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    MeSH term: Skin Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ansai SI
Topics in histopathology of sweat gland and sebaceous neoplasms.
J Dermatol. 2017; 44(3):315-326 [PubMed] Related Publications
This article reviews several topics regarding sweat gland and sebaceous neoplasms. First, the clinicopathological characteristics of poroid neoplasms are summarized. It was recently reported that one-fourth of poroid neoplasms are composite tumors and one-fourth are apocrine type lesions. Recent progress in the immunohistochemical diagnosis of sweat gland neoplasms is also reviewed. CD117 can help to distinguish sweat gland or sebaceous tumors from other non-Merkel cell epithelial tumors of the skin. For immunohistochemical differential diagnosis between sweat gland carcinoma (SGC) other than primary cutanesous apocrine carcinoma and skin metastasis of breast carcinoma (SMBC), a panel of antibodies may be useful, including p63 (SGC(+) , SMBC(-) ), CK5/6 (SGC(+) , SMBC(-) ), podoplanin (SGC(+) , SMBC(-) ) and mammaglobin (SGC(-) , SMBC(+) ). Comparison of antibodies used for immunohistochemical diagnosis of sebaceous carcinoma (SC) suggests that adipophilin has the highest sensitivity and specificity. Some authors have found that immunostaining for survivin, androgen receptor and ZEB2/SIP1 has prognostic value for ocular SC, but not extraocular SC. In situ SC is rare, especially extraocular SC, but there have been several recent reports that actinic keratosis and Bowen's disease are the source of invasive SC. Finally, based on recent reports, classification of sebaceous neoplasms into three categories is proposed, which are sebaceoma (a benign neoplasm with well-defined architecture and no atypia), borderline sebaceous neoplasm (low-grade SC; an intermediate tumor with well-defined architecture and nuclear atypia) and SC (a malignant tumor with invasive growth and evident nuclear atypia).

Park JH, Lee DY, Kim N
Nail neoplasms.
J Dermatol. 2017; 44(3):279-287 [PubMed] Related Publications
Nail neoplasms include all tumors occurring in the nail or periungual apparatus tissue. While some nail tumors can be similar to tumors located on the skin, others are unique. Both benign and malignant lesions can affect the nail apparatus. In particular, early malignant tumors like melanoma and squamous cell carcinoma can present similarly to onychomycosis or benign melanonychia and frequently missed by clinicians. Therefore, physicians should be aware of nail structures and the characteristics of nail tumors. Our review covers the normal nail structure and the most common nail tumors from benign to malignant.

Ho J, Bhawan J
Folliculosebaceous neoplasms: A review of clinical and histological features.
J Dermatol. 2017; 44(3):259-278 [PubMed] Related Publications
Numerous benign and occasionally malignant tumors arise from the folliculosebaceous apparatus. Confusing terminology, rarity of malignant variants and overlapping histological features can lead to diagnostic uncertainty. This review highlights the clinical and histopathological features that help to classify these entities, as well as the various syndromes associated with certain members of this large family of tumors.

Prabhakaran S, Fulp WJ, Gonzalez RJ, et al.
Resection of Gastrointestinal Metastases in Stage IV Melanoma: Correlation with Outcomes.
Am Surg. 2016; 82(11):1109-1116 [PubMed] Related Publications
The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival.

Valeriani M, Nicosia L, Agolli L, et al.
Mono- and Bi-weekly Hypofractionated Radiation Therapy for the Treatment of Epithelial Skin Cancer in Very Elderly Patients.
Anticancer Res. 2017; 37(2):825-830 [PubMed] Related Publications
BACKGROUND/AIM: Epithelial skin cancer frequently occurs in the elderly population, sometimes in an advanced stage, when intensive treatments are needed. Radiotherapy can achieve high response rates. We evaluated efficacy and tolerability of hypofractionated radiotherapy in a population of very elderly patients with locally advanced epithelial skin cancer.
PATIENTS AND METHODS: Two different hypofractionated schedules were administered (21 patients): 6 Gy in 10 bi-weekly fractions (13 lesions) and 5 Gy in 12 bi-weekly fractions (13 lesions). Median age at treatment was 88 years, life expectancy was ≤5 years in 90.5%.
RESULTS: The overall response rate was 96.1%, with 92.4% complete responses. All patients experienced an improvement of their symptoms and a reduction of pain and medication. The median overall survival time was 28 months (95% confidence interval=4.7-51.2 months). At the time of analysis, 52.3% of patients had died.
CONCLUSION: Hypofractionated radiotherapy is an effective option of treatment, with low toxicity and optimal results, and can also be safely administered to these frail patients.

