Keywords pregnancy - lymphoma - radiation - chemotherapy
Introduction
With the average age of pregnancy increasing globally, the prevalence of cancer in
pregnancy is also likely to increase. Currently, cancer is diagnosed in 0.1% of all
pregnancies.[1 ] Data regarding the clinical characteristics and outcomes of superior mediastinal
syndrome during pregnancy is limited.[2 ]
[3 ] An accurate and timely diagnosis, along with appropriate staging of the malignancy,
is essential for achieving an optimal outcome. The tendency to avoid radiation exposure
for diagnostic imaging and the administration of chemotherapy for treatment of malignancy
throughout the entire gestational period may be harmful in certain cases of high-grade
neoplasms. This is because delays in diagnosis and administration of curative intent
chemotherapy itself can considerably increase the maternal morbidity as well as risk
the fetus. With the advent of newer modalities of imaging (with limited or no radiation
exposure) and the accumulating evidence for safety of chemotherapeutic drugs in select
situations, successful management of pregnancy with cancers is now possible. Available
data, although scarce, suggest feasibility of combination chemoimmunotherapy with
optimal fetomaternal outcomes for primary mediastinal B cell lymphoma (PMBCL) in pregnancy.[4 ]
We successfully managed a pregnant young woman in whom the intention to avoid radiation
exposure for a chest X-ray delayed the diagnosis of a malignant chest mass for 2 months.
As a result, the patient landed up with a life-threatening superior mediastinal syndrome
due to compression by a rapidly enlarging mediastinal lymphoma.
Case Report
A 26-year-old primigravida presented to our institute at 32 weeks of gestation with
complaints of progressive dyspnea for one-and-a-half months, followed by orthopnea
and chest pain for 2 weeks. There was a history of increasing weakness and loss of
appetite, which were attributed to the pregnancy. She was initially advised bronchodilators,
antihistamines, and antibiotics. Later, her echocardiography revealed moderate pericardial
effusion. At this point, a chest X-ray was avoided due to fear of radiation exposure
to the fetus. She was empirically started on antitubercular therapy with no improvement.
Hence, she was referred to our institute. At presentation, her pulse rate was 140/min,
Blood pressure was 100/60 mm Hg with a pulse-paradox of 20 mm Hg. She had a respiratory
rate of 40 per minute and room air saturation of 86% with edematous suffused face
and nonpulsatile elevated jugular venous pulse. She had multiple dilated veins over
her arms and anterior chest wall with flow from above downward. There was no palpable
lymphadenopathy or hepatosplenomegaly and she had an Eastern Cooperative Oncology
Group performance status of 4. On auscultation, the heart sounds appeared muffled
and there was decreased air entry in the anterior mammary areas. She was managed in
a propped-up position, with oxygen and diuretics. Echocardiography ruled out massive
pericardial effusion. She had a hemoglobin of 10.6 g/dL, total leucocyte count of
11,600 cells/μL, and platelet count of 2.6 × 10/μL with no circulating atypical cells.
As the previous chest X-ray had revealed a mediastinal widening, a contrast-enhanced
computed tomography (CT) scan of chest (with abdominal shielding) was done that revealed
a heterogeneously enhancing soft tissue mass measuring 7.9 × 10.1 × 8.1 cm in the
mediastinal/retrosternal region, encasing the ascending aorta, the arch of the aorta,
the origins of major arteries, and the main pulmonary artery and its branches ([Fig. 1A ], [B ]). The mass was also encasing the trachea causing significant luminal narrowing.
There was complete nonopacification of the superior vena cava and bilateral internal
jugular veins (IJV) with multiple tortuous collaterals seen along the chest wall.
Obstetric ultrasonography (USG) revealed a single live fetus of ~30 weeks of gestation
with reduced amniotic fluid and a biophysical profile score of 8/10 with good fetal
movements, breathing, tone, and heart rate pattern.
Fig. 1 (A ) Axial image of contrast-enhanced computed tomography chest revealing a large lobulated
heterogeneous solid mass in the anterior mediastinum, encasing the tracheobronchial
tree and great vessels, with nonopacification of the superior vena cava; (B ) Coronal image of contrast-enhanced computed tomography chest revealing a large lobulated
heterogeneous solid mass in the anterior mediastinum, encasing the tracheobronchial
tree and great vessels, with nonopacification of the superior vena cava.
