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The outcome of childhood adrenocortical carcinoma in Egypt: A model from developing countries
Wael Zekri, Mahmoud Hammad, Wafaa M. Rashed, Gehad Ahmed, Maged Elshafie, Marwan H. Adly, Yasser Elborai, Badr Abdalla, Hala Taha, Naglaa Elkinaae, Amal Refaat, Alaa Younis & Ahmad S. Alfaar
To cite this article: Wael Zekri, Mahmoud Hammad, Wafaa M. Rashed, Gehad Ahmed, Maged Elshafie, Marwan H. Adly, Yasser Elborai, Badr Abdalla, Hala Taha, Naglaa Elkinaae, Amal Refaat, Alaa Younis & Ahmad S. Alfaar (2020): The outcome of childhood adrenocortical carcinoma in Egypt: A model from developing countries, Pediatric Hematology and Oncology, DOI: 10.1080/08880018.2019.1710309
To link to this article: https://doi.org/10.1080/08880018.2019.1710309
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The outcome of childhood adrenocortical carcinoma in Egypt: A model from developing countries
Wael Zekria,b (D, Mahmoud Hammada,b iD, Wafaa M. Rashed“ (D, Gehad Ahmedd,e (D, Maged Elshafiee,f, Marwan H. Adly9, Yasser Elboraia,b,h (D, Badr Abdalla’, Hala Taha”,k, Naglaa Elkinaae”,k, Amal Refaat”,m, Alaa Younise,f, and Ahmad S. Alfaar”, İD
aPediatric Oncology Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; bPediatric Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt; ‘Research Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; “Surgery Oncology Department, Faculty of Medicine, Helwan University, Cairo, Egypt; eSurgery Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; “Surgery Department, National Cancer Institute, Cairo University, Cairo, Egypt; 9Armed Forces College of Medicine, Cairo, Egypt; “Pediatric Hematology- Oncology Division, Prince Sultan Military Medical City, Riyadh, Saudi Arabia .; ‘Gastroenterology Department, Hospital of Llandough, Cardiff, UK; ‘Pathology Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; k Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt; ‘Radiodiagnosis Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt; mRadiodiagnosis Department, National Cancer Institute, Cairo University, Cairo, Egypt; “Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, a Corporate Member of Freie Universität, Humboldt University, the Berlin Institute of Health, Berlin, Germany; °Department of Ophthalmology, University of Leipzig, Leipzig, Germany
ABSTRACT
Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine neo- plasm. Complete surgical resection is the single most important treatment. Most available information has been learned from experi- ence with its more frequent adult counterpart. In this study, we assessed the features and survival outcome of patients with ACC at Children’s Cancer Hospital Egypt (CCHE). Patients diagnosed at CCHE between July 2007 and November 2016 were followed up on until November 2018. Patients with stages I and II were operated upon, while stages III and IV had received combinations of doxorubicin, etoposide, platinol, and mitotane (DEPM) beside the attempt to con- duct surgery when feasible. Data belonging to 18 patients (7 men and 11 women) were analyzed; median age at diagnosis was 48.5 months. Sixteen patients had presented with secreting tumors. Six patients were diagnosed with stage I disease; four with stage II; three with stage III; and five with stage IV carcinoma. By the end of this study, 10 patients have survived; five-year overall survival of 66.3%. Surviving patients were all of stage I or II diseases and were all in remission. Seven patients who did not survive died due to tumor progression, while one patient died after chemotherapy. The prognosis of ACC is essentially dependent on a successful complete resection of the tumor and thus on the initial tumor stage. The mito- tane and DEP protocols may help control tumor growth in the advanced stages for only short periods.
