Differential diagnostic significance of epithelial and stromal CD10 expression in tumors of trichogenic origin.

BACKGROUND AND OBJECTIVES: The histological differential diagnosis between benign trichogenic skin tumors and basal cell carcinoma may be challenging. We therefore set out to investigate whether expression of CD10, a cell surface protein with neutral endopeptidase activity, might be a suitable marker for the histological differential diagnosis of trichogenic skin tumors. PATIENTS AND METHODS: We immunohistochemically analyzed 119 cases of benign trichogenic skin tumors and basal cell carcinoma. These included 28 nodular and 15 sclerosing basal cell carcinomas, 21 Pinkus tumors, 20 trichoblastomas, nine trichofolliculomas, eleven trichoepitheliomas, five desmoplastic trichoepitheliomas, and ten seborrheic keratoses. RESULTS: The majority of nodular basal cell carcinomas expressed CD10 in tumor cells at the peripheral (22/28 [75 %]). On the other hand, trichoblastomas revealed peripheral CD10 expression in only 10 % (2/20) of cases, whereas 50 % showed central expression (10/20). Peripheral epithelial expression of CD10 was also found in Pinkus tumors (9/21 [42.9 %]) and trichoepithelioma (4/11 [36.4 %]). Desmoplastic trichoepithelioma showed no tumoral CD10 expression at all (0/5 [0 %]), while the majority of sclerosing basal cell carcinomas was positive for CD10 (13/15 [86.7 %]). CONCLUSIONS: Our findings suggest that epithelial expression of CD10 - and not peritumoral stromal CD10 expression, as has been postulated - may well be of differential diagnostic significance. The pattern of distribution of CD10-positive neoplastic cells in particular can be useful in the diagnosis of trichogenic tumors.

Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. METHODS: To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). RESULTS: SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%). CONCLUSION: SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.

Angiolymphoid hyperplasia with eosinophilia and Kimura's disease - a clinical and histopathological comparison.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign vascular neoplasm mainly affecting middle-aged women. Lesions typically affect the head and neck region. ALHE is considered a distinct disease entity different from Kimura's disease, a benign reactive lymphoid proliferation that is predominantly seen in young Asian men although it can affect all ethnic groups. In contrast to ALHE, Kimura's disease is typically associated with peripheral blood eosinophilia, increased serum IgE and lymphadenopathy. Several case reports suggest an overlap between ALHE and Kimura's disease. We review the current literature and discuss whether AHLE and Kimura's disease might represent two extreme variants of the same disease entity.

Microvessel density and expression of vascular endothelial growth factor and its receptors in different subtypes of primary cutaneous B-cell lymphoma.

A proangiogenic micromilieu is associated with a worse prognosis in systemic lymphoma. Hence, targeting the tumour microenvironment and its vasculature has evolved as a promising novel treatment strategy. The role of tumour neoangiogenesis in cutaneous B-cell lymphoma, however, has not yet been elucidated. Therefore, we examined the expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2, as well as microvessel density by immunohistochemistry in paraffin-embedded specimens of different subtypes of primary cutaneous B-cell lymphomas, systemic diffuse large B-cell lymphoma, and cutaneous B-cell pseudolymphoma. Primary cutaneous large B-cell lymphoma (PCLBCL) were characterized by significantly higher intratumoral expression levels of VEGF and its receptors in comparison with the indolent lymphoma subtypes. Moreover, PCLBCL exhibited significantly higher intratumoral microvessel counts. Our study provides evidence that the most aggressive subtype of cutaneous B-cell lymphoma, PCLBCL, is characterized by a proangiogenic micromilieu.

High-risk human papillomavirus infection in Bowen's disease of the nail unit: report of three cases and review of the literature.

