1.Prognostic factors in carcinoma breast

2. Carcinoma of breast is most common malignancy and is the leading cause of death in women. A woman who lives to age 90 has a one in eight chance of developing breast cancer. 3. WHO classification of carcinomas of breast: Noninvasive- Intraductal carcinoma. With Pagets disease. Lobular carcinoma in situ. Invasive- Invasive ductal carcinoma. With Pagets disease. Invasive ductal carcinoma with a predominant intraductal component. 4. Invasive lobular carcinoma. Medullary carcinoma. Mucinous carcinoma. Invasive papillary carcinoma. Tubular carcinoma. Adenoid cystic carcinoma. Secretory (juvenile) carcinoma. Apocrine carcinoma. Carcinoma with metaplasia. Inflammatory carcinoma. 5. Age Tumours size. Site. Tumour configuration or shape. Cytoarchitechtural type. Presence or absence of invasion. Extent of ductal carcinoma in situ associated with invasive cancers. Grading. Axillary lymph node metastases. Local recurrence. Sentinel lymph node. 6. Lymphatic invasion. Vascular invasion. Skin invasion. Nipple invasion. Types of margins. Tumour Necrosis. Stromal reaction. Mononuclear inflammatory cell infiltrate. Perineural invasion. Microvessel density. Elastosis. 7. Pregnancy and oral contraceptives. BRCA1 status. Hormone receptors. Keratin staining pattern CEA staining pattern. Vimentin staining pattern. Cathepsin D. P53 and nm23. Bcl2 and cyclin D1. Cell proliferation. Cell kinetics and DNA ploidy. 8. Patients age: Women < 50 years Best prognosis. > 50 years- Bad prognosis. < 35 years- Same as older patients Higher risk of recurrence. Distant metastases. 9. Size: One of the strongest predictors of dissemination and rate of relapse in node negative Ca breast. Inverse correlation with survival. Size determination has a greater prognostic significance when measured microscopically than grossly . Tumor size can be assessed macroscopically in the fresh state (in three planes) and subsequently confirmed following fixation. 10. Size is one of the two criteria's for the definition of minimal breast carcinomas which includes all in situ carcinomas regardless of size and invasive carcinomas of 1 cm or less in diameter. < 10 mm in diameter/ Large in situ component- Vernier scale. 9-10 mm- Minimally invasive carcinoma with good prognosis. < 15 mm- good prognosis. The frequency of axillary lymph node metastases in small carcinomas is approximately 15-20% in contrast to >40 % in tumours measuring > 15mm in diameter. 11. In tumours having both an in situ and invasive component , the size of latter is the better predictor than is the total tumour size. Women with node negative carcinomas 2cm in diameter present with lymph node metastases. 12. Site: No relationship found between prognosis and quadrant location. However, in one recent large study it was found that medial location of the tumour was associated with 50% risk of systemic relapse and tumour death when compared with lateral location. 13. Tumour configuration or shape: Stellate ( Spiculated, infiltrative, radial and serrated) Circumscribed (Rounded, pushing, encapsulated, smooth) Mixed contour. Carcinomas having circumscribed margins grossly or mammographically may exhibit an invasive growth pattern microscopically. Infiltrative tumours tend to be larger and are more likely to have nodal metastases than those with circumscribed margins. Tumours with stellate configuration with focal necrosis- Poor prognosis. 14. Cytoarchitechtural type: No significant prognostic difference between invasive ductal and invasive lobular carcinoma. Favourable prognosis- Tubular carcinoma, medullary carcinoma, cribriform carcinoma, pure mucinous carcinoma, papillary carcinoma, adenoid cystic carcinoma and juvenile carcinoma. Bad prognosis: Signet ring carcinoma. Aggressive than ductal carcinoma with little difference in survival rates- Squamous cell carcinoma, metaplastic carcinoma and carcinomas with neuroendocrine features. 15. Presence or absence of invasiveness: Single most important prognostic determinator in Ca breast. In situ- Curable with mastectomy. Tumours of ductal type that have both in situ and invasive component , a relationship exists between the proportion of the invasive component and the probability of nodal metastases. Amount of in situ component correlates with the incidence of multicentricity and indirectly with the probability of occult invasion. 16. Extent of ductal carcinoma in situ associated with invasive cancers: Infiltrating carcinoma with prominent DCIS within the confines of the invasive tumour or adjacent to it or cases of DCIS with foci of invasion. Presence of an extensive intraductal component is a prognostic factor for local recurrence in the breast in patients treated with conservative surgery and radiation therapy when the status of excision margin is unknown. 