Extratumoral invasion: A unique phenomenon of aggressive recurrent oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous carcinomas cause significant morbidity and mortality. Poor prognosticators include lymphovascular and perineural invasion. Extratumoral phenotypes of these histologic findings confer worse prognoses. METHODS: We report eight cases of recurrent oropharyngeal cancer with diffuse extratumoral lymphovascular invasion (ELVI) or extratumoral perineural invasion (EPNI) and review the existing literature. RESULTS: On salvage resection for recurrence following primary radiation or chemoradiation, six patients manifested ELVI and two showed EPNI. These patterns conferred difficulty with complete surgical clearance; final pathologic analysis demonstrated positive margins for all eight patients. The six patients with ELVI were p16+ and the two with EPNI were p16-. Currently, two patients are deceased and six patients are alive at an average follow-up of 17.4 months. Of the six living patients, 2 have a new recurrence and are in hospice while 4 have no evidence of disease. CONCLUSIONS: ELVI and EPNI have received little consideration in the literature as unique histopathologic features of oropharyngeal squamous carcinoma. We present the first series on these adverse extratumoral features in recurrent disease. We call attention to these unique histologic features in the setting of recurrent oropharyngeal cancer to encourage others to track the results of therapeutic intervention and to identify successful strategies for treatment.

The anatomical basis for preserving the blood supply to the parathyroids during thyroid surgery, and a review of current technologic advances.

BACKGROUND: Devascularization of the parathyroid glands is generally accepted as the most common mechanism for iatrogenic hypocalcemia, a frequently seen complication of both total and completion thyroidectomy procedures. Much has been written about iatrogenic hypoparathyroidism, but few papers have precisely delineated the arterial supply of the parathyroid glands and the common anatomical variations that may impact parathyroid preservation during thyroid surgery. METHODS: We offer an illustrated review and discussion of the only two anatomic studies published in the medical literature focusing on parathyroid vasculature. In addition, we examine current techniques of parathyroid identification, preservation, and classification. FINDINGS: A surgical technique that preserves the parathyroid arteries is vital to preserving the viability of the parathyroid gland(s) during thyroid surgery. In 1907, Halsted and Evans described a technique of ligating the distal branches of the thyroid arteries beyond the origin of the parathyroid arteries, a technique termed ultra-ligation. In 1982, Flament et al.. reported three distinct anatomical variations of the parathyroid arteries which place the parathyroid blood supply at risk for devascularization during thyroid surgery. Our review also highlights novel techniques that aid surgeons in identification and assessment of the parathyroid glands. CONCLUSIONS: Recognition of the variations of parathyroid anatomy and their potential to lead to devascularization aids thyroid surgeons in their pursuit of parathyroid preservation. An awareness of the variety of novel parathyroid identification and preservation techniques can assist surgeons to achieve this goal.

Reconstruction of the external auditory canal: The tragal flap revisited and review of contemporary reconstructive techniques.

BACKGROUND: Primary malignancies arising in the external auditory canal (EAC) are rare and usually are treated surgically. We review techniques to reconstruct the EAC following ablative surgery, and introduce a rarely utilized tragal skin flap which has particular advantages for reconstruction of limited anterior EAC defects. METHODS: The terms "tragal flap", "external auditory canal", "preauricular tragal flap", "reconstructive techniques" were searched on PubMed and Google Scholar. RESULTS: Our review identified one description of a tragal flap to reconstruct the EAC following resection of a malignancy. We add an additional case of a preauricular tragal flap to reconstruct the anterior EAC following resection of a recurrent basal cell carcinoma located in the EAC that led to a circumferential defect. CONCLUSION: There are several surgical techniques that can be utilized to reconstruct the EAC. We describe a novel tragal flap used to reconstruct the anterior EAC following resection of a recurrent tumor.

Diagnosis and management of pharyngoesophageal stenosis: A comprehensive approach to prophylactic, endoscopic, and reconstructive treatment options.

BACKGROUND: Pharyngoesophageal stenosis (PES) is a serious complication that substantially impacts functional outcomes and quality of life (QOL) for up to a third of head and neck cancer patients who undergo radiotherapy. Dysphagia is often multifactorial in nature and is a devastating complication of treatment that impacts patients' QOL, general health and overall wellbeing. The authors detail the clinical presentation, risk factors, imaging characteristics, preventive measures, and multimodality treatment options for PES. METHODS: The authors present a comprehensive management algorithm for PES, including treatment by dilation, stenting, spray cryotherapy and dilation, and reconstructive treatment options utilizing different pedicled and free flaps. RESULTS: The authors advocate for a thorough assessment of the extent and degree of pharyngoesophageal involvement of PES to determine the optimal management strategy. CONCLUSIONS: The development of post treatment dysphagia requires appropriate imaging and biopsy, when indicated, to rule out the presence of persistent/recurrent cancer. Multidisciplinary management by a team of physicians well-versed in the range of diagnostic and therapeutic interventions available for PES is critical to its successful management.

