Clinical Paper Oral Medicine
Oral Burkitt’s lymphoma in children: the Moroccan
experience
N. Otmani, M. Khattab: Oral Burkitt’s lymphoma in children: the Moroccan experience. Int. J. Oral Maxillofac. Surg. 2008; 37: 36–40. # 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
N. Otmani, M. Khattab
Department of Pediatric Hemato-Oncology, Children’s Hospital of Rabat, Morocco
Abstract. Thirty-seven children with Burkitt’s lymphoma of the oral region diagnosed between 1998 and 2005 were reviewed. There were 31 boys and 6 girls. The mean age at diagnosis was 6.64 years (range 2–15 years) with a mean delay to diagnosis of 41 days (range 10 days–2 months). There was a predominance of maxillary over mandibular involvement: 1.44:1. Complaints included exophytic mass with dental displacement (100%), abdominal pain (68%), nerve palsy (28%) and orbital swelling (21%). Toothache as initial complaint led to dental extraction in 12 cases.
According to the Murphy classification, there were 4 stage II, 11 stage III and 22 stage IV tumours; 43% and 41% had bone marrow and central nervous system involvement, respectively. After chemotherapy, complete remission was seen in 59% of cases. Remission in two children was relatively brief, lasting no more than 3 months. After a median follow-up of 45 months (range 9–99 months), the disease- free survival rate was 54%. In conclusion, in this series, oral presentation of Burkitt’s lymphoma was a component of more widely disseminated disease. The pattern seemed to fall between that of the endemic and the sporadic types. Even with intensive chemotherapy, patients with advanced disease maintained a poor prognosis.
Key words: Burkitt’s lymphoma; oral location;
children; Morocco.
Accepted for publication 8 June 2007 Available online 5 September 2007
Non-Hodgkin’s lymphomas (NHL) are tumours of the immune system with a variable range of incidence depending on age, geographic location, race and Epstein–
Barr virus (EBV) exposure. According to their clinical and cytological characteris- tics, they are classified into low, medium and high grades of malignancy. High-grade NHL affects mainly young people, while low-grade malignancies are more frequent in advanced age1. The majority of lympho- mas arise in lymphoid tissue, especially the
cervical nodes, and only 24% arise at extra- nodal sites5. The most frequent extranodal locations include gastrointestinal tract, skin, bones and Waldeyer’s ring, with a greater frequency of concomitant relapse in the gastrointestinal tract and Waldeyer’s ring1,19. Only rarely do these lesions arise in the oral cavity. The most common sites are the hard palate, gums, salivary glands and tongue4,20.
Immunohistochemical features of NHL are subdivided into T-cell and B-cell lym-
phomas. Oral extranodal lymphomas are predominately of B-cell origin (92%), and less commonly of T-cell origin (8%)4,20. Burkitt’s lymphoma (BL) is a high- grade B-cell non-Hodgkin’s lymphoma which occurs as endemic, sporadic and human immunodeficiency-associated sub- types2,15. It accounts for 3–5% of all lym- phomas15. There is a high incidence of BL (endemic or African BL) in endemic regions such as equatorial Africa and Papua New Guinea, where it accounts
doi:10.1016/j.ijom.2007.06.010, available online at http://www.sciencedirect.com
0901-5027/01036 + 05 $30.00/0 # 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
for almost half of all childhood can- cers3,15. Elsewhere in the world, BL occurs with a much lower frequency, and is referred to as sporadic or American BL2. The two forms of the disease have different clinical presentations. Age dis- tribution, abdominal and jaw involvement, central nervous system (CNS) dissemina- tion and EBV incrimination prompted the subdivision of this malignant condition (Table 1). The aim of this paper is to discuss cases of oral lymphoma diagnosed at the authors’ institution and to compare them to the described endemic and non- endemic forms.
