Poorly Differentiated Cutaneous Squamous Cell Carcinoma (cSCC) or Lymphoepithelioma-like Carcinoma of the Skin (LELCS) with Squamous Pearls: A Case Presentation with Emphasis on Histomorphological Features and Classification Debates.

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare primary skin cancer, with an annual incidence of 1/100,000 and about 85 cases published in the literature. It is considered the cutaneous counterpart of undifferentiated nasopharyngeal carcinoma (UNC, Schmincke-Regaud tumor) but has no association with EBV. We present an interesting case with features of LELCS in a 93-year-old man, right frontal-orbital region, diagnosed histologically and with immunohistochemical features. We also emphasize contrasting morphologic features for correct nosographic classification and address current issues, suggesting potential insights. Finally, we briefly reviewed other cases described in the literature.

Polymorphic Malignant Melanoma (PMM) of the Left Helix: Case Report with Clinical-Pathological Correlations.

Malignant melanoma (MM) is known to be the great mimic in dermatopathology. Over time, several variants have been described, not all of which have repercussions on the clinical/oncological management of the affected patient. The existence, however, of these alternative forms of MM is of great interest to the pathologist, as they are potentially capable of inducing diagnostic errors affecting the diagnostic-therapeutic care pathway (PDTC). In this paper, we present a very rare case of polymorphic MM, in which five different morphological aspects coexisted in the same lesion, confirmed by immunohistochemical investigation and by RT-PCR for mutation of the BRAF gene and discuss the importance of correct recognition of these different morphological features to avoid misdiagnosis.

Granular cell dermatofibroma: A potential diagnostic pitfall.

Dermatofibroma, also known as "fibrous histiocytoma", is one of the most common cutaneous soft-tissue tumours. Many variants of dermatofibromas have been described and knowledge of these variations is important to avoid a misdiagnosis of a possibly more aggressive tumour. Histological features of different variants can coexist in the same lesion, but typical common fibrous histiocytoma features are generally found, at least focally, in all cases. However, when cellular changes make up the majority of the lesion, the histopathological diagnosis can become more complex and requires immunohistochemical investigations for a correct nosographic classification. We report on the case of a cutaneous fibrous histiocytoma, "granular cell" variant, found on the left leg of a 74- year-old woman.

Dermatopathology of Malignant Melanoma in the Era of Artificial Intelligence: A Single Institutional Experience.

The application of artificial intelligence (AI) algorithms in medicine could support diagnostic and prognostic analyses and decision making. In the field of dermatopathology, there have been various papers that have trained algorithms for the recognition of different types of skin lesions, such as basal cell carcinoma (BCC), seborrheic keratosis (SK) and dermal nevus. Furthermore, the difficulty in diagnosing particular melanocytic lesions, such as Spitz nevi and melanoma, considering the grade of interobserver variability among dermatopathologists, has led to an objective difficulty in training machine learning (ML) algorithms to a totally reliable, reportable and repeatable level. In this work we tried to train a fast random forest (FRF) algorithm, typically used for the classification of clusters of pixels in images, to highlight anomalous areas classified as melanoma "defects" following the Allen-Spitz criteria. The adopted image vision diagnostic protocol was structured in the following steps: image acquisition by selecting the best zoom level of the microscope; preliminary selection of an image with a good resolution; preliminary identification of macro-areas of defect in each preselected image; identification of a class of a defect in the selected macro-area; training of the supervised machine learning FRF algorithm by selecting the micro-defect in the macro-area; execution of the FRF algorithm to find an image vision performance indicator; and analysis of the output images by enhancing lesion defects. The precision achieved by the FRF algorithm proved to be appropriate with a discordance of 17% with respect to the dermatopathologist, allowing this type of supervised algorithm to be nominated as a help to the dermatopathologist in the challenging diagnosis of malignant melanoma.

The role of sentinel node tumor burden in modeling the prognosis of melanoma patients with positive sentinel node biopsy: an Italian melanoma intergroup study (N = 2,086).

BACKGROUND: The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients. METHODS: A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model. RESULTS: The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P < 0.0001), male gender (P = 0.04), increasing Breslow thickness (P < 0.0001), presence of ulceration (P = 0.004), SNTB size (P < 0.0001) and metastatic NSN (P < 0.0001) were independent negative predictors of OS. CONCLUSION: The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization.

Squamous Cell Carcinoma in Patients with Inherited Epidermolysis Bullosa: Review of Current Literature.

Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition.

Prevention of Secondary Lymphedema after Complete Lymph Node Dissection in Melanoma Patients: The Role of Preventive Multiple Lymphatic-Venous Anastomosis in Observational Era.

Background and Objectives: Current guidelines have limited the performance of complete lymph node dissection (CLND) for patients with clinically detectable lymphatic metastases. Despite the limitations of this surgical procedure, secondary lymphedema (SL) is an unsolved problem that affects approximately 20% of patients undergoing CLND. Preventive lymphatic-venous micro-anastomoses (PMLVA) has already demonstrated its efficacy in the prevention of SL in melanoma patients with a positive sentinel lymph node biopsy (SLNB), but the efficacy of this procedure is not demonstrated in patients with clinically detectable lymphatic metastases. Materials and Methods: This retrospective cohort study, was performed in two observation periods. Until March 2018, CLND was proposed to all subjects with positive-SLNB andPMLVA was performed in a subgroup of patients with risk factors for SL (Group 1). From April 2018, according to the modification of melanoma guidelines, all patients with detectable metastatic lymph nodes underwent PMLVA during CLND (Group 2). The frequency of lymphedema in subjects undergoing PMLVA was compared with the control group. Results: Database evaluation revealed 172 patients with melanoma of the trunk with follow-up information for at least 6 mounts. Twenty-three patients underwent PMLVA during CLND until March 2018, 29 from April 2018, and 120 subjects underwent CLND without any preventive surgery (control Group). The frequency of SL was significantly lower in both Group 1 (4.3% vs. 24.2%, p = 0.03) and Group 2 (3.5%, p = 0.01). Patients undergoing PMLVA showed a similar recurrence-free periods and overall survival when compared to the control group. Conclusions: PMLVA significantly reduces the frequency of SL both in immediate and delayed CLND. This procedure is safe and does not lead to an increase in length of hospitalization.

Real Life Clinical Management and Survival in Advanced Cutaneous Melanoma: The Italian Clinical National Melanoma Registry Experience.

BACKGROUND: Cutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR). METHODS: Melanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. RESULTS: The median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by anti-PD-1 (HR=0.25), globally immunotherapy was significantly associated with improved survival, either for anti-CTLA4 monotherapy or combined with anti-PD-1 (HR=0.47 and 0.26, respectively) and BRAFI+MEKI (HR=0.62). CONCLUSIONS: The nivolumab/pembrolizumab in combination of ipilimumab and the addition of ant-MEK to the BRAFi can be considered the best therapies to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.

SARS-CoV-2 and Skin: The Pathologist's Point of View.

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real "sentinel" of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature.

Skin Reducing Mastectomy and Prepectoral Breast Reconstruction in Large Ptotic Breasts.

Large and/or ptotic breasts demonstrate significant difficulty in breast reconstruction and that the rates of perioperative complications are higher compared with the general population. The authors aim to clarify some details on their previously published technique on skin reducing mastectomy and prepectoral ADM breast reconstruction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Microvascular coupler device versus hand-sewn venous anastomosis: A systematic review of the literature and data meta-analysis.

BACKGROUND: Successful vascular anastomosis is essential for the survival of free tissue transfer. The aim of the study is to review the current literature and perform a meta-analysis to assess the potential advantages of a mechanical anastomosis coupler device (MACD) over the hand-sewn (HS) technique for venous anastomoses. METHODS: A systematic Medline search was performed to gather all reports of articles related to MACD from 1984 until now. The following data were extracted: first author and publication date, study design, number of patients and anastomosis, coupler size, site and type of reconstruction, venous anastomotic time, flap failure. A meta-analysis was performed on articles that met the following inclusion criteria: studies comparing MACD and HS technique in venous anastomosis, reporting anastomotic time, and postoperative complications. RESULTS: Thirty-three studies were included for the analysis. Twenty-four were retrospective case series and nine were retrospective comparative studies. A total of 12,304 patients were enrolled with a mean age of 49.23 years (range 31-72). A total of 13,669 flaps were accomplished. The thrombosis rate recorded with MACD was 1.47%. The meta-analysis revealed that MACD significantly decreased anastomotic time (standard difference in means = -0.395 ± 0.105; Z = -3.776; p < .001) and postoperative flap failure risk (odds ratio [OR] = 0.362, 95% confidence interval [CI] = 0.218-0.603, Z = -3.908, p < .001), but it did not decrease postoperative venous thrombosis risk (OR = 0.504, 95% CI = 0.255-1.129, Z = -1.666, p = .096). CONCLUSIONS: MACDs are a safe and effective alternative to traditional anastomosis. The anastomotic coupler is easier, much faster, and requires less technical skills than a HS microvascular anastomosis.

