ORBITAL AND ADNEXAL LYMPHOMAS AMONG ADULT PATIENTS IN GHANA

Abstract

Background

Non Hodgkin’s lymphomas (NHLs) present variously in different ethnic communities. Orbital and adnexal disorders have been reported among NHLs in Africa. They can involve the orbit, the eyelid, the conjunctiva, alone or in combinations. To our knowledge there are no reports in the literature about the clinical presentation of lymphomas in Ghana.

Aim

To explored orbital and adnexal disorders among adult patients attending the Korle-Bu Teaching hospital, Accra.

Methodology

Histological case notes of patients reporting to the orbital clinic of Korle-Bu Teaching Hospital, Eye Department from November 2004 to October 2016 with orbital and adnexial lympho-proliferative tumors were retrieved. Histopathology was performed at Sheffield Teaching hospital. Data collected included age, sex, symptoms at presentation and anatomic site of involvement. Histology and immune histochemistry data were generated.

Results

A total of 18 patients were examined and entered into the study. The male to female ratio was 1.25:1. Twelve patients (70.6) presented with proptosis and 14 (77.8%) had orbital involvement. Two patients had isolated eyelid disease. Of those with orbital disease, three had simultaneously upper eyelid involvement. Out of the 18 cases, 11 (61.1%) were mucosa-associated lymphoid tissue (MALT) lymphomas. Only males 40 years and above were affected, compared with females who presented at any age. Patients above 60 years reported early (i.e. <3 months) compared with patients below 40 years who mostly reported after 1 year.

Conclusion

This study reports pattern of epidemiological and clinical presentation of orbital and adnexal lymphomas as seen in Ghana, West Africa. Though there were some variations in the clinical presentation the histological subtypes represented seem to be similar to those reported in other parts of the world.

Introduction

Non Hodgekin’s lymphoma (NHL) is comprised of a group of heterogeneous neoplasms deriving from clonal proliferations of either B or T cell lymphocytes. They can arise in lymphatic nodal or extranodal (outside of lymph nodes, spleen, thymus and Waldeyer’s ring) sites1.

Lymphomas are the most common primary orbital and ocular adnexal lymphomas tumours. Staging and classification systems for ophthalmic and other forms of lymphomas have undergone multiple revisions. The most widely used staging systems for both nodal and extranodal NHL were the Ann Arbor2 and the modified Ann Arbor systems3. Currently, the Revised European–American Lymphoma (REAL)4 classification system is used for ocular and adnexal lymphomas. The most common histologic subtype of orbital and ocular adnexal lymphoma is mucosa-associated lymphoid tissue (MALT) lymphoma. Other subtypes less commonly found in the orbit and adnexia include follicular lymphoma, diffuse large-cell lymphoma and mantle cell lymphoma5. The clinical presentations of ocular adnexal lymphomas are diverse depending on the location of tumour rather than the histological type6. These tumours can involve the orbit, the eyelid, the conjunctiva, alone or in combinations7.

A review of orbital and adnexial tumours seen in Korle Bu Teaching Hospital (KBTH) between November 2005 and October 2009 showed a prevalence of about 6.2% of lymphomas (11 cases)8. There is however no comprehensive data on its clinical presentation in Ghana and the literature is scarce in clinical and histological presentation in West Africa. In this study we assessed the clinical pattern, and histological findings of patients presenting with orbital and adnexal lymphomas to the Korle-Bu Teaching Hospital, Accra. This study is meant to add unto fundamental epidemiological and clinical data in this part of the world.

Patients & Methods

Study design

This is a retrospective cross-sectional study of patients with orbital and adnexial lympho-proliferative tumours presenting at the Eye Department of the Korle Bu Teaching Hospital in Accra.

Study site

The study was done at the Eye Department of the Korle Bu Teaching Hospital, Accra.

Clinical data

Histological notes of patients reporting to the orbital clinic of Korle-Bu Teaching Hospital, Eye Department from November 2004 to October 2016 with orbital and adnexial lympho-proliferative tumours were retrieved. Histopathology was performed at Sheffield Teaching hospital. Data collected included age, sex, symptoms at presentation, anatomic site of involvement (orbit, eyelid, conjunctiva, or a combination of these structures) and laterality were recorded. The patients were referred to haematology department of the Korle bu Teaching Hospital for clinical staging and further workup and management.

