Graefes Arch Clin Exp Ophthalmol (2016) 254:413–420 DOI 10.1007/s00417-015-3261-2
REVIEW ARTICLE
The epidemiology, clinical characteristics, histopathology and management of juvenile- and adult-onset corneoscleral limbus xanthogranuloma G. Kontos 1 & S. Borooah 2 & A. Khan 2 & B. W. Fleck 2 & S. E. Coupland 3
Received: 5 October 2015 / Revised: 24 December 2015 / Accepted: 30 December 2015 / Published online: 21 January 2016 # Springer-Verlag Berlin Heidelberg 2016
Abstract Purpose Adult-onset xanthogranuloma (AOX) of the corneoscleral limbus is a rare inflammatory condition of unknown aetiology. Similar to limbal juvenile xanthogranuloma (JXG), it presents as a growing mass at the corneoscleral junction. Limbal AOX and JXG can lead to sight-threatening complications if not managed in a timely manner. This systematic review summarises the main clinical and histopathological features of limbal AOX/JXG and discusses the management of this uncommon disease. Methods We performed a literature search in the MEDLINE database for all historical entries, using the search terms Blimbus^, Blimbal^ and Bxanthogranuloma^, and retrieved all articles reporting on limbal xanthogranuloma. After refining the search to articles relevant to limbal AOX, we were able to identify ten adult cases of limbal AOX and compare those with all reported cases of limbal JXG. Results Clinically, AOX usually presents as an isolated smooth, yellowish, dome-shaped nodule at the corneoscleral junction, similar to an ocular presentation of JXG, with which it also shares similar histopathological features.
* G. Kontos
[email protected]
1
Department of Ophthalmology, Royal Glamorgan Hospital, Ynysmaerdy, Pontyclun, Mid Glamorgan CF72 8XR, Wales, UK
2
Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh EH3 9HA, Scotland, UK
3
Pathology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
Conclusion Limbal JXG and AOX may represent the same disease entity. Diagnosis relies on the clinical presentation, pathology and immunohistochemical profile. Spontaneous regression is unlikely, and thus prompt surgical intervention should be considered to prevent sight-threatening complications. Xanthogranuloma should be included in the differential diagnosis of corneoscleral limbal masses in patients of all age groups. Keywords Adult-onset limbal xanthogranuloma . Juvenile limbal xanthogranuloma . Corneoscleral limbal mass
Introduction Juvenile xanthogranuloma (JXG) is a well-described and characterised disease [1]. It is a benign condition of unclear aetiology that can affect any organ or system. Typically, it presents as a solitary red, yellow or yellow-to-brown cutaneous papule, plaque or nodular lesion. JXG may, however, occur as multiple lesions [2], and may even arise extra-cutaneously and/ or as disseminated systemic disease [3]. JXG typically involves the skin of the upper trunk head and neck. The condition has a good prognosis, as it is usually self-limiting, with most lesions resolving within 1 to 5 years [1]. Ocular manifestations of JXG have been reported in approximately 10 % of affected individuals [4]. Ocular JXG mainly involves the iris [5, 6], and can present with spontaneous hyphema [7]; JXG is the most common cause of hyphema in children [8]. Infiltration of the anterior chamber angle and trabecular meshwork can lead to secondary unilateral glaucoma [7] and potentially to blindness [9]. Presentation with uveitis has also been reported [10]. In contrast to cutaneous JXG, which is self-limiting, the ocular presentation is more persistent and sight-threatening, and thus often requires treatment [11].
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An adult form of JXG, termed adult-onset xanthogranuloma (AOX), was first reported by Gartmann and Tritsch [12], and shares many clinical and histological characteristics of the juvenile form. The most common ocular site of AOX is the orbit, and it is included in the spectrum of four xanthogranulomatous disorders that can occur here (the others being adult-onset asthma and periocular xanthogranuloma, necrobiotic xanthogranuloma and Erdheim–Chester disease) [13]. AOX tends to be solitary and may present as large persistent nodules [14], or it may present as a solitary corneoscleral limbal lesion [15, 16] (see Fig. 1). Limbal AOX is rare, with only 10 cases having been reported to date (see Table 1).