Brunet V, Marouan S, Routy JP, et al.
Retrospective study of intravascular large B-cell lymphoma cases diagnosed in Quebec: A retrospective study of 29 case reports.
Medicine (Baltimore). 2017; 96(5):e5985 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Intravascular large B-cell lymphoma (IVL) is an extremely rare malignancy, mainly studied through European and Asian series. Due to the low incidence of this condition, our understanding of the clinical presentation as well as the management of IVL relies on a limited number of patients.We report the largest North American study to date on IVL with 29 cases from Quebec hospital diagnosed between 1990 and 2016. The aim of our study is to describe the clinical presentations, diagnostic and staging procedures, therapeutic management and clinical outcomes of IVL patients in our population and compare the disease phenotype to European and Asian series reported.In our cohort, all patients had stage IV IVL at diagnosis, with a median age of 66.7 years (range 47.2-90.8). Clinical presentation was characterized by constitutional symptoms (100%), poor ECOG-PS (100% ≥ 2), cytopenias (93% anemia), and elevated lactate dehydrogenase (97%) and C-reactive protein (96%). Our cohort presented with mainly cutaneous and neurological symptoms. However, neurological involvement (75.9%) was predominant and no "cutaneous variant" was observed; this differs from European literature, where "classical" IVL is reported with mainly cutaneous involvement. Two of our Caucasian patients presented "Asian variant" IVL; this observation is not unusual, as cases of "classical" IVL have been reported in Asians and "Asian variant" IVL has been reported in Europeans. All patients were classified according to their immunophenotypic features in 3 different subgroups (CD5 or CD5CD10, CD5CD10, CD5CD10) with no difference in outcome. Finally, 62% of our cohort received anthracycline-based chemotherapy and 53% of them achieved a complete response. After a median follow-up of 328 days, OS at 3 years was 42.7% for the entire cohort and 47.4% for the cases with in vivo diagnosis.
CONCLUSION: Unlike European studies on "classical" IVL, our study showed that the French Canadian presentation of this subtype of IVL is more frequently observed with neurological rather than cutaneous involvement. Finally, an early diagnosis is of primary importance since almost a quarter of patients receive a post-mortem diagnosis. A prompt diagnosis allows the introduction of an early treatment, associated with a CR in 53% of patients.

Fernandez-Flores A, Saeb-Lima M, Rodriguez-Peralto JL
Polypoid Spitz Nevus With a Halo Reaction.
Am J Dermatopathol. 2017; 39(2):130-133 [PubMed] Related Publications
Approximately, 2% of Spitz nevi are polypoid; between 3.6% and 7.4% present with a halo reaction. In tandem, these low percentages make the presence of a polypoid Spitz nevus with a halo reaction uncommon; we have not found reports of any previous cases. In the current report, we present a polypoid Spitz nevus with a halo reaction on the back of a 10-year-old male and discuss the morphologic findings. The lesion showed preserved nuclear expression of BAP1. There was no immunohistochemical expression of BRAF and ALK, while the melanocytic cells expressed p16. Comparative genomic hybridization was performed, and no significant aberrations were found. Only 2 small losses were evidenced in chromosome 8. The patient has been followed now for 2 years with no recurrence.

Rieger KE, Kim J, Kim YH
Zosteriform Mycosis Fungoides: A New Clinical Presentation With a Dermatomal Distribution.
Am J Dermatopathol. 2017; 39(2):e17-e18 [PubMed] Related Publications
Classic mycosis fungoides (MF) presents with patches and plaques on the trunk and proximal extremities. However, numerous clinicopathologic variants have been described, making diagnosis challenging. Here, the authors report a 21-year-old woman with immunophenotypically and molecularly confirmed MF occurring in a dermatomal distribution. Awareness of this and other rare variants of MF is critical to avoid misdiagnosis.

