Clinical, histological, and molecular differences in melanoma due to different TERT promoter mutations subtypes. A retrospective cross-sectional study in 684 melanoma patients.

Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.

Tumor Microenvironment and Its Clinicopathologic and Prognostic Association in Cutaneous and Noncutaneous Angiosarcomas.

OBJECTIVES: We explored features of the angiosarcoma (AS) tumor microenvironment to discover subtypes that may respond to immunotherapy. METHODS: Thirty-two ASs were included. Tumors were studied by histology, immunohistochemistry (IHC), and gene expression profile using the HTG EdgeSeq Precision Immuno-Oncology Assay. RESULTS: Comparing cutaneous and noncutaneous ASs, the second group showed 155 deregulated genes, and unsupervised hierarchical clustering (UHC) delineated two groups: the first mostly cutaneous AS and the second mainly noncutaneous AS. Cutaneous ASs showed a significantly higher proportion of T cells, natural killer cells, and naive B cells. ASs without MYC amplification revealed a higher immunoscore in comparison with ASs with MYC amplification. PD-L1 was significantly overexpressed in ASs without MYC amplification. UHC showed 135 deregulated genes differentially expressed when comparing ASs from the non-head and neck area with patients who had AS in the head and neck area. ASs from the head and neck area showed high immunoscore. PD1/PD-L1 content was significantly more highly expressed in ASs from the head and neck area. IHC and HTG gene expression profiling revealed a significant correlation between PD1, CD8, and CD20 protein expression but not PD-L1. CONCLUSIONS: Our HTG analyses confirmed a high degree of tumor and microenvironment heterogeneity. Cutaneous ASs, ASs without MYC amplification, and ASs located in the head and neck area seem to be the most immunogenic subtypes in our series.

Trichoepithelioma on the Finger: A Rare Location and Dermoscopic-Histopathologic Correlation.

ABSTRACT: Trichoepithelioma is a benign adnexal neoplasm of follicular germinative cells, with bulbs, papillae, and sheaths of perifollicular connective tissue as signs of follicular differentiation. Accordingly, trichoepithelioma may arise in any hair-bearing location, mostly on the face. That is why trichoepithelioma cannot appear in glabrous skin, and, although the dorsum of the hands and feet are a hair-bearing area, acral location is exceptional. We report the first case of trichoepithelioma localized in the finger of a 79-year-old man. It was a brown-pink, firm, 7-mm diameter, solid papule on the dorsal aspect of his left index finger. The lesion was completely asymptomatic, and he remembered to have it for many years. We describe this case highlighting its rare anatomical location and correlate its dermoscopic features with the histopathological appearance.

Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology.

Mesenchymal neoplasms with GLI1 alterations (rearrangements and/or amplification) have been reported recently in several anatomic locations, which include head and neck, soft tissue, and gastrointestinal tract. Herein, to the best of our knowledge, we describe the first three cases of superficial/subcutaneous mesenchymal neoplasm with GLI1 amplification. The neoplasms exhibited low-grade cytologic features with predominant round cell morphology, glomangioma-like areas and a rich background capillary network. There were two to three mitotic figures per 10 HPF and focal necrosis in one case. The tumors exhibited variable expression of CDK4, MDM2, STAT6, D2-40, CD56 and cyclin D1. p16 had strong and diffuse nuclear and cytoplasmic expression in two cases. Numerous other stains were negative. Fluorescence in situ hybridization detected GLI1, DDIT3, and CDK4 coamplification in all cases, while next generation sequencing did not detect a GLI1 gene fusion. The overall features were compatible with a GLI1-amplified mesenchymal neoplasm. In Case 1 a new distant skin lesion appeared 1 month after the surgery exhibiting similar morphology albeit with a higher mitotic index. In Cases 2 and 3, there is no evidence of local recurrence or systemic disease after 8 years and 1 month of follow-up, respectively. These new cases of superficial GLI1-amplified neoplasm expand its clinical spectrum and enter the realm of dermatopathology. The combination of CDK4, cyclin D1, D2-40, and p16 expression with variable MDM2, STAT6, CD56, and S100 immunoreactivity in a low-grade neoplasm with round/ovoid cytomorphology resembling a vascular or adnexal neoplasm may suggest the possibility of GLI1-amplified neoplasm.

Combined Merkel cell carcinoma and cutaneous squamous cell carcinoma with lymph node metastases: Report of two cases.

