Burkitt's lymphoma

International Journal of Pediatric Otorhinolao,ngologv, 12 (1986) 73-84 Elsevier

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POR 00395

Burkitt's lymphoma Donald B. Kearns, Richard J.H. Smith and James K. Pitcock Depariment of Otorhinolar),ngologv and Communicative Sciences, Barlor College of Medicine, Houston TX 77030 (U.S.A.) (Received 23 April 1986) (Revised version received 26 June 1986) (Accepted 29 July 1986)

Key words: Burkitt's lymphoma; Epstein-Barr virus; 8-14 q Chromosome translocation; Starry sky pattern

Summary Cancer is the second leading cause of death in children and, among cancers, lymphoma is the third most frequently diagnosed type. The majority of these are non-Hodgkin's lymphomas (NHL). Although NHL have been grouped in a variety of confusing ways, recent research in cytogenetics and immunology, coupled with a better understanding of the normal pathways of lymphoid differentiation, has greatly lessened this confusion. Burkitt's lymphoma (BL) is a type of B-cell NHL which is sub-classified as either endemic (African) or non-endemic (American). Kinetic studies have demonstrated a doubling time of only 24 h. As a result of this extremely rapid growth, symptomatic complaints occur early in the disease course. Structures contiguous to the primary become compressed and metabolic derangements occur. Signs of chronic debilitation such as cachexia, diarrhea, generalized lymphadenopathy, and weight loss usually are not found. Thirteen cases of American BL have been treated since 1980 at the Texas Children's Hospital and form the basis of this review. Ten patients had obstructive abdominal symptoms including constipation and pain, and 3 had masses in the neck, maxilla, or tonsil. Systemic manifestations included ascites, jaundice, fever, and hepatosplenomegaly. Two patients ultimately developed central facial nerve paralysis.

Introduction In 1958, Denis Burkitt described a highly malignant neoplasm which affected children in East Africa [4]. Now known as Burkitt's lymphoma (BL), this tumor has

Correspondence: R.J.H. Smith, Department of Otorhinolaryngology and Communicative Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, U.S.A.

74 TABLE I Malignant lymphoma - Rappaport classification

Well differentiated lymphocytic Poorly differentiated lymphocytic (nodular and diffuse) Mixed cellularity (nodular and diffuse) Histiocytic lymphoma (nodular and diffuse) Undifferentiated lymphoma Burkitt's lymphoma Lymphoblastic lymphoma Mycosis fungoides Immunoblastic lymphoma

been the subject of intense epidemiologic, immunologic, and etiologic interest. Although endemic to regions of Africa, in 1965, O'Connor et al. described a histologically identical type occurring in the United States [19]. This led to the subclassification of BL as either endemic (African) or non-endemic (American). Both types are non-Hodgkin's lymphomas (NHL). N H L are the most common head and neck solid tumors in children. Although characterized by a natural history which can be very aggressive, prognosis has improved during the past 15 years reflecting the advances in chemotherapy that have been made [17,25]. The improved life expectancy has significantly increased knowledge of lymphomas and has shown that childhood varieties differ significantly from their adult counterparts. For this reason, the staging system which is of prognostic relevance for adult N H L is probably not suitable for children [9]. Unfortunately, most histologic and clinical classification systems of N H L do not provide reliable indicators of disease prognosis. This failure is reflected in the number of classification systems that have been used [25]. The most familiar, the Rappaport classification, emphasizes the relationship between histology and prognosis. It divides N H L into diffuse and nodular patterns and then further subdivides those patterns according to the predominant cell type, i.e. lymphocytic, histiocytic, mixed, or undifferentiated. Patients with nodular or well differentiated diffuse lymphomas tend to have smoldering disease and a longer survival than patients with other types of N H L [3] (Table I). Luke's and Collin's classification integrates morphologic, cytochemical, and immunologic markers permitting separation of B and T cell subtypes. This reduces some of the heterogeneity inherent in the Rappaport system. Studies using this classification suggest that B cell lymphomas carry a better prognosis than T cell lymphomas [14,25] (Table II). The Ann Arbor staging system, though originally intended for Hodgkin's disease, has been used by many oncologists to classify N H L despite significant shortcomings. The greatest of these is that the Ann Arbor staging system relates prognosis to anatomic presentation, however, histology is generally considered to be a more reliable prognostic indicator of disease survival in N H L (Table III).

