Lymphomas of the head and neck in the pediatric population

International Journal of Pediatric Otorhinolaryngology (2007) 71, 1471—1477

www.elsevier.com/locate/ijporl

Lymphomas of the head and neck in the pediatric population Jong-Lyel Roh a,*, Jooryung Huh b, Hyung Nam Moon c a

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea b Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea c Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Received 24 April 2007; received in revised form 29 May 2007; accepted 2 June 2007

KEYWORDS Pediatric lymphomas; Head and neck; Incidence; Early response; Prognosis

Summary Objective: Little is known about the incidence and survival outcomes of pediatric patients with head and neck (HN) lymphomas in Asian populations. This study sought to identify the incidence of HN involvement of pediatric lymphomas and to identify factors prognostic of patient survival. Methods: We reviewed the medical records of all children aged 0—14 years with previously untreated lymphomas of HN region and compared patient clinicopathologic characteristics and final outcomes in patients with Hodgkin’s disease (HD) and nonHodgkin’s lymphoma (NHL). Potential prognostic factors for patient survival were investigated. Results: Of 106 eligible lymphoma patients, 45 (42.5%; 31 boys and 14 girls) showed HN involvement. Overall, NHL (n = 37) showed more unusual and aggressive presentations than did HD (n = 8) in the head and neck region. Cervical lymphadenopathy was frequently observed (30/45, 66.7%) in these patients. Involvement of extralymphatic head and neck sites was found in 15 of 37 NHL patients (40.5%) but not in any HD patients ( p = 0.027). Five-year disease-free survival (DFS) of all HN lymphoma patients was 76.0%. On multivariate analysis, advanced stage and absence of complete remission following 3 cycles of chemotherapy were poor prognostic indicators of patient survival ( p < 0.05). Conclusions: The incidence of HN involvement in pediatric lymphomas was 42.5% in the studied population. Stage of the lesion and early response to chemotherapy were independent factors prognostic of patient survival. # 2007 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author. Tel.: +82 2 3010 3965; fax: +82 2 489 2773. E-mail address: [email protected] (J.-L. Roh). 0165-5876/$ — see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2007.06.004

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1. Introduction Lymphoma is the third most common pediatric cancer in Western countries, accounting for 10% of all solid tumors in children and with an annual incidence of 11—20 per million children [1—3]. The incidence of lymphomas varies geographically, with 50% of childhood cancers in equatorial Africa being lymphomas, due to the very high incidence of Burkitt’s lymphoma [4]. In nonendemic areas of the world, head and neck lymphomas are relatively rare in children, accounting for only about 10% of childhood lymphomas [5]. In developed countries, the incidence of childhood malignancies, including lymphomas, is increasing, with survival rates found to be enhanced by more effective chemotherapy and less radiotherapy [6,7]. It is unclear, however, whether this trend also applies to pediatric head and neck lymphomas, particularly in Asian populations. East Asia is endemic for Epstein-Barr virus (EBV) infection, which is associated with virusrelated malignancies, including nasopharyngeal carcinoma and natural killer/T-cell lymphomas [8,9]. To the best of our knowledge, the incidence of pediatric patients with head and neck lymphomas has not been reported from Asian populations. Furthermore, little study has been on analyses of treatment outcomes and factors prognostic of survival in children with head and neck lymphomas. We therefore retrospectively reviewed the medical records of all children aged 0—14 years with head and neck lymphomas treated at our institution between 2000 and 2005, and analyzed their clinicopathologic patterns, treatment outcomes and prognostic factors.

2. Patients and methods 2.1. Study design and treatment The medical records of all pediatric patients aged 0—14 years with primary lymphomas in the head and neck region with or without lesions in other regions at Asan Medical Center between 2000 and 2005 were reviewed. All lesions were confirmed histologically and all patients were followed up for a minimum of 12 months. Two patients who did not receive complete treatment because of toxicity and two who died prior to completion of their first 3 cycles of chemotherapy due to treatment complications were excluded. This study was reviewed and approved by the ethics committee of our institution. Patients were diagnosed histologically according to the Revised European-American Classification of Lymphoid Neoplasms (REAL) and staged according