Methods We searched the MEDLINE database for Blimbal xanthogranuloma^, which generated 21 results. One of the articles reported on a case of Langerhans cell histiocytosis (LCH), and was excluded from this review [24]. We looked into all articles reporting on limbal xanthogranuloma in children and adults, concentrating on ten articles relating to limbal xanthogranuloma in adults. Nine of them were in English and one in French. A case of ocular xanthogranuloma in a 43-yearold man reported by Lee et al. [5] was excluded from this review because it describes a pair of conjunctival lesions and not a limbal lesion. We looked into all paediatric cases published from 2004 onwards, as 18 cases of limbal JXG between 1958 and 2004 have already been reported by Chaudhry et al. [1]. We last searched the electronic databases on 20 August 2015.
Discussion Epidemiology Limbal AOX is extremely rare [23], and like JXG in children, it occurs predominantly in males [25]. Eight of 11 cases in this review affected male patients. The oldest reported case of
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limbal AOX concerns an otherwise asymptomatic 67-yearold man [17]. The mean age among all patients was 36 years (SD = 14.4). Clinical presentation Solitary JXG lesions at the corneoscleral limbus can cause foreign body sensation or cosmetic concerns [26]. Visual acuity remains unaffected unless the visual axis is compromised. Limbal AOX is described as a corneoscleral nodule rapidly increasing in size. Kobayashi et al. described recurrent AOX becoming more yellow over 4 months [20]. This was also demonstrated in the images from Hermel et al., possibly suggesting a maturation of the lipid deposition with time. Extensive xanthogranulomatous inflammation at the limbus can infiltrate the cornea, resulting in complete destruction of the stromal architecture, with focal infiltration into the overlying epithelium [17]. The differential diagnosis of limbal lesions comprises dermoid, lipodermoid, pterygium, pyogenic granuloma, foreign body granuloma, nodular fasciitis, primary xanthoma, histiocytoma, lymphoproliferative lesions, and neoplasia [4, 11, 27–31]. The majority of these conditions can be ruled out on the basis of the patient’s age at presentation, the clinical history and the appearance of such limbal growths [1]. Systemic manifestations Whilst children with JXG carry an increased risk of developing systemic disease, e.g. juvenile chronic myelogenous leukaemia [32], AOX has rarely been associated with such diseases. Systemic manifestations have been reported in only one case of limbal AOX, in a 39-year old man [21]. The patient also had an orange-red maculopapular facial rash involving the trunk, axillae and groin. No other evident systemic or ocular pathology was reported. Blood tests and chest X-ray were reported as normal. The lesion was excised 18 months after the initial presentation and had no sign of recurrence up to 4 months postoperatively. The remainder of the reported cases had no systemic manifestations. In addition, no systemic inflammatory disease has been reported in any of these patients. Disease associations
Fig. 1 Image depicts a solitary adult limbal xanthogranuloma. It is presented as a smooth, yellowish, dome-shaped, well-circumscribed mass at the 7 o’ clock position of the corneoscleral limbus. The mass is traversed by the conjunctival blood vessels
Researchers have suggested a possible association between JXG/AOX and cytomegalovirus (CMV) infection [33]; however, this remains to be substantiated by other groups. No infective cause was identified by any of the authors. In contrast, juvenile JXG has been associated with neurofibromatosis and chronic juvenile myeloid leukemia [18].
