Effectiveness of a patient decision aid for patients with superficial basal cell carcinoma: A pre- and post-implementation study.

OBJECTIVE: This study evaluates whether using a patient decision aid (PDA) for patients with superficial basal-cell carcinoma (sBCC) results in a decreased decisional conflict level and increased knowledge. METHODS: In a prospective multicentre study, patient groups were included before and after implementation of a PDA. Decisional conflict levels were compared directly after making the treatment decision, measured once as the mean score on the decisional conflict scale (DCS). Higher scores correspond with higher conflict levels (0-100). Secondary outcomes were knowledge on treatment options, recognizing a BCC, and risk factors for developing a BCC measured on an adapted version of a validated knowledge questionnaire for melanoma patients, and patient satisfaction with the PDA. RESULTS: Data was available for 103 patients in the control-group and 109 in the PDA-group. The mean DCS score in the control-group was 22.78 (SD 14.76) compared to 22.34 (SD 14.54) in the PDA-group; the decrease was non-significant (p = 0.828). The average percentage correct answers on the knowledge questionnaire increased from 76.5% in the control-group to 80.5% in the PDA-group (p = 0.044). According to the majority of patients in the PDA-group (73.7%) the PDA had added value. CONCLUSION: Using the PDA had no significant effect on decisional conflict levels, but increased overall knowledge on relevant issues concerning sBCC. PRACTICE IMPLICATIONS: The PDA can be used as an informational tool by patients with sBCC.

Randomized Trial of Four Treatment Approaches for Actinic Keratosis.

BACKGROUND: Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred. METHODS: We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm2, were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed. RESULTS: A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented. CONCLUSIONS: At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov number, NCT02281682.).

New mutations and an updated database for the patched-1 (PTCH1) gene.

BACKGROUND: Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched-1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly. METHODS: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). We included 117 new PTCH1 variations, in addition to 331 previously published unique PTCH1 mutations. These new mutations were found in 141 patients who had a positive PTCH1 mutation analysis in either the VU University Medical Centre (VUMC) or Maastricht University Medical Centre (MUMC) between 1995 and 2015. RESULTS: The database contains 331 previously published unique PTCH1 mutations and 117 new PTCH1 variations. CONCLUSION: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). The database provides an open collection for both clinicians and researchers and is accessible online at http://www.lovd.nl/PTCH1.

Five-Year Results of a Randomized Controlled Trial Comparing Effectiveness of Photodynamic Therapy, Topical Imiquimod, and Topical 5-Fluorouracil in Patients with Superficial Basal Cell Carcinoma.

For the treatment of superficial basal cell carcinoma, a prospective, noninferiority, randomized controlled multicenter trial with 601 patients showed that 5% imiquimod cream was superior and 5-fluorouracil cream not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) at 1 and 3 years after treatment. No definite conclusion could be drawn regarding the superiority of imiquimod over 5-fluorouracil. We now present the 5-year follow-up results according to the intention-to-treat analysis. Five years after treatment, the probability of tumor-free survival was 62.7% for methyl aminolevulinate photodynamic therapy (95% confidence interval [CI] = 55.3-69.2), 80.5% for imiquimod (95% CI = 74.0-85.6), and 70.0% for 5-fluorouracil (95% CI = 62.9-76.0). The hazard ratio for treatment failure of imiquimod and 5-fluorouracil were 0.48 (95% CI = 0.32-0.71, P < 0.001) and 0.74 (95% CI = 0.53-1.05, P = 0.09), respectively, when compared with methyl aminolevulinate photodynamic therapy. Compared with 5-fluorouracil, imiquimod showed a hazard ratio of 0.65 (95% CI 0.43-0.98, P = 0.04). In conclusion, 5 years after treatment, the results of this trial show that 5% imiquimod cream is superior to both methyl aminolevulinate photodynamic therapy and 5-fluorouracil cream in terms of efficacy for superficial basal cell carcinoma. We therefore consider 5% imiquimod cream as the first choice for noninvasive treatment in most primary superficial basal cell carcinomas.

Aesthetic outcome and complications of simple interrupted versus running subcuticular sutures in facial surgery: A randomized controlled trial.

