Graefe'sArchive

Graefe's Arch Clin Exp Ophthalmol (1992)230:352 357

Ior Clinical and Experimenlal

Ophthalmology © Springer-Verlag 1992

Exuberant epibulbar tumor penetrating into the orbit in xeroderma pigmentosum Mihai Calugaru ~ and Marina Barsu 2 1 Department of Ophthalmology, Medical School, University of C1uj-Napoca, and 2 Department of Pathology, Oncological Institute, Cluj-Napoca, Romania Received April 5, 1991 / Accepted August 20, 1991

Abstract. The clinical a n d histopathological findings are described in a 10-year-old girl with x e r o d e r m a pigmentosum a n d multiple o p h t h a l m i c complications, including the eyelids, conjunctiva, orbit, c o r n e a a n d iris; some o f these complications t o o k an unusual form. Histological e x a m i n a t i o n following right orbital exenteration revealed an epibulbar s q u a m o u s cell c a r c i n o m a penetrating the orbit a n d building a n o o s e all a r o u n d the ocular globe with subsequent strangulation. M o r e o v e r , a palpebral s q u a m o u s cell c a r c i n o m a developed independently f r o m the right lower lid and, u n c o n n e c t e d with the epibulbar t u m o r , penetrated to the orbit.

Introduction X e r o d e r m a p i g m e n t o s u m is an actinic precancerous dermatosis. T h e disorder occurs in a p p r o x i m a t e l y 1 in 250000 persons in the general p o p u l a t i o n and is considered to be a genetically determined disease with an irregular, autosomal, recessive f o r m o f inheritance [3, 5, 9, 19]. Parental c o n s a n g u i n i t y is encountered in 1 7 - 5 9 % o f cases [1]. X e r o d e r m a p i g m e n t o s u m occurs in patients between 6 m o n t h s a n d 3 years o f age, affecting b o t h sexes with the same frequency. Defective repair o f ultraviolet-damaged D N A [4, 14] subsequent to an i n b o r n deficiency o f D N A p o l y m e r a s e is p r o b a b l y involved [3]. The disorder is clinically characterized b y the develo p m e n t o f pigmentation, a t r o p h y , keratose and various neoplasms at the skin level, which are primarily localized on sun-exposed areas. T h e disorder is considered to represent a m o d e l for ultraviolet carcinogenesis [9]. The m a i n d a n g e r for patients lies in the f o r m a t i o n o f usually multiple m a l i g n a n t t u m o r s , occurring in the 3rd stage o f the disease a n d progressively leading to cachexia in the patient. Correspondence to." M. Calugaru, Aleea Peana 3, bloc 3400 Cluj-Napoca, Romania

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We h a d the o p p o r t u n i t y to follow up a little girl with x e r o d e r m a p i g m e n t o s u m . Taking into a c c o u n t the multiplicity o f the opthalmic complications, some o f t h e m with an u n c o m m o n manifestation, we think this case is o f g o o d general interest.

