ganglioneuroma

Thoracic Neuroblastoma/Ganglioneuroma By D. G. Young

Glasgow, Scotland 9 The Executive Committee of t h e B.A.P.S, instituted a c o l l a b o r a t i v e s t u d y of patients with thoracic neuroblastoma treated by members in t h e British Isles. T h e study covers patients diagnosed in t h e decade 1 9 7 0 - 1 9 7 9 . There is clear evidence of t h o racic disease in all patients reported but there is a problem in defining w h e t h e r t h e thoracic disease is primary or p a r t of disseminated disease. In 9 o f t h e deaths the thoracic component at presentations seems likely to be part of a generalised disease w i t h o u t definition of a primary site. Overall m o r t a l i t y in this series is 3 5 % indicating the better prognosis of the patients presenting with thoracic neuroblastoma compared to other primary sites. If t h e 9 patients considered to have generalised disease are excluded t h e n t h e m o r t a l i t y in t h i s collected series is 22% (10 of 45). T h e investigations and management are outlined and the complications of therapy are considered.

INDEX WORDS: Neuroblastoma, thoracic; ganglioneuroma, thoracic.

D V A N C E S in the management of children with solid tumors have resulted in significantly improved survival in those with nephroblastoma and sarcoma but the current results of treatment of neuroblastoma remain disappointing. Patients with neuroblastoma arising in the thorax have been reported to have a better prognosis than patients with a primary lesion elsewhere ~-3 but this observation has been disputed. 4 Neuroblastoma arising primarily in the thoracic cavity accounts for 14% of patients with neuroblastoma. Hence even the large pediatric centers have limited experience of treatment of the disease and clinicians have insufficient case material to form valid conclusions on their individual series. This study was initiated by the Executive Committee of the British Association of Paediatric Surgeons to collect information from the pediatric surgeons in the British Isles. It was agreed to seek information from the surgeons on patients with neuroblastoma and/or ganglioneuroma treated by them in the last decade. From this study it was hoped to determine if thoracic neuroblastoma did have a more benign course than neuroblastoma elsewhere, to see if there were any common features which helped to indicate a better or worse prognosis in these individ-

A

Journal of Pediatric Surgery, Vol. 18, No. 1 (February), 1983

ual patients and to assess if there has been a significant mortality as a result of therapy. PROCEDURE

Each Center in the British Isles in which there was a B.A.P.S. Member was circulated with a letter explaining the study. Information was sought on all patients treated in that center in the decade 1970-1979. The surgeon contacted was asked to liaise with his colleagues in an attempt to ensure as complete a return as possible and also t h e minimum of duplication of returns. Thirty-five circulars were sent and no reply was received from five surgeons: only one of these surgeons is still in active pediatric practice. Two surgeons have not been able to trace their patients and one individual preferred not to return his two patients for inclusion in the review. Replies from the remaining 27 have been received although many of these were of a zero return. Details of 60 patients were recorded of whom 14 have been excluded: 3 of these have been excluded on account of age at diagnosis (18-21 yr); 2 were excluded because diagnosis was made outwith the decade under study; and 9 were excluded as it appeared clear from the return that the thoracic element was of secondary neuroblastoma rather than it being the primary site of the disease. Of this latter group six were returned from one center where the request for information was passed from the surgeons to a medical colleague. SEX AND AGE

The sex and age are shown (Figs. 1 and 2). There were 17 males and 29 females in the series.

From the Department of Paediatric Surgery, Royal Hospital for Sick Children, Glasgow, Scotland. Presented before the XX1X Annual Congress of the British Association of Paediatric Surgeons, Madrid, Spain, July 21-23, 1982. Address reprint requests to D. G. Young, Department of Paediatric Surgery, Royal Hospital for Sick Children, Glasgow, Scotland. 9 1983 by Grune & Stratton, Inc. 0022-3468/83/1801-0009501.00/0 37

38

D.G. YOUNG No. of Patients 17~

162 151413" 1211. 10" 9. 69

7"

9 Died [] Alive

I

Alive

Dead

Respiratory

14

4

A]imentary

8

2

Urinary

2

]

Neuro]ogical

9

3

13

5

Others

6"

Fig. 3.

5" 4" 3"

Presenting symptoms,

INVESTIGATIONS

2"11 1.

0-1/12-1 -2 -3 -4 -5 - 6 - 7 -8-9-10-11-12-13 13+ Age, years Fig. 1.

Age at presentation and outcome.

