of surgery, RT and CT were well developed and where the site within the larynx was specified. Of the 11 cases including 2 of our cases with T1-T4 glottic primaries reported since 1970, the treatment was cord stripping in 1 [5], PL in 2 [2,8], TL in 2 ([10]; present study), RT in 3 [1,6,11], TL plus RT in one (present study) and CT plus RT in 2 children [3,7]. Though long-term follow-up is not reported for all these 11 pediatric Lx cancers, local recurrence was seen in only two patients, both of which were successfully salvaged [1,11]. All three of the cases with supraglottic primaries prior to ours, died from rapidly progressive disease [4,12,16]. Our case #3 (Table I) remains controlled for almost 3 years. Of the five children with hypopharyngeal SCC, the initial treatment was radical surgery in one [13], radical RT in two of our cases and RT plus CT in two cases ([11]; present study). Unfortunately, there was a very rapid progression of disease in all these five children leading to their death within 3-6 months of diagnosis. A similar rapidly fatal course has been recently reported in a child with supraglottic carcinoma and five other children or young adults with midline upper respiratory tract carcinoma with character- istic cytogenetic abnormality of translocation 15;19 [12].
On the basis of these results, we would caution against neoadjuvant CT for hypopharyngeal cancers. All five children succumbed soon after the diagnosis and we, therefore, would favour radical surgery followed by RT plus CT. Whether more aggressive surgery and post-operative RT plus CT would prevent such a rapidly fatal course is not known but seems to be the logical choice in a desperate situation. For laryngeal cancers, however, radical RT with or without cisplatin-based concurrent CT may be an appropriate option. This presupposes a detailed assessment ruling out either an impending airway obstruction or very advanced local disease. The “natural history” and aberrant behaviour of pediatric SCC of the larynx and hypopharynx suggests these SCCs constitute a distinct clinical entity. Glottic carcinomas are associated with RRP, have a long history of dysphonia, a favourable outcome and laryngeal preservation should be preferred. In contrast, supra- glottic larynx or hypopharyngeal carcinomas have not been
associated with RRP or HPV, have a short duration of symptoms, have a rapidly progressive fatal course and require early multimodal management.
REFERENCES
1. Gindhart TD, Johnston WH, Chism SE, et al. Carcinoma of the larynx in childhood. Cancer 1980;46:1683-1687.
2. Ossoff RH, Tucker GF, Norris CM. Carcinoma of the larynx in a 11 year old boy with late cervical metastasis: Report of a case with a ten year follow up. Otolaryngol Head Neck Surg 1980;88:142-145.
3. Laurian N, Sadov R, Strauss M, et al. Laryngeal carcinoma in childhood. Report of a case and review of the literature. Laryngoscope 1984;94:684- 687.
4. Zalzal GH, Cotton RT, Bove K. Carcinoma of the larynx in a child. Int J Pediatr Otorhinolaryngol 1987;13:219-225.
5. Singh W, Kaur A. Laryngeal carcinoma in a six year old child with a review of literature. J Laryngol Otol 1987;101:957-958.
6. Chaput M, Ninane J, Gosseye S, et al. Juvenile laryngeal papillomatosis and epidermoid carcinoma. J Pediatr 1989;14:269-272.
7. Ohlms LA, McGill T, Healy GB. Malignant laryngeal tumors in children: A 15-year experience with 4 patients. Ann Otol Rhinol Laryngol 1994;103: 686-692.
8. Simon M, Kahn T, Schneider A, et al. Laryngeal carcinoma in a 12-year-old child. Association with human papillomavirus 18 and 33. Arch Otolaryngol Head Neck Surg 1994;120:277-282.
9. de Carvalho MB, Sobrinho JA, Rapoport A. Head and neck squamous cell carcinoma in childhood. Med Pediatr Oncol 1998;31:96-99.
10. McDermott A, Raj P, Glaholm J, et al. De novo laryngeal carcinoma in childhood. J Laryngol Otol 2000;114:293-295.
11. Barnes C, Sexton M, Sizeland A. et al. Laryngo-pharyngeal carcinoma in childhood. Int J Pediatr Otorhinolaryngol 2001;61:83-86.
12. Vargas SO, French CA, Faul PN, et al. Upper respiratory tract carcinoma with chromosomal translocation 15;19: Evidence for a distinct disease entity of young patients with a rapidly fatal course. Cancer 2001;92:1195- 1203.
13. Rao PB, Narayanan PS, Gupta KR, et al. Carcinoma of the hypopharynx at an early age. J Laryngol Otol 1972;86:1069-1072.
14. McWhirter WR, Dobson C, Ring I. Childhood cancer incidence in Australia, 1982-1991. Int J Cancer 1996;65:34-38.
15. Amichetti M. Squamous cell carcinoma of the oral tongue in patients less than fifteen years of age. J Craniomaxillofac Surg 1989;17:75-77.
16. Bhatia PL, Gupta OP, Samant HC, et al. Juvenile epithelial malignancy of head and neck. J Otolaryngol 1977;6:208-214.
