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Surgical treatment of adrenal carcinoma
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REVIEW
Surgical treatment of adrenal carcinoma S. Gaujoux a,b,c,d,∗, M. Weinandt a,b, S. Bonnet a, V. Reslinger a, J. Bertherat b,c,d,e, B. Dousset a,b,c,d a
Service de chirurgie digestive, hépato-biliaire et endocrinienne, hôpital Cochin, AP — HP, 75014 Paris, France b Université Paris-Descartes, 75014 Paris, France c Inserm U567, CNRS UMR8104, institut Cochin, département d’endocrinologie, métabolisme et cancer, 75014 Paris, France d Centre expert national cancer de la surrénale, 75014 Paris, France e Service d’endocrinologie, AP — HP, hôpital Cochin, 75014 Paris, France
KEYWORDS Adrenocortical carcinoma; Adrenal incidentaloma; Adrenal gland; Adrenalectomy
Summary Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The presence of a mass syndrome or signs of hormonal hypersecretion often lead to its discovery, but more and more frequently, adrenocortical malignancy is fortuitously discovered as an incidentaloma. Cross-sectional imaging (CT and MRI) often points to the malignant character of the adrenal mass. Needle biopsy is contraindicated. Laboratory testing showing combined hypersecretion of cortisol, androgens or inactive corticosteroid precursors is highly suggestive of ACC. An 18F-fluoro-deoxyglucose Positron Emission Tomography (PET scan) should be performed to evaluate the malignancy of an adrenal mass and to detect regional or distant metastases. Although the majority of ACC are diagnosed at a locally advanced or metastatic stage, radical resection offers the only hope of cure. The peri-operative management of patients with ACC is not yet standardized. The aim of this review is to summarize the actual knowledge of the surgical management of ACC. © 2017 Elsevier Masson SAS. All rights reserved.
Introduction Although the incidental discovery of adrenal masses by cross-sectional imaging now occurs frequently, adrenocortical carcinoma (ACC) remains a rare tumor, with an estimated annual incidence in Europe and North America of 0.5 to 2 cases per one million inhabitants [1]; ACC accounts for 0.04—0.2% of cancer deaths. ACC is one of the most dangerous malignant endocrine tumors with metastatic disease found in 20—40% of patients at the time of diagnosis, mostly involving liver, lung or bone [2]. Radical resection offers the
∗ Corresponding author at: service de chirurgie digestive, hépatobiliaire et endocrinienne, hôpital Cochin, 27, rue du Faubourg-SaintJacques, 75679 Paris cedex 14, France. E-mail address: [email protected] (S. Gaujoux).
only hope of cure, but overall survival at five years varies between 30 and 40% [3] and depends mainly on tumor stage. Stage is now evaluated according to the European Network for the Study of Adrenal Tumors classification (ENSAT) [4]. Despite recent recommendations from the European Society of Endocrine Surgeons (ESES) and ENSAT [5], several questions concerning the surgical management of ACC remain unanswered including: • the need for lymph node dissection and its extent; • the place of the laparoscopic approach; • the indications for resection of loco-regional recurrences and resectable metastases; • the place of adjuvant mitotane treatment. This review is devoted to the surgical management of sporadic ACC in adults, which is generally associated with a worse prognosis than ACC occurring in children [6].
http://dx.doi.org/10.1016/j.jviscsurg.2017.06.010 1878-7886/© 2017 Elsevier Masson SAS. All rights reserved.
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Key points • Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis; metastatic disease (hepatic, pulmonary or bone) is present in 20—40% at diagnosis. • Clinical or subclinical hormonal hypersecretion is present in 75% of cases, which makes it possible to orient the diagnosis. • Approximately 10% of ACC are discovered fortuitously (incidentaloma). • The only indication for adrenal biopsy (pheochromocytoma must first be ruled out) is to eliminate the diagnosis of secondary adrenal metastasis, if necessary. • The surgical treatment of ACC is wide en-bloc resection. Nephrectomy is not necessary in all cases. • Lymphadenectomy must include peri-adrenal and peri-renal fat nodes of the renal hilum (although this approach is disputed). • The laparoscopic approach is conceivable only for lesions smaller than 6 cm, stage I or II, and performed by highly experienced teams.