17. Some studies have shown that even in patients with negative margins the amount of DCIS near the margins is predictive of breast recurrence. 18. Microscopic grade: Higher grade- Distant metastases and poor survival rate. May provide information with regard to response to chemotherapy. Several studies have suggested that the presence of high histologic grade is associated with a better response to certain chemotherapy regimens than low histologic grade. Nottingham, Modification of the Scarff-Bloom-Richardson histologic grading system by Elston and Ellis. Combines nuclear grade, tubule formation and mitotic rate. 19. Glandular or tubule formation- Score 1. > 75% of tumour area forming glandular or tubular structures. 2. 10-75% of tumour. 3.< 10 % of tumour. 20. Nuclear pleomorphism- Score1- Nuclei small with little increase in size in comparison with normal breast epithelial cell. Regular outline. Uniform nuclear chromatin. Little variation in size. 21. Score 2- Cells larger than normal with Open vesicular nuclei. Visible nucleoli. Moderate variability in both size and shape. Score 3- Vesicular nuclei often with prominent nucleoli. Marked variation in size and shape. Occasionally very large and bizzare forms. 22. Mitotic count. Depends on number of mitosis per high power fields. Size of high power fields is very variable so it is necessary to standardize the mitotic count. Field diameter of the microscope is measured using the stage graticule or Vernier scale and the scoring categories are read from following table. 23. Leitz Ortholux Nikon Leitz Diaplan Objective X 25 X 40 X40 Field diameter (mm) 0.59 0.44 0.63 Field area (sq mm) 0.274 0.152 0.312 Mitotic count 1 point 0-9 0-5 0-11 2 points 10-19 6-10 12-22 3 points > 20 > 11 > 23 24. Overall grade: Scores are added together and are assigned grades as Grade 1- scores 3-5. Grade 2- scores 6 or 7. Grade 3- scores 8 or 9. 25. Grade 1 carcinomas- Pure tubular and invasive cribriform carcinomas. Grade 2- Infiltrating lobular carcinomas. Minority of lobular carcinomas fall into grade 1 or 3. Grade 3- Medullary carcinomas. 26. H&E stained section of a well differentiated breast cancer with a tubular pattern, little nuclear pleomorphism and occasional mitosis (Score 1+1+1=3). This is a Grade 1. 27. Large foci of invasive breast cancer with no tubules (Score 3). Nuclei show moderate variation in size and shape (Score 2). No mitotic figures are noted (Score 1). This is another moderately differentiated invasive ductal 28. This invasive ductal carcinoma forms no tubules (Score 3). Nuclei are displaying marked variation in size and shape (Score 3). Arrows point to mitoses that are seen at a rate of 10-19/ten high power fields (Grade 2). This is a poorly differentiated breast cancer 29. Combining prognostic factors: Nottingham prognostic index takes into consideration tumor size, lymph node status and histologic grade. Tumour size in cm X 0.2 + Histologic grade (1-3) + lymph node stage (1-3). Higher the value worse the prognosis. 30. Five prognostic groups- Excellent- NPI score 5.4, 15 year survival 18%. Adjuvant chemotherapy is not indicated in an excellent prognostic group and good prognostic group. Moderate prognostic group and poor prognostic group may benefit from adjuvant polychemotherapy. 31. Axillary lymph node metastases: Most important prognostic indicator. Survival rate also depends on - 1. level of axillary nodes involved 2. absolute number 3. the amount of metastatic tumour 4. the presence or absence of extranodal spread and 5. the presence or absence of tumour cells in the efferent vessels. 32. Pattern of lymph node reaction: Microscopic appearance of the regional node is an indication of the type of host response to the tumour and it relates to prognosis. Internal mammary lymph node metastases: Lower survival rate. Local recurrence: Poor prognosis. 33. Sentinel lymph node The sentinel node procedure in breast cancer was pioneered by surgical oncologist Armando Giuliano, MD at the John Wayne Cancer Institute in the 1990s. Based on the concept that if the sentinel node is negative, the other nodes of that group will also be negative in nearly all instances, whereas if its positive, the chance that there will be additional metastases in that nodal group is about one third. 34. Most breast carcinomas drain to one or two sentinel nodes. Highly predictive of the status of the remaining nodes. Biopsy can spare women the increased morbidity of a complete axillary dissection. 