cytology of the breast

here is the detail cytology of breast . i think it will give you a lot of informations

1. Cytopathology of breast Presenter: D r. H ayelom k Modulators: Dr,Mesele B ezabih (Pathologist, Epidemiologist, Associate professor) Dr.serka addis (year three resident)

2. OUTLINE OF PRESENTATION The normal breast Patient approach with breast disease Role of FNAC &technical considerations Inflammatory conditions fibrocystic change & hyperplasia Benign tumours and tumour Malignant breast tumours Other malignant tumours

3. Normal breast 3

4. The normal breast FNA from normal, adult breast tissue will contain variable amounts of ductal epithelial cell groups , small stromal fragments and fatty tissue. 4

5. Breast cells 1. Normal epithelial cells /Ductal Cells / Small cohesive groups; Often in Monolayer sheets The nuclei are relatively uniform, oval to round and have smooth nuclear membranes . The nuclear size is less than twice the diameter of a RBC The chromatin is fine, Evenly distributed; Nucleoli are inconspicuous & single Scanty cytoplasm 8

6. 2. Myoepithelial cells Appear as Naked , bipolar, dense, bland nuclei No clearly visible nucleoli The length of naked, bipolar nuclei is about the diameter of an RBC at the periphery of ductal sheets and groups or across the background of the smear Is a hallmark of a benign breast aspirate Tubular carcinomas and some low-grade ductal carcinomas are an exception How to differentiate from naked epithelial & stromal cells?? 12

7. Foam cells They have abundant, multivacuolated cytoplasm and relatively distinct cell borders. The cytoplasm sometimes contains various pigments or inclusions. The nuclei are bland and round to oval . Multinucleated giant foam cells also occur. Foam cells are usually associated with benign breast lesions and cysts but can also be seen in cancer . Origin ? controversy

8. Apocrine Cells Apocrine cells represent metaplasia of the lobular epithelium abundant and finely granular cytoplasm eccentrically located nuclei with fine chromatin

9. The breast in pregnancy The aspirate may be moderately or markedly cellular The cells are single and well dispersed cells and their nuclei are large Acinar cells have abundant granular or vacuolated cytoplasm that is unusually fragile Bare nuclei are common The nuclei are round and uniform with active granular or vesicular , but evenly distributed chromatin . Single prominent nucleoli → larger than in most malignant breast tumours 18

10. mass during pregnancy may be due to An uneven response to hormonal stimulation or Enlargement of a preexisting lesion such as a fibro adenoma. Lactating adenoma and galactocele can also arise de novo in pregnancy. Development of an abscess Tumours and tumour -like lesions that occur during pregnancy and lactation are usually benign. 20

11. Difference b/n male and female breast x

12. Patient approach with breast ds The cytological findings should always be evaluated in conjunction with the clinical and radiological findings ( triple assessment ) . P/E alone is ~ 70% to 90% accurate; Mammography alone,~ 85 % to 90% accurate ; FNA biopsy alone , ~ 90 % to 99% accurate Indication for biopsy after FNA Equivocal cytological diagnoses Discordant FNA and radiological results 22

13. Clinical Assessment of the Breast A firm, painless mass is usually the major clinical finding in breast cancer. In addition, skin retraction, edema, peau d'orange , inflammation, ulceration, fixation of the mass to surrounding structures, and lymphadenopathy, as well as nipple inversion, crusting, or discharge, may all be observed . 24

14. Clinical Assessment of the Breast… Palpable → at least 1 cm in diameter The average size detected with self-examination is ~ 2.5 cm; about half of these women have axillary lymph node metastases P/E = sensitivity ranges from ~50%-90%, specificity from ~70%-90 % 25

15.     Fibro- adenoma Cysts Cancer Usual Age 15-25, usually puberty and young adulthood, but up to age 55 30-50, regress after menopause except with estrogen therapy 30-90, most common over age 50 Number Usually single, may be multiple Single or multiple Usually single, may coexist with other nodules Shape Round, disclike, or lobular Round Irregular or stellate Consistency May be soft, usually firm Soft to firm, usually elastic Firm or hard Delimitation Well delineated Well delineated Not clearly delineated from surrounding tissues Mobility Very mobile Mobile May be fixed to skin or underlying tissues Tenderness Usually nontender Often tender Usually nontender Retraction Signs Absent Absent May be present 26

16. Clinical Assessment of the Breast… The risk that a mass is malignant increases with age Breast masses – At age < 40, ~ 10 % are malignant; at > 50 yrs 60 % are malignant Mammographic lesion - At age 40, ~ 10% are cancer; but at > 50 yrs > 25 %. Nipple discharge – at age < 60, 7% are associated with carcinoma; but in 30% of older women About 10 % of breast cancers present with noncyclic pain. 27

17. Clinical characteristics of lesions sampled by FNA sensation when the needle enters the lesion and the Clinical characteristics of lesions: Soft : fibroadenoma , mucoid carcinoma, medullary carcinoma Rubbery : fibrocystic change, lobular carcinoma, fibroadenoma Variable resistance with popping sensation : fibrocystic change Leathery : dense fibrous change, ancient fibroadenoma Gritty : carcinoma, partial calcification , a few fibroadenomas Solid : completely calcified ancient fibroadenomas . 28

