Carcinomas in Childhood A Registry-Based Study of Incidence and Survival
W. R. MCWHIRTER, MD, FRCP, FRACP,* C. A. STILLER, MA, MSC,t AND E. L. LENNOX, MB, CHBt
During a 10 year period, 1971-80, there were 234 children in Great Britain younger than 15 years with a diagnosis of carcinoma registered in Great Britain. These cases represented approximately 2% of all childhood malignant disease. The most common primary site was the thyroid, followed by the nasopharynx and the adrenal cortex. With the exception of adrenocortical tumors, most of the carcinomas occurred in children older than 10 years. In some patients there was a genetic predisposition to neoplasia. Children with carcinomas of the thyroid and female genital tract have an excellent prognosis with 5-year survival rates of over 90%. The prognosis for other sites was generally less favorable; 60% of children with nasopharyngeal tumors were alive at 5 years from diagnosis but <20% of those with carcinomas of the gastrointestinal tract or the adrenal cortex.
Cancer 63:2242-2246, 1989.
T HE DOMINANT TYPE of histology of malignant tu- mors in adults is the carcinoma. In children, how- ever, such tumors are rare and few series have been pub- lished containing sufficient numbers of cases to permit a reliable account of the incidence and survival of children with carcinomas. Hospital-based series may not give an accurate picture because there is often some degree of selection of the cases reflecting the particular skills and interests of the staff of that hospital. The objectives of this study were to estimate the incidence of carcinoma in childhood and to document the relative frequency by site and the survival rates.
From the *Department of Child Health, University of Queensland, Royal Children’s Hospital, Herston, Queensland, Australia, and the +Childhood Cancer Research Group, Radcliffe Infirmary, Oxford, United Kingdom.
Supported by the Department of Health and Social Security, the Scot- tish Home and Health Department, and the Marie Curie Memorial Foundation.
The authors thank the many consultants and general practitioners who provided information on which the paper is based; the Office of Population Censuses and Surveys, the Information Services Division of the Common Services Agency of the Scottish Health Service, the General Register Office for Scotland and regional cancer registries for providing copies of notifications of childhood cancer cases; the National Health Service Central Registers for notification of deaths and the flagging of survivors, E. M. Roberts for her part in collecting the medical records and secretarial help; H. Fearnley for extensive computing work; and Dr. L. M. Kinnier Wilson for providing data from the Oxford Survey of Childhood Cancers.
Address for reprints: W. R. McWhirter, MD, Department of Child Health, Royal Children’s Hospital, Herston, Queensland 4029, Australia. Accepted for publication December 16, 1988.
Patients and Methods
The Childhood Cancer Research Group (CCRG) maintains the national registry of childhood tumors for Great Britain. The primary source of ascertainment is notification to the national cancer registration schemes for England, Scotland, and Wales; the CCRG receives a copy of the registration for each patient younger than 15 years of age at diagnosis. Comparison with other sources of ascertainment has suggested that over 90% of childhood cases are registered.1 Confirmation of diagnosis and sum- mary information on treatment and follow-up are ob- tained from the hospitals at which the children were treated or from their family doctors. All children who are not already known to have died are notified to the Na- tional Health Service Central Registers (NHSCR) for flag- ging. NHSCR then notify CCRG of any deaths or em- barkations (which result in loss to follow-up) thereafter.
The current study includes the 234 children registered during 1971-80 with a histologic diagnosis of carcinoma of sites other than skin, i.e., all malignant tumors with morphology codes in the International Classification of Diseases for Oncology2 in the ranges M8010/3 to 8580/ 3 and M9110/3. The data were tabulated using the Sta- tistical Package for the Social Sciences, version X (SPSS- X). Survival rates were calculated by standard actuarial methods.
Results
The 234 children represent 2% of all childhood cancer registered during the period. The total annual incidence
rate was 0.2/100,000. Table 1 shows the distribution of the tumors according to primary site. The 23 carcinomas of the liver are included in a more detailed study of child- hood liver tumors currently in preparation, and they are not therefore considered further in the present review. The distributions by age at diagnosis and sex for the prin- cipal sites are shown in Table 2. Two thirds of the children were 10 years of age or older. The overall female excess was largely accounted for by a preponderance of girls with tumors in the endocrine glands and in gonadal and other sex-specific sites. Table 3 shows the actuarial survival rates for the principal sites at 5 years following diagnosis.
