Squamous cell carcinoma of the oral cavity in nonsmoking women: a new and unusual complication of chemotherapy for recurrent ovarian cancer?

PURPOSE: To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer. PATIENTS AND METHODS: In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed. RESULTS: All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m2 given over 30-132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD. CONCLUSION: Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.

Anterior Approach to the Subaxial Cervical Spine: Pearls and Pitfalls.

Since its introduction by Smith and Robinson, the anterior approach to the subaxial cervical spine has become one of the standard procedures for numerous cervical spine pathologies, including, but not limited to degenerative disease, trauma, tumor, deformity, and instability. Along with its increasing popularity and improvements in anterior instrumentation techniques, a comprehensive knowledge of the surgical anatomy during the anterior exposure is critical for trainees and experienced spine surgeons alike to minimize the infrequent but potentially devastating risks associated with this approach. Understanding the anatomy and techniques to minimize damage to relevant structures can reduce the risks of developing notable postoperative complications and morbidity.

Prognostic potential of mid-treatment nodal response in oropharyngeal squamous cell carcinoma.

BACKGROUND: We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy. METHODS: In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1. RESULTS: At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND <43%. On multivariate analysis, D20 ≥43% was independently prognostic for LRC (HR 1.17, P = .05). CONCLUSION: Patients with low-risk oropharynx cancer with ND of ≥43% by treatment day 20 had significantly improved LRC. The prognostic benefit of ND may assist in identifying candidates for treatment de-escalation.

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant.

Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype-phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

The basis of racial differences in the incidence of thyroid cancer.

BACKGROUND: The incidence of thyroid cancer in black Americans is half that in white Americans. It is unknown whether this gap represents a population difference in disease or is attributable to inferior cancer screening in the black population. METHODS: A population-based cohort study of 53,990 patients (1973-2003) was performed using the National Cancer Institute's Surveillance Epidemiology End Results database. Socioeconomic variables were explored using the Healthcare Cost and Utilization Project database and macroeconomic data. RESULTS: Since 1973, thyroid cancer incidence among whites has increased 150.2% (4.0 to 9.9 of 100,000), while incidence among blacks has increased 73.2% (3.0 to 5.1 of 100,000). Across 17 regions, the incidence correlated with the percentage of the population with health insurance (r = 0.56, P = .02). Regression analysis suggested that half of the black-white incidence gap might be attributable to differences in health insurance status. Patients with thyroid cancer were more likely to be insured or reside in wealthier ZIP codes. Black patients were more likely to present at advanced age (RR 1.08, P < .0001) and with tumors >4 cm in size (RR 1.13, P <.0001). Black patients were slightly less likely to present with advanced disease (RR 0.96, P = .0008). Cancer-specific mortality was identical in the two populations. DISCUSSION: Sociodemographic data and differences at presentation support a small detection disparity in thyroid cancer, which may contribute to part of the incidence gap. However, this effect is not sufficiently strong to fully explain the incidence gap. A population difference in the incidence of disease may be coexistent.

Malpractice litigation after surgical injury of the spinal accessory nerve: an evidence-based analysis.

