- Email: [email protected]
Ocular tumors in Africa
0277-9536/83$3.00+ 0.00 Pergamon Press Ltd
Sot. Sci. Med.
Vol. 17. No. 22. pp. 1743.-1750.1983 Printed in Great Britain
OCULAR
TUMORS
IN AFRICA
VOLKER KLAUSS’ and HARJINDER S. CHANA’ ‘Department of Surgery, Faculty of Medicine, University of Nairobi, P.O. Box 30588, Nairobi and 2Central Province Kenya, P.O. Box 1323, Nyeri, Kenya
Abstract-This paper is an analysis of 470 cases of oculo-orbital tumors in Kenya. The present series is compared with the major works conducted in other African and Western countries. We refer to age, sex and geographic characteristics and prevalence of tumors in different populations and stress the differences found. The major emphasis is on retinoblastoma, Burkitt’s lymphoma and nasopharyngeal carcinoma. Orbital Hydatidosis is included as a differential diagnosis of unilateral propotosis. Considering all the reviews, retinoblastoma is reported in high numbers in African countries whereas uveal melanoma is extremely rare. Among the tumors of the lids and conjunctiva, squamous cell carcinoma occurs more frequently than in Caucasians. Besides retinoblastoma infiltracting the orbit, Burkitt’s lymphoma is the most common orbital tumor. nasopharyngeal carcinoma in Kenya has the third highest incidence in the world. Proptosis is the hallmark of orbital disease and is the commonest manifestation sign at first attendance, a fact which validates the late presentation of most of our patients. The difficulties encountered in early diagnosis and hence the appropriate management are discussed and in concluding remarks some recommendation are made.
INTRODUCTION
Thinking in terms of numbers of affected patients, ocular tumors in Africa are not as important as the major blinding diseases: cataract, trachoma and glaucoma. But because many ocular tumors threaten the patient’s life, it is justifiable to discuss them among Africa’s important ocular diseases. The topic is subdivided into 3 sections: (A) intraocular tumors (B) tumors of lids, lacrimal system and conjunctiva (C) orbital tumors
INTRAOCULAR TUMORS
Reviewing the literature on intraocular tumors in Africa only two have been mentioned: retinoblastoma and melanoma of the choroid. This fact is surprising as there is a long list of benign and malignant intraocular tumors that have been described elsewhere [I]. There is no reason to assume that these diseases do not occur among Africans, but they may not have been reported because of lack of ocular pathologists or lack of time by ophthalmologists in Africa. Retinoblastoma
Retinoblastoma is the commonest intraocular tumor in childhood throughout the world. The disease has been extensively studied in Europe and U.S.A. for its epidemiology, prevalence, genetics, symptoms, diagnosis, therapy and histologic characteristics. But only few reports are available from African countries. Incidence. heredity, and laterality. The incidence figures vary between 1 per 14,000 births in Holland and 1 per 23.000 births in Michigan [2]. BenEzra [3] reports an annual incidence in Malawi of 2 cases per 100.000 children under 5, or 1 case per
10,000 live births. As in all other studies these are hospital figures which cannot present the true picture;
there is an unknown number of retinoblastoma children who are never seen or treated by an ophthalmologist. Olurin [4] found in a series of 191 oculaorbital tumors in Nigeria that 64 (34%) were retinoblastomas. Malik [5] reports from Sudan that out of 279 malignant tumors of eye and adnexa, 57 (20.4%) were retinoblastomas. Jn our own series of 73 retinoblastomas seen at Kenyatta National Hospital in Nairobi over a 54 month period, we found an incidence rate of 1: 18.750 live births [6]. This figure is certainly far too low as these are hospital data, not population-based data. Also there are six provincial ophthalmologists working outside Nairobi who treat retinoblastoma; an attempt failed to have all retinoblastoma cases treated in provincial hospitals recorded. We cannot answer the questions if retinoblastoma occurs more frequently among African than among European children, but all figures’ available indicate that the tumor is not less frequent in Africa. We could expect that retinoblastoma is less frequent than in Europe as there are no inherited cases, because in previous generations treatment was not available and all patients with retinoblastoma died before the age of reproduction. In statistics from outside Africa the percentage of familiar cases is 10% as compared to 90% for sporadic cases (Kitchin quoted by Reese [2]. Among our 73 cases we found only one family where retinoblastoma was possibly inherited. BenEzra [3] reports one familiar case out of 48 in his study from Malawi. Though heredity can be almost totally excluded in African retinoblastoma patients today, it is surprising to find a high number of bilateral cases. Ixi our series 26 out of 73 patients had bilateral retinoblastoma (35.6% [6]. In Malawi [3] 25% were bilateral, in the Nigerian [4] and Sudanese
1744
VOLKER KLAUSS and HARJINDER S. CHANA
[5] studies the laterality is not recorded. In the U.S.A. 25% of cases are to be bilateral [2]. Sex distribution. In our series from Kenya 39 patients out of 73 were females, 34 males. In Malawi [3] 27 out of 48 were females. In Nigeria [4] 38 out of 64 were females. In an earlier study from Kenya (1967-1972) Bhimani [7] found 27 males among a total of 45 cases. Pendergrass [8] found a ratio of boys to girls as 1.12: 1. We can conclude out of these figures that there is no sex preference for retinoblastoma in Africa. Age. The average age at first diagnosis is reported to be high in Africa. Olurin [4]: 3.2 years; BenEzra [3]: 2-3 years; Klauss [6]: 2.53 years as compared to Reese [2], U.S.A. 1.5 years. A report from Malaysia [9] gives an average age of 2.5 years and thus resembles the African findings. The age range in our study is 4 months to 6 years. In one extraordinary case that we observed the first eye was enucleated at age 8 months, the second eye was found to have a retinoblastoma when the child was 6 years old. There are several explanations for the higher age in African children like lack of diagnostic facilities. Also, 5 parents in our study admitted to have consulted a traditional doctor which meant the loss of a precious 2-6 months. BenEzra [3] estimates that in Malawi 25% of eye patients seek the advice of a traditional healer before coming to a government hospital. Thus it is not surprising that our patients are seen by an ophthalmologist an average of 3.5 months after the first symptom was detected [6]. Another reason for the late age of first treatment may be that the vast majority of cases in Africa are sporadic. In Balmer’s [lo] statistic from Lausanne the average age of first symptom was 7 months in bilateral, inherited cases and 25 months in unilateral, sporadic cases. It appears that bilateral tumors occur earlier in life. Also parents in retinoblastoma families are more aware of the problem than the general population, which may lead to earlier diagnosis. First symptom. BenEzra (Malawi) [3] reports that leucocoria was the first symptom in 70% of the cases, inflammation of the involved eye in 30%. This compares with our findings where leucocoria was the first symptom in 65% of patients, a painful red eye in 32%. Treatment. In our hospital we can do photocoagulation, cryotherapy, radiation and chemotherapy besides surgery. Again this is an exceptional situation for an African Hospital. Ophthalmologists in smaller hospitals can do surgery only. In 8 of our 73 patients we observed a recurrence after enucleation although the histologist had not reported any extraocular growth. After this experience we routinely radiate the orbit after enucleation with 4.500 rad. Table
I.
Comparison
of frequencies
of lid
Kenya
Uganda
Awan
Templeton
Out of 99 affected eyes in our series 75 had to be enucleated, and in a further 10 cases an exenteration of the orbit was done. In 9 cases (12Y$ the patients refused enucleation. Three eyes could be preserved through photocoagulation and cryotherapy. We did not admit 2 children because they were in a terminal state at the time of initial presentation. We know of 8 deaths (1 l”/@among our 73 patients, but the figure is certainly much higher. Bhimani reports the mortality rate in his series as being 9Y0 (assuming that patients who failed to attend for follow up died). Melanoma of the choroid
Melanoma of the choroid is the commonest intraocular malignancy in man [l]. This statement appears to be true only for Caucasians as a review of African literature shows. Bisley [l 1] did not see a single case in Kenyan Africans over 30 years. We can add to this experience as we have not seen one case in 4 years. Also Templeton [ 121in Uganda does not report on any case out of 312 orbito-ocular tumors. Miller [ 131 has observed 8 cases of primary ocular malignant melanoma in Africans in Transvaal over 25 years, but only one of them had a uveal melanoma, four among the others arose from the conjunctiva and three from the orbit. Over the same period of time he found 153 cases of primary ocular malignant melanomas in whites. Hogan and Zimmermann [ 1] give a ratio of 175 : 1 between Caucasians and non-caucasions for malignant melanoma of the choroid in the U.S.A. Olurin [4] from Nigeria reports on two patients with choroidal melanoma out of 191 cases with orbito-ocular tumors. In a series from Dakar/Senegal 2 cases were seen among 195 orbito-ocular tumors [14]. Malik (Sudan) [5] found 6 intraocular malignant melanomas but they all occurred in the Arab population and none in ‘black Africans. From these figures we can conclude that malignant choroidal melanoma occurs only exceptionally in Africans. No conclusive explanation has been given for this finding. Miller [ 131 quotes Boniuk and suggests “that there is a genetically determined resistance of the Negro to ocular melanoma”. TUMORS OF LIDS, LACRIMAL SYSTEM, CONJUNCTIVA
Lid tumors
One fact becomes obvious from a consideration of lid tumors in Africa: basal cell carcinoma is very rare or non existent among Africans (Table 1). (All cases from Sudan were observed in non-Africans.) It is generally accepted that basal cell carcinoma is comtumors
(all
orbito-ocular Sudan
Nigeria
Malik
tumors
= 1009/,)
Baltimore lllif
[I51
WI
[41
[51
[I61
279
375
No. of cases 1487
312
191
Basal cell carcinoma
(Total)
0
0
0
Squamous cell carcinoma
4
3
1.5
7
2.0
Pap
1.2
1.0
0.5
0
11.0
illoma
6.1
9.0
Ocular Table
2. Comparison
Tumor Squamous cells carcinoma Mal. Mel.
