[Metastatic malignant melanoma. Successfull treatment with ipilimumab]. / Metastasiertes malignes Melanom. Erfolgreiche Behandlung mit Ipilimumab.

A 73-year-old man, in whom 26 years ago a malignant melanoma with cervical lymph node metastases of the right retroauricular region was diagnosed, developed BRAF V600E-negative distant metastases, which progressed during both monochemotherapy and polychemotherapy. Therefore he was started on ipilimumab in a dose of 3 mg/kg body weight four times in intervals of 3 weeks. Subsequently, there was an almost complete regression of distant metastases. In several phase III trials a significant survival benefit has been identified for patients treated with ipilimumab. The human monoclonal antibody has been approved since July 2011 as a second-line treatment in Germany and was incorporated in January 2013 into the new guidelines for the treatment of malignant melanoma. The CTLA-4 antibody is the first drug that can improve significantly survival in patients with metastatic melanoma. In advanced (unresectable or metastatic) melanoma, immunostimulatory treatment with ipilimumab represents a new therapeutic option.

[Epithelioid sarcoma of the right hand]. / Epitheloidzelliges Sarkom der rechten Hand.

A 35-year-old man presented with swelling, indurations and nodules on the thumb, wrist and fingers of the right hand. History revealed that the findings were slowly progressive and had been present for at least eight years. Histopathologic analysis of a nodule showed a diffuse infiltrate with atypical spindle-shaped cells and expression of cytokeratin, epithelial membrane antigen (EMA) and CD34; the diagnosis of epithelioid sarcoma (ES) was made. Because of diffuse extension of the tumor, forearm amputation was performed along with axillary dissection and local radiotherapy because of axillary lymph node metastases. ES is a rare subtype of soft tissue sarcoma with a harmless appearance and indolent course over years. ES represents a diagnostic challenge, with consequent delay in diagnosis and adequate treatment. The most important measure in the treatment of ES is early surgical excision with adjuvant radiotherapy if local metastases are present.

Sunitinib induced pyoderma gangrenosum-like ulcerations.

Pyoderma gangrenosum is a non-infectious neutro?philic skin disease commonly associated with underlying systemic diseases. Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture. Here, we report the case of a 69-year old man with progredient pyoderma gangrenosum-like ulcerations under treatment with sunitinib due to hepatocellular carcinoma. A conventional ulcer therapy did not lead to a regression of the lesions. Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations. Sunitinib is a multikinase inhibitor that targets the PDGF-α- and ?ß-, VEGF-1-3-, KIT-, FLT3-, CSF-1- and RET-receptor, thereby impairing tumour proliferation, pathological angiogenesis and metastasation. Here, we demonstrate that pyoderma gangrenosum-like ulcers may represent a serious side effect of sunitinib-based anti-cancer treatment.

[Linear localized scleroderma. Successful treatment with prednisolone pulse therapy and methotrexate]. / Lineare zirkumskripte Sklerodermie. Erfolgreiche Behandlung mit einer Prednisolon-Pulstherapie plus Methotrexat.

Linear localized scleroderma is a variant of localized scleroderma characterized by linear bands and sclerotic plaques of the skin, which can result in contractures, muscle atrophy and debilitating deformities. The etiology remains unknown and no specific therapy is available. Regimens combining pulsed high-dose corticosteroids with methotrexate therapy seem promising. Our patient responded well to intravenous prednisolone (500 mg/d) for 3 consecutive days monthly combined with an oral dose of methotrexate of (15 mg/wk).

[Langerhans cell histiocytosis. Solitary facial lesion]. / Langerhans-Zell-Histiozytose. Isolierte kutane Manifestation im Bereich des Gesichtes.

Langerhans cell histiocytosis is the general term for all clinical entities characterized by a proliferation of dendritic cells that are phenotypically identical to the Langerhans cells of the skin. As dendritic cells are present in nearly every tissue of the body, Langerhans cell histiocytosis shows a broad spectrum of clinical manifestations, mostly in the bone (approximately 80%) and skin (approximately 60%). Langerhans cell histiocytosis is basically a disease of the childhood and early youth, but can rarely occur in the elderly. Here, we report on a 70-year-old man presenting with a single facial lesion of Langerhans cell histiocytosis and summarize the most important clinical aspects as well as current therapeutic concepts.

