Fine needle aspiration biopsy of ophthalmic tumors q

Transcription

1 Saudi Journal of Ophthalmology (2012) 26, Ophthalmic Pathology Update Fine needle aspiration biopsy of ophthalmic tumors q Arun D. Singh, MD a, ; Charles V. Biscotti, MD b Abstract A majority of intraocular tumors can be diagnosed based on clinical examination and ocular imaging studies, which obviate the need for diagnostic ophthalmic fine needle aspiration biopsy (FNAB). Overall, diagnostic accuracy of ophthalmic FNAB is high but limited cellularity can compromise the diagnostic potential of ophthalmic aspirate samples. The role of ophthalmic FNAB is limited in retinal tumors. Orbital FNAB should be considered in the evaluation of lacrimal gland tumors, orbital metastasis, and lymphoproliferative lesions. Negative cytologic diagnosis of malignancy should not be considered unequivocal proof that an intraocular malignancy does not exist. With improved understanding of genetic prognostic factors of uveal melanoma, ophthalmic FNAB is gaining popularity for prognostic purposes in combination with eye conserving treatment of the primary tumor. In special clinical indications, ancillary studies such as immunohistochemistry and FISH can be performed on ophthalmic FNAB samples. Assistance of an experienced cytopathologist cannot be overemphasized. Keywords: FNAB, Cytology, Uvea, Melanoma, Metastases Ó 2012 Saudi Ophthalmological Society, King Saud University. All rights reserved. doi: /j.sjopt Introduction Fine needle aspiration biopsy (FNAB) of ophthalmic tumors is being increasingly performed. 1 5 In this article we discuss indications, techniques, complications, and the limitations of the ophthalmic FNAB. History Although relatively recently accepted in the evaluation of ophthalmic tumors, FNAB of tumors has a long history The first intraocular biopsy was performed by Hirschberg in ,12 17 In 1979, Jakobiec published a major report on the use of FNAB for the diagnosis of intraocular tumors. 18 Since then others have reported on safety and reliability of ophthalmic FNAB with adequacy rates of 88 95%. 23,26 Technique and instrumentations The technique and instrumentation for FNAB vary depending upon the involved tissue (retina, choroid, subretinal space, vitreous, and aqueous), 27,28 suspected diagnosis, size, location, associated retinal detachment, and clarity of the media. 25,29 35,5 Most frequently used needles for ophthalmic FNAB are of gauge (Fig. 1). 5 Likelihood of insufficient samples may be lower with a 22 gauge needle 36 and higher with a 30 gauge needle. 37 Some authors have recommended bending the needle tip to 90 degrees and entering the tumor tangentially rather than radially. 35 A prototype needle with a short bevel and mm graduations has also become available. 38 Specifically designed intraocular forceps to retrieve tumor sample through retinotomy (Essen Forceps) allows histological and immunohistochemistry typing. 39 Received 12 January 2012; accepted 14 January 2012; available online 24 January a Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA b Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA q Reproduced in part from: Biscotti CV and Singh AD. FNA Cytology of Ophthalmic Tumors. Monogr Clin Cytol, 2012; 21: Corresponding author. Address: Department of Ophthalmic Oncology, Cole Eye Institute (i3-129), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: ; fax: address: singha@ccf.org (A.D. Singh). Peer review under responsibility of Saudi Ophthalmological Society, King Saud University j Production and hosting by Elsevier Access this article online:

2 118 A.D. Singh, C.V. Biscotti Figure 1. A short 25 gauge needle attached to short tubing is inserted through the scleral bed into the tumor and aspiration performed (A). The aspirate sample is placed in a preservative solution, such as CytoLyt Ò and the needle rinsed to optimize cell yield (B). Reproduced with permission from: Singh AD, Pelayes DE, Brainard JA, Biscotti CV. History, indications, techniques and limitations. Monographs in clinical cytology 2012; 21: Iris tumors In the case of iris tumors the entry is through the anterior chamber. 40 A gauge needle is swept over the surface of the lesion aspirating about 0.5 ml of the aqueous humor. 40 Direct insertion of the needle into the tumor may increase the cellular yield. 41 Complications such as persistent hyphema, prolonged hypotony, lens damage or endophthalmitis are rarely observed (<1%). 41 Ciliary body and pre equatorial tumors Tumors located in the ciliary body or anterior choroid are approached trans-sclerally. A 3-mm square scleral flap to a depth of approximately 80% is fashioned. A short 25 gauge needle attached to short tubing is inserted through the scleral bed. Post equatorial tumors Posterior choroidal tumors are most accessible by a transvitreal approach. A gauge needle attached to a 5 ml syringe by a short tubing is introduced into the mid vitreous cavity through parsplana 4 mm behind the limbus. The meridian of insertion is selected based upon the location of the tumor. The needle can be guided into the tumor either under indirect ophthalmolscopic control or a microscope depending upon the surgeon s preference. 35 Ultrasonic guidance is rarely used in the presence of a clear media. 18 The needle tip is inserted into the tumor avoiding major retinal or tumor vessels. Gentle aspiration is performed by pulling the plunger. Once the suction force has balanced out the needle is withdrawn along the path of insertion. 35 Localised subretinal and/or vitreous hemorrhage is controlled by applying pressure at the entry site by a cotton tipped applicator. 33,35 37 If the globe softens, balanced salt solution can be injected into the vitreous cavity. Sample handling At our institution, we use the ThinPrep Ò processing system for ophthalmic FNAB samples. We place all material in Cytolyt Ò solution for ThinPrep processing (Fig. 1). 42 The sample in Cytolyt Ò is then subjected to one or more centrifugation and concentration steps (Fig. 2). 42 The pellet obtained is resuspended in a cell preservative solution, PreservCyt Ò for automated processing. The ThinPrep Ò processor mixes the sample and then, using a gentle vacuum, collects cells on a filter in a monolayer. This filter is then inverted and its cellular contents transferred to a microscope slide. This method optimizes cell yield and preservation and standardizes slide preparation for interpretation in this setting of limited material. If abundant aspirate material is obtained, paraffin-embedded cell block can be processed. While we rarely perform immunostains on preparations other than a cell block, some authors have reported successful immunohistochemical analyses on thin layer cytology preparations. 25,42 44 Indications The major indication for ophthalmic FNAB is when clinical examination and ancillary testing fail to establish an accurate diagnosis. 23,25,43,45 Potential scenarios include those with atypical clinical presentation, dense media opacity, possible uveal metastasis without known primary tumor, and patients requesting histopathologic confirmation before undergoing recommended therapy such as enucleation. 35 In our experience, ophthalmic FNAB is an effective technique to confirm a clinical diagnosis of malignancy including uveal metastasis and uveal melanoma. 5,21