Shamsuyarova A, Kamil Z, Delabie J, et al.
Primary Cutaneous Follicular Helper T-cell Lymphoma in a Patient With Neurofibromatosis Type 1: Case Report and Review of the Literature.
Am J Dermatopathol. 2017; 39(2):134-139 [PubMed] Related Publications
Patients with neurofibromatosis type 1 (NF-1) have a well-known predisposition for certain types of malignancies, including lymphoproliferative disorders. Cutaneous T-cell lymphoma (CTCL) has been reported in patients with NF-1, although it is considered a rare entity in this subset of patients. Cutaneous follicular helper T-cell lymphoma (CTFHCL) is a recently emerged rare subtype of CTCL with peculiar clinical and histopathological features and represents a diagnostic and therapeutic challenge. Only a few cases of CTFHCL have been reported in the literature. We report a case of CTFHCL in a patient with NF-1 and compare our findings with previously reported cases. We aim to raise awareness among pathologists regarding this rare subtype of CTCL and emphasize characteristic histological features of CTFHCL, which can be confused with B-cell lymphomas and lead to mismanagement.

Abdaljaleel MY, North JP
Sclerosing Dermatofibrosarcoma Protuberans Shows Significant Overlap With Sclerotic Fibroma in Both Routine and Immunohistochemical Analysis: A Potential Diagnostic Pitfall.
Am J Dermatopathol. 2017; 39(2):83-88 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) is an uncommon, low-to-intermediate grade sarcoma with several histologic variants, including pigmented (Bednar tumor), sclerosing, myxoid, atrophic, and DFSP with fibrosarcomatous changes. Two patterns of sclerosis in DFSP can be observed, a sclerotic fibroma-like pattern and a morphea/lichen sclerosus-like pattern. Partial biopsies of sclerosing DFSPs with the sclerotic fibroma pattern can be misdiagnosed as sclerotic fibroma or other benign sclerosing tumors (eg, perineurioma, dermatofibroma). DFSPs from our tissue archives were screened for tumors with a sclerosing pattern, and then studied with epithelial membrane antigen (EMA), CD34, and elastic tissue staining to investigate whether such stains can differentiate sclerosing DFSP from sclerotic fibroma. Ten cases of sclerotic fibroma were similarly studied. Two of the 27 DFSPs were predominantly sclerosing and 5 additional DFSPs had a mixed histopathologic pattern including a sclerosing component. Immunohistochemically, all DFSPs with sclerosing (predominant or mixed) pattern were positive for CD34, and 5/7 were at least focally positive for EMA. Elastic tissue staining was reduced or absent in the sclerotic areas. All cases of sclerotic fibroma were either positive or focally positive for CD34, whereas EMA was focally positive in 5/10. Elastic tissue staining ranged from reduced to totally absent in the sclerotic fibromas. In conclusion, the similar histopathologic and immunophenotypic characteristics in sclerotic fibroma and sclerosing DFSP found in this analysis highlight the importance of obtaining clinical information and potentially additional excision for partial biopsies showing a sclerotic fibroma-like pattern.

Kosari F, Saffar H, Aghaei S
Cutaneous Involvement in Plasma Cell Myeloma: Report of a Case.
Acta Med Iran. 2016; 54(12):817-819 [PubMed] Related Publications
Plasma cellmyeloma constitutes about 10% of all hematologic malignancies. Metastatic cutaneous lesions without underlying bony involvement are rare and associated with advanced disease, poor prognosis and high tumor burden. IgG is the most common subtype and IgD is believed to have a more aggressive course.

Zangarini M, Rajan N, Danilenko M, et al.
Development and validation of LC-MS/MS with in-source collision-induced dissociation for the quantification of pegcantratinib in human skin tumors.
Bioanalysis. 2017; 9(3):279-288 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
AIM: Pegcantratinib is a mini-PEGylated K252a derivative, under clinical evaluation as an anticancer agent acting through inhibition of the tropomyosin receptor kinase. A method for quantifying pegcantratinib in skin tumor biopsies of patients was required to determine tumor drug penetration.
METHODS & RESULTS: A sensitive and PEGylated molecule specific HPLC-MS/MS method coupled with in-source collision-induced dissociation was developed. The method exhibited excellent precision (coefficient of variation ≤8.5%), accuracy in the range 95-102%, high and consistent recovery and no matrix effect. The assay was linear across a range of 1-500 ng/ml, with a limit of quantitation of 2.5 ng/ml.
CONCLUSION: We have developed and validated a method for analyzing pegcantratinib in human tumor biopsies, with the approach successfully applied to clinical trial samples.

