Neoplastic diseases of the breast CYT 23.03.21.pptx

Both malignant and benign lesions

1. Neoplastic diseases of the breast Hawa Nalwoga

2. Outline Part 1 Normal breast Common lesions Breast cancer Other neoplasms Part 2 C ytology of the breast

3. breasts consist of a group of modified sweat glands develop from 15–25 down-growths of the epidermis The first solid cords develop a lumen and become the major (segmental) ducts each of which opens separately at the nipple Each segmental duct gives rise to the branching duct system of a segment of breast tissue At puberty the duct system proliferates Lobules bud from subsegmental ducts to form physiologically functional terminal duct lobular units composed of acini and intralobular stroma The normal breast

4. interlobular stroma connective tissue between the terminal duct lobular units: is less cellular and more densely collagenous becomes infiltrated with fatty tissue during puberty accounts for most of the enlargement of the breast at puberty ducts and ductules are lined by a two-layered epithelium an inner layer of cuboidal or columnar epithelial cells an outer discontinuous layer of smaller , contractile, myoepithelial cells The normal breast

5. Terminal duct-lobular unit ETD = Extralobular terminal duct lTD =intralobular terminal duct Diagrammatic representation of TDLU

6. The normal breast

7. Normal breast Most of the breast is composed of stromal tissue, largely mature adipose and fibrous tissue. Within this lie the physiologically & pathologically important breast epithelial structures, from which most breast lesions are derived lobules form well-defined islands of small tubular structures ( acini ) (e.g. lower left) surrounded by intralobular stroma ducts are lined by a double layer of inner cuboidal or columnar-shaped epithelium over a layer of myoepithelial cells (centre)

8. Breast Pathology Developmental abnormalities Benign breast lesions Benign tumours of the breast Malignant tumours of the breast Breast cancer Other malignant tumours The male breast

9. The most common benign breast lesions Infections Acute pyogenic mastitis/abscess Non-infectious inflammatory lesions Duct ectasia Fat necrosis Non-neoplastic Fibrocystic change Sclerosing lesions: sclerosing adenosis Radial scar/complex sclerosing lesion Hamartoma Benign tumours Fibroadenoma Papilloma Phyllodes tumour

10. Malignant tumours of the breast

11. most common malignant tumour of the breast is an adenocarcinoma generally referred as breast carcinoma or breast cancer Arises from the glandular epithelial component of the breast Other breast malignancies are rare sarcoma lymphoma Malignant tumours of the breast

12. In Uganda Breast cancer incidence is increasing rapidly 11:100,000 in 1961 to 31:100,000 in 2006 Peak age: 30-39 years Screening services are unavailable 2 nd main cause of cancer-related deaths among women after cervix excluding KS BC treatment guidelines were launched in 2000 revised 2008 Overrepresented by the aggressive phenotypes BC in Uganda highlights

13. Age distribution of BC in Uganda Age Frequency Percentage <19 4 1 20-29 61 8 30-39 156 21 40-49 200 27 50-59 150 20 60-69 92 13 70-79 52 7 80-89 16 2 90-99 2 Total 733 100

14. Breast cancer incidence rates: Uganda

15. Breast cancer epidemiology BC is the most common of female cancers worldwide incidence and mortality of BC are high and remarkably constant in most developed countries BC may occur at any age rare before age 25 years most common between 40 and 70 yrs in the DC incidence of breast ca , increases with age increase occurs earlier than for most cancers most rapid between the ages of 30 and 50 years more slowly to a maximum in old age

16. incidence of breast cancer is 4 – 7 times higher in the US and Europe than in other countries rates are rising worldwide and by 2020 it is estimated that 70% of cases will be in developing countries change in incidence likely stems from adoption of Western social lifestyles: delayed pregnancy fewer pregnancies decreased breastfeeding Breast cancer epidemiology

