Diagnosis Of Burkitt Lymphoma Research Articles

Intussusception as a presenting feature of Burkitt lymphoma: implications for management and outcome

Intussusception is a recognised but unusual presenting feature of Burkitt lymphoma. We sought to identify the clinical features associated with intussusception in this setting, and assess the outcome following protocol directed chemotherapy. A retrospective case note review was performed on patients treated for Burkitt lymphoma at our institution between 1976 and 2010. Cases presenting with intussusception were identified from hospital records and oncology database. Fourteen of the 210 children seen with a diagnosis of Burkitt lymphoma during the study period (6.7%) developed intussusception. Median age was 6.1 years (range 2.5-10.9). Twelve patients presented with recurrent abdominal pain, and two patients with a jaw mass associated with endemic Burkitt lymphoma. Nine patients underwent a right hemicolectomy with ileo-colic anastomosis, and five had segmental small-bowel resections. Three patients had bone marrow involvement at diagnosis, two of whom died. All patients received chemotherapy. Median follow-up was 6.07 years (range 0.1-28.8). Small bowel lymphoma should be considered in children presenting with intussusception above the normal infantile peak age range. The presentation is often insidious, and complete obstruction may not be apparent. However, when surgically resected, the majority can achieve a good outcome with additional chemotherapy.

Abstract B93: Clinical characteristics, treatment, and outcome of childhood Burkitt's lymphoma in the Uganda Cancer Institute

Abstract Introduction: Burkitt's lymphoma (BL), the most common type of childhood cancer in Africa, is a major cause of cancer death among Ugandan children. We conducted a study about trends in the clinical characteristics and outcome of childhood BL over time in the Uganda Cancer Institute (UCI). Subjects and methods: Medical records of individuals with BL aged less than 18 years admitted to the UCI between 1985 and 2005 were reviewed. The study period was divided into the following periods of diagnosis: 1985–1990, 1991–1995, 1996–2000, and 2001–2005. Results: Of the 1,237 medical records of children with BL obtained from UCI patient registers, 1,217 had sufficient recorded information and could be included in our study: 766 (62.94%) boys and 451 (37.60%) girls; the mean age at diagnosis was 6.69 years. There were no significant changes in the proportion of boys and girls diagnosed, nor in the mean age at diagnosis throughout the study period. The most common tumor presentations were facial tumor (77.65%), abdominal disease (69.19%), systemic presentation with generalized lymphadenopathy (42.07%), and hepatic mass (37.80%). Presentation with hepatic mass (p=0.001) and malignant pleocytosis (p<0.001) increased during the study period, whereas other tumor presentations remained similar. Most children presented with stage C (32.12%) or D (26.67%) BL, and there was an increase in the proportion of children presenting with advanced-stage BL during the study period (p=0.005). Overall 89.97% of children in the present study received at least one cycle of chemotherapy, and overall remission was observed in 75.71% of them. The most common symptoms at BL diagnosis were fever (51.03%), anemia (48.73%), and weight loss (48.32%). Significant increases in the proportion of children presenting with fever were observed during the study period (p=0.007), as well as significant changes in the proportion of children presenting with anemia, night sweats (p<0.001 each) and severe infection (p=0.002) between periods of diagnosis. HIV positivity was 3.87%, and no substantial differences in the proportion of children who where HIV positive were revealed in different periods of diagnosis (p=0.205). Five-year mortality was not significantly different during the study period. Conclusions: Mortality was similar in boys and girls, but higher in older children with BL compared to younger ones. Mortality was lower in children who presented with facial tumors compared to other tumor presentations, and higher in those presenting with advanced-stage BL and HIV-positive children. Mortality was substantially lower among those who received chemotherapy. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B93.

Burkitt lymphoma in adults

The diagnosis of Burkitt Lymphoma (BL) and B-cell lymphomas unclassifiable with features intermediate between Diffuse Large B-cell Lymphoma and BL (BLU) in adults remains problematic even with immunophenotyping and MYC gene analysis. Gene expression profiling may improve categorization but is not routinely available. BL and its variants should be treated with specific regimens incorporating intensive courses of chemotherapy with fractionated alkylating agents and cell cycle phase-specific agents that readily cross the blood brain barrier. Subsequent courses should be given as soon as haematological recovery occurs, with the whole course completed within a few months. A number of regimens have been developed that encompass these principles but there have been no comparative randomized trials. The results from several studies suggest that the addition of rituximab is highly efficacious and this may be particularly valuable in older patients. It is usual to employ 'risk-adapted' strategies in the treatment of BL but these must be continually re-evaluated, and 'response-adapted' approaches should be explored. The role of transplantation is limited and largely confined to autologous transplants in patients who only achieve a partial response on front-line therapy or who have a chemosensitive relapse. Further advances will be greatly facilitated by randomized trials, which will require international collaboration.