As the patient was unable to lie supine due to orthopnea, a CT-guided core biopsy
was not feasible. Therefore, she underwent a bedside USG-guided fine-needle aspiration
through a subcostal approach in the semirecumbent position. The smears showed many
scattered large atypical lymphoid cells on a hemorrhagic background. The cells had
scanty cytoplasm with fine vacuolation and large nuclei with opened-up chromatin with
one or two peripheral nucleoli ([Fig. 2A ]). Upon flow cytometric immunophenotyping, these cells that were CD45+ were gated
and showed strong positivity for B cell markers, CD19 and CD20 ([Fig. 2B ]), along with human leukocyte antigen–DR. They were negative for CD5, CD10, CD23,
other T cell markers including CD3, 4, 5, 8, CD34 and TdT. Light chain restriction
was inconclusive. Cell block ([Fig. 2C ]) for immunohistochemistry showed strong diffuse membranous positivity for CD20 ([Fig. 2D ]) and weak positivity for CD30 ([Fig. 2E ]) and CD10 ([Fig. 2F ]). The bone marrow examination was normal. Based upon her clinical and cytomorphological
findings, a diagnosis of PMBCL, it was stage II bulky disease. Staging bone marrow
is done as a part of protocol in all high grade Non-Hodgkin lymphoma (NHL), particularly
if the PET is not done at baseline. After detailed discussion with the patient and
the family, regarding the need for chemotherapy and its possible effects on the fetus,
treatment was initiated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,
and prednisolone) along with a therapeutic dose of enoxaparin for anticoagulation.
Fetal evaluation showed intrauterine growth restriction with oligohydramnios. She
was followed up with biweekly biophysical profiles and nonstress testing. After 2
weeks of chemotherapy, her orthopnea had resolved. Ascertaining the resolution of
tracheal compression was deemed necessary by the anesthetists as she might have required
emergency cesarean section and intubation during labor. Repeat CT scan revealed partial
reduction of the mediastinal mass to 7.5 × 10 × 5.5 cm and resolution of the tracheal
compression. At 3 weeks post-chemotherapy, following a course of antenatal corticosteroids
for fetal lung maturity, labor was induced with a combined mechanical and pharmacological
approach (intracervical Foley catheter plus intracervical prostaglandin E2 gel 0.5
mg) for cervical ripening for 12 hours, followed by oxytocin infusion. Pethidine was
used for labor analgesia and she delivered vaginally 1.6 kg preterm, small for gestational
age (weight less than 10th centile for gestational age) and at 35+1 weeks with Apgar score of 8 at 1 and 5 minutes. Breastfeeding was withheld and the
baby did well on top feeds and did not require any neonatal intensive are. The patient
initially received three cycles of standard dose RCHOP considering her peripartum
status and preference for an outpatient regimen. The interim CT scan showed residual
5 × 4 × 5.5 cm mass. Therefore, the regimen was escalated to DA-EPOCH-R (dose adjusted
etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab). She
received five additional cycles of DA-EPOCH-R. After discussing the added risk of
cardiotoxicity and breast cancer versus a possible progression-free survival benefit,
she was given 30 Gy (15 fractions over 3 weeks) involved-field radiotherapy, and attained
complete remission. Both mother and child are doing well at a follow-up of 18 months
from diagnosis.
Fig. 2 Image panel of primary mediastinal B cell lymphoma. (A ) Smear showing lymphoma cells. (B ) Flow cytometric immunophenotyping showing CD20 positivity. (C ) Cell block section (hematoxylin–eosin stain). (D–F ) Cell block section showing CD20, CD30, and CD10 immunohistochemistry (immunoperoxidase
stain).
Discussion
There is a significant paucity of awareness among the medical fraternity regarding
the radiation risks to fetus when imaging pregnant women.[5 ] Undoubtedly, modalities that do not use ionizing radiation, such as USG and magnetic
resonance imaging (MRI), must be preferred for evaluating any condition in a pregnant
lady as these have been consistently found to be safe.[6 ] At the same time, it must be remembered that no imaging study should be withheld
when deemed necessary for maternal safety. Frequently, fatigue, weight loss, low-grade
fever, and abdominal discomfort are attributed to pregnancy itself rather than a malignancy.
This frequently delays the diagnosis of cancers in pregnancy.[7 ] Moreover, avoidance of X-rays or CT scans can further add to the diagnostic delay,
as had happened in this case. We wish to reiterate that these inadvertent delays can
lead to increased fetomaternal morbidity and mortality.
The effects of prenatal exposure to ionizing radiation can vary based on the dose
and the length of gestation. There is significant data regarding the safety of single
X-rays during pregnancy.[8 ]
[9 ]
[10 ] The fetal effects of X-ray exposure may be in the form of teratogenesis (fetal malformations),
carcinogenesis (induced malignancies), or mutagenesis (alteration of germline genes).
With regard to teratogenesis, an embryo is most susceptible during organogenesis (2–7
weeks after conception) and in the early fetal period (8–15 weeks after conception).
