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Background The last revision of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included a specific system for cutaneous squamous cell carcinoma (CSCC) of the head and neck. Here, we assessed the prognostic performance of six candidate modified T-classification models in head and neck CSCC patients. Methods Analysis of 916 patients with head and neck CSCC given treatment with curative intent at The University of Texas MD Anderson Cancer Center between 1995 and 2019 was performed. The main outcome was disease-specific survival (DSS), and the impact of depth of invasion (DOI) was analyzed using multivariable regression models. Candidate models were developed using the optimal DOI cut points for each AJCC T classification based on goodness of fit of the model and the simplicity of the model. Staging systems were compared using Harrell's concordance index. Results Median age was 70 years (range, 19–97years) and median follow-up time of 22 months (range, 1–250months). The median DOI was 6.0 mm (range, 0.1–70.0 mm). The five-year DSS rate was 80.7% (95%CI, 77.4–83.7%). We found significant association between DOI (hazard ratio, 1.21 [95%CI: 1.01–1.43]) and DSS on multivariable analysis. Based on a low Akaike information criterion score, improvement in the concordance index, and Kaplan–Meier curves, model 6 surpassed the AJCC staging system. Conclusions Incorporation of DOI in the current AJCC staging system improves discrimination of T classifications in head and neck CSCC patients. Lay summary The current staging system for head and neck cutaneous squamous cell carcinoma demonstrates wide prognostic variability and provides suboptimal risk stratification. Incorporation of depth of invasion in the T-classification system improves risk prediction and patient counseling. Precis We propose improved head and neck cutaneous squamous cell carcinoma T staging that will include depth of invasion and should be considered in future versions of the American Joint Committee on Cancer after external validation.

Background The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. Methods This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. Results No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). Conclusions The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.

Background/aimsTo identify prognostic factors for local recurrence, distant metastasis and disease-specific survival (DSS) for lacrimal gland carcinoma.MethodsAll consecutive patients with lacrimal gland carcinoma treated from January 1998 through December 2018 were included. Log-rank tests and univariate Cox proportional hazards regression models were used to study risk factors and survival.ResultsOverall, 55 patients were included in this study, and 5 patients were excluded from the survival analysis. Median age was 46 years (range: 10–76). 43 patients (78%) had adenoid cystic carcinoma (ACC). 31 patients (56%) had T2 disease at presentation. 28 patients (51%) underwent orbital exenteration with or without adjuvant radiotherapy or chemoradiation, 26 (47%) underwent eye-sparing surgery with or without adjuvant radiotherapy or chemoradiation, and 1 received palliative chemoradiation. 11 patients (22%) experienced local recurrence; 14 (29%) experienced distant metastasis. Five- and 10-year local-recurrence-free survival rates were 0.71 (95% CI 0.58 to 0.88), and 5- and 10-year distant-metastasis-free survival rates were 0.67 (95% CI 0.53 to 0.85) and 0.49 (95% CI 0.30 to 0.81), respectively. There was no significant difference in risks of local recurrence, distant metastasis or DSS between ACC patients who had orbital exenteration and those who had eye-sparing surgery. Perineural invasion was negatively associated with local-recurrence-free survival (p=0.02). Among patients with ACC, basaloid/solid histologic type was associated with significantly worse DSS than non-basaloid/solid histologic type (pConclusionsFor lacrimal gland carcinoma, orbital exenteration with adjuvant therapy and eye-sparing surgery with adjuvant therapy are associated with similar recurrence outcomes. Eye-sparing surgery is associated with better DSS. Perineural invasion is a risk factor for local recurrence. ACC with basaloid/solid subtype correlates with worse DSS.

BACKGROUND Salivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (adeno-NOS), are rare salivary gland cancers. Data on the efficacy of systemic therapy for these diseases are limited. METHODS Data were retrospectively collected from patients seen at The University of Texas MD Anderson Cancer Center during 1990 to 2020. Objective response rate (ORR) was assessed per RECIST v1.1. Recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were assessed by Kaplan-Meier method. Cox regression model was performed to identify predictors of survival. RESULTS The analysis included 200 patients (110 with SDC and 90 with adeno-NOS); 77% had androgen-receptor-positive tumors and 47% had HER2-positive (2+-3+) tumors. Most patients without metastasis at diagnosis underwent surgery (98%) and postoperative radiotherapy (87%). Recurrence rate was 55%, and the median RFS was 2 years. Nodal involvement and positive surgical margins were associated with recurrence (P < .005). Among patients with stage IVA-B disease, addition of systemic therapy to local therapy increased OS (P = .049). The most-used palliative-systemic-therapy regimen was platinum doublet ± trastuzumab. For first-line therapy, the ORR and median PFS were 33% and 5.76 months, respectively, and for second-line therapy the ORR and median PFS were 25% and 5.3 months, respectively. ORR and PFS were higher with HER2-targeting agents. Median OS was 5 years overall and 2 years for metastatic disease. Older age and higher stage were associated with worse OS. CONCLUSION Adding systemic therapy to local therapy may improve outcomes of patients with locoregionally advanced SDC or adeno-NOS. Except for HER2-targeted therapy, response to palliative systemic therapy is limited. These findings may be used as a benchmark for future drug development.

