Preneoplastic lesions of the breast Sarah E Pinder

Early neoplastic lesions of the breast

Lobular in Situ Neoplasia • • • •

Follow-up of 39 of 48 patients 0.5% of 10,542 benign breast biopsies Higher risk with LCIS (9x) [8 cells across acinus] Lower risk with ALH (4-5x) Page DL. Human Pathol. 1991; 22; 1232-1239

LCIS Vs DCIS

LCIS Vs. Low Grade Solid DCIS • Both - filling of membrane-bound spaces by uniform, regularly-placed cells • Low power - lobulo-centricity of LCIS, more haphazard lobular & duct distortion in DCIS • DCIS - sharply defined cell membranes • LCIS - discohesion • Intracytoplasmic lumina more often in LCIS

E-cadherin

E-cadherin

• Heterogeneous E-cadherin staining in indeterminate carcinoma in situ Jacobs TW et al. Am J Surg Pathol 2001;25:229-36

Cases 140 LN or ILC

Absent Weak/partial 121 (86%) 16 (12%)

Focal/dot-like 3 (2%)

Choi YJ et al. Mod Pathol. 2008;21:1224-37

Update - Risk with LISN

• Meta-analysis 9 studies of 228 patients • 15% ipsilateral, 9% contralateral carcinoma • Ipsilateral 3x more likely than contralateral • “…model of premalignancy for ALH intermediate between a local precursor and a generalised risk for both breasts” Page. Lancet. 2003;361:125-9 • SEER data - 4490 LCIS patients • “LCIS may be a precursor rather than just an ambiguous risk factor for invasive breast cancer”. Li CI et al. Cancer. 2006;106:2104-12

Effect of LCIS on Cancer Recurrence Moran. Int J Radiat Biol Phy 1998 Abner. Cancer 2000

1096 WLE + RT 51 with LCIS

Ipsilat rec free survival 77% with LCIS, 84% without (NS)

1181 invasive ca BCT+RT 137 with LCIS

8 yr LR 13% with LCIS, 12% without (NS)

Ben-David. Cancer 2006

121 stage 0-II Ca without LCIS & 64 with LCIS

Jolly. Int J Radiat Oncol Bio Phys 2006

607 invasive breast ca 56 LCIS present

Adepoju. Cancer 2006

307 DCIS - BCT

No difference in LR if LCIS present. (100% & 99% local control for LCIS vs no LCIS) LCIS independently predicted for ipsilat rec. (10 yr ipsilat rec 14% if LCIS, 7% without) No difference in LR if LISN present. (overall 14% LR).

Ciocca. Ann Surg Oncol 2008

2894 BCT stage 0-II 290 with LCIS; 84 LCIS at margin

No difference in LR if LCIS present, even if at margin (6% 10 yr LR rate for both)

Pleomorphic LCIS

Pleomorphic LCIS (& Pleomorphic Apocrine LCIS (PALCIS)) • • • •

Lack E-cadherin Gain of 1q & loss of 16q - typical of lobular carcinoma Amplification of c-myc and HER2 Same precursor/genetic pathway as classic lobular carcinoma Reis-Filho J et al. J Pathol. 2005.

• • •

Lobular immunohistochemical profile & genetics More “aggressive” re proliferation, HER2 etc Very limited data on clinical behaviour

Columnar cell lesions

• Columnar cell change • Columnar cell hyperplasia • Flat epithelial atypia Columnar cell lesions: recommendations for terminology and diagnostic criteria. NHSBSP EQA Website

Columnar Cell Change Columnar Cell Hyperplasia

• • • • • • •

Columnar epithelial cells (1 or 2 cell depth) line TDLU, often mildly dilated Uniform, ovoid nuclei Perpendicular to basement membrane Cytologically bland Mitotic figures rare Apical snouts often present Intraluminal secretions often with Ca2+

• • • • • •

Similar to CCC, but stratification > 2 cells depth Nuclei morphology as in CCC May be more crowding & overlapping of nuclei Tufts or hummocks mimicking micropapillae Exaggerated apical snouts hobnail appearance Intraluminal secretions often with Ca2+

Flat Epithelial Atypia

• TDLUs often darker than normal at low power • 1 or more layers of monotonous, cuboidal to • • • • • •

columnar cells, as in ADH/low grade DCIS Round nuclei Mild increase in nuclear/cytoplasmic ratio Dispersed or marginated chromatin Nucleoli sometimes more prominent Mitotic figures rare May be scattered lymphoid cells

May be subtle Not necessarily flat

But, if complex architecture then diagnosis is ADH/DCIS

Is not high grade

May co-exist with other low grade neoplastic lesions

Flat epithelial atypia

• •

•

FEA is clonal Genetic changes relatively few in number; on multiple chromosomes – LOH: losses on 3p & 11q, 2p, 16q, 17q – CGH: losses on 16q, 17p, X; gains on 15q, 16p, 19 Genetic alterations similar to those of associated DCIS & invasive carcinoma