[Accumulation of tattoo pigment in sentinel lymph nodes]. / Akkumulation von Tatoo-Pigment im Sentinellymphknoten.

A 22-year-old woman presented with a superficial spreading melanoma on her right thigh (tumor thickness 1.0 mm, Clark-Level III). She also had decorative tattoos on her right ankle, right groin and coccyx. The staging results gave no indication for metastases. Intra-operatively, we observed a black pigmented lymph node highly suspicious for metastatic disease, but histological examination excluded metastatic spread and detected the accumulation of black pigment within the lymph node. Clinical differentiation between tattoo pigments and metastatic disease within lymph nodes is not possible. Histological confirmation of an enlarged pigmented lymph node is therefore essential before radical surgery is performed. Hence, accumulation of tattoo pigment within enlarged and pigmented lymph nodes needs to be included into the differential diagnosis and the documentation of decorative tattoos is important during skin cancer screening as well as during the follow-up of melanoma patients.

[Subungual squamous cell carcinoma. An important differential diagnosis of subungual tumors]. / Subunguales Plattenepithelkarzinom. Eine wichtige Differenzialdiagnose subungualer Tumore.

A 63-year-old patient presented with a 12-month history of a subungual tumor on the right middle finger. The patient had had a similar lesion involving his left index finger 5 years ago, which was identified as a subungual squamous cell carcinoma. Ablation of the nail plate, the nailbed and the matrix was performed. Histopathology confirmed another subungual squamous cell carcinoma. The patient received a full thickness skin graft. Subungual squamous cell carcinomas are among the most frequently reported types of subungual malignancies. However, subungual squamous cell carcinomas arising in more than one digit have been reported only rarely. The cause of subungual squamous cell carcinoma has not been clearly identified, they has been associated with radiation, chronic infection, arsenic ingestion, HPV infection and trauma.

[Giant condyloma of the penis with malignant transformation associated with lichen sclerosus et atrophicus]. / Riesenkondylom des Penis mit maligner Transformation bei vorbestehendem Lichen sclerosus et atrophicus.

A 72-year old patient presented with a 6 months history of a rapidly growing tumor of the glans and foreskin. He had a long history of phimosis with lichen sclerosus et atrophicus-like lesions on the foreskin which had not been treated. The rest of the personal, family and sexual history was unremarkable. Treatment consists of circumcision and tumor excision. Histopathology confirmed a squamous cell carcinoma within a giant condyloma with a concomitant lichen sclerosus et atrophicus. CT- and ultrasound scans showed no metastases. Giant condylomas are a rare sexually transmitted disease usually caused by human papilloma virus subtypes 6, 11, but also by 16 and 18 among others. They are expansive, cauliflower-like destructive lesions that most frequently affect the anogenital region. In about 30 percent a giant condyloma progresses into a squamous cell carcinoma. Therapy of choice is the histopathologically controlled excision. Recurrences are often seen, so the patients should be monitored frequently after therapy.

[Cutaneous side effects of hydroxyurea treatment for polycythemia vera]. / Kutane Nebenwirkungen einer Hydroxyurea-Therapie bei Polycythaemia vera.

A 68-year-old women with polycythemia vera was treated with hydroxyurea for 8 years and developed painful ulcers on her lower legs, multiple hypertrophic actinic keratoses and a squamous cell carcinoma. After discontinuing hydroxyurea therapy the leg ulcers resolved within 8 weeks. The hypertrophic actinic keratoses and squamous cell carcinoma were treated with cryotherapy and excision, respectively. Hydroxyurea induces a variety of cutaneous side effects such as painful leg ulcers and squamous cell carcinomas. Given the wide variety of adverse cutaneous side effects associated with long-term hydroxyurea therapy, the first step in management is to insure that physicians and patients are aware of the specific risks of this treatment. Patients under hydroxyurea therapy should be monitored closely by dermatologists to early detect and treat the cutaneous side effects.

[Shulman's syndrome (eosinophilic fasciitis)]. / Shulman-Syndrom (eosinophile Fasziitis).

