Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE: Testicular adrenal rest tumours (TART) are a well-known complication in adult male patients with congenital adrenal hyperplasia (CAH), with a reported prevalence of up to 94%. In adulthood, the tumours are associated with gonadal dysfunction most probably due to longstanding obstruction of the seminiferous tubules. The aim of our study was to determine the presence of TART and their influence on gonadal function in childhood. DESIGN: Retrospective study. PATIENTS AND METHODS: Scrotal ultrasound was performed in 34 children with CAH due to 21-hydroxylase deficiency who were between 2 and 18 years old. FSH, LH, testosterone and inhibin B concentrations were measured in serum of 27 patients. RESULTS: TART were detected by ultrasound in 8 out of 34 (24%) children. In two of them, bilateral tumours were found. All lesions were located in the rete testis. Seven patients had the salt-wasting type of CAH; one patient had the simple virilising type of CAH. Mean tumour size was 4.1 mm (range 2-8 mm). In none of the patients were the tumours palpable. Two children with TART were between 5 and 10 years old, the other six children were above 10 years old. In all children with TART, LH, FSH, testosterone and inhibin B levels were similar to the patients without TART. CONCLUSION: TART can be found in CAH children before the age of 10 years. The absence of gonadal dysfunction in our group of children suggests that gonadal dysfunction as frequently reported in adult CAH patients with TART develops after childhood.     

Adult hepatoblastoma: learning from children

Hepatoblastoma is the most common malignant liver tumour in infants and young children. Its occurrence in the adult population is debated and has been questioned. The aim of this paper is to review the histological and clinical features of adult hepatoblastoma as described in the adult literature, and to compare the findings with those of paediatric hepatoblastoma. The developmental and molecular aspects of hepatoblastoma are reviewed and their potential contribution to diagnosis of adult hepatoblastoma discussed. Case reports of adult hepatoblastoma identified by a PubMed search of the English, French, German, Italian, and Spanish literature through March 2011 were reviewed. Forty-five cases of hepatoblastoma were collected. Age at presentation was variable. Survival was uniformly poor, except for the rare patients who presented with the relatively differentiated, foetal type. The common denominator between adult and paediatric cases is the occurrence of embryonal or immature aspect of the tumours. Whether the adult cases of hepatoblastoma represent blastemal tumours, stem cell tumours, or unusual differentiation patterns in otherwise more frequent adult liver tumours remains to be established. Adult tumours labelled as hepatoblastoma are characterised by malignant appearing mesenchymal components. Surgical management is the cornerstone of therapy in children and also appears to confer an improved prognosis in adults. Whether adult hepatoblastoma exists, remains controversial. Indeed, several features described in adult cases are markedly different from hepatoblastoma as it is understood in children, and other differential diagnoses should also be entertained. Nonetheless, hepatoblastoma should be considered in adults presenting with primary liver tumours in the absence of pre-existing liver disease. Adult and paediatric patients with immature hepatoblastoma appear to have worse outcomes, and adults presenting with presumed hepatoblastoma have an overall poorer prognosis than children with hepatoblastoma. In all patients, surgery should be the treatment of choice, neoadjuvant chemotherapy is advisable.     

Cushing's disease in childhood as the first manifestation of multiple endocrine neoplasia syndrome type 1

OBJECTIVE: To describe three cases of Cushing's disease in children with multiple endocrine neoplasia type 1 (MEN1), as clinical manifestations of MEN1 are very rare in childhood. DESIGN AND METHODS: A retrospective review of three cases of Cushing's disease diagnosed between 1997 and 1999. Genetic screening for MEN1 gene mutation was performed in each patient. RESULTS: An ACTH-secreting microadenoma was diagnosed in three children, aged 11-13 years, presenting with growth retardation and weight gain over a period of 3-4 years. All patients had successful transsphenoidal adenomectomies. Primary hyperparathyroidism was subsequently diagnosed in two of the patients, and in the monozygotic twin of one of the patients. A new mutation in the MEN1 gene (Tyr351His) was identified in two of the patients and the affected members of their families. In the third patient a de novo MEN1 gene mutation (Leu444Pro) was found. CONCLUSIONS: MEN1 has to be considered in all children with tumours of the pituitary gland, and in those presenting with primary hyperparathyroidism. The children and their families should be advised to seek genetic counselling. We suggest that careful growth records be kept for children at risk of developing inherited MEN1 and, in the event of a decelerating growth rate, further diagnostic evaluation be undertaken with regards to ACTH-secreting pituitary tumours.     

