Hodgkin’s lymphoma in pregnancy: case report and review of literature

Introduction/Objective: The incidence of Hodgkin lymphoma (HL) is high during the reproductive years, making the occurrence of this malignancy during pregnancy a significant issue in everyday clinical practice. The aim is to present a case study demonstrating the characteristics of clinical courses and analyze published data through a literature review.

Case report: A 33-year-old pregnant woman in her third trimester developed neck swelling, night sweats, itching, and weight loss. Ultrasound examination revealed significant lymphadenopathy in the supraclavicular region. Surgical excision of the lymph node and pathological verification confirmed the diagnosis of Hodgkin lymphoma. Given the pregnancy and the limited use of radiographic diagnostics, magnetic resonance imaging (MR) was performed and confirmed generalized lymphadenopathy with resultant hydronephrosis of the right kidney. After diagnosing advanced-stage HL, it was decided to initiate specific hematologic treatment with chemotherapy. Delivery was carried out at 37 weeks of gestation via vaginal delivery, with no complications for the mother or newborn. Following delivery, a complete disease reevaluation was conducted, and it was decided to continue treatment with a total of six cycles of chemotherapy according to the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) protocol. After six cycles of chemotherapy, metabolic remission of the disease was achieved.

Conclusion: Managing Hodgkin lymphoma during pregnancy presents a complex challenge requiring a coordinated multidisciplinary approach and a personalized treatment plan.

INTRODUCTION

Hodgkin’s lymphoma is a chronic malignant lymphoproliferative disease with a bimodal distribution of occurrence in the third decade of life as well as in the sixth decade [1]. Considering that the first peak also includes women in the reproductive period, the literature incidence of occurrence during pregnancy is about 3% of total patients. [2]. According to a systematic review of the literature published in 2022, where the study aimed to assess the final outcome of pregnant women and the fetus after the diagnosis of Hodgkin’s lymphoma during pregnancy, the conclusion was that the incidence of congenital malformations as well as spontaneous abortions is not statistically significantly different in pregnant women with HL compared to pregnant women in whom the mentioned disease was not diagnosed. Among the other possible outcomes, a higher frequency of premature births, anemic syndrome requiring the use of blood components, and venous thromboembolism [3] were singled out. This paper aims to present a characteristic clinical course through a case report and analyze the data published so far through a literature review.

CASE REPORT

A pregnant woman, aged 33, during the third trimester of her third pregnancy, developed swelling of the neck, night sweats, and itching with loss of body weight, an ultrasound examination of the soft tissues of the neck described significant lymphadenopathy dominantly in the lower jugular floor and supraclavicular left, diameter 30x24mm, and 43x20mm. Then, in the laboratory analysis, leukocytosis with neutrophilia and monocytosis (Le 23.9x10⁹ /L, Neu 20.3x10⁹ /L, Mon 1.6x10⁹ /L), microcytic anemia of medium severity (Hgb 86 g/L, MCV 72.4 fL) were distinguished., thrombocytosis (Tr 626x10⁹ /L), and in biochemical analyzes hypoalbuminemia (albumin 30g/L), hypoferremia with hyperferritinemia (Fe 4.1 umol/l, TIBC 59.1 umol/L, ferritin 798.7 ug/L), elevated level of alkaline phosphatase (ALP 274 U/L), lactate dehydrogenase (LDH 674 U/L), beta 2 microglobulin (beta 2 M 3.59 mg/L), C reactive protein (CRP 162.9 mg/L), and in hemostasis tests hyperfibrinogenemia (fibrinogen 8.1 g/L). Other findings were within reference values. The gynecological examination was in order. It was decided to extirpate the said lymph node of the left supraclavicular region in its entirety. Based on the received histopathological findings, a diagnosis of HL, a type of nodular sclerosis, with a characteristic immunophenotype: LCA-, CKPAN-, OCT2-, BOB1-, Pax-5- /+, CD79alfa -, CD20-, CD19-, CD15-/+, CD30+, Fascin +, MUM-1+, EBV-, bcl-6+, CD34-, CD3-, CD5-, CD4-, CD8-, ALK-. As part of additional diagnostics, an examination of the neck, chest, abdomen, and pelvis was performed with magnetic resonance imaging (MR), where lymphadenopathy was observed supraclavicularly (with the largest diameter up to 44x22 mm, mediastinally in all groups (with the largest diameter up to 28x15 mm), abdominally in the form of conglomerates, dominantly in hilus of the liver (diameter 61x28x46 mm), paraaortic (diameter 31x18x30 mm), with described hydronephrosis gr. II of the right kidney. The echocardiographic examination was regular, with a preserved global systolic function (ejection fraction of 70%). Hematological treatment was postponed due to SARS-CoV-2 positivity and a milder clinical picture of COVID-19. The patient was treated with empiric broad-spectrum antibiotic therapy, thromboprophylaxis, low molecular weight heparin, and other symptomatic-supportive therapy. Type of nodular sclerosis, in the IIIB clinical stage, EORTC/LYSA and GHSG - “advanced stage,” it was decided to start the treatment of the underlying disease according to the ABVD protocol, initially by applying two cycles, after which an interim PET/CT examination is planned, with regular monitoring from the perinatological side (biometry, cervicometry and monitoring of the condition of the fetus) immediately before the application of antineoplastic therapy. Two weeks after the d15 II cycle of the ABVD protocol, cesarean delivery was planned in the 37th week of gestation, but the patient gave birth naturally at that time without complications. The neonatologist noted that the clinical and laboratory findings of the fetus were normal. An interim PET/CT examination was performed in February 2024 and indicated discretely elevated glucose metabolism in lymph nodes in the IV jugular group in the neck bilaterally, mediastinal lymph nodes retrosternal and hepatogastric lymph nodes - Deauville score 3. Considering the above finding, as well as the initial stage of the disease, it was decided to continue the treatment with four more cycles of chemotherapy according to the ABVD protocol. She tolerated the therapy well, and there were no accompanying complications or indicated hospitalizations between cycles. The treatment was completed with a total of six cycles of the ABVD protocol. At the end of the treatment, the control PET/CT indicated a metabolic remission of the underlying disease.

