Publications by authors named "William H Westra"

253 Publications

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Head Neck Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.
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http://dx.doi.org/10.1007/s12105-021-01331-7DOI Listing
May 2021

Tissue-Based SARS-Cov-2 Detection in Fatal COVID-19 Infections: Sustained Direct Viral-Induced Damage is Not Necessary to Drive Disease Progression.

Hum Pathol 2021 May 4. Epub 2021 May 4.

Departments of Pathology, Molecular and Cell-Based Medicine, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY. Electronic address:

Background: Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues.

Methods: We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in-situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative PCR (qPCR)-based detection.

Results: SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues.

Conclusions: In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple organ pathogenic pro-inflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression.
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http://dx.doi.org/10.1016/j.humpath.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095022PMC
May 2021

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Mod Pathol 2021 Apr 1. Epub 2021 Apr 1.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41379-021-00793-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015313PMC
April 2021

Salivary Mucinous Adenocarcinoma Is a Histologically Diverse Single Entity With Recurrent AKT1 E17K Mutations: Clinicopathologic and Molecular Characterization With Proposal for a Unified Classification.

Am J Surg Pathol 2021 Feb 24. Epub 2021 Feb 24.

*Departments of Pathology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD †Department of Biochemistry, Molecular Biology, and Biophysics, College of Biological Sciences ‡Howard Hughes Medical Institute, University of Minnesota §Division of Oral and Maxillofacial Pathology, School of Dentistry, University of Minnesota, Minneapolis, MN ∥Southern California Permanente Medical Group, Department of Pathology, Woodland Hills Medical Center, Woodland Hills **Departments of Orofacial Sciences, Pathology, and Radiation Oncology, University of California San Francisco, San Francisco, CA ¶Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX #Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY.

Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001688DOI Listing
February 2021

De-Escalated Adjuvant Therapy After Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Carcinoma: The Sinai Robotic Surgery (SIRS) Trial.

Oncologist 2021 Jun 18;26(6):504-513. Epub 2021 Mar 18.

Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity.

Methods: This study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin).

Results: Fifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease.

Conclusion: The results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC.

Implications For Practice: Transoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.
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http://dx.doi.org/10.1002/onco.13742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176976PMC
June 2021

Redefining risk of contralateral cervical nodal disease in early stage oropharyngeal cancer in the human papillomavirus era.

Head Neck 2021 May 21;43(5):1409-1414. Epub 2021 Jan 21.

Department of Radiation Oncology, Mount Sinai Health System, New York, New York, USA.

Background: The optimal extent of surgery and/or radiation to the contralateral lymph node region is unknown in early-stage human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC).

Methods: To investigate the pathologic incidence of and risk factors for contralateral nodal disease (CND) in cT1-T2 HPV-related OPSCC treated with transoral robotic surgery (TORS) and bilateral neck dissection (BND), the records of 120 patients were reviewed.

Results: Eleven patients displayed pathologic contralateral nodal disease (pCND), including 7.1% of tonsil and 10.9% of base of tongue (BOT) cases. Medial hemistructure involvement and cN2 disease were significantly associated with pCND. Zero cN0 patients had pCND, and on multivariate analysis only cN classification remained significantly associated with pCND. Four percent of BOT patients and 2% of tonsil patients with a well-lateralized primary and cN0/N1 neck demonstrated pCND.

Conclusions: HPV-related OPSCC that are cN0-N1 have exceedingly low rates of pCND. Well-lateralized HPV-related BOT primaries with limited clinical nodal disease may be candidates for ipsilateral only treatment.
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http://dx.doi.org/10.1002/hed.26607DOI Listing
May 2021

The Decline of Salivary Adenocarcinoma Not Otherwise Specified as a Tumor Entity: Reclassification Using Contemporary Immunohistochemical Profiling and Diagnostic Criteria.

Am J Surg Pathol 2021 Jun;45(6):753-764

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.

