Managementul terapeutic al glioblastomului în timpul sarcinii: prezentare de caz subliniind caracteristicile clinice şi radiologice la diagnostic şi după intervenţie

Introduction

Heterogeneous malignant cerebral tumors include the following types: anaplastic astrocytoma, glioblastoma multiforme type, gliosarcoma and analplastic oligodendroglioma. Glioblastoma is the most common primary brain malignancy in adults with a mean age of 55-60 years old^(1-3). The therapeutic management in most patients involves surgery, postoperative radiotherapy and adjuvant chemotherapy. Glioblastoma has a high recurrence rate, the average survival being 1-2 years despite maximum therapy.

The patients present with subacute neurological symptoms that progress in days to weeks and vary depending on the intracerebral location of the tumor. The most common symptoms at presentation include: (i) headache (50-60%); (ii) seizures (20-50%); (iii) focal neurological symptoms, such as memory loss, decreased motor strength, visual symptoms, language impairment, cognitive and personality changes (10-40%).

Brain CT examination reveals a hypodense lesion with often irregular contrast. The lesion is frequently surrounded by edema. The fixation of the contrast substance is directly proportional to the degree of neovascularization. MRI examination is superior, allowing the definition of tumor boundaries⁽⁴⁾.

The treatment is multimodal and includes surgical treatment, radiotherapy and chemotherapy. The surgical treatment is the first step. For a satisfactory quality of life and a survival of at least three months, a radical resection is often attempted. In case of severe neurological disorders that will not improve postoperatively or in the elderly, a biopsy will be performed for diagnostic purposes. Reintervention for recurrence is justified under circumstances of satisfactory clinical condition. In radiotherapy, most protocols recommend taking a divided dose of 50-60 Gray for six weeks. Lately, it is preferable to perform focal (conformational) radiotherapy of the tumor bed and the brain in the immediate vicinity over the irradiation of the whole brain in order to minimize side effects. The treatment prolongs the average survival by 50-100%, to around six months. In cases of tumor recurrence, interstitial radiotherapy with Iodine 125 is effective. Regarding chemotherapy, the most effective chemotherapeutic agents are nitrosoureas. The percentage of therapeutic response is about 50%, with the improvement of the clinical condition or the stabilization of the general condition with a duration of six to nine months. A relatively recently introduced alkylating agent, temozolomide, has a favorable effect on prolonging survival and the quality of life in patients with glioblastoma and anaplastic astrocytoma, and is relatively well tolerated. The pharmaceutical treatment consists in administering anticonvulsants, corticosteroids and anticoagulants.

Clinical case

A 34-year-old woman is referred to our emergency room for a decrease in muscle strength in the right hemibody and language disorder, with onset of approximately 10 days. It should be mentioned that the patient is 15 weeks pregnant, with no medical, surgical or obstetrical pathology in history. Hospitalization is decided in order to establish the appropriate therapeutic conduct.

The sudden onset of symptoms and the rapid progres­sion of neurological symptoms, combined with the location of the tumor in the adjacency of the left sensitive-motor cortex next to the area of the language (which prevented the total tumor ablation), are a rare combination of glioma characteristics. Also, the neurosurgical pathology detected at the beginning of the second quarter implies a reserved prognosis.

The gynecological clinical examination excluded any pathology related to the pregnancy. The ultrasound examination indicated a single-fetus intrauterine pregnancy with the placenta inserted on the anterior uterine wall, the amniotic fluid within normal limits and corresponding biometrics.

The neurological clinical examination showed a right hemiparesis motility, with possible walking in orthostatism with support, normal coordination and Babinski positive right skin reflexes. Osteotendinous reflexes are exaggerated on the right side. The sensitivity characteristics presented a right hemicorp hypoesthesia, with continent and controllable sphincters, central facial parenthesis of the cranial nerves and blurred speech.

The cerebral native MRI identified the left frontal expansive tumor, as shown in Figure 1.
 

The differential diagnosis of intracranial tumor formation includes: benign intracranial tumor, intracranial malignancy (primary/secondary), cerebral aneurysm, cerebral vascular malformation, congenital intracranial malformation.

After corticosteroid therapy and anticonvulsant treatment are instituted, it is decided to practice surgery (under general anesthesia and orotracheal intubation) under the operating microscope and neuronavigation guidance, and we practised subtotal ablation (due to tumor adjacency to the left sensory-motor cortex and language area) of the left parietal formation.

The histopathological examination diagnosed a malignant glioma (anaplastic oligodendroglioma or glioblastoma). The oncological evaluation recommended immunohistochemistry and genetic testing for MGMT and IDM. Adjuvant chemotherapy and radiation therapy with temozolomide are contraindicated in pregnancy. Also, a radiotherapy consult was recommended.

The patient remained under neurosurgical and gynecological supervision for 10 days postoperatively. The recommended available imaging evaluation (cerebral CT) was not performed because of the patient refusal. Favorable clinical and paraclinical evolution was established (improved symptomatology, laboratory tests within normal limits, except for a secondary mild anemia) under antibiotic, anticonvulsants, corticosteroid and anticoagulant treatment.