of series of conjunctival
tumors
tumors
from dilferent
system
countries
tumors = IOOY,,)
(all orbito-ocular
Kenya [15] (1487 cases)
Uganda [ 121 (312 cases)
Nigeria (41 ( I91 cases)
Senegal [ 141 (195 cases)
Sudan (51 (279 cases)
21.x 0.7
16.0 0.3
6.2 1.6
22.0
50.5 0.7
mon in skin unprotected by pigment against sunlight, but does not--or very rarely-occur in pigmented skin. The incidence varies inversely with the degree of skin pigmentation [S]. It is surprising that Awan [l5] does not report a single case of squamous cell carcinoma out of 1487 tumors seen in Kenya but we believe that the 4 cases in his series termed as ‘Xeroderma pigmentosum malignant’ were in fact squamous cell carcinomas. We have treated three patients in Nairobi over the last four years. With exception of the Nigerian [4] study all others from Africa give a higher incidence of squamous cell carcinoma of the lids than in Baltimore [ 161. Lacrimal
1745
in Africa
tumors
The data available on lacrimal gland and lacrimal sac tumors are too scarce to allow any specific conclusions. Awan [15] reports 4 (0.3%) benign and 19 (1.3”,/,) malignant mixed and carcinomatous lacrimal gland tumors in Kenya out of 1487 orbitoocular tumors. Olurin (Nigeria) describes 5 pleomorphic adenomas (2.6%) I fibroma (0.5%) and 1 adenoid cystic carcinoma (0.5%) among I91 orbitoocular tumors. Malik (Sudan) [5] records 8 lacrimal gland (2.97;) adenocarcinomas among 279 malignant tumors of eye and adnexa. Templeton [I21 has found I7 (5.4%) lacrimal gland tumors in his series of 312 orbito-ocular tumors, but he does not specify the histological type. No case of melanoma of the lacrimal sac has been reported in the available literature.
(a) Ultraviolet light. (b) Dry air, wind. dust, trachoma and vernal catarrh are all factors that contribute to chronic irritation of the conjunctiva and which may facilitate the development of a carcinoma. All these factors are common in Africa. (c) Race and skin colour: It is still undetermined if race or degree of pigmentation are of any importance. In Malik’s study [5] the tumor was more common in people from northern Sudan with a lighter skin colour. Though we still need more information it is apparent that Africans are not protected against squamous cell carcinoma of the conjunctiva as they are against the basal cell carcinoma of the lids.
2
Malignant conjunctiva occurs at a comparable outside Africa (see Table 2). Miller conjunctival melanomas out of 8 melanomas in South Africa.
Malignant melanoma of the conjunctiva.
melanoma of the rate to countries [I 31 mentions 4 ocular malignant
ORBITAL
TUMORS
Orbital disease is rare. Comprehensive studies in the African patient have been carried out in Uganda [12, 171, Nigeria [4], Sudan [5] and among South African blacks in Johannesburg [ 131 and Cape Town [l81. Our series is an integrated prospective and retrospective study of 470 patients with orbital disease. All the patients in this study are from Kenyatta National Hospital, Nairobi. Most of the patients were followed up in the outpatient department in the Eye Unit though some were hospitalized when necessary. This integrated study establishes the major causes of proptosis in a referral hospital in Kenya. A general survey of orbital disease is presented with spedal emphasis on prevalent tropical diseases such as Hydatidosis and the Burkitt’s Lymphoma. The present series of 470 cases is broken down by diagnosis in Table 4 (see Table 3). Table
3. Causes
of proptosis Present series [26] 1982 [27] 470 Cases Number
Cortjunctiva/tumors Squamous cell carcinoma. Looking at figures from different African countries the incidence of squamous cell carcinoma of the conjunctiva is striking (Table 2). Templeton [12] concludes that this tumor is more common in tropical Africa than in other parts of the world. The following etiological factors have been mentioned to explain the high prevalence of conjunctival carcinoma in Africa:
U.S.A. [Ih] (Baltimore 375 cases)
Retinoblastoma infective processes: Orbital cellulitis Panophthalmitis Endophthalmitis Rhinogenic carcinoma Endocrine ophthalmopathy Burkitt’s Lymphoma Pseudotumor Mucoceles Malignant lymphoma and leukemia (chloroma) Miscellaneous Carcinoma of palpebral region t_acrimal gland tumors Carcinoma of epibulbar region Post-traumatic retrobulbar Hematoma Hydatidosis Haemangioma Rhabdomyosarcoma Dermoid cysts Meningioma Malignant melanoma Craniofacial dysostosis Glioma of optic nerve Metastatic carcinoma UnditTerentiated sarcoma Osteoma Exophthalmos of unknown origin
“‘,
73 70
5.5 14.9
66 51 43 29 21
14.0 10.9 9.2 6.2 4.5
18 17 11 9 9
3.8 3.6 2.3 1.9 1.9
9 9 8 5 4 4 4 3 2
1.9 1.9 1.7 1.1 0.9 0.9 0.9 0.6 0.4 0.2 0.2 0.2 0.2
I 1 1 1
VOLKER KLAIJSS and HARJINDER S. CHANA
1746
Table 4. Primary orbital disease age (at first attendance and sex) Max. Number Rhabdomyosarcoma Optic nerve glioma Hamartoma Lipoma Hydatid Pseudotumor
A detailed analysis is presented mentioned Kenyan data: (1) (2) (3) (4)
5 2
I 1 9 29
(of270) ______. 1.1 0.4 0.2 0.2 1.9 6.2
of the afore-
Primary disease Secondary disease Systemic disease Paediatric orbital disease.
Primary orbital disease Rhabdomyosarcoma.
Rhabdomyosarcoma (see Table 4) is a highly malignant tumor usually arising from rests of striated muscle and characteristically presenting as rapidly increasing proptosis. Death occurs either through direct extension or metastatsis. It is the commonest primary malignant tumor in children in certain series. The average age of our rhabdomyosarcoma patients at first presentation is 11.2 years which is higher than that stated in literature (Duane 7.8 years) [19]. With only five cases in our series, this age structure may not be significant [20]. However, it does signify the delayed and neglected presentation at first attendance. Reports of rhabdomysarcoma in non-whites in the western countries are rare. Knowles [21] interpreted this disproportion socioeconomic factors governing diagnosis and treatment rather than true predilection of orbital rhabdomyosarcoma for whites. All the patients were treated with radiation and cytostatic therapy after the exenteration of the orbit. Evidence has accumulated that radiation therapy alone (or combined with chemotherapy) can be successfully employed against this tumor with a cure rate of 80% [22]. However, we have resorted to surgery in addition because of the very advanced stage of the disease, and the fact that the eyes are destroyed when the patients are first seen. Idiopathic inflammatory pseudotumors. Reese [23] reported pseudotumor (see Table 4) as the most common cause of unilateral proptosis in adults. Whereas Illif [16] found 3.4% of his cases with pseudotumor, the present series shows 6.2%. The average age of presentation was 17 years with the youngest patient manifesting the condition at 7 years. The commonest signs were proptosis and chemosis. Diminished visual acuity was found in 9 cases (31%). The visual acuity improved and proptosis regressed with steroid therapy. Surgery was not done in any of the cases. Echinococcus cyst. This disease is prevalent in Turkana District in North Kenya where the highest prevalence in the world has been documented [24]. Nine cases were seen at Kenyatta National Hospital (see Table 4). All had unilateral proptosis, the minimum age was 6 years and the maximum 25 years. It
age (Yr) 13 25 35 35 35
Min. age ._~(Y0 7 18 4 29 6 7
Average age (Yr)
Male
10.2 21.5 32.0 18.8 17.0
3
Female
Total
2 ,
5 2
I I
I
I ’
’ 9
7 20
9 29
has been documented that the prevalence in Turkana is highest in the world, being three times as high as the nearest country. Data of the prevalence in Kenya was obtained from the African Medical Research and Education Foundation (AMREF) [24] and the orbital hydatidosis cases presented in Kenyatta National Hospital are reviewed. Epidemiology
At present there are some 100,000 Turkana occupied in traditional nomadic herding while the remaining 80,000 are occupied in fisheries, irrigation or urban development around Lodwar. In addition. about 30,000 have emigrated to other parts of Kenya. There is a ten-fold difference from around 200 cases of hyatid disease per 100,000 per annum in the North West part of Turkana District to less than 20 cases per 100,000 per annum in the South. Of the total of 516 hydatid disease cases in the AMREF study, 19.2% were under age 10 years, 78.9% were age 30 and under and only 6.2:/, were over age 40. 34.3% were males and 65.7”,/, were females, a sex ratio of 1 : 1.9. In most cases only one member of a family was affected. This may be due to separation of the members of the family in order to cater for the differing needs of livestock at different parts of the year. Additionally, it has been observed that the specially trained pet dogs are very much attached to a single person. The duration of the disease at the time of presentation averaged 3 years, and is the same for the interval between treatment and reporting a recurrence. Location of cysts 70-80% of the cysts were intra-abdominal. In, the orbit, they usually appear in the superior nasal quadrant in or about the muscular cone. Proptosis, and sometimes pain, are the classical manifestations of a fully developed cyst. Exposure keratitis due to extreme protrusion of the eyeball, and other evidence of pressure of an orbital mass, such as papilloedema. are occasionally noticed. Recurrence
Recurrence means: (a) A cyst or daughter cysts grow in the cavity left by the original cyst. (b) A cyst grows in the surgical scar. (c) In the case of intra-abdominal cysts, one or more mesentaric cysts develop post-operatively. The Recurrence rate is about 28%.
