Ferdinand Toberer

Merkel cell carcinoma induces lymphatic microvessel formation

BACKGROUND Merkel cell carcinoma (MCC) is a rare, highly malignant neuroendocrine tumor of the skin characterized by frequent lymphatic metastasis. OBJECTIVE We sought to identify lymphovascular anatomy and expression profiles of lymphangiogenic cytokines to give an opinion on lymphangiogenesis in MCC. METHODS We studied lymphatic microanatomy and lymphangiogenic cytokines in 27 MCC by immunohistology or immunofluorescence (D2-40, lymphatic vessel endothelial hyaluronan receptor [LYVE-1], vascular endothelial growth factor [VEGF] receptor-3, VEGF-C, VEGF-D, Ki67/MiB-1, CD68/PG-M1, CD68/KP1, CD163), Merkel cell polyomavirus-specific polymerase chain reaction, and coanalysis with clinical and histologic data. RESULTS We found a more than 3-fold increase in the mean density of absolute numbers of small lymphatic capillaries (diameter <10 μm) and a more than 8-fold increase in the median ratio of the number of small to large lymphatics (<10/≥10 μm) paratumorally compared with intraindividual controls. VEGF-C(+)CD68(+) CD163(+) cells (interpreted as M2 macrophages) could be identified as an important potentially lymphangiogenesis-inducing cell type. LIMITATIONS Partially lacking follow-up data limited the analysis of the prognostic impact. CONCLUSIONS Our findings strongly indicate lymphangiogenesis in MCC driven by VEGF-C(+)CD68(+) CD163(+) M2 macrophages.

Apoptotic signal molecules in skin biopsies of cutaneous lupus erythematosus: analysis using tissue microarray

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease. Different pathogenetic mechanisms, including the accumulation of apoptotic keratinocytes in CLE, have been reported. Therefore, we investigated whether CLE and other inflammatory skin diseases differ with regard to the epidermal expression of molecules that are crucial for the initiation and regulation of apoptosis. In this study, 241 skin biopsies from patients with CLE, psoriasis (PSO), lichen planus (LP) and healthy controls (HCs) were analysed immunohistochemically using the tissue microarray (TMA) technique. The TUNEL assay and anti‐activated caspase‐3 antibodies revealed a significant increase of apoptotic keratinocytes in CLE lesions compared with HCs. Furthermore, we detected a significant increase in the epidermal expression of CD95 in CLE specimens compared with PSO, LP and HCs. These data suggest that the accumulation of apoptotic keratinocytes in CLE might be due to the increased epidermal expression of CD95, resulting in increased activity of the extrinsic apoptotic pathway in the disease.

Tissue microarray analysis of RANKL in cutaneous lupus erythematosus and psoriasis

Abstract:  Recently, it was discovered that the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) is part of an important signal transduction pathway for tissue homoeostasis. Therefore, we were interested in investigating RANKL expression in the epidermis of skin lesions from patients with different subtypes of cutaneous lupus erythematosus (CLE) and psoriasis as well as normal healthy donors. Using the tissue microarray technique, skin biopsy specimens were evaluated by immunohistochemistry. RANKL showed a significantly increased expression in the epidermis of skin biopsy specimens from patients with psoriasis (median: 4, range: 0–5) compared to patients with CLE (median: 0, range: 0–4) (P < 0.001). No significant differences in epidermal RANKL expression between the CLE subtypes were detected. These data show a different expression of RANKL in the epidermis of skin lesions from patients with CLE compared to those with psoriasis suggesting that RANKL might play an important role in the pathogenesis of the disease.

Keratitis-Ichthyosis-Deafness Syndrome: Response to Alitretinoin and Review of Literature

to 75% of patients achieving a psoriasis area severity index of 75 by week 12. Ustekinumab was well tolerated in initial clinical studies, with very few serious adverse events (0.8% to 1.4%). However, concerns persist regarding long-term susceptibility to infection and malignancy. Patients with congenital deficiency of IL-12 have increased risk of severe infections with intracellular pathogens such as mycobacteria and salmonella. Thus far, no increased infection risk has been shown in patients treated with ustekinumab compared with controls. In addition, animal studies have demonstrated antitumor activity of IL-12 against murine tumors, including melanoma. Although these studies raise the concern for the potential malignancy in patients treated with ustekinumab, it is reassuring that patients with congenital deficits of IL-12 do not have increased rates of malignancy. Though ustekinumab appears to be an efficacious medication for the treatment of psoriasis, long-term follow-up will be required to monitor safety.