75 TABLE II

Luke's and Collin's classification u cell T-cell Small lymphocyte Convoluted lymphocyte Sezary cell - myosis fungoides Immunoblastic sarcoma Lennert's lymphoma B-cell Small lymphocyte Plasmacytoid lymphocyte Follicular center cell Small cleaved Large cleaved Small transformed (non-cleaved) Large transformed (non-cleaved) Immunoblastic sarcoma Hairy cell leukemia Histiocytic

I n order to c o o r d i n a t e a n d c o m p a r e these classification systems, the Working Formulation of N H L for Clinical Usage was p u b l i s h e d in 1982. This a m a l g a m a t i o n of previous classification systems defines 10 categories of N H L d e t e r m i n e d b y morphologic, prognostic, a n d clinical features. Studies using this system are curr e n t l y in progress [18] (Table IV). A separate staging system for BL has also been developed b y Zeigler to reflect the t u m o r ' s u n i q u e characteristics a n d growth patterns. T h e system emphasizes t u m o r location, bulk, a n d degree of h e m a t o g e n o u s d i s s e m i n a t i o n [29] (Table V).

Historical perspective D e n i s Burkitt was a surgeon practicing at the U n i v e r s i t y T e a c h i n g Hospital in K a m p a l a , U g a n d a , in 1957, w h e n he first n o t e d children with rapidly growing

TABLE III Amz Arbor classification Stage I: Stage It:

Stage III:

Stage IV:

Involvement of a single lymph node region (I) or of single extralymphocytic organ or site (IE). Involvement of two or more lymph node regions on the same side of the diaphragm (It) or localized involvement of extra lymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE). Involvement of lymph node region on both sides of the diaphragm (III) which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIs). Diffuse or disseminated involvement of more than one extralymphatic organ or tissue with or without associated lymph node enlargement,

76 TABLE IV Working formulation of the non-Hodgkin's I.vmphomasfor clinical usage

Low Grade ML, small lymphocytic ML, follicular, predominantly small cleaved cell ML, follicular, mixed small cleaved and large cell Intermediate Grade ML, follicular, predominantly large cell ML, diffuse small cleaved cell ML, diffuse, mixed small and large cell ML, diffuse large cell High Grade ML, large cell immunoblastic ML, lymphoblastic ML, small non-cleaved cell Miscellaneous Composite Mycosis fungoides H.istiocytic Extramedullary plasmacytoma Unclassifiable

t u m o r s of the jaw. T h e tumors appeared to be very c o m m o n in the region in which he worked and histologically were f o u n d to be " s o m e sort of l y m p h o m a " [6]. F r o m his famous t u m o r safari, Burkitt realized that if he deleted f r o m a m a p of Africa all areas in which either the temperature fell below 1 5 . 5 ° C or the annual rainfall was less than 60 cm, he was left with an area that closely a p p r o x i m a t e d the distribution of this l y m p h o m a [5]. W h e n he returned to England, he presented these findings at a medical meeting. A y o u n g m a n in attendance, M.A. Epstein, asked for specimens of the t u m o r and, in 1964, described the virus associated with BL which now bears his n a m e [8]. Because of the impracticalities of radiotherapy, when Burkitt returned to Africa he used cytotoxic agents to treat his patients. F r o m this work, he f o u n d that m a n y children could be cured following a course of c y c l o p h o s p h a m i d e .

TABLE V Staging of Burkitt's lymphoma Stage

Extent of tumor

A

Single extra-abdominal site Multiple extra-abdominal sites Intra-abdominal tumor Intra-abdominal tumor with involvement of multiple extra-abdominal sites Stage C but with 90% of tumor surgically resected

B

C D AR

77 The discovery of the BL associated DNA virus by Epstein, Achong and Barr was the harbinger of a period of intense research to determine if a causal relationship with BL existed. African children with BL were found to have significantly elevated antibody titers to a variety of EBV determinant antigens and 80-90% of tumor cells were shown to contain multiple copies of the EBV DNA genome. EBV antibody titers were also markedly higher in children in whom BL later developed. This association, however, has not proved to be as strong in American cases. Only 15-20% are found to have positive EBV antibody titers [29]. Whether EBV plays a role in the oncogenesis of BL is controversial. One hypothesis suggests that the virus may be pathogenic only in concert with cofactors such as malaria which was implicated with BL on a geographic basis by Burkitt [28]. Another hypothesis suggests that the virus is only an incidental passenger and does not play an etiologic role in BL. And yet a third suggests that antigenic stimulation results in activation of endogenous oncogenic RNA viruses [23]. Most scientists feel that BL results when a host with a prerequisite susceptibility is exposed to select endemic factors. The prerequisite susceptibility may be genetic as the well described incidence of 8-14 q chromosome translocation in association with BL suggests. There is also an increase in the incidence of disease in siblings of affected patients.