J.-L. Roh et al. to the modification of the Ann Arbor system [10,11]. Tumors were staged on the basis of complete diagnostic work-ups, including biopsy, history, laboratory tests, physical and radiological examinations and bone marrow biopsy. All patients received intensive multiagent chemotherapy with regimens in current use: 6—8 cycles of MOPP (nitrogen mustard, vincristine, procarbazine and prednisolone) or ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin’s disease (HD), and 6 cycles of COMP (cyclophosphamide, vincristine, methotrexate and prednisolone), COPA (cyclophosphamide, vincristine, prednisolone and doxorubicin) or LSA2L2 (cyclophosphamide, vincristine, methotrexate, prednisolone, daunomycine, cytarabine, 6-thioguanine, asparginase, carmustine, hydroxyurea) for non-Hodgkin’s lymphoma (NHL) [12]. Four patients received multiagent chemotherapy followed by low-dose involved-field irradiation (20—25 Gy) for localized primary head and neck lymphomas. Follow-up information included therapy regimen, response, survival status and survival time in months.

2.2. Immunohistochemistry for Ki-67 Ki-67 expression was assayed using the immunoperoxidase ABC method using antibody to Ki-67 (Dako, Glostrup, Denmark), at a dilution of 1:200. The fraction of Ki-67-positive cells (Ki-67 labeling index) was determined by counting the number of positively labeled tumor cells among 1000 tumor cells in 10 random regions in 400-fold fields [13].

2.3. Statistical analysis The x2-test was used to compare HD/NHL and other clinical variables (sex, age, stage and tumor involvement sites). SPSS 12.0 for Windows (SPSS Inc., Chicago, IL) was used for statistical analysis. Actuarial disease-free survival (DFS) and overall survival rates were calculated by the Kaplan—Meier method. The log-rank test was used to assess the correlation between survival end point and clinicopathologic variables (sex, age, HD/NHL, lymphoblastic/mature cell neoplasms of NHL, extralymphatic involvement, EBV positivity, Ki-67 labeling index, stage category I—II/III—IV and early response to chemotherapy). Patients with complete remission after the first 3 cycles of multiagent chemotherapy were regarded as responders. The Cox proportional hazards model was used for multivariate analysis. Variables shown to be significant in univariate analysis were selected for the Cox model with stratification of HD and NHL. A p-value less than 0.05 was considered statistically significant.

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Table 1 Demographic and clinical characteristics of the study population (n = 45) Characteristics

No. of patients

%

Gender Male Female Agea, years (range)

31 14

68.9 31.1 8.0  4.1 (1—14)

Involved tumor site Cervical lymph nodes Extralymphatic head and neck sites Chest Supraclavicular lymph nodes Abdomen Waldeyer’s ring Systemic Multiple site involvement

30 15 11 9 8 7 7 25

66.7 33.3 24.4 20.0 17.8 15.5 15.5 55.6

Stage b I II III IV

18 14 6 7

40.0 31.1 13.3 15.5

Follow-up period of survivorsa, months (range) a b

48  20 (12—85)

Mean  standard deviation. Ann Arbor staging system.

3. Results 3.1. Clinical characteristics Of the 106 pediatric lymphoma patients diagnosed during the period, 45 (42.5%) initially presented with lesions in the head and neck region (8 out of 11 patients with HD, and 37 out of 95 patients with NHL). These 45 patients comprised 31 boys and 14 girls, of mean age 8 years (Table 1). Cervical lymphadenopathy was the most common presentation, found in 30 patients (66.7%), with chest and abdominal lymph node involvement and systemic dissemination found in 11 (24.4%), 8 (17.8%) and 7 (15.5%) patients, respectively. Specific anatomic sites of extranodal involvement were Waldeyer’s ring in 7

patients (15.5%) and other extralymphatic head and neck regions in 15 patients (33.3%). Thirty-two patients (71.1%) had early stage (I or II) and 13 patients (28.9%) had advanced stage (III or IV) disease.

3.2. Pathology Of these 45 patients, 37 (82.2%) had NHL and 8 (17.8%) had HD. All HD cases involved cervical lymph nodes with/without mediastinal or axillary lymph nodes, with one patient showing involvement of both palatine tonsils and cervical lymph nodes. Of the 8 patients with HD, 4 had nodular sclerosis and 4 showed mixed cellularity (Fig. 1). Of the 37 patients with NHL, 24 had B-cell neoplasms (64.9%), with

Fig. 1 Histologic types of head and neck lymphomas (n = 45). B-cell non-Hodgkin’s lymphomas (NHL) were most frequently seen (left column), with Burkitt’s and precursor B-lymphoblastic lymphomas being the most common pathologies of NHL (right column). MALT, mucosa-associated lymphoid tissue (extranodal marginal zone B-cell lymphoma).

