Malignant endocrine tumours in childhood and adolescence - results of a retrospective analysis
Thomas Parlowsky’, Peter Bucsky’, Marita Hof’, Peter Kaatsch2 ‘Klinik für Pädiatrie, Medizinische Universität zu Lübeck
2Institut für Medizinische Statistik und Dokumentation, Johannes-Gutenberg-Universität Mainz
Abstract
Background Malignant endocrine tumours (MET) are rare neoplasms in childhood and data on such tumours are scarcely available. The aim of this retrospective study was to collect data over a period of 11 years (1984-1995) and to give the basis for a prospective study.
Patients and method 180 departments of paediatrics, nu- clear medicine and children’s surgery were asked for re- porting of patients with MET by a questionnaire. 35% of the departments answered (however, 75% of the paedi- atric departments).
Results 96 children with MET were reported: 73 with thyroid cancer (50 papillary, 15 follicular, 7 medullar, 1 an- aplastic; 1:1,9 boys to girls, both mean and median age 113/4 years), 12 with adrenocortical cancer and 11 with other malignant endocrine tumours.
Metastases were found at diagnosis in 41 of 65 children with papillary or follicular carcinoma. 37 patients (pts.) are in first continuous complete remission (CCR), 4 in partial remission (PR) and in 24 (!) children the remission state or the outcome is not known. 6 of 7 children with medul- lary cancer have had metastases at diagnosis. 1 patient is in CCR, 1 patient is living in PR, 1 in relapse. 4 children are lost of follow up (lfu.).
In sex-ratio no difference was found in 12 pts. suffering from adrenocortical cancer (mean age 51/4 years, median age 21/2 years). 11 tumours showed hormonal activity. 5 children disclosed metastases at diagnosis. All patients were treated by surgery, 6 received chemotherapy addi- tionally. 4 children are living in CCR, 3 pts. in remission of unknown state, 4 died (all of them with metastases at diagnosis), 1 patient is Ifu.
The other MET reported: 8 carcinoids (7 x appendix, 1 x lung), 2 phaeochromocytomas, 1 islet cell cancer. 8 pts. are in CCR, 2 are Ifu. The child with the islet cell carci- noma died.
Conclusions Since only 35% of the clinics answered this retrospective analysis cannot give any statement about the incidence of MET in children. As to the prognosis thyroid cancer seems to have a favourable prognosis in childhood and adolescence. In contrast, metastatic adrenocortical cancer is incurable in this age group. Carcinoids of the ap- pendix can be treated curatively by appendectomy. To better understand the biology of MET in children and ad-
Maligne endokrine Tumoren im Kindes- und Jugend- lichenalter - Ergebnisse einer retrospektiven Analyse
Hintergrund Maligne endokrine Tumoren (MET) sind selten im Kindesalter. Angaben zur Häufigkeit und Pro- gnose sind in der Literatur kaum zu finden. Diese retro- spektive Analyse umfaßt einen Zeitraum von 11 Jahren (1984-1995) und soll als Grundlage für eine prospektive Erfassung dieser Tumoren im Kindes- und Jugendli- chenalter dienen.
Patienten und Methode Zur Datenerhebung wurden per Fragebogen 180 Pädiatrische, Nuklearmedizinische und Kinderchirurgische Kliniken in Deutschland ange- schrieben. 35% der Kliniken antworteten insgesamt, je- doch 75% der Pädiatrischen Kliniken.
Ergebnisse 96 Kinder mit MET wurden ermittelt: 73 mit Schilddrüsenkarzinomen (50 papillär, 15 follikulär, 7 me- dullär, 1 anaplastisch; Mädchenwendigkeit 1,9: 1, Durch- schnittsalter 11 3/4 Jahre, Median 11 3/4 Jahre), 12 mit Ne- bennierenrindenkarzinomen und 11 mit anderen malig- nen endokrinen Neoplasien.
