WHAT IS NEW IN LOBULAR LESIONS?

Transcription

1 WHAT IS NEW IN LOBULAR LESIONS? JOSE PALACIOS HOSPITAL UNIVERSITARIO RAMÓN Y CAJAL MADRID FEBRUARY 7th MADRID

2 SUMMARY 1.- LOBULAR NEOPLASIA: Morphological subtypes. 2.- PLEOMORPHIC LOBULAR CARCINOMA: Diagnostic criteria. 3.- E-CADHERIN AND CATENINS: Role of immunohistochemistry in diagnosis. 4.- MOLECULAR ALTERATIONS IN LOBULAR CARCINOMA: HER2 mutations.

3 16q22.1 LOBULAR NEOPLASIA LOBULAR CARCINOMA E-CADHERIN p120 JMD CBD -catenin E-CD actin D16S3057 D16S265 D16S398 CDH1 D16S496 D16S752 p120

4 To subdivide lobular changes into ALH or LCIS is subjective and is not of prognostic significance. LIN (Lobular Intraepithelial Neoplasia), subdivided in three grades based on extensionan nuclear atypia: LIN 1, LIN 2, LIN 3. LOBULAR NEOPLASIA The term LIN dissapears The distinction between ALH and CLCIS is clinically relevant (risk of subsequent neoplasm). Florid or Bulky and Pleomorfic variants of LCI are considered.

5 LOBULAR NEOPLASIA WHO 2012 Lakhani, Schintt, O`Malley, Van de Vijver, Simpson, Palacios Spectrum of atypical epithelial lesions originating in terminal-duct lobular unit. Proliferation of generally small, non cohesive cells. Frecuent pagetoid involment of terminal ducts % bening breast biopsies. Mean age 49 years Multicentric (85%) and bilateral (30-67%)

6 LOBULAR NEOPLASIA The terms Atypical Lobular Hyperplasia (ALH) and Lobular Carcinoma in Situ (LCIS) are based on the extent of involvement of individual lobular units. The term ALH is used when involved terminal duct-lobular units are not completely distended by neoplastic cells, or when residual lumens are present, while LCIS is used for fully developed lesions (> 50% lobular units).

7 LOBULAR NEOPLASIA LN CONSTITUTES A RISK FACTOR AND A NON-OBLIGATE PRECURSOR FOR THE SUBSEQUENT DEVELOPMENT OF INVASIVE CARCINOMA. Relative Risks for subsequent invasive carcinoma are 4-5 for ALH and 8-10 times for LCIS. Cancer development in the same area or site (invasive carcinoma is three times more likely to develop in the ipsilateral compared with the contralateral breast).

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9 LOBULAR NEOPLASIA (LN) Atypical Lobular Hiperplasia < 50% lobular units affected In Situ Lobular Carcinoma > 50% lobular units affected Classic LCIS Mild to moderate nuclear atypia Florid LCIS Mild to moderate nuclear atypia Marked distention Necrosis Pleomorphic LCIS High grade nuclei. Necrosis

10 PLEOMORPHIC LOBULAR CARCINOMA IN SITU (PLCIS)

11 APOCRINE PLEOMORPHIC LOBULAR CARCINOMA IN SITU

12 FLORID LCIS

13 Shin et al; Hum Pathol 2013

14 MANAGEMENT OF LOBULAR NEOPLASIA CORE NEEDLE BIOPSY - Excision if associated lesions (ADH; DCIS) and/or mass on radiology and/or radiological/pathological discordance, florid and pleomorphic LCIS EXCISIONAL BIOPSY LN ONLY - No further excision IVASIVE CANCER WITH ONLY LN AT MARGINS - No further excision

15 16q22.1 LOBULAR BREAST CANCER Invasive breast carcinoma composed by non-cohesive cells individually dispersed or arranged in single-file linear pattern in a fibrous stroma. INCREASING INCIDENCE (HRT?) HIGHER AGE AT DIAGNOSIS HIGHER SIZE AT DIAGNOSIS LOWER SENSITIVITY OF RX TO DETECT ILC DIFFUSE GROWTH PATERN POOR RESPONSE TO CHEMOTHERAPY METASTATIC PATTERN D16S3057 D16S265 N Absence of E-cadherin >80% D16S398 CDH1 D16S496 D16S752 T D16S496

