In vivo non-invasive staining-free visualization of dermal mast cells in healthy, allergy and mastocytosis humans using two-photon fluorescence lifetime imaging.

Mast cells (MCs) are multifunctional cells of the immune system and are found in skin and all major tissues of the body. They contribute to the pathology of several diseases including urticaria, psoriasis, atopic dermatitis and mastocytosis where they are increased at lesional sites. Histomorphometric analysis of skin biopsies serves as a routine method for the assessment of MC numbers and their activation status, which comes with major limitations. As of now, non-invasive techniques to study MCs in vivo are not available. Here, we describe a label-free imaging technique to visualize MCs and their activation status in the human papillary dermis in vivo. This technique uses two-photon excited fluorescence lifetime imaging (TPE-FLIM) signatures, which are different for MCs and other dermal components. TPE-FLIM allows for the visualization and quantification of dermal MCs in healthy subjects and patients with skin diseases. Moreover, TPE-FLIM can differentiate between two MC populations in the papillary dermis in vivo-resting and activated MCs with a sensitivity of 0.81 and 0.87 and a specificity of 0.85 and 0.84, respectively. Results obtained on healthy volunteers and allergy and mastocytosis patients indicate the existence of other MC subpopulations within known resting and activated MC populations. The developed method may become an important tool for non-invasive in vivo diagnostics and therapy control in dermatology and immunology, which will help to better understand pathomechanisms involving MC accumulation, activation and degranulation and to characterize the effects of therapies that target MCs.

A Rare Case of Spinal Mastocytosis Presenting as an Extradural Mass.

BACKGROUND: Systemic mastocytosis is a hematopoietic disorder of mast cell deposits in various systemic tissues that can include skin, spleen, liver, and bone marrow. When accumulation occurs within bone it has been reported to cause osteoporosis, osteosclerosis, or sometimes a mixed pattern. In exceptionally rare circumstances, it has been reported to present as an exophytic mass causing neural compression. CASE DESCRIPTION: A 72-year-old man was admitted with progressive worsening in his mobility and heavy and numb sensation in his bilateral lower limbs that worsened on walking. His weakness subsequently progressed such that he was no longer able to mobilize for 48 hours prior to admission. On examination he was found to be myelopathic with a sensory level noted at approximately the T10/11 area. Whole spine magnetic resonance imaging was conducted, which revealed a heterogeneous lesion involving the vertebral body and posterior elements of T10. The patient underwent T9-T11 laminecetomy with intralesional debulking of metastatic spinal column tumor. Postoperatively, the patient was noted to have improved anti-gravity power in the lower limbs. Intraoperative biopsy samples revealed focal paratrabecular infiltrates of abnormal mast cells with collagen fibrosis and focal bone destruction, along with cytogenetic features in keeping with systemic mastocytosis. CONCLUSIONS: We describe a rare case of systemic mastocytosis presenting as an extradural lesion causing compressive myelopathy and paraparesis. To our knowledge, this has only been described once before in literature. The patient underwent decompression surgery with improvement in neurology postoperatively. He was subsequently referred to the hematology team for further investigation and management.

Ultrasound is a poor predictor of early or overt liver or spleen metastasis in dogs with high-risk mast cell tumours.

Conflicting evidence exists regarding the importance of routine abdominal ultrasound (US) with hepatic and splenic fine needle aspiration (FNA) cytology during staging of canine mast cell tumours (MCT). The objective of this study was to correlate ultrasonographic and cytologic findings in dogs with strictly defined high-risk MCTs and to determine the influence on outcome. Our hypothesis was that US poorly predicts visceral metastasis in high-risk MCTs and that early metastasis is associated with improved outcome when compared to overt metastasis. US of liver and spleen correlated to cytologic results, categorized as no metastasis, early metastasis or overt metastasis. Of 82 dogs prospectively enrolled, 18% had early visceral metastasis and 7% had overt metastasis on cytology; 67% with visceral metastasis had regional LN metastasis. US was a poor predictor of metastasis with sensitivity, specificity, positive predictive value and negative predictive value for the spleen of 67%, 68%, 21% and 94%, respectively and for the liver of 29%, 93%, 56% and 82%, respectively. Median time to progression (TTP) for dogs with no metastasis, early metastasis and overt metastasis was not reached, 305 and 69 days, respectively (P < .001). Median survival time (MST) for the 3 groups were not reached, 322 and 81 days, respectively (P < .001). High Patnaik or Kiupel grade, early metastasis, overt metastasis and adequate local control were significantly associated with outcome. Early visceral metastasis was associated with poorer outcome compared to dogs without metastasis, however, a subset of dogs experienced long-term control.