Background: Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm with a characteristic trabecular growth pattern and hyalinization. This lesion has been the subject of long-term controversy surrounding its genetic mechanisms, relationship to papillary thyroid carcinoma (PTC), and malignant potential. Due to the presence of nuclear features shared with PTC, HTT frequently contributes to a false-positive cytology, which hampers patient management. The goal of this study was to apply genome-wide sequencing analyses to elucidate the genetic mechanisms of HTT and its relationship to PTC. Methods: Whole-exome, RNA-Seq, and targeted next-generation sequencing analyses were performed to discover and characterize driver mutations in HTT. RNA-Seq results were used for pathway analysis. Tissue expression of GLIS3 and other proteins was detected by immunohistochemistry. The prevalence of GLIS fusions was studied in 17 tumors initially diagnosed as HTT, 220 PTC, and 10,165 thyroid fine-needle aspiration samples. Results: Using whole-exome and RNA-Seq analyses of the initial three HTT, no known thyroid tumor mutations were identified, while in-frame gene fusion between PAX8 exon 2 and GLIS3 exon 3 was detected in all tumors. Further analysis identified PAX8–GLIS3 in 13/14 (93%) and PAX8–GLIS1 in 1/14 (7%) of HTT confirmed after blind pathology review. The fusions were validated by Sanger sequencing and FISH. The fusions resulted in overexpression of the 3′-portion of GLIS3 and GLIS1 mRNA containing intact DNA-binding domains of these transcription factors and upregulation of extracellular matrix genes including collagen IV. Immunohistochemistry confirmed upregulation and deposition of collagen IV and pan-collagen in HTT. The analysis of 220 PTC revealed no PAX8–GLIS3 and one PAX8–GLIS1 fusion. PAX8–GLIS3 was prospectively identified in 8/10,165 (0.1%) indeterminate cytology fine-needle aspiration samples; 5/5 resected fusion-positive nodules were HTT on surgical pathology. Conclusions: This study demonstrates that GLIS rearrangements, particularly PAX8–GLIS3, are highly prevalent in HTT but not in PTC. The fusions lead to overexpression of GLIS, upregulation of extracellular matrix genes, and deposition of collagens, which is a characteristic histopathologic feature of HTT. Due to unique genetic mechanisms and an indolent behavior, it is proposed to rename this tumor as “GLIS-rearranged hyalinizing trabecular adenoma.”

Purpose: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence. Patients and Methods: Newly diagnosed or recurrent stage III–IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response. Results: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9–54.3] had partial responses by RECIST, 15 patients (75%; 95% CI, 50.9–91.3) had a pCR (n = 11) or MPR (n = 4). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7–26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9–100), 89.5% (95% CI, 76.7–100), and 95% (95% CI, 85.9–100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR. Conclusions: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Background The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. Methods The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. Results A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. Conclusions Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

Background The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN). Methods Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival. Results Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score. Conclusions Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy.

OBJECTIVES To evaluate the incidence of histopathologic diagnostic discrepancy for patients referred to our institution, identify pathologies susceptible to diagnostic error, and assess the impact on survival of histopathologic diagnostic discrepancies. METHODS Three hundred ninety-seven patients with sinonasal cancers were identified, and discordance between the outside pathologic report and MD Anderson Cancer Center pathologic report was assessed. Overall survival and disease-specific survival were analyzed using Kaplan-Meier and log rank methods. RESULTS Discordance of major histopathologic diagnoses was present in 24% (97 of 397) of reports, with sinonasal undifferentiated carcinoma, sarcoma, neuroendocrine carcinoma, and poorly differentiated carcinoma pathologies having the highest change in diagnosis (P

The pathology of thyroid and parathyroid nodules represents a spectrum of disorders from reactive hyperplasias and benign neoplasms to carcinomas with metastatic potential. Thyroid nodules are common in adults and will be frequently encountered for pathologic evaluation by fine needle aspiration (FNA). Surgical resection allows for a definitive diagnosis for the 20–30% of indeterminate thyroid nodules by FNA and for tumor staging in the 10% that will be malignant. Conversely, parathyroid disease is relatively rare with biochemical and imaging allowing for a preoperative diagnosis in the majority of cases. Localized parathyroid surgery for primary hyperparathyroidism then allows for both definitive treatment and diagnostic tissue to confirm parathyroid adenoma. On a cellular level, recognizing the relationship of tumors to the cells of origin including “follicular-derived” in thyroid versus from C-cells also creates a framework to diagnose thyroid cancers and utilize correlative biochemical markers for both diagnosis and clinical follow-up. The following chapter outlines the fundamentals for pathologic evaluation and associated molecular alterations for these endocrine organs.

The anterior skull base is a complex anatomic site which may be involved by a large number of biologically heterogenous neoplasms. They arise from the epithelium, both surface mucosa and glands, as well as soft tissues, bone, and cartilage. Many benign and malignant tumours in the anterior skull base are similar to their counterparts in other anatomic sites. Interestingly, unique tumours including teratocarcinosarcoma, olfactory neuroblastoma, and angiofibroma can also be found. Recognition of overlapping morphologic features of entities encountered in this anatomic site and the corresponding differential diagnosis is critical. The integration of both morphologic features and immunohistochemical evaluation is essential for correct diagnostic interpretation. This is particularly notable in small round blue cell tumours for which morphologic lineage differentiation is lacking, thus requiring immunohistochemical characterisation. Moreover, challenges in accessing tissue for diagnosis leads to limited biopsies that require proper handling for adequate assessment. Histologic evaluation combined with communication between surgeons and pathologists are necessary components in the work-up and evaluation of these rare tumours.

The sinonasal and skull base regions are comprised of complex anatomical sites and give rise to widely varied lineage tumors. The diagnosis and differential diagnosis of these entities often pose diagnostic and management challenges. The chapter presents a systematic approach for the substratification of these tumors. A simplified stratagem integrating morphologic and marker profiling in the final categorization of the tumors is detailed for efficient and timely diagnosis. The chapter also introduces newly accepted entities and addresses their implications in the characterization and management of patients with these entities.

