Reconstruction for Salvage Laryngectomy With Limited Pharyngectomy.

Importance: Closure technique for optimization of postoperative and functional outcomes following salvage laryngectomy remains an area of debate among head and neck surgeons. Objective: To investigate the association of salvage laryngectomy closure technique with early postoperative and functional outcomes. Design, Setting, and Participants: This retrospective cohort study included patients from 17 academic, tertiary care centers who underwent total laryngectomy with no or limited pharyngectomy after completing a course of definitive radiotherapy or chemoradiotherapy with curative intent between January 2011 and December 2016. Patients with defects not amenable to primary closure were excluded. Data were analyzed from February 14, 2021, to January 29, 2024. Exposures: Total laryngectomy with and without limited pharyngectomy, reconstructed by primary mucosal closure (PC), regional closure (RC), or free tissue transfer (FTT). Main Outcomes and Measures: Patients were stratified on the basis of the pharyngeal closure technique. Perioperative and long-term functional outcomes were evaluated with bivariate analyses. A multivariable regression model adjusted for historical risk factors for pharyngocutaneous fistula (PCF) was used to assess risk associated with closure technique. Relative risks (RRs) with 95% CIs were determined. Results: The study included 309 patients (256 [82.8%] male; mean age, 64.7 [range, 58.0-72.0] years). Defects were reconstructed as follows: FTT (161 patients [52.1%]), RC (64 [20.7%]), and PC (84 [27.2%]). A PCF was noted in 36 of 161 patients in the FTT group (22.4%), 25 of 64 in the RC group (39.1%), and 29 of 84 in the PC group (34.5%). On multivariable analysis, patients undergoing PC or RC had a higher risk of PCF compared with those undergoing FTT (PC: RR, 2.2 [95% CI, 1.1-4.4]; RC: RR, 2.5 [95% CI, 1.3-4.8]). Undergoing FTT was associated with a clinically meaningful reduction in risk of PCF (RR, 0.6; 95% CI, 0.4-0.9; number needed to treat, 7). Subgroup analysis comparing inset techniques for the RC group showed a higher risk of PCF associated with PC (RR, 1.8; 95% CI, 1.1-3.0) and predominately pectoralis myofascial flap with onlay technique (RR, 1.9; 95% CI, 1.2-3.2), but there was no association of pectoralis myocutaneous flap with cutaneous paddle interposition with PCF (RR, 1.2; 95% CI, 0.5-2.8) compared with FTT with cutaneous inset. There were no clinically significant differences in functional outcomes between the groups. Conclusion and Relevance: In this study of patients with limited pharyngeal defects, interpositional fasciocutaneous closure technique was associated with reduced risk of PCF in the salvage setting, which is most commonly achieved by FTT in academic practices. Closure technique was not associated with functional outcomes at 1 and 2 years postoperatively.

Air pollution is associated with increased incidence-rate of head and neck cancers: A nationally representative ecological study.

INTRODUCTION: Early studies show conflicting findings regarding particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and development of head and neck cancers (HNC). We analyzed the relationship between PM2.5 exposure and various types of HNC in a nationally representative ecological sample. METHODS: We determined HNC incidence in 608 US counties from 2011 to 2019 using the Surveillance, Epidemiology and End Results (SEER) Program from the National Cancer Institute. We also collected information on sociodemographic factors from SEER and data on smoking and alcohol intake from CDC data frames (county level). PM2.5 exposure levels were estimated using satellite and meteorological data via previously validated general additive models. Flexible semi-nonparametric regression models were used to test the relationship between PM2.5 exposure levels and HNC incidence, adjusting for demographics, socioeconomic factors, and comorbidity. RESULTS: Increased PM2.5 exposure levels were associated with higher incidence-rates of oral cavity and pharyngeal cancers controlling for confounders in our primary analyses (IRR = 1.04, 95 % CI 1.01, 1.07, p = 0.02 per 1 µg/m3 increase in PM2.5). This relationship was maintained after adjusting for multiple testing (Holm s method, p = 0.04) and in ordinary least squares (OLS) regression (ß = 0.17, 95 % CI 0.01, 0.57, p = 0.01). Increased exposure was also associated with other HNC: esophagus (IRR = 1.06, 95 % CI 1.01, 1.11, p = 0.02), lip (IRR = 1.16, 95 % CI 1.03, 1.31, p = 0.01), tonsil (IRR = 1.10, 95 % CI 1.03, 1.16, p < 0.01). However, these relationships were not maintained in secondary analyses. CONCLUSIONS: This nationally representative ecological study shows that increased levels of air pollution are associated with increased incidence of overall oral cavity and pharyngeal cancers in the US.