10 year review of cardiac tumours in childhood.

OBJECTIVE--To review the commonest types of cardiac tumours in childhood, their different presentations, and management. DESIGN--A retrospective study of patients with cardiac tumours. SETTING--Cardiac department of a teaching hospital. PATIENTS--Six patients with an age range between one day to three years presented over a period of 10 years. MAIN OUTCOME MEASURES--To determine different presentations, management, and prognosis of cardiac tumours. RESULTS--Three patients presented with an arrhythmia, two with an asymptomatic heart murmur, and the sixth was discovered accidentally. Surgical resection of the tumours was performed in five cases, one patient died during the operation, one developed new tumours after surgery, and the remaining three have had an excellent result. Histology of those operated on showed benign rhabdomyomas in three and fibromas in the other two. The sixth patient was managed conservatively and the multiple tumours he had showed gradual resolution over a period of 10 months follow up. One baby with rhabdomyoma had signs of tuberous sclerosis whereas the others were normal at follow up five months to three years after diagnosis. None of them had a positive family history. CONCLUSION--Cardiac tumours in childhood are extremely rare. The commonest types are rhabdomyomas, then fibromas. Most cases are diagnosed by echocardiography. The prognosis for most patients is excellent.     

Transplacental oncogenic effect of ethylnitrosourea in rabbits (author's transl)]

50 mg/kg ethylnitrosourea (ENU) per dose, diluted in a 0.9%NaCl/1%NaH2PO4 solution (pH 6.2) were administered intravenously to three pregnant rabbits. The injections were carried out on the following days of gestation: 21., 26., and 30./21., 25., and 31./22., 25., and 30. From the total offspring (22), 16 rabbits could be raised. In 12 animals, kidney tumours were observed after a latent period of 2--2 1/2 years. The induced tumours are generally composed of both epithelial and mesenchymal tissue elements. Two tumours of the series are of a pure epithelial or a pure mesenchymal nature respectively. In most of the mixed tumours, classified as Adenocarcino-Sarcomas (10), the epithelial and mesenchymal elements are closely integrated, sometimes one component predominated over the other one. Histologically the ENU-induced mixed tumours of kidney in rabbits and the "dysontogenetic" kidney tumours of children (WILMS) show comparable structural characteristics.     

Primary tumors of the heart. Diagnostic, anatomic and therapeutic aspects

Primary cardiac tumours are rare. They are usually benign, the most common ones being left atrial myxomas. The authors report their experience of 16 cardiac tumours operated between 1978 and 1985. The patients were 12 adults and 4 children. The tumours were benign in 14 cases and malignant in 2 cases. Complete (14 cases) or incomplete ablation of the tumour was carried out under cardiopulmonary bypass with an early mortality of 6.25 per cent (1 case) and late mortality of 12.5 per cent (the two malignant tumours). The tumours were identified as myxomas in 11 cases, rhabdomyomas in 2 cases, fibroma in 1 case and malignant sarcomas in 2 cases. The average follow-up period of the 13 survivors is 30 months (range 4 months to 5 years) with excellent clinical and anatomical results. Clinical and paraclinical diagnosis of these tumours does not pose any major problems nowadays because of the reliability of the methods of investigation. However, the nature of the tumour is not always predictable and the operative findings are fundamental, not so much for the treatment which is relatively stereotyped but for the prognosis. Age is not a significant prognostic factor as excellent results may be obtained in the very young and the very old despite a sometimes precarious preoperative clinical condition. The benign or malignant nature of the tumour is the only real factor which affects the prognosis.     

