Russian Journal of Woman and Child Health
ISSN 2618-8430 (Print), 2686-7184 (Online)

Burkitt’s lymphoma and pregnancy. Advantages of today’s medicine

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DOI: 10.32364/2618-8430-2020-3-3-211-216

T.S. Kotomina, E.A. Baryakh, E.N. Misyurina, E.I. Zhelnova, I.Yu. Kokoya, V.M. Grabovskiy, M.A. Lysenko

City Clinical Hospital No. 52, Moscow, Russian Federation


Recent years have seen the increase in the rate of childbirth after the age of 30 years. This is associated with higher risks for a mother and a child as well as higher rate of cancers diagnosed during pregnancy including non-Hodgkin’s lymphoma (NHL). The data on pregnancy-associated NHLs are limited by individual case studies. This makes difficult to develop a therapeutic strategy for lymphoma and pregnancy management in women with hematologic malignancies. The paper addresses the case study of a rare combination of Burkitt’s lymphoma and pregnancy. At 20 weeks of the pregnancy, right ovarian tumor was identified by magnetic resonance imaging. Burkitt’s lymphoma was verified by the biopsy of the excised ovary. Progressive tumor growth required chemotherapy. R-DA-EPOCH chemotherapy program was successful and also allowed for pregnancy prolongation and led to favorable perinatal outcome.

Keywords: pregnancy, Burkitt’s lymphoma, non-Hodgkin’s lymphoma, chemotherapy, remission, adnexectomy.

For citation: Kotomina T.S., Baryakh E.A., Misyurina E.N. et al. Burkitt’s lymphoma and pregnancy. Advantages of today’s medicine. Russian Journal of Woman and Child Health. 2020;3(3):211–216. DOI: 10.32364/2618-8430-2020-3-3-211-216.



Background 

The life of many women of developed countries has changed greatly over the recent years as family formation and childbirth are postponed to a later date while a professional carrier is the first priority. Therefore, the rate of childbirth after the age of 30 years has significantly increased being associated with higher risks for a mother and a child as well as higher rate of cancers diagnosed during pregnancy [1].

It is still common in Russian clinical practice that hematological malignancies diagnosed during pregnancy require its immediate termination [2]. However, the recent appearance of novel therapeutic strategies using medicines that are not harmful to a developing fetus makes us redefine this approach [3].

Lymphoma is the fourth most common malignancy diagnosed during pregnancy. Hodgkin’s lymphoma (HL) is more common in pregnant women than non-Hodgkin’s lymphoma (NHL). The prevalence of high-grade lymphomas in pregnancy is much higher than in non-pregnant women of reproductive age [1]. The involvement of reproductive organs is reported in almost a half of pregnant women with NHL [1].

Burkitt’s lymphoma (BL) is a rare adult NHL accounting for 2% of all lymphomas. BL is characterized by an aggressive clinical course, predominantly extranodal localization, rapid growth, and chemoresistance. BL affects 2 to 3 times more men that women. Median age of onset in adults is 25 to 30 years [4].

Disease history is generally several weeks. In most patients, characteristic clinical presentations allow for suspecting BL as early as during the primary examination. Most patients are admitted to hospital when they are in serious condition due to a large tumor mass, intoxication (or even cachexy), and electrolyte imbalance. BL generally affects the terminal ileum and ileocecal region of the bowel and mesentery, stomach, the ascending, transverse, and descending colon, peritoneum and retroperitoneal space, liver, spleen, and (in women) ovaries. The disease manifests with rapid abdominal swelling resulting from aggressive tumor growth and ascites [5].

Histologically, BL is composed of multiple monomorphic lymphoid cells that are held tightly against each other. Rounded or oval nuclei contain several basophilic nucleoles. The “starry sky” appearance is accounted for by the ability of macrophages to phagocytose apoptotic bodies that are abundant in BL [6].

Immunohistochemistry demonstrates that tumor cells are sIgM+BCL6+CD10+ and express B cell antigens (i.e., CD19, CD20, CD22, CD79a) but no BCL2, T cell markers (i.e., CD3, CD5, CD7), and progenitor cell antigens (CD34 and TdT) [6]. Tumor substrate originates from the cells of the germinal center of lymphoid follicle as demonstrated by the expression of CD10 and BCL-6 [6-8]. The Ki-67 proliferation index is very high being almost 100% [4]. The t(8;14)(q24; q32) translocation occurs in 80% of BL patients and is characterized by с-MYC (8q24) and Ig heavy chain (14q32) rearrangement [9]. Variant translocations and с-MYC and Ig light chain rearrangement are much less common, i.e., t(8;22)(q34; q11) translocation (с-MYC and Ig λ chain rearrangement) occurs in 15% and t(2;8)(p11; q24) translocation (с-MYC and Ig κ chain rearrangement) in 5% [4, 10].

