Neoplasia 1

Neoplasia part-1 with tumour immunity and diagnosis of tumour.

1. Neoplasia Part-1 DR. MARUF RAZA Associate Professor of Pathology Based on Robbins and Cotran, 9 th .

2. Neoplasia/ Neoplasm: Neoplasia/ neoplasm means new growth. Tumor was originally applied to the swelling caused by inflammation, but the term is now applied to neoplasm. Oncology is the study of tumors or neoplasms. Cancer: A common term for all malignant neoplasm.

3. Neoplasia definition: Neoplasm : According to British Oncologist Willis- “A neoplasm is an abnormal mass of tissue , the growth of which exceeds and is uncoordinated with that of normal tissues and persist in the same excessive manner after cessation of stimuli which evoke the change.”

4. Neoplasia definition: In modern molecular pathology: A neoplasm can be defined as a disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny.

5. Neoplasia: Components All neoplasm have two basic component: 1) Neoplastic cells: Cells that forms the tumour parenchyma. 2) Reactive Stroma : The connective tissue, blood vessels and cells of the adaptive and innate immune system.

6. Neoplasia: Components The classification and biologic behavior of tumors are based on the parenchymal component (Tumor cells). Tumour growth and spread depends on the stroma of the tumor. Some tumors with scant connective tissue are soft and fleshy. Some with abundant collagenous stroma called desmoplasia ( scirrhous breast carcinoma).

7. Classification on Biological behavior On the basis of biological behaviour and morphologic characteristics tumor is divided into: i. Benign tumor ii. Malignant tumor

8. Benign Tumor A tumor is benign when: i. Tumours gross and microscopic appearances are innocent ii. remain localized will not spread to other sites iii. local surgical removal is possible.

9. Benign Tumor The patient having benign tumour generally survives. Benign tumors are designated by attaching the suffix -oma to the name of the cell type from which the tumor originates. Cell type+ OMA example: fibroma, chondroma, lipoma.

10. Benign Tumor Adenoma : Benign epithelial neoplasms derived from columner epithelium or glands. Papilloma: Benign epithelial tumor producing microscopically or macroscopically visible finger-like projection from the epithelial surfaces. Polyp: A non neoplastic or neoplastic macroscopically visible projection above a mucosal surface is termed a polyp.

11. Papilloma

12. Polyp

13. Papilloma vs Polyp Papilloma Polyp Benign epithelial tumour Neoplastic or Non neoplastic Microscopically or macroscopically visible projection Macroscopically visible projection Exp. Squamous Papilloma Exp. Juvenile polyp in rectum, Adenomatous polyp.

14. Malignant Tumors Malignant tumors are collectively referred to as cancer. Malignant tumors invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death.

15. Malignant Tumors When the tumor has: 1. gross and microscopic appearances are aggressive 2. which invade and destroy adjacent structures. 3. spread to distant sites (metastasis).

16. Malignant Tumors: nomenclature Malignant tumors arising in mesenchymal tissues are usually called sarcoma. e.g. fibrosarcoma , chondrosarcoma , leiomyosarcoma , rhabdomyosarcoma . Malignant tumors arising from blood-forming cells are designated leukemia or lymphoma.

17. Malignant Tumors: nomenclature Malignant tumors arising from epithelial cell origin are called carcinoma. E.g : Squamous cell carcinoma, adenocarcinoma . Squamous cell carcinoma is a cancer arising from squamous epithelium. Adenocarcinoma is a cancer arising from glandular/ columner epithelium or forms glandular pattern.

18. Squamous cell carcinoma

19. Adenocarcinoma

20. Mixed tumor Tumor arising from a single clone of cell capable of forming epithelial, myoepithelial cells, myxoid stroma containing cartilage and bone is called mixed tumour. Cells of mixed tumors arises from a single germ layer. e.g : Pleomorphic adenoma of salivary gland.

21. Teratoma,Hamartoma,Choristoma Teratoma is a tumor arising from more than one germ layer , usually all three. Teratoma is seen in the ovary and testis (ovarian dermoid cyst). Choristoma is the heterotopic (abnormal place) rest of normal cells. Hamartomas are disorganized masses of cells composed of cells native to that site.