Yamada S, Kirishima M, Hiraki T, et al.
Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.
Diagn Pathol. 2017; 12(1):11 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Epithelioid schwannoma as a rare variant poses a challenge to all pathologists, as this uncommon entity is extremely difficult to conclusively diagnose by morphological analyses on a resected sample alone owing to its unique histopathological features. However, few papers have described the detailed clinicopathological characteristics of epithelioid schwannoma.
CASE PRESENTATION: A 65-year-old female presented with a history of a flat and slightly elevated firm and tan plaque accompanied by occasional tenderness, measuring 10 × 8 mm, in the right joint of her hand 1 year before resection. A gross examination of a locally resected specimen revealed an encapsulated nodular lesion, yellow-whitish in color, partly filled with blood. A microscopic examination showed that the tumor predominantly consisted of a solid proliferation of epithelioid cells having mildly enlarged and round to partially spindled nuclei and abundant vacuolated or clear cytoplasm with very few mitotic figures and modest nuclear size variation, associated with focal hyalinized, cystic and hemorrhagic degeneration. This well-demarcated tumor was surrounded by dense, hyalinized and layered fibrocollagenous stroma. Immunohistochemically, these tumor cells were diffusely positive for S-100 protein and had a very low MIB-1 labeling index, and type IV collagen was strongly reactive with reduplicated basal lamina of them. We ultimately made a diagnosis of cutaneous epithelioid schwannoma.
CONCLUSION: We should be aware that, since pathologists might misinterpret epithelioid schwannoma as other soft tissue tumors, including its malignant counterpart, a wide panel of immunohistochemical antibodies can be powerful supplementary tools for identifying a very rare entity of conventional schwannoma.

Huang C, Lai Z, He M, et al.
Successful surgical treatment for squamous cell carcinoma arising from hidradenitis suppurativa: A case report and literature review.
Medicine (Baltimore). 2017; 96(3):e5857 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
RATIONALE: Hidradenitis suppurativa (HS) is a disabling inflammatory disease mainly affecting apocrine glands. Marjolin ulcer (MU) is a term used to describe a rare type of squamous cell carcinoma (SCC) arising within sites of chronic wounds or preexisting scars. Chronic HS may result in a rare type of SCC, MU, which has a poor prognosis due to its high metastatic rate.
CONCERNS OF THE PATIENT: Here we reported a 60-year-old male who developed SCC on the right buttock after suffering from HS for 15 years.
INTERVENTIONS: Radical resection with clear margin was performed, after which topical negative pressure (TNP) was applied followed by split-thickness skin grafting.
OUTCOMES: In a 1-year follow-up, there was no recurrence of malignancy.
LESSONS: Cases reported in English literature since 1991 were reviewed to get a general grasp of status quo. The authors conclude that chronic HS lesion especially in the gluteal region should be cautiously observed. Once tumor arisen from HS lesion, immediate radical excision should be performed. With assured clear margin, TNP could be chosen to offer a favorable environment for the survival of skin grafting.

Mikhailenko DS, Efremov GD, Safronova NY, et al.
Detection of Rare Mutations by Routine Analysis of KRAS, NRAS, and BRAF Oncogenes.
Bull Exp Biol Med. 2017; 162(3):375-378 [PubMed] Related Publications
Molecular genetic analysis of KRAS, NRAS, and BRAF genes was carried out in order to develop an optimal algorithm for detection of minor mutations. We analyzed 35 melanoma and 33 colorectal cancer specimens. Frequent G12D/V/A/C/S mutations were detected in KRAS. The most frequent BRAF mutation in melanoma was V600E, the percentage of rare mutations is significant for DNA diagnosis (24%). Identification of rare BRAF mutations 1790C→G (L597R), 1798_1799delinsAA (V600K), 1798_1799delinsAG (V600R), and 1799_1800delinsAA (V600E) and NRAS mutation 38G→T (G13V) was possible only by Sanger sequencing. The combination of real-time PCR and sequencing can improve analysis sensitivity and ensure concordance of the tested loci with the international recommendations.

Kinsella FA, Amel Kashipaz MR, Scarisbrick J, Malladi R
Donor-derived mycosis fungoides following reduced intensity haematopoietic stem cell transplantation from a matched unrelated donor.
BMJ Case Rep. 2017; 2017 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
A 46-year-old woman with a history of dasatinib-resistant chronic myeloid leukaemia, clonal evolution and monosomy 7 underwent reduced intensity conditioned in vivo T-cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor. Following the transplantation, she developed recurrent cutaneous graft versus host disease (GvHD), which required treatment with systemic immunosuppression and electrocorporeal photophoresis. Concurrently, she developed a lichenoid rash with granulomatous features suggestive of cutaneous sarcoidosis. Additional treatment with hydroxychloroquine was initially successful, but 2 months later, she developed erythroderma with palpable lymphadenopathy. Repeated histological analysis established a diagnosis of folliculotropic mycosis fungoides stage IVA2, and the malignant clone was confirmed to be of donor origin. A positive response to brentuximab has been shown. This is the first reported case of primary mycosis fungoides after matched unrelated donor HSCT, and in a patient still undergoing treatment for GvHD.

