A xanthomatous lesion resembling balloon cell melanoma of the iris and ciliary body of a dog

A slow-growing xanthomatous tumour which diffusely infiltrated the iris and ciliary body of a dog was composed of large, pale, vacuolated cells which contained scattered fine pigment granules. Electron microscopy revealed coalescing vacuoles, lamellar membranous structures, and small groups of melanosomes in the cytoplasm, suggesting melanocytic origin. The lesion resembled balloon cell melanoma of the ciliary body of man. The behaviour of the tumour was benign. This is a clinical and pathological entity which has not been reported previously in the dog.     

Iris melanoma

The iris is the least common site of primary uveal melanoma. The prognosis of iris melanoma is better than that of melanoma of the ciliary body and choroid, but the reason for this difference is unclear. One possible explanation is that iris melanoma is smaller than its posterior segment counterparts at the time of diagnosis. Most iris melanomas are spindle cell types, according to a modified Callender classification system. There is evidence that the proliferation of melanocytes of the anterior iris surface (iris plaque) and diffuse stromal invasion may be risk factors for local recurrence and metastasis, respectively.     

Non-random abnormalities of chromosomes 3, 6, and 8 associated with posterior uveal melanoma.

We present ten cases of posterior uveal melanoma which were karyotyped after short-term culture. One tumour had a normal chromosome complement. The remaining nine tumours were cytogenetically abnormal, with chromosomes 3, 6, 8, 11, and 13 most frequently involved. Abnormalities of chromosome 13 were seen in two cases, chromosome 11 in three cases, and chromosomes 3, 6, and 8 in five cases. Four tumours, all derived from the ciliary body, demonstrated monosomy 3 and i(8q), confirming the involvement of these aberrations with a subgroup of uveal melanomas arising from the ciliary body.     

Immunoregulatory properties of bone marrow-derived cells in the iris and ciliary body.

Iris and ciliary body of mouse eyes have been examined for the presence of bone marrow-derived cells possessing the capability of functioning as antigen-presenting cells (APC). We have determined that iris and ciliary body contain significant numbers of cells bearing T200, indicating their bone marrow origin. Most of these express the F4/80 marker typically found on mature macrophages. However, approximately one-third of the cells express Ia and a similar number express Mac-1 markers. Virtually none of the cells express Thy-1 or surface immunoglobulin. Whole preparations of excised iris/ciliary body, or single cell suspensions prepared from these tissues were then assayed for their capacity to induce proliferation among allogeneic lymphocytes. It was discovered that iris/ciliary body tissues or cells did not function as alloantigen-presenting cells, although tissue and cells derived from the corneal limbus were allostimulatory. In addition, iris/ciliary body tissues and cells displayed the ability to suppress mixed lymphocyte reactions to which they had been added as regulatory cells. We conclude that normal iris and ciliary body contain bone marrow-derived cells that fail to function as alloantigen-presenting cells. However, cells were present that have the capacity to inhibit alloimmune lymphocyte proliferation. The strategic location of inhibitory cells in the tissues that line the anterior chamber of the eye raises the possibility that these cells may play a role in the phenomenon of immunological privilege that is characteristic of this site.     

Comparison of contrast in brightness mode and strain ultrasonography of glial brain tumours

ABSTRACT: BACKGROUND: Image contrast between normal tissue and brain tumours may sometimes appear to be low in intraoperative ultrasound. Ultrasound imaging of strain is an image modality that has been recently explored for intraoperative imaging of the brain. This study aims to investigate differences in image contrast between ultrasound brightness mode (B-mode) images and ultrasound strain magnitude images of brain tumours. METHODS: Ultrasound radiofrequency (RF) data was acquired during surgery in 15 patients with glial tumours. The data were subsequently processed to provide strain magnitude images. The contrast in the B-mode images and the strain images was determined in assumed normal brain tissue and tumour tissue at selected regions of interest (ROI). Three measurements of contrast were done in the ultrasound data for each patient. The B-mode and strain contrasts measurements were compared using the paired samples t- test. RESULTS: The statistical analysis of a total of 45 measurements shows that the contrasts in the strain magnitude images are significantly higher than in the conventional ultrasound B-mode images (P < 0.0001). CONCLUSIONS: The results indicate that ultrasound strain imaging provides better discrimination between normal brain tissue and glial tumour tissue than conventional ultrasound B- mode imaging. Ultrasound imaging of tissue strain therefore holds the potential of becoming a valuable adjunct to conventional intraoperative ultrasound imaging in brain tumour surgery.     