17. About 50 % upper outer quadrant of the breast greatest proportion of breast parenchymal tissue remainder equally distributed in the rest of the breast main presents as a palpable mass all lumps in the breast are regarded as possibly malignant until proved otherwise Regardless of age of the patient Ca. in the axillary tail may mimic an enlarged LN all breast masses should be investigated definitive diagnosis made by FNAC, or needle-core biopsy Triple assessement : BC treatement guidelines for Uganda Breast cancer clinical presentation

18. Clinical presentation of breast disease

19. No single causal agent has been found for breast ca. predisposing factors have been identified strongest aetiological factor is a positive family history definite increased risk if a female relative i.e. mother, maternal grandmother, or sister Genetic predisposition: very high incidence inherited cases account for only 5–10% of BC Several genes have been implicated E.g. Breast cancer-associated genes 1 ( BRCA1 ) and BRCA2 autosomal dominant inheritance Aetiology : breast cancer genetics

20. major known susceptibility genes for familial breast cancer are all tumor suppressor have normal roles in DNA repair and maintenance of genomic integrity BRCA1 , BRCA2 , TP53 , and CHEK2 —genes Mutations in BRCA1 and BRCA2 are responsible for 80 % to 90% of “single gene” familial breast cancers and about 3% of all breast cancers BRCA1 is on chromosome 17q21 and BRCA2 is on chromosome 13q12.3 and both are large genes Aetiology : breast cancer genetics

21. Aetiology : breast cancer genetics BRCA1 mutation: lifetime risk of 85% of developing BC BRCA1 mutation implicated in ≈45% of cases BRCA2 mutation accounts for 40 % of cases BRCA2 is associated with hereditary BC in males Other genes account for about 5% of hereditary BC TP53 mutation on the short arm of chromosome 17 also seen in sporadic breast cancer Li– Fraumeni syndrome is a cancer family syndrome with a germline mutation in TP53 causing BC autosomal dominant inherited condition associated with <5% of familial breast cancers

22. Factors affecting the risk of breast carcinoma Personal risk factors Female Older age High risk Strong FH of BC e.g. relative with cancer at young age bilateral carcinoma Moderate risk Born in the USA northern Europe Lower risk Any first-degree relative with breast ca. Postmenopausal obesity marked weight gain in adult life Early menarche: < 12 yrs Late menopause Late first pregnancy: After 28yrs nulliparity

23. Factors affecting the risk of breast carcinoma Lower risk Prolonged use of hormone replacement therapy combined oestrogen and Progesterone preparations Prolonged OCP use Moderate alcohol intake Histological risk factors Atypical hyperplasia – ductal or lobular moderate risk: 4x Usual epithelial hyperplasia low risk: 2x

24. Classification of breast cancer TNM criteria WHO criteria Histopathological classification (histologically) Two broad types Carcinoma in situ Invasive breast cancer Molecular classification Gene expression studies IHC biomarkers : ER, HER2, PR, EGFR, CK5/6

25. TNM criteria

26. Histologic types In situ carcinoma Ductal carcinoma in situ (DCIS) Comedocarcinoma (in situ) papillary carcinoma Other forms Lobular carcinoma in situ (LCIS) Invasive carcinoma Invasive ductal carcinoma Cytoarchitectural variants Spread-related variants Invasive lobular carcinoma (LLC) Mixed ductal and lobular carcinoma Undetermined (unclassified ) carcinoma Microinvasive breast carcinoma

27. Invasive ductal carcinoma Spread-related variants Inflammatory carcinoma Paget's disease Cytoarchitectural variants Classic (NOS) invasive ductal carcinoma Tubular carcinoma . Cribriform carcinoma Mucinous carcinoma Medullary carcinoma Invasive papillary ca Apocrine carcinoma Metaplastic carcinoma

28. Malhotra, G.K., et al., Cancer Biology & Therapy, 2010. 10: 955-960.

29. Carcinoma in situ Ca. arises from the lining epithelium of the duct system related to the terminal duct lobular unit tumour cells remain confined within the duct system for a variable length of time, in the form of DCIS before breaching the basement membrane To invade the breast stroma cytological changes of malignancy are present in the epithelial cells of a carcinoma in situ But the basement membrane remains intact no invasion is seen