Shebaby WN, Mroueh MA, Boukamp P, et al.
Wild carrot pentane-based fractions suppress proliferation of human HaCaT keratinocytes and protect against chemically-induced skin cancer.
BMC Complement Altern Med. 2017; 17(1):36 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Previous studies in our laboratory showed that the Lebanese Daucus carota ssp. carota (wild carrot) oil extract possesses in vitro and in vivo anticancer activities. The present study aims to examine the cytotoxic effect of Daucus carota oil fractions on human epidermal keratinocytes and evaluate the chemopreventive activity of the pentane diethyl ether fraction on DMBA/TPA induced skin carcinogenesis in mice.
METHODS: Wild carrot oil extract was chromatographed to yield four fractions (F1, 100% pentane; F2, 50:50 pentane:diethyl ether; F3, 100% diethyl ether; F4 93:7 chloroform:methanol). The cytotoxic effect of fractions (10, 25, 50 and 100 μg/mL) was tested on human epidermal keratinocytes (non-tumorigenic HaCaT cells and tumorigenic HaCaT-ras variants) using WST a ssay. Cell cycle phase distribution of tumorigenic HaCaT-ras variants was determined by flow cytometry post-treatment with F2 fraction. Apoptosis related proteins were also assessed using western blot. The antitumor activity of F2 fraction was also evaluated using a DMBA/TPA induced skin carcinoma in Balb/c mice.
RESULTS: All fractions exhibited significant cytotoxicity, with HaCaT cells being 2.4-3 times less sensitive than HaCaT-ras A5 (benign tumorigenic), and HaCaT-ras II4 (malignant) cells. GC-MS analysis revealed the presence of a major compound (around 60%) in the pentane/diethylether fraction (F2), identified as 2-himachalen-6-ol. Treatment of HaCaT-ras A5 and HaCaT-ras II4 cells with F2 fraction resulted in the accumulation of cells in the sub-G1 apoptotic phase and decreased the population of cells in the S and G2/M phases. Additionally, F2 fraction treatment caused an up-regulation of the expression of pro-apoptotic (Bax) and down-regulation of the expression of anti-apoptotic (Bcl2) proteins. A decrease in the phosphorylation of AKT and ERK was also observed. Intraperitoneal treatment with F2 fraction (50 or 200 mg/kg) in the DMBA/TPA skin carcinogenesis mouse model showed a significant inhibition of papilloma incidence (mice with papilloma), yield (number of papilloma/mouse) and volume (tumor relative size) at weeks 15, 18 and 21.
CONCLUSION: The present data reveal that F2 fraction has a remarkable antitumor activity against DMBA/TPA-induced skin carcinogenesis, an effect that may be mediated through inhibition of the MAPK/ERK and PI3K/AKT pathways.

Hitchen N, Warnapala D, Fisher RM, et al.
Jejunal perforation: an unusual presentation of metastatic cutaneous squamous cell carcinoma (SCC) in an immunosuppressed patient.
BMJ Case Rep. 2017; 2017 [PubMed] Related Publications
We report the rare occurrence of a small bowel perforation secondary to a metastatic cutaneous squamous cell carcinoma (cSCC). A 70-year-old woman, who had previously undergone renal transplantation, presented with severe, sudden-onset abdominal pain. She was peritonitic on initial examination, with evidence of free intra-abdominal air on radiographic imaging. During an exploratory laparotomy, she was found to have a perforated jejunum secondary to disseminated metastases seen throughout her peritoneum. Following histopathological analysis, as well as further imaging studies, the primary malignancy was eventually identified as a cSCC on her upper back. Palliative care was started and the patient died 8 weeks following her initial presentation.