18. Use of FNAC & Technical considerations Full beast examination including axillary LNDS should be done before taking specimens. Any ulcerative lesions should be accessed tangentially Needles = 23 – 25G in palpable lesions are ideal . FNA of non-palpabl e lesions is performed under ultrasound guidan ce, in conjunction with the radiologists. Avoid passing through jell → cell lysis 29

19. Indications of FNAC breast Investigation of any clinically palpable lump, clinically benign or malignant as a guide to clinical management As a complement to mammography in the screening situation Diagnosis of simple cysts The investigation of suspected recurrence or metastasis in cases of previously diagnosed cancer Confirmation of inoperable, locally advanced cancer Preoperative confirmation of clinically suspected cancer To obtain tumor cells for special diagnosis

20. Adequacy of smears: Presence of at least four - six clusters of epithelial cells in all smears each having 5-10 epithelial cells ? at least 200 well-preserved malignant cells be present for an unqualified diagnosis of cancer m

21. Accuracy and limitations of cyto diagnosis Accuracy is operator-dependent : Sensitivity for malignancy ranges from 65% to 98%, and specificity from 34% to 100% False negative diagnoses < 5% Mainly due to sampling error About 70% of the target lesions are < 1cm False positive diagnoses Are usually interpretation errors (evaluation of rare lesions, diagnostic pitfalls and look-alikes) Should be less than 1% 32

22. Accuracy and limitations of cyto diagnosis FNA Cannot distinguish between an in situ and an invasive ductal carcinoma. It cannot identify the presence of lymphatic or vascular invasion . It is less sensitive in tumors with low-grade cancer histology (e.g., tubular and lobular), papillary proliferations, and mucinous lesions. Low-grade and lobular carcinomas may be mistaken for a hyperplastic process Impact subsequent tissue biopsies Hemo siderosis , hemorrhage, and, rarely, partial necrosis of breast tissue 33

23. Core Needle biopsy VS FNA CNB more often used for mammographically identified calcifications . FNA is preferred In pregnant or postpartum patients , in order to avoid a draining, nonhealing wound FNA is also useful for assessment of recurrent lesions, nonpalpable lesions with US guidance The nondiagnostic rate for FNA is higher, and FNA has a lower negative predictive value. Combination of FNA and CNB may be superior to either alone. CNB - more sensitivity and ability to distinguish between ductal carcinoma in situ and invasive carcinoma. CNB - more abundant material for the determination of ER, PR, and HER2 status. 34

24. Cytological evaluation of the nipple and nipple secretion N ipple discharge Bloody or serous discharges are most commonly due to large duct papilloma's and cysts . During pregnancy → rapid growth and remodeling is possibility It is associated with carcinoma in 7% of women younger than age 60 but in 30% of older women. Worrisome when it is spontaneous and unilateral . Cytology of nipple discharge has a low sensitivity 35

25. Placing a glass slide tangentially to the nipple in such a way as to touch the drop of secretion, making sure not to touch the surrounding skin in order to avoid contamination. Ulceration or eczematous changes on the nipple Remove carefully any debris covering the ulceration Using the non-cutting edge of a scalpel blade or the edge of a clean slide scrape cells from the surface. 36

26. Complications of FNA breast Are few and seldom serious . Formation of a hematoma . Minimized by prolonged pressure following aspiration As a rule, the radiological investigation should be completed before FNA is done . Pneumothorax In the axillary tail of a thin patient. Needle tract seeding Rare in breast cancer . Partial infarction of the lesion , particularly fibroadenomas , hinder histologic confirmation 37

27. Reporting of aspirations Normal Inflammatory Benign Suspicious of malignancy Atypical/indeterminate Malignant Unsatisfactory

28. Modified reporting categories in breast FNA according to NHSBSP ( National Health Service Breast Screening Program (UK) ) guidelines Reportig category Description C1 Inadequate . Assessment is based on the presence of a sufficient number of epithelial cells to provide sample adequate for confident assessment. E.g. Fat and fibrous tissue only Aspirates from cysts, abscesses, fat necrosis and nipple discharge should not be classified as inadequate. Apart from hypocellularity , crush, air-drying, blood and thickness of smea r could cause inadequate sample. It is helpful to comment on the cause of inadequate specimens . C2 Benign . Adequate sample without evidence of atypia , composed of regular epithelial cells, usually in monolayers; background composed of dispersed individual or paired nuclei. Benign specific : - Cyst; fibroadenoma ; intramammary lymph node . Benign – non specific diagnosis 39

29. categy Description C3 Atypia, probably benign . In addition to benign features, certain features not commonly seen in benign aspirates may be present : nuclear pleomorphism , loss of cell cohesion, nuclear or cytoplasmic changes (pregnancy, pill, hormone replacement therapy) and increased cellularity. C4 Suspicious of malignancy . This category should be used for aspirates with highly atypical features , that is almost certain that they come from a malignant lesion, although a confident diagnosis cannot be made due to the following : (a) specimen is scanty , (b) the sample shows some malignant features in the absence of overt malignant features, (c) the sample has an overall benign pattern with large numbers of naked nuclei and/or cohesive sheets of cells but with occasional cells showing distinct malignant features . Definitive therapeutic surgery SHOULD NOT be done on based on C3 or C4. C5 Malignant . Adequate sample containing cells characteristic of carcinoma. Malignancy should not be diagnosed on the basis of a single criterion. 40