OBJECTIVE: To review the background, case characteristics, and outcomes of malpractice litigation resulting from surgical injury of the spinal accessory nerve. DESIGN: Retrospective review of indemnity insurance cases (part 1) and court trials (part 2) between January 1, 1985, and January 1, 2007. In part 1, records of the Medical Liability Mutual Insurance Company identified 41 lawsuits in New York State; part 2 was a review of a national legal database (WestLaw) that identified 81 court trials. Case details were analyzed, and awards were adjusted for inflation. RESULTS: For part 1, of 41 indemnity insurance cases, 39 (95%) involved a posterior triangle lymph node biopsy. Defendants were mainly general surgeons and otolaryngologists. Most lawsuits against surgeons (22 of 34 [65%]) were settled before trial, and only 4 of 34 (12%) were discontinued. Of these 34 cases, 28 (82%) ultimately compensated the plaintiff. The mean inflation-adjusted pretrial settlement was $264 395, and the mean settlement at trial was $443 538. Cases reaching trial received significantly higher settlements (P = .01). For part 2, 81 cases of alleged surgical injury to the spinal accessory nerve were identified. Defendant physicians were mainly general surgeons and otolaryngologists. Most operations were cervical lymph node biopsies (55 [68%]), followed by sebaceous cyst excisions (6 [7%]), neck dissections (4 [5%]), and other procedures (12 [15%]). Morbidity included weakness (81 patients [100%]), pain (30 patients [37%]), inability to work (20 patients [25%]), need for a nerve repair procedure (16 patients [20%]), deformity (9 patients [11%]), and numbness (4 patients [5%]). Types of malpractice alleged included negligent surgical technique (79 cases [98%]), lack of informed consent (17 cases [21%]), and failure to diagnose the injury (16 cases [20%]). Thirty-seven cases (46%) were decided for the defendant, 32 (40%) were decided for the plaintiff, and 12 (15%) were settled (percentages do not total 100 because of rounding). The mean inflation-adjusted settlement was $356 132, and the mean jury award was $515 968. Jury awards were significantly higher than settlements (P = .003). CONCLUSIONS: Unintended injury to the spinal accessory nerve after head and neck surgery is a significant source of malpractice litigation. Timely diagnosis and treatment of this complication are essential. Regardless of whether the medical community considers careful surgical technique and nerve preservation to be the standard of care, the legal system clearly treats it as such, awarding compensation in 82% of cases. Strategies for optimal surgical care and litigation risk reduction are discussed.

Oropharyngeal kaposi sarcoma in related persons negative for human immunodeficiency virus.

OBJECTIVES: Kaposi sarcoma (KS) is a vascular tumor that can affect the mucosa of the upper aerodigestive tract. Although KS is the most common malignancy in patients with acquired immunodeficiency syndrome, it is rare in immunocompetent persons. We describe an unusual presentation of KS in 2 related individuals and describe our attempts to determine whether oropharyngeal KS is associated with human herpesvirus 8 (HHV-8). METHODS: All relevant clinical and surgical information, including information on tumor histopathologic and human immunodeficiency virus (HIV) serologic tests, was abstracted from the patient charts and electronic databases. HHV-8 immunohistochemistry was performed on paraffin-fixed specimens. RESULTS: Both patient 1 and patient 2 (the nephew of patient 1) were referred for workup of a tonsillar mass that was pathologically confirmed to be KS. In each case, HIV serologic testing was negative, and a screening immunologic workup, including a quantitative natural killer cell count, a B- and T-lymphocyte count, and immunoglobulin analysis, also yielded findings that were within normal limits. Immunohistochemistry performed on 1 pathological specimen showed positive staining for the presence of HHV-8, the etiologic agent of KS. CONCLUSIONS: The presence of oropharyngeal KS in 2 related HIV-negative individuals supports a role for genetic factors in susceptibility to KS, a common exposure to an infectious agent such as HHV-8, or both. Whereas most KS cases in industrialized countries are associated with immunodeficiency, clinical and laboratory data do not suggest that either of the patients described in this report are immunodeficient. Their susceptibility to KS may be secondary to a subtle inherited defect in host resistance to HHV-8, or another unknown factor.

Quantitative evaluation of transtemporal and facial translocation approaches to infratemporal fossa.

OBJECTIVE: To compare the extent of exposure and surgical maneuverability provided by facial translocation and transtemporal approaches for access to the infratemporal fossa and anterolateral skull base. MATERIALS AND METHODS: Surgical procedures were performed on five fresh frozen adult cadavers (ten sides) with no known pathology. Facial transfacial approaches with and without a mandibulotomy and transtemporal approaches were evaluated. OBJECTIVE measures were (1) the distance from the surgical plane to designated anatomic landmarks and (2) the surgical angle of exposure. RESULTS: Distances from the surgical plane to the anatomic reference points were comparable for most of the access procedures (3 to 6 cm). The extended midfacial translocation and bilateral facial translocation approaches did, however, provide a shorter operative distance (1 to 3 cm) for access to the infratemporal fossa and contralateral structures, respectively. The transtemporal approaches facilitate a better angle of exposure (74 to 84 degrees) to the petrotemporal region, while the transfacial approaches were superior for access to the infratemporal structures. CONCLUSIONS: Based on the results, we propose a clinical algorithm for selecting a surgical approach based on the position and extent of an infratemporal or petrotemporal lesion.

Early experience with minimally invasive esophagectomy in head and neck surgical patients.

