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Cutaneous melanoma is a public health issue and the head and neck region is of particular interest, despite accounting for only 9.0% of the total body surface, it harbours 20% of melanoma cases. Data from the literature show that scalp melanomas (SM) carry high mortality rates, with a 10-year survival rate of 60% which lead them to be named as the “invisible killer”. Moreover, SMs are more common in the elderly than in young population, and they occur six times more frequently in men than in women. This is probably related to the higher incidence of androgenetic alopecia and a higher cumulative and intermittent ultraviolet damage on the scalp. Histologically, SM is a heterogenous group, including lentiginous melanoma (LM), desmoplastic melanoma, superficial spreading and nodular melanoma. Thin melanomas tend to display an atypical network or pseudo-network and regression in dermoscopy. Blue-white veil, irregular pigmented blotches and an unspecific pattern are most commonly detected in thick lesions. On reflectance confocal microscopy (RCM), the most frequent pattern is irregular meshwork, but also ringed and disarranged pattern have been described. Differential diagnosis includes benign solar lentigo, actinic keratoses, lichen planus like keratosis, melanocytic nevi and blue nevi. All suspicious lesions should be biopsied; therefore, an excisional biopsy with 2 mm margins is usually the best option. The management of SM is the same as for melanoma on other body sites. However, sentinel node biopsy tends to be more challenging, as well as achieving adequate excision margins of the primary tumor. In this review, we summarize clinical, pathologic, dermoscopic and RCM features of SM, and focus on its epidemiology, risk factors and best management options.

Desmoplastic melanoma (DMM) is a rare variant of melanoma that presents major diagnostic challenges. It can mimic both benign or other malignant tumors and may be easily confused by clinicians and pathologists. We report a patient who presented with a pink-colored papule on the left lateral neck. Histopathology revealed a nodular spindle cell tumor in the dermis resembling a neurofibroma at low power. However, higher-power evaluation and the use of immunohistochemical staining confirmed the diagnosis of DMM.We present this case to highlight the ongoing challenges of diagnosing DMM both clinically and histologically and to review the salient features of this often benign-appearing tumor. Advancing age, male gender, and head and neck location are associated with an increased risk of DMM-specific death. It is important that new or changing lesions in the correct cohort and location are biopsied promptly.

Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer-generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.

BACKGROUND Perineuriomatous nevi are rare and diagnostically problematic. We report a series of eight perineuriomatous nevi to highlight the diagnostic features. METHODS Cases were retrospectively reviewed and characterized. RESULTS Median age was 42.5 years (range 25-64), with equal sex distribution. Lesions occurred on the arm (n = 4), trunk (n = 2), and head/neck (n = 2). Median size was 7.5 mm (range 5-12 mm). Clinical differential diagnoses included atypical nevus (3), blue nevus (1), neurofibroma (1), and dermatofibroma (1). Lesions were circumscribed, dome-shaped (5/8), and biphasic (8/8) with nested epithelioid cells and wavy spindled cells arranged in whorled fascicles in a myxocollagenous stroma. When present, junctional growth was lentiginous (4/8). No cases displayed pleomorphism or mitotic figures. The perineuriomatous component stained positively for epithelial membrane antigen (8/8 focal to diffuse) and CD34 (4/5 focal to diffuse). SOX10 and S100 protein stained all nevoid cells and in some cases a subset of intermingled spindled cells in perineuriomatous areas, where other melanocytic markers were negative. p16 protein expression was uniformly retained (3/3), and p53 negative (0/2). Nevoid cells in most lesions were positive for BRAFV600E (5/7). Ki67 was mildly elevated (~5%) in 3/3 cases. CONCLUSIONS Recognizing the histopathologic and immunophenotypic features in these unusual nevi helps avoid overdiagnosis.

