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Editorial Indian Pediatrics 2001; 38: 583-588 |
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Pediatric Non-Hodgkin Lymphomas in Children: Diagnosis and Current Management |
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Pediatric NHLs are divided into three major histological categories: lymphoblastic lymphoma, small non cleaved cell lymphoma and the large cell lymphoma. According to the working formulation for clinical usage, all lymphomas are high grade(4). Recently, a new classification called The Revised European American Lymphoma classifica-tion (REAL) has been devised in which an attempt is made to classify lymphomas based on histology, immunology and genetic features(5). The small non cleaved cell lymphomas are classified into Burkitt’s and Burkitt’s-like lymphomas, lymphoblastic lymphomas are categorized as Precursor T and Precursor B type, while large cell lym-phomas are divided into large B and large T cell type. The majority of large T cell lym-phomas are CD30+ Anaplastic large cell lymphomas (ki-1). Burkitt’s lymphoma, Burkitt’s-like lymphoma and about half of large cell lymphomas in children are of B cell origin. They express surface immunoglobulin of IgM type asociated with Kappa or Lambda chain and B cell specific antigens CD19 and CD20(2,6). They express the common acute lymphoblastic leukemic antigen (CALLA) CD10 but do not express terminal deoxyribo-neucleotidase (TdT). T cell lymphoblastic lymphomas are histologically similar to acute lymphoblastic leukemia. Immunologically, they are of precursor T cell antigen and express CD7, CD5, CD1, CD3, CD4, CD8 and CD2(1,2). A small proportion of T cell lymphomas express CALLA positivity and may be of Pre B phenotype (CD19+, CD20+, HLADR+) but without surface immuno-globulins. Large cell lymphomas for the most part are of B cell origin. The distinction between subtypes of large B cell lymphomas is controversial but they do exist like large B cell lymphoma of the mediastinum. The CD30+ large anaplastic lymphomas have been devided into a "small cell variant" and a "Hodgkin’s-like variant" which may cause confusion in differential diagnosis of Hodgkin’s disease(2). About 25% of ana-plastic large cell lymphomas contain Ebstein-Barr Virus (EBV). Some pleomorphic T cell lymphomas do not express CD30 and are called peripheral T cell lymphomas(2,7). The characteristic chromosomal transloca- tion in 80% of Burkitt’s lymphoma is the 8;14 translocation where C-myc is translocated from chromosome 8 to the heavy chain locus on chromosome 14. In the variant transloca-tion, a part of the light chain constant region is translocated to chromosome 8 distal to the C-myc gene. It is probable that the inappro-priate expression of C-myc occasioned by the translocation maintains the cell in a proli-ferative state(1,2,8). Nearly, 60% of small non cleaved cell lymphomas also contain mutations in the coding region of C-myc which cause further deregulation at a func-tional level. There is correlation between the location of breakpoint associated with 8;14 translocation and geographical origin of the tumor(8). In African Burkitt’s, the breakpoint is mostly upstream of the gene. In North American tumors, the breakpoint is within the gene and in South American tumors, it’s in the immediate upstream flanking sequences of C-myc. These genetic and molecular abnormalities will lead to a better under-standing of pathogenesis of these tumors resulting in novel approaches for the treatment that are highly tumor specific. The maturity of lymphoblastic lymphomas don’t bear any specific translocation except in some cases where it involves T cell receptor genes particularly T" and T* situated on chromo-some 14q11 and T$ situated on chromosome 7(1,2). Anaplastic large cell lymphomas manifest 2;5 translocation which is found in 50% of the cases(9). Molecular characteriza-tion of this translocation has led to the development of a reverse transcriptase poly-merase chain reaction (RT-PCR) assay that detects the over expression of Tyrosine kinase gene (ALK) in these tumors(2,9) Clinical Presenation Clinical presentation of NHLs correlate well with their rapid growth and doubling time. Majority of the patients will have widespread disease involving bone marow and/or central nervous system(1,2). Patients