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Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly 5% of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector yes-associated protein (YAP1). The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 binds and degrades the tumor suppressor protein tyrosine phosphatase non-receptor type 14 (PTPN14). E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis., Competing Interests: JH, PC, HK, SS, KM, DB, EW No competing interests declared, (© 2022, Hatterschide et al.)

Objectives/hypothesis: Delineate factors impacting the creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs)., Study Design: Laboratory-based translational study., Methods: Fifty-one surgically resected HNSCCs, including 31 HPV + cancers, were implanted into NOD/SCID/IL-2Rγ -/- (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV + PDXs were analyzed in comparison to their tumors of origin., Results: Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV + HNSCC cases that failed to engraft. Successfully established HPV + PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV + nodal metastases. They also maintained elevated p16 INK4A levels and expression of E6/E7 viral oncogene transcripts., Conclusion: Reduced engraftment by HPV + tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV + lymphomas in NSG mice further reduces the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the retention of distinctive pathologic traits and viral oncogene expression by HPV + PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models., Level of Evidence: NA. Laryngoscope, 127:2777-2783, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment., Objective: To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy., Design, Setting, and Participants: In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy., Main Outcomes and Measures: Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy., Results: Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy., Conclusions and Relevance: Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.

The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B(high) fraction of cells with stem cell-like function. JARID1B(high) cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B(high) cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1B(high) cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538-49. ©2016 AACR., Competing Interests: All authors declare no conflict of interest related to this work., (©2016 American Association for Cancer Research.)

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: The inclusion of level I in neck dissections for oropharyngeal carcinoma remains controversial. Our objectives were to evaluate the feasibility and relevance of substation node counts in level I of the neck dissection and to determine the specific substation location of metastases in level I in oropharyngeal carcinoma., Methods: Sixty specimens were retrospectively analyzed after an orientation using a new paradigm of demarcating level I specimens into 8 substations., Results: Three of the specimens (5%) in this study showed nodal metastasis in level I, one each in 3 different substations. All positive nodes in level I were associated with N+ disease in level II with 2 being radiographically occult (3.3%). Average total node count for level I was 8.1 (range, 2-19)., Conclusion: In oropharyngeal carcinoma, substation level I node quantification is feasible and relevant. This study shows a 5% risk to level I with metastasis in 3 different substations. © 2016 Wiley Periodicals, Inc. Head Neck 38:1194-1200, 2016., (© 2016 Wiley Periodicals, Inc.)

Objective: To characterize the clinicopathologic features of metastatic carcinomas at percutaneous endoscopic gastrostomy (PEG) tube sites., Methods: We reviewed the metastatic malignancies at PEG tube sites (2002-2011)., Results: Five patients were identified, each with primary head and neck keratinizing squamous cell carcinoma. The metastases had a mean size of 6.08 cm (95% confidence interval [CI], 3.75-8.41). The time from PEG tube placement to metastasis diagnosis was 9.8 months (95% CI, 6.59-13.01). The survival times from PEG tube placement and from metastasis diagnosis were 23.5 (95% CI, 7.65-39.35) and 13.7 (95% CI, 0-31.08) months, respectively. Compared with a meta-analysis of the largest case series, our male patients were significantly older (mean, 73 years; 95% CI, 62.2-83.9 vs mean 59 years, 95% CI, 56.0-62.0) but had similar survival times., Conclusions: Despite their older ages, our male patients had similar survival times to those reported previously. Larger series are needed to confirm our findings and explore the causes.

Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial-mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high-risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin-positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin-positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy., (©2013 AACR.)