The classification of salivary gland carcinomas has become increasingly specific over the last decade with the definition of new tumor types, documentation of novel molecular and immunohistochemical findings, and development of more refined diagnostic criteria. In this setting, it is unclear how many salivary tumors still cannot be easily categorized-and whether such tumors represent undifferentiated malignancies or include additional definable entities. Relying largely on current classification schemes and contemporary immunohistochemical panels, we reassessed salivary tumors previously diagnosed as adenocarcinoma, not otherwise specified (ACA NOS) from 2 large academic medical centers. Fifty-seven ACA NOS (72%) could be reclassified as more specific entities including 31 salivary duct carcinomas (39%), 7 polymorphous adenocarcinomas (9%), 5 epithelial-myoepithelial carcinomas (6%), 4 myoepithelial carcinomas (5%), 4 secretory carcinomas (5%), 1 acinic cell carcinoma (1%), 1 basal cell adenocarcinoma (1%), 1 intraductal carcinoma (1%), and 1 clear cell carcinoma (1%) as well as 2 metastatic squamous cell carcinomas (3%). Of reclassified cases, 21 (37%) represented variant histologies within these categories. ACA NOS comprised 11% of salivary malignancies before reclassification, but only 4% after reclassification. The remaining 22 ACA NOS demonstrated heterogeneous features, with an association between histologic grade and clinical outcome. In effect, ACA NOS is becoming a bygone entity as modern classification schemes and ancillary techniques now permit more specific typing of a majority of these tumors, potentially facilitating more specific prognostication and treatment. Additional distinctive entities such as mucinous adenocarcinoma may still be definable within the ACA NOS category.
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http://dx.doi.org/10.1097/PAS.0000000000001636DOI Listing
June 2021

Liquid phase human papillomavirus genotype analysis of aspirated metastatic head and neck squamous cell carcinoma: Fine needle aspiration supernatant is a rich source of tumor DNA that can increase the diagnostic yield.

Diagn Cytopathol 2021 Jan 5;49(1):25-30. Epub 2020 Sep 5.

Departments of Pathology, Molecular and Cell-Based Medicine, The Icahn School of Medicine at Mount Sinai Hospital, New York, New York, USA.

Background: Most patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSC) present with lymph node metastasis. In these patients, fine needle aspiration (FNA) is not only a diagnostic tool, but a means for determining HPV status. HPV status, in turn, is used to determine tumor origin, prognosis, and even guide therapy. Thus, the limited sampling afforded by FNA must be optimized to meet heavy clinical demands.

Purpose: The purpose of this study was to determine whether the residual supernatant portion of the FNA could serve as a resource for reliable determination of HPV status DESIGN/METHOD: 25 FNAs from 24 patients with metastatic HNSC underwent HPV genotyping of post-centrifuged supernatant fluid from FNA needle rinses. HPV genotyping was performed using two real time PCR-based assays, the two-step LightCycler and the one-step automated cobas HPV tests. HPV status of the supernatant was compared with the paired FNA cell blocks and/or surgical tissue samples.

Results: The supernatant was adequate for HPV testing in 24 (96%) of 25 cases. Of these, 14 (56%) were HPV positive and 11 (44%) negative by the LightCycler assay. HPV16 was the most commonly detected genotype (n = 12). When results of supernatant and paired cell block testing were compared, HPV status was concordant in all cases. The LightCycler method was more sensitive than the cobas assay due to its ability to detect an expanded profile of HPV variant genotypes.

Conclusion: The current standard of practice for patients with HNSC who undergo FNA is to construct a cell block and then discard the supernatant. This supernatant is a rich source of tumor DNA that can be used to detect HPV status. It should not be wasted.
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http://dx.doi.org/10.1002/dc.24603DOI Listing
January 2021

A new face of the HPV epidemic: Oropharyngeal cancer in the elderly.

Oral Oncol 2020 Aug 31;109:104687. Epub 2020 Aug 31.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, 1184 Fifth Avenue, New York, NY 10029, United States. Electronic address:

Objectives: As the human papillomavirus (HPV) epidemic continues to grow, the number of elderly patients with oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing. Despite this observation, this cohort remains understudied. We aimed to understand HPV prevalence and characteristics within this cohort as well as its impact on disease control in elderly patients.

Methods And Materials: We identified patients aged ≥70 with newly diagnosed, non-metastatic, OPSCC treated with curative intent at our institution from 2007 to 2018. Logistic regression and survival analyses were used for outcome-specific endpoints.