BACKGROUND: The suturing technique and its associated complications could affect cosmetic outcome after facial surgery. Literature on this topic is limited. OBJECTIVE: To compare the cosmetic results 12 months after treatment and complications associated with simple interrupted sutures (SIS) versus running subcuticular sutures (RSS) in facial surgery. METHODS: A randomized, controlled multicenter trial was performed. Adults receiving dermatologic surgery on the face were randomized to receive SIS or RSS for wound closure. The primary outcome was the overall opinion score on the Patient and Observer Scar Assessment Scale (POSAS) 12 months after surgery. Secondary outcomes were the complication rates and scores according to alternative methods for assessment of cosmetic outcome. The observer of cosmetic outcome was blinded to treatment assignment. RESULTS: 142 patients were randomized to receive SIS (n = 73) or RSS (n = 69). Twelve months after surgery, the median score of the overall opinion on the POSAS was 2.0 (range 1-8) according to the patients and 3.0 (range 1-8) according to the observer in both groups. In the RSS group, hyper- or hypoesthesia was reported more often. LIMITATIONS: The cosmetic result was assessed by 1 observer. CONCLUSION: SIS and RSS in facial surgery resulted in comparable cosmetic outcomes. RSS was more often associated with hyper- or hypoesthesia.

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease.

The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey-Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal-dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%-40% of DD patients and 12%-55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype-phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.

Three-Year Follow-Up Results of Photodynamic Therapy vs. Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, Randomized Controlled Trial.

A randomized controlled trial including 601 patients previously showed that the effectiveness of imiquimod and fluorouracil cream were not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) in patients with superficial basal cell carcinoma after 1 year of follow-up. We now present the 3-year follow-up results. The probability of tumor-free survival at 3 years post-treatment was 58.0% for MAL-PDT (95% confidence interval [CI] = 47.8-66.9), 79.7% for imiquimod (95% CI = 71.6-85.7), and 68.2% for fluorouracil (95% CI = 58.1-76.3). The hazard ratio for treatment failure comparing imiquimod with MAL-PDT was 0.50 (95% CI = 0.33-0.76, P = 0.001). Comparison of fluorouracil with MAL-PDT and fluorouracil with imiquimod showed hazard ratios of 0.73 (95% CI = 0.51-1.05, P = 0.092) and 0.68 (95% CI = 0.44-1.06, P = 0.091), respectively. Subgroup analysis showed a higher probability of treatment success for imiquimod versus MAL-PDT in all subgroups with the exception of elderly patients with superficial basal cell carcinoma on the lower extremities. In this subgroup, the risk difference in tumor-free survival was 57.6% in favor of MAL-PDT. In conclusion, according to results at 3 years post-treatment, imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of superficial basal cell carcinoma.

Correlation between histological findings on punch biopsy specimens and subsequent excision specimens in cutaneous squamous cell carcinoma.

Diagnosis and subsequent treatment of cutaneous squamous cell carcinoma are frequently based on punch biopsies. Regarding the current TNM classification and stage grouping for cutaneous squamous cell carcinoma, it is important to identify the high-risk features (infiltration depth > 4 mm, perineural and/or lymphovascular invasion and poor differentiation). This study investigates the agreement of histological high-risk features and TNM grouping stage on 3 mm punch biopsies and subsequent surgical excision in 105 patients diagnosed with cutaneous squamous cell carcinoma. On punch biopsy, infiltration depth > 4 mm is not identified in 83.3% (30/36), perineural invasion in 90.9% (10/11) and poor differentiation in 85.7% (6/7) of cases. The TNM stage was underestimated on punch biopsy in 15.4% (16/104). This study shows that on a 3 mm punch biopsy, high-risk features in cSCC can remain undetected and that the actual TNM stage is not identified in 1 out of 6 tumours.

Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: A randomised clinical trial with 10 year follow-up.

BACKGROUND: Basal cell carcinoma (BCC) is the most common form of cancer among Caucasians and its incidence continues to rise. Surgical excision (SE) is considered standard treatment, though randomised trials with long-term follow-up are rare. We now report the long-term results of a randomised trial comparing surgical excision with Mohs' micrographic surgery (MMS) for facial BCC. METHODS: 408 facial, high risk (diameter at least 1cm, H-zone location or aggressive histological subtype) primary BCCs (pBCCs) and 204 facial recurrent BCCs (rBCCs) were randomly allocated to treatment with either SE or MMS between 5th October 1999 and 27th February 2002. The primary outcome was recurrence of carcinoma. A modified intention to treat analysis was performed. FINDINGS: For primary BCC, the 10-year cumulative probabilities of recurrence were 4.4% after MMS and 12.2% after SE (Log-rank test χ(2) 2.704, p=0.100). For recurrent BCC, cumulative 10-year recurrence probabilities were 3.9% and 13.5% for MMS and SE, respectively (Log-rank χ(2) 5.166, p=0.023). A substantial proportion of recurrences occurred after more than 5years post-treatment: 56% for pBCC and 14% for rBCC. INTERPRETATION: Fewer recurrences occurred after treatment of high risk facial BCC with MMS compared to treatment with SE. The proportion of recurrences occurring more than 5years post-treatment was especially high for pBCC, stressing the need for long-term follow-up in patients with high risk facial pBCC.

