Bilateral Lacrimal Gland Mantle Cell Lymphoma in 11-Year Follow-Up: Case Report and Review of 48 Cases With Ocular Adnexal Presentation in the Literature

Abstract

A 63-year-old woman, with 11-year history of breast cancer, showed bilateral lacrimal gland enlargement on magnetic resonance imaging. Gallium-67 scintigraphy, as the standard at that time in 2004, demonstrated abnormally high uptake only in bilateral lacrimal glands. The lacrimal glands were extirpated and the pathological diagnosis was mantle cell lymphoma (MCL). She underwent bilateral orbital radiation, based on no uptake of gallium-67 in other sites of the body. In a month, bone marrow biopsy revealed the infiltration with MCL, positive for cyclin D1. She showed hepatic lymphadenopathy and splenomegaly, and so received 2 cycles of alternating Hyper-CVAD therapy and high-dose methotrexate with cytarabine, combined with rituximab, in 2 months, leading to complete remission. She underwent autologous peripheral blood stem cell transplantation and was well until the age of 68 years when she showed a recurrent intratracheal submucosal lesion of lymphoma and underwent one course of reduced-dose CHOP combined with rituximab. Next year, the left rib resection revealed the metastasis of breast adenocarcinoma, leading to daily oral letrozole. Further 2 years later, computed tomographic scan demonstrated multiple submucosal nodular lesions in the trachea and bronchi, together with cervical and supraclavicular lymphadenopathy, and intratracheal lesion biopsy and bone marrow biopsy proved the involvement with MCL. She underwent 2 courses of bendamustine and rituximab, resulting in complete remission but died of metastatic breast cancer at the age of 74 years. Clinical features in 48 previous cases with ocular adnexal MCL in the literature were summarized in this study.

Keywords

mantle cell lymphoma lacrimal gland autologous peripheral blood stem cell transplantation breast cancer tracheal and bronchial infiltration

Background

Lymphoma is the most frequent malignancy encountered in the field of ophthalmology where malignant diseases are basically rare. Two major clinical entities of lymphoma in the ophthalmic presentation are intraocular lymphoma^1-4 and ocular adnexal lymphoma.^5-8 The intraocular lymphoma is classified into primary and secondary intraocular lymphoma. The primary intraocular lymphoma develops in association with primary central nervous system lymphoma^1-4 while the secondary intraocular lymphoma is caused by infiltration of lymphoma which initially occurs at the other sites of the body.^9-11 The clinical manifestations of the intraocular lymphomas are vitreous opacity and retinal infiltrates and must be differentiated from inflammatory presentation of uveitis.^12,13

The ocular adnexa is the anatomical term to indicate all tissues which support the eyeball in the orbit such as lacrimal glands and sacs, eyelids, conjunctiva, extraocular muscles, and the soft tissue. The ocular adnexa is the site not only for lymphoma but also for inflammatory diseases such as IgG4-related disease,^14-17 sarcoidosis,¹⁸ and other inflammatory entities.^19,20 In the ocular adnexa, the lacrimal glands and conjunctiva^21-24 are 2 major sites for both lymphoma and inflammatory diseases. Inflammatory diseases in these sites might play a role in predisposing the development of lymphoma.^17,18,20

Lymphoma has been classified into different histopathological types which are associated with different clinical prognosis.^25-27 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, so-called MALT lymphoma, is the most frequent diagnosis in the ocular adnexal lymphoma and has favorable outcome based on its slow progression and less infiltration to other sites of the body. The other types of lymphoma such as mantle cell lymphoma (MCL)^28-32 are relatively rare, and their prognosis is not so favorable compared with MALT lymphoma. In this study, we presented a patient with primary MCL in bilateral lacrimal glands who, after all, underwent autologous peripheral blood hematopoietic stem cell transplantation in the background of breast cancer. In the end of the long-term follow-up, the relapse of MCL occurred in parallel with the metastatic lesion of breast cancer. We also summarized 48 patients with MCL in the literature who presented with ocular adnexal lesions in order to elucidate their clinical features.^33-77

Case Report

A 63-year-old woman noticed upper eyelid swelling on the right side half a year previously and visited a local eye doctor. She underwent laser peripheral iridotomy in both eyes for shallow anterior chamber and was referred to Okayama University Hospital. At that time, she did not take any medication. In the past history, she had undergone left mastectomy for breast ductal adenocarcinoma at 52 years old and discontinued postoperative oral medication for breast cancer due to allergic skin reaction.

At the initial visit, the best-corrected visual acuity in decimals was 1.5 in both eyes and the intraocular pressure was 12 mm Hg in both eyes. She had nothing particular in both eyes except for peripheral iridotomy in the superonasal quadrant. The lacrimal glands on both sides were palpable at the orbital bony edge. Gallium-67 scintigraphy showed abnormally high uptake only in bilateral lacrimal glands (Figure 1A) and magnetic resonance imaging demonstrated the enlargement of bilateral lacrimal glands (Figure 1B and C). She underwent lacrimal gland extirpation on both sides in August 2004 and the pathological diagnosis was MCL, based on the infiltration with small monotonous cells (Figure 2A) which were positive for cyclin D1 (Figure 2B), CD5, CD20 (Figure 2D), and CD79a, but negative for CD3. Ki-67 labeling index was less than 1 % (Figure 2C).

Figure 1.

Gallium-67 scintigraphy (A), showing high uptake in bilateral lacrimal glands, and magnetic resonance imaging, showing bilateral lacrimal gland masses in axial (B) and coronal section (C) at the initial visit at the age of 63 years.

Figure 2.

Right lacrimal gland extirpated at the age of 63 years. Infiltration with monotonous cells (A, hematoxylin-eosin), positive for cyclin D1 (B) and CD20 (D). Ki-67 labeling index was less than 1 % (C). Cyclin D1 was re-stained in 2021 with anti-cyclin D1 antibody (Abcam SP4, rabbit monoclonal, ×150 dilution). Ki-67 was re-stained in 2023 (NCL-Ki67p, Leica Biosystems, rabbit polyclonal, ×500 dilution). Scale bar = 200 µm.