Morphological, immunophenotypic and molecular characterization of mature aggressive B-cell lymphomas in Chinese pediatric patients

Differential diagnosis of Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B cell lymphoma, unclassifiable, with features intermediate between BL and DLBCL (intermediate BL/DLBCL) can be difficult. We studied 97 Chinese pediatric mature aggressive B-cell lymphomas including 81 BL cases, eight DLBCL cases and eight intermediate BL/DLBCL cases using immunohistochemistry, interphase fluorescence in situ hybridization (FISH) and Epstein–Barr virus (EBV) in situ hybridization. Our results showed that there were no significant differences in the expression of CD10 and BCL6 among cases of BL (91% and 86%, respectively), DLBCL (75% and 63%, respectively) and intermediate BL/DLBCL (75% and 63%, respectively) (p > 0.05). The expression of BCL2 (3% in BL, 50% in DLBCL, 50% in intermediate BL/DLBCL), expression of MUM1 (17% in BL, 63% in DLBCL, 63% in intermediate BL/DLBCL) and mean Ki-67 proliferation index (PI) (93% in BL, 83% in DLBCL, 80% in intermediate BL/DLBCL) were significantly different between BL and DLBCL and between BL and intermediate BL/DLBCL. The frequency of an extra copy of BCL6 (0% in BL, 37.5% in DLBCL, 25% in intermediate BL/DLBCL) and EBV-encoded RNA (EBER) positivity (48% in BL, 0% in DLBCL and intermediate BL/DLBCL) were also significantly different between BL and DLBCL and between BL and intermediate BL/DLBCL. The frequency of C-MYC rearrangement in BL (98%) was much higher than in DLBCL (37.5%) and intermediate BL/DLBCL (50%). Our findings suggest that diagnosis of the mature aggressive B-cell lymphomas in pediatrics should be based on the comprehensive review and integration of morphological, immunohistochemical and molecular genetic features. The expression of CD10 and BCL6 but not BCL2, a high Ki-67 PI (>90%) and a C-MYC rearrangement but not BCL2 or BCL6 rearrangement are the features of BL. MUM1 is not an exclusionary diagnostic marker for BL. As the immunophenotype and molecular genetic features of DLBCL and intermediate BL/DLBCL are similar, intermediate BL/DLBCL is more likely a subgroup of DLBCL in the pediatric population. Regardless of the expression of CD10 and BCL6, strong staining for BCL2, Ki-67 PI below 90% and the presence of extra copies of BCL6 favor a diagnosis of DLBCL or intermediate BL/DLBCL.

Therapeutic interventions for Burkitt lymphoma in children.

Burkitt lymphoma (BL) is an important cancer found mostly in children but uncertainty remains as to the most effective form of management. In endemic areas, late-stage presentation as a result of delayed access to treatment compounds the situation. To assess the evidence for chemotherapy, surgery, radiotherapy and immunotherapy in the treatment of children with endemic BL. We updated and re-ran the searches in the following electronic databases from the time of the first publication; the Cochrane Controlled Trials Register (CENTRAL) (Issue 1, 2011); MEDLINE (January 2011); EMBASE (January 2011); and the clinical trials registry (up to January 2011) to identify relevant trials. In addition, we also updated the search of the US clinical trials register for on-going and completed trials up to January 2011. We also updated the search terms and used the Cochrane filter for identifying randomised trials in MEDLINE. We included randomised controlled trials (RCTs) of any duration. We included studies conducted in children with a confirmed diagnosis of BL. We did not restrict studies by geographical location or by language of publication. We considered any therapeutic intervention. The primary outcome was overall survival. Two review authors assessed studies for relevance. We assessed studies that met the entry criteria for study quality. We independently extracted data and entered the data into Review Manager (RevMan). In this update, two review authors independently assessed citations from the updated search and reviewed abstracts for relevance. We included one new study in this update. In total, 13 trials involving 1824 participants met the inclusion criteria for this review however, data in usable format were only available in 10 trials (732 participants). Inadequate reporting of study methodology was a common feature of the trials preventing thorough assessment of study quality. We were unable to pool data for any of the outcomes due to the differences between the interventions assessed in the studies. Eight studies aimed to induce remission; overall survival did not differ significantly between treatment groups. Five studies aimed to maintain remission. In two out of three studies reporting survival, this was substantial but the difference was not statistically significant between treatment groups. Less aggressive treatment schedules appear to produce similar effects with less adverse event profiles. This review notes a preference in more recent studies for less aggressive care options for treatment of BL. However, the evidence for the relative effectiveness of interventions to treat BL is not strong as studies were small, underpowered and prone to both systematic and random error. We included one additional trial without change of conclusions.

Diagnosis of Burkitt lymphoma using an algorithmic approach – applicable in both resource‐poor and resource‐rich countries

Distinguishing Burkitt lymphoma (BL) from B cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL (DLBCL/BL), and DLBCL is challenging. We propose an immunohistochemistry and fluorescent in situ hybridization (FISH) based scoring system that is employed in three phases - Phase 1 (morphology with CD10 and BCL2 immunostains), Phase 2 (CD38, CD44 and Ki-67 immunostains) and Phase 3 (FISH on paraffin sections for MYC, BCL2, BCL6 and immunoglobulin family genes). The system was evaluated on 252 aggressive B-cell lymphomas from Europe and from sub-Saharan Africa. Using the algorithm, we determined a specific diagnosis of BL or not-BL in 82%, 92% and 95% cases at Phases 1, 2 and 3, respectively. In 3·4% cases, the algorithm was not completely applicable due to technical reasons. Overall, this approach led to a specific diagnosis of BL in 122 cases and to a specific diagnosis of either DLBCL or DLBCL/BL in 94% of cases that were not diagnosed as BL. We also evaluated the scoring system on 27 cases of BL confirmed on gene expression/microRNA expression profiling. Phase 1 of our scoring system led to a diagnosis of BL in 100% of these cases.

