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Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. Prevention Relevance: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

To examine the microRNA (miRNA) expression profile of cutaneous squamous cell carcinoma (cSCC) tumors from aggressive head and neck locations compared with nonaggressive anatomic sites and normal controls.Retrospective analysis of miRNA expression.Tertiary care center.Tissue samples were collected from 3 anatomic regions: aggressive head and neck sites (ie, ears/lip), nonaggressive locations (ie, extremities/trunk), and adjacent normal skin. RNA was isolated from tissue cores of 45 samples (18 aggressive sites, 15 nonaggressive sites, and 12 normal-adjacent skin). miRNA expression analysis was completed for approximately 800 miRNAs using the NanoString nCounter panel. Five candidate miRNAs were selected for validation. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the original samples plus 30 additional tissue samples (7 aggressive sites, 14 nonaggressive sites, and 9 normal-adjacent skin).Five candidate miRNAs with significant differences in miRNA expression (cSCC behaves more aggressively when originating from specific anatomical subsites of the head and neck. Of 5 miRNAs evaluated, only

Among sarcomas with a round-cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC-rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC-rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under-recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC-rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology.

Although beta 2 adrenergic receptors (β(2)ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective β(2)ADR antagonists by inhibiting β(2)ADR actions in the keratinocytes significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

Background Variants at the Oculocutaneous albinism 2 (OCA2)/ HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2 (HERC2) locus have been associated with pigmentation phenotypes as well as risk of developing multiple types of skin cancer. Objectives The goal of this study was to evaluate OCA2/HERC2 locus variants for impact on time to develop cutaneous squamous cell carcinoma (cSCC) in organ transplant recipients (OTRs) who are at elevated risk of developing cSCC. Methods Participants were solid organ transplant recipients ascertained from two centers (n=125 and 261) with an average of 13.1 years follow-up post-transplant. DNA was available for genotyping for all participants in addition to medical records and questionnaire data. The Ohio State University (OSU) study design was a case-control with prospective follow-up, and the University of California San Francisco (UCSF) study design was a national cross-sectional survey with retrospective chart review. Results OCA2 variants rs12913832 and rs916977 were significantly associated with time to first cSCC post-transplant. OTRs homozygous for the brown eye alleles of rs916977 (GG) and rs12913832 (AA) had significant delays of time to first cSCC post-transplant compared to individuals homozygous for the blue eye alleles [HR=0.34, p

BACKGROUND Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease. METHODS Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs. RESULTS The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P

Identification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior.RNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (n = 62) and children (n = 28). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction.Benign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (p 0.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (p 0.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (p 0.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (p 0.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (p 0.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts1 and depth of invasion1 mm, suggesting miR-155 expression is associated with histological characteristics.miR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential.

Melanoma is a highly aggressive cutaneous malignancy with considerable risk for metastasis. These malignant tumors are typically pigmented given that they arise from melanocytes capable of producing melanin. Amelanotic melanomas are a rare variant and there is often a delay in diagnosis owing to lack of pigmentation. Although there are various presentations of amelanotic melanoma, a solitary polypoid nodule is unusual and warrants further reporting. Herein, we present a patient with a 3-year history of a tender firm, skin-to-pink colored polypoid nodule. Excisional biopsy and work up showed an aggressive amelanotic melanoma with depth of 20mm and nodal metastasis consistent with stage IIIC disease. This case highlights the necessity of recognition and prompt management of this rare subtype of melanoma.

Erythema elevatum diutinum (EED) is a rare, chronic, cutaneous small vessel vasculitis of unclear pathogenesis. Classically, lesions present as symmetric red to purple plaques, papules, and nodules overlying joints. First-line therapy is dapsone. We present a case of EED with widespread lesions involving the hands, extensor arms and legs, and trunk. Multiple biopsies showed concentric intradermal perivascular inflammation with dermal fibrosis and leukocytoclastic vasculitis (LCV) suggesting EED in various stages of evolution. An extensive workup was positive for underlying hepatitis B infection. Our case represents the clinicopathologic spectrum that EED can present and emphasizes the importance of searching for an underlying etiology.