Treatment of solid tumours in children with tumour-lysate-pulsed dendritic cells

Dendritic cells are potent stimulators of antigen-specific immune responses, including antitumour responses. We explored the use of tumour-lysate-pulsed dendritic cells in children with relapsed solid tumours. Dendritic cell treatment in children was feasible and apparently not toxic. The treatment was able to produce significant tumour regression in a child with metastatic fibrosarcoma.     

Catecholamine-producing tumors]

We report 93 patients with catecholamine producing tumors that were analyzed at the Hormone Laboratory of the Institute of Cardiology. They are 75 pheochromocytoma patients and 18 children with neuroblastoma. Fluorimetric methods were used to measure urinary and plasma catecholamines on neuroblastoma and pheochromocytoma patients. Dopamine high excretion (mean value 2889 micrograms/24 hs), was constantly observed in the neuroblastoma children as were adrenaline and noradrenaline in the benign and malignant pheochromocytoma patients. The mean values for the malignant tumours were 53 for adrenaline and 1436 micrograms/24 hs for noradrenaline. Structural and biochemical differences of the catecholamine producing tumours are reflected on the clinical manifestations which are observed in the patients bearing such neoplasms.     

Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults

OBJECTIVE: Differentiated thyroid cancer (DTC), including papillary (PTC) and follicular (FTC) variants, is unusual in children and accounts for only 10% of all cases. For that reason, knowledge of the clinical features which predict recurrence is limited. We reviewed 170 cases of childhood DTC to determine if specific clinical or pathological findings were associated with increased risk of recurrence. DESIGN: This was a retrospective study of children and adolescents with DTC registered in the Department of Defense Automated Centralized Tumor Registry. PATIENTS: We reviewed 137 cases of PTC and 33 cases of FTC diagnosed between 1953 and 1996 at < or = 21 years of age. RESULTS: In the PTC group (median follow-up 6.6 years, range 2 month-39.5 years), only one patient died, but 21 developed local and 6 developed distant recurrence. By univariate analysis, recurrence was more common in patients with multifocal (odds ratio 7.5) or large tumours (odds ratio 4.1), and in those with palpable cervical lymphadenopathy (odds ratio 3.0) or metastasis at diagnosis (odds ratio 2.8). By multivariate analysis focality was the best predictor of recurrence (P = 0.0019). In the FTC group (median follow-up 5 years, range 6 month-38.1 years), no patient died of disease, but 5 developed recurrence. As with PTC, recurrence was more likely in patients with multifocal tumours (odds ratio 22.0). CONCLUSIONS: Differentiated thyroid cancer in children and adolescents has low mortality, but a high risk of recurrence. Young patients with large, multifocal tumours that are already metastatic at diagnosis have the greatest risk of recurrence.     

Non-myxomatous cardiac tumours: twenty-year experience

Eighty-eight patients underwent surgery for various cardiac tumours from January 1978 to June 1998 at our Institute. Seventy-seven tumours were myxomas, 10 were non-myxomatous and one was secondary cardiac tumour. Case records of the patients with non-myxomatous primary cardiac tumours and one secondary tumour were reviewed. Six of these primary tumours were benign and four, malignant. Age of the patients ranged from 26 days to 47 years. Among patients (3 children, 8 adults) with non-myxomatous primary cardiac tumours, dyspnoea on exertion was the commonest symptom and was the cause of presentation in seven out of 11 patients. Of the eight adults, six were in New York Heart Association functional class II/III and two in class IV. Echocardiographic diagnosis was possible in all the patients. Complete excision of the tumour was possible in all benign and two of the four malignant tumours. Incomplete resection was done in the secondary tumour. Of the six benign tumours, three were rhabdomyomas and one each of fibroma, haemangioma and lipoma. The malignant tumours were one each of fibrosarcoma, angiosarcoma, unclassified sarcoma and malignant mesothelioma. The secondary tumour was a malignant thymoma. Follow-up ranged from 1 to 10 years (mean 7.2 years). Of the patients with benign tumours, four out of six are alive; one patient died on the first post-operative day and one lost to follow-up. Two of the four patients with malignant cardiac tumours died, one was lost to follow-up and one is alive two years after surgery. The patient with secondary malignant thymoma to the superior vena cava was lost to follow-up three months after an uneventful recovery from surgery.     

