Setting: Burkitt’s lymphoma is a rare form of cancer and is an extremely rare diagnosis during pregnancy. This form of lymphoma is a very fast growing B cell neoplasm and chemotherapy is the treatment of choice for the disease in all its stages.
Case report: The authors describe the case of a Caucasian 40-year-old nulliparous woman, with previous known Epstein–Barr virus infection, that presents at 28 weeks gestation with supraclavicular adenopathy and multiple bilateral breast nodules, in which biopsy showed non-Hodgkin lymphoma, Burkitt’s type.
Discussion: There are few described cases of Burkitt’s lymphoma during pregnancy and in general the outcomes have been poor. In most of the cases, the patients were not treated by current standards or instead had a late diagnosis. This neoplasia is the most rapidly progressive human tumor, and any delay in initiating therapy can adversely
aVect patient’s prognosis. The authors discuss treatment options in pregnancy and its perinatal implications

Alves, MJ

Borges, A

Cordeiro, A

Frade, MJ

Machado, AI

Repositório do Centro Hospitalar de Lisboa Central, EPE

Arch Gynecol Obstet (2009) 280:297–300DOI 10.1007/s00404-008-0873-3CASE REPORTBurkitt’s lymphoma related to Epstein–Barr virus infection during pregnancyAlexandra Cordeiro · A. I. Machado · A. Borges · M. J. Alves · M. J. Frade Received: 9 June 2008 / Accepted: 27 November 2008 / Published online: 24 December 2008©  Springer-Verlag 2008AbstractSetting Burkitt’s lymphoma is a rare form of cancer and isan extremely rare diagnosis during pregnancy. This form oflymphoma is a very fast growing B cell neoplasm and che-motherapy is the treatment of choice for the disease in allits stages.Case report The authors describe the case of a Caucasian40-year-old nulliparous woman, with previous knownEpstein–Barr virus infection, that presents at 28 weeks ges-tation with supraclavicular adenopathy and multiple bilat-eral breast nodules, in which biopsy showed non-Hodgkinlymphoma, Burkitt’s type.Discussion There are few described cases of Burkitt’slymphoma during pregnancy and in general the outcomeshave been poor. In most of the cases, the patients were nottreated by current standards or instead had a late diagnosis.This neoplasia is the most rapidly progressive humantumor, and any delay in initiating therapy can adverselyaVect patient’s prognosis. The authors discuss treatmentoptions in pregnancy and its perinatal implications.Keywords Burkitt’s lymphoma · Pregnancy · ChemotherapyIntroductionBurkitt lymphoma (BL) is a rare non-Hodgkin lymphomathat results from B lymphocytes monoclonal proliferation,making less than 1% of non-Hodgkin lymphomas in adults.This high-grade B cell neoplasm is one of the most aggres-sive malignancies known and, although it is typically achildhood disease, it can be observed in adults. However,BL is rare during pregnancy. The infection with Epstein–Barr virus (EBV) has strong association with the Africanform, while it is associated only with about 15–30% of spo-radic cases [6, 8, 10]. The purpose of this report is to pres-ent a case of BL related to EBV infection during pregnancyand to discuss obstetric and perinatal implications ofadequate treatment.Case reportA 40-year-old Caucasian woman, G2 P0, with a preg-nancy of 27 weeks gestation was referred to our maternal–fetal department for evaluation of supraclavicular lym-phadenopathy. The patient had no history of fever orweight loss but referred night sweats and recent breastenlargement. She had a history of EBV infection withcervical lymphadenopathies 2 years before, and preg-nancy had been uneventful until that time. On examination,there was a left supraclavicular lymphadenopathy with2 £ 1.5 cm and multiple tender nodules with less than2 cm on both breasts. The chest and abdominal examina-tion had no other alterations and pelvic examinationA. Cordeiro · A. I. Machado · M. J. AlvesDepartment of Maternal-Fetal Medicine, Maternidade Dr. Alfredo da Costa, Lisbon, PortugalA. BorgesDepartment of Internal Medicine, Maternidade Dr. Alfredo da Costa, Lisbon, PortugalM. J. FradeHematology Department, Portuguese Institute of Oncology, Lisbon, PortugalA. Cordeiro (&)Rua Virgilio Correia, Lisbon, Portugale-mail: alexandra.cordeiro@sapo.pt123298 Arch Gynecol Obstet (2009) 280:297–300revealed the uterus to be the size of 27 weeks gestationwith fetal heart tone audible with Doppler instruments.Ultrasound demonstrated an