BACKGROUND: Minimally invasive esophagectomy (MIE) via thoracoscopy and laparoscopy have reduced the morbidity and mortality of total esophagectomy at experienced centers. MIE has not been evaluated in combination with major head and neck surgery, or in the otolaryngology literature. METHODS: Case series of 11 consecutive patients undergoing either open or MIE with an ablative neck procedure. RESULTS: Comparing 4 MIEs and 7 open operations, similar operative time, blood loss, and ICU and hospital length of stay were observed. There was one mortality in the open group. A 100% rate of major complications was observed in the MIE group. CONCLUSION: Our multidisciplinary team was unable to achieve improved outcomes in a series of head and neck surgical patients undergoing MIE. This result may represent an early stage of the learning curve for MIE, but may also be attributed to the escalated surgical requirements of head and neck patients.

Factors in Successful Elimination of Elective Tracheotomy in Mandibular Reconstruction With Microvascular Tissue.

IMPORTANCE: Limited data exist on performing major oral cavity resections and reconstructions without elective tracheotomy. OBJECTIVES: To describe a group of patients who successfully underwent major microvascular mandibular reconstruction without an elective tracheotomy and to perform a literature review to identify commonalities between our group and the available literature to identify potential common factors that might contribute to the success of this approach. DESIGN, SETTING, AND PARTICIPANTS: Case series with retrospective medical chart review of 15 patients who underwent fibula microvascular free flap reconstruction of mandibular defects without tracheotomy between 2000 and 2014 (the most common indication was osteoradionecrosis) conducted at a tertiary referral hospital center. EXPOSURES: Mandibular reconstruction with fibula free flap without elective tracheotomy. MAIN OUTCOMES AND MEASURES: Perioperative morbidity and mortality with a focus on airway management and perioperative complications. RESULTS: The median age of 15 patients (11 males and 4 females) at the time of reconstruction was 42 years (range, 10-64 years). The indication for surgery was nonmalignant pathologic abnormalities in 8 patients (53%), osteosarcoma in 4 patients (27%), and oral cavity squamous cell carcinoma in 3 patients (20%). All patients were intubated endonasally and, excepting 1 pediatric case, were extubated the day following surgery. The fibula spanned the parasymphysis and/or symphysis in 2 patients, and was limited to the mandibular body in others (mean length, 7.6 cm [range, 4.0-15.0 cm]). The flap design was osteocutaneous in 3 patients and osseous in the rest. No patient required reintubation or tracheotomy. No complications due to endonasal intubation occurred. The average hospital length of stay was 11 days. CONCLUSIONS AND RELEVANCE: Major oral cavity resection and reconstruction with microvascular free flaps can be performed safely without elective tracheotomy in a select group of patients. Limited data exist on patient selection criteria. Further studies are needed to identify favorable factors and develop protocols for safe patient selection.

Comparison of quality of life outcomes in laryngeal cancer patients following chemoradiation vs. total laryngectomy.

OBJECTIVE: To evaluate quality of life issues in patients with laryngeal cancer after treatment with either chemoradiation or total laryngectomy and radiation therapy. METHODS: Forty-nine patients with a history of stage II-IV laryngeal squamous cell carcinoma treated primarily with either chemoradiation or by total laryngectomy with postoperative radiation completed the University of Washington Quality of Life instrument, version 4. Patients were identified on a volunteer basis in an academic university head and neck clinic setting. Each patient completed the above instrument, and statistical analysis was performed by Wilcoxon and chi 2 tests. RESULTS: Instruments were completed by all 49 patients: 15 patients who underwent primary chemoradiation and 34 patients who underwent a total laryngectomy followed by radiation. Domains reported in both treatment groups without significant differences were appearance, activity, recreation, moods, taste, saliva, anxiety, and general questions. However, there were significant differences between the 2 groups in the domains of pain, swallowing, chewing, speech, and shoulder function. The laryngectomy patients reported greater impairment of speech (P = 0.001), and shoulder function (P = 0.018), whereas the chemoradiation patients suffered from greater pain, difficulty swallowing (P = 0.061), and problems chewing (P = 0.027). CONCLUSIONS: Most patients with laryngeal cancer, whether treated primarily with chemoradiation or total laryngectomy, reported excellent functional outcomes and health-related quality of life. Pain, swallowing, chewing, saliva, and shoulder function were recorded as significant factors affecting their daily quality of life.