30. FNAC Futures of selected Disease of the breast

31. CLASSIFICATION OF LESIONS OF FEMALE BREAST INFLAMMATORY LESIONS Acute & chronic inflammatory processes LESIONS CAUSED BY TRAUMA Fat necrosis Reaction to foreign bodies Lesions resulting from breast augmentation /reduction BENIGN PROLIFERATIVE DISEASES Cysts Fibrous mastopathy & other fibrous lesions BENIGN TUMORS Fibroadenoma Lactating Adenoma Intraductal papilloma Granular cell tumor MALIGNANT TUMORS Carcinomas of various types Sarcomas Rare tumor & tumor like conditions METASTATIC TUMORS

32. Inflammatory conditions Characteristically manifest by the presence of pain, redness, swelling & hotness . Accounting for less than 1% of breast symptoms 44

33. Abscess and acute mastitis Breast abscesses and acute mastitis occur most commonly, but not invariably, in the puerperium . The diagnosis is usually made clinically FNA: - R/O inflammatory carcinoma Aspirates contain neutrophils and macrophages in considerable numbers as well as abundant cell debris . Reactive epithelial cells , derived from adjacent inflamed and possibly lactating breast tissue may also be found. 45

34. 47 Regenerative epithelial atypia in mastitis ( A) Atypical, reactive/ regenerating epithelial cells with a background of histiocytes , inflammatory cells and debris (MGG, HP );

35. Sub areolar abscess Squamous metaplasia of lactiferous ducts resulting in ductal obstruction Keratin shed from metaplastic cells plugs the ductal system, causing dilation and eventually rupture of the duct . There is often a history of the recurrent formation of a tender mass in the sub areolar region, sinus tract formation and discharge with partial healing . Histologically , inflammatory sinus tract lined by granulation tissue but often partially by squamous epithelium . Squamous Metaplasia of Lactiferous Ducts, recurrent subareolar abscess, periductal mastitis, More than 90% of the afflicted are smokers . 48

36. Epithelial cells stained with Diff- Quik (A) and Pap stain (B). In A, the cells are columnar or oddly shaped. In B, the cytoplasmic stain suggests squamous derivation. C. Multinucleated giant cell. D. Tissue section showing squamous metaplasia of a breast duct surrounded by inflammatory infiltrate

37. Multinucleate giant cells Macrophages Epithelium showing reactive atypia . Anucleate squames 51

38. Mammary duct ectasia Histologically there is dilatation of large or intermediate ducts that are filled with secretion, and to a variable extent foamy macrophages , siderophages and cholesterol crystals Forming the inspissated , pasty material seen on gross examination Epithelial proliferation is not a feature, but reparative changes in epithelium next to areas of inflammation may give rise to a spurious impression of atypia both histologically and cytologically . Rupture of the epithelial layer and basement membrane cause chronic inflammation, fibrosis and scarring of the surrounding stroma . 52

39. Mammary duct ectasia ( plasma cell mastitis ) Usually in the 5 th -6 th decade Poorly defined periareolar mass with Skin retraction Thick , white nipple secretion pain & erythema- uncommon May confuse with carcinoma

40. pathogenesis

41. Morphology Dilation of ducts with inspissated secretion with Lipid-laden macrophages Marked Periductal & interstitial granulomatous inflammation Sometimes plasma cell rich inflammation ‘’ plasma cell mastitis ’’ Fibrosis - skin and nipple retraction No epithelial proliferation

42. cytology Thick & white aspirate which appear amorphous granular back ground secretory debris and a variable number of foamy macrophages . No other significant finding on cytology

43. Paget’s disease 1-2% A type of in situ carcinoma that arises in main excretory ducts of breast and extends intraepithelially into skin of nipple Associated with underlying DCIS or invasive disease (50% have underlying lump or mass) Gross: skin is fissured, oozing, ulcerated; resembles eczema

44. Paget disease

45. cytology Background of keratin, squamous cells, inflammatory cells & debris(scrape smears from nipple) Large malignant cells, single and in small groups, closely associated with squamous & inflammatory cells Abundant pale cytoplasm with distinct borders Obvious nuclear features of malignancy

46. Paget`s disease smear

47. Fat necrosis Fat necrosis of the breast may be associated with Rupture & extravasation of contents in mammary duct ectasia and fibrocystic changes Following surgery and radiotherapy . Traumatic fat necrosis – tends to be more superficial (often in subcutaneous fat), history of injury “grandmothers' disease” The lesion is often tender on palpation. 63

48. Cytological findings: fat necrosis background of granular debris, fat droplets Foamy macrophages and multinucleate giant cells with foamy cytoplasm Small irregular groups of (reactive) histiocytic cells Fragments of normal as well as degenerate fatty tissue Variable numbers of other inflammatory cells but usually sparse Few if any epithelial cells 64

49. Diagnostic pitfalls Abnormalities of the macrophage Reactive epithelial cells Giant cells Clinical feature, the background & fat droplets are important clues

50. . A. Cluster of ductal cells with enlarged nuclei. B. Markedly atypical macrophages with enlarged, irregular nuclei. (Diff- Quik stain.)

