Table of Contents

HK J Paediatr (New Series)
Vol 2. No. 2, 1997

HK J Paediatr (New Series) 1997;2:123-128

Original Article

Paediatric Non-Hodgkin's Lymphoma: The Current Experience at the Queen Mary Hospital and a Review of the Literature

GCF Chan, SY Ha, ACW Lee, DCK Chiu, MY Cheng, YL Lau


Abstract

Non-Hodgkin's lymphoma (NHL) is a common group of paediatric malignant tumours. It usually presents in 3 forms in children, namely (1) small non-cleaved cell (SNCC); (2) lymphoblastic (LB) and (3) large cell (LC) NHL. Their clinical presentation and response to treatment differ from each other but all are highly aggressive. Between January 86 and December 96, 21 patients were diagnosed to have NHL in the Paediatric Unit of Queen Mary Hospital. Nineteen of them received treatment by us and their data were analyzed. Four had SNCC; 5 had LB and 10 had LC (4/10 had Ki-1 positive NHL) NHL. The median age at presentation was 8.5 years and most (13/19) were male. Advanced stage (Stage III & IV) disease was found in 14/19 (74%) patients. The primary site of the disease depended on its histologic form and abdominal or thoracic origin was more common (9/19). Eleven of 19 were treated according to the UKCCSG-NHL protocol. The overall survival was 80% and event free survival (EFS) was 65%. The overall and event free survival (EFS) for early stage (stage I & II) disease were both 100%, and was 76% and 58% for advanced stage (stage III & IV) disease respectively. According to histologic type, the EFS was 100% (SNCC); 45% (LB) and 75% (LC) respectively. Patients who suffered from relapse were all from the lymphoblastic (n=3) or large cell NHL groups (n=2). Two patients with Burkitt's lymphoma developed therapy-related cardiac complication and one required regular anti-failure treatment. The prognosis of paediatric NHLs are related to histology and clinical stage, both of which reflect differences in tumour biology. Current direction in management is to decrease treatment toxicity in the good risk group and to increase treatment intensity in the high risk group; this approach demands accurate diagnosis and staging process.

Keyword : Biology; Chemotherapy; Children; Non-Hodgkin's Lymphoma


Abstract in Chinese

Introduction

Non-Hodgkin's lymphoma (NHL) is the third most common group of paediatric malignancy. In contrast to its adult counterpart, paediatric NHLs often present as diffuse, high-grade tumour. The low grade follicular NHL which is common in adult is extremely uncommon in children.1 Paradoxically, majority of these high-grade NHLs in children can be cured whereas the low-grade NHLs in adult tend to recur and are hard to eradicate.2 The complicated, highly variable histologic pictures in adult NHL are not as problematic in the childhood NHL. More than 85% of the paediatric NHL belong to the three histological subtypes, namely (1) small non-cleaved cell; (2) lymphoblastic and (3) large cell categories.3 (Fig. 1) The frequent changes of NHL classification do cause difficulty in the diagnosis of paediatric NHL. (Table I)

Table I Histopathologic Classification of Non-Hodgkin's Lymphoma
High grade NHL commonly found in children
Kiel Rappaport Working Formulation REAL Immuno. type
Burkitt's Diffuse undifferentiated Small, non-cleaved, Burkitt's Burkitt's B
  Diffuse undifferentiated Small, non-cleaved, non-Burkitt's High grade B-cell, Burkitt-like B
Lymphoblastic Diffuse lymphoblastic Lymphoblastic Lymphoblastic
(T or B-precursor)
T, rarely pre-B
Centroblastic Diffuse histiocytic Diffuse, large cell (cleaved or non-cleaved) Diffuse large B-cell B
Large cell anaplastic Diffuse histiocytic Large cell immunoblastic Anaplastic large cell T, rarely pre-B
B-immunoblastic Diffuse histiocytic Large cell immunoblastic Diffuse large B cell B

Recent advances of paediatric NHL are in the areas of achieving highly effective treatment and understanding of the biology. Basically, the lymphoblastic form of paediatric NHL would benefit from the multi-agents chemotherapy as used in childhood acute lymphoblastic leukaemia (ALL) whereas the small non-cleaved cell and large cell NHLs have a better outcome with a shorter but intensive multi-agents chemotherapy regimen. This observation was demonstrated by a randomized clinical trial especially in the advanced stage NHL.4 Except in certain instances (ie. CNS disease), radiation therapy is not routinely given and surgical resection is rarely required. In most clinical trials, the long term event free survival for early stage disease was around 90% and for advanced stage disease would be around 60 to 80%, depending on the histology type. 1 We studied our experience at Queen Mary Hospital and reviewed the current treatment results of other developed countries.