Pathology BL typically grows in a concentric fashion as an expanding nodular mass which causes encasement of organs and viscera. Histologically, a diffuse monotonous overgrowth of undifferentiated lymphoreticular cells occurs with very little variation in shape and size. Mitotic activity is high and numerous macrophages are found which contain abundant clear cytoplasm, tumor cells, and intracellular debris. It is the presence of these macrophages that produces the well described 'starry sky' pattern [26]. The African variety usually contains primitive lympho-reticular cells with very little ergastoplasm (granular cytoplasmic reticulum). Lymphoreticular cells in the American variety, in contrast, show a greater degree of differentiation characterized by more ergastoplasm, more mitochondria, and a lesser tendency toward deep nuclear indentation. Notwithstanding this spectrum of differentiation, ultrastructural analysis permits both African and American varieties to be reliably classified as BL [3]. Patients and Methods A 5-year retrospective analysis of patients seen at the Texas Children's Hospital with the diagnosis of BL was done. All patients were native Americans with the exception of one Guatemalan boy and one Panamanian girl. Thirteen cases of BL were found, with a male : female distribution of 11 : 2. The mean age at presentation was 6 years but ranged from 31 months to 13 years. Most patients had symptoms for less than 3 weeks when the diagnosis was made although the range extended from 9 days to 7 weeks. In spite of this short symptomatic period, 3 children had Stage 4 disease, 7 had Stage 3 disease, and only 3 had Stage 2 disease.

78 TABLE VI

Patient profiles

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Sex

Age

Presentation

Stage (Ann Arbor)

M M M F M M M M F M M M M

5 3 6 4 4 3 12 5 7 5 8 13 5

Bilateral cervical and maxillary sinus masses Right maxillary and abdominal masses Right tonsillar mass and paraplegia Abdominal mass and right facial nerve paralysis Abdominal mass and right facial nerve paralysis Abdominal distention and jaundice Abdominal mass Abdominal mass Abdominal pain and mass Abdominal mass and intussusception Abdominal distention Abdominal mass and intussusception Abdominal pain

II III IV IV IV IV III III II II III III III

The most common symptom at presentation was abdominal pain and the most common finding on physical examination was an abdominal mass. This occurred in 10 o f t h e 13 c a s e s . T w o c h i l d r e n d e v e l o p e d f o r e h e a d - s p a r i n g u n i l a t e r a l f a c i a l n e r v e

Fig. 1. Photograph of Case 1 showing right maxillary mass involving the hard palate.

79 paralysis; both had evidence of central nervous system disease and died soon after presentation. Three children presented with head and neck disease. These cases are described in detail (Table VI). Case 1. A 3-year-old Latin American male presented with a 4-week history of lethargy. On physical examination, he was noted to have a distorted right maxilla with infiltration of a mass into the hard palate producing loose maxillary teeth. The examination was also remarkable for a right upper quadrant abdominal mass. CT of the head showed mass involvement of the right maxillary antrum with associated bony destruction. A similar study of the abdomen confirmed the presence of a bulky right retroperitoneal mass. The maxilla was biopsied and the diagnosis of BL was

Fig. 2. Photograph of Case 1 showing fight maxillary mass.

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Fig. 3. Intraoperative photograph of Case 2 demonstrating right tonsillar mass. made. Bone marrow biopsy and lumbar puncture were normal and the patient was treated with COMP and is currently free of disease (Figs. 1, 2). Case 2. A 6-year-old Asian boy presented with a right tonsillar mass which had been treated for two weeks with antibiotics. He had associated paresis of his lower extremities. A presumptive diagnosis of BL was made and arrangements were made for an emergency tonsillectomy. Histopathologic examination confirmed this diagnosis and further studies showed the presence of a paraspinal mass compressing the spinal cord at T4. Systemic and intrathecal chemotherapy were administered resulting in disease remission. Full function returned to both legs (Fig. 3). Case 3. A 5-year-old white boy presented with a 7-week history of bilateral cervical masses and low grade fever. CT examination showed bilateral maxillary and ethmoid sinus opacification ,~ith bony destruction and a Gallium scan confirmed the presence of nasopharyngeal disease. Biopsy of the neck mass was positive for BL. COMP and cytosine arabinoside were begun and this child is currently free of disease (Figs. 4, 5).