Ocular tumors in Africa Table 5. Processes secondary
Diagnosis Retinoblastoma Lid and conj. tumor Lacrimal gland tumor Carcinoma nasopharynx Meningioma Encephalocele Malignant melanoma MUCOC&
Hydatid
in orbit from adjacent structures (age in years at first attendance)
NO. total 73 23 9 66 4
I 4 21
(0f?70) - 15.5 4.9 I .9 14 0.Y 0.2 0.9 4.5
cycle
This is a disease of animals and humans. It is caused by two species of dog tapeworm, Echinococcus granulosus and Echinococcus multilocularis. The life cycle of these are similar and occur in two stages: Stage I: The adult tapeworm, which is about i in. long, lives in the intestine of the dog (or other carnivorous animals, chiefly the hyena). These tapeworms produce thousands of eggs which contaminate the ground, the water and the dog’s fur as well. Humans become infected by stroking their pet dogs or by touching objects contaminated by dog faeces. Stage 2: After the eggs are consumed by humans or herbivorous animals, they hatch in the intestine and become larvae and spread through the blood stream to any part of the body, and develop into cysts. Investigations
Four diagnostic
tests are available:
(a) (b) (c) (d)
Stool and urine. Immunoelectrophoresis test. Casoni’s skin test. Histology: demonstration of a unilocular cyst to Echinococcus granulosus and the contents of the cyst. Hydatid disease occurs in every country in the world. To date only Iceland has eradicated the disease. As a disease of domestic animals, it causes an enormous reduction in the yield of meat and milk. Secondary
orbital disease
Retinoblastoma is the most common intraocular tumor in childhood. Orbital extension of retinoblastoma is very common in our series because of the very late presentation, 72% of the patients manifesting proptosis when first seen (see Table 5). The unusually high incidence of retinoblastoma with orbital extension, 20 out of 65 cases (310,) in the Silva [25] study, can be explained by the fact that Silva reviewed only children referred for radiotherapy and/or chemotherapy in the oncology clinic. Similar reasoning, however, can be applied to our hospital, the radiotherapy unit of which caters for the East and Central Africa [6]. A detailed discussion on retinoblastoma is presented in the previous chapter. Carcinoma qf the naso-pharlwx (NPC). The relative frequency (third highest ‘in the world next to Retinoblastoma.
China and Malaysia and the highest in Africa). the histopathological features (the majority were anaplastic) and a more advanced stage of the disease at
Max. age 10 60 80 82 62 60 69
Min. age 4.12 18 25 12 13 0.5 41 12
Average age 2.53 36.4 46.6 42.6 36.7 48.0 39. I
Male
%
Female
34 10 6 53 3 1 1 9
47 44 67 80 75 100 25 43
39 13 3 13
I 3 12
% 53 56 33 20 25 75 57
first attendance makes it a significant disease entity in our series. The aetiological factors implicated are of genetic, viral and chemical origin. Consistently high titres of Epstein-Barr-related antigens occur in NPC. Genetic factors determine the susceptibility to the disease. HLA haplotypes AZ-Bsm 2, Bw 17-AW 19 and BW 17-Ablank have been shown to be implicated in NPC (in studies by Simons et al. [26]). Prasad [27] has done a clinical analysis and his results are as presented in Table 6. In a series by Clifford [28] 68% of his 61 cases presented with ophthalmological manifestations which included blindness, diplopia and proptosis. Sawaki [29] in his classical analysis of 766 cases of NPC showed only 7% ophthalmic involvement with dysfunction of extraocular muscle movements, ophthalmoplegia and disturbance of visual acuity due to the bony distruction of the optic canal, but no case of proptosis was cited. In the present series (see Table S), 232 cases of NPC over a period of three years are reviewed. 28.5% of these presented with mild to severe proptosis; the disease was well advanced when the patients first consulted the ophthalmologist. The following is our analytical data: Youngest patient Oldest patient Average age
12 years 82 years at first attendance 41.9 years 1
Male: female ratio 4: 1 (as compared to M: F 2.7: 1 which is relatively constant in the world). That the orbit is involved relatively late in the disease process, is evident from the proposed classification adapted from Ho [30] (it is based on the primary tumor, cervical lymph nodes and the haematogenous metastasis): Tl Tumor confined to nasopharyngeal or no tumor visible, but biopsy positive. Table 6. Geographical
Nation I. 2. 3. 4. 5. 6. 7. 8. 9. 10. II. 12.
Canada China (Canton) Hong Kong India Indonesia Japan Kenya Malaysia/Singapore Scandinavia Taiwan U.K. U.S.A.
distribution % Head and neck malignancy NA 56.9 NA NA NA NA 25.5 NA NA NA 2.0 2.0
mucosa,
of NPC % all malignancy 0.3 NA 18.0 0.5 13.9 0.1 NA 13.2 0.4 21.0 1.3 0.3
1748
VOLKER KLAUS and HARJINDERS. CHANA
T2 Tumor extended to the nasal fossa, oropharynx or adjacent muscles or nerves below the base of the skull. T3 Tumor extended beyond T2 limits and subclassified as follows: T3a: Bone involvement below the base of the skull (floor of the sphenoid sinus is included in this category.). T3b: Involvement of the base of the skull. T3c: Involvement of the cranial nerve(s). T3d: INVOLVEMENT OF THE ORBIT, laryngopharynx (hypopharynx), or infra temporal fossa. 28.5% of our patients presented with T3c and T3d staging at first attendance. Mucoceles. Mucoceles involving the ethmoidal and frontal sinuses may project into the orbit. A frontal mucocele usually presents under the superior orbital rim and displaces the globe downwards and outwards rather than forwards. The ethmoidal mucocele causes a lateral proptosis. The mass is not invasive but space-occupying and hence the symptomatology is indicative of pressure and interference in the motion of the eyeball. Painless proptosis is the first sign. Ultrasonography and X-ray provide diagnostic aids. In our series, 21 cases are presented (see Table 5). The ethmoidal mucocele was common in children and the frontal in the adults. Generally, the ratio of ethmoidal to frontal mucocele was 1:9. AN mucoceles presented with proptosis. Whereas proptosis is the earlier sign in mucocele, it was a later one in the carcinoma of nasopharyngeal space. All cases were treated surgically. Systemic disease affcting
the orbit
Burkitt’s Lymphoma.
Burkitt’s Lymphoma is the commonest childhood tumor in tropical Africa where malaria is endemic. Clifford first recognized this condition in Kenya in 1961 [31]. A suggestion has been made that persistent immunological stimulation by malarial infection and consequent lymphoreticular hyperplasia may be important factors in the development of this malignancy. Circumstantial evidence is accumulating in favour of linking this condition with Epstein-Barr Virus (EBV). Burkitt’s cells harbour virus particles and many investigators feel .that EBV may be the first proven human cancer virus as suggested by Klein and Clifford [32]. EBV is also felt to be the aetiological agent in infectious mononucleosis and the anti-EBV antibody observed in mononucleosis is identical to that found in patients with Burkitt’s Lymphoma [33]. The tumor involving the maxilla is the commonest presentation. Involvement of the antero-ethimoidal Table 7. Systematic
diseases
with
area may cause gross proptosis and thus may be confused with a retinoblastoma [34]. Ninety-two cases of Burkitt’s Lymphoma involving only the jaw were selected for this study (see Table 7). 42 (469;) of these presented with ophthalmological signs. 51 (55%) were males and 41 (45”J were females. The average age at initial presentation was 7.25 years, ranging from 1.25 to 17. Detailed accounts of Burkitt’s Lymphoma in Kenya were documented by Khan in 1964 [35] and by Rupani in 1977 [36]. Leukemia. Kasili [37] has done a preliminary study of the various aspects of leukemia in the Kenyan community. Factors which may contribute to the high frequency of myeloid leukemia (twice as prevalent as the lymphocytic types) such as the background terrestrial and solar radiation, medicinal herbs, agricultural insecticides, the high carrier rate of HbSAg and the relevance of genetic markers have been examined. Immunogenetic marker studies of African population afflicted by leukemia, as well as in vitro studies of the leukemia cell growth kinetics, are being carried out to establish whether the very advanced stage of disease at presentation is due to lateness on the part of those seeking medical advice or whether the disease is generally more aggressive than in Caucasians. Chloromas were documented in 14 cases of acute myeloblastic and myelomonocytic leukemia and in 2 cases of chronic granulocytic leukemia (see Table 7). This shows a frequency of 10% chloroma in acute myelogenous leukemia. Thirteen were orbital tumors and commonly presented with asymmetrical, bilateral proptosis. Only one case occurred in an adult (male. 25 years). The rest occurred in children, a frequency of chloromatous tumors in children with AML of 23%. Grave’s Disease. In Kenya, thyrotoxicosis in early literature was documented as a rare entity by Trowel [38]. Exophthalmos is present both in Graves’ Disease and in Hashimoto’s Disease. The current thinking is that the thyroid auto-immune diseases are a spectrum with Graves’ on one hand and Hashimoto’s on the other. Ophthalmopathy of Graves’ is usually not severe in Kenya but 10% required sympatholytic eye drops and 2 cases (2.57;) were advised to have tarsorraphy because of exposure keratitis. In our series, the following ophthalmological findings were noted (see Table 8): Number of cases reviewed = 82 Male: female ratio = 1 : 4.7 Mean age (at first presentation) = 32.4 years. Paediatric orbital disease
The largest series dealing with childhood
orbital
manifestation
by age and
sex
0, Diagnosis Burkitt’s
Lymphoma
Lymphosarcoma Hodgkin’s Leukemia
and
Plasmacytoma Neurofibroma Hyperthyroldism
lymphoma
Number
(of ‘i70)
43
9.2
I
0.2
I
0.2
I6
3.4
I
0.2
Max. 17
Min. 1.25
Average 7.25 30.0
3.12
3
0.6
8
51
10.9
9
Male 24
36.0
I
5.2
6
_
30.0
I
0.3
19
I
25.0
60.0
F.Xl&
4.4
3
32.4
9
IO
42
diseases
I749
Ocular tumors in Africa Table 8. Graves’
Disease: Infiltrative ophthalmopathy ber of cases = 82)
(total
num%
72 5 51 34 24 24 20 17 17
Stare/lid lag Lid retraction Exophthalmos Lateral rectus injection Irntation Red lids Blurred vision Chemosis Tearing
87.5 6.5 62.5 41.7 29.2 29.2 25.0 20.7 20.7
of the orbit are from the Toronto Hospital for Sick Children (257 cases) [39], Children’s Hospital in Washington, DC (61 cases-Youseffi) [40] and by Porterfield (214 cases) [41]. The series of Templeton [ 171 on orbital tumors in African children (conducted in Uganda) analyses 60 cases. The largest single cause in the Toronto study was inflammatory disease (30%) followed by the combination of metabolic and general systemic disease (21%). As mentioned earlier, the frequency of 23% chloromatous tumours in children with Acute Myeloblastic Leukemia is very high when compared with the Western population (see Table 9). Its high frequency is an expression of the frequency of acute myeloblastic leukemia in Africa. Most series indicate a higher prevalence of metastatic lesions to the orbit, such as neuroblastoma and Ewing’s sarcoma.