Objectives/hypothesis: To determine the prognostic influence of p16(INK4a) immunohistochemistry on the survival of resectable oropharyngeal carcinomas (OPSCC)., Study Design: Retrospective pathologic evaluation of a prospective single-arm cohort study at a tertiary referral center., Methods: There were 48 patients with resectable OPSCC who consented for transoral robotic surgery (TORS) and banked tissue specimen for assessment. TORS was with or without adjuvant radiation or chemoradiation. Main outcome measures were p16(INK4a) status, human papillomavirus status, local-regional disease control, and overall, disease-specific, and disease-free survival., Results: p16(INK4a) and HPV positivity were identified in 73% and 74% of patients respectively. With a median follow-up of 38.8 months (2.5-63.3 months), only one local-regional relapse has occurred in both the p16(INK4a)-positive and p16(INK4a) -negative cohorts. No disease-specific, disease-free, and overall survival differences were observed between p16(INK4a) -positive and p16(INK4a)-negative patients (P = .446, P = .277, P = .643, respectively)., Conclusions: p16(INK4a) was not prognostic in resectable OPSCC when treated with an initial TORS approach., (Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objective: To evaluate local control following transoral robotic surgery (TORS) with the da Vinci Surgical System (Intuitive Surgical Inc) as a single treatment modality for oropharyngeal squamous cell carcinoma (OSCC)., Design: Prospective, single-center, observational study., Setting: Academic university health system and tertiary referral center., Patients: Thirty adults with previously untreated OSCC., Intervention: Transoral robotic surgery with staged neck dissection as indicated., Main Outcome Measures: Local control and margin status., Results: Thirty patients were enrolled with previously untreated OSCC and no prior head and neck radiation therapy. Follow-up duration was at least 18 months. At the time of diagnosis, 9 tumors were T1 (30%); 16 were T2 (53%); 4 were T3 (13%); and 1 was T4a (3%). The anatomic sites of these primary tumors were tonsil in 14 (47%), tongue base in 9 (30%), glossotonsillar sulcus in 3 (10%), soft palate in 3 (10%), and oropharyngeal wall in 1 (3%). There was only 1 patient (3%) who had a positive margin after primary resection; further resection achieved a final negative margin. Perineural invasion was noted in 3 tumors (10%). No patient received postoperative adjuvant therapy. At a mean follow-up of 2.7 years (range, 1.5-5.1 years), there was 1 patient with local failure (3%)., Conclusion: As the only modality used for treatment of pathologically low-risk OSCCs, TORS provides high local control and is associated with low surgical morbidity.

Curative eradication of all cells within carcinomas is seldom achievable with chemotherapy alone. This limitation may be partially attributable to tumor cell subpopulations with intrinsic resistance to current drugs. Within squamous cell carcinoma (SCC) cell lines, we previously characterized a subpopulation of mesenchymal-like cells displaying phenotypic plasticity and increased resistance to both cytotoxic and targeted agents. These mesenchymal-like (Ecad-lo) cells are separable from epithelial-like (Ecad-hi) cells based on loss of surface E-cadherin and expression of vimentin. Despite their long-term plasticity, both Ecad-lo and Ecad-hi subsets in short-term culture maintained nearly uniform phenotypes after purification. This stability allowed testing of segregated subpopulations for relative sensitivity to the cytotoxic agent cisplatin in comparison to salinomycin, a compound with reported activity against CD44(+)CD24(-) stem-like cells in breast carcinomas. Salinomycin showed comparable efficacy against both Ecad-hi and Ecad-lo cells in contrast to cisplatin, which selectively depleted Ecad-hi cells. An in vivo correlate of these mesenchymal-like Ecad-lo cells was identified by immunohistochemical detection of vimentin-positive malignant subsets across a part of direct tumor xenografts (DTXs) of advanced stage SCC patient samples. Cisplatin treatment of mice with established DTXs caused enrichment of vimentin-positive malignant cells in residual tumors, but salinomycin depleted the same subpopulation. These results demonstrate that mesenchymal-like SCC cells, which resist current chemotherapies, respond to a treatment strategy developed against a stem-like subset in breast carcinoma. Further, they provide evidence of mesenchymal-like subsets being well-represented across advanced stage SCCs, suggesting that intrinsic drug resistance in this subpopulation has high clinical relevance.

Variable drug responses among malignant cells within individual tumors may represent a barrier to their eradication using chemotherapy. Carcinoma cells expressing mesenchymal markers resist conventional and epidermal growth factor receptor (EGFR)-targeted chemotherapy. In this study, we evaluated whether mesenchymal-like sub-populations within human squamous cell carcinomas (SCCs) with predominantly epithelial features contribute to overall therapy resistance. We identified a mesenchymal-like subset expressing low E-cadherin (Ecad-lo) and high vimentin within the upper aerodigestive tract SCCs. This subset was both isolated from the cell lines and was identified in xenografts and primary clinical specimens. The Ecad-lo subset contained more low-turnover cells, correlating with resistance to the conventional chemotherapeutic paclitaxel in vitro. Epidermal growth factor induced less stimulation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways in Ecad-lo cells, which was likely due to lower EGFR expression in this subset and correlated with in vivo resistance to the EGFR-targeted antibody, cetuximab. The Ecad-lo and high E-cadherin subsets were dynamic in phenotype, showing the capacity to repopulate each other from single-cell clones. Taken together, these results provide evidence for a low-turnover, mesenchymal-like sub-population in SCCs with diminished EGFR pathway function and intrinsic resistance to conventional and EGFR-targeted chemotherapies.

