Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

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.

Topical Imiquimod in Primary Cutaneous Extramammary Paget's Disease: A Systematic Review.

Extramammary Paget's disease (EMPD) is subclinical in extent and multifocal in nature. There is no global consensus for treatment, so its management represents a challenge in clinical practice. Therefore, we conducted a systematic review through the main electronic databases to assess the effectiveness of topical imiquimod in cutaneous EMPD and to discuss its management. Finally, 24 studies involving a total of 233 EMPD patients treated with topical imiquimod were selected. The topical imiquimod response rate was 67%, and the complete response (CR) rate was 48%. Patients were treated with a three-four times a week regimen in most cases, ranging between 2 to 52 weeks. In addition, imiquimod was applied as an adjunctive treatment in 21 patients, achieving a CR rate of 71%. Consequently, imiquimod therapy could achieve a good response ratio as a first-line treatment, as adjuvant and neo-adjuvant therapy, and as a treatment for recurrent disease. The heterogeneity between studies and the lack of a control arm made it impossible to conduct a meta-analysis. To improve the quality of evidence on EMPD, multicenter studies are essential to collect a larger number of patients and, consequently, obtain high-quality evidence to standardize treatment. The Prospero registration number is CRD42023447443.

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.

Allergic contact versus irritant contact dermatitis in patients with hard-to-heal leg ulcer: clinical and diagnostic approach.

BACKGROUND: Dermatitis of surrounding skin may complicate hard-to-heal leg ulcers, delaying wound healing. The coexistence of hard-to-heal leg ulcers and irritant or allergic contact dermatitis may create difficulties for both diagnostic and therapeutic management. OBJECTIVE: The aim of our study was to evaluate the incidence of dermatitis occurring in the surrounding skin in a population affected by hard-to-heal leg ulcers during treatment, and to differentiate between allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) with the use of a patch test. Furthermore, we investigated which medications were most probably related to these conditions. METHOD: We conducted an observational study from 21 February to 21 July 2017, enlisting all patients affected by hard-to-heal leg ulcers who attended the Wound Care Service of the Dermatologic Department of ASST, Spedali Civili, Brescia, Italy. RESULTS: We enrolled 95 patients; 81 patients did not develop dermatitis, while 14 patients developed dermatitis of the surrounding skin. These patients underwent a patch test which gave a positive result in seven patients, permitting the diagnosis of ACD. CONCLUSION: Our study confirmed the incidence of dermatitis of the surrounding skin reported in the literature but reassessed the incidence of ACD as opposed to ICD.

Surgical procedures in melanoma: recommended deep and lateral margins, indications for sentinel lymph node biopsy, and complete lymph node dissection.

Surgery is the main treatment for cutaneous melanoma including the primary melanoma as well as lymph node metastases. The recommended margins have changed over time. Similarly, indications for sentinel lymph node biopsy and complete lymph node dissection are constantly evolving if knowledge on the biological behavior of melanomas increases. The current guidelines and the most relevant literature were reviewed to provide an update on the existing recommendations for surgical management of melanoma. Wide excision margins are evidenced-based but not for all situations. Melanoma in situ requires 0.5-1 cm with increasing evidence for 1 cm particularly those presenting on the head-and-neck in the setting of chronic sun damage. Invasive melanomas need 1-2 cm margins, 2 cm for tumors thicker than 2 mm and some large tumors with >1-2 mm thickness and with a lentiginous growth pattern. Lentigo maligna, subungual melanoma, and acral lentiginous melanoma require surgical techniques with complete circumferential peripheral margin assessment. Sentinel lymph node biopsy provides relevant information for melanoma staging. Therefore, it is consistently recommended for melanomas >1-4 mm and highly recommended for melanomas >4 mm, >0.8-1.0 mm or ≤0.8 mm with additional risk factors. Complete lymph node dissection has high morbidity and no impact on survival and is restricted to regional control for clinically detected metastasis. Although the trend is to reduce progressively the recommended surgical margins, further evidence is needed to clarify its role in patients' survival. Sentinel lymph node biopsy is important for establishing a prognosis especially upon considering adjuvant therapy; complete lymph node dissection is only relevant for regional disease control.

Nested graft for chronic ulcer in scar tissue after heroin extravasation in a drug addict.

