[Metastasized occult melanomas?]. / "Okkulte" metastasierte Melanome?

CASE REPORTS: We present two patients who were referred to us from other hospitals for further therapy as metastasized occult melanoma patients with extensive stage III and stage IV disease, respectively. On thorough clinical examination, we found a slightly thickened nail plate on the right thumb with barely visible pigmentation and a tiny skin-colored tumor at the proximal nail fold of a 60-year-old man. In a 60-year-old woman, we saw an anatomically almost hidden small nonpigmented tumor on the labia majora close to the posterior commissure. The patients were histologically diagnosed with an ulcerated acrolentigineous melanoma and a nodular mucosal melanoma, respectively. CONCLUSION: With these two case reports we want to emphasize that although extensive radiographic and invasive diagnostic procedures to detect a primary in patients with suspected melanoma of unknown primary are no longer recommended by current guidelines, repeated and thorough clinical examinations can sometimes revise the diagnosis metastasized "occult" melanoma.

Perianal streptococcal dermatitis in adults: its association with pruritic anorectal diseases is mainly caused by group B Streptococci.

AIM: Although perianal streptococcal dermatitis (PSD) is well known in children, it has only rarely been documented in adults. The incidence and necessity for treatment may be underestimated. We have retrospectively identified adult patients with perianal streptococcal dermatitis. METHOD: Patients with streptococcal anal dermatitis were identified from a prospective office database. Treatment was with oral antibiotics according to the organism sensitivity. Additional concomitant anorectal disease was treated according to standard guidelines. Patients were compared with a control group, without eczema or erythema, for the presence of ß-haemolysing Streptococci on perianal swab. Demographic and microbiological data were assessed and compared between and within treatment and control groups. RESULTS: Fifty-three (22 female) patients older than 20 (mean = 49) years of age were diagnosed with perianal streptococcal dermatitis between 2005 and 2009. In most cases group B ß-haemolytic Streptococci were found. Fifty patients received antibiotics for 14 days. In 28 of 33 patients who had a post-treatment swab, the result was negative. Five patients showed Streptococci of different groups in the post-treatment swab. Of the 50 patients, 21 (42%) had no further anorectal complaint and 29 (58%) required continuing treatment for another anorectal condition. In the control group ß-haemolysing Streptococcus was found in 34%. Men over 60 years of age more often required no further anorectal treatment compared with women (P < 0.05). CONCLUSION: Perianal streptococcal dermatitis occurs in adult patients more often than reported. It is mainly caused by group B ß-haemolysing Streptococcus. Its diagnosis is important because it can cause serious systemic infections, especially in the elderly and in newborns. Antibiotics resolve the condition in a high proportion of patients.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

[Histamine intolerance mimics anorexia nervosa]. / Histaminintoleranz imitiert Anorexia nervosa.

Histamine intolerance is a clinically heterogeneous disease. We present a woman who suffered from weight loss, diarrhea, abdominal pain, headache, flushing and bronchial asthma for several years. When placed on a histamine-poor diet, she experienced weight gain and improvement of other all signs and symptoms, supporting the diagnosis of histamine intolerance. Therefore, this disease should be included in the differential diagnosis of anorexia nervosa.

Loss of heterozygosity for 10q22-10qter in malignant melanoma progression.

Karyotypic and molecular data indicate that genetic events involving the chromosome region 10q22-10qter may be related to tumorigenesis in malignant melanoma. To test this we analyzed 10 polymorphic microsatellite repeats in the region 10q22-qter, using a polymerase chain reaction-based assay for loss of heterozygosity and DNA isolated from normal and tumor tissue from 26 individuals with malignant melanoma. The samples included 19 paired normal and malignant tissues representing various stages of melanoma as well as 7 cases in which samples from at least 2 different points in time during tumor progression were available. Our findings indicate that loss of heterozygosity of 10q22-10qter is a frequent event, that the observed loss of heterozygosity does not result from whole chromosome loss, and that it is associated with tumor progression. Finally, the appearance of new alleles in two of the tumors may indicate the involvement of DNA replication errors in melanoma analogous to such events in other tumor types.

The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci.