Melanoma is a highly aggressive cutaneous malignancy with considerable risk for metastasis. These malignant tumors are typically pigmented given that they arise from melanocytes capable of producing melanin. Amelanotic melanomas are a rare variant and there is often a delay in diagnosis owing to lack of pigmentation. Although there are various presentations of amelanotic melanoma, a solitary polypoid nodule is unusual and warrants further reporting. Herein, we present a patient with a 3-year history of a tender firm, skin-to-pink colored polypoid nodule. Excisional biopsy and work up showed an aggressive amelanotic melanoma with depth of 20mm and nodal metastasis consistent with stage IIIC disease. This case highlights the necessity of recognition and prompt management of this rare subtype of melanoma.

Numerous dermal diseases, including congenital anomalies, benign and malignant neoplasms, and manifestations of various dermatoses, may involve the skin of the breast. These disorders may involve solely the breast or the breast may be involved as a result of a systemic dermatosis. In reviewing a dermatologic disorder of the breast, one useful approach is to divide these diverse entities into those primary diseases that are specific, nearly specific, or common for the skin of the breast and those secondary disorders that predominantly affect other dermatologic areas of the body but affect the breast incidentally or less commonly. The decision to classify a cutaneous disease of the breast as primary versus secondary may prove difficult and, at times, is best left unstated. Both types of dermatologic disorders may also mimic primary or secondary diseases of the breast parenchyma. For all these reasons, it is important for both the breast generalist as well as the breast specialist to be versed in these primary and secondary dermatologic disorders of the breast.

Immune reconstitution inflammatory syndrome (IRIS) is an immuno-pathologic reaction to quiescent opportunistic microbial pathogens upon restoration of underlying immune defects. Here we report a Honduran patient with HIV/AIDS who developed a facial rash worsening on antiretroviral therapy and increasing CD4 count. Culture and PCR analysis from the skin biopsy identified Leishmania panamensis, which was effectively treated with long-term liposomal amphotericin B. This is the first report of mucocutaneous leishmaniasis (MCL)-associated IRIS due to L. panamensis.

More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in ∼10% of cSCC tumors. Here, we show that an additional 15–22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis.

The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients.

Background Melanoma skin cancer remains the leading cause of skin cancer–related deaths. Spitz lesions represent a subset of melanocytic skin lesions characterized by epithelioid or spindled melanocytes organized in nests. These lesions occupy a spectrum ranging from benign Spitz and atypical Spitz lesions all the way to malignant Spitz tumors. Appropriate management is reliant on accurate diagnostic classification, yet this effort remains challenging using current light microscopic techniques. The discovery of novel biomarkers such as microRNAs (miR) may ultimately be a useful diagnostic adjunct for the evaluation of Spitz lesions. miR expression profiles have been suggested for non-Spitz melanomas but have yet to be ascribed to Spitz lesions. We hypothesized that distinct miR expression profiles would be associated with different lesions along the Spitz spectrum. Materials and methods RNAs extracted from paraffin-embedded, formalin-fixed tissues of 11 resected skin lesions including benign nevi (n = 2), benign Spitz lesions (n = 3), atypical Spitz lesions (n = 3), and malignant Spitz tumors (n = 3) were analyzed by the NanoString platform for simultaneous evaluation of over 800 miRs in each patient sample. Results Benign Spitz lesions had increased expression of miR-21-5p and miR-363-3p compared with those of benign nevi. Malignant Spitz lesions exhibited overexpression of miR-21-5p, miR-155-5p, and miR-1283 relative to both benign nevi and benign Spitz tumors. Notably, atypical Spitz tumors had increased expression of miR-451a and decreased expression of miR-155-5p expression relative to malignant Spitz lesions. Conversely, atypical Spitz lesions had increased expression of miR-21-5p, miR-34a-5p, miR-451a, miR-1283, and miR-1260a relative to benign Spitz tumors. Conclusions Overall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.