Soler et al. 2009 Hirata et al. [8]
Kobayashi et al. [20]
Mohamed et al. [21]
Wang et al. [22] Harvey et al. [23]
Collum & Mullaney [16] 17
5 6
7
8
9 10
11
M = male, F = female, NR = not reported
45 30
39
40
18 48
Castro-Gómez et al. [18] 25 Callejo et al. 2011 33 Hermel et al. [19] 35
M
M M
M
F
M F
F M M
Inferior
Inferior Superior
Inferior
Inferior
Inferior Superior
Superior Inferior Superior
No
No No
NR No No
No
No
No
Surgical
Nil
Nil Nil
Nil
Nil Betamethasone eye drops for 1 month *
Nil NR Nil
Yes; superficial keratectomy and a lamellar patch keratoplasty & *stat subconjunctival triamcinolone acetonide injection No
No NR Yes; two injections of triamcinolone acetonide No No
No
Recurrence
Simple excision
5 months 4 months
4 months
2 years
9 months 15 months
5 years NR 6 months
10 months
Follow-up
Yes, after 8 months; therefore 4 years (no treated with superficial recurrence) keratectomy and lamellar graft
Simple excision No Lamellar dissection No
Simple excision
Simple excision
Simple Excision NR Simple excision 3 times Simple excision Simple excision
TobraDex for 1 week Simple Excision
Biochemical Management abnormalities Conservative
Yes (maculopapular No rash, face, trunk, axillae and groin) No No No No
No
No No
No NR NR
No
2 3 4
Inferior
67
Kontos et al. [17]
1
M
Age (years) Sex Limbal Site AOX lesions elsewhere
Case Source
Table 1 Demographics, location of limbal AOX, systemic xanthogranulomatous lesions and biochemical abnormalities, clinical management, recurrence and follow-up of adult limbal xanthogranuloma cases reported in the literature
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Fig. 2 Histological section demonstrates a mixed cellular infiltrate composed of numerous foamy macrophages (black arrows), some multinucleate macrophages with ring-formed nuclei (Touton cell; star), scattered lymphocytes (red arrows) and eosinophils (white arrows). H&E stain, original magnification, ×40
Fig. 3 Photomicrograph of the cornea with a dense infiltration of macrophages within the stroma, leaving the overlying epithelium intact; the macrophages are highlighted by the CD68 stain. DAB, original magnification, ×20)
Histopathology
Plasma cells, eosinophils and fibroblasts have also been identified to a lesser extent within the area of granulomatous inflammation. Importantly, no cell atypia was identified by any of the authors, supporting the notion that AOX is a benign reactive inflammatory condition. Periodic acid Schiff and Ziehl–Neelsen stains were also applied to exclude an infectious origin of the lesion [19] (Table 2). Immunostaining confirms the morphological diagnosis of JXG/AOX, with the histiocytes highlighted in the CD68 (see Fig. 3) and CD163 stains. JXG is negative for protein S-100P and CD1a [25], differentiating this lesion from LCH. Several immunohistochemical markers have been employed for the diagnosis of limbal AOX. The majority of the authors characterized AOX based on positive immunoreactivity for macrophage markers, i.e. CD68 [18, 20, 24, 26–28], C163 [24, 26], and Mac387 [16], and negativity to
JXG/AOX represents the commonest type of non-Langerhans cell histiocytosis (LCH). Histologically, it consists of a welldemarcated mixed infiltrate of mononuclear histiocytes with eosinophilic vacuolated cytoplasm and multinuclear giant cells (so-called Touton giant cells) on a background of scattered lymphocytes, eosinophils, neutrophils and mast cells (see Fig. 2). Some authors have relied on establishing a diagnosis of adult AOX based solely on the haematoxylin-eosin stain [8, 16, 20, 21] (Table 2). The recognition of inflammatory cell types within the area of the xanthogranulomatous inflammation is adequate to provide a diagnosis of AOX. Touton giant cells are considered to be pathognomonic for AOX (see Table 2). In addition, histiocytes and lymphocytes have also been identified in most specimens examined by various authors. Table 2 Inflammatory cells encountered in adult limbal xanthogranulomatous lesions after hematoxylin and eosin staining, with shaded area showing positivity or negativity to commonly used Case
Source
Hematoxylin and eosin stain Histiocytes
1 2 3 4 5 6 7 8 9 10 11
Kontos et al. [17] Castro-Gómez et al. [18] Callejo et al. 2011 Hermel et al. [19] Soler et al. 2009 Hirata et al. [8] Kobayashi et al. [20] Mohamed et al. [21] Wang et al. [22] Harvey et al. [23] Collum & Mullaney [16]
immunohistochemical markers that characterise xanthogranulomatous inflammation
+
+ + + +
Touton giant cells + + + + + + + + + + +
Lymphocytes
+
+ + +
Immunohistochemistry Plasma cells
+
Eosinophils
Fibroblasts
+
CD68
CD163
S100P
CD1a
+ + + + +
+
− − − + −
− −
−
+ + + +
− +
− −
5 years
Niu et al. [6]
Lau et al. [7]
Longmuir et al. [10]
De Keyser et al. 9 months [11] case 1
De Keyser et al. 4 years [11] case 2
Mocan et al. [29] case 1
Mocan et al. [29] case 2
Nishi et al. [28]
Lim-I-Linn & Li [26]
Chaudhry et al. [1]
1
2
3
4
5
6
7
8
9
10
F
F
M
M
F
No
No
Inferior nasal
Inferior temporal
No
No
Superior-temporal No
Superior
Nasal
NR
NR
No
No
No
No
NR
NR
Cataract surgery 24 months of age he developed a white cataract.