Results: In total, 88 patients were identified with a median age of 73 (interquartile range [IQR]: 71-78) and a median Charlson Comorbidity Index of 6 (IQR: 5-7). Eighty-two percent were ECOG 0 or 1 performance. Of note, 70% of the cohort had HPV+ tumors. Fifty-one percent of patients were AJCC 8th edition stage I/II and 49% were stage III/IV. Median follow-up time was 2.5 years (IQR: 0.9-4.7). Eight percent had surgery alone, 27% underwent adjuvant RT, and 64% received definitive RT. Sixty-four percent received concurrent chemotherapy. By both univariate and multivariable analyses, HPV+ status was significantly associated with improved locoregional control (LRC), overall survival (OS), and disease specific survival (DSS).

Conclusions: In our cohort of elderly patients with OPSCC, the majority was HPV+, which was associated with improved clinical outcomes. There are many challenges when managing elderly patients with OPSCC, but as the population ages and the HPV epidemic evolves, these patients should be considered for elderly specific clinical trials.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104687DOI Listing
August 2020

Dermal Filler Presenting as Parotid Mass: A Case Report.

Head Neck Pathol 2021 Jun 8;15(2):638-641. Epub 2020 Jul 8.

Department of Otolaryngology - Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1189, New York, NY, 10029, USA.

Dermal filler injections are common cosmetic procedures and are growing in popularity. While frequently performed, dermal filler injections carry a risk of adverse events including vascular compromise and foreign body granulomas. Here, we discuss an unusual case of a patient with a history of dermal filler injections presenting with a parotid mass and an eyebrow mass requiring surgical resection. This case demonstrates the risk of delayed granuloma formation many years after dermal filler injection and highlights the importance of awareness and management of these potential long-term complications.
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http://dx.doi.org/10.1007/s12105-020-01197-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134640PMC
June 2021

Risk factors for human papillomavirus-positive nonoropharyngeal squamous cell carcinoma.

Head Neck 2020 08 26;42(8):1954-1962. Epub 2020 Feb 26.

Department of Otolaryngology Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer (HPV-OPC) is distinct from HPV-unassociated head and neck cancer. However, whether risk factors for HPV-positive oropharyngeal and nonoropharyngeal squamous cell cancer are the same is unclear.

Methods: Incident cases of HPV-positive head and neck cell cancer and matched non-cancer controls were enrolled in a multi-institutional, prospective study examining risk factors, biomarkers, and survival.

Results: HPV-nonOPC (n = 20) were more likely to be ever smokers than controls (n = 80, OR 3.49, 95%CI 1.11-10.9) and HPV-OPC (n = 185, OR 3.28, 95%CI 1.10-10.2). Compared with HPV-OPC, HPV-nonOPC were less likely to have had over 3 oral sexual partners (OR 0.29, 95%CI 0.06-0.9), more likely to have multimorbidity (OR 3.30, 95%CI 1.04-10.5), and less likely to have antibodies to HPV16 E6 (90% vs 28%, OR 0.05, 95%CI 0.02-0.2). HPV-nonOPC had worse 4-year OS (77% vs 96%, P = .001) and RFS (69% vs 94%, P < .001) than HPV-OPC.

Conclusions: HPV-positive nonoropharyngeal are distinct from HPV-positive oropharyngeal cancers.
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http://dx.doi.org/10.1002/hed.26116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369227PMC
August 2020

HPV-positive Squamous Cell Carcinoma of the Larynx, Oral Cavity, and Hypopharynx: Clinicopathologic Characterization With Recognition of a Novel Warty Variant.

Am J Surg Pathol 2020 05;44(5):691-702

Departments of Pathology.

Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n=27), oral cavity (n=21), and hypopharynx (n=4). While most cases (n=34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n=13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P=0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.
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http://dx.doi.org/10.1097/PAS.0000000000001433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885126PMC
May 2020

Distinct biomarker and behavioral profiles of human papillomavirus-related oropharynx cancer patients by age.

Oral Oncol 2020 02 24;101:104522. Epub 2019 Dec 24.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, United States. Electronic address:

Background: HPV-positive oropharynx squamous cell cancer (HPV-OPC) patients were initially described as younger, however incidence has increased among older age-groups. It is unknown why some patients present at a younger age and others at a later age.

Methods: Multi-institutional prospective study of HPV-OPC cases (n = 163) and matched controls (n = 345) with detailed behavioral survey, and serum tested for HPV antibodies by fluorescent bead-based technology. Age at diagnosis was used to stratify patients into younger (≤50 years), middle-age (51-65), and older (>65).