Proptosis is the hallmark and the main presenting sign of orbital disease and this is validated by the present study with 410 cases of mild to severe proptosis out of 470 cases of orbital disease. The patients generally come late for treatment for various reasons. The patients have to travel long distances for specialised medical care and even to the nearest health centre. The education of the population is a significant factor. Health education does not reach the public adequately. The lack of health education contributes to absconding from the hospital once the patient is admitted. Consequently, defaulting from treatment is a major reason for the high mortality in cases of retinoblastoma. The follow-up of patients is very poor, making the assessment of mortality, prognosis and cure-rates difficult. A large section of the population primarily seeks treatment of their ills initially from the herbalist, the practitioner of native
Rd,,al,t;i;(’
9. Paediatric
orbital
disease
Orbital disease in children in Kenya m order of frequency) (195 cases) Total
Burkitt’s Lymphoma Infective processes Leukemia (chloroma) Idiopathic inflammatory Trauma Hydatid cyst Rhabdomvosarcoma Graves’ disease Miscellaneous
~~~~~~~~ ~~~ ~~~
pseudotumor
REFERENCES
Hogan M. J. and Zimmerman L. E. Ophthalmic Purhology. W. B. Saunders, Philadelphia, 1962. 2. Reese A. B. Tumors of the Eye, Third Edition, pp. 89-123, 125-132. Harper & Row, New York, 1976. 3. BenEzra D. and Chirambo M. C. Incidence of retinoblastoma in Malawi. J. Pediut. Ophrhul. 13, 340-343, I.
1976. 4.
5.
CONCLUSION
Table
systems of healing. The traditional doctor attempts to diagnose and treat conditions such as retinoblastoma and, on the failure of his management, the patients then seek medical attention when the disease has progressed beyond control. We have to resort, for example, to orbital exenteration in rhabdomyosarcoma initially unlike Western centres reporting 80% success with chemotherapy and radiotherapy alone. Finally, only a few of those with established diagnosis benefit from specific therapy because of shortage of drugs, the cost of which may be prohibitive. The therapeutic regimens are thus interrupted or even stopped, and this leads to great difficulties in checking certain disease processes. Relapse rates are consequently high and median survivals short. This multitude of factors contribute to the different mode and extent of presentation of oculo-orbital disease in Africa as compared with the Western world.
~~~-T-_* 43 32 18 9 4 4 4 2 11
22.0 16.4 9.2 4.6 2 2 2 I 5.6
6. I. 8.
Oyin 0. and William A. 0. Orbito-ocular tumors in Nigeria. Cancer 30, 580-587, 1972. Malik M. 0. A. and Sheikh E. H. Tumors of the eye and adnexa in the Sudan. Cancer 44, 293-303, 1979. Klauss V.. Chana H. and Khan F. Retinoblastoma in Kenyatta National Hospital, Nairobi. Fortsch. Ophthul. In press. Bhimani M. H. Retinoblastoma in Kenya-a five-year survey of cases admitted in K.N.H. E. Afr. med. J. 50, 310-316, 1973. Pendergrass T. W. and Da& S. Incidence of retinoblastoma in the U.S. Archs Ophthul. 98, 1204-1210, 1980.
9. Sinniah D., Narasimha G. and Prathap K. Advanced retinoblastoma 819-284,
1980.
in Malaysian children. Acra Ophrhul. 58,
10. Balmer A. and Gailloud C. Le retinoblastome, une tumeur curable. Klin. Mbl. Auaenheilk. 178. 323-325. 1981.
11. Bisley G. G. A Handbook of Ophthalmology for Developing Counrries, DR. 75-76. Oxford Universitv Press. London, 1980. _. 12. Templeton A. C. Tumors of the eye and adnexa in Africans of Uganda. Cancer 20, 16891698, 1967. 13. Miller B., Abraham C., Cole G. C. C. and Proctor N. S. P. Ocular malignant melanoma in South African blacks. Er. J. Ophrhul. 65, 720-722, 1981. 14. Quere M. A. and Lambert D. Zur Pathologie der Orbitookularen Tumoren im tropischen Afrika. Klin. Mbl. Augenheilk. 144, 829-840, 1964. IS. Awan A. M. and Shah A. K. Orbito-ocular tumors in Kenya Africans. E. Afr. J. Ophrhul. 4, I-37. 1980. 16. Illif C. E. Tumors of the orbit. Trans. Am. Ophrhul. Sot. 55, 505, 1957.
17. Templeton A. C. Orbital tumors in African children. Er. J. Ophrhul. 55. 254, 1971. 18. Van’Salem J. L. Proptosis in paediatrics. S. A,fr. med. J. 662, 1980.
19. Duane T. D. Rhubdomvosurcomu: Clinical Ophrhuimolog),, Vol. 2, Chap. 43, pp. 2. Harper & Row, New York, 1980.
1750
VOLKERKLAUSSand HARJINDERS. CHANA
20. Klauss V. and Chana H. S. Orbital tumors in Kenya children. Proceedings Association of Surgeons of Easf Africa. In press. 21. Knowles D. M. and Jakoiec F. A. Rhabdomyosarcoma of the orbit. Am. J. Ophthai. 80, 1011, 1975. 22. Heyn R. M., Holland R., Newton W. A. et al. The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. Cancer 34, 2128, 1974. 23. Reese A. B. Expanding lesions of the orbit: Bowman Lecture. Trans. Ophrhal. Sot. 91, 85. 1971. 24. AMREF (African Medical and Research Foundation). Fifth Annual Progress Report. Studies on the Epidemiology and Treatment of Hydatid Disease in the Turkana District of Kenya, 1981. 25. Silva D. Orbital tumors. Am. J. Ophthaf. 65, 318, 1968. 26. Simons M. J., Chana H. S., Wee G. B., Shanmugratnam K., Goh E. H., Chan J. C. W., Darmalingam S., Prasad V., Betuel G., Day N. E. and de The G. Naropharyngeal Carcinoma and Control (Edited by de The G. and Ito Y.), pp. 271-282. IARC Lyon, France 1978. 27. Prasad V. Cancer of the nasopharynx. A clinical analysis with anatomico-pathological orientation. JI R. COIL Surg. Edin. 17, 108, 1972.
28. Clifford P. Malignant disease of the nose, paranasal sinuses and post-nasal space in East Africa. J. Laryng. 75, 707-733,
1961.
29. Sawaki S., Sugano H. and Hiaryama T. Analytical aspects of symptoms of nasopharyngeal malignancy. IARC Scientific Publication No. 20, pp. 147-163, 1978.
30. Ho H. C. The natural history and treatment of NPC oncology. Proceedings af the X International Cancer Congress, Vol. 4, pp. 1-14. Chicago Year Book Medical
Publishers, Chicago, pp. l-14.
-
31. Clifford P. Further studies in the treatment of Burkitt’s Lymphoma. E. Afr. med. J. 180-199. 1966. 32. Klein G., Clifford P.. Klein F. er al. Membrane
immunofluorescence
reaction of Burkitt’s Lymphoma.
J. natn Cancer Inst. 30, 1027, 1967. 33. O’Connor G. T. Persistent immunologic stimulation as
a factor in oncogenesis with special reference to Burkitt’s Lvmohoma. Am. J. Med. 40. 279. 1970. 34. McMoh T. E.. Ogunmekan A. 0. and Ojunjo E. 0. Orbital Burkitt’s Tumor presented as advanced Retinoblastoma. J. Paediat. Ophthal. 17, 147. 35. Khan A. G. The multifocal lymphoma syndrome in African Children in Kenya. J. Larnyng. 74, 480, 1964. 36. Rupani H. Jaw tumors. Thesis, University of Nairobi,
1977. 37. Kasili E. M. Med. Thesis, University of Nairobi, 1979. 38. Trowel H. C. Non-Infectke Diseases in Africa. Church-
ill, London, 1960. 39. Crawford J. S. Diseases of the orbit. Toronto
Hospital for Sick Children. Chicago Year Book, 1967. 40. Youseffi B. Orbital tumors in children: a clinical study of 62 cases. J. Paediat. Ophthal. 6, 177. 1969. 41. Porterfield J. F. Orbital tumors in children: a report on 214 cases. Int. Ophthal. Clin. 2, 319, 1962.
