Eye socket lymphoma

Image A – 74-year-old woman who presented with swelling in the eye socket and a lump in the socket and on the left cheek for three months. In addition, there is temporal and upward displacement of the eyeball.

Image B – Computed tomography (CT) of the orbital bones, coronal section, demonstrates a well-defined, homogeneous, space-occupying process in the inferior temporal quadrant of the orbital cavity, infiltrating the lacrimal drainage system and maxillary sinus. An orbital biopsy demonstrated MALT lymphoma. The patient was referred for radiation therapy.

Decreased vision, impaired eye movement with double vision are rarer, due to the lymphoma’s ability to mold around orbital structures, including the eyeball, nerve, and muscles. Most patients present with stage 1E at the first clinical presentation (involvement of one extralymphatic organ), with 10% of cases having a prior history of lymphoma or more disseminated lymphoma. [1,2] Lymphomas arise in acquired lymphatic tissue (in an extra-nodal organ) and in the case of ocular lymphoma following chronic inflammation of the eye socket or autoimmune disease. Reports from recent years indicate an association between lymphoma and infection with Chlamydia psittaci and some have found the effectiveness of antibiotic treatment in remission of lymphoma, although other studies have ruled out such an association – and concluded that exposure is likely dependent on geographic location.

Most cases of non-Hodgkin’s lymphoma are of the Marginal zone B-cell lymphomas of the mucoassociated lymphoid tissue or MALT type. 

What is Malt Lymphoma?

A slow and benign process, with excellent local response to radiation to the chimney. Local remission is achieved in 98%-100% of cases with 75% distant relapse-free survival in stage 1E. Overall survival is between 73% and 81% at 10 years, and there are almost no deaths secondary to lymphoma.[3] Cases of lymphoma with high grade malignancy or systemic involvement are treated with systemic chemotherapy. Secondary lymphoma of the chimney from systemic disease is usually intermediate or high grade follicular lymphoma. As a rule, treatment is carried out at the hemato-oncology institute, a combination of radiation and medical oncology.

In the conjunctiva, almost 100% of cases are MALT when they are discovered on incidental examination in the upper or lower fornix, as a diffuse, soft, pinkish-colored fullness or salmon patch –

Image A – Clinical image of the right eye of a 65-year-old man who presented for examination due to ptosis of the right upper eyelid. A raised, soft, salmon-pink mass is observed in the conjunctiva of the superior fornix.

Image B – A core biopsy showed grade III follicular lymphoma.

Imaging [4,5]

Imaging features include a space-occupying, homogeneous process with ill-defined margins, isointense signal on T1-weighted images and iso-hyperintense on T2-weighted images. Enhancement is variable after contrast agent, and the enhancement is homogeneous. Low values of diffusion coefficient on diffusion-weighted MRI. CT shows a process with ill-defined borders that is moderately enlarging. Location in the orbit – most common is the upper temporal quadrant (lacrimal gland fossa) followed by the upper medial quadrant, unilateral involvement but in rare cases both orbits can be involved, extra-conal is more common than intra-conal and the latter is more common in the presence of the former. Common organs – lacrimal gland, extraocular muscles (SR & LR), eyelid, conjunctiva. The process does not destroy bone (and if it does – there is an association with aggressiveness in the histological type of lymphoma), does not compress the eye and there is no indentation of the eyeball, it embraces the organs in the socket / eyeball, muscles, nerve (molding around orbital structures).

MRI of the orbit of an 80-year-old patient who presented with a right eye bulge.

Image A – T1WI sequence, before contrast injection, shows a well-defined, circumscribed mass in the superior temporal quadrant in the lacrimal gland fossa (black arrow). The process is iso-intense to the gray matter of the brain, and is molding around the globe. There is no bone destruction or erosion in the bone.

תמונה B – לאחר הזרקת גדוליניום, רצף T1WI, חתך אקסיאלי, מציג האדרה הומגנית של המסה. 

תמונה C – הלזיה היא hyper-intense ב T2WI, חתך קורונלי. בביופסיה נמצאה לימפומה ארובתית.

Computed tomography (CT) of the orbits of a 35-year-old patient with a history of non-Hodgkin’s lymphoma and recent appearance of a right orbital mass.

Image A – An axial section showing the location of the process at the top of the chimney.

Image B – The lesion is located in the upper temporal quadrant of the orbit, encompassing the eyeball without destructive features.

Image C – Sagittal section demonstrating the anterior-posterior boundaries of the process and the extra-conal location. A core biopsy revealed a diagnosis of non-Hodgkin’s lymphoma.

In most hemato-oncology centers, it is common to supplement the systemic evaluation with whole-body positron emission tomography (PET) to assess systemic spread of the disease and examine alveolar changes. [6, 7] 

Staging

Staging of lymphoma includes blood count + differential, bone marrow, histological/immunotype, imaging of the neck, back, abdomen, and PET. In an article by Sullivan et al. [7] that examined the efficacy of PET versus conventional imaging in 6 patients with alveolar lymphoma, PET identified systemic disease in 5 of the 6 patients, while CT/MRI showed abnormal findings in only 4.
In this article, PET changed the staging of the disease in 4 patients (66%) and accordingly the treatment and clinical course. The limitations of PET are low sensitivity in diagnosing chimney lesions (27% compared to 73% with CT or MRI), but this can be overcome with PET/CT, which contains the advantages of both tests.