Patients and methods
A retrospective study was undertaken of cases of oral BL diagnosed between 1998 and 2005 at the Pediatric Hemato- Oncology Department of Rabat. Tumours of the pharynx, parotid and sinuses were excluded. The study only included patients in whom the lymphoma was iden- tified in the oral region on initial diagnosis.
The diagnosis in each case was based on histopathological findings. Staging of the disease was determined according to Mur- phy’s classification11(Table 2). CNS dis- ease was defined as the presence of blasts in cerebrospinal fluid, cranial nerve palsy not related to facial tumour, clinical signs of spinal compression or an intracranial mass.
The patients were reviewed for age, sex, delay before hospitalization, location of tumour, treatment and outcome. Disease extension was assessed by a physical examination, blood cell count, panoramic radiograph of the jaws, cranial computed tomography, chest X-ray, abdominal ultrasound, bone marrow (BM) aspirate and lumbar puncture.
Chemotherapy was administered by means of combined agents according to the French LMB regimen (Fig. 1). Neuro- meningeal (NM) prophylaxis consisted of intrathecal injections of high-dose metho- trexate, high-dose Ara-C and hydrocorti- sone. Irradiation of the skull (24-Gy) was indicated in three cases. Survival was calculated from the first day of chemother- apy to death due to any cause or to the last follow-up contact for patients who were alive.
Results
Of a total of 452 NHL at all sites, 37 (8%) cases of intraoral BL were recorded. The clinical presentation of these patients is summarized in Table 3. The ages of the patients ranged from 2 to 15 years, with a mean of 6.64 years. There was a predo- minant presentation in males (31 boys and 6 girls); the male-to-female ratio was 5.1:1. Median delay to diagnosis was 41 days (10 days, 2 months). The most com- mon symptoms seen at diagnosis were a
fast-growing gingival mass (that may or may not be ulcerated), associated with toothache or dental displacement (100%), abdominal pain (68%), nerve palsy (28%) and orbital swelling (21%). Less often epistaxis, otalgia and trismus were rep- orted. Displacement of teeth led to dental extraction in 12 patients. A total of 39 maxillary quadrants and 27 mandibular quadrants showed tumour invasion. This indicates a 1.4:1 preference for involve- ment of the maxilla. The premolar/molar region was the location most frequently affected. In the maxillary cases, the sinuses and the orbits were involved to some degree.
According to Murphy’s distribution (Table 4), most cases (89%) involved a secondary location, with only 11% being an isolated oral tumour. Bone marrow and neuro-meningeal involvement was noted initially in 43% and 41% of patients, respectively. Following therapy, 59% of patients achieved complete remission with the planned protocol, while 35% were non-responders and died within a mean of 48 days following admission. Relapse occurred in two patients (one BM, one CNS) after a median of 4 months (range 3–6 months) from diagnosis, and they both died from related treatment toxicity after a second line of therapy. After a follow-up of 45 months (range 9–99 months), 54%
were considered long-term survivors, with 100%, 91% and 27%, respectively, for stage II, III and IV; and 50%, 33% and 0%, respectively, for BM+ patients, CNS+
patients and BM-CNS+ patients.
Discussion
In this first study of the paediatric distribu- tion of NHL in Morocco, it was found that oral Burkitt-type lymphomas account for 8% of total childhood NHL in this country.
The age at onset of symptoms ranged from 2 to 15 years with a mean 6.64 years. Like the endemic form, the results suggest that it afflicts younger children between 5 and 7 years3,8, whereas sporadic BL is associated with slightly older children (10–12 years).