Pilot study utilizing Fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography for glycolytic phenotyping of canine mast cell tumors.

The goal of this prospective pilot study was to use naturally occurring canine mast cell tumors of various grades and stages as a model for attempting to determine how glucose uptake and markers of biologic behavior are correlated. It was hypothesized that enhanced glucose uptake, as measured by 2-[fluorine-18]fluoro-d-glucose-positron emission tomography/computed tomography (F18 FDG PET-CT), would correlate with histologic grade. Dogs were recruited for this study from a population referred for treatment of cytologically or histologically confirmed mast cell tumors. Patients were staged utilizing standard of care methods (abdominal ultrasound and three view thoracic radiographs), followed by a whole body F18 FDG PET-CT. Results of the F18 FDG PET-CT were analyzed for possible metastasis and standard uptake value maximum (SUVmax ) of identified lesions. Incisional or excisional biopsies of the accessible mast cell tumors were obtained and histology performed. Results were then analyzed to look for a possible correlation between the grade of mast cell tumors and SUVmax . A total of nine animals were included in the sample. Findings indicated that there was a correlation between grade of mast cell tumors and SUVmax as determined by F18 FDG PET-CT (p-value = 0.073, significance ≤ 0.1). Based on the limited power of this study, it is felt that further research to examine the relationship between glucose utilization and biologic aggressiveness in canine mast cell tumors is warranted. This study was unable to show that F18 FDG PET-CT was a better staging tool than standard of care methods.

Neuroimaging evidence of brain abnormalities in mastocytosis.

Mastocytosis is a rare disease in which chronic symptoms are related to mast cell accumulation and activation. Patients can display depression-anxiety-like symptoms and cognitive impairment. The pathophysiology of these symptoms may be associated with tissular mast cell infiltration, mast cell mediator release or both. The objective of this study is to perform morphological or functional brain analyses in mastocytosis to identify brain changes associated with this mast cell disorder. We performed a prospective and monocentric comparative study to evaluate the link between subjective psycho-cognitive complaints, psychiatric evaluation and objective medical data using magnetic resonance imaging with morphological and perfusion sequences (arterial spin-labeled perfusion) in 39 patients with mastocytosis compared with 33 healthy controls. In the test cohort of 39 mastocytosis patients with psycho-cognitive complaints, we found that 49% of them had morphological brain abnormalities, mainly abnormal punctuated white matter abnormalities (WMA). WMA were equally frequent in cutaneous mastocytosis patients and indolent forms of systemic mastocytosis patients (42% and 41% of patients with WMA, respectively). Patients with WMA showed increased perfusion in the putamen compared with patients without WMA and with healthy controls. Putamen perfusion was also negatively correlated with depression subscores. This study demonstrates, for we believe the first time, a high prevalence of morphological and functional abnormalities in the brains of mastocytosis patients with neuropsychiatric complaints. Further studies are required to determine the mechanism underpinning this association and to ascertain its specificity.

Differences in the imaging features and distribution of non-indolent and indolent mastocytosis: a single institution experience of 29 patients.

