GYNECOLOGIC ONCOLOGY 43, 305-312 (1991)

CASE REPORT

Non-Hodgkin’s Lymphoma during Pregnancy MARK SPITZER, M.D., *J MARC CITRON, M.D.? CARL F. ILARDI, M.D.$ AND BRUCE SAXE, M.D.§

Departments of *Obstetrics and Gynecology and $Pathology and TDivision of Hematology/Oncology of the Department of Medicine, Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York, New York 11042; and

$Department of Radiotherapy, Winthrop University Hospital, Mineola, New York 11501

Received March 11, 1991

A rare case of non-Hodgkin’s lymphoma stage IE complicating pregnancy is presented. The diagnosis was made by biopsy at 28 weeks gestation and treated with 2635 rad of external radio- therapy with abdominal and pelvic shielding bef?jMhg at 30 weeks gestation. Following delivery, the patient received com- bination chemotherapy and is disease-free 6 years later. The baby, weighing 2015 g, was delivered by cesarean section at term. The effects of radiotherapy on a fetus are reviewed and the factors that were considered in the treatment of this patient are discussed. Radiotherapy with protective shielding can be an effective initial modality of treatment in this setting. Q 1~1 Academic press, IIIC.

INTRODUCTION

The diagnosis of any malignancy during pregnancy is uncommon and requires the treating physician to carefully balance the needs of the mother with the effects that the cancer and its treatment will have on the fetus. When the malignancy is rarely found in association with preg- nancy the lack of information makes the decision more difficult. Thirty-five cases of non-Hodgkin’s lymphoma have been reported in association with pregnancy [l-5]. Many of these cases occurred several decades ago and the outcomes were generally poor [l]. In six cases radio- therapy for non-Hodgkin’s lymphoma was instituted dur- ing the second or third trimester of pregnancy without any apparent ill effects on the baby. However, in all but two of the cases [4,5], the mother died of her disease [2,6-S]. Non-Hodgkin’s lymphoma was treated success- fully during pregnancy and resulted in the delivery of a normal, full-term fetus and survival of the mother in only

’ To whom reprint requests should be addressed at Department of Obstetrics and Gynecology, Queens Hospital Center, 82-68 164 St., Jamaica, NY 11432.

four cases [4,5,9,10]. Two of these patients were treated with combination chemotherapy [9,10], one with chemo- therapy and radiotherapy [4] and one with radiotherapy alone [5]. We are reporting a case of non-Hodgkin’s lym- phoma diagnosed and treated successfully with radio- therapy during pregnancy and with chemotherapy postpartum.

CASE REPORT

A 35-year-old, gravida 3, para 2, patient presented at 13 weeks gestation complaining of a “breast mass.” Ex- amination showed that the mass was not related to the breast, but rather a smooth, bony-hard, nontender mass centered over the left third and fourth costosternal joints. The evaluation was initially deferred to the postpartum period. The mass, which was not seen on chest X ray, continued to grow and at 23 weeks gestation computerized tomography of the chest with abdominal shielding re- vealed a 4 x 7-cm anterior mediastinal mass that ex- tended to the parasternal area of the chest wall. Wedge resection of the mass under local anesthesia revealed a diffuse large cell non-Hodgkin’s lymphoma infiltrating into the skeletal muscle of the chest wall (Fig. l), stage IE (localized involvement of one lymph node region with extralymphatic organ involvement). Electron microscopy confirmed the lymphoid nature of the cells. The patient was now at 28 weeks gestation. She denied dysphagia, shortness of breath, pain, and pruritus. Her appetite was good and her weight gain to this point in the pregnancy 17 pounds. The physical examination of the chest now revealed an 8 x 4-cm chest wall mass.

The patient’s past medical history included genital herpes (though never confirmed by culture) and removal of a fibroadenoma from her left breast at age 27, during

309 OO!%-8258/91 $1.50

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310 SPITZER ET AL.

G. 1. Large malignant lymphoid cells diffusely infiltrating the soft tissue. The tumor cells are large cleaved and noncleaved lymphocyi ( x 225, hematoxalin and eosin).

her second pregnancy. Her obstetrical history (from a previous marriage) included two spontaneous vaginal de- liveries. The first child was diagnosed as being a carrier for the x-linked form of retinitis pigmentosa. The second child died of hemolytic uremic syndrome at the age of 4 years. The patient smoked one pack of cigarettes per day for 20 years but quit 1 year prior to this pregnancy. Her family history includes a sister with multiple sclerosis and a form of minimal brain dysfunction.

