Long-Term Sequential Digital Dermoscopy of Low-Risk Patients May Not Improve Early Diagnosis of Melanoma Compared to Periodical Handheld Dermoscopy.

Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84, p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.

Connective tissue panniculitis and vitiligo in a patient with stage IV melanoma achieving complete response to dabrafenib and trametinib combination therapy.

The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

Impact of delay in follow-up due to COVID-19 pandemic on skin cancer progression: a real-life experience from an Italian hub hospital.

BACKGROUND: The COVID-19 pandemic required the setting of a national lockdown in Italy from March 9, 2020, until May 18, 2020; therefore, most of the non-COVID-19 activities were postponed. As a consequence, many follow-up visits in patients with previously excised skin cancers were delayed. The aim of this retrospective real-life case-control study is demonstrating that delay in follow-up led to an increased incidence of advanced melanoma and keratinocyte cancers on the total of surgically excised skin cancers. METHODS: The incidence of excised advanced melanoma and keratinocyte cancers in our dermato-surgery division in the period May 18 to November 18, 2020, was compared to the same time span of 2019. All data were collected from the electronic database of our department. Odds ratio with 95% confidence interval was used to assess the risk of excised advanced skin cancers in 2020 compared to 2019. RESULTS: From May to November 2019, we performed 265 surgical excisions, while during the pandemic in 2020, we completed 280 surgeries. The number of advanced skin cancers excised between May 18 and November 18, 2020, was significantly higher compared with the same period in 2019 (54 vs. 22, OR: 2.64; 95% CI: 1.56-4.47; P = 0.0003). Significant differences were also observed regarding the number of surgically removed advanced BCCs (OR 2.15; 95% CI 1.14-4.07; P = 0.0187) and advanced SCCs (OR 4.60; 95% CI 1.31-16.18; P = 0.0175). CONCLUSION: These results confirm that delay in follow-up and, consequently, postponed surgical excisions are related to an increased incidence of advanced skin tumors, resulting in poorer prognosis lifelong. Follow-up visits should be carried on even during COVID-19 pandemic, avoiding significant delays as much as possible.

Rare exon 10 deletion in POLH gene in a family with xeroderma pigmentosum variant correlating with protein expression by immunohistochemistry.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by severe cutaneous and ocular sensitivity to sunlight, leading to skin cancer. Most XP patients belong to the XP complementation groups (XP-A to XP-G), due to mutations in genes involved in nucleotide excision repair (NER). On the other hand, the XP Variant type (XP-V, OMIM#278750), which accounts for about 20% of all XP patients, is associated with normal NER function. The disease gene is POLH, which encodes polymerase η (pol η) allowing translesion synthesis in regions of DNA damage. We observed an Italian family presenting with photosensitivity, freckling since childhood and multiple skin cancers. Complete sequence analysis of XPA, XPC, XPD/ERCC2 genes and exons 1-9 and 11 of POLH gene did not reveal pathological mutations. No PCR product was observed for exon 10 in POLH gene. By RT-PCR analysis followed by POLH exon 10 sequencing, all affected members were found to harbor a homozygous 170-nucleotide deletion. The same deletion was previously described in 3 XP-V families, one of southern Italian descent and two from Algeria, suggesting a possible founder mutation. The deletion determines a severe protein truncation and defective pol η activity. Immunohistochemical study showed markedly reduced pol η expression in skin lesions of the affected siblings compared to the normal control skin.

Specific infiltrate of Hodgkin lymphoma at site of cellulitis mimicking secondary cutaneous involvement.

Hodgkin lymphoma (HL) usually involves the lymph nodes, but concomitant cutaneous manifestations can also occur. The diagnosis of cutaneous involvement by HL must be supported by specific clinical and histopathological findings. We describe the case of a 56-year-old man recently diagnosed with HL of the left axillary nodes who developed cellulitis of the left trunk. Histopathological examination of a skin biopsy specimen revealed the presence of large atypical lymphoid cells with the same immunophenotype of those located in the lymph node affected by HL. Our case adds to the many cutaneous infiltrations by neoplastic cells during the course of an inflammatory skin disease, namely cellulitis.

Red grape (Vitis vinifera L.) flavonoids down-regulate collagen type III expression after UV-A in primary human dermal blood endothelial cells.