22. Benign tumor VS Malignant tumor 1) Neoplastic cell criteria 2) Rate of growth 3) Size of the tumor 4) Haemorrhage and necrosis 5) Capsulated or not 6) Local invasion present or not 7) Metatasis 8) Clinical effects

23. Difference between benign and malignant tumor Characteristics Benign Malignant 1) Neoplastic cells. 1) Neoplastic cells. 1) Neoplastic cells. a) Differentiation Well differentiated Well differentiated to undifferentiated b)Pleomorphism Absent Often present c)Orientation of neoplastic cells No loss of orientation. Loss of orientation. d)Nuclear cytoplasmic ratio Normal 1:4 to 1:6 Normal Increased (May be 1:1 )

24. 2) Rate of growth Grow and expand slowly Most cancers grow rapidly 3) Size Usually small Usually large 4)Haemorrhage and necrosis Little tendency Common 5)Capsule Mostly encapsulated Not capsulated 6)Local Invasion No local invasion Locally invasive 7)Metatasis Never occur Metastasis occurs 8) Clinical effects Usually not fatal Almost invariably fatal

25. Some tumor which has “oma” but are not benign: Lymphoma, Melanoma, Seminoma. Some benign tumor without capsule: Haemangioma, leiomyoma. Locally invasive/ Locally malignant tumor: Tumor have local invasion but no tendency to metastasize. i . Basal cell carcinoma of skin. ii. Giant cell tumor of bone.

26. Differentiation, Anaplasia , Dysplasia, Carcinoma in Situ

27. Differentiation Differentiation: Differentiation refers to the extent to which neoplastic tumor cells resembles the corresponding normal parenchymal cells, both morphologically and functionally. Benign tumour lipoma’s neoplastic tumour cells is closely resemble to normal adipocytes.

28. Differentiation Benign tumours are well differentiated. Grading of malignant tumor is done based on differentiation, like: 1. Well differentiated tumor is Grade I. 2. Moderately differentiated is Grade II. 3. Poorly differentiated is Grade III.

29. Anaplasia Anaplasia: Lack or loss of differentiation is called anaplasia. Lack of differentiation or anaplasia is considered as hallmark of malignancy. Anaplastic features are found in malignant tumor.

30. Characteristics of a malignant cells/ Features of Anaplasia Anaplasia is associated with cellular feature like: 1. Pleomorphism 2. Increased nuclear cytoplasmic ratio 3. Hyperchromasia 4. Increased mitosis and abnormal mitosis 5. Loss of polarity

31. Pleomorphism Pleomorphism is the variation in size and shape of the cells. Cancer cells show pleomorphism . Cells ranges from small cell to a large atypical tumor giant cell. Some tumor cells possess a huge nucleus with two or more large, hyperchromatic nuclei.

32. Abnormal nuclear morphology A normal nucleus is large in relation to cytoplasm. Normal nuclear-to-cytoplasm ratio is 1:4 to 1:6. In malignancy NC ratio may become 1:1. Nucleus is darkly stained (hyperchromatic) with coarsely clumped chromatin. Abnormally large nucleoli are also commonly seen.

33. Mitosis: In tumours many cells are in mitosis because of high proliferative activity of the tumor cells. There may be atypical, bizarre mitotic figures, sometimes tripolar, quadripolar mitoses. Loss of polarity : The orientation of anaplastic cells is markedly disturbed. Tumor cells grow in disorganized fashion.

34. Fig: Pleomorphism

35. Fig: Atypical Mitosis

36. Dysplasia Dysplasia means “disordered growth.” Dysplasia is the loss of uniformity of the individual cells and loss of their architectural orientation. Dysplasia may be a precursor to malignant transformation. but it does not always progress to cancer.

37. Dysplasia Dysplastic cells may exhibit pleomorphism and large hyperchromatic nuclei with a high nuclear-to- cytoplasmic ratio. Mitotic figures are more abundant than in the normal tissue and may be seen at all levels including surface epithelial cells.

