Hermann Kneitz

Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma.

The majority of Merkel cell carcinomas (MCCs) are associated with the recently identified Merkel cell polyomavirus (MCV). However, as it is still unclear to which extent the presence of MCV impacts tumor characteristics or clinical outcome, we correlated the MCV status of tumor lesions obtained from 174 MCC patients including 38 MCC patients from Australia and 138 MCC patients from Germany with clinical characteristics, histomorphology, immunohistochemistry, and course of the disease. MCV DNA was present in 86% of MCCs and, in contrast to previous reports, no significant difference in MCV prevalence was present between Australian and German MCC cases. When patients were stratified according to their MCV status, only tumor localization (P=0.001), gender (P=0.024), and co-morbidity, i.e., frequency of patients with previous skin tumors (P=0.024), were significantly different factors. In contrast, year of birth and diagnosis, age at diagnosis, or histological type and features representing the oncogenic phenotype such as mitotic rate or expression of p16, p53, RB1, and Ki67 were not significantly different between MCV-positive and MCV-negative MCCs. MCV status also did not influence recurrence-free, overall, and MCC-specific survival significantly. In summary, although MCV-positive and MCV-negative MCCs may have different etiologies, these tumors have comparable clinical behaviors and prognosis.

Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity

The ectonucleotidases CD39 and CD73 degrade immune stimulatory ATP to adenosine that inhibits T and NK cell responses via the A2A adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (Treg) that are associated with increased mortality in OvCA. Immunohistochemical staining of human OvCA tissue specimens revealed further aberrant expression of CD39 in 29/36 OvCA samples, whereas only 1/9 benign ovaries showed weak stromal CD39 expression. CD73 could be detected on 31/34 OvCA samples. While 8/9 benign ovaries also showed CD73 immunoreactivity, expression levels were lower than in tumour specimens. Infiltration by CD4+ and CD8+ T cells was enhanced in tumour specimens and significantly correlated with CD39 and CD73 levels on stromal, but not on tumour cells. In vitro, human OvCA cell lines SK-OV-3 and OaW42 as well as 11/15 ascites-derived primary OvCA cell cultures expressed both functional CD39 and CD73 leading to more efficient depletion of extracellular ATP and enhanced generation of adenosine as compared to activated Treg. Functional assays using siRNAs against CD39 and CD73 or pharmacological inhibitors of CD39, CD73 and ADORA2A revealed that tumour-derived adenosine inhibits the proliferation of allogeneic human CD4+ T cells in co-culture with OvCA cells as well as cytotoxic T cell priming and NK cell cytotoxicity against SK-OV3 or OAW42 cells. Thus, both the ectonucleotidases CD39 and CD73 and ADORA2A appear as possible targets for novel treatments in OvCA, which may not only affect the function of Treg but also relieve intrinsic immunosuppressive properties of tumour and stromal cells.

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.

Flagellate dermatitis caused by shiitake mushrooms.

Shiitake (Lentinus edodes) is the second most consumed mushroom in the world. It has long been known in Asian medicine for its anticarcinogenic, antihypertensive and serum cholesterol level reduction properties. Nevertheless, the consumption of raw or not well-cooked mushrooms may cause skin eruptions which usually occur 24 to 48 hours after ingestion and are characterized by linearly arranged pruritic erythematous papules and plaques. We present a 36-year-old patient that developed typical symptoms 24 hours after consumption of shiitake mushrooms and summarize therapeutic options and particularities of this disease.

Extrafacial indolent CD8-positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet.

Indolent CD8+ cutaneous lymphoid proliferation represents a recently described entity among cutaneous T‐cell lymphomas that typically presents with solitary skin lesions on the face or at acral sites and usually follows an indolent clinical course. Histopathologically, this entity is characterized by a dense dermal infiltrate of non‐epidermotropic, small‐ to medium‐sized pleomorphic CD8+ T‐cells of the non‐activated cytotoxic phenotype showing a clear‐cut grenz zone and a low proliferation index. Distinction from otherwise aggressive T‐cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental. We herein present an unusual case of indolent CD8+ cutaneous lymphoid proliferation presenting in bilateral symmetrical distribution on both feet and lacking the otherwise described grenz zone. Our case widens the spectrum of possible clinical and histomorphological variations of this entity. Taking into account the distinctive and unique clinical and microscopic features of all hitherto published cases of indolent CD8+ cutaneous lymphoid proliferation we suppose that this lymphoma subtype has to be included as a new and distinct entity in the World Health Organisation (WHO)‐/European Organisation for Research and Treatment of Cancer (EORTC)‐classification of cutaneous lymphomas.

