Sphenoid Wing Meningioma With Extraocular Muscle Involvement Mimicking Idiopathic Orbital Inflammation.

Meningiomas are slow growing, typically benign, tumors originating from arachnoid cap cells. Specifically, sphenoid wing or spheno-orbital meningiomas infiltrate the lesser wing of the sphenoid, lateral orbital wall, and orbital roof with occasional extension to the superior orbital fissure, optic canal, anterior clinoid process, and middle cranial fossa where neurologic and ophthalmologic functions are impaired by compressive injury. The extraocular muscles are rarely involved. The authors present a rare case of an spheno-orbital meningioma causing extraocular muscle enlargement mimicking idiopathic orbital inflammation and highlight important diagnostic clues to meningioma.

Survival outcomes with concurrent chemoradiation for elderly patients with locally advanced head and neck cancer according to the National Cancer Data Base.

BACKGROUND: The overall survival (OS) benefit of concurrent chemoradiotherapy (CRT) for head and neck squamous cell carcinoma patients older than 70 years is debated. This study examines the outcomes of elderly patients receiving CRT versus radiotherapy (RT) alone. METHODS: The National Cancer Data Base was queried for patients older than 70 years with nonmetastatic oropharyngeal, laryngeal, or hypopharyngeal cancer (T3-4 or N(+)). CRT was defined as chemotherapy started within 14 days of the initiation of RT. Univariate analysis, multivariate analysis (MVA), propensity score matching (PSM), and recursive partitioning analysis (RPA) were performed. RESULTS: The study included 4042 patients: 2538 (63%) received CRT. The median follow-up was 19 months. The unadjusted median OS was longer with the addition of CRT (P < .001). OS was superior with CRT in the MVA (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.58-0.68; P < .001) and PSM analyses (HR, 0.73; 95% CI, 0.66-0.80; P < .001) in comparison with RT alone. According to RPA, CRT was associated with longer OS for patients 81 years or younger with low comorbidity scores and either T1-2/N2-3 disease or T3-4/N0-3 disease. The survival benefit with CRT disappeared for 2 subgroups in the 71- to 81-year age range: those with T1-2, N1, and Charlson-Deyo 0-1 (CD0-1) disease and those with T3-4, N1+, and CD1+ disease. Patients who were older than 81 years did not have increased survival with CRT. The receipt of CRT was associated with a longer duration of RT (odds ratio, 1.74; 95% CI, 1.50-2.01; P < .001). CONCLUSIONS: Patients older than 70 years should not be denied concurrent chemotherapy solely on the basis of age; additional factors, including the performance status and the tumor stage, should be taken into account. Cancer 2016;122:1533-43. © 2016 American Cancer Society.

Genetic characterization of gliomas arising in patients with multiple sclerosis.

The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs.

Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2.

Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown. Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided. Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x10(3) cells: ALDH(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%-100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH(+) [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation. Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.

Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer.

CONTEXT: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases. OBJECTIVE: We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target. DESIGN: Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry. SETTING: The study was conducted at the University of Colorado Hospital. PATIENTS: Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURE: Immune markers were analyzed for association with disease severity. RESULTS: Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3(+) (P < .0001), PD-1(+)CD8(+) (P = .0058), and PD-1(+)CD4(+) (P = .0104) T cells were enriched in DTC biopsies. CD8(+) and FoxP3(+) T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1(+) lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAF(V600E) mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression. CONCLUSIONS: PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer.

A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: This phase 1, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), antitumor activity, and molecular correlates of IPI-926, a Hedgehog pathway (HhP) inhibitor, combined with cetuximab in patients with relapsed/metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Cetuximab was given with a 400mg/m(2) loading dose followed by 250mg/m(2) weekly. IPI-926 was given daily starting two weeks after cetuximab initiation. A "3+3" study design was used. Prior therapy with cetuximab was allowed. Tumor biopsies occurred prior to cetuximab initiation, prior to IPI-926 initiation, and after treatment with both drugs. RESULTS: Nine patients were enrolled. The RP2D was 160mg, the same as the single-agent IPI-926 MTD. Among 9 treated, 8 evaluable patients, the best responses were 1 partial response (12.5%), 4 stable disease (50%), and 3 disease progressions (37.5%). The median progression free survival was 77days (95% confidence interval 39-156). Decreases in tumor size were seen in both cetuximab-naïve patients (one HPV-positive, one HPV-negative). The most frequent treatment-emergent adverse events were fatigue, muscle cramps, and rash. No DLTs were observed. Tumor shrinkage and progression free survival were associated with intra-tumoral ErbB and HhP gene expression down-regulation during therapy, supporting the preclinical hypothesis. CONCLUSION: Treatment with IPI-926 and cetuximab yielded expected toxicities with signs of anti-tumor activity. Serial tumor biopsies were feasible and revealed proof-of-concept biomarkers.

Profiling of 149 Salivary Duct Carcinomas, Carcinoma Ex Pleomorphic Adenomas, and Adenocarcinomas, Not Otherwise Specified Reveals Actionable Genomic Alterations.

