Non-Hodgkin’s lymphoma presenting as macroscopic haematuria and acute urinary retention in pregnancy

MRI  Magnetic Resonance Imaging

R-CHOP  Rituximab-(Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone)

PCR  Polymerase Chain Reaction

FISH   Flourescent In-Situ Hybridisation

DLBCL   Diffuse Large B-Cell Lymphoma

Non-Hodgkin’s lymphoma of the female genital tract during pregnancy is rare. We present the case of a 30 year old primigravida in her third trimester with visible haematuria secondary to a genital-tract lymphoma. We describe the management of this unusual occurrence and review the relevant literature.

A 30 year old primigravida presented at 29 weeks gestation with macroscopic haematuria and intermittent acute urinary retention associated with blood clots. She had no significant past medical history, and the early pregnancy had been largely unremarkable. Three months earlier she had been treated with oral antibiotics for a presumed urinary tract infection, having presented to her general practitioner with haematuria. She was taking iron supplements because of anaemia noted at a routine antenatal check (haemoglobin 7g/dL).

Ultrasound examination revealed bilateral hydronephrosis and a complex solid mass on the posterior bladder wall. She underwent pelvic MRI, and urgent flexible cystoscopy, vaginal examination, and biopsy under general anaesthesia. MRI showed a 10cm x 8cm irregular soft-tissue mass involving the anterior vaginal wall and fornix, the proximal urethra, and the posterior bladder wall (Figure 1).

The tumour extended into the bladder, and the bilateral hydronephrosis seen on ultrasound imaging was due to involvement of both distal ureters by tumour.

Cystoscopy and examination revealed a partially fixed mass, between the anterior vaginal wall and the bladder, which was invading the trigone. Biopsies were taken from the mass in the bladder and from the portion in the vaginal wall. These were submitted for detailed immunohistochemical analysis.

On microscopy the pathological specimens showed a diffuse infiltrate of large atypical lymphoid cells. Immunostaining demonstrated expression of CD20, BCL2, CD30 and CD5, with a proportion of cells expressing MUM-1. PCR analysis detected clonal IgH and IgΚ rearrangements, while FISH showed no evidence of IgH, BCL2, BCL6, or MYC translocation but detected gain of extra copies of each of these gene loci. In summary, the immunohistochemical analyses were consistent with a diagnosis of diffuse large B cell lymphoma (DLBCL).

After multidisciplinary discussion, it was decided to commence R-CHOP chemotherapy. The fetus was delivered at 35 weeks gestation by classical Caesarian section, between the first and second cycles of chemotherapy. Both mother and fetus tolerated the first cycle of chemotherapy well, and a 2.6 kg boy was born at 35 weeks gestation as planned. The boy spent one week in a special care baby unit because of prematurity, but required no specific isolation measures. The patient’s tumour responded well to chemotherapy, and she remains under long-term follow up.

Cancer complicates approximately 1:1000 pregnancies [1]. Lymphoma is the fourth most commonly diagnosed malignancy in pregnancy, complicating approximately 1:6000 deliveries [2]. The majority of lymphomas in women of childbearing age are Hodgkin’s disease, with Non-Hodgkin’s lymphoma (NHL) being much rarer in this age group [2, 3]. When NHL does occur in pregnancy, it tends to be of an aggressive subtype such as DLBCL [4]. In general, primary extranodal disease occurs in 20-30% of lymphoma cases, most frequently involving the gastrointestinal tract or skin [5]. Only 0.5% of extranodal lymphomas originate in the female genital tract [6].

DLBCL is associated with an aggressive natural history; median survival in untreated patients is less than one year [7]. Treatment with a combination chemotherapy regime (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone; CHOP) has been standard practice for several decades [8]. The addition of rituximab (a chimeric IgG1κ anti-CD20 monoclonal antibody) to this regime (R-CHOP) significantly reduces the risk of relapse and improves overall survival [9, 10].

Because the diagnosis of cancer during pregnancy is a relatively rare event, experience with the use of chemotherapeutic agents and monoclonal antibodies in pregnancy is limited [1, 2, 11]. Almost all chemotherapeutic agents are known to be teratogenic in animals, and to lead to major malformations or fetal death if administered during the first trimester [12, 13]. Exposure during the second and third trimester is not associated with fetal malformations, but increases the risk of fetal and neonatal death, intrauterine growth retardation, preterm delivery and low birth weight [14]. Clearly, the decision to undergo chemotherapy during pregnancy is complex, and has to balance the risks and benefits to both mother and fetus.

Importantly, there are no preclinical reproductive toxicity data available for rituximab. There are only seven previously documented cases of rituximab being used for lymphoma in pregnancy [15-21]. In the majority of these cases rituximab was administered during the second trimester for an aggressive NHL [15-20]. In one case the patient was taking a maintenance dose of rituximab for relapsing follicular lymphoma during which she conceived unintentionally [21]. The rituximab was stopped and the pregnancy continued to term. Of the seven children exposed to rituximab in utero, three were found to have severely decreased CD19+ B cells as neonates. However, none experienced any significant postnatal infection, and in each case the level of B cells returned to normal within three to six months.

Rare cancers in pregnancy present diagnostic and therapeutic challenges. The successful outcome in this case required a multidisciplinary approach involving obstetrics and gynaecology, urology, and oncology specialist input. This is the eighth documented case of a fetus being exposed to rituximab, without apparent short term clinically significant effects. However, the long term effects of this exposure are unknown.

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