Based on no uptake of gallium-67 in other sites of the body, she underwent radiation at the total dose of 40 Gy (2 Gy × 20 fractions) on both sides of the orbit in 4 weeks. After the completion of radiation, bone marrow biopsy revealed the infiltration with MCL (Figure 3A), positive for cyclin D1 (Figure 3B). She showed systemic superficial lymphadenopathy, splenomegaly, and hepatic portal lymphadenopathy up to the diameter of 6 cm and was designated as Stage IV. Serum lactate dehydrogenase was 268 IU/L (laboratory upper limit of the normal range: 220 IU/L), serum soluble interleukin-2 receptor was elevated to 1860 U/L, and white blood cell counts were 5.09 × 10³/µL. There was no involvement in the liver, bilateral lung fields, or mediastinal lymph nodes. Her performance status was 1. She underwent 2 cycles of alternating Hyper-CVAD therapy (cyclophosphamide 500 mg × 2, doxorubicin 70 mg, vincristine 2 mg, and dexamethasone 40 mg) and HD-MA therapy (methotrexate 300 mg and 1200 mg, cytarabine 1400 mg × 2) in 2 months, leading to complete remission. Rituximab every 3 weeks, 8 times in total, was combined from the beginning of chemotherapy until the autologous peripheral blood stem cell transplantation. Bone marrow biopsy confirmed no involvement, and peripheral blood stem cells were collected twice after HD-VP therapy (etoposide 700 mg) and HD-MA therapy. In myeloablative conditioning with LEED therapy (cyclophosphamide 3000 mg, etoposide 700 mg, melphalan 200 mg, and dexamethasone 40 mg), she underwent autologous peripheral blood stem cell transplantation successfully in May 2005. Three years later at the age of 67 years, she underwent cataract surgery in both eyes for radiation cataract.

Figure 3.

Bone marrow biopsy at the age of 63 years. Infiltration with monotonous cells (A, hematoxylin-eosin), positive for cyclin D1 (B). Cyclin D1 was re-stained in 2021 with anti-cyclin D1 antibody (Abcam SP4, rabbit monoclonal, ×150 dilution). Scale bar = 200 µm.

She was well until the age of 68 years in May 2009 when she developed a recurrent intratracheal submucosal lesion of lymphoma and underwent one course of reduced-dose CHOP, combined with 4 courses of rituximab, nearing to complete remission. At the age of 69 years in April 2010, the left rib resection revealed the metastasis of breast adenocarcinoma, leading to the start of oral letrozole 2.5 mg daily. Two years later in July 2012, computed tomographic scan demonstrated multiple submucosal nodular lesions in the trachea and bilateral bronchi, together with bilateral cervical and supraclavicular lymphadenopathy, and intratracheal lesion biopsy and bone marrow biopsy proved the involvement with mantle cells lymphoma. She underwent 2 courses of bendamustine (60 mg/m² on Day 1 and 2) and rituximab (375 mg/m²), resulting in complete remission. In April 2014, she had no medication and visited an eye doctor with no abnormal finding. One year later in April 2015, she died of metastatic breast cancer at the age of 74 years.

Discussion

A hallmark in the diagnosis of MCL is the overexpression of cyclin D1 in the nuclei of monotonous cells with B-cell lineage. In the present patient, cyclin D1 was re-stained on paraffin sections of the extirpated lacrimal gland and the bone marrow biopsy specimen which have been preserved since the initial presentation in 2004. At that time, fluorodeoxyglucose-positron emission tomography had not yet been introduced and could not be used for the staging of lymphoma as is the current standard. Based on the absence of abnormal uptake in the other sites of the body by gallium-67 scintigraphy, the patient underwent local radiation. However, in the light of MCL as a pathological diagnosis, the bone marrow was examined by biopsy to check the systemic infiltration. Around the same time, the patient developed superficial lymphadenopathy, and computed tomography disclosed hepatic lymphadenopathy in large size as well as splenomegaly.

Retrospectively, the simplified MCL international prognostic index (MIPI) score⁷⁸ which was not available at the time before systemic chemotherapy in this patient was calculated as 5 and designated as intermediate: 2 points for the age at 64 years, zero point for the performance status at 1, 2 points for LDH/ULN (laboratory upper limit of the normal) ratio as 268/220 = 1.21, and zero point for white blood cell counts at 5.09 × 10³/µL. Therefore, systemic chemotherapy and autologous peripheral blood stem cell transplantation as a therapeutic strategy in this patient would be compatible with the current standard. From the pathological point of view, the lacrimal gland lesion in this patient showed a low Ki-67 index in small monotonous lymphoma cells. The patient presented bone marrow involvement and splenomegaly, and thus, would be diagnosed as small cell variant of MCL which might show indolent course.⁷⁹ It should be, however, noted that the relapse did occur in the present patient after the autologous peripheral blood stem cell transplantation. The relapse of MCL was diagnosed by repeat pathological examinations and managed by additional chemotherapy in the time course which was intervened by the pathological confirmation of rib metastasis of breast adenocarcinoma. The patient was healthy until the death of metastatic breast cancer.

To analyze similar cases, we reviewed the Japanese literature with key words, “mantle cell lymphoma,” “lacrimal gland,” “lacrimal sac,” “orbital,” and “ocular adnexa,” in the bibliographic database of medical literature in Japanese (Igaku Chuo Zasshi, Ichushi-Web), published by the Japan Medical Abstracts Society (JAMAS, Tokyo, Japan). Old literature was collected from references cited in the articles identified during the literature search. PubMed and Google Scholar were also searched for the same key words. A sufficient description was found in 48 patients with ocular adnexal MCL (Table 1).^33-77

Table 1.

Review of 49 Patients With Ocular Adnexal Mantle Cell Lymphoma, Including the Present Patient.