Discussion African BL is distinctly different from American BL in its clinical presentation. The mean age of onset for African cases is 7 years and there is a slight male to

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Fig. 4. CT scan of Case 3 demonstrating bilateral maxillary sinus involvement.

female predominance. Most children present with rapidly growing jaw or orbital masses that cause considerable disfigurement. Abdominal tumors are less common but when they occur, may arise from kidneys, ovaries, or retroperitoneal structures. Early neurological complications include paraplegia secondary to either vascular compromise or direct tumor invasion and cranial neuropathies or meningeal involvement from facial tumors. Cranial neuropathies and meningeal involvement, however, are more often associated with disease relapse [1]. American BL usually occurs later in childhood and the reported mean age is 11 years. There is also a more clear male to female predominance approaching 2 : 1. In contrast to the African variety, American BL usually involves the abdomen. Tumors arise in Peyer's patches in the terminal ileum and act as a leadpoint for intussusception [2,12]. Other intra-abdominal sites of disease include the kidneys, ovaries, and mesentery. Nasopharyngeal and cervical involvement, when occurring, affects

82

Fig. 5. CT scan of Case 3 demonstrating bilateral ethmoid sinus involvement.

younger children [13]. Central nervous system disease is rare and usually accompanies diffuse marrow involvement [28]. Similarities between African and American BL include the ultrastructural characteristics of tumor cells, clinical response, and prognosis. Clinical studies suggest that BL is the fastest growing human neoplasm and it may therefore cause problems which require emergency treatment as exemplified by Case 2. Manifestations of BL that are of interest to the pediatric otolaryngologist include bilateral exophthalmus, paranasal sinus disease, tonsillar enlargement and, more rarely, frontal or temporal bone involvement [10,20,21,24,27]. Diagnostic staging protocols have become streamlined and include CT scan and ultrasound to localize abdominal and head and neck masses, bone marrow aspiration, lumbar puncture, and biopsy. Gallium scans and L D H levels are useful to estimate tumor burden and to follow patients serially. Because gallium concentrates preferentially in tumor nodules, it may also be used to localize tumors in the

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nasopharynx [28]. An extensive search for all metastatic disease, however, is unnecessary as it does not influence treatment planning. Treatment of BL begins with surgical reduction to reduce tumor bulk. This aids in the achievement of metabolic stability, particularly the control of serum uric acid levels which may cause urate nephropathy. A study comparing patients having abdominal disease who underwent attempted curative resection with a second group who underwent only biopsy or incomplete resection showed survival rates to be 58% and 40% respectively [11]. Radiation is not indicated as the sole treatment of BL, however, may be of some value in conjunction with chemotherapy to reduce the size of large tumors. Immunotherapy was thought by Burkitt to hold great promise but this has not been realized. A randomized clinical trial using BCG immunostimulation following cyclophosphamide-induced remission has shown that while BCG accelerates immunologic recovery, relapse is not prevented and may parodoxically be promoted by immune stimulation [29]. Systemic chemotherapy is the treatment of choice. An intermittent high dose regimen of cyclophosphamide, vincristine, methotrexate, and prednisone is used with the occasional addition of cytosine arabinoside to further lower the relapse rate [29]. These agents cause a rapid destruction of tumor cells and the metabolic toxins that are released can be rapidly fatal. For this reason, children must be closely monitored during treatment so that the 'acute tumor lysis syndrome' can be treated [7]. Patients with CNS disease require intrathecal doses of methotrexate and cytosine arabinoside [22]. Generally, as the intensity of treatment is increased the frequency of systemic relapse is reduced and, after 6 disease-free months, it is uncommon. Because of the blood-brain barrier, however, the CNS persists as a frequent site of recurrence. For this reason, therapeutic regimens now include CNS prophylaxis and may prove successful in decreasing CNS relapse [15]. Prognosis is found to bear a direct relationship to tumor burden at initial presentation. Tumor burden, in turn, is directly reflected by LDH and uric acid levels and, probably, indirectly by anti-EBV titers. Prognosis also appears to be inversely related to age [16]. Overall complete remission rates range from 88 to 100% with cure rates of approximately 50% [29].

Conclusion

Burkitt's Lymphoma provides a model for clinical advances in oncology. Pediatricians, oncologists, surgeons, and radiotherapists have all provided concrete data on this disease and it now ranks as one of a dozen neoplasms that can be cured by drugs alone.

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