Mantle cell lymphoma and involvement of lacrimal glands and orbit

E.V. Vilchevskaia, Cand Sc (Med)
E.I. Eshchenko, Cand Sc (Med)
Gusak Institute of Urgent and Reconstructive Surgery, National Medical Science Academy of Ukraine
Kyiv (Ukraine)
Key words: non-Hodgkin’s lymphoma, mantle cell lymphoma, lacrimal gland, orbit, polychemotherapy
Lymphoma represents about 4% of all malignancies [1]. Over recent decades, the incidence of malignant lymphomas has increased from 2-3 to 5-7 per 100000 [2]. Lymphoma is a tumor that develops from cells of lymphoid tissue and is characterized by enlargement of the lymph nodes and/or involvement of various internal organs. Extranodal lymphoma is a malignant proliferation of lymphocytes arising in lymphoid tissue of various organs, including the spleen, stomach, colon, lungs, brain and eye [3, 4]. Since most of the organs contain lymphoid tissue, lymphoma may develop practically in any organ of the body. Additionally, these tumors can be found in any age group, and their etiology remains elusive.
The risk factors are as follows: heredity, ionizing radiation, working with carcinogenic chemicals (pesticides, fertilizers, and solvents), post-transplant immune deficiency, and autoimmune disorders (systemic lupus erythematosus, Sjogren’s syndrome). Individuals infected with the Epstein-Barr virus, human immunodeficiency virus (HIV), human T-cell lymphotropic virus, hepatitis C virus, and human herpes virus 8 have an increased incidence of lymphoma. Chlamidia psittaci infection is a risk factor for developing lymphoma with ocular involvement [5].
Lymphomas are classified as Hodgkin’s (HL; lymphogranulomatosis) and non-Hodgkin’s lymphomas (NHLs). Only the latter are within the scope of this paper. The incidence of NHLs has been reported to be the highest of all malignancies of the orbit [6]. The crude incidence of large cell NHL in the European Union is 5–6 per 100,000 a year [2].
The diagnosis of lymphoma may be established after biopsies from lymph node, spleen, and bone marrow, or histologic, cytologic or cytochemical assessment of excised tumors. Immunophenotyping and molecular genetics techniques have changed the diagnostic approach to lymphomas [7]. Immunohistochemistry is used to detect cluster of differentiation (CD). CD antigens are markers present on the surface of various cells (including lymphocytes). Thus, CD19, CD20, CD22 and others are present on the surface of B cells, whereas CD3, CD4, CD5, and CD8 are present on the surface of T cells. Consequently, lymphomas arising from each of these two subsets of lymphocytes also express B cell or T cell markers. CDs can be found on blood cells, bone marrow cells, lymph node cells, etc. CDs are used in immunohistochemistry to identify the presence of specific cells in tissue section. Immunophenotyping enables determination of CD antigens on cell surface. Some CDs can be targeted by therapeutic antibodies. Thus, CD20 and CD52 are targeted by rituximab (Rituxan, MabThera) and Campath-1H (Alemtuzumab), respectively.
Examination of the patient should include: chest, abdominal and pelvic ultrasonography and computer tomography; MRI; bone marrow aspiration and biopsy. Laboratory studies should include a complete blood count (CBC), lactate dehydrogenase (LDH), β2-microglobulin, and uric acid levels, as well as HIV, hepatitis B and C virus tests. In progressve lymphoma, the patient usually develops normochromal anemia and thrombocytopenia. Elevated LDH and β2-microglobulin levels in the lymphoma patient are a sign that lymphoma follows an aggressive clinical course [5].
Enlarged spleen or lymph nodes in the neck, armpits, or groin are usually the first symptom of lymphoma. At the initial stage of the disease, lymph nodes are painless, soft, and mobile, but as the disease evolves, they get harder, adhere to each other and form conglomerates up to 16-20 cm in diameter. In the case of cancers – as opposed to infectious diseases – enlarged lymph nodes do not return to normal and do not respond to antibiotics. NHL patients may present with nonspecific complaints, such as fever, night sweats, unexplained weight loss, and exceptional weakness and fatigue. The NHLs can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas. 
Treatment intensity and chemotherapy regimens depend on the histological type, immunophenotype and clinical stage of lymphoma. The multicomponent therapy for NHLs involves polychemotherapy with monoclonal antibodies (rituximab) [8].
We present a case of mantle cell lymphoma (MCL) with involvement of the orbit and the lacrimal gland arising in a 67-old female patient who has been under observation and treatment at the Adult Blood Cancer Subdepartment, Hematology Department, the Gusak Institute of Urgent and Reconstructive Surgery. This subtype of B-cell lymphoma is rather rare and accounts for 3-10% of all lymphoma diagnoses [9]. MCL was termed an aggressive lymphoma [10].