Accuracy of Burkitt Lymphoma Diagnosis in Constrained Pathology Settings: Importance to Epidemiology

Burkitt lymphoma (BL) is endemic in Uganda and because of the high incidence, diagnosis is often presumed during clinical care and epidemiologic studies. To assess the accuracy of the clinical and the local pathology diagnosis of BL as assessed by an outside pathology review diagnosis and to understand the limitations on histopathology practice in a resource-constrained setting at 1 hospital in Uganda. Clinically presumed pediatric (<15 years) BL cases with biopsies and pathology reports, from 1993 to 2007, were identified at St Mary's Hospital, Lacor (Gulu, Uganda). Local histopathology procedures, hematoxylin-eosin-stained tissue sections, and formalin-fixed paraffin-embedded blocks were reviewed onsite by an outside pathologist, followed by outside study that included tissue microarray immunohistochemistry and in situ hybridization. Local pathology laboratory procedures were inconsistent and suboptimal, especially for tissue fixation. There were 88 clinically presumed BL cases. Sixty-three could be reviewed by outside pathology (25 cases of lost blocks or no remaining tumor) and showed a clinical diagnostic accuracy of 75% (47 confirmed of 63), with a possible range of 62% to 85%, depending on the actual diagnosis of the 25 nonevaluable cases. There were 64 BL cases diagnosed by local pathology. Forty-five could be reviewed by outside pathology (19 cases of lost blocks or no remaining tumor) and showed a local pathology diagnostic accuracy of 82% (37 confirmed of 45), with a possible range of 58% to 88%, depending on the actual diagnosis of the 19 nonevaluable cases. Non-BL diagnoses included other non-Hodgkin lymphomas, Hodgkin lymphoma, and benign infectious lymphadenopathy. Accuracy of clinical diagnosis of BL was reduced by inclusion of other diseases with similar clinical presentations. Local pathology, using morphology alone, only marginally improved clinical accuracy and often could not support outside pathology review due to inadequate laboratory procedures. There is an urgent need to improve pathology services in Uganda before conducting high-quality clinical and epidemiologic studies.

T(8;22)(q24;q11) In a Context of Complex Karyotype In Two Patients with B-Cell Lymphoma with Features Intermediate Between Burkitt Lymphoma and Diffuse Large B Cell Lymphoma B (LB/LDCGB)

AbstractAbstract 5093 Background:In some cases, it is difficult to distinguish between the diagnosis of Burkitt lymphoma (LB) and Diffuse Large Cell Lymphoma B (DLCL-B) with MYC gene rearrangement. The WHO classification distinguishes three clinical entities: LB, LB/DLCL-B, DLCL-B on the basis of morphology, immunophenotype and genetic characteristics of malignant cells. The MYC gene is often rearranged with the gene that encodes the heavy chains of immunoglobulins (IgG 14q32) and, less frequently, with the gene that encodes the light chains kappa (2p12) or lambda (22q11). Objective:Describe clinical and biological characteristics of two cases of lymphoma with variant t(8;22)(q24;q11) in a complex karyotype diagnosed BL/DLCL-B according to the WHO classification. Methods and Patients:The cytogenetic study was made in the bone marrow (aspirate or biopsy). Leukocytes were incubated during 24h in RPMI without mitogens. Rearrangements of C-MYC, BCL-2, BCL-6 and IGH were studied for FISH techniques. The results were expressed according to ISCN 2009. Case 1:A man of 46 years who was admitted with symptoms of spinal cord compression with fever and weight loss. During admission were detected anti-HIV antibodies. In the biopsy were observed large cells with irregular nuclei, with clefts and some multilobulated. Imunohistochemistry: CD10 +, CD20 +, CD79 +, bcl2 + and BCL6 +. The Ki67/MIB1 was 95%. Cytogenetic study of bone cylinder showed a complex karyotype: 49, XY, +1, del (1) (p22), der (2), der (3), +7, t (8;22)(q24;q11), +10, del(10)(q24q26)x2 [3]. The FISH study demonstrated the rearrangement of C-MYC and the absence of BCL2 and BCL6 rearrangement. Case 2:A man of 67 year old was admitted for epigastric pain, nausea, vomiting and weight loss. The aspirated cells were of medium and large size, irregularly shaped nuclei, some creases and other poly-lobed with prominent nucleoli. Was detected by immunohistochemistry positivity: CD10, CD20, CD79 and BCL6 Ki67/MIB1 presented a 90%. Cytogenetic study of the bone marrow showed a complex karyotype: 49, XY, t(1;11)(q21;p13),+7, t(7;13) q32;q12), t (8;22)(q24;q11),+12,+19[40]. The FISH study demonstrated presence of the rearrangement of C-MYC and BCL2 and BCL6 rearrangement absence. Conclusions:- Both cases are representative of the clinical entity BL// DLCL-B recently recognized by the WHO: anisocitosicas cells with a nucleus of irregular or poly-lobed, with Ki67/MIB1 <90% and C-MYC rearranged with a complex karyotype. - Both cases showed the t(8;22)(q24;q11) rare variant of Burkitt lymphoma and a trisomy 7, trisomy usually observed in DLCL-B. Disclosures:No relevant conflicts of interest to declare.

