Mantle cell lymphoma in the orbital and adnexal region
- 1Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, Denmark
- 2Department of Pathology, Copenhagen University Hospital, Denmark
- Correspondence to Dr S Heegaard, Department of Neuroscience and Pharmacology, Section of Eye Pathology, Frederik V’s Vej 11, 1, DK-2100 Copenhagen, Denmark;
- Accepted 8 April 2009
- Published Online First 7 May 2009
Aims: To characterise clinicopathological features of mantle cell lymphoma (MCL) in the orbital and adnexal region.
Methods: Data on lymphoid lesions were retrieved searching the Danish Ocular Lymphoma Database 1980–2005. Specimens were collected from Danish pathological departments and re-evaluated with a panel of monoclonal antibodies. For all patients with confirmed MCL the complete clinical files were collected and reviewed.
Results: Twenty-one patients with MCL in the orbital and adnexal region were identified comprising 9% (21/230) of all lymphoma in the ocular region. There were 18 male patients and three female patients with an age range from 60 to 90 years (median 75 years). Orbital and adnexal region MCL as first presenting symptom comprised 67% of the patients. Of these, 71% had bilateral involvement. The orbit (71%) and eyelids (64%) were the most commonly affected sites. All but two presented in stage III/IV. Secondary MCL comprised 33% of the patients. Bilateral affection (29%) was less common in this patient group. The median survival was not different between the two presentation groups. Patients receiving anti-CD20 (rituximab)-containing chemotherapy had a significantly better 5-year overall survival (OS) rate (83%) than patients in treatment regimes without rituximab (5-year OS rate, 8%).
Conclusions: Orbital and adnexal region MCL presents in elderly males. The orbit and eyelid are frequently involved. There is a very high proportion of systemic involvement in general with MCL of the orbital and adnexal region. Most patients presented with stage IV disease and had multiple relapses and short survival time. Treatment with rituximab-containing chemotherapy improved survival significantly compared with combination chemotherapy without rituximab.
Mantle cell lymphoma (MCL) is a rare type of malignant lymphoma representing 3–5% of all non-Hodgkin’s lymphomas.1 In 1992 the International Lymphoma Study Group recognised MCL as an independent malignant lymphoma with origin in peripheral B cells of the inner mantle zone, characterised by t(11;14)(q13;q32) and upregulation of bcl-1 (cyclin D-1).2 MCL is a disease of older people, with a male predominance, usually presenting with widespread disease and a relatively aggressive clinical course.134 Management of MCL has been limited to palliative therapy, mainly consisting of anthracycline-based chemotherapy.5 Recently, novel strategies combining anthracyclin-containing treatment, that is cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP), anti-CD20 agent (rituximab) and autologous stem cell transplantation (ASCT), have shown improved response- and survival rates.6
Morphologically, MCL resembles low-grade lymphoma, but due to overexpression of cyclin D-1, MCL is identified with standard immunohistochemical methods.2
The aim of the present study was to correlate the clinicopathological features with prognosis in the so far largest series of unselected patients with MCL in the orbital and adnexal region.
Materials and methods
The patients were identified through the Danish Ocular Lymphoma Database covering the years 1980–2005. Formalin-fixed, paraffin-embedded specimens of identified patients were retrieved from the archives of several Danish pathology departments, and sections were examined by immunohistochemistry for: bcl-2, bcl-6, CD3, CD5, CD10, CD20, CD23, CD79α, cyclin D-1 and MIB-1 (Ki-67). The staining was performed in the Techmate 500 Immunostainer, using the DAKO Envision K5007 as a secondary antibody. The samples were examined by two independent pathologists and reviewed in consensus, to reclassify the specimens according to the World Health Organisation Classification of Tumours 2001.2
Confirmed cases of MCL had to fulfil the following criteria: (1) appearance of the characteristic morphology for MCL in a haematoxylin–eosin staining, specifically the presence of small- to medium-sized lymphoid cells with scant cytoplasm, irregular nuclei, inconspicuous nucleoli and absence of large transformed cells; (2) overexpression of nuclear cyclin D-1.