With the exception of the non-Hodgkin’s lymphoma, the course of this pregnancy was uneventful. Amniocen- tesis for cytogenetic studies showed a 46xx normal fetal karyotype. Herpes cultures were negative and serial so- nography verified normal fetal growth consistent with the patient’s gestational age.

The risks and benefits of immediate delivery and the resultant risk of prematurity, versus treatment with ra- diotherapy during pregnancy, versus a delay in therapy until fetal maturity is achieved were all discussed with the patient. Because of the aggressive nature of this malig- nancy the decision was made to begin treatment of the

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lymphoma immediately. By simulated measurement in a phantom water bath, the estimate of radiation exposure to the upper portion of the uterus was less than 10 rad. The patient chose to undergo radiotherapy and to con- tinue the pregnancy. Beginning at 30 weeks gestation, she received a combination of 1400 rad with 18 MeV elec- tronstreated to 70% with a 2/32 in. lead shield covering the abdomen and 1235 rad with 10x photons treated to 8.5 cm with a 5” angle in a cephelad direction for a total dose of 2635 rad. Following radiotherapy, the mass was completely gone. The pregnancy continued uneventfully, but the rate of growth of the fundal height slowed significantly.

At 38 weeks gestation, the patient ruptured membranes spontaneously and developed chorioamnionitis. Labor was induced with pitocin but the fetal heart rate tracing showed moderate variable decelerations and a fetal scalp pH was 7.21. A primary transverse lower segment ce- sarean section was performed through a Phannenstiel in- cision. The baby was a viable female weighing 4 pounds 7 ounces, with Apgar scores of 8 at 1 min and 9 at 5 min.

CASE REPORT 311

The mother’s postoperative course was uneventful. Fol- lowing delivery, the mother underwent a 6-month course of combination chemotherapy that included cyclophos- phamide, etoposide, methotrexate with leukovorin res- cue, cytarabine, doxorubicin, vincristine, and prednisone. She remains in complete remission 6 years later.

The baby did well in the nursery. She was small but continued to grow. At the age of 6 years she remains below the fifth percentile in height and weight. She has expressive problems and an attention deficit disorder. Her coordination and motor development are also delayed.

DISCUSSION

Large cell lymphoma, arising in the mediastinum, gen- erally strikes females after the fourth decade [ 111. Its most common clinical presentation is chest pain accompanied by cough and dyspnea. Although the disorder can infil- trate extensively in the thorax by invading the chest wall and superior vena cava, it is usually not associated with peripheral adenopathy. Our case has several important lessons for the practicing obstetrician and nonobstetrical consultants.

There is a natural reluctance on the part of physicians to perform radiologic studies and invasive procedures dur- ing pregnancy. In the cases reviewed in the literature, there was a tendency to make the diagnosis late, when the disease was well advanced. This may be because at- tention was focused on the pregnancy, or because the symptoms were masked by the pregnancy or discounted. A failure to aggressively pursue the workup in such cases can result in a delayed diagnosis, which can jeopardize the patient’s life and health. With appropriate abdominal and pelvic shielding, the fetal dose of radiation from al- most all diagnostic radiologic tests can be minimized.

The most important aspect of the decision to initiate immediate therapy in this case was the invasive nature of the rapidly enlarging chest wall mass. It has been es- tablished that in non-Hodgkin’s lymphoma, tumor masses greater than 10 cm in size represent a poor prognostic sign. Since our patient had such a large and rapidly grow- ing tumor at the time of diagnosis, treatment could not be safely delayed until fetal maturity. The optimal man- agement of non-Hodgkin’s lymphoma presenting in the mediastinum has not been established. Attempts to im- prove treatment outcome using combination chemother- apy and consolidation radiotherapy produced a 59% fail- ure-free survival in one series of 30 patients with large cell non-Hodgkin’s lymphoma presenting as a mediastinal mass [12]; however, a poorer outlook has been noted by others [13], especially in patients with bulky disease [12]. The poor outlook noted in these studies despite combi- nation therapy demonstrates the aggressive nature of this tumor and the need to avoid delay in intervention.

