Mucosal associated Lymphoid Tissue Lymphoma of the uvea: an analysis of 3 cases

doi:10.21203/rs.3.rs-1611521/v1

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Mucosal associated Lymphoid Tissue Lymphoma of the uvea: an analysis of 3 cases

https://doi.org/10.21203/rs.3.rs-1611521/v1

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Background: Ocular MALT lymphoma involving orbit and conjunctiva usually has an indolent clinical course with “salmon patch” mass as typical presentation. This study is to report a series of rare cases and investigate the clinical and pathological features of ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis.

Methods: From 2018 to 2020 in Beijing Tongren Eye Cener, 3 cases of 3 eyes (2 female patients and 1 male patient) with ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis were included in the study. All patients had complaints of blurred vision and hyperemia in their involved eyes. The average age was 56.33 ± 2.08 years old and the average time from initial diagnosis to pathological diagnosis was 3.00 ± 1.73 months. Ophthalmic examinations including BCVA, IOP, slit lamp microscope examinations, fundus photography, B-scan ultrasonography, UBM, OCT, FFA and ICGA were conducted. Systemic workups including orbital MRI, PET-CT and blood autoimmune antibody tests were also conducted. Pathological tissue from patients were obtained through surgeries. Biopsy examinations were performed to accurately determine pathological diagnosis. All the information of clinical, imaging and pathological changes were collected and analyzed.

Results: At the initial diagnosis, the BCVA of involved eyes decreased seriously while the IOP were normal. All involved eyeball showed extensive hyperemia and local thickening in the wall of eyeballs. B-scan ultrasonography showed mass with abundant blood and irregular cysts inside the eyeball wall and in the retrobulbar orbit, surrounding the ocular wall and optic nerve. UBM showed solid lesions with low and medium echo under the conjunctiva and inside the ciliary body of 2 cases. OCT showed posterior polar wavy rise of RPE and local neuroepithelial detachment in all cases. FFA and ICGA showed vascular abnormalities (patch-like strong fluorescence and fluorescence leakage) and local thickening in retina and choroid (Rectangle-like weak fluorescence below the macula). The posterior wall of the eyeball was thickened and enhanced in MRI. PET-CT also showed thickening of posterior wall of eyeballs and increased metabolic activity but there was no sign of autoimmune disease. All patients were diagnosed as MALT lymphoma through pathologic examinations of biopsy tissue.

Conclusions: The onset of primary ocular MALT lymphoma in uvea is hidden. The early clinical manifestations are lack of specificity and misleading. B-scan ultrasonography has characteristic manifestations and is valuable in diagnosis. However, pathological diagnosis through tissue biopsy is irreplaceable.

MALT lymphoma

uvea

posterior scleritis

Lymphoma is a group of lymphoproliferative malignancies of B- or T-lymphocytes with multiple subtypes and varying clinical features. It can occur in lymph nodes or spleen, or in other sites outside the lymph nodes (extranodal). Among all the extranodal presentations, ocular lymphoma is a rare manifestation accounting for 5%[1]. Among them, mucosa-associated lymphoid tissue (MALT) lymphoma is the most common type, accounting for 80%-85%[2].

MALT lymphoma was first described and characterized by the presence of small B-lymphocytes of low-grade malignancy by Issac and Wright in 1983 [3]. According to several studies, female patients in their 50s to 70s are easier to be affected while young adult and children are hardly [4–6]. It mainly involves extranodal tissue of gastrointestinal tract, salivary gland, thyroid, lung, lacrimal gland, orbit, and conjunctiva [7–10]. Ocular MALT lymphoma involving orbit and conjunctiva usually has an indolent clinical course during which “salmon patch” mass is the typical presentation. The whole uveal involvement is rare [11–13]. However, in a very few cases, it can also originate in the site of uveal tissue primarily and the clinical manifestations can be diverse and difficult to diagnose. It is often misdiagnosed as uveitis, scleritis and choroidal hemangioma.