Basal cell salivary neoplasms display similar cyto-morphologic features and are classified into adenoma and adenocarcinoma based on the presence or absence of tumor invasion at diagnosis. These neoplasms also share considerable phenotypic resemblance and co-exist with certain dermal adnexal tumors harboring the CYLD gene mutations inferring common genetic association. We sequenced the CYLD gene in both basal cell adenomas and adenocarcinomas and correlated the findings with CYLD, NF-κB, and β-catenin expression levels and clinicopathologic factors. Twenty mutations were identified and comprised of 3 synonymous and 17 non-synonymous (missense) types involving the coding exons of the CYLD gene. Mutations in exons 9-11 were identified in both adenomas and adenocarcinomas, while mutations in exons 12-20, encoding the USP domain, were exclusively found in carcinomas. Although no significant correlation between CYLD mutations and expression levels of CYLD, NF-κB, and β-catenin or clinicopathologic parameters was found, basal cell adenocarcinomas with multiple mutations showed reduction in CYLD protein expression and pursued aggressive clinical behavior. Our study revealed high incidence and sequential CYLD mutations in both basal cell adenoma and adenocarcinoma supporting a single neoplastic continuum for their evolution and provides evidence for potential diagnostic and therapeutic utility.

Perivascular epithelioid cell tumors (PEComas) in the head and neck region are rare, with 26 cases described in literature. These distinct mesenchymal tumors normally express both myoid and melanocytic markers. We here report an interesting and challenging case of malignant PEComa that showed transcription factor E3 (TFE3) protein expression and rearrangement, paucity of muscle and melanocytic marker expression, and morphologically mimicked alveolar soft part sarcoma. Awareness of this morphologic pitfall and recognition of TFE3 gene-rearranged PEComa, as a distinct subtype of PEComa, is essential to avoid misdiagnosis.

Objectives To investigate the impact of 3-Diminsional (3D) tumor volume (TV) and extent of involvement of primary tumor on treatment outcomes in a large uniform cohort of T3 laryngeal carcinoma patients treated with nonsurgical laryngeal preservation strategies. Materials and Methods The pretreatment contrast-enhanced computed tomography images of 90 patients with T3 laryngeal carcinoma were reviewed. Primary gross tumor volume (GTVp) was delineated to calculate the 3D TV and define the extent of invasion. Cartilage and soft tissue involvement was coded. The extent of invasion was dichotomized into non/limited invasion versus multiple invasion extension (MIE), and was subsequently correlated with survival outcomes. Results The median TV was 6.6 cm3. Sixty-five patients had non/limited invasion, and 25 had MIE. Median follow-up for surviving patients was 52 months. The 5-year local control and overall survival rates for the whole cohort were 88% and 68%, respectively. There was no correlation between TV and survival outcomes. However, patients with non/limited invasion had better 5-year local control (LC) than those with MIE (95% vs 72%, p = .009) but did not have a significantly higher rate of overall survival (OS) (74% vs 67%, p = .327). In multivariate correlates of LC, MIE maintained statistical significance whereas baseline airway status showed a statistically significance trend with poor LC (p = .0087 and 0.06, respectively). Baseline good performance status was an independent predictor of improved OS (p = .03) in multivariate analysis. Conclusion The extent of primary tumor invasion is an independent prognostic factor of LC of the disease after definitive radiotherapy in T3 larynx cancer.

We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P.001).Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.

Objectives To develop and characterize in vitro salivary duct carcinoma as a surrogate for functional studies. Materials and methods Cells were dispersed from tumor tissue fragments under sterile conditions in RPMI media. Disassociated cells were cultivated, immortalized with hTERT and propagated for more than 100 passages. Morphologic, linage, cytogenetic and genomic analyses were performed on different passages of cell line and primary tumor. Soft agar growth was performed. Results Analysis of cytomorphologic features, growth characteristics and lineage specific markers expression confirmed the epithelial derivation and the neoplastic nature of the cell line. DNA STRs analysis showed identical match of both cell line and primary tumor. Cultivated cells expressed Androgen Receptor (AR), PTEN, and EFGR proteins and the AR-V7 isoform transcript. Comparative exome-sequencing identified common mutated genes in both cell line and primary tumor. In-vitro colony formation of late passages is established. Conclusion We report the development of the first human salivary duct carcinoma cell line (MDA-SDC-04) that retains critical biological and genomic features of the donor tumor.

Neuroendocrine tumors are extremely rare in the middle ear. We reviewed our institutional experience with middle ear adenomatous neuroendocrine tumors (MEANTs). We searched our institution's pathology files to identify patients treated from 1990 to 2015 who had lesions classified as middle ear adenomas, adenomatous tumors, adenomatous tumors with neuroendocrine differentiation, carcinoid tumors of the middle ear, low-grade neuroendocrine tumors of the middle ear, and neuroendocrine carcinomas of the middle ear and identified 14 such patients for whom follow-up information was available. Herein, we review the pathology and differential diagnosis of these patients' tumors and discuss the management and follow-up of these patients. Our report adds to the series cases of MEANTs with recurrences, lymph node involvement, distant metastases, and tumor-related deaths. Our experience suggests that, although these tumors have long been considered to be low-aggression neoplasms, long-term follow-up studies to ascertain this supposed benignity are warranted.

Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.

