Oncology

Jakobiec FA, Callahan AB, Stagner AM, Lee GN, Rashid A, Mendoza P, Grove A, Freitag SK. Malignant rhabdoid transformation of a longstanding, aggressive, and recurrent orbital angiomyxoma. Surv Ophthalmol 2015;60(2):166-76.Abstract

A 47-year-old woman presented with a medial orbital tumor initially diagnosed as either a myxoid neurofibroma or myoepithelioma. Over 30 years the tumor recurred seven times and was serially debulked. Careful histopathologic analysis coupled with immunohistochemical studies performed on the last two biopsies established the rare diagnosis of a locally aggressive angiomyxoma (because of its local infiltrative growth) with myofibroblastic features (smooth muscle actin and calponin positivity and desmin negativity). The last recurrence manifested at a shorter interval than the earlier ones, suggesting an accelerating clinical course. By this late stage there was complete blindness, a frozen globe, and extreme, unmeasurable proptosis accompanied by massive chemosis and eyelid fullness. An exenteration was performed, and the orbital contents contained a persistent angiomyxoma, but additionally, another cellular population had emerged-mitotically active cells with a malignant rhabdoid phenotype (round shape, cytoplasmic hyaline/globoid inclusions composed of whorls of compact vimentin filaments as well as epithelial membrane antigen and focal cytokeratin positivity). This is the first orbital case of a rhabdoid transformation of a benign orbital mesenchymal tumor. Shortly after the exenteration, multifocal metastases, notably to the lungs, were found, leading to the introduction of chemotherapy, which was discontinued because of non-responsiveness of the tumor and patient intolerance. After 1 year of follow up, the patient is still alive, but has persistent active disease with widespread metastases and a guarded prognosis.

Lefebvre DR, Yoon MK. CT-Based Measurements of the Sphenoid Trigone in Different Sex and Race. Ophthal Plast Reconstr Surg 2015;31(2):155-8.Abstract

PURPOSE: In thyroid orbitopathy, surgical treatment of exophthalmos and compressive optic neuropathy is orbital decompression. Deep lateral wall decompression has been advocated alone or combined with the medial wall for a "balanced" decompression. The degree of lateral decompression is dependent on the volume of the sphenoid trigone comprising the deep lateral orbital wall. This study aims to compare the volume of the trigone in various races in men and women. METHODS: After Institutional Review Board approval, patients with normal sinus CT scans (Siemens Somatom 40-slice) were retrospectively reviewed. Inclusion criteria were men and women aged 30 to 60 years, no orbital disease or surgery, normal orbital CT scans, and self-reported race (Asian, black/African American, white). Scans were measured with imaging software (Synapse, Fujifilm USA). The superior and inferior extents of the measured trigone were the superior and inferior orbital fissures, respectively. In the axial CT plane, the areas of each slice of the right and left trigone were manually outlined with the software and volume subsequently calculated based on the slice thickness (2 mm). Comparisons between groups were made via repeated measures analysis of variance. RESULTS: One hundred twenty subjects were included, 20 from each subgroup, yielding 240 measured orbits. The overall volume of the sphenoid trigone for all groups combined was 1.53 cm (standard deviation 0.72 cm). Mean male volume was significantly larger than mean female volume (1.71 ± 0.83 cm vs. 1.35 ± 0.55 cm; p = 0.004). Average left side volume was larger than paired right side volume (1.58 ± 0.74 cm vs. 1.49 ± 0.71 cm; p = 0.02). There were no significant differences in average volumes between races (p = 0.17). CONCLUSIONS: The mean sphenoid trigone volume was larger in men than in women. There were no significant differences in volume between racial groups. The data showed significant interindividual and intraindividual variability. When analyzing these data for the purposes of orbital decompression, planning should be based on each side of each patient, as the expected degree of lateral decompression may vary greatly.