Vaccinia virus outperforms a panel of other poxviruses as a potent oncolytic agent for the control of head and neck squamous cell carcinoma cell lines.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Existing therapies for advanced tumors have high failure rates and can have severe consequences in terms of pain, disfigurement, and poor speech and swallowing function. New treatment strategies are needed to improve outcomes for patients suffering with this disease and oncolytic viruses represent a promising approach. METHODS: We infected six well-characterized HNSCC cell lines (Cal27, Detroit562, FaDu, SCC4, SCC15, SCC25), with increasing doses of a panel of poxviruses (including myxoma, vaccinia, raccoonpox and tanapox viruses) modified to express green fluorescence protein to determine which virus was the most effective oncolytic agent in cell-based assays. RESULTS: While myxoma, raccoonpox and tanapox displayed differing efficacy in the panel of cell lines, vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling cell growth in all cell lines. CONCLUSION: Oncolytic poxviruses, particularly vaccinia virus, were effective in killing HNSCC in vitro and hold promise as potential treatments for patients with HNSCC.

HPV-negative head and neck cancers with adverse pathological features carry specific molecular changes that are associated with survival.

BACKGROUND: Adverse pathological features following surgery in head and neck squamous cell carcinoma (HNSCC) are strongly associated with survival and guide adjuvant therapy. We investigated molecular changes associated with these features. METHODS: We downloaded data from the Cancer Genome Atlas and Cancer Proteome Atlas HNSCC cohorts. We compared tumors positive versus negative for perineural invasion (PNI), lymphovascular invasion (LVI), extracapsular spread (ECS), and positive margins (PSM), with multivariable analysis. RESULTS: All pathological features were associated with poor survival, as were the following molecular changes: low cyclin E1 (HR = 1.7) and high PKC-alpha (HR = 1.8) in tumors with PNI; six of 13 protein abundance changes with LVI; greater tumor hypoxia and high Raptor (HR = 2.0) and Rictor (HR = 1.6) with ECS; and low p38 (HR = 2.3), high fibronectin (HR = 1.6), low annexin A1 (HR = 3.1), and high caspase-9 (HR = 1.6) abundances with PSM. CONCLUSIONS: Pathological features in HNSCC carry specific molecular changes that may explain their poor prognostic associations.

A novel method of hard palate reconstruction utilizing a combination of the buccal fat pad and palatal island flap.

The palatal island flap is reliable for single-staged reconstruction of select oral defects. However, fistula formation is a disruptive potential complication. The authors employed this technique in five patients and present a representative case of a 65-year-old female with a left-sided palatal salivary neoplasm. The patient underwent resection and was reconstructed utilizing a combination of the buccal fat pad and palatal island flap. Four of the five patients healed uneventfully. One patient experienced partial loss of the marginal zone of the palatal island flap which successfully granulated and did not lead to an oroantral fistula. The representative patient recovered uneventfully. At 2 weeks, she felt well, with no evidence of fistula. The anterior palate demonstrated early mucosalization. We present the novel, combined use of the palatal island flap and buccal fat pad flap to create a two-layer closure and describe its advantages for posterior palate reconstruction.

Adenoid Cystic Carcinoma of the Gingiva: A Case Report and Literature Review.

OBJECTIVES: Adenoid cystic carcinoma (ACC) is a commonly encountered salivary gland malignancy. However, it rarely occurs in the gingiva, an area generally thought to be devoid of minor salivary glands. We present a case occurring in this unusual site and review other reported cases. METHODS: A 56 year-old male presented with a right-sided mandibular toothache for 1 year and underwent dental extraction. Due to persistent pain, follow up examination revealed a large gingival lesion. A biopsy was positive for adenoid cystic carcinoma. RESULTS: The patient underwent a complete right segmental mandibulectomy and was reconstructed with a fibular osteocutaneous free flap. Three months postoperatively, during the planning for adjuvant radiation therapy, the patient developed pain in the left mandible. Imaging revealed extensive involvement of the left native mandible. Deep bone biopsies in several areas of the left mandible revealed ACC. He then underwent a complete left hemi-mandibulectomy and reconstruction with a fibular osteocutaneous free flap. Tensor fascia lata suspension slings were placed due to concern for an open mouth deformity attributable to disruption of bilateral masticator slings. He will undergo adjuvant radiation therapy. Our review of the literature revealed 50 cases of gingival ACC published since 1972. Disease recurrence and distant metastases were noted in several patients, occurring at the latest after 30 years follow-up. CONCLUSIONS: Given its indolent behavior, high proclivity for late recurrence and metastasis, and overall infrequency, ACC represents a pathology that requires early diagnosis and comprehensive long-term surveillance. While ACC is well described in oral cavity sites with high densities of minor salivary glands, it is not commonly seen in the gingiva. As such, gingival ACC may display a unique biological and/or clinical character. We offer the first literature review of this rare entity.