Patients with orbital and adnexal region MCL as first presenting symptom comprised cases with primary MCL and cases with orbital and adnexal lymphoma with non-diagnosed pre-existing extraorbital disease.
Clinical data recorded for each patient included year of diagnosis, gender, age, symptoms and clinical findings, evidence of systemic involvement according to Ann Arbor staging Classification,2 presence of B-symptoms, paraclinical findings inclusive serum lactate dehydrogenase (LDH) level, performance status according to the Eastern Cooperative Oncology Group (ECOG), score according to the MCL International Prognostic Index,11 type of treatment and response, recurrence-free period, time and localisation of relapse, duration of survival, stage of disease at last follow-up, and time and cause of death. The MCL International Prognostic Index score is based on four prognostic factors: age, performance status, lactate dehydrogenase and leucocyte count.
Treatment response was measured as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Complete response was defined as disappearance of all evidence of disease with complete resolution of previous abnormal investigations. Partial response was defined as regression of at least 50% of all measurable disease and no new sites of disease. Relapsed- or progressive disease was defined as appearance of any new lesion or increase by over 50% of previously involved sites.12 Failure to reach CR/PR or PD was considered stable disease.
The study was approved by the local ethics committee (KF 01 262201) and the Danish Data Protection Agency (j no 2005-41-5098).
Overall survival (OS) was defined as the interval between the date of diagnosis in the orbital and adnexal region or at other sites for secondary MCL and last follow-up/contact or death, whichever occurred first. Progression-free survival (PFS) time was calculated from the date of diagnosis of MCL in the orbital and adnexal region to the date of first progression after initial treatment or most recent follow-up. PFS and OS were plotted using the Kaplan–Meier method. Differences in OS were analysed by the logrank test and considered significant if p<0.05.
Clinical features and location of disease
A total of 21 cases (9%) of MCL in the orbital and adnexal region were identified out of 230 Danish patients with lymphoma in the ocular region covering 25 years. These included 18 (86%) male patients and three (14%) female patients with an age range of 60–90 years (median 73.4 years). The cases were evenly distributed over the period of 25 years. Patients with orbital and adnexal region MCL as first presenting symptom comprised 67% (14/21) of the cases (table 1). The most frequent symptoms in this patient group were irritation/pain, epiphora and diplopia, whereas the most frequent clinical signs were eyelid mass, conjunctival swelling and proptosis (table 2).
Bilateral lymphoma was present in 71% (10/14) of the patients. All cases had involvement of more than one site in the orbital and adnexal region. The orbit (71%) and eyelid (64%) were the most frequently affected sites (table 3).
A complete staging procedure at the time of diagnosis that included a full body positron emission tomography (PET) and/or computed tomography (CT) and/or MRI and bone-marrow biopsy was performed in half (7/14) of the patients. The remaining seven patients had a less extensive staging that included a chest x ray, ultrasound of the orbit and/or CT of the orbit, sinuses and nasal cavity. All seven cases had bone-marrow examination.
Two patients had non-stage III/IV disease at diagnosis. One patient had bilateral involvement of the orbit and conjunctiva (stage I), and one patient had disease involving the right lacrimal gland and regional lymph nodes (stage II). In both cases, staging procedures were performed using PET to rule out systemic involvement. The patient in stage I achieved a complete response following radiotherapy, but the tumour spread to the brain 4 months later. The patient being in stage II had a complete response following CHOP but developed a relapse classified as stage IV disease 42 months after primary diagnosis. The remaining 12 patients were all classified as being in stage III/IV at diagnosis (86%, 12/14).
Secondary MCL implicated 33% (7/21) of the patients (table 1). These patients most frequently presented with swelling, irritation/pain and proptosis. Frequent clinical signs comprised a mass of the eyelid and conjunctiva along with proptosis (table 2). Bilateral ocular disease was seen in 29% (2/7) of these patients. Bone-marrow involvement was observed in four patients (57%), and of these three (75%) had anaemia. All seven patients were classified as being in stage IV.