Background: The purpose of this study was to determine the preoperative accuracy of preservation of the retropharyngeal fat plane on magnetic resonance (MR) images in predicting the absence of fixation or extension of head and neck carcinomas to the prevertebral space., Methods: The MR images of 75 patients with T3 or T4 primary pharyngeal or laryngeal cancers seen over a 5-year period and treated at our Head and Neck Cancer Center were retrospectively reviewed. The MR images were independently and blindly evaluated by two head and neck radiologists for preservation of the retropharyngeal fat plane between the tumor and prevertebral musculature. In cases in which the fat was preserved, the prevertebral muscle complex was assessed for the presence of T2 hyperintensity and enhancement. All patients underwent panendoscopy, surgery, or both., Results: Forty of 75 patients had preservation of the retropharyngeal fat plane between the tumor and the prevertebral compartment on T1-weighted images. In all 40 cases, the prevertebral muscles had a normal appearance on T2-weighted and enhanced MR images. Intraoperative assessment revealed absence of fixation of tumor to the prevertebral fascia in 39 of 40 cases, and these tumors were resectable., Conclusion: In patients with advanced head and neck carcinomas, preservation of the fat between the tumor and the prevertebral musculature on unenhanced T1-weighted images reliably predicts absence of prevertebral space fixation., (2004 Wiley Periodicals, Inc.)

Teratoma, the most common ovarian germ-cell tumor, presumably arises from a single germ cell and is composed of tissues representing all germ layers (ectoderm, mesoderm, and endoderm). Benign cystic teratomas (dermoid cyst) represent over 95% of ovarian teratomas and are comprised of entirely mature adult tissues. When malignant, almost all mature teratomas contain squamous carcinoma. We report for the first time the karyotypic comparison of an ovarian teratoma in a 36-year-old female with tissue separately taken from the benign cystic and malignant squamous components. The malignant squamous component revealed two distinct karyotypic populations: one diploid and the other polyploid. Both, however, demonstrated two common markers. The polyploid population also demonstrated numerous additional abnormalities with multiple copies of chromosome 20. Though many of the chromosomal aberrations were unique to the benign component, several karyotypes showed the same markers noted in the malignant squamous component. The significance of this finding is that it may serve to identify those histologically benign teratomas destined to undergo malignant transformation.

Objective: To evaluate head and neck squamous cell carcinomas (SCCAs) for the expression of nerve cell adhesion molecule (N-CAM). We propose that expression of N-CAM by tumor cells may be associated with perineural invasion in SCCA of the head and neck., Methods: Seventy-six archived specimens of histologically proven SCCA were analyzed by immunohistochemistry for the expression of N-CAM. Positive and negative controls were used to assess staining. Two sections of each specimen were reviewed for the presence of perineural invasion. A retrospective chart review was performed for each patient that corresponded to the above specimens., Results: Perineural invasion was present in 28 (37%) of the 76 patients evaluated for the expression of N-CAM. N-CAM expression was demonstrated in 38 (50%) of the 76 specimens. The incidence of N-CAM expression was significantly associated with perineural invasion (P = .002). There was no significant association between the presence of staining or the presence of perineural invasion and the incidence of locoregional recurrence, distant metastasis, or survival status; however, the mean follow-up was only 13.6 months (range, 1-49 mo)., Conclusion: There is a positive correlation between the presence of N-CAM expression and perineural invasion in SCCA of the head and neck. The expression of this adhesion molecule by tumor cells may facilitate both homophilic cell-to-cell and heterophilic cell-to-substrate adhesion, thereby enabling the tumor cells to use the perineural tissues or neural cells, or both as a conduit for perineural spread.