Case report A 10-year-old girl with xeroderma pigmentosum was referred to the eye clinic in Cluj-Napoca for evaluation of a tumor mass concerning the right orbit. No parental consanguinity was revealed. The ophthalmological history has lasted about 5 years and consists of photophobia, lacrimation, redness and edema of the conjunctiva with associated mucous and mucopurulent discharge. At the same time, tumor like structures of variable size occurred in both lower eyelids, but more numerous on the right side. Six months ago a tumor mass was noted in the right cornea, which gradually grew until it covered the cornea completely, leading to loss of vision. Surgical treatment was suggested, but it was turned down by the patient's relatives. Subsequently, the tumor structure rapidly increased, taking on the appearance of a grayish-yellow cauliflowerlike mass, prominent in the interpalpebral fissure. By the age of 2 years, following minimal sunlight exposure, the patient exhibited acute sun sensitivity with erythema and blistering that lasted a few days. This was followed by extensive freckling, first on the sun-exposed skin areas (the face, neck, hands, forearms) and subsequently on the other parts of the body (arms, thorax, abdomen, thighs, feet). By the age of 3 years, this led to a diagnosis of xeroderma pigmentosum. When the little girl was 5 years old, multiple cutaneous neoplasms occurred on her face and the dorsal sides of her hands, ai1 of which have been excised over the years. Our first examination was performed on 20 May 1991. The general physical examination revealed a little girl with stretched cutaneous, darkly pigmented maculae, separated by areas of hypopigmentation, with generalized atrophy, dryness and a parchmentlike skin texture. The condition was very pronounced on the skin over the face, neck and the dorsal sides of the forearms and hands and less so elsewhere. The lymph nodes, liver, and spleen were nonpalpable. The cardiovascular, pulmonary, and nervous systems showed no abnormalities, and nothing unusual was found in the abdomen. The face skin exhibited multiple tumorlike structures with a diameter of between 7 and 15 mm. They were localized to the nasogenian sulci, alae of the external nose, angles of the mouth and the lower lip.

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Fig. 1. Face teguments showing irregular pigmented cutaneous maculae with intervening hypopigmented areas, generalized atrophy, xerosis and a parchmentlike skin texture. Nodular grayish-brown tumor structures of the lower lids, nasogenian sulci, alae of the external nose, angles of the mouth and the inferior lip. In the right interpalpebral fissure, a grayish-red tumor developed covering the whole cornea like a watchglass. The left lower lid changes included mild ectropion, irregularity and ulceration of the margin, and loss of cilia Fig. 2. Face teguments exhibiting hyperpigmented areas, intervening leukodermic elements, telangiectasia and small angiomas. The patient's physiognomy resembled senilitas praecox. Nodular brownish-gray tumorlike structures of variable sizes grew on the lower lids, nasogenian sulci, alae of the external nose, angles of the mouth, lower lip, and the left ear lobe. In the right interpalpebral fissure, a tumor mass occurred measuring 70 mm in diameter and resembling cerebral matter. Ectropion of the left lower lid was present, and the edge of this lid was irregular, ulcerated and without cilia

In the ophthalmological examination (Fig. 1) visual acuity was 0 in the right eye and 0.3 in the left. The eyelids, especially the lower ones, showed the general cutaneous changes characteristic of the disease. The lower right lid displayed 8 10 nodular, welldefined tumorlike structures, which also extended to the neighboring skin. The consistency was hard with no tendency toward ulceration; they were chestnut gray and of a size between 7 and 15 mm. The right conjunctiva exhibited diffuse hyperemia with a mucopurulent discharge. In the right interpalpebral fissure, a well-defined, reddish-gray tumor structure appeared. It had a blackberrylike appearance, 14 mm in diameter, and, like a watchglass, covered the whole cornea. This tumor was pedunculated, with its insertion base in the cornea center on a surface measuring 5 mm in diameter and extending 3-4 mm to the bulbar conunctiva without adhering to it and to the limbal area. The cornea periphery, which was visualized after raising the tumor with a rod, was opalescent and vascularized. The left lower lid exhibited 3~4 nodular, welldefined, browngray structures with a hard consistency measuring 5 7 mm in diameter. There was mild ectropion of the left lower lid, and its free margin was irregular, ulcerated and without eyelashes. Blepharitis and btepharospasm were the additional eyelid findings. Conjunctival involvement included hyperemia of the left lower tarsus conjunctiva and lower conjunctival sac with a mucopurulent discharge. Several small anterior nodules were present in the left cornea, which were stromal and inflamed. They were in close proximity to the lower limbal area from the 5 to the 7 o'clock position with pannuslike neovascularization at this level. The left iris revealed stromal atrophy and loss of superficial stromal pigment over the inferior half. The lens was clear and funduscopic examination was normal in the left eye. We suggested surgical treatment in the right eye, but the patient's relatives refused. The little girl was reexamined on 19 September 1990 (Figs. 2 and 3). The face tegument changes described at the previous examination had become more pronounced. Between the brown-chestnut maculae were grayish-white depigmented atrophic areas, telangiectasia, angiomas and ulcerations, which are very hard to cure. Facial scleroatrophy and freckling resulted in the change of the patient's physiognomy taking on the appearance of senilitas praecox; the nose became sharp and lower lid ectropion as well as atrophy of the buccal and nose holes occurred; the skin turned dry, wrinkled, and weather-beaten. The tumors from the nasogenian sulci and from the alae of the external nose multiplied rapidly. The left ear lobe revealed a gray-brown cauliflowerlike tumor with a large insertion base and measuring 30 mm in diameter. The dorsal face teguments of the left hand displayed a tumor 6 mm in diameter at the base of the little finger and the other one 7 mm in diameter in the 4th intermetacarpal space. When examined again, the visual acuity was zero in the right eye and 0.3 in the left. The tumor structures described in the right lower lid had been pushed down and outward through a grey-red tumor resembling cerebral matter and measuring 70 mm in diameter; it was prominent in the interpalpebral fissure. The delimination was very distinct between the nodular, brown-gray tumorlike structures of the lower lid and the gray-red orbital tumor resembling cerebral matter, prominent in the interpalpebral fissure. The nodular three to four structures of the left lower lid previously described united to build an inhomogeneous mass that contributed, in addition to skin atrophy and tarsus destruction, to the occurrence of lower lid ectropion. The left inferior lid margin