41 von 65 Kindern mit papillärem oder follikulärem Schilddrüsenkarzinom hatten bereits Metastasen bei Dia- gnose. 37 Patienten sind in erster kompletter Remission, 4 in partieller Remission und von 24 (!) ist das Therapie- ergebnis oder der Remissionsstatus nicht bekannt. 6 von den 7 Kindern mit medullärem Karzinom hatten Meta- stasen bei Diagnose. 1 Patient ist in erster kompletter Re- mission, 1 in partieller Remission, 1 Kind lebt in Rezidiv, 4 (!) sind lost of follow up (Ifu.).
Das Nebennierenrindenkarzinom trat bei gleich vielen Jungen und Mädchen auf (Durchschnittsalter: 5 1/4 Jahre, Median: 21/2 Jahre). 11 Tumoren waren hormonaktiv. 5 Kinder hatten Metastasen bei Diagnose. Alle Patienten wurden operiert, 6 wurden zusätzlich zytostatisch behan- delt. 4 Kinder leben in erster kompletter Remission, 3 in unbekanntem Remissionsstatus. 4 Kinder verstarben (al- le mit Metastasen bei Diagnose). 1 Kind ist Ifu.
Andere erfaßte MET: 8 Karzinoide (7x Appendix, 1 x Lunge), 2 Phäochromozytome, 1 Inselzellkarzinom. 8 Kinder sind in kompletter Remission, 2 sind Ifu. Das Kind mit Inselzellkarzinom ist verstorben.
Schlußfolgerungen Aussagen zur Häufigkeit von MET bei Kindern und Jugendlichen sind bei einer Rücklauf- quote von 35% nicht möglich. Immerhin scheint das
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olescence and to achieve a better prognosis for some types of these tumours, much more data are needed. For these reason a multicenter prospective therapy study for child- hood MET seems to be necessary.
Key words Thyroid carcinoma - adrenocortical carcino- ma - endocrine tumours - childhood
Schilddrüsenkarzinom trotz Metastasen bei Diagnose eine günstige Prognose im Kindes- und Jugendlichenalter zu haben. Diese Aussage ist jedoch durch die hohe Patien- tenzahl mit unbekanntem Therapieergebnis einge- schränkt. Demgegenüber weisen metastasierte Neben- nierenrindenkarzinome eine sehr schlechte Prognose auf. Solitäre Appendixkarzinoide können mit einer Appen- dektomie kurativ behandelt werden.
Um die Biologie der MET bei Kindern und Jugendlichen besser zu verstehen bzw. um die Prognose bestimmter MET zu verbessern, scheint eine multizentrische pro- spektive Studienanalyse von Nöten zu sein.
Schlüsselwörter Schilddrüsenkarzinom - Nebennieren- rindenkarzinom - endokrine Tumoren - Kinder
Introduction
Tumours of the endocrine system are rare diseases in child- hood. According to Chrousos (3) 4-5% of all neoplasms are endocrine tumours in this age group. In this frequency all types of endocrine tumours observing in children are in- cluded: benigne and malignant tumours of the testes and the ovaries, of the pituitary gland, thyroid and adrenocor- tical gland, phaeochromocytomas and carcinoids. The most frequent malignant endocrine tumours in children and ado- lescents are the germ cell tumours. Their frequency is ab- out 4% of all malignancies in childhood and adolescence in Germany (11). These tumours are, however, already re- gistered in different prospective multicenter therapy studies in this country. However, detailed data about frequency, therapy modalities and outcome of other malignant en- docrine tumours (MET) in childhood and adolescence are very scarcely in the literature.
Therefore the first aim of this retrospective analysis is to try to give a survey about frequency, age and therapy modali- ties of various malignant endocrine tumour types in child- ren and adolescents, which are not registered in any pro- spective study until today. The mean subjects in this ana- lysis are thyroid and adrenocortical cancer. In addition, tumours producing different types of biogene amines are also subject of this evaluation.
Secondly, on the basis of this retrospective analysis a pro- spective multicenter therapy study will be planned.