Hepatocellular adenoma in the paediatric population:Molecular classification and clinical associations

Hepatocellular adenomas(HCAs) represent rare, benign liver tumours occurring predominantly in females taking oral contraceptives. In children, HCAs comprise less than 5% of hepatic tumours and demonstrate association with various conditions. The contemporary classification of HCAs, based on their distinctive genotypes and clinical phenotypes, includes hepatocyte nuclear factor 1 homeobox alpha-inactivated HCAs, beta-catenin-mutated HCAs, inflammatory HCAs,combined beta-catenin-mutated and inflammatory HCAs, sonic hedgehogactivated HCAs, and unclassified HCAs. In children, there is a lack of literature on the characteristics and distribution of HCA subtypes. In this review, we summarized different HCA subtypes and the clinicopathologic spectrum of HCAs in the paediatric population.     

The effect of hyperthermia 42.5 degrees C on the incorporation of 3H-thymidine into the DNA of solid tumours in childhood

Supranormal temperatures inhibit selectively the growth of malignant cells more than that of normal cells. The autoradiographic determination of the 3H-thymidine-labelling-index (LI) in vitro is a suitable method for the examination of thermosensitivity of individual human tumours. 44 solid tumours of children (Wilms' tumours, neuroblastomas, osteogenic sarcomas, non-Hodgkin-Lymphomas and other tumours) were studied by the temperatures 37.5 and 42.5 degrees C/120 min, with this method. 90% of the histologically undifferentiated tumours showed a highly significant inhibition of the 3H-thymidine incorporation between 28.6 and 79.9% with an average of 51.1%. In 4 histologically mature tumours (carcinoma of the adrenal cortex, malignant hepatoblastoma, fibrosarcoma, hamartoblastoma) no significant decrease of the LI was present. The inhibition of incorporation with hyperthermia cannot be correlated with the primary magnitude of the LI with normothermia. In 1 neuroblastoma a 75% rise of the LI was found possibly due to exogenic caused thermotolerance. The individuality of the reaction towards heat may contribute to the biological characterization of tumours.     

Brain tumours in the elderly.

The incidence of cerebral tumour in a geriatric department over a seven-year period was 0.9% of all admissions. The distribution of benign, malignant and secondary brain tumours and their histological types were similar to those of younger adults. Apart from small asymptomatic tumours found incidentally at post mortem, most symptomatic tumours were recognized from their characteristic history. In particular, only 0.4% of patients diagnosed as stroke were subsequently found to have a cerebral tumour.     

Experimental carcinogenesis in the thyroid follicular and C cells. A comparison of the effect of variation in dietary calcium and of radiation

It is known that tumours of several endocrine glands can be induced by a combination of a physiological stress and radiation. It was decided to assess the effect of radiation and of changes in dietary calcium on the development of thyroid tumours in the rat. Three hundred rats were given either 0, 5 or 10 micronCi of 131I in their first day of life. Each of these groups was subdivided after weaning, and maintained on a diet that was either high, normal or low in calcium. The animals were killed at intervals up to 27 months of age, and the numbers of thyroid tumours recorded. Follicular tumours were first noted at 9 months of age, and their frequency increased steadily with age. The effect of radiation was highly significant, only one tumour occurred in a non-irradiated animal. There was a small increase in frequency in follicular tumours in the high calcium diet grown as compared to the low calcium diet group. C cell tumours were first noted at 9 months of age, and their incidence again increased with age. Significantly more tumours occurred in the radiated than in the non-irradiated animals. No significant variation occurred in relation to dietary calcium. It is concluded that an increase in dietary calcium, known to be mildly goitrogenic, may also be important in the carcinogenesis of follicular but not C cell tumours, and that radiation, known to be carcinogenic for thyroid follicular cells is also carcinogenic for C cells.     