PURPOSE: We sought to identify genomic alterations (GA) in salivary gland adenocarcinomas, not otherwise specified (NOS), salivary duct carcinomas (SDC), carcinoma ex pleomorphic adenoma (ca ex PA), and salivary carcinoma, NOS. EXPERIMENTAL DESIGN: DNA was extracted from 149 tumors. Comprehensive genomic profiling (CGP) was performed on hybridization-captured adaptor ligation-based libraries of 182 or 315 cancer-related genes plus introns from 14 or 28 genes frequently rearranged for cancer and evaluated for all classes of GAs. RESULTS: A total of 590 GAs were found in 157 unique genes (mean 3.9/tumor). GAs in the PI3K/AKT/mTOR pathway were more common in SDC (53.6%) than other histologies (P = 0.019) Cyclin-dependent kinase GAs varied among all histotypes: adenocarcinoma, NOS (34.6%); SDC (12.2%); ca ex PA (16.7%); carcinoma, NOS (31.2%; P = 0.043). RAS GAs were observed: adenocarcinoma, NOS (17.3%); SDC (26.8%); ca ex PA (4.2%); and carcinoma, NOS (9.4%; P = 0.054). ERBB2 GAs, including amplifications and mutations, were common: adenocarcinoma, NOS (13.5%); SDC (26.8%); ca ex PA (29.2%); carcinoma, NOS (18.8; P = 0.249). Other notable GAs include TP53 in >45% of each histotype; NOTCH1: adenocarcinoma, NOS (7.7%), ca ex PA (8.3%), carcinoma, NOS (21.6%); NF1: adenocarcinoma, NOS (9.6%), SDC (17.1%), carcinoma, NOS (18.8%). RET fusions were identified in one adenocarcinoma, NOS (CCDC6-RET) and two SDCs (NCOA4-RET). Clinical responses were observed in patients treated with anti-HER2 and anti-RET-targeted therapies. CONCLUSIONS: CGP of salivary adenocarcinoma, NOS, SDCs, ca ex PA, and carcinoma, NOS revealed diverse GAs that may lead to novel treatment options. Clin Cancer Res; 22(24); 6061-8. ©2016 AACR.

PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer.

Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor-immune interface. These lymph node metastases persist for years, generally without progression to distant metastases. Although the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD-1)(+) T cells were enriched in tumor-involved lymph nodes (TILN). Tumor-associated leukocytes and tumor cells were collected from grossly involved lymph nodes from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1(+) T cells. PD-1(+)CD4(+) and PD-1(+)CD8(+) T cells were enriched in 8 of 12 TILN samples. PD-1(+) T cells coexpressed Tim-3 and CD69 and failed to downregulate CD27. CD8(+) T cells, but not CD4(+) T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared with control TILNs that lacked resident PD-1(+) T cells. PD-1(+)CD8(+) T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, although PD-1 expression by mDTC-associated CD8(+) T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4(+) T cells. Regulatory T cells (Treg), PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC.

Skull invaders: when surgical pathology and neuropathology worlds collide.

Skull and dura serve as effective barriers to penetration by most tumors, often preventing masses originating intracranially from extending into the contiguous bone and soft tissues, or those arising in head and neck regions from extending into the dura and brain tissue. We review our 15-year experience with extracranial tumors that had sufficiently invaded adjacent skull, dura, or brain from the "outside-in" to require a neurosurgeon to participate in the surgical resection and discuss our 40 cases in context with the literature. Sinonasal-origin tumors (n = 17) and cutaneous tumors (n = 10) were the most frequent skull-invaders. Most of the cutaneous tumor types were squamous cellcarcinomas (n = 9); diverse sinonasal-origin types included 4 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 sinonasal adenocarcinomas, and single examples each of sinonasal-origin hemangiopericytoma, solitary fibrous tumor, melanoma, mucocele, and teratocarcinoma. There were 9olfactory neuroblastomas, and middle ear-origin basal cell carcinoma,recurrent glomus jugulare, and orbital malignant hidradenoma were also seen. Unique tumors included a cutaneous cylindroma invasive of skull convexity occurring in familial cylindromatosis and a ganglioneuroma of the middle ear with massive bilateral skull base extension. Convexity dural spread, a seldom-reported pattern of dissemination, was seen in 1 olfactory neuroblastoma and 1 adenoid cystic carcinoma. The ability to show skull/dural invasion did not correlate with specific histopathologic features; even benign tumor types can show skull/dural penetration.

Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer.

The EGF receptor (EGFR)-directed monoclonal antibody cetuximab is the only targeted therapy approved for the treatment of squamous cell carcinoma of the head and neck (HNSCC) but is only effective in a minority of patients. Epithelial-to-mesenchymal transition (EMT) has been implicated as a drug resistance mechanism in multiple cancers, and the EGFR and Hedgehog pathways (HhP) are relevant to this process, but the interplay between the two pathways has not been defined in HNSCC. Here, we show that HNSCC cells that were naturally sensitive to EGFR inhibition over time developed increased expression of the HhP transcription factor GLI1 as they became resistant after long-term EGFR inhibitor exposure. This robustly correlated with an increase in vimentin expression. Conversely, the HhP negatively regulated an EGFR-dependent, EMT-like state in HNSCC cells, and pharmacologic or genetic inhibition of HhP signaling pushed cells further into an EGFR-dependent phenotype, increasing expression of ZEB1 and VIM. In vivo treatment with cetuximab resulted in tumor shrinkage in four of six HNSCC patient-derived xenografts; however, they eventually regrew. Cetuximab in combination with the HhP inhibitor IPI-926 eliminated tumors in two cases and significantly delayed regrowth in the other two cases. Expression of EMT genes TWIST and ZEB2 was increased in sensitive xenografts, suggesting a possible resistant mesenchymal population. In summary, we report that EGFR-dependent HNSCC cells can undergo both EGFR-dependent and -independent EMT and HhP signaling is a regulator in both processes. Cetuximab plus IPI-926 forces tumor cells into an EGFR-dependent state, delaying or completely blocking tumor recurrence.

Molecular Pathology of Non-Small Cell Lung Cancer.

This review offers an overview of the molecular pathology of lung cancer, with a focus on analyses that are most commonly part of the current clinical testing paradigm. Molecular testing of lung cancer has proved integral to the success of new targeted therapies, and their use is now commonplace in treatment selection. Traditional pathologic evaluation, however, plays a major role in these advances and serves an equally critical role to aid in determining optimal therapy.