appropriately grown fetuswith normal biophysical proWle. She was immediatelyreferred for hematology consultation and supraclavicularadenopathy aspirative cytology was done with the diagno-sis of Non-Hodgkin B cell lymphoma, Burkitt type, withthe translocation (8;14) on cytogenetic analysis. By thattime results of human immunodeWciency virus (HIV) anti-body tests were negative and serology for EBV conWrmedpersistent infection (with qualitative polymerase chainreaction positive for EBV-DNA). Tumor cells in situhybridization for EBER (Epstein–Barr encoded RNA)was positive. Biopsy of breast nodules also revealedbreast tumor inWltration and bone marrow aspiration andbiopsy was positive with 30% Burkitt cells inWltration.Lumbar puncture excluded central nervous system (CNS)involvement. Chest MRI showed multiple left latero-aor-tic lymphadenopathies. The abdominal and renal ultra-sound scans were unremarkable. Laboratory data revealedhemoglobin 11.1 g/dL with 32.2% hematocrit, normalwhite blood cell count and platelet count of 117,000/L.The serum chemistry proWle revealed uric acid 5.0 mg/dL,lactic dehydrogenase 937 UI/L and normal aminotrans-ferases.The patient was counseled regarding the importance ofinitiating chemotherapy, despite the potential risks to herfetus. After consultation between pediatrics and maternal–fetal medicine departments, the patient was oVered andaccepted starting aggressive chemotherapy immediatelyand, once fetal lung maturity was accomplished, having acesarean section to continue adequate treatment outsidepregnancy. At 28 weeks gestation she began inductionchemotherapy, as stated by the French R-LMB protocol:rituximab, cyclophosphamide, vincristine and metilpredn-isolone. The patient also received CNS prophylaxis consist-ing of intratecal prednisolone alone, instead of the usualprednisolone, methotrexate and arabinosylcytosine, becauseof concerns for the potential toxic eVect of the latter two onthe fetus. Betametasone was administered for fetal lungmaturation.After 5 days of induction chemotherapy, with stable lab-oratory data, she was submitted to cesarean section. Shedelivered a healthy 1,263 g girl with Apgar Scores of 9 and9 (respectively, at 1’ and 5’) with no signs of myelosup-pression. The newborn was admitted to neonatal intensivecare unit and, despite initial respiratory distress syndromeand omphalitis, had good evolution, and was discharged inadequate condition at 46 days of age. Placenta had no signsof BL inWltration on pathological examination. After deliv-ery the patient continued on the treatment protocol and wasdisease-free one year after end of therapy. The polymerasechain reaction for EBV-DNA became negative in the end ofthe treatment.DiscussionBL is a high-grade B cell neoplasm that was initiallydescribed by Dennis Burkitt as a jaw sarcoma occurring inEast African children [4]. Today, three major forms of BLare recognized: the endemic (African) form, the sporadic(non-endemic) form and the immunodeWciency-associatedform. Endemic cases occur in African children and sporadicones are seen worldwide, being also more frequent in chil-dren (it accounts for 40% of lymphomas in children) [6].On the other hand, immunodeWciency-associated lym-phoma occurs in patients with HIV infection and allographrecipients [1, 6]. EBV infection is found in nearly all casesof endemic lymphoma however, in sporadic forms, EBV isfound in only 15–30% of the cases [10].BL can be morphologically diagnosed with high degree ofaccuracy since it has typical histologic Wndings: burkitt cellsare homogeneous in size and shape, with round to oval nucleiand slightly coarse chromatin, with multiple nucleoli, andwith intensely basophilic vacuolated cytoplasm; frequentmitotic Wgures are observed; and a “starry sky” appearance isimparted by scattered macrophages with phagocyte celldebris. A deWning feature of BL is the presence of transloca-tion between the c-myc gene and the IgH gene—t(8;14)found in 80% of the cases—or between c-myc gene and thegene of either kappa or lambda light chain (IgL) in theremaining 20% [t(2;8) or t(8;22), respectively] [1, 3, 4, 6, 9].These translocations take place within regions that undergochromosome breakage during maturation of germinal centerB cells, fact that favors the argument that translocations aremistakes that occur during normal B cell development, lead-ing to c-myc expression deregulation and driving cellsthrough the cell cycle with