Adrenocortical Carcinoma in Children: A Role for Etoposide and Cisplatin Adjuvant Therapy? Preliminary Report
L. Hovi, MD, PHD,* S. Wikström, MD, PHD, K. Vettenranta, MD, PHD, P. Heikkilä, MD, PHD, and U.M. Saarinen-Pihkala, MD, PHD
Key words: adrenocortical carcinoma; childhood cancer; chemotherapy
Adrenocortical carcinoma (ACC) is a rare tumor in children. About 20% of childhood adrenocortical tumors are thought to be benign adenomas, but the exact histologic classification may be difficult even for an experienced pathologist [1,2]. Over 90% of adrenocortical tumors are hormonally active, irrespective of the histologic type or grade. The most common signs are
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland Grant sponsor: Nona and Kullervo Väre Foundation, Helsinki, Finland.
*Correspondence to: L. Hovi, Hospital for Children and Adolescents, PO Box 281, University of Helsinki, 00029 HUS, Finland.
E-mail: liisa.hovi@hus.fi
virilization and Cushing syndrome due to increased secretion of androgen and/or glucocorticoid hormones. The mortality of children with ACC is high, varying from 50 to 85% [2,3]. Treatment failure has been associated with factors like large size of the tumor, increasing age of the patient, advanced histologic grade, long interval between initial symptoms and diagnosis, and a high urinary steroid hormone output. However, the exact roles of these features have not as yet been elucidated [2-4]. Surgery continues to be the main therapeutic approach for ACC. Recurrence even after an apparently complete surgical removal of the tumor occurs in 22-40% [2,3]. The place of chemotherapy in the management of childhood ACC has not been established; and due to its rarity well-designed clinical trials have not been carried out. Our experience with five patients is, therefore, of interest.
They were diagnosed during 1990-1999 and treated at the Hospital for Children and Adolescents, University of Helsinki, Finland. Clinical and pathologic features of the patients are displayed in Table I. In one patient suffering from Beckwith- Wiedemann syndrome, an extensive tumor was detected at regular follow-up at the age of 21 years. Ultrasonography and computed tomography were performed on every patient before surgery and thereafter regularly during and after chemotherapy. Androgen secretion was evaluated by measuring the plasma levels of dehydroepiandrosterone (DHEA), DHEA sulfate, testosterone, androstenedione (specific radioimmunoassays), and urinary 17 ketosteroids (Zimmerman method). Gluco- corticoid secretion was evaluated by measuring plasma cortisol (immunoenzymatic method) and free urinary cortisol (compe- titive protein-binding assay using HPLC). Tumor histopathol- ogy was classified according to the criteria proposed by Weiss and modified by Bugg and colleagues [4,5]. TP53 gene mutation was investigated by antibody immunostaining using paraffin block specimens of the tumors. The glomerular filtration rate (GFR) and serum creatinine were measured after each chemotherapy course. Repeat audiograms were performed during and after the chemotherapy period.
All tumors were hormonally active. The primary treatment was surgical using a transverse upper abdominal approach. Three patients had local disease, one (Patient# l) had multiple juxtaregional paracaval lymph nodes affected and one (Patient# 2) had renal invasion by the primary tumor on microscopic examination for which an ipsilateral nephrectomy was then performed. A macroscopically complete resection of the primary tumour was successfully carried out in all patients. Chemotherapy was initiated in all as soon as both the post- operative and the endocrine condition had stabilized, 13 to 20 days after surgery. The chemotherapeutic agents were administered i.v. every 3-4 weeks depending on the blood counts (ANC over 1,000 × 10°/L): etoposide 165 mg/m2 and cisplatin 90 mg/m2 over 8 hr on the same day with hydration and mannitol diuresis continuing over to day 2. In one patient, the last course of cisplatin was substituted by carboplatin at 300 mg/m2 due to decreasing renal function (Patient# 2). The aim was to give six courses of chemotherapy. After therapy was completed, all GFRs were confirmed to be within the normal range. Significant loss of hearing was not observed in any of the patients. They have been regularly followed up and re- mained in complete remission 29-109 (median 44) months after primary surgery.
| Patient # | Sex | Age (year) | Hormonal production | Clinical signs | Tumor size | Histology | TP53 gene | Metastatic state | Chemotherapy courses (n) | Outcome, alive and well (months) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Weight (g) | Maximum diameter (cm) | ||||||||||
| 1 | F | 11.5 | An | Virilization | NA | 6.0 | Low grade | NA | A, Lnn | 12 | 109 + |
| 2 | M | 21.0 | An | None | 802ª | 12.0 | Low grade | Wild type | A, K | 5 | 46+ |
| 3 | F | 1.2 | C | Cushing | 90 | 5.2 | Low grade | NA | A | 6 | 44+ |
| 4 | M | 1.5 | An | Virilization | 240 | 12.5 | High grade | Mutation | A | 6 | 36+ |
| 5 | F | 3.2 | C+ An | Virlization | 28 | 4.0 | High grade | Mutation | A | 6 | 29+ |
| and Cushing | |||||||||||
An, androgen; A, adrenal tumor; C, cortisol, K, kidney; Lnn, lymph nodes; NA, not available; F, female; M, male. aKidney included.