38. Fig: Dysplasia

39. Uterine Cervix dysplasia (CIN/ Cervical intraepithelial neoplsia) CIN –I: When the dysplastic cells involves lower one third of the epithelium (Mild dysplasia). CIN –II: When the dysplastic cells involves lower two thirds of the epithelium (Moderate dysplasia). CIN –III: When the dysplastic cells involves almost full thickness of the epithelium (severe dysplasia).

40. Cervical dysplasia classification

41. Carcinoma in Situ (CIS) When dysplastic changes are marked and these atypical dysplastic cells involve the full thickness of the epithelium it is called carcinoma in situ. Carcinoma in situ is limited to the basement membrane and do not cross the basement membrane.

42. Carcinoma in Situ (CIS) Carcinoma in Situ (CIS) is a malignant condition but the malignant cells does not cross the basement membrane. Once the tumor cells cross the basement membrane, it is called invasive carcinoma. Management of CIS is same like invasive carcinoma.

43. Fig: Carcinoma in Situ

44. Invasion and Metastasis of tumor

45. Invasion All benign tumors grow as cohesive masses that remain localized. Benign tumors lack the capacity to infiltrate, invade or metastasize to distant sites. Malignant tumors always invasive and metastasis occurs.

46. Metastasis Metastasis is the spread of a tumor to sites that are discontinuous with the primary tumor site. Metastasis marks a tumor malignant. The invasiveness of cancers permits them to penetrate blood vessels, lymphatics and body cavities, causing distant spread (Metastasis) .

47. Pathways of metastasis Pathways of metastasis are : 1.Lymphatic spread (Usually Carcinoma) 2.Haematogenous spread (Usually Sarcoma) 3. Direct seeding of body cavities or surfaces (Krukenberg tumor)

48. Fig: Metastasis

49. Fig: Metastasis

50. Lymphatic Spread (LC) Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas. The lymphatic spread involves deposition of cancer cells in the draining lymphnodes. Involvement of lymph nodes is important for assessing course of the disease and selecting suitable therapeutic strategies.

51. Hematogenous Spread (HS) Hematogenous spread is typical route for metastsis of sarcoma. The liver, the lungs, bone marrow are most frequently involved in hematogenous metastasis.

52. Seeding of Body Cavities and Surfaces Peritoneal cavity mostly involved in seeding pathway but pleural, pericardial, subarachnoid spaces may also involved. Example: i . Krukenberg tumor of ovary: when GIT cancer metastasis in the ovarian surface. ii. Pseudomyxoma peritonei : When Mucous secreting carcinoma of appendix fill the peritoneal cavity with gelatinous neoplastic mass.  

53. Sentinel lymphnode A sentinel lymph node is the first draining lymphnode that receives lymph flow from the primary tumor. Sentinel node mapping is done by injection of radiolabeled tracers or colored dyes in to the tumor lymphatics. Skip metastasis: Metastasis bypassing the adjacent or first draining lymph node.

54. Clinical Aspects of Neoplasia And Diagnosis of Cancer

55. Clinical Aspects of Neoplasia The importance of neoplasms lies in their effects on patients. Effects on the patients are: i . Cancer Cachexia. ii. Local and Hormonal Effects. iii. Paraneoplastic Syndromes.

56. Cancer Cachexia Progressive loss of body fat and lean body mass in cancer bearing patient called cancer cachexia. Profound weakness, anorexia and anemia. Elevated basal metabolic rate. And evidence of systemic inflammation.

57. Local and Hormonal Effects A small pituitary adenoma, although benign can compress and destroy the surrounding normal gland and thus lead to serious hypopituitarism. A benign beta-cell adenoma of the pancreatic islets may produce sufficient insulin to cause fatal hypoglycemia.

58. Paraneoplastic syndrome Some cancer-bearing individuals develop signs and symptoms: that cannot be explained by the anatomic distribution of the tumor or by the production of hormones from the tumor is known as paraneoplastic syndrome .

