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 » Subjects and Methods
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 317-321
 

Adrenocortical carcinoma in children and adults: Two decades experience in a single institution


Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Date of Web Publication6-Jan-2017

Correspondence Address:
A Mishra
Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.197737

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 » Abstract 

Context: Adrenocortical carcinoma (ACC) occurring in children and adults show distinct characteristics. However, due to rarity of the disease no large series addressing this issue has been published. Aims: The aim of this study was to study clinico-pathologic profile and outcome of ACC in children and adults. Settings and Design: Tertiary referral center. Retrospective study (January 1990-June 2011). Subjects and Methods: Forty-five patients with ACC were included; 16children (aged < 18 years) and 29 adults. Clinical details, hormonal profile, operation records, pathology reports and follow-up findings were noted and compared. Survival analysis was performed using Kaplan-Meier method. Log rank test and Cox regressionan alysis were performed. Results: Mean age was 8 ± 5.7 (M: F = 1:2.1) in children and 44.4 ± 15 years (M: F = 1:1.1) in adult groups. Prevalence of functioning tumors was significantly high in children (87.5 vs. 31% P = 0.001), while prevalence of incidentalomas was high in adults (6.3 vs. 51.7% P = 0.05). Tumor stage distribution at presentation, mean diameter (10.9 vs. 13.7 cm), and weight (392.9 vs. 892.9 g) didn't differ significantly in two groups. Adults had better albeit non-significant 5 year overall survival (OS) than children (0 vs. 13%). On univariate analysis stage of disease (P = 0.008), surgical intervention (P = 0.004), Weiss score (P = 0.04) and hormonal secretion (P = 0.04) were significantly associated with OS in adults but not in children. No factor was found significant on multivariate analysis. Conclusions: Except for high prevalence of functioning tumors in children, clinico-pathologic attributes and outcome of ACC in the two groups didn't differ significantly.


Keywords: Adrenal tumors, Cushing's syndrome, malignant conns', virilizingtumors


How to cite this article:
Sabaretnam M, Mishra A, Agarwal G, Agarwal A, Verma A K, Mishra S K. Adrenocortical carcinoma in children and adults: Two decades experience in a single institution. Indian J Cancer 2016;53:317-21

How to cite this URL:
Sabaretnam M, Mishra A, Agarwal G, Agarwal A, Verma A K, Mishra S K. Adrenocortical carcinoma in children and adults: Two decades experience in a single institution. Indian J Cancer [serial online] 2016 [cited 2017 Oct 17];53:317-21. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/317/197737



 » Introduction Top


Adrenocortical carcinoma (ACC) is a rare malignancy associated with aggressive biological behavior and poor outcome. The reported incidence in literature is around two cases per million populations.[1],[2] A bimodal age distribution with two reported peaks of occurrence one each in early childhood and fourth to fifth decades of life have been noted.[1],[2],[3],[4] Thesetumors may be classified as functional or non-functional depending on their ability to secrete various adrenocortical hormones. Due to the rarity of the disease, few centers have experience in managing enough number of such patients. Therefore, large series originating from a single center are rarely published.[5],[6],[7],[8],[9],[10],[11] There are reported differences in clinico-pathological profile, biological behavior and outcome of ACC occurring in children and adults.[3],[4],[7],[12] However, there are not many published studies which have specifically addressed this issue. The aim of this study was to review the clinico-pathologic profile and outcome of ACC in children and adults and to correlate the outcome with various factors.


 » Subjects and Methods Top


This retrospective study consists of 45 patients with ACC managed between September 1989 and June 2011 in our department. All patients had histologically or cytologically proven ACC. The histology diagnosis of ACC was based on Weiss scoring system and tumors having a score of more than three were designated as malignant.[13],[14],[15] Patients were staged according to Union for International Cancer Control UICC/WHO staging system based on Mc Farlane classification. The diagnosis of ACC in those not operated was established by performing trucut biopsy (four patients) and Guided fine needle aspiration cytology (eight patients) from metastatic sites along with primary tumor. Patients aged <18 years were classified as children and remaining as adults. Demographics, clinical profile, hormonal profile, details of surgical procedures, histology and/or cytology reports and follow up findings were obtained from inpatient records, out-patient registers, and Hospital Information System. Contact person or family of the patients not coming for follow-up examination were contacted via postal mail, E-mail or telephone to know about the latest status of the patients. Such patients whose minimum follow-up for 6 months after diagnosis was not known were excluded from the survival analysis. Statistical analysis was performed using SPSS 15.0 software. Survival analysis was performed using Kaplan-Meier method. Log rank test and Cox regression analysis were performed to compare outcome between pediatric and adult groups and impact of various factors upon outcome. A P value of less than 0.05 was considered significant for all the tests.