Results: By age, demographic characteristics were largely similar, but HPV biomarkers and sexual acts differed. Younger cases were more likely to be HPV16-positive than older cases (100% vs 77%, p = 0.009). Similarly, younger cases were more likely to be HPV16 E6 or E7 seropositive (100% vs 82%, p = 0.03). Younger cases had a higher number of oral sex partners per year, a marker of sexual intensity (sex-years, p = 0.003), but a similar number of lifetime oral sex partners (measure of cumulative sexual exposure), compared to older cases. While sex-years were higher for younger cases and controls, cases had significantly higher sex-years than matched controls in each age-group (p < 0.001). Younger patients were also more likely to perform oral sex at sexual debut, and were younger at sexual debut (each p < 0.03).

Conclusions: Younger, middle-age and older HPV-OPC have distinct biomarker and behavioral profiles. Younger HPV-OPC cases have higher intensity of sexual exposure than older cases and controls, which may in part explain earlier disease onset. The distribution of HPV16-positive tumors among HPV-OPC differs by age group.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212394PMC
February 2020

Mucoepidermoid carcinoma of the oropharynx: a tumor type with a propensity for regional metastasis unrelated to histologic grade.

Hum Pathol 2019 11 20;93:1-5. Epub 2019 Aug 20.

Departments of Pathology at the Icahn School of Medicine at Mount Sinai Hospital, 10029 New York, NY. Electronic address:

The designation "mucoepidermoid tumor" is a historic one used in reference to a form of mucoepidermoid carcinoma (MEC) that was believed to be benign. This bygone notion was based on the observation that the vast majority of MECs arising from the intraoral minor salivary glands behave in a benign fashion, particularly when they do not exhibit high grade features. There has been a recent move to partition the oral vault into the oral cavity proper and the oropharynx based on awareness that these compartments are distinct, and that similar tumor types arising from these compartments may behave in dramatically different ways (e.g, oral cavity squamous cell carcinoma vs oropharyngeal squamous cell carcinoma). The pathology databases from 3 large academic medical centers were searched for cases of MECs arising in the oropharynx. Relevant clinical and pathological information was collected from the medical records. Twenty-five cases were identified. They were from 18 females (72%) and 7 males (28%), ranging in age from 31 to 88 years (median, 61). Twenty-two (88%) were classified as low (n = 12) or intermediate (n = 10) grade, and 3 (12%) as high grade. Most arose from the base of tongue (n = 24), but one arose from the lateral pharyngeal wall. The median tumor size was 2.0 cm. Nineteen patients underwent neck node dissections. Of these, 13 (68%) had histologically documented lymph node metastases. MECs that lacked high grade features were almost as likely to metastasize as those with high grade features (50% vs 66%, Fisher exact = 1). Of 3 metastases tested, 2 harbored the MAML2 gene fusion. MECs arising from the base of tongue are associated with an alarmingly high rate of nodal metastases. This behavior cannot be predicted by histologic grading or MAML2 status. The propensity to metastasize may to some degree reflect the unique microenvironment of the oropharynx.
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http://dx.doi.org/10.1016/j.humpath.2019.08.014DOI Listing
November 2019

Microsecretory Adenocarcinoma: A Novel Salivary Gland Tumor Characterized by a Recurrent MEF2C-SS18 Fusion.

Am J Surg Pathol 2019 08;43(8):1023-1032

Department of Laboratory Medicine and Pathobiology, University of Toronto.

