Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2020

01-12-2020 | Breast Cancer | Epidemiology

Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical features in invasive micropapillary breast carcinoma with long-term outcomes

Authors: Frederik Deman, Kevin Punie, Annouschka Laenen, Patrick Neven, Eva Oldenburger, Ann Smeets, Ines Nevelsteen, Chantal Van Ongeval, Adinda Baten, Timothy Faes, Melissa Christiaens, Hilde Janssen, Caroline Weltens, Christine Desmedt, Hans Wildiers, Giuseppe Floris

Published in: Breast Cancer Research and Treatment | Issue 3/2020

Login to get access

Abstract

Purpose

We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features.

Methods

Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS).

Results

We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001).

Conclusions

Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.
Appendix
Available only for authorised users
Literature
1.
Marchiò C, Horlings HM, Vincent-Salomon (2019) Invasive micropapillary carcinoma. In: WHO classification of tumours of the breast, 5th edn. International agency for research on cancer, Lyon, France pp. 128–130.
2.
Fisher ER, Palekar AS, Redmond C, Barton B, Fisher B (1980) Pathologic findings from the national surgical adjuvant breast project. Am J Clin Pathol 73:313–322PubMed
3.
Marchiò C, Iravani M, Natrajan R, Lambros MB, Savage K, Tamber N et al (2008) Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. J Pathol 2015:398–410
4.
Chen L, Fan Y, Lang R, Guo X, Sun Y, Cui L et al (2008) Breast carcinoma with micropapillary features: clinicopathologic study and long-term follow-up of 100 cases. Int J Surg Pathol 16:155–163PubMed
5.
Yang Y-L, Liu B-B, Zhang X, Fu L (2016) Invasive micropapillary carcinoma of the breast: an update. Arch Pathol Lab Med 140:799–805PubMed
6.
Li G, Yang S, Yao J, Wang Z, Yao G, Liu M et al (2016) Invasive micropapillary carcinoma of the breast had poor clinical characteristics but showed no difference in prognosis compared with invasive ductal carcinoma. World J Surg Oncol 14:207PubMedPubMedCentral
7.
Chen AC, Paulino AC, Schwartz MR, Rodriguez AA, Bass BL, Chang JC et al (2014) Population-based comparison of prognostic factors in invasive micropapillary and invasive ductal carcinoma of the breast. Br J Cancer 111:619–622PubMedPubMedCentral
8.
Wu Y, Zhang N, Yang Q (2017) The prognosis of invasive micropapillary carcinoma compared with invasive ductal carcinoma in the breast: a meta-analysis. BMC Cancer 17:839PubMedPubMedCentral
9.
Hao S, Zhao Y-Y, Peng J-J, Ren F, Yang W-T, Yu K-D et al (2019) Invasive micropapillary carcinoma of the breast had no difference in prognosis compared with invasive ductal carcinoma: a propensity-matched analysis. Sci Rep 9:286PubMedPubMedCentral
10.
11.
Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M et al (2019) Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 37:559–569PubMedPubMedCentral
12.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs working group 2014. Ann Oncol 26:259–271PubMed
13.
Guo X, Chen L, Lang R, Fan Y, Zhang X, Fu L (2006) Invasive micropapillary carcinoma of the breast: association of pathologic features with lymph node metastasis. Am J Clin Oncol 126:740–746
14.
Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL et al (2020) Estrogen and progesterone receptor testing in breast cancer: American society of clinical oncology/College of American pathologists guideline update. J Clin Oncol 38:1346–1366PubMed
15.
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS et al (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline focused update. J Clin Oncol 36:2105–2122PubMed
16.
Brouckaert O, Laenen A, Vanderhaegen J, Wildiers H, Leunen K, Amant F et al (2012) Applying the 2011 St Gallen panel of prognostic markers on a large single hospital cohort of consecutively treated primary operable breast cancers. An Oncol 23:2578–2584
17.
Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F et al (2018) Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the international immuno-oncology biomarker working group on breast cancer. Semin Cancer Biol 52:16–25PubMed
