ORIGINAL ARTICLE
K. L. Narasimhan . R. Samujh . A. Bhansali R. K. Marwaha . S. K. Chowdhary
B. D. Radotra · K. L. N. Rao
Adrenocortical tumors in childhood
Accepted: 26 September 2001 / Published online: 19 July 2003 @ Springer-Verlag 2003
Abstract Adrenocortical tumors (ACT) are rare in childhood. Determination of malignant potential is difficult. To assess the presentation, clinical behaviour, and histology of these tumors in our center, the records of nine patients with ACTs between 1989 and 2000 were analyzed. The age, sex, clinical presentation, investigations, treatment, follow-up data, and current status were determined. The pathological features were reanalyzed by our pathologist. The endocrine profile of the tumors was also retrieved from the records. There were two males and seven females; the median age at referral was 2.5 years. Two patients (one male, one female) presented with clinical features of Cushing’s syndrome with hypertension. Four girls had features of Cushing’s syndrome with associated virilization. One 11-year-old girl presented with hypertension, hypokalemia, and pseudoparalysis due to an aldoste- rone-secreting tumor. One girl presented with preco- cious pubic hair and clitoromegaly. One male had evidence of true precocious puberty. The endocrine profile was available in eight cases: cortisol levels were raised in four, testosterone in four, and aldosterone in
one. One boy had pubertal levels of follicle-stimulating hormone and testosterone. Surgery was the only modality of therapy used. Histopathology showed capsular invasion in four patients and vascular invasion in two. The median tumor weight was 80 g (15-550 g) and the size ranged from 1.5 x 1.5 to 12 x 12 cm. Five patients are alive without tumor recurrence at a median follow-up time of 2 years. Tumor recurrence was seen in two patients, one with capsular rupture during surgery and another with a tumor weight of 16 g with associated capsular and vascular invasion. Atypical modes of presentation like pseudoparalysis must be kept in mind. Histologic criteria for malignancy in ACT are unreliable. Tumor weight may not always be accurate in predicting tumor behaviour. Complete surgical excision remains the only effective and poten- tially curative treatment.
Keywords Adrenocortical tumors . Children
K. L. Narasimhan . R. Samujh · S. K. Chowdhary K. L. N. Rao
Department of Pediatric Surgery, Post-Graduate Medical Institute, Chandigarh 160012, India
A. Bhansali
Department of Endocrinology, Post-Graduate Medical Institute, Chandigarh 160012, India
R. K. Marwaha
Department of Pediatrics, Post-Graduate Medical Institute, Chandigarh 160012, India
B. D. Radotra Department of Pathology Post-Graduate Medical Institute, Chandigarh 160012, India
K. L. Narasimhan Department of Pediatric Surgery, PGIMER, Chandigarh 160012, India
E-mail: narasimhankannan@hotmail.com Fax: 0172-744401
Introduction
Pediatric adrenocortical tumors (ACT) are rare, potentially fatal [1-4], and often functional. The clinical manifestiations are obvious, yet delay in diagnosis is common [1-5]. Despite rapid advances in imaging and new research in the molecular biology of ACT, the treatment and outcome have remained unchanged. Total surgical excision remains the cornerstone of therapy. This paper analyzes the clinical presentation, endocrine profile, histology, and outcome of nine patients with ACTs from a university teaching hospital in India.
Patients and methods
In a retrospective review of nine patients with ACTs who were operated upon at the Postgraduate Medical Institute, Chandigarh, between 1989 and 2000, their clinical, histologic, and endocrino- logic data were analyzed. The outcome was studied from the re- cords; follow-up data were collected by letters or telephone contact.
Results
The youngest child was 1.5 months and the oldest 11 years of age. There were two males and seven females. The clinical presentation, tumor weight, treatment modalities used, and follow-up are shown in Table 1. The pathological features are shown in Table 2, the endocrine profile of the tumors in Table 3. The median age at referral was 2.5 years. Four females had clinical features of Cushing’s syndrome and virilization (Fig. 1). Two children (one male, one female) had Cushingoid features and hypertension. One female had hypokalemia, hypertension, and pseudoparalysis. One female presented with early appearances of pubic hair and clitoromegaly. One male had evidence of true precocious puberty.
All the patients were imaged by ultrasound (US) and computed tomography (CT). The tumors were surgically resected. The smallest tumor was 1.5 x 1.5 cm and the largest 12 x 12 cm. Tumor weight varied from 15 to 550 g (median 80 g). One patient had intraoperative tumor spillage and tumor recurrence after 6 months; one
died 2 years later of tumor recurrence; one was lost to follow-up. The others are symptom-free and tumor-free on imaging. The median follow-up was 2 years. Histologic analysis showed capsular invasion in four patients, vascular invasion in two, and a lymph node was positive for tumor in one. The endocrine profile for eight of the nine patients was available. One was a pure aldosterone-secreting tumor; three were secreting corti- sol, two of which also secreted androgens. Five tumors were secreting androgens or androgen metabolites.