Skin-Reducing Mastectomy and Pre-pectoral Breast Reconstruction in Large Ptotic Breasts.

OBJECTIVES: Pre-pectoral breast reconstruction is increasingly offered to breast cancer patients, as the one-stage technique has proved surgical and oncological safety and aesthetic effectiveness. Nevertheless, there are limited data on outcomes after pre-pectoral breast reconstruction in large and ptotic breasts. The aim of the paper is to present the authors' experience in performing Wise pattern mastectomy with pre-pectoral implant and complete acellular dermal matrix (ADM) coverage as a single-stage procedure in patients with large ptotic breasts. MATERIALS AND METHODS: A retrospective review of protective collected data from January 2017 to June 2019 of patients who presented with large and ptotic breasts undergoing skin-reducing mastectomy and immediate pre-pectoral breast reconstruction with complete ADM coverage and inferior dermal sling was performed. Oncological and surgical outcomes were collected. Satisfaction with reconstruction and related quality of life were evaluated through BREAST-Q questionnaire. RESULTS: Nineteen patients met the inclusion criteria. The average patient age was 55.6 years, and the mean body mass index was 31.2. Mean follow-up was 23.2 months from the initial reconstruction. One patient experienced seroma, and two cases of wound dehiscence at the T junction were observed and treated conservatively with no implant loss. All patients were satisfied with the final reconstruction. CONCLUSION: The Wise pattern skin-reducing mastectomy and pre-pectoral breast reconstruction could be offered to patients presenting with large and ptotic breasts. Future studies should better define long-term outcomes. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The Genetic Germline Background of Single and Multiple Primary Melanomas.

Background: Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing panel. Materials and Methods: A total of 39 patients, 20 with SPM and 19 with MPM, were enrolled in our study. Next generation analysis was carried out using a custom targeted sequencing panel that included 32 genes known to have a role in several carcinogenic pathways, such as those involved in DNA repair, pigmentation, regulation of kinases, cell cycle control and senescence. Results: We found a significant correlation between PIK3CA:p.I391M and MPMs, compared to SPMs, p = 0.031 and a trend for the association between CYP1B1: p.N453S and SPMs, compared to MPMs (p = 0.096). We also found that both subgroups shared a spectrum of 9 alterations in 8 genes (CYP1B1: p.N453S, BAP1: p.C39fs, PIK3CA: p.I391M, CDKAL1: c.1226_1227TG, POLE: p.V1161fs, OCA2: p.R419Q, OCA2: p.R305W, MC1R: p.V60L, MGMT: p.L115F), which suggested that these genes may play a role in melanoma development. Conclusions: In conclusion, despite the small cohort of patients, we found that germline mutations, such as those of PIK3CAand CYP1B1, might contribute to the differential development of SPM and MPM.

Microsurgical reconstruction of the isolated columellar defect with a prelaminated radial forearm free flap. A case report and a review of the literature.

The columella is one of the smallest subunits of the nose, but the loss of this structure has important aesthetic and structural implications. Few papers in literature present microsurgical techniques for the reconstruction of an isolated columellar defect. This report describes the use of a prelaminated radial forearm free flap (RFFF) for the reconstruction of an isolated columellar defect and reviews the current literature. A 45-year-old woman presented to our Unit with a history of palate squamous cell carcinoma and severe nasal deformity with an almost complete loss of the columella. A prelaminated RFFF with the fifth rib was used for a two-staged reconstruction of the isolated columellar defect. The radial pedicle was anastomosed to the facial vessels and the postoperative course was uneventful. Complete survival of the flap was achieved and, 10 months postoperatively, the patient had bilateral nasal patency, with an increased tip projection and a good aesthetic result. A prelaminated RFFF can be considered a valuable reconstructive option in cases of a large composite defect of the columella and limited availability of adjacent tissues.

Efficacy and early results after combining laparoscopic harvest of double gastroepiploic lymph node flap and active physiotherapy for lower extremity lymphedema.