Hair follicle nevus (HFN) is a rare hamartomatous lesion of the folliculosebaceous unit, with or without admixed fibroadipose or muscular tissue. It typically has a congenital presentation in the preauricular area of infants and is frequently confused with an accessory tragus. Acquired tumors with similar histopathologic features have been described infrequently during adolescence and adult life. We report yet another unique presentation of this unusual lesion in a 4-year-old girl who had a long-standing tumor of the nasal columella that started growing rapidly after trauma. Histopathologic examination revealed increased numbers of hair follicles, some of which were associated with diminutive sebaceous glands, with no associated central cystic structure. In addition, the infundibula of the follicles were dilated and filled with keratinous debris. Although these hamartomas are common in the head and neck region, to our knowledge, this is the first report of a HFN at this anatomic location. In addition, this tumor has an overall architecture of a HFN but is accompanied by features of a comedo nevus. We also present a review of the literature and summarize the current diagnostic criteria for HFN.

Radiation-induced angiosarcoma of the breast is being reported with increasing frequency as a result of the increased use of radiation therapy in conjunction with breast conservation surgery. However, this entity has not been well documented in patients undergoing mastectomy. The authors present a case of angiosarcoma occurring in a patient 6 years after undergoing mastectomy for invasive duct carcinoma with immediate transverse rectus abdominis musculocutaneous flap reconstruction followed by postoperative radiation therapy. The diagnosis of angiosarcoma was made by skin biopsy performed by the patient's reconstructive surgeon on routine follow-up examination. This is the first reported case of postradiation angiosarcoma occurring in a postmastectomy breast reconstructed with autogenous tissue and it is unusual in that the cancer invaded the musculocutaneous flap. Diagnosis and management recommendations for radiation-induced angiosarcoma are discussed.

To determine whether testosterone would increase angiogenesis in human foreskin, because of the known effects of testosterone on endothelial cells and vascular endothelial growth factor expression. Surgical management of complex hypospadias in a patient who has undergone multiple procedures is technically very challenging. It is possible that therapy to increase the blood supply to this tissue could be beneficial.We used a newly developed model of human skin transplantation, in which full-thickness human foreskin is transplanted subcutaneously onto the dorsum of a nude rat. At 10 days after transplantation, tissue was treated with either testosterone gel or vehicle control. After an additional 7 days, the tissue was harvested, embedded in paraffin, stained for factor VIII to assess vascularity, and examined histologically.The testosterone-treated tissue demonstrated increased factor VIII staining (31.14 +/- 1.53 vessels per high-power field) compared with the control group (18.25 +/- 2.3 vessels per high-power field; P0.0005). Histologic analysis revealed less collagen in the testosterone-treated group compared with the control group.Treatment of human foreskin with testosterone, in a transplant model, increased vascularity and decreased early fibrosis. Testosterone treatment may improve the surgical management of complex hypospadias repair.

Ultraviolet radiation (UVR) promotes skin cancer development by mutagenic, immunosuppressive, and oxidative-stress-inducing mechanisms; however, certain antioxidants may counteract and prevent UVR-induced photodamage. Lutein is a xanthophyll carotenoid with potent antioxidant activity. Because reactive oxygen species (ROS) are believed to have a role in UVR-induced skin damage, we investigated whether lutein can modify UVR effects including the tissue swelling response to midrange UVR (280-320 nm, ultraviolet B (UVB) radiation) and UVB suppression of contact hypersensitivity (CHS) in both the local and the systemic models of UV-induced immunosuppression. We found that compared to mice fed the standard laboratory diet, mice fed dietary lutein demonstrated significant inhibition of ear swelling owing to UVB radiation. Mice exposed to 1700 J per m2 UVB radiation four times at daily intervals and then sensitized to dinitrofluorobenzene at the site of irradiation showed a decreased CHS response upon challenge. This suppression by UVB radiation was significantly inhibited by lutein feeding. When UVB radiation was given at a single dose of 10,000 J per m2 to inhibit the induction of CHS at a distant, nonirradiated site, no effect of lutein was seen. Finally, lutein accumulated in the skin of mice following diet supplementation and was shown to decrease ROS generation following UVR exposure. Thus, lutein modulates the skin's response to UVR and may contribute to the defense against some of the deleterious effects of solar radiation.