We previously demonstrated that precancers (actinic keratoses and dysplasias) and squamous cell carcinomas (SCCs) develop in one quarter of human neonatal foreskins grafted onto recombinase-activating gene-1-knockout mice treated once with 7,12-dimethylbenz[a]anthracene (DMBA) followed by chronic intermediate-range ultraviolet (UV) B light irradiation. The goals of this study were to determine if a longer UVB exposure followed by further observation would increase the number of precancers and invasive cancers and to evaluate whether this model results in changes in p53 expression and cell proliferation similar to those seen in sun-damaged normal skin, actinic keratoses, and SCCs. The treatment consisted of a single dose of DMBA followed by 500 J/m2 UVB radiation administered three times weekly for at least 5 mo. Histologic changes (cysts, hyperplasias, precancers, and/or invasive cancers) were seen in 24 of 25 treated xenografts but not in controls. Ten of 25 grafts (40%) had two or more histological changes, and two human SCCs developed. After seven or more months of UV exposure and a total time from DMBA treatment to killing of 12-18 mo, 83% (15 of 18) of specimens developed squamous precancer or SCC of human origin, and 44% (eight of 18) developed melanocytic hyperplasia or melanoma. The change from moderate dysplasias to SCC required longer UV exposure (median, 11 mo), and 5 mo more observation than did the development of mild dysplasias (median UV exposure, 7 mo; median DMBA to death time, 12 mo). There was a direct correlation between both p53 expression and cell proliferation and the degree of histologic alteration both in squamous epithelial and melanocytic cells.

Objective: The purpose of this study was to determine the accuracy of MR imaging in determining fixation of squamous cell carcinomas to the prevertebral space., Materials and Methods: MR images of 15 patients with large pharyngeal carcinoma (n = 13) or laryngeal carcinomas with pharyngeal extension (n = 2) were retrospectively reviewed independently by two head and neck radiologists who were unaware of the surgical findings. MR images were evaluated for four criteria in the prevertebral longus muscle complex: muscle concavity, irregular tumor-muscle interface, T2 hyperintensity, and enhancement. All patients underwent panendoscopy where fixation or mobility of the tumor relative to the prevertebral fascia was assessed by manual manipulation. Tumors in six patients were fixed to the prevertebral space and inoperable. In nine patients whose tumors were not fixed, open neck explorations were performed and tumors were resected in seven patients. MR findings were compared with panendoscopy in all patients and with intraoperative assessment in nine patients., Results: Eleven of 15 patients had at least two of the MR imaging criteria present. None of the MR findings were both sensitive and specific for tumor fixation. Although muscle concavity and enhancement each had a sensitivity of 88%, both criteria suffered from low specificity (14% and 29%, respectively). An irregular tumor-muscle interface and muscle T2 hyperintensity were criteria that suffered from both low sensitivity and specificity. Accuracy of the imaging criteria independently ranged from 53% to 60%., Conclusion: Although abnormal muscle contour, T2 hyperintensity, and enhancement are frequently present in neck carcinomas that are fixed to the prevertebral space, these findings may also be present in patients in whom the tumor is mobile and resectable. MR imaging may not be able to differentiate between neoplastic fixation and nonneoplastic changes in the prevertebral space.

Objective: The purpose of this study was to evaluate whether observers of MR imaging can accurately predict invasion of the preepiglottic fat (PEF) in patients with oropharyngeal and supraglottic laryngeal squamous cell carcinoma., Materials and Methods: For 41 patients with pathologically proven squamous cell carcinoma of the oropharynx and supraglottic larynx, we retrospectively analyzed their MR images for the presence or absence of PEF neoplastic invasion. Unenhanced T1-weighted, fat-suppressed T2-weighted, and contrast-enhanced fat-suppressed T1-weighted scans were analyzed independently by two neuroradiologists who were unaware of the surgical findings. Proof of diagnosis was determined by pathologic analysis, intraoperative assessment, or both., Results: Sixteen patients had neoplastic infiltration of the PEF. All infiltration was correctly predicted by the two observers of MR imaging, resulting in a sensitivity of 100%. Twenty-five patients had no invasion of the PEF by pathologic or surgical evaluation or both. Of these patients, negative findings were correctly predicted on MR imaging in 21 patients, whereas positive findings were incorrectly predicted on MR imaging in the remaining four patients, resulting in a specificity of 84% and an accuracy of 90%. In two of the four false-positive cases, effacement of the fat in the preepiglottic space by large tumors was mistaken for invasion. In a third patient, spread to the paraglottic space was mistaken for PEF extension. In the fourth false-positive case, glandular tissue along the ventral epiglottis may have been mistaken for tumor. The observers believed that unenhanced sagittal and axial T1-weighted scans were particularly useful because fat saturation artifacts may degrade T2-weighted and contrast-enhanced T1-weighted scans., Conclusion: Unenhanced T1-weighted MR images are highly sensitive for neoplastic infiltration of the preepiglottic space in patients with oropharyngeal and supraglottic laryngeal carcinoma who are at risk for such spread. Identification of PEF invasion is important because it affects prognosis and may affect surgical management.