OUTCOMES FOLLOWING SURGICAL MANAGEMENT OF ADRENOCORTICAL CARCINOMA: A SINGLE-CENTER EXPERIENCE
Morena Turco1,2, Jorge Huguet1, Angelo Territo1, Matteo Fontana1,3, Oscar Rodríguez Faba1, Joan Palou1 and Alberto Breda1.
1Urology Department. Fundació Puigvert. Autonomous University of Barcelona. Barcelona. Spain.
2Urology Department. University of Perugia. Department of Surgical and Biomedical Sciences.
3Urology Department. Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico. Department of Clinical Sciences and Community Health. University of Milan. Milan. Italy.
Summary .- OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare and heterogeneous disease, with chal- lenging management and poor prognosis. Surgery with curative intent is the preferred treatment option for lo- calized disease, with a reported 5-year survival rate of 55% for complete resections. However, owing to the high risk of recurrence there is a need for adjuvant ther- apies, such as mitotane, an adrenolytic drug, or irradi- ation, while in advanced disease the standard of care is a combined chemotherapy scheme. The aim of this study was to report our experience in the surgical man- agement and outcomes of ACC patients.
MATERIALS AND METHODS: A retrospective observa- tional study was performed in a cohort of ACC patients who had undergone surgical resection (open or laparo- scopic approach) and were followed up at our tertiary
a
CORRESPONDENCE
Jorge Huguet Department of Urology Fundació Puigvert Autonomous University of Barcelona Carrer de Cartagena 340-350 08009 Barcelona (Spain)
Accepted for publication: February 6th, 2021
hospital. Patients with localized or locally advanced dis- ease were included in the analysis. All medical records, including clinical, surgical, pathologic, and follow-up data, were collected and analyzed.
RESULTS: A total of 19 ACC patients were managed at our center between August 1990 and August 2013. The median age at diagnosis was 50.5 years (range 19-72), and most patients were males. Abdominal pain was the most common clinical presentation (n=9, 47.4%). Abdominal contrast-enhanced computed to- mography (CT) was performed in all cases. Only 3 tu- mors (15.8%) were functional and most were stage II at diagnosis (n=9, 47.4%). No patient presented metasta- sis. Of the 19 patients, 18 (94.7%) underwent surgery with curative intent, while one (5.3%) received adjuvant radiotherapy (ART). The open approach was used in 17 patients (89.5%), while the remaining 2 (10.5%) underwent laparoscopy. Postoperative complications occurred in 8 patients (42.1%); none were of grade IV or V. Median follow-up was 66 months (range 3-312). The majority of patients (n=15, 78.9%) were disease free with surgery alone. None received adjuvant mito- tane therapy (AMT). Four patients (21%) experienced metachronous metastases and 3 (15.8%) local recur- rence after a median time of 10.5 months (range 2-60) and 9.3 months (range 1.5-30), respectively. The 5-year overall survival rate was 47.4%.
CONCLUSIONS: Our findings confirm both the unpre- dictable nature of ACC and the accepted primary role of surgery. The use of adjuvant therapy was less frequent in this series than is supported currently. However, a mul- tidiscipinary approach should be the initial step in the management of this rare malignancy.
Keywords: Adrenalectomy. Adrenocortical carci- noma. Adrenal gland. Adrenal tumors. Surgery.
Resumen .- OBJETIVO: El carcinoma adrenocortical es una enfermedad heterogénea y rara que conlleva un manejo complicado y cuyo pronóstico es malo. Ante una enefermedad localizada el manejo quirúrgico es de elección, observando una tasa de supervivencia a los 5 años del 55% en resecciones completas. Sin embargo, debido a la alta tasa de recurrencias, se requiere com- plementar el manejo con una terapia adyuvante como es el caso del mitotane, un agente adrenolítico, o la radioterapia. En casos de enfermedad avanzada la te- rapia de elección incluye una pauta de quimioterapia combinada. El objetivo del presente estudio es reportar nuestra experiencia en el manejo quirúrgico y resultados obtenidos de los pacientes con diagnóstico de carcino- ma adrenocortical.
