The pathology of ocular cancer.

Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. Most retinoblastomas are caused by sporadic somatic mutations in the RB1 gene, but about one-third arise in infants with germline mutations. The latter tend to develop earlier, are often bilateral and are transmissible to offspring as an autosomal dominant trait. Retinoblastoma displays varying degrees of differentiation including Homer Wright and Flexner-Wintersteiner rosettes and photoreceptor differentiation (fleurettes). Rosettes are more common in eyes enucleated from very young infants. Tumors composed entirely of fleurettes (retinoma/retinocytoma) are thought to be retinoblastoma precursors, and like retinoblastoma, harbor mutations in both copies of the RB1 gene. Retinoblastoma is a major cancer treatment success story in developed countries where most deaths are caused by secondary tumors in germline mutation carriers. High-risk histopathological features that are an indication for adjuvant chemotherapy include massive uveal invasion and retrolaminar optic nerve invasion. Eye-sparing therapies including brachyradiotherapy and systemic and intra-arterial chemotherapy have reduced the number of eyes with retinoblastoma requiring enucleation in recent years.

Association of a nonsynonymous single-nucleotide polymorphism of matrix metalloproteinase 9 with giant cell arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is the most common type of primary vasculitis. Matrix metalloproteinase 9 (MMP-9) is present in arterial lesions of GCA and may be involved in its pathogenesis. We investigated whether certain genotypes of 4 single-nucleotide polymorphisms (SNPs) of MMP-9 are overrepresented in patients with histologically confirmed GCA. METHODS: Four SNPs of MMP-9, rs3918242 in the promoter region and 3 nonsynonymous coding SNPs (rs3918252, rs17576, and rs2250889) were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 58 white patients for whom there was a clinical suspicion of GCA. Thirty of these patients had histologically confirmed GCA (group 1), and 28 patients had negative results of a temporal artery biopsy for GCA (group 2). Estimates of the genotype distributions of each of these SNPs in a white population were determined using publicly available genotype data for a panel of 23 individuals (group 3). RESULTS: Although 1 SNP was monomorphic in all 3 groups, we observed statistically significant differences in the genotype distributions for rs2250889 between group 1 and group 2 (P = 0.005) and between group 1 and group 3 (P = 0.009), but not between groups 2 and 3 (P = 0.965). CONCLUSION: These data derived from a sample of patients with GCA suggest that the G allele of MMP-9 polymorphism rs2250889 is overrepresented in patients with histologically confirmed GCA. Clearly, larger sample sizes will be necessary to confirm this suggestive association and better characterize a possible linkage disequilibrium structure among polymorphisms.

Significant head cooling can be achieved while maintaining normothermia in the newborn piglet.

BACKGROUND: Hypothermia has been shown to be neuroprotective in animal models of hypoxia-ischaemia. It is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischaemic encephalopathy. However, significant hypothermia has adverse systemic effects. It has also recently been found that the stress of being cold can abolish the neuroprotective effects of hypothermia. It is hypothesised that selective head cooling (SHC) while maintaining normal core temperature would enable local hypothermic neuroprotection while limiting the stress and side effects of hypothermia. OBJECTIVE: To determine whether it is possible to induce moderate cerebral hypothermia in the deep brain of the piglet while maintaining the body at normothermia (39 degrees C). METHODS: Six piglets (<48 hours old) were anaesthetised, and temperature probes inserted into the brain. Temperature was measured at different depths from the brain surface (21 mm (T(deep brain)) to 7 mm (T(superficial brain))). After a 45 minute global hypoxic-ischaemic insult, each piglet was head cooled for seven hours using a cap circulated with cold water (median 8.9 degrees C (interquartile range 7.5-14)) wrapped around the head. Radiant overhead heating was used to warm the body during cooling. RESULTS: During SHC it was possible to cool the brain while maintaining a normal core temperature. The mean (SD) T(deep brain) during the seven hour cooling period was 31.1 (4.9) degrees C while T(rectal) remained stable at 38.8 (0.4) degrees C. The mean T(rectal)-T(deep brain) difference throughout the cooling period was 9.8 (6.1) degrees C. The mean T(skin) required was 40.8 (1.1) degrees C. There was no evidence of skin damage secondary to these skin temperatures. During cooling only one piglet shivered. CONCLUSIONS: It is possible to maintain systemic normothermia in piglets while significantly cooling the deeper structures of the brain. This method of cooling may further limit the side effects associated with systemic hypothermia and be feasible for premature infants.

Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture.

PURPOSE: To report the demographics and clinical features of a large series of patients with orbital metastasis. METHODS: Retrospective chart review on 100 consecutive patients and a literature review on orbital metastasis. RESULTS: Of 100 patients, the primary tumor site was breast in 53 (53%), prostate gland in 12 (12%), lung in 8 (8%), skin (melanoma) in 6 (6%), kidney in 5 (5%), gastrointestinal tract in 5 (5%), choroid (melanoma) in 2 (2%), parotid gland in 1 (1%), and adrenal gland (neuroblastoma) in 1 (1%). Of patients in whom a detailed history was available, there was no history of cancer at the time of presentation in 19%. In 10%, the primary tumor remained undetected despite systemic evaluation. There were 36 male patients and 64 female patients whose mean age at diagnosis was 62 years (median 60 years, range 5 to 91 years). Both the right and left orbits were affected equally, and 4 cases (4%) were bilateral. The most frequent clinical findings were limited ocular motility (54%), proptosis (50%), and palpable mass (43%). The diagnoses were established by history, systemic survey, imaging studies, and biopsy. Treatment included chemotherapy, hormone therapy, irradiation, surgical excision, or observation, depending on clinical circumstances. Among patients with sufficient follow-up, 95% died of metastasis, with overall mean survival of 15 months (median 15 months; range 3 to 96 months) after orbital diagnosis. CONCLUSIONS: The most common primary cancers that metastasize to the orbit are breast, prostate gland, and lung cancer. In 19%, there is no history of cancer when the patient presents with ophthalmic symptoms and in 10% the primary site remains obscure despite systemic evaluation. The systemic prognosis is generally poor.

Unilateral corneal lattice dystrophy.

PURPOSE: To report three cases of seemingly unilateral dystrophy indistinguishable from type I classic lattice corneal dystrophy. METHODS: Case study of three patients. Three patients, a 31-year-old man, a 44-year-old woman, and a 41-year-old man had multiple lattice lesions in one eye and an apparently healthy fellow eye. Two of these patients underwent penetrating keratoplasty because of poor vision. RESULTS: Histopathologic examination of the excised corneal button of patient 2 showed amyloid deposits consistent with lattice. In the third patient, lattice lesions were noted in the other eye nearly 13 years after he was first examined. CONCLUSIONS: Lattice corneal dystrophy is rarely unilateral. Lattice, even in unilateral cases, may cause significant vision loss to warrant penetrating keratoplasty. Lattice lesions may develop in the fellow eye many years later. This possibility should be explained to all patients with apparently unilateral lattice corneal dystrophy.

Ring melanoma of the anterior chamber angle: a report of fourteen cases.

PURPOSE: Ring melanoma of the anterior chamber angle is a rare variant of uveal melanoma that manifests as circumferential, flat tumor growth predominantly confined to the trabecular meshwork and other anterior chamber angle structures. We report the clinical and histopathological features, management, and prognosis of ring melanoma of anterior chamber angle. METHODS: A retrospective review of clinical features, management, histopathologic features, and prognosis was performed. Of 8800 patients with uveal melanoma examined on the Oncology Service at Wills Eye Hospital over a 25-year period, only 14 patients (0.2%; 14 eyes) were classified clinically as ring melanoma of the anterior chamber angle. In no case was there appreciable involvement of the iris or ciliary body on clinical examination. RESULTS: The patients were followed elsewhere for a mean of 8 months before intraocular malignancy was suspected. Upon referral to the Oncology Service, the intraocular pressure was greater than 22 mm Hg in the affected eye in all patients (mean, 36 mm Hg; median, 35 mm Hg; range, 24 to 48 mm Hg), and all patients were using at least two glaucoma medications. The melanoma infiltrated the anterior chamber angle for a mean of 10 clock hours (range, 8 to 12 clock hours). Tumor management consisted of enucleation in 13 cases and plaque radiotherapy in one case. Histopathologic examination revealed epithelioid cell type melanoma in one case, mixed cell type in nine, and spindle cell type in four. Of the 13 patients who underwent enucleation, tumor cells were found within the Schlemm canal in all cases. Five cases displayed invasion of the intrascleral canals, and three showed episcleral invasion. With the exception of two recent cases, 12 patients were followed for a mean of 64 months (median, 47 months; range, 23 to 225 months). Distant metastasis to the liver was detected in three of 12 patients (25%) after a mean follow-up of 78 months (median, 70; range, 37 to 128 months). CONCLUSIONS: Ring melanoma of the trabecular meshwork and angle structures is a rare variant of diffuse uveal melanoma. It often masquerades as unilateral glaucoma and can be difficult to recognize clinically unless careful comparative gonioscopy is performed. Despite the relatively small tumor volume, life prognosis is guarded with distant metastasis in 25% at mean 6 years follow-up.