Here we report a series of rare cases of ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis. The clinical and imaging features of the 3 patients were analyzed retrospectively.

This retrospective, observational study was conducted at Beijing Tongren Hospital. All patients have consented for their anonymized data to be published.

From 2018 to 2020, 3 cases of 3 eyes (3 patients) with ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis were included in the study. All patients were diagnosed by pathological examination in Beijing Tongren Hospital. The basic information was shown in Table 1. Among them, there were 2 females and 1 male. The age of patients ranged from 54 to 58 years old and the average age was (56.33 ± 2.08) years old. The involved eyes were 2 right eyes and 1 left eye. The time from initial diagnosis to pathological diagnosis was 2 ~ 5 months, and the average time was (3.00 ± 1.73) months.

Table 1

The basic information of involved patients.
Patient No.	Gender	Age (years)	Left/ Right Eyes	Time from initial diagnosis to pathological diagnosis (months)
1	Female	57	Left	2
2	Male	58	Right	2
3	Female	54	Right	5

All patients had complaints of blurred vision and hyperemia in their involved eyes, which were previously diagnosed as posterior scleritis and were treated with oral glucocorticoids. All patients declared no previous history of systemic lymphoma. Primary lymphoma was excluded by systemic examination. Several ophthalmic examinations were conducted including best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp microscope examinations and fundus photography. B-scan ultrasonography and ultrasound biomicroscope (UBM, conducted in 2 cases) examinations were conducted to reveal the extent, shape and internal blood flow of the lesion. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA, conducted in 2 cases) examinations were conducted to detect the damage of the lesion to the retinal and choroidal structures and blood vessels. Systemic workups, including orbital magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT, conducted in 2 cases) and blood autoimmune antibody tests were also conducted to exclude systemic autoimmune diseases and neoplasm. In order to accurately determine pathological diagnosis, the clinicians obtained the pathological tissue from patients through surgeries and performed biopsy examinations. All the information of clinical, imaging and pathological changes were collected and analyzed.

The initial ophthalmic examinations revealed that the BCVA of their involved eyes were 20/63, HM/20cm and 20/200. The IOP were 16mmHg, 14mmHg and 16mmHg. The slit-lamp examination and dilated fundus of all these 3 eyes was unmarkable except for extensive hyperemia in the whole wall and local thickening of their involved eyeball compared with their normal eye (Fig. 1). There was no sign of inflammation in the anterior chamber.

Besides, further examinations provided evidence for precise diagnosis (Table 2). B-scan ultrasonography showed mass with abundant blood and irregular cysts inside the eyeball wall. Irregular hypoechoic areas could also be detected in the retrobulbar orbit, surrounding the ocular wall and optic nerve (Fig. 2). In addition, UBM showed solid lesions with low and medium echo under the conjunctiva and inside the ciliary body of 2 cases (Fig. 3). To further reveal the damage of the lesion to the retinal and choroidal structures and blood vessels, the results of OCT showed posterior polar wavy rise of retinal pigment epithelium (RPE) and local neuroepithelial detachment in all 3 cases (Fig. 4). Local thickening of choroidal were clearly shown in 2 cases. As shown in Fig. 5 and Fig. 6, the results of FFA and ICGA showed changes of eyeballs which mainly involved vascular abnormalities (patch-like strong fluorescence and fluorescence leakage) and local thickening in retina and choroid (Rectangle-like weak fluorescence below the macula).

