Oral Cavity Quantitative Histomorphometric Risk Classifier (OHbIC) in Oral Cavity Squamous Cell Carcinoma (OC-SCC)

摘要：2018年，美国近34，000名成年人和全球超过275，000名成年人被诊断患有口腔疾病 鳞状细胞癌（OC-SCC）。仅在美国，2018年就有超过6,600人死于这种疾病。除了舞台， 神经周围浸润、淋巴管浸润、浸润深度、切缘接近或明显阳性 用于帮助将患者分为低风险、中等风险或高风险类别。目前，所有OC-SCC患者 主要通过手术切除来治疗。术后治疗取决于患者风险类别。低风险 患者仅接受手术，研究显示PORT（术后放射治疗）的益处 在选定的患者中。回顾性分析了1467例低风险OC-SCC患者，其中740例（50.4%）接受了 与727例单纯手术治疗的患者相比，PORT改善了总生存率。识别这些 患者和更好地分层他们的进展风险是至关重要的。与此同时， 晚期（即中度和高风险）疾病的治疗标准是PORT。选择高风险患者 可以同时进行放化疗或后续化疗。因此，迫切需要 开发伴随诊断工具，以更好地确定哪些患者将从PORT中受益，或者，如果是中间或 高风险，将受益于全身治疗强化。 最近，我们小组开发了一种基于OC-SCC组织形态学的图像风险分类器（OHbIC） 它使用计算机测量细胞核的方向，纹理，形状，结构， H& E染色的肿瘤切片，以识别可能复发的患者与不复发的患者。OHbIC是 在N=115例OC-SCC患者中进行了培训和验证，与疾病相关性高2倍和7倍 与第7版AJCC N-和T-分期（用于患者预后的临床变量）相比的特异性生存率。 在这篇NIH R 01中，我们试图通过结合 涉及基质形态学，肿瘤前沿的侵袭模式， 肿瘤浸润淋巴细胞的密度和模式，以及肿瘤细胞多核化，这些特征现已被认识到 作为OC-SCC预后相关性的潜在组织病理学标志物。此外，我们寻求1）验证 OHbIC作为临床定义的低风险患者生存的预后，并识别那些 将受益于PORT，2）证实OHbIC不仅是生存的预后，而且是获益的预测 局部晚期疾病患者的化疗强化。 这种伙伴关系将利用长期的合作，在（1）数字病理学从马达布胡希 （2）来自范德比尔特的口腔癌外科病理学和肿瘤学专业知识 大学、克利夫兰诊所、弗吉尼亚州旧金山弗朗西斯科和孟买塔塔纪念中心建立OHbIC作为 为OC-SCC患者提供组织无损和经济实惠的精准医学（APM）解决方案。

SUMMARY: In 2018, nearly 34,000 adults in the US and over 275,000 worldwide were diagnosed with oral cavity squamous cell carcinoma (OC-SCC). In the US alone >6,600 died from the disease in 2018. In addition to stage, perineural invasion, lymphovascular invasion, depth of invasion, and close or frankly positive resection margins are used to help stratify patients into low-, intermediate-, or high risk categories. Currently, all OC-SCC patients are treated primarily by surgical resection. Post-operative treatment depends on patient risk category. Low-risk patients receive surgery alone and studies have shown the benefit of PORT (Post-operative radiation therapy) in selected patients. A retrospective analysis of 1467 patients with low-risk OC-SCC where 740 (50.4%) received PORT had improved overall survival compared to 727 patients treated with surgery alone. Identifying these patients and better stratifying their risk of progression is critical. Meanwhile, patients with loco-regionally advanced (i.e. intermediate and high risk) disease are treated with PORT as standard. Select high risk patients may be treated with concomitant chemoradiation or subsequent chemotherapy. There is thus an urgent need to develop companion diagnostic tools to better define which patients will benefit from PORT, or, if intermediate or high risk, who will benefit from systemic therapy intensification. Recently, our group has developed a OC-SCC histomorphometric based image risk classifier (OHbIC) that uses computerized measurements of nuclear orientation, texture, shape, architecture from digital images of H&E-stained tumor sections to identify patients who are likely to recur versus those who are not. OHbIC was trained and validated on N=115 OC-SCC patients, and it had a 2 and 7-fold higher-correlation with disease specific survival compared to the 7th edition AJCC N- and T-stage (clinical variables used in patient prognosis). In this NIH R01, we seek to further improve the prognostic and predictive accuracy of OHbIC by incorporating new classes of image features relating to stromal morphology, pattern of invasion at the tumor leading edge, density and patterns of tumor infiltrating lymphocytes, and tumor cell multi-nucleation, features now recognized as potential histopathological markers of prognostic relevance in OC-SCC. Additionally, we seek to 1) validate OHbIC as prognostic of survival in clinically defined low-risk patients and identify those low-risk patients who would benefit from PORT and 2) validate OHbIC as not only prognostic of survival but also predictive of benefit from chemotherapeutic intensification for patients with loco-regionally advanced disease. This partnership will leverage long-standing collaborations in (1) digital pathomics from the Madabhushi group at Case Western Reserve, (2) surgical pathology and oncology expertise in oral cancer from Vanderbilt University, Cleveland Clinic, San Francisco VA, and Tata Memorial Centre, Mumbai to establish OHbIC as a tissue non-destructive and Affordable Precision Medicine (APM) solution for OC-SCC patients.