Diagnosis / Differential Diagnosis

There are a large number of space-occupying processes in the orbit that can manifest as orbital lymphoma. We will discuss the clinical and imaging characteristics of the most common of them.

Clinical picture (A) of a 60-year-old female patient who presented with a superior temporal orbital mass. Visual acuity was preserved in both eyes. Computed tomography of the orbital cavities, coronal (B) and axial (C) sections, demonstrated a homogeneous, circumscribed/well defined, space-occupying process in the lacrimal gland fossa surrounding the eyeball. An orbital biopsy demonstrated lacrimal gland atrophy with abundant lymphocytic infiltration. No malignancy was observed.

A patient with benign enlargement of the lacrimal gland on the background of reactive lymphoid hyperplasia is shown. In addition, it should be remembered that orbital lymphoma can be accompanied by inflammatory signs (orbital / eyelid edema & inflammation) in approximately 30% of cases (Figure 1A). In any case of clinical suspicion of lymphoma, an incisional biopsy of the process should be performed and it is recommended to avoid needle biopsy. There is no clinical and prognostic advantage to performing an excisional biopsy, and in fact in all cases treated with excisional biopsy alone there was local recurrence of the tumor.

Comprehensive differential diagnosis

Intra-conal processes – Meningioma: Clinically – decreased visual acuity, bulging eye, Imaging – tram-track and perioptic cyst sign, 40% calcifications, Glioma: decreased visual acuity with posterior fusiform mass on imaging, Cavernoma: bulging eye, well defined ovoid mass, central glomerulonephritis. Extra/intra-conal processes – Idiopathic orbital inflammation: bulging eye, diffuse involvement, late glomerulonephritis, low signal on T2WI, Thyroid Associated Orbitopathy: Protrusion of the eye, eyelid retraction, blepharitis, on imaging – pusiform enlargement of the extraocular muscles, or orbital fat proliferation and bulging of the eye without muscle enlargement. Metastases: old history of tumor, prominent sclera, bone destruction/erosion, epithelial processes of the lacrimal gland – displacement + indentation of the eyeball (inferior-medial), on imaging – heterogeneous signal, calcifications.

Treatment

Irradiation to the orbit is the common treatment for low-grade disease but may be accompanied by ocular/orbital morbidity such as dry eye, poor formation (cataracts, more in cases where an eye shield cannot be used). Rarer side effects – retinal vasculopathy, optic neuropathy, ororbital fat atrophy. Even rarer complications are conjunctival scarring and punctal narrowing. Several studies have shown a significant rate of distant relapse after targeted radiation therapy to the chimney. Radiation therapy requires patients to visit the oncology center daily for several weeks.[3,8] In cases of MALT lymphoma, the radiation dose in fractions is 30 Gy. The observed efficacy of external beam radiation therapy (XRT) – a high rate of local control up to 100%, disease-free survival after 5 and 7 years of 76% and 55% respectively, and overall survival after the same time periods of 89% and 80%.

Several years ago, we reported on oral chlorambucil therapy for adult patients with MALT of the esophagus who had difficulty getting to the oncology center for daily radiation therapy.[9] The patients were treated with four cycles of oral chlorambucil at a total dose of 600 mg. Complete response (CR) occurred in 26/33 patients (79%). Four patients (12%) presented with local or distant relapse of the disease. Complications such as hematopoietic suppression did not occur in the patient group, nor were symptoms of nausea/vomiting observed. One patient with malignant transformation died 12 months after diagnosis and initial treatment. Our conclusion was that oral chlorambucil therapy is a good alternative for patients with MALT alveolar lymphoma, without systemic side effects. Theoretically, the treatment could also be effective in distant subclinical disease.

Since most MALT lymphoma cells express CD20, rituximab, a chimeric antibody against CD-20, has been reported to be effective in treating lymphoma with a response rate of 73%.[10, 11] Side effects of this treatment include fever, chills, and shivering, usually with the first infusion of the agent. These side effects are self-limited and respond well to temporary interruption of the infusion and supportive symptomatic treatment. Repeated infusions of rituximab are well tolerated. Recently, intralesional rituximab has also been reported to be administered once a week for a month [12]. Complete responses occurred in 2 of the 5 patients, partial responses occurred in two additional patients treated with rituximab at an increasing dose, and one patient did not respond to treatment and was switched to systemic rituximab.

In cases of secondary orbital lymphoma in the presence of systemic disease, the main treatment is chemotherapy with or without irradiation to the orbit. Secondary orbital lymphoma is usually of a more aggressive histological type. The current standard chemotherapy for B cell lymphoma is RC(H)OP – Rituximab, Cyclophosphamide (Cytoxan/Neosar), Doxorubicin (Adriamycin), Vincristine (Oncovin) and Prednisolone. Other treatments such as surgery are not accepted as primary treatment, with patients treated with surgery alone showing a local recurrence rate of 100%. Cases of conjunctival involvement only – can be treated with radiation, 5FU or observation alone.

To make an appointment with Prof. Guy Ben Simon, call 050-2971663 or email clinicgbs@gmail.com