Ageing, testicular tumours and the pituitary-testis axis in dogs

Dogs of different ages without testicular diseases were evaluated to study possible age-related changes in hormone concentrations in serum. Dogs with testicular tumours were also investigated to study the relation between tumour type and hormone concentrations; in this study, dogs with Sertoli cell tumours, Leydig cell tumours and seminomas were included. We measured testosterone, oestradiol, LH, FSH and inhibin-like immunoreactivity concentrations in peripheral venous and testicular venous blood of these animals. In normal dogs there appeared to be no age-related changes in the concentrations of the investigated hormones, except for a significant age-related decrease in oestradiol concentrations in testicular venous blood (P<0.02). Dogs with a Sertoli cell tumour had greater oestradiol concentrations and inhibin-like immunoreactivity in both peripheral and testicular venous blood than did dogs without a neoplasm (P<0. 05). Testosterone concentrations were reduced in dogs with Sertoli cell tumours, as were FSH and LH. Feminisation occurred in eight of 13 dogs with a Sertoli cell tumour and in two of 14 dogs with a Leydig cell tumour; it was accompanied by a significantly greater oestradiol concentration than in normal dogs and in dogs with Sertoli cell tumours without signs of feminisation. Dogs with a Leydig cell tumour had greater concentrations of oestradiol and inhibin-like immunoreactivity in both peripheral venous and testicular venous blood than did dogs without a neoplasm (P<0.05). The testosterone concentration in testicular venous blood of these dogs was lower than that in dogs with normal testes. The concentration of LH in peripheral venous blood was also reduced (P<0. 05). Hormone concentrations in dogs with a seminoma were not different from those in normal dogs. It was concluded that seminomas are not endocrinologically active. In contrast, both Sertoli cell tumours and Leydig cell tumours can cause increased oestrogen production leading to signs of feminisation. These tumours also have considerable amounts of inhibin-like immunoreactivity, but only in Sertoli cell tumours does this result in a reduction in FSH concentrations, suggesting that Sertoli cell tumours secrete dimeric inhibin, whereas Leydig cell tumours presumably produce loose alpha-subunits that cross-react in the inhibin assay but are not biologically active.     

Major hepatic resections in infancy and childhood

Nineteen infants and children who had hepatic lobectomy or segmental resection of the liver for tumours are described. Fourteen had lobectomy for malignant tumours but only three survived for more than a year. Four of the five patients who had resections for hamartomas have survived for 18 months or more. The main problem encountered at operation was haemorrhage, which was responsible for the entire operative mortality of 31%. A transient disturbance of liver function occurred after operation in both patients who had preoperative radiotherapy.     

Cardiac rhabdomyoma in children and Bourneville's tuberous sclerosis

Cardiac rhabdomyomas are rare congenital tumours resulting from an early dysembryoplastic disorder of organogenesis. They are generally benign hamartomas which may be the first manifestation of a phakomatosis, tuberous sclerosis (TS) (Bourneville disease), present in over half of cases. The cases of 11 children with cardiac rhabdomyomas are reported. All of them also had extracardiac lesions of TS. Their ages ranged from 1 day to 6 years of age. In one case, the diagnosis was made antenatally by foetal echocardiography. The clinical expression may be very serious when there are hemodynamic disturbances resulting from an obstructive syndrome (N = 3) or arrhythmias (N = 2). Nevertheless, the cardiac evolution is usually favorable (N = 9) in contrast to the neuropsychiatric outcome which is generally catastrophic (N = 8). The diagnosis is made by two-dimensional echocardiography and magnetic resonance imaging. Surgical resection of the tumours is reserved for forms complicated by cardiac failure due to intracardiac obstruction (N = 2) of life-threatening resistant arrhythmias. Genetic counseling should be directed towards prevention of TS because it is transmitted in an autosomal dominant mode. However, most of the cases are sporadic. Echocardiography should be systematic in all children with TS and is also recommended for members of their families, even those apparently unaffected, in order not to miss paucisymptomatic forms of TS.     

