Sexy again: the renaissance of neutrophils in psoriasis.

Notwithstanding their prominent presence in psoriatic skin, the functional role of neutrophilic granulocytes still remains somewhat enigmatic. Sparked by exciting scientific discoveries regarding neutrophil functions within the last years, the interest in these short-lived cells of the innate immune system has been boosted recently. While it had been known for some time that neutrophils produce and respond to a number of inflammatory mediators, recent research has linked neutrophils with the pathogenic functions of IL-17, possibly in conjunction with the formation of NETs (neutrophil extracellular traps). Antipsoriatic therapies exert their effects, at least in part, through interference with neutrophils. Neutrophils also appear to connect psoriasis with comorbid diseases. However, directly tampering with neutrophil functions is not trivial as evinced by the failure of therapeutic approaches targeting redundantly regulated cellular communication networks. It has also become apparent that neutrophils link important pathogenic functions of the innate and the adaptive immune system and that they are intricately involved in regulatory networks underlying the pathophysiology of psoriasis. In order to advocate intensified research into the role of this interesting cell population, we here highlight some features of neutrophils and put them into perspective with our current view of the pathophysiology of psoriasis.

Squared-Off Nuclei and "Appliqué" Pattern as a Histopathological Clue to Periocular Sebaceous Carcinoma: A Clinicopathological Study of 50 Neoplasms From 46 Patients.

The histopathological diagnosis of periocular sebaceous carcinoma can be difficult in poorly differentiated cases showing few mature sebocytes. The authors examined 50 periocular sebaceous carcinomas from 46 patients to determine the frequency of 2 features seen in this neoplasm, namely cells with squared-off nuclei and so-called "appliqué" pattern (peritumoral subnecrosis of peripherally located neoplastic cells). Neoplastic cells with squared-off nuclei were found in varying numbers in both the intraepithelial and dermal (invasive) components in all neoplasms, whereas the appliqué pattern was observed in a third of the cases. It is concluded that these features, taken together, may serve as a clue for the diagnosis of periocular sebaceous carcinoma.

Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.

BACKGROUND: Neutrophilic urticarial dermatosis (NUD) comprises a particular autoinflammatory condition within the spectrum of aseptic neutrophilic dermatoses characterized by a distinct urticarial eruption clinically and a neutrophilic dermatosis histopathologically. OBJECTIVE: In this study, we reviewed skin biopsies of lesional skin of patients seen in our outpatient clinic for autoimmune dermatoses and in allergy department from 1982 to 2014 that fulfilled these criteria. METHODS: A total of 77 biopsies from 50 patients were analyzed histopathologically. Included were cases of Schnitzler syndrome, Still disease, systemic lupus erythematosus, Sjögren syndrome, cryopyrin-associated periodic syndrome, primary biliary cirrhosis, inflammatory bowel disease, and those that had signs of systemic inflammation not otherwise specified, that is, fever, arthritis, leukocytosis, and elevated erythrocyte sedimentation rate. A control cohort was defined as including a total of 70 biopsies from 50 patients comprising neutrophilic urticaria (pressure-induced and not pressure-induced), conventional urticaria, lupus erythematosus expressing neutrophils, and exanthematous drug reaction of macular type expressing neutrophils. RESULTS: Skin biopsies of NUD revealed a perivascular and interstitial neutrophilic infiltrate focally extending into the epithelia of epidermis, hair follicles, sebaceous and sweat glands, a feature which we termed neutrophilic epitheliotropism. This neutrophilic epitheliotropism proved to be of high sensitivity (83.1%) and lower specificity (74.3%). The histological findings could be substantiated by immunohistochemical markers for leukocytes (elastase and myeloperoxidase), in particular in cases where neutrophils showed uncharacteristic band-like nuclei. CONCLUSIONS: Neutrophilic epitheliotropism is a new sensitive and specific histopathological clue for NUD, a histopathological reaction pattern within the spectrum of neutrophilic dermatoses that needs to be differentiated from conventional urticaria.