•

Very low risk of subsequent cancer FEA on Surgical Excision

101 patients with FEA: – 17 simultaneous cancers – 84 alone: No recurrences, median F-U 106 months De Mascarel et al, Virchows Arch (2007) 451: 1-10

•

25 patients with monomorphic/low grade “clinging” carcinoma: 1 “recurrence” of same lesion, mean follow-up of 17.5 years Eusebi et al, Semin Diagn Pathol (1994) 11: 223 – 235

•

59 patients with low grade “clinging” carcinoma: no recurrences after 5.4 years Bijker et al, J Clin Oncol (2001) 19: 2263 - 2271

“Intraductal” Epithelial Proliferations UEH

ADH

LG DCIS Punched-out spaces, rigid bars, micropapillae

Irregular, peripheral slits. Streaming

Features of UEH & of low grade DCIS

Uneven distribution & overlapping of nuclei. Variation in appearance, including oval nuclei

Cells similar to low Evenly-spaced. grade DCIS. Small, regular cells. Microfocal; < 2 Round nuclei duct spaces with complete involvement (or 1 quadrant 23% Central 11% 81 cases 1 duct system 1 case Multiple ducts systems = a unicentric process Holland. Lancet 1990; 335; 519

DCIS Grade

• • •

High grade Intermediate grade Low grade

Nuclear size, pleomorphism, nucleoli, mitoses Growth pattern, necrosis & polarisation

DCIS – ipsilateral recurrence NSABP B17 Cancer 1999

EORTC 10853 J Clin Oncol 2001

UKCCCR DCIS I BJC 2010

Margins

û (trend)

ü

ü

Grade

û (trend)

Type & diff ü

Grade ü

Comedo necrosis

ü

û

û

Histological type

ü

ü

ü

Size

û

ü

ü

Lymphoid infiltrate Focality

ü

û

ü

ü

UK DCIS I Trial - Ipsilateral recurrence Grade Nuclear Grade 1 2 3

N

N events

86 6 (7.0%) 225 13 (5.8%) 913 135 (14.8%)

H.R.

95 % C.I.

0.51 0.41 1.00*

0.22 - 1.15 0.23 – 0.72

• High grade, predominantly solid architecture, >50% ducts with comedo-type necrosis

Grade Low Intermediate High “Very High”

N

N events

86 6 225 13 430 47 483 88

H.R. 0.42 0.33 0.62 1.00

95 % C.I. 0.18 - 0.95 0.19 - 0.60 0.43 - 0.88 BJC 2010

“Very High” Grade = High cytonuclear grade, comedo-type necrosis in >50% ducts, >50% solid architecture

Years since randomisation BJC 2010

Ellis IO et al. J Clin Pathol 2006;59;138-145.

0.00 – 0.20 0.21 – 0.40 0.41 – 0.60 0.61 – 0.80 0.81 – 1.00

Slight Fair Moderate Substantial Almost perfect

Nuclear Grade of DCIS Feature

Low grade

Intermediate

High

Monotonous

Intermediate

Markedly pleomorphic

1.5x to 2x RBCs or normal duct epithelial nucleus

Intermediate

>2.5 RBCs or normal epithelial nucleus

Chromatin

Usually diffuse, finely dispersed

Intermediate

Usually vesicular, regular chromatin distribution

Nucleoli

Only occasional

Intermediate

Prominent, often multiple

Mitoses

Only occasional

Intermediate

May be frequent

Polarized

Intermediate

Usually not polarized

Pleomorphism Size

Orientation

Arch Pathol Lab Med 2009; 133: 15-25

Progression of DCIS to Invasive Carcinoma • In tumours with both DCIS & invasion is significant correlation between grade of DCIS & of invasive carcinoma Lampejo, Sem Diag Pathol 1994; 11:215-222 Gupta, Cancer 1997; 80 : 1740-1745 Cadman, The Breast 1997;6:132-137 Millis, BJC 2004; 90; 1538-42

• No progression in grade between the in situ, invasive, locally recurrent & metastatic phases Millis, Eur J Cancer 1998; 34:548-553

Progression of DCIS to Invasive Carcinoma Genetic studies • CGH studies show a high degree of genetic homology between DCIS and invasive carcinoma Buerger et al, J Pathol 1999; 189:521-526; Bocker et al, J Pathol 2001; 195:415-421 Synchronous DCIS & invasive cancer

Low grade DCIS

Grade 1 NST Courtesy of JS Reis-Filho

Low grade

ADH

Low grade DCIS

FEA

Tubular/ cribriform carcinoma LISN

16q- (>85%) 1q+ 16p+

Normal

High grade 8q+ 1q+ 17q+ 20q+ 13q16q- (