Patient’s History and Complaints
In September, 2012, the patient sought advice from ophthalmologist at a local polyclinic for the first time, and complained of bilateral eyelid swelling. Her uncorrected visual acuity (UCVA) was 0.6 OD and 0.43 OS, and the best-corrected visual acuity (BCVA) was 0.80 with 2.5 D OD and 0.90 with 1.5 D OS. Her visual field evaluation was normal. The IOP was 19.0 mmHg OU. On examination, the bilateral lacrimal gland enlargement was noted, and the glands were painless on palpation. Additionally, a full range of globe movement was noted. The initial diagnosis of bilateral dacryoadenitis was made. The patient was prescribed Tobrex instillation four times a day and was referred to a rheumatologist for advice. The rheumatologist diagnosed her with and prescribed treatment for polyarticular rheumatoid arthritis.
Six months later, in April, 2013, the patient sought advice from ophthalmologist at a local polyclinic for the second time. According to her outpatient medical record, she complained of enlarged tumor-shaped masses on her upper eyelids, palpebral fissure narrowing, and enlarged submandibular and neck lymph nodes. Additionally, she experienced no change in her visual function. Her physical examination revealed bilateral palpable elastic dense masses at the superotemporal aspect of the anterior orbital rim, measuring 3cm x 2cm, which were painless on palpation. The pars palpebralis of the lacrimal gland was enlarged. Fundus evaluation was unremarkable. The suspected diagnosis was bilateral lacrimal gland neoplasm and bilateral chronic dacryoadenitis.
The CT of the orbit and ultrasonography of the salivary and parotid glands were performed to clarify the diagnosis. Orbital CT showed two extraorbital lateral soft tissue masses extending intraorbitally along the lateral orbital margin to the orbital roof and measuring about 32mm x 20mm x 23 mm (right-hand) and 33mm x 18mm x 28mm (left-hand). It was concluded that there was bilateral orbital tumor. Ultrasonography of the salivary and parotid glands showed enlarged submandibular and parotid glands (both right and left) containing numerous enlarged lymph nodes with poor corticomedullar misdifferentiation. All the groups of submandibular and left neck lymph nodes were enlarged to 2-2.5 cm, with poor corticomedullar misdifferentiation. It was concluded that there were echo signs of (a) sialodenitis of mandibular and parotid glands and (b) bilateral submandibular and neck lymphadenopathy. The patient was diagnosed with Sjogren’s syndrome.
She was hospitalized at the ophthalmology department of local hospital with the diagnosis of chronic dacryoadenitis (Mikulicz disease). According to her abstract from the hospital registry, there was no change in her visual function at admission and she had bilateral ptosis. Physical examination showed two bilateral symmetrical mobile smooth below-upper-lid masses measuring 3 cm x 2 cm each and extending into the orbits. Hertel exophthalmometry was 15.0mm OD and 16.0mm OS at base 110.0 mm. In the ophthalmology department, the patient received intramuscular and intravitreal injections of anti-inflammatory and dehydration medications, local calcium chloride electrophoresis with hydrocortisone, and parabulbar injections of dexamethasone and neostigmine. Prior to discharge from the hospital, physical examination found swollen lids and bilateral partial upper lid ptosis and Hertel exophthalmometry was 15.0mm OD and 16.0mm OS at base 110.0 mm. The patient was discharged home with recommendations to continue receiving parabulbar injections of dexamethasone 3 times a day at local polyclinic on outpatient basis.
Six months later, she was again hospitalized at the ophthalmology department of local hospital with the diagnosis of chronic dacryoadenitis (Mikulicz disease). There was no change in her visual function at admission. Physical examination showed two bilateral symmetrical mobile smooth below-upper-lid masses measuring 4cm x 3cm each and extending into the orbits. Hertel exophthalmometry was 16.0mm OD and 17.0mm OS at base 110.0 mm. At the ophthalmology department, the patient underwent treatment similar to that accorded her during her first hospitalization. On completion of inpatient treatment, in accordance with recommendations on discharge, parabulbar injections of dexamethasone were continued 5 times a day at local polyclinic on outpatient basis.
 In May, 2014, the patient underwent the third course of anti-inflammatory therapy (similar to previous ones) at the ophthalmology department of local hospital. The patient was referred to the Filatov Institute of Eye Disease and Tissue Therapy for consultation and underwent a biopsy of lacrimal gland mass there based on the following reasons: (a) an enlargement of the size of the existing masses to 5cm x 4cm; (b) increased exophthalmometry measurements (17.0mm OD and 18.0mm at base 110.0 mm) and (c) no response to medical treatment. Since biopsy results revealed B-cell lymphoma, the patient was recommended to consult an oncologist and a hematologist.
