Mucosa Associated Lymphoid Tissue (MALT): A Clinical Overview of Orbital Lymphoma
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ABSTRACT
BACKGROUND
Orbital lymphoma is the most common primary orbital cancer in adults, and it predominantly affects the elderly population. Ocular adnexal lymphomas originate from the conjunctiva, eyelids, lacrimal glands, and orbital soft tissues, whereas intraocular lymphomas arise from the retina, uvea, vitreous, Bruch’s membrane, and optic nerve. Mucosa-associated lymphoid tissue (MALT) is a form of non-Hodgkin lymphoma and the most common subtype of ocular adnexal lymphomas (OAL) that affects the conjunctiva. Diagnosis of MALT is difficult due to subtle clinical presentation and the need for histological analysis for accurate confirmation.
CASE REPORT
A 69-year-old Caucasian male presented for a problem-focused exam due to a red eye. He was asymptomatic and did not use any topical eye drops. Upon examination, an elevated, mobile, pinkish lesion was found extending from the superior nasal to the superior temporal aspect of the bulbar conjunctiva in the left eye. A diagnosis of MALT lymphoma was eventually made.
CONCLUSION
Mucosa-associated lymphoid tissue lymphoma is a subtype of OAL and is a form of non-Hodgkin lymphoma. Preliminary diagnosis is usually made during slit lamp examination and confirmed by biopsy. A multidisciplinary team approach and diagnostic tools such as optical coherence tomography (OCT), bloodwork, computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) are essential to help guide treatment, staging, and prognosis.
Keywords: conjunctiva, non-Hodgkin, lymphoma, orbital, radiation
INTRODUCTION
Lymphoma is a type of blood malignancy that can originate from B cells or T cells and is classified as either Hodgkin or non-Hodgkin lymphoma based on the presence of Reed Sternberg cells, which are characteristic of Hodgkin lymphoma.1 Non-Hodgkin lymphoma, however, is more prevalent and most orbital lymphomas fall into this category.1,2 Mucosa-associated lymphoid tissue (MALT) lymphoma is a subtype of non-Hodgkin lymphoma that commonly occurs in mucosal sites such as the gastrointestinal tract, but in rare cases it can also affect the conjunctiva.3
MALT lymphoma is fairly uncommon, accounting for 5 to 10% of non-Hodgkin lymphomas. 1 It is a specific type of ocular adnexal lymphoma (OAL) that falls under the category of orbital lymphoma. Orbital lymphoma primarily affects the elderly, with most cases occurring in patients over the age of sixty and presenting unilaterally.2 Epidemiological data regarding gender predilection is inconsistent; however, there may be a slight predominance among females.1
MALT is the most common OAL that affects the conjunctiva. OALs are typically primary malignancies and metastasis to ocular structures is rare.1,2,4 Diagnosing MALT lymphoma can be challenging due to its often subtle clinical presentation, which often requires a biopsy and histopathological examination.
CASE REPORT
A 69-year-old Caucasian male presented for a problem-focused exam due to a red eye. He was asymptomatic and denied the use of any ocular medications. He reported using reading glasses but had no distance correction. He denied any eye pain, irritation, blurred vision, flashes, floaters, or double vision. His last eye exam was three years prior.
His past medical history included Type II diabetes, hyperlipidemia, chronic obstructive pulmonary disease, headaches, history of skin cancer, depression, and anxiety. His past ocular history included Fuchs’ endothelial dystrophy in both eyes, Descemet’s stripping endothelial keratoplasty (DSAEK) in the right eye, cataract surgery in the right eye, and a cataract in the left eye.
On initial examination, his visual acuity without correction was 20/25- in the right eye and 20/80 in the left eye. Pupil examination, confrontation visual fields, and extraocular movements were normal in both eyes. Refraction did not improve his visual acuity. Slit lamp examination revealed normal lids, lashes, and ocular adnexa. The cornea of the right eye had a clear corneal graft status-post DSAEK while the left eye showed central corneal haze with microcystic corneal edema, temporal scarring, central Descemet folds, and grade 2 guttata (Figure 1). The sclera and conjunctiva of the right eye were clear and quiet, but the left eye had an elevated, mobile, pinkish lesion in the bulbar conjunctiva extending from the superior nasal quadrant to the superior temporal quadrant (Figures 2 and 3). The anterior chamber and iris were normal in both eyes. Intraocular pressures were 10 mmHg in the right eye and 9 mmHg in the left eye. Both eyes were dilated for further examination.