Nineteen (41%) were under 1 yr of age at diagnosis and 28 (61%) were less than 2 yr at diagnosis.

The hemoglobin and white cell counts on admission varied considerably. Hemoglobin was less than 7 g in one patient and less than 10 g/100 ml in 4. All of these patients survived. The white cell count was over 16,000/cu mm in 6 patients, only one of them died. Chest x-ray showed a paravertebral mass to No. of Patients

PRESENTATION

The presenting signs or symptoms have been related to the major systems and are shown in Figure 3. The totals in Figure 3 exceeds the numbers of patients as some presented with signs or symptoms related to more than one system. Two patients were diagnosed on a routine chest x-ray which had been taken prior to Ear, Nose and Throat surgery and had no symptoms related to the tumor. The majority of patients presenting with neurologic signs had spinal cord compression but others included one with myocolonic encephalopathy and another with Horner's Syndrome. The period from the parents noticing the initial sign or symptom until the diagnosis of thoracic neuroblastoma was less than 1 mo in 49% and greater than 6 mo in 12% (Fig. 4).

Alive

Dead

Total

Male

13

4

17

Fema]e

23

6

29

Fig. 2.

Mortality statistics.

20.

B

II

9 Died [ ] Alive

Omitted:

15"

2-routine chest X Ray prior to ENT surgery

1- unknown duration

II

I

5"

<1/12 -3/12 -6/12 >6/12 Duration, years Fig. 4. Interval between the development of signs and symptoms and establishing diagnosis.

THORACIC NEUROBLASTOMA/GANGLIONEUROMA

39

Site of lesion

Alive

Dead

Right side

]5

9

Left side

17

l

Fig. 5.

Site of lesion.

the right of the midline in 24 and to the left in 18. In the remaining 4 it was not clear from the returns which side was the site of the initial lesion. For some unexplained reason the mortality was much lower in those presenting with a left-sided lesion (Fig. 5). Other investigations were done less frequently and the more commonly performed are shown in Figure 6. Along with the number of each of the examinations performed the number considered to be normal are shown in brackets in Figure 6. In the latter part of the series ultrasound examination was being used to differentiate solid from cystic masses and other investigations that are not tabulated include bone scan, skeletal survey and liver scans which were performed infrequently. Catechol amine excretion was recorded in 40 of the returns and was not done in 5 patients. In 22 patients the levels were elevated but the levels were normal in a higher proportion of those who subsequently died (56%) compared with that in

Investigations

Alive

Dead

I.V.P.

13 (9)*

2 (2)

Barium swallow

1] (7)

-

Ultrasound

8 (3)

-

Myelogram

8 (2)

5

E.E.G.

3 (2)

V.M.A. Bone Marrow

TREATMENT

With the varied size and extent of the tumors at presentation and the wide spectrum of clinicians involved a summary of the treatment given is presented in Figure 7. During the decade under review chemotherapy was used increasingly in the latter part but with the small total numbers Alive

Oead

Surgery

9

3

-

Radiotherapy

]

-

31 (13)

9 (5)

Chemotherapy

l

]

Surgery + Radiotherapy

7

-

26 (21)

8 (5)

Surgery + Chemotherapy

5

Surgery + Radiotherapy+ Chemotherapy

lO

6

3

-

* Figures in parenthesis are the number of examinations which were within the normal range. Fig. 6.

the survivors (42%). Subsequent V.M.A. estimations were higher in 4 patients and each of these survived. In 9 patients subsequent V.M.A. levels were still elevated but to a lesser degree and 9 of these survived. In 10 patients the subsequent urinary catechol amine excretion was normal having been elevated initially and in this group one patient died. Bone marrow examination was recorded in 34 patients. Eight of these patients had abnormal cells in the marrow, possibly neuroblastoma cells. Five of these 8 patients survived. Five of the 10 who died had a normal marrow and 3 an abnormal marrow on presentation. Staging of the tumor was not widely used and in only 18 patients was this returned. The staging was I - - 4 , I I - - 3 , 11--8 (4 deaths), I v - - 3 and I V s - - 1 . The lesion was also assessed by the person completing returns from the information in the patient's notes. In 16 patients the lesion was considered discrete (0 deaths) while in 15 there was a discrete lesion but with local extension (9 deaths). In 5 there was considered to be distant spread at the time of diagnosis and in this group there were no deaths. Assessment was not made in the 10 remaining patients by those making the returns.

Investigations.

Treatment

Radiotherapy + Chemotherapy Fig. 7.

Treatment.