30. Carcinoma in situ Conventionally two types are recognized: ductal and lobular But the name lobular carcinoma in situ is misleading predictors to accurately determine the risk of progression to invasion are lacking Further research is required to define not all cases of DCIS will develop invasive ca. within the patient’s lifetime distinction between in situ and invasive ca is extremely important

31. Ductal carcinoma in situ frequency of DCIS is ≈ 2–5% of in symptomatic patients with breast cancer disease presents as a palpable mass in most cases Paget’s disease of the nipple described by Sir James Paget in 1874 DCIS extends along the major ducts as far as the nipple neoplastic cells enter the deeper layer of the epidermis spread within it through the nipple and areola affected skin shows reactive inflammatory changes in the dermis Producing a characteristic eczematous appearance

32. DCIS is usu. confined to one duct system in the breast Small tumours now identified mammographically associated microcalcification Increased breast-conserving therapy complete local excision tumour -free wide margins typically with postoperative radiotherapy Adequate primary therapy has excellent long-term prognosis 10-year survival rate of >95 % Ductal carcinoma in situ

33. Invasive carcinoma Histological classification of invasive breast ca. # different morphological types ca. are recognized different microscopic features Some tumours may have mixed appearances Invasive c arcinoma of no special type (NST) (NOS) is the most common (> 50 %): ≈ 75% of all cases Invasive lobular carcinoma is the second most common type (10 – 15%) Tubular carcinoma is more common in screen-detected Medullary-like , mucinous, invasive cribriform , metaplastic and a variety of other types are rare

34. Invasive Carcinoma of No Special Type ( NST) form a firm, often hard, moderately defined lump usu measuring 10–40 mm in diameter Cut like an unripe pear traditionally referred to as ‘ scirrhous ’ ca. composed of cords and sheets of large epithelial cells Infiltrating between dense bands of collagen in a disorganized fashion cells vary in size and shape some tubule formation may be seen mitoses are usually present there are no special morphological features

35. Invasive Lobular Carcinoma Variants of ILC have been described tumours may have a scirrhous macroscopic appearance similar to NST ca. more freq they are softer with an ill-defined outline more difficult to palpate clinically and to identify macroscopically Patients have a relatively high freq of bilateral ca. composed of small to moderately sized, regular epithelial cells with infrequent mitoses

36. Invasive lobular carcinoma linear cords of cells infiltrate diffusely as discrete or single cells within fine collagen bands: ‘ single file’ pattern discohesive growth pattern reflects loss of function of the E-cadherin–catenin cell adhesion system

37. Tubular Carcinomas uncommon in symptomatic series ≈ 2 % of all cases prevalence higher in screened populations ≈15 % often small impalpable lesions detected mammographically as spiculate masses less than 10 mm in diameter, firm, and have an irregular star-shaped, stellate outline elongated tubular structures that radiate through a cellular fibroblastic stroma

38. Tubular Carcinomas tubules are lined by a single layer of relatively regular epithelial cells without an associated myoepithelial layer central luminal spaces present Mitoses are infrequent Occasionally a mixture of tubular and invasive cribriform structures is seen

39. Invasive breast carcinoma of no special type (NST) Invasive lobular carcinoma: linear cords of ca cells ‘single files’ Invasive carcinoma

40. Tubular carcinoma: formed from elongated tubular structures infiltrating cellular fibroblastic stroma Invasive carcinoma

41. Routes of spread Breast carcinomas may spread by three ways: direct infiltration of skin, skeletal muscle, and chest wall locally advanced BC via the lymphatic system to axillary and internal mammary LNs: metastatic ca may be found in axillary LNs in up to 40% of ‘ operable’ tumours internal mammary LNs: esp inner quadrant primary via haematogenous spread: distant metastasis lungs , bone, and liver

