Nonfunctioning Adrenocortical Carcinoma in a Young Girl
Hirotaka KISHIKAWA, * Tsutomu MIZUNO, * Itaru TAKAGI, * Yosuke YAMAKAWA, * Takuya SHIMOZATO, * Kyuji HONDA* and Masae TATEMATSU **
ABSTRACT: A 9 year old Japanese girl was admitted complaining of left hypochondrial pain and a large upper left abdominal tumor. There were no clinical or laboratory signs of hormonal abnormality. Intravenous pyelo- graphy showed marked compression and deformity of the kidney by a tumor. This tumor was excised together with the left kidney. The pathological diag- nosis was adrenocortical carcinoma. Postoperatively, the child was given neither irradiation nor chemotherapy. Twenty-one months after the surgery, there was a hepatic metastasis, and she died 40 months after surgery from a combination of hepatic metastases and local tumor recurrence.
KEY WORDS: nonfunctioning tumor, adrenocortical carcinoma
INTRODUCTION
Adrenocortical carcinoma is an unusual tumor in children, comprising only 0.002 per cent of all childhood malignancies.1 In con- trast to adults, most tumors in children ex- crete hormones that produce clinical signs and symptoms which may alarm patients and puzzle physicians. However, nonfunctioning adrenocortical carcinoma remains a continu- ing challenge regarding both early diagnosis and successful management, because there are no clinical signs or symptoms in the early stages. Diagnosis is often delayed and progno- sis is poor. The rarity of this condition prompted us to report the findings in case of a large, nonfunctioning adrenocortical car- cinoma in a young girl.
Departments of Surgery* and Pathology, ** Nagoya City Higashi General Hospital, Nagoya, Japan
Reprint requests to: Hirotaka Kishikawa, MD, Department of Surgery, Nagoya City Higashi General Hospital, 1-2-23 Wakamizu, Chikusa-ku, Nagoya 464, Japan
CASE REPORT
A 9 year old Japanese girl was admitted complaining of rapidly increasing swelling in the left upper abdomen. She had been a healthy child until 3 months previously when she had started to complain of abdominal pain. She was a thin, cheerful child in no ap- parent distress. Physical examination re- vealed a mass in the left hypochondrium, 13 x 10 cm in size, below the left costal margin. There were no clinical signs of hormonal ab- normality. Blood pressure was normal. Rou- tine laboratory findings were normal with the exception of hemoglobin of 11.7 g/dl. Uri- nary 17-hydroxysteroids, 17-ketosteroids and plasma cortisol were within normal limits. Vanillyl-mandelic acid (VMA) and a-fetopro- tein were negative (Table 1). Intravenous pyelogram showed marked compression and deformity of the kidney by the tumor. Cres- cent shaped calcification was present within the mass (Fig. 1). Computer tomography of the abdomen showed a huge tumor occupying the entire left abdominal cavity (Fig. 2). The
| Blood Analysis | RBC 410×104/mm3, WBC 6300/mm3, Hb 11.7 g/dl, Ht 34.7%, Plat 17×104/mm3, |
| Urinalysis | Protein (-), Sugar (-), |
| Urobilinogen (±), Occult blood (-), | |
| Electrolytes | Na 142 mEq/1, K 3.9 mEq/1, Cl 104 mEq/1, |
| Renal Function | BUN 11.8 mg/dl, CRE 0.67 mg/dl, |
| Hepatic Function | GOT 14 KU, GPT 12 KU, |
| ALP 15.4 KA-U, LDH 467 IU/ml, TP 7.6 g/dl, | |
| ALB 4.3 g/dl | |
| Endocrine Function | Plasma cortisol 7.7 u/dl (3.7~13.0), |
| Urinary 17-hydroxysteroids 2.7 mg/day (1.5~5.8) | |
| Urinary 17-ketosteroids 1.6 mg/day (1.5~6.5) | |
| Others | FBS 90mg/dl, VMA (-), |
| a-Fertoprotein (-) |
patient underwent laparotomy through a thoracoabdominal incision. A large, oval tumor arising from the region of the left ad- renal gland was found displacing the dia- phragm upward and the kidney downward. The tumor was densely adherent to the supe-
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rior surface of the kidney. It was excised with the left kidney. Renal hilar and paraaortic lymph nodes were also removed. There was no macroscopic evidence of direct tumor infil- tration to the parietal wall or to any other vis- cera, nor intraabdominal metastatic involve- ment. Despite marked compression by the tumor, the kidney parenchyma was not in- vaded. The tumor was enclosed by a thin cap- sule, measured 18 x 12 x 12 cm, and weighed 1220 g. The cut surface was reddish-brown and showed several areas of hemorrhage and necrosis (Fig. 3). Microscopic examination