Discussion

Studies have shown that the association of malignant glioma with pregnancy involves a faster negative clinical evolution, an accelerated tumor growth, and possible changes in the histopathological grade^(5-8).

The indication for neurosurgery depends very much on the location of the tumor, on size, histopathological type, neurological signs and symptoms, gestational age, and on patient’s preferences. Some authors recommend timing the intervention after the first trimester or even after 30 weeks, if the patient’s condition is stable. If the intervention cannot be postponed, the second trimester would be preferable considering that the fetus is the most vulnerable in the first trimester and the risk of intraoperative hemorrhage is increased in the third trimester^(9,15,19).

Some authors suggest avoiding the use of nitric oxide and isoflurane due to possible teratogenic implications. The neonatal neurotoxic effects of desfluran and sevoflurane are still under evaluation. Propofol is relatively safe, considering that the main side effect is uterine relaxation, but seizures, ataxia and hallucinations have been reported in newborns when exposure had exce­eded 6 hours.

In patients with glioma, the fetus is exposed to radio­therapy. Especially in the first trimester, radiotherapy should be avoided due to teratogenic effects. Doses >50 cGy present a risk to the fetus regardless of the trimester. The literature recommends calculating and minimizing the dose using coplanar waves <10 mV, axially through the head, and additional pelvic protection⁽¹⁶⁾.

The epidemiological studies have shown teratogenic effects of chemotherapy on the fetus, especially in the first trimester⁽¹⁵⁾. The analysis of exposure to chemotherapeutics in pregnancy has shown a 4-fold higher risk of incidence of malformations compared to the general population. The literature describes an increased risk of malformations associated with the use of procarbazine, lomustine and vincristine in the first trimester. The use of carmustine did not report the occurrence of malformations, but data on systemic use and long-term effects on the fetus are inconclusive. Temozolomide, a recently introduced chemotherapeutic drug, is not indicated in pregnancy^(10-12). Studying six cases of pregnant women with glioma who were exposed to chemotherapy in the first trimester did not show fetal malformations. There is currently no consensus on the risk of chemotherapy in pregnancy; for this reason, the literature recommends their use as an absolute indication⁽²⁰⁾.

Seizures in pregnant women with glioma can cause hypoxia and fetal acidosis. The literature suggests that the best performed prophylactic and therapeutic an­ti­convulsant treatment has several advantages over their teratogenic effects. Lamotrigine, levetiracetam and carbamazepine alone are indicated due to their low te­ra­to­genic effects.

Some authors encourage the use of corticosteroids especially in the second and third trimesters to promote fetal lung maturation. Prednisolone is indicated when lung maturation is not a priority, while dexamethasone is indicated in acute situations. For the long-term use, betamethasone is preferred over dexamethasone due to its side effects profile.

In patients with high-grade glioma, the risk of venous thromboembolism is increased. Pregnancy itself presents an increased risk of occurrence. Prophylactic anticoagulation is indicated, but specific guidelines have not yet been established.

The incidence of malignant glioma associated with pregnancy is quite rare, thus an adequate therapeutic conduct is important. Despite the fact that during pregnancy glioma progression is more aggressive and can be proven through MRI, the survival average for pregnant woman does not differ from the general population⁽¹³⁾. The ideal therapeutic conduct is surgery, preferred after the first trimester of pregnancy, followed by radiotherapy and chemotherapy. Radiotherapy presents teratogenic risks on the fetus. However, the few studies which discuss this type of pregnancy complication did not highlight postnatal neurocognitive and cardiac affliction, because the median follow up of patients described in literature is 24 months. Chemotherapy can be administrated beginning with the second trimester, noting that in addition to malformation risks on the fetus (rarely described in the literature) it may be associated with an increased risk of premature birth or restriction⁽¹⁴⁾.

Anticonvulsive therapy is imperious. Lamotrigin and levetiracetam have the lowest risks of congenital malforma­tions used in monotherapy, while valproat is associated with an increased risk. The use of corticosteroids is indicated, with the mention of the adaptation of the therapy depending on the necessary effect (acute, chronic treatment, or pulmonary maturation). Taking into account the risk of venous thromboembolism both in pregnancy and because of neurological oncological pathology (glioma), anticoagulant therapy is recommended. The specific guidelines based on evidence regarding the use of general anesthesia in pregnancy are not established, but the general consensus recommends the use of general anesthesia in cases in which the untreated pathology presents vital risk^(17,18,21).

The literature does not describe the benefit of performing the caesarean operation in detriment of vaginal birth, with the mention of using epidural anesthesia in case of vaginal birth to prevent the possible growth of pregnancy.

Glioblastoma is an aggressive malignant tumor, being extremely rarely found in patients with similar age as in our patient. The association of malignant pathology with pregnancy complicates the medical conduct both for gynecologists and neurosurgeons in this case. The best outcomes can be expected when the malignancy is diagnosed early in the pregnancy, and also if the neurosurgical intervention can remove the entire tumor. Although being part of the therapeutic conduct for this type of pathology, chemotherapy and radiotherapy must be used with caution due to the negative effects on the fetus.