51. Granulomatous mastitis Various systemic and local conditions can give rise to the formation of a granulomatous response in the breast. Tuberculosis – is more common in developing countries. Fungal infections, Part of the spectrum of duct ectasia . Foreign body reaction to implanted silicone and tumours . Idiopathic granulomatous mastitis 68

52. Clues to the most probable aetiology of the granulomatous infiltration may be found from history and P/E findings Special stains (, Ziehl-Neelsen , PAS, methenamine silver ) is important to identify specific organisms . 69

53. Cytological findings : Sheets or clusters of epithelioid cells with abundant cytoplasm and elongated nuclei Multinucleate giant cells associated with epithelioid cells. The giant cells often have epithelioid cell characteristics. Langhans type giant cells may be identified A variable number of inflammatory cells : lymphocytes, plasma cells, neutrophilic granulocytes In tuberculosis and fungal infections, a mixture of necrotic debris and inflammatory cells is often the dominant finding Admixture of ductal or lobular epithelial cells which may be reactive with enlarged nuclei and distinct nucleolus. 70

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55. BREAST DISEASE IN MALES GYNECOMASTIA: Enlargement of the male breast due to hypertrophy and hyperplasia of glands and stroma , unilateral (common) or bilateral Caused by increase in estrogen to androgen ratio (liver cirhosis ; drugs= marijuana, steroids, ART; hormone producing tumors ,puberty ; often idiopathic

56. Cytological findings:gynaecomastia Scanty or moderately cellular smears Small- to medium-sized epithelial fragments that may be hyperplastic and three-dimensional Resembles fibroadenoma Small to moderate numbers of bipolar cells . 73

57. BENIGN EPITHELIAL BREAST LESIONS Non proliferative breast disease Cysts with apocrine metaplasia Fibrosis Adenosis Proliferative disease without atypia Epithelial hyperplasia Sclerosing adenosis Complex sclerosing scar Papillomas Proliferative disease with atypia Atypical ductal hyperplasia Atypical lobular hyperplasia

58. Breast cysts Cyst – A lesion that contain fluid The great majority of cyst fluids are benign ; only about 2% prove to be carcinoma . On the other hand, a small number of carcinomas are cystic and yield fluid that looks grossly that of benign cysts . Fluid types range from thin, clear, straw­ colored fluid to thick, opaque, green or brown material 75

59. Two main forms of cyst Those lined by a single layer of cuboidal or flattened attenuated epithelium and, More commonly, those lined by apocrine epithelium 76

60. A. Macrophages, some binucleated , with foamy cytoplasm. B. Exceptionally large “foam” cells. C. Clusters of epithelial cells, some of which have aprocrine features .

61. Fibrocystic change(FCC ) The most common cause of a palpable breast lump , The typical between 30 and 50 years old (rare before 25 and after menopause) Often, fibrocystic lumps shows cyclic change and are more commonly tender or painful than malignant ones. Presents as a mass of variable size that may be ill defined or well defined; as solitary lesion or bilaterally 78

62. Basic spectrum of Histologic ‘ fibrocystic change’ are: The formation of cysts Apocrine metaplasia of cyst lining cells and of duct and lobular epithelium Rupture of the cyst lining with extravasation of contents and associated inflammation Fibrosis of the stroma Chronic inflammation of non-specific type Adinosis ( increase nu of acinai ) Fibroadenomatoid change . 79

63. Cytological findings: FCC Scanty , often watery smear Low or moderate cellularity Fat or fibrous stroma in variable quantities. Three-dimensional epithelial aggregates representing intraductal hyperplasia Macrophages and granular debris form microscopical cysts 80

64. Cytological findings: FCC Sheets or fragments of ductal epithelium with bland nuclei arranged in a honey-comb pattern with admixed myoepithelial cells and dispersed bipolar nuclei 81

65. Benign Apocrine cells either dominating the cellular picture or in variable numbers Form large cohesive sheets or dispersed singly or in small groups Large, round and relatively hyperchromatic nuclei Large and prominent nucleoli Abundant, well-defined and usually granular cytoplasm. 82

66. Foam cells Fibrous stroma Fibrocystic changes

67. Ductal cells with apocrine features Apocrine cells

68. Proliferative Breast Diseases without atypia They rarely form palpable mass More commonly, detected as a mammographic densities or incidental finding in biopsies characterized by proliferation of ductal epithelium or stroma without cellular abnormalities suggestive of malignancy slightly increased risk (1.5 - 2 x normal) for breast carcinoma

69. Histologically , the basic appearances described as fibrocystic changes frequently include epithelial proliferative changes of various types. Cytologically , this may be suspected when an aspirate, otherwise typical of ‘ simple ’ fibrocystic change, is cellular with the additional cells being non-apocrine type It is preferable to report the cytological findings in this category of lesions as consistent with ‘ proliferative fibrocystic change’ with or without atypia .