Salivary gland adenocarcinoma not otherwise specified (NOS) is a heterogenous group, likely containing distinct tumors not yet characterized. A growing number of low to intermediate-grade salivary carcinomas are now known to harbor tumor-specific gene fusions. On occasion, identifying a novel fusion allows for recognition of a new salivary tumor type, in addition to representing a potential diagnostic tool. We sought to characterize a distinctive salivary gland adenocarcinoma that would previously have been regarded as adenocarcinoma NOS. On the basis of the recognition of 5 morphologically identical, distinct low-grade salivary adenocarcinomas, we used targeted RNA sequencing (RNA-Seq) to determine whether these could be differentiated from other fusion-associated salivary gland tumors. RNA-Seq was performed on all 5 low-intermediate grade adenocarcinomas NOS with near-identical histologic appearances, as well as 23 low-intermediate grade control adenocarcinoma NOS cases that did not resemble the index cases. All 5 index cases harbored a novel MEF2C-SS18 gene fusion, which was independently confirmed by reverse transcriptase-polymerase chain reaction. The MEF2C-SS18-positive cases arose in the oral cavity (4/5) and parotid gland (1/5) of 3 women and 2 men ranging from 21 to 80 years (mean: 46) and shared near-identical histologic features: intercalated duct-like cells with eosinophilic to clear cytoplasm and small, uniform oval nuclei, infiltrative microcysts and cords, abundant intraluminal secretions, and cellular fibromyxoid stroma. Mitotic rates were low; necrosis was absent. All MEF2C-SS18-positive tumors were positive for S100 and p63 and negative for p40, smooth muscle actin, calponin, and mammaglobin. One of the 23 control cases, a parotid tumor, was found to contain a SS18-ZBTB7A gene fusion; it demonstrated similar, but not identical histologic and immunophenotypic features compared with the MEF2C-SS18 cases. The remaining control cases were negative for SS18 and MEF2C rearrangements. A novel MEF2C-SS18 gene fusion and unique histologic and immunophenotypic features characterize a heretofore undefined low-grade salivary adenocarcinoma for which we propose the term "microsecretory adenocarcinoma." RNA-Seq helped establish this entity as a distinct tumor type, and identified one possibly related case with a different SS18-related fusion. The recognition of microsecretory adenocarcinoma and its separation from other adenocarcinomas NOS will facilitate a more complete understanding of the clinical and pathologic characteristics of this previously unrecognized neoplasm.
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http://dx.doi.org/10.1097/PAS.0000000000001273DOI Listing
August 2019

Variant, Immune Signatures, DNA Methylation, and Social Determinants Linked to Survival Racial Disparities in Head and Neck Cancer Patients.

Cancer Prev Res (Phila) 2019 04 18;12(4):255-270. Epub 2019 Feb 18.

Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland.

To inform novel personalized medicine approaches for race and socioeconomic disparities in head and neck cancer, we examined germline and somatic mutations, immune signatures, and epigenetic alterations linked to neighborhood determinants of health in Black and non-Latino White (NLW) patients with head and neck cancer. Cox proportional hazards revealed that Black patients with squamous cell carcinoma of head and neck (HNSCC) with ( = 0.06) and ( = 0.017) promoter methylation had worse survival than NLW patients, after controlling for education, zipcode, and tumor-node-metastasis stage ( = 118). We also found that promoter methylation of and P ( = 78), was correlated with neighborhood characteristics at the zip-code level ( < 0.05). Analyses also showed differences in the frequency of mutations ( = 32) and tumor-infiltrating lymphocyte (TIL) counts ( = 24), and the presence of a specific C → A germline mutation in , chr19:17954215 (protein P132T), in Black patients with HNSCC ( = 73; < 0.05), when compared with NLW ( = 37) patients. TIL counts are associated ( = 0.035) with long-term (>5 years), when compared with short-term survival (<2 years). We show bio-social determinants of health associated with survival in Black patients with HNSCC, which together with racial differences shown in germline mutations, somatic mutations, and TIL counts, suggests that contextual factors may significantly inform precision oncology services for diverse populations.
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800037PMC
April 2019

Human papillomavirus-related multiphenotypic sinonasal carcinoma: An emerging tumor type with a unique microscopic appearance and a paradoxical clinical behaviour.

Oral Oncol 2018 12 16;87:17-20. Epub 2018 Oct 16.

Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA. Electronic address:

Human papillomavirus (HPV) is well established as a causative factor in most squamous cell carcinomas of the oropharynx (OPSCC). Indeed, a growing awareness over the past two decades that HPV-OPSCC is a distinct form of head and neck cancer has had a profound impact on diagnostic and clinical practices. The sinonasal tract is a second anatomic "hot spot" for HPV-related head and neck carcinomas, but certain pathologic features and the clinical behavior of HPV-related carcinomas at this site remain unclear. The enigmatic nature of HPV-positive sinonasal carcinomas is especially true for an emerging form recently designated as HPV-related multiphenotypic sinonasal carcinoma (HMSC). HMSC has come to the attention of the pathology community largely owing to its highly unusual microscopic appearance: it exhibits mixed salivary gland (e.g. adenoid cystic carcinoma) and squamous differentiation. At the same time, HMSC is largely unknown by the clinical community despite an unexpected clinical behavior that could affect therapy. HMSC is characterized by high grade histologic features, locally destructive growth, advanced T stage, and a propensity for local recurrence; and yet it appears to have little potential for metastatic spread or lethal behavior. This review will describe the unique pathologic features of HMSC, discuss its distinction from adenoid cystic carcinoma and squamous cell carcinoma, and draw attention to a behavior that departs from the expected clinical course of most high grade carcinomas of the head and neck.
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http://dx.doi.org/10.1016/j.oraloncology.2018.10.011DOI Listing
December 2018

SOX10 Immunoexpression in Basaloid Squamous Cell Carcinomas: A Diagnostic Pitfall for Ruling out Salivary Differentiation.