35. Procedure: Limphoscintigraphy is performed wherein a harmless radioactive substance is injected in the dermis over the tumour. The injected substance, Filtered Sulfur Colloid, is tagged with the radionuclide Technetium-99m. Scintigraphic imaging is usually started within 5 minutes of injection and the node appears from 5 min to 1 hour. This is usually done several hours before the actual biopsy. 36. About 15 minutes before the biopsy the blue dye is injected in the same manner. Then, during the biopsy, lymph nodes are inspected for staining and Gamma Probe or Geiger counter are used to assess which lymph nodes have taken up the radionuclide. One or several nodes may take up the dye and radioactive tracer, and these nodes are designated the sentinel lymph nodes. 37. Pitfalls: Keratin positive reticulum cells, mesothelial cell inclusions, ectopic breast tissue, traumatic displacement of breast tissue by the biopsy procedure and floater. Macrometastases: > 2 mm Micrometastases: 0.2 2 mm Isolated tumor cells: 2 mm 39. Subcapsular micrometastasis - this deposit is < 2mm on the H&E but the immuno stain for pan CK was on a section taken after cutting into the block further and measures just over 0.2mm qualifying as a micrometastasis. 40. Isolated tumor cells 41. Lymphatic vessel invasion: Important prognostic factor. With no involvement the 10 year diease survival rate- 70-80%. 1-3 positive nodes- 35-40%. > 10 poisitive nodes- 10-15%. Identifies node negative patients at increased risk for axillary lymph node involvement and adverse outcome. Increased risk of tumour recurrence. 42. Blood vessel invasion: Predominantly seen in thin walled channels and rarely in muscular blood vessels. Higher correlation with tumour size, histologic grade, tumour type, lymph node status, development of distant metastases and poor prognosis. Skin invasion: Decreased survival rate. Nipple invasion: Associated with higher incidence of axillary metastases. 43. Types of margins: Tumours with pushing margins have better prognosis than tumours with infiltrating margins. Tumour necrosis: Associated with increased incidence of lymph node metastases and decreased survival rate . Stromal reaction: Absence of inflammatory reaction at periphery have lesser degree of nodal metastases and thus better prognosis. 44. Mononuclear inflammatory cell infiltrate: Its presence has been correlated with high histologic grade. Perineural invasion: Seen in association with lymphatic vessel invasion but it has not been shown to be an independent prognostic factor. 45. Microvessel density: Invasive breast carcinomas having a prominent vascular component in the surrounding stroma are more aggressive. Microvessel density is a phenomenon independent from intratumoural endothelial cell proliferation and increase in microvessel density has also been noted in intraductal carcinoma particularly of comedo type. Elastosis: Breast carcinomas with no associated elastosis have a lower rate of response to endocrine therapy than those with gross elastosis. 46. Pregnancy and oral contraceptives: Carcinoma breast manifesting during pregnancy or lactation are generally aggressive tumour with low expression of hormone receptors and high expression of Her2/neu---Poor prognosis. No convincing evidence has found that prior use of OCPs has an effect on evolution or survival of Ca breast. 47. BRCA1 status: Risk increases if there are multiple affected first degree relatives. Mutated BRCA1- risk of developing ovarian carcinoma. Mutated BRCA2- small risk for ovarian carcinoma but it is associated more frequently with male breast cancers. BRCA1 and BRCA2 are also susceptible to colon, prostate and pancreatic cancers. 48. BRCA 1 associated breast cancers are poorly differentiated, with pushing margins, do not express hormone receptors or over express HER2/neu. BRCA1 mutation carriers- Worse prognosis if they have not received adjuvant therapy. Others: Cell cycle check point kinase gene(CHEK2) Li-Fraumeni syndrome. Muttion in p53. Cowden syndrome. Peutz-Jeghers syndrome. 49. Hormone receptor status: Estrogen stimulation of cells takes place through binding of the hormone to the estrogen receptor. Coupling the hormone receptor complex to regulatory DNA regions which initiate transcription of various genes. Production of proteins Regulation of DNA synthesis . Cell growth. 