Novel technique to prevent or correct open-mouth deformity after bilateral mandibular resection: Use of tensor fascia lata slings.

Open-mouth deformity after mandibular resection presents a challenge for surgeons and patients, contributing to significant functional and cosmetic morbidity. We present an innovative surgical technique to prevent or correct open-mouth deformity. Tensor fascia lata slings were utilized in combination with maxillomandibular fixation to surgically correct or prevent open-mouth deformity in four patients who had previously undergone mandibulectomy or at the time of a contralateral mandibulectomy following prior hemimandibulectomy and reconstruction. Two patients achieved favorable outcomes, including oral competence and improved resting jaw position, while open-mouth deformity could not be corrected for one patient. Another patient remains in the early postoperative period following a secondary procedure to correct open-mouth deformity. Open-mouth deformity is a functional/aesthetic problem that has not been addressed in the literature. Use of tensor fascia lata slings to suspend the mandible is a novel approach to the surgical management of open-mouth deformity.

Staged Head and Neck Reconstruction: Heresy or a Reasoned Approach in a Select Group of Patients?

Study Design: case series. Objective: The restoration of defects in a single procedure with microvascular free flap reconstruction has become a mainstay of head and neck surgery. Yet in patients with complex defects and pre-existing comorbid medical conditions, a staged-reconstructive approach can enhance the safety of the procedure and improve the patient's outcome. Methods: We present 3 representative case examples of a larger series of patients who underwent reconstruction of major defects and discuss the usefulness of a staged-reconstructive approach in the management of complex patients. Results: All 3 patients, with an existing composite defect in the setting of prior radiation therapy, underwent successful staged-reconstructive surgery using a variety of free tissue and regional flap transfers. Conclusions: A staged approach facilitates the reconstruction of complex composite defects, increases vessel availability, and mitigates the risk of flap failure. Although this approach commits the patient to multiple procedures and a more prolonged plan of care, it is preferable to 1 operation in specific complex situations with adverse, high-risk clinical features.

Transoral robotic surgery for the identification of unknown primary head and neck squamous cell carcinomas: Its effect on the wait and the weight.

BACKGROUND: Neck carcinoma of unknown primary (CUP) is a frequent scenario. Transoral robotic mucosectomies (TORM) of pharynx have increased rate of primary identification, but come with cost of treatment delay. METHODS: We reviewed patients who underwent CUP protocol from 2014 to 2020. Patients with cervical nodes carcinoma and failure to localize a primary source were classified as CUP. We determined primary identification rate and postoperative complications. RESULTS: We included 65 patients underwent TORM. Surgical approach consisted of lingual and/or palatine tonsillectomies. The primary detection rate was 49.2%. Average weight reduction was 2.5 ± 4.3 kg. The average number of days from consultation to definitive treatment was 52.2 ± 18.3. CONCLUSION: A systematic approach to patients with CUP showed a promising primary identification rate compared to panendoscopy alone. TORM carries a small risk of complications. The benefits of primary identification must be weighed with the morbidity and delay to definitive treatment.

Cuneiform (cuniculatum) variant of oral squamous cell carcinoma revisited: Presentation of two cases and literature review of a rare entity.

BACKGROUND: Oral carcinoma cuniculatum (OCC) is a rare, locally aggressive tumor, which tends to invade underlying bone. We present two cases of OCC, one demonstrating invasion of the mandible and the other limited to the tongue. METHODS: An 87-year-old male presented with a right-sided buccogingival lesion. Biopsy results led to a diagnosis of verrucous hyperplasia, which was later revised to OCC. Additionally, a 94-year-old female presented with a left lateral tongue lesion. A biopsy showed in-situ and invasive keratinizing squamous cell carcinoma that was later defined as a soft tissue OCC. RESULTS: Following surgical resection, the diagnosis of OCC was established in both patients. We provide a comprehensive literature review of OCC in the context of both case presentations. CONCLUSIONS: OCC is a rare entity, which has a tendency to be misdiagnosed. We emphasize the importance of recognizing the common features of OCC in order to aid in accurate diagnosis.