The male-to-female ratio was 5.1:1 (31 males, 6 females), which is similar to the Oral Burkitt’s lymphoma in children
Table 1. Clinical features of BL3,8,14,18
Endemic Sporadic
Epidemiology Africa USA, Europe
Incidence 50–70% of all childhood malignancies 3–6% of all childhood malignancies
Age at incidence 5–8 10–12
EBV titres 90–95% 15–67%
Clinical presentation Jaw and facial bone diseases 50–100% Jaw diseases 6–40%
Abdominal diseases 25% Abdominal disease 72–90%
Treatment outcome 54–79% 76–90%
Table 2. Murphy’s tumour staging11
Stage I A single tumour (extranodal) or involvement of a single anatomical area (nodal), with the exclusion of the mediastinum and abdomen
Stage II A single tumour (extranodal) with regional node involvement Two or more nodal areas on the same side of the diaphragm
Two single (extranodal) tumours, with or without regional node involvement on the same side of the diaphragm
A primary gastrointestinal tract tumour (usually in the ileo-caecal area), with or without involvement of associated mesenteric nodes, that is completely resectable
Stage III Two single (extranodal) tumours on opposite sites of the diaphragm Two or more nodal areas above and below the diaphragm
Any primary intrathoracic tumour
Any paraspinal or epidural tumour, whether or not other sites are involved Stage IV Any of the above findings with initial involvement of the CNS, bone marrow
or both
gender distribution ratio for African and American patients8,14.
In general, the clinical features of the disease depend on the location of the
primary lesion. The signs of oral BL include a combination of oral masses, jaw expansion and mobile teeth, accom- panied by characteristic radiographic
features of jaw rarefaction and poorly circumscribed lytic lesions18,24. In the present study, pain and displacement of teeth were the most common chief com- plaints followed by swelling and sensory disturbances. Jaw and facial bone invol- vement closely resembled that reported in African BL3,8, and was dissimilar to the pattern of jaw involvement in Amer- ican BL17. Additionally, the maxilla appears to be involved at a higher rate than the mandible (1:4.1), which is Otmani and Khattab
Table 4. Distribution of patients according to Murphy tumour staging
Stage Total no. of patients % Patients in given stage Deaths % Survivors
II 4 11 0 100
III 11 30 1 91
IV 22 59 16 27
Total 37 100 17 54
Table 3. Characteristics of patients, oral location, response to chemotherapy and overall survival
Patient Gender Age
Duration of
symptoms Facial bones Other structures
BM or
NM Staging
Response to therapy
Survival (months from diagnosis)
1 M 12 1 month R mand Kidney, spleen BM IV NR <1
2 M 6 10 days L mand Pleural effusion, mesentery BM IV CR 41+
3 M 3 2 months B max Mediastinum BM IV NR <1
NM
4 M 4 1 month B max Mesentery BM IV CR 44+
B mand
5 F 9 2 months L max Pancreas III CR 50+
6 M 3 2 months B max Pleural effusion, humerus BM IV NR <1
R mand NM
7 M 15 2 months R mand Mesentery, paraspinal BM IV NR <2
NM
8 M 5 15 days B max Kidney NM IV NR <1
9 M 3 20 days B max Mesentery, kidney III CR 32+
10 M 7 2 months R mand Mesentery, mediastinum III CR 61+
11 M 13 2 months B max Pancreas, liver, pleural effusion NM IV R-NM 9
L mand
12 M 3 1 month L max Kidney III R-BM 4
13 M 6 1 month B max II CR 89+
14 M 7 1 month B max Mesentery, liver kidney, pancreas NM IV CR 39+
B mand
15 M 6 40 days L max NM IV CR 99+
L mand
16 M 13 1 month L max Nasopharynx BM IV NR <2
NM
17 M 8 40 days B mand Mesentery BM IV NR <2
18 M 6 2 months L mand Liver III CR 99+
19 M 3 1 month L max Kidney III CR 82+
20 M 7 40 days R max II CR 96+
21 M 4 25 days B mand Mesentery NM IV NR <1
22 M 7 1 month B max Kidney, liver, pleural effusion BM IV NR <1
23 M 3 2 months R max Kidney, liver, mesentery III CR 32+
24 M 11 20 Days L mand Liver, mediastinum, mesentery III CR 30+
25 M 4 20 days B max Mesentery III CR 30+
26 F 8 1 month B max Kidneys, pleural effusion BM IV CR 25+
B mand
27 F 3 2 months B max BM NM IV NR <1
28 M 3 1 month B max Kidney, mesentery, testicle BM NM IV NR <1
29 F 3 1 month L max Kidney, mesentery, ovary BM IV NR <1
30 M 4 2 months L mand Sphenoid BM NM IV NR 4
31 M 3 1 month B mand B max Kidney, liver, pancreas, mesentery BM IV CR 12+
32 M 2 1 month L mand Kidney, pancreas, testicle III CR 13+
33 M 4 2 months R mand Pterygoid, infratemporal fossa NM IV NR 5
R max
34 F 8 2 months R mand II CR 12+
35 M 5 2 months L mand Tibia, humerus, sternum III CR 9+
L max
36 M 14 2 months L max Kidney, pancreas, intracranial BM IV NR <1
NM
37 F 13 2 months R max II CR 9+
M, male; F, female; R, right; L, left; B, bilateral; max, maxilla; mand, mandibula; BM, bone marrow involvement; NM, neuro-meningeal involvement; R-NM, relapse with neuro-meningeal involvement; R-BM, relapse with bone marrow involvement; CR, complete response; R, relapse; NR, no response.