3 Fine needle aspiration biopsy of ophthalmic tumors 119 Figure 2. Automated ThinPrep Ò processing. The Thin Prep Ò filter rotates in the sample separating cellular material from background debris. A vacuum collects cells on the exterior surface of the filter membrane. The filter is then inverted and gently pressed against the ThinPrep Ò slide. Surface tension and air pressure cause the cells to adhere to the slide, resulting in even distribution of cells in a central circular region of a slide. Reproduced with permission from: Brainard JA, Biscotti CV. Cytological preparation. Monographs in clinical cytology 2012; 21: Amelanotic uveal tumor (primary vs metastasis) Shields and associates have reported on the diagnostic effectiveness of intraocular FNAB on 140 patients with intraocular malignancies such as uveal melanoma, uveal metastasis, retinoblastoma, lymphoma, and leukemia (Fig. 3). 23,46 Histologic correlation was available in 57 of cases; with histology cytology diagnostic concordance in 54 of 57 (95%) cases. Augsburger and colleagues examined 71 ophthalmic FNA samples. 21 Histologic correlation was available for 9 of those and the cytologic diagnoses were confirmed in 8 out of 9 cases. In addition, all 11 aspirates done to confirm benign conditions were read as benign. 21 Nevus vs melanoma (indeterminate melanocytic lesions) Given that cellular yield is lower with smaller tumors 45,47,48 and even an expert cytopathologist may not be able to unequivocally distinguish a nevus from melanoma, 25 we feel that such indeterminate melanocytic lesions (large nevus vs small melanoma) should not be readily subjected to diagnostic FNAB. 46 Melanoma: diagnostic A number of studies have shown that FNAB has a diagnostic accuracy rate of over 90%. 4,23,25,43,49,50 Char observed FNA to be accurate in both the diagnosis and cytologic typing of uveal melanomas. 51 Shields have also reported similar results, with 26 of 27 (96%) patients diagnosed on FNAB with uveal melanoma being subsequently proven to have melanoma on enucleation. 23 Regardless of the differential diagnosis, cytologists must interpret the cellular features within the clinical context. This emphasizes the importance of communication between cytologists and ophthalmologists. We have found a stepwise diagnostic approach for uveal melanoma very useful. 50 Cytologists should first look for cytoplasmic melanin pigment (Fig. 4A). 50 Melanin has a finely granular cytoplasmic distribution that can be focal and inconspicuous. We have observed melanin in 78% of uveal melanomas in our series. 52 The spindle type melanoma cell (Fig. 4B) 50 is the next most helpful diagnostic criterion in the differential diagnosis with metastasis because the vast majority of uveal metastases are carcinomas, mostly from the breast and lung. 53 These tumors have an epithelioid appearance and cohesive cell clusters. Spindle cell carcinomatous metastases occur rarely. 54 Immunohisto- Figure 3. A 42 year old woman was evaluated for a partially amelanotic choroidal mass OD (A). Her past medical history was non contributory. Systemic evaluation including CT scans of the chest, abdomen, and pelvis and mammography were negative. As possibility of choroidal metastasis could not be completely excluded based upon clinical examination, a diagnostic transvitreal FNAB was performed (B). Note biopsy site [arrow], and localized subretinal hemorrhage [black arrow head] and pocket of pre retinal hemorrhage [white arrowhead]). FNA determined the mass to be choroidal melanoma (C). Reproduced with permission from: Biscotti CV, Singh AD. Uveal metastases. Monographs in clinical cytology 2012; 21:

4 120 A.D. Singh, C.V. Biscotti Figure 4. Presence of melanin and spindle cells are helpful cytologic diagnostic features. This uveal melanoma cell has melanin and is spindle shaped (A). A spindle cell without melanin (B). Though rarely needed, immunohistochemical stains for melanoma markers, such as HMB45 illustrated here, can help identify amelanotic melanoma cells (C). Reproduced with permission from: Biscotti CV, Singh AD. Uveal melanoma: diagnostic features. Monographs in clinical cytology 2012; 21: chemistry for epithelial markers including cytokeratins, neuroendocrine markers, and melanoma markers such as S100 and HMB45 can be helpful especially in cases of amelanotic epithelioid cell melanoma (Fig. 4C). 