Histological Examination of Specimen

Specimen were preserved in formalin, packaged in water-tight containers and sent by regular mail to the National Specialist Eye Pathology Service, Department of Histopathology, Royal Hallamshire Hospital Sheffield (UK), for histopathological analysis. Briefly, ocular tissue was fixed in standard 10% buffered formalin and shipped to the Ophthalmic Histopathology Service in Sheffield. On receipt, the tissue was described macroscopically, cut, representative pieces taken and these processed to paraffin wax. Four (4) micron sections were cut and stained with haematoxylin and eosin using standard methodology. Ancillary investigations, including tinctorial stains, immunohistochemistry and electron microscopy were conducted. The report was then sent by email and later the hard copy was sent by post to Accra.

Statistical analysis

Data was entered into Microsoft Excel Version 2010 and STATA 11 software and analyzed accordingly. Descriptive statistics of the patients were computed. Age group distribution with sex, laterality and duration at presentation were presented. Association of presenting symptoms, sex with duration at presentation and association of duration at presentation with histology type was illustrated using a Poisson model (p>/z/ at 95% confidence interval).

Results

A total of 18 patients were examined and entered into the study. The age range was 20 to 73 years with a mean of 51.8 years (SD +/-12.7). Duration of disease at presentation ranged from 3months to 10 years. The mean duration was 27months (range3-120months). Majority of the patients {7/13 (53.9%)} presented between 11 and 24 months and 3 (all of them MALT lymphomas) presented between 48 and 120 months (Table 1). The male to female ratio was 1.25:1. Table 1 shows the clinical and histological presentation of patients.

Table 1. Clinical and histological presentation of the patients.

Patient no.	Age	Sex	Laterality	Presenting Symptom	Duration at presentation	Location	Histology	Histochemistry
1	42	F	L	Proptosis	11months	Orbit	MALT Lymphoma profound plasmacytic differentiation	CD20
2	40	M	L	Proptosis	10 years	Orbit	MALT Lymphoma	CD20
3	55	M	R	Proptosis		OrbitUpper lid	MALT Lymphoma Low proliferation faction	CD20
4	41	M	Bil	Proptosis Scleritis	11months	Orbit	Nodular lymphoid infiltrate with secondary amyloid deposition Indolent B cell lymphoma	CD20
5	52	F	Bil	Proptosis	6 years	Orbit/ Upper lid	MALT Lymphoma Low proliferation faction	CD20
6	47	F	L	Proptosis	12 months	orbit	MALT Lymphoma	CD20
7	55	M	R	Severe Proptosis Visual loss Hepatosplenomegaly	18 months	Orbit Abdomen intracranial	EBV positive extra-nodal NK/T-cell lymphoma, of nasal type High proliferation factor	CD45, membranous CD3, CD2, CD7 and focally CD30.
8	66	M	R	Proptosis	4 years	Inferior orbit	MALT Lymphoma low to moderate proliferation fraction.	CD20
9	52	F	Bil	Lacrimal gld swellings		Orbit, lacrimal gland	MALT Lymphoma	CD20
10	23	M	R	Severe Proptosis		orbit	High grade T cell lymphoma of anaplastic type. >90% proliferation factor	CD45, DC3
11	69	M	L				MALT Lymphoma	CD20
12	62	F	R	Eyelid ulcer with nodular base	4 months	Eyelid	High grade, aggressive T-cell lymphoma of peripheral type	CD3, CD30
13	63	F	R	Multiple nodules upper lid	12 months	Eyelid	MALT Lymphoma	CD20
14	66	F	R	Ptosis lid swelling. Multiple nodules in anterior orbit		Anterior orbit, eyelid	MALT Lymphoma	CD20
15	64	F	R	Upper lid swelling rapidly increasing in size	3 months	Eyelid, conjunctiva	High grade T-cell lymphoma 80-90% proliferation	CD 2+ve, CD3 loCD20-ve
16	20	M	L	Marked Proptosis, lymphadenopathy	24 months	orbit	Diffuse Large B-cell lymphoma 95% proliferation fraction	CD 20
17.	42	M	L	Proptosis, periorbital swelling, lymphadenopathy	4 months	Orbit, lacrimal gland	NHL of lymphoplasmocytic type WHO Grade 1
18.	73	M	R	Proptosis, Ptosis, mass anterior superior-lateral orbital margin	12 months	Orbit, lacrimal gland	MALT lymphoma

Twelve (70.6%) of 17 patients for which data was available presented with proptosis; four (23.5%) presented with various eyelid lesions and one presented with lacrimal gland swellings (Table 1). A total of 14(77.8%) patients had orbital involvement; six (33.3%) had eyelid involvement and only one had conjunctival lesions. Two patients had isolated eyelid disease; one with an eyelid nodule was a (MALT) lymphoma and the other with an upper eyelid ulcer with a nodular base had T-cell lymphoma. Of those with orbital disease, four(28.6%) had simultaneously eyelid involvement, three (21.4%) had simultaneously lacrimal gland and one patient with Epstein Barr virus positive T-cell lymphoma with orbital tumour had in addition abdominal involvement and intracranial extension. Out of the 18 cases, 11 (61.1%) were mucosa-associated lymphoid tissue (MALT) lymphomas, four were T-cell lymphomas, 2 B-cell lymphomas and one a lymphoblasmablastic lymphoma.