DISCUSSION

Hodgkin’s lymphoma is one of the most common malignancies in pregnancy, considering the fact that the incidence of its occurrence is most common in the reproductive period. According to Korkontzelos I. and colleagues [4], the incidence of occurrence is 1 case of HL per 6000 pregnancies. The characteristics of this malignancy do not differ in pregnant women compared to the general population. Patients diagnosed with HL during pregnancy have a three-year survival rate of 85% [5].

Making a diagnosis of HL during pregnancy can be significantly prolonged, bearing in mind that symptoms indicating the existence of HL can be attributed to complaints that also occur during pregnancy (fatigue, weakness, dyspnea, night sweats). A similar sequence of events happened with our patient, bearing in mind that less than two months passed from the appearance of the first symptoms to the definitive diagnosis. Another problem is the limited availability of various diagnostic procedures. While biopsy of the lymph gland poses no risk to either the mother or the fetus, certain radiographic methods, such as computed tomography (CT) and positron emission tomography (PET), can be somewhat risky, primarily for the fetus [6]. The application of magnetic resonance and ultrasound methods is considered safe, and possible radiography can be considered to assess the spread of the disease or, in some acute conditions, with the mandatory use of a protective apron. Nevertheless, it is crucial to carry out planned diagnostics and evaluation of the hematological status to make an adequate decision on treatment. A multidisciplinary approach is necessary to assess the optimal moment of starting a specific hematological treatment, with a personalized approach to each patient and the coordination of hematologists, gynecologists, and neonatologists, where it is necessary to take into account the potential benefits and risks of applying or delaying targeted therapy. It is certainly essential to respect the patient’s wish to continue or terminate the pregnancy at a given moment. If the patient decides to terminate the pregnancy, the approach to treatment is identical to that of the general population.

In the early stages of the disease (IA and IIA, according to the Ann Arbor classification), there is no official consensus on the use of antineoplastic therapy. Recommendations are that, if possible, treatment should be delayed until childbirth. Thomas, P.R. et al. [7] showed in a study of 19 patients that postponing therapy until childbirth really represents an adequate choice without endangering either the mother or the fetus. On the other hand, Aviles, A. et al. [8] in their study, which included 44 patients diagnosed with HL during pregnancy in the early stages of the disease, pointed out the importance of applying the ABVD protocol, which represents the gold standard in the treatment of HL. The study’s results showed no congenital malformations and that PFS (period to disease progression) and OS (overall survival) during a median follow-up of 120.4 months were 95% and 93%, respectively.

