Breast Pathology Evening Specialty Conference Case #4 K.P. Siziopikou, MD, PhD Professor of Pathology Director of Breast Pathology and Breast Pathology Fellowship Program Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Siziopikou has nothing to disclose. Clinical Case Mammography and ultrasound findings Clinical Case Needle core biopsy findings 33 yo G1P1 female presented with self-detected right breast mass at 3 months post partum Breast imaging showed an 1.9 cm mass at 1 o clock at 3 cm from the nipple corresponding to the palpable area of concern Ultrasound evaluation revealed a mass with posterior acoustic shadowing corresponding to the mammographic findings Breast Imaging also showed an enlarged axillary lymph node An US guided NCB was performed H-E PR ER Clinical Case: Pathologic Features Mastectomy: Breast Tumor Markers Following the NBC the patient underwent bilateral mastectomies, intraoperative evaluation of the sentinel node and right sided AXLD Final Pathology: Right breast mastectomy IDC, grade 3/3, 1.9 cm, with prominent lymphocytic reaction Breast mass ER/PR/: negative 1/14 lymph nodes with metastatic disease pt1c, N1a, Mx. Stage IIa Left breast mastectomy Benign breast findings Lymph node ER PR Ki 67
PABC: Definition Pregnancy Associated Breast Cancer (PABC) Breast cancer diagnosed during gestation, lactation and within 1 to 5 years postpartum Epidemiology A Ann Surg. 1907 September; 46(3): 487 488 nn Surg. 1907 September; 46(3): 487 488 Malignancy in pregnancy 1:2000 in 1964 to 1:1000 deliveries in 2000 Ann Surg. 1907 September; 46(3): 487 488 Voulgaris E, Pentheroudakis G and Pavlidis N. Cancer and pregnancy: a comprehensive review. Surg Oncol 2011;20:e175 85. Breast Cancer and Pregnancy Epidemiology (cont d) 6,000,000 pregnancies/year in the US 1 in 3,000 to 1 in 10,000 are associated with BC PABC constitutes 0.2-3.8% of all breast cancer cases PABC constitutes 25-30% of all premenopausal women diagnosed with breast cancer Breast cancer is the leading cause of cancer death in US women age 15-29. Source: SEER data, 2013 12 DeSantis C, Ma J, Bryan L and Ahmedin J. Breast Cancer Statistics, 2013. CA: A Cancer Journal for Clinicians 2013;64(1):52 62.
Dual effects of Pregnancy on Breast Cancer Development Stages of Breast Development Meier Abt Trends Mol Med. 2014 Mar;20(3):143 53 Lyons, TR, Schedin PJ and Borges VF. Pregnancy and breast cancer: when they collide. J Mammary Gland Biol Neoplasia 2009;14:87-98. Dual effects of Pregnancy on Breast Cancer Development Protective Pregnancy induced epithelial cell differentiation Changes in estrogen responsiveness of parous gland Diminution in number of mammary stem cells Britt et al. Pregnancy and the risk of breast cancer. Endocrine-Related Cancer (2007) 14 907 933 Dual effects of Pregnancy on Breast Cancer Development Promoting Involutional changes post pregnancy, simulate wound healing/inflammatory environment increasing propensity for metastasis Altered hormone levels in parous women especially GH and prolactin Schedin, P. Pregnancy-associated breast cancer and metastasis. www.nature.com/reviews/cancer (2006) 6 281-291. Britt et al. Pregnancy and the risk of breast cancer. Endocrine-Related Cancer (2007) 14 907 933 Involution hypothesis Involution Hypothesis Mammary gland involution: fully differentiated milk-producing breast regresses to a pre-pregnant-like state Involves apoptotic cell death of 50-80% of the mammary epithelium Tissue-remodeling programs similar to wound healing and inflammation Wound healing and inflammation tumor progression, dissemination and metastasis Lyons, TR, Schedin PJ and Borges VF. Pregnancy and breast cancer: when they collide. J Mammary Gland Biol Neoplasia 2009;14:87-98.