Secretory carcinoma of the salivary gland is a newly recognized entity that morphologically resembles breast secretory carcinoma and has a characteristic t(12;15)(p13;q25) ETV6-NTRK3 translocation. Fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) analyses can detect the ETV6-NTRK3 fusion; however, both tests are expensive and not widely available. In this study, we aimed to determine whether pan-Trk immunohistochemistry (IHC) could detect ETV6-NTRK3 fusions as reliably as RT-PCR and FISH. We performed pan-Trk IHC in 70 salivary gland cancer samples, including secretory carcinomas, acinic cell carcinomas, and hybrid carcinomas. Nineteen tumors exhibited positive pan-Trk staining, including 16 secretory carcinomas, 2 hybrid carcinomas with a secretory carcinoma component, and 1 acinic cell carcinoma. Pan-Trk IHC staining was localized in the nucleus in 16 (84.2%) cases and in the cytoplasm and/or membrane in 3 (15.8%) cases. RT-PCR analysis for the ETV6-NTRK3 transcript was conducted in 45 samples; the fusion transcript was present in 11 of 12 secretory carcinomas and absent in 32 acinic cell carcinomas and 1 mucoepidermoid carcinoma. Pan-Trk IHC was positive in 10 of 11 salivary tumors that were positive for ETV6-NTRK3 by RT-PCR and negative in all 34 tumors that were negative for the fusion by RT-PCR. Therefore, in comparison with RT-PCR, pan-Trk IHC had a sensitivity of 90.9% and specificity of 100%. In conclusion, our data showed that pan-Trk IHC is a reasonable screening test for diagnosing secretory carcinoma of the salivary gland.

Primary salivary gland neoplasms are rare and are known for their varied phenotypic and biological presentations and behavior. They originate from three major, and numerous minor, salivary glands m...

We report a rare case of Cushing’s syndrome in a 59-year-old man who initially presented with concurrent acinic cell carcinoma of the parotid with high-grade transformation and co-existing papillary and medullary thyroid carcinomas, without noticeable cushinoid symptoms. Six-months later, he developed clinical features of Cushing’s syndrome which coincided with disease progression in the form of lung metastasis and mediastinal lymphadenopathy. Ectopic adrenocorticotropic hormone (ACTH) production and protein expression was limited to the high-grade transformed component of acinic cell carcinoma and in the lymph node metastasis, and was absent in the conventional acinic cell carcinoma as well as in the papillary and medullary thyroid carcinoma. He received adjuvant chemotherapy and supportive management with interval improvement for 8 months followed by disease progression with increasing serum cortisol levels and bone metastasis. He was offered palliative chemotherapy, however, declined further therapy and was lost to follow up. We discussed clinical and pathologic implications of ectopic ACTH production associated with acinic carcinoma and also reviewed the literature of this rare paraneoplastic syndrome.

The pharynx comprises two anatomic sites, the oropharynx and nasopharynx, which contain mucosal and lymphoid tissues. Both regions are sites of some of the most well-studied viral-associated malignancies, including human papillomavirus-related oropharyngeal carcinomas and Epstein-Barr virus-related nasopharyngeal carcinomas. In this chapter, we will discuss the classification and pathogenesis of the most common carcinomas of the pharynx and recent advances in ancillary testing of these entities.

The pathology chapter in this text is primarily aimed at presenting pertinent diagnostic information to the oncologic management of patients with salivary gland malignancies. Therefore, detailed descriptions of cytomorphologic features of individual entities are briefly presented and lineage-related markers used in differential diagnosis of certain subtypes are highlighted. The role and utilization of fine needle aspiration technology in early classification, differential diagnosis, and follow-up are addressed in the context of their relevance to surgical planning, confirmation of progression and biomarker studies. Current and emerging genetic findings and their potential diagnostic and management implications are discussed.

6014 Background: Chemoradiation (CRT) with cis or anti-EGFR Ab has been shown to improve survival of patients with stage III-IV HNC. Since Lap, a dual EGFR and HER2 inhibitor, has shown effectiveness with CRT in a pilot non-HPV HNC cohort, the RTOG Foundation launched a phase II trial to test the hypothesis that adding Lap to the RT-cis for frontline therapy of stage III-IV Non-HPV HNC improves progression-free survival (PFS). Methods: Patients with stage III-IV carcinoma of the oropharynx (p16-negative), larynx, and hypopharynx, having Zubrod performance of 0-1, and meeting predefined blood chemistry criteria were enrolled after providing consent. Patients were randomized (1:1) to 70 Gy (6 weeks) + 2 cycles of CDDP (q3 weeks) plus either Lap (1500 mg daily, Arm A) or placebo (Arm B) starting 1 week prior to RT and concurrent with RT and for 3 months post RT. PFS was the primary endpoint. The protocol specified 69 PFS events (142 patients) for the final analysis based on HR = 0.65, 80% power, 1-sided alpha 0.20, and one interim efficacy and futility analysis at 50% information. PFS rates between arms for all randomized patients were compared by 1-sided log-rank test (1-sided alpha 0.1803). Overall survival (OS) was a secondary endpoint. Results: From 10/’12 to 04/’17, 142 patients were enrolled, of whom 127 were randomized, 63 to Arm A and 64 to Arm B. Arms A vs B, respectively, were similar in baseline patient characteristics, radiation delivery, completing ≥ 70 Gy (85.7% vs. 82.8%) and cisplatin delivery, completing 200 (±5%) mg/m2 (65.1% vs 70.3%), but dissimilar in Lap/placebo delivery (median dose, 87000 mg vs. 125250 mg). Median follow-up was 4.1 years for surviving patients. The final analysis suggests no improvement in PFS of adding Lap to CRT (HR [A/B]: 0.91, 95% confidence interval CI 0.56-1.46; P= 0.34; 2-year rates: 50.6%, CI 37.5-63.7% vs. 56.2% CI 43.0-69.4%), or in OS (HR: 1.06, CI 0.61-1.86; P = 0.58; 2-year rates: 71.8% CI 60.1-83.5% vs. 76% CI 64.5-87.4%), death within 30 days of therapy (3.3% vs. 3.4%), and overall treatment-related grade 3-5 adverse event rate (86.7% vs. 84.7%). Grade 3-4 mucositis rates on Arm A and Arm B were 21.7% vs. 23.7%, all grade dysphagia and rash rates were 43.3% vs. 59.3%, and 13.3% vs. 6.8%, respectively. Conclusions: The addition of Lap to the radiation-cisplatin platform did not improve progression-free or overall survival in unselected non-HPV HN. Thus, dual EGFR, HER-2 inhibition does not appear to enhance the effects of chemoradiation. Although we showed that accrual to a non-HPV HN specific trial is feasible, new strategies must be investigated to improve the outcome for this poor prognosis HN population.