Eosinophilic fasciitis is a rare disease characterized by edema, painful indurations, and progressive muscle weakness. Mainly the extremities are involved. We report on a 22-year-old woman with eosinophilic fasciitis presenting with progressive muscle weakness of both hands and feet and a reduced general condition. She showed symmetrical and firm swelling of the extremities with painful restriction of joint movement. Systemic treatment with glucocorticosteroids as well as physiotherapy and manual lymphatic drainage led to continuous improvement of her symptoms. The differentiation from other diseases, such as systemic scleroderma, eosinophilia-myalgia syndrome, and pseudoscleroderma, might be difficult at the beginning of the disease. The gold standard for diagnosis is--as was done in our case--a deep skin-to-muscle biopsy. Further imaging, especially magnetic resonance imaging, can support the diagnostic procedure.

[Tuberculosis cutis colliquativa. Even today an important differential diagnosis]. / Tuberculosis cutis colliquativa. Auch heute eine wichtige Differenzialdiagnose.

An 82-year-old woman presented with perforating abscesses in the cervical and axillary region over 7 months. Histopathological and extensive microbiological examinations lead to the diagnosis of tuberculosis cutis colliquativa, a form of postprimary cutaneous tuberculosis. Tuberculosis cutis colliquativa can be caused by either contiguous spread from an underlying structure, direct inoculation or hematogenous dissemination. Morphologically it is characterized by a subcutaneous node forming an abscess with secondary perforation of overlying skin. The parotid, submandibular, and supraclavicular regions are the sites most likely to be affected. Today it still remains an important differential diagnosis for an abscess with fistulas. Correlation with histopathologic findings and microbiological examinations including polymerase chain reaction and mycobacterial culture being the most reliable method is required. Standard therapy regimens consist of 2 months of quadruple therapy followed by another 4 months of a continuation phase using a two-drug regimen.

[Merkel cell carcinoma. Viral genesis and new therapeutic options?]. / Merkel-Zell-Karzinom. Virale Genese und neue Therapieoptionen?

Merkel cell carcinoma (cutaneous neuroendocrine carcinoma) is a rare, highly malignant, neuroendocrine tumor of the skin with predominance in older patients. The tumor is most often located in the sun-exposed skin of the head, the neck and -as in our patient - the extremities. Notably, the tumor bears a high risk of an early regional lymph node as well as distant metastases. Clinically, only a presumptive diagnosis of Merkel cell carcinoma can be established. The definite diagnosis is made by histological and immunohistological methods. Surgical excision with a safety margin should be combined with sentinel lymph node biopsy. In advanced tumor stages (lymph node or visceral metastasis), a remission can be achieved by different chemotherapy schedules in combination with radiation. Recently, a previously unknown polyomavirus, named Merkel cell polyomavirus (MCV or MCPyV), has been identified in 80% of Merkel cell carcinomas. In the near future, these novel findings could be utilized to distinguish Merkel cell carcinoma from small round cell cancers and could lead to the development of new therapeutic options.

Late adverse effects after soft X-ray therapy of cutaneous malignancies: pruritus, burning, epiphora and insufficient occlusion of the mouth.

BACKGROUND: Pruritus, burning, epiphora and insufficient occlusion of the mouth have been less extensively studied than cosmetic changes in irradiated fields. OBJECTIVES: How frequent are these late adverse effects? Do they usually occur permanently? Are they influenced by treatment and tumour parameters, sex and age of the patients? METHODS: Patients were interviewed at least once later than 90 days after soft X-ray therapy. RESULTS: Pruritus has been reported in 18.5% of the interviews, burning in 7.7%, epiphora in 36.2% and insufficient occlusion of the mouth in 11.5%. Patients were usually not permanently troubled and irritated by these symptoms: pruritus more than once per week was reported in every interview for 0.6% of the fields, burning for 0.2%, epiphora for 6.4% and insufficient occlusion for 0%. Irritation by these symptoms has been stated in every interview for 5.1% of fields around the eye and for 1.4% of fields at other sites. Late pruritus, burning and epiphora were less frequently reported after irradiation with lower total doses, lower time-dose-fractionation factor (TDF) and by men. Patients older than 70 years of age experienced pruritus and burning less frequently. The largest diameter of the irradiated field influenced pruritus and the half value depth of the X-rays influenced burning and epiphora. CONCLUSIONS: Late pruritus, burning, epiphora and insufficient occlusion of the mouth do not considerably reduce the value of soft X-ray therapy because these adverse effects usually are not experienced permanently. Total dose and TDF should not be chosen higher than necessary.