PABC: Clinical Presentation Pathologic features of PABC Palpable breast mass Physiologic changes of pregnancy increased breast volume palpable nodularity firmness increased parenchymal density Usually presents as advanced disease Largest proportion of stages II-IV breast cancers Can be any subtype of BC Invasive ductal carcinoma (75-90%) Larger tumor size Higher grade Higher stage at presentation Higher rates of lymph node involvement (56-89%) PABC: Histologic Features PABC: IHC High frequency of hormone negative status 70% ER and PR negative with high ki67 ER PR More frequently triple negative ER, PR and Ki 67 Breast mass Lymph node If not TN, then often overexpression of Prognosis PABC: Genomic Signatures Worse prognosis in a matched case study (stage, age and year of diagnosis) 5-year OS 30.7% PABC vs. 48.7% non-pabc (p < 0.0001) Dimitrakakis C, Zagouri F, Tsigginou A et al. Does pregnancy-associated breast cancer imply a worse prognosis? A matched case-case study. Breast Care 2013;8:203-7. Hormonal milieu of pregnancy contributes to the aggressiveness of PABC PABC samples clustered with established breast cancer subtypes Harvell DME, Kim J, O Brien J, et al. Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Canc 2013;4:140-53.
PABC: Genomic Signatures of Tumor Cells PABC: Genomic Signatures of Stroma Hormone regulated genes differed in PABC vs. non PABC (malignant epithelium) Hormone regulated genes differed in PABC vs. non PABC (tumor associated stroma) Cell proliferation Cell metabolism Lipid metabolism Immune response immune related genes (macrophage response) Harvell DME, Kim J, O Brien J, et al. Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Canc 2013;4:140-53. Harvell DME, Kim J, O Brien J, et al. Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Canc 2013;4:140-53. PABC: Genomic Signatures The Inflammatory Microenvironment in Cancer Development and Progression 1,097 genes differentially expressed between PABC and non-pabc Overrepresented in PABC Cellular proliferation Cellular lipid catabolism Positive regulation of the immune system Lymphocyte activation Leukocyte differentiation The significant differences in genomic pathways support the involution hypothesis Development and prognosis of PABC May aid in the identification of unique therapeutic targets Tumor microenvironment: Blood vessels Fibroblasts Signaling molecules Extracellular matrix Inflammatory cells Inflammatory tumor microenvironment contributes to the biological behavior of cancer Harvell DME, Kim J, O Brien J, et al. Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Canc 2013;4:140-53. The Inflammatory Microenvironment in Cancer Development and Progression Inflammation Immune system: dual effect on human tumors: Immune responses against cancer CD8-positive lymphocytes in colon cancer favorable clinical course Permissive or tumor-promoting microenvironment Abundant CD68-positive macrophages in Hodgkin s lymphoma and Ewing s sarcoma adverse prognosis PABC diagnosed within 2 years of pregnancy grade 3 (76% vs. 26%) triple negative (34% vs. 3%) positive lymph nodes (61% vs. 45%) Kruger JM, Wemmert C, Sternberger L, et at. Combat or surveillance? Evaluation of the heterogeneous inflammatory breast cancer environment. J Pathol TAI 1+ TAI 2+ TAI 3+ L.Z. Blanco, Jr., A. Mahajan and K.P. Siziopikou: Tumor associated inflammation correlates with poor prognosis in pregnancy associated breast cancer. Modern Pathology, 26:30A, 2013.