Pigmented conjunctival squamous cell carcinoma simulating a conjunctival melanoma.

PURPOSE: To report a pigmented conjunctival squamous cell carcinoma that clinically simulated a conjunctival melanoma. DESIGN: Interventional case report. METHODS: Ocular examination, surgical excision, and clinicopathologic correlation. RESULTS: A 78-year-old white man developed a lightly pigmented mass at the temporal limbus of his right eye. The differential diagnosis included pigmented squamous cell carcinoma and malignant melanoma. Histopathologic examination revealed a malignant squamous cell tumor that contained foci of melanin pigment. The final diagnosis was pigmented conjunctival squamous cell carcinoma. CONCLUSION: Conjunctival squamous cell carcinoma may rarely be pigmented and simulate a conjunctival melanoma.

Metastatic renal cell carcinoma to the palpebral lobe of the lacrimal gland.

PURPOSE: To describe a clinicopathologic correlation of a metastatic renal cell carcinoma to lacrimal gland. METHODS: Case report. RESULTS: A 59-year-old man with a history of renal cell carcinoma had a hemorrhagic mass involving the palpebral lobe of the right lacrimal gland. Fundus examination disclosed two lesions with typical features of choroidal metastasis. The lacrimal gland mass was excised, and histopathologic examination revealed metastatic renal cell carcinoma. The patient was treated for systemic metastasis but required no further ocular treatment. CONCLUSIONS: Renal cell carcinoma can metastasize to the lacrimal gland, where it may appear as a hemorrhagic mass.

Primary intraepithelial sebaceous gland carcinoma of the palpebral conjunctiva.

Sebaceous gland carcinoma usually arises from meibomian or Zeis glands deep within the eyelid, but it can rarely arise within the conjunctival epithelium without a deep component. We describe a woman with a history of chronic blepharoconjunctivitis unresponsive to topical medications. Examination disclosed confluent papillary hypertrophy of the upper palpebral conjunctiva and deposits of white flaky material. Tarsoconjunctival punch biopsy revealed intraepithelial sebaceous gland carcinoma. Management consisted of frozen section-controlled complete tumor excision with removal of the entire posterior lamella of the right upper eyelid, cryotherapy to the margins, and reconstruction. Histopathologic analysis confirmed primary sebaceous gland carcinoma localized to the conjunctival epithelium without involvement of underlying meibomian or Zeis glands or the caruncle. Patients with unexplained chronic unilateral blepharoconjunctivitis or papillary hypertrophy of the palpebral conjunctiva should be considered for biopsy to rule out neoplasia, even when there is no sign of an underlying eyelid mass.

Basal cell carcinoma of the eyelid associated with Gorlin-Goltz syndrome.