DISCUSSION
Cisplatin and etoposide in an adjuvant setting appears to be a promising approach to adrenocortical carcinoma (ACC), a disease with a poor prognosis and no established curative therapy so far. All five of our patients continue in complete remission after initial surgery.
The histopathologic distinction between adrenocortical adenoma and adrenocortical carcinoma may be difficult or even impossible, and the prognostic significance of histologic structure is controversial. Commonly used criteria are those proposed by Weiss et al. and later modified by Bugg et al. [4,5]. They divided the adrenal neoplasms into three different groups: adenoma, low-grade carcinoma, and high-grade carcinoma. In their series of pediatric patients, the histologic type was a statistically significant indicator of outcome. All of our five patients were primarily diagnosed as ACC, according to the criteria of Weiss and colleagues and were further assessed as low grade or high grade carcinoma according to Bugg et al.
In accordance with other pediatric series, the tumors of all our patients secreted elevated amounts of adrenal cortical hormones, although one child did not present with symptoms. Endocrine signs of virilization and Cushing syndrome are more readily detected in children than in adults, thus increasing the possibility of an early diagnosis. Hormonal secretion also offers a useful tool for the evaluation of response and in the follow-up.
Surgery with complete tumor resection is the primary mode of therapy and may be curative in a proportion of children with ACC, but many relapse with a poor outcome. Adjuvant chemo- therapy might thus be of benefit, even after supposed successful surgical treatment. Mitotane, an insecticide derivative produ- cing adrenocortical necrosis, is commonly used in adults, es- pecially in cases of nonresectable, recurrent, and/or metastatic ACC. With mitotane, the endocrinologic symptoms may be alleviated with a response rate of 10-60%. However, the drug is not curative, and does not influence the mortality rate [3,6,7]. Mitotane has occasionally been used in children with consi- derable toxicity, mainly gastrointestinal and neurologic [1]. A response rate of 30% (6/20) in children has been demonstrated
[3]. Two patients died of adrenal insufficiency and three experienced neuropsychiatric toxic symptoms. Cisplatin is commonly used in different combinations for other pediatric malignancies, and alone or in combination has shown some efficacy in about one-third of adult ACC cases [8,9]. Cisplatin has been used occasionally in children, too. It was shown to be effective when combined with etoposide in two out of three children with ACC [3]. No larger series are available so far.
Chemotherapy with cisplatin and etoposide was well tolerated in our patients. Problems during therapy were manageable and no one suffered from significant permanent sequelae. Since ACC has a high relapse rate, and none of our patients has failed so far, adjuvant chemotherapy with cisplatin and etoposide appears to have promise and merits further study.
REFERENCES
1. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab 1997;82:2027-2031.
2. Ribeiro RC, Sandrini Neto R, Schell MJ, et al. Adrenocortical carcinoma in children: A study of 40 cases. J Clin Oncol 1990;8:67-74.
3. Teinturier C, Pauchard MS, Brugieres L, et al. Clinical and prognostic aspects of adrenocortical neoplasms in childhood. Med Pediatr Oncol 1999;32:106-111.
4. Bugg MF, Ribeiro RC, Roberson PK, et al. Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Am J Clin Pathol 1994;101:625-629.
5. Weiss LM, Medeiros U, Vickery AL, Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202- 206.
6. Haak HR, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: Results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-951.
7. Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, et al. Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 1995;75:2587-2591.
8. Bukowski RM, Wolfe M, Levine HS, et al. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: A Southwest Oncology Group study. J Clin Oncol 1993;11:161- 165.
9. Bonacci R, Gigliotti A, Baudin E, et al. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Reseau Comete INSERM. Br J Cancer 1998;78:546-549.
Hypothalamic Dysfunction Associated With Neuroblastoma: Evidence for a New Paraneoplastic Syndrome?
Nicolas Sirvent, MD,1* Etienne Bérard, MD,1 Pascal Chastagner, MD, PHD,2 François Feillet, MD,2 Karin Wagner, MD,1 and Danièle Sommelet, MD2
Key words: hypothalamic dysfunction; paraneoplastic syndrome; neural crest tumor
Various paraneoplastic syndromes, the majority neurologi- cal, have been associated with both localized and disseminated neuroblastoma: opsoclonus-myoclonus syndrome, cerebellar ataxia, Kerner-Morrison syndrome, etc. [1]. Nunn et al. [2] were the first to suggest that the idiopathic hypothalamic syndrome might represent a new paraneoplastic syndrome associated with neural crest tumors. We report, herein, two
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1Service de Pédiatrie, Unité d’Oncologie et Hématologie Pédiatrique, CHU de Nice, France
2Service de Médecine Infantile II, Hôpital d’enfants, CHU de Nancy, France
*Correspondence to: Nicolas Sirvent, MD, Service de Pédiatrie, Hôpital de l’Archet, BP 3079, 06202 Nice cedex 3, France.
E-mail: sirvent.n@chu-nice.fr