Evolution of superficial spreading melanoma to resemble desmoplastic melanoma: case report.

Desmoplastic melanoma commonly occurs on the head and neck in a pure form, but occasionally, it occurs in a mixed tumor with another type, usually superficial spreading melanoma (SSM), and rarely as a metastasis from a primary SSM. We report here a primary SSM on the leg of a 32-year-old male which metastasised to lymph nodes, and 10 years later recurred at the primary site initially with mixed features but evolving to resemble a uniformly desmoplastic, deeply invasive melanoma. This unusual case has implications for clinical management and is additionally notable for its reversal in behavior, from metastatic to local infiltrative type, correlating with the change in morphology.

Acne Keloidalis Nuchae: A Staged Reconstruction.

Acne keloidalis nuchae (AKN) is a chronic scarring folliculitis that affects the occipital area. It is characterized by papule and pustule formation which eventually leads to tumor-like mass. Early cases can be managed by medical treatment that may require months, and, usually, lesions recur. In more severe cases, surgical excision is the mainstay of treatment. In our case, we proposed a staged approach when dealing with advanced stages of AKN. This includes deep excision of the lesion down to deep subcutaneous tissue with application of negative-pressure wound therapy (NPWT) for a week followed by resurfacing of the resultant defect with a split-thickness skin graft and NPWT for another week. This approach achieved quicker wound healing with no recurrence compared with other techniques such as healing by secondary intention. To our knowledge, this case is one of the most extensive cases published in the literature.

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node-positive melanoma without the need for completion lymph node dissection.

PURPOSE: Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). METHODS: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. RESULTS: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. CONCLUSIONS: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.

Aggressive digital papillary adenocarcinoma and sentinel node biopsy: A case report and literature review.

Aggressive digital papillary adenocarcinomas (ADPA) are malignant tumours of the sweat gland. Due to the high tendency to recur and metastasise, wide local resection of the lesion is recommended. However, there are a limited number of cases reporting the use of sentinel node biopsy in the management of ADPA, thus its effectiveness remains unclear. We present a case of ADPA of the right middle finger treated with digital amputation and sentinel node biopsy, and review the current literature focusing on the usefulness of sentinel node biopsy.

Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation in disease.

Following wound damage to the skin, the scarring spectrum is wide-ranging, from a manageable normal scar through to pathological keloids. The question remains whether these fibrotic lesions represent simply a quantitative extreme, or alternatively, whether they are qualitatively distinct. A three-way comparison of the extracellular matrix (ECM) composition of normal skin, normal scar and keloids was performed using quantitative discovery-based proteomics. This approach identified 40 proteins that were significantly altered in keloids compared to normal scars, and strikingly, 23 keloid-unique proteins. The major alterations in keloids, when functionally grouped, showed many changes in proteins involved in ECM assembly and fibrillogenesis, but also a keloid-associated loss of proteases, and a unique cartilage-like composition, which was also evident histologically. The presence of Aggrecan and Collagen II in keloids suggest greater plasticity and mis-differentiation of the constituent cells. This study characterises the ECM of both scar types to a depth previously underappreciated. This thorough molecular description of keloid lesions relative to normal scars is an essential step towards our understanding of this debilitating clinical problem, and how best to treat it.

Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations.

BACKGROUND: In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB). METHODS: A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC). RESULTS: In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived. CONCLUSIONS: Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences.

Plaque-like Myofibroblastic Tumor: 2 Cases of This Unusual Dermal Tumor Which Occurs in Infancy and Early Childhood.

Plaque-like myofibroblastic tumor (PLMT) is a rare dermal spindle cell tumor which occurs in infancy or childhood within the first 4 years of life. The tumor is often pruritic and mostly presents on the lower back. We describe 2 cases with characteristic clinical and histological features of this entity, thus adding to the 10 cases which have so far been reported. Histologically, the lesion resembles a dermatofibroma. However, diffuse and uniform immunohistochemical staining with smooth muscle actin favors a myofibroblastic lineage. PLMT should be considered in the differential diagnosis of a dermal spindle cell tumor in the pediatric age-group.

Is sentinel lymph node biopsy warranted for desmoplastic melanoma? A systematic review.