Pemberton JD, MacIntosh PW, Zeglam A, Fay A. Naphazoline as a confounder in the diagnosis of carotid artery dissection. Ophthal Plast Reconstr Surg 2015;31(2):e33-5.Abstract

Diagnosing Horner Syndrome can be difficult in the setting of an incomplete triad. A 27-year-old man presented with unilateral eyelid droop and intermittent ipsilateral headaches, having already seen 7 physicians. Physical examination revealed unilateral ptosis but no pupillary miosis or facial anhidrosis. Inspection of his clinical photographs revealed elevation of the ipsilateral lower eyelid, suggesting sympathetic dysfunction. On further questioning, he admitted to naphazoline dependence. Reexamination after ceasing the naphazoline unveiled the anisocoria. Vascular imaging subsequently revealed carotid dissection, and the patient was started on anticoagulant and antiplatelet therapy. The ptosis persisted after conjunctival Müllerectomy. External levator resection was recommended, but patient declined. This case underscores the importance of clinical photography, meticulous medical record review, and complete medication history including over-the-counter preparations. Clinicians should meticulously inspect the lower eyelid in cases of atypical blepharoptosis and consider the effects of eye drops when inspecting pupils for miosis.

de Waard NE, Cao J, McGuire SP, Kolovou PE, Jordanova ES, Ksander BR, Jager MJ. A murine model for metastatic conjunctival melanoma. Invest Ophthalmol Vis Sci 2015;Abstract

Purpose: Conjunctival melanoma (CM) is an ocular malignancy with a high rate of local recurrences after treatment, and can give rise to deadly metastases. The establishment of a murine model will further our understanding of this disease and allows in vivo testing of new therapies. We therefore analyzed the ability of three CM cell lines to grow orthotopically and spread to distant sites. Furthermore, we determined the characteristics of the xenografts and their metastases. Methods: Orthotopic xenografts of human CM were established by subconjunctival injection of three different CM cell lines into NOD/SCID IL2 rγnull mice. Singe cell suspensions were generated from the primary tumors and placed subconjunctivally in another set of mice, which were then screened for metastases. The presence of melanoma markers were determined on the cell lines and during tumor development. Results: Subconjunctival injection of cultured CM cells into immunodeficient mice led to excellent subconjunctival tumor growth in all inoculated mice (n=101) within two weeks; however, no metastases were found at the time of autopsy. Serial in vivo passage of primary tumor cells resulted in metastatic tumors in the draining lymph nodes (n=21). The CM cell lines as well as the tumor xenografts and their metastases were positive for the melanoma markers HMB-45, S100B, and MART-1. Two cell lines and their corresponding xenografts carried a BRAF mutation, the third showed an NRAS mutation. Conclusions: We established a murine model for CM which shows excellent the formation of metastases in a pattern that accurately resembles metastatic human CM following in vivo passaging.

Jakobiec FA, Kool M, Stagner AM, Pfister SM, Eagle RC, Proia AD, Korshunov A. Intraocular Medulloepitheliomas and Embryonal Tumors with Multilayered Rosettes of the Brain: Comparative Roles of LIN28A and C19MC. Am J Ophthalmol 2015;Abstract

PURPOSE: To compare immunohistochemical and genetic overlaps and differences between intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain. DESIGN: Retrospective histopathologic, immunohistochemical and genetic analysis of 20 intraocular medulloepitheliomas. METHODS: 1) Review of clinical data and hematoxylin and eosin stained sections with 2) immunohistochemical staining of paraffin sections using a polyclonal antibody against the protein LIN28A, and 3) FISH testing for the amplification of the genetic locus 19q13.42 involving the C19MC cluster of miRNA. Ten retinoblastomas served as controls and to determine the specificity of these biomarkers for intraocular medulloepitheliomas. RESULTS: Nineteen of the 20 intraocular medulloepitheliomas were either diffusely or focally LIN28A positive (weak, moderate or strong). The most intense positivity correlated with aggressive behavior such as intraocular tissue invasion or extraocular extension. None of the cases studied by fluorescence in situ hybridization (FISH) harbored an amplicon for C19MC. The ten retinoblastomas were LIN28A and C19MC negative. CONCLUSION: LIN28A has a putative role in oncogenesis and is found only in embryonic cells and malignancies. Intraocular medulloepitheliomas and embryonal tumors with multilayered rosettes of the brain both display LIN28A positivity. Only the latter, however, display amplification of the 19q13.42 locus involving C19MC, implying that other causative factors are at play in intraocular medulloepitheliomas. More aggressive tumor behavior within the eye can be partially predicted by LIN28A staining intensity.