[Treatment of carcinoma in situ of erythema ab igne with photodynamic therapy]. / Behandlung eines Carcinoma in situ bei Erythema ab igne mittels photodynamischer Therapie.

Erythema ab igne (EAI) occurs at skin locations that have been repeatedly exposed to heat or infrared radiation, a single dose of which results in erythema but the intensity of which does not suffice to cause a burn. The clinical picture of EAI is characterized by reticulate erythema, desquamation, and teleangiectasias. Complications of EAI include increasing cutaneous atrophy and predisposition to malignant tumors. The paramount goal of therapy is to eliminate the cause. Individual case reports of EAI with established epithelial dysplasia in the sense of carcinoma in situ have described good response of the neoplastic alterations to topical application of 5-fluorouracil or imiquimod. In our case we achieved successful results with photodynamic therapy.

Differential accumulation of iodine-123-iodobenzamide in melanotic and amelanotic melanoma metastases in vivo.

UNLABELLED: Iodine-123-iodobenzamide (IBZM) is a specific antagonist of dopamine D2 receptors and usually is used to study neuropsychiatric disorders. It also has a substantial affinity for malignant melanomas. This has been attributed to specific dopamine D2 receptor binding on melanoma cells because melanocytes and dopaminergic neurons share the same ectodermal origin and are both able to produce melanin. However, IBZM binding to melanoma metastases occurs predominantly 24 hr after injection, which is much later than maximal specific D2 receptor binding is expected. Furthermore, IBZM binding is not consistent in melanoma patients. This points to another mechanism of IBZM binding to melanoma cells. The aim of this study was to characterize IBZM-binding metastatic melanoma patients clinically and histologically to shed light on the nature of this mechanism. METHODS: Twenty-one patients with proven or suspected metastases of a malignant melanoma entered this prospective study after surgical removal of the primary tumor. Whole-body scans, planar scintigrams and SPECT scans were performed 2-5 hr and 1 day after intravenous injection of 185 MBq IBZM. RESULTS: The suspected diagnosis of metastatic cancer was later confirmed in 17 patients by histology, clinical follow-up, x-ray, CT or other radiologic methods. Four patients were free of tumor tissue at the time of investigation and remained stable for 2 yr thereafter. Twelve of the 17 patients had a melanotic and 5 had an amelanotic subtype of the tumor. Iodine-123-IBZM accumulation occurred in the metastases of 10 of the 12 patients with melanotic melanoma and in 0 of the 5 patients with the amelanotic tumor type (p < 0.01; chi-square test). Furthermore, IBZM accumulation occurred in 0 of the 11 amelanotic metastases but in 20 of the 25 melanotic metastases (p < 0.001). The sensitivity is, thus, 83% for the detection of melanotic melanoma metastases on a patient basis and 80% on a lesion basis. Iodine-123-IBZM scintigraphy demonstrated one previously unknown metastasis. Six initially suspected lesions were not due to melanoma metastases and were IBZM-negative. No false-positive IBZM accumulations occurred in our patients. CONCLUSION: Iodine-123-IBZM binds to melanotic malignant melanomas with high specificity and moderate sensitivity but not to amelanotic melanomas. Our data suggest that the tracer does not bind to membrane dopamine receptors of the tumor but is built in or closely bound to intracellular melanin.

Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas.

Malignant melanomas frequently show loss of alleles on the long arm of chromosome 10. The PTEN (MMAC1) gene has been identified as a tumour suppressor gene at 10q23.3 that is mutated in various types of advanced human cancers. We have investigated a series of 40 sporadic melanomas from 37 patients (15 primary cutaneous melanomas and 25 melanoma metastases) for allelic losses on chromosome 10, as well as for deletion and mutation of the PTEN gene. Microsatellite analysis revealed loss of heterozygosity at loci located on 10q in tumours from 15 of 34 patients investigated (44%). Somatic PTEN mutations were identified in melanomas from 4 of 37 patients (11%), all of whom had metastatic disease. In two of these patients, the tumours had additionally lost one PTEN allele, indicating complete loss of wild-type PTEN in the tumour cells. Our findings corroborate that loss of heterozygosity on chromosome 10 is a frequent aberration in malignant melanomas and implicate PTEN as a tumour suppressor gene inactivated by somatic mutation in a fraction of these tumours.