Management-protocol

Pre-operative evaluation consisted of detailed clinical examination including family history. It was followed by assessment of various adrenocortical hormone estimation and radiological investigations to assess the local extent and metastatic spread of the malignancy. Biochemical tests to assess hypercortisolism and virilization were carried out in all the patients. Adrenogenic hypercortisolism was established with overnight dexamethasone suppression test, low-dose dexamethasone suppression test and estimating serum adrenocorticotropic hormone concentration. To assess virilization serum testosterone and dehydroepiandrosterone (DHEA-S) concentration were measured. The facility for routine estimation of serum aldosterone and plasma renin activity (PRA) was not available to us before the year 2003. Therefore, these tests were performed selectively prior to this period and only hypertensive patients with hypokalaemia and hyperkaliuresis with no evidence of other hormone over production had PRA and aldosterone estimation performed in commercial laboratories. Similarly serum oestradiol concentrations were measured only in patients exhibiting feminizing features. Most of the patients were referred to our center with ultrasonography report. Contrast enhanced computerized tomography (CECT) and/or magnetic resonance imaging scan of abdomen were performed to assess the local extent of disease and abdominal metastases. Chest X-ray and/or CECT scan of chest; and methylene-diphosphonate (MDP) bone scan were performed for excluding pulmonary and skeletal metastases respectively. Facility for positron emission tomography is not yet available at our institute and a couple of patient only had undergone this test elsewhere.

As per department protocol all patients with pre-operative diagnosis or suspicion of ACC undergo open adrenalectomy either via trans-peritoneal or thoraco-abdominal approach (large invasive tumors). Patients with local infiltrative disease had involved organs resected en-block along with adrenal tumor and those with enlarged retroperitoneal lymph nodes underwent lymph node resection. Adjuvant or palliative therapy was customized according to patient's need, preference, and affordability. Hence, Mitotane was used in few patients only. Ketoconazole was prescribed for medical management of hypercortisolismto patients with intractable Cushing's syndrome. Radiotherapy was administered for palliation of painful bone metastases and brain metastases. Chemotherapy was used as last resort in patients with widespread disease. Patients were kept under close follow-up after surgery and had abdominal ultrasonography (USG) examination performed every 3 months in the 1st year and 6 monthly thereafter. Those with functioning tumors had hormone estimation done along with imaging. Further imaging to look for local invasive and metastatic disease is performed only if some abnormality is picked-up in previous tests.


 » Results Top


Sixteen children and 29 adults with ACC were included in this study. Mean age of the cohort was 31.4 ± 21.5 years. Female patients slightly outnumbered males (M:F = 1:1.1). Two peaks of age distribution were observed one each in first and sixth decades of life. Among children five each were <5 years, and between 5 years and 10 years of age; and six were >10 years old. Mean duration of symptom was 9.2 ± 6.6 months and didn't differ significantly among functioning (hormone secreting) and non-functioning tumors (8.4 vs. 10.2 months, P = 0.4). Forty two patients had unilateral (24 right and 18 left sided) and three bilateraltumors. Patients with bilateral tumors were adults (aged 52, 74 and 52 years). The distribution of functioning and non-functioning tumors was almost equal (51% vs. 49%). Among functioning tumors mixed hormone secreting (hypercortisolism + virilizing) were most prevalent (39.1%) followed by cortisolsecreting (34.8%), and virilizing tumors (17.4%). Malignant feminizing and Conns' tumors were observed in one patient each. Majority of non-functioning tumors (68.2%) were detected as adrenal incidentalomas whereas 27.3 and 4.5% presented with abdominal pain and palpable abdominal lump respectively. None of the patients presented with Stage I disease. Stage wise distribution of the tumors was: Stage II = 35.6%, Stage III = 6.7% and Stage IV = 57.8%. Metastatic involvement of liver, lungs, and brain was observed in 39.2, 17.8, and 7.1% of patients respectively. Metastases to urethra and lumbar vertebra were noted in one patient each. Prevalence of metastases didn't differ significantly between functioning and non-functioning tumors (43.5 vs. 83%, P = 0.13). Clinico-pathological attributes of children and adult patients are presented in the [Table 1].
Table 1: Clinico-pathological attributes of adrenocortical carcinoma in children and adults

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Overall 71.1% patients underwent surgery. All those not operated upon belonged to Stage IV, majority had non-functioning tumors (22.2%) and a minority with Cushing's syndrome (6.7%) refused offer for palliative surgery. Unilateral adrenalectomies (18 left and 12 right sided) were performed in 30 patients. None of the patients had laparoscopic resection (Trans peritoneal approach = 29, thoracoabdominal = 2). Among those operated upon two patients had bilateral tumors, while successful resection of both the tumors was done in one, surgery had to be abandoned in another an elderly male who developed severe hemodynamic instability after resection of left adrenal tumor. After recovery, this patient refused for further surgical intervention. En-block resection of adjacent organs was done in 18.7% and retroperitoneal lymph node dissection in 6.7% patients. Tumor thrombectomy was performed in 2 patients. Wedge resection of liver was performed in one child for symptomatic palliation of Cushing's syndrome. The mean tumor weight was 533 ± 528 g (32-2000) and tumor diameter 12.7 ± 4.9 cm (4-25). Patients with incidentaloma had largertumors in comparison to those with symptomatic ACC (13.2 vs. 12.5 cm) however the difference was not significant (P = 0.7).