Excision & lamellar keratoplasty Excisional biopsy
Surgical
No
Topical antibiotics and steroids for 1 month after excision No
No
Total excision and biopsy with lamellar graft Lamellar dissection
Excisional biopsy
Excisional biopsy
Subconjunctival Simple excision betamethasone after excision Topical prednisolone 0.5 % one month postoperatively. Simple excision Sub conjunctival injection of betamethasone Topical prednisolone 0.5 % postoperatively. No Excisional biopsy
Topical prednisolone Oral Prednisolone Oral MTX
Unresponsive to topical antibiotics and steroids
No
Biochemical Management abnormalities Medical
Yes; widespread skin lesions NR Iris mass, uveitis subretinal mass (managed with Posterior sub-Tenon’s injection of triamcinolone (16 mg) No NR
Superior-temporal Multiple cutaneous xanthogranulomas, Neurofibromatosis 1
Inferior
NR
No
NR
Other lesions
F = female, M = male, NR = not reported, MTX = methotrexate
18 months F
11 years
3 years
7 years
7 months
F
M
14 months M
NR
NR
Sex Limbal site
31 months M
Age
Case Source
6 months
No
No
No
14 months
1 Year
Yes; 6 months 1 year (no post-excision treated recurrence) with 2 intralesional injections of triamcinolone acetonide (20 mg/0.5 mL) performed at 3-month intervals Small residual lesion 3 years (no resolved with topical recurrence) fluorometholone drops No 1 year
1 year
3 years on MTX
14 months (no recurrence)
2 years
Follow-up
No
Enlargement of lesion prompting excision and partial sclerectomy, and conjunctival graft New skin lesion when MTX tapered
No
Recurrence
Table 3 Demographics, location of limbal JXG, systemic xanthogranulomatous lesions and biochemical abnormalities, clinical management, recurrence and follow-up of paediatric limbal xanthogranuloma cases reported in the literature
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+
−
− −
−
− −
− −
−
CD1a S100P CD68 Histiocytes
+ + + +
+ +
+ + +
+
+
Nishi et al. [28] Lim-I-Linn & Li [26] Chaudhry et al. [1] 8 9 10
+ + +
+
+ −* Only case where Touton giant cells not observed + + +
+
Mocan et al. [29] case 1 Mocan et al. [29] case 2 6 7
+ +
+ + + +
+ + + + Niu et al. [6] Lau et al. [7] Longmuir et al. [10]*skin biopsy De Keyser et al. [11] case 1 De Keyser et al. [11] case 2 1 2 3 4 5
Touton giant cells
Lymphocytes
Plasma cells
+ +
+
+
Macrophages Fibroblasts Eosinophils
+ +
CD163
Immunohistochemistry
Limbal AOX is managed surgically (see Table 1). An initial short course of topical steroids was utilized by Soler et al. (4 days) and by Kontos et al. (7 days). However, in both cases, the lesions were excised soon afterwards on the basis of continued growth. In fact, all reported cases were ultimately treated surgically (see Table 1). Intrusion of the visual axis by a limbal AOX was reported in a 30-year-old man with a 5month history of a painless rapidly growing nodule on the superior limbus [23]. Total excision in such cases is necessary to prevent sight loss, recurrence and complications such as astigmatism [19]. In some cases of deep stromal infiltration, lamellar keratoplasty may be appropriate. Lamellar grafting should be considered in advanced or recurring lesions [16, 19, 20]. Ultrasound biomicroscopy is useful for the evaluation of the relation of limbal masses and physiological ocular structures [6, 7]. When ultrasonography is available, it can be helpful for determining the level of corneal infiltration and can thus guide treatment [22]. None of the reported cases required fullthickness corneal transplantation. A bolus subconjunctival injection of triamcinolone acetonide was administered after a superficial keratectomy and lamellar patch, with no reported complications after 2 years of follow-up [20]. Intralesional administration of triamcinolone acetonide injections has been successful in treating limbal AOX, but carries risks, including that of elevated intraocular pressure [19]. In addition, the visual outcome may not be satisfactory if lipid deposits remain in the cornea after the inflammation regresses [19]. Nevertheless, intralesional steroid injections might be reserved