Epidemiology and clinical presentation There are two frequency peaks, the first in childhood, the second between the fourth and fifth decades; there is a slight female predominance (sex ratio 1.5) [2,7]. There are no proven environmental risk factors. Although tobacco and oral contraceptive medications have been suggested as risk factors, their roles appear to be negligible. ACC’s are sporadic in more than 95% of cases, although some hereditary diseases such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome and Lynch syndrome [8] are associated with an increased risk of ACC development. Cases have also been reported in patients with Multiple Endocrine Neoplasia Type I or familial adenomatous polyposis [9], but no certain causation can be imputed. Three main clinical pictures may be seen at presentation: • nearly half of ACC’s are associated with clinical signs of hormonal hypersecretion, which entails, by decreasing frequency, a mixed hypersecretion of cortisol and androgens, an isolated hypersecretion of cortisol, virilization due to androgenic hypersecretion, or other varied associations of steroidal hypersecretion [2]. ACC’s that secrete aldosterone, estradiol or corticosteroid precursors alone are more rare. Overall, complete testing for adrenal hormones is likely to reveal clinical or subclinical hypersecretion in 75% of the cases, which makes it possible to orient the diagnosis [2]; • presentation with a palpable mass is frequent in nonsecreting ACC. Palpable ACC’s have an average weight of > 500 grams and a diameter of 12—15 cm on pathological exam [2,10]. Symptoms may include abdominal or lumbar pain, palpable mass, weight loss, tumor fever, or signs of inferior vena cava (IVC) compression. It should be noted that ACC patients maintain a good general clinical condition for a long time, explaining the frequency of late diagnosis of these tumors; • more rarely, the diagnosis of ACC is made during the investigation of an incidentaloma, that is to say, following the fortuitous discovery of an adrenal tumor on an imaging study carried out for another indication. Currently, about 10% of ACC’s are discovered incidentally, and these are
most often in early stages [2]. It is important to note that the probability of malignancy increases with the size of the adrenal mass [11]: malignancy is extremely rare for lesions < 4 cm and about 15—20% for lesions > 6 cm. The frequency of incidental diagnosis seems to be increasing [3], although this observation is not always confirmed, particularly in the United States [12]. The discovery of malignant lesions at an early stage is a major challenge in the management of incidentalomas. Finally, it is not uncommon for ACC to be discovered in the context of the assessment of its metastatic lesions.
Confirmation of malignancy when faced with an adrenal mass suspicious for ACC Above all, every adrenal mass must be subjected to specific clinical, laboratory and radiological assessment, the details of which are beyond the scope of this review.
Clinical and laboratory criteria Presentation with a voluminous palpable adrenal mass causing pain and signs of caval compression, while not specifically diagnostic, is highly suspicious of malignancy. Laboratory findings of a combined hypersecretion of cortisol and androgens, the presence of androgens with virilization, or estrogens with feminization, or the hypersecretion of inactive steroid precursors (17-hydroxy-progesterone, Deoxy cortisone, compound S) are very suggestive of the diagnosis of ACC [2].
Radiological criteria On CT, the typical aspect of ACC is that of a large adrenal mass, > 6 cm in diameter, with poorly-defined borders, containing areas of intra-lesional necrosis, with heterogeneous contrast uptake after injection, and possibly containing calcifications due to intra-tumoral hemorrhages. The presence of aorto-caval or para-aortic lymphadenopathy, invasion of adjacent organs, thrombus within the IVC or left renal vein, or hepatic and/or pulmonary metastases strongly suggest the diagnosis of ACC. For intermediate-sized lesions between 3 and 6 cm, well-established radiological CT criteria suggest malignancy. For this purpose, millimeter-thin slice CT should be performed, with measurement of the non-injected density and the density at one minute and 10 minutes after contrast injection. The density ratio allows calculation of the wash-out percentage. Several concordant studies have established that the vast majority of malignant lesions have a spontaneous density greater than 20 Hounsfield units (HU) with relative or absolute washout less than 40% or 60% at 10 minutes [13], respectively. CT can exclude the diagnosis of benign adenoma with a sensitivity and specificity greater than 90% [14]. On MRI, ACC appears as a hypo- or iso-intense tumor on the T1 sequences with heterogeneous contrast enhancement after gadolinium injection [13], and an iso- or hyper-intense signal on T2 sequences. Morphologic findings on MRI that favor the diagnosis of malignancy are similar to those observed on CT scan [15]. Benign adrenal adenomas, unlike ACC’s, have high lipid content. With in-phase sequences and out-of-phase sequences (fat subtraction), MRI can differentiate adenomas from suspected malignant lesions with excellent sensitivity (85—100%) and specificity (92—100%) according to reported series [13,14]. For adenomas, there
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Surgical treatment of adrenal carcinoma is a drop in intensity in out-of-phase imagery greater than 20%.
