1. -NEOPLASIA- -212 - (2012-2013) Dr.H.M.Zahawi,FRC.Path

2. Definitions : Neoplasm = New growth of transformed (changed ) cells producing a mass (tumor) Benign neoplasm = Limited new growth without invasion or spread Malignant neoplasm = invasive growth that invades & spread Cancer is a general term for all malignant growths of whatever type

3. Neoplasia This is a Progressive, Purposeless, Pathologic, Proliferation of cells characterized by loss of control over cell division. DNA damage at growth control genes is the main mechanism leading to development of neoplasm. DNA damage is probably due to various Carcinogens

4. NEOPLASMS grow from growth of TRANSFORMED CELLS

5. Features of transformed cells : ANY CELL IN THE BODY CAN TRANSFORM & ACQUIRE NEW FEATURES Uncontrolled growth exceeding normal Useless Persistent even after removal of the stimulus which produced the change

6.  What is the purpose of classification?  To provide help in diagnosis  To allow correct treatment Classification of neoplasms :

7. How are tumors Classified ? Cell of origin ( Parenchymal cell ) Epithelial Connective tissue Nevus cells Lymphocytes Others Behavior of tumor: Benign or malignant Degree of differentiation

8. Benign Epithelial tumors : Adenoma - glandular epithelium tumor often producing a secretion e.g. (mucin) which may be intraepithelial or intraluminal Papilloma / Polyp – epithelial tumor forming finger like projections from epithelial surface with a connective tissue core, often projecting from the dermal or mucosal surface of a hollow organ

9. Structure of Polyp

10. Malignant epithelial tumor : Carcinoma Squamous cell carcinoma grow from squamous epithelium e.g. skin,mouth cervix, bronchus….etc Adenocarcinoma from glandular origin, e.g.G.I.T.,endometrium,breast, kidney, thyroid…..etc

11. Connective tissue cell origin : Benign : Named by tissue of origin with attached suffix – oma e.g. fibroma, lipoma, chondroma…etc

12. Malignant connective tissue tumors: SARCOMA : Prefix (origin)+ suffix (sarcoma) e.g. Osteosarcoma, liposarcoma, angiosarcoma leiomyosarcoma, rhabdomyosarcoma…

13. CarcinomaSarcoma Derived from Epithelium Derived from Connective tissue Always malignant CommonLess Common Spread mostly by lymphatics Spread by blood May have a pre-malignant phase (or in situ phase) Not believed to have a pre- malignant phase Older patientsYounger patients Two main sub groups of malignant tumours

14. Nomenclature: Cell of origin + Suffix Suffix - oma Fibroma Osteoma Adenoma Papilloma Chondroma Carcinoma / Sarcoma Fibrosarcoma Osteosarcoma Adencarcinoma Squamous cell carcinoma Chondrosarcoma Exceptions: Leukemia, Lymphoma, Melanoma, Glioma ………. others Glioma ………. others

15. Malignant tumors are classified into : Carcinoma : Malignant tumor of epithelial cells Sarcoma : Malignant tumor of connective tissue cells ( Mesenchymal origin) Lymphoma: Malignant tumor of lymph nodes Melanoma : Malignant tumor of nevus cells

16. Not all endings (– oma) are benign tumors e.g. : granuloma, lymphoma, hamartoma, choristoma…etc

17. NOT tumors : Granuloma : Chronic inflammation Hamartoma :Tumor like malformation in which there is abnormal mixing of normal components of the organ e.g. Lung Hamartoma Choristoma : Different types of tissue, ectopic to the region.e.g. Meckel’s ‘Pouch” Both are present at birth & do not become malignant.

18. How do benign & malignant tumors differ? Differentiation & anaplasia Rate of growth Presence of capsule Local invasion Distant metastases

19. Benign versus malignant tumors

20. - This indicates the degree of resemblance of the tumor cell to its cell of origin, functionally & morphologically. e.g – Cells of a lipoma may look exactly like normal fat cells. 1- Differentiation:

21. LIPOMALIPOSARCOMA

22. Features of differentiation include : Epithelial cells : example : formation of glands, ± secretion Connective tissue cells : example: formation of osteoid in bone tumors or fat cells in tumors of fatty tissue (lipoma)

23. Well formed glandular architecture

25. No acini !

26. - When a tumor cell loses its differentiation it gradually gains features of DYSPLASIA DYSPLASIA is a process of gradual loss of differentiation It is an abnormal growth which may precede malignancy Complete loss of differentiation  ANAPLASIA

27. Cytological Features of Dysplasia Increased nuclear size,  N/C ratio Variation in nuclear & cell size : PLEOMORPHISM Loss of differentiating features Increased nuclear DNA content HYPERCHROMATISM

28. Features of dysplasia (continued) :- Nucleoli :Prominent, sometimes multiple Mitotic figures : Increased Abnormal mitoses: may be present

29. Severe Dysplasia/ Anaplasia

30. Intraepithelial Neoplasia Dysplasia involving an epithelial surface Low grade & High grade High grade dysplasia,limited by epithelial basement membrane  CARCINOMA IN SITU