Lack of Correlation between IGFBP7 Expression and BRAF Mutational Status in Melanoma

TO THE EDITOR Although the incidence of melanoma is still rising in many countries, the exact molecular pathogenesis for this tumor is unknown. Consequently, the publication of the study by Davies et al. (2002) reporting a high frequency of activating BRAF mutations in melanoma attracted much attention in the research community. Indeed, many independent groups have confirmed the high frequency of BRAF mutations in patients with melanoma; the mutation data on the COSMIC website (http://www.sanger.ac.uk/ genetics/CGP/cosmic/) indicate that BRAF mutations were detected in 46% of melanoma patients (n1⁄43,634), with BRAF V600E being the predominant mutation, found in 37.2% of the analyzed patients. However, given that in benign melanocytic nevi the frequency of BRAF mutations is similarly high (35% total mutations; 29.5% BRAF V600E; n1⁄4830, including 358 Spitz and blue nevi having a BRAF mutation frequency of B7%), BRAF mutations alone are not sufficient to initiate malignant melanoma. This thesis is sustained by experimental data showing that ectopic expression of constitutive active BRAF leads to senescence of primary cells (Michaloglou et al., 2005). An autocrine/paracrine regulatory loop explaining this observation was recently described by Wajapeyee et al. (2008), who demonstrated the presence in normal cells of a basal expression of insulin-like growth factor– binding protein 7 (IGFBP7) that inhibits BRAF–MEK–ERK signaling and thereby restrains apoptosis. In nevi, BRAF mutations activating the MAP kinase pathway lead to an increased expression of IGFBP7, which not only inhibits BRAF–MEK–ERK signaling but also activates senescence. In contrast, in BRAFmutated melanoma lesions, IGFBP7 expression is absent, enabling the cells to escape from senescence and thereby exhibit uncontrolled proliferation. Besides delivering the explanation for the observed effects of constitutive BRAF activation, the article by Wajapeyee and colleagues demonstrates a potential therapeutic application of this knowledge: treatment with recombinant

Mycosis fungoides bullosa: a case report and review of the literature.

IntroductionMycosis fungoides, the most common type of cutaneous T-cell lymphoma, can manifest in a variety of clinical and histological forms. Bulla formation is an uncommon finding in mycosis fungoides and only approximately 20 cases have been reported in the literature.Case presentationWe present a case of rapidly progressive mycosis fungoides in a 68-year-old Caucasian man who initially presented with erythematous plaques characterised by blister formation.ConclusionAlthough mycosis fungoides bullosa is extremely rare, it has to be regarded as an important clinical subtype of cutaneous T-cell lymphoma. Mycosis fungoides bullosa represents a particularly aggressive form of mycosis fungoides and is associated with a poor prognosis. The rapid disease progression in our patient confirms bulla formation as an adverse prognostic sign in cutaneous T-cell lymphoma.

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis.

Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.

Periocular cutaneous oncocytoma with signs of disrupted oxygen metabolism

Oncocytomas are benign tumors most often occurring in salivary or lacrimal glands and thyroid tissue. As cutaneous oncocytoma is exceptionally rare, this tumor is uncommonly encountered by dermatopathologists. Herein, we illustrate the case of an 80‐year‐old man who presented with a slowly growing papule of the lower eyelid. Histopathologically, the adenomatous tumor was composed of large monomorphic cells with eosinophilic granular cytoplasm. Electron microscopy revealed abundant, enlarged and abnormally shaped mitochondria. These findings were consistent with an oncocytoma of the skin. The presented case is unique in that the thorough work‐up of the tumor tissue revealed not only hyperplastic mitochondria, representing the ultrastructural correlate of the observed granular cytoplasm, but additionally disclosed functional consequences with elevated levels of reactive oxygen specimen (ROS) within the tumor. Disrupted oxygen metabolism may result from cellular aging processes and may putatively represent the underlying pathogenesis of oncocytoma.

Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency

Multiple lymphoma subtypes occurring within one patient is rare in the context of B‐cell lymphoma, and only few such cases have been reported in association with primary cutaneous marginal zone lymphoma (PCMZL). We herein describe the case of a 43‐year‐old patient who was diagnosed with PCMZL and subsequently developed a clonally unrelated nodal marginal zone lymphoma (MZL). At the time of diagnosis of PCMZL, multiple skin lesions were present. The atypical lymphoid infiltrate showed monotypic expression of immunoglobulin light chain lambda and heavy chain (IgM) on immunohistochemistry and an identical B‐cell clone. No sign of systemic lymphoma was present in staging examinations. Complete remission was achieved utilizing rituximab. After a 3‐year clinical course of repetitive cutaneous relapses and remissions, the patient additionally developed nodal lymphoma involvement by MZL which, however, harbored an immunophenotype and a genetic clone distinct from the cutaneous lymphoma counterpart. Therefore, the rare occurrence of two different types of MZL with sequential evolution was diagnosed. In this uncommon case, we hypothesize that selective immunoglobulin A deficiency may play a promoting role for the metachronous development of the two MZL that occurred in our patient.