activated antiapoptotic pathways.So, in all BL variants the key factor in the oncogenesis is theconstitutive activation of the c-myc oncogene through itstranslocation into one of the immunoglobulin loci [10, 13].The role of EBV infection in the pathogenesis of BLremains hypothetical. EBV-positive cases usually exhibit ahighly restrictive pattern of expression of latent encodedproteins, (called type I latency program), expressing onlyEBNA1 (Epstein–Barr Nuclear Antigen-1, considered theviral genome maintenance protein) and EBERs (Epstein–Barr Enconded RNAs, nonpolyadenylated RNAs used forclinical detection because of their abundant expression).One hypothesis is that EBV works as a potentiator of tumorformation acting early in the lymphomagenic process byincreasing the frequency of genomic instability within theinfected B cell population and thus increasing the probability123Arch Gynecol Obstet (2009) 280:297–300 299of a new c-myc translocation. Alternatively persistent EBVinfection could provide a biological advantage for thetumor cell somehow increasing the lymphomagenic poten-tial of a c-myc translocation-positive cell. In fact, it isknown that EBNA1 plays a crucial role in the maintenanceand replication of the viral genome and that EBERs seem tohave antiapoptotic activity and also have the ability toinduce the expression of interleukin-10 and thus promotingcell growth and survival [3, 9, 13]. In our patient BL cellswere positive for EBER and the EBV-DNA PCR becamenegative after treatment, and so the case was considered asporadic BL related to EBV infection.Most patients with non-endemic BL present with periph-eral lymphadenopathy or intraabdominal mass. Lymphnode involvement is more common among adults thanamong children. The abdomen, especially the ileocecal areais the most common site of involvement; the ovaries, kid-neys, omentum and other sites may be involved. Bilateralinvolvement of the breasts, as in our patient, may occur inassociation with puberty, pregnancy or lactation. The exis-tence of B-symptoms (night sweats, weight loss or fever) ismore frequent in BL than in other non-Hodgkin lymphomas[1, 6]. The disease is typically rapidly progressive and hasthe propensity to metastasize to CNS [1, 8].Various staging systems have been proposed for ana-tomic staging in BL, but Ann Arbor and StJude/Murphysystems are the most used. During pregnancy CT scans arereplaced by MRI to avoid radiation exposure to the fetus.Bone marrow aspiration and biopsy should be performedfor every patient since it is frequent the presence of unex-pected bone marrow involvement witch has implicationsfor treatment. Lumbar puncture is necessary for evaluationof CNS involvement [8]. BL, as other hematological malig-nancies, has the potential risk of maternal–fetal transmis-sion of malignant cells. Pathological examination of theplacenta should be undertaken, so that appropriate neonatalfollow-up can be done [8].BL is a very fast growing tumor and systemic chemo-therapy is the treatment of choice for this aggressive dis-ease in all its stages. There are several possible treatmentprotocols, all of them involving the use of intensive combi-nation chemotherapy regimens incorporating administeredhigh doses of cyclophosphamide. Prophylactic therapy tothe CNS is mandatory and incorporated in all modern regi-mens. The overall survival rate of BL depends upon thestage of the disease at initial diagnosis—localized diseaseresponds better and has higher survival rates than dissemi-nated disease. Salvage therapy has been generally ineVec-tive in patients failing initial treatment, emphasizing theimportance of the initial treatment approach [8, 9].The decision to use chemotherapy during pregnancymust be weighed against the eVect of treatment delay onmaternal survival. When possible, chemotherapy should bepostponed until the end of the Wrst trimester. Unfortunatelymost pregnant women with non-Hodgkin lymphomas,including BL, have aggressive and advanced-stage disease,so starting chemotherapy should not be delayed.The teratogenicity of any drug depends on the timing ofexposure, the dose, and the characteristics aVecting placen-tal transfer. Due to ethical concerns, the best available datadocumenting eVects of chemotherapy during pregnancy arederived primarily from case reports and limited retrospec-tive studies.Use of chemotherapy during Wrst trimester increasesthe risk of spontaneous abortion, fetal death