OBJECTIVE:To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). METHODS:Retrospective cohort of cases diagnosed with HPV-positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV-positive cases with appropriate International Classification of Diseases-0-3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression. RESULTS:Cases that were ENE-negative had the highest 5-year survival (92.6%; 95% confidence interval [CI]: 90.5%-94.7%). ENE-positive cases had the lowest 5-year survival (84.0%; 95% CI: 80.7%-87.4%). After adjusting for confounding variables, ENE-positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35-2.67) compared to ENE-negative cases. Nodal (N) category 1, ENE-positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26-2.80) compared with N1, ENE-negative status. Compared to N1/ENE-negative cases, N2/ENE-positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94-4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node-positive/ENE-negative status. CONCLUSION:The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much-improved framework to develop and discuss treatment plans for HPV-positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV-positive OPSCC. LEVEL OF EVIDENCE:4 Laryngoscope, 130:939-945, 2020.

Ameloblastomas are the most common odontogenic tumors, excluding odontomas. Several morphologic variants have been described including follicular, plexiform, acanthomatous, granular cell, basaloid and desmoplastic. Desmoplastic ameloblastoma differs from other conventional ameloblastomas microscopically, clinically, and radiographically. Ameloblastic carcinoma, the malignant counterpart of ameloblastoma is characterized by cytologic features of malignancy combined within the overall histologic features of conventional ameloblastoma. Malignant transformation of ameloblastoma to squamous cell carcinoma is a controversial subject. Here we report a case of a desmoplastic ameloblastoma with malignant transformation to squamous cell carcinoma in a 49 year old African American man. The patient underwent tumor resection and radiation therapy with no evidence of disease recurrence or progression 16 months post operatively. To our knowledge malignant transformation of a desmoplastic ameloblastoma to squamous cell carcinoma has not so far been reported. This observation may lend some support to the argument that desmoplastic ameloblastoma is phenotypically and biologically distinct entity.

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.

Introduction: Lymphatic malformations (LM) are non-malignant, congenital masses that contain fluid-filled lymph channels. These lesions typically present in childhood, but they can rarely present as a new head and neck mass in adults, which may not be on the differential diagnoses of clinicians. We present a case of an intraparotid mass that expanded rapidly secondary to hematoma after a diagnostic fine needle aspiration was performed. Case details: A 24 year-old male presented with a right parotid mass. CT imaging revealed a 3.2 × 1.8cm cystic lesion in the parotid gland. Ultrasound-guided fine needle aspiration was performed, resulting in a parotid hematoma and compression of the buccal branch of the right facial nerve. The patient was taken to the operating room urgently for evacuation of hematoma, and a superficial parotidectomy was performed. Pathology revealed an intraparotid lymphatic malformation with organized hematoma. Conclusions: We present a case of hematoma following fine needle aspiration of a lymphatic malformation. While these lesions typically present in the pediatric population, they may be first diagnosed in adulthood. Hematoma following FNA is exceedingly rare and may increase the clinical suspicion for LM.

Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy with great morphological resemblance to invasive ductal carcinoma (IDC) of the breast. Rarely, female patients may have a past history of both SDC and IDC. When these patients present with distant metastasis, accurate identification of the primary tumor is particularly difficult. Additionally, rare metastasis of SDC to the breast and IDC to the salivary (parotid) gland can also present a diagnostic challenge. Our aim was to develop an immunohistochemical panel that reliably distinguishes SDC from IDC. We included all SDCs diagnosed from 1989 to 2016 (23 cases) and 29 treatment naïve and histologically similar IDCs. All cases were stained with androgen receptor (AR), estrogen receptor-alpha (ER-α), progesterone receptor (PR), HER-2, CK5/6, p63, and beta-catenin. The great majority (> 90%) of both SDCs and IDCs reacted positively to AR. The main discrepancy in the immunohistochemical profiles was a distinctly different reactivity to ER-α, PR and HER-2. While 28 IDCs (96.6%) reacted positively to ER-α and/or PR, the majority expressing both (82.8%) with a moderate to strong staining intensity, only 2 SDCs expressed ER-α (8.7%) and 5 others expressed PR (21.7%) with only one case expressing both (P value < 0.05). On the other hand, 8 SDC (34.8%) were positive for HER-2 while none of the IDCs were positive (P value < 0.05). ER-α, PR, and HER-2 may be helpful to distinguish SDC from IDC. Positive reactivity to ER-α, PR or both and negative HER-2 favors a diagnosis of IDC while ER-α, PR negative, HER-2 positive tumors are more likely SDC.

Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm that most commonly occurs in cervical lymph nodes. It has histologic and clinical overlap with the much more common p16-positive human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx, which characteristically has nonkeratinizing morphology and often presents as an isolated neck mass. Not surprisingly, follicular dendritic cell sarcomas are commonly misdiagnosed as squamous cell carcinoma. Immunohistochemistry is helpful in separating the 2 entities. Follicular dendritic cell sarcoma expresses dendritic markers such as CD21 and CD23 and is almost always cytokeratin negative. However, in many cases of HPV-related oropharyngeal carcinoma, only p16 immunohistochemistry as a prognostic and surrogate marker for HPV is performed. p16 expression in follicular dendritic cell sarcoma has not been characterized. Here, we investigate the expression of p16 in follicular dendritic cell sarcoma and correlate it with retinoblastoma protein expression. A pilot study of dendritic marker expression in HPV-related oropharyngeal squamous cell carcinoma was also performed. We found that 4 of 8 sarcomas expressed p16 with strong and diffuse staining in 2 cases. In 2 of the 4 cases, p16 expression corresponded to loss of retinoblastoma protein expression. Dendritic marker expression (CD21 and CD23) was not found in HPV-related oropharyngeal squamous cell carcinomas. As such, positive p16 immunohistochemistry cannot be used as supportive evidence for the diagnosis of squamous cell carcinoma as strong and diffuse p16 expression may also occur in follicular dendritic cell sarcoma. Cytokeratins and dendritic markers are critical in separating the two tumor types.

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n = 5; T4, n = 27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radio-chemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n = 14) and nonkeratinizing/basaloid squamous cell carcinoma (n = 5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.

The clinical and pathologic characteristics of human papillomavirus (HPV)-related premalignant lesions in the upper aerodigestive tract have not been adequately studied. There are a few reports of oral cavity HPV-related severe dysplasia with unique morphology (prominent apoptosis/karyorrhexis imparting a ‘bowenoid’ appearance) and a single case report of HPV-related squamous cell carcinoma in situ with nonkeratinizing histology distinct from the ‘bowenoid’ pattern that extensively involved the upper aerodigestive tract. The aim of this study was to characterize the morphologic and clinical features of HPV-related severe dysplasia/carcinoma in situ. All cases of upper aerodigestive tract severe dysplasia/carcinoma in situ (111 cases from 98 patients) at Washington University from July 2012 to March 2015 were categorized into histologic types: keratinizing, nonkeratinizing, mixed or ‘bowenoid’. There were 83 (85 %) patients with keratinizing, 3 (3 %) nonkeratinizing and 12 (12 %) mixed patterns. The previously reported ‘bowenoid’ morphology was not identified. All 3 (100 %) nonkeratinizing and 6 (50 %) mixed cases were p16 and HPV RNA in situ hybridization (RNA ISH) positive (100 % concordance between p16 and RNA ISH). Only 2 of 73 keratinizing cases were p16 positive, 1 of which was also HPV RNA ISH positive (1.4 % of keratinizing cases HPV-related). Thus, nonkeratinizing morphology was a strong predictor of transcriptionally-active HPV in severe dysplasia/carcinoma in situ. HPV-related cases most commonly occurred in the floor of mouth and were frequently extensive (≥4 cm) or unresectable.

Oropharyngeal squamous cell carcinomas (OPSCCs) associated with human papillomavirus (HPV) represent a distinct clinical and pathologic entity. The majority of HPV-related OPSCCs have a characteristic nonkeratinizing morphology. This study sought to determine the strength of the association between nonkeratinizing histology and HPV status compared with other squamous cell carcinoma variants in 4 years of routine clinical practice on a high-volume head and neck service. Primary and/or nodal metastatic tumors in all cases of OPSCC from 2010 to 2013 were typed by 1 of 3 head and neck pathologists as keratinizing, nonkeratinizing, nonkeratinizing with maturation, or another defined variant. All were assessed for p16 by immunohistochemistry with a 70% nuclear and cytoplasmic positivity cutoff as part of routine clinical practice. In addition, 70 consecutive cases from 1 year were "audited" for high-risk HPV mRNA by reverse transcription polymerase chain reaction and in situ hybridization. Of the 435 cases, the majority (90%) consisted of 1 of the 3 main types described and the rest (10%) of uncommon variants. Nonkeratinizing morphology had 99.1% and 100.0% positive predictive value for p16 and high-risk HPV mRNA positivity, respectively. Nonkeratinizing with maturation, keratinizing, and other specific squamous cell carcinoma variants were p16 positive in 91.8%, 22.8%, and 79.5%, respectively. All 47 nonkeratinizing OPSCCs tested for HPV mRNA were positive. In summary, strictly defined nonkeratinizing OPSCC (which constitutes ∼55% of all tumors) essentially implies positivity for both p16 and transcriptionally active high-risk HPV.