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Table 2 Clinical characteristics of patients with Hodgkin’s and non-Hodgkin’s lymphomas Characteristics

Lymphoma group (%) Hodgkin (n = 8)

p Non-Hodgkin (n = 37)

Sex Male Female

62.5 37.5

70.3 29.7

Age (years) 0—4 5—9 10—14

12.5 12.5 75.0

24.3 48.6 27.0

Stage I II III IV

50.0 37.5 12.5 0

37.8 29.7 13.5 18.9

0 100 50.0 12.5

40.5 59.5 18.9 18.9

Involvement Extralymphatic sites Cervical lymphadenopathy Mediastinal node Abdominal node

0.667

0.035

0.596

Burkitt’s and precursor B-lymphoblastic lymphomas being most common. The groups of patients with HD and NHL differed in age distribution and extranodal involvement of the head and neck (Table 2). HD was significantly more common in children 10 years old (75%), whereas NHL was more predominant in younger children ( p = 0.035). Involvement of extralymphatic head and neck sites was found in 15 of 37 NHL patients (40.5%) but not in any HD patients ( p = 0.027). Of the 15 patients presenting with involvement of extralymphatic sites, 8 had Burkitt’s lymphoma, with 3 showing involvement of the paranasal sinus/orbit/cranial base, 2 showing involvement of the mandible and 1 each showing involvement of the maxilla, submandibular gland, conjunctiva and central nervous system (Fig. 2). Of 9

Fig. 2 Extralymphatic site distribution of head and neck lymphomas (n = 15). The mandible or maxilla, paranasal sinus and orbit were the most common involved sites and Burkitt’s lymphoma was the most common pathology.

0.027 0.073 0.161 0.667

patients with precursor B-lymphoblastic lymphoma, 5 had the involvement of extralymphatic head and neck sites, with 2 each showing involvement of the nose/nasal cavity and scalp and 1 showing involvement of the paranasal sinus/orbit/cranial base. One patient had an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in the left parotid gland. The mean  S.D. Ki-67 labeling index was 49.6  39.4%, with 25 patients (55.6%) having an index of 50% or higher.

3.3. Survival analysis At last follow-up, 36 patients (80.0%) were alive, including one alive with disease, whereas 9 (20.0%) had died of tumor-related disease. The mean follow-up for surviving patients was 48  20 months (range, 12—85 months). The 5-year disease-free survival rate was 76.0%, and the 5-year overall survival rate was 78.3%. Thirty-four of 45 patients (75.6%) showed complete remission after their first 3 cycles of multiagent chemotherapy (early responders). Univariate analysis of all 45 patients showed that stage category and response to chemotherapy were statistically significant predictors of DFS ( p < 0.01) (Table 3). The 5-year DFS rates of patients with early and advanced stage tumors were 90.5% and 44.9%, respectively ( p = 0.002); those of responders and non-responders to chemotherapy were 92.7% and 11.1%, respectively ( p < 0.001). In multivariate analysis, both variables remained a significant determinant of DFS ( p < 0.05) (Table 4; Fig. 3).

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Table 3 Univariate analysis for disease-free survival Variable

No. of patients

% 5-year DFS

p

Sex, male/female Age, 7/>7 years HD/NHL NHL, B-/T-cell origin NHL, precursor/mature cell neoplasms Extralymphatic involvement, no/yes Ki-67 index, 50/> 50% Stage, I—II/III—IV Response to chemotherapy, yes/no

31/14 22/23 8/37 24/13 15/22 30/15 20/25 32/13 34/11

71.4/85.7 77.0/74.0 100/71.1 74.2/67.1 71.8/70.8 81.7/65.2 81.4/70.7 90.5/44.9 92.7/11.1

0.428 0.946 0.123 0.655 0.946 0.229 0.326 0.002 <0.001

Abbreviations: DFS, disease-free survival; HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma.

Table 4 Cox proportional hazards models for disease-free survival Variable Stage, I—II/III—IV Response to chemotherapy, yes/no

Disease-free survival Relative risk

95% CI

p

2.24 36.47

1.10—6.09 8.25—168.44

0.015 <0.001

Abbreviation: CI, confidence interval.

4. Discussion

Fig. 3 Actuarial disease-free survival curve using (a) univariate and (b) multivariate analyses. Stage category and response to initial chemotherapy were independent determinants of patient survival.