also showed massive tumor necrosis with marked vascularity and extensive hemor- rhage. The viable portions of the tumor were composed of relatively regular cells with uni- formly abundant lipid, arranged in nodules and cords with a vaguely fasciculate pattern. A few tumor cells had prominent nuclei and pleomorphic cytoplasm. Calcification and mitotic figures were present. Capsular and blood vessel invasion of tumor cells were found. However, there was no invasion of the kidney nor metastasis to lymph nodes. Micro- scopic findings were compatible with adreno- cortical carcinoma (Fig. 4). The child re- ceived neither chemotherapy nor irradiation postoperatively because: 1), questionable benefit obtainable from adjunctive therapy; 2), anticipated side effects in a 9 year old pa- tient; and 3), pathological examination re- vealed complete removal of tumor. She re- mained well until 21 months after surgery, when she was found to have a round hepatic metastatic nodule, evidenced at routine fol- low up computer tomography. When a recur- rence was evident, biochemical evaluation
was thoroughly performed. This entailed measurement of: plasma cortisol, androste- rone, cortisone, androstenedione, aldo- sterone, dehydro-epiandrosterone sulfate (DHEA-S), desoxycorticosterone (DOC), de- hydroepiandrosterone (DHEA), corticoste- rone, and hydroxy-corticosteroid (OHCS), and urinary excretion of 17-ketosteroid, 17- hydroxycorticosteroid, and 17-ketogenic ste- roid levels. All of these steroid levels were nor- mal (Table 2). The tumor progressively en- larged, and she died 3 years and 4 months after the surgery from hepatic metastases and local tumor recurrence. All through her short life, there was no clinical evidence of hir- sutism, Cushing’s syndrome, or inappropriate feminization, which are the most commonly reported presentations of this tumor in this age group and during childhood.
DISCUSSION
Adrenocortical carcinoma is an unusual tumor in children and represents a small per- centage of adrenal carcinomas. In a review by Stewart et al.,2 only 6 per cent of adrenal can- cers in children originated in the adrenal cortex. Neuroblastoma is certainly the most common carcinoma, representing over 90 per cent of all adrenal cancers. Adrenal carcino-
| Hormones in Serum and Urine | Normal Range | |||
|---|---|---|---|---|
| Serum | Cortisol (ng/dl) | 10.5 | 3.7-13.0 | |
| Androsterone (ng/ml) | 0.185 | 0.1-1.2 | ||
| Cortisone (ng/ml) | 4.67 | 5-30 | ||
| Androstenedione (ng/ml) | 1.5 | 0.5-2.4 | ||
| Aldosterone (pg/ml) | 167 | 52-180 | ||
| DHEA-S (ng/ml) | 200 ¥ | 500-3000 | ||
| DOC (ng/ml) | 0.028 | 0.02-0.2 | ||
| DHEA (ng/ml) | 0.14 | 1.2-7.5 | ||
| Corticosterone (ng/ml) | 3.32 | 1.0-10.0 | ||
| OHCS (ug/dl) | 17.4 | 7-23 | ||
| Urine | 17-KS (mg/day) | 1.8 | 1.5-6.5 | |
| 17-OHCS (mg/day) | 1.5 | 1.5-5.8 | ||
| 17-KGS (mg/day) | 2.8 | 2.9-14.8 | ||
| 11-deoxy | 0.7 | 0.4-3.2 | ||
| ( 11-oxy | 2.1 | 2.5-11.4 | ||
| And | 0.01 | 0.39-2.92 | ||
| Etio | 0.01 | 0.31-2.24 | ||
| 17-KS (mg/day) | DHEA | 0.06 | 0.01-1.76 | |
| 11-Keto And | 0.01 | 0.06+ | ||
| 11-Keto Etio | 0.03 | 0.07-0.49 | ||
| 11-OH And | 0.03 | 0.26-1.08 | ||
| 11-OH Etio | 0.02 | 0.02-0.37 | ||
mas are classified into functioning and non- functioning types, according to the clinical syndromes with which they are associated. Most of these tumors in children are hor- monally functional, producing Cushing’s syn- drome, virilization, feminization, or a com- bination of these features. 2-4 Adrenocortical tumors are considered to be nonfunctioning if there is no clinical or laboratory evidence of increased hormone production. These are very rare. Lewinsky et al.5 in 1974 reviewed 178 cases of nonfunctioning adrenocortical carcinoma of which only 9 occurred in pa- tients under 20 years of age. Sefczek et al. 6 re- viewed the English literature since 1974 and found only one report of a pediatric patient. There is no report of such an occurrence in children in the Japanese literature. Patients with nonfunctioning tumor do not, as a rule, present with clinical symptoms. A palpable mass is the most common clinical feature, but patients may also have pain, weakness, ano- rexia, or, uncommonly, fever.7 The onset of clinical disease in these patients is insidious