INTRODUCTION: Nested graft is a surgical technique that allows to manage difficult-to-treat medical conditions such as chronic cutaneous ulcers, thanks to the high efficacy it has in reverting the fibroblasts senescence. Because of its peculiar regenerative property, nested graft is a surgical technique suitable also for the treatment of cutaneous ulcers developing on fibrotic scar tissue. CASE REPORT: We reported the case of a 45-year-old man, drug-addict, with a large ulcer on the back of the right forearm in the context of scar fibrotic tissue. This lesion resulted from a previous heroin extravasation treated with a dermo-epidermal skin graft, that was accidentally scratched away by mechanical trauma. After several therapeutic failures with topical medications, we decided to treat the ulcer performing a skin graft using the nested graft technique. No adverse events were reported by the patient during or after the surgery. At the clinical evaluation performed three years later the wound was completely healed. CONCLUSIONS: Nested graft represents a safe and easy-to-use technique that can be successfully used to treat ulcers on scar tissue, ensuring the achievement and the long-term maintenance of optimal resistance and aesthetic results.

Tattoo: Ancient art and current problems.

The popularity of tattoos in the today's society brings with it a significant increase of the incidence of associated cutaneous reactions. Among the several complications that may occur after a tattooing procedure, allergic and photo-allergic reactions, infections, and Koebner phenomenon are the most common ones observed. Most of these complications may be avoided by identifying, before tattooing, the presence of risk factors or comorbidities that may increase the risk of their onset.

Correlation between chronic skin ulcers dimension and burden of suffering evaluated with PRISM test.

BACKGROUND: In the practice of dermatology, many tools are available to help the physician measure the patient's quality of life. The Pictorial Representation of Illness and Self Measure (PRISM) is a novel and simple method to measure personal suffering. The aim of our study was to evaluate, using PRISM, whether the reduction of the ulcers' size positively correlated with an improvement of the patients' suffering. METHODS: This was a multicenter national prospective study. 143 patients from five dermatological centers were enrolled in the study. At times T0 and T1 (after 1 month), the size of the ulcers was collected for each patient. At the same time, the PRISM test was also administered, in order to calculate the Self-Illness-Separation (SIS). RESULTS: First, a substantial decrement of the size of the ulcer seemed to correlate with a significant difference between the SIS score obtained at T0 and T1. On the contrary, the duration of the wound did not seem to influence the SIS value. No relationship between the age of the patient and the SIS value was found either. CONCLUSIONS: Our study showed that the decrease in the wound dimension positively affects the patient's suffering. In fact, ulcer's size reduction is correlated with an improvement in the patient's disease perception.

Prognostic Role of Non-Identification of Sentinel Lymph Node in Cutaneous Melanoma Patients: An Observational Retrospective Study.

Background: Sentinel lymph node (SLN) status is recognized as the most important prognostic factor for patients with cutaneous melanoma. However, sometimes it is not possible to identify SLN. The phenomenon of non-identification of SLN and its prognostic role have not been thoroughly evaluated in melanoma literature. The objective of this study was to identify which patient or tumor variables may be associated to non-identification of SLN and to evaluate the prognostic role of non-identification of SLN. Methods: Observational retrospective study of 834 cutaneous melanoma patients who underwent SLN biopsy at Instituto Valenciano de Oncología. Results: Forty-two patients (5%) presented non-identification of SLN. Patients with age at diagnosis of ≥ 64 years, obesity (BMI ≥ 30), and head and neck localization were at higher risk of non-identification of SLN. Non-identified SLN patients had worse nodal disease-free survival with respect to negative SLN patients, but not worse melanoma-specific survival. Conclusions: Our findings suggest a need to follow-up patients with non-identified SLN in the same way as patients with positive SLN.

Locoregional Lymph Node Recurrence of Trunk Melanoma in Non-sentinel Lymph Node Basins: An Observational Retrospective Study.

Locoregional lymph node recurrences of primary trunk melanoma can occur in basins not identified during sentinel lymph node biopsy. However, the factors associated with recurrences in non-sentinel lymph node basins are unknown. To evaluate these factors, this observational retrospective study examined the patterns of first lymph node recurrence and the factors associated with recurrence in non-sentinel lymph node basins. A total of 305 patients with primary trunk melanoma who had undergone sentinel lymph node biopsy from 2000 to 2015 were evaluated. Twenty-three patients presented locoregional lymph node recurrence; 8 of which (34.8%) were in non-sentinel lymph node basins. Non-sentinel lymph node recurrences were more frequent in patients with positive sentinel lymph nodes and in those patients whose number of tumour-involved nodes was > 3. These results suggest that clinical examination and ultrasound surveillance should be performed on all potential lymph node drainage basins of trunk melanomas.

Intralesional Methotrexate for the Treatment of Advanced Keratinocytic Tumors: A Multi-Center Retrospective Study.