The intraocular lens in the right eye was well-centered but showed grade 1 posterior capsular opacification. The left eye revealed grade 1 nuclear sclerosis and grade 1 posterior subcapsular cataract. Fundus examination was unremarkable in both eyes.
Figure 1. The anterior segment photo of the left eye shows a subtle, pinkish lesion at the nasal aspect of the bulbar conjunctiva (without lifting lids) along with corneal edema at the temporal aspect of the cornea.
Figure 2. The anterior segment photo of the left eye shows a large elevated, pinkish lesion extending from the superior nasal bulbar conjunctiva to the superior temporal bulbar conjunctiva.
Figure 3. The anterior segment photo of the left eye shows a large elevated, pinkish lesion extending across the superior bulbar conjunctiva with poor visualization of the posterior aspect of the lesion.
He was diagnosed with a conjunctival lesion in the left eye with the primary differential diagnosis being lymphoma due to the lesion’s appearance and poor visualization of the posterior aspect. At the time, his reduced vision in the left eye was attributed to central corneal haze and edema secondary to Fuch’s endothelial dystrophy. He was referred to a cornea and external disease specialist within one week due to concerns about potential malignancy.
Cornea and External Disease Exam – Initial and Post Op visit
Although the patient was referred semi-urgently, he did not attend his referral appointment until two months later. At the initial visit, it was recommended that he undergo an excisional biopsy with cryotherapy within two weeks. During his one-week post-operative visit, his visual acuity was 20/150, improving to 20/100 with pinhole testing in the left eye. The ocular examination revealed a superior amniotic graft on the conjunctiva and grade 3+ guttata in the cornea of the left eye. The pathology report confirmed extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The patient was subsequently referred to hematology and oncology. A PET scan and an MRI of the orbits (with and without contrast) were recommended to assess for intraorbital extension and systemic involvement. He was advised to return for an additional post-op visit in 3 to 4 weeks, however the patient did not return.
Hematology and Oncology – Initial visit
At his initial hematology and oncology visit, it was further confirmed that his MALT lymphoma consisted of a low-level clonal B-cell population intermixed with reactive B cells. He was negative for rearrangements involving the MALT 1 gene region via fluorescence in situ hybridization (FISH). It was recommended that he complete a PET scan for staging and an MRI of the orbits with and without contrast. Additionally, a complete blood count (CBC), complete metabolic panel (CMP), lactate dehydrogenase (LDH), human immunodeficiency virus (HIV), and hepatitis panel were ordered to rule out any pathogens. He was prescribed doxycycline 100 mg BID for 4 weeks due to the association of Chlamydia psittaci with MALT. A referral to radiation oncology was also made to evaluate whether he might benefit from radiation therapy to the left ocular adnexal region.
Hematology and Oncology – Follow-up visit
After his MRI (Figure 4) and PET scan, the patient had a follow-up visit to discuss the results and evaluate the outcome of his doxycycline trial. The results of the MRI and PET scan revealed a 25 mm anteroposterior by 22 mm transverse by 9 mm craniocaudal left hypermetabolic orbital mass that was consistent with lymphoma. However, there were no other orbital masses or signs of intracranial extension. The globes and lacrimal glands were normal. He was diagnosed with Stage IE extranodal marginal zone lymphoma involving the left orbit (see table 1). HIV, hepatitis, Epstein-Barr virus, and cytomegalovirus panels were negative.
He reported gastrointestinal intolerance to doxycycline, which made the trial unsuccessful. He was advised to discontinue doxycycline, and no further systemic treatment was recommended as the lesion was localized to the orbit.
Figure 4. There is an intermediate T1 enhancing lesion along the superolateral margin of the left orbital myofascial cone that extends to involve the left superior rectus muscle and possibly into the orbital apex.
