Occult Nodal Disease and Occult Extranodal Extension in Patients With Oropharyngeal Squamous Cell Carcinoma Undergoing Primary Transoral Robotic Surgery With Neck Dissection.

IMPORTANCE: The historically reported rates of subclinical cervical nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) predate the emergence of human papillomavirus as the predominant causative agent. The rate of occult nodal disease with changing etiology of OPSCC is not known, and it is challenging to anticipate which patients will be upstaged postoperatively and will require adjuvant therapy. OBJECTIVE: To assess the rate of nodal upstaging and occult extranodal extension (ENE) in a multi-institutional population of patients with pathologic (p)T1-2 OPSCC treated by transoral robotic surgery and neck dissection. DESIGN, SETTING AND PARTICIPANTS: This retrospective, multicenter cohort study of 92 participants at 2 US institutions (Albert Einstein College of Medicine, Bronx, New York [n = 38], and Icahn School of Medicine at Mount Sinai, New York, New York [n = 39]) and 1 Canadian institution (Princess Margaret Hospital, Toronto [n = 15]) examined the rate of postoperative pathologic upstaging for 92 patients with pT1-2 OPSCC undergoing transoral robotic surgery with neck dissection from August 2007 to December 2016. A neuroradiologist at each site blinded to final pathologic diagnosis reviewed preoperative imaging; these findings were compared with operative pathology and applied for tumor staging using the eighth edition of the American Joint Committee on Cancer Cancer Staging Manual. The statistical analysis was performed on December 18, 2018. MAIN OUTCOMES AND MEASURES: Occult pathologic nodal disease and change in nodal category postoperatively. RESULTS: Of 92 patients who met the inclusion criteria, 76 (83%) were male, and they had a mean (SD) age at surgery of 59.5 (10.5) years; 70 patients (84%) with available p16 status were positive. Five of 18 patients (28%) who had no evidence of nodal disease on imaging had occult pathologic nodal disease. Seven of 32 patients (22%) presenting with no nodal disease or with a single metastatic node on imaging received pathologic upstaging because of multiple positive nodes, indicating implementation of additional adjuvant treatment not anticipated after a priori imaging. Changes included 12 patients (13%) who had pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging in the eighth edition of staging. In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence. CONCLUSIONS AND RELEVANCE: Predicting pathologic staging preoperatively for patients with OPSCC undergoing transoral robotic surgery and neck dissection remains a challenge. Although nodal size, tumor size, and location do not help predict ENE, the presence of nodes on imaging and nodal category may help predict ENE. Our findings suggest a small proportion of patients might benefit from further adjuvant therapies not predicted by preoperative imaging based on occult nodal upstaging and ENE.

Occult contralateral nodal disease in oropharyngeal squamous cell carcinoma patients undergoing primary TORS with bilateral neck dissection.

BACKGROUND: Knowledge of the rate of occult contralateral nodal disease for oropharynx cancers (OPSCC) in the era of Human Papillomavirus-dominated disease would inform practitioners as to who may be a candidate for unilateral neck management. The objective of this study was to determine the rate of pathologic contralateral positive nodes in patients in OPSCC patients with pT1 and pT2 disease treated with TORS and bilateral neck dissections (BND). METHODS: Retrospective review of medical records was performed at Princess Margaret Cancer Center, Toronto; Icahn School of Medicine at Mount Sinai, New York City; and Montefiore Medical Center, New York City. Patients with pT1-2 N0-3 (AJCC 8th Edition) OPSCC disease treated with TORS and BND were included. RESULTS: Thirty-two patients met inclusion criteria. Twelve patients (37.5%) had a tonsil primary site, 19 (59.4%) patients had a base of tongue primary site, and 1 (3.1%) patient had a pharyngeal wall primary. Twenty-four (75%) patients were known to be p16+. Twenty-seven patients (84.4%) were radiographically negative in the contralateral neck preoperatively, and two of these patients had pathologic contralateral positive nodes. The occult pathologic contralateral nodal metastasis rate was 7.4% (2/27). The sensitivity, specificity, positive predictive value, and negative predictive value of suspicious contralateral nodes on preoperative imaging for pathologically positive nodes were 33.3%, 86.2%, 20% and 93% respectively. In the p16+ subgroup, the occult nodal positive rate in the contralateral neck was 5%. CONCLUSIONS: pT1-2 OPSCC patients undergoing TORS and elective contralateral neck dissection have a low rate of pathologic contralateral nodal positivity.

Salivary mucoepidermoid carcinoma: a multi-institutional review of 76 patients.