Primary Burkitt Lymphoma of the Chest Wall

Abstract Introduction Burkitt lymphoma (BL) originating in the skin and soft tissue is very rare. To our knowledge, this case of primary sporadic BL presenting as an isolated chest wall mass arising from the soft tissue in an adult may be the first report. Case Report A previously healthy 33-year-old Caucasian man presented with a 1-month history of a painful lump over the left breast that he initially noticed as a small “pimple-like” lesion in the area. After a week, the skin lesion became larger, erythematous, and painful. At a local hospital, he underwent an incision and drainage procedure for a presumed chest wall abscess. Several days after debridement, a similar lump recurred around the incised area, which rapidly grew in size. He also started experiencing fever and chills for which he was readmitted with a diagnosis of necrotizing chest wall infection. A second debridement with excisional biopsy of the chest wall revealed atypical lymphoid cells, prompting transfer to our institution. Upon transfer, a large, gaping, erythematous and indurated wound with indistinct, thickened borders and extensive edema and necrosis of subcutaneous tissue and musculature of almost the entire left chest wall was noted. No palpable peripheral lymphadenopathy or organomegaly were observed. He underwent minimal debridement and partial excision. The histopathology revealed atypical lymphocytes with prominent nucleoli, deeply basophilic cytoplasm, and abundant lipid vacuoles in a “starry-sky” pattern. The lymphoid population was CD-20 and CD-10 positive, negative for CD-5 and BCL-2, nearly 100% Ki-67 positive, and indeterminate for light chain restriction. Molecular cytogenetic analysis revealed fusion signals with IgH/Myc t(8;14) dual fusion probe, supporting the diagnosis of BL. Staging positron emission tomography (PET)/computed tomography (CT) scan showed a large subcutaneous defect of the left hemithorax involving the dermis, subcutaneous tissue, and musculature, measuring 19.3 × 13.9 × 31.0 cm, with maximal SUV of 9.8 and an average of 6.2. No additional involved sites were seen. The bone marrow biopsy showed minimal involvement by BL and abnormal hybridization pattern for IgH/Myc t(8;14) and Epstein-Barr virus, while the peripheral blood and cerebrospinal fluid showed no involvement. HIV and hepatitis serologies were negative. Three days after surgery, chemotherapy with granulocyte colony-stimulating factor (G-CSF) support was initiated for high-risk disease. He received CODOX-M (intravenous cyclophosphamide, doxorubicin, vincristine, methotrexate; intrathecal cytarabine, methotrexate) as cycle 1 followed by IVAC (intravenous ifosfamide, etoposide, cytarabine; intrathecal methotrexate) with rituximab as cycle 2. He developed tumor lysis without end-organ damage. However, a few days after completion of cycle 2, he developed neutropenic fever and pneumonia, and died in septic shock. Discussion Primary chest wall tumors are uncommon. Approximately 50% are malignant, and chest wall lymphoma accounts for Conclusion This case illustrates a primary sporadic BL originating in skin and soft tissue in an adult. Whether this case represents a BL that began in the skin and soft tissue and spread to the bone marrow, or began in the bone marrow and spread to the chest wall cannot be determined. The role of tumor debulking procedure is uncertain, although aggressive chemoimmunotherapy with central nervous system (CNS) prophylaxis is warranted as with other BL presentations.

Detection of cryptic and variant IGH-MYC rearrangements in high-grade non-Hodgkin's lymphoma by fluorescence in situ hybridization: implications for cytogenetic testing

In recent years it has become increasingly evident that MYC rearrangements are not confined to classical Burkitt lymphoma (BL), but also occur in diffuse large B-cell lymphoma (DLBCL) and in the new subtype, “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL” (BCLU), which was recently described in the 2008 revision of the World Health Organization classification. The accurate identification of MYC rearrangements in these three subtypes of high-grade lymphoma is becoming increasingly critical both in terms of diagnosis of classical BL and in light of the prognostic implications in cases of DLBCL and BCLU. We describe three cases of high-grade lymphoma in which cryptic insertion events, resulting in clinically significant IGH-MYC rearrangements, were detectable using an IGH/MYC three-color, dual-fusion fluorescence in situ hybridization (FISH) probe set, but were not detected using break-apart MYC FISH probes, thus highlighting the limitations of using break-apart probes as a stand-alone test, particularly with the increased use of interphase FISH analysis of formalin-fixed, paraffin-embedded tissue sections in the diagnostic work-up of these patients.