Three patients died in perioperative period. Two children one each with Cushing's and malignant Conn's syndrome died due to multiple organ dysfunction syndrome on the 8th and 9th post-operative days respectively and another adult with Cushing's syndrome succumbed to refractory hypotensionsecondary to intraoperative bleeding on the day of surgery itself. Perioperative morbidity was noted in seven patients (15.5%) 4 of those with Cushing's syndrome. One patient who developed pneumothorax required intercostal tube drainage whereas three each had wound infection and atelectasis, managed conservatively.

Two patients with Cushing's syndrome received adjuvant Mitotane therapy for 2 and 3 months each and the treatment had to be discontinued due to side-effects. Radiotherapy to the tumor bed was administered in one patient who had accidental rupture of tumor capsule during surgery. Radiotherapy to spinal metastases was administered to two patients including one with widespread visceral metastases who in addition received chemotherapy (Cisplatin + doxorubicin).

Three patients with insufficient follow-up information were excluded from the survival analysis (all had Stage IV disease). The mean follow-up was 12.1 ± 13 months (median = 9.5 months) and mean survival was 18.8 ± 3.5 months (median = 12 months). The longest surviving patient was still alive after 72 months of follow-up [Figure 1]. Stage wise median survival was 17, 3, and 10 months for Stage II, III and IV respectively. Overall survival (OS) at 12 months, 24 months, and 60 months was 48%, 16%, and 8% respectively. Five year OS for patients with Stage II disease at presentation was 22%, none of the patients presenting with Stage III and IV survived for 5 year. Comparative survival figures for the pediatric and adult groups are given in [Table 2]. Median disease free survival was 9.7 months. Four patients developed metastases in follow-up two each hepatic and pulmonary. 60% patients died of disseminated disease in the follow-up. On univariate analysis tumor stage (P = 0.004), functioning tumors (P = 0.04) and surgical intervention (P = 0.001) were the factors significantly associated with survival. Patients with Stage IV disease undergoing surgery fared better than those not (P = 0.01). Survival of patients with symptomatic tumors though better than those with incidentalomas (P = 0.41) did not differ significantly, similarly, gender (P = 0.52), tumor size (P = 0.12) and weight (P = 0.31) also did not have significantly influence on survival. Survival of children in comparison to adult though not significant was worse (.72). On analyzing different factors in children and adult groups separately, stage of disease (P = 0.008), hormonal secretion (P = 0.04) surgical intervention (P = 0.004), and Weiss scores (P = 0.04) were significantly associated with OS in adults but not in children. On multivariate analysis none of the factors was found to be significant.
Figure 1: Kaplan-Meier plot for the whole cohort of patients with adrenocortical carcinoma

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Table 2: Outcome of adrenocortical carcinoma in children and adults

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 » Discussion Top


In accordance with the previously published literature we also noticed two distinct peaks of occurrence of ACC.[1],[2],[3],[4] The mean age of the patients in comparison to the other published reports was less in our study because more than one third of our patients were children.[8],[9],[10],[11] In concurrence with previous reports, women outnumbered men.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] Despite extensive technological advances in the genetic field over the last 10 years, the molecular pathogenesis of adrenal tumors still remains largely unknown.[16] Pediatric ACC can be associated with several geneticsyndromes namely Carney complex, congenital adrenal hyperplasia,  Li-Fraumeni syndrome More Details, McCune–Albright syndrome, multiple endocrine neoplasia type 1 and  Wiedemann-Beckwith syndrome More Details. These should be ruled out with detailed history taking and relevant investigations. Although, there is no consensus regarding routine genetic screening, it is suggested by some researchers that patients with ACC should be at least be screened for TP 53 mutation as the results have great implication for other family members.[17],[18],[19] None of our patients had any clinically identifiable genetic syndrome or significant family history and none had genetic testing. Functioning tumors were present in 51% of the patients and this figure is at par with the earlier reports.[9],[12] However, recent literature report slightly higher incidence of the functioning tumor. The reason of this shift lies in the extent of hormonal evaluation undertaken by different centers. The incidence of functioning tumors goes upif more biochemical tests to look for different hormone precursor are included in the evaluation of the patient.[1],[2],[10] More children than adults had functioning tumorsin our study and virilizingtumors were more prevalent in children. These finding were similar to other studies.[3],[4],[7],[20] The proposed explanation for more prevalent virilizing tumors in children is that their ACC originate from persistent fetal zone of adrenal cortex which has propensity to produce DHEA-S.[7]