with precursor T cell lymphoblastic lympho-mas usually present with a mediastinal mass, often accompanied by pleural effusion. The lymphadenopathy is usually supradiaphrag-matic. Patients may present with pain, dys-phagia, dyspnea, swelling of neck, face and upper limbs due to superior venacaval obstruction. Hepatosplenomegaly may occur but abdominal involvement is rare. Bone marrow involvement is common and CNS involvement though rare may present as cranial nerve palsy or pleocytosis of cere-brospinal fluid. If tumor cells in the bone marrow exceed 25%, patient is classified and treated as acute leukemia. Patient with spora-dic Burkitt’s lymphoma primarily manifest in the abdomen with picture-like appendicitis (Ileocecal area), intussusception, abdominal pain, change in bowel habits, gastrointestinal bleeding or perforation. Other organs such as bone, testis, breast, salivary glands or thyroid gland may also be involved. Bone marrow and CNS may be involved quite commonly(1,2). Endemic Burkitt’s lym-phoma manifest with jaw involvement (70%) and may involve orbit, paraspinal region and CNS. Abdominal involvement can occur but does not include ileocecal area(10). Large cell lymphomas can involve anterior mediastinum or abdomen depending upon the immuno-logical subtype. The Ki-I lymphoma typically involves lymphs nodes but can involve skin, lungs and muscle. Bone marrow and CNS involvement is rare(1,2). Diagnosis needs to be made expeditiously due to the rapidity of growth of these tumors. Histology is the primary mode of establishing a diagnosis with support from immunology, karyotype and molecular genetics. Always obtain adequate amount of tissue by open biopsy. If patient’s condition doesn’t allow anesthesia, diagnosis can be made by percutaneous fine needle aspiration of lymph node or examination of pleural ascitic fluid, or bone marrow. Most common staging system used is the St. Jude Staging System which separates patients with limited stage from the ones with disseminated stage and goes from Stage I to IV depending on localized disease to disseminated disease, respectively(1,2). Other relevant investiga-tions in a newly diagnosed patient include: complete blood count, liver panel, renal panel, mineral panel, lactic dehydrogenase and uritc acid. A CSF examination and bilateral bone marrow aspirate and biopsies are mandatory. Radiological investigation should include computerized tomorgaphy (CAT) of chest, abdominal, pelvis, ultrasonography, gallium scan and bone scan. A staging laparotomy is not indicated as systemic chemotherapy is the main modality of treatment. Prognostically, the treatment delivered for a specific histological type is the most important determinant of outcome(11,12). Tumor burden at presentation also remains one of the important prognostic factors. In large cell lymphomas, a T cell or indeter-minate subtype with bone marrow involve-ment carries a grave prognosis. Role of surgery and radiation therapy is again very limited(1,2). Management Management of NHL is best carried out in specialized centers where physicians are familiar with the management of these tumors. Patients presenting with extensive disease may have a number of complications that require management prior to the initiation of specific chemotherapy treatment(13). The initial step in management is to address emer-gency situations, such as airway obstruction, cardiac tamponade or arrythmia, raised intracranial pressure, superior or inferior venacaval obstruction and renal obstruction. Metabolic complications, such as uricosemia, hypercalcemia and hyperkalemia which occur due to tumor lysis syndrome need to be corrected with hydration and Allopurinol and Uricase(2,13). Fever and pancytopenia also need to be treated with antibiotics after obtaining appropriate cultures. Colony stimulating factors have a definite role in reducting the duration of neutropenia and minimizing hospital days. Once patient is stabilized, the diagnosis needs to be established histologically and immuno-phenotypically as expeditiously as possible by the least invasive method. The extent of disease and risk categories need to be determined and specific chemotherapy ini-tiated as soon as possible. Chemotherapy regimens initially were same as those for acute leukemia but results were better in lymphoblastic lymphoma