Red grape (Vitis vinifera L.) flavonoids including flavan-3-ols (eg, catechin and epicatechin), flavonols (eg, quercetin) and anthocyanins (eg, malvidin) exert anti-inflammatory and antioxidant activities. In the skin they also have a photoprotective action, and their effects have been extensively investigated in keratinocytes, melanocytes and fibroblasts. Despite their known effects also on blood vasculature, little is known on their activities on human dermal blood endothelial cells (HDBECs), which are critically involved in skin homeostasis as well as in the pathogenesis of neoplastic and inflammatory skin diseases. We sought to study the biological effects of selected red grape flavonoids in preventing the consequences of ultraviolet (UV)-A irradiation in vitro. Our results show that red grape flavonoids prevent UV-A-induced sICAM-1 release in HDBECs, suggesting that this cell type could represent an additional target of the anti-inflammatory activity of flavonoids. In addition, flavonoids effectively inhibited UV-A-induced synthesis of collagen type III at both RNA and protein level, indicating that dermal blood microvasculature could be actively involved in ECM remodelling as a consequence of skin photo-ageing, and that this can be prevented by red grape flavonoids.

Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A>T) mutation in melanoma-prone families from Italy.

Genetic susceptibility to primary cutaneous melanoma (PCM) may account for up to 12% of PCMs, presenting as the familial atypical mole/multiple melanoma syndrome (FAMMM), an autosomal dominant condition with incomplete penetrance and variable expressivity, characterized by PCM in at least two relatives and/or more than one PCMs in the same patient. To identify individuals at high genetic risk of PCM, from 1 January 2012 to 31 December 2015, we offered genetic counselling and molecular analysis of the two high-penetrance FAMMM susceptibility genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), to 92 consecutive, unrelated patients with FAMMM. Age at diagnosis and number of PCMs were obtained from medical records; the number of PCMs and affected relatives were recorded for each family. The diagnostic work-up consisted of genetic counselling and cascade genetic testing in patients and further extension to relatives of those identified as mutation carriers. All exons and exon/intron boundaries of CDKN2A and CDK4 genes were screened by direct bidirectional sequencing. We identified CDKN2A mutations in 19 of the 92 unrelated patients (20.6%) and in 14 additional, clinically healthy relatives. Eleven of these latter subsequently underwent excision of dysplastic nevi, but none developed PCM during a median follow-up of 37.3 months. In three patients from unrelated families, the novel CDKN2A p.D84V (c.251A>T) mutation was observed, associated with PCM in each pedigree. Genetic screening of FAMMM patients and their relatives can contribute towards specific primary and secondary prevention programmes for individuals at high genetic risk of PCM. The novel CDKN2A p.D84V (c.251A>T) mutation adds to the known mutations associated with FAMMM.

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.

Hypoxia-Inducible Factor-1α and CD271 inversely correlate with melanoma invasiveness.

Melanoma is characterized, among other features, by microenvironmental factors and by an altered apoptotic machinery. Melanoma cell response to a hypoxic environment is transcriptionally regulated by the Hypoxia-Inducible Factor (HIF)-1α. p75 neurotrophin receptor (p75(NTR) ), also called CD271, mediates apoptosis in several cell systems. The purpose of this study was to analyze the expression of HIF-1α and CD271 in melanomas at different phases of progression, as evaluated by histology and reflectance confocal microscopy (RCM). By RCM, 41.67% tumors were characterized by the presence of a population of dendritic and pleomorphic cells (D+P), corresponding to in situ melanoma; 25% exhibited a predominantly round-cell (RN) proliferation with histologic features of superficial melanoma, and 33.33% showed the presence of cells aggregated in nests (DN), typical of invasive melanoma. HIF-1α was scarcely detected in D+P and in RN melanomas, while it was highly expressed in DN tumors. By contrast, CD271 positive cells were mostly detected in D+P population, and barely observed in the other subtypes. This work demonstrates that CD271 expression inversely correlates with hypoxia in melanoma, and that the two markers may be used in the future as diagnostic/prognostic tools for this neoplasm.

Usefulness of in vivo photodiagnosis for the identification of tumor margins in recurrent basal cell carcinoma of the face.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequent malignant tumor of the skin. The high prevalence of BCC, the risk of local recurrence, and the difficult clinical identification of the excision margins emphasize the importance of studying new approaches, ensuring complete surgical excision that allows preservation of normal tissue, especially for BCCs located on cosmetically important areas such as the mid face. Photodiagnosis (PD) is a pre-operative technique that allows a more accurate distinction of neoplastic lesions from surrounding healthy skin in vivo. PURPOSE: The aim of this study is to assess the usefulness of PD for the evaluation of tumor margins in 10 patients with recurrent BCC of the face. METHODS: We study the red fluorescence emitted by neoplastic tissue under a Wood's lamp irradiation, after accumulation of methyl amino levulinate (MAL) cream in 10 patients with recurrent BCC. RESULTS: Our histologic analysis of perilesional skin by PD allowed to delineate more precise tumor margins, thus achieving radical excision in 90% of patients. CONCLUSION: PD represents a diagnostic method that helps to distinguish between tumor tissue and surrounding healthy tissue especially in case of recurrent BCC of the face when the clinical delimitation is not clear.