Case no./gender/age at onset	Ophthalmic symptoms	Laterality	Involvement	Preceding diagnosis of mantle cell lymphoma	Biopsy route	Other sites involvement at ophthalmic presentation	Treatment	Outcome	Authors
1/Male/56	Right conjunctival mass	Right	Conjunctiva Inferior fornix	No	Conjunctival biopsy	None	Radiation	Not described	Lee et al³³
2/Male/58	Bilateral proptosis	Bilateral	Orbital	No	Cervical lymph node biopsy	Nasopharyngeal Bilateral submandibular, hilar, bilateral inguinal lymphadenopathy Bone marrow involvement with leukemic manifestation	Hyper-CVAD, High-dose MTX & Ara-C	Not described	Sato et al³⁴
3/Male/75	Left blepharoptosis	Left	Orbital	No	Left excisional biopsy	None	VEMP	No relapse in 2 years	Tsuchiya et al³⁵
4/Female/70	Left upper eyelid palpable mass	Bilateral	Lacrimal glands	No	Left excisional biopsy	None	Bilateral orbital radiation 36 Gy	No relapse in 6 months	Tsuchiya et al³⁵
5/Female/76	Right blepharoptosis	Right	Lacrimal gland to conjunctival fornix	No	Right conjunctival biopsy	None	Not described	Not described	Coffee et al³⁶
6/Male/62	Bilateral upper eyelid swelling	Bilateral	Lacrimal glands	No	Left upper eyelid biopsy	Maxillary and oral masses Bone marrow involvement	Hyper-CVAD Autologous hematopoietic stem cell transplantation	Complete remission	de Albuquerque et al³⁷
7/Male/78	Right conjunctival mass	Right	Conjunctival Nasal mass	No	Conjunctival biopsy	None	No	No relapse in 4 months	Aspiotis et al³⁸
8/Male/58	Left conjunctival mass	Left	Conjunctival Lower tarsal	No	Conjunctival biopsy	Bone marrow involvement Hepatosplenomegaly	CVP	Not described	Yoo et al³⁹
9/Female/81	Left lower eyelid swelling	Left	Orbital Inferior	5-year history of lymphoma	Eyelid biopsy	Bone marrow Submandibular, bilateral axillary, mediastinal, abdominal para-aortic lymphadenopathy	Previous R-CHOP and R-chlorambucil Current eyelid brachytherapy	No relapse in 3 years	Franco et al⁴⁰
10/Male/60	Bilateral upper eyelid swelling, stomachache	Bilateral	Lacrimal glands	No	Endoscopic gastrointestinal biopsy	Bilateral maxillary sinuses	Alternating R-Hyper-CVAD and R-MTX-AraC	Complete remission	Pajares-Hachero et al⁴¹
11/Male/47	Diplopia Left proptosis	Left	Orbital	No	Left excisional biopsy	Not described	Rituximab-based chemotherapy Bilateral orbital radiation	History of Graves disease	Abdullah et al⁴²
12/Female/59	Diplopia Bilateral proptosis	Bilateral	Lacrimal glands	9-year history of stable lymphoma	Lacrimal gland biopsy	Cervical, submandibular, axillary lymphadenopathy	Needle-guided local photodynamic therapy with mTHPC (temoporfin)	Stable disease in 14 months	Hamdoon et al⁴³
13/Female/31	Right proptosis Right vision loss	Right	Orbital retrobulbar	No	Right orbital exenteration	Right axillary lymphadenopathy	Surgery only	No relapse in 2.5 years	Kumar⁴⁴
14/Female/63	Bilateral eyelid swelling	Bilateral	Lacrimal glands	6-month history of lymphoma	Inguinal lymph node biopsy	Cervical, mediastinal, hilar, abdominal, pelvic, inguinal lymphadenopathy Bone marrow involvement	Chemotherapy	Not described	Ozkan et al⁴⁵
15/Male/79	Pain around the right eye, right visual decrease Right temporal headache	Right	Orbital	4-year history of lymphoma	Right temporal artery biopsy	Spleen, large intestine, bone marrow, 4 years previously Lung, recently	Chemotherapy 4 years previously Chemotherapy for lung and orbital mass	Not described	Masood et al⁴⁶
16/Male/64	Right Conjunctival mass	Right	Conjunctival Medial canthal bulbar	No	Conjunctival biopsy	Cervical lymphadenopathy Bone marrow involvement	FCR	Not described	Khanlari et al⁴⁷
17/Male/84	Bilateral proptosis	Bilateral	Lacrimal glands	No	Excisional biopsy	No lymphadenopathy No bone marrow involvement	Rituximab-CHOP	Complete remission	Maaroufi et al⁴⁸
18/Male/78	Bilateral eyelid swelling	Bilateral	Lacrimal gland	No	Bilateral excision	Not described	Not described	Not described	Vali Khojeini et al⁴⁹
19/Male/66	Bilateral lower eyelid swelling	Bilateral	Conjunctival Lower fornix	Lymphocytic leukemia with observation 1.5 years previously	Bilateral conjunctival biopsy	Systemic lymphadenopathy	Fludarabine and cyclophosphamide Rituximab/bendamustine	No relapse in 3 years	Matsuo et al⁵⁰
20/Male/73	Bilateral eyelid swelling and proptosis	Bilateral	Orbital	No	Bilateral excisional biopsy	Not described	CHOP FCR Radiation	Skin basal cell carcinoma Intestinal adenocarcinoma	Medrado et al⁵¹
21/Female/59	Right upper eyelid mass	Right	Lacrimal gland	No	Excision	Not described	Chemotherapy	Not described	Cai et al⁵²
22/Male/52	Left eye redness	Left	Lacrimal gland to bulbar conjunctiva	No	Excisional biopsy	Not described	RCVP	Not described	Sahu et al⁵³
23/Male/55	Left eyelid swelling Left blepharoptosis	Left	Orbital medial	No	Fine needle aspiration biopsy	Not described	R-CHOP	Not described	Sahu et al⁵³
24/Female/73	Diplopia Bilateral eyelid swelling	Bilateral	Lacrimal glands to conjunctiva	No	Biopsy	Not described	R-GIFOX	Relapse 18 months later Died 29 months after the initial diagnosis	Falcone et al⁵⁴
25/Female/74	Bilateral proptosis	Bilateral	Orbital	No	Biopsy	Cervical, mediastinal lymphadenopathy	R-CVP	Not described	Martínez-Esteve et al⁵⁵
26/Male/70	Redness in both eyes	Bilateral	Conjunctival Fornix	No	Conjunctival biopsy	Hepatosplenomegaly	CVP	Not described	Bellan et al⁵⁶
27/Female/56	Pink subconjunctival nodule	Left	Conjunctival Limbal	No	Excisional biopsy	Leukemic manifestation	Systemic chemotherapy	Not described	Choi et al⁵⁷
28/Male/24	Right proptosis	Right	Orbital Lateral	No	Fine needle aspiration biopsy	Not described	Not described	Not described	Verma et al⁵⁸