59. Example of paraneoplastic syndrome: Clinical syndrome Underlying cancer Cushing syndrome Small cell carcinoma of lung. Pancreatic carcinoma Hypercalcaemia Squamous cell carcinoma of lung Breast carcinoma Renal carcinoma Polycythaemia Renal carcinoma Hypoglycemia Ovarian carcinoma Fibrosarcoma

60. Grading and Staging of Tumors

61. Grading of cancer Grading of a cancer is based on the degree of differentiation of the tumor cells. Grading correlates with the neoplasms aggressiveness. Grading of cancer are classified as grade I to grade IV with increasing anaplasia (well to poorly differentiated).

62. Staging of cancer The staging of cancer is based on: 1. The size of the primary lesion. 2. Its extent of spread to regional lymph node. 3. The presence or absence of blood-born metastasis. Two staging system are in use, Union for International Cancer Control (UICC) and the American Joint Committee (AJCC) on cancer staging.

63. Staging of cancer The staging of tumor is very important for treatment strategies and for the evaluation of prognosis of the tumor. Two staging system are in use: i . Union for International Cancer Control (UICC). ii. The American Joint Committee on cancer staging (AJCC).

64. Staging of cancer The UICC employs TNM system: T for size of the primary tumor. N for regional lymph node involvement. M for metastasis. In general, staging has proved to be of greater clinical value than grading.

65. Laboratory diagnosis of cancer

66. Laboratory diagnosis of cancer 1.Histologic and Cytologic method: 1) Biopsy followed by Histopathology (2) Fine Needle aspiration cytology (FNAC) 3) Cytologic smear (Cervical smear). 2.Molecular diagnosis. 3.Tumor marker.

67. Histologic method Histologic method is the biopsy followed by histopathology. Biopsy is either excitional or incisional and is done by surgeon. Histopathology is the test for the diagnosis of the tumor.

68. Cytologic method 1. Fine needle aspiration cytology (FNAC): It is a less invasive, less expensive, reliable and quick method of diagnosis. It may be : 1) Immage guided (2) Non- immageguided. 2. Pap smear. 3. Brush cytology. 4. Imprint cytology 5. Cytology of body fluids.

69. Molecular diagnosis Molecular methods are not the primary modality of cancer diagnosis: 1) Gene diagnosis and diagnosis of translocation in certain haematopoietic malignancy (CML). 2) Certain genetic alteration are associated with poor prognosis. 3) Diagnosis of hereditary predisposition.

70. Tumor marker Tumor marker are tumor-associated enzymes, hormones and proteins found in blood for detection of the presence of a tumor. Tumor marker cannot confirm the diagnosis of cancer. For the diagnosis of a tumor histopathology test should be done.

71. Tumor marker Its main utility is to support the diagnosis. Some tumor marker are also of value in determining prognosis of treatment of tumor. Prognostic indicator like after prostatectomy in prostatic carcinoma the level of PSA becomes normal, indicating no residual tumor.

72. Some selected tumor markers Tumor Marker Associated cancer α - Fetoprotein Liver cell cancer Carcinoembryonic antigen (CEA) Carcinoma of colon, Pancreas, Stomach Prostatic specific antigen (PSA) Prostate cancer CA- 125 Ovarian cancer

73. Tumor Immunity The tumor cells can be recognized as foreign and eliminated by the immune system. A normal function of the immune system is to constantly scan the body for emerging malignant cells and destroy them, which is called immune surveillance.

74. Mechanisms of tumors resistance to immune system i . H igh variability of tumor cells and low expression of tumor antigens . ii. S ialylation . iii. T umor cells do not provide costimulus signals →T lymphocyte anergy . iv. P roduction of factors inactivating T lymphocytes v. E xpression of FasL → T lymphocyte apoptosis . vi. I nhibition of the function or durability dendritic cells (NO, IL-10, TGF -ß).

75. Evidence for tumor immunity The presence of lymphocytic infiltrates around tumors. Reactive changes in lymph nodes draining sites of cancer. Direct demonstration of tumor-specific T cells and antibodies in patients, which protects against cancer.

76. Evidence for tumor immunity Response of advanced cancers to therapeutic agents that act by stimulating latent host T-cell responses Increased cancer risk in patients with immunosuppression and immunodeficiency.

77. Thank You ALL