Burkitts lymphoma of the small intestine: A cytological diagnosis

Sir, We describe a case of Burkitt’s lymphoma (BL) of the small intestine diagnosed on ultrasound-guided fine needle aspiration cytology (FNAC). BL is a high-grade lymphoma usually involving the mandible and the intestines. An early diagnosis is paramount for prompt and effective management. FNAC forms a rapid and effective tool towards an early detection of these lymphomas. A 5-year-old boy presented with abdominal discomfort and progressively increasing abdominal mass. The computed tomography (CT) scan revealed markedly thickened bowel loops with multiple enlarged lymph nodes. There were well-defined hypoechoic nodular lesions in both the kidneys. A suspicion of lymphomatous origin was raised. Ultrasound-guided FNAC was performed through the thickened bowel. Smears were stained with Giemsa and Papanicolaou stains. Many monomorphic, round to oval single cells were identified. These cells displayed a high nucleo-cytoplasmic ratio, vesicular chromatin and prominent cytoplasmic vacuolization [Figure 1]. Many lymphoglandular bodies were seen scattered in the background. A cytological diagnosis of BL of the small intestine was made. The patient was put on a chemotherapeutic regimen, which resulted in the regression of the abdominal mass. Figure 1 Lymphoma cells with vesicular chromatin and prominent cytoplasmic vacuolization. Background shows lymphoglandular bodies (Giemsa, ×400) The small intestine is a common site of BL in children and is associated with multisystem lesions. Abdominal mass, bone marrow and central nervous system involvement are poor prognostic markers.[1] Total tumor burden is the principal determinant of prognosis. FNAC, along with other ancillary techniques, provides a rapid and simple tool for early diagnosis and treatment. Ogawa et al.[2] used FNAC as a primary tool in the diagnosis of BL of bilateral breasts. Das et al.[3] studied 40 cases of BL and found the intra-abdominal location as a common location in Indian patients. FNAC under guidance can help in a rapid diagnosis, thereby assisting in an early treatment in these high-grade lesions.

Chromosomal Alterations in Gene Expression-Defined Pediatric Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL).

Abstract 2922Poster Board II-898 Introduction:Lymphomas derived from mature lymphocytes in children and adolescents are predominantly aggressive B-cell non-Hodgkin lymphomas (B-NHL), including Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Differences in the clinical course between pediatric and adult aggressive B-NHL suggest distinct pathogenetic mechanisms. This study sought to identify both shared and unique genetic alterations between gene expression-defined pediatric and adult cases of BL and DLBCL. Patients and Methods:Gene expression profiling (GEP) was done on 45 BL and 18 DLBCL specimens from patients 18 years of age or younger, and 38 BL and 106 DLBCL from adult patients. Pediatric specimens were collected from the Cooperative Human Tissue Network (CHTN) pediatric NHL repository through the Children's Oncology Group (COG) and adult specimens were collected from the Nebraska Lymphoma Study Group Registry and Tissue Bank through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). Previously-published gene signatures were used to classify lymphomas molecularly into mBL and mDLBCL groups (Dave et al., NEJM, 2006). The mDLBCL tumors were further classified into activated B-cell-like (ABC), germinal center B-cell-like (GCB), and primary mediastinal B-cell lymphoma (PMBL) subtypes (Rosenwald et al., JEM, 2003). High resolution array comparative genomic hybridization (aCGH) was done on a subset of the pediatric cases using the 250K NspI Human Mapping Array (Affymetrix) to detect DNA copy number alterations (CNA). Results:Molecular classification of the pediatric cases resulted in a 20% reclassification rate for cases with a morphologic diagnosis of BL or DLBCL. Among the 63 pediatric cases, there were 38 mBL (3 of which were DLBCL by morphology), 23 mDLBCL (9 of which were BL by morphology) and two cases which were unclassifiable by the molecular gene signatures. Comparison of the GEP profiles for adult and pediatric mBL failed to identify pathways that differed significantly; however high resolution aCGH analysis revealed a number of abnormalities in the pediatric cases not previously reported in BL, including gains of 3q21, 11q13 and 16p11. A predominance of the GCB to ABC subtype (3:1) was found among pediatric mDLBCL patients. Two cases with mediastinal tumors were classified as PMBL molecularly. Both PMBL cases were female and carried copy number gains of the Rel/BCL11A locus. Comparison of adult and pediatric GCB mDLBCL gene expression revealed enrichment in B-cell surface molecules and markers of antigen-dependent B-cell activation in the adult cases. aCGH analysis identified abnormalities that were both shared (+12q15, +19q13, -6q) between adult and pediatric mDLBCL and unique (-4p14, -19q13.32, +16p11.2) to the pediatric cases. Correlation of DNA copy number and gene expression revealed potential candidate genes for these loci. Conclusions:Pediatric BL and DLBCL classified by morphology were reclassified molecularly in a significant fraction of cases. Although pediatric BL and DLBCL are treated similarly, defining homogeneous molecular entities will be relevant for developing new therapies and future clinical trials. In general, pediatric cases have a more favorable outcome relative to adult patients. However, it is unclear whether this is due to the ability of children to tolerate very intensive therapies or whether distinct pathogenetic mechanisms modulate the disease course. Higher B-cell receptor signaling in adult relative to pediatric GCB DLBCL may be relevant to the outcome. The identification of previously undetected chromosomal alterations unique to the pediatric cases also suggests distinct pathogenetic mechanisms. Elucidation of the underlying genes may provide insight into factors which modulate outcome and could provide novel therapeutic targets with reduced toxicity. Disclosures:Gascoyne:Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Immunohistochemical study using T-cell lymphoma antibody 1 and CD44 in diagnosis of Burkitt's lymphoma