Distant metastases are relatively common in breast cancer, but spread to the head and neck region is uncommon and can be diagnostically challenging. Pathology databases of two academic hospitals were searched for patients. The diagnoses were by morphologic comparison with the primary breast specimen (when available) or through the use of immunohistochemical stains characteristic of breast carcinoma (cytokeratin 7, mammaglobin, GCDFP15, and/or GATA3 positive—excluding new primary tumors at the respective head and neck sites). Of the 25 patients identified, only 22 (88.0 %) had a known history of breast carcinoma. Time from primary diagnosis to head and neck metastasis was highly variable, ranging from 1 to 33 years (mean = 10.9 years). The most common locations were neck lymph nodes (8 cases), orbital soft tissue (5), oral cavity (3), skull base (3), mastoid sinus (2), nasal cavity (1), palatine tonsil (1), and facial skin (1). Clinical presentations were highly variable, ranging from cranial nerve palsies without a mass lesion to oral cavity erythema and swelling to bone pain. Histologically, two cases showed mucosal (or skin)-based mass lesions with associated pagetoid spread in the adjacent epithelium, a feature normally associated with primary carcinomas. Three tumors were misdiagnosed pathologically as new head and neck primary tumors. This series demonstrates the extreme variability in clinical and pathologic features of breast cancer metastatic to the head and neck, including long time intervals to metastasis.

Verrucous carcinomas (VC) recur locally but do not metastasize in the absence of an invasive squamous cell carcinoma (SCC) component. Although excluded from the definition of pure VC, some tumors harbor only dysplasia or minimal invasion, findings of unknown clinical significance. Surgically resected VC cases from two institutions were collected and categorized into three types: VC, VC with dysplasia or minimal invasion (VCDMI), defined as SCC less than or equal to 2 mm in depth, and SCC arising in VC (SCC-VC) where the SCC was greater than 2 mm in depth. Cases were also matched with conventional SCC based on location and T and N-stages, and clinical follow up was obtained. Of the 58 total cases, 18 were VC, 26 VCDMI, and 14 SCC-VC. Only 1 of 18 (5.6 %) VC and 5 of 26 (19.2 %) VCDMI cases recurred locally (p = 0.37) versus 7 of 14 (50 %) SCC-VC (p = 0.01). All VC and VCDMI cases were node negative at presentation whereas SCC-VC had nodal metastases in 2 of 14 (14.3 %) cases. No patients with VC or VCDMI died from disease, whereas 5 of 14 (35.7 %) patients with SCC-VC died from disease. T-stage matched conventional SCC cases from institutional databases had worse outcomes than VC and VCDMI, but not after they were matched for both T and N-stages. Our findings suggest that dysplasia and/or minimal invasive SCC do not adversely affect outcomes in tumors otherwise showing diagnostic features of VC.

The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1-2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy.

ContextMedical error is a significant problem in the United States, and pathologic diagnoses are a significant source of errors. Prior studies have shown that second-opinion pathology review results in clinically major diagnosis changes in approximately 0.6% to 5.8% of patients. The few studies specifically on head and neck pathology have suggested rates of changed diagnoses that are even higher.ObjectivesTo evaluate the diagnostic discrepancy rates in patients referred to our institution, where all such cases are reviewed by a head and neck subspecialty service, and to identify specific areas with more susceptibility to errors.DesignFive hundred consecutive, scanned head and neck pathology reports from patients referred to our institution were compared for discrepancies between the outside and in-house diagnoses. Major discrepancies were defined as those resulting in a significant change in patient clinical management and/or prognosis.ResultsMajor discrepancies occurred in 20 cases (4% overall). Informative follow-up material was available on 11 of the 20 patients (55.0%), among whom, the second opinion was supported in 11 of 11 cases (100%). Dysplasia versus invasive squamous cell carcinoma was the most common (7 of 20; 35%) area of discrepancy, and by anatomic subsite, the sinonasal tract (4 of 21; 19.0%) had the highest rate of discrepant diagnoses. Of the major discrepant diagnoses, 12 (12 of 20; 60%) involved a change from benign to malignant, one a change from malignant to benign (1 of 20; 5%), and 6 involved tumor classification (6 of 20; 30%).ConclusionsHead and neck pathology is a relatively high-risk area, prone to erroneous diagnoses in a small fraction of patients. This study supports the importance of second-opinion review by subspecialized pathologists for the best care of patients.