Grob SR, Jakobiec FA, Rashid A, MacIntosh P, Kelly H, Fay A. Pediatric Optic Nerve Meningioma: Diagnostic and Therapeutic Challenges. Ophthal Plast Reconstr Surg 2015;Abstract

A 13-year-old female presented with left unilateral proptosis, blurry vision, and diplopia. Clinical examination showed left sided visual acuity of 20/50, limited extraocular movement, 5-mm proptosis, and optic disc edema. CT and MRI displayed a large, intraconal, well-demarcated soft tissue mass with inferotemporal displacement of the optic nerve. The imaging appearance was unusual and diagnosis remained uncertain. Histopathologic analysis of the biopsy specimen confirmed the diagnosis of atypical syncytial meningioma. The tumor cells were positive for both androgen and progesterone receptors and the Ki67 stain was positive (proliferation index of 8%). The patient was treated with proton beam radiation therapy (total dose 50.4 GyE) that suppressed tumor growth and has preserved visual acuity to date (20/40). Differential diagnosis and approaches to therapy are explored.

Wan MJ, VanderVeen DK. Eye disorders in newborn infants (excluding retinopathy of prematurity). Arch Dis Child Fetal Neonatal Ed 2015;100(3):F264-9.Abstract

A screening eye examination is an essential part of the newborn assessment. The detection of many ocular disorders in newborn infants can be achieved through careful observation of the infant's visual behaviour and the use of a direct ophthalmoscope to assess the ocular structures and check the red reflex. Early diagnosis and subspecialty referral can have a critical impact on the prognosis for many ocular conditions, including potentially blinding but treatable conditions such as congenital cataracts, life-threatening malignancies such as retinoblastoma and harbingers of disease elsewhere such as sporadic aniridia and its association with the development of Wilms tumour.

Papakostas TD, Lee NG, Callahan AB, Freitag SK. Reactivation of thyroid associated orbitopathy following trauma with intraorbital foreign body. Orbit 2015;34(1):6-9.Abstract

A 63-year-old female with mild, bilateral, stable thyroid-associated orbitopathy sustained trauma resulting in glass foreign bodies embedded on the left ocular surface and left lateral orbital extraconal and intraconal space. After 2 orbitotomies including a failed attempt to remove the intraconal foreign body and poor response to oral steroids, she developed severe, progressive left periorbital edema and 9 mm of relative proptosis. Serial, post-operative imaging demonstrated worsening inflammatory changes along the surgical tract, which slowly improved over several months, with simultaneously worsening proptosis and enlargement of the left inferior and medial rectus muscles consistent with worsening thyroid orbitopathy. She subsequently underwent unilateral 3-wall orbital decompression with improvement in her symptoms. Periorbital trauma with orbital foreign bodies and related surgical trauma may result in reactivation of thyroid-associated orbitopathy.