Scintigraphic criteria Studies have reported that 18-fluoro-desoxyglucose PET scan has a high sensitivity (95—100%) and specificity (91—94%) to differentiate benign adrenal cortical tumors from ACC [16,17]. A multicenter prospective study of 77 adrenal tumors found the sensitivity and specificity for distinguishing adenoma from ACC were 100% and 88%, respectively, using a relative adrenal/liver SUV ratio (standard uptake value) of 1.45 [18]. Several studies [19,20] have since confirmed the value of PET scan in the management of ACC, although using different criteria or cut-offs [19,21].
3 since wide resection may entail the need for nephrectomy, although in practice it is rarely necessary. The hormonal assessment must be complete in order not to underestimate a subclinical hypersecretion; this is particularly important as a tumor marker for longterm follow-up and for immediate post-operative hormone replacement. This includes 8 am cortisol level, the urine free cortisol, the cyclical level of serum or salivary cortisol (the midnight time being the most informative), ACTH assay, 1 mg dexamethasone suppression test, aldosterone and plasma renin activity, testosterone, Dehydroepiandrosterone, delta-4 androstenedione, estradiol, intermediate derivatives (17-hydroxyprogesterone, Deoxycorticosterone, compound S), and urinary methoxylated derivatives.
Imaging studies Summary For any adrenal tumor suspected of being an ACC, thoracoabdomino-pelvic CT, MRI and 18F-fluoro-desoxyglucose PET scan should be systematically performed. If there is invasion of the IVC, these examinations must include delayed vascular sequences to properly visualize the relationship of the lesion with the IVC. Performance of pre-operative biopsy is generally contraindicated because of its low sensitivity and specificity for the diagnosis of ACC and the theoretical risk of capsular rupture and seeding on the needle track. The only indication for pre-operative adrenal biopsy is to obtain histological evidence of a secondary adrenal metastasis from a known primary or adrenal lymphoma, if doubt persists after all the above-mentioned investigations. Before needle biopsy, the diagnosis of pheochromocytoma must be excluded [22].
Pre-operative evaluation The pre-operative evaluation includes clinical, laboratory and hormonal evaluation, and imaging studies to specify the stage, the secretory profile, the resectability of the tumor, and the surgical risk.
Clinical evaluation Clinical evaluation includes assessment for a palpable mass, peripheral signs of hormonal hypersecretion (Cushingoid syndrome, virilization, gynecomastia), signs of IVC compression (which increases the risk of peri-operative thrombophlebitis especially in the case of excessive hormone secretion), and lower extremity edema for right-sided ACC, or segmental portal hypertension for left-sided ACC. The clinical examination should also assess nutritional status, WHO status and co-morbidities prior to major surgery.
Biochemical and hormonal evaluation Pre-operative blood chemistries are important to detect: hyperglycemia (hypercorticism), hypokalemia (excess mineralocorticoid secretions or severe hypercorticism), hypoalbuminemia and disorders of hemostasis (malnutrition), anemia (inflammatory response, portal hypertension), thrombocytopenia (hypersplenism due to segmental portal hypertension), or renal insufficiency. In patients with renal impairment, measurement of creatinine clearance and fractional clearance by MAG3 scintigraphy are important
The imaging assessment includes thoraco-abdominal angioCT with contrast injection, abdominal MRI, and PET scan. These examinations allow for definitive diagnosis, evaluation of loco-regional or metastatic extension, and assessment of resectability (vascular anatomy, venous extension). In the case of a large IVC extension, transesophageal cardiac ultrasound is essential to determine the upper level of a tumor thrombus [23]. A lower limb venous echo-Doppler can be performed pre-operatively to rule out lower extremity thrombophlebitis, whose risk is increased with large tumors, IVC compression, hypercorticism or hyperestrogenism.