D. G. YOUNG

40

Histology

Alive

Dead

Deaths 1. Hypertensive crisis at laminectomy - died shortly after.

NeurobIast oma

23

7

2.

Pneumocystis carinii + C.M.M. pneumonia.

3, Respiratory failure.

Gang]i oneuroma

5

Mixed

7 Fig. 8.

] ]

Histology.

Werdnig Heffman. Tumour free.

4. Paraplegic marasmic infant. 5.

5 died of disseminated disease. Fig. 9.

available it is impossible to draw firm conclusions from the varied management given. MORTALITY

In the figures and tables presented mortality has been indicated in each group. Ten of the 46 patients died, i.e., mortality of 22%. The mortality in relation to the histological diagnosis given at the time of operation is presented in Figure 8. At present the histology of these tumors has not been reviewed. The cause of death in 5 patients was disseminated disease. The remaining 5 had different causes for the death of the patient and these are listed in Figure 9. The first can be classed as a surgical death as the operation was being performed to remove residual ganglioneuroma and intraoperative problems developed. The second patient was on chemotherapy when developing infection probably related to the immunosuppression from chemotherapy. The third patient, also tumor free, developed respiratory failure and muscle biopsy just prior to death showed changes of Werdnig Hoffman disease. He also had been on chemotherapy. The fourth and fifth patients appear to have been considered to have a poor prognosis and their overall outlook contributed to their ultimate demise. DISCUSSION

From this collective review a number of points appear to be more clear. The thoracic primary does have a better prognosis than the abdominal primary of this spectrum of disease from frank neuroblastoma to ganglioneuroma. The series does not support the contention that age is the main factor in prognosis. 5 The Toronto series

Pneumonia.

Neonate: died 3 weeks after operation.

Deaths.

which included 17 mediastinal neuroblastoma (13 survivors) concluded that age, the nonadrenal site and lower staging were responsible for the better prognosis. Thoracic neuroblastoma does appear to remain more localized and have a greater tendency to maturation than neuroblastoma in other primary sites. This results in a lower rating of the stage of the tumor at diagnosis. There seems to be no evidence to support the idea that patients with these lesions present earlier and instead an explanation is required for the fact that these tumors remain more localized. Despite attention to the histology 7'8 and biochemistry as well as the staging reliable indicators on which to base prognosis are not available. Treatment should be safe and surgeons must keep in mind that they are not necessarily dealing with a lethal disease. It is important that those liaising with oncologists are fully aware of the natural clinical history of the disease rather than simply relying on a histological diagnosis in planning management of a child with thoracic neuroblastoma. The minimum therapy necessary to cure the patient should be given as this would help eliminate some of the mortality which has been reported in neuroblastoma. 9 The question remains why do these patients do relatively well or conversely one can ask why do few of the patients with primary thoracic neuroblastoma do poorly. ACKNOWLEDGMENT

I wish to acknowledge the cooperation received from colleagues throughout the British Isles in making this B.A.P.S. Review on Thoracic Neuroblastoma/Ganglioneuroma possible.

THORACIC NEUROBLASTOMA/GANGLIONEUROMA

41 REFERENCES

1. Filler RM, Traggis DG, Jaffe N, et al: Favourable outlook for children with mediastinal neuroblastoma. J Pediatr Surg 7:136-143, 1972 2. Evans A: Advances in Neuroblastoma Research. New York, Raven Press, 1979 3. McLatchie GR, Young DG: Presenting features of thoracic neuroblastoma. Arch Dis Child 55:958-962, 1980 4. Pochedly C: Neuroblastoma. Acton, Mass., Publishing Sciences, 1976, p 285 5. Catalano PW, Newton WA, Williams TE, et al: Reasonable surgery for thoracic neuroblastoma in infants and children. J Thoracic Cardiovasc Surg 76:459-462, 1978

6. Coldman A J, Fryer CJH, Elwood JM, et al: Neuroblastoma: Influence of age at diagnosis, stage, site, and sex on prognosis. Cancer 46:1896-1901, 1980 7. Beckwith JB: Observations of the histopathology of neuroblastomas. J Pediatr Surg 3:106-110, 1968 8. Adam A, Hochholzer L: Ganglioneuroblastoma of the posterior mediastinum. Cancer 47:373-381, 1981 9. Ninane J, Pritchard J, Morris-Jones PH, et al: Stage II Neuroblastoma: Adverse prognostic significance of lymph node involvement. Arch Dis Child 57:438-442, 1982