and tumors remain silent until symptoms are produced by advanced malignancy. It has been stated in the literature that these tumors are much larger than the functioning type be- cause they do not produce clinical signs or symptoms in the early stages, 8 besides which, the adrenal glands are located deeply within the abdomen. This explains the advanced stage of the disease at the time of diagnosis. The radiological examination of most value has traditionally been intravenous pyelo- graphy (IVP), which usually shows a supra- renal mass displacing and deforming the kidney. However, computer tomography (CT) is an excellent diagnostic method that provides useful information in terms of locali- zation, extent of local invasion, and presence of metastatic disease. Although nonfunction- ing carcinomas do not produce hormonally active compounds, they are capable of form- ing precursor steroids lacking hormonal ac- tivity. Fukushima and Gallagher9 reported that these tumors can secrete pregnenolone. An enzyme defect probably accounts for non-
conversion of pregnenolone to hormonally ac- tive forms. Metabolic products of pregneno- lone detected in the urine may aid in diagno- sis, and in monitoring of treatment. Nonfunc- tioning adrenocortical carcinoma carries a poor prognosis. Mortality rate in the first year is 69 per cent more than half the number of deaths occurring within two months of diag- nosis.5 Neither age nor sex influence the sur- vival. Survival, however, appears to depend on the size of the primary lesion and the de- gree of local and distant extension of the neo- plasm at the time of the initial diagnosis. Cri- teria for staging adrenocortical carcinoma have been suggested.10,11 Table 3 shows the staging criteria of Macfarlane12 modified by Sullivan et al .. 11 According to Henley et al., 13 curative surgical resection for stages I, II, and III lesions resulted in a 32 per cent, 5 year sur- vival rate with a 0 per cent operative mortality rate. However, despite the complete excision of the tumor for a stage II lesion, our patient died of carcinoma 3 years and 4 months after surgery. Metastases, if occurring are most fre- quently found in the lung, liver, and the re- gional lymph nodex.14 Spread to bone and brain is highly unusual. Like other retroperi- toneal tumors, adrenocortical carcinoma spreads locally and invades mesentery, omen- tum, and kidney, forming large intra-
| Staging Criteria | |
|---|---|
| T1 | Tumor ≤5 cm, no invasion |
| T2 | Tumor >5 cm, no invasion |
| T3 | Tumor any size, locally invading to but not involving adjacent organs |
| T4 | Tumor any size, locally invading adjacent organs |
| NO | No regional positive nodes |
| N1 | Positive regional nodes |
| M0 | No distant metastatic disease |
| M1 | Distant metastatic disease |
| Stage | |
| I | TINOM0 |
| II | T2NOM0 |
| III | T1 or T2NIM0, T3NOM0 |
| IV | Any T, any N M1, T3N1, T4 |
abdominal tumors that may erode viscera or invade the large vessels. For nonfunctioning adrenocortical carcinoma, surgical resection offers the best chance of cure. Irradiation and chemotherapy produce inconsistent results, although mitotane has been used with some success. 15,16 Multiple surgical approaches have been advocated.7,8 Although the size, location, and vascularity of the tumor influ- ence the type of approach, wide and direct exposure is imperative. Generally, this can be achieved by long transabdominal or thoraco- abdominal incision. Attempts should be made to resect the entire tumor mass, when- ever feasible, even if this necessitates the re- moval of adjacent adherent organs, e.g. kidney, or spleen. Repeated aggressive resec- tion of a recurrent tumor may prolong sur- vival. 10
ACKNOWLEDGEMENT
Gratitude is extended to Prof. A Masaoka, Director of the Second Department of Sur- gery, Nagoya City University School of Medi- cine, for helpful suggestions.
(Received for publication on Mar. 13, 1985)
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