Table 2

The examination results of the patients.
Patient No.	B-scan	UBM	OCT	FFA	ICGA	MRI	PET-CT
1	Significantly thickened eyeball with reduced internal echo could be seen. Irregular hypoechoic areas with abundant blood flow surrounded the bulbar wall and optic nerve.	Hypoechoic lesions under the conjunctiva with uneven internal echo could be seen. The boundary between the lesion and sclera was still clear.	Wavy rise of RPE and local neuroepithelial detachment could be seen.	Patch-like strong fluorescence could be seen around the optic disc in the venous phase, with radial weak fluorescent strips between them.	Patch-like strong fluorescence could be seen in the early stage, mixed with radial low fluorescence (choroidal folds); rectangular low fluorescence below the macula could be seen in both early and late stage.	The posterior wall of the eyeball was unevenly thickened (equal signal intensity on T1and T2 weight images); the anterior wall was thickened (equal T1 and higher T2); irregular soft tissue image could be seen around the eyeball and the optic nerve (equal T1 and equal / higher T2 signals), the boundary is unclear and the mass could be enhanced.	/
2	Irregular bulge lesions on the global wall of eyeball could be seen. Irregular hypoechoic lesions with abundant blood flow could be seen in the orbit.	Hypoechoic solid lesions could be seen in the ciliary body, with uniform internal echo and clear boundary with sclera.	Wavy rise of RPE and local neuroepithelial detachment could be seen. Local thickening of choroidal could be seen.	Strong fluorescence appeared on the nasal side of the optic disc during the venous phase. Fluorescence leakage occurred in the late stage.	ICGA showed strong fluorescence, but no obvious abnormal blood vessels were found. The lower half of retina was raised	Arc and spindle signal shadow (equal T1 and equal T2) could be detected on the posterior wall of the eyeball. The mass could be moderately enhanced.	The soft tissue behind the vitreous body of the eyeball was thickened and the metabolism was enhanced.
3	Thickened eyeball with uniform reduced internal echo and abundant blood flow signals could be seen. Irregular hypoechoic areas surrounding the eyeball wall and optic nerve could be seen in the retrobulbar orbit. CDFI showed rich blood flow signals	/	Wavy rise of RPE and local neuroepithelial detachment could be seen. Local thickening of choroidal could be seen.	Rising lesions with patch-like strong fluorescence could be seen in the inferior temporal side of the macula. Fluorescence leakage occurred in the late stage around the optic disc.	/	The eyeball wall was diffusely thickened, easpecially the posterior wall. Arc soft tissue shadows were seen in the space within the retrobulbar muscle cone, showing equal T1 and equal T2 signal shadows.The optic disc was involved in the lesion, which surrounded the intraorbital segment of the optic nerve. The optic nerve was compressed and narrowed in the front. The anterior chamber became shallow.	The soft tissue behind the vitreous body of the eyeball was thickened and the metabolism was enhanced.

Systemic workups, including orbital MRI, PET-CT and blood autoimmune antibody tests were also conducted. According to results of MRI, all the eyeball walls were diffusely thickened. In 2 cases, the lesion surrounded the intraorbital segment of the optic nerve, and the optic nerve was compressed and narrowed. PET-CT also showed thickening of posterior wall of eyeballs and increased metabolic activity, indicating the possibility of malignant tumors. However, there was no other evidence and the result of blood test showed no evidence of infection and systemic autoimmune diseases.

Due to the suspicion of uveal neoplasm, all patients were referred to an oncologist and underwent diagnostic surgeries with conjunctiva biopsy of their eyes. The pathology report of the surgical biopsy confirmed the diagnosis of the lesion as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in choroidal (Fig. 7). Immunohistology of conjunctiva was positive for CD10(+), CD20(++), CD79a(+), κ(+),LCA(+) and bcl-2(+). Because there was no evidence of MALT lymphoma in other sites of this patient, the tumor stage was IE according to the Ann Arbor grading system.

All the patients received intravitreal injection of 400 µg/0.1 ml of methotrexate (MTX) monthly for 3 months and were referred to an oncologist for further treatments. There was no sign of systemic lymphoma on the latest follow-up.

