Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer
Authors: Kos Zuzana , Roblin Elvire , Kim Rim S. , Michiels Stefan , Gallas Brandon D. , Chen Weijie , van de Vijver Koen K. , Goel Shom , Adams Sylvia , Demaria Sandra , Viale Giuseppe , Nielsen Torsten O. , Badve Sunil S. , Symmans W. Fraser , Sotiriou Christos , Rimm David L. , Hewitt Stephen , Denkert Carsten , Loibl Sibylle , Luen Stephen J. , Bartlett John M. S. , Savas Peter , Pruneri Giancarlo , Dillon Deborah A. , Cheang Maggie Chon U. , Tutt Andrew , Hall Jacqueline A. , Kok Marleen , Horlings Hugo M. , Madabhushi Anant , van der Laak Jeroen , Ciompi Francesco , Laenkholm Anne-Vibeke , Bellolio Enrique , Gruosso Tina , Fox Stephen B. , Araya Juan Carlos , Floris Giuseppe , Hudeček Jan , Voorwerk Leonie , Beck Andrew H. , Kerner Jen , Larsimont Denis , Declercq Sabine , Van den Eynden Gert , Pusztai Lajos , Ehinger Anna , Yang Wentao , AbdulJabbar Khalid , Yuan Yinyin , Singh Rajendra , Hiley Crispin , Bakir Maise al , Lazar Alexander J. , Naber Stephen , Wienert Stephan , Castillo Miluska , Curigliano Giuseppe , Dieci Maria-Vittoria , André Fabrice , Swanton Charles , Reis-Filho Jorge , Sparano Joseph , Balslev Eva , Chen I-Chun , Stovgaard Elisabeth Ida Specht , Pogue-Geile Katherine , Blenman Kim R. M. , Penault-Llorca Frédérique , Schnitt Stuart , Lakhani Sunil R. , Vincent-Salomon Anne , Rojo Federico , Braybrooke Jeremy P. , Hanna Matthew G. , Soler-Monsó M. Teresa , Bethmann Daniel , Castaneda Carlos A. , Willard-Gallo Karen , Sharma Ashish , Lien Huang-Chun , Fineberg Susan , Thagaard Jeppe , Comerma Laura , Gonzalez-Ericsson Paula , Brogi Edi , Loi Sherene , Saltz Joel , Klaushen Frederick , Cooper Lee , Amgad Mohamed , Moore David A. , Salgado Roberto ,   the International Immuno-Oncology Biomarker Working Group, Hyytiäinen Aini , Hida Akira I. , Thompson Alastair , Lefevre Alex , Gown Allen , Lo Amy , Sapino Anna , Moreira Andre M. , Richardson Andrea , Vingiani Andrea , Bellizzi Andrew M. , Guerrero Angel , Grigoriadis Anita , Garrido-Castro Ana C. , Cimino-Mathews Ashley , Srinivasan Ashok , Acs Balazs , Singh Baljit , Calhoun Benjamin , Haibe-Kans Benjamin , Solomon Benjamin , Thapa Bibhusal , Nelson Brad H. , Ballesteroes-Merino Carmen , Criscitiello Carmen , Boeckx Carolien , Colpaert Cecile , Quinn Cecily , Chennubhotla Chakra S. , Solinas Cinzia , Drubay Damien , Sabanathan Dhanusha , Peeters Dieter , Zardavas Dimitrios , Höflmayer Doris , Johnson Douglas B. , Thompson E. Aubrey , Perez Edith , ElGabry Ehab A. , Blackley Elizabeth F. , Reisenbichler Emily , Chmielik Ewa , Gaire Fabien , Lu Fang-I , Azmoudeh-Ardalan Farid , Peale Franklin , Hirsch Fred R. , Acosta-Haab Gabriela , Farshid Gelareh , Broeckx Glenn , Koeppen Harmut , Haynes Harry R. , McArthur Heather , Joensuu Heikki , Olofsson Helena , Cree Ian , Nederlof Iris , Frahm Isabel , Brcic Iva , Chan Jack , Ziai James , Brock Jane , Weseling Jelle , Giltnane Jennifer , Lemonnier Jerome , Zha Jiping , Ribeiro Joana , Lennerz Jochen K. , Carter Jodi M. , Hartman Johan , Hainfellner Johannes , Le Quesne John , Juco Jonathan W. , van den Berg Jose , Sanchez Joselyn , Cucherousset Joël , Adam Julien , Balko Justin M. , Saeger Kai , Siziopikou Kalliopi , Sikorska Karolina , Weber Karsten , Steele Keith E. , Emancipator Kenneth , El Bairi Khalid , Allison Kimberly H. , Korski Konstanty , Buisseret Laurence , Shi Leming , Kooreman Loes F. S. , Molinero Luciana , Estrada M. Valeria , Van Seijen Maartje , Lacroix-Triki Magali , Sebastian Manu M. , Balancin Marcelo L. , Mathieu Marie-Christine , van de Vijver Mark , Rebelatto Marlon C. , Piccart Martine , Goetz Matthew P. , Preusser Matthias , Khojasteh Mehrnoush , Sanders Melinda E. , Regan Meredith M. , Barnes Michael , Christie Michael , Misialek Michael , Ignatiadis Michail , de Maaker Michiel , Van Bockstal Mieke , Harbeck Nadia , Tung Nadine , Laudus Nele , Sirtaine Nicolas , Burchardi Nicole , Ternes Nils , Radosevic-Robin Nina , Gluz Oleg , Grimm Oliver , Nuciforo Paolo , Jank Paul , Kirtani Pawan , Watson Peter H. , Jelinic Peter , Francis Prudence A. , Russell Prudence A. , Pierce Robert H. , Hills Robert , Leon-Ferre Roberto , de Wind Roland , Shui Ruohong , Leung Samuel , Tabbarah Sami , Souza Sandra C. , O’Toole Sandra , Swain Sandra , Dudgeon Sarah , Willis Scooter , Ely Scott , Bedri Shahinaz , Irshad Sheeba , Liu Shiwei , Hendry Shona , Bianchi Simonetta , Bragança Sofia , Paik Soonmyung , Luz Sua , Gevaert Thomas , d’Alfons Timothy , John Tom , Sugie Tomohagu , Kurkure Uday , Bossuyt Veerle , Manem Venkata , Cámaea Vincente Peg , Tong Weida , Tran William T. , Wang Yihong , Allory Yves , Husain Zaheed , Bago-Horvath Zsuzsanna 
Published: May 2020

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.