29/Male/66	Bilateral proptosis Vision decrease in both eyes	Bilateral	Orbital	No	Bilateral incisional biopsy	Bone marrow involvement	R-CHOP R-DHAP	Dead 13 months after initial presentation	Rašić et al⁵⁹
30/Female/57	Bilateral upper eyelid swelling	Bilateral	Lacrimal glands to right conjunctiva	No	Left lacrimal gland biopsy	Generalized lymphadenopathy Subcutaneous infiltration of the trunk	Rituximab/bendamustine	Complete remission	Khodarahmi et al⁶⁰
31/Male/69	Left blepharoptosis	Bilateral	Orbital	No	Incisional biopsy	Myasthenia gravis Bilateral axillary, cervical, submandibular lymphadenopathy	Rituximab/bendamustine	Complete remission No relapse in 6 months	Karlin et al⁶¹
32/Female/53	Diplopia, blurred vision	Right	Orbital Bilateral optic nerve sheath involvement	No	Skin biopsy Lymphoma cells in spinal tap	Splenomegaly, pancytopenia, lymphadenopathy	Previous rituximab/bendamustine Current R-CHOP with intrathecal MTX & AraC	Response	Shaikh et al⁶²
33/Female/61	Right medial canthal conjunctival nodule	Right	Conjunctival Medial canthal bulbar	No	Conjunctival biopsy	Bone marrow involvement Splenomegaly Axillary, mediastinal, hilar, retroperitoneal, mesenteric, external iliac lymphadenopathy	Rituximab/bendamustine with AraC	No relapse in 10 months	Zhang et al⁶³
34/Female/76	Left upper eyelid mass	Left	Lacrimal gland	Gastric lesion biopsy 5 years previously Ileocecal lesion biopsy 3 years previously	Lacrimal gland incisional biopsy	Hilar, mediastinal lymphadenopathy Gastric lesion	R-CHOP R-THP-COP 5 years previously Rituximab/bendamustine 3 years previously Current rituximab/bendamustine	No relapse in 2 years	Ana-Magadia et al⁶⁴
35/Female/59	Bilateral upper eyelid swelling	Bilateral	Lacrimal glands	No	Bilateral incisional biopsy	Muscular lesions in bilateral upper and lower extremities	CHASER with R-high-CHOP Autologous peripheral blood stem cell transplantation		Ana-Magadia et al⁶⁴
36/Male/65	Left proptosisDiplopia	Left	Orbital	24-year history of lymphoma	Biopsy	Preceding multisite involvement	Previous chemotherapyCurrent orbital palliative radiation	Dead 8 months after initial presentation	De Niear et al⁶⁵
37/Male/76	Right proptosisBlurred vision	Right	OrbitalMedial	7-year history of lymphoma: splenic, bone marrow, nasopharyngeal involvement	Orbital excisional biopsy	Left parapharyngeal mass	R-Hyper-CVAD and R-MTX-AraC 7 years and 3 years previouslyCurrent oral ibrutinib	Complete remissionNo relapse in 3 months	Nishiyama-Fujita et al⁶⁶
38/Male/58	Bilateral upper eyelid and submandibular swelling	Bilateral	Lacrimal glands	No	Right lacrimal gland excisional biopsy	Right ethmoid sinusCervical spine (C4)Systemic lymphadenopathyRelapse 1 year and 4 months later	R-Hyper-CVAD/MTX-AraCRituximab/bendamustineAutologous peripheral blood stem cell transplantationVR-CAP, allogeneic hematopoietic stem cell transplantation	No relapse in 3 months	Kondo et al⁶⁷
39/Male/70	Blurred vision in both eyes	Bilateral	OrbitalBilateral optic nerve sheath involvement	No	Spinal tap	Central nervous system	Rituximab/bendamustineHigh-dose MTXIntrathecal AraC	Improvement in vision	Aldrees et al⁶⁸
40/Male/60	None	Bilateral	ConjunctivalBilateral lacrimal sacs and nasolacrimal ducts	No	Previous conjunctival biopsyRight lacrimal sac biopsy	Not described	Not described	Not described	Cruz et al⁶⁹
41/Male/61	Bilateral proptosis	Bilateral	Lacrimal glands	No	Left lacrimal gland excisional biopsy	Cervical, mediastinal, inguinal lymphadenopathy	R-CHOP with high-dose AraCAutologous hematopoietic stem cell transplantation	No relapse in 3 months	Iqbal et al⁷⁰
42/Male/70	Right vision decrease	Right	ConjunctivaPseudo-hypopyon and choroidal mass	7-year history of lymphoma	Conjunctival biopsyAnterior chamber tap	Not described	Previous alternating R-Hyper-CVAD/MTX-AraCR-ICEAutologous hematopoietic stem cell transplantationIbrutinib & rituximab	Dead in a few months	Bou Ghanem et al⁷¹
43/Male/58	DiplopiaLeft vision decrease	Left	OrbitalLeft orbital apex syndrome	8-year history of lymphoma	Not described	Axillary lymphadenopathyColonic lesions	Previous R-CHOPCurrent oral venetoclax	No relapse in 1 year	Toumi et al⁷²
44/Male/72	Bilateral conjunctival nodules	Bilateral	ConjunctivaUpper and lower bulbar	1-year history of lymphoma with observation	Left conjunctival biopsy	Systemic lymphadenopathy	Low-dose palliative radiation	Not described	Hafeez et al⁷³
45/Male/77	Left proptosis	Bilateral	OrbitalMedial & superior	No	Bilateral orbital biopsy	SplenomegalySystemic lymphadenopathy	Abdominal radiation 4 GyRituximab & lenalidomide	Stable disease in 11 monthsConcurrent left eyelid sweat gland carcinoma resection	Shah et al⁷⁴
46/Male/80	Upper eyelid entropion	Bilateral	OrbitalAnteriorEyelids	No	Conjunctival biopsy	Bone marrow involvementNasopharyngeal lesionColonic lesions	Ibrutinib & rituximab	Not described	Kiernan et al⁷⁵
47/Male/71	Right proptosis	Right	Orbital	No	Total extirpation	None	Radiation 36 Gy	No relapse in 2.5 years	Gundez et al⁷⁶
48/Male/65	Left vision decrease	Bilateral	OrbitalBilateral optic nerve sheath involvement	History of central nervous system lymphoma	Lymphoma cells in spinal tap	Not described	Rituximab/AraC and Rituximab/bendamustineIbrutinib & intrathecal MTXBilateral orbital radiation	Not described	Savjani et al⁷⁷
49/Female/63	Bilateral upper eyelid swelling	Bilateral	Lacrimal glands	No	Bilateral lacrimal gland extirpation	Bone marrow involvementSuperficial and hepatic lymphadenopathySplenomegaly	Bilateral orbital radiation 40 GyAlternating R-Hyper-CVAD and high-dose MTX-AraCAutologous peripheral blood stem cell transplantationRituximab/bendamustine	Left breast cancer at 53 years oldDied of breast cancer metastasis 12 years after initial visit	This case