To study the values of immunohistochemistry using T-cell lymphoma antibody (TCL) 1 and CD44 in the diagnosis of Burkitt's lymphoma. Immunohistochemical study for TCL1, CD44, CD10, bcl-2, bcl-6, c-myc and Ki-67 was performed on paraffin-embedded sections of lymphoma cases, including 25 cases of Burkitt's lymphoma and 25 cases of diffuse large B-cell lymphoma. Burkitt's lymphoma commonly expressed TCL1 (96%, 24 cases), CD10 (88%, 22 cases), bcl-6 and c-myc (92%, 23 cases). Only 1 case (4%) expressed CD44 and bcl-2. The Ki-67 proliferation index ranged from 95% to 100%. On the other hand, diffuse large B-cell lymphoma expressed CD44 (84%, 21 cases), CD10 (32%, 8 cases), bcl-6 (72%, 18 cases) and bcl-2 (72%, 18 cases). Four cases (16%) were weakly positive for TCL1. The staining for c-myc was all negative. The Ki-67 proliferation index ranged from 40% to 90%. Immunohistochemical staining for TCL1 and CD44 is a useful ancillary tool in the pathologic diagnosis of Burkitt's lymphoma which is also helpful for the differential diagnosis from diffuse large B-cell lymphoma.

Burkitt lymphoma of the oral cavity: an atypical presentation

Burkitt lymphoma (BL) is an aggressive form of non-Hodgkin B-cell lymphoma with 3 variants: endemic, sporadic, and immunodeficiency-associated types. The sporadic form, most commonly involving the abdomen and ileocecal region, presents as an abdominal mass, rarely presenting in the orofacial region. A 36-year-old Indian female presented to the Hospital of the University of Pennsylvania for evaluation of a persistent intraoral swelling ulceration of the lower right mandibular alveolar ridge with minimal bony invasion. Progressive systemic symptoms of fatigue, weakness, and fever developed without resolution following treatment for a presumed odontogenic infection in the 4 weeks before presentation. An incisional biopsy revealed a diffuse proliferation of intermediate- to large-sized lymphocytes with multiple small peripheral nucleoli, scant cytoplasm, and nuclear pleomorphism. Nearly all cells displayed Ki67 expression. A final diagnosis of BL was rendered following confirmation of a cMYC translocation by fluorescence in situ hybridization. This article presents a case of the sporadic form of BL with atypical presentation clinically and morphologically, primarily involving the oral soft tissue.

Translocations Involving 8q24 in Burkitt Lymphoma and Other Malignant Lymphomas: A Historical Review of Cytogenetics in the Light of Todays Knowledge

Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined bya histologic diagnosis of BL,the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, andthe absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint.These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile.The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.

Excellent Immune Recovery Following the Intensive Chemotherapy CODOX-M/IVAC, An Effective Therapy for HIV-Associated Burkitt's Lymphoma (BL)

Background and aim: The outcome of patients with HIV-associated Burkitt's lymphoma (HIV-BL) treated with infusional regimens remains poor, even in the highly active anti-retroviral (HAART) era. In contrast, promising results have been published in HIV-BL with the same intensive chemotherapies used in the non-HIV population. However, scarce data on immunological recovery following these regimens are available. The objective of this multicentre study was to analyse the outcome of patients with HIVBL treated with the intensive chemotherapy regimen CODOX-M/IVAC and HAART, with a particular emphasis on the analysis of immunological recovery after treatment.Patients and methods: 29 patients (22 male; median age: 38) from 3 UK centres consecutively treated with CODOX-M/IVAC from 2003 to 2008 were included in the study. CODOX-M/IVAC consisted of 2 alternating cycles of CODOX-M (cyclophosphamide 800mg/sqm day 1 and 200mg/sqm days 2–5, doxorubicin 40mg/sqm day 1, vincristine 1.5mg/sqm days 1 and 8, methotrexate 3g/sqm day 10) and IVAC (etoposide 60mg/sqm days 1–5, ifosfamide 1g/sqm days 1–5, cytarabine 1g/sqm bd days 1 and 2) for patients with high-risk disease and 3 cycles of CODOX-M for patients with low-risk disease. High-risk disease was defined by the presence of at least 2 of the following: stage III–IV, ECOG≥2, extranodal sites≥2 or high serum LDH. All patients received concomitant treatment with HAART (NRTI + NNRTI: 21; NRTI + PI: 8) and prophylactic antimicrobials as well as intrathecal prophylaxis and G-CSF as per protocol. Four patients received rituximab in combination with the chemotherapy. Lymphocyte subsets and plasma HIV-1 viral load (VL) were measured during chemotherapy and at 3-month intervals during follow-up.Results: HIV was diagnosed concomitantly with BL in 12 patients. The median CD4 count at BL diagnosis was 167/mm3 (range: 4–848), with CD4>200/mm3 in 41% of patients and VL being undetectable in 5 (18%) patients. Eight (28%) of the patients previously known to have HIV infection were on HAART before the diagnosis of BL. The majority of the patients (72%) had high-risk disease. Twenty patients (69%) were diagnosed in advanced stage (III–IV), with bone marrow (BM) involvement in 6 (21%) and central nervous system (CNS) infiltration in 5 (17%). The International Prognostic Index (IPI) was high (3–5) in 14 (48%) patients. Grade 3–4 non haematological toxicity was as follows: infection, 66% of the cycles; mucositis, 12%; and diarrhoea, 13%. Nine patients died during treatment, due to disease progression in 3 cases, toxicity in 5 (3 infections, 2 GI bleeding) and 1 patient died with a CNS lesion that was not biopsed. Response at the end of treatment amongst 23 assessable patients was as follows: complete response (CR)/CR uncertain (CRu): 16 patients (69%); partial response (PR): 4 (17%); progression: 3 patients (13%). After a median follow-up of 17 months (range: 9–67), 17 of 20 responding patients remain alive without disease progression, whilst 2 patients (1 CR, 1 PR) relapsed at 2 and 1 months after finishing treatment and died. One HAART non-compliant patient died in CR of HIV-related causes. Three patients in PR at the end of treatment survive without evidence of disease progression at 28, 37 and 51 months. Overall survival (OS) and disease-free survival (DFS) at 3 years were 49% and 70% respectively. Blood samples for immune recovery analyses were available for the majority of the patients during follow-up (81% 6 months after finishing chemotherapy, 86% at 12 and 24 months). VL was undetectable in 85% and CD4>200/mm3 in 53% of assessable patients 6 months after completing chemotherapy.Time (no. patients at risk)% CD4>200/mm3VL undetectableno./no. assessed%no./no. assessed%At BL diagnosis (29)12/29415/28181 month after finishing chemotherapy (21)5/172910/15676 months after finishing chemotherapy (16)8/155311/138512 months after finishing chemotherapy (14)9/127510/1283Conclusions: This retrospective analysis demonstrates that the intensive regimen CODOX-M/IVAC is feasible and effective in HIV positive patients on HAART with BL. Immunological recovery after treatment, not previously reported after such intensive chemotherapy, is excellent. Whether concomitant treatment with rituximab will improve outcome warrants further study.