Pediatric CD8⁺CD56⁺ non-poikilodermatous mycosis fungoides: case report and review of the literature.

Mycosis fungoides (MF) displays a broad spectrum of clinical, histological, and phenotypic variants with different prognostic impact. CD8⁺CD56⁺MF is very rare. So far, only 5 patients with CD8⁺CD56⁺ MF were reported to date. All of the previously described patients with this phenotypic variant were adults at the time of diagnosis and often manifested with widespread poikilodermatous skin lesions. Here we describe the clinicopathological features of a juvenile form of CD8⁺CD56⁺ non-poikilodermatous MF in a 10-year-old girl. In our patient, the disease displayed an indolent course and excellent prognosis with complete remission after treatment with UV light, topical steroids, and methotrexate. The differential diagnosis of CD8⁺ epidermotropic lymphocytic infiltrates in children is discussed, and the cases of CD8⁺CD56⁺ MF reported in the literature are reviewed.

Multisystem Langerhans cell histiocytosis: successful treatment with thalidomide.

A 57-year-old woman presented with a 1-year history of non-healing inguinal and perianal ulcers as well as a 2-year history of polydipsia. The clinical picture and histology suggested Langerhans cell histiocytosis, which was confirmed by immunohistochemistry and electron microscopy. Magnetic resonance imaging of the brain revealed hypothalamic-pituitary axis involvement. Treatment was started with thalidomide and desmopressin. The skin lesions resolved over 2 months. Over the next 24 months of continued therapy, the cerebral involvement remained stable and the skin lesions did not recur.

Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma-New Therapeutic Targets.

Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma.

Comparative study of presurgical skin infiltration depth measurements of melanocytic lesions with OCT and high frequency ultrasound.

A reliable, fast, and non-invasive determination of melanoma thickness in vivo is highly desirable for clinical dermatology as it may facilitate the identification of surgical melanoma margins, determine if a sentinel node biopsy should be performed or not, and reduce the number of surgical interventions for patients. In this work, optical coherence tomography (OCT) and high frequency ultrasound (HFUS) are evaluated for quantitative in vivo preoperative assessment of the skin infiltration depth of melanocytic tissue. Both methods allow non-invasive imaging of skin at similar axial resolution. Comparison with the Breslow lesion thickness obtained from histopathology revealed that OCT is slightly more precise in terms of thickness determination while HFUS has better contrast. The latter does not require image post-processing, as necessary for the OCT images. The findings of our pilot study suggest that non-invasive OCT and HFUS are able to determine the infiltration depth of lesions like melanocytic nevi or melanomas preoperatively and in vivo with a precision comparable to invasive histopathology measurements on skin biopsies. In future, to further strengthen our findings a statistically significant study comprising a larger amount of data is required which will be conducted in an extended clinical study in the next step. Comparison of optical coherence tomography and high frequency ultrasound B-Scans and a H&E stained histology of a melanocytic nevus.

Genetic and morphologic features for melanoma classification.

Melanoma is comprised of biologically distinct subtypes. The defining clinical, histomorphologic, and molecular features are not fully established. This study sought to validate the association between genetic and histomorphologic features previously described and to determine their reproducibility and association with important clinical variables. Detailed clinical and histomorphologic features of 365 primary cutaneous melanomas were assessed by 11 pathologists and correlated with mutation status of BRAF and NRAS. There was substantial agreement in the quantitative assessment of histomorphologic features showing similar or better interobserver reproducibility than the established World Health Organization classification scheme. We confirmed that melanomas with BRAF mutations showed characteristic morphologic features (P < 0.0001) and metastasized more frequently to regional lymph nodes (P = 0.046). Importantly, melanomas without mutations were a heterogeneous group, with a subset having very similar clinical and morphological features as those with BRAF mutation raising the possibility that they are biologically related. Our study confirms an association between histomorphologic features, mutation status, and pattern of metastasis, providing criteria for a refined melanoma classification aimed at defining biologically homogeneous disease subgroups.