Mind your head: two cases of mucosal metastasis of BRAF-mutated melanoma of the scalp.

Mucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after a malignant melanocytic mucosal lesion with a BRAF mutation was found, the primary cutaneous source was identified and clonality confirmed between the lesions. In both cases, primary lesions occurred on the scalp, an often-overlooked site. Both lesions showed signs of regression implying that in due time these lesions could have been fully regressed and might never have been detected. In that case, the metastatic mucosal lesion would erroneously be identified as a BRAF-mutated mucosal melanoma. These cases give warrant; a careful dermatological inspection should be instigated when confronted with a BRAF-mutated mucosal melanoma. We hypothesize that some BRAF-mutated mucosal melanomas might actually represent metastases of regressed cutaneous melanomas.

Expanding spectrum of "spitzoid" lesions: a small series of 4 cases with MAP2K1 mutations.

The molecular background of a significant proportion of spitzoid neoplasms is still unknown. Recently, activating mutations in MAP2K1 have been described in a few spitzoid lesions, but not in benign Spitz nevi. We report four cases of melanocytic tumors with spitzoid features in which a MAP2K1 mutation was detected. The lesions did not show a single distinct phenotype and ranged from benign to malignant. Two cases resembled desmoplastic Spitz nevi. Based on the combination of morphological, immunohistochemical, and molecular findings, one case was classified as benign, one as probably benign, possibly intermediate low-grade (MELTUMP-melanocytic tumor of unknown malignant potential), one case was classified as intermediate (MELTUMP), and one case was considered a superficial spreading melanoma with spitzoid features. Based on this, we conclude that MAP2K1 mutations can indicate a spitzoid genetic signature and can be found in both benign and malignant spitzoid neoplasms.

Is a single day patient friendly methyl aminolevulinate photodynamic therapy illumination scheme for superficial basal cell carcinoma feasible? A randomized multicenter pilot trial.

BACKGROUND: Topical methyl aminolevulinate photodynamic therapy (MAL-PDT) is highly effective for the treatment of superficial basal cell carcinoma (sBCC). Current European treatment protocol requires two hospital visits, which is costly and unpractical. The aim of this study was to evaluate the efficacy of fractionated MAL-PDT, using two light fractions at 3 and 4 h compared to illumination at 3 and 5 h after MAL-application. METHODS: Thirty patients were randomized into two groups. The first group received illumination at 3 and 4 h (20 + 55 J/cm2) after MAL-application (3/4 group). In the other group, two light fractions were performed at 3 and 5 h (20 + 55 J/cm2) after MAL-application (3/5 group). The lesion response was evaluated at 3 and 12 months posttreatment. RESULTS: In the 3/5 group, 70.0% showed a complete response (CR) at 3 months compared to 63.6% in the other group. At 12 months, 100% showed a CR in the 3/5 group compared to 80.0% in the other group. However, most failures/recurrences were eventually due to the presence of a more aggressive BCC subtype, mostly caused by sampling error of the primary punch biopsy. CONCLUSION: Single day protocol for MAL-PDT for sBCC is feasible and this study shows promising results.

Cutaneous hyperpigmentation induced by doxycycline: a case series.

Cutaneous hyperpigmentation is a well-known side effect of tetracyclines, but doxycycline-induced cutaneous hyperpigmentation has only been described in one patient with a therapeutic dosage of doxycycline, and in one patient using suprapharmacological doses. We describe four patients with cutaneous hyperpigmentation in previously unaffected skin, and speculate that this was due to treatment with doxycycline in therapeutic doses. After cessation of therapy, the hyperpigmentation diminished in all four patients, illustrating the need for recognition and timely cessation of therapy.

Prospective differentiation of clinically difficult to distinguish nodular basal cell carcinomas and intradermal nevi by non-invasive Reflectance Confocal Microscopy: a case series study.