Male patients presented only above 40 years compared with female patients who presented at all ages (Table 2). Nine (50%) affected the right eye, six (33.3%) the left and 3 (16.7%) were bilateral. Patients within age group 41 to 60 years presented with either eye or bilateral involvement whilst patients below 40 years and above 60 years had only unilateral disease. Patients aged 60 years and above reported earlier (<3 months) compared patients below 40 years who reported much later, that is after 1 year (Table 3). figure 1 shows the age- sex distribution with presenting symptoms and duration of symptoms at presentation. Symptoms presented by subjects and sex of subjects showed a statistically significant association with duration of the symptoms at presentation (p =0.000 Poisson regression model (P>/Z/ at 95% confidence interval). Duration of symptoms of subjects at presentation also showed a statistically significant association with histology of tumor (p =0.000 Poisson regression model (P>/Z/ at 95% confidence interval).

Table 2. Age group distribution with sex, laterality and duration at presentation.

SEX (%)		LATERALITY (%)			DURATION AT PRESENTATION (%)
Age group	Female	Male	Left	Right	Bilateral		Less than 3months	3months to 1 year	Greater than 1 year
LESS THAN 40 YEARS	11.11	0.00	5.6	5.6	0.00		0.00	0.00	11.11
41 to 60 YEARS	27.78	22.22	16.7	16.7	16.7		0.00	22.2	27.8
ABOVE 60 YEARS	16.67	22.22	11.1	27.8	0.00		5.56	27.78	5.56

Table 3. Association of presenting symptoms, sex with duration at presentation and association of duration at presentation with histology type (poisson regression model (p>/z/ at 95% confidence interval).

	DURATION AT PRESENTATION	HISTOLOGY TYPE
1. PRESENTING SYMPTOM	p value 0.000	-
2. SEX	p value 0.000	-
3. DURATION AT PRESENTATION	-	p value 0.000

FIGURE 1 . AGE- SEX DISTRIBUTION WITH PRESENTING SYMPOMS AND DURATION OF SYMPTOMS AT PRESENTATION.

Discussion

Data on ocular adnexal lymphoma in sub-Saharan Africa is very scarce in the literature. This study is meant to add unto fundamental epidemiological and clinical data in this part of the world. Although orbital and adnexal lymphomas are rare, lymphomas are the most common primary orbital tumor in adults 60 years of age and older.9 These tumors can occur at all ages, but they are most commonly seen in patients in the fifth to seventh decades of life 10 as found in this study. However, the disease has been reported to occur at a younger age among Asians. Studies among Korean patients with ocular adnexal lymphomas have reported the mean age of patients with MALT lymphoma to be 44-48 years11.

Sex predilection varies in different studies. While a report based on the analysis of incidence data from 13 Surveillance, Epidemiology, and End Results (SEER) areas in the USA spanning 1992–2007 revealed nearly equal male and female rates among cases of ocular adnexal NHL12as in our study, other studies suggest ocular adnexal NHL occur more frequently in males13^-15. Yet others reported a female preponderance16.

Small cell B-cell lymphomas (the extranodal marginal zone B-cell lymphomas) represent the most common subtype of B-cell lymphoma in the ocular adnexa17. These tumours possess minimal lymphoid tissue. They commonly develop in the stomach but may also occur in the salivary glands, the thyroid, and the ocular adnexa18. In this study, histological diagnosis and sub-classification was based on microscopic examination of stained specimen as well as immunohistochemistry. Most studies report 50-79.5% all ocular adnexal lymphomas to be MALT lymphomas19,20, which is consistent with our findings. The majority of non–B-cell lymphomas are said to represent secondary manifestations of a systemic T-cell lymphoma or extensions of the tumor stage of mycosis fungoides, usually involving the eyelid.10 Only a very few cases of primary T-cell lymphomas of the ocular adnexa have been reported in the literature to date. The three patients in our study with T-cell lymphomas presented with disseminated systemic disease with abdominal and intracranial involvement, a large ulcerated eyelid lesion proptosis respectively.