Tumours may be innervated

It is generally assumed that tumours are not innervated. However, following an accidental observation of a nerve fibre within an adenoma of the ciliary body epithelium of the eye, we have further examined two such tumours. One pigmented and one non-pigmented adenoma of the ciliary body epithelium (APCE and ANCE, respectively) that had been surgically removed from two human eyes were processed for ultrastructural evaluation and systematically screened and analysed for the occurrence of nerve tissue under a transmission electron microscope. The adenomas were composed of epithelial tumour cell strands and interposed vascularised connective tissue. Both tumours contained a small number of fine unmyelinated nerve fibres containing clear and dense core vesicles. In both adenomas, the nerve fibres were located in the tumour periphery close to blood vessels and tumour cells. In the APCE, they were also seen in more central areas. Since nerves always have a function, this finding, if confirmed in other neoplasms, may influence our understanding of such innervated tumours.     

3D MRI-based tumor delineation of ocular melanoma and its comparison with conventional techniques

The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heights < or = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.     

Substance P and opioid peptidergic innervation of the anterior eye segment of the rat: an immunohistochemical study

Recently discovered endogenous opioid peptides such as nociceptin are known to modulate neurotransmitter release of primary afferent neurons (especially substance P, SP) and they have also been demonstrated in peripheral nerve fibres. The aim of this study was to investigate the opioid peptidergic innervation of the anterior eye segment and to compare it with the innervation pattern of SP in order to shed light on the functional relationship between these peptides. Anterior eye segments of 20 rat eyes were cut in a tangential plane and the sections stained with antibodies against SP, nociceptin, nocistatin, endomorphin 1 and 2, leu-enkephalin and met-enkephalin. Sections of the spinal cord or brain were used as positive controls. Numerous SP-immunoreactive nerve fibres were found in the conjunctiva, cornea, episclera, trabecular meshwork, iris and ciliary body. A weak staining for met-enkephalin and leu-enkephalin could only be found in the iris and anteriormost ciliary body. Nerve fibres immunoreactive for nociceptin, nocistatin, and endomorphin 1 or 2 could not be detected in any part of the anterior eye segment. It is tempting to speculate that the opioid peptidergic innervation of the anterior ciliary body may play a role in the modulation of intraocular inflammation.     

High‐resolution MRI of uveal melanoma using a microcoil phased array at 7 T

High‐field MRI is a promising technique for the characterisation of ocular tumours, both in vivo and after enucleation. For in vivo imaging at 7 T, a dedicated three‐element microcoil array was constructed as a high‐sensitivity receive‐only device. Using a dedicated blink/fixation protocol, high‐resolution in vivo images could be acquired within 3 min in volunteers and patients with no requirement for post‐acquisition image registration. Quantitative measures of axial length, aqueous depth and lens thickness in a healthy volunteer were found to agree well with standard ocular biometric techniques. In a patient with uveal melanoma, in vivo MRI gave excellent tumour/aqueous body contrast. Ex vivo imaging of the enucleated eye showed significant heterogeneity within the tumour. Copyright © 2013 John Wiley & Sons, Ltd.     

