Melanin-laden Macrophages Research Articles

Leflunomide for the Treatment of Immune-Mediated Uveitis in a Dog.

A 5 yr old castrated male bichon frise presented with chronic bilateral uveitis that had previously been controlled with systemic steroid administration for 6 mo, resulting in weight gain, polyuria, and polydipsia. To control the uveitis without systemic side effects, oral cyclosporine was started after discontinuing oral steroid, but discontinued one month later because of severe vomiting. Leflunomide (2 mg/kg q 12 hr) was initiated, and the uveitis symptoms resolved after 2 mo. The dose was tapered according to the remission of clinical signs, with no relapse during the following 13 mo. Leflunomide therapy was then discontinued due to vomiting caused by severe gastroenteritis and pancreatitis, and topical prednisolone monotherapy was continued . At 8 mo after discontinuation of leflunomide, bilateral uveitis recurred, and leflunomide therapy was resumed. However, the patient lost vision due to the progression of clinical signs at 33 mo after commencing leflunomide, and evisceration of the glaucomatous right eye was performed at 43 mo. Histopathologic examination revealed lymphocyte and plasma cell infiltration and melanin-laden macrophages in the uveal tissue, and the patient was diagnosed with immune-mediated uveitis. This case indicated that oral leflunomide may be a viable treatment option for canine idiopathic immune-mediated uveitis.

Linear atrophoderma of Moulin on the neck

Linear atrophoderma is a rare disease, first described by Moulin in 1992 in 5 patients. It is an acquired unilateral hyperpigmented, depressed band-like areas following the lines of Blaschko. It affects children or adolescents of both genders involving the trunk or the limbs. It is considered to be a rare cutaneous form of mosaicism. A 39-year-old woman with a 22 years history of unilateral slightly depressed hyperpigmented lesion on her neck was admitted to us. The skin texture was normal and there were no signs of induration or sclerosis. The histopathological examination revealed a normal epidermis outlined by a hyperpigmented basal layer. In the papillary dermis proliferation of superficial vessels with mild lymphocytic infiltrate and melanin-laden macrophages were present. The collagen fibres and elastic fibres were normal. The clinical and histopathological features confirmed the diagnosis of linear atrophoderma of moulin. We discussed the case according to the other cases reported in the literature. Approximately 28 cases of linear atrophoderma have been reported in literature. The present case has the charecteristic clinical and histopathological features of linear atrophoderma as defined by Moulin, but the localization of the lesion is unusual.

Predominant exudative retinopathy in incontinentia pigmenti and clinical course after peripheral laser photocoagulation