Mental retardation and growth restriction, including microcephaly, are the most common
malformations after significant radiation exposure.[11 ] The teratogenic health effects are not observed until the radiation exposure crosses
0.05 Gy (5 rad) at any gestation; the threshold dose for teratogenicity increases
to 10 to 20 rad in at around 16 weeks of gestation, and up to 50 to 70 rad beyond
16 weeks. On the contrary, exposure to as little as 1 or 2 rad (which may be reached
by some radiographic studies) has been associated with a slight increase in childhood
malignancies, especially leukemia from a background risk of ~3.6 per 10,000 to 5 per
10,000. The actual fetal X-ray exposure in most diagnostic investigations is much
lower than this threshold (8). Chest radiography (two views) exposes the fetus to
less than 0.0001 Gy (< 0.01 rad), while a contrast-enhanced CT abdomen (10 slices)
typically has an estimated exposure of 0.00240 to 0.0260 Gy (0.240 to 2.60 rad).[12 ] Besides, there are concerns regarding the causation of germ-line mutations with
fetal exposure to X-rays, potentially affecting future generations.[13 ] Ionizing radiation increases the frequency of mutations occurring naturally in the
general population. The radiation dose required to double the baseline mutation rate
is between 50 and 100 rads.[14 ] Most health care providers are highly sensitized to these risks associated with
intra-uterine X-ray exposure. At times this fear of radiation exposure to the fetus
leads to an unrealistic avoidance of diagnostic imaging. However, the benefits accrued
from the early diagnosis of a malignancy with the help of imaging in a pregnant female
with suspected cancer outweigh the risk frequently. Therefore, using safe modalities
such as USG and MRI and even X-rays and CT scan with adequate shielding maybe desirable
in certain cases. The physicians must include the couple in the decision-making process
whenever such situations arise.
Lymphoma is the fourth most common malignancy diagnosed during pregnancy.[7 ] Fine-needle aspiration played a pivotal role in establishing the diagnosis within
a few hours in this case. The decision favoring the use of cytotoxic chemotherapy
and targeted immunotherapy during pregnancy was based on the staging, the histologic
subtype of tumor, and the gestational maturity of the fetus. In the first trimester,
a wait and watch approach can be undertaken for low-grade lymphomas, whereas aggressive
lymphomas often warrant a discussion with the family regarding the pros and cons of
medical termination of pregnancy. However, in the second- and third-trimesters of
pregnancy, there is significant literature to support the safety of RCHOP-based chemotherapy
with favorable fetomaternal outcomes.[15 ]
[16 ] In a retrospective analysis of 90 patients who were diagnosed with lymphoma during
pregnancy, there were no differences in maternal complications, perinatal events,
or median infant birth weight based on deferred versus antenatal therapy beyond the
first trimester.[17 ]
In the current case, one cycle of RCHOP chemotherapy led to a marked improvement in
the patient’s orthopnea and the pregnancy could be safely prolonged for three more
weeks, and fetal lung maturity was ensured. The current case supports the prior findings
that in utero exposure to nonantimetabolite chemotherapy including anthracycline exposure
in second and third trimesters is not known to affect fetomaternal outcomes including
cardiac functions.[18 ] However, we strongly believe that the significant delay in diagnosing the disease
due to the avoidance of imaging after the onset of initial symptoms and the empiric
use of anti-tubercular therapy hampered the timely institution of chemotherapy in
the current case. This contributed to the progression of the lymphoma to a bulky stage
II disease with a life-threatening superior mediastinal syndrome. As DA-EPOCH-R is
associated with higher short-term treatment-related toxicities as well as requires
frequent inpatient admissions; therefore, the patient initially received three cycles
of RCHOP in the initial perinatal period.[19 ] However, it was later escalated to DA-EPOCH-R considering the bulky nature of disease
at baseline and suboptimal interim response.[20 ]
[21 ]Currently, there is lack of robust evidence to omit radiotherapy in a patient with
bulky high-grade lymphoma. However, recent data suggest the feasibility of omitting
radiotherapy in patients of PMBCL with bulky disease treated with DA-EPOCH-R regimen.[21 ]
Conclusion
The challenging situation of a cancer diagnosis during pregnancy must be approached
in a systematic and multidisciplinary manner. The necessary cautions must not become
unreasonable. A pregnant woman with suspected malignancy who requires emergent radiographic
imaging potentially faces risks arising from malignancy to her own health, as well
to the health of the fetus. These risks usually outweigh the minor hazards posed by
low-dose radiation exposure. Similarly, combination chemoimmunotherapy is feasible
with the continuation of pregnancy in most cases, after the first trimester. In short,
a multidisciplinary approach can lead to gratifying outcomes in many patients diagnosed
with malignancy during pregnancy.