Immunolocalisation studies of matrix metalloproteinases-1, -2 and -3 in human melanoma

The matrix metalloproteinases (MMPs) are considered to have an important role in connective tissue degradation and have been implicated in the mechanisms of tumour invasion and metastatic spread. We have used immunohistochemistry to examine and compare the tissue distributions of collagenase-1 (MMP-1), gelatinase A (MMP-2) and stromelysin-1 (MMP-3) in 18 specimens of malignant melanoma, viz. 10 superficial spreading and 8 nodular melanomas. MMPs-1, -2 and -3 were demonstrated within melanoma and host tissue cells, especially at the periphery of some tumours, but were usually restricted to less than 10% of total melanoma cells. The MMPs were absent from ’normal’ skin tissue distant from the tumour. MMP-2 was localised to discrete groups of cells and was especially evident at the epidermal:tumour interface, whereas MMP-3 was mainly confined to the deeper margins of melanoma. No regular pattern of MMP expression was observed for either the superficial spreading or the nodular melanomas. The variable distributions of the MMPs suggested that enzyme expression was subject to local microenvironmental regulation, possibly in response to matrix components and the cellular heterogeneity observed at the tumour margins. These in situ observations add weight to the concept that specific MMPs contribute to the mechanisms of tumour invasion. Received: 10 March 1999 / Accepted: 6 July 1999     

Transition zone carcinoma of the prostate gland: a common indolent tumour type that occasionally manifests aggressive behaviour

AIMS: Tumours arising in the transition zone (TZ) of the prostate gland are often well differentiated and considered clinically unimportant. We have observed examples of high-grade TZ cancers that prompted this study. METHODS: Review of 654 radical prostatectomy specimens previously assessed by systematic whole organ histology identified 187 (29%) TZ cancers of which 76 (11.6%) represented the index (main) tumour. These were compared with a volume-matched group of 76 peripheral zone (PZ) carcinomas. RESULTS: Fifty-nine of 76 TZ index carcinomas had additional minor tumours mainly located in the PZ. Compared to PZ tumours of similar size, TZ tumours had significantly lower Gleason scores, less Gleason grade 4/5 and lower rates of capsular penetration and positive surgical margins. However, within this TZ tumour group, seven carcinomas had a major Gleason grade 4 or 5 component with high rates of capsular penetration (57%) and positive surgical margins (43%). Positive anterior and bladder neck margins were more common in TZ carcinoma than peripheral tumours and transperineal biopsy was the method of choice for TZ cancer diagnosis. CONCLUSIONS: A subset of TZ carcinoma characterised by high tumour grade has a significant risk of extraprostatic spread, margin positivity and possible biochemical failure. We recommend transperineal prostate biopsy for TZ tumour diagnosis and histological sampling of the anterior TZ at radical prostatectomy, even if macroscopically normal, to detect patients at risk from aggressive TZ carcinoma.     

Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis

Posterior uveal melanomas have nonrandom alterations affecting chromosomes 3, 6, and 8. Loss of chromosome 3 in uveal melanoma has been shown to act as a predictor of disease-free and overall survival. To confirm the significance of chromosome 3 loss and to extend the observations to include those of the associated alterations of chromosome 8, we have conducted a cytogenetic analysis on a series of 42 tumours from patients with primary uveal melanoma who were followed up for a median of 31 months (range = 8-96 months). Abnormalities of chromosomes 3 and 8 were the commonest changes and were confirmed in 10 tumours using flourescence in situ hybridization. Monosomy of chromosome 3 was found in 21 (50%) of the tumours, and 23 (54%) tumours had additional copies of 8q. Alterations of chromosomes 3 and 8 were found occurring together in 19 (45%) of the tumours and were significantly associated with a ciliary body component (P < 0.0001). Prognostic indicators and changes of chromosomes 3 and 8 were analysed for correlation with patient survival. Of the chosen parameters, only ciliary body involvement (P = 0.003), monosomy of chromosome 3 (P = 0.0007), and additional copies of 8q (P = 0.003) correlated with reducted survival. Evaluation of the dosage effect of additional copies of chromosome arm 8q showed a significant association with reduced survival (P = 0.0001), which was also predictive of a decreased disease-free interval (P = 0.01). Thus, the cytogenetic analysis of uveal melanoma may provide a valuable predictor of prognosis. Genes Chromosom. Cancer 19:22–28, 1997. © 1997 Wiley-Liss, Inc.     