Adult-onset tufted angiomas associated with an arteriovenous malformation in a renal transplant recipient: case report and review of the literature.

Tufted angioma (TA) is a rare benign vascular neoplasm characterized histopathologically by the proliferation of endothelial cells arranged in lobules in the dermis and subcutaneous fat. To date, about 200 cases have been reported, most of which are of Japanese ethnicity. TA predominantly affects children and young adults, developing in 80% of patients younger than 10 years. A white 72-year-old renal transplant recipient presented with 2 asymptomatic dusky red papules on his right leg. The lesions appeared 5 years after the start of immunosuppressive treatment. Histopathologic examination showed a proliferation of poorly canalized capillary-sized vascular structures with typical "cannonball" pattern in the dermis and subcutaneous fat. Eccrine glands were also evident focally in the stroma of capillary lobules. On immunohistochemistry, endothelial cells in the vascular tufts stained positive for CD31 and CD34 but were negative for factor VIII-related antigen, human herpes virus 8, and podoplanin (clone D2-40); α-smooth muscle actin stained pericytes disposed in a single layer in capillary-sized vessels and in 2-3 or more layers in vessels of larger size, respectively. The microscopic findings were suggestive of TA. In the deep dermis, venules with smooth muscle wall and arterioles, as shown by Van Gieson staining, normally not found at that level, were present and appeared surrounded by capillary lobules. Onset of TA in adulthood is rare and may be associated with pregnancy, varicella zoster virus infection, and pharmacological immunosuppression. A case of acquired adult-onset TA associated with an arteriovenous malformation in an elderly transplanted patient is described.

Incomplete penetrance of GLMN gene c.395-1G>C mutation in a family with glomuvenous malformations.

Glomuvenous malformations (GVMs, OMIM 138000) are hamartomas presenting in childhood as multiple, bluish, soft papules and nodules that tend to grow slowly in size and number with age. They are caused by autosomal dominant mutations in glomulin (GLMN) gene; penetrance varies from 80% at 20 to about 100% at age 30 years. We report on the c.395-1G>C mutation of GLMN gene in two siblings showing variable penetrance.

Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting.

Glomuvenous malformations (OMIM 138000) are hamartomas presenting in childhood as multiple, bluish papules and nodules in the skin, which are characterized histopathologically by irregular vascular spaces surrounded by typical glomus cells. Glomuvenous malformations are caused by autosomal dominant mutations of the GLMN gene. A 34-year-old woman and her 16-year-old son presented with bluish papules and nodules since childhood. Biopsy specimens from both patients showed histopathologic features of glomuvenous malformations, unusually in consistent and close association with smooth muscle, hair follicles and eccrine glands. Sequencing of the GLMN gene revealed the p.C36X (c.108C>A) mutation in germline DNA from both patients. This is probably the first report describing the hamartomatous features of familial glomuvenous malformations consistently associated with a prominent smooth muscle component and eccrine glands.

Risk of acute postoperative hypertension after topical photodynamic therapy for non-melanoma skin cancer.

BACKGROUND: Topical photodynamic therapy with methyl aminolevulinate (MAL-PDT) is a non-surgical treatment for actinic keratoses, Bowen's disease and basal cell carcinoma. MAL-PDT is particularly useful in elderly patients, who often present co-morbidities and/or in whom surgical excision could be contraindicated. MAL-PDT is generally well tolerated; the most frequent acute adverse events include pain and burning sensation localized to the treatment area. We describe our observation of the occurrence of acute postoperative hypertension (APH) and hypertensive crisis, after a MAL-PDT. METHODS: BP measurement was taken twice at 2-min intervals, both before and shortly after the MAL-PDT session. APH was defined as an increase in systolic BP by more than 20% or an increase in diastolic BP to above 110 mmHg. Hypertensive crisis was defined as a systolic BP ≥ 180 mmHg or a diastolic BP ≥ 110 mmHg, with or without acute target organ involvement. RESULTS: Prevalence of post-MAL-PDT APH was 22%; 11% of patients developed hypertensive crisis after MAL-PDT, requiring immediate treatment. CONCLUSION: We highlight the importance of blood pressure measurement both before and after MAL-PDT session to identify high-risk patients and to prevent potentially severe organ involvement subsequent to hypertensive crisis.