Radiation Oncology – Initial visit
At this visit, it was recommended to use external beam radiation therapy and start with 24 Gray (Gy) in 12 fractions to the left orbit for treatment of orbital lymphoma. A CT simulation will be completed to help plan the angles and shapes of the radiation beams needed for radiation treatment.
DISCUSSION
Epidemiology and Pathophysiology
Ocular adnexal lymphomas are a localized form of systemic lymphoma affecting the orbit, lacrimal gland, eyelids, and/or conjunctiva. This type of lymphoma makes up 6 to 8% of orbital tumors and 10 to 15% of adnexal lesions.4 Most of these lesions are non-Hodgkin lymphomas with about 80% arising from B-lymphocytes, 14% from T-cells, and 6% from natural killer (NK) cells.4 There are four histological subtypes of lymphomas: extranodal marginal zone lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma. Conjunctival lymphomas are the most commonly malignant extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which accounts for 80% of all conjunctival B-cell non-Hodgkin lymphomas.4 Conjunctival lymphomas make up roughly 25% of all ocular adnexal lymphomas.4 This form of non-Hodgkin lymphoma predominantly arises from marginal zone B-cells and originates outside the lymph nodes.
MALT lymphoma primarily affects elderly individuals, usually presenting between the fifth to seventh decade, with a slight predilection for females. It is often associated with chronic inflammation or irritation, which can be triggered by both endogenous and exogenous antigens. This persistent antigenic stimulation leads to sustained lymphocyte proliferation. A notable genetic mutation in MALT lymphoma is the API2-MALT1 fusion gene, which promotes uncontrolled cell growth by continuously activating NF-kB (nuclear factor kappa-light chain enhancer of activated B cells).4 This fusion gene results from chromosomal translocations and is a key driver in the development and progression of MALT lymphoma. In the case of conjunctival lymphomas, approximately 98% are of B-cell lineage.4
Infectious pathogens play a significant role in the pathogenesis of MALT lymphoma. Key pathogens associated with MALT lymphoma include Helicobacter pylori, Chlamydia psittaci, Chlamydia pneumoniae, and Hepatitis C virus. Among these, Chlamydia psittaci is more commonly associated with conjunctival MALT lymphoma and prevalence rates range from 5 to 10% of cases, which can be higher in certain geographic regions.5 Despite this, Helicobacter pylori remains the most common pathogen linked to MALT lymphoma, especially in the gastric form with prevalence rates of 70 to 90% in affected patients.6 All these pathogens can induce chronic antigenic stimulation, which increases the risk of lymphoma development.
Signs, Symptoms, and Differentials
Clinical presentation of orbital lymphomas is generally non-specific and can vary based on the tumor’s location and size.1 There are no pathognomonic signs or symptoms for orbital lymphoma, but certain distinguishing clinical features can help raise suspicion. A common clinical presentation is proptosis, particularly in unilateral cases.1,4 This occurs due to the space-occupying effect of the lymphoma within the orbit. Another common clinical sign is a pink or red swollen area of conjunctiva, which is frequently described as a “salmon patch.” This “salmon patch” is a palpable, painless mass often observed in the superolateral quadrant of the conjunctiva and orbit.1,4,7 In addition to these clinical signs, patients may present with symptoms of a red eye that appears inflamed. The patient will rarely report pain or blurred vision. When pain does occur, it is usually indicative of an advanced or aggressive disease. Blurred vision and vision loss are uncommon because intraocular or optic nerve involvement is rare in orbital lymphoma.1,7
Less common clinical signs include diplopia, restricted eye movements, and dry eye symptoms.7,8 These are usually dependent on the tumor’s size and proximity to orbital structures like the extraocular muscles or lacrimal gland. If the lacrimal gland is involved, dry eye symptoms may occur but are not frequently reported.8 Diplopia and restricted eye movements can result from the lymphoma compressing or infiltrating the extraocular muscles.1,4 When examining patients with suspected orbital lymphoma, it is important to consider key differential diagnoses such as orbital pseudotumor, lacrimal adenoma, cavernous hemangioma, and other orbital metastases.1,4 A thorough ocular examination and detailed patient history are key factors when differentiating between these conditions. Imaging techniques such as MRI and CT, along with fine-needle aspiration and biopsy, are essential diagnostic tools and techniques. Ultimately, a pathology biopsy analysis is needed to form an accurate diagnosis.1,7
Diagnostic Testing
During routine biomicroscopy of the conjunctiva, MALT frequently presents as an elevated lesion with a “salmon patch” appearance.9 A definitive diagnosis of MALT is confirmed through incisional biopsy and histopathological analysis.9 Histopathologic evaluation is performed by staining tissue sections with hematoxylin and eosin. Common histological features of MALT include reactive follicles, abundant aggregated plasma cells, dutcher bodies, and polykaryocytes.10