The vast majority of patients newly diagnosed with melanoma present with clinically localized disease, and sentinel lymph node biopsy (SLNB) is a standard of care in the management of these patients, particularly in intermediate thickness cases, in order to provide important prognostic data. However, SLNB also has an important role in the management of patients with other subtypes of melanoma such as thick melanomas, certain thin melanomas, and specific histologic variants of melanoma such as desmoplastic melanoma. Furthermore, there have been technical advances in the SLNB technique, such as the development of newer radiotracers and use of SPECT/CT, and there is some data to suggest performing a SLNB may be therapeutic. Finally, the management of patients with a positive sentinel lymph node (SLN) has undergone dramatic changes over the past several years based on the results of recent important clinical trials. Treatment options for patients with SLN metastases now include surveillance, completion lymph node dissection, and adjuvant therapy with checkpoint inhibitors and targeted therapy. SLNB continues to play a crucial role in the management of patients with melanoma, allowing for risk stratification, potential regional disease control, and further treatment options for patients with a positive SLN.

Malignant peripheral nerve sheath tumors are rare soft tissue sarcomas that are often associated with neurofibromatosis type-1. These tumors share common immunohistochemistry findings which can make diagnosis difficult. We present the case of a woman who presented with a diagnosis of metastatic melanoma of the index finger of her left hand but was eventually diagnosed with primary epithelioid malignant peripheral nerve sheath tumor. We will be highlighting the diagnostic challenge of differentiating between these two very different malignancies.

The synchronous incidence of 2 different subtypes of melanoma is very rare. Desmoplastic melanoma (DM) can be a diagnostic challenge because of its frequent appearance as a dermal banal spindle cell proliferation. We present a case of a 30-year-old man who developed an irregular, purple, tender plaque measuring 2.5 cm on the right pretibial region. Wide excision of the right leg lesion showed superficial spreading melanoma with epithelioid cells and no spindle cell component. Sentinel lymph node (SLN) biopsy showed an atypical melanocytic proliferation involving one inguinal lymph node with subcapsular and intraparenchymal components. There were spindled tumor cells in lymph node capsule with hyperchromatic nuclei, which were nested within desmoplastic stroma, and were S100- and SOX10-positive and MART1- and HMB-45 negative; in addition to epithelioid tumor cells, which were S100-, SOX10-, and MART1-positive. Multiple discontinuous foci, subcapsular atypical melanocytes, and extracapsular extension helped in excluding capsular nevus. These findings were consistent with DM. Herein, we present an unusual case of primary cutaneous superficial spreading melanoma of the right leg with a predominantly epithelioid morphology that developed metastases to the SLN. The metastasis exhibited divergent differentiation, including both epithelioid morphology identical to the primary, but with additional features of DM that were nonoverlapping with the primary lesion.

Dermatofibrosarcoma protuberans (DFSP) is a spindle cell neoplasm of the skin and superficial soft tissue with a tendency for locally aggressive behavior; metastatic potential coincides with fibrosarcomatous transformation. The vast majority of DFSPs harbor the t(17;22) translocation resulting in a COL1A1-PDGFB fusion that drives autocrine growth stimulation via PDGFB overexpression. Here, we examined the utility of PDGFB RNA chromogenic in situ hybridization (CISH) for the diagnosis of DFSP. A total of 337 tumors represented in whole tissue sections and tissue microarrays, including 37 cases of DFSP and 300 histologically similar spindle cell tumors, were subjected to PDGFB RNA CISH using commercially available probes. PDGFB overexpression was observed by light microscopy in 24 of 26 conventional DFSPs (92%) and 11 of 11 fibrosarcomatous DFSPs (100%). One of two DFSPs negative for PDGFB by RNA CISH was found to harbor an uncommon alternative rearrangement involving PDGFD. All examined cases of histologic mimics were negative for PDGFB overexpression; limited PDGFB expression, not reaching an empirical threshold of greater than 5 puncta or one aggregate of chromogen in more than 25% of cells, was observed in 7 of 300 mimics (2.3%), including desmoplastic melanoma, malignant peripheral nerve sheath tumor, angiosarcoma, and pleomorphic dermal sarcoma. Vascular PDGFB expression was seen in several tumor types. We conclude that PDGFB RNA CISH, with careful interpretation and the use of appropriate thresholds, may serve as a surrogate marker of PDGFB rearrangement and a useful ancillary tool for the diagnosis of DFSP.