Despite aggressive clinical course, BL is a highly curable cancer. Intensive chemotherapy involving rituximab and high-dose cytarabine and methotrexate provides remission in 80-90% of BL patients, the 5-year survival rate is 70-85% [11-13].

In Russia, NHLs account for 2.6% of all malignancies and are the 5th most common cancers in women (after breast, lung, colorectal, and uterine cancers) [3]. NHL during pregnancy is much less common than HL due to higher median age of disease manifestation.

BL occurs mainly in men (boys) and is a rare variant of NHLs. Considering this, we report the first Russian case of the management and successful pregnancy prolongation in a woman with BL.

Case report

A 39-year-old woman was referred to an antenatal clinic of the Republic of Crimea due to spontaneous pregnancy (3rd pregnancy, 1st delivery is scheduled).

Anamnesis of life: 1st pregnancy (2005) has ended in abortion at 12 weeks of pregnancy (dilation and curettage, no complications). 2nd pregnancy (2011) has ended in abortion at 9 weeks of pregnancy (dilation and curettage, no complications).

Medical history: at 6 weeks of the present pregnancy, right ovarian cyst was diagnosed. The woman was under the observation of an obstetrician gynecologist of the antenatal clinic of the Republic of Crimea. Since October 2016, the woman lost 20 kg. However, she presented with no complaints.

On December 01, 2016, magnetic resonance imaging (MRI) was performed. Impression: 20 weeks of pregnancy, MR signs of right ovarian tumor (the right ovary is not seen in its typical location). A mass sized 46 × 31 × 30 mm is seen above the uterus on the right (MR signal resembles ovarian MR signal). A tumor sized 174 × 152 × 128 mm with sharp (somewhere irregular) borders presumably originating from the right ovarian is identified. This tumor is closely adjacent and moderately comprises the fundus of the uterus. Inguinal lymph node enlargement (right, up to 18 mm; left, up to 14 mm). Collection of fluid in the retrouterine space and abdominal cavity (mainly right-sided).

Considering MRI data, the woman was referred and admitted to a Moscow hospital for additional medical tests and further management. Pelvic MRI (December 09, 2016) revealed a tumor presumably originating from the right ovary and ascites.

On December 20, 2016, laparotomic right-sided adnexectomy, omental biopsy, and partial omentectomy were performed.

Histologically, the tumor is a diffuse infiltrate of monomorphic cells with eosinophilic cytoplasm, large nucleus with 2-3 nucleoles, high mitotic activity, and diffusely located macrophages (the “starry sky” appearance). Impression: diffuse large-cell ovarian lymphoma (presumably BL).

Immunohistochemistry: cytoplasmic expression of CD45 and CD79a (100% of positive cells), tumor stromal expression of vimentin, no expression of inhibin alpha, S100, and keratin pan.

FISH: t(8;14)(q24; q32) translocation, no rearrangements of BCL2 and BCL6 genes.

The woman was admitted to the City Clinical Hospital No. 52 for additional medical tests, treatment, and management.

At admission, the woman presented with complaints of intoxication, body weight loss by 20 kg, and night sweats.

Abdominal and pelvic MRI, T1- and T2-weighted, fat suppression, DWI, no intravenous contrast (December 30, 2016): liver enlargement – 123 × 82 × 230 × 160 mm (right lobe anteroposterior × left lobe anteroposterior × frontal × right lobe vertical diameter), regular sharp borders, no abnormal parenchymal signal. No enlargement of intrahepatic bile ducts. No focal parenchymal lesions. Gallbladder sized 70 × 32 mm, heterogenous fluid collection (gallbladder sludge). Common bile duct enlargement up to 5.5 mm. No visible gallbladder or duct stones. Left-sided postoperative scars and mild subcutaneous fat edema. No enlargement of the pancreas (22 × 19 × 22 mm), sharp borders, heterogenous structure due to fine fat inclusions, no tumor masses. No enlargement of the duct of Wirsung (diameter 2.5 mm), the duct is visible along the whole length, no deformities. No clear signs of the inflammation or infiltration of the pancreatic fat. Spleen sized 116 × 46 × 98 mm (sagittal × frontal × vertical diameter), regular sharp borders, homogenous structure. No abnormalities of the right and left adrenal glands. Usual position of the kidneys, right kidney sized 108 × 58 × 56 mm, left kidney sized 119 × 53 × 58 mm, no parenchymal thinning, no focal parenchymal lesions. No enlargement or deformities of the pelvicalyceal system. No enlargement of lymph nodes, no increase in the number of mesenterial lymph nodes. No fluid collection in the abdominal cavity or retroperitoneal space. No fluid collection in the pelvis. No visible lesions of the rectum, no wall thickening or tumors. The urinary bladder is partially filled, no abnormal signal (including DWI). No fluid collection or stones. Normal appearance of paravesical fat.