16 HISTOLOGICAL GRADING

17 LOBULAR BREAST CANCER VARIANTS Solid (sheets of neoplastic cells) Alveolar (rounded aggregates of invasive neoplastic cells) Tubulo-lobular (classic pattern + small-calibre tubules) Pleomorphic (nuclear pleomorphism) Lobular mixed type (any combination of classic and/or variants ) Classic ILC TLC Pleomorphic ILC

18 PLEOMORPHIC LOBULAR CARCINOMA Authors Journal Diagnostic Criteria Butler and Rosa. Arch Pathol Lab Med 2013 Greater degree celullar pleomorphism Khoury et al. Histopathology 2012 Nuclear pleomorphism equivalent to high grade DCIS in 10% of the tumor Monhollen et al. Histopathology 2012 Pleomorphic cells: GN3. Jacobs M et al. Ann Diag Pathol 2012 Enlarged nuclei, irregular membrane, nucleoli, increased mitotic activity Ercan et al. Cell Oncol 2012 Polygonal, eccentric pleomorphic nuclei and frecuent mitosis. Jung et al. J Breast Cancer 2012 Enlarged nuclei, irregular nuclear contour, hyperchromasia, abundant cytoplasm.

19 PLEOMORPHIC LOBULAR CARCINOMA WHO 2012: PLC Retains the distinctive growth pattern of lobular carcinoma but exhibits a greater degree of cellular atypia, pleomorphism and a higher mitotic rate than classic conventional lobular carcinoma

20 PLEOMORPHIC LOBULAR CARCINOMA

21 Classification as the pleomorphic subtype (based on NG) added no useful additional prognostic information to histological grade in invasive lobular carcinomas. Histological grade should still be used for clinical decision making in invasive lobular carcinomas.

22 The E-cadherin/catenin adhesion complex E-CADHERIN p120 CBD JMD -catenin 16q22.1 actin Protein Mw Gene location E-cadherin 120 kda 16q22.1 -catenin 102 kda 5q31 b-catenin 92 kda 3p21 g-catenin 83 kda 17q21 p120ctn 120 kda 11q11 CDH1 is a tumor and invasion suppressor gene C-terminal

23 Lobular carcinomas completely lack E-cadherin expression Lobular carcinoma in situ Invasive lobular carcinoma Invasive Ductal carcinoma Absence of E-cadherin >80% Reduced E-cadherin: 50% Gamallo, Palacios, Suárez et al; Am J Pathol 1993

24 INTRINSIC MOLECULAR SUBTYPES AND CDH1 ALTERATIONS IN 35 ILC LA 71% LB 17% HER2 6% BL 3% NL 3% SM 66% DR 69% HD 3% HL 80% PAM50

25 Complete loss of E-cadherin is accompanied by reduction in b-catenin and g-catenin levels b-catenin Most of lobular carcinomas (80-90%) have strong reduction or complete loss of b- and g-catenin levels.

26 ND IF IS IF IS ND E-CD p120 p120 ND p120 p120 p120

27 E-CD E-CD p120 p120

28 E-CADHERIN/CATENIN ALTERATIONS IN LOBULAR LESIONS p120 CDE p120 Palacios et al, Mod Pathol 2003 Sarrió et al; Oncogene 2004

29 ROLE OF E-CADHERIN/CATENIN IMMUNOHISTOCHEMISTRY Diagnosis of LC is based on morphological criteria. E-CD IHC can be used to differentiate ambigous lesions: LCIS vs solid LG-DCIS PLC vs HG-IDC Mixed lobular/ductal carcinomas Other lesions

30 E-CADHERIN/CATENINS IN MIXED LCIS/DCIS E-CADHERIN p120

31 LOBULAR NEOPLASIA IN SCLEROSING ADENOSIS E-CD SMMHC SMMHC

32 ROLE OF E-CADHERIN/CATENIN INMUNOHISTOCHEMISTRY 15% of LC can express E-CD (dysfunctional?). Membranous vs aberrant cytoplasmic expression. Residual epithelial cells.

33 ERBB2 mutations in Lobular Carcinoma 3/35 (9%) ILC in TCGA serie had mutations in the kinase domain of ERBB2. This frequency was significantly higher than in IDC. 4/22 (18%) relapsed clasical ILC reported by Ross et al. had ERBB2 mutations. Tumors were negative by IHQ and FISH Anti-ERBB2 therapy?. TCGA,Nature 2013 Ross et al; Clin Cancer Res 2013