Surgical treatment Indications for surgery The dogma remains that surgical excision is indicated for any potentially resectable ACC [24,25]. Based on the now widely used ENSAT classification, (Table 1), adrenalectomy encompassing the cellular and nodal surroundings is the rule for stage I and II tumors. Resection is also indicated in ENSAT stage III ACC’s with evidence of loco-regional invasion, including nodal extension to neighboring organs or the vena cava or in case of loco-regional recurrences. In most cases, the resection of ACC is a complex open surgery that may require an extended excision to access neighboring organs that may be invaded. However, ACC surgery can be performed by laparoscopy for lesions less than 6 cm at expert centers. The value of resection for stage IV metastatic ACC is much more debatable since recidivism is the general rule [26]. Synchronous metastases, usually to the liver or lung, are present in 17—42% [3,7,10,27]. Palliative chemotherapy for stage IV ACC has very limited efficacy. A prospective randomized international study (FIRM-ACT) determined that the gold-standard first-line treatment is combination chemotherapy with etoposide, doxorubicin, cisplatin and mitotane [28]. In an Italian phase II trial, 10 of the 72 patients (13%) with non-resectable metastatic ACC could be operated secondarily following an objective response to mitotane-associated chemotherapy [29] (Table 1).
Operative strategy In view of the rarity of ACC, these lesions should be managed in expert centers. However, there is no consensus on what constitutes an expert center. Different thresholds of
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ENSAT classification.
Stage
ENSAT
Definition
I II III
T1 T2 T1 T3
IV
M1
T1: tumor ≤ 5 cm, localized T2: tumor >5 cm, localized T3: tumor infiltrating adjacent adipose tissue T4: tumor infiltrating adjacent organs, or thrombus within the renal vein or IVC Metastases
(≤ 5 cm), N0, M0 (> 5 cm), N0, M0 or T2, N1, M0 or T4, N0/1, M0
activity have been proposed in the literature, varying from 4 to 10 adrenalectomies for ACC or from 10 to 20 laparoscopic adrenalectomies [30—32]. Beyond the obvious necessity of technical expertise, multidisciplinary management of these patients is also necessary, including surgeons, endocrinologists, oncologists, radiologists, pathologists, biologists and nuclear medicine specialists. The role of laparoscopy for stage I and small stage II ACC remains a subject of debate [33,34]. While there is consensual agreement among experts that the laparoscopic approach has become the reference technique for the removal of benign adrenal tumors [35], this is also increasingly discussed for ACC. Reported series are limited and heterogeneous [33,34,36] but some teams feel that laparoscopy has been associated with an increased risk of capsular rupture [34], loco-regional recurrence or peritoneal carcinomatosis. The grave implications of capsular rupture and the overall poor prognosis of ACC should lead the surgeon to favor quality of excision over the choice of the approach. However, for stage I and small stage II ACC, laparoscopic resection of ACC can be considered, provided that a confirmed diagnosis of malignancy is made pre-operatively and the operative team has a wide experience with laparoscopic adrenal surgery and a rigorous technique (removal of the entire peri-adrenal cellulo-fatty envelope without tumor spillage, skeletonization of the renal vessels, extraction of the specimen in a bag), and that this approach is only used for small lesions < 6 cm [5]. If there is any doubt pre-operatively or intra-operatively, initial open surgery or conversion should be the rule. Most ACC’s present as locally advanced stage II, III or IV tumors depending on the presence of loco-regional or metastatic spread, and with a weight and size that contraindicate the laparoscopic approach. The main objective of the surgical procedure for ACC is to obtain a complete R0 excision without tumor rupture, including at least a nodal dissection of the renal pedicle, in order to minimize the risk of loco-regional recurrence. The risk of tumor invasion should not be underestimated. It increases with the size of the ACC, its deeply placed anatomical situation, the existence of a fragile capsule, the presence of hypervascular adhesions to the adjacent parenchymatous organs, and increased tissue fragility in the case of cortisol hypersecretion; these factors require a choice of surgical approach that allows good exposure and atraumatic tumor manipulation [37,38]. The opening of invaded anatomical planes between the ACC and neighboring organs (kidney, diaphragm, right liver, spleen, left pancreas) appears to be an important factor in loco-regional recurrence, due to capsular invasion, hemorrhage, or insufficient margins [39—41]. This invasion is often difficult to determine pre- or intra-operatively. In 30% of cases, tumors that were initially classified as stage II are reclassified stage III after pathological examination has revealed the invasion of the adjacent tissues [42]. The excision of locally advanced adrenal tumors may