24-25 weeks of pregnancy. One fetus in the uterine cavity. Normal amniotic fluid volume.  Anterior placenta. A solid heterogeneous (mainly hypointensive on T1- and T2-weighed and fat-suppressed images, high signal on DWI images) tumor sized 46 × 21 × 48 mm (anterior × bilateral × vertical) with irregular sharp borders is adjacent to the uterus from the its right side. The left ovary sized 38 × 21 × 30 mm with regular sharp borders, few follicles sized up to 7.5 × 3.0 mm, no fluid collection around the ovary. No restricted diffusion on DWI images. No lymph node enlargement (ileac lymph nodes sized 4-5 mm, right-sided inguinal lymph nodes sized 11 × 5 mm, left-sided inguinal lymph nodes sized 8 × 12 mm), normal differentiation. No bone destructions. Impression: MR signs of a right ovarian tumor. 24-25 weeks of pregnancy. Mild hepato- and splenomegaly. Sluggish gallbladder. Diffuse changes in the pancreas (see Fig. 1).

Рис. 1. Данные МРТ брюшной полости и малого таза пациентки П. (описание в тексте) Fig. 1. MRI of the abdomen and pelvis (description in text)

Myelogram (December 31, 2016): blasts 0.8%, lymphocytes 6%.

Lumbar puncture (December 31, 2016): cytosis 2/3.

Ultrasound and fetal Doppler (January 09, 2017): 26-27 weeks of pregnancy, breech position. Normal fetal blood flow parameters.

The woman was diagnosed with Burkitt’s lymphoma stage III (Murphy staging system) affecting the right ovary (bulky tumor) with continuous tumor growth, ascites (laparotomic right-sided adnexectomy, omental biopsy, and partial omentectomy on December 20, 2016), and 27 weeks of pregnancy. The diagnosis was based on the complaints and laboratory instrumental tests.

An initial cytoreductive prephase treatment (cyclophosphamide 400 mg plus dexamethasone 20 mg) was performed from December 31, 2016 to January 04, 2017.

R-DA-EPOCH chemotherapy program (rituximab, etoposide, prednisone, vincristine, cyclophosphane, and doxorubicin) with the intrathecal administration of cytostatic agents to prevent CNS leukemia was initiated on January 05, 2017. After two treatment courses, no tumor was revealed, remission was diagnosed. The 3rd course of R-DA-EPOCH was performed.

During the intervals between treatment courses the woman was observed in the Department of Pathological Pregnancy of the City Clinical Hospital No. 52. At 29-30 weeks of pregnancy, gestational hypertension (140/90 to 150/90 mm Hg) and moderate proteinuria were diagnosed. Antihypertensive therapy resulted in the improvement of hypertension while the level of proteinuria remained unchanged (daily urine protein loss less than 0.3 g/l, proteinuria in urinalysis less than 0.3 g/l).

On February 27, 2017, critical uteroplacental blood flow abnormalities and null diastolic flow were revealed by Doppler. Considering decompensated placental insufficiency and critical uteroplacental blood flow abnormalities in a 39-year-old woman with compromised obstetrical gynecological and somatic anamnesis, emergency С-section for fetal reasons was scheduled.

On February 27, 2017, low midline laparotomy, lower segment C-section via transverse incision was performed under spinal and epidural anesthesia. Alive premature girl (weight 1,930 g, length 46 cm, Apgar score 6/6) was delivered. Neither intraoperative technical challenges nor early postoperative complications were reported.

On March 02, 2017, agranulocytosis was diagnosed after regular chemotherapy course. On March 05, 2017, febrile temperature (38.1°C) without an apparent source of infection was reported. Considering this, the woman was referred to the Department of Hematology.

Spiral CT of the neck, thoracic and abdominal cavity, and pelvis (March 09, 2017): no enlargement of axillary and mediastinal lymph nodes. No pleural fluid collection. Normal appearance of lung parenchyma. No enlargement of mesenteric and retroperitoneal lymph nodes. Solitary left-sided inguinal lymph node sized 23 × 8 mm. Normal shape and sizes of the spleen (vertical diameter 81 mm), regular sharp borders, normal structure and parenchymal density. No liver enlargement, liver density 47 HU, no CT lesions. No tumors of parenchymal organs or interenteric spaces. Impression: no CT signs of lymphadenopathy. No focal lesions of the thoracic and abdominal cavity, retroperitoneal space, and pelvis (BL remission).

Antibiotics (IV piperacillin, tazobactam, and amikacin) were prescribed for febrile neutropenia. The result was the improvement of hematological parameters and body temperature.

From March 16 to May 17, 2017, additional 3 courses of R-DA-EPOCH chemotherapy we performed. Positron emission tomography (PET) with CT demonstrated a complete metabolic response after 6 courses of chemotherapy.