Sot. Sci. Med.
Vol. 17. No. 22. pp. 1743.-1750.1983 Printed in Great Britain
OCULAR
TUMORS
IN AFRICA
VOLKER KLAUSS’ and HARJINDER S. CHANA’ ‘Department of Surgery, Faculty of Medicine, University of Nairobi, P.O. Box 30588, Nairobi and 2Central Province Kenya, P.O. Box 1323, Nyeri, Kenya
Abstract-This paper is an analysis of 470 cases of oculo-orbital tumors in Kenya. The present series is compared with the major works conducted in other African and Western countries. We refer to age, sex and geographic characteristics and prevalence of tumors in different populations and stress the differences found. The major emphasis is on retinoblastoma, Burkitt’s lymphoma and nasopharyngeal carcinoma. Orbital Hydatidosis is included as a differential diagnosis of unilateral propotosis. Considering all the reviews, retinoblastoma is reported in high numbers in African countries whereas uveal melanoma is extremely rare. Among the tumors of the lids and conjunctiva, squamous cell carcinoma occurs more frequently than in Caucasians. Besides retinoblastoma infiltracting the orbit, Burkitt’s lymphoma is the most common orbital tumor. nasopharyngeal carcinoma in Kenya has the third highest incidence in the world. Proptosis is the hallmark of orbital disease and is the commonest manifestation sign at first attendance, a fact which validates the late presentation of most of our patients. The difficulties encountered in early diagnosis and hence the appropriate management are discussed and in concluding remarks some recommendation are made.
INTRODUCTION
Thinking in terms of numbers of affected patients, ocular tumors in Africa are not as important as the major blinding diseases: cataract, trachoma and glaucoma. But because many ocular tumors threaten the patient’s life, it is justifiable to discuss them among Africa’s important ocular diseases. The topic is subdivided into 3 sections: (A) intraocular tumors (B) tumors of lids, lacrimal system and conjunctiva (C) orbital tumors
INTRAOCULAR TUMORS
Reviewing the literature on intraocular tumors in Africa only two have been mentioned: retinoblastoma and melanoma of the choroid. This fact is surprising as there is a long list of benign and malignant intraocular tumors that have been described elsewhere [I]. There is no reason to assume that these diseases do not occur among Africans, but they may not have been reported because of lack of ocular pathologists or lack of time by ophthalmologists in Africa. Retinoblastoma
Retinoblastoma is the commonest intraocular tumor in childhood throughout the world. The disease has been extensively studied in Europe and U.S.A. for its epidemiology, prevalence, genetics, symptoms, diagnosis, therapy and histologic characteristics. But only few reports are available from African countries. Incidence. heredity, and laterality. The incidence figures vary between 1 per 14,000 births in Holland and 1 per 23.000 births in Michigan [2]. BenEzra [3] reports an annual incidence in Malawi of 2 cases per 100.000 children under 5, or 1 case per
10,000 live births. As in all other studies these are hospital figures which cannot present the true picture;
there is an unknown number of retinoblastoma children who are never seen or treated by an ophthalmologist. Olurin [4] found in a series of 191 oculaorbital tumors in Nigeria that 64 (34%) were retinoblastomas. Malik [5] reports from Sudan that out of 279 malignant tumors of eye and adnexa, 57 (20.4%) were retinoblastomas. Jn our own series of 73 retinoblastomas seen at Kenyatta National Hospital in Nairobi over a 54 month period, we found an incidence rate of 1: 18.750 live births [6]. This figure is certainly far too low as these are hospital data, not population-based data. Also there are six provincial ophthalmologists working outside Nairobi who treat retinoblastoma; an attempt failed to have all retinoblastoma cases treated in provincial hospitals recorded. We cannot answer the questions if retinoblastoma occurs more frequently among African than among European children, but all figures’ available indicate that the tumor is not less frequent in Africa. We could expect that retinoblastoma is less frequent than in Europe as there are no inherited cases, because in previous generations treatment was not available and all patients with retinoblastoma died before the age of reproduction. In statistics from outside Africa the percentage of familiar cases is 10% as compared to 90% for sporadic cases (Kitchin quoted by Reese [2]. Among our 73 cases we found only one family where retinoblastoma was possibly inherited. BenEzra [3] reports one familiar case out of 48 in his study from Malawi. Though heredity can be almost totally excluded in African retinoblastoma patients today, it is surprising to find a high number of bilateral cases. Ixi our series 26 out of 73 patients had bilateral retinoblastoma (35.6% [6]. In Malawi [3] 25% were bilateral, in the Nigerian [4] and Sudanese
1744
VOLKER KLAUSS and HARJINDER S. CHANA
[5] studies the laterality is not recorded. In the U.S.A. 25% of cases are to be bilateral [2]. Sex distribution. In our series from Kenya 39 patients out of 73 were females, 34 males. In Malawi [3] 27 out of 48 were females. In Nigeria [4] 38 out of 64 were females. In an earlier study from Kenya (1967-1972) Bhimani [7] found 27 males among a total of 45 cases. Pendergrass [8] found a ratio of boys to girls as 1.12: 1. We can conclude out of these figures that there is no sex preference for retinoblastoma in Africa. Age. The average age at first diagnosis is reported to be high in Africa. Olurin [4]: 3.2 years; BenEzra [3]: 2-3 years; Klauss [6]: 2.53 years as compared to Reese [2], U.S.A. 1.5 years. A report from Malaysia [9] gives an average age of 2.5 years and thus resembles the African findings. The age range in our study is 4 months to 6 years. In one extraordinary case that we observed the first eye was enucleated at age 8 months, the second eye was found to have a retinoblastoma when the child was 6 years old. There are several explanations for the higher age in African children like lack of diagnostic facilities. Also, 5 parents in our study admitted to have consulted a traditional doctor which meant the loss of a precious 2-6 months. BenEzra [3] estimates that in Malawi 25% of eye patients seek the advice of a traditional healer before coming to a government hospital. Thus it is not surprising that our patients are seen by an ophthalmologist an average of 3.5 months after the first symptom was detected [6]. Another reason for the late age of first treatment may be that the vast majority of cases in Africa are sporadic. In Balmer’s [lo] statistic from Lausanne the average age of first symptom was 7 months in bilateral, inherited cases and 25 months in unilateral, sporadic cases. It appears that bilateral tumors occur earlier in life. Also parents in retinoblastoma families are more aware of the problem than the general population, which may lead to earlier diagnosis. First symptom. BenEzra (Malawi) [3] reports that leucocoria was the first symptom in 70% of the cases, inflammation of the involved eye in 30%. This compares with our findings where leucocoria was the first symptom in 65% of patients, a painful red eye in 32%. Treatment. In our hospital we can do photocoagulation, cryotherapy, radiation and chemotherapy besides surgery. Again this is an exceptional situation for an African Hospital. Ophthalmologists in smaller hospitals can do surgery only. In 8 of our 73 patients we observed a recurrence after enucleation although the histologist had not reported any extraocular growth. After this experience we routinely radiate the orbit after enucleation with 4.500 rad. Table
I.
Comparison
of frequencies
of lid
Kenya
Uganda
Awan
Templeton
Out of 99 affected eyes in our series 75 had to be enucleated, and in a further 10 cases an exenteration of the orbit was done. In 9 cases (12Y$ the patients refused enucleation. Three eyes could be preserved through photocoagulation and cryotherapy. We did not admit 2 children because they were in a terminal state at the time of initial presentation. We know of 8 deaths (1 l”/@among our 73 patients, but the figure is certainly much higher. Bhimani reports the mortality rate in his series as being 9Y0 (assuming that patients who failed to attend for follow up died). Melanoma of the choroid
Melanoma of the choroid is the commonest intraocular malignancy in man [l]. This statement appears to be true only for Caucasians as a review of African literature shows. Bisley [l 1] did not see a single case in Kenyan Africans over 30 years. We can add to this experience as we have not seen one case in 4 years. Also Templeton [ 121in Uganda does not report on any case out of 312 orbito-ocular tumors. Miller [ 131 has observed 8 cases of primary ocular malignant melanoma in Africans in Transvaal over 25 years, but only one of them had a uveal melanoma, four among the others arose from the conjunctiva and three from the orbit. Over the same period of time he found 153 cases of primary ocular malignant melanomas in whites. Hogan and Zimmermann [ 1] give a ratio of 175 : 1 between Caucasians and non-caucasions for malignant melanoma of the choroid in the U.S.A. Olurin [4] from Nigeria reports on two patients with choroidal melanoma out of 191 cases with orbito-ocular tumors. In a series from Dakar/Senegal 2 cases were seen among 195 orbito-ocular tumors [14]. Malik (Sudan) [5] found 6 intraocular malignant melanomas but they all occurred in the Arab population and none in ‘black Africans. From these figures we can conclude that malignant choroidal melanoma occurs only exceptionally in Africans. No conclusive explanation has been given for this finding. Miller [ 131 quotes Boniuk and suggests “that there is a genetically determined resistance of the Negro to ocular melanoma”. TUMORS OF LIDS, LACRIMAL SYSTEM, CONJUNCTIVA
Lid tumors
One fact becomes obvious from a consideration of lid tumors in Africa: basal cell carcinoma is very rare or non existent among Africans (Table 1). (All cases from Sudan were observed in non-Africans.) It is generally accepted that basal cell carcinoma is comtumors
(all
orbito-ocular Sudan
Nigeria
Malik
tumors
= 1009/,)
Baltimore lllif
[I51
WI
[41
[51
[I61
279
375
No. of cases 1487
312
191
Basal cell carcinoma
(Total)
0
0
0
Squamous cell carcinoma
4
3
1.5
7
2.0
Pap
1.2
1.0
0.5
0
11.0
illoma
6.1
9.0
Ocular Table
2. Comparison
Tumor Squamous cells carcinoma Mal. Mel.