MATERIALES Y MÉTODOS: Se realizó un estudio ob- servacional de una cohorte de pacientes diagnostica- dos de carconinoma adrenocortical que requirieron un manejo quirúrgico (abierto o laparoscópico) y que realizaron su seguimiento en nuestro hospital terciario. Se incluyó a pacientes con enfermedad localizada y localmente avanzada en el análisis. Todos los dados clí- nicos, quirúrgicos, patológicos y de seguimiento fueron recolectados para el análisis.
RESULTADOS: Entre agosto del 1990 y agosto del 2013 un total de 19 pacientes diagnosticados de carcinoma adrenocortical fueron tratados en nuestro centro. La mediana de edad al diagnóstico fue 50,5 años (rango 19-72), siendo la mayoría hombres. El síntoma inicial mas frecuente fue el dolor abdominal (n=9, 47,4%). Una tomografía computarizada con con- traste fue realizada en todos los casos. Sólo 3 tumores (15,8%) eran funcionales y la mayoría correspondía a un estadio Il al diagnóstico (n=9, 47,4%). Ningún paciente presentaba metástasis. De los 19 pacientes, 18 (94,7%) requirieron cirugía con intención curativa, mientras que a uno (5,3%) se le realizó radioterapia adyuvante. El abordaje abierto se usó en 17 pacientes (89,5%), mientras que a 2 pacientes (10,5%) se les rea- lizó una técnica laparoscópica. Complicaciones post- quirúrgicas ocurrieron en 8 pacientes (42,1%), de las cuales ninguna fue de grado IV o V. La mediana de se- guimiento fue de 66 meses (rango 3-312). La mayoría de los pacientes (n=15, 78,9%) permanecieron libres de enfermedad únicamente con un manejo quirúrgico. Ninguno recibió terapia adyuvante con mitotane. Cua- tro pacientes (21%) presentaron metástasis metacróni- cas y 3 (15,8%) recurrencia local tras una mediana de tiempo de 10,5 meses (rango 2-60) y 9,3 meses (rango 1,5-30), respectivamente. La tasa de supervivencia glo- bal a los 5 años fue del 47,4%.
CONCLUSIONES: Nuestros resultados confirman tanto la naturaleza impredecible del carcinoma adrenocortical como la aceptación del rol primario de la cirugía en su manejo. El uso de un agente adyuvante fue menos frecuen- te en esta serie respecto a lo respaldado actualmente. Sin embargo, un manejo multidisciplinar debería ser el primer paso a seguir en el tratamiento de esta rara enfermedad.
Palabras clave: Adrenalectomía. Carcinoma adrenocortical. Glandula suprarenal. Tumores adre- nales. Cirugía.
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex (1) that poses man- agement challenges due to its heterogeneous biology and presentation, and its frequently unpredictable behavior. For these reasons a multidisciplinary ap- proach to disease management is required. The annu- al incidence ranges between 0.7 and 2 cases per mil- lion (2,3). When ACC is suspected, it is essential to perform biochemical, hormonal, and imaging studies comprising computed tomography (CT) or magnetic resonance imaging (MRI). Prognosis is influenced by clinical characteristics, such as patient age, as well as by pathologic (e.g., initial tumor stage, resection margin status, Ki67 proliferation index) and molecu- lar factors, but overall the prognosis is poor, with a reported 5-year overall survival (OS) of 60-80% for stage I and up to 13% for stage IV ACC (4).
Surgery is currently considered the first-line treatment for localized disease (stages I-III) and has a curative intent. The risk of recurrence is reduced if the surgery is performed by skilled surgeons in high-vol- ume centers (5). In cases with negative resection mar- gins, the reported 5-year survival rate is 55% (6). Open adrenalectomy is the recommended technique for tumors >6 cm or when locoregional infiltration is suspected (7), while the laparoscopic approach can be used in patients with smaller tumors.