Abbreviations: Hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; MTX, methotrexate; VEMP, vincristine, cyclophosphamide, mercaptopurine, prednisolone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisolone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; AraC, cytarabine; mTHPC, 5,10,15,20-tetra(m-hydroxyphenyl)chlorin; FCR, fludarabine, cyclophosphamide, rituximab; R-GIFOX, rituximab, gemcitabine, ifosfamide, oxaliplatin; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, cisplatin; R-THP-COP, rituximab, pirarubicin, cyclophosphamide, vincristine, prednisolone; CHASER, cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, rituximab; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisolone; R-ICE, rituximab, ifosfamide, carboplatin, etoposide.

The 49 patients, including the present patient, were 33 men and 16 women with the age at the initial ophthalmic presentation ranging from 24 to 84 years (median, 65 years). The bilateral involvement was noted in 26 patients while the unilateral involvement was in 23 patients: 13 on the right side and 10 on the left side. Lacrimal gland MCL was diagnosed in 17 patients, conjunctival lymphoma in 10, and lacrimal sac lymphoma in one while lymphoma in the other regions of the orbit was diagnosed in the remaining 21 patients. Two of these 21 patients with orbital lymphoma showed the involvement of the bilateral optic nerve sheath which caused optic neuropathy. One of the 10 patients with conjunctival lymphoma also showed intraocular involvement which manifested uveitis and choroidal infiltration. The ophthalmic presentation was the initial symptoms at the onset of MCL in 37 patients while the previous diagnosis of MCL had been made in the remaining 12 patients. Most patients developed systemic infiltration except for 6 patients with the description of localized lesions in the ocular adnexa. As for the treatment, most patients underwent systemic chemotherapy and autologous peripheral blood stem cell transplantation was done in 6 patients. Local radiation was done as a sole treatment or additional palliative treatment in 7 patients. The follow-up periods were not described or otherwise short up to 3 years.

Other than the direct involvement of ocular adnexa with MCL as described above, neurological consequences of the central nervous system infiltration have to be considered in making a diagnosis.⁸⁰ Indeed, acute bilateral ophthalmoplegia has been reported as an initial manifestation of MCL as the result of central nervous system infiltration.⁸¹ Regarding a new mode of treatment, proton beam therapy has been applied to the residual lesions in the orbit after systemic chemotherapy.⁸² In the present patient, the initial lacrimal gland lesions of MCL were locally controlled in a successful manner by radiotherapy. Autologous hematopoietic stem cell transplantation has been established as the standard treatment option in relapsed or newly diagnosed MCL,^83,84 as shown in the present review. In conclusion, we described a long-term outcome of 11 years in a patient who underwent autologous peripheral blood stem cell transplantation for the systemic infiltration of bilateral lacrimal gland MCL as an initial presentation. To the best of our knowledge, the follow-up period in this patient is longest in the literature.

Footnotes

Authors’ Note

Data are available upon reasonable request to the corresponding author.

Author Contributions

T.M., as an ophthalmologist, performed surgery, followed the patient, and wrote the manuscript. T.T. and K.N., as pathologists, made pathological diagnoses. K.O., K.F., and N.F., as oncologists, treated the patient. All authors approved the final version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval

Ethics committee review was not applicable due to the case report design, based on the Ethical Guidelines for Medical and Health Research Involving Human Subjects, issued by the Government of Japan.

Informed Consent

Verbal informed consent was obtained from the patient for her anonymized information to be published in this article.

ORCID iD

Toshihiko Matsuo

References

Matsuo

Yamaoka

Shiraga

Matsuo

Two types of initial ocular manifestations in intraocular-central nervous system lymphoma. Retina. 1998;18(4):301-307.