According to the WHO classification, MALT lymphoma is defined as an extranodal lymphoma composed of morphologically heterogeneous small B-cells including marginal zone cells, cells resembling monocitoid cells, small lymphocytes, scattered immunoblast cells and centroblast-like cells [3, 8]. MALT lymphoma can arise in a variety of sites. To the best of our knowledge, ocular MALT lymphoma usually involves ocular adnexa primarily and was defined as the MALT type of primary ocular adnexal lymphoma (POAML). It generally develops in females after the fourth decades of life [14]. Except for the "salmon patch" symptom related to conjunctival involvement, most of the other clinical features are related to orbital invasion, including exophthalmia (27%), palpable mass (19%), decreased visual acuity and ptosis (6%) and diplopia (2%) [14]. POAML has been reported to account for 35–90% of ocular lymphoma [15–18]. However, in a very few cases, MALT lymphoma can involve uvea, which makes these series of cases special.

Ocular MALT lymphoma involving uvea primarily can masquerade as posterior scleritis and can be easily misdiagnosed as uveitis and choroidal hemangioma. Posterior scleritis is a unilateral disease with strong female predominance. The most common presenting symptoms are pain and decreased vision [19]. The patients in our study complained about their blurred vision and hyperemia but had no typical symptoms like “salmon patch” initially. Unfortunately, they were initially misdiagnosed as scleritis and treated with corticosteroid before the first visit in our hospital.

Among all the clinical examinations of ocular MALT lymphoma in uvea, B-scan ultrasonography is the most valuable imaging modality [20]. Typical ultrasonographic features are hollow (hypoechoic) choroidal thickening and local hypoechoic extrascleral extension (ESE). The combination of these two signs is highly suggestive of ocular MALT lymphoma in uvea, but it should be noted that similar ultrasound findings can also be seen in diffuse choroidal melanoma with ESE [21]. They still need to be differentiated through pathologic examinations of biopsy. In our study, the result of B-scan ultrasonography showed significantly thickened eyeball with reduced internal echo in all cases. Besides, irregular hypoechoic lesions with abundant blood flow were found in the orbit (ESE in all cases). The lesions surrounded the bulbar wall and optic nerve in 2 cases. These results of ultrasonography not only indicated the mass with abundant blood and irregular cysts in the eyeball wall, but were helpful to the extent of involvement of ocular lymphoma in uveal tissue.

Compared with ultrasonography, FFA, ICGA and MRI are of limited value in the diagnosis of ocular MALT lymphoma in uvea. FFA could show weak fluorescence at early phase and strong fluorescence at middle and late phase in the lesions of ocular MALT lymphoma in uvea [22]. Both early and late ICGA could show weak choroidal fluorescence (choroidal folds) in the lesions. In our cases, all the FFA results showed patch-like strong fluorescence during the venous phase and fluorescein leakage in the late stage. The ICGA results of 2 cases both showed strong fluorescence. Both of these examinations lacked characteristics. Conversely, MRI is helpful to find orbital involvement of ocular MALT lymphoma by showing thickened and enhanced wall of the eyeballs [3, 23]. Also, it is much easier to detect lesions with different shapes and invasive growth through MRI, which often surround the eyeball, extraocular muscles and optic nerve. However, the signal of the lesions in our case is irregular and lack of characteristics, and the resolution is lower than that of ocular ultrasonography.

Although the accuracy of typical ocular manifestations and ultrasonography in the diagnosis of ocular MALT lymphoma in uvea is high, the gold standard of diagnosis are histopathology examination and immunophenotyping examination of surgical biopsy [21, 24]. Histologically, Suzuki et al proposed several main pathological features for the diagnosis of MALT lymphoma, including (1) infiltrating lymphocytes are centrocyte-like cells (marginal zone cells) with irregular nuclei and abundant pale cytoplasm, (2) plasmocytic differentiation with or without Dutcher bodies (intracytoplasmic inclusions), (3) follicular colonization with infiltration of germinal centers by centrocyte-like cells or atrophic germinal center, (4) lymphoepithelial lesion (LEL) [25]. However, the characterization of ocular MALT lymphoma in uvea is not as simple. Similar to POAML, some of the histological features observed in this special lymphoma, such as invasive lesions, reactive B-cell follicles and LELs overlap with the histological features of reactive lymphoepithelial infiltration in the ocular adnexa and uvea, which may make it difficult to diagnose precisely [26]. In our study, the diagnosis of all the patients in our study were eventually confirmed by biopsy of their involved tissue. Furthermore, compared with the histological examination, immunophenotyping and molecular diagnostic techniques have greatly improved the diagnostic level of ocular MALT lymphoma. The characteristic immunophenotypic profiles are CD10^neg, CD20^pos, CD23^neg, BCL2^neg, BCL6^neg and Cyclin D1^negwith a few interspersed CD3^posT lymphocytes [8]. However, there is still a lack of specific markers and more research is needed.

