ABSTRACT Lymphoma is the most common malignancy arising in the oc- ular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular mus- cles. Ocular adnexal lymphoma (OAL) accounts for 1%–2% of non-Hodgkin lymphoma and 5%–15% of extranodal lym- phoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the vari- ous lymphoma variants that could arise in the ocular adnexa, marginal zone B-cell lymphoma (OA-MZL) is the most com- mon one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B-cell lym- phoma and mantle cell lymphoma. Additional lymphoma en- tities, like T-cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Be- cause they are so rare, related literature mostly consists of an- ecdotal cases included within series focused on OA-MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, be- havior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommenda- tions for therapeutic management. The Oncologist 2013;18: 876 – 884 Implications for Practice: The vast majority of literature’s data on ocular adnexa lymphomas focus on the most frequent herein encountered histotype, i.e., marginal zone B-cell lymphoma. However, when a physician encounters less common histologies in this anatomical site, difficulties in their recognition and management may arise, because these tumors are usually reported as minor groups within large series describing marginal zone B-cell lymphomas or under case report format. The present review aims to offer a comprehensive, easily accessible review on these uncommon histologies in order to collect and present available patho- logic, clinical, and therapeutic data other than providing own authors’ experience in individual considered entities. INTRODUCTION Orbital lymphomas can be divided into three main groups: (a) the primary ocular adnexal lymphomas (POALs), which includes those forms arising in the conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles, account- ing for 1%–2% of all non-Hodgkin lymphomas (NHLs) and 5%– 15% of extranodal lymphomas [1–3]; (b) the secondary ocular adnexal lymphomas (SOALs), including disseminated lympho- mas affecting the ocular adnexa at diagnosis or relapse, which are diagnosed and treated like their systemic counterparts; and (c) intraocular lymphoma, which is usually a diffuse large B-cell lym- phoma (DLBCL) arising in the eyeball, classified within the aggres- sive primary central nervous system (CNS) lymphoma category. The most frequent and better studied POAL is ocular adnexal marginal zone lymphoma (OA-MZL) of mucosa-associated lym- phoid tissue (MALT) type. Although there is a large amount of data covering both the clinical and biological properties of OA- MZL, the available literature on POALs of other histology is repre- sented by sporadic case reports and a few cases included within the series, mostly OA-MZL cases. This review summarizes the available clinical, pathologi- cal, molecular, and therapeutic data on rare forms of POAL other than OA-MZL, aiming to better characterize their clinical and molecular features and to provide practical guidelines for their correct recognition, which is critical to avoid confusion with OA-MZL and, most importantly, to drive the best thera- peutic management. To allow reliable comparison among Correspondence: Maurilio Ponzoni, M.D., Pathology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. Telephone: 0039-02-26432544; Fax: 0039-02-26432409; E-Mail: ponzoni.maurilio@hsr.it Received November 2, 2012; accepted for publication March 25, 2013; first published online in The Oncologist Express on June 28, 2013. ©AlphaMed Press 1083-7159/2013/$20.00/0 http://dx.doi.org/ 10.1634/theoncologist.2012-0425 A Reappraisal of the Diagnostic and Therapeutic Management of Uncommon Histologies of Primary Ocular Adnexal Lymphoma MAURILIO PONZONI, a,b SILVIA GOVI, a,c GIADA LICATA, a,c SILVIA MAPPA, a,c ANTONIO GIORDANO RESTI, d LETTERIO S. POLITI, e LORENZO SPAGNUOLO, b ELIANA SARA DI CAIRANO, b CLAUDIO DOGLIONI, a,b ANDRE ´S J. M. FERRERI a,c a Unit of Lymphoid Malignancies, b Pathology Unit, c Division of Onco-Hematological Medicine, d Ophthalmology Unit, and e Neuroradiology Unit, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Ocular adnexal lymphoma • Diffuse large B-cell lymphoma • Follicular lymphoma • Mantle cell lymphoma • T-cell lymphoma T he Oncologist ® Lymphoma The Oncologist 2013;18:876 – 884 www.TheOncologist.com ©AlphaMed Press 2013 by guest on November 4, 2016 http://theoncologist.alphamedpress.org/ Downloaded from