Search

Supplementary Table S2. Clinical response and outcomes to everolimus in patients with advanced differentiated thyroid cancers by histologic subgroup

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results: Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions: BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC. Clin Cancer Res; 23(9); 2367–73. ©2016 AACR.

Supplementary Figure 1 The most frequent phylogenetic tree based on sampling mutations according to their detection power (276/1000 samples). Supplementary Figure 2 Allelic copy number profiles generated by ABSOLUTE (see Methods).

BACKGROUND Metastatic cutaneous squamous cell carcinoma (cSCC) carries a poor prognosis. Increased numbers of CD8+ cytotoxic T cells are associated with a favorable prognosis and programmed cell death receptor-1 is a suppressor of the CD8+ cytotoxic T cell response. We aim to define their expression in metastatic cutaneous squamous cell carcinoma. METHODS Cytotoxic T cell infiltrates and tumoral PD-L1 expression in lymph node metastases from patients with cSCC of the head and neck were analyzed. RESULTS High tumoral PD-L1 expression, intratumoral and peritumoral CD8+ cell density in metastases were significantly associated with poor primary tumor differentiation. Low PD-L1 expression, intratumoral and peritumoral CD8+ density were associated with lower grade primary tumor differentiation. Low PD-L1 expression correlated with disease progression. CONCLUSIONS Increased expression of PD-L1 correlates with increased CD8+ cell density. Increased expression of PD-L1 in poorly differentiated tumors may be more likely to benefit from anti PD-1/PD-L1 therapy.

We describe a sequential multistaining protocol for immunohistochemistry, immunofluorescence and CyTOF imaging for formalin-fixed, paraffin-embedded specimens (FFPE) in the formalin gas-phase (FOLGAS), enabling sequential multistaining, independent from the primary and secondary antibodies and retrieval. Histomorphologic details are preserved, and crossreactivity and loss of signal intensity are not detectable. Combined with a DAB-based hydrophobic masking of metal-labeled primary antibodies, FOLGAS allows the extended use of CyTOF imaging in FFPE sections.

Background Angiotropism is the histopathological correlate of pericytic mimicry and extravascular migratory metastasis (EVMM), a mechanism of melanoma spread by migration along the external surface of blood and lymphatic vessels. The frequency of angiotropism in primary cutaneous melanoma and the clinical utility of its detection remain unclear. Methods We investigated angiotropism in 179 primary cutaneous melanomas by hematoxylin and eosin (H&E), CD31, and S100/D240 stains. Results We detected angiotropism in 31 cases (17%) by H&E. CD31 immunohistochemistry increased detection to 59 cases (33%). When lymphatic vessels were included by using S100/D240 stains, 67 cases (37%) cases were positive. Angiotropism was associated with lymphatic invasion and mitotic rate with all detection methods. There was an association with increased tumor thickness when detected by H&E and CD31. No association with sentinel lymph node status was seen. By H&E and CD31 staining, angiotropism was associated with disease progression and distant metastases by univariate, but not multivariate analysis. Overall survival was not affected by the presence of angiotropism. Conclusions Angiotropism is relatively common in primary melanoma when immunohistochemical stains are used for detection and associated with mitotic rate and intravascular lymphatic invasion. The association with disease progression and distant metastasis suggests that it represents an alternative pathway of metastasis, that is, EVMM/pericytic mimicry vs intravascular spread.

Breast cancer tumor draining lymph nodes (TDLNs) display distinct morphologic changes depending on the breast cancer subtype. For triple-negative breast cancers (TNBC), draining LNs display a higher amount of secondary lymphoid follicles, which can be regarded as a surrogate marker for an activated humoral immune response. In the present study, we focus on PD1+ T-follicular helper cells (Tfh) in TDLNs of TNBC, since PD1+ Tfh are drivers of the germinal center (GC) reaction. We quantified PD1+ Tfh in 22 sentinel LNs with 853 GCs and interfollicular areas from 19 patients with TNBC by morphometry from digitalized immunostained tissue sections. Overall survival was significantly worse for patients with a higher number and area density of PD1+ Tfh within GCs of TDLNs. Further, we performed T-cell receptor gamma chain (TRG) analysis from microdissected tissue in the primary tumor and TDLNs. Eleven patients showed the same TRG clones in the tumor and the LN. Five patients shared the same TRG clones in the tumor and the GCs. In two patients, those clones were highly enriched inside the GCs. Enrichment of identical TRG clones at the tumor site vs. the TDLN was associated with improved overall survival. TDLNs are important relays of cancer immunity and enable surrogate approaches to predict the outcome of TNBC itself.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated. Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13 ‘mixed’ desmoplastic, and 8 ‘pure’ desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P

Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma.

Due to increasing restrictive legislation, modern DF-engines become more and more important, especially in marine application to meet the IMO Tier III limits in coastal areas, without using complex exhaust gas after-treatment systems. Compared to conventional combustion processes in diesel or gas engines, the characteristics of the Dual-Fuel process are not fully understand and the increased degree of freedom leads to a demanding application and test effort. To handle the resulting complexity for the development of engine control functions, it is essential to support the development process with suitable simulation methods.

IgG4-related disease (IgG4-RD) is a recently recognized entity that causes progressive fibrosis and formation of mass lesions. IgG4-RD can be diagnosed histologically by its hallmarks of storiform fibrosis, prominent lymphoplasmacytic infiltrate, and obliterative phlebitis, accompanied by the infiltration of excessive numbers of IgG4-positive plasma cells as well as elevations in serum IgG4 concentrations. A recent publication reported a case of IgG4-RD in the mastoid sinus, representing a new anatomic location for this disease. We report two additional cases of IgG4-RD occurring in the mastoid and causing clinical mastoiditis. The presenting symptoms were varied—tinnitus, hearing loss, and cranial nerve palsies. All three cases showed a dense lymphoplasmacytic infiltrate, storiform type fibrosis as well as elevated numbers of IgG4 positive plasma cells. The three patients responded to immunosuppressive therapy that included steroids and Rituximab. We further investigated 162 consecutive mastoiditis cases at our institution in order to determine the frequency of IgG4-RD as a previously unrecognized cause of mastoiditis. Within this latter cohort we identified nine cases of mastoiditis that had two of the histologic features of IgG4-RD, specifically storiform fibrosis and a dense lymphoplasmacytic infiltrate. Two of these cases showed >50 IgG4-positive plasma cells per high-power field with IgG4–IgG ratio of >40 %, thus fulfilling histological criteria for IgG4-RD. However, both were due to severe acute or chronic infection. In conclusion, we reaffirm IgG4 related mastoiditis as a distinct but uncommon cause of recurrent mastoiditis. The diagnosis of IgG4-related mastoiditis should be rendered with caution, and only after the exclusion of potential mimickers, particularly infection.

Background The progression from a benign pigmented lesion on the skin to cutaneous melanoma is better understood, and it could be presumed that a similar progression occurs with mucosal lesions. However, to our knowledge, there has never been documentation of melanosis transforming into melanoma over time. Objective To describe a transformation of a mucosal melanosis into melanoma. Methods A 53-year-old man with diffuse melanosis of the nasal cavity underwent surgical resection. Results Pathology revealed melanocytic hyperplasia without evidence of melanoma. The patient was serially examined, with excisions for new areas of melanosis. The pathology progressed to severely atypical melanocytic proliferation and melanoma in situ over a 4-year period. Conclusion Nasal melanosis may be a precancerous lesion and may transform into melanoma. All melanosis should be biopsied with close endoscopic observation. Lesions with dysplasia or atypia should be excised due to potential transformation to melanoma.

