Hydrochlorothiazide and increased risk of atypical fibroxanthoma and pleomorphic dermal sarcoma.

BACKGROUND AND OBJECTIVES: Previous work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro-photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet-induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS-development. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time-period of 7 years (2013-2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus. RESULTS: Overall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients. CONCLUSIONS: This study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.

Atypical Fibroxanthoma: Outcomes from a Large Single Institution Series.

BACKGROUND: Atypical fibroxanthomas (AFX) are rare malignant cutaneous neoplasms. Unfortunately, limited clinicopathologic and outcomes data on this cancer exists. OBJECTIVE: We report the clinical, pathologic, and treatment characteristics, as well as oncologic outcomes in this single-institution retrospective analysis. METHODS: This retrospective cohort study compiled clinical, pathologic, treatment, and outcome data for all patients with AFX on definitive excision diagnosed, evaluated, and treated primarily by surgical resection at a single institution between 2000-2020. Descriptive statistics evaluated clinical and pathologic characteristics. Kaplan-Meier method and Cox proportional-hazards models were used to evaluate overall survival and recurrence-free survival. RESULTS: 78 patients with AFX were identified. The majority were elderly, immunocompetent, Caucasian men. 85% of tumors were located on the head and neck. 63% of patients were correctly diagnosed only after complete resection of the index lesion. The median surgical margin was 1.0 cm. Overall, only 1.3% (1/78) of patients developed a local recurrence (RFS). No patients died of disease. CONCLUSION: This study suggests that resection margins of 1 cm achieve excellent local control with close to 99% RFS and 100% disease-specific survival.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: Local recurrence and metastasis in a nationwide population-based cohort of 1118 patients.

BACKGROUND: The prognosis of patients with atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) remains uncertain and no standardized follow-up programs have been established. OBJECTIVE: To recommend a standardized follow-up program of patients with AFX and PDS based on nationwide long-term estimates of local recurrence and metastasis. METHODS: All patients with AFX and PDS in Denmark between 2002 and 2022 were included. Danish National Registries were used to estimate the risks of local recurrence and metastasis for AFX and PDS. RESULTS: The 5-year risk of local recurrence was 10% for AFX and 17% for PDS. The 5-year risk of metastasis was 0.8% for AFX and 16% for PDS. PDS metastasized within 3 years in >90% of the patients with the lungs as the primary metastasis site (50%). Invasion beyond the subcutis, perineural/intravascular infiltration, and increasing age significantly increased the risk of PDS relapse. LIMITATIONS: Risk of misclassification and lack of detailed surgical information. CONCLUSION: The follow-up of patients with AFX can be limited to clinical visits for 4 years. Patients with PDS should be followed with clinical visits and PET/CT twice a year for the first 3 years and once a year for a minimum of 1 year.

Atypical fibroxanthoma and pleomorphic dermal sarcoma - gene expression analysis compared with undifferentiated cutaneous squamous cell carcinoma.

BACKGROUND: The histogenetic origin of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) has not been definitively elucidated. In addition to a fibroblastic origin, a keratinocytic differentiation is discussed due to strong clinical, histomorphological and molecular genetic similarities with undifferentiated cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: 56 cases (36 AFXs, 8 PDSs, 12 undifferentiated cSCCs) were evaluated for their clinical, histomorphological, and immunohistochemical characteristics. RNA transcriptome analysis was performed on 18 cases (6 AFXs/PDSs, 6 undifferentiated cSCCs, 6 differentiated cSCCs). RESULTS: Clinically, the strong similarities in age, gender and tumor location were confirmed. Without further immunohistochemical staining, histomorphological differentiation between AFX/PDS and undifferentiated cSCC is often impossible. Principal component analysis of the RNA transcriptome analysis showed that AFX/PDS and differentiated cSCC each formed their own cluster, while the undifferentiated cSCCs fall in between these two groups, but without forming a cluster of their own. When examining differentially expressed genes (DEGs), the heat maps showed that there were cases within the undifferentiated cSCC that were more likely to be AFX/PDS than differentiated cSCC based on their expression profile. CONCLUSIONS: The results provide evidence of molecular similarities between AFX/PDS and undifferentiated cSCC and suggest a common histogenetic origin.

Lymphovascular Invasion and High Mitotic Count Are Associated With Increased Risk of Recurrence in Pleomorphic Dermal Sarcoma. / La presencia de infiltración linfovascular y de un alto número de mitosis se asocia a un mayor riesgo de recidiva en sarcoma pleomórfico dérmico.