BACKGROUND: Desmoplastic melanoma (DM) is an uncommon malignancy associated with a high local recurrence rate. The aim of this systematic review was to determine the positivity rate of sentinel lymph node biopsy (SLNB) in patients with DM. The secondary outcome was to establish if SLNB is warranted for both pure DM (PDM) and mixed DM (MDM). METHODS: A full systematic literature review of SLNB in DM was performed by two authors in January 2016. Ovid MEDLINE, Ovid EMBASE and the Cochrane Central Register of Controlled Trials were searched. RESULTS: Sixteen studies involving 1519 patients having SLNB in DM were included, of which 99 patients had positive SLNB (6.5%). Two articles reported a significantly reduced disease-free survival (DFS) with positive SLNB and three published a reduced melanoma-specific survival (MSS). Six studies compared SLNB in MDM and PDM. Of the 275 patients, 38 (13.8%) had a positive SLNB in MDM compared to 17 of 313 patients (5.4%) with positive SLNB in PDM. CONCLUSIONS: Rates of positive SLNB in DM are reduced compared to other variants of melanoma; however, nodal status may still predict DFS and MSS. MDM is associated with a higher rate of micro-metastases to regional lymph nodes than PDM, and DFS and MSS may be lesser in MDM than in PDM. We would recommend the consideration of SLNB in MDM. However, with such low rates of positive SLNB in PDM, and in the absence of high-risk features to stratify patients, we would not recommend SLNB in PDM.

To Mohs or not to Mohs.

BACKGROUND: The preferred method of treatment of Dermatofibrosarcoma Protuberance (DFSP) is surgery. Clear margins are achieved by wide local excision (WLE) or by Mohs micrographic surgery. Mohs surgery and reconstruction always requires two or more procedures. This study aims to assess the ability of WLE to accomplish clear histopathological margins and low recurrence rate with a single procedure. We present our results from ten years experience of wide local excision. METHODS: This is a retrospective analysis of data of all cases of DFSP treated with WLE by a single operator in our department between 2002 and 2012. RESULTS: Twenty patients were identified. The surgical excision and reconstruction were performed on the same day in all cases. The mean histological peripheral margin was 17 mm and the deep 9 mm. There was no incomplete excision and no recurrence recorded. There were no postoperative complications or tumour recurrences reported for an average period of 5.6 years follow-up. CONCLUSION: Mohs surgery offers clear histological margins but requires multiple patient visits to achieve complete excision and later reconstruction. We show that WLE can achieve these in one procedure, the excision margins making little difference when planning the eventual reconstruction.

Regulation of bone morphogenetic protein signalling and cranial osteogenesis by Gpc1 and Gpc3.

From birth, the vault of the skull grows at a prodigious rate, driven by the activity of osteoblastic cells at the fibrous joints (sutures) that separate the bony calvarial plates. One in 2500 children is born with a medical condition known as craniosynostosis because of premature bony fusion of the calvarial plates and a cessation of bone growth at the sutures. Bone morphogenetic proteins (BMPs) are potent growth factors that promote bone formation. Previously, we found that Glypican-1 (GPC1) and Glypican-3 (GPC3) are expressed in cranial sutures and are decreased during premature suture fusion in children. Although glypicans are known to regulate BMP signalling, a mechanistic link between GPC1, GPC3 and BMPs and osteogenesis has not yet been investigated. We now report that human primary suture mesenchymal cells coexpress GPC1 and GPC3 on the cell surface and release them into the media. We show that they inhibit BMP2, BMP4 and BMP7 activities, which both physically interact with BMP2 and that immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity. In contrast, increased levels of GPC1 and GPC3 as a result of overexpression or the addition of recombinant protein, inhibit BMP2 signalling and BMP2-mediated osteogenesis. We demonstrate that BMP signalling in suture mesenchymal cells is mediated by both SMAD-dependent and SMAD-independent pathways and that GPC1 and GPC3 inhibit both pathways. GPC3 inhibition of BMP2 activity is independent of attachment of the glypican on the cell surface and post-translational glycanation, and thus appears to be mediated by the core glypican protein. The discovery that GPC1 and GPC3 regulate BMP2-mediated osteogenesis, and that inhibition of endogenous GPC1 and GPC3 potentiates BMP2 responsiveness of human suture mesenchymal cells, indicates how downregulation of glypican expression could lead to the bony suture fusion that characterizes craniosynostosis.

