Mefloquine causes selective mast cell apoptosis in cutaneous mastocytosis lesions by a secretory granule-mediated pathway.

Mastocytosis is a KIT-related myeloproliferative disease characterised by abnormal expansion of neoplastic mast cells (MC) in the skin or virtually any other organ system. The cutaneous form of adult-onset mastocytosis is almost invariably combined with indolent systemic involvement for which curative therapy is yet not available. Here we evaluated a concept of depleting cutaneous MCs in mastocytosis lesions ex vivo by targeting their secretory granules. Skin biopsies from mastocytosis patients were incubated with or without mefloquine, an antimalarial drug known to penetrate into acidic organelles such as MC secretory granules. Mefloquine reduced the number of dermal MCs without affecting keratinocyte proliferation or epidermal gross morphology at drug concentrations up to 40 µM. Flow cytometric analysis of purified dermal MCs showed that mefloquine-induced cell death was mainly due to apoptosis and accompanied by caspase-3 activation. However, caspase inhibition provided only partial protection against mefloquine-induced cell death, indicating predominantly caspase-independent apoptosis. Further assessments revealed that mefloquine caused an elevation of granule pH and a corresponding decrease in cytosolic pH, suggesting drug-induced granule permeabilisation. Extensive damage to the MC secretory granules was confirmed by transmission electron microscopy analysis. Further, blockade of granule acidification or serine protease activity prior to mefloquine treatment protected MCs from apoptosis, indicating that granule acidity and granule-localised serine proteases play major roles in the execution of mefloquine-induced cell death. Altogether, these findings reveal that mefloquine induces selective apoptosis of MCs by targeting their secretory granules and suggest that the drug may potentially extend its range of medical applications.

Purpura fulminans, TEN, and disseminated herpes simplex: An unexpected combination.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and purpura fulminans (PF) are all rare conditions. A combination of these 3 conditions together with a viral infection is very rare. A 52-year-old, previously healthy woman which developed SJS, potentially due to a reaction to CT contrast, although this is still unknown. This developed into TEN on day 10 of the initial admission, the patient scored 3 points on SCORTEN. On day 12 from initial admission, she developed unexpected multiorgan failure and PF. The patient passed away 2 days later, the autopsy demonstrates herpes simplex virus in the bladder and lungs on immunohistological staining. Our clinical case encountered the challenge of differentiating TEN and PF. The microscopic and immunochemical examination confirmed the clinical suspicion of PF but also a disseminated herpes simplex infection. We speculate the clinical route of this case started SJS and TEN, leading to superimposed infection with three different types of bacteria, confirmed in blood cultures, and a disseminated viral infection. The combination of all these diagnoses are very rare, no similar case has been described in adults to the authors' knowledge. We recommend a prompt diagnosis and early recognition of both bacterial and viral infections to prevent the development of PF.

Fibroblastic Connective Tissue Nevus Mimicking Lipoma on Ultrasound: Case Report and Brief Review.

Fibroblastic connective tissue nevus (FCTN) is a rare, benign, and recently described dermal mesenchymal lesion characterized by CD34-positive spindle cells. We present a case of FCTN on the upper back of a 9-month-old boy who was diagnosed with a benign lipoma by ultrasound.

Clear Cell Proliferations of the Skin: A Histopathologic Review.

ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.