Multifocal perineural invasion is a better prognosticator than depth of invasion in oral squamous cell carcinoma

Hasmat, Shaheen; Ebrahimi, Ardalan; Gao, Kan; Low, Tsu-Hui Hubert; Gupta, Ruta; Clark, Jonathan

doi:10.1002/hed.25940

Cited by 21 publications

(29 citation statements)

References 26 publications

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“…To address these issues, also two staging parameters, DOI and RM, which can be assessed during pathohistological examination of HE-slides, were evaluated separately. In concordance with other publications [43,47,48] resection margin could not be identified as a significant predictor of survival or LM, even when summarizing patients into subgroups (RM ≤ 1 mm, ≤ 5 mm, > 5 mm) according to values previously published as significant prognostic indicators [26,27]. These findings can possibly be explained with complete (R0) tumor resection being achieved in all patients of this collective and because mean RM was 6.0 mm and the number of patients with involved (RM ≤ 1 mm) margins was only 5.…”

Section: Resection Marginssupporting

confidence: 92%

Staging more important than grading? Evaluation of malignancy grading, depth of invasion, and resection margins in oral squamous cell carcinoma

et al. 2020

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Objectives The present study evaluated the predictive value of staging and grading parameters concerning the presence of lymph-node metastases, overall survival (OS), and relapse-free survival (RFS) of patients with oral squamous cell carcinoma (OSCC). Materials and methods HE-stains of 135 surgically treated (R0) primary OSCCs were analyzed using a both microscopic and software-based approach. Depth of invasion (DOI) and resection margins (RM) were measured, and each case was graded according to the malignancy grading system as described by Anneroth et al. and Bryne et al. on two different sites of the tumor (surface and invasion front; TS and IF). Results Parameters that could be identified as significant predictors of OS and RFS were UICC cancer stage (p = 0.009 and p = 0.012); pT-stage as defined in the 7th edition (p = 0.029 and 0.015) and, after restaging using DOI, 8th edition (p = 0.023 and p = 0.005) of the TNM classification of malignant tumors; the presence of lymphonodular metastases (LM) (p = 0.004 and p = 0.011); degree of keratinization (p = 0.029 and p = 0.042); and pattern of growth (p = 0.029 and p = 0.024) at the TS after applying a binary scale for both parameters. Also, when directly comparing the most extreme subgroups (scores 1 and 4) of lymphoplasmacytic infiltration at the IF, there was a significant difference in OS (p = 0.046) and RFS (p = 0.005). Invasion of blood vessels (p = 0.013) and perineural invasion (p = 0.023) were significantly associated with a lower OS. Age lower than 60 years (univariate p = 0.029, multivariate p = 0.031), infiltration of lymphatic vessels (p = 0.003), infiltration of nerves (p = 0.010), pT-stage (8th edition) (p = 0.014), degree of keratinization at the IF (p = 0.033), and nuclear polymorphism at the IF (p = 0.043) after conversion to a binary scale were found to be significant prognostic parameters regarding the presence of LM. DOI evolved as a significant predictor for OS (p = 0.006), RFS (p = 0.003), and LM (p = 0.032) in metric and grouped analysis. Conclusions The current evaluation revealed depth of invasion as strongest histologic predictor of metastatic tumor growth, overall survival, and relapse-free survival in OSCC, confirming the current adaption of the T-classification. Other distinct histologic grading parameters investigated during this study can give valuable indications of a tumor’s potential aggressiveness, but the exact site, mode, and procedure need further exploration. Clinical relevance Integrating measurement of DOI also into the pretherapeutic staging process could aid in treatment planning.

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Section: Resection Marginssupporting

confidence: 92%

Staging more important than grading? Evaluation of malignancy grading, depth of invasion, and resection margins in oral squamous cell carcinoma

et al. 2020

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“…Hence, the inclusion of PNI in the AJCC staging system might contribute in improving survival prediction of patients and their adverse risk stratification (Mattavelli et al, 2020;Rahman et al, 2020;Tai, Li, Yang, et al, 2012). In support to this statement, Hasmat et al demonstrated a better prognostication of multifocal PNI than depth of invasions in OSCC (Hasmat et al, 2019). We included PNI characteristics in the 8th AJCC Staging system, by upstaging by two classes patients with multifocal and both intra-peritumoral PNI.…”