Later on, the mother and the healthy newborn girl were discharged and departed to their place of origin.

During the next two years, the woman was observed by the hematologists of the City Clinical Hospital No. 52, i.e., CT scan with contrast and physical examination were performed every 6 months. Final examination (PET-CT) was performed on March 12, 2019 (BL remission). As late BL relapses are lacking (all events occur within the first year after the completion of treatment), the woman may be considered cured [14].

Discussion

By 2009, 101 case reports on pregnancy-associated NHLs were published [3]. By 2013, 74 papers describing 121 case reports were published in foreign journals [15]. Over the last decades, the incidence of NHL increases, therefore, this issue is important [16-18]. Primary mediastinal B-cell lymphoma is the most common NHL diagnosed during pregnancy [16].

Major data on pregnancy-associated NHLs are limited to individual case reports. This makes difficult to develop a therapeutic strategy for lymphoma and pregnancy management in women with hematologic malignancies [15]. The association of pregnancy and BL is even less common as only isolated case reports were published (see Table 1).

Таблица 1. Клинические наблюдения сочетания ЛБ и беременности Table 1. Case studies on Burkitt’s lymphoma and pregnancy

Further prospective studies are needed to address the pathophysiological and clinical features of this disease complicating the course of pregnancy [15].

The management of pregnancy is currently governed by the Order No. 736 of the Ministry of Healthcare and Social Development of Russian Federation (December 3, 2007) “A list of the indications to induced abortion”. Induced abortion up to 12 weeks of pregnancy is indicated in high-risk lymphomas (i.e., follicular NHL, diffuse NHL, peripheral and cutaneous T-cell lymphomas, other NHLs, and NHLs of unspecified types, malignant immunoproliferative diseases, multiple myeloma), lymphogranulomatosis stage 3 or 4. In the second and third trimesters of pregnancy, a decision on induced abortion is taken individually by a concilium that includes hematologists, oncologists, obstetrician-gynecologists, neonatologists, therapists, and, obviously, the expectant mother and her relatives.

Treatment protocols which include high doses of methotrexate and cytarabine (i.e., R-HyperCVAD, R-CODOX–M/IVAC, NHL-BFM) are the gold standard for BL. However, these protocols cannot be used in pregnancy as these drugs penetrate placental barrier. R-DA-EPOCH chemotherapy protocol is included in the national clinical guidelines to be prescribed in patients in whom more intense chemotherapy cannot be performed. Here, R-DA-EPOCH chemotherapy protocol resulted in the remission and also allowed for pregnancy prolongation.

Conclusions

This case report describes a rare combination of Burkitt’s lymphoma and pregnancy, the possibility of successful treatment for lymphoma, pregnancy prolongation, and adequate decision both for the mother and the child. Polychemotherapy is not contraindicated in the second and third trimesters of pregnancy.

We addressed one of the management strategies for NHL in pregnancy. Behind this apparently simple description is the work of a multidisciplinary team of a hospital of a big city.

Late 1990s and early 2000s are considered to be the rise of perinatal obstetrics. Meanwhile, almost any woman will experience the joy of motherhood thanks to a current multidisciplinary approach in obstetrics.


About the authors:

Tat’yana S. Kotomina — Cand. of Sci. (Med.), Head of the Maternity Department, Branch of the City Clinical Hospital No. 52, 11, Sosnovaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0002-5660-2380.

Elena A. Baryakh — Doct. of Sci. (Med.), Head of the Department of Hematology and Chemotherapy, City Clinical Hospital No. 52, 3, Pekhotnaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0001-6880-9269.

Elena N. Misyurina — Cand. of Sci. (Med.), Head of the Hematological Service, City Clinical Hospital No. 52, 3, Pekhotnaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0003-2419-4850.

Evgeniya I. Zhelnova — Cand. of Sci. (Med.), Head of the Department of Hematology and High-Dose Chemotherapy, City Clinical Hospital No. 52, 3, Pekhotnaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0002-0343-9348.

Inga Yu. Kokaya — Cand. of Sci. (Med.), Head of the Maternity Department, Branch of the City Clinical Hospital No. 52, 11, Sosnovaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0002-0637-1537.

Vasiliy M. Grabovskiy — Deputy Head Doctor for Obstetrical Gynecological Service, Branch of the City Clinical Hospital No. 52, 11, Sosnovaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0002-7048-4827.

Mar’yana A. Lysenko — Doct. of Sci. (Med.), Head Doctor, City Clinical Hospital No. 52, 3, Pekhotnaya str., Moscow, 123182, Russian Federation, ORCID iD 0000-0001-6010-7975.

Contact information: Tat’yana S. Kotomina, e-mail: tatakotomina@mail.ru. Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 23.01.2020, revised 06.02.2020, accepted 20.02.2020.

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