Orbital lymphomas missed by first biopsies of orbital masses.

A 68-year-old man presented with an 18-month history of painful eye movements, diplopia and proptosis of the right eye, and no past medical history. On examination, a relative proptosis of 5 mm was measured and a computed tomography scan (CT) showed a right inferior muscle swelling (Fig. 1A). Full systemic work-up and positron emission tomography-CT (PET-CT) showed no abnormalities. A biopsy was performed, showing striated muscle with some fibrosis and a small lymphocytic infiltrate in histopathology (Fig. 1B). Additional staining showed a cluster of differentiation (CD) 20+ B-cells and CD3+ T-cells consistent with a reactive infiltrate. The patient was treated for idiopathic orbital inflammation (IOI) with steroids. Five months later however, symptoms recurred with progression of the mass on CT. A secondary biopsy showed a diffuse infiltrate of small CD20+ lymphocytes (Fig. 1C), admixed with plasma cells with lambda clonality. Monoclonality was confirmed by polymerase chain reaction (PCR) for B-cell receptor gene rearrangement. A low grade stage I-E non-Hodgkin orbital lymphoma (NHOL) was diagnosed, with a differential diagnosis of extranodal marginal zone lymphoma (EMZL) or lymphoplasmacytic lymphoma, and treated with curative radiotherapy (30 Gray). One year after treatment, an associated stage IIIa extranodular marginal zone non-Hodgkin lymphoma was found in the soft tissue adjacent to the vertebrae thoracic 6–10, for which chemotherapy (6x R-chlorambucil) is currently given. A 76-year-old man with a history of a centrocytic lymphoma in the neck region 24 years earlier was referred with diplopia and proptosis of the right eye. Full systemic work-up yielded no abnormalities, but a CT demonstrated a supero-lateral orbital mass (Fig. 1D). A biopsy showed atrophic lacrimal glands with several foci of small lymphocytes composed of B-cells as well as T-cells in histopathology (Fig. 1E). No B-cell clonality was present. The patient was diagnosed with IOI and treated with steroids. One year after treatment, the proptosis recurred with progression of the mass on CT. A secondary biopsy revealed tissue fragments almost completely infiltrated by small B-lymphocytes (Fig. 1F). B-cell monoclonality was confirmed with PCR. After systemic investigation, an EMZL NHOL stage I-E was diagnosed and curative radiotherapy (30 Gray) resulted in full regression. A 50-year-old man presented with diplopia and no past medical history. Examination revealed a restriction of ocular muscles, and magnetic resonance imaging (MRI) showed an apical mass (Fig. 1G). The patient was treated for IOI with steroids, but a slight radiological progression was found on a follow-up MRI 2 months later. A biopsy revealed connective and adipose tissue without lymphocyte infiltrates (Fig. 1H). Four months later, the disease progressed and a secondary biopsy showed striated muscle, diffusely infiltrated by small B-lymphocytes (Fig. 1I), and monoclonality was proven by PCR. Without systemic abnormalities, an EMZL NHOL stage I-E was diagnosed and curative radiotherapy (30 Grey) was given. A 55-year-old man was referred for a second opinion of a painless swelling under his right eye, noticed after a fistula treatment of the right upper jaw. Magnetic resonance imaging (MRI) showed a mass in the right orbit (Fig. 1J), of which a biopsy revealed adipose tissue, diagnosed as lipoma. Due to incoherence of the biopsy diagnosis with the clinical course, a second biopsy was taken revealing connective tissue diffusely infiltrated by a small cell lymphoid cell population (Fig. 1K,L), and monoclonality was proven by PCR. Without systemic abnormalities, an EMZL NHOL stage I-E was diagnosed and curative radiotherapy (30 Gray) was given. Currently, the patient is suspected of a systemic recurrence. Orbital lymphoma can mimic inflammatory orbital disease and other diseases in clinical presentation and imaging (Polito et al. 1996; Gordon 2006; Igarashi et al. 2013; Hwang et al. 2014). In present report, a secondary biopsy was necessary in each case because of either recurring symptoms during treatment, or clinical presentation that did not match with pathology diagnosis. In retrospect, all initial biopsies were not representative, and larger or deeper biopsies were required. Although orbital biopsies are considered the golden standard for orbital lymphoma diagnosis, in some cases, biopsies are inconclusive or unjustifiably reported as normal (Gordon 2006; Igarashi et al. 2013; Ting et al. 2015). Also, some localizations of orbital masses can be difficult to approach. Sometimes, a biopsy is not taken deep enough and the diagnosis IOI is only the inflammatory infiltrate surrounding the actual tumour. Ambiguous biopsies can lead to a delay in appropriate treatment, potentially leading to a worse prognosis. When the clinical course shows signs of malignancy, treatment effect is deferred or symptoms/signs return under treatment, a secondary biopsy should not be delayed. Orbital biopsies should match clinical presentation, and a secondary biopsy must be considered otherwise.