of series of conjunctival
tumors
tumors
from dilferent
system
countries
tumors = IOOY,,)
(all orbito-ocular
Kenya [15] (1487 cases)
Uganda [ 121 (312 cases)
Nigeria (41 ( I91 cases)
Senegal [ 141 (195 cases)
Sudan (51 (279 cases)
21.x 0.7
16.0 0.3
6.2 1.6
22.0
50.5 0.7
mon in skin unprotected by pigment against sunlight, but does not--or very rarely-occur in pigmented skin. The incidence varies inversely with the degree of skin pigmentation [S]. It is surprising that Awan [l5] does not report a single case of squamous cell carcinoma out of 1487 tumors seen in Kenya but we believe that the 4 cases in his series termed as ‘Xeroderma pigmentosum malignant’ were in fact squamous cell carcinomas. We have treated three patients in Nairobi over the last four years. With exception of the Nigerian [4] study all others from Africa give a higher incidence of squamous cell carcinoma of the lids than in Baltimore [ 161. Lacrimal
1745
in Africa
tumors
The data available on lacrimal gland and lacrimal sac tumors are too scarce to allow any specific conclusions. Awan [15] reports 4 (0.3%) benign and 19 (1.3”,/,) malignant mixed and carcinomatous lacrimal gland tumors in Kenya out of 1487 orbitoocular tumors. Olurin (Nigeria) describes 5 pleomorphic adenomas (2.6%) I fibroma (0.5%) and 1 adenoid cystic carcinoma (0.5%) among I91 orbitoocular tumors. Malik (Sudan) [5] records 8 lacrimal gland (2.97;) adenocarcinomas among 279 malignant tumors of eye and adnexa. Templeton [I21 has found I7 (5.4%) lacrimal gland tumors in his series of 312 orbito-ocular tumors, but he does not specify the histological type. No case of melanoma of the lacrimal sac has been reported in the available literature.
(a) Ultraviolet light. (b) Dry air, wind. dust, trachoma and vernal catarrh are all factors that contribute to chronic irritation of the conjunctiva and which may facilitate the development of a carcinoma. All these factors are common in Africa. (c) Race and skin colour: It is still undetermined if race or degree of pigmentation are of any importance. In Malik’s study [5] the tumor was more common in people from northern Sudan with a lighter skin colour. Though we still need more information it is apparent that Africans are not protected against squamous cell carcinoma of the conjunctiva as they are against the basal cell carcinoma of the lids.
2
Malignant conjunctiva occurs at a comparable outside Africa (see Table 2). Miller conjunctival melanomas out of 8 melanomas in South Africa.
Malignant melanoma of the conjunctiva.
melanoma of the rate to countries [I 31 mentions 4 ocular malignant
ORBITAL
TUMORS
Orbital disease is rare. Comprehensive studies in the African patient have been carried out in Uganda [12, 171, Nigeria [4], Sudan [5] and among South African blacks in Johannesburg [ 131 and Cape Town [l81. Our series is an integrated prospective and retrospective study of 470 patients with orbital disease. All the patients in this study are from Kenyatta National Hospital, Nairobi. Most of the patients were followed up in the outpatient department in the Eye Unit though some were hospitalized when necessary. This integrated study establishes the major causes of proptosis in a referral hospital in Kenya. A general survey of orbital disease is presented with spedal emphasis on prevalent tropical diseases such as Hydatidosis and the Burkitt’s Lymphoma. The present series of 470 cases is broken down by diagnosis in Table 4 (see Table 3). Table
3. Causes
of proptosis Present series [26] 1982 [27] 470 Cases Number
Cortjunctiva/tumors Squamous cell carcinoma. Looking at figures from different African countries the incidence of squamous cell carcinoma of the conjunctiva is striking (Table 2). Templeton [12] concludes that this tumor is more common in tropical Africa than in other parts of the world. The following etiological factors have been mentioned to explain the high prevalence of conjunctival carcinoma in Africa:
U.S.A. [Ih] (Baltimore 375 cases)
Retinoblastoma infective processes: Orbital cellulitis Panophthalmitis Endophthalmitis Rhinogenic carcinoma Endocrine ophthalmopathy Burkitt’s Lymphoma Pseudotumor Mucoceles Malignant lymphoma and leukemia (chloroma) Miscellaneous Carcinoma of palpebral region t_acrimal gland tumors Carcinoma of epibulbar region Post-traumatic retrobulbar Hematoma Hydatidosis Haemangioma Rhabdomyosarcoma Dermoid cysts Meningioma Malignant melanoma Craniofacial dysostosis Glioma of optic nerve Metastatic carcinoma UnditTerentiated sarcoma Osteoma Exophthalmos of unknown origin
“‘,
73 70
5.5 14.9
66 51 43 29 21
14.0 10.9 9.2 6.2 4.5
18 17 11 9 9
3.8 3.6 2.3 1.9 1.9
9 9 8 5 4 4 4 3 2
1.9 1.9 1.7 1.1 0.9 0.9 0.9 0.6 0.4 0.2 0.2 0.2 0.2
I 1 1 1
VOLKER KLAIJSS and HARJINDER S. CHANA
1746
Table 4. Primary orbital disease age (at first attendance and sex) Max. Number Rhabdomyosarcoma Optic nerve glioma Hamartoma Lipoma Hydatid Pseudotumor
A detailed analysis is presented mentioned Kenyan data: (1) (2) (3) (4)
5 2
I 1 9 29
(of270) ______. 1.1 0.4 0.2 0.2 1.9 6.2
of the afore-
Primary disease Secondary disease Systemic disease Paediatric orbital disease.
Primary orbital disease Rhabdomyosarcoma.
Rhabdomyosarcoma (see Table 4) is a highly malignant tumor usually arising from rests of striated muscle and characteristically presenting as rapidly increasing proptosis. Death occurs either through direct extension or metastatsis. It is the commonest primary malignant tumor in children in certain series. The average age of our rhabdomyosarcoma patients at first presentation is 11.2 years which is higher than that stated in literature (Duane 7.8 years) [19]. With only five cases in our series, this age structure may not be significant [20]. However, it does signify the delayed and neglected presentation at first attendance. Reports of rhabdomysarcoma in non-whites in the western countries are rare. Knowles [21] interpreted this disproportion socioeconomic factors governing diagnosis and treatment rather than true predilection of orbital rhabdomyosarcoma for whites. All the patients were treated with radiation and cytostatic therapy after the exenteration of the orbit. Evidence has accumulated that radiation therapy alone (or combined with chemotherapy) can be successfully employed against this tumor with a cure rate of 80% [22]. However, we have resorted to surgery in addition because of the very advanced stage of the disease, and the fact that the eyes are destroyed when the patients are first seen. Idiopathic inflammatory pseudotumors. Reese [23] reported pseudotumor (see Table 4) as the most common cause of unilateral proptosis in adults. Whereas Illif [16] found 3.4% of his cases with pseudotumor, the present series shows 6.2%. The average age of presentation was 17 years with the youngest patient manifesting the condition at 7 years. The commonest signs were proptosis and chemosis. Diminished visual acuity was found in 9 cases (31%). The visual acuity improved and proptosis regressed with steroid therapy. Surgery was not done in any of the cases. Echinococcus cyst. This disease is prevalent in Turkana District in North Kenya where the highest prevalence in the world has been documented [24]. Nine cases were seen at Kenyatta National Hospital (see Table 4). All had unilateral proptosis, the minimum age was 6 years and the maximum 25 years. It
age (Yr) 13 25 35 35 35
Min. age ._~(Y0 7 18 4 29 6 7
Average age (Yr)
Male
10.2 21.5 32.0 18.8 17.0
3
Female
Total
2 ,
5 2
I I
I
I ’
’ 9
7 20
9 29
has been documented that the prevalence in Turkana is highest in the world, being three times as high as the nearest country. Data of the prevalence in Kenya was obtained from the African Medical Research and Education Foundation (AMREF) [24] and the orbital hydatidosis cases presented in Kenyatta National Hospital are reviewed. Epidemiology
At present there are some 100,000 Turkana occupied in traditional nomadic herding while the remaining 80,000 are occupied in fisheries, irrigation or urban development around Lodwar. In addition. about 30,000 have emigrated to other parts of Kenya. There is a ten-fold difference from around 200 cases of hyatid disease per 100,000 per annum in the North West part of Turkana District to less than 20 cases per 100,000 per annum in the South. Of the total of 516 hydatid disease cases in the AMREF study, 19.2% were under age 10 years, 78.9% were age 30 and under and only 6.2:/, were over age 40. 34.3% were males and 65.7”,/, were females, a sex ratio of 1 : 1.9. In most cases only one member of a family was affected. This may be due to separation of the members of the family in order to cater for the differing needs of livestock at different parts of the year. Additionally, it has been observed that the specially trained pet dogs are very much attached to a single person. The duration of the disease at the time of presentation averaged 3 years, and is the same for the interval between treatment and reporting a recurrence. Location of cysts 70-80% of the cysts were intra-abdominal. In, the orbit, they usually appear in the superior nasal quadrant in or about the muscular cone. Proptosis, and sometimes pain, are the classical manifestations of a fully developed cyst. Exposure keratitis due to extreme protrusion of the eyeball, and other evidence of pressure of an orbital mass, such as papilloedema. are occasionally noticed. Recurrence
Recurrence means: (a) A cyst or daughter cysts grow in the cavity left by the original cyst. (b) A cyst grows in the surgical scar. (c) In the case of intra-abdominal cysts, one or more mesentaric cysts develop post-operatively. The Recurrence rate is about 28%.