PURPOSE: Compare imaging features of indolent and non-indolent mastocytosis. METHODS: For 29 patients, imaging features, imaging indications, and distribution of indolent and non-indolent mastocytosis subtypes were analyzed. RESULTS: 16/29 (55%) patients had three distinct patterns of osseous abnormality, not significantly differing between cohorts. Non-indolent disease was more likely to present with hepatomegaly (p=0.0004), splenomegaly (p=0.0097), and lymphadenopathy (p=0.0079). CT, was the most common initial imaging modality, ordered to stage disease in 20 of 29 patients (69%). CONCLUSION: Understanding patterns of involvement of indolent and nonindolent mastocytosis across modalities could assist radiologists in evaluating mastocytosis.

Cardiovascular symptoms in patients with systemic mast cell activation disease.

Traditionally, mast cell activation disease (MCAD) has been considered as just one rare (neoplastic) disease, mastocytosis, focused on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, the MC activation syndrome, has been recognized featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. Increasing expertise and appreciation has been established for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic theme. We describe the pathogenesis of MCAD with a particular focus on clinical cardiovascular symptoms and the therapeutic options for MC mediator-induced cardiovascular symptoms.

The utility of staging in canine mast cell tumours.

Current staging of canine mast cell tumours (MCTs) practiced by many veterinarians involves a minimum of lymph node (LN) assessment, abdominal ultrasound and thoracic radiography. Historically, some have advocated buffy coat and bone marrow evaluation. Two hundred and twenty dogs with MCT seen at a referral clinic were staged using LN palpation/cytology, thoracic radiography and abdominal ultrasound. The utility of each method was evaluated by considering prevalence of spread and future behaviour. At presentation, 30.9% of dogs had metastases to the local LN; 6.8% of all the dogs also had distant metastases. No dog had or developed distant metastasis in the absence of LN metastasis. No dog had convincing evidence of pulmonary metastasis. In this series, the local LN was sentinel to metastasis and in the absence of local LN metastasis, the utility of further staging was low. Thoracic radiography was not useful in the staging of canine MCT.

Bone complications of mastocytosis: a link between clinical and biological characteristics.

OBJECTIVES: Mastocytosis is a heterogeneous group of clonal mast cell disorders in which bone manifestations are frequently seen, but poorly understood. In this study, we analyzed correlation of clinical findings in mastocytosis patients with bone mineral density and bone turnover markers. METHODS: Serum levels of bone turnover markers were measured in mastocytosis patients and healthy volunteers. Bone disease was evaluated using radiographic imaging, and measurement of bone mineral density. RESULTS: Of 45 adult mastocytosis patients, bone abnormalities were detected in 34 (75%). Bone lesions were documented on radiographic imaging in 16 patients (36%), and bone mineral density in 24 patients (53%), of which 9 patients (20%) had osteoporosis and 15 (33%) had osteopenia. Serum levels of bone turnover markers that evaluate bone resorption (C-telopeptide, deoxypyridinoline), bone formation (bone-specific alkaline phosphatase), and bone remodeling (osteoprotegerin) were significantly higher in the patient population than in the control population (n=28). Levels of C-telopeptide and osteoprotegerin were higher in patients with advanced systemic mastocytosis than in patients with cutaneous or indolent systemic mastocytosis. Moreover, C-telopeptide and osteoprotegerin levels were significantly correlated with those of serum tryptase, a diagnostic marker of mastocytosis. CONCLUSION: The observed bone turnover markers variations indicate a complex process of bone turnover in mastocytosis-related bone manifestations. The highly significant correlation between serum tryptase and serum bone turnover markers levels, and the positive correlation of levels of bone turnover markers with advanced disease, support the existence of a link between bone remodeling and mast cell burden.

Ultrasonographic characteristics of soft tissue tumours in dogs.