Simeone E, Grimaldi AM, Festino L, et al.
Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care.
BioDrugs. 2017; 31(1):51-61 [PubMed] Related Publications
Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance. The addition of a MEK inhibitor can improve blockade of the MAPK pathway and may help to overcome resistance and thereby prolong efficacy, as well as reduce cutaneous toxicity. Combinations of BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have been approved for the treatment of BRAF-mutant metastatic melanoma and may become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy, and other strategies are being investigated, including the use of sequential and intermittent schedules. The combination of BRAF or MEK inhibitors with immunotherapy has been shown to hold considerable promise, with several combinations being evaluated in clinical trials. Preliminary results from clinical trials involving triple combination therapy with BRAF-MEK inhibitors and anti-PD-L1 antibodies appear promising and may indicate a new strategy to treat patients with BRAF-mutated metastatic melanoma. Biomarkers are needed to help identify patients with BRAFV600 mutations most likely to benefit from first-line BRAF/MEK inhibitor therapy rather than immunotherapy and vice versa.

Carlson JA, Caldeira Xavier JC, Tarasen A, et al.
Next-Generation Sequencing Reveals Pathway Activations and New Routes to Targeted Therapies in Cutaneous Metastatic Melanoma.
Am J Dermatopathol. 2017; 39(1):1-13 [PubMed] Related Publications
BACKGROUND: Comprehensive genomic profiling of clinical samples by next-generation sequencing (NGS) can identify one or more therapy targets for the treatment of metastatic melanoma (MM) with a single diagnostic test.
METHODS: NGS was performed on hybridization-captured, adaptor ligation-based libraries using DNA extracted from 4 formalin-fixed paraffin-embedded sections cut at 10 microns from 30 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X and evaluated for genomic alterations (GAs) including point mutations, insertions, deletions, copy number alterations, and select gene fusions/rearrangements. Clinically relevant GAs (CRGAs) were defined as those identifying commercially available targeted therapeutics or therapies in registered clinical trials.
RESULTS: The 30 American Joint Committee on Cancer Stage IV MM included 17 (57%) male and 13 (43%) female patients with a mean age of 59.5 years (range 41-83 years). All MM samples had at least 1 GA, and an average of 2.7 GA/sample (range 1-7) was identified. The mean number of GA did not differ based on age or sex; however, on average, significantly more GAs were identified in amelanotic and poorly differentiated MM. GAs were most commonly identified in BRAF (12 cases, 40%), CDKN2A (6 cases, 20%), NF1 (8 cases, 26.7%), and NRAS (6 cases, 20%). CRGAs were identified in all patients, and represented 77% of the GA (64/83) detected. The median and mean CRGAs per tumor were 2 and 2.1, respectively (range 1-7).
CONCLUSION: Comprehensive genomic profiling of MM, using a single diagnostic test, uncovers an unexpectedly high number of CRGA that would not be identified by standard of care testing. Moreover, NGS has the potential to influence therapy selection and can direct patients to enter relevant clinical trials evaluating promising targeted therapies.

Michalova K, Kazakov DV, Michal M, et al.
Differentiated squamous intraepithelial lesion (dSIL)-like changes in the epidermis overlying anogenital melanocytic nevi: A diagnostic pitfall.
Ann Diagn Pathol. 2017; 26:43-46 [PubMed] Related Publications
BACKGROUND: Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemically analogous in the whole anogenital region. dSIL is a premalignant lesion frequently misinterpreted histopathologically as a benign dermatosis. The authors describe a peculiar change in the basal cell layer of the epidermis/epithelium overlying anogenital melanocytic nevi that may histopathologically imitate dSIL. The aim of this study is to familiarize the pathologists with this pitfall to avoid its possible overdiagnosis as dysplasia. Further, we tried to explore the biological characteristics of the dSIL-like changes and to focus on the differential diagnostic aspects.
DESIGN: Seventy cases of anogenital nevi were retrieved from our registry. All cases were stained with hematoxylin and eosin (H&E) and reviewed. Cases in which the epidermis overlying nevi featured atypical appearing basal keratinocytes in otherwise fully differentiated epithelium, variable degrees of acanthosis and parakeratosis were selected for additional investigation.
RESULTS: Thirty cases meeting the above described criteria were identified. The patients were 8 males and 22 females, with age at the time of diagnosis ranging from 4 to 68years. Follow-up data were available for 28 patients (range 0.5-19years, mean 5.1), and to date, no signs of epithelial malignancy have been recorded. Immunohistochemically (IHC), the epidermis overlying nevi showed insignificant positivity for p53 in all tested cases. Melanocytic markers (S-100 protein, SOX10, Melan A) and cytokeratin AE1/3 labeled melanocytes and keratinocytes, respectively, enabling their distinction, especially in nevi featuring a junctional component.
CONCLUSIONS: Differentiated squamous intraepithelial lesion-like changes seem to occur relatively often in the epidermis overlying anogenital melanocytic nevi. Since morphologically they are virtually identical to the "true" dSIL, their distinction largely depends on p53 expression in basal keratinocytes with normal p53 expression in dSIL-like changes and diffuse nuclear/p53-null immunostaining in the "true" dSIL serving as an essential differential diagnostic tool. dSIL-like alterations seem to have no malignant potential, as to date, none of the patients included in this study have shown any signs of epithelial malignancy.