70. The following entities are included Moderate or florid epithelial hyperplasia Sclerosing adenosis Papilloma Complex Sclerosing lesions(Radial scar) Fibroadenoma with complex features

71. Epithelial hyperplasia presence of more than two cell layers Hyperplasia is moderate to florid when there are more than four cell layers Usual ductal hyperplasia and lobular hyperplasia

72. Cytological findings: epithelial hyperplasia Low or moderate cellularity with small epithelial groups Nuclei may be enlarged, but the chromatin pattern is fine and nucleoli inconspicuous The epithelial groups contain the smaller darker ovoid nuclei of myoepithelial cells An absence of nuclear atypia , widespread loss of cell cohesion or necrotic debris 90

73. 91

74. number of acini per terminal duct is increased to at least 2x the number found in uninvolved lobules the acini are compressed & distorted in central portion & dilated at periphery accompanied by prominent stromal fibrosis There is hyperplasia of both epithelial and myoepithelial cells with distortion of the lobular structure Sclerosing adenosis

75. Cytological findings Moderate to high cellularity Small groups of uniform epithelial cells and myoepithelial cells The relationship of sclerosing stroma and microacinar epithelium may be preserved. 95

76. Papillomas can be large duct or small duct LDP is a papillary benign growth within the major lactiferous duct commonly present with serous or bloody breast discharge Usually soft on palpation; rarely exceed 30mm small mass may be felt in the region of the nipple

77. Small duct papilloma(SDP)- are commonly multiple & located deeper within the ductal system SDP-increased risk of Ca than LDP Epithelial hyperplasia & apocrine metaplasia are frequently present

78. Cytological findings : Variable cellularity with a basic benign pattern The epithelial cells are often dispersed or in small groups Complex , folded three-dimensional epithelial aggregates Papillary clusters may be preserved Papillary stromal fragments may be present Rows of palisaded columnar epithelial cells , Small numbers of bipolar cells Apocrine cells may be present A small amount of debris and macrophages may be present. 99

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80. 101

81. Lactating adenoma and lactational change in benign mass lesions Lactating adenoma occurs more commonly during rather than after pregnancy. Regard as a fibroadenoma or tubular adenoma modified by the hormonal influences of pregnancy. Foci of lactational change may occasionally be seen within fibroadenomas and other benign breast changes outside of the context of pregnancy. 102

82. Cytological findings : Moderately cellular aspirates composed of dispersed cells singly or in small groups in a foamy background containing cell fragments and lipid droplets The cytoplasm is vacuolated or wispy and stripped epithelial nuclei may be present The nuclei are uniform, round or ovoid with a smooth nuclear membrane and show fine , stippled chromatin and a prominent nucleolus . 103

83. (Proliferative DS) Hyperplasia with atypia There is correlation between the degree of hyperplasia and the risk of subsequent development of invasive carcinoma. 5x increased risk Atypical ductal hyperplasia (ADH) has been defined as being less than 3mm in maximum diameter with low-grade cytology. Any atypical ductal proliferation with high-grade cytology must be called DCIS whatever the size . 104

84. Cytological findings: hyperplasia with atypia Increased crowding and overlapping of cells within the groups Three-dimensional epithelial aggregates Obvious papillary groups Decreased cohesion of epithelial cells More variation in nuclear size More prominence of nucleoli Less evidence of cells of apocrine type. The features used are highly subjective. Where there is any doubt as to the presence of atypia, the triple assessment findings should be considered and excision biopsy or follow-up undertaken, as appropriate . 105

85. 106

86. 107

87. 108

88. Lobular hyperplasias Characterised by a proliferation of small and often loosely cohesive cells originating in the TDLU . Encompasses LCIS and ALH These lesions are usually not palpable and have no radiologic appearance. 109

89. Cytological findings : Loosely cohesive groups Uniform cells with occasional intracytoplasmic lumina Slightly irregular and eccentric nuclei . There are no reliable cytological criteria that help in differentiating between lobular neoplasims and from invasive lobular carcinoma (ILC ) 110

90. Benign tumours and tumour Fibroadenoma Typically present as firm, discrete and highly mobile lump Commonly presents between the ages of 20 and 35 years, though it can be seen in women of any age The size usually range from 5–30mm On mammograms, fibroadenomas typically present as round, well-defined lesions. Fibroadenoma result from both stromal and glandular proliferation. Malignant change is exceedingly uncommon 111

91. Cytological findings: Fibroadenoma The cytologic studies of fibroadenoma characteristically display a triad of numerous epithelial cells, naked oval nuclei, and stromal fragments Moderate or high cellularity large sheets or LP = three-dimensional clusters with antler- or staghorn -shaped epithelial groups. Some loss of epithelial cohesion

92. 113 antlers of stags

93. Cytological findings: Fibroadenoma Epithelium : - Have regular nuclear spacing Approximately one or two erythrocytes sized, round or slightly ovoid, nucleus with finely granular chromatin pattern Small, 1-2, round nucleolus & A few nuclear atypia Generally Best visualized by papanicolaou stained smear In air-dried preparations – sometimes satisfactory close examination is possible only at the edge of the epithelial group 114

94. Cytological findings: Fibroadenoma Many naked bipolar cell nuclei in the background If apocrine or foamy cells are present they are few . Fibrillar stromal fragments Bluish-gray with the Papanicolaou stain Magnita with a Romanowsky -type stain 115