Section: Survival Analysismentioning

confidence: 94%

“…1.372-5.367, p-value = 0.004). Effects of number PNI foci were investigated in a dichotomous approach(Hasmat et al, 2019) and according to Wei et al (2019) and Chinn et al (2013) and classifications. Although the promising results coming from multivariate analysis, only 3 patients reported a number of foci greater of 5 (Wei et al DSS, HR = 6.530, 95% C.I.…”

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confidence: 99%

Pattern and localization of perineural invasion predict poor survival in oral tongue carcinoma

et al. 2021

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Background Survival rate for oral tongue squamous cell carcinoma (OTSCC) is still poor and, despite Tumor–Node–Metastasis staging system has been recently updated, patients included under the same stage still show difference in prognosis. Perineural invasion (PNI) emerged to be an indicator of tumor aggressive behavior and unfortunate events. In this study, we investigate the clinic and prognostic value of PNI in a cohort of OTSCC patients. Methods About 200 patients with OTSCC were retrospectively evaluated the presence of PNI. PNI was furtherly descripted as uni‐/multifocal and as intra‐/peritumoral. Disease‐Specific and Relapse‐Free Survival (DSS; RFS) were estimated; moreover, we included PNI in the current AJCC 8th Staging System, improving the prognostication model. Results Perineural invasion was found in 40.5% of patients. Intratumoral PNI predicted patients at high risk of being diagnosed with lymph–node metastasis. Tumors with positive PNI reported a worse DSS (Hazard Ratio=1.878, p‐value = 0.008). Moreover, patients exhibiting both multifocal intra‐ and peritumoral PNI reported poorest DSS (Hazard Ratio = 2.409, p‐value = 0.010). Patients were reclassified in a new staging system in case of multifocal PNI, providing better stratification capacity. Conclusions Perineural invasion might serve as an additional prognostic factor in OTSCC, and by integrating PNI in the staging system, further improvements in prognostication might be reached.

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“…This has led to great variability in clinical studies focused on PNI (15). To overcome this limitation, some studies investigated parameters associated with PNI to enhance its significance as a predictor of prognosis (11,16,(22)(23)(24)(49)(50)(51)(52). These include number (16,22,23,52), location (51,52), and diameter of PNI-positive nerves (11,22,49,51,53).…”

Section: Discussionmentioning

confidence: 99%

Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer

Schmitd

Perez-Pacheco

Bellile

et al. 2022

Clinical Cancer Research

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Purpose: Perineural invasion (PNI), a common occurrence in oral squamous cell carcinomas, is associated with poor survival. Consequently, these tumors are treated aggressively. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. To address these knowledge gaps, we investigated spatial and transcriptomic profiles of PNI-positive and PNI-negative nerves. Experimental Design: Tissue sections from 142 patients were stained with S100 and cytokeratin antibodies. Nerves were identified in two distinct areas; tumor bulk and margin. Nerve diameter and nerve-to-tumor distance were assessed; survival analyses were performed. Spatial transcriptomic analysis of nerves at varying distances from tumor was performed with NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas. Results: PNI is an independent predictor of poor prognosis among patients with metastasis-free lymph nodes. Patients with close nerve-tumor distance have poor outcomes even if diagnosed as PNI-negative using current criteria. Patients with large nerve(s) in the tumor bulk survive poorly, suggesting that even PNI-negative nerves facilitate tumor progression. Diagnostic criteria were supported by spatial transcriptomic analyses of >18,000 genes; nerves in proximity to cancer exhibit stress and growth response changes that diminish with increasing nerve-tumor distance. These findings were validated in vitro and in human tissue. Conclusions: This is the first study in human cancer with high-throughput gene-expression analysis in nerves with striking correlations between transcriptomic profile and clinical outcomes. Our work illuminates nerve-cancer interactions suggesting that cancer-induced injury modulates neuritogenesis, and supports re-classification of PNI based on nerve-tumor distance rather than current subjective criteria.

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Multifocal perineural invasion is a better prognosticator than depth of invasion in oral squamous cell carcinoma

Cited by 21 publications

References 26 publications

Staging more important than grading? Evaluation of malignancy grading, depth of invasion, and resection margins in oral squamous cell carcinoma

Staging more important than grading? Evaluation of malignancy grading, depth of invasion, and resection margins in oral squamous cell carcinoma

Pattern and localization of perineural invasion predict poor survival in oral tongue carcinoma

Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer

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