therefore require en bloc surgery that includes not only the tumor, but also the kidney, adjacent invaded organs, and the entire continuity of peri-adrenal and perirenal fat. There are only scant data from the literature showing a benefit of extensive lymph node dissection. However, one study showed that ACC was associated with a 73% lymph node invasion rate, and a recent study suggests that ACC resection with clearing of at least 5 lymph nodes was associated with a reduction in the risk of local recurrence and ACC mortality [43]. Lymph node dissection also allows a more accurate staging of the disease, although its influence on survival remains uncertain [44]. Thus, a lymph node dissection should be performed and must include at least peri-adrenal and peri-renal fat including the lymph nodes of the renal hilum. It is less clear and still debated whether there is value to a latero-aortic and inter-aortocaval nodal dissection and such nodal clearing should not be considered as a standard. On the right side, if there is hepatic invasion, resection may require right hepatectomy. On the left side, it may be necessary to divide the pancreatic isthmus to gain access to the spleno-mesenteric venous confluence and the mesenteric arterial take-off from the aorta. In more favorable situations (voluminous stage II), an extended adrenalectomy encompassing the ensemble of the adrenal and peri-renal fat allows a complete locoregional lymph node dissection including the renal hilum and makes it possible to preserve the homolateral kidney (Fig. 1). Nephrectomy is not recommended unless it is necessary to obtain an R0 margin, especially for tumors adjacent to the renal pedicle, regardless of their size. Extension into the IVC occurs in less than 10% of patients; it is usually associated with venous extension of a tumor thrombus most commonly arising in the main adrenal vein, and it occurs more frequently for right-sided ACC (Fig. 2). IVC involvement consists more often of a caval tumor thrombus than direct tumor extension into the venous wall. This is associated with a high risk of hepatic and/or pulmonary metastases [23]. Depending on the upper level of thrombus extension (subhepatic IVC, retrohepatic IVC, suprahepatic IVC), thrombectomy may require supra-renal vena cava clamping under hepatic vascular exclusion with supra-hepatic sub-diaphragmatic or intra-pericardial vena cava clamping, or, in exceptional cases, extracorporeal venous circulation when thrombus extends into the right atrium. [23]. Direct invasion of the IVC wall is often quite limited and accessible to partial caval resection with direct closure or a prosthetic, autologous (peritoneal) or heterologous (bovine pericardium) patch (Fig. 2).
Post-operative management Post-operative morbidity depends directly on the extensiveness of the surgical gesture, but is also strongly
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Figure 1.
Operative view after removal of a stage II ACC and preservation of the kidney. A. Right-sided ACC. B. Left-sided ACC.
Figure 2.
Operative view after removal of a right-sided ACC invading the inferior vena cava.
influenced by cortisol secretion and how well it is controlled pre-operatively [45]. In a North American registry study (SEER) involving more than 2000 patients, post-operative mortality approached 2% [30], confirming the results of another multicenter North American study [46]. In the latter study, the overall morbidity was 37% [46]; morbidity was increased by thoraco-abdomino-pelvic approaches, and in surgery for a secreting tumor. In the immediate post-surgical period, care should be taken to prevent acute adrenal insufficiency, particularly in patients with glucocorticoid secreting tumors. Initial intravenous supplementation (hydrocortisone hemisuccinate) is
followed by oral supplementation of hydrocortisone. One of the risks associated with lymph node dissection at the level of the aortico-caval axis is the occurrence of postoperative lymphorrhea. This can occur late, after the patient has resumed oral alimentation and is manifested by the appearance of an opalescent lymphatic fluid leak, rich in triglycerides, lymphocytes and chylomicrons. If chylous fluid appears in the drain, management includes a strict fatfree diet for a period of six weeks, with supplementation in medium-chain triglycerides, which is absorbed directly by the portal venous network without passing through the lymphatic vessels.