The availability of refined techniques for delivering ra- diation, while protecting the fetus, influenced us to select this as initial treatment. In one study of pregnant women who received 1500-2000 rad to supradiaphragmatic sites during the second or third trimester for disease other than non-Hodgkin’s lymphoma, the calculated fetal doses were between 2 and 50 rad, with most being in excess of 10 rad [14]. All patients had spontaneous deliveries of nor- mal fetuses.

The effects of radiotherapy during pregnancy have been reported. Radiation exposure of 200-300 rad before 20 weeks causes mental retardation, microcephaly, cataracts, retinal degeneration, low birth weight, and skeletal and genital abnormalities [15,16]. Between 20 and 25 weeks no organ abnormalities occurred and children were ap- parently normal just with radiation skin changes similar to those expected in postnatal radiation exposure [15,16]. The long-term sequela of fetal radiation exposure are unknown, but may include childhood leukemias or other cancers, chromosomal aberrations, or impaired future fer- tility [17]. There is no safe dose of radiation during preg- nancy but radiation damage does follow a dose-response curve. Most authorities agree that a fetal dose of less than 10 rad is probably safe [18].

When supradiaphragmatic structures are radiated in late pregnancy, the fetal dose of radiation from scatter (despite abdominal shielding) can be as high as 1.2-7.1% of the total radiation dose [19,20]. In the cases of non- Hodgkin’s lymphoma during pregnancy taken from the literature that were treated with radiotherapy, the disease was localized in the head or neck in three of the four cases; therefore the distance from the fetus to the radia- tion field was relatively large. Zucali et al. [21], using an Alderson phantom, human equivalent, estimated the dose of radiation to the top of the uterus to be 25-52 rad using a linear accelerator to radiate the mediastinum with 3000 rad late in pregnancy. Scattered radiation to the pelvis was only 2-4 rad. Radiation of the supraclavicular region resulted in a dose of only 4-6 rad to the upper uterus and l-2 rad to the pelvis. No shielding was used in this study.

Finally, it must be said of radiation during pregnancy that there are no absolutely definitive studies in the lit- erate and that no controlled studies are ever likely to be done. Important factors that influence the fetal effect of radiation include gestational age; the dose, technique, and chronicity of the radiation given; and whether shielding is used. Therefore, it is impossible to predict with cer- tainty, in individual cases, the fetal effects of all but the smallest doses of radiation.

Combination chemotherapy could also have controlled her disease. However, the long-term effects of chemo- therapy on the fetus, particularly, delayed onset of apla- sia, are of concern. Congenital malformations due to

312 SPITZER ET AL.

chemotherapy are most commonly encountered when drugs are given in the first trimester [22]. Available in- formation about the toxicity of combination drug therapy in this setting is limited and does not provide a firm basis for its safe use. Single-agent vinblastine, if unsuccessful, posed a risk to the mother because of the life-threatening nature of her illness. For this reason, this option was not considered.

The etiology of the baby’s delayed cognitive and motor development is not clear. A review of the literature in- dicates that few, if any adverse fetal effects can be ex- pected from radiation at this gestational age, especially with such a low dose of radiation (<lo rad) to the top of the uterus. Congenital anomalies are more likely to occur if radiation is given during the first 8 weeks of gestation [15,16]. When administered after 30 weeks ges- tation, congenital defects are rare [15,16]. The timing of the slowing in fundal height growth is, however, suspi- cious for a possible radiation effect. Still, other factors must be considered. There is a 3% incidence of mental retardation found in the general population. Attention deficit disorders are found in 1.2-20% of the pediatric population, depending on the ages studied and on the parameters used to define the disorder. It is found with increased frequency among close family members of chil- dren with the disorder and, while less frequent in girls, those girls who are affected tend to be more severely affected [23]. The patient has a sister with minimal brain dysfunction. Patients with idiopathic asymmetric intra- uterine growth retardation would also present with growth delay at the same gestational age, and these babies are at higher risk to have the type of developmental delay exhibited in this case. These facts suggest that the baby in this case was at high risk for developing the disorders that she is exhibiting, unrelated to a radiation effect.

The good outcome in this case can be attributed to the thorough nature of the patient’s workup despite her preg- nancy and the team approach to her care. In this case, radiation therapy proved to be an effective initial modality in the treatment of this rare malignancy. However, be- cause of the uncertain etiology of the child’s disorder, the absolute safety of radiotherapy during late pregnancy can- not be inferred from this case.

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