Primary Cutaneous CD4+ Small- to Medium-Sized Pleomorphic T-cell Lymphoma: Temporary Remission by Oral Doxycycline

IMPORTANCE In the recent World Health Organization-European Organisation for Research and Treatment of Cancer classification, primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma is listed as a provisional entity that is histopathologically characterized by pleomorphic CD3+/CD4+/CD8-/CD30- T lymphocytes. Clinically, it is characterized by solitary tumors mostly affecting the head and neck area and by an indolent clinical course with an estimated 5-year survival of about 60% to 80%. Currently, therapeutic options include topical or systemic treatment with glucocorticoids, local excision of solitary lesions, radiotherapy, and chemotherapy (e.g., cyclophosphamide) in cases of aggressive clinical behavior or systemic disease. OBSERVATIONS We present the case of a 21-year-old female patient with a 5-year history of a solitary, slowly growing tumor of the right cheek. Histopathologic findings revealed a primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma with an admixture of numerous CD20+ B cells representing almost half of the infiltrate. In this patient we achieved a temporary (13 months) complete remission of the lymphoma by oral treatment with doxycycline monohydrate, 200 mg per day. CONCLUSIONS AND RELEVANCE Doxycycline is a relatively nontoxic and well-tolerated oral agent and should be considered as a therapeutic option in primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma, especially in cases with a high percentage of B lymphocytes and no signs of systemic disease.

Metastatic Crohn's disease: a diagnostic and therapeutic challenge

A 35-year-old patient presented with an asymptomatic nodule on the right elbow (Figure 1). He had a known history of Crohn’s disease (treated for three years with infliximab 5 mg/ kg every 8 weeks). Upon clinical remission, immunosuppressive therapy had been discontinued. The remainder of the integument as well as the mucous membranes were unremarkable. Internist follow-up of Crohn’s disease showed no disease activity. Differential diagnoses included metastatic Crohn’s disease, atypical mycobacteriosis, and (eczematous) psoriasis. Histology revealed a deep granulomatous inflammatory reaction with numerous multinucleated giant cells (foreign-body type), surrounded by a lymphocytic inflammatory infiltrate. There were also focal areas of necrosis in the dermis (Figure 2). Various special stains (PAS, Giemsa, auramine, Ziehl-Neelsen) failed to identify any pathogen, and no foreign-body material was detected under polarized light. Culture for (atypical) mycobacteria and PCR to find Mycobacterium tuberculosis complex DNA were negative. The Quantiferon test was negative. Chest X-ray was normal and consistent with the patient’s age. Initially, psoriasis was clinically suspected and topically treated with mometasone cream, leading to worsening of the skin lesion with development of a purulent secretion. Topical therapy with calcipotriene was likewise unsuccessful. Wound healing was delayed following biopsy. The patient was offered excision of the solitary lesion. In the meantime, there was another flare-up of his Crohn’s disease, resulting in small bowel resection and systemic corticosteroid therapy (prednisolone 1 mg/kg daily). On this treatment, the skin lesion healed completely.

At first sight or second glance: clinical presentation of mosaic manifestations of autosomal dominant skin disorders – a case series

Several autosomal dominant disorders may manifest in mosaic patterns with cutaneous involvement. Genomic mosaicism results from postzygotic autosomal mutations, giving rise to clonal proliferation of two genetically distinct cell groups, which clinically present as lesions following the lines of Blaschko.

Juckende erythematöse Papeln und bräunliche Maculae an Rumpf und Beinen

Zur Diagnosesicherung erfolgten zwei Probebiopsien (Abbildung 2 ). Histologisch zeigen sich in der ersten Biopsie (Abbildung 2 a) fokal basale Epithelproliferate, intraepidermale zystische Strukturen sowie eine diskrete suprabasale Akantholyse. Das Stratum corneum weist eine kompakte Orthohyperkeratose auf und es fi ndet sich ein kräftiges unterliegendes lymphohistiozytäres Infi ltrat. In der zweiten Biopsie (Abbildung 2 b) fi ndet sich deutlich weniger entzündliches Begleitinfi ltrat, jedoch ebenfalls „füßchenförmige“

Prurigo Pigmentosa in a 21-year-old Caucasian Man: A Clinicopathological Correlation

is missing (Short communication).

Limitations of Ber-EP4 for distinction of Bowen disease from basal cell carcinoma.

Diagnostic differentiation between Bowen disease a variant of squamous cell carcinoma in situ (SCCIS) and basal cell carcinoma (BCC) can be difficult on the basis of hematoxylin and eosin (routine) staining in small or fragmented biopsy samples. Ber‐EP4 staining is diagnostically reliable for differentiation between BCC and cutaneous squamous cell carcinoma [Dasgeb et al. Biomark Cancer, 5: 7, (2013); Tellechea et al. Am J Dermatopathol, 15: 452 (1993)]. The objective of this study was to determine the usefulness of Ber‐EP4 staining for differentiation of SCCIS from BCC.