OBJECTIVE: To identify and describe the ultrasonographic features of soft tissue tumours in dogs. PROCEDURE: Superficial soft tissue tumours of various histological types, including mast cell tumours (MCTs) and soft tissue sarcomas (STSs), were evaluated. Ultrasound was used to visualise internal characteristics of the tumour, including vascularity. Tumours were categorised according to size, shape, margin definition, tissue plane mobility, echogenicity, echotexture, acoustic shadowing or enhancement and vessel distribution. Objective measurements of intratumoural blood flow included velocities and maximal perfused cross-sectional area (fractional area). Logistic regression models incorporating a variety of data were used in an attempt to predict the histopathological type of tumours. RESULTS: The logistic regression model defined by the parameters echotexture, margin definition and presence of subcapsular vessels was highly predictive of MCTs (> 73%; P = 0.024). Several other trends, including a larger size for STSs and less vascularity for both MCTs and STSs, were observed, but did not reach statistical significance. CONCLUSION: This preliminary study has shown the potential diagnostic value of ultrasound in differentiating soft tissue tumours. However, at present, ultrasound cannot replace biopsy and histopathological evaluation for tumour diagnosis.

Osseous mastocytosis of the knee.

Mastocytosis is a rare pathology with possible bone involvement. This report describes an unusual case of solitary osteolytic lesion of the proximal right tibia, revealing an osseous mastocytosis, treated by bone cement injection. Follow-up showed a good clinical and radiological outcome, and the patient remains symptom-free 9 months after her surgery. To our knowledge, this is the first case reported in the literature.

FDG positron emission tomography in patients with systemic mastocytosis.

OBJECTIVE: Systemic mastocytosis is a hematologic neoplasm characterized by abnormal accumulation and growth of mast cells in one or more organ systems. We analyzed five patients with systemic mastocytosis referred for FDG positron emission tomography who had biopsy-proven mast cell infiltrates in various organs. CONCLUSION: Our findings indicate that FDG positron emission tomography is not useful for staging and follow-up of aggressive systemic mastocytosis.

Systemic mast cell disease (SMCD) and bone pain. A case treated with radiotherapy.

BACKGROUND: Systemic mast cell disease (SMCD) is a rare disease characterized by a multitopic proliferation of cytologically and/or functionally abnormal tissue mast cells. SMCD preferentially involves the skin, spleen, liver, lymph nodes and the bone marrow. The cause of SMCD is unknown. Bony pain, caused by mast cell infiltration of the marrow cavity, is present in up to 28% of cases and is frequently chronic and difficult to palliate with medical therapy. CASE REPORT: We report one case of refractory bone pain in a 54-year-old female Caucasian patient with advanced SMCD and associated bony involvement, which was treated with radiotherapy for pain palliation. Between 1995 and 1998, the patient was irradiated at four different locations: 1) right shoulder and proximal right humerus, 2) both hands, 3) both knees, 4) left humerus with a total dose of 40 Gy in 2.0 or 2.5 Gy daily fractions. RESULTS: Different results of pain palliation were achieved. In one location the pain was reduced for 55 months until her death due to disease progression, whereas in two other locations a pain control was maintained for 3 and 6 months after radiotherapy. In one location, no pain reduction was achieved. Severe side effects were not observed. CONCLUSION: Palliative radiotherapy has a role in the control of severe intractable bone pain in patients with advanced SMCD, though in some cases the effect may be short or incomplete. The observed palliation of pain can even differ in the same patient.

An unusual presentation of systemic mastocytosis.

A 47 year old man presented with mastocytosis, a disease process characterised by proliferation of mast cells. The clinical features and outcome are discussed.

Systemic mastocytosis with involvement of the pelvis: a radiographic and clinicopathologic study--a case report.

The musculoskeletal manifestations of systemic mastocytosis have been described in the literature. We present a case of systemic mastocytosis involving the pelvis. Conventional radiographs and CT imaging may demonstrate diffuse sclerotic, or mixed lytic and sclerotic lesions. On MRI, the lesions, if sclerotic, may show low signal on T1- and T2-weighted images. However, if lytic, the lesions may demonstrate low signal on T1, and increased signal on T2. As there are numerous disease entities included within the differential diagnosis, the clinical and pathological findings are crucial for establishing the correct diagnosis.