A Nationwide Analysis of Head and Neck Fibromatoses.

BACKGROUND: Head and neck fibromatoses (HNFs) are a rare, diverse group of soft tissue tumors characterized by an abnormal proliferation of fibroblasts. Available literature on these tumors is limited to case reports and small single-institutional studies. OBJECTIVE: We aim to provide demographic, socioeconomic, tumor-related, and treatment characteristics of HNFs. DESIGN: Retrospective cohort analysis using the National Cancer Database (NCDB). METHODS: The NCDB was queried for fibromatosis-related histologic codes located within the head and neck region. Various factors were analyzed. Univariate and multivariate survival analyses were performed. RESULTS: Between 2004 and 2016, 130 patients were included in the analyses. Average age was 57.4 years old with a predominance of White (83.6%) males (61.5%). Non-desmoid HNFs accounted for 60%-70% of the tumors. The salivary gland was the most common location (38.5%) and more than half of the tumors were high grade. The majority were treated surgically (90.8%) and 25% had positive margins. Mean and median overall survival (OS) were 98.9 and 135.4 months, respectively. Surgery is associated with better OS than nonsurgical alternatives. Addition of adjuvant treatments was not associated with differences in survival. CONCLUSION: In the largest study to date, we describe demographic, socioeconomic, tumor-related, and treatment patterns of patients with this rare disease. These tumors are most frequently present in middle-aged males with high-grade histology. Most are treated surgically and positive surgical margins are common. Surgery has better OS than nonsurgical alternatives. While adjuvant radiation has become more common, we found no difference in survival compared to surgery alone. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:2228-2235, 2024.

A Novel Immobilization Method for the Treatment of Head and Neck Cancer Using 3D Printing.

Proper immobilization is critical for the delivery of high-quality radiation therapy. In cases when traditional immobilization is not feasible, 3-dimensional (3D) printing may provide a better-tolerated custom immobilization that is comparably effective. We present the successful treatment of a patient with inoperable oropharyngeal squamous cell carcinoma who was unable to tolerate traditional immobilization. To avoid covering the face, we created a 3D-printed cradle for the back of his head and neck. This design enabled the patient to tolerate traditional simulation scans with and without intravenous contrast and was subsequently able to undergo volumetric modulated arc therapy treatment. He successfully underwent treatment without evidence of disease more than 2 years after completion. The effect of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of treatment options available to patients.

Infratemporal Fossa Abscess Drainage via a Trans-Oral Image Guided Approach.

Deep neck space infections can cause antibiotic-resistant abscesses that can impinge on vital anatomical structures. Image-guided surgery systems using preoperative computed tomography (CT) imaging can be utilized to characterize pathology and assist surgeons in avoiding iatrogenic injury. This manuscript explores the presentation and unique CT-guided surgical management of an infratemporal fossa abscess in a 48-year-old male who presented with left-sided dental pain and facial swelling that had progressed despite antibiotics and dental extraction. CT-guided imaging can assist in localizing and protecting vital anatomical structures during deep neck abscess drainage and can prevent the potential risks and complications of classic surgical approaches.

A nationwide analysis of salvage surgery for laryngeal cancer in the elderly.