BACKGROUND AND OBJECTIVE: Atypical fibroxanthoma and pleomorphic dermal sarcoma (PDS) are rare mesenchymal tumors. Due to the low incidence of PDS and a historically confusing nomenclature, little is known about the true aggressiveness of this tumor. The aim of this study was to investigate clinical and histologic risk factors for recurrence in PDS. MATERIAL AND METHODS: Retrospective, observational, bicentric study of 31 PDSs diagnosed and treated at Hospital Clínico Universitario de Valencia and Instituto Valenciano de Oncología in Valencia, Spain, between 2005 and 2020. We described the clinical and histologic features of these tumors and performed univariate analysis and multivariate Cox regression analysis. RESULTS: In the univariate analysis, tumor recurrence (P<.001), necrosis (P=.020), lymphovascular invasion (P=.037), perineural invasion (P=.041), and mitotic count (<18 vs ≥18 mitoses per 10 high-power fields) (P=.093) were associated with worse disease-free survival. In the multivariate Cox regression analysis, mitotic count and lymphovascular invasion retained their significance as predictors of worse disease-free survival (P<.05). CONCLUSIONS: PDS is an aggressive tumor in which a high mitotic count (≥18) and lymphovascular invasion are associated with a higher risk of recurrence and worse disease-free survival. Necrosis and perineural invasion are also probably linked to increased tumor aggressiveness.

Primary de-differentiated, trans-differentiated and undifferentiated melanomas: overview of the clinicopathological, immunohistochemical and molecular spectrum.

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in-situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S-100, SOX10, Melan-A and HMB-45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de- and trans-differentiation in melanoma is rare but probably under-recognised and under-reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun-damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre-existing conventional melanoma. The de-differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans-differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre-existing but often focal conventional melanoma together with molecular analysis.

Surgical excision margins for fibrohistiocytic tumors, including atypical fibroxanthoma and undifferentiated pleomorphic sarcoma: A probability model based on a systematic review.

BACKGROUND: Mohs micrographic surgery or wide local excision is the treatment of choice for fibrohistiocytic tumors with metastatic potential, including atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS). Since margin clearance is the strongest predictor of clinical recurrence, improved recommendations for appropriate surgical margins help delineate uniform excision margins when intraoperative margin assessment is not available. OBJECTIVE: To determine appropriate surgical wide local excision margins for AFX and cUPS. METHODS: Literature search (Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to March 2020) to detect case-level data. Estimation of margins required using a mathematical model based on extracted cases without recurrences. RESULTS: Probabilistic modeling based on 100 cases extracted from 37 studies showed peripheral clearance margin (ie, wide local excision margin) calculated to clear 95% of all tumors was 2 cm for AFX and 3 cm for cUPS. AFX tumors 1 cm or less required a margin of 1 cm. LIMITATIONS: Data were extracted from published cases. CONCLUSIONS: Atypical fibroxanthoma removed with at least a 2-cm peripheral excision margin is less likely to recur. Smaller tumors 1 cm or less can be treated with a more conservative margin. Margin-control surgical techniques are recommended to ensure complete removal while minimizing surgical morbidity.

Clear cell variant of atypical fibroxanthoma and pleomorphic dermal sarcoma: Molecular characterization and review of the literature.

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are unusual cutaneous tumors that typically arise in sun-damaged skin of elderly individuals. Several histopathologic variants have been described, but the clear cell variant is particularly rare with only 18 cases of AFX and one case of PDS reported. Here, we present two cases of clear cell AFX and PDS highlighting key histopathologic findings and molecular alterations assessed by next-generation sequencing.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: Is superficial infiltration in subcutaneous tissue acceptable in AFX?

BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous neoplasms forming a spectrum. Case reports with recurrences and metastasis have been published despite the current view that AFX is benign. The aim of this study was to identify clinical and histopathological features that predict tumor recurrence. METHODS: A retrospective review of AFX and PDS cases was performed. Clinical characteristics were obtained from patient records. RESULTS: A total of 29 AFX and 23 PDS cases were identified. Review led to re-classification of 12 cases (18%). In 14/50 (26.9%) cases a recurrence occurred. Recurrences were significantly more likely to occur when the tumor showed any infiltration in the subcutaneous fat (100% vs 43.2%, p = 0.000) or when the tumor diameter exceeded 2 cm (46.2% vs 16.2%, p = 0.030). CONCLUSIONS: This study shows that histopathological distinction between AFX and PDS remains difficult with reclassification in 12 out of 52 (18%) cases upon review. All AFX cases solely confined to the dermis behaved benign. We therefore advocate to classify all cases with any form of subcutaneous extension as PDS, and only lesions without as AFX. This contrasts with the current general opinion in which superficial subcutaneous invasion is still accepted in AFX.