consistent with previous reports in ende- mic areas22.
In addition to oral and maxillofacial location, most of our patients presented a more disseminated disease (>89%), including abdominal, bone marrow and/
or CNS involvement. Although the abdominal and bone marrow involvement resembled more closely the American form14,23, bone lesions and CNS invasion, which are less often encountered in the sporadic form16,18, are more similar to the findings of African BL8.
The role of EBV in the development of BL of all types is well established21, but this infection appears to be a more significant cofactor in endemic areas (95%)10. Testing for the presence of EBV was not done in the present series because of the lack of avail- ability of special techniques. The finding of 88% EBV-associated cases with greater incidence of abdominal tumours and infre- quent jaw involvement in Algeria9suggests a new histopathological subtype of BL in North African countries that remains to be elucidated. The variable incidence rate of EBV and existence of variant transloca- tions or different breakpoint locations give support for the existence of several mole- cular subtypes of BL throughout the world6.
Intensive combination chemotherapy is the treatment of choice for childhood BL;
radiotherapy is limited to CNS prophy- laxis2,15. Currently, patients with BL at the authors’ institution receive chemotherapy according to the French LMB protocol for an African setting7. This treatment is
based on intravenous cyclophosphamide, vincristine, prednisone, high-dose me´tho- trexate, cytarabine, doxorubicin and etopo- side12. Results of multicentre studies using this type of protocol showed a90% 5-year event-free survival with localized child- hood B-cell lymphoma (Burkitt and large B-cell) or L3ALL, and slightly inferior event-free survival rates in patients with CNS involvement12,13. The 54% overall survival rate in the present study may be due to the greater number of patients at advanced stages at diagnosis (89% were stage III and IV) with CNS involvement in 38% of patients. CNS disease at onset in children is associated with a worse out- come16. These findings must be considered with caution because of the small number of patients and toxicity-related deaths. Such morbidity (metabolic disorders, febrile neutropenia and mucositis) may compro- mise the use of such intensive protocols in less privileged countries12. In view of this, determining optimal therapy that is equally or less toxic remains an important chal- lenge. Delineation of clinical and biologi- cal features specific to this geographical area can help in prognosis improvement and prediction of treatment failure.
It is concluded from this series that clin- ical aspects of these cases may represent a form of BL that is distinct from the well- described endemic and sporadic subtypes.
Future investigations are needed to attain a better understanding of the behaviour of BL in North Africa. Chemotherapy is the main- stay of treatment, but patients at advanced stages continue to have a dismal outcome.
Continuing refinements in therapy are required to improve prognosis, specifically in advanced disease.
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Address:
Naı¨ma Otmani
Department of Pediatric Hemato-Oncology Children’s Hospital of Rabat
Morocco
E-mail:[email protected] Otmani and Khattab