ARTICLE HISTORY
Received 28 March 2019 Revised 14 October 2019 Accepted 23 December 2019
KEYWORDS
Adrenocortical carcinoma; childhood cancer; developing countries; rare tumors
CONTACT Wael Zekri waelzekri@gmail.com @ Children’s Cancer Hospital Egypt (CCHE-57357), Sekket Al-Imam Street, Sayeda Zainab, Cairo, Egypt; Ahmed Samir Alfaar ahmed.alfaar@charite.de, ahmadsfar@gmail.com Department of Ophthalmology, Leipzig University Hospital, University of Leipzig, Liebigstrasse 10-14, 04103 Leipzig, Germany
*These authors had equal contributions. + Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2019.1710309
KEY POINTS
. Initial stage and resectability are the main indicators of outcomes in adrenocortical carcinoma.
· Chemotherapeutic agents used in developed countries did not achieve the same outcomes.
· Further molecular-pharmacology differentiation is needed for various ethnic populations.
Importance of the study
Although many studies showed improving outcomes of childhood adrenocortical tumors in developed countries, the outcome remains worse in developing countries, especially in advanced stages. The study signifies the importance of multicenter studies and pooling of patients in rare cancers.
Introduction
Adrenocortical carcinomas (ACCs) in childhood and adolescence are rare with aggres- sive heterogeneous biological behavior and poor outcome. The incidence of ACC differs across geographic regions. Worldwide cancer registries do not provide enough informa- tion about adrenocortical tumors (ACT). Available reported incidences, however, range from 0.3 to 3.4 per million children diagnosed below the age of 15.1,2 According to data from the Surveillance Epidemiology End Results registries, about 14 new patients younger than 20 are diagnosed with ACT in the United States per year.3 The incidence of ACCs appears to exhibit a bimodal age distribution, with peaks in childhood and the fourth to fifth decades of life.4-6 Several genetic diseases have been associated with ACC, including congenital adrenal hyperplasia, and Li-Fraumeni syndrome. Patients with ACC typically present with signs and symptoms of an endocrine disturbance such as increased production of androgens (virilization) and/or cortisol-level-related distur- bances (hypercortisolism or Cushing syndrome) representing secreting tumors.5,
Complete tumor resection is currently the only documented effective method of treat- ment.7 Different chemotherapy agents have been tested for the treatment of ACC; how- ever, surgery remains the only effective modality.
There are limited reports about the incidence of childhood ACC in developing coun- tries including Africa. In this report, we aimed at determining the features, prognosis, and survival outcome of the ACC patients among patients presented to Children’s Cancer Hospital Egypt (CCHE), a major referral center in one of the developing coun- tries. This patient cohort will be of value on a worldwide level since this is rare cancer with scanty publications.
Materials and methods
Retrospective data of all ACC patients, below 18 years, treated from July 2007 till November 2016 at CCHE were retrieved from the hospital-based cancer registry. The
study was approved by ethical and scientific committees at Children Cancer Hospital - Egypt 57357. Consents have been obtained from patients’ guardians after a full explan- ation of the purpose and nature of all procedures used. Data collected included age, gender, clinical findings at presentation and during treatment, results of the initial workup (hormonal profile, radiology, and biopsy), as well as radiology results during follow-up. Data about disease stage, modalities of treatment, Surgical Details as well as survival outcome were also collected.
We adopted a system based on the modified Children’s Oncology Group (COG) stag- ing system for pediatric ACC.8 Assessment and management of all patients were con- ducted by a multidisciplinary team. COG-ARAR0332 protocol was adopted for management. Patients diagnosed with stages I and II carcinoma received no neo-adju- vant or adjuvant chemotherapy, while patients with stages III and IV disease received induction and or adjuvant chemotherapy in the form of doxorubicin, etoposide, plati- nol, and mitotane (DEPM). The number of cycles required was determined according to disease stage and initial response to treatment.9
Evaluation of the secondary sexual characters was done using the Tanner scoring sys- tem.10-12 The modified Weiss criteria were used to determine the malignant nature of potential ACC tumors.13 In clinical practice, reaching conclusions based on the Weiss system is not feasible. Some of its diagnostic criteria, such as necrosis, as well as vascu- lar and capsular invasions, are subjective (regarding presence and quantification) or their accuracy affected by inadequate tumor sampling.14
Both data collection and data cleaning were done using Research Electronic Data Capture (REDCap), a secure, Web-based application designed to support data capture for research studies.15 IBM SPSS version 22 was used for data analysis.16 Kaplan-Meier method was used for survival analysis.