44,50 Melanoma: prognostic Significant progress has been made in understanding of the role of tumor histopathology, cytogenetics, and gene expression patterns in predicting metastatic potential of uveal melanoma (Fig. 5). 55 Therefore, it has become increasingly common to perform FNAB for prognostic purposes. Fluorescence in situ hybridization (FISH), single-nucleotide polymorphism (SNP) array, and gene expression profiling (GEP) are frequently employed to assess metastatic risk. 55 Intraocular lymphoma Vitrectomy is required to diagnose primary vitreo retinal lymphoma (ophthalmic variant of primary central nervous system lymphoma) as it predominantly manifests as lymphocytic infiltration of the vitreous. 56 Cellular assessment is often done in conjunction with ancillary studies, such as immunohistochemistry or flow cytometry Retinoblastoma and other retinal tumors FNAB in cases of retinoblastoma or suspected retinoblastoma is considered to be a relative contraindication because the risk of seeding of the tumor outside the eye is of particular concern. 23,25,60,61 FNAB is recommended only in highly selected cases of retinal tumors where there is a true diagnostic dilemma after all possible clinical investigations including an opinion by an expert ophthalmic oncologist have been obtained. 61 Even so, the FNAB should be done by a modified technique, wherein the needle is passed parallel to the visual axis through the peripheral cornea, anterior chamber, peripheral iris, zonules (avoiding the lens), and into the suspicious area. 23 Orbital tumors Role of orbital FNAB particularly for lacrimal gland tumors, lymphoproliferative tumors, and metastatic lesions of the orbit is discussed elsewhere. 62 Limitations False negative biopsy Figure 5. FISH using directly labeled fluorescent probes to the alphacentromeric region of chromosome 3 (CEP3) (SpectrumOrange) and the 3p25 locus (SpectrumGreen) with 4,6-Diamidino-2 Phenylindole (DAPI) counterstain is illustrated, demonstrating eusomy (disomy) of chromosome 3 (two orange signals) and deletion of the 3p25 locus (one green signal). Reproduced with permission from: Turell ME, Tubbs RR, Biscotti CV, Singh AD. Uveal melanoma: prognostication. Monographs in clinical cytology 2012; 21: Limited cellularity can compromise the diagnostic potential of ophthalmic aspirate samples. 5,63 In our series of 30 unpublished cases, 4 cases had limited cellularity. In one patient whose biopsy was read as negative subsequently underwent incisional biopsy which revealed a uveal schwannoma. 64 Augsburger in his case series, reported 2 false negatives out of 5 totally negative reports. 21 A negative cytologic diagnosis of malignancy should not be considered unequivocal proof that an intraocular malignancy does not exist. 21 Others have also echoed similar views regarding unreliability of negative diagnoses. 25,45 Care must be given to important practical considerations to reduce likelihood of a negative biopsy (Table 1). False positive biopsy Overall concordance between histologic findings and cytologic diagnosis (in experienced centers) may be as high

5 Fine needle aspiration biopsy of ophthalmic tumors 121 Table 1. Practical considerations to reduce likelihood of a false negative ophthalmic fine needle aspiration biopsy (Personal recommendations). Factors Tumor size Needle size Aspiration Sample Experience Personnel Guidance Avoid small tumors (less than 2.5 mm in height) Avoid thinner needle (such as 30 gauge) Avoid plunger retraction once aspiration has been completed Avoid dry smears. Rinse the needle into a transport medium flushing the contents of the needle and syringe several times Practice on enucleated globes to familiarize with the techniques