Unusual location of a second branchial cleft cyst presenting in the suprasternal notch.

BACKGROUND: Second branchial cleft cysts (SBCCs) are congenital benign tumors that comprise up to 90% of all branchial cleft anomalies. SBCCs typically present in the lateral neck along the anterior border of the upper third of the sternocleidomastoid muscle. We describe a case of a SBCC presenting in an unusual location in the lower neck close to midline. METHODS: An 18-year-old male presented with a 2-year history of a neck mass in the suprasternal notch. Imaging findings were reviewed with a head and neck radiologist who felt that the findings were highly suggestive of a fourth branchial cleft cyst. RESULTS: The patient underwent surgical excision of the mass. Final pathologic evaluation confirmed the diagnosis of a second branchial cleft cyst. CONCLUSIONS: Though extremely uncommon, second branchial cleft cysts can extend to the suprasternal notch and should not be excluded from the differential diagnoses of lower neck masses.

First reported PET positive, FDG avid free flap pedicle ossification and review of the literature.

The fibular free flap (FFF) is commonly used for head and neck bony reconstruction. Ossification of the vascular pedicle has been reported but is an uncommon complication of this procedure. Ossification of the pedicle with FDG avidity has not been identified in the literature. Here we present a case of FDG avid free flap ossification seen on PET/CT imaging in a patient who developed trismus after fibular free flap reconstruction of a maxillary defect for a primary squamous cell carcinoma of the palate. The FDG avidity of the free flap ossification and trismus were both concerning for recurrent squamous cell carcinoma.

Rare case of metastatic liposarcoma to the thyroid gland and a review of the literature of metastatic sarcomas to the thyroid.

BACKGROUND: Liposarcomas are the second most common type of soft tissue sarcomas. Typically, myxoid liposarcomas have a metastatic rate of 10%, usually involving the retroperitoneal space, abdomen, and spine. Metastasis to the thyroid is extremely rare. DESIGN/METHOD: A 62-year-old male with a history of metastatic myxoid liposarcoma in his right thigh presented to our clinic for evaluation of a thyroid nodule incidentally identified on a CT scan. A subsequent FNA biopsy was suggestive of a metastatic liposarcoma. RESULTS: The patient underwent a left thyroid lobectomy and final pathology confirmed a grade II/III metastatic myxoid liposarcoma that measured 3.3 cm. The patient tolerated the procedure well. CONCLUSIONS: Our case highlights the role of a patient's medical history when evaluating thyroid nodules to optimize accurate diagnosis, as liposarcomas do not typically metastasize to the thyroid. We also provide an updated review of the literature on all cases of metastatic sarcomas to the thyroid.

Rare case of anaplastic plasmacytoma in the sinonasal tract.

BACKGROUND: Extramedullary plasmacytomas are tumors that develop from plasma cells and rarely express anaplastic features. To our knowledge, there have only been three reported cases of anaplastic plasmacytomas of the sinonasal tract in the English literature. We detail the fourth case. METHODS: A 70-year-old male was seen with a 4-month history of nasal congestion, bloody mucous, and left sided nasal obstruction. On positron emission tomography/computed tomography, the lesion was FDG-avid with an SUVmax of 25.1. A biopsy of the lesion and subsequent immunohistochemical staining confirmed the diagnosis of an anaplastic plasmacytoma. RESULTS: The patient is undergoing a 5-week course of curative-intent radiation therapy. CONCLUSION: Extramedullary plasmacytomas with anaplastic features are very rare. We highlight the value of thorough histopathological review and detailed immunostains to arrive at a diagnosis of anaplastic extramedullary plasmacytoma.

Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis.

BACKGROUND: Frequent mutations in the nuclear receptor binding SET domain protein 1 (NSD1) gene have been observed in head and neck squamous cell carcinomas (HNSCC). NSD1 encodes a histone 3 lysine-36 methyltransferase. NSD1 mutations are correlated with improved clinical outcomes and increased sensitivity to platinum-based chemotherapy agents in human papillomavirus-negative (HPV-) tumors, despite weak T-cell infiltration. However, the role of NSD1 and related family members NSD2 and NSD3 in human papillomavirus-positive (HPV+) HNSCC is unclear. METHODS: Using data from over 500 HNSCC patients from The Cancer Genome Atlas (TCGA), we compared the relative level of mRNA expression of NSD1, NSD2, and NSD3 in HPV+ and HPV- HNSCC. Correlation analyses were performed between T-cell infiltration and the relative level of expression of NSD1, NSD2, and NSD3 mRNA in HPV+ and HPV- HNSCC. In addition, overall survival outcomes were compared for both the HPV+ and HPV- subsets of patients based on stratification by NSD1, NSD2, and NSD3 expression levels. RESULTS: Expression levels of NSD1, NSD2 or NSD3 were not correlated with altered lymphocyte infiltration in HPV+ HNSCC. More importantly, low expression of NSD1, NSD2, or NSD3 correlated with significantly reduced overall patient survival in HPV+, but not HPV- HNSCC. CONCLUSION: These results starkly illustrate the contrast in molecular features between HPV+ and HPV- HNSCC tumors and suggest that NSD1, NSD2, and NSD3 expression levels should be further investigated as novel clinical metrics for improved prognostication and patient stratification in HPV+ HNSCC.