Kruger JM, Yonekawa Y, Skidd P, Cestari DM. Ocular flutter as the presenting sign of lung adenocarcinoma. Digit J Ophthalmol 2014;20(1):4-6.Abstract
Ocular flutter is a rare ophthalmic finding that could represent paraneoplastic phenomena. In adults it is most commonly associated with small cell lung cancer (SCLC). Most patients also present with other neurological defects. We report the case of a 75-year-old woman who presented with isolated ocular flutter. The ensuing workup was significant for an early lung adenocarcinoma that would not have been biopsied otherwise due to its small size. To our knowledge, this is the first reported case of isolated ocular flutter as the presenting symptom of non-SCLC.
Jakobiec FA, Werdich XQ, Chodosh J, Freitag SK. An analysis of conjunctival and periocular venous malformations: clinicopathologic and immunohistochemical features with a comparison of racemose and cirsoid lesions. Surv Ophthalmol 2014;59(2):236-44.Abstract
Vascular tumors (in contrast to dilations or ectasias) of the conjunctiva and other adnexal tissues are rare, with no previous convincing example of a congenital, purely venous conjunctival malformation having been described. A 33-year-old man with a previously well-tolerated racemose conjunctival lesion present from birth developed bothersome symptoms when it underwent multifocal thrombosis with papillary endothelial cell hyperplasia as part of the process of thrombotic organization. Conservative subtotal excision with placement of an amniotic graft led to an acceptable cosmetic appearance, abatement of symptoms, and retention of full ocular function. Histopathologically, the lesion was composed of patulous vascular channels with thin walls displaying a negligible and irregular muscularis, diffuse supportive mural fibrosis, and the absence of an elastic lamina. Immunohistochemically the endothelial cells were CD31- and CD34-positive (vascular origin) but D2-40-negative (lymphatic origin). An associated neovascular capillary bed was not detected. Venous (racemose or grape-like) malformations should be distinguished from: arteriovenous (cirsoid or twisted) malformations in which the vessels possess thicker and more uniform muscular walls, some of which are endowed with an elastica; varices (hemorrhoidal dilations typically of a pre-existent vein); and venous angiomas (noncongenital lesions acquired in middle life) composed of regularly structured muscular channels devoid of an elastic lamina. Other conditions not to be confused with congenital venous malformations include hemorrhagic lymphangiectasia (of Leber), hemorrhagic lymphangiomas, and complex lymphaticovenous malformations.
Jakobiec FA, Rai R, Yoon MK. Fibrous histiocytoma of the tarsus: clinical and immunohistochemical observations with a differential diagnosis. Cornea 2014;33(5):536-9.Abstract
PURPOSE: To describe the diagnostic clinical findings and immunopathology of a fibrous histiocytoma of the upper eyelid tarsus of a 42-year-old man. METHODS: Analysis of clinical features and results of histopathologic and immunohistochemical evaluations using antibodies against the biomarkers smooth muscle actin, S100, CD1a, CD3, CD20, CD31, CD34, CD68, CD163, factor XIIIa, adipophilin, androgen receptor, and Ki-67. RESULTS: The skin moved over a firm lesion that was situated in the tarsus and protruded from the palpebral conjunctiva as a whitish flat-domed noninflamed mass that had caused an irritating corneal epitheliopathy. Histopathologically, there was a storiform or spiral nebular growth pattern, a moderate amount of intercellular collagen, and no nuclear atypia or mitotic activity. The main immunohistochemical findings were CD34 and smooth muscle actin negativity among the tumor cells and a scarcity of CD68/163 histiocytes. Androgen receptors were identified in the tumor cells. CONCLUSIONS: CD34 histiocytoma of the tarsus is a rare, benign, and separate entity from a CD34 solitary fibrous tumor. Conservative tarsectomy is curative.
Thanos A, Jakobiec FA, Mendoza PR, Hatton MP. Ectopic (choristomatous) orbital respiratory cyst: histopathology and immunohistochemistry. Surv Ophthalmol 2014;59(3):328-33.Abstract
A 24-year-old woman underwent excision of a slowly growing mass located in the right superomedial orbit that had histopathologic and immunohistochemical findings consistent with a choristomatous respiratory cyst. This rare condition may either arise primarily from embryologic respiratory epithelium rests in the orbit or develop secondarily as the result of trauma or chronic sinus disease complicated by mucocele formation.

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