There is a high risk of recurrence following complete surgical resection (about 60-70%) even if the surgery is performed in a referral center, and ad- juvant therapies are consequently needed. Mitotane, an adrenolytic drug, is the most common agent for this purpose; current guidelines recommend its use in high-risk patients (stage III, or R1-Rx resection, and/ or Ki67 >10%) (8,9), in whom it yields improved outcomes (10). On the other hand, for advanced inoperable and metastatic ACC the first line thera- py is mitotane alone or a combined chemotherapy with Etoposide, Doxorubicin, Cisplatin and Mitotane (EDP-M) (9).
Despite the recent advances in our knowl- edge of this malignancy, its management remains a serious problem.
In this analysis, we describe the clinical char- acteristics, treatment, and oncologic outcomes of ACC patients followed up at our tertiary expert cen- ter, and relate our experience to other reports in the literature.
MATERIALS AND METHODS
This retrospective observational study was conducted in a cohort of patients with histologically proven ACC who underwent surgery at our center. Patients with localized or locally advanced disease were enrolled in the analysis. All data (clinical, demo- graphic, surgical, and follow-up) were retrospectively collected from our archives. Imaging and pathology records were also extracted to evaluate the tumor characteristics (e.g. Ki67 proliferation index and his- tologic scores).
Tumor size was defined as the largest diam- eter depicted on CT axial reconstruction. The Europe- an Network for the Study of Adrenal Tumors (ENSAT) grading system (Table I) was used for tumor staging (4). Postoperative complications were reported ac- cording to the Clavien-Dindo classification system (11). Resection margins were described according to the histopathologic and surgical reports, as either RO (microscopically margin-negative resection) or R1 (macro- or microscopically margin-positive resection). A patient was considered disease free after surgical treatment in the absence of macro- and microscopic residual disease. OS was defined as the interval be- tween diagnosis and death.
Statistical analysis was performed using IBM SPSS for Mac v.22 (IBM SPSS Corp.) Results are de- scribed as median (range), while categorical vari- ables are shown as frequencies and percentages. Student’s t-test was using to compare variables. The statistical significance was set at p<0.05.
RESULTS
A total of 19 patients underwent surgery for ACC at our tertiary center between August 1990 and August 2013. Table Il reports the clinical and patho- logic characteristics of the patients of our series. The median age at diagnosis was 50.5 years (range 19- 72), and most patients were males (n=11, 57.9%). The most frequent clinical presentation was abdomi- nal pain (n=9, 47.4%), while an incidentaloma was detected in six patients (31.6%) without correlation with tumor size. Hormonal hypersecretion was discov- ered in three patients (15.8%); two with aldosterone excess and one with cortisol excess, representing the clinical presentation in only one patient (5.3%). However, two patients (10.5%) were not assessed for endocrine status at baseline because of lack of symp- toms of hormone overproduction. Abdominal con- trast-enhanced CT scan was performed in all cases. No patient presented metastatic disease at diagnosis. Most of the tumors were stage II (n=9, 47.4%).
Treatment and follow-up
The median time to surgery from the detec- tion of ACC on CT scan was 63.5 days (range 7-720 days). A total of 18 patients (94.7%) underwent sur- gery with curative intent, while only one (5.3%) with R1 received adjuvant radiotherapy (ART) of the adre- nal bed. An open thoracoabdominal approach was
| ENSAT stage | Definition | |
|---|---|---|
| I | T1, N0, M0 | T1: tumor ≤5 cm, limited to the adrenal gland |
| II | T2, N0, M0 | T2: tumor >5 cm, limited to the adrenal gland |
| III | T1-2, N1, MO or | T3: tumor of any size with infiltration into surrounding tissue |
| T3-4, NO-1, MO | T4: tumor of any size with invasion into adjacent organs or venous | |
| IV | T1-T4, N0-N1, M1 | tumor thrombus in vena cava or renal vein |
| N0: No positive regional lymph node metastasis N1: Positive regional lymph node(s) M0: No distant metastasis M1: Distant metastasis |
used in the majority of cases (n=17, 89.5%), while laparoscopy was performed in the remaining two (disease stage I and II). Most patients (n=10, 52.6%) underwent adrenalectomy alone (one laparoscopy) with transperitoneal access. Of six patients (31.6%) who underwent nephrectomy with adrenalectomy, two (10.5%) also presented synchronous renal cell carcinoma (RCC; one clear cell RCC pT2 and one chromophobe RCC pTla), as proven at the postop- erative pathology examination. Adrenalectomy plus thrombectomy was performed in two patients (10.5%) due to the presence of inferior vena cava thrombus (disease stage III). The remaining patient underwent nephrectomy and resection of the adrenal mass (T4, stage III). Complete resection was achieved in 17 pa- tients (89.5%) in whom surgery was the only treat-
ment, while R1 was detected in two patients (10.5%) (disease stage III). A total of 15 patients (78.9%) were disease free with surgery alone. None of the operated patients received adjuvant mitotane therapy (AMT) either as monotherapy or in combination with other treatment modalities.