Eleven patients with orbital and adnexal region MCL as first presenting symptom and six patients with secondary MCL had sufficient clinical data to construct the MCL International Prognostic Index score. All the cases were located in the low-risk group (score <5,7).
Histological and immunohistological findings
Diffuse growth pattern was demonstrated in 95% (20/21) of the cases, whereas one case (1/21, 5%) presented a nodular growth pattern (fig 1). The cellular marker for proliferation MIB-1 (Ki-67 labelling index) was assessed in all cases with a median of 13% (range 5–40%).
Immunohistochemically, all 21 specimens were positive for CD20, CD79α, BCL-2 and cyclin D-1, and negative for CD3, CD10, CD23 and bcl-6. All but five showed CD5 coexpression.
Six of the 21 patients were given CHOP in combination with anti-CD20 treatment (rituximab). Two of these patients had additionally an autologous stem cell transplantation (ASCT). Another seven patients were treated with anthracyclin-containing regimes without rituximab, and two patients received additional orbital radiotherapy. Six patients received an alkylating agent, chlorambucil or cyclophosphamide, in combination with prednisolone, and two of these were also treated with orbital radiotherapy. Two patients received only radiotherapy.
Treatment outcome and survival data
Twelve patients (86%) with orbital and adnexal region MCL as first presenting symptom experienced a relapse or progression of disease with a median of 27.5 months during a follow-up period ranging from 1 to 62 months. Eight of the patients (67%) had their relapse in the orbital and adnexal region, four (50%) with bilateral involvement.
Five patients (71%) with secondary lymphoma had a relapse or progression with involvement of the orbital and adnexal region in one case, orbital and adnexal region and systemic disease in three cases and systemic relapse in one case.
The estimated median PFS for all patients was 17 months from the time of diagnosis in the orbital and adnexal region. The median OS rate for patients with orbital and adnexal region MCL as first presenting symptom was 43 months and 51 months for patients with systemic presentation of MCL (fig 2). Patients with orbital and adnexal region mantle cell lymphoma as first presenting symptom had a significantly shorter maximum survival (p<0.04) than patients with systemic presentation of MCL. Patients treated with CHOP, rituximab and bone-marrow transplantation were lumped with patients receiving only CHOP plus rituximab (n = 6), since the number of patients was too small to perform a statistical analysis. This group had a 5-year OS of 83%, which was significantly higher (p<0.027) than the group of patients (n = 13) receiving chemotherapeutic treatment without rituximab (5-year OS rate, 8%) (fig 3). Among the 14 patients who died during follow-up (14/21, 67%), 13 (93%) died from lymphoma progression 3–62 months after diagnosis (median 27 months).
Mantle cell lymphoma is a non-Hodgkin’s lymphoma, described almost four decades ago as centrocytic lymphoma and recognised by the small cleaved cells with irregular nuclei, fine chromatin and small or absent nucleoli.13 In 1992, MCL was recognised as an independent lymphoma subtype by the International Lymphoma Study Group.14 The European Task Force on Lymphoma further defined MCL in 1994.15 With the availability of fluorescence in situ hybridisation (FISH) it became evident that the t(11;14)(q13;q32) causing cyclin D-1 overexpression was present in virtually all cases.16 Clinically, MCL is a lymphoma with a male predominance with multiple lymph-node involvement and also bone-marrow involvement.14
In the orbital and adnexal region, MCL has previously been described in reports primarily from centres in North America and Europe,717 but only two studies with a limited number of cases focused on orbital and adnexal region MCL with clinical data.910 In our study, we have analysed 21 patients with orbital and adnexal region MCL in a relatively stable population of 5.2 million people over a period of 25 years and correlated the clinicopathological features with prognosis.