MicroRNAs Distinguish Burkitt Lymphoma from the Molecular Subsets of Diffuse Large B Cell Lymphoma.

Background: Burkitt lymphoma (BL) is a highly aggressive lymphoma that can be cured in up to 80% of patients when treated with intensive multi-agent chemotherapy. The distinction between BL and diffuse large B-cell lymphoma (DLBCL) is critical because there are important differences in their clinical management. However, the distinction can be difficult because of an overlap between DLBCL and BL in morphology, immunophenotype and cytogenetics. Previous work has shown that gene expression profiling can distinguish these entities with a high degree of certainty. Our previous work has demonstrated that microRNAs play a direct role in regulating key transcription factors in normal and malignant B cells. We investigated whether microRNA expression could be used to reliably distinguish BL from DLBCL.Methods: Biopsy samples were collected from 104 patients with a diagnosis of either sporadic BL (N=25) or DLBCL (N=79). All cases were reviewed for pathology diagnosis and profiled for microRNA expression using microarrays. Using the 30 most highly differentially expressed microRNAs with the highest t-statistic, we applied singular value decomposition to identify the 10 most predictive microRNAs. Using those 10 microRNAs, we constructed a Bayesian predictor to distinguish BL from DLBCL. The predictor performance was tested using leave-one-out cross-validation. We further applied gene expression profiling to 52 cases of DLBCL to identify the molecular subsets of DLBCL: activated B cell type and germinal center B cell type DLBCL. We constructed a Bayesian predictor to distinguish these molecular subsets based upon their gene expression. A separate predictor was created from the microRNA profiles of these DLBCL subsets and tested using leave-one-out cross-validation. In order to understand the effects of lineage-specific microRNAs in B cell lymphomas, we applied FACS-sorting to isolate mature B cell subsets including naïve B cells, germinal center B cells, plasma cells and memory cells. We compared the microRNAs involved in germinal center differentiation to those expressed highly in Burkitt lymphoma.Results: The predictor constructed based on microRNA expression was 90% accurate in distinguishing Burkitt lymphoma from DLBCL, using pathology diagnosis as the standard. The microRNA-based predictor was also over 90% accurate in the distinction of the molecular subsets of DLBCL, compared to the gold standard of gene expression-profiling. Further, we found that the Burkitt lymphoma cases consistently expressed microRNAs related to normal germinal center B cell differentiation, suggesting that they also maintain expression of B cell stage-specific microRNAs.Conclusion: This study demonstrates that the microRNA expression profiles can be used to accurately distinguish Burkitt lymphoma from DLBCL. The ability of the predictor to identify the molecular subsets of patients with DLBCL and those with BL suggests that it will be useful in the diagnosis and management of patients with Burkitt lymphoma. Further, the patterns of microRNA expression and their target genes suggests a role for microRNAs in the pathophysiology of these tumors.