Background Cutaneous melanomas (CMs) account for only a small proportion of skin cancers, however these are responsible for most skin cancer deaths. There has been a consistently increasing trend in their incidence across the globe. Methods This prospective case series study spanned over a period of three years. All patients with histologically confirmed CMs were included. Results There were 31 patients including 28 males and 3 females with the mean age of 58.25±11.33 years. The histological subtypes included 13 cases (41.93%) of nodular melanoma (NM), 11 patients (35.5%) of acral lentiginous melanoma (ALM), 3 cases (9.67%) of superficial spreading melanoma (SSM) and lentigo maligna melanoma (LMM) and one case (3.22%) of desmoplastic melanoma. Two patients (6.45%) presented with stage II, whereas 21 patients had (67.74%) stage III melanoma. There were 8 patients (25.80%) with stage IV. Time interval between onset of the lesion and first presentation to hospital ranged from 6 to 17 weeks with a mean of 12.45±3.2 weeks. The overall median survival for patients with stage III and IV was 8.75 months. The overall survival for stage II at one year was 100%. Conclusion CMs more frequently affected males aged ≥58 years. Feet, face, trunk, hands and scalp were the affected anatomical body parts in decreasing order of frequency. NM and ALM were the more common histological subtypes. Majority of patients presented late and advanced stages of melanoma. Awareness about the sinister course of the disease will ensure early presentation with better treatment outcome.

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.

Facial swelling has several etiologies. In patients with head and neck malignancies, this can include primary disease progression or iatrogenic causes. A 66-year-old man presented with increased facial swelling and erythema for 18 months. He had a history of baseline postoperative facial lymphedema following head and neck surgery and radiotherapy for desmoplastic melanoma approximately 20 years ago. However, his facial edema acutely worsened 18 months prior to presentation. A medication review revealed that he was regularly taking melatonin for the past two years. Approximately two weeks after cessation of melatonin therapy, the patient's facial appearance returned to baseline. In conclusion, it is important for clinicians to perform a thorough medication review for patients with facial swelling and erythema.

Background Desmoplastic melanoma (DM) is an uncommon type of melanoma. Two histological subtypes of DM can be distinguished: pure and mixed (PDM and MDM). We hypothesized that discrimination between these subtypes is associated with sentinel lymph node biopsy (SLNB) status and survival. Methods Clinicopathological data from PALGA, the Dutch Pathology Register were retrieved from patients diagnosed with DM in The Netherlands between 2000 and 2014. Clinical and pathological variables were extracted from pathology text files, including pure or mixed desmoplastic morphology. A Cox proportional hazard model was performed for overall and recurrence‐free survival (OS and RFS). Results A total of 239 patients with DM were included, representing 0.4% of all primary cutaneous melanoma in The Netherlands. A total of 114 PDM and 125 MDM patients were identified. MDM was significantly associated with positive SLNB status (P = .035). In multivariable analysis, age (HR 1.10, 95% CI 1.07‐1.14, P, MDM is significantly associated with a positive SLNB status. Mixed subtype is significantly correlated with RFS, but not with OS. The distinction between pure and mixed desmoplastic subtype therefore seems to be of clinical importance.

Differential diagnosis of destructive osteolytic spinal lesions can be a diagnostic challenge. In this study, we described a rare case of spinal metastases from primary desmoplastic melanoma which had incorrectly been diagnosed and treated as tuberculous spondylodiscitis. An 82-year-old male patient with ongoing low back pain and a history of lumbar localized Pott’s performed a lumbar spine MRI that showed osteolytic lesion with first hypothesis of spondylodiscitis L2-L3. The patient was hospitalized and cause of worsening of the lumbar pain underwent a following series of non-diagnostic CT-guided and open lumbar biopsy at L2-L3 with unsuccessful antibiotic-antitubercular therapy. A new MRI revealed a worsening of previous lesions, extension of the osteolytic lesion at the level of L1-L2 and L3-L4 with neurological impairment. The diagnosis of metastatic melanoma was obtained with surgical decompression and open posterior biopsy procedure. The case described is pathognomonic of the difficulty in detecting the correct diagnosis in front of similar clinical and radiological manifestations. The presence of a previous Pott’s disease in the same involved vertebral site was of crucial importance in deflecting the correct diagnostic classification of the pathology, which was possible to ascertain only following an extensive biopsy sampling in the last surgery performed.