BACKGROUND: Clinical differentiation between a nodular basal cell carcinoma (nBCC) and a benign intradermal nevus can be difficult. Even with additional dermoscopic evaluation, a correct diagnosis may be difficult. Currently, histopathological examination of a biopsy is the gold standard to differentiate between these lesions. However, this is an invasive technique and sampling errors can occur. In vivo Reflectance Confocal Microscopy (RCM) is a non-invasive technique to evaluate a skin lesion at a microscopic level. RCM features of nBCCs and intradermal nevi have been described in research setting. However, the use of RCM for prospective differentiation between difficult to diagnose nodules into nBCCs and intradermal nevi in clinical practice has not been demonstrated yet. OBJECTIVE: In this study, we aim to address a common clinical scenario; to differentiate clinically and dermoscopically difficult to distinguish nodules, into nBCCs and intradermal nevi by RCM. MATERIAL AND METHODS: Six patients with clinically and dermoscopically difficult to distinguish nodular skin lesions were evaluated by RCM to differentiate prospectively between nBCCs and intradermal nevi. In five out of six cases, a 3 mm punch biopsy was obtained to confirm the RCM diagnosis. RESULTS: Observed RCM features that allowed differentiation between nBCCs and intradermal nevi were the dermal-epidermal junction patterns, the appearance of the nests and the degree of vascularization. CONCLUSIONS: This case series study demonstrates the value of non-invasive in vivo RCM imaging in routine patient care, with respect to the prospective diagnosis of clinically difficult to distinguish nBCCs and intradermal nevi. Subsequently, biopsies of benign lesions in cosmetic areas could be avoided.

Limited role for histopathological examination of re-excision specimens of completely excised melanomas.

The Dutch melanoma guideline advises to examine one central block of the re-excision scar in case of a complete primary excision. To increase the evidence for this recommendation, we re-evaluated how often residual melanoma was found in re-excision specimens of a large series of completely excised melanomas. Of 1,209 Dutch melanoma cases, pathology reports of primary excisions were reviewed. Presence of melanoma in the margins was scored. All melanomas with a complete primary excision were included and pathology reports of re-excisions were reviewed. Presence of residual melanoma in the re-excision specimen and the number of blocks were scored. Slides of re-excision specimens containing residual melanoma were reviewed. Eventually, in four out of 812 melanomas (0.5 %) with a complete primary excision, residual melanoma was found in the re-excision specimen. The free margins of the primary melanomas in these cases ranged from 0.5-3.5 mm. In one case, the margin for melanoma in situ was 0.2 mm. In <1 % of initially completely excised melanomas, residual melanoma was found in the re-excision specimen. Histopathological examination of these re-excision specimens may not be cost-efficient. Our findings even imply that a re-excision could safely be omitted in selected cases of completely excised melanomas.

Impact of mitotic activity on the pathological substaging of pT1 cutaneous melanoma.

BACKGROUND: In the transition from the sixth to the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, mitotic activity was incorporated, while Clark level of invasion was abandoned. OBJECTIVES: To investigate the effect of this change on the pathological tumour (pT)1 substaging of primary cutaneous melanomas and the possible clinical implications. METHODS: Patients with pT1 melanomas, diagnosed in the period January 2003 to March 2011, were selected from a population-based cohort study on cutaneous melanoma in the eastern part of the Netherlands. The pT1 melanomas were systematically reviewed by an expert pathologist and classified according to both the sixth and the seventh editions of the AJCC staging system. The shift of melanomas between pT1 substages, classified according to the two staging systems, was determined. RESULTS: In total, 260 pT1 melanomas were included. Overall 28% (57/207) of all pT1a melanomas shifted to pT1b when classified according to the new seventh staging classification, because of the presence of mitoses. Some 32% (17/53) of all pT1b melanomas shifted to pT1a. The percentage of pT1b melanomas relative to all pT1 melanomas increased from 20% to 36%. CONCLUSIONS: The addition of mitotic activity to the pathological staging system, according to the seventh edition of the AJCC staging system, resulted in a considerable change in the classification of thin cutaneous melanomas. This shift has clear clinical implications, as it is advised in the Dutch guideline that patients with pT1b melanoma should be offered a sentinel lymph node biopsy.

Invasive extramammary Paget's disease and the risk for secondary tumours in Europe.

The aim of this study was to determine the incidence and survival of Extramammary Paget's disease (EMPD) and to describe the possible increased risk of tumours after EMPD. All invasive cases diagnosed between 1990 and 2002 were selected from the RARECARE database. Incidence was expressed in European standardized rates. Relative survival was calculated for the period 1995-1999, with a follow-up until 31st December 2003. Standardized incidence ratios of second primary tumours were calculated to reveal possible increased risk after EMPD. European age standardized Incidence of EMPD within Europe is 0.6 per 1000,000 person years. Five-year relative survival for invasive EMPD was 91.2% (95%CI; 83.5-95.4), 8.6 percent of the EMPD patients developed other malignancies. The highest increased risk of developing a second primary tumour was found in the first year of follow-up (SIR:2.0 95%CI; 1.3-2.9), living in the South European region (SIR:2.3 95%CI; 1.5-3.5) or being female (SIR:1.5 95%CI; 1.1-1.9). Female genital organs displayed greatest increased risk of developing a second primary tumour after EMPD (SIR:15,1 95%CI; 0.38-84.23). Due to the increased risk of a second primary tumour after EMPD a thorough search for other tumours during their follow-up is recommended.