Increase of atypical fibroxanthoma and pleomorphic dermal sarcoma: a retrospective analysis of four German skin cancer centers.

BACKGROUND AND OBJECTIVES: In recent years, considerable insight has been gained into the pathogenesis, diagnosis and treatment of cutaneous sarcomas, including atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Both entities have shown increasing incidence rates in the last decade. This study was initiated to evaluate how these new insights impact the number of diagnoses of AFX/PDS compared to other cutaneous sarcoma entities. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, all histopathological reports of cutaneous sarcomas (AFX, PDS, dermatofibrosarcoma protuberans, cutaneous leiomyosarcoma, angiosarcoma, and Kaposi sarcoma) confirmed by board-certified dermatopathologists were analyzed during a time-period of seven years (2013-2019). Additionally, utilization of immunohistochemical markers (including pan-cytokeratin, S100, desmin, CD34, CD10, procollagen-1, CD99, CD14, and CD68) as an adjunct to diagnose AFX/PDS was recorded. RESULTS: Overall, 255 cutaneous sarcomas were included in the present study. The diagnosis of a cutaneous sarcoma has consequently risen from 2013 to 2019 (from 16 to 52 annual cases). The results of AFX/PDS revealed 4.6 times more diagnoses in 2019 than in 2013. Atypical fibroxanthoma represented the most common subtype, displaying 49.3 % of all diagnosed cutaneous sarcomas. Additionally, the increase of AFX/PDS was linked to the use of immunohistochemistry, with specific immunohistochemical markers used in 57.1 % of cases in 2013 compared to 100 % in 2019. CONCLUSIONS: This retrospective study of four German skin cancer centers demonstrates a substantial rise of AFX/PDS, possibly due to recently established diagnostic and terminology standards. This rise is probably linked to increased utilization of specific immunohistochemical markers. Atypical fibroxanthoma/PDS may be more common than previously thought and seems to represent the most frequent cutaneous sarcoma subtype.

The role of radiation therapy in the management of cutaneous malignancies. Part II: When is radiation therapy indicated?

Radiation therapy may be performed for a variety of cutaneous malignancies, depending on patient health status, tumor clinical and histologic features, patient preference, and resource availability. Dermatologists should be able to recognize the clinical scenarios in which radiation therapy is appropriate, as this may reduce morbidity, decrease risk of disease recurrence, and improve quality of life. The second article in this 2-part continuing medical education series focuses on the most common indications for radiation therapy in the treatment of basal cell carcinoma, cutaneous squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi sarcoma, angiosarcoma, cutaneous lymphoma, melanoma, undifferentiated pleomorphic sarcoma, and sebaceous carcinoma.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: A reappraisal.

BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) share clinical, pathological, immunohistochemical and molecular features, though PDS is associated with a more aggressive behavior. METHODS: We reviewed 71 tumors fulfilling criteria for AFX and PDS to further stratify their biological potential. RESULTS: Lesions were mainly located on the scalps of elderly men, and were often ulcerated. One case was necrotic, one showed vascular invasion, and one showed perineural invasion. Fifty-one tumors were limited to reticular dermis (71.8%), 20 invaded subcutaneous tissue, focally in 13 cases (18.3%), and diffusely in seven (9.9%). Subcutaneous invasion was present significantly more often in tumors showing predominantly spindle compared to pleomorphic/mixed cell morphology (P = 0.02). At a follow-up of 17-125 months, 4 cases recurred locally, 4, 6, 10 and 13 months after surgery; no metastases were observed. Three tumors were composed of spindle cells, and one of clear cells. Three cases had margins focally involved, while the fourth case had clear margins. CONCLUSION: Depth of invasion and state of margins are criteria predicting prognosis in AFX/PDS; in addition, spindle cell morphology seems to be related to a more infiltrative pattern of growth and to aggressiveness. Grouping these tumors on a morphologic base could help to clarify their different biological behavior.

Expression of connexin 43 by atypical fibroxanthoma.

INTRODUCTION: Connexins are transmembrane channel proteins that interconnect adjacent cells and allow the exchange of signaling molecules between cells and the extracellular milieu. They have been investigated in many tumors to obtain information about tumor nature, behavior, and prognosis. METHODS: Herein, we present a study on the immunohistochemical expression of connexin (Cx) 43 in 16 cases of atypical fibroxanthoma (AFX). For the immunohistochemical staining, a tissue array was obtained from the paraffin-embedded blocks. RESULTS: The expression was membranous and cytoplasmic in all cases. Thirteen cases (81.25%) showed strong staining. In the other three cases (18.75%), the staining was medium. None of the cases showed nuclear staining. Fifteen out of 16 cases showed a diffuse pattern, and only one case showed a focal pattern. CONCLUSIONS: Our results suggest that Cx43 may play an important role in the natural behavior of AFX.