95. Cytological findings: Fibroadenoma Aspirate in different variants of fibroadenomas may lead to Scant cellularity in older or fibrotic lesions or Abundant cellular stroma that merge with phyllodes tumours Highly myxoid stroma on smears, that can mimic the pattern mucinous carcinoma. Occurrence of apocrine metaplasia, haemorrhagic infarction, especially during pregnancy, squamous metaplasia (more common in phyllodes tumour) and stromal metaplasias , including the formation of smooth muscle, cartilage, bone or dystrophic calcification. 117

96. Cytological findings: Fibroadenoma Bare nuclei in the background could be Stripped epithelial nuclei Myoepithelial nuclei, Some stromal cells nuclei – more spindly nuclei and a strand of pale blue cytoplasm at each pole 118

97. Tubular adenoma Are part of fibroepithelial neoplasms . The clinically indistinguishable from fibroadenoma Histologically : -densely packed benign tubular structures with a double layer of epithelial and myoepithelial cells but with very little stroma. Softer than the average fibroadenoma . Relatively rare 119

98. Cytological findings: tubular adenoma Moderate to highly cellular aspirate with a basic benign pattern No large antler-like groups are seen The epithelial cells are cytologically benign and in small groups , some displaying a microacinar arrangement Bipolar cells are fewer than seen in fibroadenomas . 120

99. Lactating adenoma and lactational change in benign mass lesions Lactating adenoma occurs more commonly during rather than after pregnancy. Regard as a fibroadenoma or tubular adenoma modified by the hormonal influences of pregnancy. Foci of lactational change may occasionally be seen within fibroadenomas and 121

100. Cytological findings: lactating adenoma and lactational change in benign mass lesions Moderately cellular aspirates dispersed cells singly or in small groups in a foamy background containing cell fragments and lipid droplets The cytoplasm is vacuolated The nuclei are uniform, round or ovoid with a smooth nuclear membrane and show fine , stippled chromatin and a prominent nucleolus . 122

101. Phyllodes tumour fibroepithelia l tumors from benign with a strong resemblance to fibroadenomas , through borderline with notable stromal overgrowth and proliferation to malignant , in which the stroma is frankly sarcomatous . Accounting for less than 1% of all breast tumors. The enucleation that would be adequate for a fibroadenoma may result in a local recurrence if applied to a phyllodes . A margin of normal tissue around a known or suspected phyllodes tumour is removed. 123

102. Count…. Histologic distinction among phylodes is based on the degree of; cellular atypia of stromal cells mitotic activity of the stromal cells and the appearance of the margin of the tumour This classification is highly subjective and the important is to DX this tumor

103. Benign phyllodes tumour There is considerable overlap with fibroadenoma . The differentiation between giant fibroadenoma and benign phyllodes tumour depends entirely on the histological appearance of the stroma . and the distinction is frequently impossible cytologically . Tend to be larger on presentation Majority of phyllodes tumors are benign (>60%) 125

104. Count…. On examination, these tumours are softer, less mobile and less well-defined than fibroadenomas . The smears are usually very cellular and the differentiation from a cellular fibro adenoma can be impossible. The clinical features are of assistance in balancing the probabilities .

105. histology

106. Cytological findings: benign phyllodes tumour Cellular smears with occasional large sheets of benign epithelium Numerous plump & single stromal cells little cellular pleomorphism The prominence and number of bipolar cells are usually greater than in fibroadenomas Obvious stromal fragments , some large and with high cellularity 128

107. 129

108. Borderline phyllodes tumours Often present with a large tumour that has grown rapidly. histologically characterised by modest stromal hypercellularity , moderate cellular pleomorphism , an intermediate number of mitoses with heterogeneous stromal expansion . 130

109. Cytological findings : Cellular smears Numerous plump, single stromal cells with moderate cellular pleomorphism ( Predominant) Occasionally bizarre, degenerative type nuclear abnormalities Occasional mitoses. 131

110. high-grade malignant phyllodes tumour : Cytological findings : abundantly cellular Large atypical stromal cells, often in cohesive groups obvious mitoses are seen The epithelial content sparse epithelial content is benign but may demonstrate hyperplasia and mild atypia . 133

111. Malignant Breast Tumors No single morphological feature can be relied upon to distinguish benign from malignant cells at any site. It is the complete picture with the ‘pattern of the smear ’ , the nuclear and cytoplasmic details in conjunction with the radiological and clinical findings that leads to an accurate diagnosis.

112. Criterion Benign Malignant Cellularity Poor or moderate Usually high Cell-to-cell cohesion Good, with large defined clusters of cells Dissociated cells Cell arrangement Even, usually in flat sheets Irregular, overlapping, often three-dimensional Cell types Mixture of epithelial, myoepithelial and other cells, e.g. stromal Usually uniform cell population Bipolar (elliptical) bare nuclei Present Not conspicuous Background Generally clean Occasionally with necrosis and macrophages 137

113. Criterion Benign Malignant Nuclear characteristics Size (in relation to RBCs) Small Variable, often large, depending on tumour type and grade Pleomorphism Rare Common Nuclear membranes (PAP) Smooth Irregular with indentations Nucleoli (PAP) Indistinct or small and single Variable, may be prominent Chromatin Smooth or fine Clumped, may be irregular Additional features Apocrine metaplasia, foamy macrophages Mucin , intracytoplasmic lumina 138