A triad of facial palsy, facial edema, and furrowed tongue characterizes Melkersson-Rosenthal syndrome, a rare, noncaseating granulomatous disease of unknown cause. Although most reported cases of Melkersson-Rosenthal syndrome involve swelling of the perioral area, the authors present a case of Melkersson-Rosenthal syndrome involving the periocular area. Because of its rarity, the syndrome is usually ignored and misdiagnosed; however, the syndrome should not only be considered in the classic perioral presentation but also in the rare periocular form, which may be confused with orbital tumors and orbital pseudotumors. Biopsies should be performed routinely in all patients who present with eyelid edema of unknown etiology. The physician and surgeon who see patients with head and neck pathology should be familiar with Melkersson-Rosenthal syndrome, and with the possibility of its presentation in the orbit and periocular region.

BACKGROUND The increase in the number of childhood thyroid carcinoma cases in Ukraine after the Chernobyl nuclear accident in 1986 prompted the development of a registry of thyroid carcinoma cases at the Institute of Endocrinology and Metabolism in Kiev. In the current study, the authors report the statistical data and clinicomorphologic features of the cases included in this registry. METHODS To study the incidence, and age and gender distribution of thyroid carcinoma in Ukraine, the authors compiled complete clinical information from cases diagnosed and treated at the Institute of Endocrinology and Metabolism and statistical reports submitted to the registry from 27 regions of Ukraine. Morphologic features of the resected tumors were examined and were included in the database. RESULTS During the 5 years preceding the Chernobyl nuclear accident, a total of 59 cases of thyroid carcinoma were identified in the birth to 18 years age group (25 in children age ≤ 14 years and 34 in adolescents ages 15–18 years). Between 1986 and 1997, the total number of thyroid carcinomas in Ukrainian children and adolescents was 577 (358 children and 219 adolescents). Morphologically, the thyroid tumors overwhelmingly were papillary carcinomas, and the majority of these also showed a follicular and/or solid growth pattern. Lymph node metastases and other extrathyroidal spread were common, thus necessitating total thyroidectomy and lymph node dissections in many patients. CONCLUSIONS Between 1990 and 1997, a significant increase in the incidence of thyroid carcinoma was noted in children and adolescents in Ukraine; the group most affected was comprised of the individuals who were age ≤ 5 years in 1986 (the year of the Chernobyl nuclear accident). The largest number of cases occurred in patients living in areas of thyroid radiation doses of ≥0.50 grays. The morphologic features of those thyroid tumors suggest that they are aggressive tumors with a high frequency of lymph node metastases, venous invasion, and extrathyroidal spread. Cancer 1999;86:149–56. © 1999 American Cancer Society.

The purpose of this study was to evaluate the prenatal characteristics of congenital nephrosis of the Finnish type (CNF). Patients presenting with elevated maternal serum and/or amniotic fluid α-fetoprotein levels, normal ultrasound examinations and normal fetal karyotypes were included. A retrospective cohort study was conducted using questionnaires sent to all board certified clinical geneticists. Perinatal outcome, including histologic verification of CNF, was obtained. Forty index cases met the above criteria. Ten cases ultimately did not have the diagnosis of CNF, with a median MSAFP level of 7.59 MoM (range 2.7–27.64 MoM) and a median AFAFP level of 10.99 MoM (range 1.47–128.6 MoM). In the affected cohort of index pregnancies, the initial median MSAFP level was 14.49 MoM (range 3.1–38.0 MoM); the median AFAFP level was 40.0 MoM (range 2.4–80.9). MSAFP and AFAFP levels may be lower than previously recognized in patients carrying fetuses with CNF. There is significant overlap between the affected and unaffected patients. J. Matern.-Fetal Med. 6:164–167, 1997. © 1997 Wiley-Liss, Inc.