Merkel cell carcinoma (MCC) is an infrequent, aggressive cutaneous neoplasm, that typically affects the photodamaged skin of elderly individuals, and immunosuppressed patients. Because a subset of MCC is closely related to UV radiation, MCC can develop concurrently with other tumors, most commonly, as a combined tumor with squamous cell carcinoma (SCC). These combined tumors appear to represent a distinct disease process from pure MCC, as they are mostly Merkel cell polyomavirus (MCPyV) negative, and show a more aggressive behavior. We present two additional cases of combined MCC and SCC with nodal metastases, one of which was MCPyV positive. Two different subtypes of MCC have been proposed based on their origin: a true neuroendocrine carcinoma, that is MCPyV positive and has a dermal origin, and a UV-related SCC with neuroendocrine differentiation. This theory could explain why MCC can develop concurrently with SCC, and why these combined cases are generally MCPyV negative. However, it fails to explain the minority of combined MCC and SCC tumors that are MCPyV positive. Because both our patients had a history of chronic UV exposure, we hypothesize that UV radiation probably played a major role in the pathogenesis of these tumors, while MCPyV integration probably acted as an additional trigger.

Cutaneous Ossifying Amyloidoma.

ABSTRACT: Amyloidoma, otherwise known as tumoral amyloidosis, is a localized deposition of amyloid (AL-type or AA type) without systemic amyloidosis. It is the rarest form of tissue amyloid deposition, and up to 7% of amyloidomas develop systemic amyloidosis.Cutaneous AL-type amyloidoma is considered by many authors as an unusual variant of primary cutaneous marginal zone lymphoma. Although cutaneous amyloidoma can form calcifications, ossification is extremely unusual, with only 1 case previously published to date.We report the case of a 75-year-old woman with voluminous and strikingly ossifying AL-type amyloidoma in the left pretibial skin. Her medical history included excision of hepatic hydatidic cysts 25 years prior and diffuse large B-cell lymphoma of the left parotid gland 8 years prior treated with chemotherapy and radiotherapy with complete response. After the diagnosis of amyloidoma, an extension study with cervical, chest, abdominal, and pelvic TC was performed, with no additional lesions found. Serum and protein electrophoresis revealed elevations in kappa light chain and IgA immunoglobulin levels but did not reveal monoclonal bands. In situ hybridization for immunoglobulin light chains showed monotypic kappa expression in plasma cells infiltrating the amyloidoma.Extensive ossification in amyloidomas can make diagnosis difficult; therefore, we describe an interesting case of this histopathologically peculiar amyloidoma.

Differences by Anatomical Site of Non-Acral Lentiginous Melanomas of the Lower Limb.

BACKGROUND: Acral location of melanomas is associated with poor survival. It can be due, at least in part, to the fact that acral lentiginous melanoma, a distinct melanoma subtype, has a particular biological profile and a bad clinical behavior. However, since almost 50% of acral melanomas are not of acral lentiginous melanoma subtype, the worse clinical behavior could also be attributable to the intrinsic characteristics of the location. OBJECTIVE: This study aimed to investigate if melanomas of the lower limb excluding acral lentiginous melanoma differ by location. METHODS: This retrospective, observational study recruited patients from an oncology referral center in Spain. We included 285 patients with superficial spreading and nodular melanomas of the lower limb. We compare melanomas by site, clinical and pathological characteristics, and the differences by location of disease-free and melanoma-specific survival by the Kaplan-Meier method and Cox proportional hazard method. RESULTS: Patients with melanomas on the foot, compared to those on the rest of the limb, were older and reported having suffered less sunburns; the melanoma more frequently appeared in areas that had been rarely sun exposed, were more frequently of nodular type, presented thicker tumors, with more ulceration, less regression, and more advanced stage of the disease. Foot location increased the risk of relapse and decreased melanoma-specific survival. CONCLUSION: Melanoma development in foot is less related to sun exposure and is associated with pathological features that can account for the worse prognosis and poorer survival.

[Cutaneous Rosai-Dorfman disease with lack of BRAF-V600, KRAS or NRAS mutations: A reactive or neoplastic disorder?] / Enfermedad de Rosai-Dorfman con presentación cutánea y ausencia de mutaciones BRAF-V600, KRAS y NRAS: ¿trastorno neoplásico o reactivo.