Development of a non-invasive murine infection model for acute otitis media.

Otitis media (OM) is one of the most frequent diseases in childhood, and Streptococcus pneumoniae is among the main causative bacterial agents. Since current experimental models used to study the bacterial pathogenesis of OM have several limitations, such as the invasiveness of the experimental procedures, we developed a non-invasive murine OM model. In our model, adapted from a previously developed rat OM model, a pressure cabin is used in which a 40 kPa pressure increase is applied to translocate pneumococci from the nasopharyngeal cavity into both mouse middle ears. Wild-type pneumococci were found to persist in the middle ear cavity for 144 h after infection, with a maximum bacterial load at 96 h. Inflammation was confirmed at 96 and 144 h post-infection by IL-1beta and TNF-alpha cytokine analysis and histopathology. Subsequently, we investigated the contribution of two surface-associated pneumococcal proteins, the streptococcal lipoprotein rotamase A (SlrA) and the putative proteinase maturation protein A (PpmA), to experimental OM in our model. Pneumococci lacking the slrA gene, but not those lacking the ppmA gene, were significantly reduced in virulence in the OM model. Importantly, pneumococci lacking both genes were significantly more attenuated than the DeltaslrA single mutant. This additive effect suggests that SlrA and PpmA exert complementary functions during experimental OM. In conclusion, we have developed a highly reproducible and non-invasive murine infection model for pneumococcal OM using a pressure cabin, which is very suitable to study pneumococcal pathogenesis and virulence in vivo.

Palifermin-induced flexural hyperpigmentation: a clinical and histological study of five cases.

Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem-cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with palifermin. All patients showed ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin-induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.

Expert review remains important in the histopathological diagnosis of cutaneous melanocytic lesions.

AIMS: To assess the type of problems encountered in diagnosing melanocytic lesions and to evaluate the contribution of expert review. METHODS AND RESULTS: Data from 1887 lesions submitted for consultation to one of the expert pathologists of the Dutch Melanoma Working Group Pathology Panel between 1991 and 2004 were analysed. Referring pathologists can voluntarily submit lesions which are difficult to classify to the panel. Most cutaneous melanocytic lesions (n = 1217) were submitted with a presumed diagnosis by the referring pathologists. Relevant underdiagnoses of melanoma (in situ) and overdiagnoses of naevi were prevented in 12% (144/1217) and 15% (178/1217) of cases, respectively. Problematic melanocytic lesions were (i) spitzoid and dysplastic lesions, (ii) lesions with histological features that hampered the diagnosis such as regression, lymphocytic infiltrate, or a combination with other melanocytic lesions, and (iii) lesions with unusual clinical features, e.g. childhood melanoma. Remarkably, the features of the lesions that were submitted and the types of over- and under-diagnosis remained consistent from 1991 to 2004. CONCLUSIONS: A second opinion from an expert pathologist on problem-prone melanocytic lesions improves patient care, in our series in 27% of cases.

Epidemiology and treatment of extramammary Paget disease in the Netherlands.

AIM: To determine the incidence of EMPD and to describe its epidemiology, treatment, survival and the risk of developing other malignancies. METHOD: All cases of EMPD, diagnosed between 1989 and 2001, were selected from the Netherlands Cancer Registry. RESULTS: In total, 178 cases of invasive and 48 cases of in situ EMPD had been registered. The overall relative 5-year survival for invasive tumours was 72%. Most patients with invasive as well as in situ cancer underwent surgery. Other malignancies were found in 32% of patients with invasive EMPD and 35% of patients with in situ EMPD. Patients had an increased risk of developing a second primary cancer (standardized incidence ratio: 1.7; 95% confidence interval 1.2-2.4). The most frequent localizations of the other cancers were the colorectum, the prostate, the breast and the extragenital skin. CONCLUSIONS: For EMPD, which is a rare disease in the Netherlands, there are no clear diagnostic and treatment guidelines. The prognosis is fairly good. A thorough search for other tumours is recommended for these patients.