We must admit that there were still some limitations in our study. Due to the rare incidence of ocular MALT lymphoma in uvea, only 3 cases were included in our study. The follow-up period was short and the data were incomplete. More studies will be conducted to summarize the clinical manifestations, ocular imaging features and pathological changes ocular MALT lymphoma in uvea in the future.

In conclusion, the onset of primary ocular MALT lymphoma in uvea is hidden. The early clinical manifestations are lack of specificity, which may mislead the diagnosis. Although the accuracy of diagnosis of ocular MALT lymphoma in uvea is high through typical ocular manifestations and ultrasonography, the gold standard of diagnosis is pathological examination of tissue biopsy.

Ethics approval and consent to participate

All participating individuals provided informed consent. The study was conducted according to the Declaration of Helsinki. The Medical Ethics Committee of Beijing Tongren Hospital (Beijing, China) approved all procedures of the present study.

Consent for publication

Consents for publication were obtained from all patients.

Availability of data and material

The raw data of this study was included in the supplementary file 1.

Competing of interests

The authors declare that they have no conflicts of interest.

Funding statement

Not applicable.

Authors’ contributions

ZW and YL collected all the clinical information. JM, XC, XX and LS analyzed the information and prepared the figures and tables. ZW and YL were the major contributors in drafting the work. HW and WW reviewed and edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Moslehi R, Coles FB, Schymura MJ. Descriptive epidemiology of ophthalmic and ocular adnexal non-Hodgkin's lymphoma.Expert Rev Ophthalmol 2011;6(2):175-180.
Incesoy-Ozdemir S, Yuksek N, Bozkurt C, Sahin G, Memis L, Dizman A, et al. A rare type of cancer in children: extranodal marginal zone B-cell (MALT) lymphoma of the ocular adnexa.Turk J Pediatr 2014;56(3):295-298.
Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma.Cancer 1983;52(8):1410-1416.
Lucas RS, Mortimore R, Sullivan TJ, Waldie M. Interferon treatment of childhood conjunctival lymphoma.Br J Ophthalmol 2003;87(9):1191.
Waisbourd M, Leibovitch I, Sayar D, Elhasid R. Conjunctival lymphoma in a child.Cornea 2011;30(5):598-599.
Hoh H, Armbrust S, Decker T, Holland U, Balschat S. [MALT Lymphoma of the Conjunctiva in a 13-year old Child--5-Year Relapse-free Follow-up Following Antibiotic Treatment].Klin Monbl Augenheilkd 2016;233(1):79-84.
Wotherspoon AC, Hardman-Lea S, Isaacson PG. Mucosa-associated lymphoid tissue (MALT) in the human conjunctiva.J Pathol 1994;174(1):33-37.
Annibali O, Sabatino F, Mantelli F, Olimpieri OM, Bonini S, Avvisati G. Review article: Mucosa-associated lymphoid tissue (MALT)-type lymphoma of ocular adnexa. Biology and treatment.Crit Rev Oncol Hematol 2016;100:37-45.
Celiker H, Toker E, Kaygusuz Atagunduz I. A case of conjunctival MALT lymphoma: successfully treated with solely extended rituximab therapy.Int Ophthalmol 2019;39(3):687-691.
Ong SJ, Jung SM, Lin HC. Conjunctival lymphoma during pregnancy: a case report.BMC Ophthalmol 2017;17(1):131.