CD10 and p63 expression in a sarcomatoid undifferentiated melanoma: A cautionary (and molecularly annotated) tale.

Undifferentiated melanoma should be considered in the differential diagnosis of sarcomatoid cutaneous malignancies to ensure that patients receive the correct treatment. Dermatopathologists should recognize the pitfalls of relying too heavily on immunohistochemistry to establish this diagnosis and consider ancillary tests, including single-nucleotide polymorphism (SNP) copy number arrays and targeted next-generation sequencing (NGS), when a definitive diagnosis cannot be rendered on a primary or metastatic tumor. This technology can also help to exclude a collision of melanoma and sarcoma when both differentiated and undifferentiated components are juxtaposed. We describe an exceedingly rare, illustrative example of undifferentiated sarcomatoid melanoma presenting as a pedunculated nodule. The clinical context and presence of a small differentiated component helped to establish the diagnosis; however, the transition from differentiated to undifferentiated melanoma was accompanied by an abrupt loss of S100, Sox10, MITF, MelanA, and HMB45 with gain of CD10 and p63 staining. SNP copy number array and NGS revealed shared chromosomal copy number changes and overlapping mutations with additional aberrances detected exclusively in the sarcomatoid component, thereby excluding a collision tumor and confirming our putative impression of melanoma with progression to an undifferentiated sarcomatoid phenotype.

Atypical fibroxanthoma: An analysis of 105 tumors.

Atypical fibroxanthoma (AFX) is a rare, low-grade dermal sarcoma. We analyzed our files from January 2001 to January 2020 for AFX. Clinical parameters, histopathology, treatment and outcome have been investigated. We identified 87 patients (mean age of 80.0 ± 8.4 years) with 105 confirmed tumors. Of these patients 86.2% were males. The most common clinical presentation was nodular (93.3%). The majority of AFX was located on the head with a mean tumor diameter of 15.0 mm ± 3.5 mm. All tumors showed a dermal localization, in 46.4% with a focal infiltration of the deeper layers. Second skin cancer was reported in 62.1% of patients. Collision tumors were seen in six patients. Treatment was surgical with three-dimensional margin control. Relapses were noted in 11.4% of tumors with a mean delay of 11.7 ± 17.3 months. Focally deeper infiltration of AFX was a risk factor (P = .014). None of the purely dermal AFX relapsed. No metastasis was observed. AFX is a rare mesenchymal tumor of elderly patients. Treatment of choice is the complete surgical excision. Due to the high rate of other skin malignancies among patients with AFX, a regular follow-up is recommended.

Incidence rate and clinicopathological features of 62 atypical fibroxanthomas in a North-Western Spanish population.

BACKGROUND/OBJECTIVES: Atypical fibroxanthoma (AFX) is a mesenchymal neoplasm of unknown incidence. It has been determined that AFX is a tumour with low aggressiveness as long as it is properly diagnosed. Our objectives were to exclude pleomorphic dermal sarcomas or other skin tumours incorrectly diagnosed as AFX in our centre after applying strict diagnostic criteria and to assess the behaviour of appropriately diagnosed AFX. METHODS: We conducted an observational retrospective analysis of 73 patients diagnosed with AFX in our centre between 1998 and 2018. After selecting cases fulfilling AFX criteria, we made an analysis of predictive factors for local recurrence. Crude and sex-adjusted incidence rates were calculated. RESULTS: Out of 73 cases, 62 were eventually diagnosed as AFX. We examined for absence of tumour necrosis, lymphovascular or perineural invasion and infiltration of deep structures. Cytokeratin AE1-AE3, desmin and CD34 were negative in all cases. The remaining tumours were reclassified. The incidence of AFX in our health-care area was estimated at 0.59 cases every 100 000 inhabitants per year. In our series, 72.6% of the patients were men with mean age at diagnosis of 81 years. Average tumour diameter was 12 mm. The most common location was head and neck (96.8%). Only four local recurrences were detected over a mean of 47-month follow-up. CONCLUSIONS: We report a series of AFX in our health-care area. We verify its indolent course when it is properly diagnosed.

Atypical fibroxanthoma/pleomorphic dermal sarcoma of the scalp with aberrant expression of HMB-45: a pitfall in dermatopathology.