Fig. 3. The right hemiface seen in profile. In addition to the pigmented cutaneous maculae separated by areas of hypopigmentation, the tumor structures can be seen at this level, namely, the exuberant tumor within the interpalpebral fissure, the tumors of lower lid, nasogenian sulcus, ala of the external nose, angle of the mouth and the lower lip

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Fig. 4. The two tumoral blocks are distinct from one another, which is obvious after right orbital exenteration. The palpebral block (top) belongs to the inferior lid and the orbital tumor block (bottom), including all of the contents of the orbit, with the ocular globe

Fig. 5. Macroscopic cross-section of the two tumoral blocks revealed after right orbital exenteration, namely, the palpebral block (top) belonging to the lower lid and the orbital tumoral block (bottom), including the contents of the orbit, with the ocular globe in the middle

was irregular, exulcerated, and without cilia. In the external onethird of the left inferior conjunctival sac there was symblepharon. The left conjunctiva was dry and atrophic; its changes had the appearance and distribution of the bulbar form of spring catarrh. There was an anterior stromal inflammatory infiltration with pannuslike superficial neovascularization in the lower one-third of the left cornea. The left iris showed stromal atrophy with loss of superficial stromal pigment over its lower half. The funduscopic examination was normal. A metastatic survey, including a general physical examination, chest roentgenogram and liver function tests, displayed submammary lymph node adenopathy without any other evidence of metastasis. Right oribital exenteration and removal of the tumors of the left nasogenian sulcus and the left ear lobe were performed under general anesthesia. The right orbital exenteration showed two entirely different and clearly separate tumor blocks (Fig. 4), ilamely, an orbital block and another palpebral one; the orbital tumor block was well defined and grayish-red. It was 70 mm in diameter with an appear-

ance like cerebral matter and numerous signs of necrosis and hemorrhage on its surface, with a consistency like fish meat. It contained whole content of the orbit, including the ocular globe. The palpebral tumor block was made up of the 8M0 confluent nodular structures of the inferior lid, brownish-gray and 60 mm in size. Division into sections of the orbital tumor block (Fig. 5) displayed the ocular globe in the center and a proper well-defined tumor structure lying like a noose all around the globe, which was ultimately throttled by its incessant growth. The tumor structure excised from the left nasogenian sulcus was well-defined, grayish-brown, 15 mm in diameter, and with the appearance of cerebral matter. The tumor removed from the left ear lobe was well defined, grayish-brown, 30 mm in diameter, with a wide insertion base and a cauliflowerlike appearance. The postoperative course was normal, with general epithelialization in the entire right orbit, and rapid healing of the wounds as a result of removing the tumors in the left nasogenian sulcus and the left ear lobe (Fig. 6). Tissues for light microscopic examination were fixed in 15% formalin solution, processed in accordance with routine proce-