Dear Editor, Incontinentia pigmenti (IP) (Bloch-Sulzberger syndrome) is an X-linked condition with dermatological, dental, neurological and ocular abnormalities. Ocular abnormalities occur in 25–77% cases of IP.[1] The characteristic manifestation is a proliferative retinopathy which includes peripheral retinal vascular nonperfusion, preretinal neovascularization, preretinal or vitreous hemorrhage and infantile tractional retinal detachment.[2] In contrast, an early presentation of IP as predominant exudative retinopathy is not commonly reported.[3] We report a case of IP with predominant exudative retinopathy and successful resolution after laser photocoagulation. A 50-day-old female infant was referred for ophthalmology examination from pediatric neurology. The infant was born with an uneventful normal delivery at term and a birth weight of 3000 g. The infant had a vesicular rash on extremities at birth and seizures since second day of life. The infant was diagnosed as IP based on the typical skin lesions [Fig. 1a], magnetic resonance imaging (MRI) findings and pathological findings on skin biopsy.Figure 1: (a) Skin lesions on the trunk and the arm; (b) fundus right eye shows abnormally dilated and tortuous posterior pole vessels, exudative retinal detachment and multiple hemorrhages; (c) right eye, 1 month after laser with residual lipid exudates and nasal falciform fold; (d) right eye, 6 months after laser shows nasal falciform fold and submacular scar (arrow)On fundus examination of right eye, there were dilated and tortuous vessels with exudative retinal detachment at the posterior pole [Fig. 1b]. On indirect ophthalmoscopy with scleral indentation, there was 360° peripheral avascular retina with multiple preretinal hemorrhages. The left eye revealed dilation of posterior pole vessels, minimal exudation in posterior pole, few preretinal hemorrhages and peripheral avascular retina. In view of severe vascular abnormalities, the infant underwent bilateral laser photocoagulation of the entire peripheral avascular retina with diode laser (IRIS Medical Oculight SL, 810 nm infrared laser, Iris Medical Inc., Mountain View, CA, USA) (right eye 1123 spots, left eye 925 spots;400 msec, 400 mW). One-week post laser, there was reduction in vascular tortuosity and exudative retinal detachment in the right eye. There was complete resolution of exudative retinal detachment with a nasal falciform fold at 1-month follow-up [Fig. 1c]. The subretinal exudates resolved over a 3-month period with submacular scar. The left eye changes resolved completely without any sequelae. The infant shows a stable clinical course at 6 months [Fig 1d]. The present case had a predominant exudative response in contrast to the usual proliferative retinopathy seen in majority of cases of IP. These unusual findings are similar to a rare case described previously, which postulated these changes as an inflammatory chorioretinitis.[3] The exact etiology of these changes was unknown and the outcome not described. Subsequently, subretinal exudation containing melanin laden macrophages and lipofuscin was documented in eyes enucleated for total retinal detachment in IP.[4] The etiology of the neovascular retinopathy is more clear, which may result due to oxygen insufficiency caused by peripheral retinal non-perfusion.[2] The extensive exudation seen in the present case appears similar to other disorders like familial exudative vitreo-retinopathy and Coats disease with avascular retina and an abnormal capillary bed. Similar to these disorders, laser photocoagulation was successful in resolution of exudation. A previous study reports successful outcome after laser photocoagulation for proliferative retinopathy of IP.[5] In conclusion, exudative retinopathy in IP is uncommon and can be successfully treated with laser photocoagulation of peripheral avascular retina.

Melanin-Laden Macrophages in the CSF to Diagnose Vogt-Koyanagi-Harada Simulating Ocular Syphilis

Purpose: To describe a case of Vogt-Koyanagi-Harada (VKH) disease initially presenting as ocular syphilis. Methods: A 51-year-old woman presented with counting fingers vision in both eyes. She underwent a complete ophthalmic examination, serological testing, fluorescein angiography, and CSF analysis. Results: Serological testing revealed positive titers for syphilis. Fluorescein angiography demonstrated findings suggesting VKH. CSF cytology showed macrophages containing melanin granules consistent with VKH. Subsequent treatment with corticosteroids and cyclosporine resulted in significant improvement of vision. Conclusion: The presence of melanin-laden macrophages within the CSF allows for the differentiation of VKH from ocular syphilis.

Conditional N-rasG12V expression promotes manifestations of neurofibromatosis in a mouse model

Human clinical neurofibromatosis type 1 (NF1) and type 2 (NF2) result from mutations and inactivation of neurofibromin and merlin genes, respectively, which negatively regulate Ras pathways. To evaluate the contribution of N-Ras activity to the development of NF, we generated a novel transgenic mouse expressing oncogenic N-ras specifically in central nerve cells, neural crest-derived cells and lens epithelial cells. Soon after birth, the mouse skin showed hyperpigmentation of the epidermis and melanin-laden macrophages in the dermis, as observed in the café-au-lait spots of human cases. At 3 months of age, all the mice had neurofibromas in the skin and neurofibroma-like tumors with structure similar to Wagner-Meissner bodies in the adrenal medulla. At 4 months of age, all the mice developed subcapsular cataract. In the 5th month, some developed protruding dermal neurofibromas involving subcutaneous fat. However, plexiform neurofibroma, schwannoma, astrocytoma and pheochromocytoma were not observed in the mice, suggesting a requirement for signal(s) other than the activated N-Ras pathway to induce these tumors. Thus, the activated N-Ras signal may be a main pathway for the development of the disease phenotypes characteristic of NF.