114. moderate or abundant cellularity. On the other hand, carcinomas with a scirrhous stroma , and those in which tumour density is low, notably many of the lobular carcinomas, yield a more scantily cellular specimen. Also, many benign lesions found in younger women may provide intensely cellular smears. 139 Cellularity of the specimen

115. Lack of cell-to-cell cohesion is a characteristic malignant feature, but it is not diagnostic of an invasive lesion. Most in situ lesions yield a variable amount of single cells. some benign lesions may show discohesion , either genuinely or as an artefact due to too much pressure when smearing the material. . 140 Dispersal of cells

116. myoepithelial cell nuclei are missing, both in the background and in the periphery of the tumour cell aggregates . Tubular carcinomas and some low-grade ductal carcinomas are an exception. The naked myoepithelial nuclei in the background of the smear are also missing in in situ lesions. However, remnants of myoepithelial cells are found in the periphery of the cell aggregates in a substantial proportion of non-high-grade ductal carcinoma in situ (DCIS ) 141 Absence of biphasic pattern with myoepithelial cells

117. In PAP-stained preparations, the appearance of a coarsely and unevenly stippled nucleus with variable but prominent chromocentres suggests malignancy . MGG-stained preparations give a more subtle, but no less characteristic appearance of a coarse ‘ rope-like ’ texture that , when marked, can give the impression of small nuclear holes . 147 Chromatin texture

118. Histopathology Classification of Primary Breast Cancer :- Non Invasive Epithelial Cancers :- Ductal C arcinoma I n Situ ( DCIS ) :- Papillary Cribriform Solid & Comedo types Lobular Carcinoma I n S itu ( LCIS ) Invasive Cancers :- Invasive Ductal Carcinoma :- Invasive Lobular C arcinoma

119. Range of Ductal Carcinoma in situ (DCIS )

120. Ductal Carcinoma I n S itu ( DCIS ) :- D x has increased dramatically with the introduction of mammography neoplastic population of cells limited to ducts by basement membrane Mastectomy for DCIS is curative in 95% of cases ! C ategorized by :- The size of the lesion Nuclear grade The presence & extent of comedo necrosis

121. Papillary DCIS Papillary growth within ductal lumina L ined by Tall C olumnar cells.

122. 2. Cribriform DCIS Malignant looking cells surrounding free spaces Spaces are evenly distributed & regular in shape L umen filled with calcifying material.

123. 3. Solid DCIS Pleomorphic cancer cells proliferate , obliterate the lumina , distend the duct .

124. 4. Comedo DCIS The cells outstrip their blood supply X- ized by large central zone of necrosis with calcified debris.

125. Classification of DCIS HISTOLOGY SUBTYPE NUCLEAR GRADE NECROSIS DCIS GRADE COMEDO HIGH EXTENSIVE HIGH INTERMEDIATE INTERMEDIATE FOCAL INTEDMEDIATE NONCOMEDO LOW ABSENT LOW

126. II. Lobular Carcinoma In Situ ( LCIS ) :- The true incidence in the general population is unknown , due to the lack of clinical & mammographic signs. 80 – 90% of cases occur in premenopausal women LCIS cells have a higher level of estrogen receptor ( ER ) positivity Multicentricty identified in 60 – 80% & B ilateral disease is present in 23 – 35% .

127. LCIS Small , rounded , loosely cohesive cells fills & expands the acini of the lobule .

128. Histological grading is an integral part of the histopathology report on all breast carcinomas. Preoperative (cytological) grading is possible, but is not commonly done. cytological grading based on nuclear futures . show a good correlation with both histological grading and ploidy . 159 Cytological grading of invasive breast carcinoma and DCIS

129. 160 Cytological grading according to Robinson et al. 1 994 Score 6 – 11, Grade 1; Score 12 – 14, Grade 2 ; Score 15 – 18, Grade 3 .

130. DCIS cytology Specific diagnosis or classification of DCIS cannot be made on FNAC Epithelial cells mainly cohesive forming large sheets,often with holes or papillary fragments bipolar nuclei absent Variable ,mild to moderate epithelial atypia Necrotic debris Macrophages

131. more heterogeneous in appearance than high-grade DCIS both histologically and cytologically . The criteria overlap with criteria for epithelial hyperplasia. A diagnosis or suggestion of a low-grade/non-high-grade DCIS should lead to a local excision only. 162 Low- and intermediate-grade DCIS

132. Very large three-dimensional epithelial aggregates, cribriform and solid, often more cohesive than high-grade lesions Cell monotony with moderate atipia Micropapillary groups or t rue papillary structures Monolayer sheets Variable number of single cells usually few , Recognizable myoepithelial cell nuclei in epithelial aggregates and sheets not rare (!). 163 Cytological findings: low- and intermediate grade DCIS

133. Usually cell-rich smears , Solid or cribriform, three-dimensional aggregates of epithelial cells with high-grade nuclear atypia structures as well as monolayer sheets Variable number of single cells; occasional cases may present as an almost exclusively single cell population Microcalcifications (without a tumor ) Comedo type necrosis . A few myoepithelial cells may be seen 165 Cytological findings: high-grade DCIS

134. 166 High-grade DCIS

135. Proliferation of fibroblasts (a sign of tumor induced stromal reaction) Cell poor elastoid stromal fragments Invasion of single or small groups of 2 – 3 carcinoma cells in stromal tissue and fatty fragments Intracytoplasmic vacuoles Tubular structures 167 Criteria suggestive of invasive lesion!!