42. Prognosis of invasive carcinoma Prognostic factors are applied to identify how a tumour is likely to behave in terms of tumour recurrence and patient survival which patients require subsequent systemic therapies most important prognostic factors for are Lymph node stage Histological grade Tumour size

43. Prognosis of invasive carcinoma Lymph node stage stage 1: node negative stage 2 : one to three nodes involved stage 3: four or more positive lymph nodes axillary LNs are excised and examined histologically the number the level of locoregional lymph nodes the more nodes involved and the higher the level in the axilla, the worse the prognosis

44. Histological grade determined by three histological features combination : amount of gland (tubule ) formation size of the tumour cells and degree of nuclear pleomorphism mitotic count Three grades are defined: From grade 1 to grade 3 grade 1: much tubule formation, little pleomorphism , and low mitotic counts Grade 3: little or no tubule formation, marked pleomorphism , and high mitotic counts Prognosis of invasive carcinoma

45. Histological grade grade 1 tumours : 85% of females are alive 10 years after diagnosis grade 3 tumours only 35% Tumour size size at diagnosis is important the smaller the tumour the better the survival Prognosis of invasive carcinoma

46. Prognosis of invasive carcinoma Histologic types special tumour types such as tubular and mucinous carcinomas carry an excellent long-term survival infiltrating lobular ca. has an intermediate prognosis infiltrating NST ca. has a relatively poor prognosis lymph node stage and the histological grade of each tumour are the two most important predictors of survival for patients with invasive breast cancer Tumour size is the third most valuable feature

47. Nottingham Prognostic Index combines these features incorporates the value of each feature into a single score provides the best prediction of tumour behaviour for each female Prognosis of invasive carcinoma

48. Predictive factors in invasive b reast ca predictive factors are analysed to determine which treatments are most likely to benefit the individual oestrogen receptor (ER ) Assessment of ER protein in tumour samples provides a good prediction of likely response to endocrine therapy favourable response is unlikely if ER negative ER status is routinely examined in tissue sections from all invasive breast cancers using IHC about 80 % of cases are positive But they are racial differences

49. Predictive factors in invasive b reast ca oestrogen receptor (ER ) positivity tamoxifen or aromatase inhibitors have been used successfully in the treatment of HR positive metastatic disease high-risk operable disease

50. human epidermal growth factor receptor 2 (HER2) expressed in ≈ 15 % of primary invasive breast ca. Positivity associated with a poorer patient outcome ca. that overexpress the protein the tumour cells or have amplification of the gene Can respond to targeted drug therapy using monoclonal antibodies against the HER2 protein Herceptin ( trastuzumab ) is efficacious in metastatic cancer early breast cancer ( without metastasis ) Predictive factors in invasive b reast ca

51. human epidermal growth factor receptor 2 (HER2) All invasive breast ca. are now tested for presence of excess protein on the cell surface by IHC amplification of the gene by fluorescent or chromogenic in situ hybridization Predictive factors in invasive b reast ca

52. evolving molecular tests MammaPrint test MammaPrint test may eventually be widely used to help make treatment decisions based on the cancer's risk of coming back (recurrence) within 10 years after diagnosis The Oncotype DX figure out a woman's risk of early-stage, ER-positive breast cancer coming back (recurrence ) how likely she is to benefit from chemotherapy after breast cancer surgery Predictive factors in invasive b reast ca

53. Diagnosis Triple assessment Clinical examination Mammography Pathological assessment Cytology Needle core biopsy Open biopsy and frozen section

54. Other malignant tumours of the breast Uncommon breast tumours Apocrine Carcinoma Adenoid Cystic Carcinoma Lymphomas: Non-Hodgkin Lymphoma Sarcoma Metastatic tumors

55. Non-Hodgkin lymphoma can involve the breast either as a primary neoplasm or secondary to systemic disease that also involves lymph nodes. The breast is an unusual primary site of lymphomas The majority have a B-cell phenotype Most subtypes are diffuse large B-cell lymphomas (DLBL ) follicular center cell lymphomas lymphomas of mucosa-associated lymphoid tissue (MALT ) Its distinction from carcinoma preoperatively is important in order to avoid unnecessary surgery Lymphomas