BACKGROUND: Lymph node flap transfer has gradually gained popularity for the treatment of upper and lower limb lymphedema. The aim of this study is to present the outcomes of an integrated treatment protocol based on double gastroepiploic lymph node flap (DG-VLN) and active physiotherapy in patients affected by Stage II and III lower extremity lymphedema. METHODS: All Stage II and III lower limb lymphedema patients operated between September 2015 and December 2017 were retrospectively identified and only those treated with an integrated approach of DG-VLN flap and active physiotherapy were included. Outcomes were assessed clinically with limb circumference measurement and radiologically with lymphoscintigraphy. Flap viability was evaluated through indocyanine green lymphography. Lymphedema related quality of life was evaluated preop and at 1 year follow up through LYMQOL questionnaire. RESULTS: Sixteen patients met inclusion criteria. Mean follow up was 26.2 months. Significant reduction in lower limb volume was observed for all patients from pre to post intervention. At 3 months of follow up, the mean CRR was 42.4% at below knee (BK) level and 25.4% at above knee (AK) level. At 12 months of follow up, the mean CRR was 58.3% at BK level (p = .001*) and 43.4% at AK level (p < .04*). LYMQOL metrics showed significantly better scores in all domains. CONCLUSIONS: Patients with lower limb lymphedema can benefit from combined DG-VLN flap and active physiotherapy, as this approach seem to fasten the onset of improvement and to have a positive impact on patients' quality of life.

The medial-central septum based mammaplasty: A reliable technique to preserve nipple-areola complex sensitivity in post bariatric patients.

INTRODUCTION: Massive weight loss is associated with the ptosis of the breast, loss of the upper pole fullness, medialization of the nipples and volume depletion. Post bariatric patients often need breast reshaping with mastopexy or breast reduction. We report the author's experience with the medial central septum based mammoplasty for breast reshaping after massive weight loss. METHODS: We retrospectively reviewed the records of 85 women who underwent a medial-central septum based mammaplasty, analyzing patients (age, BMI, comorbidities) and operation specific characteristics' (surgical technique, complications) to identify the advantages and the drawbacks of the adopted technique. All the procedures were performed at a single institution by the senior author of this article. RESULTS: 85 patients were included in the review, in total 170 medial-central septum based mammaplasty were performed over a five years period. Early complications, as hematoma and seroma occurred in 2 patients. No total or partial nipple-areola losses were recorded and the viability of the nipple-areola complex (NAC) was excellent in all the treated patients. Sensation was retained in all breasts. Nine patients showed delayed wound healing at the joint of the T scar; in 5 patients we observed spreading scars. CONCLUSION: The medial-central septum based mammaplasty seems to be an effective and safe choice for breast reshaping after massive weight loss, as none of our patients experienced nipple loss and all of them reported good nipple sensation. Moreover, the technique is versatile and can be applied to patients with hypertrophic breasts or gigantomastia.

Multiple lymphatic-venous anastomoses in reducing the risk of lymphedema in melanoma patients undergoing complete lymph node dissection. A retrospective case-control study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an indispensable surgical procedure in staging and management of intermediate-to-thick melanomas. Although recent studies have demonstrated that complete lymph node dissection (CLND) does not improve 3-year specific survival, its utility in increasing the disease-free period and the control of local disease remains confirmed. The most frequent complication related to CLND is lymphedema, which may affect up to 20% of patients undergoing CLND. The preventive use of lymphatic-venous micro-anastomoses could avoid this complication. MATERIALS AND METHODS: We performed a single-institution retrospective case-control study. CLND was proposed to all subjects with positive-SLNB; a preventive procedure involving multiple lymphaticovenular anastomoses (PMA) was performed in a cohort of subjects undergoing CLND. Frequency of lymphedema was compared among subjects undergoing and not-undergoing PMA during CLND. RESULTS: We selected patients affected by melanoma of the trunk and with a minimum follow-up of 3 years, identifying 23 patients who underwent PMA during CLND (PMA group) and 120 subjects who underwent CLND without PMA (control group). The frequency of lymphedema was significantly lower in the PMA group than in the control group (4.3% vs. 24.2%, p = 0.03). Patients of the PMA group and the control group showed similar 3-year recurrence-free period (65.2% vs. 62.5%, log-rank test p = 0.88) and 3-year overall survival (73.9% vs. 72.5%, log-rank test p = 0.97) and frequency of nonsentinel-node metastases (26.7% vs. 30.4%, p = 0.71). CONCLUSION: PMA appear to represent a useful and safe procedure in reducing the risk of lymphedema in patients with melanoma undergoing CLND.