Among the 17 salivary gland tumors, nine were situated in the parotid gland and four in the submandibular gland (in four the exact site was not recorded). The most com- mon type of histology was epidermoid or mucoepidermoid carcinoma (eight cases) followed by adenocystic carci- noma (three cases) and acinar cell carcinoma (three cases). Three of the tumors were of unspecified type. None of the children presented with metastatic disease at diagnosis. Complete macroscopic excision was achieved in 13 cases; two children had partial removal of tumor, one had no surgery other than biopsy, and the extent of surgery was unknown for the remaining child. Radiotherapy was given to six of the 13 whose tumors were wholly removed, and to all of the others. Chemotherapy was only given in one case, a child who was initially thought to have sarcoma and was treated with vincristine, dactinomycin, and cy- clophosphamide. There were five deaths; one girl died of metastases from osteosarcoma of the tibia 4 years after treatment for her carcinoma and the other four deaths were all due to the original tumor.
Four children had oral carcinomas. Three were mu- coepidermoid tumors (two in the hard palate and one in the cheek) and one was a squamous cell carcinoma of the floor of the mouth. All four have survived following total removal of the tumor and, in two cases, radiotherapy.
The 35 nasopharyngeal tumors accounted for 15% of all cases. Twelve of the tumors were classified as lym- phoepithelial and eight as squamous cell carcinoma. Me- tastases, generally to cervical lymph nodes, were recorded as present in 27 children in our series and absent in six with no recorded spread in two. Surgery was limited to biopsy of the nasopharyngeal mass or cervical lymph nodes. All but one of the children received radiotherapy, the highest recorded tumor dose being 68 Gy. Sixteen (46%) were given chemotherapy with a wide variety of combinations of agents that included methotrexate, vin- cristine, and cyclophosphamide. However, in this series the use of chemotherapy did not seem to influence the outcome.
Five children had primaries in other sites in the head, two in the orbit, and one each in the maxillary antrum,
| ICD-O codes | Site | Number |
|---|---|---|
| 142.0-142.9 | Salivary gland | 17 |
| 144.9-145.2 | Other parts of mouth | 4 |
| 146.8-149.0 | Nasopharynx | 35 |
| 150.5-154.1 | Gastrointestinal tract | 12 |
| 155.0 | Liver | 23 |
| 156.1 | Extrahepatic bile duct | 1 |
| 157.0-157.9 | Pancreas | 5 |
| 160.2 | Maxillary antrum | 1 |
| 162.1-162.9 | Bronchus, lung | 9 |
| 164.0-164.2 | Thymus | 6 |
| 174.9 | Female breast | 1 |
| 180.9-184.0 | Female genital tract | 12 |
| 186.9 | Testis | 2 |
| 188.9 | Bladder | 2 |
| 189.0 | Kidney | 17 |
| 190.1-190.7 | Orbit, cornea, lacrimal duct | 4 |
| 193.9 | Thyroid | 49 |
| 194.0 | Adrenal | 25* |
| 199.9 | Unknown primary site | 9 |
| Total | 234 |
* Includes one tumor in ectopic paratesticular adrenal tissue.
cornea, and lacrimal duct. The boy with the anaplastic carcinoma of the maxillary antrum had regional spread to orbit and cheek at diagnosis and died 11 months later. The remaining four patients have survived.
Of the 12 gastrointestinal tumors, two were in the lower third of the esophagus, one in the pyloric antrum, one in the small intestine, seven in the colon, and one in the rectum. One girl with adenocarcinoma of the sigmoid co- lon also had four adenomatous polyps; her father also had a colonic polyp and she had a brother who died of a brain stem tumor. Eight of the children died within a year of the diagnosis and another died at 19 months. Of the re- maining three children, one, who had a carcinoma of the
| Site | Age at diagnosis (yr) | Male | Female | Total | ||
|---|---|---|---|---|---|---|
| 0-4 | 5-9 | 10-14 | ||||
| Salivary glands | 3 | 4 | 10 | 7 | 10 | 17 |
| Nasopharynx | 0 | 7 | 28 | 21 | 14 | 35 |
| Gastrointestinal tract | 0 | 0 | 12 | 8 | 4 | 12 |
| Female genital tract | 2 | 2 | 8 | 0 | 12 | 12 |
| Kidney | 0 | 5 | 12 | 10 | 7 | 17 |
| Thyroid | 2 | 10 | 37 | 15 | 34 | 49 |
| Adrenal cortex | 17 | 5 | 3 | 7 | 18 | 25 |
| Other and unknown | 3 | 9 | 32 | 16 | 28 | 44 |
| Total | 27 | 42 | 142 | 84 | 127 | 211 |
| Site | N | Actuarial survival rate (% at 5 y) | Proportion receiving | |
|---|---|---|---|---|
| Radio- therapy | Chemo- therapy | |||
| Salivary glands | 17 | 71 | 59 | 6 |
| Nasopharynx | 35 | 60 | 97 | 46 |
| Gastrointestinal tract | 12 | 17 | 33 | 50 |
| Female genital tract | 12 | 92 | 8 | 25 |
| Kidney | 16 | 56 | 63 | 44 |
| Thyroid | 49 | 98 | 35 | 0 |
| Adrenal cortex | 17 | 29 | 28 | 16 |
Children who died without treatment or postoperatively have been excluded.
descending colon originally totally resected, developed multiple intraperitoneal deposits after 51 months and died 54 months after the original diagnosis; a boy with an ad- enocarcinoma of the transverse colon and a girl with ad- enocarcinoma of the ileum are still alive 13 and 9 years, respectively, after diagnosis. These two survivors had total tumor removal and no additional treatment. Chemo- therapy that included 5-fluorouracil was given to six pa- tients.