Does HPV Subtype Predict Outcomes in Head and Neck Cancers?

BACKGROUND: Recently, reanalysis of The Cancer Genome Atlas study demonstrated that human papillomavirus (HPV) genotypes in head and neck cancers other than HPV-16 have inferior survival to HPV-16-positive tumors. We aimed to examine the association of HPV subtypes and survival in a large cohort of patient samples from our institution. METHODS: Fresh frozen primary site biopsy samples were collected either in clinic or at the time of surgery. Patient demographic, staging, and survival data were also collected. Tumors were tested for HPV subtypes by quantitative polymerase chain reaction (qPCR). Univariable and multivariable analyses were performed using Cox proportional hazards regression. RESULTS: 280 patient biopsy samples were collected between 2011 and 2017. Mean ± standard deviation (SD) age was 61.9 ± 11.1 years and most patients (78%) were male. The majority of cancers were of the oral cavity (60%) or oropharynx (25%) and 30% had HPV-positive disease. Median follow-up was 3.76 years and 96/280 patients (34%) developed recurrences. Patients with p16-positive versus negative disease had significantly improved 5-year overall survival (OS, 77.6% vs. 53.3%; p=0.009) and progression-free survival (PFS, 67.3% vs. 41.0%, p=0.006). Similarly improved 5-year OS and PFS were observed for patients with HPV-positive versus negative disease (65.0% vs. 55.0%, p=0.084; 53.3% vs. 43.2%, p=0.072, resp.). Patients with HPV-16 compared to other HPV diseases had worse 5-year OS and PFS (62.1% vs. 88.9%, p=0.273; 49.0% vs. 88.9%, p=0.081, resp.). CONCLUSIONS: In contrast to the data derived from The Cancer Genome Atlas, patients with HPV-16 tumors trended towards decreased PFS and OS compared with tumors driven by other HPV genotypes. Further larger multi-institutional studies are necessary to understand the relationship between other HPV genotypes and survival in head and neck squamous cell carcinomas.

All HPV-negative head and neck cancers are not the same: Analysis of the TCGA dataset reveals that anatomical sites have distinct mutation, transcriptome, hypoxia, and tumor microenvironment profiles.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) affects various anatomical sites, which often dictates whether the cancer is managed with primary surgery or radiation. This study aimed to assess differences in single nucleotide variation (SNV), copy number, mRNA abundance, methylation, and tumor microenvironment (TME) between HPV-negative oral cavity (OC), oropharyngeal (OPC), hypopharyngeal (HPC), and laryngeal (LC) cancers within The Cancer Genome Atlas (TCGA). METHODS: We downloaded the clinical information and molecular data for the TCGA HNSCC cohort from the data portal and published literature. The TME was estimated using mRNA abundance data. We conducted our analyses within the Bioconductor statistical framework in the R environment. CNA and mRNA abundance results were correlated and grouped with SNV results for downstream pathway analysis. RESULTS: LC had a higher mutational burden than OC and OPC (p <10-4). LC tumors were enriched in CSMD3, NSD1, DCHS2 and ANK2 SNVs, while OC tumors were enriched in CASP8 SNVs (FDR < 0.1). LCs were enriched for neuronal and glycosylation pathways, while OCs were enriched for extracellular matrix pathways. B cells and endothelial cells were more abundant in LC while monocytes were more abundant in OC (FDR < 0.1). OPC was the most hypoxic, followed by OC then LC (FDR < 0.05). OC had greater methylation of Hox genes than LC. Subsite analysis revealed that oral tongue cancers had fewer CASP8 and FBN2 mutations and higher dendritic cell abundance than other oral cavity cancers. CONCLUSIONS: We identified significant genomic, transcriptional, and microenvironmental differences between HPV-negative HNSCC. Further study is warranted to determine if these findings portend differential response to specific treatment modalities.

Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models.

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.