50. Estrogens stimulate tumour proliferation via growth factors as secondary messengers such as PDGF, TGF , IGF-I. G1 phase. G1 to S phase. Estrogen antgonists results in inhibition of the production of autocrine stimulatory factors thus impending tumour growth. They stimulate secretion of TGF by tumour cells which inhibits proliferation of epithelial cells. In ER positive tumours. The expression of PR, which is also estrogen regulated gives a better prediction of estrogen responsivness. 51. 70-80% of breast carcinomas express ER and are thought to arise from intrinsically ER positive luminal cells. Hormone receptor positive cancers have better prognosis than hormone negative carcinomas. ER positive ductal carcinomas are usually well to moderately differentiated and often show tubule formation. ER positive Ca- Lobular, tubular, mucinous and papillary. 52. Estrogen receptor concentration are lower in tumours of premenopausal women than in those of post menopausal women. Immunohistochemistry is used to detect estrogen receptor expression. Positive tumours show distinct nuclear staining with antibodies against this receptor. 53. HER2/neu: Controls cell growth. 20-30% of breast cancers are associated with overexpression of HER2/neu--- Poor prognosis. Trastuzumab is a humanized monoclonal antibody to HER2/neu developed to specifically target tumour cells. In clinical trails, the combination of Trastuzumab with chemotherapy have improved response in patients with carcinomas expressing HER2/neu. 54. Scoring of HER-2 immunohistochemistry: Score 0- No staining is observed or cell membrane staining is observed in less than 10% of the tumour cells. (negative). Score 1+ A faint perceptible membrane staining can be detected in more than 10% of the tumour cells. The cells are only stained in part of their membrane. (negative). Score 2+ A weak to moderate complete membrane staining is observed in more than 10% of the tumour cells. (weakly positive). Score 3+ A strong complete membrane staining is observed in more than 10% of the tumour cells. 55. Keratin staining pattern: CK17, CK 5- Worse clinical outcome. CEA staining pattern: No relation with prognosis. Vimentin staining pattern: Poor prognosis in node negative ductal carcinomas. Cathepsin D: Overexpression of CD in breast cancer is associated with high risk of recurrence and poor survival. 56. p53and nm23: Accumulation of p53 and low expression of nm23 correlates with reduced patient survival. However some studies concluded that p53 was not a reliable prognostic indicator. Loss of heterozygosity for p53- high histologic and nuclear grade. 57. Bcl-2: Long term survival in breast carcinoma and Correlates with estrogen receptor status. Cyclin D1: Over expression does not indicate prognosis. Telomerase activity: Level indicates proliferative index of breast carcinoma. 58. Cell proliferation: Can be measured by flow cytometry as the S phase fraction by thymidine labeling index, mitotic counts or by immunohistochemical detection of cellular proteins. Cyclin E content when detected is very strong predictor of survival. Tumours with high proliferation rate have a worse prognosis. 59. Cell kinetics and DNA ploidy: It reflects the growth rate and aggressivness of malignant tumours. Determined by flow cytometry. According to the DNA distribution, euploid and aneuploid tumours are distinguished. Euploid tumours- DNA of 2 or 4 fold diploid values, low S phase compartment. Aneuploid tumours: Irregular DNA expression, higher S phase rate, faster growth. 60. Major prognostic factors by American joint committee on Cancer: Stage 0- DCIS or LCIS (5 year survival rate: 92%). Stage I- Invasive carcinoma 2 cm or less in diameter (including carcinoma in situ with microinvasion) without nodal involvement (or any metastases< 0.02 cm in diameter) (5 year survival rate:87%). StageII- Invasive carcinoma 5 cm or less in diameter with up to three involved axillary nodes or invasive carcinoma greater than 5 cm without nodal involvement (5 year survival rate :75%). 61. Stage III: Invasive carcinoma 5 cm or less in diameter with 4 or more involved axillary nodes. invasive carcinoma greater than 5 cm in diameter with nodal involvement invasive carcinoma with 10 or more involved axillary nodes invasive carcinoma with involvement of the ipsilateral internal mammary lymph nodes or invasive carcinoma with skin involvement, chest wall fixation or clinical inflammatory carcinoma (5 year survival rate: 46%). 62. Stage IV- Any breast cancer with distant metastases (5 year survival rate :13%) 63. References Robbins and Cotran, Pathologic basis of disease, 7th edition. Rosai and Ackermans, Surgical Pathology, 9th edition. Steven Silverberg, Surgical Pathology and Cytopathology, 14th edition. Paul Peter Rosen, Rosens Breast Pathology, 3rd edition. Oxford textbook of Pathology.