There was one 2-year-old girl with a bile duct carci- noma, which was treated by radiotherapy. She developed liver secondaries and died after 7 months.
Five children, all but one of whom were girls, had pan- creatic carcinomas. One died within 2 months with wide- spread metastases from a rapidly growing tumor for which no treatment was attempted. One child’s tumor was ini- tially thought to be an atypical nephroblastoma and was treated as such with chemotherapy and radiotherapy; this child survived 2 years and 11 months. One child died 4 months after biopsy of an adenocarcinoma, which was treated with streptozotocin but with no response. The other two children have both survived, one with slowly progressive disease.
Four of the nine tumors of lung and bronchus were carcinoid type bronchial adenomas and one was a mu- coepidermoid carcinoma. All of these five children have survived following total excision of their tumors and no other treatment. Of the other four, one had an oat cell carcinoma and one an undifferentiated carcinoma; these two survived 12 and 4 months, respectively. One child had multiple secondaries from a squamous cell carcinoma and one was thought to have tuberculosis until the post- mortem revealed a tumor. Neither child had any treat- ment for their tumors.
Six children (three boys and three girls) had malignant thymoma. The youngest was 8 years old at diagnosis. Two were diagnosed postmortem and another died immedi- ately following partial excision of his tumor. Two other
children died within 6 months of diagnosis. The only sur- vivor was an 8-year-old boy who had a thymectomy fol- lowed by chemotherapy.
One 13-year-old girl had an anaplastic carcinoma of the left breast with regional lymph node metastases. She was treated with tamoxifen chemotherapy and oophorec- tomy and died after 3 months.
There were 12 girls with tumors of the genital tract. Six had ovarian adenocarcinoma, and all of these were 11 years of age and older; four of these were included in a previous series of cases of ovarian carcinoma in childhood, which were reviewed histologically.3 One girl with exten- sive local spread died after 5 months despite bilateral oo- phorectomy and chemotherapy with a wide variety of agents. The other five are all alive at least 5 years after diagnosis after total surgical removal alone (four cases) or partial removal and a course of cyclophosphamide (one case). Six girls had adenocarcinomas of the cervix or va- gina. Three of the tumors were of clear cell or mesone- phroid type. Another was a papillary adenocarcinoma of the cervix whose mother had taken stilboestrol during pregnancy. No deaths have been reported among these six patients. Four were treated by surgery alone, one by surgery and a short course of dactinomycin chemotherapy, and one by pelvic irradiation following biopsy.
There were two boys registered with testicular carci- noma. One was 2.5 years of age, and his tumor was re- ported as anaplastic adenocarcinoma. The other was 14 years old and had an adenocarcinoma arising in a tera- toma. Both patients were treated by orchidectomy and radiotherapy and have survived for over 13 years.
There were two boys with low-grade transitional cell carcinoma of the bladder, both of whom have survived following surgery alone.
Thirteen of the 17 kidney tumors were described as renal cell carcinoma or hypernephroma; three as papillary adenocarcinoma, and one as undifferentiated carcinoma. One patient with a renal cell tumor had already been treated for a Wilms’ tumor of the opposite kidney 5 years earlier. One child who had lung metastases at diagnosis was given no treatment following biopsy and died 2 weeks later. All the other 16 children underwent nephrectomy, in one case with only partial tumor removal. Six had no additional treatment after surgery, three had radiotherapy alone, and seven had radiotherapy and chemotherapy. The only treated child with metastatic disease at diagnosis died after 7 months, and six of the others died between 5 and 38 months; nine survivors have been followed up for at least 5 years.
The thyroid was the most common primary site in this series, the 49 cases representing 21% of the total. Thirty- three (67%) were reported as having papillary, follicular, or mixed papillary and follicular carcinoma. One child with a mixed papillary and follicular tumor had undergone
radiotherapy for a cystic hygroma of the neck at the age of 11 months. Ten children were reported to have med- ullary carcinoma and six of these were known cases of multiple endocrine neoplasia syndromes (two type IIa and four type IIb). All but one of the 49 children with thyroid carcinoma underwent partial or total thyroidectomy. Seventeen children had radiotherapy. Only two patients are known to have died: one from medullary carcinoma after 57 months and one from follicular carcinoma after 70 months. The latter patient was also reported as having visceral neurofibromatosis.