Mazloom SE, Stallings A, Kyei A
Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.
Am J Dermatopathol. 2017; 39(1):33-39 [PubMed] Related Publications
Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Nguyen AH, Detty SQ, Agrawal DK
Clinical Implications of High-mobility Group Box-1 (HMGB1) and the Receptor for Advanced Glycation End-products (RAGE) in Cutaneous Malignancy: A Systematic Review.
Anticancer Res. 2017; 37(1):1-7 [PubMed] Related Publications
Inflammation and the immune system play a role in the development and progression of melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The pro-inflammatory and tumor-promoting effects of the high-mobility group box-1 (HMGB1) protein and the receptor for advanced glycation end products (RAGE) have been investigated in these cutaneous malignancies. The clinical implication of these molecules is not fully described. The National Library of Medicine database was searched for articles addressing the clinical relevance of HMGB1 and RAGE in melanoma, BCC, and SCC. This systematic review includes nine articles, with six summarizing RAGE in cutaneous malignancies and three involving HMGB1. RAGE has been found to be up-regulated in SCC lesions, as well as melanoma. Levels of RAGE were highest in stage IV melanomas. Lower levels of soluble RAGE have been associated with poor overall survival in melanoma. Sporadic extracellular expression of HMGB1 was evident in BCC and SCC lesions, which could be released by necrotic tumor cells. HMGB1 was found to be a prognostic marker in melanoma, and HMGB1 levels were elevated in patients who were non-responders to ipilimumab treatment. HMGB1 and RAGE could serve as potential prognostic markers or therapeutic targets in treating melanoma, BCC, and SCC, but further research regarding the clinical utility of the HMGB1-RAGE axis in cutaneous malignancies is warranted.

Robinson CL, Guo M
Fingolimod (Gilenya) and melanoma.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
The Food and Drug Administration (FDA) had approved fingolimod usage for multiple sclerosis in 2010. Melanoma after the usage of fingolimod immunomodulation was reported rarely in clinical trials, and only two case reports exist in the published literature, both occurring in Europe. Most of the incidences reported in clinical trials were in-situ, whereas both case reports were of malignant melanoma. Fingolimod has been found to inhibit metastatic melanoma growth in a mouse model that depends on vascular endothelial growth factor (VEGF)-induced angiogenesis for metastasis. However, there are numerous pathways of angiogenesis and tumour growth found in vivo by which melanoma can expand that do not mandate VEGF. We report a case of superficial spreading malignant melanoma occurring after fingolimod therapy in the USA.

Handa U, Kundu R, Dimri K
Cutaneous Metastasis: A Study of 138 Cases Diagnosed by Fine-Needle Aspiration Cytology.
Acta Cytol. 2017; 61(1):47-54 [PubMed] Related Publications
BACKGROUND: Cutaneous metastases can occur in a wide variety of internal malignancies and may be the first sign of a clinically silent visceral cancer.
STUDY DESIGN: A retrospective analysis was made of 138 cases diagnosed with cutaneous and subcutaneous metastasis on fine-needle aspiration cytology (FNAC). Primary tumors of the skin/subcutis were excluded.
RESULTS: Of 138 cases, the primary was known in 101 cases and unknown in 37 cases. The age of the patients ranged from 5 to 86 years, and 76 (55.1%) were male and 62 (44.9%) were female. Clinically, the most common lesion was a single nodule (n = 77, 55.8%). The chest wall was the predominant site (n = 53, 38.4%). In males and females, the most common primary sites were the lung (n = 16) and breast (n = 24), respectively. On cytology, the most common diagnosis was metastatic adenocarcinoma (n = 41, 29.7%). Of 37 cases with an unknown primary, FNAC helped to locate the primary site in 17 (45.9%) cases, while in 20 cases it remained undiagnosed.
CONCLUSIONS: FNAC is a rapid and safe technique that can be used as a first line of investigation for confirmation of metastatic lesions of the skin. Critical evaluation of cytomorphological features along with relevant clinical details could help in the localization of an unknown primary site in some cases.