and majormalformations. The fetus is especially vulnerable duringthe organogenesis period (from 2 to 8 weeks of gestation)and so, during this critical period, damage to any develop-ing organ may lead to fetal death or to major malformation.First trimester exposure has been associated with a 10–20%risk of major malformation, with lower rates in single agentexposure (compared to combination regimens). Afterorganogenesis, the eyes, the genitalia, the hematopoieticsystem and the CNS remain vulnerable to chemotherapy.Exposure during the second and third trimesters is not asso-ciated with malformations but increases the risk fetal andneonatal death, intrauterine growth restriction, pretermdelivery, low birth weight and transient neonatal myelosup-pression [5, 12, 14]. Several studies have focused on theneurodevelopment of children exposed to chemotherapy inutero and revealed no major impact in acquisition anddevelopment of cognitive capacities. Also current evidencesuggests that children exposed to chemotherapy in uterohave no increased long term risk of malignancies and infer-tility [2].The majority of chemotherapeutic agents are classiWedas C or D based on the Food and Drug Administration preg-nancy risk categories. Category C and D drugs were shownto have an adverse eVect on the fetus in at least animal and/or human studies, respectively. Depending on the clinicalcase, the potential beneWts of using these drugs to maximizematernal survival may sometimes outweigh the risk of fetalharm. A few agents, like methotrexate, are classiWed ascategory X (shown to cause fetal abnormalities or toxicityin animal or human studies), and so these drugs are notgenerally used as the risks are considered to outweigh anybeneWts.Our case illustrates a sporadic case of BL associatedwith EBV infection with a second trimester diagnosis.According to Ann Arbor staging system this case was a BLstage IV (extra-nodal, bone marrow and breast, involve-ment). The chemotherapy regimen followed (French R-LMBprotocol) included rituximab, cyclophosphamide, vincris-tine and metilprednisolone.Cyclophosphamide and vincristine are D category drugsfor use during pregnancy. Cyclophosphamide belongs to123300 Arch Gynecol Obstet (2009) 280:297–300the alkylating chemotherapy agents group. There arereports of several malformations after Wrst trimester expo-sure to cyclophosphamide (including absent toes, eyeabnormalities, low-set ears and cleft palate). On the otherway, second and third trimester exposures are not associ-ated with malformations but are linked to potential growthrestriction and, possibly, neonatal pancytopenia. Vincris-tine is a vinca alkaloid agent. There are some sporadic ref-erences to vincristine Wrst trimester exposure associatedmalformations (namely atrial septal defect and renal hypo-plasia) as well as neonatal pancytopenia [5, 11]. In our casethe newborn had adequate growth and no signs of myelo-suppression despite the Wve days of chemotherapy.On the other way, rituximab is a genetically engineeredchimeric murine/human monoclonal antibody directedagainst the CD20 antigen found on the surface of normaland malignant B lymphocytes. This agent is C category foruse during pregnancy. Animal studies revealed potentialreversible fetal immunosuppression. A recent human study[7] demonstrated that fetal rituximab concentrations arehigher than maternal concentrations, and also that, despitethe complete absence of fetal B cells at birth, there was arapid recovery without associated neonatal immune dys-function, and authors concluded that rituximab can be anoption for lymphoma treatment during pregnancy.ConXict of interest statement None.References1. Armitage JO, Longo DL (2001) Malignancies of lymphoid cells.In: Braunwald E et al (eds) Harrison’s principles of internal medi-cine, 15th edn. McGraw-Hill, New York, p 7152. Aviles A, Neri N (2001) Hematological malignancies and preg-nancy: a Wnal report of 84 children who received chemotherapy inutero. Clin Lymphoma 2:173–177. doi:10.3816/CLM.2001.n.0233. Brady G, MacArthur GJ, Farrell PJ (2007) Epstein Barr virus andBurkitt lymphoma. J Clin Pathol 60:1397–14024. Burkitt DP (1958) A sarcoma involving the jaws in African chil-dren. Br J Surg 46:218. doi:10.1002/bjs.180046197045. 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Burkitt’s Lymphoma Related to Epstein–Barr Virus Infection During Pregnancy

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