Methods

We performed a retrospective chart review of paediatric patients (<15-year-old) who were diagnosed to have non-Hodgkin's lymphoma in our department from January 1986 to December 1996. The diagnosis was based on standard cytochemical staining method. The histopathologic classification was based on the Working Formulation guidelines.5 (Table I) The lymphoid lineage and immunophenotype were determined by immunochemical method. The clinical staging was according to the St. Jude (Murphy's) staging system.6 (Fig. 2) Staging was established by the results of CT scan or MRI of the primary site and of the other lymphoid regions (ie. chest and abdomen); bilateral bone marrow aspirate and trephine biopsy; examination of the cerebrospinal fluid by lumbar puncture and bone scan. Staging laparotomy was not performed.

Treatment regimens depended on the era when the patients were diagnosed. Patients who were diagnosed after 1991 were treated with the UKCCSG-NHL 1990 regimen (Chessels JM. Personal Communication). This regimen has 4 components, namely 901; 902; 903 and 904. The 901 protocol is a short and relatively mild regimen targeted at the stage I and II non-lymphoblastic NHL patients. The 902 protocol is a more intensive regimen designed for the stage III and IV non-lymphoblastic disease without CNS involvement. Patients with stage IV non-lymphoblastic NHL with CNS involvement will receive 903 protocol. 904 protocol is identical to the current UKALL-XI protocol7 for T cells acute lymphoblastic leukaemia and is used for patients with all stages of lymphoblastic NHL. Patients who were diagnosed before 1990 were treated with CCSG-LSA2L2 or LMB 86 protocols.4,8 Patients after therapy were followed-up at regular intervals even when they reached the adult age. Long term therapy-related organ toxicity was assessed in patients who were 2 and 5 years off therapy. That included cardiac assessment by echocardiogram, hepatic status by serum liver function test, renal assessment by 24 hours urine for glomerular filtration determination and serum renal function test, endocrine assessment including TSH, T4, fasting morning cortisol and LH, FSH level.

Event free survival was defined as survival without relapse or disease. The overall and event free survival were estimated by the Kaplan Meier method. Stage I and II are considered as early stage disease and stage III and IV as advanced stage disease. The difference between the event-free and overall survival was examined by log-rank test. Due to the small sample size, we do not attempt to look for any prognostic factors from our study.

Fig. 1 Distribution of Histologic Subtypes of NHL

 

Fig.2 St. Jude (Murphy's) staging system for childhood NHL
Stage I A single tumour (extranodal or single anatomic area[nodal]) with the exclusion of mediastinum or abdomen.
Stage II A single tumour (extranodal) with regional node involvement.
Involvement of 2 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 ileocecal area, with or without involvement of associated mesenteric nodes.
Stage III Two or more tumour (extranodal) on opposite sides of the diaphragm.
Two or more nodal areas above and below the diaphragm
Presence of the primary intrathoracic tumours (mediastinal, pleural, thymic).
Presence of extensive primary intra-abdominal disease.
Presence of paraspinal or epidural tumours, regardless of other tumour site(s).
Stage IV

Any of the above with initial CNS or/and bone marrow involvement.

Results

Within this 11 years period, 21 patients were diagnosed to have non-Hodgkin's lymphoma (NHL) in our unit. Two patients were not included in our analysis. One Caucasian boy was brought back to England after diagnosis and another patient defaulted treatment 5 months after starting chemotherapy. In the 19 patients that we analyzed, all were Chinese except with one Indonesian boy. The median age was 8-year-old (range 2.5 yrs to 12 yrs) and 13 of them are male. 4/19 (21%) patients had small non-cleaved cell NHL (all Burkitt's); 5/19 (26%) had lymphoblastic NHL and 10/19 (53%) had large cell NHL (4/10 had Ki-1 positive NHL or immunoblastic NHL);. The clinical stages were distributed as followings Stage I (n=3), Stage II (n=2), Stage III (n=8), Stage IV (n=6). The overall survival of all our NHL patients was 80% and the event free survival was 65%. (Fig. 3 a,b,) The event free survival for the early stage disease was 100% and for the advanced stage disease was 58%. (Fig. 3c) The median follow-up period was 3 years (range 6 months to 10 years).