In advanced stages of the disease, delaying the application of specific therapy may, on the other hand, represent a greater risk than starting specific treatment. Even in this group of patients, the ABVD protocol is still the therapy of choice. An alternative may be the A-AVD protocol (brentuximab vedotin, adriablastine, vinblastine, dacarbazine), but for now, there is not enough data on the potential teratogenic effect of brentuximab [9],[10]. Alkylating agents are known to be highly teratogenic and should be avoided in pregnant women, especially in the first trimester of pregnancy [11]. Given the fact that organogenesis takes place during the first trimester and that then the fetus is highly vulnerable, it is not recommended to use any antineoplastic therapy during this period. In a large number of studies, the application of the ABVD protocol in the second and third trimesters of pregnancy in pregnant women with HL has been shown to be safe without causing complications in either the mother or the fetus [12],[13],[14],[15],[16],[17],[18]. Nevertheless, Cotteret, C., and co-workers concluded that the administration of doxorubicin during pregnancy can lead to transient left ventricular dysfunction in the newborn, with complete restitution one month after delivery [19]. A study [20] that included 405 patients diagnosed with HL treated with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) protocol concluded that as many as 51.4% of patients developed permanent amenorrhea, with a higher rate in female patients treated with an escalating BEACOPP protocol compared to the standard one. Because of all the above, the ABVD protocol is considered relatively safe for the treatment of HL in pregnancy.

Radiotherapy carries a consequent risk of congenital anomalies in infants and adolescents who were exposed to radiation in utero, especially if we consider doses higher than 50 Gy. Therefore, the use of radiotherapy during pregnancy does not represent an absolute contraindication, especially when it comes to supradiaphragmatic tumor localization, but this is also one of the decisions that must be considered multidisciplinary because of the potential risks it carries [21].

Another challenge is the altered pharmacokinetics during pregnancy. Hypoalbuminemia, which can occur in pregnancy, increases the free fraction of drugs in plasma, thus changing their distribution. Many cytostatics are excreted through milk, so breastfeeding during the use of cytostatics is contraindicated. Certain antineoplastic drugs can persist in milk for a certain period after the drug is administered, so it is advised to postpone breastfeeding for at least 3-6 weeks after completing the treatment.

A personalized approach is necessary when deciding on the ideal date of birth. If possible, childbirth should be postponed until at least the 35th week of pregnancy. Also, due to the myelosuppressive effect of certain cytostatics and potential iatrogenic bone marrow aplasia, childbirth should be planned at least three weeks after the completion of therapy; that is when appropriate recovery of hematological parameters is achieved. The birth of our patient was planned according to current recommendations, three weeks after the application of d15 of the second cycle of the ABVD protocol, in the 37th week of gestation, when, according to the clinical and laboratory status, it was completed naturally, without accompanying complications.

A systematic review by Houlihan et al. [3] indicated that there is no statistically significant difference in the incidence of congenital malformations and spontaneous abortions in pregnant women diagnosed with HL compared to pregnant women in the general population. However, in patients diagnosed with HL, premature births occur more often, which may be related to planned premature termination of pregnancy, more often than spontaneous, either as a decision of the medical team or the decision of the patient herself to avoid the use of therapy during pregnancy. Also, venous thromboembolic events (VTE) are more common, which is expected, given the fact that pregnancy itself contributes to hypercoagulability and venous congestion. Our patient was given a prophylactic dose of low-molecular-weight heparin after the start of treatment, bearing in mind the well-known concept of thrombosis associated with cancer, where active malignancy and the use of antineoplastic therapy additionally increase the risk of VTE.

CONCLUSION

Hodgkin’s lymphoma is a hematological malignancy with a good prognosis and a high cure rate. Treatment of patients with HL during pregnancy brings with it numerous challenges, starting from diagnosis, through the selection of appropriate therapy and the moment of starting treatment, to deciding on the date of termination of pregnancy. The complexity of the treatment confirmed the fact of the necessity of the presence of a multidisciplinary team to review the aforementioned decisions. Studies indicate promising results in pregnant women treated with the ABVD protocol. However, additional research is necessary for further knowledge, as well as long-term monitoring of potential post-therapy consequences in children born to mothers diagnosed with HL who were treated during pregnancy.