Extracranial neuroblastomas and neurological complications

Child’s Nerv Syst (1998) 14: 713–718 © Springer-Verlag 1998

Erol Tas¸demirogˇlu I˙nci Ayan Rejin Kebudi

Received: 24 December 1997 Revised: 15 July 1998

E. Tas¸demirogˇ lu (½)1 Neurosurgery Service, Eyüp Social Security Hospital, Eyüp, ˙Istanbul, Turkey ˙I. Ayan · R. Kebudi Department of Pediatric Oncology, Institute of Oncology, University of ˙Istanbul, ˙Istanbul, Turkey Mailing address: 1 ˙ Incirli Caddesi, Deniz Apt 74/7, TR-34740 Bakırköy, ˙Istanbul, Turkey Tel./Fax: +90-212-542-8816

ORIGINAL PAPER

Extracranial neuroblastomas and neurological complications

Abstract Between October 1989 and March 1997, 25 pediatric inpatients were treated for primary extracranial neuroblastoma (NB; n = 20) or ganglioneuroblastoma (GNB; n = 5) at the University of ˙Istanbul, Institute of Pediatric Oncology, and these children were the subjects of this retrospective study. Seventeen (68%) of these patients experienced 19 neurological complications during the course of their disease. Fourteen had nervous system metastases or invasion. Nonmetastatic complications, including CNS infections (n = 3) and new onset of seizures (n = 2) secondary to metabolic encephalopathy were seen in 5 cases. By the time of the final analysis of the results, 8 of the 17 patients with neurological complications had died, 7 had either been lost to follow-up (n = 4) or were in the terminal stage of their disease (n = 3), and 2 were in remission. Both of the patients who were in remission had dumbbell

Introduction

The sympathogon, which is the presumptive stem cell of the neural crest, differentiates into sympathoblasts, the cells of origin of neuroblastoma (NB), and into the more mature forms of neuroblastoma, ganglioneuroblastoma (GNB) and ganglioneuroma (GN), while the chromaffin or non-chromaffin paraganglionic cells are the progenitors of paraganglioma (PG) and pheochromocytoma (PC) [11]. Among these tumors, NB is the most common intra-abdominal malignancy in children, and represents 7% of all

neuroblastoma (DNB), and 1 of them, with congenital DNB, also had neurological sequelae, characterized by paraplegia and neurogenic bladder. Neurological complications occurred in 68% of NB and GNB cases. Metastatic complications were more common than nonmetastatic complications and had a poor prognosis. Neurological complications were the primary cause of mortality in this study, mortality being related to neurological complications in 63% of cases, and the final outcome was worse than expected. However, regardless of any differences in social, economic and geographic factors and different treatment protocols for NB in different pediatric oncology institutions, neurological complication rates in pediatric NB are similar in all. Key words Neuroblastoma · Seizures · Metastasis · Infection

cases of childhood cancer [7]. Approximately half of all NBs arise from the adrenal gland, and half from other intraabdominal sites, including paravertebral sympathetic ganglia and autonomic primordia buried in other organs. Some patients inherit the potential to develop NB in an autosomal dominant fashion. NB has also been associated with von Recklinghausen disease, trisomy 18, risidinoblastosis, Beckwith-Wiedemann syndrome (omphalocele, macroglossia, visceromegaly, neonatal hypoglycemia), Hirschsprung disease and the fetal alcohol or hydantoin syndrome [11, 16]. Human NBs are characterized cytogenetically by partial monosomy for the short arm of Ch1 (1p-) and ab-

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normality of chromosome 17 [11, 16]. NB has a unique biological characteristic among the human cancers, which is the capacity for spontaneous differentiation and regression [2]. NB is very rare in the adolescent or adult, and it is an exacerbation of growth of a tumor that has been clinically dormant since early adulthood. The so-called cerebral NB is a supratentorial tumor of primitive neuroectoderm that is more closely related to a family of primitive CNS tumors [7, 11]. The olfactory NB (esthesioneuroblastoma) arises in the nasal cavity and presents with obstruction. It is most commonly seen in adults and is most probably a peripheral neuroepithelioma. The related adult tumor of childhood NB is small cell lung cancer [16]. The therapeutic management of NB includes surgery, multiagent chemotherapy, and radiotherapy. Such therapies have increased the median survival of patients even with stage IV disease up to 48 months [7, 11, 16]. Patients who live longer are likely to exhibit different patterns of disease recurrence and related systemic or neurological complications. Two-thirds of all cancer patients develop some type of neurological problem during the course of their illness. Neurological complications can be caused by direct involvement of metastatic tumor or by indirect causes related in some way to systemic tumor or its treatment. Types of the neurological complications of systemic cancer are given below. • Metastatic complications: Brain metastases, metastatic epidural spinal cord compression, leptomeningeal metastases (carcinomatous or neoplastic meningitis), and metastases to peripheral nerves or nerve plexus. • Nonmetastatic complications: Metabolic encephalopathies, nervous system infections, cerebrovascular complications, paraneoplastic syndromes, and complications of treatment. The occurrence of neurological complications might be influenced by prognostic factors in systemic cancer. For NB, these prognostic factors are patient’s age, stage of disease, histopathology [18], presence of tumor markers in urine and blood, tumor cell DNA ploidy and N-myc oncogene activation [16]. To evaluate the range and type of neurological complications of NB in the pediatric population of Turkey, 25 pediatric NB cases who were admitted to the University of I˙stanbul, Institute of Pediatric Oncology for treatment between October 1989 to March 1997 were studied retrospectively. The results of a similar study, which was conducted and published earlier by the senior author [19], were compared with those of the current work.