INTRODUCTION: Keratinocyte tumors (KT) are frequently observed. Surgery is the treatment gold standard. In some cases, a surgical approach might not be the best option. Radiotherapy (RT) and systemic treatments can frequently cause side effects or be contraindicated. Intralesional methotrexate (MTX) can be a conservative yet effective alternative. We decided to evaluate the effectiveness and safety of intralesional chemotherapy with MTX for the treatment of squamous cell carcinoma (SCC), keratoacanthoma (KA), and basal cell carcinoma (BCC). METHODS: All patients had a histologically confirmed diagnosis of BCC, SCC, or KA and no indication to surgery or RT. MTX was injected subcutaneously proceeding from the periphery of the lesion toward the center. Different protocols in terms of dose, frequency, and length of treatment were used to compare them. Treatment efficacy was evaluated in terms of tumor size reduction. Patients were divided into three groups: responders (improvement of more than 50%), partial responders (< 50%), and non-responders (no improvement or worsening). All data were analyzed using the chi-squared test (χ2). RESULTS: Thirty-five patients were included. Twenty-one patients suffered from SCC, 12 from KA, and 2 from BCC. KA showed a higher response rate than SCC and BCC. For AK, 92% of patients had a complete resolution; 8% were partial responders. For SCC, 47.6% of cases were responders and 14.3% partial responders, while 38% non-responders. All BCCs showed no improvement. A treatment protocol of weekly injections, performed for 4 to 6 weeks, was the most efficient. Doses of 25 mg/ml per session seemed to be most effective. About one third of our patients developed side effects with mild anemia being the most frequent. CONCLUSIONS: For selected cases, intralesional MTX can be a safe and effective option for the treatment of KT, especially in case of KA and, to a lesser extent, SCC.

Pediatric dermatologic surgery: our experience.

BACKGROUND: Surgical treatment for pediatric skin disorders is used for diagnostic and therapeutic reasons. We underline these procedures are usually easy and uncomplicated without the need for general anesthesia. Objective of this study was to share our experience in the field of pediatric dermatologic surgery. METHODS: We retrospectively analysed records of all pediatric patients receiving surgical therapy at the Dermatology Department of Spedali Civili of Brescia. Demographic data and treatments characteristics were recorded and analyzed. RESULTS: During the study period of one year, 670 surgical treatments concerning pediatric patients were collected. Number of procedures progressively grows with increasing age. All treatments were performed under local anesthesia except for a dermatofibrosarcoma protuberans for which general anesthesia was needed. CONCLUSIONS: Our data show that cryosurgery, electrodessication and excisional surgery constitute with equal proportion almost the whole of surgical procedures in dermatologic pediatric patients. Dermatologist's habit to perform surgery in local anesthesia avoids the risk of overtreatments, limits discomfort, anxiety, and pain perception linked to procedures performed.

Incontinentia Pigmenti Associated with Aplasia Cutis Congenita in a Newborn Male with Klinefelter Syndrome: Is the Severity of Neurological Involvement Linked to Skin Manifestations?

We report a rare case of a newborn male affected by incontinentia pigmenti, Klinefelter syndrome, and aplasia cutis congenita, who developed severe cutaneous, neurological, and ophthalmological manifestations. Genetic analysis showed the presence of the common mutation of NEMO (exon 4-10 deletion), Klinefelter syndrome karyotype (47 XXY), and random X inactivation. This is in accordance with the severity of involvement of the affected tissues (skin, central nervous system, and retina). Indeed, the patient developed typical skin lesions all over the body, except the head. Equally, multiple lesions diffusely involving both the cortical grey matter and subcortical white matter of the cerebellum and cerebral hemispheres were observed. Discussing current knowledge about the etiopathogenesis of skin and brain lesions in incontinentia pigmenti, our case seems to support the proapoptotic origin of central nervous system involvement. Possibly, incontinentia pigmenti patients suffer an impaired protection against apoptosis at the level of cerebral endothelial cells of small vessels, leading to vascular damage and subsequent ischemic brain lesions.

Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by painful, necrotic ulcerations. PG is described as a rare disease: the world-wide incidence is estimated to be around 3 to 10 cases per million population per year. These estimations are based mostly on case reports and retrospective case series; there are no prospective, multicentre studies on the matter. The apparent rarity of PG is in contrast with our clinical perception as dermatologists: in our opinion, PG is not so uncommon. Therefore, we decide to investigate the epidemiology of PG in the Italian population and confirm our clinical suspicions that it is not an orphan disease. We enrolled all patients diagnosed with PG in 8 Italian Dermatological Departments from 1st October 2014 to 1st November 2015, and we recorded their features. Our data, collected from 64 patients, are in accordance with those of the published literature regarding the epidemiology and features of PG. In an Italian population of roughly 8 million inhabitants of 7 provinces, we found an incidence of 5.17 new cases per million population per year. Unlike our predictions before the study, we confirmed the world-wide incidence of PG. To our knowledge, this is the first observational, multicentre study on PG. We hope that it provides a stimulus for further researches on PG and for the creation of an Italian register.