Head Neck Pathol 2019 Dec 29;13(4):543-547. Epub 2018 Nov 29.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

SOX10 immunoexpression is increasingly recognized in salivary gland tumors, including but not limited to those with myoepithelial, serous acinar, and intercalated duct differentiation. However, SOX10 expression has not been extensively evaluated in other epithelial tumors that can mimic salivary origin. Basaloid squamous cell carcinoma (SCC) is a unique variant of SCC that shows morphologic overlap with several salivary tumors, including adenoid cystic carcinoma, basal cell adenocarcinoma, and myoepithelial carcinoma. We performed SOX10 immunohistochemistry on 22 basaloid SCCs and 280 non-basaloid SCCs. If tissue was available, we also performed immunohistochemistry for S100 and p16, and in-situ hybridization for high-risk HPV RNA. SOX10 was positive in 13/22 basaloid SCCs (59%), including 5/6 (83%) that were HPV-positive and 6/12 (50%) that were HPV-negative. Only 2/12 basaloid SCC (17%) demonstrated focal S100 expression. All non-basaloid SCCs were SOX10 negative. Frequent positivity for SOX10 in basaloid SCC presents a significant diagnostic pitfall for distinguishing these tumors from various basaloid salivary carcinomas. The preponderance of SOX10 expression in the basaloid variant of HPV-positive SCC also presents a diagnostic challenge in separating it from HPV-related multiphenotypic sinonasal carcinoma. SOX10 may be more broadly considered a marker of basal differentiation and should not be assumed to be specific for salivary origin in epithelial head and neck tumors.
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http://dx.doi.org/10.1007/s12105-018-0990-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854191PMC
December 2019

Adamantinoma-like Ewing Sarcoma of the Salivary Glands: A Newly Recognized Mimicker of Basaloid Salivary Carcinomas.

Am J Surg Pathol 2019 02;43(2):187-194

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD.

Adamantinoma-like Ewing sarcoma (ALES) is a rare tumor that demonstrates the EWSR1-FLI1 translocation characteristic of Ewing sarcoma despite overt epithelial differentiation including diffuse expression of cytokeratins and p40. Most cases of ALES described to date have occurred in the head and neck where they can mimic a wide range of small round blue cell tumors. Because distinguishing ALES from basaloid salivary gland carcinomas can be particularly difficult, we analyzed a series of 10 ALESs that occurred in the salivary glands with the aim of identifying features that allow for better recognition of this entity. The salivary ALESs included 8 parotid gland and 2 submandibular gland tumors in patients ranging from 32 to 77 years (mean: 52 y). Nine were initially misclassified as various epithelial neoplasms. Although these tumors displayed the basaloid cytology, rosette formation, infiltrative growth, and nuclear monotony characteristic of ALES, peripheral palisading and overt keratinization were relatively rare in this site. Salivary ALESs not only displayed positivity for AE1/AE3, p40, and CD99, but also demonstrated a higher proportion of synaptophysin reactivity than has been reported for nonsalivary ALESs. These morphologic and immunohistochemical findings make ALES susceptible to misclassification as various other tumors including basal cell adenocarcinoma, adenoid cystic carcinoma, squamous cell carcinoma, NUT carcinoma, large cell neuroendocrine carcinoma and myoepithelial carcinoma. Nevertheless, monotonous cytology despite highly infiltrative growth and concomitant positivity for p40 and synaptophysin can provide important clues for consideration of ALES, and identification of the defining EWSR1-FLI1 translocations can confirm the diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115302PMC
February 2019

Detection of AR-V7 transcript with RNA in situ hybridization in human salivary duct cancer.

Oral Oncol 2018 09 28;84:134-136. Epub 2018 Jun 28.

Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.oraloncology.2018.06.026DOI Listing
September 2018

Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma.