Results
Presentation
Records of all patients of adrenocortical carcinoma were reviewed (N=18), seven (39%) boys and 11 (61%) girls. Half of the patients were less than four years of age. The median age at diagnosis was 48.5 months. Median age at diagnosis was 45 months for stages I and II, and 52 months for stages III and IV.
Clinical characteristics and endocrinal abnormalities at presentation are detailed in Table 1. Nearly all patients included in this cohort presented with secreting tumors (n =16). One male patient had presented with an abdominal mass only. Initial clinical data for one female patient were incomplete. Both patients have been diagnosed as ACC only after surgical resection.
The most common isolated endocrinal abnormality in female patients was primary hypercortisolism (n =3), followed by virilization (n =2). All but one male patient pre- sented with manifestations of precocious puberty in the form of hirsutism. Also, two of them presented with premature penile enlargement. All male patients had elevated tes- tosterone levels with or without elevated cortisol level. Further details can be found in Table 1 and Supplementary Table 1.
| Variables | n (%) n = 18 patients |
|---|---|
| Age (in months) | Mean: 62 months |
| Sex | |
| Man | 7 (39%) |
| Woman | 11 (61%) |
| Type of hormonal disorder | |
| Non-functioning | 2 (11%) |
| Functioning | 16 (89%) |
| Clinical findings (shared): | |
| Hypertension | 7 (39%) |
| Cushing syndrome | 7 (39%) |
| Virilization in woman | 10 (56%) |
| Increased pubic hair | 15 (83%) |
| Acne vulgaris | 5 (28%) |
| Enlarged clitoris | 5 (28%) |
| Deepening of voice | 3 (17%) |
| Precocious puberty | 12 (67%) |
| Stage | |
| I | 6 (33.3%) |
| II | 4 (22.2%) |
| III | 3 (16.7%) |
| IV | 5 (27.8%) |
| No. of chemotherapy cycles (DEPM): | |
| 0 | 10 (55.6%) |
| 1 | 1 (5.6%) |
| 4 | 3 (16.7%) |
| 8 | 4 (22.3%) |
| Outcome | |
| Alive | 10 (55.5%) |
| Dead | 8 (44.5%) |
Patients’ hormonal profile: Elevated cortisol levels were found in nine patients. Of these nine patients, three women and one male patient had isolated primary hypercor- tisolism on initial workup, while another four women and one man had concomitant elevations of other hormones. Five patients (two women and three men) had isolated high testosterone levels, while seven patients (two men and five women) had concurrent elevations of testosterone and other hormonal abnormalities. Three female patients had simultaneous high estrogen levels as well as other hormonal abnormalities. Thyroid function profile was within normal in all children (Supplementary Table 1).
Staging: Six patients were diagnosed after the initial workup with stage I disease; four with stage II; three with stage III; and five with stage IV (Table 1). Detectable sites of metastases in patients with stage IV disease included lung, liver, and lymph nodes (Supplementary Table 2). Metastasis to the bone was not detected upon bone scan in any patient. Six patients underwent CT-guided biopsies because upfront complete surgi- cal excision was not possible; five of the six were in stage IV.
Treatment
Surgery: Fourteen patients underwent surgery; 12 patients underwent upfront adrena- lectomies, while two patients received chemotherapy first, and then underwent delayed adrenalectomies (Figure 1). Successful complete excisions were achieved in 11 surgeries; another three ended with partial excisions with residuals (Table 2). The procedure used in most patients was an en bloc open adrenalectomy and was performed through a
A
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C
subcostal incision. This approach was used in 12 patients. An extension of the incision (bilateral subcostal incision) was required in one case only. Resection of adjacent organs, including partial liver resection, was performed in two surgeries. Two patients required dissection of their tumors from adjacent structures (complete dissections from
| Surgical details | Frequency (%) (n = 14 patients) |
|---|---|
| Excision | |
| Complete | 11 (78.6%) |
| Partial | 3 (21.4%) |
| Biopsy | 6 (2 of them then got delayed surgery) |
| Surgery | |
| Upfront | 12 (85%) |
| Delayed | 2 (15%) |
| Laterality | |
| Left | 4 (28.5%) |
| Right | 10 (71.5%) |
| Lymph nodes | |
| Lymph node sampling | 3 (21.3%) |
| Lymph node positivity | 2 (14.2%) |
the liver, pancreas, kidney, and spleen). No tumor thrombus was found during any of the surgeries. In one case, the tumor was <5 cm in its maximum diameter, allowing for laparoscopic adrenalectomy to be performed.