Fig. 3a Overall Survival of Paediatric NHL Patients (QMH)

 

Fig. 3b Event free Survival of Paediatric NHL Patients (QMH)

 

Fig. 3c Event free Survival of Paediatric NHL Patients (QMH)

Small Non-cleaved Cell NHL

All of our 4 patients with small non-cleaved cell NHL had Burkitt's type. Three of them presented with intestinal obstruction, 2 of 3 in the form of intussusception. Of these 3 patients, 2 were treated with the contemporary protocol in the mid 80's and both of them are long term survivors (9 and 10 years respectively). Unfortunately, both of them had therapy-related cardiac complication and one required regular anti-failure treatment. For the patient who was on anti-failure treatment, she had extensive disease at diagnosis. She developed severe vincristine hypersensitivity with anaphylactic shock during her fourth course of chemotherapy and whether this would predispose her to the cardiac toxicity effect of other agents (ie. adriamycin) remained unknown. Both of them received less than 300 mg/m2 of accumulative adriamycin dose. The other one patient with stage II disease was treated with 901 protocol and has been disease free for 4 years now. The fourth patient had mandibular swelling compatible with the endemic form of Burkitt's lymphoma commonly found in equatorial Africa. Cytogenetic analysis showed typical t(8;14)(q24;q32) abnormality. He had stage III disease and responded well to the 902 protocol. None of these 4 patients developed tumour lysis syndrome. The event free survival of our patients with small non-cleaved NHL was 100% with a median follow-up period of 6.5 years.

Lymphoblastic NHL

Five patients were diagnosed to have lymphoblastic NHL, all except one had stage IV disease. The only early stage patient presented with an asymptomatic inguinal lymphadenopathy and was incidentally found to have localized lymphoblastic NHL, of pre-B immunophenotype. She was treated with the 904 regimen. She was extremely sensitive to the chemotherapy and suffered from prolonged neutropenia with pulmonary aspergillosis after the first intensification therapy. A modified and shorten version of 904 treatment regimen was given and she was off treatment for 4 months now. Whereas the other 4 patients, all with T-lymphoblastic NHL, had more extensive disease with mediastinal enlargement. They were treated with ALL type of therapy. Since most of them presented in the mid to late 80's, the old UKALL-VIII therapy9 was given to 2 patients and LSA2-L2 regimen to one patient. Only one patient received the 904 regimen. In fact, our result was quite poor with this subgroup of patients. 3 of them relapsed (the three who were treated with UKALL-VIII and 904 regimen, 2 with hematologic and one with CNS + hematologic relapse). Two of them subsequently died (one because of relapse and the other died of bone marrow transplantation related complication). One patient with relapse was salvageable by chemotherapy alone. The event free survival of our patients with lymphoblastic NHL was 40% with a median follow-up of 6 years.

Large Cell NHL

Large cell NHL of childhood is a clinically and biologically heterogenous group of neoplasms of large lymphoid cells. In childhood NHL, there are two main subgroups namely 1) large cell immunoblastic (Ki-1 positive NHL) and 2) diffuse, large cell (cleaved and non-cleaved).

For the 10 patients with large cell NHL in our series, four of them had Ki-1 positive (expressed CD30 antigen) NHL. This form of NHL is now considered as a separate disease entity with different biology and treatment outcome.10 It is classified as large cell immunoblastic NHL by working formulation and anaplastic NHL by REAL classification. Of our 4 patients with Ki-1 NHL, 3 presented with mediastinal mass associated with pleural effusion (Stage III). The remaining one presented with isolated skin nodule (stage I). They all have T immunophenotype. Constitutional symptoms (ie. fever, malaise) are prominent in all the 3 stage III patients and the presenting history were (< 3 weeks) usually short and rapidly progressing. Two of the three stage III patients were treated with the UKCCSG-NHL 902 protocol and the other one with CCSG-LSA2-L2 protocol. One patient who was treated with the 902 protocol relapsed 11 months after completing his therapy and was retreated with LSA2-L2 protocol again. He finished his relapse-therapy 6 months ago and was still in second remission. His peripheral stem cell was harvested and autologous stem cell transplant would be performed should his disease relapse. None of our Ki-1 NHL patient has bone marrow involvement. The patient with stage I disease had surgical excision alone. There was a question whether this patient actually had lymphomatoid papulosis, which also expressed Ki-1 antigen, but the clinical course and the appearance of the lesion was not typical of that of lymphomatoid papulosis.