There were 25 children with adrenocortical carcinoma. One of the tumors was an incidental finding at postmor- tem, the child having died at 3 years of age following surgery for Fallot’s tetralogy. Two children died within 1 hour of admission to hospital, with no treatment having been attempted. Five other children died postoperatively. Of the remaining 17 children, two had extensive metastatic disease and removal of the primary was not attempted. One girl with a massive tumor originally thought to be a neuroblastoma underwent laminectomy for extradural compression, followed by radiotherapy and chemotherapy and died 10 months later with widespread lung second- aries.4 The other 14 all had an adrenalectomy. Of these, four received radiotherapy alone, two had radiotherapy and chemotherapy, and one child whose tumor was not irradiated was treated with 2,4’-dichlorodiphenyldichlo- roethane (methane) (O,p’-DDD). The 5-year survival rate for the 14 children undergoing radical surgery and sur- viving the postoperative period was 36%. The tumor in one patient arose in ectopic adrenal tissue in the parates- ticular region; this child’s brother had died of a rhabdo- myosarcoma of the chest wall.
There were nine children with metastatic carcinoma and no known primary site. Seven died within 18 months of diagnosis, and another child emigrated and was lost to follow-up 5 months after diagnosis. The remaining child has survived for over 6 years. This was a girl 11 years of age who presented with metastatic undifferentiated car- cinoma in cervical lymph nodes and was treated with che- motherapy for 4 months.
Discussion
Carcinomas in children are extremely rare. The annual incidence of 0.2/100,000 for all sites except skin was sim- ilar to that in other large population-based series from Europe, North America, and Australia.1 In contrast to most other childhood tumors, the incidence increases with age, and in the present series 65% of patients were 10 years of age or older. The main exception to this pattern was the adrenocortical tumors, which occur predomi- nantly in young children; more than 50% of the cases reported here were younger than 5 years. The female pre-
ponderance in childhood carcinoma is also unusual. It is partly accounted for by the extreme rarity of carcinoma of sex-specific sites in boys, but there is also an excess of girls with tumors in endocrine sites.
The distribution of primary sites was sharply different from that of carcinomas in adults. The most common sites were the thyroid and nasopharynx, whereas tumors of the sites most frequently seen in adults, such as lung, female breast, and gastrointestinal tract, were rare.
Childhood carcinomas of several sites are known com- ponents of familial cancer syndromes, and various other genetic associations have been noted. Some cases of bowel cancer in children are associated with polyposis of the gastrointestinal tract.5 The patient in our series with a probable family history of polyposis and whose brother had a brain tumor could represent an example of Turcot syndrome, although malignant gastrointestinal tract tu- mors have not previously been reported as part of the syndrome.
Medullary carcinoma of the thyroid may be associated with multiple endocrine neoplasia type IIa, also known as type II or Sipple’s syndrome,6 or with multiple endo- crine neoplasia type IIb, which is also referred to as type III or multiple mucosal neuroma syndrome.7 The mother of one of the patients in whom there was a strong family history of medullary carcinoma of the thyroid and mul- tiple endocrine neoplasia syndrome type IIa died of a brain tumor.
We believe that our finding of an ectopic adrenal tumor and rhabdomyosarcoma in members of the same family has not been previously reported, although the familial occurrence of adrenocortical carcinoma and rhabdomyo- sarcoma is well documented.8.9 Both sarcoma and adre- nocortical carcinoma occur in patients with Beckwith- Wiedemann syndrome.10 The association of adrenocor- tical tumors with hemihypertrophy and other congenital abnormalities has raised the hypothesis that oncogenic factors may operate during genetic development.11
The survival rate in the series varied widely between primary sites. The best prognosis was for thyroid tumors for which the 5-year survival rate of 98% was comparable, for example, with the 92% reported by Exelby and Fra- zell.12
It was not possible to compare survival rates directly with those in the recently reported series of patients di- agnosed during 1962-86 from St. Jude Children’s Re- search Hospital13 because rates were quoted only for all patients younger than 20 years and the numbers of cases at most sites were extremely small. Their 5-year survival rate of 56% for nasopharyngeal carcinoma, however, was similar to that observed in the present series. One (13%) of the eight patients with colorectal tumors in our series survived more than 5 years, compared with the 7% re- ported from St. Jude.
The relatively poor prognosis for childhood carcinomas in some sites may improve with advances in treatment; an increased survival rate has already been reported for children with nasopharyngeal carcinoma treated with ad- juvant chemotherapy in conjunction with radiotherapy.14
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