Bai M, Yu NZ, Long F, et al.
Effects of CDKN2A (p16INK4A/p14ARF) Over-Expression on Proliferation and Migration of Human Melanoma A375 Cells.
Cell Physiol Biochem. 2016; 40(6):1367-1376 [PubMed] Related Publications
OBJECTIVE: This study aims to investigate the effects of CDKN2A (p16INK4A/p14ARF) over-expression on the proliferation and migration of human melanoma A375 cells.
METHODS: Melanoma tissues and pigmented nevi tissues were collected. Human melanoma A375 cells were transfected by CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expressing vectors and then assigned into blank, negative control (NC), p16INK4A and p14ARF groups. The expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein was detected by qRT-PCR and Western blotting. CCK-8, flow cytometry and Transwell assays were applied to observe cell proliferation, the cell cycle and apoptosis, and migration and invasion, respectively. The model of subcutaneous xenografts in nude mice was established to measure cell growth in vivo.
RESULTS: Compared with pigmented nevi tissues, CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein expression were significantly decreased in melanoma tissues. CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expression inhibited proliferation, migration, invasion and progression from G0/G1 to S phase of A375 cells and xenograft tumor growth, but promoted apoptosis.
CONCLUSION: Our study demonstrated that over-expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) suppressed proliferation and migration of human melanoma A375 cells.

Bommareddy PK, Patel A, Hossain S, Kaufman HL
Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma.
Am J Clin Dermatol. 2017; 18(1):1-15 [PubMed] Related Publications
Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; Imlygic™), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. T-VEC demonstrated significant improvement in durable response rate, objective response rate, and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non-melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses.

Incel Uysal P, Yalcin B, Ozhamam E, Bozdogan O
Coexistence of Adult Onset Eruptive Syringoma and Bilateral Renal Cell Carcinoma: A Case Report.
Am J Dermatopathol. 2017; 39(1):56-58 [PubMed] Related Publications
Eruptive syringoma is an unusual variant of syringoma, which usually presents before or during puberty. It typically occurs in large numbers as multiple yellow-brown-colored papules, which may show spontaneous regression. Because some authors have proposed that it could present as a reactive process of eccrine ducts to an inflammatory reaction caused by an unknown trigger, the exact pathomechanism is still unclear. There are also reports in the literature on the association of eruptive syringoma in Down syndrome, diabetes, milium, sarcoidosis, and psychiatric disorders. Some reports in the literature highlighted the association of eruptive syringomas and neoplasms. We describe here a case of adult-onset eruptive syringoma in a 53-year-old man and discuss the possibility of its association with renal cell carcinoma as a paraneoplastic phenomenon.

Epperson J, Libow L
A Case of Trichogerminoma With Pilomatrical Differentiation and a Unique Immunohistochemical Profile.
Am J Dermatopathol. 2017; 39(1):e13-e16 [PubMed] Related Publications
Trichogerminomas are rare adnexal neoplasms first described by Sau et al in 1992. Including the initial report, 20 cases have been reported, all with similar histological features, namely tumor nodules composed of basaloid cells that form densely packed, round nests or "cell balls" and which demonstrate variable degrees of pilosebaceous differentiation. In this study, the authors report a case of a trichogerminoma with pilomatrical differentiation and a unique immunohistochemical profile. The patient is a 71-year-old man with a well-delineated nodule on the top of the scalp. Histologically, the lesion measured 16 mm in greatest dimension and was composed of nodules of basaloid cells with central, compact, slightly eosinophilic cells nests. Immunohistochemically, the tumor nodules diffusely expressed cytokeratins 34βE12, AE1/3, and CK5/6. Diffuse expression of β-catenin and nuclear expression of p63 were also evident. The peripheral basaloid cells, but not the cell balls, expressed CD10, Ber-EP4, BCL-2, and CK7, the latter a previously unreported finding. The histological findings and immunohistochemical profile are compatible with a diagnosis of a trichogerminoma.

Gil da Costa RM, Aragão S, Moutinho M, et al.
HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.
Life Sci. 2017; 169:11-19 [PubMed] Related Publications
Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome.

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