The median estimated blood loss was 680 ml (range 50-4600 ml). A total of seven (36.8%) patients required intraoperative blood transfusions. Postoper- ative complications according to the Clavien-Dindo grading system occurred in eight patients (42.1%): three were grade I, two grade II, and three grade IIIa (Table III). The median length of hospital stay was 10 days (range 3-31 days). Neither of the two patients in whom the laparoscopic approach was used expe-
| Variable | |
| Age, yr (median, range) | 50.5 (19-72) |
| Sex, n (%) | |
| o Female ☐ | 8 (42.1) |
| o Male ☐ | 11 (57.9) |
| BMI, kg/m2 (median, range) | 25 (19.8-50.8) |
| ASA score at treatment (median, range) | 2 (1-4) |
| CCI (median, range) | 3 (2-8) |
| Clinical presentation, n, (%) | |
| o Suspected hormonal excess ☐ | 1 (5.3) |
| o Abdominal/back pain ☐ | 9 (47.4) |
| o Incidentaloma ☐ | 6 (31.6) |
| o Constitutional symptoms ☐ | 3 (15.8) |
| Non-functional tumors, n (%) | 14 (82.4) |
| Tumor size, cm (median, range) | 10 (0.5-12) |
| Side, n (%) | |
| Left | 11 (57.9) |
| Right | 8 (42.1) |
| Pathologic T stage, n (%) | |
| o T1 ☐ | 2 (10.5) |
| o T2 ☐ | 9 (47.4) |
| o T3 ☐ | 2 (10.5) |
| o T4 ☐ | 6 (31.6) |
| Pathologic N stage, n (%) | |
| o N0 ☐ | 17 (89.5) |
| o N1 ☐ | 2 (10.5) |
| Tumor staging, n (%) | |
| o I ☐ | 2 (10.5) |
| o II ☐ | 9 (47.4) |
| o III ☐ | 8 (42.1) |
| o IV ☐ | 0 |
ASA: American Society of Anesthesiologists; BMI: body mass index; CCI: Charlson Comorbidity Index.
rienced postoperative complications or metachronous metastasis. One of these patients died from non-tu- mor-related causes, while the other is still alive.
The median follow-up was 66 months (range 3-312 months). Metachronous metastases occurred in four patients (21.1%), among whom one (5.3%) was surgically managed for a 5-cm pelvic mass very close to the right psoas muscle and sigmoid colon. The median time to occurrence of metachronous me- tastasis was 10.5 months (range 2-60 months). These patients had a significantly lower mean survival time than those without metachronous metastasis after sur- gery (27.1 vs. 115.2 months, p=0.036). A total of three patients (15.8%) experienced locally disease relapse, with a median time to recurrence of 9.3 months (range 1.5-30 months). At last follow-up, 13 (68.4%) patients were still alive. After a median fol- low-up of 5.5 years, the median OS was 6.9 years with an estimated 5-year OS rate of 47.4%.
DISCUSSION
A limited number of ACC patients were sur- gically managed at our experienced center over 23 years, stressing the low incidence of this malignancy. Most of our patients were referred because of abdom- inal pain, but in a considerable proportion the finding of ACC was incidental.
According to the literature, surgery was the treatment of choice, and complete resection was achieved in 17 (89.5%) patients.
With a median follow-up of 66 months, most patients (78.9%) were disease free with surgery
alone and no patients received AMT. Local relapse and metachronous metastases occurred in three and four patients, respectively. The 5-year OS rate was of 47.4%.