Purpose: Hidradenoma papilliferum (HP) is a cystic lesion of apocrine gland origin that occurs most commonly in the perineal region. Although there are scattered reports of HP involving the eyelid, to our knowledge, we present the first case of HP of the orbit. Methods: A 63 year-old female presented with progressive left upper eyelid fullness over an 18 month period. Results: The lesion was excised via transconjunctival anterior orbitotomy without incident. Conclusions: The pathologic features of HP are presented.

Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.

We report three patients with papillary thyroid carcinoma in whom fine-needle aspiration (FNA) showed neutrophils within tumor cells. All three patients presented with large neck masses; at excision, two proved to be tall cell variants of papillary cancer. Nodal metastasis, extrathyroidal extension, and vascular invasion were found in both cases. One patient has experienced recurrent disease; the other has an increasing thyroglobulin titer but no clinically appreciable recurrence. The third patient refused further therapy, but brain metastases were noted clinically; this patient died of disease. In each case, FNA showed tumor clusters with characteristic nuclear features, papillary groups, and psammoma bodies. Neutrophils were present in the cytoplasm of tumor cells in the absence of necrosis. Immunostaining for proliferating cell nuclear antigen (PCNA), MIB-1 (Ki-67), and p53 tumor suppressor gene product was markedly positive. lntraepithelial neutrophils have not been previously reported in differentiated thyroid tumors. We postulate that these neoplasms produce specific leukocyte-attracting cytokines analogous to those produced by anaplastic and poorly differentiated thyroid carcinomas. We believe the finding of intraepithelial leukocytes in the absence of necrosis in thyroid FNA specimens represents a characteristic of clinically aggressive differentiated papillary neoplasms; in our small series, each represented a tall cell variant of papillary carcinoma.

Although only a small proportion of cutaneous squamous cell carinomas (cSCC) metastasize, approximately 3900-8800 individuals in the United States die of metastatic cSCC each year. Little is known about the molecular events that lead approximately 2-6% of cSCCs to metastasize. Treatment efforts are hampered by a lack of ability to predict which lesions are more likely to recur or metastasize as these known correlates do not have high specificity for prediction. Furthermore, there is no FDA approved therapy that is specifically indicated for metastatic cSCC. Deep-sequencing efforts have identified targetable mutations and pathways for several cancers. Exome and targeted sequencing of primary cSCCs led to the discovery that inactivating mutations in NOTCH pathway genes occur in over 75% of tumors; however NOTCH mutations are not indicative of metastasis. Published studies identified frequent mutations in KMT2C and KMT2D in cSCCs with aggressive features. To identify mutations that are unique to or enriched in metastatic samples which may help to identify novel therapeutics for treating aggressive cSCCs, we performed exome sequencing of 37 samples consisting of matched normal DNAs, primary tumors and metastatic cSCCs. Many of the mutations found in the metastatic samples were also observed in the matched primary tumors. We found an enrichment of mutations in chromatin remodeling genes. Epigenetic regulatory genes mutated in the metastatic samples included KMT2D (64%), KMT2C (44%), SETD2 (45%), KAT6A (36%), EP300 (18%), and KDM6A/UTX (9%). We performed additional targeted deep-sequencing to evaluate whether candidate genes were frequently mutated in non-aggressive cSCCs. Initial analyses of targeted-sequencing of 10 non-aggressive primary cSCCs and 7 additional metastatic cSCCs as well as data from published exome studies on non-aggressive cSCCs suggest that chromatin remodeling genes are mutated at a much higher rate in metastatic cSCCs. These data provide potential pathways for therapeutic intervention for this deadly cancer. Citation Format: Amanda Ewart Toland, Dawn Allain, Jessica Gillespie, Priyaharsini Nagarajan, Sara Peters, Hatice Gulcin Ozer, Thomas Olencki, Ayse Selen Yilmaz, Theodoros Teknos. Exome sequencing identifies frequent histone methyltransferase mutations in metastatic SCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 147.