Atypical fibroxanthoma (AFX) has been considered as the non-infiltrating precursor lesion of pleomorphic dermal sarcoma (PDS), which shows an aggressive clinical behavior, because of its extensive invasion of the deeper skin layers. Although these two tumors may represent two stages of the same disease, it can be difficult to differentiate between them, because of their similar clinical and histological features 1. Furthermore, they must be distinguished from a spindled variant of squamous carcinoma, melanoma and leiomyosarcoma 2. AFX/PDS still remains a diagnosis of exclusion, that needs to combine immunohistochemical markers for a definitive diagnosis. Usually AFX/PDS shows positivity for CD10, CD99, CD68, vimentin and lysozyme, while S100, HMB45, MART-1, cytokeratins, CD34, CD31, desmin and h-caldesmon are absent.We report a case of 89-year-old male, with a history of squamous cell carcinoma removed from the right ear, presented to our department with a recently growing, ulcerated and bleeding 2 cm nodule on the scalp. After surgery the tumor recurred with infiltration to the cranial theca. The final histological diagnosis was "pleomorphic dermal sarcoma" (PDS), which showed an unexpected positivity for HMB45. We present, to the best of our knowledge, the first case of AFX/PDS with an aberrant diffuse expression of HMB45 and an aggressive biological behavior, that leads us to a difficult exclusion diagnosis.

Immune-phenotyping of pleomorphic dermal sarcomas suggests this entity as a potential candidate for immunotherapy.

BACKGROUND: Pleomorphic dermal sarcomas (PDS) are sarcomas of the skin with local recurrences in up to 28% of cases, and distant metastases in up to 20%. Although recent evidence provides a strong rational to explore immunotherapeutics in solid tumors, nothing is known about the immune environment of PDS. METHODS: In the current study, a comprehensive immune-phenotyping of 14 PDS using RNA and protein expression analyses, as well as quantitative assessment of immune cells using an image-analysis tool was performed. RESULTS: Three out of 14 PDS revealed high levels of CD8-positive tumor-infiltrating T-lymphocytes (TILs), also showing elevated levels of immune-related cytokines such as IL1A, IL2, as well as markers that were very recently linked to enhanced response of immunotherapy in malignant melanoma, including CD27, and CD40L. Using a multivariate analysis, we found a number of differentially expressed genes in the CD8-high group including: CD74, LYZ and HLA-B, while the remaining cases revealed enhanced levels of immune-suppressive cytokines including CXCL14. The "CD8-high" PDS showed strong MHC-I expression and revealed infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. Tumor-associated macrophages (TAMs) predominantly consisted of CD68 + , CD163 + , and CD204 + M2 macrophages showing an accentuation at the tumor invasion front. CONCLUSIONS: Together, we provide first explorative evidence about the immune-environment of PDS tumors that may guide future decisions whether individuals presenting with advanced PDS could qualify for immunotherapeutic options.

Expression of proton-sensing G-protein-coupled receptors in selected skin tumors.

BACKGROUND: In humans, there are four known proton-sensing G-Protein-coupled receptors (pH-GPCRs): GPR4 (GPR19), TDAG8 (GPR65, T-cell death-associated gene 8), OGR1 (GPR68, ovarian cancer GPCR1) and G2A (GPR132, G2 accumulation protein). They are known to be involved in sensing changes of extracellular proton concentrations in the acidic microenvironment of tumors, which leads to altered cell proliferation, migration, metastasis, immune cell function and inflammation. However, little is known about the expression of pH-GPCRs in the skin and especially skin cancers. AIM: We studied the expression of pH-GPCRs in selected skin cancers, that is Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). METHODS: We did immunohistochemistry and immunofluorescence to analyse the expression of GPR4, TDAG8, OGR1 and G2A using paraffin-embedded tissue samples (n = 4, exceptions: PDS GPR4/GPR65 n = 5, AFX GPR132 n = 3) from patients suffering from MCC, DFSP, AFX and PDS. RESULTS: (a) GPR4 was expressed on all AFX and PDS specimens. All AFX and MCC showed a positive expression of G2A. All PDS exhibited a strong positive expression of G2A. (b) MCCs neither expressed GPR4 nor TDAG8. All DFSP showed no expression of TDAG8. (c) For any other combination of GPCR and skin disease, we found positive/negative mixed results. CONCLUSIONS: These are the first results on pH-GPCRs in selected skin cancers. We provide evidence that these GPCRs are differentially expressed on the various types of skin cancers and that they can potentially be addressed as a therapeutic target in extensive disease.