BACKGROUND: We aim to describe outcomes of elderly patients undergoing salvage surgery for laryngeal cancer and to characterize the interplay of age with various other factors in this growing population. METHODS: Using the National Cancer Database, we identified cases of salvage laryngectomy in patients who failed chemoradiation. An age cutoff of 70 years was used to separate subjects into two groups. Various factors were compared. RESULTS: Of the 825 patients included, 166 (20.1%) were elderly. Elderly patients had worse overall survival (p = 0.001), higher 30-day and 90-day mortality (p = 0.006, p < 0.001), and a longer length of stay (LOS) (p = 0.015). LOS over 1 week was associated with worse survival (p = 0.032). CONCLUSION: Elderly patients had worse overall perioperative survival than their younger counterparts. LOS and 30-day readmissions were associated with higher risk of mortality in this group. We provide a contemporary set of relevant information for head and neck cancer providers to consider in this growing population.

Impact of Routine Surveillance Imaging on Recurrence in Sinonasal Malignancies.

BACKGROUND/AIM: There is significant variation in post-treatment surveillance imaging for sinonasal malignancies. This study examined the utility of surveillance imaging in detecting recurrence in patients treated for sinonasal malignancies. PATIENTS AND METHODS: We performed a retrospective review on an IRB-approved dataset of patients with sinonasal malignancies treated at a single institution between 2005 to 2021. Patients were categorized into groups based on the frequency of annual imaging and total number of imaging studies. We compared time-to-recurrence between the groups using log-rank test. A two-sided p-value of <0.05 was considered as the threshold for significance. RESULTS: A total of 93 patients were eligible for this study with a median follow up of 42.3 months and 25.8% (n=24) of patients had documented recurrence. Sensitivity and specificity for recurrence based on computed tomography (CT) scans within one year of treatment completion were 50.0% and 19.5%; positron emission tomography/CT was 90.0% and 19.5%; and magnetic resonance imaging was 60.0% and 61.0%, respectively. Regardless of the type of imaging, symptomatic presentation after treatment had a specificity of 91.0% with a positive likelihood ratio of recurrence of 2.95 (95%CI=1.06-8.22). The frequency of scans was not associated with the risk of recurrence (HR=0.55; 95%CI=0.23-1.29, p=0.17). Similarly, no association was noted between the total number of scans and risk of recurrence (HR=0.64; 95%CI=0.27-1.51, p=0.31). CONCLUSION: The total number of frequency of scans within the first year after treatment had no association with time to recurrence of sinonasal malignancies. Symptomatic presentation was strongly associated with recurrence and should be investigated with appropriate imaging.

Patient safety and quality improvements in parotid surgery.

Parotidectomy is the mainstay treatment for tumors of the parotid gland. In an effort to improve clinical outcomes, several modern surgical techniques and perioperative interventions have been evaluated and refined. This review discusses current and actively debated perioperative interventions aimed at improving patient safety and the quality of parotidectomy. Relevant high-impact literature pertaining to preoperative diagnostic modalities, intraoperative surgical techniques, and postoperative care will be described.

Designing an evidence-based free-flap pathway in head and neck reconstruction.

Background: The use of autologous free-tissue transfer is an increasingly utilized tool in the ladder of reconstructive options to preserve and restore function in patients with head and neck cancer. This article focuses on the evidence surrounding perioperative care that optimizes surgical outcomes and describes one tertiary center's approach to standardized free-flap care. Data Sources: This article examines English literature from PubMed and offers expert opinion on perioperative free-flap care for head and neck oncology. Conclusion: Free-flap reconstruction for head and neck cancer is a process that, while individualized for each patient, is best supported by a comprehensive and standardized care pathway. Surgical optimization begins in the preoperative phase and a thoughtful approach to intraprofessional communication and evidence-based practice is rewarded with improved outcomes.

Association of HPV status with survival after surgical salvage of oropharyngeal cancers.