Anterior segment OCT provides a non-invasive approach to assessing conjunctival lesions and can be especially useful in distinguishing MALT lymphoma from other conjunctival pathologies.11 On anterior segment OCT, the features of MALT include an epithelium with normal thickness (mean 53 um) with a hypo-reflective and homogenous sub-epithelial mass, hyper-reflective substantia propria and shadowing of underlying tissue.11 This presentation differs from ocular surface squamous neoplasia, which typically has a thickened (mean 390 um) and hyper-reflective epithelium.11
Once MALT lymphoma is confirmed by biopsy, a systemic workup is necessary to determine the stage, extent of the disease, and to monitor for systemic effects of lymphoma. Bloodwork typically includes a CBC, CMP, renal and liver function tests, as well as screening panels for HIV, hepatitis, and LDH.4,9,12 In particular, elevated serum LDH has been shown to be correlated with poorer prognosis and survival rates in patients with non-Hodgkins lymphoma.12 A study found an estimated 41% of patients diagnosed with non-Hodgkins lymphoma had an elevated LDH.12 MRI of the orbits is also completed to assess for posterior extension in the orbits and to determine laterality.4,9 Of note, a study found that 82% of patients with conjunctival MALT lymphoma had negative MRI results for orbital extension.13 Hybrid PET/CT scans have been shown to be more beneficial than PET scans alone in the staging of lymphoma as they provide better localization of potential dissemination.9 Bone marrow infiltration occurs in 2 to 20% of MALT lymphoma cases, which is why bone marrow aspirate and biopsy is often recommended.4,9 Other systemic evaluations may also include CT imaging of the chest, abdomen, and pelvis to further determine systemic involvement.
Table 1. The Ann Arbor Staging classification based staging system for OAL.4
Management and Treatment
Care coordination among multiple specialists is essential for the effective management and treatment of orbital lymphomas, which require involvement from both ophthalmology, hematology, and oncology.1 Treatment modalities for orbital lymphoma include surgery, radiation, and chemotherapy. The primary function for surgical intervention is biopsy, but it can also be used therapeutically for resection and removal of the tumor, but it is a less conventional treatment method.7 Surgical resection alone often leads to higher rates of recurrence and creates challenges in preserving normal ocular function while trying to achieve complete removal of the tumor.2,14,15
Radiation therapy is the primary treatment modality for orbital lymphomas and has been the first-line treatment option for many years.1,7 Since a majority of orbital lymphomas are confined to the orbit, it is easier to provide effective treatment with radiation as it can be applied to the entire orbit. It can be used as a stand-alone treatment option or in combination with surgery and/or chemotherapy. In some cases, radiation can completely eradicate the tumor, while in others, it may be used to shrink the size of the tumor before surgical excision or treatment with chemotherapy. However, it is important to monitor patients for potential adverse effects associated with radiation therapy, which include cataracts, dry eye, macular degeneration, retinopathy, and corneal ulceration.1,7,15
Chemotherapy is typically reserved for systemic spreading or high-grade lymphomas.1,15 It is not a first-line treatment option for patients with isolated, primary orbital lymphoma.15 Oncologists assess a variety of factors when deciding if chemotherapy is the most appropriate treatment for patients with orbital lymphoma. In cases of high-grade lymphoma or systemic metastasis, chemotherapy is commonly used alongside other treatment modalities such as radiation, steroids, or immunotherapy to achieve the best outcome.1,4,15
CONCLUSION
Orbital lymphoma is the most common primary orbital tumor affecting elderly individuals with a slight predilection for females. MALT is typically a B-cell non-Hodgkin lymphoma arising from the extranodal marginal zone B-cells outside the lymph nodes. It has been associated with chronic inflammation and certain pathogens, including Helicobacter pylori, Chlamydia psittaci, Chlamydia pneumoniae, and the Hepatitis C virus. The most common presentation is a “salmon patch” lesion. Other clinical signs include proptosis, or less commonly: pain, blurred vision, diplopia, and restricted eye movements. Definitive diagnosis is made through biopsy, and referrals to oncology are necessary for conducting a full-body workup and creating a treatment plan. Diagnostic tests such as MRI of the orbits, PET/CT scans, and bone marrow biopsy are commonly used for staging and guiding treatment. Treatments for MALT include surgery, radiation, and chemotherapy. With prompt diagnosis, appropriate referrals and a multidisciplinary approach, the prognosis for patients with MALT is highly favorable.
