal in origin). It contains multiple skin appendages such as hair, hair follicles, teeth, or sweat glands and sometimes nerves. Dermoid cysts usually located at the junction of dermis and sub cutis of face, inside the skull, on the lower back and in the ovaries. Dermoid cysts grow slowly. DERMOID CYST IN OVARY  TERATOMA Teratoma is a rare and compound type of tumor arising due to embryonic defects and consist tissue developing from all germ layers. Usually totipotential or multipotential embryonic cells give rise teratomas. Cohnheim’s cell rest theory explains the origin of teratoma. Commonly in ovaries, and testicles, but can occur elsewhere in the body. Teratomas also comprise mesodermal and endodermal elements.  TypeS of teratoma Mature teratomas are usually benign (not malignant). But they may grow back after being surgically removed. More in horse in testes, less common in ovaries in cattle and dog. Immature teratomas are more likely to develop into a malignant cancer of any cell. 1- HISTOLOGICAL & CYTOLOGICAL METHODS- ❖ Pleomorphism ❖ Disturbed orientation ❖Mitotic count ❖Tumor body giant cell ❖Changed ratio of cytoplasm and nucleus ❖Changed ratio of nucleus and nucleolus PLEOMORHISM OF CELL DISTURBED ORIENTATION  Mitotic count Mitotic activity should be reported as an average over 10 hpf (40×) be counted to determine a statistically valid average. Generally, 30 hpf are sufficient. But occasionally 50 or more hpf may be needed. TUMOR BODY GIANT CELL  Nuclear morhometry Anisokaryosis Nuclear Enlargement Changes in nuclear chromatin pattern Any nuclear abnormality This is important feature of neoplasm. CHARACTER OF CANCEROUS CELLS  2-Papanicolaou test (Pap Test)  It is a method of cervical screening used to detect potentially precancerous and cancerous processes.  In the Cervix (opening of the uterus or womb)  In the Colon (in both men and women). Stained Smear of Pap Test  3-BIOPSY Some of biopsy techniques are : ❖ Fine Needle Aspiration Cytology (FNAC) ❖ Core needle ❖Vacuum assisted ❖Image guided Ultrasound.  4-AgNOR COUNT Nucleolar organiser regions (NORs) are loop of DNA present in nucleoli which encode AgNOR staining solution A- 1% Gelatin + 2% formic acid ribosomal RNA and transcribed by RNA B- 50% Aqueous silver nitrate Polymerase I. Mix- Solution A & B at ratio of 1:2 The certain Argyrophilic proteins called NOR associated proteins. Theses proteins are accumulated in highly proliferating cells of tumour appearing as black dot with AgNo3 that is widely used in tumour pathology as a diagnostic and prognostic marker. It is believed that the mean AgNOR count in tumor cells with >5 AgNORs per nucleus represents the proliferative activity.  5-PCNA (proliferating-cell nuclear antigen) PCNA plays an essential role in DNA replication as the assisting protein. Proliferating cell nuclear antigen (PCNA) is a DNA that acts as a factor for DNA Polymerase and is essential for replication. Proliferating cell nuclear antigen (PCNA) is known as a molecular marker for proliferation. PCNA was first shown to be involved in DNA replication.  6-Flow cytometry Flow cytometry is a laser based technology used to count and sort cells, detect biomarkers and engineer proteins. This is done by suspending cells in a stream of fluid and passing them by an electronic detection system.  7-BIOCHEMICAL ASSAY Assay of tumour associated enzymes Hormones Tumour markers ✓ Carcino-embryonic antigen ✓ Alpha foetoproteins  8– MOLECULAR DIAGNOSIS- Two most imp. Molecular diagnosis is- 1) Polymerase chain reaction (PCR) 2) Fluorescent in situ hybridization technique.  TREATMENT Immunosuppressive drugs Therapy Robotic Surgery Chemo-therapy Radiation- Therapy Hormonal therapy THANK YOU