Mucoepidermoid carcinoma (MEC) is a relatively common salivary tumor with varying potential for aggressive behavior. Mucoepidermoid carcinoma grading has evolved from descriptive two-tiered schemata to more objective three-tiered systems. In 2001, we published a grading system Brandwein et al. in Am J Surg Pathol 25:835-845, (2001) which modified the prevailing criteria of Auclair et al. in Cancer 69:2021-2030 (1992), and included additional features of aggressive MEC. Here we seek to validate our modified grading system in a new multicenter cohort. The retrospective cohort consisted of 76 patients with confirmed MEC and known outcome data. The resection specimens were reviewed and uniformly graded according to our modified criteria Brandwein et al. in Am J Surg Pathol 25:835-845 (2001), and the Auclair criteria Auclair et al. in Cancer 69:2021-2030, (1992), Goode et al. in Cancer 82:1217-1224, (1998). Case distribution was as follows: Montefiore Medical Center: 41 (1977-2009), University of Alabama at Birmingham: 21 (1999-2010), and Rhode Island Hospital: 14, (1995-2011). Patient age ranged from 7 to 81 years (mean 51 years). The female to male ratio was 3:1. The most commonly involved sites were: parotid: n = 39 (51%), palate: n = 10 (13%), retromolar trigone: n = 6 (8%), buccal: n = 5 (7%), and submandibular gland: n = 5 (7%). The modified criteria upgraded 41% MEC; 20/25 MEC from AFIP Grade 1 to Grade 2 and 5/25 from AFIP grade 1 to grade 3. Eleven patients had positive lymph nodes; the AFIP MEC grade for cases were: grade 1-3/11, Grade 2-1/11, and grade 3-7/11; the modified grading criteria distribution for these cases were Grade 1: 0/11, grade 2: 1/11, and grade 3: 10/11. Nine patients developed disease progression after definitive treatment. High-stage and positive lymph node status were significantly associated with disease progression (p = 0.0003 and p < 0.0001, respectively). For the nine patients with disease progression, the modified grading schema classified eight MEC as grade 3 and one as grade 2. By comparison, the AFIP grading schema classified three of these MEC as grade 1, and the remaining six as grade 3. Despite the fact that this multicenter retrospective study accrued 76 patients with outcome, the predictive performance of the two grading schema could not be compared due to the few patients who experienced disease progression and were also reclassified with respect to grade (n = 3).

Hypermethylation of a cluster of Krüppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal squamous cell carcinoma.

Identification of epigenetically affected genes has become an important tool for understanding both normal and aberrant gene expression in cancer. Here we report a whole-genome analysis of DNA methylation profiles in fresh-frozen oropharyngeal squamous cell carcinoma (OPSCC) tissues and normal mucosa samples using microarray technology with patient genomic DNA. We initially compared whole-genome patterns of DNA methylation among 24 OPSCC primary tumors and 24 matched normal mucosal samples. From a survey of 27,578 CpG dinucleotide loci spanning more than 14,000 genes, we identified 958 CpG loci in which measurements of DNA methylation were altered in the primary tumors relative to the normal mucosal samples. These alterations were validated in an independent set of 21 OPSCC patients. A survey of these loci by chromosomal location revealed an abnormally high number of differentially methylated loci on chromosome 19. Many of the loci on chromosome 19 are associated with genes belonging to the Krüppel-type zinc finger protein genes. Hypermethylation was accompanied by a significant decrease in expression of these genes in OPSCC primary tumors relative to adjacent mucosa. This study reports the epigenetic silencing of Krüppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal cancer. The aberrant methylation of these genes represents a new avenue of exploration for pathways affected in this disease.

Validation of the histologic risk model in a new cohort of patients with head and neck squamous cell carcinoma.

BACKGROUND: Half of the patients with head and neck squamous cell carcinoma (HNSCC) can be expected to fail therapy, indicating that more aggressive treatment is warranted for this group. We have developed a novel risk model that can become a basis for developing new treatment paradigms. Here we report on the performance of our model in a new multicenter cohort. DESIGN: Eligible patients from 3 institutions (Montefiore Medical Center, University of Manitoba, and New York University Medical Center) were identified and pathology slides from their resection specimens were reviewed by Margaret Brandwein-Gensler; risk category was assigned as previously published. Kaplan-Meier analysis was performed for disease progression and survival. Cox proportional hazards regression was performed, adjusted for potential confounders. A teaching module was also developed; attending pathologists were asked to score coded slides after a lecture and multiheaded microscope teaching session. Agreement was assessed by calculating Cohen unweighted kappa coefficients. RESULT: The validation cohort consisted of 305 patients, from the above institutions, with 311 primary HNSCC of the oral cavity, oropharynx, and larynx. The median follow-up period for all patients was 27 months. Risk category predicts time to disease progression (P=0.0005), locoregional recurrence (P=0.013), and overall survival (P=0.0000) by Kaplan-Meier analysis. High-risk status is significantly associated with decreased time to disease progression, adjusted for clinical confounders (P=0.015, hazard ratio 2.32, 95% confidence interval 1.18-4.58) compared with collapsed intermediate and low-risk groups. We also demonstrate substantial interrater agreement (kappa=0.64), and very good rater agreement when compared with the standard (kappa=0.87). CONCLUSIONS: We demonstrate significant predictive performance of the risk model in a new cohort of patients with primary HNSCC, adjusted for confounders. Our training experience also supports the feasibility of adapting the risk model in clinical practice.