The changing demographics of head and neck squamous cell carcinoma in the United States.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma (HNSCCA) has declined in the United States since the late 1970s. During this time, substantial immigration from other countries has occurred, and the average lifespan has increased. We tested the hypothesis that these trends have altered the HNSCCA patient population. STUDY DESIGN: Retrospective analysis was made of population-based data from the SEER database, a national registry capturing roughly 10% of all U.S. cancer diagnoses. METHODS: We examined all unique diagnoses of HNSCCA in the database from 1976 to 1999 and determined the breakdown of cases by age, sex, and race. RESULTS: The absolute number of new HNSCCA diagnoses per year declined overall by 5% during the time period of the study, whereas new diagnoses in patients older than 74 years of age increased by more than 20%. The rate of HNSCCA per 100,000 person-years in elderly women did not change, and the rate in elderly men decreased, indicating that the observed increase in cases is explained by a growing population of elderly persons at risk. An increase in the absolute number of cases, but not the incidence rate, was also seen among persons younger than 50 years of age. Although both the absolute number of new cases and the incidence rates of HNSCCA in white male patients declined substantially, the percentage of HNSCCA patients classified as minorities increased from 14.5% to more than 20% of all cases. During the time period of the study, the overall number of HNSCCA cases in nonwhite and Hispanic patients increased by 36%. CONCLUSION: Increasing numbers of elderly and minority patients with HNSCCA are likely to alter patterns of disease and utilization of health care resources.

Tissue-specific gene expression of head and neck squamous cell carcinoma in vivo by complementary DNA microarray analysis.

OBJECTIVES: To identify distinct gene expression profiles of human head and neck squamous cell carcinomas (HNSCCAs) using complementary DNA (cDNA) microarray analysis and to create a preliminary, comprehensive database of HNSCCA gene expression. PATIENTS AND METHODS: Nine patients with histologically confirmed HNSCCAs, staged according to the American Joint Committee on Cancer, were enrolled. The HNSCCA tumor tissue and normal mucosal tissue were harvested at the time of surgery. A cDNA library was constructed from the paired fresh-frozen human surgical specimens of HNSCCAs and nonmalignant epithelial tissues. Biotinylated RNA was transcribed from the cDNA library and hybridized to high-density microarrays containing approximately 12 000 human genes. Altered gene expression of HNSCCAs was identified by comparison to corresponding normal mucosal tissues after a bayesian statistical analysis of variance. Results were analyzed using the gene database of the National Institutes of Health. Hierarchical clustering of the genomic data sets was determined by similarity metrics based on Pearson correlation. RESULTS: Hierarchical clustering analysis revealed that the gene expression profiles obtained from the nonselected panel of 12 000 genes could distinguish the tumors from nonmalignant tissues. Gene expression changes were reproducibly observed in 227 genes representing previously identified chemokines, tumor suppressors, differentiation markers, matrix molecules, membrane receptors, and transcription factors that correlated with neoplasia, including 46 previously uncharacterized genes. Moreover, significant expression of the collagen type XI alpha1 gene and a novel gene was reproducibly observed in all 9 tumors, whereas these genes were virtually undetectable in their corresponding, adjacent nonmalignant tissues. CONCLUSIONS: Complementary DNA microarray analysis of human HNSCCAs has produced a preliminary, comprehensive database of tumor-specific gene expression profiles and provided important insights into modeling gene expression changes implicated in carcinogenesis. A large-scale analysis of gene expression carries the future potential of identifying sensitive molecular markers for early tumor detection, prognosis, and novel targets for interceptive therapeutics.

A precision method for contouring bioresorbable implants in craniomaxillofacial surgery.

Bioresorbable implants (meshs and plates) are increasingly used in reconstructive craniofacial and skull base surgery. Usually these implants must be contoured to fit the complex craniofacial anatomy ex vivo; occasionally final contouring is performed in vivo and must be done without damaging surrounding structures (e.g., dura, brain). We report a precision method for in vivo contouring of bioresorbable implants using the Shaw hemostatic thermal scalpel.

Changes in abundance of oral microbiota associated with oral cancer.

Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.

Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation.

Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORγt, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.