The demographic and clinical characteris- tics of our cohort are comparable to those in other published studies, with a median age at diagnosis of 40-60 years (12) and a unilateral presentation. All ACCs were sporadic. Literature reports cases of ACC as part of endocrine and familial syndromes (e.g. Li-Fraumeni, Lynch, multiple endocrine neoplasia type 1, familial adenomatous polyposis, and Beckwith- Wiedemann syndromes) (3). However, we did not find any association in our cohort.
On the other hand, in comparison with pre- vious reports (1,13,14), we recorded a higher preva- lence in males than females and a lower incidence of hormone hypersecretion. In our cohort, only one pa- tient (male) presented hormonal excess as the initial presentation, and only three (17.6%) patients showed hormonal overproduction at subsequent investigation; in contrast, other analyses have reported rates of 42- 76% (1,14). Hyperaldosteronism with hypertension and cortisol excess were reported in two and one cases, respectively. However, the hormonal status was not evaluated in two patients (10.5%) due to the lack of symptoms suggestive for hormone excess. ACC may present a single autonomous hormone or a mixed overproduction. About 50-60% of ACC pa- tients have hormonal hypersecretion, with hypercor- tisolism (Cushing syndrome) being the most frequent finding (50-70%), followed by excess of androgens with women virilization (20-30%), estrogens with men feminization (5%), and mineralocorticoids (2-3%) (15). The only patient with cortisol-producing ACC
| Complications | n (%) | Treatment |
|---|---|---|
| Grade I | ||
| o Vomiting | 2 (10.5) | Serotonin 5-HT3 receptor antagonists |
| o Atelectasis and 7-cm hematoma in the surgical bed | 1 (5.3) | Conservative treatment (analgesics) |
| Grade II | ||
| o Atelectasis with pneumonia | 1 (5.3) | Antibiotic therapy |
| o VI cranial nerve palsy with bilateral transient diplopia | 1 (5.3) | Anti-inflammatory and muscle relaxant drugs |
| Grade IIIa | ||
| o Pleural effusion | 1 (5.3) | Thoracentesis |
| o Intra-abdominal collection | 2 (10.5) | Drain placement |
| Grade IIIb | 0 | |
| Grade IV | 0 | |
| Grade V | 0 |
experienced both local relapse and metachronous metastasis, with a cancer-specific survival (CSS) of 12 months; this accords with literature reports of a worse prognosis and higher recurrence rates of functioning tumors (14,16). However, in our series non-functional disease was not related to a significantly better OS compared with hormonally active tumors (p=0.186), probably because it may present at a higher initial clinical stage. This is itself a factor associated with poor survival (14). Most of our patients (n=9, 47.4%) exhibited abdominal and/or back pain as the clinical presentation, and among these patients, seven had locally advanced disease (T3-4, stage III), with a tu- mor larger than 5 cm in six cases. Furthermore, in our cohort the rate of incidental detection of ACC on im- aging was higher than previously reported (10-15%) (16). Table IV summarizes the hormonal diagnostic work-up in patients with suspected or proven ACC, as reported by Fassnacht et al. (9).
Surgical management is the first option in ACC, with a curative intent for stage I-III disease. All patients in our cohort (with disease stage I-III) under- went surgery as primary treatment. Only one patient with Hodgkin lymphoma underwent surgery with debulking plans after 24 months from ACC inciden- tal detection, once the hematologic disease was clin- ically stabilized. This patient received ART (total dose 60 Gy) without achieving a disease-free status for the occurrence of metachronous metastasis. A complete resection of the primary tumor (R0) was performed in
most of the patients, with a 5-year OS rate of 47.4%, which is close to that reported in the literature (6). An open approach is generally preferred, even if lapa- roscopy may be proposed for tumors <6 cm and in selected patients (17,18). Although a comparison be- tween the two surgeries in ACC <6 cm is difficult, due to the lack of trials with this aim (16,19), literature reports have suggested a shorter time to locoregional recurrence and a worse OS after minimally invasive resection (20,21). In our series the open approach was preferred over the laparoscopic one, that was used in 2 (10.5%) cases. No high grade post-oper- ative complications occurred nor local relapse/meta- chronous metastasis were recorded in these patients. The median estimated blood loss during surgery was 680 (50-4600) ml. Seven (36.8%) patients required intraoperative blood transfusions, including one case of considerable bleeding during surrenalectomy and thrombectomy for a large and highly vascularized adrenocortical mass with inferior cava thrombus (dis- ease stage III).