Of the 106 pediatric lymphoma patients, 45 showed primary lesions in the head and neck region, suggesting that a high proportion of pediatric lymphomas can initially present as space-occupying lesions of the head and neck. Most children with head and neck lymphomas had cervical lymphadenopathy, but a considerable percentage (48.9%) showed involvement at extranodal sites, including Waldeyer’s ring, maxilla/mandible, paranasal sinus, orbit, nasal cavity and salivary gland. Extranodal involvement was more frequent in NHL than in HD. In the present study, the incidence of extranodal involvement in HD was similar to that (5/15, 33.3%) reported earlier [14], but the incidence in NHL was lower than that (547/911, 63.3%) of a large multi-center study that included all age groups of the Korean population [15]. Taken together, these results indicate that lymphoma of the head and neck in children can present with a confusing clinical picture and that these tumors may be initially confused with inflammatory disease and/or other neoplasms [16]. To our knowledge, our study is the first to report the actual incidence of head and neck presentations in all pediatric lymphomas. Understanding the propensity of lymphomas to involve atypical extranodal head and neck and central nervous system sites can lead to proper diagnosis and treatment of pediatric patients. Consistent with earlier reports, we found that the clinical presentation patterns of pediatric HD and NHL differed [4,5,14]. Pediatric lymphomas show

1476 male predominance, of 2.5:1—3:1 [5]. Moreover, HD presents in children and adolescents older than 10 years of age, whereas the incidence of NHL increases steadily throughout life [17]. Indeed, we found that 2 of 11 HD patients (18.2%) and 74 of 95 NHL patients (77.9%) were younger than 10 years old. Rapid tumor growth, suggestive of NHL rather than HD, results in progressive mass effect and facial asymmetry, swelling and pain [5,14]. These unusual presentations of NHL result from extranodal involvement. Pediatric NHL tends to be more diffuse and prone to bloodborne dissemination; thus, bone marrow and intracranial involvement are much more common in NHL than in HD [5]. In addition, Burkitt’s lymphomas, which are usually detected in children and represent 40% of childhood NHL, frequently show locally aggressive growth patterns [18]. The overall 5-year survival rate for children with NHL, following prompt institution of effective multiagent chemotherapy, is approximately 70% [5]. HD, which is usually detected during its early stages, has a cure rate greater than 90% with multiagent chemotherapy [12]. In both children and adults, the extent of disease at diagnosis is the most important predictor of outcome [19,20]. Moreover, systemic dissemination and intracranial extension are significant negative prognostic variables [5,12]. In agreement with these findings, we observed that stage at presentation and response to the first 3 cycles of multiagent chemotherapy were independent prognostic indicators of patient survival. Early response to chemotherapy may be a surrogate for final outcomes in patients with both HD [21—23] and NHL [24], reflecting both tumor burden and activity. Because early response to chemotherapy may be the most important prognostic indicator, the speed of response to initial chemotherapy can be adapted into treatment programs of pediatric lymphoma patients, based on risk. Although extranodal involvement of pediatric head and neck NHL has been associated with poor prognosis [25], this association was not found in our study. Moreover, although surface staining with Ki-67 monoclonal antibody was significantly more frequent in high-grade lymphomas and associated with a negative prognostic factor in 29 patients with head and neck lymphomas [26], we did not observe a relationship between Ki67 labeling index and survival outcomes. Because Ki67 staining may be a marker for grade rather than an independent predictor of outcome, its significance as a prognostic indicator in pediatric head and neck lymphomas remains speculative [16,27,28]. Our study had several limitations, including its retrospective design and the inclusion of a relatively small number of patients. The rare overall incidence of pediatric head and neck lymphomas may hinder

J.-L. Roh et al. prospective diagnostic or therapeutic trials. However, our study is the first to systematically review the clinicopathologic patterns of pediatric head and neck lymphomas, as well as the first to determine potential prognostic indicators in children with head and neck lymphomas. In conclusion, lesions of the head and neck at initial presentation were present in a considerable number of children with lymphomas (42.5%). Compared with HD, NHL showed more unusual and aggressive presentations in the head and neck region, and at younger ages. Multivariate analysis showed that stage at presentation and early response to chemotherapy were independent prognostic indicators of patient survival. These results may help guide the management of pediatric lymphoma patients initially presenting with lesions in the head and neck region.

Acknowledgment This work was supported by the Ministry of Health & Welfare, the National R&D Program for Cancer Control, Grant No. 0620160-1, Republic of Korea.

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