Burkitt lymphoma in Uganda: 50 years of ongoing discovery

W hile working in Uganda, a physician by the name of Denison Parson Burkitt first described the tumor that now carries his name. In 1957, Dr. Burkitt, along with his colleagues, examined a child with what appeared to be swelling along the jaw. After observing a second child with the same clinical presentation, his curiosity prompted him to study hospital records for similar cases. He found that these tumors affecting the mandible and maxilla were not unusual [1]. He began to record cases that presented to hospital as well as contacting colleagues throughout sub-Saharan Africa to determine whether or not this characteristic tumor had been observed elsewhere. Colleagues in Kenya, (then) Tanganyika, Nigeria, (then) Belgian Congo, and (then) Rhodesia all confirmed seeing cases similar to the ones he was observing in Uganda. He published these findings in 1958 in the British Journal of Surgery in an article titled ‘‘A sarcoma involving the jaws of African children’’ [2]. In this issue of Pediatric Blood & Cancer, Orem et al. [3] continue Dr. Burkitt’s work by compiling medical records, summarizing their observations, and trying to improve the prognosis of children diagnosed with cancer in Uganda today. Estimates predict that by 2020, the number of new cancer cases will increase by 15 million, with the burden of cancer morbidity and mortality carried by developing countries. By this date, the total number of new cases in developed nations is expected to increase by 29% while the total number of cases in developing countries is expected to increase by 73% [4]. Currently only 5% of all global cancer resources are spent in developing countries [5]. In conjunction with the increase in cases, mortality is estimated to be approximately fivefold greater in economically disadvantaged countries when compared to industrialized nations [6], even though one third of these cancers are preventable and another third are treatable if detected early. Unfortunately, approximately 75% of cancer patients in developing countries are in advanced stages of the disease by the time they reach a health care facility with the capacity to diagnose and treat cancer [7]. In order to increase cancer awareness in Africa, the World Health Organization (WHO) has delineated overarching priorities. This strategy involves cancer prevention, registries, early diagnosis and treatment, and palliative care; including provisions that ‘‘responses should be culturally appropriate, economically feasible, and evidence-based’’ [8]. This renewed global interest parallels increased cancer research conducted in Africa within the context of public health priorities faced by these communities. This is especially true due to the prevalence of AIDS-related lymphomas [9] that did not exist during Denis Burkitt’s tenure in Uganda. For childhood cancer in Africa, the study by Orem et al. [3] was able to analyze an impressive number of medical records that were available from 1994 to 2004 to determine the impact of HIV infection on the response to cytotoxic treatment and prognosis of children with Burkitt lymphoma. This is the first report of its kind and offers clinicians a slight reprieve by demonstrating that children diagnosed with Burkitt lymphoma had similar response rates to chemotherapy irrespective of their HIV status. While the study found that the overall survival in children with HIV was poorer than HIV-seronegative children, these patients were seen prior to the wide-spread rollout of anti-retroviral therapy in Uganda. Unlike in adults, where Burkitt lymphoma is an AIDS-defining malignancy, HIV does not appear to be a risk factor for pediatric Burkitt lymphoma [10]. However, the authors raise the issue that concomitant HIV infection may influence clinical presentation (i.e., tumor site) or rate of tumor progression. Their finding that HIVseropositive children present more commonly with lymphadenopathy was also reported in a study conducted in Malawi [11]. Most HIV-infected children arrived at hospital in advanced stage of disease, which also contributed to poor prognosis. Unlike Kaposi sarcomas, there has not been a dramatic decrease in the incidence of HIV-associated non-Hodgkin lymphomas since the introduction of highly active antiretroviral therapy [12]. These clinicalepidemiologic observations emphasize differences in risk factors and tumorigenesis of AID-defining malignancies and reinforce the need to understand etiologic mechanisms leading to a diagnosis of Burkitt lymphoma. The role of another viral co-infection was described for Burkitt lymphoma in 1964 after the isolation of the Epstein–Barr Virus (EBV) by Drs. Epstein, Barr and Achong from a Ugandan patient tumor sample [13]. After the discovery of EBV as a risk factor, a geographic association with high malaria transmission was mapped for endemic Burkitt lymphoma in Africa [14]. This led to the hypothesis that malaria suppressed immune surveillance to EBV and thereby allowed tumorigenesis. However, malaria is not ‘‘immunosuppressive’’ but rather ‘‘immune-modulating’’ concluded by the fact that children with malaria are not at increased risk for opportunistic infections such as those observed in people

Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge

Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, that is, the translocation t(8;14)(q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this review the 'Mitelman Database of Chromosome Aberrations in Cancer,' harboring the majority of all published neoplasia-related karyotypes, was explored to define a cytogenetic profile of 'true' BL. This core subset of BL showed a very low complexity of chromosomal abnormalities with 40% of the cases having the IG-MYC fusion as the sole abnormality. In the remaining cases, additional recurrent but partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. Within the core subset, no differences were found between pediatric and adult patients. In addition, the genetic profile of the core subset was significantly different from BL with an 8q24 breakpoint not affecting one of the three immunoglobulin loci, BL with a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1, additionally to a breakpoint at 8q24/MYC, and from other morphological types of lymphomas with an 8q24/MYC breakpoint. These groups showed a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint might be heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. In addition, a high number of nonspecific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL.

Primary ovarian Burkitt lymphoma

Primary ovarian Burkitt lymphoma (BL) is a rare neoplasm in adults. We report a 30-year-old woman diagnosed with primary bilateral ovarian BL. She presented features of a twisted ovarian cyst and underwent bilateral salpingo-oophorectomy. The histopathologic evaluation yielded the diagnosis of BL and subsequently she received chemoimmunotherapy with CODOX-M-IVAC plus rituximab (anti-CD20 monoclonal antibody).