Sox10 immunostaining is used for the diagnosis and margin evaluation of melanocytic lesions. Sox10 was initially thought not to stain fibrohistiocytic processes. Consequently, it was believed to reliably distinguish desmoplastic melanoma from scar. However, recent data from formalin sections suggest Sox10 is less specific than previously thought. In this report, we demonstrate that Sox10-stained Mohs sections commonly show strong, fractional staining of scar. When using Sox10 with frozen section immunohistochemistry, Mohs practitioners should recognize the potential of this marker to stain scar to avoid overdiagnosis of desmoplastic melanoma.

Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).

Importance: The clinical and dermoscopic features of the vast majority of uncommon variants of cutaneous melanoma have been rarely reported, leading to difficulty in making accurate diagnoses. Objective: To define the main clinical and dermoscopic features of the most frequently reported but uncommon histologic variants of cutaneous melanoma. Evidence Review: A 2-step systematic review of the literature was performed (from inception to November 2018) using PubMed, Embase, and Cochrane Central Register of Controlled Trials databases. The first step identified those uncommon variants of melanoma for which at least 1 case reporting dermoscopy was described in the literature. The keywords searched were melanoma, uncommon, rare, dermoscopy, and dermatoscopy. In the second step, each previously identified uncommon variant was searched for in the same databases by combining the following terms with melanoma, dermoscopy, and dermatoscopy: Amelanotic, hypopigmented, animal, melanocytoma, balloon, desmoplastic, follicular, nested, nevoid, dermal, spitz, spindle, and verrucous. The institution's database was also searched from January 2012 to September 2019 for histopathologically confirmed cases of the same melanoma variants. Each reviewer also assessed the quality of reporting in the included articles based on previously described guidelines. Findings: In total, 62 articles met the inclusion criteria, reporting 433 melanoma cases. An additional 56 cases of uncommon melanoma variants were retrieved from the institution's database for a total of 489 cases: 283 cases of amelanotic superficial spreading melanoma, 18 cases of animal-type and pigmented epithelioid melanocytoma, 7 cases of balloon cell melanoma, 71 cases of desmoplastic melanoma, 3 cases of follicular melanoma, 10 cases of nested melanoma, 33 cases of nevoid melanoma, 2 cases of primary dermal melanoma, 57 cases of spitzoid melanoma, and 5 cases of verrucous melanoma. These variants of melanoma occurred more frequently in women than men (147 cases vs 132 cases). Clinically, these tumors were mainly palpable (162 of 217 [74.7%]) or amelanotic (283 of 489 [57.9%]) lesions that could resemble other benign or malignant skin conditions; dermoscopy typically revealed a homogeneous pinkish background, white structures, and polymorphic vessels. The mean age of all included was 58 years (range, 1-89 years). Conclusions and Relevance: Uncommon melanoma variants may resemble both inflammatory disorders and other cutaneous neoplasms, representing a diagnostic pitfall even for the most experienced dermatologist. The purpose of this systematic review was to provide an extensive and detailed overview of specific clinical and dermoscopic features of each uncommon melanoma variant, highlighting the main criteria for differentiating these variants from other benign or malignant skin lesions..

This review presents the main challenges encountered when diagnosing unusual variants of malignant melanoma with the aim of raising awareness to allow application of the most appropriate treatment strategies. Although these melanomas are often rare, their misdiagnosis potentially jeopardizes patients' health and survival, and has medicolegal implications. The clinical and histologic presentations of melanoma vary greatly, and assessment of uncommon melanomas can be difficult for practitioners because of their scarcity and resemblance to other dermatologic entities. The most problematic melanoma types are desmoplastic melanoma, polypoid melanoma, primary dermal melanoma, verrucous malignant melanoma, pigmented epithelioid melanocytoma, mucosal melanoma, follicular melanoma and melanoma with non-melanocytic differentiation. The two most difficult-to-diagnose subtypes of melanoma are the nevoid and the amelanotic melanomas. Some specific attributes of these variants can be more easily recognized with digital dermatoscopy, facilitating early detection and possibly avoiding invasive procedures. Key cases with the most notable clinical, dermatoscopic, and histopathologic features are presented, highlighting the practical issues of making an accurate diagnosis and choosing the best therapy.