Immunogenicity of a two-dose regime of varicella vaccine in children with cancers

OBJECTIVE: Live-attenuated varicella vaccine is effective and safe in immunocompetent children. In this study, we assess the immunogenicity and adverse events following varicella vaccination in immunosuppressed cancer children. METHODS: Varicella-zoster virus (VZV)-seronegative cancer children received two doses of live-attenuated VZV vaccine (Varilrix) in a span of 3 months. Patients with acute lymphoblastic leukaemia (ALL) were in the maintenance phase of chemotherapy, whereas those with solid tumours joined the study around 3-6 months from treatment discontinuation. VZV-specific cellular and humoral immune responses were measured before and after VZV vaccination. RESULTS: The median (range) age of the 17 patients was 4.4 yr (2.0-14.5). Thirteen had ALL, one had myelodysplastic syndrome and three had solid tumours. Following vaccination, the VZV-specific stimulation index (SI) increased from 1.7 (0.9-2.9) to 17.9 (5.9-36.0) (P < 0.001). Similarly, SI to phytohaemagglutinin mitogen increased from 1136 (499-1930) to 1714 (848-2518) (P = 0.028). There were also significant increases in CD4+ cells and CD4:CD8 ratio as well as a reduction in CD16/56+ cells in peripheral blood lymphocytes. Seroconversion rate to VZV was 19% after one dose and increased to 94% after the second dose of VZV vaccine. Serum VZV-specific IgG concentrations also increased significantly following two doses when compared with one dose of VZV vaccine (P = 0.0004). One subject developed possibly vaccine-related chickenpox with self-limiting hepatitis at 5 wk following vaccination. None of the patients developed herpes-zoster at a median (range) follow-up of 27.5 months (24.0-30.0). CONCLUSIONS: Non-immune cancer children can be effectively vaccinated against chickenpox at the defined period. However, the safety of chickenpox vaccine in these immunosuppressed children needs to be further studied.     

Testing of solid tumors in childhood for sensitivity against cytostatic agents using an autoradiographic in vitro method (short-term method) (author's transl)]

The sensitivity of 37 solid tumours of children was tested in vitro towards cytostatic agents by means of an autoradiographic short-term method. Sensitivity was measured as the magnitude of inhibition of 3 H-thymidine incorporation. The test was performed with the cytotoxic agents Cyclophosphamide, Trenimon, Bleomycin, Adriamycin, Daunomycin, Actinomycin D, and Cytosin-Arabinosid in 9 Wilms' tumours, 9 neuroblastomas, 7 non-Hodgkin-lymphomas, 5 osteogenic sarcomas, 3 soft tissue sarcomas, and 4 special tumours. None of the tumours is resistant to all cytotoxic substances. The tumours show a marked individual sensitivity pattern, and, with few exceptions, they are sensitive against 2 or more cytostatics. This behaviour is explained mainly by the usually high proliferative activity of dysontogenetic tumours, malignant lymphomas and various sarcomas. The possibilities and limits of the short-term methods for sensitivity-testing are discussed critically and in detail. For the evaluation of the results of in vitro testing and of in vivo effectiveness the close coreelations are not always taken into consideration between the type of cytostatic agent and effect on tumour metabolism, cytostatic agent and proliferation kinetics of the tumour as well as the effect of the cytostatics and the nucleic acid precursor used for the test. Despite the methodological limitations preclinical testing should be preferred in comparison with unselected chemotherapy.