MRI correlates of pathology in parkinsonism:: segmented inversion recovery ratio imaging (SIRRIM)

The two commonest, clinically well-defined, forms of parkinsonism are idiopathic Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Both involve, inter alia, pathological changes in the substantia nigra pars compacta (SNC). In PD there is neuronal loss with associated Lewy body pathology and microglial activation. Three morphological features have been identified [Brain 114 (1991), 2283; Greenfield's Neuropathology 2 (1997), 289]. First, there is a gradient of pathological change such that the lateral segments are more affected than the medial. Second, there is thinning of the pigmented tissue, and third, there is a broadening of the overall structure in a dorsal-ventral direction, possibly caused by the migration of melanin-laden macrophages [Greenfield's Neuropathology 2 (1997), 289]. In contrast, PSP is characterized pathologically by intraneuronal neurofibrillary tangles. There are two morphological features in the SNC [Brain 114 (1991), 2283]. First, the gradient of pathological change is in the opposite direction to that of PD (i.e., the medial segments are more affected than the lateral). Second, there is atrophy. Any technique sensitive to neuropathology should be capable of detecting these features. We have previously reported on a new approach to detecting signal change in the substantia nigra in PD. This makes use of a ratio of images acquired by two distinct inversion recovery sequences [J. Neurol, Neurosurg. Psychiatry 67 (1999), 815; Am. J. Neuroradiol. 21 (2000) 697]. The prior work suggests that the technique is sensitive to, but not necessarily specific for, PD. We present here a preliminary report on an extension of the work. This is a semiautomated segmentation analysis that enables the substantia nigra to be displayed as an isolated structure. The technique is now given the acronym SIRRIM (segmented inversion recovery ratio imaging). In contrast to our earlier work, it allows for a more accurate assessment of the gross abnormalities. We report typical SIRRIM images of the SNC. Images are shown for three subjects: a normal control, a patient with PD, and a “disease control” (a patient with PSP). In these examples all three morphological features of PD, as well as both morphological features of PSP, have radiological correlates. These preliminary findings suggest that SIRRIM may be specific for both diseases.

Effect of melanin on traumatic hyphema in rabbits.

To investigate the role of melanin in influencing the clearance of traumatic hyphema and in the incidence of rebleeds following the hyphemas. Hyphemas were induced in 30 eyes of New Zealand white albino rabbits using an Nd:YAG laser. A total of 3.75 mg of synthetic melanin suspended in 0.1 mL of balanced salt solution was introduced into the anterior chambers of 16 animals. A total of 0.1 mL of balanced salt solution was injected into 14 control eyes. Hyphema levels were measured by a masked observer (V.D.B.) daily for 15 days. Pairs of animals were sacrificed at 1, 3, 5, 10, and 15 days and the eyes studied histologically. Hyphemas were consistently produced in all eyes with mean+/-SD levels of 1.44+/-0.22 mm and 1.57+/-0.24 mm in the melanin-treated and control eyes, respectively. The clearance of hyphemas in the melanin-treated eyes was significantly prolonged throughout the study (P<.001). The rate of rebleed in the melanin-treated group was 18.8% and in the control group was 7.1% (P<.01). Histologically, both groups showed variable degrees of blood in the anterior chambers and trabecular meshwork. In addition, the melanin-treated eyes showed free melanin, melanin-laden macrophages, and an inflammatory response in the anterior chamber and trabecular meshwork that was greater than that in the control eyes. Melanin-treated eyes with rebleeds showed organized hemorrhage with neovascularization. The presence of melanin results in a significantly prolonged course of hyphemas and may influence the rate of rebleeds. Occlusion of the trabecular meshwork with melanin-laden macrophages and inflammation may be the mechanisms responsible for these effects. The release of melanin into the anterior chamber during ocular trauma may be partly responsible for the susceptibility of darker-pigmented individuals to more serious complications following a traumatic hyphema.