Experienced cytopathologist is essential Reproduced with permission from: Singh AD, Pelayes DE, Brainard JA, Biscotti CV. History, indications, techniques, and limitations. Monographs in clinical cytology 2012; 21: Figure 6. Hemorrhage. Localised sub retinal hemorrhage at the biopsy site (A, appearance 2 days later). Note total resolution of hemorrhage at 4 weeks (B). Reproduced with permission from: Singh AD, Pelayes DE, Brainard JA, Biscotti CV. History, indications, techniques and limitations. Monographs in clinical cytology 2012; 21: Figure 7. Retinal detachment. Pre biopsy appearance (A). Spontaneous closure of the retinal break created during trans vitreal fine needle aspiration biopsy (B, arrow). Reproduced with permission from: Singh AD, Pelayes DE, Brainard JA, Biscotti CV. History, indications, techniques and limitations. Monographs in clinical cytology 2012; 21: as 95%. 4,5,21 In particular, uveal melanocytoma can pose a diagnostic challenge. 21,44 Complications Needle tract seeding The risk of needle tract seeding associated with FNAB decreases with the diameter of the needle. A study performed at the Karolinska Institute in Sweden followed 656 patients who underwent cervical lymph node diagnostic FNAB for a metastatic malignancy using 22 gauge needles. These patients were followed for 5 years and none of the patients showed evidence of local tumor growth. Also, in experimental models 65 and in studies of survival rates of patients with breast cancer 66 and thyroid nodules, 67 there were no differences noted between groups with and without FNAB. In ophthalmic FNAB, the number of tumor cells in the scleral tracts of the 30 gauge needle was lower when the needle transversed aqueous or vitreous. 68 Even so, the number of cells was not enough to cause tumor growth in an experimental model. 68 In more than 200,000 cases of transocular FNAB in the literature, there has been no evidence of local or systemic spread of tumor cells with the use of 25 gauge or smaller diameter needles. 5,21,23,41,43,68 70 Hemorrhage The most frequent complications are localized subretinal and vitreous hemorrhage at the biopsy site. 23,35 The hemorrhage is controlled by gentle pressure on the globe immediately after withdrawal of the needle. The hemorrhages typically resolve within a few weeks (Fig. 6). 5 Retinal detachment The retinal break created when a subretinal tumor is biopsied transvitreally almost never leads to rhegmatogenous

6 122 A.D. Singh, C.V. Biscotti retinal detachment. The break is sealed by the blood clot at the biopsy site (Fig. 7). 5 Endophthalmitis FNAB induced endophthalmitis is extremely rare as ophthalmic FNAB is performed under sterile conditions. Only 2 such cases have been reported. 5,44,47 Conclusions The vast majority of intraocular tumors can be diagnosed based on clinical examination and ocular imaging studies, which obviate the need for diagnostic ophthalmic FNAB. Overall, diagnostic accuracy of ophthalmic FNAB is high but limited cellularity can compromise the diagnostic potential of ocular aspirate samples. References 1. Sanders TE. Intraocular biopsy: an evaluation. Trans Am Ophthalmol Soc 1952;50: Long JC, Black WC, Danielson RW. Aspiration biopsy in intraocular tumors. AMA arch ophthalmol 1953;50(3): Andersen SR. Biopsy in intraocular tumours; a preliminary report. Acta ophthalmol 1954;32(5): Augsburger JJ. Fine needle aspiration biopsy of suspected metastatic cancers to the posterior uvea. Trans Am Ophthalmol Soc 1988;86: Singh AD, Pelayes DE, Brainard JA, Biscotti CV. History, indications, techniques and limitations. Monogr clin cytol 2012;21: Long SR, Cohen MB. Classics in Cytology VII: Kun, Lebert, and early efforts at fine-needle aspiration biopsy. Diagn Cytopathol 1996;14(2): Webb AJ. Early microscopy: history of fine needle aspiration (FNA) with particular reference to