Patients and methods
To obtain data 180 departments (of paediatrics, nuclear medicine and children’s surgery) were asked for patients with any type of MET <18 years of age. For this reason a detailed questionnaire has been worked out, including information for age, sex, histolo- gy, localisation, extension of disease, therapy and outcome. The data collection was confined to the last eleven years. This retro- spective study was conducted by permission of and in agreement with the Gesellschaft für Pädiatrische Onkologie und Hämatolo- gie (GPOH) and in collaboration with the Children’s Cancer Re- gistry at the University of Mainz.
Results
About 35% of the 180 departments have answered, whe- reas the compliance of the paediatric departments was sig- nificantly better: 75% of them have reported data by the questionnaire. Altogether 96 patients (pts.) with MET have been reported and included in this analysis. 73 children disclosed thyroid cancer and 12 adrenocortical cancer. In 11 pts. other types of MET were diagnosed: 8 carcinoids, 2 phaeochromocytomas, 1 islet cell cancer, respectively. Unfortunately the number of patients reported with MET is much lower as expected, which is due by the very low re- turn rate of 35%. Because of this patient number statistical analyses were not possible.
As to the malignant thyroid tumours, 73 pts. could be eva- luated. 48 pts. were female, 25 male (sex-ratio: 1,9:1). Both the mean and median ages were 11 years and 8 months. The youngest child has been 41/4 years, the oldest adolescent has been 173/4 years at diagnosis.
Pathohistologically 50 of the thyroid malignancies showed a papillary structure and 15 a follicular one. In seven fur- ther cases medullary and in one child the anaplastic type were diagnosed.
In the group of papillary and follicular thyroid cancer 41 pa- tients disclosed metastases at diagnosis: in 27 cases exclu- sively in regional lymph nodes and in 10 children addition- ally in the lung. In four children informations were not giv- en about the localisations of metastases.
In patients with papillary or follicular thyroid cancer for therapy the following modalities were carried out: thyroi- dectomy only in 12, thyroidectomy plus radioiodine ther- apy in 37, thyroidectomy plus radioiodine therapy plus per- cutane radiotherapy in 13 cases. Thyroidectomy with radio- iodine therapy plus chemotherapy (Adriamycin) has been applied in 1 child. In two children no data about therapy modalities applied were reported.
As to the remission after therapy, data were available on- ly for 41 pts. 37 of them are in first continuous complete re- mission (CCR) and 4 in partial remission (PR) (Tab. 1). The follow up ranges from one to 112 months.
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| Therapy | n.d. met | sur met | sur + ri met | sur +ri+r met | sur +r + cyto met | total met | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| yes | no | yes | no | yes | no | yes | no | yes | no | yes | no | |
| 1. CCR | 1 | 1 | 1 | 7 | 15 (4) | 5 | 8 (1) | 1 | 1 | 1 | 24 (5) | 13 |
| PR | 1 | 1 | 1 | 1 | 3 (3) | 1 | 1 | 1 | 1 | 1 | 4 (3) | 1 |
| Alive but n.d. to | ||||||||||||
| remission state | 1 (1) | 1 | 1 | 2 | 5 | 4 | 2 | 1 | 1 | 1 | 8 (1) | 7 |
| Ifu | 1 | / | 1 | 2 | 3 (1) | 2 | 1 | 1 | 1 | 1 | 5 (1) | 4 |
| Total | 1 (1) | 1 | 1 | 11 | 26 (8) | 11 | 12 (1) | 1 | 1 | 1 | 41 (10) | 24 |
As already mentioned seven patients have had the medul- lary histological type of thyroid cancer. Six of them have al- ready had metastases at diagnosis (two in regional lymph nodes, two in lung, one in lymph node and lung and one in lung and liver) . An important fact is, that 5 of the 7 patients have disclosed the symptom of multiple endocrine neopla- sia type IIb (MEN IIb), an autosomal dominant disease with praedisposition for medullary thyroid malignancy. The only child without metastases received radiotherapy (50 Gray) after surgery. The other patients were treated by sur- gery alone.