Wound complications following cardiac surgery are typically infectious and associated with a high morbidity and mortality. Calciphylaxis, vascular calcification of small and medium sized vessels, often associated with end-stage renal disease, can result in extensive tissue necrosis. We hypothesize that calciphylaxis is an under-recognized and under-reported precipitating wound and breast complication following coronary artery bypass surgery and thereby necessitates further study.

The application of CD markers to medicine has advanced our understanding of several dermatological diseases, most notably primary cutaneous lymphomas. CD markers are monoclonal antibodies that target cell surface molecules on leukocytes and antigens from other cells. T-cell processes are typically CD3+, CD20-, CD45+ while B-cell processes are typically CD3-, CD20+, and CD45+. Other CD markers are used to further delineate cutaneous lymphomas. Although an imperfect system, CD markers empower dermatologists to synthesize immunophenotyping with clinical findings and formulate an appropriate diagnosis.

Squamous cell carcinoma (SCC) is the second most frequently diagnosed skin cancer. It has a higher incidence in immunosuppressed individuals such as organ transplant recipients and human immunodeficiency virus (HIV) carriers. Recently, a newly described polyoma virus, Merkel cell polyomavirus (MCPyV), was found in Merkel cell carcinoma (MCC), a rare aggressive skin cancer also associated with immunosuppression. We hypothesized that MCPyV would be present in SCCs. To test for the presence of MCPyV in immunocompetent SCC patients, we used PCR primer sets directed against the large T (LT) antigen and VP1 gene of MCPyV. We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied. We did not detect MCPyV in any matched normal blood DNA (0/57), but observed the presence of MCPyV DNA in 1 of 12 normal mouthwash DNAs. All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration. The presence of MCPyV in approximately 15% of SCCs from immunocompetent individuals warrants evaluation of MCPyV as an etiologic agent in the carcinogenesis of SCC.

It is intuitively obvious that the ability of a cell to repair DNA damage is saturable, either by limitation of enzymatic activities, the time allotted to achieve their function, or both. However, very little is known regarding the mechanisms that establish such a threshold. Here we demonstrated that the CUL4A ubiquitin ligase restricts the cellular repair capacity by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector. We generated Cul4a conditional knockout mice and observed that skin-specific Cul4a ablation dramatically increased resistance to UV-induced skin carcinogenesis. Our findings reveal that wild-type cells do not operate at their full DNA repair potential, underscore the critical role of CUL4A in establishing the cellular DNA repair threshold, and highlight the potential augmentation of cellular repair proficiency by pharmacological CUL4A inhibition.

Intraoperative histopathology consultation during Mohs micrographic surgery (MMS) with a dermatopathologist is advantageous in some cases requiring a clarification of a diagnosis but may be difficult because in comparison to the Mohs laboratory, the dermatopathology facility can be remote. Telepathology technology provides a time-efficient means of consultation during MMS via the electronic transmission of pathology images, which can foster case discussions, and expedite the confirmation of diagnosis and treatment decisions.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme which catalyzes the covalent attachment of methyl groups to arginine residues of various proteins. PRMT5 binds and/or methylates both nuclear (e.g. histones) and cytoplasmic (e.g. p53, CRAF) proteins to regulate cellular functions including gene expression, cell cycle, and apoptosis among others. PRMT5 has been characterized in leukemia, lymphoma, glioma, and breast cancer; however little is known regarding its role in malignant melanoma. We hypothesized that PRMT5 plays a unique role in regulating melanoma cell biology. PRMT5 expression was measured by IHC analysis of formalin-fixed samples from patients with melanoma (n=133 primary; n=66 metastases), benign nevi (n=24), and normal adjacent epidermis (n=21). PRMT5 expression was significantly elevated in melanoma samples compared to normal adjacent epidermis (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-254. doi:1538-7445.AM2012-LB-254

