1.6 Clinical Features

Fig. 1.9 Mantle cell lymphoma diagnosed rapidly by FISH using an IGH/CCND1 dual-color, dual-fusion translocation probe. The IGH probe is labeled with spectrum green, and the CCND1 probe is labeled with spectrum orange. The mantle cells can be seen as background shadows containing the t(11;14) (q13;q32) translocation shown by the fused green/orange nuclei (arrows)

Fig. 1.10 NK T-cell lymphoma histology showing tumor invading small vessel. Hematoxylin and eosin ×400

1.6Clinical Features

Patients with OALD may present with a range of symptoms and signs. Proptosis, eyelid swelling, a palpable mass or conjunctival salmon patch, are common [35, 149]. Less frequently, patients may show visual disturbance (e.g., diplopia, visual loss), pain, or inflammation and occasionally dacryocystitis [85, 149] (Figs. 1.12 and 1.13). Pain and inflammation tend to be associated with more aggressive histologies. The typical patient is in the sixth or seventh decade, and there may be a history of autoimmune disease or thyroid eye disease [45, 85, 120, 149]. There does not appear to be any sex predilection, with some series having almost equal sex distribution [85] and others showing a slight female [45, 149] or male [35] predominance.

Fig. 1.12 Clinical appearance of left orbital MALT lymphoma showing left proptosis

1.7Imaging Findings

The classic descriptions of early articles on the CT appearance of OALD are still current. Yeo et al. stated

1that these lesions molded or plastered themselves to preexisting orbital structures, such as the globe, extraocular muscles, lacrimal gland, or bony orbital walls, without eroding bone or enlarging the orbit (Fig. 1.14). Where lymphoid tumors abutted orbital fat, they adopted a streaky profile, presumably due to irregular infiltration reflecting involvement of microfascial structural elements [158]. The molding pattern has also been described as “puttylike” or having a pancake contour, following the fascial planes of the orbit [63, 134]. Other typical CT features include circumscription, homogeneity, greater than brain density, and moderate enhancement. Atypical appearances that show an infiltrative pattern, are inhomogeneous, or have calcification or bone changes may also be seen [147] (Fig. 1.15).

Investigators have generally been unable to correlate clinical behavior with imaging appearance [126, 147, 152]. One study showed a statistically significant association between the CT appearance of molding and indolent histology [147]. Bone destruction has been associated with DLBCL by a number of authors [84, 134, 147].

Magnetic resonance imaging studies are complementary to CT, possibly showing extraorbital extension and central nervous system (CNS) involvement better than CT but not showing bony changes as well as CT. OALD lesions are usually isointense to extraocular muscle on both T1-and T2-weighted MRI images and show moderate enhancement with gadolinium in the majority of cases [35, 134, 147] (Figs. 1.16 –1.18). The imaging features of PET are considered in the staging section.

Fig. 1.15 Coronal CT DLBCL arising in the right lacrimal sac showing the bone destruction commonly seen in DLBCL

Fig. 1.16 T1-weighted MRI showing follicular lymphoma R lacrimal gland with no response to systemic chemotherapy

Fig. 1.14 Coronal CT MALT lymphoma showing molding of left lacrimal gland to the globe

Fig. 1.17 T2-weighted fat saturation MRI follicular lymphoma R lacrimal gland from the same patient as Fig. 1.16

Fig. 1.18 T1-weighted fat saturation MRI with gadolinium, follicular lymphoma R lacrimal gland from the same patient as Figs. 1.16 and 1.17. Post rituximab, showing good response to immunotherapy, having failed chemotherapy

1.8 Staging

Although a diagnosis of OALD might be suspected on the basis of clinical findings and imaging studies, tissue analysis using the techniques described is necessary for confirmation and to allow classification of the lymphoma. Once a diagnosis of OALD has been established, the patient should be referred to an oncology center familiar with the management of hematological malignancy. Systemic investigation and staging, according to the Ann Arbor system, should be performed [17]. This is also true of reactive lymphoid hyperplasia (RLH) and atypical lymphoid hyperplasia (ALH) as a proportion of these will have systemic involvement with lymphoma. A full medical history, including any prior hematological malignancy, autoimmune disease, or history of thyroid eye disease should be taken. Clinical examination should include palpation of lymph nodes, liver, and spleen. Blood tests, including complete blood counts with cytologic examination, protein electrophoresis, lactate dehydrogenase, and beta-2-mi- croglobulin levels; evaluation of renal and hepatic function; and serology for HCV and HIV infections. Bone marrow analysis is mandatory, and many advocate bilateral iliac crest samples. Chest radiographs and imaging of the cervical region, thorax, abdomen, and pelvis should be performed. While this has previously been performed utilizing CT images, increasingly, combined PET–CT scans are being used for initial staging.