Alteration of chromosome 10 is common in human melanomas and usually entails the loss of an entire chromosome homologue. Although the reasons for monosomy in cancer has remained obscure, one possibility is that multiple tumor suppressor genes residing on this chromosome must be lost in unison during tumor progression, and this is easier to accomplish by chromosome segregation rather than by multiple mutational and/or deletion events. The localization and identification of these genes has been hampered by the monosomy itself, which has resulted in a paucity of small defining deletions in tumors. Here, we have addressed the issue of monosomy in tumor development by using functional complementation mapping to localize and demonstrate the existence of different melanoma suppressor genes on chromosome 10 and assigned each locus a distinct tumorigenic phenotype. We report that a locus on 10q distal to 10q23.1, likely involving the PTEN tumor suppressor, causes a severe reduction in the kinetics of melanoma tumor formation in animals. In contrast, a previously unrecognized region at 10p15.3 has a distinct, but lesser, effect on in vivo melanoma growth. Thus, the loss of both of these regions, which is accomplished by tumor-associated monosomy, provides a significant growth advantage over the individual loss of either region, thereby explaining the monosomy observed in sporadic melanomas.

A defined region of loss of heterozygosity at 11q23 in cutaneous malignant melanoma.

Karyotypic and molecular data indicate that genetic alterations of the long arm of chromosome 11 (11q) may be involved in malignant melanoma. To test this we analyzed 5 polymorphic microsatellite repeats on 11q using a PCR-based assay for loss of heterozygosity in normal and tumor tissues from 24 individuals with cutaneous malignant melanoma of various stages. Our findings indicate that a tumor suppressor gene that plays a role in malignant melanoma is located on the long arm of chromosome 11, likely within a 51 cM region at 11q23. Its loss appears to be a late event in tumor progression and may serve as an indicator for a less favorable clinical outcome.

The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma.

Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expression cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1. The cDNA retrieved from morphologically transformed cells contained the full-length protein coding region and detected an abundant transcript in the same cells. Sequence analysis revealed identity with the wild-type sequence of p44S10, a highly conserved subunit of the 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 family of signaling molecules. p44S10 gene copy number and mRNA expression were increased in association with segmental 1.8 - 11-fold chromosomal gains in cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%), and in breast cancer MCF-7 cells. Likewise, malignant progression of human radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44S10, and increased expression of p44S10 was sufficient to induce proliferation of WM35 cells in vivo. The results demonstrate segmental copy number gains within chromosome 3p in cutaneous malignant melanoma and suggest that deregulation of a proteasome regulatory particle subunit may contribute to the malignant phenotype.

11q23 allelic loss is associated with regional lymph node metastasis in melanoma.

Genetic alterations of the long arm of chromosome 11 have been implicated in melanoma pathogenesis, and we recently identified two distinct regions of common allelic loss in chromosomal band 11q23. To establish the point in time of melanoma tumorigenesis at which these two putative tumor suppressor loci become relevant, we investigated allelic loss [loss of heterozygosity (LOH)] in both chromosomal regions in tumors of progressing patients. We analyzed 102 tumor samples from 23 patients for whom at least two (10 patients) or three (13 patients) tumor samples from different clinical progression steps (such as primary tumor and/or in-transit metastasis and/or regional lymph node metastasis and/or distant metastasis) were available. We detected no 11q23 LOH at any stage in 3 of 23 patients and detected LOH at all stages tested in 8 of 23 patients. In 8 of the remaining 12 (67%) patients with 11q23 LOH at some stage during tumor progression, we found this to occur first at regional lymph node metastasis. Two of these patients retained constitutional heterozygosity in several in-transit metastases that developed up to 7 months after lymph node metastases that already had loss. We therefore conclude that 11q23 LOH is associated with regional lymph node metastasis in melanoma. Finally, we detected an allele shift restricted to a histomorphologically distinct part of a primary melanoma and found that the same parental chromosome was affected by allelic loss in a subsequently occurring lymph node metastasis. These findings support our conclusion and give additional evidence for the hypothesis of molecular heterogeneity of early tumor cell populations in melanoma.

Patient with trisomy 6 mosaicism.

Trisomy 6 and trisomy 6 mosaicism were found in chorionic villi cell culture and short term incubation in a prenatal diagnosis at 12 weeks of gestation in a pregnancy with a growth retarded fetus showing nuchal translucency. The child was born in the 25th gestational week with a number of malformations including heart defects, deep-set ears, cleft right hand, cutaneous syndactylies, and overlapping toes of irregular shape and length. Trisomy 6 was not found in peripheral blood lymphocytes but was confirmed in umbilical cord fibroblasts. Currently, at the age of 2-3/4 years, the development of the child is relatively normal despite considerable growth delay. At the age of two years, she developed a papular erythema clinically suggestive of epidermal nevi. Cytogenetic analysis of fibroblast cultures derived from skin from a right hand finger and the inguinal area confirmed the presence of a trisomy 6 mosaicism. This is the first observation of a liveborn with trisomy 6 mosaicism.

Mutation and expression of TP53 in malignant melanomas.