BACKGROUND: Bowen's disease (BD) of the nail unit is associated with human papillomavirus (HPV) infection. OBJECTIVE: This study aimed to investigate the frequency of high-risk HPV infection, gender, age and digital distribution in this condition. METHODS: Biopsy specimens of 3 consecutive cases with periungual BD were investigated for the presence of HPV DNA by in situ hybridization and by polymerase chain reaction (PCR). Furthermore, 74 cases of ungual BD conducted with HPV genotyping as reported in the literature were reviewed. RESULTS: PCR of biopsy specimens revealed in 2 cases infection with HPV-16 and in 1 case with HPV-73. Additionally, in 1 HPV-16-positive case HPV-31/33 was detected by in situ hybridization. In line, review of the literature demonstrated a clear association of HPV-positive BD with high-risk HPV types. Interestingly, age at diagnosis was significantly lower in women. Whereas in both genders the second to fourth fingers on both hands were commonly diseased, only in men the thumbs were also prominently affected. CONCLUSIONS: Infection with high-risk HPV types is common in BD of the nail unit suggesting the aetiological cause. Therefore, patients and partners should be closely followed up for digital and genital HPV-associated lesions.

A red cheek as first clinical sign of a sebaceous lymphadenocarcinoma of the parotid gland with lymphangiosis carcinomatosa and lymph node metastases.

Sebaceous lymphadenoma is a rare benign neoplasm presenting predominantly in the parotid gland or in periparotid lymph nodes. It rarely transforms into a malignant tumor. We present a sebaceous lymphadenoma with an unusual clinical presentation with a malignant component, infiltration of lymph nodes, and lymphangiosis carcinomatosa. Sebaceous lymphadenoma usually presents as a well-circumscribed, painless, infraauricular mass. In our 87-years-old male patient, the clinical presentation was confluent reddish livid plaques at the left cheek and the left neck. In addition, cervical lymph node metastases were suspected. After skin biopsy, the tumor was excised by parotidectomy, skin excision, and neck dissection followed by a postoperative radiotherapy. To our knowledge, this is the sixth reported case of sebaceous lymphadenocarcinoma and the first case presenting with cervical lymph node metastases and dermatological symptoms revealing lymphangiosis carcinomatosa.

Primary cutaneous diffuse large B-cell lymphoma, leg-type, treated with a modified R-CHOP immunochemotherapy - diagnostic and therapeutic challenges.

BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma (PCLBCL) represents a rare subtype among primary cutaneous B-cell lymphoma exhibiting a characteristic genetic background, an aggressive clinical course and a high relapse rate under different therapeutic regimen. Therefore, PCLBCL has a rather restricted prognosis. PATIENTS AND METHODS: Four patients with PCLBCL were treated at our institution with age- and toxicity-adapted first-line immunochemotherapy with rituximab and modified CHOP (cyclophosphamid, vincristin, liposomal doxorubicin, prednisolon). On relapse, the same regimen with R-CHOP or different antineoplastic strategies (radiation, polychemotherapy, immunotherapy, stem cell transplantation) were applied. Toxicity, clinical response and overall survival was documented. RESULTS: Under this regimen, clinical response to modified R-CHOP was achieved in all patients with tolerable toxicity - however, being characterized by a rapid disease progression with inconsistent response towards the subsequent therapeutic armentarium and unsecure impact on overall survival. CONCLUSIONS: So far, it is still unknown, if an extensive multimodal therapy for PBLBCL improves overall survival. Immunochemotherapy with R-CHOP currently represents the most effective treatment.

Typically atypical: histiocytoid Sweet syndrome, associated with malignancy.

Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by a dramatic onset of high fever, neutrophilia and typical skin lesions. About 20 % of patients have an associated malignancy, most commonly hematologic diseases. Chronic and paucisymptomatic manifestations of Sweet syndrome may be misdiagnosed or misinterpreted as harmless, resulting in delayed diagnosis. "Atypical" manifestations are especially suspicious for associated malignancies. This is demonstrated by a 39-year old patient with chronic and afebrile disease who was referred to our clinic only after symptoms had persisted for several months. By that point, an underlying nodular lymphocyte predominant Hodgkin's lymphoma had already reached an advanced stage. Skin biopsies revealed dermal infiltrates of histiocytoid cells of myelogenous origin, supporting a diagnosis of histiocytoid Sweet syndrome. Specific cutaneous infiltrates associated with myelogenous leukemia were ruled out.