Objectives. Transducer-like enhancer of split 1 (TLE1) immunohistochemistry is widely used as a biomarker of synovial sarcoma. Spindle cell or desmoplastic melanoma can morphologically mimic synovial sarcoma. The aim of this study was to investigate the expression of TLE1 in melanomas with a spindle cell morphology. Methods. A search of the surgical pathology files resulted in 57 cases of melanomas diagnosed with a spindle cell or desmoplastic component. After review, 8 cases had no definitive dermal spindle cell component and 7 cases had insufficient tissue remaining and were excluded from the study. A total of 42 melanomas were examined for TLE1 immunohistochemistry using a mouse monoclonal antibody (Cell Marque, clone 1F5). Strength and percentage of nuclear TLE1 positivity was graded on a scale from 0 to 3+. Staining for TLE1 was considered positive for 2 to 3+ and negative for 0 to 1+. Results. Nuclear TLE1 expression was identified in 24 (57%) of the 42 melanoma cases with spindle cell morphology (2+, n = 14; 3+, n = 10). TLE1 was considered negative in 18 cases (43%), of which most contained weak staining (1+, n = 14 [33%]) and only a small subset did not show any staining (0, n = 4 [10%]). Conclusion. TLE1 frequently highlights melanomas with spindle cell morphology and is a potential diagnostic pitfall. Therefore, when evaluating spindle cell tumors in which the differential may include both a melanoma and synovial sarcoma, TLE1 expression should be interpreted with caution and in conjunction with an immunohistochemical panel.

Desmoplastic melanomas (DM) have unique and challenging clinical presentations and histomorphology. A characteristic feature is the presence of scattered lymphoid aggregates. However, the nature of these aggregates is not defined. We hypothesized that they may be tertiary lymphoid structures (TLS), and may be associated with programmed death ligand 1 (PD-L1) expression. We searched our tissue database for 'pure' DMs and for scars as control tissues, collected clinical information, and reviewed H&E histology. We performed multispectral imaging after staining for CD8, CD20, PNAd, FoxP3, CD83, and Ki67, and assessed PD-L1 expression by immunohistochemistry. Pure DM samples were evaluable in 11 patients. All had desmoplastic stroma and lymphoid aggregates on H&E. The lymphoid aggregates of eight of the 11 (72%) DM samples and only three of the 11 scars contained features of TLS, defined as distinct clusters of B cells and CD8 T cells, CD83 dendritic cells in T-cell zones, and PNAd vasculature resembling high endothelial venules. PD-L1 was expressed by at least 1% of melanoma cells in six and by at least 5% of immune cells in 10 of the 11 DM samples. We found that most lymphoid aggregates in DM are organized, classical TLS. PD-L1 expression was detected in most cases and was highest in two cases of DM with TLS. However, low PD-L1 expression in some cases suggests that some DM cells may be unresponsive to interferon-γ. TLS support antigen presentation and T-cell responses in chronic inflammation and cancer. Their presence in DM likely reflects an adaptive immune response, which may be enhanced with immune therapies.