goitres. Cytopathology 2001;12(1): Ansari NA, Derias NW. Fine needle aspiration cytology. J Clin Pathol 1997;50(7): Rosa M. Fine-needle aspiration biopsy: a historical overview. Diagn Cytopathol 2008;36(11): Frable WJ. Fine-needle aspiration biopsy: a review. Hum Pathol 1983;14(1): Hajdu SI, Ehya H. Foundation of diagnostic cytology. Ann Clin Lab Sci 2008;38(3): Veasey Jr CA. Intraocular biopsy. Am J ophthalmol 1951;34(3): Jensen OA, Andersen SR. Late complications of biopsy in intraocular tumors. Acta ophthalmol 1959;37: Takemura T, Tomatsu Y. Studies on malignant melanoma of the choroid. I. Needle biopsy, light microscopy, and electron microscopy. Nippon Ganka Gakkai zasshi 1967;71(8): Makley Jr TA. Biopsy of intraocular lesions. Am J ophthalmol 1967;64(3):591 9, Suppl. 16. Sagiroglu N, Ozgonul T, Muderris S. Diagnostic intraocular cytology. Acta cytologica 1975;19(1): Grgic Z, Ljustina-Ivancic N. Cytomorphologic findings in the diagnosis of intraocular lymphocytic tumors (author s transl). Klinische Monatsblatter fur Augenheilkunde 1978;173(3): Jakobiec FA, Coleman DJ, Chattock A, Smith M. Ultrasonically guided needle biopsy and cytologic diagnosis of solid intraocular tumors. Ophthalmology 1979;86(9): Czerniak B, Woyke S, Domagala W, Krzysztolik Z. Fine needle aspiration cytology of intraocular malignant melanoma. Acta cytologica 1983;27(2): Char DH, Miller TR. Fine needle biopsy in retinoblastoma. Am J Ophthalmol 1984;97(6): Augsburger JJ, Shields JA, Folberg R, et al. Fine needle aspiration biopsy in the diagnosis of intraocular cancer Cytologic-histologic correlations. Ophthalmology 1985;92(1): Midena E, Segato T, Piermarocchi S, Boccato P. Fine needle aspiration biopsy in ophthalmology. Surv ophthalmol 1985;29(6): Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology 1993;100(11): Eide N, Syrdalen P, Walaas L, Hagmar B. Fine needle aspiration biopsy in selecting treatment for inconclusive intraocular disease. Acta ophthalmologica Scandinavica 1999;77(4): Eide N, Walaas L. Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review. Acta Ophthalmol 2009;87(6): Char DH, Miller T. Accuracy of presumed uveal melanoma diagnosis before alternative therapy. Br J Ophthalmol 1995;79(7): Fastenberg DM, Finger PT, Chess Q, et al.. Vitrectomy retinotomy aspiration biopsy of choroidal tumors. Am J ophthalmol 1990;110(4): Arbour JD, Mukai S. Biopsy of the retina and the choroid. Int ophthalmol clin 1999;39(1): Foulds WS. The uses and limitations of intraocular biopsy. Eye 1992;6(Pt 1): Bechrakis NE, Foerster MH, Bornfeld N. Biopsy in indeterminate intraocular tumors. Ophthalmology 2002;109(2): Kvanta A, Seregard S, Kopp ED, et al. Choroidal biopsies for intraocular tumors of indeterminate origin. Am J ophthalmol 2005;140(6): Sen J, Groenewald C, Hiscott PS, et al. Transretinal choroidal tumor biopsy with a 25-gauge vitrector. Ophthalmology 2006;113(6): Char DH. Intraocular biopsy. In: Singh AD, Damato BE, Pe er J, et al., editors. Clinical Ophthalmic Oncology. Philadelphia: Saunders- Elsevier; Green WR. Diagnostic cytopathology of ocular fluid specimens. Ophthalmology 1984;91(6): Augsburger JJ, Shields JA. Fine needle aspiration biopsy of solid intraocular tumors: indications, instrumentation and techniques. Ophthalmic surg 1984;15(1): Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected intraocular tumors. Int ophthalmol clin 1993;33(3): Young TA, Burgess BL, Rao NP, et al. Transscleral fine-needle aspiration biopsy of macular choroidal melanoma. Am J ophthalmol 2008;145(2): Singh AD, Pelayes D, Zarate JO, Biscotti CV. FNAB of uveal melanoma with a graded prototype needle. ARVO Meeting Abstr 2011;52(6): Akgul H, Otterbach F, Bornfeld N, Jurklies B. Intraocular biopsy using special forceps: a new instrument and refined surgical technique. Br J ophthalmol 2011;95(1): Grossniklaus HE. Fine-needle aspiration