Concerning the therapy results, one patient is in first CCR, one in PR (with persisting metastases in the lung) and one child is living in relapse. The follow up ranges from 3 to 93 months.
The only child with the anaplastic type of thyroid cancer (11 year old boy) is alive 6 years after diagnosis. He was treated by radical thyroidectomy.
Adrenocortical cancer was reported only in 12 children (6 boys and 6 girls) with mean and median ages at diagnosis of 5 1/4 years and 21/2 years, respectively (range ten months to 14 years). 11 tumours were hormonally active: five pro- duced androgens, two androgens and cortisol, two only cor- tisol, one aldosterone and in one case information about endocrine activity was not available.
At diagnosis five patients showed metastases (liver, lungs and lymph nodes), seven children were free of metastases. In all but one patient, who was treated by enucleation of the tumour, a total adrenalectomy was carried out. In six children an additional cytostatic therapy was applied.
Four patients without metastases are in first CCR, three are alive without any reported specification of their remission state. One child is lost of follow up. Four children with met- astatic disease died in spite of cytostatic therapy by various drug combinations (Tab. 2). The follow up ranges from two to 81 months.
In further 11 patients several other types of malignant en- docrine tumours were diagnosed: carcinoids of the appen- dix (seven pts.), carcinoid of the lung (one pt.), phaeo- chromocytoma (two pts.) and in one case malignant islet cell tumour. All carcinoids of the appendix (six girls, one boy) were diagnosed by chance at appendectomy. All these children are living without any evidence of disease, also the only child (10 year old girl) with the carcinoid of the lung.
| Therapy | sur metastases | sur+cyto metastases | total metastases | |||
|---|---|---|---|---|---|---|
| yes | no | yes | no | yes | no | |
| 1. CCR | 1 | 3 | 1 | 1 | 1 | 4 |
| Died | 1 | 1 | 4 | 1 | 4 | 1 |
| Alive but n.d. to | ||||||
| remission state | / | 3 | / | 1 | / | 3 |
| Ifu | 1 | 1 | 1 | / | 1 | 1 |
| Total | 1 | 6 | 5 | 1 | 5 | 7 |
In two boys (9 and 12 1/4 years old) the adrenal mass proved to be a phaeochromocytoma. One of them has been treat- ed by surgery and radioiodine therapy, the other boy by sur- gery alone. Unfortunately both are lost of follow up!
The only patient (133/4 year old boy) with the malignant islet cell tumour, disclosing metastases in the liver already at diagnosis, was treated both by surgery and cytostatic therapy. Subsequently, a liver transplantation was per- formed. However, he died 22 months after diagnosis because of rejection of the transplanted liver.
Discussion
Neither incidence nor therapy results of malignant endo- crine tumours in children and adolescence in Germany are known. Also, data about incidence, therapy strategies and therapy results are very scarcely in literature (3). For this reason a retrospective analysis was initiated. Aim of this study was to collect data on MET in childhood and adoles- cence <18 yrs. of age, for the last ten years. By questionnaire 180 departments, possibly dealing with MET in this age group, were asked to cooperate. A detailed questionnaire was developed and sent out in agreement with the GPOH and in cooperation with the Children’s Cancer Registry in Mainz. The most important points of the questionnaire were as follows: type, number, localisation of tumours, gen- der, age, therapy modalities applied, therapy results, out- come and remission state. The most frequent types of MET < 18 yrs. of age seem to be malignant neoplasms of the thy- roid gland. There is an imbalance in gender in favour of girls to boys (1,9:1) (4, 5, 6, 8, 9, 18). The cause for it is not known.
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Most of the children and adolescents were diagnosed be- tween the tenth and 16. year of age with a mean and me- dian age of 113/4 years. Samaan et al. (18) point out, that the incidence of thyroid neoplasias increases with rising age of children. So it is possible, that many adolescent patients aged between 15-18 years, being treated in medical clinics for adults, could not be reached for this analysis.