Ocular tumors in Africa Table 5. Processes secondary
Diagnosis Retinoblastoma Lid and conj. tumor Lacrimal gland tumor Carcinoma nasopharynx Meningioma Encephalocele Malignant melanoma MUCOC&
Hydatid
in orbit from adjacent structures (age in years at first attendance)
NO. total 73 23 9 66 4
I 4 21
(0f?70) - 15.5 4.9 I .9 14 0.Y 0.2 0.9 4.5
cycle
This is a disease of animals and humans. It is caused by two species of dog tapeworm, Echinococcus granulosus and Echinococcus multilocularis. The life cycle of these are similar and occur in two stages: Stage I: The adult tapeworm, which is about i in. long, lives in the intestine of the dog (or other carnivorous animals, chiefly the hyena). These tapeworms produce thousands of eggs which contaminate the ground, the water and the dog’s fur as well. Humans become infected by stroking their pet dogs or by touching objects contaminated by dog faeces. Stage 2: After the eggs are consumed by humans or herbivorous animals, they hatch in the intestine and become larvae and spread through the blood stream to any part of the body, and develop into cysts. Investigations
Four diagnostic
tests are available:
(a) (b) (c) (d)
Stool and urine. Immunoelectrophoresis test. Casoni’s skin test. Histology: demonstration of a unilocular cyst to Echinococcus granulosus and the contents of the cyst. Hydatid disease occurs in every country in the world. To date only Iceland has eradicated the disease. As a disease of domestic animals, it causes an enormous reduction in the yield of meat and milk. Secondary
orbital disease
Retinoblastoma is the most common intraocular tumor in childhood. Orbital extension of retinoblastoma is very common in our series because of the very late presentation, 72% of the patients manifesting proptosis when first seen (see Table 5). The unusually high incidence of retinoblastoma with orbital extension, 20 out of 65 cases (310,) in the Silva [25] study, can be explained by the fact that Silva reviewed only children referred for radiotherapy and/or chemotherapy in the oncology clinic. Similar reasoning, however, can be applied to our hospital, the radiotherapy unit of which caters for the East and Central Africa [6]. A detailed discussion on retinoblastoma is presented in the previous chapter. Carcinoma qf the naso-pharlwx (NPC). The relative frequency (third highest ‘in the world next to Retinoblastoma.
China and Malaysia and the highest in Africa). the histopathological features (the majority were anaplastic) and a more advanced stage of the disease at
Max. age 10 60 80 82 62 60 69
Min. age 4.12 18 25 12 13 0.5 41 12
Average age 2.53 36.4 46.6 42.6 36.7 48.0 39. I
Male
%
Female
34 10 6 53 3 1 1 9
47 44 67 80 75 100 25 43
39 13 3 13
I 3 12
% 53 56 33 20 25 75 57
first attendance makes it a significant disease entity in our series. The aetiological factors implicated are of genetic, viral and chemical origin. Consistently high titres of Epstein-Barr-related antigens occur in NPC. Genetic factors determine the susceptibility to the disease. HLA haplotypes AZ-Bsm 2, Bw 17-AW 19 and BW 17-Ablank have been shown to be implicated in NPC (in studies by Simons et al. [26]). Prasad [27] has done a clinical analysis and his results are as presented in Table 6. In a series by Clifford [28] 68% of his 61 cases presented with ophthalmological manifestations which included blindness, diplopia and proptosis. Sawaki [29] in his classical analysis of 766 cases of NPC showed only 7% ophthalmic involvement with dysfunction of extraocular muscle movements, ophthalmoplegia and disturbance of visual acuity due to the bony distruction of the optic canal, but no case of proptosis was cited. In the present series (see Table S), 232 cases of NPC over a period of three years are reviewed. 28.5% of these presented with mild to severe proptosis; the disease was well advanced when the patients first consulted the ophthalmologist. The following is our analytical data: Youngest patient Oldest patient Average age
12 years 82 years at first attendance 41.9 years 1
Male: female ratio 4: 1 (as compared to M: F 2.7: 1 which is relatively constant in the world). That the orbit is involved relatively late in the disease process, is evident from the proposed classification adapted from Ho [30] (it is based on the primary tumor, cervical lymph nodes and the haematogenous metastasis): Tl Tumor confined to nasopharyngeal or no tumor visible, but biopsy positive. Table 6. Geographical
Nation I. 2. 3. 4. 5. 6. 7. 8. 9. 10. II. 12.
Canada China (Canton) Hong Kong India Indonesia Japan Kenya Malaysia/Singapore Scandinavia Taiwan U.K. U.S.A.
distribution % Head and neck malignancy NA 56.9 NA NA NA NA 25.5 NA NA NA 2.0 2.0
mucosa,
of NPC % all malignancy 0.3 NA 18.0 0.5 13.9 0.1 NA 13.2 0.4 21.0 1.3 0.3
1748
VOLKER KLAUS and HARJINDERS. CHANA
T2 Tumor extended to the nasal fossa, oropharynx or adjacent muscles or nerves below the base of the skull. T3 Tumor extended beyond T2 limits and subclassified as follows: T3a: Bone involvement below the base of the skull (floor of the sphenoid sinus is included in this category.). T3b: Involvement of the base of the skull. T3c: Involvement of the cranial nerve(s). T3d: INVOLVEMENT OF THE ORBIT, laryngopharynx (hypopharynx), or infra temporal fossa. 28.5% of our patients presented with T3c and T3d staging at first attendance. Mucoceles. Mucoceles involving the ethmoidal and frontal sinuses may project into the orbit. A frontal mucocele usually presents under the superior orbital rim and displaces the globe downwards and outwards rather than forwards. The ethmoidal mucocele causes a lateral proptosis. The mass is not invasive but space-occupying and hence the symptomatology is indicative of pressure and interference in the motion of the eyeball. Painless proptosis is the first sign. Ultrasonography and X-ray provide diagnostic aids. In our series, 21 cases are presented (see Table 5). The ethmoidal mucocele was common in children and the frontal in the adults. Generally, the ratio of ethmoidal to frontal mucocele was 1:9. AN mucoceles presented with proptosis. Whereas proptosis is the earlier sign in mucocele, it was a later one in the carcinoma of nasopharyngeal space. All cases were treated surgically. Systemic disease affcting
the orbit
Burkitt’s Lymphoma.
Burkitt’s Lymphoma is the commonest childhood tumor in tropical Africa where malaria is endemic. Clifford first recognized this condition in Kenya in 1961 [31]. A suggestion has been made that persistent immunological stimulation by malarial infection and consequent lymphoreticular hyperplasia may be important factors in the development of this malignancy. Circumstantial evidence is accumulating in favour of linking this condition with Epstein-Barr Virus (EBV). Burkitt’s cells harbour virus particles and many investigators feel .that EBV may be the first proven human cancer virus as suggested by Klein and Clifford [32]. EBV is also felt to be the aetiological agent in infectious mononucleosis and the anti-EBV antibody observed in mononucleosis is identical to that found in patients with Burkitt’s Lymphoma [33]. The tumor involving the maxilla is the commonest presentation. Involvement of the antero-ethimoidal Table 7. Systematic
diseases
with
area may cause gross proptosis and thus may be confused with a retinoblastoma [34]. Ninety-two cases of Burkitt’s Lymphoma involving only the jaw were selected for this study (see Table 7). 42 (469;) of these presented with ophthalmological signs. 51 (55%) were males and 41 (45”J were females. The average age at initial presentation was 7.25 years, ranging from 1.25 to 17. Detailed accounts of Burkitt’s Lymphoma in Kenya were documented by Khan in 1964 [35] and by Rupani in 1977 [36]. Leukemia. Kasili [37] has done a preliminary study of the various aspects of leukemia in the Kenyan community. Factors which may contribute to the high frequency of myeloid leukemia (twice as prevalent as the lymphocytic types) such as the background terrestrial and solar radiation, medicinal herbs, agricultural insecticides, the high carrier rate of HbSAg and the relevance of genetic markers have been examined. Immunogenetic marker studies of African population afflicted by leukemia, as well as in vitro studies of the leukemia cell growth kinetics, are being carried out to establish whether the very advanced stage of disease at presentation is due to lateness on the part of those seeking medical advice or whether the disease is generally more aggressive than in Caucasians. Chloromas were documented in 14 cases of acute myeloblastic and myelomonocytic leukemia and in 2 cases of chronic granulocytic leukemia (see Table 7). This shows a frequency of 10% chloroma in acute myelogenous leukemia. Thirteen were orbital tumors and commonly presented with asymmetrical, bilateral proptosis. Only one case occurred in an adult (male. 25 years). The rest occurred in children, a frequency of chloromatous tumors in children with AML of 23%. Grave’s Disease. In Kenya, thyrotoxicosis in early literature was documented as a rare entity by Trowel [38]. Exophthalmos is present both in Graves’ Disease and in Hashimoto’s Disease. The current thinking is that the thyroid auto-immune diseases are a spectrum with Graves’ on one hand and Hashimoto’s on the other. Ophthalmopathy of Graves’ is usually not severe in Kenya but 10% required sympatholytic eye drops and 2 cases (2.57;) were advised to have tarsorraphy because of exposure keratitis. In our series, the following ophthalmological findings were noted (see Table 8): Number of cases reviewed = 82 Male: female ratio = 1 : 4.7 Mean age (at first presentation) = 32.4 years. Paediatric orbital disease
The largest series dealing with childhood
orbital
manifestation
by age and
sex
0, Diagnosis Burkitt’s
Lymphoma
Lymphosarcoma Hodgkin’s Leukemia
and
Plasmacytoma Neurofibroma Hyperthyroldism
lymphoma
Number
(of ‘i70)
43
9.2
I
0.2
I
0.2
I6
3.4
I
0.2
Max. 17
Min. 1.25
Average 7.25 30.0
3.12
3
0.6
8
51
10.9
9
Male 24
36.0
I
5.2
6
_
30.0
I
0.3
19
I
25.0
60.0
F.Xl&
4.4
3
32.4
9
IO
42
diseases
I749
Ocular tumors in Africa Table 8. Graves’
Disease: Infiltrative ophthalmopathy ber of cases = 82)
(total
num%
72 5 51 34 24 24 20 17 17
Stare/lid lag Lid retraction Exophthalmos Lateral rectus injection Irntation Red lids Blurred vision Chemosis Tearing
87.5 6.5 62.5 41.7 29.2 29.2 25.0 20.7 20.7
of the orbit are from the Toronto Hospital for Sick Children (257 cases) [39], Children’s Hospital in Washington, DC (61 cases-Youseffi) [40] and by Porterfield (214 cases) [41]. The series of Templeton [ 171 on orbital tumors in African children (conducted in Uganda) analyses 60 cases. The largest single cause in the Toronto study was inflammatory disease (30%) followed by the combination of metabolic and general systemic disease (21%). As mentioned earlier, the frequency of 23% chloromatous tumours in children with Acute Myeloblastic Leukemia is very high when compared with the Western population (see Table 9). Its high frequency is an expression of the frequency of acute myeloblastic leukemia in Africa. Most series indicate a higher prevalence of metastatic lesions to the orbit, such as neuroblastoma and Ewing’s sarcoma.