6084 Background: Salivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (Adeno-NOS) are rare and aggressive subtypes of salivary gland cancers. Biomarker studies revealed targetable alterations such as androgen receptor (AR) and HER2 overexpression; nevertheless, chemotherapy (CT) remains the cornerstone treatment of patients (pts) with locally advanced or metastatic disease based on limited efficacy data. We sought to describe the treatment patterns and outcomes of SDC and Adeno-NOS pts. Methods: We retrospectively collected clinicopathological, treatment, and outcomes data of SDC or Adeno-NOS pts that were seen at MD Anderson from 1990-2020. AR positivity was defined by IHC staining in ≥ 10% of tumor cells, and HER2 by IHC 2+ or 3+ scores. Overall response rate (ORR) was assessed by an independent radiologist per RECIST v1.1. Recurrence-free survival (RFS) and overall survival (OS) from diagnosis were estimated using log-rank test. A multivariable cox regression model was performed to estimate the hazard-ratio (HR) of risk factors on pts outcomes. Results: 200 pts were included, 110 had SDC and 90 Adeno-NOS. Most pts (61%) presented with locoregional disease (stage III-IVB), while 13% had distant metastasis (IVC). AR was positive in 77% of cases, and HER2 in 47%. In the curative setting (N=174), 98% pts underwent surgery and 90% radiotherapy (RT); 15 pts with stage IVA-B disease had aggressive trimodality therapy including surgery, RT, and systemic therapy. Overall, 55% pts recurred. The mRFS and 5-y RFS rate were 24 mos (95%CI, 16-43) and 34.5%, respectively. For pts with IV-A-B stage, trimodality therapy was associated with an improved OS in comparison to surgery and/or RT (39 mos vs NA, p=0.04). In the metastatic setting, 82 pts received ≥1 line of systemic therapy; the preferred 1st line regimen was platinum/taxane with or without trastuzumab (50%). Table summarizes the ORR and mPFS to each therapy line. ORR and PFS was higher for HER2-targeted therapy (1st line: 47% and 11 mos; 2nd line 29% and 6 mos; respectively); only 10 pts received androgen blockage. At a median follow-up of 7.5 y, the mOS was 5 ys and the 5-y OS rate was 50%. In multivariate analysis, higher T and N stages (HR 2.1 and 3.8, p

p53 (TP53) is the most frequently mutated gene in squamous cell carcinomas (SCCs) of the skin and head and neck. Certain p53 mutations are oncogenic and promote invasion and metastasis in SCCs. However, it is unclear how the oncogenic function of mutant p53 is modulated by other molecular alterations that co-exist in SCCs. Here, we show that deletion of the p53 gene and activation of an endogenous p53(R172H) gain-of-function mutation in the skin induce carcinomas with similar kinetics and penetrance. Deletion of p53 induced primarily well-differentiated SCCs. However, most of the tumours induced by p53(R172H) were poorly differentiated SCCs, the only metastatic tumours in this model. These tumours expressed higher levels of cyclin D1 than the well-differentiated SCCs and spindle carcinomas that developed in these mice. Unexpectedly, metastasis was not observed in mice that developed spindle carcinomas, which expressed high levels of the tumour suppressors p16(Ink4a) and p19(Arf) , encoded by Cdkn2a, a gene frequently deleted in human SCCs. Remarkably, deletion of the Cdkn2a gene in p53(R172H) -induced SCCs promoted a dramatic increase in metastasis rates and a shorter survival in mice that developed these tumours, compared with those observed in mice with tumours in which Cdkn2a was deleted in the presence of a p53 loss-of-function mutation or wild-type p53. Accordingly, the survival of patients with head and neck SCCs bearing co-occurring high-risk p53 mutations and CDKN2A homozygous deletions was much shorter than that of patients with tumours in which high-risk p53 mutations did not contain CDKN2A homozygous deletions, or that of patients with tumours in which homozygous CDKN2A deletions co-existed with either low-risk p53 mutations or potential loss-of-function mutations in p53. These findings genetically identify a population of SCC patients with worst outcomes and will help to predict outcomes according to the p53 status and alterations in CDKN2A. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

We report a rare translocation involving chromosomes 1q23 and 3p21 regions in a basaloid salivary carcinoma. Our case together with a previously reported instance of translocation involving chromosome 1q 21-24 region defines a specific chromosomal segment that may house a gene associated with the development of a subset of basaloid salivary tumors.