OBJECTIVES: This study used the National Cancer Database to determine the effect of human papillomavirus (HPV) on survival outcomes for recurrent oropharyngeal cancer treated with salvage surgery after initial treatment with radiation therapy or chemoradiation therapy. METHODS: Patients with recurrent oropharyngeal cancer receiving salvage surgery after initial treatment with adjuvant therapy were identified through the National Cancer Database. Demographics, tumor characteristics, and survival data were collected. The data were analyzed to identify factors that may be associated with survival. RESULTS: A total of 169 patients were included, 59% of which were HPV-positive cases and 41% were HPV-negative. On univariate analysis, HPV-positive cases had higher overall survival compared to HPV-negative cases. However, on multivariate analysis, the association with HPV status was no longer statistically significant while positive surgical margins, higher T-stage at initial diagnosis, and a greater comorbidity burden were significantly associated with poorer survival. CONCLUSION: In the salvage setting for treatment of recurrent oropharyngeal squamous cell carcinoma, HPV status may not be associated with improved survival.

Effect of histopathological grade on treatment and survival in base of tongue adenocarcinoma.

OBJECTIVES: The purpose of this study was to investigate survival differences between low-grade and high-grade base of tongue (BOT) adenocarcinoma by examining demographics, tumor characteristics, and treatment modalities. METHODS: The National Cancer Database was queried for patients with BOT adenocarcinoma between 2004 and 2017. Univariate and multivariate analyses were performed for all cases of BOT adenocarcinoma. Subsequent analysis focused on low-grade (grade 1 and grade 2) and high-grade (grade 3 and grade 4) BOT adenocarcinoma. RESULTS: A total of 286 patients with BOT adenocarcinoma were included in the main cohort and divided into low grade (n = 137) and high grade (n = 66). The 5-year overall survival for all patients, low-grade, and high-grade was 67%, 85%, and 58%, respectively. Prognostic factors associated with decreased survival for the main cohort include advanced age (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02-1.06), non-white race (HR: 1.79; 95% CI: 1.04-3.25), public insurance (HR: 1.79; 95% CI: 1.02-3.14) and high-grade 3,4 (HR: 2.63; 95% CI: 1.51-4.56). The prognostic factor associated with increased survival for the main cohort was surgery (HR: 0.59; 95% CI: 0.36-0.96). Radiotherapy was associated with improved overall survival for high-grade BOT adenocarcinoma (HR: 0.09; 95% CI: 0.02-0.49) but not for low-grade BOT adenocarcinoma (HR: 0.93; 95% CI: 0.38-2.32). CONCLUSIONS: This investigation is the largest to date analyzing the association of treatment modalities with overall survival in BOT adenocarcinoma. Surgery remains standard of treatment, particularly in low-grade cases, with radiotherapy offering additional survival benefit for high-grade BOT adenocarcinoma.

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics.

Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles "ACPSVs" for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation.

Management of Cutaneously Exposed Carotid Stents in Recurrent and Unresectable Head and Neck Cancer.

Objective Carotid blowout syndrome (CBS) is a rare but potentially life-threatening complication of head and neck cancer (HNC) treatment. Patients with CBS are managed with covered stents, limited published information exists regarding the management of delayed complications, specifically cutaneous exposure of stents. Here, we present our experience managing cutaneously exposed carotid artery stents (CAS) in patients with recurrent and unresectable HNC. Methods A single-institution retrospective analysis was performed to identify recurrent HNC patients who underwent CAS placement for CBS and complicated with cutaneous exposure of the stent between 2014 and 2016. Medical records were reviewed with attention to treatment history, pre-, intra-, and postoperative courses, anticoagulation needs, and durability of the reconstruction. Results We identified three patients who presented with a right CAS fully exposed in a large, ulcerative wound. All patients underwent a right pectoralis major myocutaneous flap (PMMF) to cover the exposed stent within 30 days of presentation to our institution. Two of three patients attained adequate coverage of the stent for more than 30 days, while one experienced partial flap dehiscence within 12 days. Two patients developed postoperative chest hematomas, which were managed conservatively. Two of three patients were able to undergo further palliative adjuvant treatments within 60 days of the initial surgical procedure. Conclusion In this small series, durable coverage of an exposed carotid artery with PMMF was successful in two of three patients with extensive disease burden and complex prior treatment history. No mortalities occurred within 30 days postoperatively.