Non-melanoma skin cancer (NMSC) is the most common cancer in the world. More than 3.5 million NMSCs were treated in 2006; of those, 700,000 were cutaneous squamous cell carcinomas (cSCC). There are several predisposing factors to cSCC; however, little is known about the genetic risk factors. Identification of genetic factors contributing to cSCC will enable the identification of those at risk and will lead to improved therapeutic options. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis of F1 backcrosses between resistant Mus Spretus (Spret/GS) and susceptible Mus Musculus (NIH/Ola) mice. Other susceptibility loci identified in these crosses show preferential allelic imbalance in skin tumors, indicating that allele-specific somatic genetic alterations in these regions may be markers for cancer susceptibility loci. Skts5 spans a 14 megabase region with 65 coding elements. Based on sequence variations and differential gene expression between Spret/GS and NIH/Ola we were able to identify 11 candidate genes. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. Previous studies conducted in our lab show gains on 7p and 7q31 in 10% of cSCC tumors. An additional 3% of cSCC tumors were found to have copy-neutral loss of heterozygosity. Further analysis revealed that microsatellite markers on 7p21 and 7q31 demonstrated preferential allelic imbalance in cSCC tumors. The question of this study is whether genetic variations at SKTS5 are playing a role in human cSCC susceptibility. We hypothesize that human cSCC tumors will show allele-specific somatic genetic changes at SKTS5 and that these alterations contribute to cSCC risk. In order to identify candidate genes at SKTS5, we performed genotyping of 70 single nucleotide polymorphisms (SNPs) encompassing our top mouse candidate genes using Sequenom MassARRAY. Three SNPs at SKTS5, two in HDAC9 (rs6959028 and rs12540872) and one in IFRD1 (rs2074796) showed statistically significant evidence of preferential allelic imbalance in cSCC tumors. Conversely, when SNPs were tested in two cSCC case/control collections no significant association for risk was seen. Because our study analyzed 40 SNPs in HDAC9 and two showed preferential allelic imbalance in tumors, we hypothesized that there might be HDAC9 haplotypes demonstrating preferential imbalance. We generated 4,5,6 and 7 marker haplotypes. Following multiple comparisons testing, significant haplotypes of each size containing rs6959028 and/or rs12540872 were identified with differential frequencies between normal blood and tumor DNA. From these studies our data identifies HDAC9 as a candidate gene for cSCC tumorigenesis. Risk with this locus needs to be further evaluated. Future studies will be needed to determine which HDAC9 SNPs are causal, as well as to identify the molecular mechanism(s) by which the variants contribute to cSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4857. doi:1538-7445.AM2012-4857

Five cases of lipofibromatous hamartoma of the median nerve are reported. The initial onset of symptoms and recognition of a mass occurred in adults in four cases. The fifth patient was an infant when the mass was first noticed, and she also had macrodactyly. Treatment included carpal tunnel release in three patients, one of whom required a second procedure for excision of the mass and sural nerve grafting. Nerve ablation without grafting was performed in the other two patients; one of these patients noticed no sensory or motor deficit after surgery. From this small series we cannot recommend a preferred treatment for these patients; each case must be approached on an individual basis. The diagnosis is best confirmed by biopsy.