biopsy of the iris. Arch ophthalmol 1992;110(7): Shields CL, Manquez ME, Ehya H, et al. Fine-needle aspiration biopsy of iris tumors in 100 consecutive cases: technique and complications. Ophthalmology 2006;113(11): Brainard JA, Biscotti CV. Cytological preparation. Monogr clin cytol 2012;21: Pelayes DE, Zarate JO. Fine needle aspiration biopsy with liquidbased cytology and adjunct immunohistochemistry in intraocular melanocytic tumors. Eur J Ophthalmol 2010;20(6): Faulkner-Jones BE, Foster WJ, Harbour JW, et al.. Fine needle aspiration biopsy with adjunct immunohistochemistry in intraocular tumor management. Acta cytologica 2005;49(3): Seregard S. To biopsy or not to biopsy? Acta Ophthalmol 2009;87(6): Biscotti CV, Singh AD. Uveal metastases. Monogr clin cytol 2012;21: Cohen VM, Dinakaran S, Parsons MA, Rennie IG. Transvitreal fine needle aspiration biopsy: the influence of intraocular lesion size on diagnostic biopsy result. Eye (Lond) 2001;15(Pt 2): Shields CL, Ganguly A, Materin MA, et al. Chromosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases: the Deborah Iverson, MD, Lectureship. Arch ophthalmol 2007;125(8): Davila RM, Miranda MC, Smith ME. Role of cytopathology in the diagnosis of ocular malignancies. Acta Cytol 1998;42(2): Biscotti CV, Singh AD. Uveal melanoma: diagnostic features. Monogr clin cytol 2012;21: Char DH, Miller TR, Ljung BM, et al. Fine needle aspiration biopsy in uveal melanoma. Acta Cytol 1989;33(5):

7 Fine needle aspiration biopsy of ophthalmic tumors Baker SESA, Fu E, Weber D, Biscotti CV. The Role of Fine Needle Aspiration in the Evaluation of Uveal Tumors: A Clinicopathologic Analysis of 26 Consecutive Cases. Can Cytopathol 2008;114(5): Shields CL, Shields JA, Gross NE, et al.. Survey of 520 eyes with uveal metastases. Ophthalmology 1997;104(8): Trichopoulos N, Augsburger JJ. Neuroendocrine tumours metastatic to the uvea: diagnosis by fine needle aspiration biopsy. Graefes Arch Clin Exp Ophthalmol 2006;244(4): Turell ME, Tubbs RR, Biscotti CV, Singh AD. Uveal melanoma: prognostication. Monogr clin cytol 2012;21: Char DH, Ljung BM, Deschenes J, Miller TR. Intraocular lymphoma: immunological and cytological analysis. Br J ophthalmol 1988;72(12): Davis JL, Solomon D, Nussenblatt RB, et al.. Immunocytochemical staining of vitreous cells. Indications, techniques, and results. Ophthalmology 1992;99(2): Davis JL, Viciana AL, Ruiz P. Diagnosis of intraocular lymphoma by flow cytometry. Am J ophthalmol 1997;124(3): Farkas T, Harbour JW, Davila RM. Cytologic diagnosis of intraocular lymphoma in vitreous aspirates. Acta cytologica 2004;48(4): Karcioglu ZA. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina 2002;22(6): Ali MJ, Honavar SG, Vemuganti GK, Singh AD. Fine needle aspiration biopsy of retinal tumors. Monogr clin cytol 2012;21: Seregard S, Tani E. Fine needle aspiration cytology in orbital tumors. Monogr clin cytol 2012;21: Char DH, Kemlitz AE, Miller T, Crawford JB. Iris ring melanoma: fine needle biopsy. Br J Ophthalmol 2006;90(4): Turell ME, Hayden BC, McMahon JT, et al.. Uveal schwannoma surgery. Ophthalmology 2009;116(1):163, e Eriksson O, Hagmar B, Ryd W. Effects of fine-needle aspiration and other biopsy procedures on tumor dissemination in mice. Cancer 1984;54(1): Liebens F, Carly B, Cusumano P, et al. Breast cancer seeding associated with core needle biopsies: a systematic review (Structured abstract). Maturitas, Polyzos SA, Anastasilakis AD. A systematic review of cases reporting needle tract seeding following thyroid fine needle biopsy. World J Surg 2010;34(4): Glasgow BJ, Brown HH, Zargoza AM, Foos RY. Quantitation of tumor seeding from fine needle aspiration of ocular melanomas. Am J Ophthalmol 1988;105(5): Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92(12): Char DH, Kemlitz AE, Miller T. Intraocular biopsy. Ophthalmol Clin North Am 2005;18(1):