According to our study the papillary carcinoma seems to be the most frequent histological subtype of thyroid can- cer in childhood (50 of 73). It is followed by the follicular (15) and medullary (7) subtypes. The anaplastic type of thy- roid cancer could be found only in one child (11 year old boy), confirming the rarity of this tumour in childhood (10). The medullary cancer type of the thyroid gland can be di- agnosed in children mostly in connection with MEN type IIb (5). This fact could be confirmed by this retrospective analysis: five out of 7 children with medullary thyroid can- cer disclosed a MEN IIb.
Our analysis shows a rather high tendency for metastases in childhood thyroid cancer at diagnosis: in papillary/follic- ular cancer types 41 of 73 patients (56% ) and in medullary type six of 7 patients have shown metastases. They fre- quently appeared in the cervical lymph nodes (38 pts.), but in 12 pts. also in the lung. According to the data of Harness et al. (8) 88% of the children with differentiated (i.e. pap- illary or folliculary) thyroid cancer disclose metastases at diagnoses.
Regarding the outcome, differentiated childhood thyroid cancer seems to have a favourable prognosis. 37 children are in first CCR, four pts. (all with metastases) in PR. None of the reported patients died. However, for 24 further chil- dren the remission state was not available or they are lost of follow up! In our opinion such a high number in this re- spect cannot be accepted.
As to the prognostic factors, in metastatic disease lung me- tastases exert a negative influence, in contrast to lymph node metastases (8, 9). This fact could not be confirmed by our analysis, although the number of registred patients in our study is low. For the same reason it is not possible to make evaluation in any respect for medullary thyroid can- cer. In addition, in four out of 7 pts. the outcome is not known, they are lost of follow up. In childhood metastatic medullary cancer the extend of the disease at diagnosis is the critical prognostic factor (14).
The therapy of choice in all types of thyroid malignancies is surgical intervention. However, the question whether in all cases a thyroidectomy has to be performed, cannot be answered by our data. In any case the efficacy of radio- iodine therapy after surgery is well established for the differentiated thyroid cancers. Nevertheless, there is no consense about its indication. Some authors consider the postoperative radioiodine therapy by all means necessary (8, 9), others do not share this opinion (4, 18). In our opi- nion children and adolescents with metastatic disease have to be treated by surgery, followed by radioiodine therapy.
The sex-ratio in the 12 patients reported with adrenocor- tical cancer (ACC), does not correspond with sex-ratios ob- served in the literature. Ribeiro et al. (16) and Sabbaga et
al. (17) have published more girls than boys with a sex- ratio of 1,2: 1 and 4: 1, respectively. This difference is prob- ably caused by the very small number of patients reported in our retrospective analysis.
As to the age distribution in ACC eight out of our 12 re- ported patients were aged between ten months and four years. The remaining four children were between ten years and 13 years of age. So, in this respect our data correlate with that of the literature. Namely, according to the data published by Knöpfle et al. (13) and Ribeiro et al. (16) the age peak for diagnosis of ACC is between the first and the third year of life.
A large number of ACC are hormone producing tumours (1, 2, 7, 12, 13, 16, 17). Most of them are producing corti- coids and/or androgens. Due to it these children present at diagnosis virilisation and/or cushingoid symptoms. In our study eight pts. show virilisation and/or pubertas praecox, one Cushing’s disease, one presented both. Two children were without any endocrine symptoms, they suffered from abdominal pain at diagnosis.
Five of the 12 reported patients with ACC have disclosed metastases in the liver and/or in the lung at diagnosis. Knöpfle et al. (13) have published in their review article on 150 children with ACC, that about 1/3 of them have had metastases at diagnosis, first of all in the liver and in the lung. They state, the presence of metastases at diagnosis seems to be a negative prognostic factor.