BACKGROUND: Desmoplastic melanoma (DM) is a sub-variant of spindle cell melanoma, accounting for less than 4 percent of all cutaneous melanomas. It occurs later in life and is associated with chronic sun exposure. DM prognosis is considered more favorable than other variants, with lower rates of metastasis and higher survival. Recently DM has been further sub-classified into pure and mixed, calling into question surgical management and patient outcomes as well as viability of current nationwide databases without this distinction. METHODS: We identified all patients with a histopathologic diagnosis of desmoplastic melanoma from the Cleveland Clinic electronic melanoma database (n=58) from 1997–2013. Clinical and histopathologic data were collected. Comparison in clinical variables was performed between patients who had pure (n=15) and mixed (n=43) variants of DM. RESULTS: There were no differences in age, gender, location of lesion, Breslow depth, ulceration, or regression. Patients with mixed desmoplastic melanoma were more likely to have lymphovascular invasion (p=0.03) compared to pure desmoplastic melanoma. There was no difference in performance of sentinel lymph node biopsy (p=0.25) or sentinel lymph node positivity (p=0.31) between the two groups. Recurrence was present in 13.3% of pure and 30.2% of mixed patients. Overall Kaplan Meier 3 year survival was 75% for pure and 80% for mixed desmoplastic melanoma (p=0.53). CONCLUSION: Pure and mixed desmoplastic melanomas appear to have similar clinical characteristics and outcomes. This indicates that analysis of national datasets without this sub classification remains viable.

The clinical and pathological diagnosis of desmoplastic melanoma is difficult, because almost 50% of desmoplastic melanoma cases involve non-pigmented lesions and the tumor cells can resemble fibroblasts or Schwannian cells based on their frequent amelanotic features. Moreover, desmoplastic melanoma typically has low positive rates for melanoma markers, with the exception of the S-100 protein. We report the case of an 81-year-old Japanese man with an 8-mm desmoplastic melanoma. He initially noticed a painless and non-pigmented skin lesion that did not grow noticeably for 6 months. It was unlikely that he had von Recklinghausen disease, and the mass was initially considered a dermatofibroma. Excisional biopsy revealed an intradermal mass, with the superficial portion mimicking neurofibroma and the deeper portion exhibiting nodular growth of sarcomatoid spindle cells. The tumor region lacked intradermal proliferation of atypical melanocytic cells, intracytoplasmic melanin, and expression of melanoma markers (except S-100 protein and Sox10). Although a malignant peripheral nerve sheath tumor derived from neurofibroma was possible, the slow growth with diffuse and strong immunoreactivity to the S-100 protein and Sox10 favored a diagnosis of desmoplastic melanoma. Pathologists should recognize that desmoplastic melanoma may not involve in situ lesions or the immunohistochemical expression of standard melanoma markers. Keywords: Desmoplastic melanoma, Malignant peripheral nerve sheath tumor, Neurofibroma, Neurotrophic melanoma

The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced desmoplastic melanoma.

Desmoplastic melanoma (DM) represents an infrequently occurring and distinct histologic pattern of melanomas, often lacking mutations in genes typically altered in conventional melanomas including BRAF , NRAS , and KIT . We aimed at better characterizing the genetic profile of this subgroup of melanomas to match patients with available therapies. Pathology reports were reviewed for 1,240 consecutive melanoma cases sequenced by comprehensive genomic profiling (CGP) using a hybrid-capture based next generation sequencing during the course of clinical care. The mutational profile of the 12 DM identified was compared with the remaining 1,228 melanomas examined. We report a median tumor mutational burden (TMB) of 77 mutations per megabase (mut/Mb) in DM, which was significantly greater than a median of 35 mut/Mb in non-DM. A UV DNA damage signature was detected in 10/12 (83%) DM. For a subset of patients with available clinical course, we report that 100% (5/5) had clinical benefit from treatment with PD-1 inhibitors as monotherapy. TMB and UV signature show significant promise as an approach to identify patients who are likely to benefit from PD-1 targeted immunotherapy.

Palisaded encapsulated neuromas (PENs) are benign cutaneous nerve sheath proliferations that typically occur as flesh-colored papules solitarily on the head and neck in adults, with a slight predilection for females. Histopathologically, they are partially or completely encapsulated intradermal nodules with Schwann cells and axons in fascicles separated by clefts. Although these features are often characteristic, the hypercellular variant of PEN can pose a diagnostic challenge in distinguishing between other cellular neural and melanocytic lesions. We herein report a case of hypercellular PEN, which showed striking similarity to desmoplastic melanoma.

Desmoplastic melanoma (DM) is a rare form of malignant melanoma. DMs may present with a non-specific appearance which can make diagnosis difficult. Surgical excision with wide margins is the preferred treatment. DMs tend to be locally aggressive and adjuvant radiotherapy may improve local control of disease.