Background The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers. Methods We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011. Results The 10-year overall survival (OS) was 35%; disease-specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status

Purpose To review our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity. Methods and Materials We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients. Results Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7 months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade ≥3 toxicity were 32% at 2 years and 48% at 5 years, with dysphagia or odynophagia being most common. Increased grade ≥3 toxicity was associated with retreatment volume >50 cm 3 and concurrent chemotherapy. Conclusions Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.

Simple Summary Cytopathology cannot distinguish benign from malignant follicular lesions in 20–30% of cases. These indeterminate cases includes the so-called follicular neoplasms (FNs) according to The Bethesda System for Reporting Thyroid Cytopathology. Frozen samples from 66 classic follicular adenomas (cFAs) and carcinomas (cFTCs) studied by array-comparative genomic hybridization identified three specific alterations of cFTCs (losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X) confirmed by fluorescent in situ hybridization (FISH) in a second independent series of 60 touch preparations from frozen samples of cFAs and cFTCs. In a third independent set of 27 cases of already stained pre-operative fine-needle aspiration cytology samples diagnosed as FNs and histologically verified, FISH analysis using these three markers identified half of cFTCs. Specificity of our assay for identifying cFTCs is higher than 98% which might be comparable with BRAF600E testing in cases of suspicion of classic papillary thyroid carcinomas. Abstract Although fine-needle aspiration cytology (FNAC) is helpful in determining whether thyroid nodules are benign or malignant, this distinction remains a cytological challenge in follicular neoplasms. Identification of genomic alterations in cytological specimens with direct and routine techniques would therefore have great clinical value. A series of 153 cases consisting of 72 and 81 histopathologically confirmed classic follicular adenomas (cFAs) and classic follicular thyroid carcinomas (cFTCs), respectively, was studied by means of different molecular techniques in three different cohorts of patients (pts). In the first cohort (training set) of 66 pts, three specific alterations characterized by array comparative genomic hybridization (aCGH) were exclusively found in half of cFTCs. These structural abnormalities corresponded to losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X. The second independent cohort (validation set) of 60 pts confirmed these data on touch preparations of frozen follicular neoplasms by triple DNA fluorescent in situ hybridization using selected commercially available probes. The third cohort, consisting of 27 archived cytological samples from an equal number of pts that had been obtained for preoperative FNAC and morphologically classified as and histologically verified to be follicular neoplasms, confirmed our previous findings and showed the feasibility of the DNA FISH (DNA fluorescent in situ hybridization) assay. All together, these data suggest that our triple DNA FISH diagnostic assay may detect 50% of cFTCs with a specificity higher than 98% and be useful as a low-cost adjunct to cytomorphology to help further classify follicular neoplasms on already routinely stained cytological specimens.

Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti PD-1 (programmed cell death protein 1) and PD-L1 (programmed cell death protein-ligand 1) monoclonal antibodies are emerging as standard oncology treatments in various tumor types. The indications will expand as immunotherapies are being investigated in various tumors with promising results. Currently, there is inadequate identification of predictive biomarkers of response or toxicity. Unique response patterns include pseudoprogression and delayed response. The use of immune checkpoint inhibitors exhibit an unique toxicity profile, the immune-related adverse events (irAEs). The most notable immune reactions are noted in skin (rash), gastrointestinal track (colitis, hepatitis, pancreatitis), lung (pneumonitis), heart (myocarditis), and endocrine system (thyroiditis, hypophysitis). We present a patient with metastatic adenoid cystic carcinoma of the left submandibular gland with granulomatous inflammation of the lacrimal glands and axonal neuritis of the cervical and paraspinal nerves following treatment with ipilimumab and radiation therapy.

BACKGROUND Unexpected malignancy is common in major salivary gland tumors due to variability of workup, creating challenging treatment decisions. The purpose of this study was to define treatment-related outcomes for patients with incompletely treated major salivary gland tumors. METHODS A retrospective cohort study was completed of patients with incompletely treated major salivary gland tumors. Tumor burden at presentation was established and treatment categorized. The Cox Proportional Hazards model was used to determine predictors of survival and failure. RESULTS Of the 440 included patients, patients with gross residual or metastatic disease had a worse overall survival (OS; P < .001). Presentation status was an independent predictor of OS on multivariate analysis (gross residual disease adjusted hazard ratio [HRadjusted ] 2.55; 95% confidence interval [CI] 1.20-5.30; metastatic disease HRadjusted 9.53; 95% CI 3.04-27.06). CONCLUSION Failure to achieve gross total resection during initial surgery resulted in worse OS. Adequate preoperative planning is required for initial surgical management to optimize tumor control and survival.

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The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

Background This was a retrospective study of patients with human papillomavirus (HPV)-associated oropharyngeal cancer treated with concurrent systemic therapy and radiation. Methods Data were extracted through chart review, and statistical analyses included frequency tabulation, chi-square, and Kaplan–Meier tests. Results Three hundred thirty-nine patients were analyzed; 166 received neoadjuvant chemotherapy. One hundred thirty-six patients were treated with cisplatin, 123 with cetuximab, and 59 with carboplatin. The 2-, 3-, and 5-year actuarial overall survival rates were 92%, 88%, and 78%, respectively. There were no significant differences in survival or disease control when analyzed by systemic agent. Platin-treated patients had greater hematologic toxicity, and required more intravenous hydration. The incidence of confluent mucositis was highest among patients treated with cetuximab. Conclusion Platin and cetuximab seem to have similar efficacy when delivered concurrently with radiation in our retrospective population study. Although platin did cause greater hematologic toxicity, radiation-specific side effects seemed relatively comparable. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Background Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear. Methods Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining. Results EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02). Conclusion P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459–E1466, 2016