56. Lymphomas Involvement of the breast in disseminated lymphomas & in myeloid leukaemia is more common young females with Burkitt’s lymphoma may develop bilateral breast involvement The cytologic features are identical to those of lymphomas that arise in lymph nodes. Rarely plasmacytoma or myeloma can also involve the breast with typical findings. Disseminated lymphoma, chronic myeloid leukaemia, and myeloma may rarely present with breast masses before disease elsewhere becomes evident .

57. Sarcomas Primary sarcomas of the breast are rare & include: liposarcoma , leiomyosarcoma , rhabdomyosarcoma , hemangiopericytoma , angiosarcoma osteosarcoma and fibrosarcomas The most common is angiosarcoma . association with radiotherapy have been described after irradiation following wide local excision for breast cancer in the overlying subcutis Features are similar to the findings on soft tissue aspiration

58. Summary Risk factors for BC include female sex, increasing age , northern European or American descent, family history of BC, uninterrupted menses , and atypical epithelial proliferative disease

59. Summary Ductal carcinoma in situ is a precursor of invasive tumour often identified mammographically as microcalcifications Invasive BC is heterogeneous microscopic in appearance and variable prognosis most important features in predicting prognosis are lymph node stage histological grade tumour size Diseases of the male breast are rare most common abnormality is gynaecomastia (hypertrophy) due to changes in sex hormone levels

60. Cytology of breast lesions

61. Types of samples Fine-needle Aspiration cytology Nipple Discharge , Nipple Aspiration, and Ductal Lavage Core needle biopsy Lumpectomy Mastectomy

62. Fine-needle aspiration (FNA) procedure

63. 3/24/2021 Educational material Fine needle aspiration

64. 3/24/2021 Educational material

65. Cytology of the breast lesions two methods can used to obtain cytologic material aspiration of nipple secretion aspiration of the lesion with a fine needle Nipple secretion aspiration cytology is, of limited use: Diagnosis: clinically or mammographically detectable lesion screening purposes Some carcinomas will undoubtedly be found # of false-positive results is so high as to render this technique of only marginal value use as a screening procedure: negative cytologic diagnosis may give a false sense of security and delay recognition of the carcinoma

66. F ine needle aspiration The average sensitivity is ≈ 87% the specificity close to 100 % Positive predictive value nearly 100 % Negative predictive value between 60% and 90% accuracy of breast FNA is highly operator dependent Sensitivity for malignancy is high ranges from 65% to 98% specificity ranges from 34% to 100% in a variety of clinical environments

67. False + ve results are uncommon : % - 2% of cases False-suspicious results are higher: range 1 % to 13 % sensitivity of FNA for palpable and non palpable malignant lesions is comparable False-negative results occur because of errors in sampling, interpretation, or both F ine needle aspiration

68. satisfactory specimens are more likely when pathologists rather than physicians perform the FNA practice makes perfect, and the one with more FNA experience obtains the more accurate result The use of p63 immunostaining as an adjunct increase the accuracy of FNA Differentiates the well-differentiated ca from benign lesions FNA material is also suitable for HR determination , kinetic studies and oncoprotein expression F ine needle aspiration

69. FNA of the breast has its limitations Although generally quite sensitive in detecting ductal ca , it cannot distinguish between an invasive ductal carcinoma and a ductal carcinoma in situ cannot identify presence of lymphatic or vascular invasion diagnosis of lobular ca and tubular ca requires considerable experience in FNA interpretation FNA is less than ideal for some types of breast carcinoma Ca associated with very extensive fibrosis intraductal carcinoma tubular and cribriform carcinoma in general the very small tumours