Proptosis is the hallmark and the main presenting sign of orbital disease and this is validated by the present study with 410 cases of mild to severe proptosis out of 470 cases of orbital disease. The patients generally come late for treatment for various reasons. The patients have to travel long distances for specialised medical care and even to the nearest health centre. The education of the population is a significant factor. Health education does not reach the public adequately. The lack of health education contributes to absconding from the hospital once the patient is admitted. Consequently, defaulting from treatment is a major reason for the high mortality in cases of retinoblastoma. The follow-up of patients is very poor, making the assessment of mortality, prognosis and cure-rates difficult. A large section of the population primarily seeks treatment of their ills initially from the herbalist, the practitioner of native
Rd,,al,t;i;(’
9. Paediatric
orbital
disease
Orbital disease in children in Kenya m order of frequency) (195 cases) Total
Burkitt’s Lymphoma Infective processes Leukemia (chloroma) Idiopathic inflammatory Trauma Hydatid cyst Rhabdomvosarcoma Graves’ disease Miscellaneous
~~~~~~~~ ~~~ ~~~
pseudotumor
REFERENCES
Hogan M. J. and Zimmerman L. E. Ophthalmic Purhology. W. B. Saunders, Philadelphia, 1962. 2. Reese A. B. Tumors of the Eye, Third Edition, pp. 89-123, 125-132. Harper & Row, New York, 1976. 3. BenEzra D. and Chirambo M. C. Incidence of retinoblastoma in Malawi. J. Pediut. Ophrhul. 13, 340-343, I.
1976. 4.
5.
CONCLUSION
Table
systems of healing. The traditional doctor attempts to diagnose and treat conditions such as retinoblastoma and, on the failure of his management, the patients then seek medical attention when the disease has progressed beyond control. We have to resort, for example, to orbital exenteration in rhabdomyosarcoma initially unlike Western centres reporting 80% success with chemotherapy and radiotherapy alone. Finally, only a few of those with established diagnosis benefit from specific therapy because of shortage of drugs, the cost of which may be prohibitive. The therapeutic regimens are thus interrupted or even stopped, and this leads to great difficulties in checking certain disease processes. Relapse rates are consequently high and median survivals short. This multitude of factors contribute to the different mode and extent of presentation of oculo-orbital disease in Africa as compared with the Western world.
~~~-T-_* 43 32 18 9 4 4 4 2 11
22.0 16.4 9.2 4.6 2 2 2 I 5.6
6. I. 8.
Oyin 0. and William A. 0. Orbito-ocular tumors in Nigeria. Cancer 30, 580-587, 1972. Malik M. 0. A. and Sheikh E. H. Tumors of the eye and adnexa in the Sudan. Cancer 44, 293-303, 1979. Klauss V.. Chana H. and Khan F. Retinoblastoma in Kenyatta National Hospital, Nairobi. Fortsch. Ophthul. In press. Bhimani M. H. Retinoblastoma in Kenya-a five-year survey of cases admitted in K.N.H. E. Afr. med. J. 50, 310-316, 1973. Pendergrass T. W. and Da& S. Incidence of retinoblastoma in the U.S. Archs Ophthul. 98, 1204-1210, 1980.
9. Sinniah D., Narasimha G. and Prathap K. Advanced retinoblastoma 819-284,
1980.
in Malaysian children. Acra Ophrhul. 58,
10. Balmer A. and Gailloud C. Le retinoblastome, une tumeur curable. Klin. Mbl. Auaenheilk. 178. 323-325. 1981.
11. Bisley G. G. A Handbook of Ophthalmology for Developing Counrries, DR. 75-76. Oxford Universitv Press. London, 1980. _. 12. Templeton A. C. Tumors of the eye and adnexa in Africans of Uganda. Cancer 20, 16891698, 1967. 13. Miller B., Abraham C., Cole G. C. C. and Proctor N. S. P. Ocular malignant melanoma in South African blacks. Er. J. Ophrhul. 65, 720-722, 1981. 14. Quere M. A. and Lambert D. Zur Pathologie der Orbitookularen Tumoren im tropischen Afrika. Klin. Mbl. Augenheilk. 144, 829-840, 1964. IS. Awan A. M. and Shah A. K. Orbito-ocular tumors in Kenya Africans. E. Afr. J. Ophrhul. 4, I-37. 1980. 16. Illif C. E. Tumors of the orbit. Trans. Am. Ophrhul. Sot. 55, 505, 1957.
17. Templeton A. C. Orbital tumors in African children. Er. J. Ophrhul. 55. 254, 1971. 18. Van’Salem J. L. Proptosis in paediatrics. S. A,fr. med. J. 662, 1980.
19. Duane T. D. Rhubdomvosurcomu: Clinical Ophrhuimolog),, Vol. 2, Chap. 43, pp. 2. Harper & Row, New York, 1980.
1750
VOLKERKLAUSSand HARJINDERS. CHANA
20. Klauss V. and Chana H. S. Orbital tumors in Kenya children. Proceedings Association of Surgeons of Easf Africa. In press. 21. Knowles D. M. and Jakoiec F. A. Rhabdomyosarcoma of the orbit. Am. J. Ophthai. 80, 1011, 1975. 22. Heyn R. M., Holland R., Newton W. A. et al. The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. Cancer 34, 2128, 1974. 23. Reese A. B. Expanding lesions of the orbit: Bowman Lecture. Trans. Ophrhal. Sot. 91, 85. 1971. 24. AMREF (African Medical and Research Foundation). Fifth Annual Progress Report. Studies on the Epidemiology and Treatment of Hydatid Disease in the Turkana District of Kenya, 1981. 25. Silva D. Orbital tumors. Am. J. Ophthaf. 65, 318, 1968. 26. Simons M. J., Chana H. S., Wee G. B., Shanmugratnam K., Goh E. H., Chan J. C. W., Darmalingam S., Prasad V., Betuel G., Day N. E. and de The G. Naropharyngeal Carcinoma and Control (Edited by de The G. and Ito Y.), pp. 271-282. IARC Lyon, France 1978. 27. Prasad V. Cancer of the nasopharynx. A clinical analysis with anatomico-pathological orientation. JI R. COIL Surg. Edin. 17, 108, 1972.
28. Clifford P. Malignant disease of the nose, paranasal sinuses and post-nasal space in East Africa. J. Laryng. 75, 707-733,
1961.
29. Sawaki S., Sugano H. and Hiaryama T. Analytical aspects of symptoms of nasopharyngeal malignancy. IARC Scientific Publication No. 20, pp. 147-163, 1978.
30. Ho H. C. The natural history and treatment of NPC oncology. Proceedings af the X International Cancer Congress, Vol. 4, pp. 1-14. Chicago Year Book Medical
Publishers, Chicago, pp. l-14.
-
31. Clifford P. Further studies in the treatment of Burkitt’s Lymphoma. E. Afr. med. J. 180-199. 1966. 32. Klein G., Clifford P.. Klein F. er al. Membrane
immunofluorescence
reaction of Burkitt’s Lymphoma.
J. natn Cancer Inst. 30, 1027, 1967. 33. O’Connor G. T. Persistent immunologic stimulation as
a factor in oncogenesis with special reference to Burkitt’s Lvmohoma. Am. J. Med. 40. 279. 1970. 34. McMoh T. E.. Ogunmekan A. 0. and Ojunjo E. 0. Orbital Burkitt’s Tumor presented as advanced Retinoblastoma. J. Paediat. Ophthal. 17, 147. 35. Khan A. G. The multifocal lymphoma syndrome in African Children in Kenya. J. Larnyng. 74, 480, 1964. 36. Rupani H. Jaw tumors. Thesis, University of Nairobi,
1977. 37. Kasili E. M. Med. Thesis, University of Nairobi, 1979. 38. Trowel H. C. Non-Infectke Diseases in Africa. Church-
ill, London, 1960. 39. Crawford J. S. Diseases of the orbit. Toronto
Hospital for Sick Children. Chicago Year Book, 1967. 40. Youseffi B. Orbital tumors in children: a clinical study of 62 cases. J. Paediat. Ophthal. 6, 177. 1969. 41. Porterfield J. F. Orbital tumors in children: a report on 214 cases. Int. Ophthal. Clin. 2, 319, 1962.