Transl Res 2018 12 26;202:109-119. Epub 2018 Jul 26.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

We have recently performed the characterization of alternative splicing events (ASEs) in head and neck squamous cell carcinoma, which allows dysregulation of protein expression common for cancer cells. Such analysis demonstrated a high ASE prevalence among tumor samples, including tumor-specific alternative splicing in the GSN gene.In vitro studies confirmed that overall expression of either ASE-GSN or wild-type GSN (WT-GSN) isoform inversely correlated with cell proliferation, whereas the high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion. Additionally, a change in expression of either isoform caused compensatory changes in expression of the other isoform. Our results suggest that the overall expression and the balance between GSN isoforms are mediating factors in proliferation, while increased overall expression of ASE-GSN is specific to cancer tissues. As a result, we propose ASE-GSN can serve not only as a biomarker of disease and disease progression, but also as a neoantigen for head and neck squamous cell carcinoma treatment, for which only a limited number of disease-specific targeted therapies currently exist.
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http://dx.doi.org/10.1016/j.trsl.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218276PMC
December 2018

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

Cancer 2018 07 30;124(14):2993-2999. Epub 2018 Apr 30.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients.

Methods: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models.

Results: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (P = .01) but not among p16-negative patients (P = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (P = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status.

Conclusions: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033632PMC
July 2018

Age Profile of Patients With Oropharyngeal Squamous Cell Carcinoma.

JAMA Otolaryngol Head Neck Surg 2018 Jun;144(6):538-539

Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1001/jamaoto.2018.0310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933458PMC
June 2018

Human Papillomavirus-Related Neuroendocrine Carcinomas of the Head and Neck.

Authors:
William H Westra

Head Neck Pathol 2018 Mar 20;12(1):9-12. Epub 2018 Mar 20.

Department of Pathology, The Icahn School of Medicine at Mount Sinai Hospital, Annenberg Bldg, Room 15-54, 1468 Madison Ave, New York, NY, 10029, USA.

Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.
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http://dx.doi.org/10.1007/s12105-018-0886-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873494PMC
March 2018

Prognostic factors for human papillomavirus-positive and negative oropharyngeal carcinomas.

Laryngoscope 2018 08 14;128(8):E287-E295. Epub 2018 Mar 14.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland.

Objectives/hypothesis: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) are distinct disease entities. Prognostic factors specific to each entity have not been adequately explored. Goals for this study were: 1) to determine whether HPV-positive and HPV-negative OPSCCs have distinct prognostic factors, and 2) to explore the prognostic significance of sex and race in OPSCC after HPV stratification STUDY DESIGN: Retrospective case series.

Methods: A retrospective review of 239 incident OPSCC patients from 1995 to 2012, treated at Johns Hopkins and University of California-San Francisco was conducted. Women and nonwhite races were oversampled. All analyses were stratified by tumor HPV in situ hybridization status. The effects of sex and race on survival were considered in Kaplan-Meier and unadjusted and adjusted Cox regression models.

Results: One hundred thirty-four (56.1%) OPSCC patients were HPV positive. On univariate analysis, women had better overall survival than men among HPV-positive (hazard ratio [HR]: 0.47, 95% confidence interval [CI]: 0.20-1.07; P = .06) but not HPV-negative (HR: 0.73, 95% CI: 0.43-1.24; P = .24) OPSCCs. On multivariate analysis, women with HPV-positive OPSCCs remained at lower risk of death (adjusted hazard ratio [aHR]: 0.34, 95% CI: 0.12-0.96; P = .04). Survival did not vary significantly by race among HPV-positive patients. Among HPV-negative patients, Hispanic patients had significantly better survival in unadjusted (HR: 0.27, 95% CI: 0.08-0.91; P = .04) but not adjusted (aHR: 0.93, 95% CI: 0.11-7.36; P = .94) analysis.

Conclusions: Women with HPV-positive OPSCC may have improved overall survival compared to men. Sex does not play a prognostic role in HPV-negative OPSCC. There are no differences in prognosis by race among HPV-positive or HPV-negative patients.

Level Of Evidence: 4 Laryngoscope, E287-E295, 2018.
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http://dx.doi.org/10.1002/lary.27130DOI Listing
August 2018

INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors.

Am J Surg Pathol 2018 05;42(5):665-671

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.