Background Mucoepidermoid carcinoma arises from major or minor salivary glands, making up 10% of salivary gland tumors. Intraosseous mucoepidermoid carcinomas are rare, and make up only 2% to 3% of all mucoepidermoid carcinomas. The t(11;19) and its CRTC1-MAML2 fusion gene transcript have been identified in mucoepidermoid carcinoma and are associated with a subset of mucoepidermoid carcinomas. The extent to which the transcript influences disease features and patient survival is unclear. Methods We conducted a retrospective analysis of records for clinical features, surgical interventions, and prognoses. Reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) used to assess the t(11;19) fusion gene in intraosseous mucoepidermoid carcinoma. Results Twenty-five patients with intraosseous mucoepidermoid carcinoma treated between 1998 and 2013 were identified. The t(11;19) fusion gene transcript CRTC1-MAML2 manifested in 9 intraosseous mucoepidermoid carcinomas, whereas is was not detected in another 9 intraosseous carcinomas. Although the incidence of this fusion in mucoepidermoid carcinoma varies, it is generally accepted that more than 50% of this entity manifest the CRTC1-MAML2. Conclusion Intraosseous mucoepidermoid carcinoma diagnosis should be based on clinical and pathologic manifestations and complete resection is the first choice for patient treatment. The need for neck dissection and adjuvant treatment are debatable. Radiotherapy may improve prognosis and may be recommended in the postoperative period. Primary intraosseous mucoepidermoid carcinoma can manifest the fusion transcript in a subset of tumors. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Background Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy. Methods The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]). Results Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p = .015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p = .038 and p = .004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis. Conclusion For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. © 2015 Wiley Periodicals, Inc. Head Neck 38: E925–E933, 2016

Purpose: The physical properties of proton therapy allow for decreased dose delivery to nontarget structures. The purpose of this study was to determine if this translates into a clinical benefit by comparing acute and chronic morbidity between patients with nasopharyngeal carcinoma who are treated with intensity-modulated proton therapy (IMPT) and those treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: Patients receiving IMPT for nasopharyngeal cancer from 2011-13 were matched in a 2:1 IMPT to IMRT ratio. Matching criteria were, in order, T-stage, N-stage, radiation dose, chemotherapy type, World Health Organization classification, sex, and age. Results: Ten patients treated with IMPT and 20 matched patients treated with IMRT were included. By the end of treatment, 2 IMPT-treated patients (20%) and 13 IMRT-treated patients (65%) required gastrostomy tube (GT) insertion (P = .020). Patients receiving IMPT had significantly lower mean doses to the oral cavity, brain...

Objective Squamous cell carcinoma of the oral tongue (SCCOT) exhibits high risk for recurrence and regional metastasis even after surgical resection. We assessed the clinicopathologic and prognostic significance of a group of functionally related biomarkers. Study Design We used a tissue microarray consisting of SCCOT from 32 patients for this study. These patients were treated at the University of Texas MD Anderson Cancer Center from 1995 to 2008. Biomarker expression levels were examined by immunohistochemistry and graded semiquantitatively to determine their prognostic significance. Results CD147 and Tp63 expressions were significantly associated with a higher T stage and Ki-67 labeling index, as well as a shorter overall survival (OS) rate. Expression of Tp63 associated positively with poorly differentiated histology. There was significant association of Tp63 with the expression levels of CD147 and Glut-1. Glut-1 overexpression was marginally associated with a higher T stage. There was no prognostic significance of CD44 v6 expression in SCCOT. Conclusion SCCOT with CD147 overexpression in combination with high Ki-67 labeling index had poor OS. CD147 and Ki-67 overexpression is associated with aggressive disease with poor prognosis in SCCOT.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) of the thyroid is a rare traditionally "low-grade" tumor that predominantly occurs in women. Approximately 50 cases have been reported in the literature. It arises in a background of Hashimoto thyroiditis and is characterized by nests of epidermoid and mucin-secreting cells located within an eosinophil-rich sclerotic stroma. Herein, we outline the clinicopathological and immunohistochemical characteristics of 6 cases of thyroid SMECE. All tumors were detected in women (age, 36-89 years; average, 59 years), and all patients underwent total thyroidectomies. Clinicopathological findings included extensive tumor invasion into the adjacent soft tissues, trachea, pharynx, and esophagus. Of 6 specimens, 5 had positive surgical margins. Cervical lymph node metastases were seen in 4, and distant metastases were in 3 patients. Immunohistochemically, all tumors were positive for CK19, galectin 3, and p63 and negative for calcitonin, calponin, S-100, and smooth muscle actin. Interestingly, 2 tumors also showed faint focal staining for thyroglobulin, and 2 others had focal positivity for thyroid transcription factor 1. Together, galectin 3 and CK19 expression supported the malignancy of these lesions, and p63 expression raised the possibility that these tumors originated from the ultimobranchial body. In summary, SMECE tumors in our series exhibit a clear female predominance with aggressive behavior and appear to arise from pluripotent solid cell nests. A correct diagnosis is crucial to providing SMECE patients with the appropriate treatment options, and we recommend a closer follow-up schedule than previously considered.