Of the other 6 patients with large cell NHL, all had diffuse, large cell NHL (non-cleaved) with B immunophenotypes. Three of them presented as swelling in the head and neck region (one with central nervous system involvement); 2 presented as thoracic mass (one with pleural effusion) and one as intrahepatic mass. All except one had advanced stage disease (3 stage III and 2 stage IV). The only patient with early stage disease in this group presented as progressive snoring and was found to have a nasopharyngeal NHL. He responded well to the 901 treatment regimen. The other two patients with head and neck involvement had more aggressive clinical course. Both had proptosis at presentation and one had 7th nerve palsy as well. One was treated with 902 treatment regimen and the other received LSA2L2 treatment format. Both survived and are long term survivors (3 and 4 years off therapy respectively). Of the three patients with thoracic and hepatic primary NHL, 2 of them had primary immunodeficiencies (Wiskott Aldrich syndrome and ataxic telangiectasia respectively). Both of them responded to 902 treatment regimen quite well. The child with Wiskott Aldrich syndrome subsequently underwent matched unrelated donor transplantation and has been disease-free for almost 4 years now. The third child had an unknown syndromal condition with congenital cerebral atrophy and presented with extensive thoracic disease with central nervous system (CNS) involvement. She was treated with the LMB-0281 protocol11 but suffered from CNS relapse 9 months after therapy. She died of E. coli septicemia shortly after her reinduction therapy 3 months later. The event free survival of our large cell NHL (including Ki-1 positive NHL) was 80% with a median follow-up period of 3.5 years.

Discussions

The three main groups of paediatric NHL are (1) small non-cleaved cell NHL, which can be subdivided as the (la) Burkitt's and (lb) non-Burkitt's type; (2) the lymphoblastic NHL and (3) the large cell NHL, which can be subdivided into (3a) diffuse large cell, cleaved or non-cleaved type, (3b) large cell immunoblastic (including the Ki-1 positive NHL) NHL. (Table I) All our patients belonged to these 3 histologic groups. There are still some confusion about the histologic description of paediatric NHL because of the mixing of terminology from different classifications in the literature. Frequent changes of histologic classifications also make the situation worse. The accurate histologic distinction of the paediatric NHLs is important because their clinical presentation; choice of treatment and prognosis are very different from each other.

Paediatric NHLs progress rapidly. As reflected in our patients population, the presenting history of our patients were usually quite short (mostly less than a few weeks). The involved lymph nodes were often non-tender and firm in consistency. The location of the lymphoid mass depends on the histologic types. Our patients with small non-cleaved cell NHL, Burkitt's type commonly presented as intestinal obstruction in the form of intussusception (sporadic form). Jaw swelling, a common finding of Burkitt's lymphoma in equatorial Africa (endemic form), was uncommon in our children. Constitutional symptom was not a prominent feature until in the more advanced stage. In contrast, patients with lymphoblastic NHL often had prominent constitutional symptoms such as fever with diffuse lymphadenopathy and hepatosplenomegaly. Bone marrow involvement was a very common event in this type of lymphoma. (so called T-lymphoma-leukaemia spectrum) Large cell NHL had a more diverse clinical pictures. For patients with the diffuse, large cell non-cleaved NHL, they could present as head and neck mass, abdominal mass or thoracic mass. Central nervous system involvement was more common in this subgroup. The NHLs of patients with primary immunodeficiency often belonged to this histologic type. Patients with Ki-1 positive NHL usually presented as massive mediastinal mass with pleural effusion and dyspnea. Bone marrow involvement was uncommon but late localized relapse could occur.

The reasons behind the differences in the clinical behavior of the different types of paediatric NHLs may be due to their intrinsic variation in tumour biology. One of the recent advances in paediatric NHL is the identification of their underlying molecular abnormalities. This greatly enhanced our understanding in the biology and pathogenesis of this tumour.12-14 As in lymphoid leukaemia, structural abnormality in the form of chromosomal translocation is common in paediatric NHL.15 The chromosomal translocation will form an abnormal fusion gene product, usually involves a transcription factor (eg. MYC in Burkitt's lymphoma; TAL in T-lymphoblastic NHL) and a lymphoid lineage specific gene (eg. Immnunoglobulin receptor gene in Burkitt's lymphoma; T-cell receptor gene in T-lymphoblastic NHL).12,13 This abnormal fusion gene causes dysregulation or inappropriate expression of the encoded transcription factor and results in the abnormal transformation of the lymphoid cells. In paediatric NHL, the molecular abnormalities of the common histologic types had been identified and the abnormalities are found to be relatively uniform within each histologic type. For example, t(8;14); t(2;8) and t(8;22) are found in Burkitt's lymphoma.12 The t(1;14); t(10;14) and t(11;14) etc. are found in lymphoblastic NHL.13 The t(2:5) is found in large cell NHL, mainly Ki-1 positive NHL.14 These information may help us not only in the understanding of the biology of these tumours but also in confirming the diagnosis, predicting the prognosis and even guiding the therapy in the future. Currently, in addition to the traditional cytogenetic analysis by karyotyping, molecular diagnosis by Southern analysis or reverse transcriptase polymerase chain reaction (RT-PCR) has become more popular and user friendly.1 For example, the RT-PCR for t(2;5) is currently available in our unit.