Mutations of the TP53 gene are the most common genetic alterations in human malignancies. Overexpression of the p53 protein has been reported in high frequencies in all types of skin cancer. To determine the role of TP53 in the pathogenesis of malignant melanoma, we investigated the expression of p53 in 12 cell lines and 145 primary and metastatic lesions by immunohistochemistry. Overexpression of p53 was predominantly detected in the cytoplasm of the cells in 96 (66%) tumor and 12 (93%) cell lines. In contrast to findings in other tumor types, in melanomas immunoreactive cells were found in clusters or as scattered single cells. In primary melanomas, the frequency of p53 overexpression did not correlate with tumor thickness. Nucleotide sequencing of TP53 genes of 24 melanoma tumors/cell lines demonstrated point mutations in seven samples, all coding for mutant p53 protein species. The frequency of TP53 alterations of 20%-30% is lower than in other skin tumor types. Notably, immunohistochemistry was not a suitable method to distinguish overexpression of wild-type p53 from mutant species, since cell lines/tumors with TP53 mutations did not show distinctive staining patterns. The mutation pattern in six out of seven lesions was similar to that caused by ultraviolet light damage. This finding may be regarded a further indication for a pathogenetic role of UV light damage in at least a subgroup of malignant melanomas.

[Malignant melanoma of the skin. Pathogenesis, clinical aspects and prognosis]. / Das maligne Melanom der Haut. Pathogenese, Klinik und Prognose.

Cutaneous malignant melanoma is not among the most frequent cancer types at an incidence of 10-12/100,000 persons/year in Central Europe. However, the number of melanomas has doubled within the last 10-15 years. This increase is higher than that of most other malignancies. It has been attributed to an increased UV-light exposure, whereby the latency period probably reaches decades. Persons at high risk for melanoma were identified in various studies: those from families with other melanoma patients and those who have more than 50 benign nevi, atypical nevi and actinic freckles. The majority of melanomas develops de novo and not from preexisting nevi. Treatment of choice is complete surgical excision of the tumors. Prognosis of these patients is mainly determined by tumor thickness. Metastatic spread occurs most frequently within lymph vessels, local recurrences as well as regional metastases significantly impairing the prognosis. From long-term experience in Australia it is evident that the dilemma "melanoma" can only be addressed effectively by rigorous prophylaxis and early diagnosis of the tumors.

Contact dermatitis caused by allergy to ophthalmic drugs and contact lens solutions.

Although a common cause of allergic reactions, topically applied ophthalmic drugs and contact lens solutions are seldom verified as such. This review documents reported allergens and suggests an 'ophthalmic tray', based on the literature search, to simplify patch test verification. The criteria for literature selection were that each patient had a history of allergic reaction to local application of ophthalmic drugs or contact lens solutions, and tested positive to putative allergen patch tests. We established 38 chemicals causing allergic reactions. 5 authors published suggestions for patch test trays.

[SAPHO syndrome. Case description of 3 patients with acne conglobata and osteoarticular symptoms]. / Das SAPHO-Syndrom. Fallbeschreibung von drei Patienten mit Akne conglobata und osteoartikulären Symptomen.

We report three new cases of the SAPHO syndrome. This acronyme consists of synovitis, acne, pustulosis, hyperostosis and osteitis. Symptoms of this syndrome, which may not all be present, are pustulotic skin diseases (pustulosis palmoplantaris or severe acne) associated with osteoarticular lesions (mainly sternoclavicular hyperostosis, spondylarthropathies or chronic recurrent multifocal osteomyelitis). The dermatological aspects of this syndrome are discussed in detail.

Guttate psoriasis triggered by perianal streptococcal dermatitis in a four-year-old boy.

Perianal streptococcal dermatitis (PSD) is a superficial bacterial infection usually with group A beta-hemolytic streptococci. PSD is often misdiagnosed for long periods and patients are subjected to treatments for a variety of differential diagnoses without success. We report a 4-year-old boy with PSD who presented to our clinic with guttate psoriasis for 2 reasons: first, to make dermatologists aware of PSD and second, to emphasize the necessity to examine patients, particularly pediatric patients, with guttate psoriasis very thoroughly and swab both the pharynx and perianal and/or perigenital areas even when they are, or seem to be, asymptomatic for bacterial infections. Once PSD has been diagnosed, systemic antibiotic therapy with penicillin, erythromycin, roxithromycin, or azithromycin (probably augmented by topical mupirocin ointment) should be the treatment of choice. Therapy should be monitored by posttreatment perianal and throat swabs as well as a urine analysis to monitor for poststreptococcal glomerulonephritis.