Fine Needle Aspiration Cytology of Dermatopathic Lymphadenitis

To delineate and describe the cytomorphologic features of dermatopathic lymphadenitis on fine needle aspirated material. Thirteen cases of previously diagnosed dermatopathic lymphadenitis (DLN) and 10 cases of reactive lymphadenitis (RLN) (5 each of sinus histiocytosis and follicular hyperplasia) were reexamined by two independent observers. The cytologic features were semiquantitated (0-3+). Histology was available in two cases. A variable amount of melanin pigment was seen in all 13 cases of DLN and in only 3 cases of RLN. DLN had large histiocytic collections with blood vessels at the center (12/13). The histiocytic cells had an elongated nucleus (13/13) with nuclear grooves (13/13) and pseudonucleoli (11/13). Many of these nuclei had a convoluted and crumpled appearance (11/13). On immunocytochemistry these cells were S-100 positive (six cases) and CD68 negative (one case). In contrast, in RLN with sinus histiocytosis, the histiocytes were polygonal and had rounded nuclei. Spindle-shaped histiocytes were rare, while pseudonucleoli and nuclear grooves were absent. Sinus histiocytes were CD68 positive and S-100 negative on histologic sections. Tingible body macrophages were rare (2/13) in DLN and prominent (8/10) in RLN. Mitoses were seen in DLN (6/13) and RLN (9/10). The morphologic features found to be helpful in the diagnosis of DLN on fine needle aspiration cytology are melanin-laden macrophages with variable pigment; large, histiocytic clusters with blood vessels at the center; characteristic histiocytes, with elongated vesicular nuclei, nuclear grooves, crumpled and convoluted nuclei and pseudonucleoli; and absence of or very few tingible body macrophages. Positivity on immunostaining for S-100 and negativity for CD68 aid in the diagnosis.

Melanin-laden macrophages in cerebrospinal fluid in Vogt-Koyanagi-Harada syndrome.

To identify basophilic granules in the cytoplasm of macrophages in cerebrospinal fluid (CSF) smears from patients with Vogt-Koyanagi-Harada (VKH) syndrome as melanin pigment. Morphological and immunocytochemical studies were performed on CSF smears obtained from 7 patients with VKH syndrome. Specimens were stained with May-Grünwald and evaluated by a silver impregnation method (Fontana-Masson staining). For immunocyto-chemical study, the smear was reacted with mouse anti-human melanoma cell (HMB-45) monoclonal antibody. Basophilic granules were detected in the cytoplasm of macrophages in CSF cell smears obtained from 6 of 7 patients with VKH syndrome in the early stages (within 25 days). Using the silver impregnation method, these basophilic granules were strongly stained black. Moreover, they were identified as melanin by positive immunocytochemical staining. The total number of cells containing cytoplasmic granules ranged from 3 to 8 per 10,000 total cells in CSF. In contrast, no cells containing cytoplasmic granules were found in control CSF cell smears from patients with viral, bacterial, or noninflammatory diseases. The identification of melanin-laden macrophages in the CSF of patients with VKH syndrome suggests that these cells are responsible for pleocytosis in the immunopathologic process of VKH syndrome.

Treatment of nevus of Ota by Q-switched ruby laser

There are few reports on therapy for nevus of Ota. Moreover, traditional treatments are largely palliative or risk permanent pigmentary changes and/or scarring. The efficacy of the Q-switched ruby laser (694 nm, 40 nsec) as a therapy for nevus of Ota was investigated. Nine nevi or portions thereof were irradiated up to six times with 4.5 and/or 7.5 J/cm2 at a mean exposure interval of 3 weeks. Sequential skin biopsy specimens were processed for light microscopy, immunohistochemistry, and electron microscopy. Cosmetic improvement occurred at both doses in the irradiated parts of the six nevi available for follow-up. No appreciable difference was noted between single and multiple treatments. There was no gross scarring. Light microscopy revealed dose-related immediate injury with more melanophages and fewer dermal melanocytes after irradiation in comparison with control areas. Electron microscopic distinction between dermal melanocytes and melanin-laden macrophages was difficult. A monoclonal antibody to human melanosome-specific antigen type 1 (HMSA-1) was used to distinguish between the two cell populations. Our findings suggest that the Q-switched ruby laser is useful for treating nevus of Ota.

A nude rat model for neutron capture therapy of human intracerebral melanoma

Purpose : The present study was carried out to determine the efficacy of Boron Neutron Capture Therapy (BNCT) for intracerebral melanoma using nude rats, the human melanoma cell line MRA 27, and boronophenylalanine as the capture agent. Methods and Materials : Pharmacokinetic and tissue distribution studies: MRA 27 cells (2 X 10 5) were implanted intracerebrally, and 30 days later, 120 mg of 10B-L-BPA were injected intraperitoneally into nude rats. Therapy experiments: Thirty days following implantation, tumor bearing rats were irradiated at the Brookhaven Medical Research Reactor. Results : Pharmacokinetic experiments: Six hours following administration of BPA, tumor, blood, and normal brain boron-10 levels were 23.7, 9.4, and 8.4 μ/g respectively. Therapy experiments: Median survival time of untreated rats was 44 days compared to 76 days and 93 days for those receiving physical doses of 2.73 Gy and 3.64 Gy, respectively. Rats that had received both 10B-BPA and physical doses of 1.82, 2.73, or 3.64 Gy had median survival times of 170, 182, and 262 days, respectively. Forty percent of rats that had received the highest tumor dose (10.1 Gy) survived for > 300 days and in a replicate experiment 21% of the rats were longterm survivors (> 220 days). Animals that received 12 Gy in a single dose or 18 Gy fractionated (2 Gy X 9) of gamma photons from a 137Cs source had median survival times of 86 and 79 days, respectively, compared to 47 days for untreated animals. Histopathologic examination of the brains of longterm surviving rats, euthanized at 8 or 16 months following BNCT, showed no residual tumor, but dense accumulations of melanin laden macrophages and minimal gliosis were observed. Conclusion : Significant prolongations in median survival time were noted in nude rats with intracerebral human melanoma that had received BNCT thereby suggesting therapeutic efficacy. Large animal studies should be carried out to further assess BNCT of intracerebral melanoma before any human trials are contemplated.

Malignant melanotic neuroectodermal tumor arising from the pineal body

A case of a melanotic neuroectodermal tumor arising from pineal region of a 4-year-old girl is presented. The tumor had spread diffusely to the meninges, consistent with malignant behavior. Histologically, the tumor consisted primarily of epithelial elements arranged in tubules, cords and nests separated by fibrous vascular tissue in addition to a small neuroblastomatous focus. Melanin pigment was frequently observed in the epithelial tumor cells, and melanin-laden macrophages were also often observed. No teratoid elements were found. Immunohistochemically, tumor cells were positive for neuron-specific enolase but were nonreactive for S-100 protein, epithelial membrane antigen, glial fibrillary acidic protein, vimentin, alpha-fetoprotein and human chorionic gonadotrophin. Ultrastructurally, the epithelial nature of the tumor cells could be easily demonstrated. In addition, melanosomes in various stages in maturation were observed, indicating melanogenesis of the tumor. On the basis of the tumor location and the histological similarities previously observed for the fetal pineal body, it is very likely that this melanotic epithelial tumor could have originated from the fetal pineal gland.

Gibt es zirkumskripte Melanosen beim Melanomkranken?

Regarding the rare phenomenon of diffuse melanosis of the skin secondary to widespread melanoma, the possibility of a circumscribed melanosis in melanoma patients is hypothetically discussed on the basis of a personal observation. Microscopically, such a circumscribed melanosis appears as clusters of melanin-laden macrophages.