31. Intraepithelial Neoplasia

32. Point of invasion into deeper tissue

33. Note : Although all features of dysplasia can occur in both carcinomas & sarcomas, THERE IS NO IN-SITU stage in Sarcoma i.e. There is NO Sarcoma in-situ

34. Rate of growth usually correlates with level of differentiation & behavior Benign tumor ---------- SLOW Malignant tumor--------- RAPID Exceptions are present !!!! Growth of some tumors is hormone dependent 2- Rate of growth

35. Benign tumors frequently have a capsule Malignant tumors progressively invade & destroy surrounding tissue e.g.Breast cancer infiltrating skin * Second most important feature distinguishing malignant tumors 3- Local invasion & Encapsulation

36. Fibroadenoma of the breast surrounded by the fibrous capsule (below)

37. breast carcinoma illustrates invasion & NO CAPSULE

38. Spread of malignant tumors from their original (Primary) site to distant sites away from the main tumor Most important in diagnosing malignancy All malignant tumors can potentially metastasize (few exceptions ) 4- Metastasis :

39. Invasion and Metastasis Not all cancer have equal ability to metastasize: Example : basal cell carcinoma of the skin and most primary tumors of the CNS (Gliomas) are highly invasive at their primary sites but rarely metastasize. OPPOSITE: Osteogenic (Bone) sarcomas usually have metastasized to the lungs at the time of initial discovery.

40. Metastatic Pathway:

41. Pathways of metastases : Lymphatic channels Blood vessels Within body cavities (Transcelomic Spread)

42. 1- Lymphatic Spread : More characteristic in Carcinoma Spread follows the anatomical route of drainage unless skip “metastases” EXAMPLE : Breast cancer in left upper upper quadrant  Left axillary L.N. L

43. 2- Hematogenous (blood) spread : Usually venous first following anatomical drainage : Lung & Liver More characteristic of Sarcoma,but may in occur in later stages of carcinoma

44. 3- Transcoelomic spread: Peritoneal cavity: Spread across the peritoneal surface from one organ to another Example :CA of stomach to ovary Pleural cavity : Spread of primary lung cancer or a Metastatic cancer across the pleura from one lung to the other

45. Sites most commonly affected by metastases : 1- Lymph nodes 2- Liver 3- Lung 4- Bone 5- Pleura & Peritoneum 6- Many others

47. Metastatic Carcinoma in liver

48. Lung Metastases

49. Transcelomic spread along peritoneum

50. BENIGN vs MALIGNANT  Anaplastic  High mitotic index  Rapid growth  Infiltrative growth without capsule  Invasion  Metastases  Well-differentiated  Low mitotic index  Slow Growth  With capsule  No invasion  No metastases Summary : Differences between benign & malignant neoplasms

51. Grading & Staging of Tumors : Must be documented for all malignant tumours : To quantify the aggressiveness of tumor To outline types of therapy (surgery, radiation, drugs …? ) To compare different types of therapy To give an approximate prognosis

52. Grade of tumor: Based on level of differention : This indicates the degree of resemblance of tumor cells to cell of origin and is always based on microscopic criteria. Grade I : Well differentiated tumor Grade II :Moderately differentiated tumor Grade III : Poorly differentiated tumor Grade IV : Anaplastic tumor

53. STAGE of Tumor : This indicates the extent of spread of tumor. Clinical,investigative procedures and pathological appearance of tumor have to be used to assess it. It depends on : * Size of tumor * Regional lymph node involvement * Metastases to distant organs

54. Stage TNM System is developed by The International Union against Cancer (UICC) T: Size of tumor N : The presence or absence of lymph node metastases M: the presence or absence of distant metastasis

55. TNM Staging

56. Why is stage so important ? –determinant of PROGNOSIS : –forecast of the probable course and outcome of a disease, especially of the chances of recovery. –Stage  Prognosis –determining type of treatment options available such as (Surgery, Radiotherapy or Chemotherapy )

57. EPIDEMIOLOGY of CANCER

58. Cancer is the 2nd leading cause of death in most areas of world, after heart disease More than 1.3 million estimated new cancer cases occur every year Incidence of cancer related death is also rising !

59. CANCERS common in JORDAN 2008 : Colorectal Lung Urinary Bladder Prostate Leukemia --------------------------------------------- Breast Colo-rectal Uterus Thyroid Non- Hodgkins Lymphoma MALESMALES FEMALESFEMALES

60. WHAT FACTORS may influence the incidence of cancer ?

61. 1- Environment / Geographic location: Diet Occupation Sunlight Personal habits Overweight = 50% increase in cancer 2- Age : Malignancy ↑with ↑age 3- Heredity: AD, AR, or familial cancers(5%) Familial cancer syndromes Early age at onset Two or more primary relatives with the cancer Multiple or bilateral tumors

62. 4- Some acquired chronic diseases example : Chronic Inflammatory processes Precancerous process like Cirrhosis of the liver Many others

63. How & Why does cancer occur ?

64. Principles : Tumors arise from growth of transformed cells that have developed mutations in four classes of normal genes leading to uncontrolled cell division: Growth promoting proto-oncogenes Growth inhibiting tumor suppressor genes Genes regulating apoptosis Genes involved in DNA repair More than one mutations in above result in abnormal growth of cells