Ex vivo application of delta-aminolevulinic acid induces high and specific porphyrin levels in human skin tumors: possible basis for selective photodynamic therapy.

In photodynamic therapy with topically applied delta-aminolevulinic acid porphyrins are acting as photosensitizers. The profile of porphyrin metabolites in normal or in neoplastic skin after administration of delta-aminolevulinic acid has not been determined in detail yet. Thus, to study porphyrin biosynthesis in human skin an organ culture model was developed. Explant pieces of normal skin, keratoacanthoma, and basal cell carcinoma were incubated with 1 mM delta-aminolevulinic acid for 36 h. Levels of delta-aminolevulinic acid, porphyrins and porphyrin metabolites were measured in tissues and supernatants. After incubation with delta-aminolevulinic acid, higher porphyrin levels were demonstrated in tumors as compared to normal skin. In supernatants, most of formed porphyrins, preferentially highly carboxylated porphyrin metabolites, were measured. The pattern of synthesized porphyrins differed between normal and neoplastic skin explants. In tissues of basal cell carcinomas protoporphyrin was preferentially shown and tissues of keratoacanthomas were characterized by a predominance of coproporphyrin as compared to normal skin. The results show that explant cultures offer an easy approach to examine the porphyrin biosynthesis of various tissues. The tumor-specific delta-aminolevulinic acid metabolism indicates additional porphyrin metabolites such as coproporphyrin apart from protoporphyrin as effective photosensitizers and may offer a novel approach to tumor-selective photodynamic damage.

Plantar malignant melanoma -- a challenge for early recognition.

The incidence of malignant melanoma has been continuously increasing over the last few decades. Non-plantar melanomas are nowadays usually diagnosed and treated surgically at an early stage. In contrast, melanoma in a plantar location is usually diagnosed at an advanced tumour stage, conferring a poor prognosis. To discover the reasons for this remarkable difference in recognition and prognosis, we analysed our cases of plantar malignant melanoma in a retrospective study. From 1990 to 1997, we treated 925 melanoma patients. Of these, 68 cases (7%) were classified as plantar melanoma. For non-plantar melanoma patients the mean age was 52.6 years, the mean Clark level was 2.8 and the mean tumour depth was 1.22 mm. In contrast, the mean age of patients with plantar melanoma was 63.3 years, the mean Clark level was 3.61 and the mean tumour depth was 2.55 mm. The mean time between the first observation of the plantar skin lesion and the first consultation with a physician (patients' delay) was 4.8 years and, on average, it took an additional 7 months before adequate surgical treatment was performed (physicians' delay). The prognosis of our patients was poor. In 98.5% (n = 67) further metastases were observed on follow-up. Since there is still no cure for advanced plantar malignant melanoma, the early detection and subsequent surgical treatment of plantar melanoma is decisive for the prognosis. Based on our results, the poor survival can be improved by a significant reduction in the time period between the first observation of a plantar skin lesion and surgical treatment. Therefore there is an urgent need for special preventive health care campaigns to reduce significantly both the patients' and the physicians' delay.

Aminolevulinic acid (Levulan) in photodynamic therapy of actinic keratoses.

The role of photodynamic therapy (PDT) in the treatment of in situ neoplasias and tumors of the skin is steadily increasing. Its principles of photodynamic action include an intratumoral enriched photosensitizer and light activation. Aminolevulinic acid (ALA) has demonstrated highest efficacy in topical PDT, and has become the most clinically useful. For actinic (solar) keratoses, topical ALA-PDT using Levulan Kerastick (20% topical solution, DUSA Pharmaceuticals) is already postulated to be the treatment of choice. In December 1999, the US FDA approved this topical product for the treatment of actinic keratoses. Levulan is well tolerated and leads to excellent cosmetic results with only minor side effects.