1.9Positron Emission Tomography

The role of PET in staging, restaging, treatment monitoring, and follow-up of lymphoma is well accepted but is constantly evolving [6, 67]. Nearly all PET scanners sold currently are combined PET–CT scanners, giving functional and anatomic correlation and a diagnostic advantage over either PET or CT alone [5].

PET utilizes the decay physics of positron-emitting isotopes, with 18F-fluorodeoxyglucose (18F-FDG) the most common PET tracer [88]. Increased glucose metabolism is a hallmark of malignancy, and this can be quantified by fluorine-18 labeling of FDG, a glucose analogue, which becomes trapped within tumor cells. Positron emission by 18F is then detected by the PET scanner [6].

The application of PET to extranodal disease such as OALD, including EMZL and MALT lymphoma, is still being defined [52, 123] (Fig. 1.19). There are a small number of studies reporting the application of PET to OALD [18, 57, 128, 147, 151]. PET is superior to CT in detecting systemic disease associated with OALD and can result in the upstaging of disease by detecting systemic disease not detected by conventional imaging, which may have implications for treatment and outcome (Fig. 1.20). PET does have some limitations in detecting disease in the orbit due to the small volume of orbital disease as well as background physiological uptake of the extraocular muscles and the frontal lobes [147, 151]. One important role of PET is in the distinction between viable tumor and necrosis or fibrosis in residual masses [88]. PET has also been shown to have a role as an adjunct to conventional imaging in evaluating the response to treatment in OALD [57].

1.10 Treatment

There are currently no universally accepted guidelines for the management of OALD. Treatment options for many decades mainly consisted of external beam radiotherapy

Summary for the Clinician

■Long-term follow-up showed there is an overall 25% mortality with OAL.

■Radiotherapy remains the most common treatment for primary OAL.

■The advent of immunotherapy has seen a major change in treatment of OAL and is being used alone or in combination with systemic chemotherapy.

■Radioimmunotherapy offers even more targeted therapy and is currently under investigation.

and chemotherapy. There has been a paradigm shift last 5 years since 2004 with the application of immunotherapy and radioimmunotherapy to the management of lymphoma. There is no doubt that the management approach in 5 years will be very different from that in the recent past.

General principles of management should be evidence based, considered broadly, and then applied to the individual case. There are factors that relate to the patient (e.g., age, comorbidities, performance) and to the tumor (histological type, stage, and site of involvement) as well as the impact on the eye from treatment that will influence the management approach [44, 144]. Ocular adnexal disease can be broadly divided into more indolent lymphoma subtypes (e.g., MALT, follicular, small cell lymphoma) and aggressive disease processes (DLBCL, MCL, and T- and NK cell lesions). There are international prognostic indicators for aggressive disease and for FL [135, 141].

Various clinical, histopatholoical, immunophenotypic, and other markers have been found to influence the prognosis and outcome of OALD. Assessing 326 patients with OAL, Jenkins et al. found that a greater than 1-year history of adnexal involvement was associated with less likelihood of disseminated disease [85]. They also found

extraorbital spread and tumor-related death were more common with bilateral adnexal disease, a finding confirmed by other authors [35, 149]. This is in contrast to earlier studies in which bilateral adnexal disease was not felt to have had an effect on extraorbital spread [76]. Advanced age, stage at presentation, aggressive histology, and tumor growth cell fraction are also associated with a poorer prognosis [26–28, 84, 85, 149].

Decaudin et al. recommend combined immunotherapy and chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone, R-CHOP) if there are perjorative prognostic factors present, radiotherapy if there are no perjorative factors but there is visual threat, and a range of treatments can be considered if there are no perjorative factors and no visual threat. These treatments include radiotherapy, immunotherapy with the monoclonal anti-CD20 antibody, rituximab, chlorambucil, antimicrobial therapy, and a “wait-and-see” approach for the elderly and frail with comorbidities [33].

Before looking at individual treatment modalities, some comments are relevant for different lymphoma categories. One emerging principle of management in the management of MALT lymphoma is to reduce or