There is interest in providing a heat release rate based flammability requirements for interior finish materials on railcars. As a result, a research study was performed to develop a simple empirical model that can predict the real scale fire performance of an interior finish material from ASTM E1354 cone calorimeter data. A simple to use model has been developed to predict whether a material will contribute significantly to the growth of a fire inside of a railcar. The model consists of a flammability parameter, defined as the difference between the average heat release rate and the ratio of the ignition time and the burn duration. As indicated by the model, the relative flammability of materials is based on the balance between the heat release rate and the ease of ignition relative to burning duration. This work is focused on the use of the model in predicting material fire growth performance in full scale NFPA 286 room/corner tests, which has not previously been performed. The empirical flammability model was developed to use parameters which were obtained from cone calorimeter tests at 50 kW/m2 and provides a single value for a material. Generally, materials that have a flammability parameter of greater than 0.7 were determined to cause flashover in the NFPA 286 test, while those less than 0.6 did not cause flashover. The materials in the region between these values are borderline, with some causing flashover and some not. An initial assessment of a database of passenger railcar materials using the flammability parameter model revealed that about 50% of materials that meet NFPA 130 flammability requirements using ASTM E162 have the potential to cause flashover in the NFPA 286 room-corner test.

The molecular circuitry directing tissue development and homeostasis is hardwired by genetic programs but may also be subject to fine-tuning or major modification by environmental conditions. It remains unclear whether such malleability is at work-particularly in tissues directly in contact with the environment-and contributes to their optimal maintenance and resilience. The protein kinase p38α is activated by physiological cues that signal tissue damage and neoplastic transformation. Here, we found that p38α phosphorylated and thereby destabilized p63, a transcription factor essential for epidermal development. Through this regulatory mechanism, p38α limited the frequency of keratinocytes with stem cell properties and tumorigenic potential. Correspondingly, epidermal loss of p38α expression or activity promoted or correlated with carcinogenesis in mouse and human skin, respectively. Genetic mouse models revealed a tumorigenic mechanism from p38α loss through p63-mediated suppression of the matrix metalloprotease MMP13. These findings illustrate a previously uncharacterized epidermal tumor-suppressive mechanism in which stress-activated signaling induces the contraction of stem cell-like keratinocyte pools.

Cutaneous squamous cell carcinomas mainly affect older, predominantly male patients. Most are due to chronic ultraviolet exposure, and associated with actinic keratoses. On the lower extremities, they occur more commonly in women. However, data on these tumors as a distinct group are scarce. We evaluated 61 squamous cell carcinomas of the lower extremities. Overall, 69% of patients were female. Mean age was 75 years. More than 90% of tumors were well differentiated, 3% showed perineural invasion, and none lymphovascular invasion. In all, 63.9% showed evidence of severe chronic sun damage. Associated actinic keratoses were identified in only 13% of cases. By contrast, 80% were associated with distinctive basal epidermal proliferations with a retiform growth pattern. These proliferations were evaluated immunohistochemically for keratinocyte stem cell markers, p53 and Notch1 in 15 cases. All cases were positive for cytokeratin 14, p53, and Notch1 (with variable intensity in the latter 2), and predominantly negative for cytokeratin 19. Interestingly, basal retiform proliferations were positive for cytokeratin 15 in 66% of cases. Fifteen head and neck squamous cell carcinomas were evaluated in comparison. Those lacked associated basal retiform proliferations except in 1 case. In contrast, 87% were associated with actinic keratoses and 100% with severe chronic sun damage. Actinic keratoses associated with head and neck tumors showed cytokeratin 15 staining only in 7% of cases ( P = .003 compared with cytokeratin 15 in basal retiform proliferations associated with leg carcinomas). These findings support the hypothesis that lower extremity squamous cell carcinomas are distinct and may exhibit a pathogenesis less reliant on actinic damage.

In support of future x-ray telescopes ESA is developing new optics for the x-ray regime. To date, mass and volume have made x-ray imaging technology prohibitive to planetary remote sensing imaging missions. And although highly successful, the mirror technology used on ESA’s XMM-Newton is not sufficient for future, large, x-ray observatories, since physical limits on the mirror packing density mean that aperture size becomes prohibitive. To reduce telescope mass and volume the packing density of mirror shells must be reduced, whilst maintaining alignment and rigidity. Structures can also benefit from a modular optic arrangement. Pore optics are shown to meet these requirements. This paper will discuss two pore optic technologies under development, with examples of results from measurement campaigns on samples. One activity has centred on the use of coated, silicon wafers, patterned with ribs, that are integrated onto a mandrel whose form has been polished to the required shape. The wafers follow the shape precisely, forming pore sizes in the sub-mm region. Individual stacks of mirrors can be manufactured without risk to, or dependency on, each other and aligned in a structure from which they can also be removed without hazard. A breadboard is currently being built to demonstrate this technology. A second activity centres on glass pore optics. However an adaptation of micro channel plate technology to form square pores has resulted in a monolithic material that can be slumped into an optic form. Alignment and coating of two such plates produces an x-ray focusing optic. A breadboard 20cm aperture optic is currently being built.