Table 1 The Pediatric Oncology Group’s staging system for neuroblastoma Stage A:

Complete gross resection of primary tumor with or without microscopic residual disease; attached lymph nodes may be positive Stage B: Grossly unresected tumor remains postoperatively Stage C: Completely or incompletely resected tumor with unattached positive lymph nodes Stage D: Disseminated disease Stage Ds: Localized primary tumor with dissemination limited to skin, liver and bone marrow (limited to infants less than 1 year of age)

Table 2 The histological findings and stages of 25 patients (Neurol compl + with neurological complications, Neurol compl – without neurological complications, NB neuroblastoma, GNB ganglioneuroblastoma) Stage

NB Neurol NB Neurol GNB Neurol GNB Neurol Total compl + compl – compl + compl –

A B C D Ds

– – 4 10 1

– – 3 2 –

– 1 – 1 –

– 1 2 – –

– 2 9 13 1

Total

15

5

2

3

25

Table 3 Neurological complications of 17 patients Type of neurological complications

No. of neurological complications

Metastatic complications

14

Cranial metastases Spinal column involvement Spinal column and cranial metastases

6 5 3

Nonmetastatic complications

5

Metabolic encephalopathy and seizures CNS infections

2 3

Total

19

Ages ranged from 0 to 13 years of age (mean age was 4.2 years). The male:female ratio was 12 : 13. Diagnoses were ascertained by tissue examination/bone marrow biopsy, detection of tumor markers in the blood and urine and radiological studies, including abdominal and pelvic ultrasound, axial CT scans and MR imaging. Bone scan was used for detection of metastases. The Pediatric Oncology Group’s staging system for NB was used [11] (Table 1).

Results Patients and methods Between October 1989 to March 1997, 25 children with NB (n = 20) or GNB (n = 5) were treated, and these were all included in the study.

The histological diagnoses and stages of the 25 patients are summarized in Table 2. One patient had congenital NB. In 17 cases a total of 19 neurological complications arose during the course of the disease (Table 3); 2 patients each had

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Table 4 Summary of the data on the 17 cases with neurological complications (var Varicella, DNB Dumbbell neuroblastoma, DIC disseminated intravascular coagulation, CT chemotherapy, XRT radiotherapy, FU follow-up) Age, sex

Pathology and grade

Types and number of neurological complications

Treatment of neurological complication

Outcome of neurological complications

4, M

NB, D

DNB×2, asymptomatic skull mets; (1)

CT

1. Complete remission 2. Recurrence and death

5, F

NB, D

Skull, epidural-cranial mets and varicella zoster encephalitis; (2)

CT + XRT

Died with encephalitis (13th month after diagnosis)

2.5, M

NB, D

Retro-orbital metastasis

CT

Lost to FU (9th month of treatment)

7, F

NB, D

Varicella zoster infection

CT

Died with infection (14th month after diagnosis)

NB, C

DNB a

CT + surgical

Died postop. day 15 with DIC

16/12, F 4, F

NB, D

Multiple cranial and L1 metastases

CT

Improved

5, M

GNB, D

Cranial-epidural metastases

CT + XRT

Improved

2, M

NB, D

Cranial (retro-orbital and temporalepidural) metastases

CT + surgical

Improved

2, M

NB, D

Metabolic encephalopathy (hyponatremic seizures)

–

Died with complication

NB, D

DNB a × 2 and skull metastases

CT + XRT

Improved with neurological sequelae (neurogenic bladder)

0, M

NB, Ds

Congenital DNB a

Surgical + CT

Remission 72nd month with neurological sequelae (paraplegia)