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Pathology and classifications
Place of local treatments
Histological scores
Radiofrequency (RF) ablation has been demonstrated to be feasible and effective in the treatment of primary tumors, hepatic and pulmonary metastases or in the palliative treatment of symptomatic bone metastases. RF therapy may therefore appear to be an alternative to surgical treatment for solitary hepatic or pulmonary metastasis of ACC in patients in whom surgery is contraindicated, although only one very heterogeneous series has been published [58]. In fact, no randomized prospective study has yet proved the equivalence of RF to surgery, particularly in terms of survival.
The histologic definition of whether an adrenal mass is malignant, apart from evident signs of malignancy (metastases, loco-regional invasion, vascular or lymph node involvement), is difficult and is based on different histological scores [47,48]. In clinical practice, the Weiss score is the most widely used (Table 2), while the Bisceglia score is applied to oncocytic tumors [49]. A number of immunohistochemical criteria may also be used as diagnostic tools. Ki-67 is especially important [48—52]; it has major prognostic value either after primary tumor surgery or in the management of metastatic disease. Increasing values of Ki-67 (<10%, 10—19%, and ≥ 20%) are associated with a corresponding decrease in recurrence free and overall survival. Other immuno-histochemical markers include P53, IGF-2, catenin [53] or Cyclin E, but these are not commonly used as histo-prognostic markers.
Staging Various staging systems have been used, but the one proposed by ENSAT is currently the most commonly used [4].
Place of neo-adjuvant and adjuvant therapy Neo-adjuvant chemotherapy There is only one study on the role of neo-adjuvant chemotherapy in the treatment of primary or metastatic ACC, the results of which remain difficult to interpret [59]. Surgery first is the general rule for all primary or metastatic ACC whenever they are resectable.
Mitotane (O, p’DDD)
Re-operation After resection of the primary tumor, 60—85% of the patients will develop loco-regional or metastatic recurrence despite initial surgery that is a priori complete [39—41,54,55]. These recurrences usually occur within two years and are usually not amenable to surgical salvage. The risk of recurrence is influenced by the ENSAT stage and thus the size of the tumor, its Ki-67 status, the association with cortisol secretion, but also the quality of the initial surgical management (in particular, the absence of tumor capsular violation) [39—41,54,55]. However, these recurrences may nevertheless be amenable to curative resection if an R0 resection is still feasible. This must be discussed in the context of a multidisciplinary expert consultation meeting.
Used for the first time in 1959, o,p’DDD or mitotane, ® (Lysodren , HRA-Pharma, France), is the most commonly used adjuvant treatment and the one on which the literature is most abundant. Several series have reported the efficacy of mitotane [7], albeit with response rates less than 25% [60,61]. Mitotane is associated with many side effects and, for maximum efficacy and tolerance, measurement of plasma levels must be performed, which should fall within a narrow therapeutic range of 14—20 mg/L [60]. While the effectiveness of adjuvant mitotane therapy remains limited, the current standard of care is to offer adjuvant mitotane chemotherapy, with serial measurement of plasma levels for all patients [62]. A prospective randomized international trial (ADIUVO) is currently underway comparing mitotane vs. surveillance in ACC patients with low or intermediate recurrence risk, defined as stage I to III tumors with complete excision and Ki-67 <10% (http://www.ensat.org).
Loco-regional recurrences
Chemotherapy
For recurrence in the tumor bed, re-operation is justified if an R0 resection is possible, because up to 40% of the patients are alive five years after R0 excision for this type of recurrence, with a significant improvement in symptoms [56], thus justifying this aggressive attitude [3]. These loco-regional recurrences often invade the right liver, the mesocolon, the diaphragm, or the tail of the pancreas. They may therefore require extensive surgery, especially if this has not been done during the initial procedure.
For a long time, systemic treatment of ACC has been limited to mitotane (o.p’DDD), whose response rates are low; effects on overall survival have not been demonstrated. However, a randomized, multicenter prospective study on chemotherapy of non-resectable ACC stages III and IV (FIRMACT) compared EDP chemotherapy (etoposide, doxorubicin and cisplatin) + mitotane to streptozotocin + mitotane. The final results of this trial showed better response rates and progression-free survival with the EDP + mitotane regimen with equivalent toxicity but no significant effect on overall survival [61].