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.

BACKGROUND: Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma. METHODS: In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845). FINDINGS: 601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting. INTERPRETATION: Topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients. FUNDING: Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations.

Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.

Differentiation between basal cell carcinoma and trichoepithelioma by immunohistochemical staining of the androgen receptor: an overview.

Clinical and histopathological differentiation between basal cell carcinoma (BCC) and trichoepithelioma (TE) is a frequent problem. Attempts have been made to identify immunohistochemical markers helpful in differentiating them. A correct diagnosis is important because the tumours are treated differently. Recent studies showed the absence of androgen receptor (AR) expression in benign hair follicle tumours like TE. This study examines whether AR immunostaining is a useful diagnostic test to differentiate between BCC and TE. We randomly selected 75 cases with histological diagnoses of either BCC (subtypes: superficial, nodular or infiltrative) or TE (subtypes: classic or desmoplastic) from the database of the pathology department of Maastricht University Medical Centre. The available haematoxylin & eosin (H&E) slides were reviewed by three independent investigators using predetermined characteristics. Fifty-six slides (38 BCC and 18 TE) with unequivocal histological characteristics of either tumour were used for immunohistochemistry with AR antibodies. Any nuclear expression within the tumour was considered positive. AR expression was present in 5/8 classic TE, 0/10 desmoplastic TE, 22/23 superficial or nodular BCC and in 10/15 infiltrative BCC. Immunohistochemical stain for AR is useful to differentiate between TE and BCC; particularly in desmoplastic TE versus infiltrative BCC (specificity and positive predictive value of 100%).

Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma.

BACKGROUND: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC. OBJECTIVE: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen. METHODS: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist. RESULTS: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy. LIMITATIONS: Intraobserver variation may have affected the results of this study. CONCLUSIONS: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications.

The R439C mutation in LMNA causes lamin oligomerization and susceptibility to oxidative stress.

Dunnigan-type familial partial lipodystrophy (FPLD) is a laminopathy characterized by an aberrant fat distribution and a metabolic syndrome for which oxidative stress has recently been suggested as one of the disease-causing mechanisms. In a family affected with FPLD, we identified a heterozygous missense mutation c.1315C>T in the LMNA gene leading to the p.R439C substitution. Cultured patient fibroblasts do not show any prelamin A accumulation and reveal honeycomb-like lamin A/C formations in a significant percentage of nuclei. The mutation affects a region in the C-terminal globular domain of lamins A and C, different from the FPLD-related hot spot. Here, the introduction of an extra cysteine allows for the formation of disulphide-mediated lamin A/C oligomers. This oligomerization affects the interaction properties of the C-terminal domain with DNA as shown by gel retardation assays and causes a DNA-interaction pattern that is distinct from the classical R482W FPLD mutant. Particularly, whereas the R482W mutation decreases the binding efficiency of the C-terminal domain to DNA, the R439C mutation increases it. Electron spin resonance spectroscopy studies show significantly higher levels of reactive oxygen species (ROS) upon induction of oxidative stress in R439C patient fibroblasts compared to healthy controls. This increased sensitivity to oxidative stress seems independent of the oligomerization and enhanced DNA binding typical for R439C, as both the R439C and R482W mutants show a similar and significant increase in ROS upon induction of oxidative stress by H2O2.

Eruption of lymphocyte recovery or autologous graft-versus-host disease?

Maculopapular exanthemas have a particular high incidence among patients treated with autologous hematopoietic stem cell transplantation (HSCT). In most cases, a viral or drug induced origin is easily identified. However, the transplantation itself may also induce similar skin changes. These exanthemas are known under various names, such as autologous graft-versus-host disease (GVHD), engraftment syndrome (ES) or eruption of lymphocyte recovery (ELR). Given the clinical and histopathological similarities of these disorders, it can prove difficult to establish a diagnosis. Here, we describe a patient who developed a maculopapular exanthema after autologous stem cell transplantation for multiple myeloma, diagnosed as autologous GVHD. We also briefly review the current knowledge of the pathogenesis of autologous GVHD, ES, and ELR. Based on these data we would like to suggest that the latter two do not reflect own disease entities but rather different presentations of autologous GVHD.