5, F

NB, C

Skull and intracranial-epidural metastases

CT + XRT

Improved

4, F

NB, D

Skull metastases

CT + XRT

Lost to FU in 15th month of treatment

7, F

NB, C

Metabolic encephalopathy×2 and zona zoster infection

CT

Improved

1, F

NB, D

Sacral bone and epidural mets

CT

Lost to FU in 25th month of diagnosis

4, F

GNB, B

DNB-asymptomatic

Surgical

Remission in postop. 6th month

NB, C

DNB and spinal column metastases

CT + XRT

Improved

11, F

13, F a

DNB cases whose primary clinical signs and symptoms were characterized with spinal cord compression

two neurological complications. Table 4 summarizes the data for the 17 cases with neurological complications. Metastatic complications Nervous system metastasis or invasion occurred (n = 14) more frequently than any other neurological complications, and cranial (skull epidural space, dura mater and/or brain parenchym) metastasis was the most frequent metastatic complication. Cranial metastases Cranial metastases (skull dura mater or brain parenchyma) were seen in 9 patients; 3 patients had also spinal column involvement. One patient in this group had an additional neurological complication, which was varicella zoster encephalitis. This patient died of varicella zoster encephalitis.

Retro-orbital metastasis were seen in 2 patients, and in 1 of these cases the retro-orbital lesion showed epidural extension through the left frontal lobe. Since the lesion caused progressive right hemiparesis, the retro-orbital metastatic lesion was partially resected. However, in the 3rd postoperative month a CT scan of the head showed multiple new calvarial epidural metastases without recurrence of the resected retro-orbital lesion. All of these 9 patients had died (n = 3), progressed to a terminal stage (n = 4), or been lost to follow-up (n = 2) by the time of the final evaluation. Although the final outcome was poor, cranial metastases in 4 cases responded to therapy, and temporary relief of the neurological symptoms was achieved. Spinal column involvement This complication was described as metastases to vertebral bodies or invasion of spinal epidural space by NB. Spinal column involvement was seen in 8 patients. Two

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Table 5 Non-neurological complications in seven patients (CHF congestive heart failure) Age, sex

Histology stage

Type(s) of complications

Outcome

7, F 1, F 4, F 2, M 11, F 5, F 7, F

NB, D NB, D NB, D NB, D NB, D NB, D NB, C

CHF, jaundice DIC Anemia Sepsis Glomerulosclerosis Renal failure, sepsis CHF, sepsis, ileus, pericarditis

Died Died Relapsed Died Lost FU Died Died

patients had spinal column metastases. The other 6 patients had spinal canal invasion and spinal cord compression caused by extension of their primary tumor (dumbbell NB), and in 1 of these cases an asymptomatic dumbbell neuroblastoma (DNB) was present. Three of the patients with DNB also had hematogenous metastases to the spinal column and the skull. Only two cases with DNB were alive and in remission. Nonmetastatic neurological complications Five nonmetastatic neurological complications were seen in 4 patients. One of these patients had two neurological complications characterized by zona zoster infection and metabolic encephalopathy. Three patients had nervous system infections: 2 of them had varicella zoster and 1 had herpes simplex infections. Two patients died with varicella zoster infection and sepsis. The third patient had metabolic encephalopathy and zona zoster infection, which improved with topical acyclovir treatment. Two patients had new onset of seizures; both had metabolic encephalopathy and hyponatremia-related seizures. One of these patients also had zona zoster infection, which was mentioned above. They responded to correction of hyponatremia and antiepileptics. Follow-up and outcome Of these 17 patients with neurological complications, 8 died during the treatment or follow-up, and 5 of the 8 deaths (63%) were caused by the neurological complications. Only 2 patients were in remission, at the time of the final analysis of the results, 4 patients having been lost to follow-up while 3 were in the terminal stage of their disease. One of the surviving patients with congenital DNB had neurological sequelae characterized by total paraplegia and neurogenic bladder at the 72-month postoperative followup. Additional nonmetastatic systemic complications were present in 7 of these 17 patients (Table 5).