136. 168 Invasive carcinoma and DCIS

137. Infiltrating duct carcinoma Cell rich smears, single population of epithelial cells no myoepithelial cells , no single bare bipolar nuclei Variable loss of cell cohesion irregular clusters and single cells Single epithelial cells with intact cytoplasm

138. Count… Mod to severe nuclear atypia , enlargement, pleomorphism , irregular nuclear membrane& chromatin Fibroblasts & fragments of collagen( stromal desmoplasia ) a/w atypical cells Intracytoplasmic neolumina in some cases Necrosis unusual

139. Ductal carcinoma NOS,low grade

140. Ductal carcinoma NOS,intermediate grade

141. Invasive duct carcinoma NOS,high grade

142. LOBULAR CARCINOMA centrally located more often bilatera l, greater tendency to be multicentirc Less stromal reaction Small sized cells in line b/c of adhesive molecule e-cadherin

143. LOBULAR CA……. Cytological findings A variable, often poor cell yield Cells single and in small clusters, single files characteristic ( Indian file ) Scanty cytoplasm; many naked nuclei; nuclear moulding in cell clusters Small hyperchromatic nuclei of relatively uniform size. Intracytoplasmic lumina / mucin vacuoles/signet ring cells Few if any naked bipolar nuclei

144. Lobular carcinoma (classic type)

145. Infiltrating lobular carcinoma,classic type

146. Common in younger age group and typically under 50 years. Soft, fleshy, mobile & well defined mass mimics benign L.N metastasis common Prognosis favourable Histologically , it is completely circumscribed (pushing border) composed of large syncytial sheets of high-grade atypical cells with no glandular structures and secretion ( comprising at least75% of tumor area ) and scant intervening stroma with a prominent lymphoplasmacytic infiltrate . 179 Medullary carcinoma

147. cellular smears Poorly cohesive large malignant cells with abundant pale staining cytoplasm, some forming syncytial aggregates Large angular nuclei with coarse chromatin and prominent nucleoli. Mitotic figures are not unusual The background of small lymphocytes and plasma cells is a vital feature but their number is very variable. Tumour giant cells are sometimes a feature . 180 Cytological findings :

148. 181

149. Colloid Carcinoma/Mucinous carcinoma well defined, mobile, soft to hard mass mimic fibro adenoma or cysts . This is typically a tumor of older post-menopausal women occurring at an age of 60 years or more . Most are low grade, slow growing and favourable prognosis with a 5-year survival of up to 86%.

150. Cytological findings On spreading, the aspirate is quite glairy , hinting at a high mucin content usually cellular The single and agrigates of cells are bathed in mucin of variable density. This is more obvious in MGG (stains violet) Bipolar cells are absent The cells are small, with small, uniform, round nuclei, smooth nuclear outlines, bland, possibly granular, chromatin and inconspicuous nucleoli Moderate atipia

151. Colloid/ mucinous carcinoma

152. Generally has a good prognosis. very slow growing lesions and having a significantly collagenous stroma , these tumours commonly present when small as firm and discrete or on screening mammogram . average: 50yrs On aspiration it can be quite difficult to obtain smears with adequate cellularity and suboptimal sampling is a major cause of not reaching a definite diagnosis of malignancy. 187 Tubular carcinoma

153. There is slight anisonucleosis and mild hyperchromasia . The chromatin is finely granular and evenly distributed Nucleoli are indistinct or small Bipolar nuclei are present in occasional cases (33%) May be from surrounding breast tissue No apocrine, or foam cells present, rare Necrosis 188 Cytological findings :

154. Charaterestic features open tubular structures , (straight and ridged, or angular, twisted or branched) Glands with pointed, arrow head outline Predominantly in Cohesive cluster s, Dissociated cells where present may have a columnar appearance 190 Cytological findings :

155. Pure apocrine carcinoma is unusual, forming only 1 –4% of all breast carcinomas. Elderly women The tumours may present with all grades of atypia . Aspirates tend to be cellular and the cells dispersed 191 Apocrine carcinoma

156. The cells are large with abundant acidophilic cytoplasm that may be granular but this is less marked than in benign apocrine epithelium The cell borders tend to be indistinct or ragged in contrast to the well-defined borders of benign apocrine cells. nucleus is large and the chromatin coarse and unevenly distributed nucleolus is very large . Multiple nucleoli are also seen in the higher-grade tumours . 192 Cytological findings :

157. Apocrine Ca

158. Hormone receptors HER 2/ (FISH) Flow cytometry Tumor markers Cytokeratin 7 (+), 20(-) S 100 (60%) Ki-67, P 53 E-cadherin (-ILC, + IDC/67%/, + medullary) 195 Ancillary techniques

159. Referances Demay,the art and science of cytopathology Orell and Sterrett’s fine needle aspiration cytology,5 th edi Comprhensive cytopathology,4 th ed Robins 8 th edi WHO gaide line of breast Cancer