70. technique should be used to supplement, and not to compete with , histologic examination negative or inconclusive cytologic findings can not definitive diagnosis if there is clinical suspicion of a malignancy FNA procedures may lead to mechanical displacement of epithelium, hemorrhage , necrosis, and other changes The former can mimic stromal and vascular invasion frequency of this complication is probably related to the type of needle used and the skill of the operator Considerable discrepancies exist between the performances of laboratories FNA of the breast has its limitations

71. Reporting terminology General categories for breast fine-needle aspiration negative for malignant cells (no malignant cells seen) Atypical Suspicious positive for malignant cells non-diagnostic (inadequate or unsatisfactory) recommended the use of general categories with the implied probability or risk of malignancy Is followed by a specific diagnosis

72. Non-diagnostic specimens contain too few well-preserved cells to permit an adequate evaluation fewer than six epithelial cell clusters of at least 5 to 10 cells or less than 10 intact bipolar cells per 10 medium-power fields (×200) A negative (benign) diagnosis should be reserved for an adequate specimen with a minimum of five to six well-preserved cell groupings A negative FNA result is more reliable when a specific diagnosis corroborates a clinical and radiological impression Reporting terminology

73. atypical category used for a specimen with a low probability of malignancy is unavoidable because of the significant overlap in the cytologic features of some benign and malignant entities It generally requires further biopsy assessment suspicious diagnosis is used for lesions that are probably malignant, but the atypical cells are too few, too poorly preserved, or too obscured by blood or inflammation for a definitive diagnosis or when the findings suggest a type of breast ca with minimal cytologic atypia , such as lobular ca , tubular ca , or papillary ca surgical biopsy should follow any specimen deemed suspicious Reporting terminology

74. Positive diagnoses are reserved for specimens with unequivocal features of malignancy . confirmation of all positive results with frozen section before definitive surgery is wise some surgeons proceed directly to mastectomy or wide local excision Reporting terminology

75. Evaluation of the specimen

76. Suspicious for malignancy Suspicious for malignancy ( comedo -type ductal carcinoma in situ [DCIS]). The cells are loosely cohesive with marked nuclear pleomorphism , nucleoli, and a dirty background. Such specimens cannot be distinguished from invasive carcinoma ( Papanicolaou stain)

77. invasive ductal carcinoma The specimen is cellular and the cells are present both singly and in loosely cohesive clusters ( Papanicolaou stain).

78. A major criterion for the diagnosis of ductal carcinoma is hypercellularity . Even at lower power, the nuclear atypia is also prominent (Diff- Quik stain ) invasive ductal carcinoma

79. invasive ductal carcinoma

80. Many of the isolated cells of ductal cancers are comet shaped, with a nucleus that protrudes from the cytoplasm. Whether or not the nuclear atypia is marked, a protuberant nucleus suggests carcinoma ( ThinPrep Papanicolaou stain) invasive ductal carcinoma

81. Note the pronounced nuclear pleomorphism , multinucleated atypical cells, and nuclear atypia with both Diff- Quik , left , and Papanicolaou , right, stains. invasive ductal carcinoma

82. The tumor cells are buried in a background of marked acute inflammation. In samples with abundant acute inflammation, a careful search must be conducted to exclude malignant cells ( Papanicolaou stain) invasive ductal carcinoma

83. mucinous carcinoma At low power, numerous tightly cohesive clusters dispersed in a mucinous background are noted ( Papanicolaou stain)

84. mucinous carcinoma At higher power, the lowgrade round, regular nuclei are noted ( Papanicolaou stain )

85. invasive lobular carcinoma

86. left , A loose single-file arrangement is apparent. right, Large solitary intracytoplasmic vacuoles are present , giving a signet ring cell appearance ( Papanicolaou stain). invasive lobular carcinoma

87. Medullary carcinoma hypercellular smears, numerous isolated cells and loose clusters many lymphocytes and some plasma cells

88. markedly enlarged, vesicular nucleus prominent and often irregular macronucleolus numerous mitoses granular scarce to abundant cytoplasm Medullary carcinoma

89. Thank you very much for your attention