Laryngeal Chondrosarcoma Characteristics and Survival Analysis in the National Cancer Database.

OBJECTIVE: To highlight various patient, tumor, diagnostic, and treatment characteristics of laryngeal chondrosarcoma (LC) as well as elucidate factors that may independently affect overall survival (OS) for LCs. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database (NCDB). METHODS: All LC cases from 2004 to 2016 were extracted from the NCDB. Several demographic, diagnostic, and treatment variables were compared between LC subgroups using χ2 and analysis of variance tests. Univariate and multivariate survival analyses were performed for LCs using univariate Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: There were 348 LCs included in the main cohort. LCs were predominantly non-Hispanic white males with similar rates of private and government insurance (49.4% vs 45.4%). Most LCs (81.6%) underwent primary surgery, particularly partial and total laryngectomy. The 1-, 5-, and 10-year survivals for LC were 95.7%, 88.2%, and 66.3%, respectively. On multivariate analysis, lack of insurance (P = .019; hazard ratio [HR], 8.21; 95% CI, 1.40-48.03), high grade (P = .001; HR, 13.51; 95% CI, 3.08-59.26), and myxoid/dedifferentiated histological subtypes (P = .0111; HR, 10.74; 95% CI, 1.71-67.33) correlated with worse OS. No difference in OS was found between partial and total laryngectomy. CONCLUSION: This is the first multivariate survival analysis and largest single cohort study of LCs in the literature. Overall, LCs enjoy an excellent prognosis, with insurance status, grade, and histology as the main predictors of survival.

Neck Dissection in Salvage Surgery for Larynx Cancer: National Cancer Database Review.

OBJECTIVE: Salvage laryngeal surgery is the preferred treatment after failure of non-surgical treatment of larynx cancer. This study aims to identify the impact of ND in salvage surgery on survival and factors predictive of nodal metastasis. METHODS: The National Cancer Database was used to identify patients who received salvage laryngeal surgery. Demographics, disease characteristics, and survival were compared between the subgroups of patients stratified according to performance of ND and presence of nodal metastasis. RESULTS: Sixty-two percent of patients underwent ND. A total of 26% of patients undergoing ND had nodal metastasis. Younger age and lesser time since radiation were associated with nodal metastasis. While undergoing ND did not significantly affect survival, those with nodal metastasis had poorer survival (P = .001). CONCLUSIONS: Although ND did not show a survival benefit, younger patients and those who have had a shorter time elapsed between the start of radiation and salvage surgery may benefit from the prognostic data provided by ND. Nonetheless, the risks and benefits of elective ND in salvage larynx cancer treatment should be evaluated on an individual case basis as the data do not support a broadly applicable recommendation.

Cytopathologic assessment of gloves and instruments after major head and neck surgery.

PURPOSE: To investigate the potential for cancer cells to be transferred between anatomic sites via instruments and other materials. MATERIALS AND METHODS: Pilot prospective study from April 2018-January 2019 at Rush University Medical Center. Glove and instrument washings were collected from 18 high-risk head and neck cancer resection cases (36 samples total). Each case maintained at least one of the following features in addition to a diagnosis of squamous cell carcinoma or sarcoma: palliative/salvage surgery, positive margins, extensive tumor burden, and/or extra capsular extension (ECE). Surgical gloves and four main instruments were placed through washings for blind cytological assessment (2 samples/case). RESULTS: 18 patients undergoing surgical tumor resection for biopsy-proven squamous cell carcinoma with at least one of the aforementioned characteristics were included. 26.7% of cases had ECE, 40.0% had positive final margins and 46.7% had close final margins. Tumor locations included: oral cavity (10), neck (4), parotid gland (2), and skin (2). Malignant cells were isolated on glove washings in 1 case (5.5%). No malignant cells were isolated from instrument washings. The single case of malignant cells on glove washings occurred in a recurrent, invasive squamous cell carcinoma of the scalp with intracranial extension. Anucleated squamous cells likely from surgeon skin were isolated from 94.4% of washings. Squamous cells were differentiated from mature cells by the absence of nuclei. CONCLUSIONS: Malignant squamous cells can be isolated from surgical glove washings, supporting the practice of changing of gloves after gross tumor resection during major head and neck cancer resections.