than in non-lymphoblastic lymphomas especially the small non cleaved cell type. In the 1970’s and 1980’s. Children Cancer Group (CCG) conducted a clinical trial where a randomiza-tion was done between a four-drug regimen COMP (Cyclophosphamide, Vincristine, Prednisone and Methotrexate) or a ten-drug regimen called LSA2L2based on an ALL trial done earlier at Memorial Sloan Kettering Cancer Institute(14). Both treatments were of 18 months duration. The results of this study were extremely important for design of further chemotherapy protocols for NHLs. The good response was seen with both types of regimens in limited disease. Patients with extensive disease responded differently. Clearly, superior results were obtained in small non-cleaved cell lymphomas with the COMP regimen while lymphoblastic lympho-mas responded well to the ALL type LSA2L2 regimen. Currently, for lymphoblastic lymphoma, the ALL type of regimens give the best results. The most successful protocols are the Berlin Frankfort Munster (BFM) protocols and the modified versions of LSA2L2 proto-cols(15-19). Chemotherapy is given over 12-32 months. In all protocols, intrathecal chemotherapy is given for CNS prophylaxis. The optimal duration of therapy for limited disease in lymphoblastic lymphoma is still controversial. Pediatric Oncology Group (POG) used nine months of therapy resulting in an event free survival of 70%(2). Some centers have used a prolonged duration of treatment even for limited disease. Event free survival is 80-90% for limited disease and 65-80% for advanced disease(1,2). Burkitt’s and Burkitt’s-like lymphomas are treated with intensified but short duration protocols lasting only few months(17-20). These protocols use alkylating agents com-bined with high dose Methotrexate, Vincris-tine, Epipodophylins, Anthracyclines and Cytarabine. Prophylactic therapy for CNS disease is given to all patients. Long-term event free survival of 90-100% for limited disease and 75-85% with advanced stage disease has been obtained with such regimen. Survival rate for patient with extensive bone marrow disease (B cell ALL) have also reached 90% with BFM regimens and the SFOP (Society Francais d-oncologic pedia-trique) regimens(19-20). CNS disease at diag-nosis is not considered to be a detrimental factor. Cranial radiation therapy is not used in BFM and US trials but is used in the French studies. The outcome in all these different studies is pretty much identical. Optimal therapy for large cell lymphoma is still not clearly defined due to the heterogeneity of these tumors. B cell immuno phenotypic patients have superior survival with Burkitt lymphoma type of treatment regimen. Peripheral T cell lymphomas are better treated with lymphoblastic lymphoma type protocols(2,21). Role of radiation therapy in these tumors is again not very clear. It appears that it seems warranted for residual disease left after appropriate induc-tion chemotherapy. Recurrent NHLs after intensive chemotherapy have extremely poor prognosis. Such patients are best treated with dose intensified chemotherapy followed by bone marrow transplant(22). The data with allogeneic transplant seemed to be superior than the autologous transplant. Such patients can also be tried on new phase II drugs to define activity and response for these drugs in an effort to move them into the front line protocol. More recent therapeutic approaches include the use of radio labeled monoclonal antibodies. g interferon or retinoic acid(2). Future considerations in the Non-Hodgkin lymphomas include more advanced know-ledge of molecular genetic and resulting bio-chemical abnormalities underlying the patho-genesis of these tumors and further stratifica-tion into different risk groups. Treatment strategies such as phenotype specific immu-notoxins, cytotoxic T lymphocytes against specific surface proteins may have application for treatment of specific lymphomas. As the survival of these patients is extremely good, efforts to reduce the long-term toxicity in these patients may be an equally rewarding exercise. Monitoring for anthracycline induced cardiomyopathy and second malig-nancies secondary to the alkylating agent and the Epipodophylins is very much needed(2,23). Trib S. Vats,
Professor and Regional Chair, Funding:
None.
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