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Tumor Budding and Cell Nest Size Are Highly Prognostic in Laryngeal and Hypopharyngeal Squamous Cell Carcinoma

Further Evidence for a Unified Histopathologic Grading System for Squamous Cell Carcinomas of the Upper Aerodigestive Tract

Boxberg, Melanie, MD*; Kuhn, Peer-Hendrik, PhD*; Reiser, Marianne, MD*; Erb, Anna, BSc*; Steiger, Katja, MD(vet)*; Pickhard, Anja, MD; Straßen, Ulrich, MD; Koob, Isabelle; Kolk, Andreas, MD, DDS; Warth, Arne, MD§,∥; Jesinghaus, Moritz, MD*; Weichert, Wilko, MD, PhD*,¶,#

The American Journal of Surgical Pathology: March 2019 - Volume 43 - Issue 3 - p 303–313
doi: 10.1097/PAS.0000000000001178
Original Articles

Squamous cell carcinoma (SCC) is the most common cancer of the head and neck region including—among others—laryngeal (LSCC) and hypopharyngeal (HSCC) subsites. LSCC/HSCC are heterogenous diseases with respect to patient outcome. Currently, tumor stage–based patient stratification is essential to predict prognosis and thus selection of the appropriate treatment modalities. In contrast, the prognostic impact of the current HSCC/LSCC grading system according to the WHO classification is limited. Recently, a novel grading system based on tumor budding activity (BA) and cell nest size (CNS) has been introduced for SCC in different anatomic regions of the upper aerodigestive tract. To test and transvalidate this grading scheme in LSCC and HSCC, we retrospectively correlated BA, CNS, and additional histomorphologic parameters with clinicopathologic data of 157 treatment-naive patients. In doing so, we demonstrate that a 3-tiered novel grading system (well-differentiated [nG1], intermediately [nG2], and poorly differentiated [nG3]) based on a sum score for BA and CNS is highly and independently prognostic for patient survival in LSCC/HSCC, strongly outperforming the current WHO grading scheme with a hazard ratio for disease-specific survival of 6.6 for nG2 and 13.4 for nG3 cases (P<0.001). This finding contributes to a growing body of evidence that a CNS and BA-based pan-entity grading system in SCC might be useful and seems to capture differences in underlying SCC biology crucial for survival.

*Institute of Pathology, Technical University of Munich

Department of Otolaryngology

Department of Head and Neck Surgery, Klinikum Rechts der Isar, Munich

§Institute of Pathology, Heidelberg University

National Center of Tumor Diseases (NCT)

Institute of Pathology, Cytopathology, and Molecular Pathology, UEGP, Gießen/Wetzlar/Limburg

#German Cancer Consortium (DKTK), Heidelberg, Germany

M.B. and P.-H.K. contributed equally.

Conflicts of Interest and Source of Funding: Supported by the German Cancer Consortium (to W.W.) and by the Else-Kröner-Fresenius Stiftung (to M.B.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Wilko Weichert, MD, PhD, Institute of Pathology, Technical University of Munich, Trogerstrasse 18, Munich 81675, Germany (e-mail:

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