Adenoid cystic carcinoma (ACC), a rare salivary gland malignancy, is a histogenetic, morphologic, and clinical heterogeneous disease. Extensive efforts have been made to characterize molecular events associated with these tumors, including the identification of prognostic and predictive biomarkers. Increased copy number gain and amplification of c-Met, the cell surface receptor for hepatocyte growth factor, has been shown to enhance tumor growth and invasiveness and promote metastasis in certain tumor types. In this study, we evaluated the expression of c-Met by immunohistochemistry (IHC) in a large cohort of salivary gland ACCs and examined its clinicopathologic implications. Archival formalin-fixed paraffin-embedded blocks from 200 ACC patients were used in this study. Pathologic patterns and phenotypic expression of c-Met were recorded and compared with clinical factors including gender, age, disease stage at diagnosis, and clinical outcomes. Correlations between c-MET expression and clinical characteristics were assessed by Pearson's chi-square test or by the 2-tailed Fisher exact test. Curves describing overall survival were generated by Kaplan-Meier product limit method. Strong c-MET expression was seen in inner ductal and outer myoepithelial cells in 53.2% of the cases. There was no correlation between c-Met overexpression and clinicopathologic parameters or patient's overall survival ( p = .94074). In conclusion, c-MET expression is high in a significant subgroup of ACC patients. While c-MET expression is not a prognostic factor in ACC, its role as a predictive marker of benefit from MET inhibitors deserves further investigation.

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma (HNSCC), with mutations occurring in over two thirds of cases; however, the predictive response of these mutations to cisplatin-based therapy remains elusive. In the current study, we evaluate the ability of the Evolutionary Action score of TP53-coding variants (EAp53) to predict the impact of TP53 mutations on response to chemotherapy. The EAp53 approach clearly identifies a subset of high-risk TP53 mutations associated with decreased sensitivity to cisplatin both in vitro and in vivo in preclinical models of HNSCC. Furthermore, EAp53 can predict response to treatment and, more importantly, a survival benefit for a subset of head and neck cancer patients treated with platinum-based therapy. Prospective evaluation of this novel scoring system should enable more precise treatment selection for patients with HNSCC. Cancer Res; 75(7); 1205–15. ©2015 AACR.

The two major goals of oral cancer chemoprevention efforts are the ability to segregate the high-risk patients and the identification of an effective pharmacologic agent that halts progression to invasive cancer. Considerable progress has recently been achieved in profiling invasive head and neck squamous cell carcinomas, particularly with the use of high-throughput technologies. A similar molecular characterization of potentially malignant oral epithelial lesions (OPML; leukoplakia and erythroplakia) is yet to be accomplished. It is postulated, though, that molecular profiling could lead to the discovery of novel markers of cancer risk that could also serve as potential targets for chemoprevention. In this perspective, we comment on the work by Izumchenko and colleagues that reports a high prevalence of NOTCH1 gain-of-function mutations in Chinese patients with OPMLs. Although additional studies are needed to validate the findings, the study is the first to link alterations in this gene in oral premalignancy. These findings could serve as a first prototype of a single gene mutation as a potential target in clinical chemoprevention setting. Cancer Prev Res; 8(4); 262–5. ©2015 AACR. See related article by Izumchenko et al., p. 277

Background The purpose of this study was to determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer. Methods We conducted a phase II study in adenoid cystic carcinoma (ACC) and non-ACC. Gefitinib was administered 250 mg orally daily. The primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rates. EGFR and human epidermal growth factor receptor 2 (HER2) expression were evaluated and correlated with outcomes. Results Thirty-seven patients were enrolled in this study, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC, respectively. The disease control rate at 8 weeks was higher in patients with ACC. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes. Conclusion We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002. © 2015 Wiley Periodicals, Inc. Head Neck 37: 644–649, 2015

BACKGROUND Salivary gland carcinomas (SGCs) are a rare malignancy with unknown etiology. The objective of the current study was to identify genetic variants modifying the risk of SGC and its major subtypes: adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS The authors conducted a genome-wide association study in 309 well-defined SGC cases and 535 cancer-free controls. A single-nucleotide polymorphism (SNP)-level discovery study was performed in non-Hispanic white individuals followed by a replication study in Hispanic individuals. A logistic regression analysis was applied to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A meta-analysis of the results was conducted. RESULTS A genome-wide significant association with SGC in non-Hispanic white individuals was detected at coding SNPs in CHRNA2 (cholinergic receptor, nicotinic, alpha 2 [neuronal]) (OR, 8.55; 95% CI, 4.53-16.13 [P = 3.6 × 10−11]), OR4F15 (olfactory receptor, family 4, subfamily F, member 15) (OR, 5.26; 95% CI, 3.13-8.83 [P = 3.5 × 10−10]), ZNF343 (zinc finger protein 343) (OR, 3.28; 95% CI, 2.12-5.07 [P = 9.1 × 10−8]), and PARP4 (poly(ADP-ribose) polymerase family, member 4) (OR, 2.00; 95% CI, 1.54-2.59 [P = 1.7 × 10−7]). Meta-analysis of the non-Hispanic white and Hispanic cohorts identified another genome-wide significant SNP in ELL2 (meta-OR, 1.86; 95% CI, 1.48-2.34 [P = 1.3 × 10−7]). Risk alleles were largely enriched in mucoepidermoid carcinoma, in which the SNPs in CHRNA2, OR4F15, and ZNF343 had ORs of 15.71 (95% CI, 6.59-37.47 [P = 5.2 × 10−10]), 15.60 (95% CI, 6.50-37.41 [P = 7.5 × 10−10]), and 6.49 (95% CI, 3.36-12.52 [P = 2.5 × 10−8]), respectively. None of these SNPs retained a significant association with adenoid cystic carcinoma. CONCLUSIONS To the best of the authors' knowledge, the current study is the first to identify a panel of SNPs associated with the risk of SGC. Confirmation of these findings along with functional analysis of identified SNPs are needed. Cancer 2015;121:2367–2374. © 2015 American Cancer Society.