Lymph node sampling was performed only in patients with radiologically or intrao- peratively suspicious lymph nodes. Regional lymphadenectomies were performed for three patients. One patient underwent two surgical resections of lung metastases. One patient’s tumor was accidentally ruptured during resection. Out of four patients who had developed local recurrence, two underwent complete resections, while the other two underwent resections with residuals.
Ten patients reported no local or distant recurrences after complete surgical resec- tions. All 10 were alive in remission at the end of this study. Three patients developed postoperative complications; one patient developed postoperative chest infection, one tachycardia with a high-volume pulse, and one suffered a postoperative surgical site infection. Surgical details are summarized in Table 2.
Postoperative pathology: Out of 18 patients diagnosed as adrenocortical carcinoma, resection specimens were collected for 14, and core biopsies for the other 4. Of the four core biopsies, two exhibited lymph node metastases. (Table 2)
Microscopic examination of samples revealed clear cells ≤25% detected in 13 patients; mitosis ≥5/50 High Power Field (HPF) in 17 patients; atypical mitosis in 12 patients; and necrosis in 11 patients (Supplementary Table 3). Out of the 14 resection specimens collected, 4 specimens showed capsular invasion. Results of KI-67 (MIB-1) labeling yielded intermediate values (5%-15%) in two patients, and high values in all remaining patients (ranging from 10% to 75% with a mean of 27%). None of the specimens tested yielded low (<5%) values. Figure 2 shows sections from pathological samples.
Chemotherapy: Patients with stages III and IV (n=8) received chemotherapy. One patient died from severe myelosuppression, sepsis, cardiotoxicity, and chest infection just after the first cycle of chemotherapy, while three patients had no response after four cycles of chemotherapy and died from tumor progression. Four patients continued the planned eight cycles of chemotherapy and showed a response to treatment but progressed and died from the disease, later. Mitotane was given intermittently due to incompliance due to gastric upset, abdominal pains, and vomiting. One patient developed speech abnor- malities that regressed after mitotane was discontinued. This limited its usage to the most tolerated dose, about 1-2 grams per day.
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Outcome
Mean follow-up time for all patients was 38.56 months (standard deviation = 23.34, median = 39.5 months). The mean follow-up time of the 10 living patients was 41.20 months (standard deviation = 21.33, median = 39.5 months).
The mean overall survival time was 53.24 months (95% CI 39.83-66.66) and median of 65 months. The five-year event-free survival probability was 52.4%, and overall sur- vival probability was 66.3% (Figure 3). All patients with stage I or II disease (10 patients) at initial diagnosis survived to the end of this study and were in remission. All patients who died (n = 8) were initially diagnosed with either stage III or IV disease.
Discussion
The median age for childhood ACC patients included in this study was 48.5 months. Similar median ages have been reported in most studies and review articles on adreno- cortical carcinoma in pediatrics. Likewise, the slight female predominance of 1:1.6 noted in our study was similar to those reported in other studies.3,17-19
Several hereditary syndromes are known to be associated with benign or malignant ACCs. Such hereditary conditions include Li-Fraumeni syndrome, multiple endocrine neoplasia type 1 (MEN-1), and Beckwith-Wiedemann syndrome.4,20 Pediatric ACC is always associated with constitutional genetic abnormalities (eg, TP53). Genetic varia- tions in the TP53 tumor suppressor gene contribute to human cancers in various ways.21 The inheritance of a TP53 mutation causes predisposition to early-onset cancers,
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including breast carcinomas, ACC, and brain tumors.22 One Brazilian study reported that at least nine out of ten Brazilian pediatric ACC patients carried a germline TP53 mutation.22 None of the patients included in this study had physical findings or a posi- tive family history of any specific syndrome, except for one woman that exhibited mul- tiple café au lait spots all over her body, a finding often associated with neurofibromatosis type 1. Unfortunately, genetic mutational analysis and sequencing were not available at our hospital at the time of this study.