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- Alfaar AS, Yousef YA, W Wilson M, Hassanain O, Kakkassery V, Moustafa M, Kunbaz A, Esmael A, Strauß O. Declining incidence and improving survival of ocular and orbital lymphomas in the US between 1995 and 2018. Sci Rep. 2024 Apr 3;14(1):7886.
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- Tanenbaum RE, Galor A, Dubovy SR, Karp CL. Classification, diagnosis, and management of conjunctival lymphoma. Eye Vis (Lond). 2019 Jul 27;6:22.
- Wotherspoon AC, Doglioni C, de Boni M, Isaacson PG. Chlamydia psittaci and conjunctival MALT lymphoma. J Pathol. 1993 Jun;170(2):229-32.
- Mönkemüller K, Wex T, Kuester D, Malfertheiner P. Helicobacter pylori infection and gastric MALT lymphoma. World J Gastroenterol. 2004 Nov 15;10(22):3327-34.
- Chung HU, Son JH. Ocular adnexal mucosa-associated lymphoid tissue lymphoma: a narrative review. J Yeungnam Med Sci. 2022 Jan;39(1):3-11.
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- Ferry JA, Fung CY, Zukerberg L, Lucarelli MJ, Hasserjian RP, Preffer FI, Harris NL. Lymphoma of the ocular adnexa: A study of 353 cases. Am J Surg Pathol. 2007 Feb;31(2):170-84.
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- Endrizzi L, Fiorentino MV, Salvagno L, et al. Serum lactate dehydrogenase (LDH) as a prognostic index for non-Hodgkin’s lymphoma. European Journal of Cancer & Clinical Oncology. 1982 Oct;18(10):945-949.
- Nasser QJ, Pfeiffer ML, Romaguera J, Fowler N, Debnam JM, Samaniego F et al. Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma. Leukemia and Lymphoma. 2014 May;55(5):1013-1017.
- Zucca E, Arcaini L, Buske C, Johnson PW, Ponzoni M, Raderer M, Ricardi U, Salar A, Stamatopoulos K, Thieblemont C, Wotherspoon A, Ladetto M. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jan;31(1):17-29.
- Min GJ, Kim SE, Kim TY, Jeon YW, O JH, Choi BO, Park G, Yang SW, Cho SG. Long-Term Clinical Outcomes in Treatment-Naïve Patients With Orbital Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma: A Single-Center Study. Front Oncol. 2022 May 6;12:769530.
Dr. Njeru is a staff optometrist at the Chillicothe VA Medical Center. He graduated from The Ohio State University: College of Optometry and completed his ocular disease residency at the Chillicothe and Columbus VA. . He is a fellow of the American Academy of Optometry.
Dr. Grangaard is a staff optometrist and serves as the co-residency director at the Chillicothe VA Medical Center. He graduated from The Ohio State University College of Optometry and completed his ocular disease residency at the Chillicothe and Columbus VA. He is a fellow of the American Academy of Optometry and board-certified in medical optometry.
Dr. Hileman graduated from the Illinois College of Optometry in 2007. He completed an ocular disease residency that the Chillicothe and Columbus VA Medical Centers from 2007-2008. He currently serves as the Chief of the Eye Clinic at the Chillicothe VA Medical Center.