Discussion
The profile of our patients is similar to that reported in the literature [1-5]. The tumors were more common in females, with clustering of patients in the first 2 years of life. All the tumors were functional. The clinical picture was commonly a combination of virilization and Cushing’s syndrome. The most unusual findings in our series were a pure aldosterone-secreting tumor, an androgen-secreting tumor inducing precocious puberty
| Patient no. | Age | Sex | Symptoms | Clinical presentation/Investigation | Tumor size | Treatment | Follow-up |
|---|---|---|---|---|---|---|---|
| 1. | 21 months | M | Virilization (pubic hair + penile length 1, testes size 1 | Lt lumbar mass 5 × 5 cm | 80 g | Surgery complet resection | Alive, tumor-free, 2 years |
| 2. | 41/2 years | F | Truncal obesity, buffalo hump, pubic hair, 1 pigmentation, clitoromegaly, hypertension | Rt. Lumbar mass 10 × 6 cm displacing IVC, extending retrocavally | 96 g | Surgery tumor spill + | 6 months, tumor recurrence |
| 3. | 11 years | F | Hypertension, hypokalemia, pseudoparalysis | No clinical mass 3 × 3 cm (L) adrenal mass on US | 30 g | Surgery | Alive 3 years no recurrence |
| 4. | 18 months | F | Î pubic hair, clitoromegaly, Cushingoid features, hypertension | No mass clinically, 1.5 cm (L) adrenal tumor on US | 15 g | Surgery | Alive, 5 years |
| 5. | 21/2 years | F | Truncal obesity, hypertension, Cushingoid features | Hepatomegaly, tumor size 3 × 3 cm | 35 g | Surgery complete resection | Alive, tumor-free, 2 years |
| 6. | 11/2 years | F | Abdominal distension, hoarseness, acne, pigmentation, clitoromegaly | (L) adrenal mass 9 x 7 cm | 180 g | (L) adrenalectomy | Lost to follow-up |
| 7. | 31/2 years | F | Abdominal distension, hirsutism, clitoromegaly, pubic hair + | (L) adrenal mass 12 × 12 cm, palpable clinically | 550 g | (L) adrenalectomy adherent to kidneys vessels, lymph nodes + | Alive, 2 years |
| 8. | 21/2 years | M | Headache, Cushingoid features, hypertension | Hepatomegaly, abdominal mass (R) 7x 8 cm | 154 g | (R) adrenalectomy | Alive, 2 years |
| 9. | 3 years | F | Clitoromegaly, pubic hair | (L) adrenal mass 1.5 × 1.4 cms | 16 g | (L) adrenalectomy | Died 2 years later, tumor recurrence |
| Patient no. | Pleomorphism | Mitosis | Necrosis | Capsular invasion | Vascular invasion | Follow-up |
|---|---|---|---|---|---|---|
| 1 | Occassional | Low | Nil | Nil | Nil | Alive 2 years |
| 2 | Marked | High | + + | + | Nil | Recurrent tumor |
| 3 | Nil | Low | Nil | Nil | Nil | Alive 3 years |
| 4 | Mild | High | Nil | Nil | Nil | Alive 5 years |
| 5 | Nil | Low | +, calcification + | Nil | Nil | Alive 2 years |
| 6 | High | High | + | + | Nil | Lost to follow-up |
| 7 | High | High | + + | + Lymph nodes | + | Alive 2 years |
| 8 | Nil | Minimal | + | Nil | Nil | Alive |
| 9 | Marked | Low | + + | + | + | Died |
| Patient no. | Cortisol (nmol/l) am/pm | 17-hydroxy progesterone | 4 4 androste nedione (ng/ml) | Serum testosterone (nmol/l) | Dihydro testosterone (ng/ml) | Estrogen (pmol/l) | Serum aldosterone | Pubertal grading (Tanners) |
|---|---|---|---|---|---|---|---|---|
| 1 | 340 (N) | 4.6 (1) | 1.7 (N) | FSH 2.9 (miU/ml) LH 2.1 miU/ml DHEA 863 mcg/dl (1) | A2, P3 | |||
| 2 | NOT AVAILABLE | |||||||
| 3 | Normal (N) | 80 (1) | ||||||
| 4 | 360 (N) ☒ | 0.7 (N) | 2.8 (1) | 3.2 (1) | 3.2 (1) | 68 (N) | A1, B1, P3, clitoromegaly | |
| 5 | >1200 (1) | |||||||
| 6 | 998 (1), 410 | >20 (1) | 15 (11) | 10 (1) | A2, P3, B1, | |||
| 7 | 290 (N), 280 (N) ☒ | ciltoromegaly A1, B1, P3, | ||||||
| 8 | 780 (1) | 17.9 (1) | 5.6 (1) | clitoromegaly | ||||
| 9 | 639 (1), 322 | 2.9 (1) | 6.9 (1) | 2.6 (1) | 3.2 (1) | A1, B1, P3, clitoromegaly |
in a male, and a cortisol-secreting tumor in a 1.5 month- old patient. The aldosterone-secreting tumor has been reported previously [5].