Due to the relatively large number of optical Earth Observation missions at ESA, this area is interesting for new space technology developments. In addition to their compactness, scalability and specific task customization, optical MEMS could generate new functions not available with current technologies and are thus candidates for the design of future space instruments. Most mature components for space applications are the digital mirror arrays, the micro-deformable mirrors, the programmable micro diffraction gratings and tiltable micromirrors. A first selection of market-pull and techno-push concepts is done. In addition, some concepts are coming from outside Earth Observation. Finally two concepts are more deeply analyzed. The first concept is a programmable slit for straylight control for space spectro-imagers. This instrument is a push-broom spectroimager for which some images cannot be exploited because of bright sources in the field-of-view. The proposed concept consists in replacing the current entrance spectrometer slit by an active row of micro-mirrors. The MEMS will permit to dynamically remove the bright sources and then to obtain a field-of-view with an optically enhanced signal-to-noise ratio. The second concept is a push-broom imager for which the acquired spectrum can be tuned by optical MEMS. This system is composed of two diffractive elements and a digital mirror array. The first diffractive element spreads the spectrum. A micromirror array is set at the location of the spectral focal plane. By putting the micro-mirrors ON or OFF, we can select parts of field-of-view or spectrum. The second diffractive element then recombines the light on a push-broom detector. Dichroics filters, strip filter, band-pass filter could be replaced by a unique instrument.

Summary The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival ( P = .023), and tumor thickness independently predicted poorer progression-free survival ( P = .05) and overall survival ( P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.

The asymmetric hydrogenation of tetrasubstituted olefins provides direct access to very useful biological molecules and intermediates. The development of the technology has been slow, due in part to the synthetic challenges involved in developing chiral catalysts for a successful asymmetric induction. We briefly recount the breakthroughs in functionalized and unfunctionalized tetrasubstituted olefins, from the reports of Zhou and Buchwald for functionalized and unfunctionalized substrates, respectively, to the advent of chiral phosphoramidite ligands. The main emphasis of this Perspective lies in bringing into focus the complexity and challenges of inducing an asymmetric reduction for these substrates, which includes a brief discussion of the mechanism, the latest developed chiral catalysts, and the enormous scientific opportunities that still exist in developing “go to” catalyst systems for the various substrate types.

A 48-year-old man was evaluated for confusion that had developed while he was traveling in Mexico. He had purplish skin lesions, pancytopenia, and pleocytosis and an elevated protein level in the cerebrospinal fluid. Diagnostic tests were performed.

Background: The prognostic role of programmed death ligand 1 (PDL1), CD8, and forkhead box p3 (FoxP3) expression in desmoplastic melanomas is unclear. Methods: We correlated PDL1, p53, and Ki-67 expression with CD8 1 and FoxP3 1 immune infiltrates with clinicopathologic variables and patient outcomes in a series of 66 desmoplastic melanomas. Results: Tumoral PDL1 expression (>= 25%), which was seen in 21% of patients (14 of 66), significantly correlated with mixed histology, tumor thickness, mitoses, recurrence, and metastasis. According to linear regression analysis, tumoral PDL1 expression correlated with thickness (P =.0041); p53 expression (P =.019); Ki-67 proliferation index (P =.0018); and tumoral CD8 (P =.0084), stromal CD8 (P