The head and neck is the site of a wide and sometimes bewildering array of neuroendocrine (NE) tumors. Although recognition of NE differentiation may be necessary for appropriate tumor classification and treatment, traditional NE markers such as synaptophysin, chromogranin, and CD56 are not always sufficiently sensitive or specific to make this distinction. Insulinoma-associated protein 1 (INSM1) is a novel transcription factor that has recently demonstrated excellent sensitivity and specificity for NE differentiation in various anatomic sites, but has not yet been extensively evaluated in tumors of the head and neck. We performed INSM1 immunohistochemistry on NE tumors (n=97) and non-NE tumors (n=626) across all histologic grades and anatomic subsites of the head and neck. INSM1 was positive in all types of head and neck NE tumors evaluated here (99.0% sensitivity), including middle ear adenoma, pituitary adenoma, paraganglioma, medullary thyroid carcinoma, olfactory neuroblastoma, small cell carcinoma, large cell NE carcinoma, and sinonasal teratocarcinosarcoma. Notably, it was positive in the vast majority of high-grade NE malignancies (95.8% sensitivity). INSM1 also was negative in almost all non-NE tumors (97.6% specificity) with the highest rates of reactivity in alveolar rhabdomyosarcoma and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1 (SMARCB1)-deficient sinonasal carcinoma. These findings confirm that INSM1 may be used as a standalone first-line marker of NE differentiation for tumors of the head and neck.
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http://dx.doi.org/10.1097/PAS.0000000000001037DOI Listing
May 2018

The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the rate of malignancy for atypia of undetermined significance subcategories.

Cancer Cytopathol 2018 05 9;126(5):309-316. Epub 2018 Feb 9.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland.

Background: The recent revision in terminology, with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) replacing noninvasive follicular variant of papillary thyroid carcinoma, has reclassified the clinically indolent tumor as nonmalignant. The objective of this study was to evaluate the impact of this change on the rate of malignancy (ROM) for subcategories of an atypia of undetermined significance (AUS) diagnosis on fine-needle aspiration (FNA) cytology.

Methods: Consecutive thyroid FNAs interpreted as AUS over a period of 4 years were retrospectively analyzed. The ROM for AUS subcategories, including atypia of undetermined significance with nuclear atypia (AUS-N), atypia of undetermined significance with a microfollicular pattern (AUS-F), atypia of undetermined significance with nuclear atypia and a microfollicular pattern (AUS-N/F), atypia of undetermined significance with Hürthle cells (AUS-H), and atypia of undetermined significance, not otherwise specified (AUS-NOS), were analyzed.

Results: Of the 426 nodules interpreted as AUS, 244 were surgically excised. The incidence of NIFTP in each subcategory was as follows: 18% for AUS-N, 18% for AUS-F, 9% for AUS-N/F, 3% for AUS-H, and 0% for AUS-NOS. After the reclassification of NIFTP as nonmalignant, the ROM based on histologic follow-up significantly decreased from 43% to 26% for AUS-N (P < .001) and from 29% to 10% for AUS-F (P = .008). The ROM for AUS-N remained significantly higher than the ROM for AUS-F (P = .030).

Conclusions: A subset of resected AUS nodules can be reclassified as NIFTP, and that significantly decreases the ROM, especially for AUS-N and AUS-F. Nonetheless, AUS-N still harbors a substantially higher ROM than AUS-F. Cancer Cytopathol 2018;126:309-16. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.21981DOI Listing
May 2018

HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

Oral Oncol 2018 02 28;77:92-97. Epub 2017 Dec 28.

Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2017.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786382PMC
February 2018

Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists.

Arch Pathol Lab Med 2018 May 18;142(5):559-597. Epub 2017 Dec 18.

From the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Department of Radiation Oncology, Stanford University Medical Center, Palo Alto, California (Dr Beadle); the Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland (Drs Bishop and Westra); the Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri (Dr Chernock); Surveys, the College of American Pathologists, Northfield, Illinois (Mss Colasacco and Thomas); Policy and Advocacy, American Society of Clinical Oncology, Alexandria, Virginia (Ms Lacchetti); the Department of Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Moncur); the Department of Otolaryngology-Head and Neck Surgery, Ohio State University Wexler Medical Center, Columbus (Dr Rocco); the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Dr Schwartz); the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Seethala); and the Department of Pathology, Massachusetts General Hospital, Boston (Dr Faquin).

Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
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http://dx.doi.org/10.5858/arpa.2017-0286-CPDOI Listing
May 2018