Liou and Kay reviewed the ACTs reported in the pediatric literature and found that the majority occurred during the first 5 years of age or less, with a female: male ratio of 2:1; 80%-100% were functional [2]. Despite the functional nature of these tumors, there was a delay in diagnosis of 2 months to 16 years [2]. We observed delays in diagnosis of 2 months to 3 years. None of our patients had any associated abnormalities. Association of ACT with abnormalities like hemihypertrophy, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome has been reported [2].
In all our patients adrenal masses were diagnosed on US. CT was done when there was doubt regarding inva- sion of the inferior vena cava or regional spread. US is the ideal modality for screening the adrenal region and assessment of tumor recurrence postoperatively. However, it cannot reliably identify smaller lesions as accurately as CT [6], which has been reported to be superior in the imaging of tumors measuring 0.5 to 1 cm, assessment of tumor thrombi in the adrenal or renal vein, regional invasion, and distant metastasis. Magnetic resonance imaging (MRI) appears to be accurate in imaging ACTs and has the added ability to show coronal
slices, which allows better distinction from adjacent tissues. MRI may replace CT as a diagnostic choice in the evaluation of ACTs [7]. Adrenal renography and arteriography are invasive and not usually used in children [2].
The differential diagnosis of virilization in children is relatively limited. Congenital adrenal hyperplasia, Leydig-cell tumors of the testis, true isosexual precocity, human chorionic gonadotropin secreting tumors, and ovarian tumors may also present with virilization [2-5]. The physical finding of unliateral or bilateral testicular enlargement in a male suggests a tumor or true isosexual precocity, respectively. An accelerated growth rate with virilism including ambiguity (clitoromegaly only and/or labial fusion) is suggestive of congenital adrenal hyper- plasia, while without genital ambiguity this points toward an ovarian or adrenal tumor. Nonfunctional adrenocortical carcinomas are rare and tend to present later and with an abdominal mass or are incidentally detected. Primary aldosteronism due to an ACT is rare, and only a few cases have been reported [1-5], but they seem to be invariably benign.
Surgical treatment has remained the cornerstone of management of adrenal tumors. Radical en-bloc resec- tion has been our approach. Assessment of the tumor, lymph-node involvement, metastastic disease, and the
contralateral adrenal gland can be done transperiton- eally. Extensive IVC involvement may necessitate a combined urologic and cardiac-surgical team. Due to the nonavailability of mitotane, we did not use adjuvant chemotherapy in any of our patients. The poor efficacy of radiotherapy discouraged us from using this modality.
Nonfunctional ACTs have a graver prognosis. The prognosis in children is relatively better compared to adults. Among the pathological features used for prog- nosis, tumor size has been found to more accurately predict the outcome than histologic features of malig- nancy, which are not reliable [1, 3, 4]. In a larger study of androgen-secreting tumors, all tumors below 150 g and less than 5 cm in size were benign and all those over 10 cm in diameter or 500 g were malignant [3]. This may not be universally true, as smaller-sized tumors have recurred (Table 1). Some authors have found that tumor
histology and vascular and capsular invasion are important in predicting the outcome [4, 8]. However, this has not been confirmed by other studies [1, 9]. Complete tumor excision is the only potentially curative treatment. In the future, the use of molecular markers like insulin-like growth factor II p53 genes, or loss of heterozygosity at the 11p13-15 locus could improve the prognosticability of pediatric tumors [4].
In conclusion, pediatric adrenal tumors carry a better prognosis than in adults provided they are recognized early, allowing microscopically complete resection. Tumor size and adequecy of excision affect the outcome. Efforts must be made to identify patients with adrenal tumors early, which is facilitated by the secretory nature of these tumors. Features like accelerated body growth, virilization, cushingoid appearance, or atypical presen- tations like pseudoparalysis must lead to a clinical suspicion of ACT. US and CT of the adrenal glands in children of both sexes who present with precocius manifestations even as mild as the appearance of pubic hair will aid in early diagnosis. Complete tumor excision is the only potentially curative treatment.
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