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Fig. 6. Right orbit after exenteration. The face teguments, left anterior eye segment and its adnexa, showing the same changes as preoperatively

dures, and serially sectioned. The sections were stained with hematoxylin and eosin. The right eye was smaller than normal, with a large tumor extending outside the cornea and sclera. The tumor mass compressed the eye, which had collapsed, with all the ocular structures folding in. The tumor extended around the exterior surface of the eye up to where the optic nerve emerged. It, however, was not involved. Histologically, the tumor was a well-differentiated invasive squamous carcinoma, with numerous horny pearls formed by prickle cells that show an increasing degree of flattening and keratinization and are arranged concentrically around a core of keratin. The corneal epithelium was completely replaced by tumor cells that aggressively dissected some areas of stromal lamellae. Descemet's membrane was not involved (Fig. 7). The cornea was thickened by proliferation of capillary vascular channels and activated fibroblasts and was scattered with lymphocytes and inflammatory cells (Fig. 8). The sclera, uveal tract, and retina were not involved. The conjunctiva was thickened. The lower lid was retracted and also had a squamous cell carcinoma, which had developed independently and was not connected with the epibulbar tumor penetrating into the orbit (Fig. 9).

Fig. 7. Cornea with a squamous cell carcinoma (SCC) involving the overlying epithelium. Descement's membrane (D) and the endothelium (E) do not have any tumor cells. The stromal lamellae (SL) are thickened and dissected by proliferation of the capillary vascular channels (CVCh), activated fibroblasts (F), edema and inflammatory cells (IC) (hematoxylin and eosin, x 100)

Fig. 8. The same image as in Fig. 7, seen with a higher magnification: capillary vascular channels (CVCh) invading the corneal stromal lamellae (SL), associated with numerous activated fibroblasts (F). The endothelium (E) and Descemet's membrane (/9) are not involved. In the bottom, an island of squamous cell carcinoma (SCC) is seen invading the corneal stroma (hematoxylin and eosin, x 200)

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Fig. 9. Squamous cell carcinoma (SCC) of the right lower lid, arising from the cutaneous surface. Numerous horny pearls appeared to destroy aggressively the structure of the lid (hematoxylin and eosin, x 50)

Fig. 10. Basal celt carcinoma (BCC) of the left nasogenian sulcus, developing under the nasal epidermis (EP) (hematoxylin and eosin, x 100)

Two other cutaneous neoplasms were excised from the one was located on the left ear lobe, with a histopathological nosis of squamous celt carcinoma; the other was removed the left nasogenian sulcus; this tumor was found to be a cell carcinoma (Fig. 10).

face: diagfrom basal

Discussion

The ophthalmic complications in our patient with xeroderma pigmentosum were extremely varied in character: inflammatory, degenerative and tumoral pathology of the adnexa and anterior eye segment. The majority of these complications are frequently encountered in patients with xeroderma pigmentosum. They include changes in the eyelids (freckling, lower lid ectropion, loss of cilia, irregularity and ulceration o f the inferior lid margin, blepharitis, blepharospasm, nodular tumorlike structures), the conjunctiva (hyperemia, mucopuru-

lent discharge, symblepharon, conjunctival involvements similar to the bulbar form o f spring catarrh), and the cornea (keratitis, pannus). As a matter of fact 85 90% of all patients with xeroderma pigmentosum exhibit ophthalmic manifestations [7], which are almost exclusively confined to the conjunctiva, eyelids, and cornea [12]. In general, corneal changes in xeroderma pigmentosum occur frequently and are well known. In addition to exposure keratitis and vascularization, which occurred in our case, keratoconjunctivitis sicca, bandlike nodules, scarring, and ulceration occur, resulting in perforation; the carcinomas and the melanomas, however, have a predilection for the limbal area [12]. The epibulbar squamous cell carcinoma penetrating the orbit in our patient represents a rare manifestation in xeroderma pigmentosum. Primitive corneal carcinomas are generally characterized by slow development without any tendency toward