PURPOSE: To describe the ophthalmic and systemic features in a series of patients initially seen with eyelid basal cell carcinoma associated with Gorlin-Goltz syndrome. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Of 105 consecutive patients with eyelid basal cell carcinoma managed at an Ocular Oncology Center between January 1973 and December 1999, four patients with Gorlin-Goltz syndrome were identified. METHODS: The ophthalmic and systemic features, management, and outcome of patients with eyelid basal cell carcinoma associated with Gorlin-Goltz syndrome were analyzed. The published literature on Gorlin-Goltz syndrome, specifically related to genetics, systemic features, ophthalmic associations, and prophylactic management strategies, was reviewed. MAIN OUTCOME MEASURES: Response of the eyelid basal cell carcinoma to treatment and the final systemic condition were the main outcome measures. RESULTS: All four patients had a family history of Gorlin-Goltz syndrome. The systemic manifestations included multiple basal cell carcinomas in all the patients, frontal bossing or increased occipitofrontal circumference in three patients, palmar pits in two patients, odontogenic keratocyst in one patient, ectopic calcification in one patient, and bifid rib in one patient. The mean age at the detection of the first basal cell carcinoma was 30 years (range, 16-38 years). All four patients had multiple basal cell carcinomas on the face and elsewhere. The eyelid basal cell carcinoma was advanced with orbital infiltration in three patients, one of whom opted for palliative radiotherapy, whereas the other two underwent orbital exenteration. The fourth patient, who had localized recurrent basal cell carcinoma in the upper eyelid, was treated with excision and eyelid reconstruction. At the final follow-up (mean, 41 months), eyelid basal cell carcinoma was cured in three patients and stable in one patient. No patient had life-threatening sequelae of Gorlin-Goltz syndrome. CONCLUSIONS: Gorlin-Goltz syndrome is a rare autosomal dominant cancer predisposition syndrome that may be associated with eyelid basal cell carcinoma. The associated systemic findings may be a clue to the diagnosis of this condition. It is important to recognize Gorlin-Goltz syndrome when a patient has multiple basal cell carcinomas or when a young patient with eyelid basal cell carcinoma is seen by an ophthalmologist, because lifelong monitoring is essential for patient management.

Bilateral breast metastases from choroidal melanoma.

PURPOSE: To report an unusual case of solitary sequential bilateral breast metastases from choroidal melanoma. METHOD: Case report. RESULTS: A 48-year-old woman with a large choroidal melanoma in the left eye was treated with Iodine-125 brachytherapy and responded satisfactorily with decrease in tumor thickness. Thirty-seven months after treatment, she developed a solitary, circumscribed melanoma metastasis to the right breast, and 54 months after treatment, a similar metastasis was detected in her left breast. Both breast tumors were managed with lumpectomy. Systemic examination including magnetic resonance imaging of abdomen, chest, and head have been performed regularly and have been normal. At 61 months after treatment, the patient has no clinical evidence of metastatic disease elsewhere. CONCLUSIONS: Uveal melanoma rarely metastasizes to breast tissue. A breast nodule in a patient with a history of uveal melanoma is most likely a primary breast tumor but may rarely represent a metastasis from uveal melanoma.

Orbital nodular fasciitis simulating a dermoid cyst in an 8-month-old child. Case report and review of the literature.

PURPOSE: To report a clinicopathologic correlation of orbital nodular fasciitis that simulated a dermoid cyst in an infant and to review the literature on orbital nodular fasciitis. METHOD: Case report; literature review. RESULTS: A progressively enlarging subcutaneous mass superotemporal to the right eye that clinically resembled a dermoid cyst developed in an 8-month-old boy. Magnetic resonance imaging disclosed an enhancing, circumscribed, solid, soft-tissue mass in the anterior part of the orbit superotemporally. The tumor was removed intact by a superolateral orbitotomy. Histopathologic and immunohistochemical studies revealed findings consistent with nodular fasciitis, a pseudoneoplastic lesion marked by a proliferation of myofibroblasts. CONCLUSIONS: Although nodular fasciitis in the ocular region usually occurs in adults and older children, it should also be considered in the differential diagnosis of orbital or adnexal masses in infants.

Adenocarcinoma arising from congenital hypertrophy of retinal pigment epithelium.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE), traditionally regarded as a benign stationary condition, has recently been shown in 5 cases to give rise to an elevated, solid tumor. However, the histopathologic nature of the tumor that arises from CHRPE has not been previously determined. A 65-year-old woman developed a progressively enlarging peripheral fundus tumor that arose from a focus of classic CHRPE. The tumor produced a localized exudative retinal detachment, cystoid macular edema, and surface-wrinkling retinopathy. The mass was removed by local resection, and histopathologic examination revealed a low-grade adenocarcinoma of the retinal pigment epithelium, apparently arising from CHRPE. Although CHRPE is usually a benign nonprogressive lesion, it can give rise to a malignant tumor. Congenital hypertrophy of the retinal pigment epithelium should be observed periodically for development of a neoplasm.