Targeted 595-gene genomic profiling demonstrates low tumor mutational burden in olfactory neuroblastoma.

BACKGROUND: Olfactory neuroblastoma (ONB) is a rare skull-base malignancy associated with delayed local recurrence. Treatment options in recurrent disease are few and unreliable. We undertook analysis of the ONB exome and immune environment in order to identify potential future immunotherapy treatment options. METHODS: Retrospective chart review and next-generation targeted 595-gene genomic profiling was performed on a cohort of 14 ONB cases utilizing Tempus proprietary DNA and RNA sequencing technology. Tempus analysis provided a measurement of tumor mutational burden (TMB) and composition of the immune cell infiltrate present in tumor samples. Clinically relevant genomic alterations and associated targeted therapies were identified using cancer.gov and clinicaltrials.gov. TMB was tested by univariate analysis against clinical stage, pathologic grade, recurrence risk, and immune cell infiltration. RESULTS: The mean age for the subjects was 50 years (range, 13 to 76 years) with a male:female ratio of 1:1. TMB for ONB samples ranged from 1.3 to 9.6 mutations/megabase (Mb) with mean of 3.8 mutations/Mb. Univariate analysis showed no association between TMB and tumor stage, pathologic grade, risk of recurrence, or immune cell infiltration. Genomic profile revealed that 6 of 13 tumors had genetic alterations with targeted therapies in clinical trials, whereas 1 tumor demonstrated KRAS Q61R mutation with U.S. Food and Drug Administration (FDA)-approved targeted therapies. CONCLUSION: TMB is a novel biomarker guiding the classification of neoplasms in the emerging era of immunotherapy. The characterization of ONB as a low-TMB pathology contributes to the overall taxonomy of all cancers and suggests limited utility of immunotherapy treatment.

Is Regional Lymph Node Metastasis of Head and Neck Paraganglioma a Sign of Aggressive Clinical Behavior: A Clinical/Pathologic Review.

BACKGROUND: Head and neck paraganglioma is a rare neoplasm of the paraganglia. It accounts for <1% of all head and neck tumors. It usually has benign clinical course; however, malignant paraganglioma can only be diagnosed by showing metastatic disease. We undertook a retrospective study to assess the clinical significance of regional lymph nodes metastases in head and neck paragangliomas. DESIGN: From 1993 to 2016, primary head and neck paragangliomas are identified. The patient clinical and histopathologic materials were reviewed. RESULTS: Sixty-five specimens from 62 patients (3 patients with more than 1 specimens) with head and neck paragangliomas were recorded (49 female and 13 males) with mean age of 54 (24-78 years). The locations of the tumors were as follows: carotid body: 30, glomus tympanicum: 11, glomus jugulare: 14, parapharyngeal space: 3, and 1 case each of larynx, skull base, paraglottic area, infratemporal fossa, mastoid, cerebellopontine (CP) angle, and pyriform sinus. On histopathology, we found 5 cases of sclerosing variant. Thirty-two (52%) of the 62 patients had regional lymph node biopsy. Four (12%) of the 32 show metastatic paraganglioma (3 females and 1 male with mean age = 35). Two of the 5 cases of sclerosing variant had positive lymph nodes. No evidence of local recurrence or distant metastasis in the patients with positive lymph nodes with a 6 to 11 years follow-up. One of the 28 patients with negative lymph nodes developed metastatic disease to lumbar spine in 5 years. CONCLUSION: Metastatic paraganglioma to regional lymph nodes may have indolent clinical behavior, with disease-free survival of up to 11 years. The incidence of metastatic disease in lymph nodes was 4 (12%) of 32. Forty percent (2/5) of the cases with sclerosing variant of paraganglioma had lymph node metastases indicating that this tumor may have a more aggressive histological behavior.