Discussion

We undertook this study to attain better documentation and comparison of the range and type of neurological complications of pediatric extracranial NBs. Since the current treatment prolongs the life of NB patients, there is enough time for neurological complications to appear. Classic extracranial NB can produce various neurological complications: compression of the underlying brain or spinal cord by bony, dural or venous sinus metastases, solitary brain metastases, spinal cord compression by tumor extending through the neural foramina (dumbbell NB), hypertensive encephalopathy, disseminated intravascular coagulation, myoclonic encephalopathy, cerebrovascular diseases and seizures [5, 7, 17]. Seventeen (68%) of our 25 NB cases had neurological complications during treatment and follow-up at the University of I˙stanbul, Institute of Pediatric Oncology. Tas¸demirogˇlu et al. [19] found the same complication rate (68.7%). The incidence of neurological complications of soft tissue and osseous sarcoma (26.5%) has been reported to be lower than that of NB [6]. Tas¸demirogˇlu et al. [19] found a 36.4% mortality rate, and only 1 case died of causes related to neurological complications. However, in the current study the mortality rate was 47%, higher than in the earlier study, even though we excluded the 7 cases that were lost to follow-up or in the terminal stage. In this study 8 patients died, and 5 of these deaths were related to neurological complications. Overall, the final outcome of the current study was worse than repeated from the earlier study [19]. However, the most interesting aspect of this study is that when both groups were compared, the incidence of neurological complications was seen to be similar in both groups. The earlier report [19] suggested that patients treated and followed up in the U.S. had better outcome and prognosis than patients in Turkey. However, the similarity between the neurological complication rates of both institutions shows that regardless of any difference in social, economic and geographic factors between the countries and differences in the treatment protocols between the institutions the neurological complication rates of NB remained the same. In our study, the most common neurological complication was nervous system metastasis, which was seen on 14 cases. Eight patients had symptomatic spinal column invasion or metastasis. The incidence of intraspinal involvement of NB varies in different series between 6% and 15% [4, 9, 12, 13], and it was 24% (6 of 25 cases) in our study. Intraspinal NB is a direct extension from a paraspinal tumor [4, 8, 13]. Dumbbell NB is the most common malignant cause of spinal cord or nerve root compression in young children and is regarded as an unresectable tumor [12]. Although dumbbell NBs respond better to surgical decompression alone than other metastatic disease, according to Plantaz et al. [12], chemotherapy should be considered for patients with partial deficits, and surgical decom-

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pression should be reserved for children who have a recent onset of severe neurological dysfunction or deterioration in a 24- to 72-hour period. During the follow-up period, dumbbell NB usually does not show the signs of disseminated disease [9]. However, in our study 4 of the 6 patients with DNB showed dissemination, and all 4 of these died with progression of the primary disease. In this study 9 cases had cranial involvement, and in all of these cases this took the form of symptomatic cranial metastases. We have not seen any case of a solitary brain metastasis in this study. The reason why brain metastases are so infrequent in children with NB appears to be the rarity of pulmonary metastases in this disease [10, 17]. The suggested mode of tumor cell entry into the CNS of NB patients is infiltration of the tumor cells into the CNS by the hematogenous route; it is thought that the tumor cells may then lie dormant for a long time without losing their proliferative and metastatic potential [10]. The incidence of cranial metastasis was 5% (44 of 950) among the ENSG (European Neuroblastoma Study Group) patients [17]. NB has an unusual predisposition to periorbital metastasis, which presents with proptosis and ecchymosis [7, 11]. This is secondary to sphenoid wing involvement or invasion of the retrobulbar tissues. We encountered 2 such cases in this study. In 1 of these cases the retro-orbital lesion showed an epidural extension through the left frontal lobe. Since the lesion caused progressive right hemiparesis, the retro-orbital metastatic lesion was partially resected. However CT scan of the head in the 3rd postoperative month showed multiple new calvarial epidural metastases without recurrence of the resected retro-orbital lesion. Although both patients initially responded to treatment, they died with progression of the primary disease. There is no established protocol for the treatment of cranial metastases in children with NB. When feasible, surgical removal of the tumor should be attempted. NB is relatively radiosensitive; therefore radiation therapy plus chemotherapy is a viable option [5, 10]. Urgent radiother-

apy is recommended for leptomeningeal spread of NB [3]. Children with recurrent CNS relapse should be re-treated with systemic chemotherapy even without evidence of extracranial disease [5]. The incidence of mental status changes (MSC) in children with cancer was 11% in another study [1], and 60% of the patients with MSC suffered with seizures [1]. The incidence of encephalopathy was 27% among the children with MSC, which corresponds to 3% of all children with systemic cancer. The encephalopathy rarely had a single etiology and was usually due to multiple factors, such as vital organ failure, electrolyte imbalance, side effects of treatment, analgesic medication and infection [1]. We observed MSC in 2 patients who had new onset of seizures related to metabolic encephalopathy secondary to hyponatremia, which itself was the result of chemotherapy, and both responded to correction of the hyponatremia. Metabolic factors are common reasons for seizures in cancer patients. High-dose cisplatin disturbs the fluid and electrolyte balance, and encephalopathy with confusion and seizures can occur [8]. In our study we had 3 neurological infections, and 2 of these patients died of varicella infection and sepsis. The 3rd case had zona zoster infection and responded to acyclovir treatment. Although stroke [14], paraneoplastic syndrome [15], and cerebral hemorrhage due to thrombocytopenia [8, 14], have been reported among the neurological complications of NB, we have not encountered any of these complications. In conclusion, neurological complications occurred in 68% of our NB and GNB cases. Nervous system metastasis was the most common neurological complication and had the most dismal prognosis. Regardless of differences in social, economic and geographic factors between countries and different treatment protocols for NB between pediatric oncology institutions, the neurological complication rates of extracranial NB were found to be similar in both institutions in Turkey (68%) and the United States (68.7%).

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