About 90% of ACCs in childhood are secreting tumors.22 As reported by studies con- ducted on multiple populations worldwide, the majority of our patients sought medical help due to symptoms resulting from autonomic hormonal hypersecretion. Androgen excess was the most common hormonal abnormality recorded in this study. As had been reported in an earlier study by Wooten et al, several patients suffered from mixed secreting tumors.6 The aforementioned findings mimicked those of other studies which reported functioning mixed hormone-secreting tumors (hypercortisolism/Cushing syn- drome and virilizing tumors) to be the most prevalent ACC tumors in the pediatric age group.25
More attention should be paid to the orientation of parents by the early presenting signs at preschool age, with the symptoms related to hypersecretion of cortisol and androgens. Family doctors and general pediatricians should be oriented with the importance of ordering CT abdomen in such cases to increase the incidence of detect- ing tumors in early stages and referral to specialized centers.
Five patients (27.8%) initially presented with metastatic disease. Comparable initial findings were reported by the International Pediatric Adrenocortical Tumor Registry (IPATR).3
Surgery is an essential part of any potentially effective plan for the treatment of ACCs.4 A successful complete surgical excision of an ACC with free margins and an intact capsule is considered the most critical step in the possible survival of a pediatric ACC patient. The current standard surgical approach involves an en bloc open
adrenalectomy through a subcostal incision, with possible extension. Extension of the subcostal incision may be necessary to avoid tumor rupture. Extensive tumor hemor- rhage and necrosis make ACC friable and susceptible to intraoperative tumor rupture and spillage. It is critical that tumor rupture be prevented due to its possible detrimental effects on the final treatment outcome. The tumor should, thus, be very carefully manipulated during surgery. One report indicated that rupture of the capsule and tumor spillage occurred in approximately 20% of patients studied.24 In our series, capsular tear with potential spillage occurred in only one patient. Resection of the kidney and sur- rounding organs may be necessary if involved. In our series, resection of adjacent organs was required in two surgeries. Resection of an apparently non-invaded organ has not been found to increase the chances of long-term survival.21 In this study, records indicated that complete resection had been achieved in 11 patients. Two of these patients later suffered a relapse. In addition, all patients that had undergone incomplete resections suffered either isolated local or both local and distant relapses.
Laparoscopy has been increasingly employed in resection of suprarenal tumors.25 Despite its seemingly obvious advantages, there have been reports in which this technique has led to tumor rupture and subsequent relapse. Therefore, it is advisable that laparoscopic resec- tion be employed only to resect small tumors that have no cystic components.26
The value of dissection of regional lymph nodes and their extensions in pediatric ACC has been briefly evaluated.27 It has, however, been advocated as an essential surgi- cal step, noting that patients with large and advanced stage tumors commonly experi- ence local relapse.28 Typically, ipsilateral modified node dissection is performed and extended from the renal vein to the common iliac vessel bifurcation. Lymph nodes contralateral to those clinically enlarged should be removed as well.29 In this study, three patients underwent lymphadenectomy, two of which were found to have positive lymph nodes on pathological examination.