Novel ELISA systems for antibodies to desmoglein 1 and 3: correlation of disease activity with serum autoantibody levels in individual pemphigus patients.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are intraepidermal blistering skin diseases. PV is characterised by autoantibodies directed against desmoglein (Dsg) 3 and in patients with the mucocutaneous variant also against Dsg 1, whereas in PF, only Dsg 1 is targeted. Here, ectodomains of Dsg 3 and Dsg 1 were recombinantly expressed in a human cell line (HEK293) and applied as authentic solid phases in ELISA test systems. Autoantibodies against Dsg 3 and/or Dsg 1 could be detected in 71 (100%) of 71 PV sera and against Dsg 1 in 48 (96%) of 50 PF sera. Control sera showed reactivity with Dsg 3 and Dsg 1 in 0.2% and 0.7%, respectively, of 401 healthy blood donors and in 2.1% of 48 randomly selected patients with bullous pemphigoid. No reactivity with Dsg 1 and 3 was detected in 21 patients with linear IgA disease. For both pemphigus variants, a statistically significant correlation between clinical severity and autoantibody levels was observed as demonstrated for 10 PV and 5 PF patients. In conclusion, the use of the ectodomains of Dsg 3 and 1 as target antigens expressed in a human cell line resulted in sensitive and specific ELISA systems for both diagnosis and monitoring of PV and PF.

Uro-dermatological problems of a construction worker: paraaminobenzoic acid as a systemic photosensitizer.

A 51-year-old man suffered from an acute eczematous rash confined to the air- and light-exposed areas of the skin. As a construction worker he was exposed to common occupational allergens such as epoxy resins, but there was also remarkable holiday-associated sun exposure. He did not use any sunscreen agents. Several weeks before the onset of skin eruptions, conservative treatment of Peyronie's disease with oral PotabaTM (potassium paraaminobenzoate) had been started. Airborne contact dermatitis to volatile allergens was ruled out, while photopatchtesting revealed photoallergy to paraaminobenzoic acid (PABA). In sunscreens, PABA has mostly been abandoned due to its known topical photosensitization properties, but it has not yet been recognized as a systemic photosensitizer.

Clinical, histological and immunpathological findings in 32 patients with dermatitis herpetiformis Duhring.

BACKGROUND: Dermatitis herpetiformis is a chronic severely pruritic dermatosis. It is a cutaneous manifestation of celiac disease. The aim of our study was to collect clinical, histological and immunopathological data on patients who were treated in the University Departments of Dermatology in Würzburg and Lübeck from 1996 to 2008. PATIENTS AND METHODS: We retrospectively analyzed 32 patients. Only patients with positive findings on direct immunofluorescence microscopy were included in this study. RESULTS: All patients demonstrated skin lesions in the predilection areas of knees, elbows, gluteal region and scalp. The male to female ratio was 1.5 : 1 and the average age was 43 years. The interval between the first symptoms and diagnosis ranged from 6 weeks to 20 years. Direct immunofluorescence microscopy showed that granular IgA deposits were more often found continuously along the dermal-epidermal junction rather than focally in the tips of the dermal papillae. Results of small intestinal biopsies were available from 29 patients and confirmed the presence of celiac disease in all cases. None of the patients reported gastrointestinal symptoms. IgA antibodies against tissue transglutaminase and epidermal transglutaminase were found in 88% and 94% of patient sera, respectively. CONCLUSIONS: The detection of IgA autoantibodies against epidermal transglutaminase is the most sensitive serological test in the diagnosis of dermatitis herpetiformis. Our observations confirm that patients with dermatitis herpetiformis usually do not demonstrate apparent gastrointestinal symptoms.

Transition from pemphigus foliaceus to bullous pemphigoid: intermolecular B-cell epitope spreading without IgG subclass shifting.

Pemphigus and the pemphigoid group of diseases are distinct autoimmune conditions in which autoantibodies with different specificities cause skin blistering by different mechanisms. Transitions and associations between these two groups of autoimmune diseases are rare. Here, we report a patient with long-standing pemphigus foliaceus, in whom clinical remission was eventually induced. Shortly thereafter, he developed the clinical, histologic, and immunopathological changes of bullous pemphigoid. This case offered the rare opportunity to serologically monitor serum levels of both anti-BP180 and BP230 during the preclinical stage of bullous pemphigoid. Of interest, although the autoimmune response clearly shifted with regard to the target antigens, the patient's autoantibodies against desmosomal and hemidesmosomal components showed the same IgG subclass distribution.