The clinical presentations of ocular adnexal lymphomas are diverse depending on the location of tumour rather than the histological type10. MALT lymphomas usually demonstrate an indolent clinical course, often remaining localized to their sites of origin for many years prior to dissemination21 as demonstrated in our study. The Most frequent site of origin of ocular adnexal lymphomas is the orbit (∼ 40%), followed by conjunctiva (35%-40%), lacrimal gland (10%-15%), and eyelid.17, 19, 22. This is consistent with our result except that conjunctival involvement was seen in only one (16.7%) of our patients. Some other studies had findings at variance with ours. In a study of 17 Korean patients the lymphoma was limited to the conjunctiva in ten eyes from six patients, limited to the orbit in 10 eyes from nine patients and was simultaneously detected in the conjunctiva and in the orbit at the time of the diagnosis in one patient.13 In a larger series of 95 patients with MALT lymphomas of the ocular adnexa in India, tumors were located most commonly in the conjunctiva (65.2%)23. In these patients the most common presenting symptoms and signs were palpable mass in 49 (51.6%), with proptosis in only seven (7.4%) patients23. In another study of 43 patients more patients, (10/23%) had conjunctival involvement, and fewer patients had simultaneous orbital and adnexal involvement 24.The higher levels of proptosis in our study may be due to the later presentation of these patients and probably the smaller sample size. One patient who presented with bilateral orbital B cell lymphoma also had in addition scleritis and his bone marrow biopsy was suggestive of Chronic lymphocytic lymphoma. This is a rare presentation as very few cases of orbital MALT lymphomas with amyloid infiltration have been reported in the literature25,26. One of our patients, a 20 year old male, with diffuse large B-cell lymphoma presented clinically will a huge tumour arising from the orbit and a cervical lymphadenopathy. Diffuse large cell B-cell lymphoma represents the second most common lymphoma subtype of B-NHL10. They may evolve either de novo or secondarily during the course of a less aggressive lymphoma most commonly from follicular lymphoma27. Another patient, a 42 year old male with lymphoplasmocytic lymphoma presented with proptosis and periorbital swelling. This patient also had lacrimal gland involvement.

A study in Benin City, Nigeria among patients with haematologcal malignacies reported ocular involvement in16 patients (31.4%) with non­Hodgkin's lymphoma but none in any of the patients with Hodgkin's lymphoma. This study did not however sub-classify the lymphomas. Of the 16 patients 6(11.8%) presented with proptosis indicating orbital disease, 3 (3.9%) had conjunctival infiltrates and only one (2.0%) had an eyelid lesion. The rest had ocular disorders which may not have been due to tumour in the eye but from paraneoplastic retinal degeneration, or increased susceptibility to infections as a result of immunosuppression28.

The duration of symptoms before presentation has been reported to vary considerably between patients, with the average duration being approximately 6 months10. In the Indian study referred to earlier the mean duration of symptoms at diagnosis was 10.5 months (range 1–54 months) 23 while in our study the majority of patients duration of presentation ranged from 3 to 130 months. In a study by Kiesewetter and others, the mean duration between first symptom and presentation was 5.2 months (median 3 months; range 1–18 months)29>. In a review by Stefanovic and Lossos, the median interval between onset of symptoms and time of diagnosis was found to be variable, ranging from 1 month to 10 years (median, 7 months)22. The difference probably reflects the earlier presentation by patients in developed countries to their doctors with health conditions. This study also revealed that duration of symptoms at presentation was significantly dependent (p=0.000) on laterality, sex and presenting symptoms (Poisson regression model, P>/Z/ at 95% confidence interval). In the review by Stefanovic and Lossos 22 bilateral tumours were found to occur in 10% to 15% of cases which is consistent with our study. Characteristics of the bilateral cases in our study were each MALT indolent lymphoma with amyloidosis with bone marrow involvement, MALT lymphoma involving both lacrimal glands, and low grade MALT lymphoma with simultaneous anterior orbital and eyelid involvement. In an Indian study of 95 patients with MALT lymphoma of the ocular adnexa, the right eye was predominantly involved just as in our study. Bilateral orbital involvement was found in 13 patients (13.7%)23. The reason for predilection for the right eye cannot be easily explained.

Associations between age of onset and duration at presentation or laterality have not been described elsewhere to the best of our knowledge. From our study, age groups below 40 years and above 60 years had only unilateral disease. With regards to duration of symptoms, patients above 60 years reported earlier (<3 months) compared with patients below 40 years who reported much later, that is after 1 year. This difference in behavior by different age groups needs to be further investigated.

Limitations

The small sample size and the retrospective nature of the study affected the results.

Conclusions

This study reports a pattern of epidemiological and clinical presentation of orbital and adnexal lymphomas as seen in Ghana, West Africa, including a rare case of bilateral disease with scleritis showing a bone marrow biopsy suggestive of Chronic lymphocytic lymphoma Though there are some variations in the clinical presentation the histological subtypes represented seem to be similar to those reported in other parts of the world. Duration of symptoms of patients at presentation is associated with histological type of the tumor.