Mitotane is a cytotoxic adrenolytic drug with an incompletely understood mechanism of action. It is given in advanced stages of ACC with residual tumor after surgery, in metastatic disease, or patients of inoperable tumors.3º Mitotane is either used alone or in combination with various chemotherapeutic agents, preferably doxorubicin, etopo- side, and cisplatin.31,32 In addition to its antitumor effect, mitotane is a potent inhibitor of adrenal steroidogenesis. Thus, in most patients with endocrine symptoms, these symptoms can be controlled by mitotane.21
In our study, the dose escalation of mitotane was employed, starting at one gram per day. None of the patients was able to tolerate the maximum dose of four grams. Mitotane is orally administered but has limited bioavailability, with vast inter-individual differences. Thus, monitoring of mitotane levels is recommended. Unfortunately, due to the rarity of ACC and lack of experience with monitoring plasma levels of mitotane, such monitoring was not performed at our center.
The higher stages (III and IV) were noted to be more common, the older the patient was, compared with the lower stages I and II. The stage at diagnosis reflected markedly on survival outcome. All patients initially diagnosed with stages III and IV passed away due to disease progression, relapse, or treatment-related toxicity. Our overall survival rate was poor (66.3%), but it is consistent with previous reports.33 Recent reports started to show better rates.27
Due to the rarity of ACT in general and childhood ACC in particular, only a few centers have managed enough patients of ACC to accumulate reasonable knowledge and experience. Studies of large series reported by a single center are rare, and strict guidelines are still lacking. Our study examined the experience of CCHE, a single refer- ral center in a low/middle-income country. This may give some explanation about the delay in approaching qualified medical facilities and diagnosis in late stages, which affects the outcome of disease. Also, there are some challenges for doing the full panel of investigations, including the full hormonal profile, abdomen MRI, and PET-CT, but this is the situation with other developing countries dealing with such a massive burden of childhood cancers.34
Moreover, this, in part, is due to the lack of a worldwide consensus on what was the complete workup for ACC. At CCHE, we had typically diagnosed ACC through radio- logical findings and the histopathological interpretation of tumor tissue collected. Recently, a complete hormonal panel was integrated into the initial workup for new patients of ACT as well as postoperatively and during the follow-up period.35,36
Although this study delineates the experience of a single institution, the number of patients reported from a period that spanned nine and a half years is large (18 patients) in comparison with reports from different centers over longer periods.17-19 Nevertheless, the aim of determining the prognosis of ACC in this cohort cannot be addressed with such number of patients.
The rarity of pediatric ACC and the current poor potential for patient survival under- scores the importance of the establishment of both national and international collabora- tions. Such levels of collaboration would help accrue enough patients for large enough studies in order to advance knowledge of this disease and enable future research and clinical trials.
Conclusion
The prognosis of ACC in low/middle-income countries is primarily dependent on the complete resection of the tumor as well as the initial tumor stage at diagnosis. The adrenolytic mitotane as well as other chemotherapeutic agents (especially cisplatin, doxorubicin, and etoposide) may control tumor growth in advanced stages, but only for short periods.
Acknowledgment
The authors would like to thank Dr. Mohamed-Ismail Rakha and Belqis Aldimshawy for revising the manuscript.
Disclosure statement
The authors declare no conflict of interest.
Authors’ contribution
WZ, MH, WMR, and ASA have shared in planning the study, drafting the work, and revising the content critically. WZ and ASA co-supervised the study. ASA, GA, ME, YE, and AY have shared in the patients’ recruitment, data acquisition, and cleaning. GA and NE drafted the work. MHA and BA have shared in data acquisition and cleaning. HT, NE, and AR have shared in the patients’ recruitment, pathology evaluation, and data acquisition and cleaning. All authors have shared in data interpretation for the work and revised and approved the current version to be published.
Funding
Dr. Ahmed Alfaar is supported by grant number 57147166 from The Deutscher Akademischer Austauschdienst.
ORCID
Wael Zekri ID http://orcid.org/0000-0002-1562-9456
Mahmoud Hammad (D http://orcid.org/0000-0003-1677-0360
Wafaa M. Rashed (D http://orcid.org/0000-0001-7531-2840
Gehad Ahmed (D http://orcid.org/0000-0002-8658-1525
Yasser Elborai (D http://orcid.org/0000-0002-5528-0025
Ahmad S. Alfaar (D http://orcid.org/0000-0002-0930-4583
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