Simultaneous onset of segmental vitiligo and a halo surrounding a congenital melanocytic naevus.

Unlike in common melanocytic naevi, an acquired leukoderma (halo) surrounding a congenital melanocytic naevus is a rare phenomenon. A 6-year-old boy developed a depigmentation around a congenital melanocytic naevus on the right thigh. Simultaneously, segmental vitiligo appeared on the thigh, lower abdomen and buttock of the same side with sharp midline demarcation. Examination for associated autoimmune diseases proved negative. The simultaneous occurrence of a halo phenomenon around a congenital melanocytic naevus and segmental vitiligo, as well as identical histological and immunohistological findings in both pigmented lesions, suggest shared immunological mechanisms.

Distinct sets of genetic alterations in melanoma.

BACKGROUND: Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light. METHODS: We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. RESULTS: We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. CONCLUSIONS: The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

Management of primary and metastasized melanoma in Germany in the time period 1976-2005: an analysis of the Central Malignant Melanoma Registry of the German Dermatological Society.

This study analysed the changes of excision margins in correlation with tumour thickness as recorded over the last three decades in Germany. The study also evaluated surgical management in different geographical regions and treatment options for metastasized melanoma. A total of 42 625 patients with invasive primary cutaneous melanoma, recorded by the German Central Malignant Melanoma Registry between 1976 and 2005 were included. Multiple linear regression analysis was used to investigate time trends of excision margins adjusted for tumour thickness. Excision margins of 5.0 cm were widely used in the late 1970s but since then have been replaced by smaller margins that are dependent on tumour thickness. In the case of primary melanoma, one-step surgery dominated until 1985 and was mostly replaced by two-step excisions since the early 1990s. In eastern Germany, one-step management remained common until the late 1990s. During the last three decades loco-regional metastases were predominantly treated by surgery (up to 80%), whereas systemic therapy decreased. The primary treatment of distant metastases has consistently been systemic chemotherapy. This descriptive retrospective study revealed a significant decrease in excision margins to a maximum of 2.00 cm. A significant trend towards two-step excisions in primary cutaneous melanoma was observed throughout Germany. Management of metastasized melanoma showed a tendency towards surgical procedures in limited disease and an ongoing trend to systemic treatment in advanced disease.

Transplantation of autologous keratinocyte suspension in fibrin matrix to chronic venous leg ulcers: improved long-term healing after removal of the fibrin carrier.

BACKGROUND: The transplantation of keratinocytes suspended in fibrin carrier represents a candidate regimen for chronic ulcer treatment in an outpatient setting. We evaluated the integration and survival of autologous individualized keratinocytes applied within fibrin matrix onto chronic venous leg ulcers in vivo. Parallel in vitro culture was used to validate keratinocyte survival and apoptosis in fibrin compared to collagen matrix carrier. METHODS: Seven patients with chronic venous leg ulcers were transplanted with autologous keratinocytes suspended in fibrin sealant after isolation and expansion from full-skin biopsy. The fibrin carrier was removed in three patients after 7 days, whereas four patients served as control with fibrin remaining. In parallel in vitro cultures, primary keratinocyte movement in fibrin as well as viability in three-dimensional (3D) fibrin versus collagen lattices was examined. RESULTS: Complete ulcer healing was observed in four of seven ulcers after a mean duration of 14.5 weeks. If the fibrin layer was removed, complete wound healing occurred in three of three patients, compared to one of four in the control group. In vitro, keratinocytes formed a monolayer underneath but remained isolated and nonmobile within the fibrin matrix, suggesting reepithelialization along the lower fibrin interphase. Keratinocyte culture in 3D fibrin at clinically used concentration (90 mg/mL) caused high levels of apoptosis, similar to 3D collagen, which was prevented by diluting fibrin concentration to 3 mg/mL. CONCLUSIONS: Transplantation of autologous keratinocytes suspended in fibrin is efficient in the treatment of chronic venous leg ulcers. Due to an antimigratory and survival-compromising effect, the presently used fibrin carrier should be removed after a few days of transplantation.