18.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy. J Clin Oncol 31:860–867PubMed
19.
Bosisio FM, Wilmott JS, Volders N, Mercier M, Wouters J, Stas M et al (2016) Plasma cells in primary melanoma. Prognostic significance and possible role of IgA. Mod Pathol 29:347–358PubMed
20.
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD et al (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16879
21.
22.
Altman DG, Bland JM (1983) Measurement in medicine: the analysis of method comparison studies. The Statistician 32:307–317
23.
Gourgou-Bourgade S, Cameron D, Poortmans P, Asselain B, Azria D et al (2015) Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the assessment of time-to-event endpoints in cancer trials). An Oncol 26:873–879
24.
Fine JP, Gray RJA (1999) Proportional hazards model for the subdistribution of a competing risk. J Am Stat Soc 94:496–509
25.
Paterakos M, Watkin WG, Edgerton SM, Moore DH, Thor AD (1999) Invasive micropapillary carcinoma of the breast: a prognostic study. Hum Pathol 30:1459–1463PubMed
26.
Vingiani A, Maisonneuve P, Dell’orto P, Farante G, Rotmensz N, Lissidini G et al (2013) The clinical relevance of micropapillary carcinoma of the breast: a case-control study. Histopathology 63:217–224PubMed
27.
Luna-Moré S, de los Santos F, Bretón JJ, Cañadas MA (1996) Estrogen and progesterone receptors, c-erbB-2, p53, and Bcl-2 in thirty-three invasive micropapillary breast carcinomas. Pathol Res Pract 192:27–32PubMed
28.
Lewis GD, Xing Y, Haque W, Patel T, Schwartz M, Chen A et al (2019) Prognosis of lymphotropic invasive micropapillary breast carcinoma analyzed by using data from the national cancer database. Cancer Commun 39:60
29.
Yu JI, Choi DH, Huh SJ, Cho EY, Kim K, Chie EK et al (2015) Differences in prognostic factors and failure patterns between invasive micropapillary carcinoma and carcinoma with micropapillary component versus invasive ductal carcinoma of the breast: retrospective multicenter case-control study. Clin Breast cancer 15:353–361PubMed
30.
Ye F, Yu P, Li N, Yang A, Xie X, Tang H et al (2020) Prognosis of invasive micropapillary carcinoma compared with invasive ductal carcinoma in breast: a meta-analysis of PSM studies. The Breast 51:11–20PubMedPubMedCentral
31.
Marchiò C, Iravani M, Natrajan R, Lambros MBK, Geyer FC, Savage K et al (2009) Mixed micropapillary-ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components. J Pathol 218:301–315PubMed
32.
Pareja F, Selenica P, Brown DN, Sebastiao APM, da Silva EM, Da Cruz PA et al (2019) Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma. Histopathology 75:139–145PubMedPubMedCentral
33.
Jackson HW, Fischer JR, Zanotelli VRT, Ali HR, Mechera R, Soysal SD et al (2020) The single-cell pathology landscape of breast cancer. Nature 578:615–620PubMed
34.
Nawaz S, Heindl A, Koelble K, Yan Y (2015) Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Mod Pathol 28:766–777PubMed
35.
Heindl A, Sestak I, Naidoo K, Cuzick J, Dowsett M, Yuan Y (2018) Relevance of spatial heterogeneity of immune infiltration for predicting risk of recurrence after endocrine therapy of ER+ breast cancer. J Nat Cancer Inst 110:166–175
36.
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE et al (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. The Lancet Oncol 19:40–50PubMed
37.
Guo X, Fan Y, Lang R, Gu F, Chen L, Cui L et al (2008) Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast. Mod Pathol 21:1101–1107PubMed
38.
Dawson S-J, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J et al (2010) BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer 103:668–675PubMedPubMedCentral
39.
Callagy GM, Pharoah PD, Pinder SE, Hsu FD, Nielsen TO, Ragaz J et al (2006) Bcl-2 is a prognostic marker in breast cancer independently of the nottingham prognostic index. Clin Cancer Res 12:2468–2475PubMed
40.
Seong M-K, Lee J-Y, Byeon J, Sohn Y-J, Seol H, Lee J-K et al (2015) Bcl-2 is a highly significant prognostic marker of hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Breast Cancer Res Treat 150:141–148PubMed