Matsuo

Ichimura

Ichikawa

Okumura

Kaji

Yoshino

Positron emission tomography/computed tomography after immunocytochemical and clonal diagnosis of intraocular lymphoma with vitrectomy cell blocks. J Clin Exp Hematop. 2009;49(2):77-87.

Matsuo

Tanaka

Are there primary intraocular lymphomas that do not develop into central nervous system lymphomas?

J Clin Exp Hematop. 2019;59:168-174.

Matsuo

Tanaka

Fujii

, et al. CD19 immunostaining of a stored paraffin-embedded vitrectomy cell block of intraocular lymphoma contributing to chimera antigen receptor T-cell therapy. J Clin Exp Hematop. 2022;62:187-189.

Matsuo

Ichimura

Shinagawa

Yoshino

Different histopathological types of orbital lymphoma 16 years after systemic follicular lymphoma: immunohistochemical and immunogenetic analyses of two cases. J Clin Exp Hematop. 2008;48(1):17-24.

Matsuo

Ichimura

Okada

, et al. Clonal analysis of bilateral, recurrent, or systemically multifocal ocular adnexal lymphoma. J Clin Exp Hematop. 2010;50:27-38.

Matsuo

Ichimura

Shinagawa

Orbital MALT lymphoma, abdominal Hodgkin lymphoma, and systemic diffuse large B-cell lymphoma develop sequentially in one patient. J Clin Exp Hematop. 2012;52(1):41-49.

Matsuo

Tanaka

Fujii

Orbital MALT lymphoma after autologous stem cell transplantation for follicular lymphoma as relapse of diffuse large B-cell lymphoma. J Clin Exp Hematop. 2017;56(3):170-175.

Matsuo

Tanaka

Ichimura

Meguri

Intraocular relapse with hypopyon and retinal infiltrates after chemotherapy and peripheral blood stem cell transplantation for extranodal NK/T-cell lymphoma. J Clin Exp Hematop. 2015;55(3):157-161.

10.

Matsuo

Tanaka

Yano

Intraocular lymphoma as relapse after chemotherapy for primary breast diffuse large B-cell lymphoma. J Clin Exp Hematop. 2018;58:180-183.

11.

Matsuo

Shimizu

Tanaka

Yamamoto

Takasuka

Pathologically proven intraocular infiltration with adult T-cell leukemia/lymphoma: two new cases with either vitreous opacity or aqueous hypopyon and literature review of 16 cases. J Investig Med High Impact Case Rep. 2020;8:2324709620966843.

12.

Matsuo

Ichimura

Immunocytochemical diagnosis as inflammation by vitrectomy cell blocks in patients with vitreous opacity. Ophthalmology. 2012;119(4):827-837.

13.

Matsuo

Shiraga

Takeuchi

Retinal pigment epithelial tear in reactive lymphoid hyperplasia of uvea. Ophthalmologica. 1990;200(1):46-54.

14.

Matsuo

Ichimura

Sato

, et al. Immunoglobulin G4 (IgG4)-positive or -negative ocular adnexal benign lymphoid lesions in relation to systemic involvement. J Clin Exp Hematop. 2010;50:129-142.

15.

Matsuo

Ichimura

Yoshino

Local recurrence as immunoglobulin G4 (IgG4)-related disease 10 years after radiotherapy to ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. J Clin Exp Hematop. 2011;51(2):125-133.

16.

Matsuo

Tanaka

Sato

, et al. Follow-up with serum IgG4-monitoring in 8 patients with IgG4-related disease diagnosed by a lacrimal gland mass. J Clin Exp Hematop. 2021;61(1):10-21.

17.

Matsuo

Tanaka

Notohara

Okada

Diffuse large B-cell lymphoma 18 years after bilateral lacrimal gland IgG4-related disease: case report and literature review. J Investig Med High Impact Case Rep. 2022;10:23247096211067894.

18.

Matsuo

Tanaka

Omote

, et al. Diffuse large B-cell lymphoma in the course of systemic sarcoidosis: a case report and review of 30 Japanese patients with sarcoidosis-lymphoma syndrome. J Clin Exp Hematop. 2022;62:226-237.

19.

Matsuo

Tanaka

Kinomura

Nephrotic syndrome during the tapering of oral steroids after pathological diagnosis of Kimura disease from a lacrimal gland mass: case report and review of 10 Japanese patients. J Clin Exp Hematop. 2017; 57(3):147-152.

20.

Matsuo

Sato

Kuroda

Matsuo

Yoshino

Systemic malignant lymphoma 17 years after bilateral orbital pseudotumor. Jpn J Ophthalmol. 2004;48(5):503-506.

21.

Matsuo

Yoshino

Long-term follow-up results of observation or radiation for conjunctival malignant lymphoma. Ophthalmology. 2004;111:1233-1237.

22.

Matsuo

Ichimura

Yoshino

Spontaneous regression of bilateral conjunctival extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. J Clin Exp Hematop. 2007;47(2):79-81.

23.

Matsuo

Ichimura

Tanaka

, et al. Bilateral conjunctival lesions in blastic plasmacytoid dendritic cell neoplasm. J Clin Exp Hematop. 2011;51(1):49-55.

24.

Matsuo

Ichimura

Tanaka

Kaji

Conjunctival lymphoma can be detected by FDG PET. Clin Nucl Med. 2012;37(5):516-519.

25.

Rasmussen

Ralfkiaer

Prause

Sjö

Siersma

Heegaard

Malignant lymphoma of the lacrimal gland: a nation-based study. Arch Ophthalmol. 2011;129(10):1275-1280.

26.

Vest

Mikkelsen

Holm

, et al. Lymphoma of the lacrimal gland: an international multicenter retrospective study. Am J Ophthalmol. 2020;219:107-120.

27.

Vest

Coupland

Esmaeli

, et al. Specific location of ocular adnexal lymphoma and mortality: an international multicentre retrospective study [published online ahead of print May 5, 2022]. Br J Ophthalmol. doi:10.1136/bjophthalmol-2021-320466.