Retinol-binding protein 4 downregulation during osteogenesis and its localization to non-endocytic vesicles in human cranial suture mesenchymal cells suggest a novel tissue function.

Craniosynostosis is a developmental disorder of the skull arising from premature bony fusion of cranial sutures, the sites of skull bone growth. In a recent gene microarray study, we demonstrated that retinol-binding protein 4 (RBP4) was the most highly downregulated gene in suture tissue during the pathological process of premature bony fusion. To gain insight into the function of RBP4 in cranial sutures, we analysed primary cells cultured from human cranial suture mesenchyme. These cells express RBP4 but not CRBP1, cellular retinol-binding protein 1, the typical cytoplasmic retinol storage protein. Using flow cytometry, we showed that suture mesenchymal cells express the RBP4 receptor, STRA6, on the cell surface. In a cell culture model of cranial osteogenesis, we found that RBP4 was significantly downregulated during mineralization, analogous to its decrease in pathological suture fusion. We found that cranial suture cells do not secrete detectable levels of RBP4, suggesting that it acts in a cell-autonomous manner. High-resolution confocal microscopy with a panel of antibody markers of cytoplasmic organelles demonstrated that RBP4 was present in several hundred cytoplasmic vesicles of about 300 nm in diameter which, in large part, were conspicuously distinct from the ER, the Golgi and endosomes of the endocytic pathway. We speculate that in suture mesenchymal cells, endogenous RBP4 receives retinol from STRA6 and the RBP4-retinol complex is stored in vesicles until needed for conversion to retinoic acid in the process of osteogenesis. This study extends the role of RBP4 beyond that of a serum transporter of retinol and implicates a broader role in osteogenesis.

Retinol-binding protein 4 is expressed in chondrocytes of developing mouse long bones: implications for a local role in formation of the secondary ossification center.

Retinol-binding protein 4 (Rbp4) is the major carrier of retinol in the bloodstream, a retinoid whose metabolites influence osteogenesis, chondrogenesis and adipogenesis. Rbp4 is mainly produced in the liver where it mobilizes hepatic retinol stores to supply other tissues. However, Rbp4 is also expressed in several extrahepatic tissues, including limbs, where its role is largely unknown. This study aimed to identify the cellular localization of Rbp4 to gain insight into its involvement in limb development and bone growth. Using immunohistochemistry, we discovered that Rbp4 was present in a variety of locations in developing embryonic and postnatal mouse hindlimbs. Rbp4 was present in a restricted population of epiphyseal chondrocytes and perichondral cells correlating to the future region of secondary ossification. With the onset of secondary ossification, Rbp4 was detected in chondrocytes of the resting zone and in chondrocytes that bordered invading cartilage canals and the expanding front of ossification. Rbp4 was less abundant in proliferating chondrocytes involved in primary ossification. Our data implicate the involvement of chondrocytic Rbp4 in bone growth, particularly in the formation of the secondary ossification center of the limb.

Dying for a tan: a survey to assess solarium adherence to world health organization guidelines in australia, new zealand, and the United kingdom.

BACKGROUND: Increased use of solariums worldwide has led to health concerns linking regular exposure to ultraviolet light with skin cancer. Most studies have attempted to delineate attitudes and motivations of users, with little inquiry into those entrusted as "service providers." METHODS: A questionnaire was designed specifically for the survey on the basis of World Health Organization guidelines. Twenty-one solariums in major cities from each country were randomly chosen via telephone directory and visited in Australia, New Zealand, and the United Kingdom. A prospective customer asked a series of questions to assess conformity with these guidelines. RESULTS: Solariums in Australia were most successful at adhering to World Health Organization guidelines, followed closely by those in the United Kingdom. Overall, solariums in New Zealand did not comply as well, especially with the use of consent forms, and did not adequately inform customers of the potential adverse side effects including skin cancer risks. CONCLUSIONS: Our data have shown several differences in the way solariums conform to guidelines in our 3 chosen countries. A plausible reason for these differences is the difference in solarium regulations worldwide. The limited number of solariums selected for the survey, together with individual country variation, does not enable firm conclusions to be drawn about the operations of solariums in each country. However, it does provide knowledge of the variation between solariums and further suggests the need to evaluate the workings of these service providers in each country.