Sentinel lymph node (SLN) metastasis is a powerful predictor of survival in primary cutaneous melanoma. Lymphatic invasion (LI) may correlate with increased risk of SLN metastasis. Intralymphatic metastases, often difficult to detect on hematoxylin and eosin (HE) stained sections, are readily identified with dual immunohistochemistry for melanocytic and lymphatic markers.We used dual S100/D240 immunohistochemistry to detect LI in 125 melanomas from patients who underwent SLN biopsy and correlated LI with melanoma staging parameters and disease status.Dual immunohistochemistry allowed for the identification of LI in 33 cases (26%), compared to only 2% on HE stained sections. Melanomas with LI showed greater thickness, higher mitotic rate and more frequent ulceration. Eleven of 33 cases with LI (33%) and 10 of 92 cases without LI (11%) were associated with a positive SLN (P = .006). More patients without LI were disease-free at last follow-up (80%) than patients with LI (50%; P = .002); LI was significantly associated with decreased progression-free survival.The detection of LI is improved by dual immunohistochemistry and predicts SLN metastasis. The presence of LI may impact therapeutic planning in melanoma, such as the decision to perform a SLN biopsy.

Objectives/Hypothesis To identify histopathologic features associated with poor correlation of frozen and permanent pathology margins following wide local excision for advanced cutaneous squamous cell carcinomas of the head and neck. Study Design Retrospective review. Methods A retrospective review of patients undergoing excision of advanced head and neck squamous cell carcinomas between the years 2010 AND 2013 was performed. Demographic, operative, and pathology data were collected. Overall correlation between frozen section margins and final margins on permanent section results was calculated. Positive and negative predictive values of several histopathologic features were determined. Results Forty-one cases were identified from the database. Perineural invasion, lymphovascular invasion, and a component of poorly differentiated carcinoma were identified in 61.3%, 34.5%, and 17.1% of cases, respectively. Discrepancy between frozen section margins and permanent margins was identified in eight cases (19.5%). The false-negative rate for poorly differentiated carcinoma, lymphovascular invasion, and perineural invasion was 14%, 36%, 26%, respectively. The positive and negative predictive value of poorly differentiated carcinoma, lymphovascular invasion, and perineural invasion in predicting discrepancy between frozen and permanent margins was 14% and 80%, 36% and 84%, and 26% and 92%, respectively. Conclusions This study demonstrated a moderate rate of discrepancy between frozen and permanent section analysis of operative margins from high-risk cutaneous squamous cell carcinomas of the head and neck. The presence or absence of certain histopathologic features appears to be associated with a higher rate of frozen section discrepancy. Evaluation of these features in a preoperative biopsy or staging excision may be useful in planning definitive excision and reconstruction. Level of Evidence 4 Laryngoscope, 125:636–639, 2015

Context.— Skin neoplasms include the most common malignancies affecting humans. Many show an ultraviolet (UV)–induced pathogenesis and often affect the head and neck region.Objective.— To review literature on cutaneous neoplasms that show a predilection for the head and neck region and that are associated with molecular alterations.Data Sources.— Literature review.Conclusions.— Common nonmelanoma skin cancers, such as basal and squamous cell carcinomas, show a UV-induced pathogenesis. Basal cell carcinomas are characterized by molecular alterations of the Hedgehog pathway, affecting patched and smoothened genes. While squamous cell carcinomas show UV-induced mutations in several genes, driver mutations are only beginning to be identified. In addition, certain adnexal neoplasms also predominantly affect the head and neck region and show interesting, recently discovered molecular abnormalities, or are associated with hereditary conditions whose molecular genetic pathogenesis is well understood. Furthermore, recent advances have led to an increased understanding of the molecular pathogenesis of melanoma. Certain melanoma subtypes, such as lentigo maligna melanoma and desmoplastic melanoma, which are more often seen on the chronically sun-damaged skin of the head and neck, show differences in their molecular signature when compared to the other more common subtypes, such as superficial spreading melanoma, which are more prone to occur at sites with acute intermittent sun damage. In summary, molecular alterations in cutaneous neoplasms of the head and neck are often related to UV exposure. Their molecular footprint often reflects the histologic tumor type, and familiarity with these changes will be increasingly necessary for diagnostic and therapeutic considerations.