Though, some selected recent studies, suggest a trend towards earlier diagnosis, increased resectability and improved survival in patients with ACC, these have not been the general observations.[9] According to a study based on report of National Cancer Institute's surveillance, epidemiology and end results 40.6% of the patients reported until the year 2000 had tumors confined to adrenal glands.[8] Though, in our study only 35.6% patients had tumors localized to the adrenal glands, the mean tumor diameter of 12.7 cmdidn't differ much from that reported previously.[6],[8],[9],[10] Similarly more than half of adult patients were initially diagnosed as adrenal incidentaloma, but the mean tumor size in them was not significantly less than those having symptomatic disease. This paradox is reported in other studies also which have noted that there is no trend towards earlier diagnosis of ACC despite of more ACC being picked up as incidentalomas.[6],[8],[21] Children seemed to have larger tumor in our study as compared to previously reported series, which might be due to delay in seeking medical advice.[3],[20] 62.1% of adults and 50% of children in our study had distant metastasis at the time of presentation. This rate is much higher than the latest available figures from the developed countries, particularly so in case of children in whom the reported incidence of metastases ranges from 14.6% to 43%.[6],[7],[8],[12],[20],[21],[22]. Therefore, overall prognosis in pediatric age group in our study remained poor.

Due to rarity of the disease, stages-wise OS of patients with ACC is often not reported in many series. Stage I and II are usually clubbed in one group (confined to adrenal) and Stage III and IV in another (invasive disease). Five year OS in the patients undergoing complete resection ranges from 32% to 48%.[6],[7],[8],[9],[10],[11],[12],[20],[21],[22],[23],[24],[25],[26] In our series OS in patients with Stage II disease was 20% (presumably with curative resection) and for whole cohort was 8%. The plausible reason for poor OS in this study seems advanced stage of disease at presentation: None of our patient had Stage I disease, only one-third Stage II, whereas two-third advanced disease (Stage III and IV). The usual reported 5 year survival for Stage III and IV is poor and ranges from 0% to 10%. Although, occasional series do report survival as high as 40% OS for Stage III, it remains universally poor for Stage IV disease almost 0% in majority of series. [Table 3] summarizes the outcome of ACC along with various reported prognostic factors in varies studies.[5],[6],[8],[9],[10],[11],[12],[20],[21],[22],[23],[24],[25] Localize dresectable disease has consistently been shown as one of the most important determinants of the survival both in adults and children.[5],[6],[7],[8],[9],[11],[23],[24],[25],[26] The other reported prognostic factors include age of the patient, gender, tumor size, Weiss score, and hormonal secretion.[6],[12],[13],[14],[15],[16],[17],[18],[19] Apart from other factors affecting prognosis, tumor weight has been considered an important factor in children.[20],[22],[27] Some studies have reported beneficial effect of adjuvant therapy upon survival in patients with Stage III and IV disease. However, this fact is not universally established.[1],[2],[6],[9] In our study OS in children was comparable to adults. Hormonal secretion, stage, surgical intervention and Weiss scores were found to be significant determinants of survival in adults, none of the factor was found to be significant in children. One important observation was that Stage IV patients undergoing surgery had significantly better survival than those who didn't.
Table 3: Stage wise survival in different studies

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Besides, advanced stage of disease at presentation, majority of our patients present with debilitating Cushing's' syndrome, which is considered a bad prognostic factor. Majority of our patients could not afford Mitotane, which could have contributed to improved survival in advanced stages of disease.[28],[29],[30] The role of adjuvant and palliative chemotherapy in improving progression free survival is controversial. In Mexican study, it was found that excision of recurrence was an independent factor affecting survival.[23] Another study reported that R0 resection affords the maximum chance of cure or palliation in such situation.[25] None of our patients underwent re-surgery for recurrent tumor.

This study suffers from some weaknesses inherent to all retrospective studies. Three patients were lost to follow-up. Cost constraints didn't permit extensive hormonal evaluation in all patients. Another observation common to all the malignancies occurring in developing countries is delay in seeking medical advice and the advanced disease at presentation. Same was true for our patients with ACC and both children and adults had advanced disease at presentation. Despite dismal OS, patients who could be operated upon fared better than those not. ACC still remains an enigma and there is need for global registry and collaborated effort to improve outcome of this dreaded malignancy.

 
 » References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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