Because of anatomical closeness between adrenal gland and kidney, it is not uncommon the involvement of the renal parenchyma in case of ACC. On the other hand, the presence of synchronous ACC and RCC is described in literature (22). Despite the rarity of this event, this condition occurred in 2 pa- tients of our series, being the immunohistochemical analysis able to differentiate among the two histo- types of tumor.
| Hormonal work-up | Test |
|---|---|
| Glucocorticoid excess | 1 mg Dexamethasone suppression test Characterisation of glucocorticoid excess: o 1 mg Dexamethasone suppression test o free cortisol in 24-h urine o basal ACTH (plasma) |
| Sex steroids and steroid precursors | o DHEA-S o 17-OH-progesterone o Androstenedione o Testosterone (only in women) o 17-B-Estradiol (only in men and postmenopausal women) o 11-Deoxycortisol |
| Mineralcorticoid excess | o Potassium |
| o Aldosterone/renin ratio | |
| Exclusion of a pheochromocytoma | Fractioned metanephrines in 24h urine or free plasma-metanephrines and methoxytyramine |
ACTH: Adrenocorticotropic hormone; DHEA-S: Deidroepiandrosterone Solfato.
One of the pathologic features influencing prognosis in ACC is the Ki67 proliferation index (23). In our analysis, it was assessed in few pathology re- ports, in which it was <10%. According to the liter- ature, better outcomes are achieved at values <10% (24), and our patients experienced neither metastasis nor local recurrence, being still alive and “cancer free”.
Recent reports have suggested the efficacy of mitotane in improving oncologic outcomes (OS and CSS) in ACC (8,10), and the high risk of recurrence even after radical surgery supports an adjuvant role for this agent. Our records, however, showed that no patient received mitotane, probably due to the lack of a high level of evidence for its use at that time (25,26). Only one patient who underwent adrenalectomy with vena cava thrombectomy for stage III disease, and who had a metachronous liver metastasis, was a can- didate for AMT, but ultimately it was not administered due to the low benefit/risk ratio. According to the European Society of Endocrinology (ESE) panel (15) and the ESMO Clinical Practice Guidelines (9), the use of ART, started as soon as clinically possible fol- lowing surgery, may be reasonable especially in R1/ Rx resection or in stage III disease. In our series, one R1/stage III patient received ART with a total dose of 60 Gy directed to the tumor bed (30 fractions of 2 Gy each), in line with the ESE recommendation; such a dose is intended to prevent the development of local relapse but not of distant spread (27,28,29).
Although the guidelines recommend fol- low-up for at least 5 years (9,15), the majority of our patients (n=10, 52.6%) underwent medical controls for a longer period, in accordance with a contempo- rary multicenter study that describes surveillance for 5 years as insufficient (30).
In summary, since the management of ACC is variable and the subject of debate, it was our aim was to evaluate the treatment modalities and outcomes in patients referred to our tertiary volume center. Our findings, even if obtained in a small cohort, indicate both the primary role of surgery in the treatment and the heterogeneous nature of the disease. We found a higher occurrence in males than females and var- ious clinical characteristics. Furthermore, the limited number of cases over the years, with the last patient operated in 2013, supports the definition of this ma- lignancy as an orphan disease (1), despite it being managed in a referral center.
The major limitation of this study was the aforementioned small cohort of patients and, in ad- dition, since its retrospective nature, it lacks some re- cords due to loss of data over a long period.
CONCLUSIONS
This single-institute analysis supports the defi- nition of ACC as a rare and variable malignancy with a poor outcome. Our data show the prevalent role of surgery with curative intent, although a multidisci- plinary approach is recommended.
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