Dosimetric consequences of inter-fraction breathing-pattern variation on radiotherapy with personalized motion-assessed margins

The data from eight patients who had undergone stereotactic body radiotherapy were selected due to their 4D-CT planning scans showing that their tumours had respiratory induced motion trajectories of large amplitude (greater than 9 mm in cranio-caudal direction). Radiotherapy plans with personalized motion-assessed margins were generated for these eight patients. The margins were generated by inverse 4D planning on an eight-bin phase-sorted 4D-CT scan. The planning was done on an in-house software system with a non-rigid registration stage being completed using freely available software. The resultant plans were then recalculated on a 4D-CT scan taken later during the course of treatment. Simulated image-guided patient set-up was used to align the geometric centres of the tumour region and minimize any misalignment between the two reconstructions. In general, the variation in the patient breathing patterns was found to be very small. Consequently, the degradation of the mean dose to the tumour region was found to be around a few percent (<3%) and hence was not a large effect.     

Volume measurement variability in three-dimensional high-frequency ultrasound images of murine liver metastases

The identification and quantification of tumour volume measurement variability is imperative for proper study design of longitudinal non-invasive imaging of pre-clinical mouse models of cancer. Measurement variability will dictate the minimum detectable volume change, which in turn influences the scheduling of imaging sessions and the interpretation of observed changes in tumour volume. In this paper, variability is quantified for tumour volume measurements from 3D high-frequency ultrasound images of murine liver metastases. Experimental B16F1 liver metastases were analysed in different size ranges including less than 1 mm3, 1-4 mm3, 4-8 mm3 and 8-70 mm3. The intra- and inter-observer repeatability was high over a large range of tumour volumes, but the coefficients of variation (COV) varied over the volume ranges. The minimum and maximum intra-observer COV were 4% and 14% for the 1-4 mm3 and <1 mm3 tumours, respectively. For tumour volumes measured by segmenting parallel planes, the maximum inter-slice distance that maintained acceptable measurement variability increased from 100 to 600 microm as tumour volume increased. Comparison of free breathing versus ventilated animals demonstrated that respiratory motion did not significantly change the measured volume. These results enable design of more efficient imaging studies by using the measured variability to estimate the time required to observe a significant change in tumour volume.     

Expression of Fas and Fas ligand in uveal melanoma: biological implication and prognostic value

The interaction between Fas and Fas ligand is one possible immune escape mechanism used by tumour cells. In the present study, melanoma tissue from 103 patients who underwent enucleation for malignant uveal melanoma (iris melanomas excluded) was stained by immunohistochemistry with monoclonal antibodies specific for Fas, Fas ligand, CD3, CD8, and CD68. Histological and clinical data for these tumours were assessed. Both Fas and Fas ligand were detected in uveal melanomas. Cells of the monocyte/macrophage lineage rather than T-cells were the predominant group of tumour-infiltrating cells. The metastasis-free 5-year survival rates in the univariate analyses were considerably lower in patients with tumours that lacked Fas ligand expression (< 35% of the tumour cells), in the presence of more than 50 CD8-positive cells in 20 high-power fields and in the presence of more than 100 CD3-positive cells in 20 high-power fields. Fas and Fas ligand expression was associated with scleral infiltration. After adjustment for scleral infiltration, the predictive value of both Fas and Fas ligand expression was markedly decreased. In addition, the CD3- and CD8-positive cell count was positively associated with the histological cell type. Cox proportional hazards models showed that the presence of CD3- and CD8-positive cells was not an independent prognostic factor after adjusting for histological cell type. This preliminary observation deserves further investigation, which may shed more light on the immune escape mechanisms of this tumour and thus enable novel therapeutic strategies. The clinical relevance of this observation is limited, as more predictive parameters have been described for uveal melanoma.     

Intraocular biocompatibility of hydroxyethyl methacrylate and methacrylic acid copolymer/partially hydrolyzed poly(2-hydroxyethyl methacrylate)

A strip of partially hydrolyzed poly (2-hydroxyethyl methacrylate) containing 65%-75% H2O was implanted into the anterior eye chamber of 11 Chinchilla rabbits. No pathological changes were found in the iris or in the ciliary body. The pathological findings in the cornea accompanying implantation of a hydrogel strip to the anterior chamber were rare and not significant. The low occurrence of the foreign body giant multinucleate cells was observed on the implant surface 6 months after the implantation. Favorable properties of this hydrogel depend probably on its high water and acidic groups content.     

The plateau iris component of primary angle closure glaucoma: developmental or acquired

Primary angle closure glaucoma has been called the most common form of glaucoma in the world, and the leading cause of bilateral blindness. Pupillary block is felt to be the main mechanism of outflow obstruction in this condition. Recent advances in morphologic assessment of angle closure, specifically by means of ultrasound biomicroscopy, have revealed that plateau iris in eyes with angle closure glaucoma is more common than had previously been thought. The most characteristic finding in this disease is thicker and more anteriorly positioned lens. This induces the pupillary block that relives by laser iridotomy. Residual angle closure after laser iridotomy is due to the plateau iris. Peripheral iridoplasty, the standard treatment of plateau iris, tights the peripheral iris and opens the angle but has no effect on the ciliary processes configuration. The ciliary processes are positioned posteriorly after lens extraction but dose not disappears completely. Considering these facts we hypothesized that the plateau iris in primary angle closure glaucoma is a developmental entity that reaches to a critical stage with aging owing to the thickening and forward movement of the lens. Cataract surgery deeps the anterior chamber, widens the irido-corneal angle and reposits the ciliary processes posteriorly, so it can prevents synechia formation and progressive lens-induced angle narrowing and plateau iris progression, the acquired component, with aging.     

Magnetic resonance imaging based volume estimation of ovarian tumours: use of a segmentation and 3D reformation software

The application of a new segmentation software, Anatomatic™ in the evaluation of volumetric measurements of ovarian tumours and the new Medimag™ three-dimensional (3D) software in the evaluation of 3D image representation of ovarian tumours with 1.5 T magnetic resonance imaging (MRI) is described. Our goal was to compare MRI based volumetry with operative findings at laparotomy for six consecutive patients with suspected ovarian tumours. Volumetric analysis and three dimensional image reconstructions of the tumours were obtained. At laparotomy, the tumour sizes were measured in situ, and the volumes were calculated. Using Anatomatic™, reproducible tumour volumes were achieved with ease and within a reasonably fast time in patients with ovarian tumours without ascites. Medimag™ helped achieve realistic 3D representations of the tumours. For the four solitary tumours segmentation based volumetry and laparotomy findings agreed in three cases. In one patient with an oval shaped tumour, the segmented volume was double as compared to that estimated at laparotomy. Of the two patients with multiple tumours, both patients had significant ascites, and volumetry misinterpreted the fluid as tumour cyst fluid and markedly overestimated the tumour size. In conclusion, the MRI based segmentation volumetry and 3D image reconstructions are rapid, and reproducible methods of measuring ovarian tumours in patients without significant ascites.     

Simulation of organ-specific patient effective dose due to secondary neutrons in proton radiation treatment

Cancer patients undergoing radiation treatment are exposed to high doses to the target (tumour), intermediate doses to adjacent tissues and low doses from scattered radiation to all parts of the body. In the case of proton therapy, secondary neutrons generated in the accelerator head and inside the patient reach many areas in the patient body. Due to the improved efficacy of management of cancer patients, the number of long term survivors post-radiation treatment is increasing substantially. This results in concern about the risk of radiation-induced cancer appearing at late post-treatment times. This paper presents a case study to determine the effective dose from secondary neutrons in patients undergoing proton treatment. A whole-body patient model, VIP-Man, was employed as the patient model. The geometry dataset generated from studies made on VIP-Man was implemented into the GEANT4 Monte Carlo code. Two proton treatment plans for tumours in the lung and paranasal sinus were simulated. The organ doses and ICRP-60 radiation and tissue weighting factors were used to calculate the effective dose. Results show whole body effective doses for the two proton plans of 0.162 Sv and 0.0266 Sv, respectively, to which the major contributor is due to neutrons from the proton treatment nozzle. There is a substantial difference among organs depending on the treatment site.