65. Outline of Gene Action : APOPTOSIS G. REPAIR G.

66. Multi-Step Theory of Cancer : Sometimes : Normal → Hyperplasia → Metaplasia → Dysplasia → Neoplasia → Metastases Transformed Cell

67. CARCINOGENIC AGENTS

68. 1- CHEMICAL Carcinogens 2- PHYSICAL Carcinogens 3- VIRAL Carcinogens 4- MICROBIAL Carcinogen

69. Direct Carcinogens - Directly produce damage without prior metabolic conversion Indirect Carcinogens- (Procarcinogen) Metabolic conversion in liver by cytochrome P-450 dependent mono- oxygenases  ultimate carcinogen RESULT : INITIATED CELLS - CHEMICAL CARCINOGENS :

70. PROMOTORS in chemical carcinogenesis HORMONES PHORBOL ESTERS (TPA), activate kinase C PHENOLS DRUGS Promoters sometimes promote growth in“Initiated” cells so that they proliferate FASTER than normal cells. They have to be used AFTER the initiator.

71. 1- Alkylating Agents : Direct, used in chemotherapy of cancer may induce Leukemia 2- Polycyclic Hydrocarbons : Indirect & very strong e.g.cigarette smoke  CA Lung 3- Aromatic Amines & Azo dyes : Rubber & Food Industry e.g.  naphthylamine  Bladder CA - CHEMICAL CARCINOGENS :

72. Chemical carcinogens ( Continued) 4- Nitrosamines : Endogenous or food preservatives e.g.Gastric & Colon CA…etc. 5- Aflatoxin B1 : Naturally occurring carcinogen present in fungus. Aspergillus flavus  Hepatocellular CA

73. U-V light : - Effect depends on intensity of exposure & quantity of melanin → Skin Cancer Squamous Cell Carcinoma Basal Cell CA Melanoma Ionizing Radiation: - Explosions or Treatment :  Leukemia, Breast,colon, thyroid, lung CA Asbestos fiber: Mesothelioma & Lung CA 2- PHYSICAL CARCINOGENS :

74. 1- DNA Viruses : Human Papilloma Viruses (HPV) may cause Benign tumors : squamous cell papilloma OR Malignant tumors : Squamous cell carcinoma of cervix, mouth, larynx. Epstein-Barr (EBV) infects B lymphocytes and epithelial cells of oropharynx and may result in malignancy. May cause : Burkitt’s Lymphoma & Nasopharyngeal carcinoma 3- VIRAL CARCINOGENESIS :

75. Hepatitis B virus (HBV) & Hepatitis C (HCV) have strong association with Liver Cancer. 2- RNA Virus : Mainly in animal cancers. May cause T cell Leukemia

76. Helicobacter Pylori Bacteria infecting stomach implicated in: peptic ulcers gastric lymphoma gastric carcinoma 4- MICROBIAL CARCINOGENS :

77. CANCERS --ASSOCIATED CARCINOGEN CA LUNG  Smoking CA CERVIX  Sexual transmission of HPV CA BLADDER  Rubber Industry CA LIVER  Aflatoxin & HBV infection CA THYROID  Radiation ANGIOSARCOMA of Liver  Plastic(PVC) MESOTHELIOMA  Asbestos

78. CANCER DIAGNOSIS

79. Tumor Diagnosis: History and Clinical examination Laboratory tests : General such as blood picture, stool for occult blood, blood sugar…….etc Imaging: X-Ray, US, CT, MRI Tumor markers Laboratory analysis

80. Histological diagnosis Microscopic tissue examination is the gold standard of cancer diagnosis. The specimen must be adequate, representative and properly preserved. Several sampling approaches are available: Cytologic smears Fine-needle aspiration

81. Surgery : Excision of tumor or organ Biopsy from tumor Processing tissue : Frozen section : Result with 15-20 min. by freezing tissue & cutting Paraffin sections : Paraffin blocks → Sectioning → Staining Result : 48hours or more

82. Tools for Cytology

84. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 December 2006 10:36 AM) © 2005 Elsevier Normal smear of Cervix

85. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 December 2006 10:36 AM) © 2005 Elsevier Dysplastic Epithelial Cells in smear

86. Other techniques may be necessary to help in diagnosis e.g.  Immunohistochemical stains  Molecular Studies  Flow cytometry  Biochemical Assays

87. Types of Bronchial Carcinoma

88. BE AWARE OF CANCER !!!

89. EARLY DIAGNOSIS of CANCER : This is very important as many cancers are curable if they are diagnosed early. Specific symptoms should be followed up : e.g. Abnormal bleeding Change of voice Change in a nevus Abnormal lump in breast An ulcer that does not heal……etc.

90. Specific procedures : - Self examination of the breast - Mammography - Serial PAP smears for the cervix - Serial sputum cytology in smokers - Serial urine cytology in some cases, e.g. bilharziasis, workers in rubber Screening for genetic mutations in familial cancers.

91. FIGHT CANCER BY AWARENESS & EARLY DETECTION …. THANK YOU !