The hematologist of the Gusak Institute of Urgent and Reconstructive Surgery found it necessary to perform histological and immunohistochemical examination of the tissue biopsy obtained. In biopsy tissue specimens, the tumor tissue was seen as lymphoid cells having heterochromous nuclei and spare cytoplasm and separated by interlayers of connective tissue. Immunophenotyping established that the tumor cells were CD5 positive, CD3 positive, cyclin-D1 positive and CD23 negative. Therefore, the histological picture and immunophenotype of tumor cells corresponded to extranodal B-cell lymphoma (namely, mantle cell lymphoma).
Given the results of immunophenotyping and histological analysis, the patient underwent thorough examination (at the Adult Blood Cancer Subdepartment) including spiral 64-slice multidetector CT for her neck, chest organs, abdominal cavity, retroperitoneal space and pelvis. The CT showed (a) bilaterally enlarged neck lymph nodes (up to 20mm x 11mm), as well as submandibular (up to 36mm x 36mm; bilaterally), splenic hilum (19mm x 13mm), retroperitoneal (20mm x 35mm), and inguinal (32mm x 15mm) lymph nodes, (b) the lymphoidal tumor component extending along the postcava from liver vessels to common iliac veins and (c) the prerenal soft tissue tumor component as thick as up to 6 mm. Therefore, the patient showed CT evidence of a lymphoproliferative process with damage to both kidneys as well as to neck, retroperitoneal and inguinal lymph nodes.
Given an extensive nature of alterations, bone marrow aspirate examination was done. It revealed no evidence of bone marrow involvement with lymphoma. The β2-microglobulin level was found to be significantly elevated (2337.00).
The examination of the patient at the Adult Blood Cancer Subdepartment included examination by the ophthalmologist from the Gusak Institute. She complained of eye redness, photophobia and sensation of sand in her eyes. Besides ptosis, physical ophthalmological examination revealed bilaterally symmetrical lacrimal gland masses at the superotemporal aspect of the anterior orbital rim, extending to the orbit and measuring 5cm x 4cm, which were palpable, elastic, soft, and painless on palpation, not attached to underlying tissue and covered with unaltered skin. Outward movement of the eyeball was slightly restricted. There was exophthalmus with the eyeball displaced somewhat downward. Hertel exophthalmometry was 17.0mm OD and 18.0mm OS at base 110.0 mm. Lagophthalmos was noted. Small infiltrates were observed in the inferior cornea. No changes were observed in the ocular media and the fundus. The patient was prescribed artificial tears, antiseptics, antibiotics and corneal trophism enhancers. Five days later, she was re-examined by the ophthalmologist, and no manifestations of keratitis were revealed.
The decision to treat with polychemotherapy combined with targeted agents (rituximab anti-CD20 antibodies) was dictated by the clinical diagnosis of the disease. Following the first cycle of rituximab-supplemented polychemotherapy, the patient’s status improved significantly. Examination by the ophthalmologist revealed (a) no pathological changes in her lids and periorbital tissue; (b) no exophthalmus; (с) full range of globe movement with no difficulty in repositioning the eye; (d) transparent ocular media and (e) normal fundus. 
After the patient underwent 8 cycles of rituximab-supplemented polychemotherapy, a repeat spiral multidetector CT was performed and revealed a significant reduction in the size of lymph nodes in all node groups. The dimensions of the maximal and minimal nodes were 10mm x 3mm and 7mm x 3mm, respectively. The β2-microglobulin level was found to be normal at repeat examination.
Re-examination by the ophthalmologist revealed (a) no alterations in the anterior segment, (b) transparent ocular media and (c) normal fundus. The patient is still under observation of the hematologist and ophthalmologist.
First, when treating the patient with dacryoadenitis, and ophthalmologist should maintain a high index of suspicion for cancer. Hematologist’s consultation and obtaining the material for morphology and histochemistry are mandatory to exclude lymphoproliferative disease.
Second, mantle cell lymphoma is a systemic disease with involvement of almost all lymph node groups and some extranodal structures (in our case, the lacrimal glands and the orbits). It is a bilateral process with the presence of painless tumor-shaped lacrimal gland-and-orbit mass(es) unresponsive to antibiotics. These masses do not reduce in size over time but rather increase slowly. Lymph nodes are enlarged, painless and not attached to underlying tissue.
Third, lymphoma management should be performed in a department specializing in hematology. The modern lymphoma treatment regimen involves 6-8 cycles of anti-CD20 monoclonal antibodies-supplemented polychemotherapy given on a monthly basis.
Finally, the ophthalmologist should be involved in the treatment of lymphoma with ocular involvement. The ophthalmologist’s task is to monitor the therapeutic treatment process, to perform ophthalmological assessment of step-by-step results during the course of polychemotherapy, and to maintain lifelong monitoring of the patient for disease recurrence.
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