Shields CL, Shields JA, Carvalho C, Rundle P, Smith AF. Conjunctival lymphoid tumors: clinical analysis of 117 cases and relationship to systemic lymphoma.Ophthalmology 2001;108(5):979-984.
Strauss EC, Warren JF, Margolis TP, Holsclaw DS. Diagnosis of conjunctival B-cell lymphoma by polymerase chain reaction heteroduplex analysis.Am J Ophthalmol 2003;136(1):207-209.
Fung CY, Tarbell NJ, Lucarelli MJ, Goldberg SI, Linggood RM, Harris NL, et al. Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes.Int J Radiat Oncol Biol Phys 2003;57(5):1382-1391.
Ferreri AJ, Dolcetti R, Du MQ, Doglioni C, Resti AG, Politi LS, et al. Ocular adnexal MALT lymphoma: an intriguing model for antigen-driven lymphomagenesis and microbial-targeted therapy.Ann Oncol 2008;19(5):835-846.
Rath S, Connors JM, Dolman PJ, Rootman J, Rootman DB, White VA. Comparison of American Joint Committee on Cancer TNM-based staging system (7th edition) and Ann Arbor classification for predicting outcome in ocular adnexal lymphoma.Orbit 2014;33(1):23-28.
McKelvie PA. Ocular adnexal lymphomas: a review.Adv Anat Pathol 2010;17(4):251-261.
Ferry JA, Fung CY, Zukerberg L, Lucarelli MJ, Hasserjian RP, Preffer FI, et al. Lymphoma of the ocular adnexa: A study of 353 cases.Am J Surg Pathol 2007;31(2):170-184.
Yen MT, Bilyk JR, Wladis EJ, Bradley EA, Mawn LA. Treatments for Ocular Adnexal Lymphoma: A Report by the American Academy of Ophthalmology.Ophthalmology 2018;125(1):127-136.
Alsarhani WK, Abu El-Asrar AM. Multimodal Imaging of Nodular Posterior Scleritis: Case Report and Review of the Literature.Middle East Afr J Ophthalmol 2020;27(2):134-138.
Theophanous C, Pekmezci M, Damato BE, Kao AA, Bloomer MM, Stewart JM, et al. Choroidal Lymphoma Discovered on Ultrasound in a Patient with Suspected Corneal Tumor.Ocul Oncol Pathol 2018;4(5):318-321.
Mashayekhi A, Shukla SY, Shields JA, Shields CL. Choroidal lymphoma: clinical features and association with systemic lymphoma.Ophthalmology 2014;121(1):342-351.
Coupland SE, Damato B. Understanding intraocular lymphomas.Clin Exp Ophthalmol 2008;36(6):564-578.
Yoo RE, Park SW, Rhim JH, Kim JE, Kim SC, Choe JY, et al. CT and MR imaging findings of ocular adnexal mucosa-associated lymphoid tissue lymphoma associated with IgG4-related disease: multi-institutional case series.Int J Ophthalmol 2020;13(8):1231-1237.
Aronow ME, Portell CA, Sweetenham JW, Singh AD. Uveal lymphoma: clinical features, diagnostic studies, treatment selection, and outcomes.Ophthalmology 2014;121(1):334-341.
Suzuki J, Ohguro H, Oguri N, Satoh M, Kon S, Kogawa K, et al. Clinicopathologic and immunogenetic analysis of mucosa-associated lymphoid tissue lymphomas arising in conjunctiva.Jpn J Ophthalmol 1999;43(3):155-161.
Lagoo AS, Haggerty C, Kim Y, Hammons M, Neufeld K, Redher C, et al. Morphologic features of 115 lymphomas of the orbit and ocular adnexa categorized according to the World Health Organization classification: are marginal zone lymphomas in the orbit mucosa-associated lymphoid tissue-type lymphomas?Arch Pathol Lab Med 2008;132(9):1405-1416.

No competing interests reported.

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Mucosal associated Lymphoid Tissue Lymphoma of the uvea: an analysis of 3 cases

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