The proportion of orbital and adnexal region MCL was 9% of all orbital and adnexal region lymphomas in Denmark.18 This is slightly higher than previously described in the literature, reporting approximately 4%.717 There was no change in incidence over the study period in contrast to an increasing incidence reported in all ocular region lymphomas.18 However, our findings of a steady incidence are in accordance with large reports on systemic MCL.1
We found that patients with MCL in the orbital and adnexal region were above 60 years of age and with a noticeable male predominance (male/female ratio = 6), that exceeds the observations of systemic MCL (male/female ratio = 3.1).4 Mantle cell lymphoma was primarily located in the orbit and eyelid, and interestingly, bilateral disease was observed in about three-quarters of the patients with primary MCL and in one-third of the patients with secondary MCL. In other orbital and adnexal region lymphoma, bilateral location is seen in only up to 10%.18 The high percentage of bilateral disease might be explained by the fact that MCL presents with widespread disease.
The majority of patients in this series presented in stage IV with nodal- and bone-marrow involvement, and corroborate that there is a very high proportion of systemic involvement in general with MCL of the orbital and adnexal region.19 Relapse or progression involving both ocular- and extraocular sites was seen in 86% of the patients and for the most part within 2 years after the diagnosis of orbital and adnexal region MCL. Bone-marrow examination confirmed that the majority of patients presented in stage IV. However, interpretation of treatment response and outcome in this series may be of limited value due to the fact that the standardised guidelines changed during the 25-year study period in line with the availability of new imaging technologies.12
The median OS was 43 months for patients with orbital and adnexal region MCL as first presenting symptom and 51 months for patients with secondary MCL. This confirms that MCL patients have a poor prognosis.3 Remarkably, there was a significantly longer maximum survival among patients with secondary MCL as opposed to patients with primary MCL. Also primary MCL had bone-marrow involvement in 79% as opposed to 57% in secondary MCL.
Recently, the MCL International Prognostic Index has been established to replace the previously used International Prognostic Index and Follicular International Prognostic Index developed for diffuse large-cell- and follicular lymphoma patients.11 When applied to the 17 patients in our material, with sufficient information to construct the score, all patients were allocated in the low-risk group with a predicted 5-year OS rate of 60%. Thus, in our cohort of patients, the MCL International Prognostic Index score was only reliable as a prognostic tool for the subgroup of secondary MCL patients with a relatively indolent course of disease.
MCL has previously been considered incurable, and treatment has been palliative, mainly in the form of anthracycline- or alkylating antineoplastic agents.20 Recently, new treatment strategies with CHOP in combination with the anti-CD20 agent, rituximab, have shown improved response and survival rates in patients with newly diagnosed MCL.6 In our study, it was only possible to compare survival data of patients receiving CHOP in combination with rituximab including bone-marrow transplantation versus CHOP alone, since the number of patients was very limited. Therefore, it was not possible to determine the impact of bone-marrow transplantation on survival. We recognise that it is possible that the improved survival in the group receiving rituximab may also be partly due to the fact that some of these patients had bone-marrow transplantation as part of their treatment. Seven patients received chemotherapy without rituximab and responded with tumour regression. However, six patients were treated with rituximab-containing chemotherapy, and two had also an ASCT (according to the 2nd Nordic MCL protocol) with a significantly better outcome compared with patients treated with chemotherapy without rituximab.
In conclusion, MCL in the orbital and adnexal region is rare and presents in elderly males. MCL is predominantly located in the orbit and eyelid. In our study bilateral involvement was frequently seen. Most patients presented with stage IV disease and had multiple relapses and short survival time. Treatment with rituximab-containing chemotherapy significantly improved survival.
Funding The study was supported by grants from the AP Møller Foundation for the Advancement of Medical Science, The Danish Eye Research Foundation and Øjenforeningen Værn om Synet.
Competing interests None.
Ethics approval Ethics approval was provided by the Ethics Committee of Copenhagen.
Patient consent Obtained.