28.

Looi

Gascoyne

Chhanabhai

, et al. Mantle cell lymphoma in the ocular adnexal region. Ophthalmology. 2005; 112:114-119.

29.

Hon

Chan

Shek

Yau

WY.

Lymphomatous proptosis as a novel feature of mantle cell lymphoma. Leuk Lymphoma. 2006;47(1):71-75.

30.

Rasmussen

Sjö

Prause

Ralfkiaer

Heegaard

Mantle cell lymphoma in the orbital and adnexal region. Br J Ophthalmol. 2009;93(8):1047-1051.

31.

Knudsen

MKH

Rasmussen

Coupland

, et al. Clinicopathological features of ocular adnexal mantle-cell lymphoma in an international multicenter cohort. JAMA Ophthalmol. 2017;135:1367-1374.

32.

Castillejo Becerra

Dalvin

Jevremovic

Hodge

Tooley

AA.

Clinical characteristics and outcomes of ocular adnexal mantle cell lymphoma. Orbit. 2022;41(1):97-104.

33.

Lee

Song

Kim

MS.

[A case of primary mantle cell lymphoma on the conjunctiva]. J Korean Ophthalmol Soc. 1999;40:2010-2014 [in Korean].

34.

Sato

Tomizuka

Hatake

, et al. [A case of mantle cell lymphoma with exophthalmos]. Naika. 2001;87:1035-1037 [in Japanese].

35.

Tsuchiya

Takamura

Mitsuhashi

, et al. [Clinicopathological study of two cases of primary orbital mantle cell lymphoma]. Atarashii Ganka. 2004;21:555-558 [in Japanese].

36.

Coffee

Lazarchick

Chévez-Barrios

Howard

Rapid diagnosis of orbital mantle cell lymphoma utilizing fluorescent in situ hybridization technology. Am J Ophthalmol. 2005; 140(3):554-556.

37.

de Albuquerque

Aguni

Correia

Vegini

de Souza

. [Mantle-cell lymphoma of the ocular adnexa: a case report.]. Arq Bras Oftalmol. 2006;69(3):421-425 [in Portuguese].

38.

Aspiotis

Gorezis

Asproudis

, et al. Primary mantle cell lymphoma of the conjunctiva: a case report. Virchows Arch. 2006;449(4):472-475.

39.

Yoo

Kim

Jeon

, et al. CD5-undetected by immunohistochemistry, t(11;14) (q13; q32)-positive conjunctival mantle cell lymphoma: a case report. Pathol Res Pract. 2008; 204:779-783.

40.

Franco

Filippi

Ricca

Raucci

Ricardi

Eyelid localization in mantle cell lymphoma: long-lasting complete remission after surface brachytherapy. Tumori. 2009;95(3):385-388.

41.

Pajares-Hachero

Torres

Hierro

Jurado

Rueda

Mantle cell lymphoma stage IV affecting lacrimal glands, retro-orbital tissue, optic nerve and ocular motor muscles. Clin Transl Oncol. 2009;11(7):484-485.

42.

Abdullah

Elsamaloty

Patel

Chang

CT and MRI findings with histopathologic correlation of a unique bilateral orbital mantle cell lymphoma in Graves’ disease: a case report and brief review of literature. J Neurooncol. 2010;97(2):279-284.

43.

Hamdoon

Jerjes

Upile

Osher

Hopper

Lacrimal gland mantle lymphoma treated with photodynamic therapy: overview and report of a case. Photodiagnosis Photodyn Ther. 2010;7(2):129-133.

44.

Kumar

Mantle cell lymphoma of orbit in a middle aged female: a case report. Nepal Med Coll J. 2010;12(4):275-276.

45.

Ozkan

Laçin

Soydal

Araz

Küçük

NÖ.

Ocular involvement in mantle cell lymphoma detected by F 18 FDG PET/CT. Mol Imaging Radionucl Ther. 2011;20(1):36-37.

46.

Masood

While

Mudhar

HS.

Perivascular mantle cell lymphoma affecting a temporal artery: a highly unusual cause of temporal headache. Cardiovasc Pathol. 2011;20(4):244-246.

47.

Khanlari

Bagheri

Vojdani

, et al. Conjunctival mass as an initial presentation of mantle cell lymphoma: a case report. BMC Res Notes. 2012;5:671.

48.

Maaroufi

Chahdi

KEO

Doghmi

, et al. [Orbital mantle cell lymphoma]. J Fr Ophtalmol. 2013;36:e55-e57 [in French].

49.

Vali Khojeini

Durham

Chen

Mantle cell lymphoma and involvement of the orbit and ocular adnexa. Case Rep Pathol. 2013;2013:581856.

50.

Matsuo

Ichimura

Kubonishi

Mantle cell lymphoma diagnosed by conjunctival salmon-pink lesion biopsy. J Clin Exp Hematop. 2014;54(2):143-147.

51.

Medrado

Dittrich

Sousa

Teixeira

Manso

PG.

Case report of a metachronous multiple tumor: mantle cell lymphoma in the orbital region associated with epithelial malignancies at other sites. Arq Bras Oftalmol. 2014;77(1): 54-56.

52.

Cai

Zhou

Mantle cell lymphoma in a lacrimal gland in a female and a review of the literature. Eye Sci. 2014;29(3):178-181.

53.

Sahu

Uthamalingam

Sampath

, et al. Ocular adnexal lymphomas: report of 2 cases of mantle cell lymphomas an short review of literature. Indian J Hematol Blood Transfus. 2014;30:163-168.

54.

Falcone

Parascandola

Ferrara

Sica

Di Martino

Guastafierro

Bilateral lacrimal gland involvement with mantle cell lymphoma. Am J Med Sci. 2015;349(3):268.

55.

Martínez-Esteve

García-Gómez

Borrero-Martin

Fajardo-Pico

Borrego-Dorado

18F-FDG PET/CT in a case of bilateral lacrimal gland infiltration by mantle cell lymphoma. Rev Esp Med Nucl Imagen Mol. 2015;34(6):396-397.