In our series in 11 out of 12 children a total adrenalectomy was performed, in one patient the tumour was enucleated. In six cases surgery was followed by cytostatic therapy. Mitotane (o’p,-DDD) was added in three out of these pa- tients. Six patients without metastases at diagnosis and who were treated by radical adrenalectomy, are alive. Three of them are in CCR, three are alive without any further specification. In one child - also without metastases - an additional cytostatic therapy with Ifosfamide, Carbopla- tinum and VP 16 was applied. This child is in CCR, as well. All children, having disclosed metastases at diagnosis died (n=4), in spite of cytostatic therapy by different drugs (with and without Mitotane). One child without metastatic disease is lost of follow up. On the basis of our small series - in accordance with the literature - extended surgical treatment seems to be the only curative therapy. Therefore a radical adrenalectomy combined with a total extirpation of tumour(s) has to be performed. However, the progno- sis of metastatic ACC is very poor, despite additionally cytostatic drugs and/or Mitotane (1, 10, 12, 13, 16). So this provocative disease seems still to remain a challenge for paediatric oncologists.
Because of the rarity of further types of childhood malig- nant endocrine tumours, they can only be mentioned very shortly: In seven children the carcinoid tumours were found accidentally by histologic examination. Namely in all chil- dren appendectomy was performed because of clinical signs of acute appendicitis. By appendectomy these children seem to be treated curative. Relapses were not document- ed. This is also the case in a study of Parkes et al. (15): In 40 paediatric patients with carcinoid of the appendix they did not find any cases of relapse or of death. Carcinoids in other localisations (e.g. lung), phaeochromocytoma and
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islet cell carcinoma are extremely rare in childhood. There- fore, concerning therapy and/or prognosis no statements are possible at this time.
In summary: Because of a very moderate number of re- turned data for this retrospective study the incidence of MET in childhood and adolescence in Germany remains unclear. However, on the basis of our analysis some facts have to be stressed:
a) the types of therapy strategies applied in the treatment of thyroid malignancies are too diverse. Some of them are no more accurate (e.g. percutane irradiation).
b) The number of patients with lost of follow up is very high. This fact cannot be accepted.
c) Although thyroid cancer seems to have a favourable prognosis in children and adolescents, metastatic adre- nal cancer still remains a therapeutic challenge for the paediatric oncology.
We think, to better understand the biology of MET in the paediatric age group and to achieve a better prognosis for some types of these tumours, more data are needed. For these reason a prospective multicenter therapy study for childhood MET is planned.
We hope this short descriptive analysis may serve as a so- lid basis for it.
Acknowledgements
We sincerely thank the following clinics, reporting data for our ana- lysis:
Kinderkliniken der Universitäten Dresden, Düsseldorf, Essen, Freiburg, Gießen, Heidelberg, Homburg, Jena, Köln, Leipzig, Magdeburg, Nürnberg, Tübingen, Würzburg; Kinderklinik des Zentralklinikums Augsburg, Kinderklinik des KAVH Berlin, Johanniter Kinderklinik Bonn, Kreiskrankenhaus Elmshorn, Kinderklinik des Klinikums Erfurt, Kinderchirurgie der Univer- sität Frankfurt, Nuklearmedizin der Universität Göttingen, Kin- derklinik des Klinikums Kröllwitz-Halle, Kinderchirurgie des St .- Barbara-Krankenhauses Halle, Kinderklinik der Medizinischen Hochschule Hannover, Kinderklinik des städtischen Klinikums Karlsruhe, Kinderklinik der städtischen Kliniken Kassel, Radio- logie der städtischen Kliniken Kassel, Nuklearmedizin der Uni- versität Magdeburg, Nuklearmedizin der Universität Marburg, Städtische Kinderklinik Nürnberg, Kinderhospital Osnabrück, Radiologie der Universität Rostock, Kinderklinik des Klinikums Schwerin, Kinderklinik des Olgahospitals Stuttgart.
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PD Dr. med. Peter Bucsky
Medizinische Universität zu Lübeck
Klinik für Pädiatrie Kahlhorststraße 31-35 D-23538 Lübeck