for patients who do not wish to undergo surgery, or in cases with extensive corneal involvement where lamellar keratoplasty is difficult [19]. Xanthogranulomas should respond to radiation [34] and steroids [19]. Systemic immunosuppressive therapy has not been utilised for any of the adult patients with solitary limbal xanthogranuloma. Methotrexate (MTX) was used as adjunctive to oral prednisolone for the treatment of systemic JXG in a 14-month-old boy, who presented with extensive skin lesions and ocular limbal mass, iris mass, choroidal mass, raised intraocular pressure, hyphema and anterior uveitis. [10]. MTX has also been
Hematoxylin and eosin stain
Management
Source
S100P [16, 18, 20, 24, 26–28] and CD1a [18, 24, 27, 28]. Staining for S100P and CD1a, markers of Langerhans cells, can be used to differentiate AOX from LCH. Although S100P is expected to be negative in all cases of AOX, Harvey et al. identified scattered S100P-positive cells, and Hermel et al. also found some positive reactivity to it. Furthermore, langerin stain negativity has also been used to differentiate AOX from Langerhans cell histiocytosis [28]. Finally, Hermel et. al. applied additional markers, including those for melanoma (MART-1/melan-A) cytokeratins and muscle markers (desmin), and found them all to be negative.
Graefes Arch Clin Exp Ophthalmol (2016) 254:413–420 Table 4 Inflammatory cells encountered in juvenile limbal xanthogranulomatous lesions after hematoxylin and eosin staining, with shaded area showing positivity or negativity to commonly used immunohistochemical markers that characterise xanthogranulomatous inflammation
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successfully used in the treatment of JXG of an adult with facial and scalp skin lesions as well as iris mass and persistent uveitis after topical radiation and systemic steroid treatments failed [35]. Systemic treatment does not appear to be indicated in those with solitary corneoscleral xanthogranulomas.
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References 1.
2.
Comparison of limbal JXG and limbal AOX
3.
Comparing the clinical characteristics of paediatric and adult forms of limbal xanthogranuloma (Tables 1 and 3), as well as the histopathology profile of the conditions (Tables 2 and 4), we speculate that the adult and child forms belong to the same spectrum of the disorder, as they share the same clinical presentation and immunopathological profile. In contrast to the solitary adult limbal AOX, the paediatric form of limbal xanthogranuloma is more often associated with systemic manifestations of JXG, as previously described [1]. In terms of management, the two entities are often managed similarly. Surgically excision has been the treatment of choice in the majority of both adult and paediatric cases (compare Tables 1 and 3).
4. 5.
6.
7.
8.
9.
10.
Conclusion The cause of corneoscleral limbus AOX/JXG remains unknown. The rarity of the condition and the lack of genetic information limits an in-depth understanding of the aetiology of this condition. Although rare, AOX/JXG should be included in the differential diagnosis of corneoscleral limbus masses in all age groups. From our review, we conclude that the diagnosis of limbal xanthogranulomatous disease should be based on its characteristic clinical and histopathological features. Surgical treatment in the form of complete excision may benefit in cases in which sight is threatened. Lesions could recur if incompletely excised. It is debatable whether topical steroidal treatments are effective in limbal AOX/JXG. Systemic treatments in the form of steroids or methotrexate are more relevant to paediatric patients with systemic manifestations of JXG rather than to adults with solitary limbal AOX lesions.
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18. Compliance with ethical standards Conflict of interest statement All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; or expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
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