357 involvement of the bulbar conjunctiva or, if that does occur, the tumor main mass continues to remain in the cornea [15]. Unlike these tumors, the epibulbar squamous cell carcinoma in our patient with xeroderma pigmentosum displayed extremely rapid development and growth. Its major aggressiveness was characterized by early penetration into the orbit, building up a noose around the globe, with subsequent strangulation. The iris involvement encountered in our case (stromal atrophy with superficial stromal pigment loss over the lower half) is also u n c o m m o n in xeroderma pigmentosum. Although the posterior segment is generally considered to be free of complications in xeroderma pigmentosum, two cases of choroidal melanoma have, however, been reported [6, 10]. The histopathological examinations carried out on all of the tumor structures removed have confirmed our clinical suspicion that the damage occurred as a result of the malignant character of the structure. In fact, the histological examination does not provide any essential information for diagnosing the disease but only for demonstrating the neoplastic character of the damage. All carcinomas histopathologically examined were squamous cell-type tumors (Figs. 8 and 9), except for the one from the left nasogenian sulcus, which was a basal cell carcinoma (Fig. 10). These tumors are clinically and pathologically indistinguishable from those in normal individuals, but occur nevertheless at a rate estimated to be 2000 times higher than expected in the general population [11, 16]. The mechanism through which all of this ophthalmic actinic damage occurred in our patient could be mostly due to the mutagenic, cytotoxic and carcinogenetic effects of ultraviolet light (highest effects for short wavelength ultraviolet light between 280 and 320 nm [8]) on the adnexa and anterior eye segment structures. Because of the background of an inborn metabolic deficiency in the system providing protection to the skin against the effects of ultraviolet radiation (genetic enzymatic deficit in endonuclease [5]), there is a defect in the mechanism for repairing ultraviolet damaged D N A in epidermal cells, dermal fibroblasts, peripheral blood lymphocytes and conjunctival cells [4, 11, 14, 16, 17]. While the ocular globe adnexa and cornea are subject to the direct action of the sun, the iris finds itself in a more privileged position in view of the fact that the normal human cornea is virtually opaque to electromagnetic ultraviolet radiation with wavelengths of less than 300 nm [2, 13]. The iris involvement in our patient with xeroderma pigmentosum (stromal atrophy with superficial stroma pigment loss only in the inferior half) might be explained, however, by the fact that the human cornea readily transmits ultraviolet light with wavelengths longer than 300 nm [2, 13], thus exposing the inferior iris to part of the carcinogenic action spectrum. The superior half of the iris of our patient was shielded by the upper lid. Johnson and associates [9] published a case of xeroderma pigmentosum complicated by a massive melanoma of the lower half of the iris, providing arguments suggesting that exposure to sunlight might be a possible causative factor in the pathogenesis of uveal melanoma:

(a) its rareness among non-white races; (b) a higher incidence in individuals with a light iris; (c) the well-documented tendency for an iris melanoma to arise from the inferior sun-exposed iris. The epibulbar squamous cell carcinoma in our patient and its extremely aggressive development with penetration into the orbit cannot be accounted for by exposure to sunlight radiation, alone, although it should be thought of as a main event in its development. If there is inborn hypersensitivity of the skin and the eyes [5, 18] in an individual, this factor could undoubtedly add to the carcinogenetic effects of ultraviolet radiation. In an individual with this particular background, the disease began and developed rapidly under the influence of sunlight.

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Exuberant epibulbar tumor penetrating into the orbit in xeroderma pigmentosum.

The clinical and histopathological findings are described in a 10-year-old girl with xeroderma pigmentosum and multiple ophthalmic complications, incl...
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