TAI 0 TAI 1+ TAI 2+ TAI 3+ PABC 1 (3.8%) 12 (46.2%) 8 (30.8%) 5 (19.2%) CONTROLS 6 (27.3%) 13 (59.9%) 3 (13.6%) 0 (0%) Majority of PABC have tumor associated inflammation (TAI - 50% moderate or severe) Severe TAI more likely in PABC (1 in 5 cases) and absent in controls All 5 cases with severe TAI grade 3 tumors with positive lymph nodes Perilobular inflammation (PLI) away from the tumor PLI 1+ PLI 2+ PLI 3+ L.Z. Blanco, Jr., A. Mahajan and K.P. Siziopikou: Tumor associated inflammation correlates with poor prognosis in pregnancy associated breast cancer. Modern Pathology, 26:30A, 2013. L.Z. Blanco, Jr., A. Mahajan and K.P. Siziopikou: Tumor associated inflammation correlates with poor prognosis in pregnancy associated breast cancer. Modern Pathology, 26:30A, 2013. Inflammation (cont d) PLI 0 PLI 1+ PLI 2+ PLI 3+ PABC 4 (15.4%) 13 (50%) 6 (23.1%) 3 (11.5%) CONTROLS 10 (45.5%) 9 (40.9%) 1 (4.5%) 2 (9.1%) Immunohistochemical stains for T cells (CD4 and CD8) CD4 1+ 2+ 3+ PABC 0 7 (35%) 13 (65%) CD8 1+ 2+ 3+ PABC 0 9 (45%) 11 (55%) PABC more likely to have perilobular inflammation (85% vs. 55%) TAI and PLI may play an important role in tumor metastasis in PABC and contribute to the poor prognosis in these patients L.Z. Blanco, Jr., A. Mahajan and K.P. Siziopikou: Tumor associated inflammation correlates with poor prognosis in pregnancy associated breast cancer. Modern Pathology, 26:30A, 2013. CONTROLS 0 6 (40%) 9 (60%) Similar amounts of CD4+ lymphocytes PABC more abundant CD8+ lymphocytes CONTROLS 1 (7%) 11 (73%) 3 (20%) L.Z. Blanco, Jr., J. Ubago and K.P. Siziopikou: Increased CD68-positive Macrophages and CD4-positive Lymphocytes in Tumor Associated Inflammation correlates in Pregnancy Associated Breast Cancer May Contribute to a Poor Prognosis. Modern Pathology, 28:36A, 2015. CD4 CD8 PABC: PD-1/PD-L-1 expression Immunohistochemical stain for macrophages (CD68) PD-L1 is highly expressed in tumor infiltrating lymphocytes in PABC CD68 1+ 2+ 3+ PABC 0 16 (80%) 4 (20%) CONTROLS 2 (13%) 13 (87%) 0 TILs PABC Controls p value PD-L1 5.86 3.07 0.03 Strong PD-L1 42.9% 0% 0.01 PABC more abundant CD68+ macrophages CD68 All 4 cases with 3+ CD68 grade 3 tumors with lymph node metastasis CD68+ macrophages may be associated with worse prognosis PD-1 6.81 5.36 0.28 PD-L1 L.Z. Blanco, Jr., J. Ubago and K.P. Siziopikou: Increased CD68-positive Macrophages and CD4-positive Lymphocytes in Tumor Associated Inflammation correlates in Pregnancy Associated Breast Cancer May Contribute to a Poor Prognosis. Modern Pathology, 28:36A, 2015. L.Z. Blanco, Jr., J. Pincus and K.P. Siziopikou: PD-L1 is highly expressed in tumor infiltrating lymphocytes in pregnancy associated breast cancer. San Antonio Breast Cancer Symposium Poster Discusssion in Issues and Challenges for Young Women with Breast Cancer, 2016.
Summary PABC is BC diagnosed during or after a recent pregnancy or lactation. PABC affects 25-30% of premenopausal women with breast cancer. Pregnancy results in a transient increase risk in breast cancer followed by a decrease risk (protection) over time. Multiple hypothesis for pregnancy s promoting and protective effects exist. Tissue remodeling during mammary gland involution are similar to wound healing and inflammation and may facilitate tumor progression and metastasis. PABC tends to present at a more advanced stage, with larger, high grade, triple negative or -positive tumors. PABC has worse prognosis compared with age and stage matched controls. Better understanding of the molecular pathways of tumor initiation and progression and prompt diagnosis and treatment in PABC may lead to better OS. Thank you!