56.

Bellan

Sole

Marcella

, et al. Bilateral lacrimal gland mantle cell lymphoma: a case report and review of literature. J Clin Exp Ophthalmol. 2016;7:1000615.

57.

Choi

Stagner

Jakobiec

Lee

NG.

Limbal mantle cell lymphoma of the conjunctiva. Ophthalmology. 2016;123(2): 377.

58.

Verma

Gupta

Mohindra

Sachdeva

Rajwanshi

Primary orbital mantle cell lymphoma: flow cytometric immunophenotyping as an adjunct to fine-needle aspiration cytology for diagnosis. Cytojournal. 2017;14:2.

59.

Rašić

Knežević

Terzić

Vlajković

Bilateral ocular panadnexal mass as initial presentation of systemic blastoid variant of mantle-cell lymphoma. Surv Ophthalmol. 2017;62(1):83-88.

60.

Khodarahmi

Ghesani

Lacrimal gland and extensive subcutaneous tissue involvement by mantle cell lymphoma. Blood. 2017;130:1174.

61.

Karlin

Peck

Prenshaw

Portell

Kirzhner

Orbital mantle cell lymphoma presenting as myasthenia gravis. Orbit. 2017;36(6):365-369.

62.

Shaikh

Jani

Shah

, et al. Mantle cell lymphoma relapsing as disease of skin, orbit and CNS: an extremely rare presentation and a review of literature. J Hematol. 2018;7:38-42.

63.

Zhang

Gordon

Zaldivar

Rajjoub

LZ.

Mantle cell lymphoma: conjunctival mass in a female patient. Can J Ophthalmol. 2018;53(3):e109-e111.

64.

Ana-Magadia

Takahashi

Valencia

MRP

, et al. Mantle cell lymphoma of the lacrimal gland. J Craniofac Surg. 2019; 30:158-160.

65.

De Niear

Greer

Seegmiller

Mawn

LA.

Blastic transformation of a mantle cell lymphoma presenting as an enlarging unilateral orbital mass. Ocul Oncol Pathol. 2019;5(4):245-251.

66.

Nishiyama-Fujita

Nakazato

Ito

, et al. Rare case of ocular adnexal relapse with mantle cell lymphoma treated with ibrutinib monotherapy. Intern Med J. 2019;49(9):1187-1189.

67.

Kondo

Yoshioka

Moriyama

, et al. [Complete remission after allogeneic bone marrow transplantation in a patient with relapsed mantle cell lymphoma]. Ann NHO Okayama Med Cent. 2020;17:281-282 [in Japanese].

68.

Aldrees

Jeeva-Patel

Margolin

Bilateral infiltrative optic neuropathy of systemic mantle cell lymphoma. Can J Neurol Sci. 2020;47(3):428-430.

69.

Cruz

AAV

Gomes

Chahud

. Bilateral mantle cell lymphoma of the lacrimal sac and nasolacrimal duct. JAMA Ophthalmol. 2020;138:e202394.

70.

Iqbal

Castano

Sher

Kharfan-Dabaja

MA.

Intraocular involvement of mantle cell lymphoma; a case report and literature review. Hematol Oncol Stem Cell Ther. 2021;14(2):147-152.

71.

Bou Ghanem

Daye

Saadé

MCW

, et al. Choroidal and ocular adnexal lymphoma extension from systemic mantle cell lymphoma: a case report. Hemasphere. 2021;5(8):e599.

72.

Toumi

Peyrade

Nahon

, et al. [Orbital mantle cell lymphoma successfully treated by Bcl-2 inhibitor: report of a case]. J Fr Ophtalmol. 2021;44:239-243 [in French].

73.

Hafeez

Mancini

Mega

, et al. Case report: ocular manifestation of mantle cell lymphoma. Optom Vis Sci. 2022;99: 186-189.

74.

Shah

Homer

Epstein

Durairaj

VD.

Simultaneous presentation of orbital mantle cell lymphoma and endocrine mucin-producing sweat gland carcinoma. Orbit. 2022;41(4): 509-513.

75.

Kiernan

Thaung

Vahdani

. Mantle cell lymphoma presenting as bilateral upper eyelid entropion [published online ahead of print February 2, 2022]. Orbit. doi:10.1080/01676830.2022.2025858.

76.

Gundez

Mirzayev

Kuzu

, et al. A rare case of orbital mantle cell lymphoma presenting as a well-demarcated mass on magnetic resonance imaging [published online ahead of print August 29, 2022]. Orbit. doi:10.1080/01676830.2022.2114501.

77.

Savjani

Ati

Sadeghi

Bonelli

Kaprealian

Hegde

JV.

Radiation therapy for mantle cell lymphoma with orbital involvement. Radiol Imaging Cancer. 2022;4(4):e220027.

78.

Hoster

Dreyling

Klapper

, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558-565.

79.

Kimura

Sato

Imamura

, et al. Small cell variant of mantle cell lymphoma is an indolent lymphoma characterized by bone marrow involvement, splenomegaly, and a low Ki-67 index. Cancer Sci. 2011;102(9):1734-1741.

80.

Cheah

George

Giné

, et al. Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann Oncol. 2013;24(8):2119-2123.

81.

Koban

Ozlece

Ayar

, et al. Mantle cell lymphoma presenting acute bilateral ophthalmoplegia. Turk J Ophthalmol. 2017;47:235-237.

82.

Kang

Hasan

Press

, et al. Using patient-specific bolus for pencil beam scanning proton treatment of periorbital disease. J Appl Clin Med Phys. 2021;22(1):203-209.

83.

Yamasaki

Chihara

Kim

, et al. Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma. Ann Hematol. 2018;97:1445-1452.

84.

Ogura

Yamamoto

Morishima

, et al. R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 study. Cancer Sci. 2018;109(9):2830-2840.