41.
Bhargava V, Kell DL (1994) Bcl-2 immunoreactivity in breast carcinoma correlates with hormone receptor positivity. Am J Pathol 145:535–540PubMedPubMedCentral
42.
Leek RD, Kaklamanis L, Pezzella F, Gatter KC, Harris AL (1994) bcl-2 in normal human breast and carcinoma, association with oestrogen receptor-positive, epidermal growth factor receptor-negative tumours and in situ cancer. Br J Cancer 69:135–139PubMedPubMedCentral
43.
Doglioni C, Dei Tos AP, Laurino L, Chiarelli C, Barbareschi M, Viale G (1994) The prevalence of BCL-2 immunoreactivity in breast carcinomas and its clinicopathological correlates, with particular reference to oestrogen receptor status. Virchows Arch 424:47–51PubMed
44.
Boyle DP, McArt DG, Irwin G, Wilhelm-Benartzi CS, Lioe TF, Sebastian E et al (2014) The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer. Histopathology 65:340–352PubMed
45.
Dumay A, Feugeas J-P, Wittmer E, Lehmann-Che J, Bertheau P, Espié M et al (2013) Distinct tumor protein p53 mutants in breast cancer subgroups. Int J Cancer 132:1227–1231PubMed
46.
Douglass S, Ali S, Meeson AP, Browell D, Kirby JA (2012) The role of FOXP3 in the development and metastatic spread of breast cancer. Cancer Metastasis Rev 31:843–854PubMed
47.
Lee AHS, Paish EC, Marchio C, Sapino A, Schmitt FC, Ellis IO et al (2007) The expression of Wilms’ tumour-1 and Ca125 in invasive micropapillary carcinoma of the breast. Histopathology 51:824–828PubMed
48.
Domfeh AB, Carley AL, Striebel JM, Karabakhtsian RG, Florea AV, McManus K et al (2008) WT1 immunoreactivity in breast carcinoma: selective expression in pure and mixed mucinous subtypes. Mod Pathol 21:1217–1223PubMed
49.
50.
Silberstein GB, Van Horn K, Strickland P, Roberts CT, Daniel CW (1997) Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 94:8132–8137PubMedPubMedCentral
51.
Zapata-Benavides P, Tuna M, Lopez-Berestein G, Tari AM (2002) Downregulation of Wilms’ tumor 1 protein inhibits breast cancer proliferation. Biochm Biophys Res Commun 295:784–790
52.
Buisseret L, Desmedt C, Garaud S, Fornili M, Wang X, Van den Eyden G et al (2017) Relevance of spatial heterogeneity of immune infiltration for predicting risk of recurrence after endocrine therapy of ER+ breast cancer. Mod Pathol 30:1204–1212PubMed
53.
Eom YH, Kim HS, Lee A, Song BJ, Chae BJ (2016) BCL2 as a subtype-specific prognostic marker for breast cancer. J Breast Cancer 19:252–260PubMedPubMedCentral
54.
Takenaka M, Seki N, Toh U, Hattori S, Kawahara A, Yamaguchi T et al (2013) FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol 1:625–632PubMedPubMedCentral
Metadata
Title
Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical features in invasive micropapillary breast carcinoma with long-term outcomes
Authors
Frederik Deman
Kevin Punie
Annouschka Laenen
Patrick Neven
Eva Oldenburger
Ann Smeets
Ines Nevelsteen
Chantal Van Ongeval
Adinda Baten
Timothy Faes
Melissa Christiaens
Hilde Janssen
Caroline Weltens
Christine Desmedt
Hans Wildiers
Giuseppe Floris
Publication date
01-12-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-020-05913-x

Other articles of this Issue 3/2020

Breast Cancer Research and Treatment 3/2020 Go to the issue

Clinical trial

Comparison of resection margin status after single or double radiopaque marker insertion for tumor localization in breast cancer patients receiving neoadjuvant chemotherapy

Clinical trial

Language impairment among patients with different types of cancer. Comparison with healthy adults

Clinical trial

Diffuse tensor imaging of lower extremities: a novel MR imaging technique for chemotherapy-induced peripheral neuropathy

Epidemiology

Risk of primary urological and genital cancers following incident breast cancer: a Danish population-based cohort study

Epidemiology

Risk factors for implant failure following revision surgery in breast cancer patients with a previous immediate implant-based breast reconstruction

Preclinical study

Correlation of circulating or disseminated tumor cells with the Oncotype DX Recurrence Score
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits