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Biomedical subjects

H Mietz

Publications and source records attributed to H Mietz.

At least 19 recordsLinked to original sources

Effect of cataract surgery on intraocular pressure in eyes with previous trabeculectomy.

PURPOSE: To determine the course of the intraocular pressure in eyes in which cataract surgery was performed after trabeculectomy. METHODS: This was a retrospective study of consecutive patients who were scheduled for routine cataract surgery. The patients had previously undergone glaucoma filtering surgery. Pre- and postoperative data were evaluated. Both the status of glaucoma and the increase in visual acuity were monitored. RESULTS: Patients operated on over a six-year period were enrolled. The mean interval between glaucoma surgery and cataract surgery was 58.1 months. The mean duration of follow-up after cataract surgery was 31.4 months, with a minimum of 12 months. The mean central visual acuity increased by 4 lines. Before cataract surgery, 53% of the eyes had complete success (group 1), while 28% had qualified success (group 2) and the remaining 19% were failures (group 3). From group 1, 61% remained a complete success until the last visit. No eye of group 1 developed a failure. In group 2, 23% were a complete success at the final follow-up, while 4% failed. In group 3, only 35% were failures while the remaining 65% were a complete or qualified success. CONCLUSIONS: Eyes with a well-controlled intraocular pressure following trabeculectomy seem to have a favorable prognosis after subsequent cataract surgery. Eyes with qualified success or failure before cataract surgery have a slight chance of improvement in intraocular pressure control. Cataract surgery had no markedly negative effect on the intraocular pressure overall. Performing trabeculectomy and cataract surgery at different times may still be a feasible option as opposed to combined procedures.

Adult↗

Effect of latanoprost and timolol on the histopathology of the rabbit conjunctiva.

PURPOSE: Long-term medical treatment of glaucoma has an effect on the conjunctiva, possibly affecting the outcome of subsequent filtering surgery. The type and extent of these tissue changes caused by frequently used medications is important. An animal study using rabbits was performed to assess the tissue changes caused by timolol, latanoprost, and a combination of both substances. METHODS: Rabbits were treated with timolol, latanoprost, or a combination of these drugs for 18 months. Conjunctival specimens were examined by light microscopy, quantitative transmission electron microscopy, and immunohistochemistry with antibodies against matrix metalloproteinase (MMP)-3 and tissue inhibitors of metalloproteinase (TIMP)-2. RESULTS: By electron microscopy, the area of subepithelial collagen was significantly larger (P: < 0.03; Mann-Whitney test) in timolol-treated eyes (71.6%) than in control (52.7%) and latanoprost-treated eyes (57.7%). An increase of amorphous material was present in timolol-treated eyes (25.6% versus 7.6% in the controls) as well as a smaller area of empty spaces (2.5% versus 39.4% in control eyes). Latanoprost-treated eyes had no significant increase of empty spaces but showed a marked staining for MMP-3 in the conjunctiva. This staining was not present in control or timolol-treated eyes. Morphologically, degenerative changes of fibrocytes were seen in timolol-treated eyes only. CONCLUSIONS: A significant increase of subepithelial collagen density was present in timolol-treated eyes, whereas this finding was not apparent in latanoprost-treated eyes. Latanoprost-treated eyes showed an upregulation of MMP-3, which may be the reason for reduced extracellular matrix accumulation in such eyes. The morphologic feature of increased subepithelial collagen density and extracellular matrix changes may relate to failure of filtering blebs.

Animals↗

Postoperative application of mitomycin for trabeculectomies.

BACKGROUND: Persistent hypotony is a severe complication following trabeculectomy with intraoperative application of mitomycin. OBJECTIVE: To reduce this rate of hypotony by using a lower concentration of mitomycin and applying the mitomycin only topically to the filtering bleb following surgery. METHODS: Patients were enrolled on a consecutive basis and prospectively followed up. Standard trabeculectomies were performed and mitomycin applied postoperatively on the 3 days following surgery (group 1). For comparison, data from previous studies were used for control eyes with intraoperative mitomycin application (group 2) and no mitomycin application (group 3). Preoperative and postoperative data, complications, and the need for further surgical procedures were evaluated. RESULTS: The study group (group 1) consisted of 22 cases. The mean follow-up was 13.4 and 13.5 months for groups 1 and 2, respectively. Average intraocular pressure values decreased from 33. 6 and 31.0 mm Hg (P =.32; t test) to 16.0 and 12.5 mm Hg in the 2 groups (P =.03; t test). The average number of medications decreased from 2.5 and 2.5 to 0.6 and 0.4 (P =.35; t test) in groups 1 and 2, respectively, at the last visit. Hypotony lasting for more than 3 months occurred only in eyes with intraoperative mitomycin application (14/22). Choroidal detachment (3/22) and hypotony maculopathy (2/22) also were only noted in eyes from group 2. In group 3, success rates were much lower. CONCLUSIONS: This is the first clinical study, to our knowledge, to evaluate the efficacy of this new technique of mitomycin application. From the results, it appears that the postoperative application of mitomycin following trabeculectomy is associated with a lower risk of severe and long-standing hypotony. This technique may be promising in eyes at low risk for failure.

Adolescent↗

Multidrug resistance-associated proteins in glaucoma surgery.

BACKGROUND: Multidrug resistance (MDR) describes the phenomenon of cross-resistance between different cytostatic agents which are structurally and functionally dissimilar. Two recently discovered proteins, lung resistance protein (LRP) and the multidrug resistance-related protein (MRP) have been implicated in the development of MDR. Since resistance to chemotherapeutic agents is a common problem in filtration surgery, especially in cases of complicated glaucoma, we decided to investigate the presence of MRP and LRP in surgically removed Tenon specimens from glaucoma patients. METHODS: The presence of MRP and LRP in surgically removed Tenon tissue (n=15) was analyzed by immunohistochemistry. The expression by cultured Tenon fibroblasts was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR) and fluorocytometry. RESULTS: LRP expression was detected in 8 of 10 Tenon specimens. Positive staining for MRP was obtained in 5 of 10 specimens. Negative controls with non-immune mouse IgG did not display any specific staining. RT-PCR and fluorocytometry revealed constitutive expression of MRP and LRP, at the RNA and protein level respectively, that was unaltered by pretreatment of the cells with mitomycin C or 5-fluorouracil. CONCLUSION: Our results demonstrate, that besides P-glycoprotein, other components of the MDR-system are present in conjunctival fibroblasts. Future developments in the use of chemotherapeutic agents in association with of filtration surgery need to take account of the presence of these counteracting mechanisms.

ATP-Binding Cassette Transporters↗

Ganciclovir for the treatment of anterior uveitis.

BACKGROUND: Ganciclovir, administered systemically or intraocularly, is effective in controlling cytomegalovirus (CMV) retinitis in immunocompromised patients. The efficacy of therapy with this antiviral substance was investigated in an immunocompetent patient with CMV uveitis causing secondary glaucoma. METHODS: To identify the presence of an intraocular viral infection, anterior chamber taps to detect the intraocular synthesis of IgG antibodies and PCR testing were carried out. Clinically, the degree of intraocular inflammation and the intraocular pressure (IOP) values were monitored. During this time, the patient was treated systemically with ganciclovir administered orally and intravenously. RESULTS: The intraocular synthesis of IgG antibodies specific for CMV was found in two samples of aqueous humor, but negative for other viruses. PCR testing was negative for HSV, VZV and CMV at each time. During this time, the patient was treated systemically with ganciclovir administered either intravenously or orally. As a response to therapy with ganciclovir, the elevated IOP values decreased to normal and the intraocular inflammation declined. After cessation of ganciclovir administration, the inflammation and secondary glaucoma recurred. CONCLUSION: In this case of anterior uveitis presumably caused by CMV inducing secondary glaucoma, treatment with ganciclovir led to a decrease of the inflammation and normalization of IOP. It appears that continuous administration may be required to control the infection in an immunocompetent patient.

Antibodies, Viral↗

Morphologic proof of the toxicity of mitomycin C on the ciliary body in relation to different application methods.

BACKGROUND: Since postoperative hypotony has been a frequent complication of glaucomatous filtration surgery with adjunctive use of mitomycin C (MMC), the question arises of whether there may be another application method which can minimize this side effect. The purpose of this study was to establish the morphologic side effects of different application methods. METHODS: MMC 0.2 mg/ml was applied to the episclera of nine eyes of six pigmental rabbits at random via collagen shield (CS), soft contact lens (CL), or lyophilisate (20 microg; LY) for 5 min. Two eyes (controls) had a subconjunctival injection of BSS only. Another control eye was left untreated (no injection). No trabeculectomy was performed. One hour later the amounts of MMC in the conjunctiva and aqueous were analyzed by reverse-phase high-pressure liquid chromatography. Ciliary bodies were dissected from the enucleated eyes, embedded and investigated by transmission electron microscopy (TEM). Cell height of the nonpigmented ciliary epithelium was morphometrically assessed by means of computer-assisted image analysis. RESULTS: The light-microscopic analysis of the sectioned cell area revealed reduction of the cell height of the non-pigmented ciliary epithelium (NPCE) after application with soft contact lens (fourfold) and collagen shield (2.5-fold) but not with lyophilisate compared to the untreated eye. The following ultrastructural changes were seen: loss of apical microvilli (CS, CL, LY), disintegrating melanin granules within NPCE (CS), lysis of entire areas with NPCE cells (CS), myelin figures within mitochondria (LY), intracellular vacuoles (CS, CL), lysis of myelinated nerves (CS), myelin figures in mitochondria of endothelial cells (LY), and lysis of stromal fibrocytes (CS). In the control eyes (injection of BSS) none of these ultrastructural changes were detected in the cylindrical NPCE cells. The concentration of mitomycin in the aqueous humor after topical application of MMC on the episclera for 5 min were all below the detection limit (<10 ng/ml). The concentration of MMC in the conjunctiva ranged from 2.1 to 3.7 microg/g. CONCLUSION: Severe morphologic alterations were seen at the electron-microscopic level after application of MMC 0.2 mg/ml with a collagen shield and with a soft contact lens. They were mildest with lyophilisate and absent in the BSS controls. A new administration device is needed if trabeculectomy is to be performed successfully using MMC in human glaucomatous eyes.

Animals↗

Acute corneal necrosis after excimer laser keratectomy for hyperopia.

OBJECTIVE: To describe a new, rare clinical complication after routine excimer laser photorefractive keratectomy to correct hyperopia. DESIGN: Case report with clinicopathologic correlation. MAIN OUTCOME MEASURES: Four weeks after treatment with excimer laser, a perforating keratoplasty was performed for persistent corneal opacities. The corneal button was examined using light and electron microscopy. Special immunohistochemical stains were used to detect apoptosis. RESULTS: The patient developed corneal opacities, endothelial precipitates, and a fibrinous exudate in the anterior chamber after the laser treatment. The changes did not respond to therapy directed against bacteria, fungi, and Acanthamoeba. All examinations and special stains were negative for micro-organisms. By light microscopy, an anterior zone of corneal necrosis was present with a moderate amount of acute inflammatory cells. At the interface between necrotic and viable corneal stroma, keratocytes with typical features of apoptosis were detected by immunohistochemistry and electron microscopy. CONCLUSION: This is the first full histopathologic report of a case of acute corneal necrosis with signs of apoptosis after excimer laser therapy of the cornea. Surgeons should be aware of this rare but potentially severe complication.

Acute Disease↗

Risk factors for failures of trabeculectomies performed without antimetabolites.

AIMS: To assess the risk profile for the failure of trabeculectomies in a large group of patients who were selected to be operated on without the use of antimetabolites. This was done in an effort to find subgroups of patients who may not need antimetabolites for primary procedures. METHODS: Consecutive patients scheduled for routine trabeculectomies were operated during a 4 year period and were followed up for at least 6 months postoperatively. Patients were regularly examined in the glaucoma unit and by their local ophthalmologists. Pre- and postoperative data were evaluated and success rates determined. RESULTS: 709 eyes of 566 patients were operated on; 534 eyes of 534 patients (94.4%) were finally evaluated. The mean follow up was 27.9 (SD 13.6) months with a range of 6-62 months. Success rates for complete surgical success ranged from 59% in the best group with pigmentary dispersion syndrome to 0% in the worst group with neovascular glaucoma. Success rates of patients with POAG, pseudoexfoliation, chronic angle closure, pigmentary dispersion syndrome, and dysgenetic glaucoma were similar. Failure rates ranged from 11% in the best group (pseudoexfoliation) to 80% in the worst group (neovascular glaucoma). Failure rates were high in complicated forms of glaucoma such as traumatic (30%), buphthalmus (40%), and uveitic (50%). For repeat trabeculectomies, the failure rate was 49% (20 of 41 eyes). The mean time until failure ranged from 2.7 months (traumatic) to 15.5 months (pigmentary dispersion syndrome) and was 4.9 months for repeat trabeculectomies. CONCLUSION: Trabeculectomy performed in selected groups of patients has a favourable outcome without the use of antimetabolites. It may be possible to avoid antimetabolites in these groups of patients for primary procedures.

Adolescent↗

Low-dose postoperative transconjunctival application of mitomycin C in rabbit trabeculectomy.

PURPOSE: Mitomycin C (MMC) is commonly administered during filtering surgery to enhance the success of the procedure. Unfortunately, the increased success rate is associated with complications, including late bleb leaks, endophthalmitis, and ciliary epithelial toxicity. The purpose of this study was to investigate a safe and effective dose regimen for MMC to reduce incidence of those complications. METHODS: Trabeculectomy was performed in 36 rabbits. MMC was applied only during surgery, only one day after surgery, or once daily after surgery for 3 days at lower concentrations. Balanced salt solution (BSS) was administered during surgery to one group as a placebo. The time to bleb failure was determined and the eyes were evaluated histopathologically. Success and toxicity were compared for the different treatment groups. RESULTS: The mean time until trabeculectomy failure was 2.83 days for the placebo group, 6.33 days with administration of MMC 0.5 mg/mL during surgery, 7.83 days with administration of MMC 0.5 mg/mL once after surgery, and 11, 9, and 4.83 days with administration of MMC 0.1 mg/mL, 0.05 mg/mL, or 0.025 mg/mL, respectively, once a day for 3 consecutive days. On electron microscopic examination of the ciliary epithelium, toxic effects were greatest with MMC concentrations of 0.5 mg/mL and were less with lower concentrations. CONCLUSION: The effect of MMC on trabeculectomy survival was dependent on both the concentration and the method of administration. Lower concentrations with multiple postoperative administrations were as effective as but caused less ciliary body toxicity than intraoperative administration of higher concentrations.

Alkylating Agents↗

A mouse model to study the wound healing response following filtration surgery.

BACKGROUND: Failure of trabeculectomy is attributed to an exaggerated wound healing response at the episcleral level. We have developed a simple technique in mice that creates corneoscleral wounds and used it to study the role of growth factors in wound healing associated with loss of fistular patency. In addition, the effect of suramin on the wound healing response has been investigated. MATERIALS AND METHODS: Using black C57B1/6 mice, we created a fistula from the subconjunctival space to the anterior chamber by external penetration with a 25-gauge needle through the bulbur conjunctiva. Eyes were examined by light microscopy at different times following surgery and evaluated for the presence of growth factors in the sclerosing wound by immunohistochemistry. In an additional group, suramin (1.0 mg/ml) was applied topically five times. RESULTS: The limbal/scleral wounds closed rapidly. Granulation tissue consisting mostly of fibroblasts developed within the first 2 days, and the collagen component increased over time. By 4 weeks, the wound was completely healed. We found that within 1 day after surgery GF beta 2 reached high intensity. TGF beta 1 and PDGF A reached maximal intensity by day 2 and remained elevated for about a week, PDGF B was present at moderate intensity even before surgery. Myofibroblastic differentiation was observed from days 2 to 7. Suramin-treated wounds showed a decrease of cells and delay in fibroblast maturation. TGF beta 1 and TGF beta 2 levels persisted longer than in the controls, while PDGF A and PDGF B levels were lower than in the controls at all time points. CONCLUSIONS: The mouse corneoscleral wound model that we have developed mimics the process of wound healing and fistulizing surgery that takes place in other animal models and in human eyes in which the outcome of the surgery is poor. Our analysis of the appearance of growth factors associated with wound healing demonstrates that PDGF A as well as TGF beta 1 and TGF beta 2 appear early in the process at high levels and are potential targets for interventive strategies to ensure channel patency. Suramin has a distinct effect on the wound healing process and expression of growth factors and may be a promising substance for clinical use.

Animals↗

Suramin inhibits wound healing following filtering procedures for glaucoma.

BACKGROUND: Trabeculectomies are the most frequently performed procedures in surgically treating eyes with glaucoma. Failures are caused by fibrosis in the external ostium of the filtering procedure. In order to inhibit the fibrotic wound healing reaction, a new pharmacological approach using suramin, which inhibits a variety of important growth factors was used. METHODS: Pigmented rabbits were used and filtering procedures performed. Suramin was applied with concentrations ranging from 10 mg/ml to 333 mg/ml once during surgery and four times following surgery. The success of the filtering procedure was assessed by intraocular pressure measurements. To evaluate possible intraocular toxic effects, treated eyes were histopathologically evaluated after 4 weeks, and the ciliary body adjacent to the site of application was examined using electron microscopy. RESULTS: With concentrations of suramin of 200 mg/ml and 333 mg/ml, the trabeculectomies were patent longer than in the controls and in eyes operated with mitomycin C, which currently is the most frequently used antiproliferative drug to enhance the outcome of surgery in humans. No severe toxic effects to the ciliary epithelium were seen in suramin treated eyes. CONCLUSIONS: This study demonstrates for the first time the efficiency of a substance that broadly inhibits the action of growth factors on target cells in the setting of ocular wound healing. In this in vivo model, suramin has been shown to be highly effective in preventing scarring and in having fewer toxic side effects than usually used antimetabolites. These results therefore may suggest a new approach to the surgical treatment of glaucoma.

Animals↗

Ocular concentrations of mitomycin C using different delivery devices.

Hypotony and its sequelae are a frequent complication of trabeculectomies performed with mitomycin C (MMC), possibly related to intraocular toxicity of the substance. In an animal model with rabbits, we used different devices for the application of MMC and measured extra- and intraocular concentrations by HPLC. In addition, the concentrations of MMC remaining in the devices were determined. The devices were (1) a regular surgical sponge, (2) a scleral shield, (3) a presoaked soft contact lens, (4) a soft contact lens with MMC application, and (5) subconjunctival injection. Ocular concentrations of MMC were similar within the first 4 groups and were highest in the last. The measurements suggest that MMC penetrates intraocularly regardless of the device used. The variability of remaining MMC concentrations in the devices was lowest in the soft contact lenses suggesting an improved delivery system compared to the usually used surgical sponges.

Administration, Topical↗

Three-year follow-up of trabeculectomies performed with different concentrations of mitomycin-C.

BACKGROUND AND OBJECTIVE: Mitomycin-C is effective for improving success rates of trabeculectomies. The authors sought to determine longterm success rates and complications by studying two widely used concentrations. PATIENTS AND METHODS: Trabeculectomies were performed with mitomycin-C (MMC) in concentrations of 0.5 mg/ml (group 1) and 0.2 mg/ml (group 2) in a prospective, nonrandomized fashion. Patients were observed for at least 3 years, and all follow-up data were analyzed in addition to the preoperative and postoperative conditions and complications. RESULTS: A total of 51 and 40 eyes (groups 1 and 2, respectively) were observed for 3 years. The majority of the eyes had repeat trabeculectomy. Complete surgical success was reached in 76% and 63%, respectively. The mean intraocular pressure (IOP) in the two groups decreased significantly, and the decrease was larger in the MMC 0.5 mg/ml group (P < .015). The mean visual acuity did decrease in the two groups, but this was not significant. Complications included short-term and long-term hypotony, conjunctival dehiscence, choroidal detachments, and endophthalmitis. Trabeculectomies failed both within the first 3 months (n = 4; 4%) and later (n = 11; 12%). CONCLUSION: Three-year results of trabeculectomies performed with MMC are promising. A dose-response effect of the concentration of MMC and IOP levels is present, suggesting that the higher concentration leads to lower IOP values. Despite the antimetabolic effect of MMC, trabeculectomies fail in both the short-term and the long-term.

Adolescent↗

Acanthamoeba keratitis with granulomatous reaction involving the stroma and anterior chamber.

Most cases of granulomatous reaction to Descemet membrane are caused by disciform herpes simplex and mycotic keratitis. To our knowledge, a clinicopathologic report of Acanthamoeba species infection has not been documented. We used standard histopathologic techniques, including light microscopy with special stains and indirect immunofluorescence. A granulomatous reaction with many multinucleated giant cells, some of which engulfed cysts of Acanthamoeba species, was present in the posterior corneal stroma and anterior chamber along the plane of Descemet membrane. A severe, acute, suppurative inflammatory response and areas of stromal necrosis also were present. The diagnosis of Acanthamoeba castellanii was confirmed by immunofluorescent studies. A granulomatous reaction to Descemet membrane and/or the corneal stroma may represent a specific tissue response to various infectious agents. Keratitis caused by Acanthamoeba species may be added to herpes simplex stromal keratitis and mycotic keratitis as a causative organism capable of producing a granulomatous reaction involving the stroma and anterior chamber.

Acanthamoeba↗

Detection of varicella-zoster virus DNA in keratectomy specimens by use of the polymerase chain reaction.

OBJECTIVE: To study the correlation of clinical findings, histopathologic features, and detection of varicella-zoster virus (VZV) DNA in keratectomy specimens. MATERIALS AND METHODS: Fourteen corneal buttons from patients with a confirmed history of herpes zoster ophthalmicus were examined by use of light microscopy and the polymerase chain reaction. The polymerase chain reaction techniques included gel electrophoresis and hybridization for the detection of VZV DNA. RESULTS: Seven (50%) of the 14 specimens were positive for VZV DNA. The positive findings in the specimens correlated with the clinical findings of uveitis (3/3) and the histopathologic features of chronic stromal keratitis (4/4). Patients with stromal scarring, granulomatous keratitis, and neurotrophic ulcers had negative findings. The largest interval between the initial appearance and detection of viral DNA was 51 years. CONCLUSIONS: The results suggest that VZV DNA is not detectable in the cornea in every patient and at every stage of zoster keratitis. This may be due to the low number of VZV particles present in the cornea or the lack of viral DNA in the keratocytes. It remains unclear whether the VZV-related keratopathy is caused by an immunologic response to a viral antigen, the viable virus itself, or both.

Adolescent↗

Decorin and suramin inhibit ocular fibroblast collagen production.

BACKGROUND: The process of ocular wound healing with respect to glaucomatous filtering procedures is of current interest. Delaying this response in patients could possibly lead to more favorable surgical results. So far, only highly toxic antimetabolites have come into frequent clinical use. The possible efficacy of other groups of substances such as growth factor inhibitors has not yet been examined in vitro. METHODS: We exposed Tenon's capsule fibroblasts in tissue culture to various concentrations of decorin and suramin. The dose responses of type I and type III collagen to these inhibitors were measured using an ELISA-type dot blot assay. Total cellular protein production was assayed by measuring the incorporation of tritiated leucine. RESULTS: At a concentration of 10 micrograms/ml, suramin reduced the collagen production by more than 80%. Decorin, at a concentration of 100 micrograms/ml, reduced type I collagen production by about 50% while type III collagen was reduced by 80%. At these concentrations, the total cellular protein production was not inhibited. CONCLUSIONS: Both suramin and decorin, which specifically inhibit the action of growth factors on target cells, reduce the production of collagen synthesis by Tenon's capsule fibroblasts. This is a specific effect, because total protein production is not influenced. This sets these substances apart from antimetabolites. Decorin and suramin may have clinical relevance in that they appear to interfere with ocular wound healing more specifically than the substances so far frequently used.

Antineoplastic Agents↗

Management of fibrous histiocytoma of the corneoscleral limbus: report of a case and review of the literature.

BACKGROUND: Fibrous histiocytomas of the corneoscleral limbus are rare tumors. We present an additional case and review the treatment approaches in the literature. So far, only light and electron microscopic studies have been performed. We used immunohistochemical stains to further characterize the cellular composition. METHODS: The excised lesion was routinely fixed and processed for light microscopy and immunohistochemical studies. For comparison, three dermal fibrous histiocytomas were also examined and processed similarly. RESULTS: The corneolimbal tumor was mainly composed of fibroblasts and histiocytes with a large amount of interstitial collagen, arranged in a storiform pattern. Immunohistochemical stains were positive for histiocytes, fibroblasts, and a marker for mesenchymal cells. The staining pattern of the dermal lesions was similar. CONCLUSION: Fibrous histiocytomas of the corneolimbal region are morphologically benign, slowly growing and infiltrative tumors. Complete resection, especially of the deep margin, is suggested. The immunohistochemical staining pattern is similar to that of dermal fibrous histiocytomas, which behave in a benign manner.

Adult↗