While the achievement in the biological research of paediatric NHL is phenomenal, the development of highly effective therapeutic approaches for this aggressive tumour is equally successful.16-20 (Fig 4) In Fig. 4, we summarized the results of the various paediatric NHL trials. Our patients sample was small and it was not valid to compare result.

The treatment regimens of paediatric NHL have been tailored according to the histologic subtype and clinical stage. For small non-cleaved cell NHL and large cell NHL, a short intensive therapeutic approach has been adopted by most centres. The treatment mainly utilized a high dose cyclophosphamide-based regimen with high dose methotrexate, vincristine, cytarabine, adriamycin and etoposide. In advanced disease, survival rates of more than 60% have been observed. (Fig. 4) The current challange is to reduce intensity and duration of therapy for patients with limited disease in order to decrease the acute and chronic therapy-related toxicity. To prevent over-treatment is important. Two of our long term survivors suffered from cardiac complications related to treatment toxicity. With the current approach, patients with small non-cleaved cell NHL + CNS involvement or advanced stage large cell NHL still have a poor chance of survival. Autologous stem cell transplantation may be useful for patients with small non-cleaved cell NHL or large cell NHL in relapse.

Fig. 4 Treatment Outcome of Paediatric NHL
Hist. Rx EFS FU No. of pts Ref
SNCC BFM-86 78% 5yr 41 13
  LMB-89 85-87% 2yr 181 14
  CCSG-LSA2L2 29% 5yr 44 4
  CCSG-COMP 50% 5yr 93 4
  QMH 100% 65% 4(2)  
LB BFM-75/81 78% 4yr 42 15
  CCSG-LSA2L2 64% 5yr 124 4
  SJCH-XII 73% 4yr 22 16
  QMH 40%(25%) 6yr 5(4)  
LC CCSG-LSA2L2 43% 5yr 18 4
  CCSG-COMP 52% 5yr 42 4
  CHOP 62% 3yr 21 17
  QMH 80% 3.5yr 10(8)s  
Results of all studies except QMH referred to advance stage disease only () represents EFS and no. of patients of advanced stage disease
Abbreviations: Hist. histology, Rx: treatment protocols, EFS: event free survivals, FU: follow-up, No. of pts.: number of patients,
Ref.: references, SNCC: Small non-cleaved cell, LB: lymphoblastic, LC: large cell.

For patients with lymphoblastic NHL, the general principle is to use the high-risk acute lymphoblastic leukaemia regimen. It requires a much longer treatment period as compared to the regimen of the other two types of NHL. Although the study from NCI suggested that a 15 months therapy may be adequate,21 most centres would still use a 2 or 2.5 years treatment regimen. (Fig. 4) The event free survival was around 60 to 70% for the patients with advanced stage disease in this category.

In conclusion, we reviewed the clinical data of our paediatric patients with NHL over the past 11 years. Majority of them presented as aggressive and advanced disease at diagnosis. Although our treatment regimens varied with time, most patients responded to the treatment and are long term survivors. Their response to treatment seems related to the histology and clinical stage, which are widely accepted as the two most important prognostic factors. Current direction in the management of paediatric NHL is to minimize therapy-related toxicity in the good risk group and to maximize the treatment intensity in the high risk group, this approach requires accurate diagnosis and staging. The treatment regimen of paediatric NHL is now standardized in the major public hospitals in Hong Kong through the effort of all the members of the Hong Kong Paediatric Haematology/Oncology Study Group. A more meaningful analysis of the local treatment outcome will likely be available in the future.

Acknowledgment

We thank Mr. Wilfred Wong of the University Paediatric Unit for the outcome data analysis.


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