Non-Langerhans cell histiocytosis, including Rosai-Dorfman disease (RDD) and xanthogranuloma are rare disorders with occasional overlapping in the histopathological and immunohistochemical (IHC) findings. We report the case of a 53-year-old woman with erythematous-violaceous plaques on the cheeks and edema in the auricular pavilions. A biopsy was performed and the histopathological examination revealed a histiocytic proliferation with emperipolesis characteristic of RDD and lymphoplasmocitic infiltrate. IHC analysis showed S100 and CD68 positivity in the histiocytes but was negative for CD1a, supporting the diagnosis of RDD. Molecular analysis failed to detect BRAF-V600, NRAS or KRAS mutation. We discuss the differential diagnosis of cutaneous non-Langerhans cell histiocytosis. Pathologist must be aware of unusual presentations of RDD and further treatment options must be explored for patients with unresectable lesions and/or resistance to the classical management of RDD.

Enfermedad de Rosai-Dorfman con presentación cutánea y ausencia de mutaciones BRAF-V600, KRAS y NRAS: ¿trastorno neoplásico o reactivo / Cutaneous Rosai-Dorfman disease with lack of BRAF-V600, KRAS or NRAS mutations: A reactive or neoplastic disorder?

Las histiocitosis de células no Langerhans, como la enfermedad de Rosai-Dorfman (ERD) y el xantogranuloma, son trastornos raros que pueden mostrar solapamiento de los hallazgos histopatológicos e inmunohistoquímicos. En el presente estudio describimos un caso clínico de una paciente femenina de 53años con placas eritematoso-violáceas en las mejillas y edema en los pabellones auriculares. Se realizó una biopsia y en el examen histopatológico se observó una proliferación de histiocitos con emperipolesis característica de la ERD junto con un infiltrado linfoplasmocítico. El estudio inmunohistoquímico mostró que la mayoría de los histiocitos fueron positivos para S100 y CD68, y negativos para CD1a, lo que confirmó el diagnóstico de ERD. El análisis molecular no detectó la mutación BRAF-V600, NRAS ni KRAS. Se discute el diagnóstico diferencial entre las histiocitosis no de células de Langerhans con presentación cutánea. El patólogo debe estar al tanto de las presentaciones clínicas o patológicas inusuales de la ERD, y en los pacientes con enfermedad no resecable/escasamente resecable o resistentes al tratamiento clásico de la ERD deberían explorarse otras opciones terapéuticas basadas en los resultados de los estudios moleculares.(AU)

Non-Langerhans cell histiocytosis, including Rosai-Dorfman disease (RDD) and xanthogranuloma are rare disorders with occasional overlapping in the histopathological and immunohistochemical (IHC) findings. We report the case of a 53-year-old woman with erythematous-violaceous plaques on the cheeks and edema in the auricular pavilions. A biopsy was performed and the histopathological examination revealed a histiocytic proliferation with emperipolesis characteristic of RDD and lymphoplasmocitic infiltrate. IHC analysis showed S100 and CD68 positivity in the histiocytes but was negative for CD1a, supporting the diagnosis of RDD. Molecular analysis failed to detect BRAF-V600, NRAS or KRAS mutation. We discuss the differential diagnosis of cutaneous non-Langerhans cell histiocytosis. Pathologist must be aware of unusual presentations of RDD and further treatment options must be explored for patients with unresectable lesions and/or resistance to the classical management of RDD.(AU)

Sentinel Lymph Node Biopsy vs. Observation in Thin Melanoma: A Multicenter Propensity Score Matching Study.

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients.

Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

Association between melanoma thickness and clinical and demographic characteristics.

The large-scale implementation of primary and secondary skin cancer prevention strategies in recent decades has led to an increase in the diagnosis of thin melanomas and a decrease in the mean thickness of tumours diagnosed. The number of newly diagnosed thick melanomas, however, has remained stable. To investigate associations between melanoma thickness, clinical presentation and demographic and phenotypic characteristics. The study is based on a cross-sectional study of 1,459 patients with melanoma from a dermatology department at a tertiary hospital in Spain between 2000 and 2017. We analysed associations between median Breslow thickness and demographic, phenotypic, and clinical characteristics, including the method of melanoma detection. Age ≥ 70 years (regression coefficient [RC] =  1.2, 95% CI: 1.1-1.3; p  <  0.001), male sex (RC  =  0.9, 95% CI: 0.8-0.9; p  <  0.001), symptom-based detection (RC  =  1.3, 95% CI: 1.1-1.4; p  <  0.001), and a history of sunburn at the melanoma site (RC  =  0.9, 95% CI: 0.8-0.9; p  =  0.04) were all associated with thicker tumours. Melanomas on the lower extremities, by contrast, were significantly thinner (RC  =  0.9, 95% CI: 0.8-0.9; p = 0.04). Thick melanomas occur preferentially in older men and show changes such as bleeding or an increase in volume or colour. This information should be incorporated into health training and education programs to design better prevention strategies and minimize diagnostic delays.

Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Longitudinal study of prognostic factors for localized cutaneous melanoma in patients who have been disease-free for five years.

Most relapses in melanoma patients occur during the first five years after diagnosis. Identifying characteristics associated with recurrence after this period could help delineate guidelines, specifically for follow-up protocols. Objectives: The aim of this study was to identify the prognostic factors for relapse and death caused by melanoma in patients who have been disease-free for five years. We designed a longitudinal retrospective cohort to study Stage I/II cutaneous melanoma patients who have been free of disease for more than five years (late relapse cohort). Prognostic factors for disease-free and melanoma-specific survival were evaluated using the Kaplan-Meier method and Cox regression models. A series of 746 patients who had Stage I-II cutaneous melanoma and were free of disease for five years was selected. After a median follow-up of 64 months (124 months since melanoma diagnosis), 51 (6.8%) patients relapsed and 18 (2.4%) died from melanoma. Acral location and presence of ulceration, as well as intermediate growth rate (0.11-0.50 mm/month), were significantly associated with relapse or death due to melanoma. The initial recurrence site was associated with distant metastasis in 48% of the cases. In this study, we have identified melanoma characteristics in patients who have been disease-free for five years that may allow us to establish groups at increased risk of relapse or death due to melanoma, which could be helpful for melanoma management.

Distribution and clinical role of KIT gene mutations in melanoma according to subtype: a study of 492 Spanish patients.

BACKGROUND: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas. OBJECTIVES: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations. MATERIALS & METHODS: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history. RESULTS: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas. CONCLUSION: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.

Protocolo de diagnóstico histológico para muestras de pacientes con melanoma cutáneo. Documento de consenso de la SEAP y la AEDV para el Registro Nacional de Melanoma / Protocol for the histologic diagnosis of cutaneous melanoma: consensus statement of the Spanish Society of Pathology and the Spanish Academy of Dermatology and Venereology (AEDV) for the National Cutaneous Melanoma Registry

El presente texto es una propuesta de protocolo de diagnóstico histológico para el melanoma cutáneo realizada a instancias del Registro Nacional de Melanoma de la Academia Española de Dermatología y Venereología. Tras una búsqueda bibliográfica, un grupo de ocho panelistas (siete patólogos) decidieron entre 36 variables del tumor primario, el ganglio centinela y la linfadenectomía incluir un total de 30 variables mediante el método de Delphi modificado. Se han consensuado las variables que deberían contener un informe histológico de melanoma cutáneo para que puedan ser utilizadas en el Registro de Melanoma o servir de modelo para los distintos Servicios de Anatomía Patológica a la hora de elaborar sus propios informes de forma rutinaria

This article describes a proposed protocol for the histologic diagnosis of cutaneous melanoma developed for the National Cutaneous Melanoma Registry managed by the Spanish Academy of Dermatology and Venereology (AEDV). Following a review of the literature, 36 variables relating to primary tumors, sentinel lymph nodes, and lymph node dissection were evaluated using the modified Delphi method by a panel of 8 specialists (including 7 pathologists). Consensus was reached on the 30 variables that should be included in all pathology reports for cutaneous melanoma and submitted to the Melanoma Registry. This list can also serve as a model to guide routine reporting in pathology departments

Usefulness of ultrasound in dermatofibrosarcoma protuberans and correlation with histopathological findings: A series of 30 cases.

BACKGROUND: Small series of ultrasound findings in dermatofibrosarcoma protuberans (DFSP) have been published, but the usefulness of this technique as a preoperative planning tool for tumor resection has not been studied. MATERIALS AND METHODS: We retrospectively reviewed patients with DFSP at our hospital that underwent ultrasound examination. Depth of invasion was evaluated by ultrasound and histopathology. Accuracy of ultrasound for assessing depth of tumor invasion was estimated. RESULTS: Thirty histopathologically confirmed DFSPs were studied. Classic finger-like projections were observed in 73.3% of cases. A posterior hyperechoic area extending deep into the subcutaneous tissue correlated with the honeycomb DFSP pattern and was observed in 53.3% of patients. Concordance between ultrasound and histopathologic depth measurements was excellent. Lateral tumor extension and Doppler activity were not evaluated in our series. CONCLUSION: Ultrasound showed excellent prediction of depth of invasion. Further studies are required to define the usefulness of ultrasound for determining lateral tumor extension.