Immunosuppressive cytokines (IL-6, IL-10, TGF-β) act to promote tumor growth and suppress immune function. Conversely, the interferons (IFNs) are critical for cancer immunosurveillance by host immune cells. The precise mechanisms in which effector functions of immune cells are regulated by these cytokines deserve further investigation. Signal transduction in response to IFNs can be negatively regulated by the Suppressors of Cytokine Signaling or SOCS proteins. Our laboratory has demonstrated that SOCS1 and SOCS3 negatively regulate the anti-tumor activity of exogenously administered IFN-α by reducing intracellular signaling responses. In fact, SOCS1-deficient mice were cured of lethal melanoma tumors, and this effect was dependent on CD8+ T cells (Zimmerer et al., J. Immunol., 2007). Therefore, we hypothesized that cytokines present in the tumor microenvironment exert their immunosuppressive actions via the up-regulation of SOCS proteins in immune cells, making them less responsive to the cytokines that mediate immune surveillance. Treatment of peripheral blood mononuclear cells with IL-6, IL-10 or TGB-β led to increased expression of SOCS1 or SOCS3 proteins and pre-treatment with these cytokines inhibited subsequent IFN-α induced signal transduction and gene expression as measured by Real Time PCR. Since expression of IL-6, IL-10 and TGF-β has been observed at the tumor site, we postulated that increased expression of SOCS1 or SOCS3 proteins might also be present and serve as an initial barrier to the actions of IFNs on immune effector cells located in the tumor microenvironment. Lymphatic tissue from sentinel node biopsies represents a unique opportunity to study the interactions between melanoma cells and immune cells in the microenvironment. We therefore characterized the expression of SOCS proteins in formalin-fixed paraffin-embedded specimens from melanoma-positive or melanoma-negative lymph node (LN) biopsies. In melanoma negative LN, SOCS1 protein showed a characteristic histologic pattern of expression as it was strongly expressed in sinusoidal or perivascular lymphatic vessels, with a small number of scattered SOCS1 positive cells in the interfollicular zones. SOCS3 protein was primarily expressed within sinusoidal cells. Little or no SOCS1 or SOCS3 proteins were expressed in germinal centers. Evaluation of melanoma-positive LN revealed the presence of SOCS1 and SOCS3 positive cells that localized to the lymphoid or monocytic cells, rather than the tumor cells themselves. Of note, immune cells in close proximity to the tumor (200µM) displayed prominent SOCS1 and SOCS3 staining. These data indicate that the presence of melanoma tumors in lymphatic tissue is associated with elevated SOCS1 and SOCS3 protein expression in immune effector cells. Together these data suggest that SOCS proteins may play a role in the immune modulation within the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1355.

Using high-density oligonucleotide arrays, we measured expression of >12,000 genes in surgical excisions of invasive human squamous cell carcinomas (SCCs) versus site-matched control skin. This analysis defined >1,900 genes with altered expression in SCCs that were statistically different from controls. As SCCs are composed of epithelial cells, which are both hyperplastic and invasive, we sought to define gene sets associated with these biologic processes by comparing gene expression to psoriasis vulgaris, which is a condition of benign keratinocyte hyperplasia without invasiveness or pre-malignant potential. Through this analysis, we found genes that were commonly upregulated in both conditions and unique genes with increased expression in SCCs. Differential gene regulation in these two conditions was confirmed by real-time reverse transcription-PCR and immunohistochemistry. We found that benign hyperplasia is associated with upregulation of genes including DEFB4 (defensin B4), SERPINB3 (serine proteinase inhibitor, member 3), STAT1 (signal transducer and activator of transcription 1), K16 (keratin 16), CEACAMs (carcinoembryonic antigen-related cell adhesion molecules), and WNT 5A (wingless-type MMTV integration site family, member 5A). WNT receptor frizzled homolog 6 (FZD6) and prostaglandin-metabolizing enzyme hydroxyprostaglandin dehydrogenase were increased in SCC alone. Growth factor pleiotrophin (PTN) was expressed at higher levels in non-tumor-bearing skin adjacent to excised SCC. SCC was further characterized by upregulation of matrix metalloproteinases 1, 10, and 13, cathepsin L2, cystatin E/M as well as STAT3 and microseminoprotein, beta (MSMB), and downregulation of inducible nitric oxide synthase, granzyme B, CD8, and CD83. The current study defines a unique gene expression signature for cutaneous SCC in humans and suggests potential roles for WNT, FZD, and PTN in the pathogenesis of SCC.