Metachronous metastasis Metachronous hepatic or pulmonary metastases can be resected [57], when an R0 excision is feasible. Although such metastases are rarely isolated, their resection is more likely to lead to complete surgical extirpation than re-intervention for local recurrences. However, 5-year recurrence-free survival is extremely rare.
Prognosis and prognostic factors Clinical ACC stage at the time of diagnosis and completeness of initial surgery (R0) appear to be the main prognostic factors
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Weiss histo-prognostic score (0—9). A score ≥ 3 is indicative of malignancy.
Histologic criteria
Semi-quantitative evaluation
Score calculation
Mitotic index Atypical mitoses High nuclear grade Low percentage of clear cells Confluent foci of necrosis Diffuse architectural structure Venous invasion Sinusoidal invasion Capsular invasion
> 5/50 high-powered fields Presence or absence Presence or absence < 25% of tumor cells Presence or absence > 33% of the tumor Presence or absence Presence or absence Presence or absence
0 0 0 0 0 0 0 0 0
for survival, but the prognosis remains bleak. Indeed, life expectancy at five years in all stages is generally between 16 and 60% [3,7,63]. In an French multicenter study involving 156 patients published in 1992, Icard et al. reported survival rates 58 to 66% for Stages I and II and 0 to 24% for Stages III and IV [3]. These figures are included in the series of patients followed in our center [2]. However, in a recent multicenter study [62] that included 177 patients enrolled over 20 years in more than 50 centers, the stage at diagnosis surprisingly did not appear as a prognostic factor in univariate or multivariate analysis, suggesting the importance of other factors such as the quality and completeness of initial resection. Similarly, 5-year survival after complete R0 resection was between 11 and 62%, versus less than one year of survival after R1 and R2 resections [10]. Examination of the evolution of survival over the last several decades shows contradictory results, and it is impossible to determine whether there has been a real improvement [10,12]. For metastatic ACC, it has recently been shown that the number of organs when the first metastasis is detected and the mitotic index influence survival [2]. Finally, depending on the various studies, tumor size, age > 40 years [7], and secretion of cortisol or cortisol and androgens [29] have been suggested as other factors of poor prognosis, although this has not been found in all studies.
or or or or or or or or or
1 1 1 1 1 1 1 1 1
Immediate post-operative period For secreting tumors, hormonal measurement must be performed following surgery as an indication of whether the resection was complete.
Late follow-up Laboratory testing For all ACC, a complete hormonal assessment must be performed every three months, including cortisol (free urinary cortisol, dexamethasone suppression test), androgens (S-DHEA, androstenedione, testosterone), and precursors. Elevated levels of any these markers indicate tumor recurrence, and are generally noted concomitant with the appearance of abnormal radiological images.
Imaging A thoraco-abdomino-pelvic CT without and with intravenous contrast should be performed every 3 months for 2 years, then every 3—6 months for 3 years, then annually to detect loco-regional recurrence or distant metastasis. CT scan is combined with an 18F-fluoro-desoxyglucose PET-scan every 3 months. If indicated by symptoms, a cerebral MRI or bone scintigraphy should be performed.
Molecular biology Other prognostic factors have been described including Ki-67 [64], overexpression of cyclin E, and mitotic index. A recent study has shown that Ki-67 is an independent predictive factor of recurrence after R0 resection [51]. Intra-tumoral hemorrhage and tumor necrosis are also considered to be factors of poorer prognosis but not consensually. The Weiss score or loss of heterozygosity at 17p13 have been described as independent factors of recurrence-free survival after complete R0 resection, but they had no influence on overall survival. Finally, in the future, molecular biology tools should not only make it possible to better differentiate malignant and benign tumors but also to more precisely determine the prognosis of malignant tumors.
Conclusion ACC is a rare cancer whose prognosis remains grim. The only potentially curative treatment is surgical resection, and the quality of the initial excision is one of the major prognostic factors. However, the quality criteria for this surgery are still poorly defined, and good-quality surgical studies are rare because of the very low incidence of the disease, which makes performance of these studies difficult. There is a need for surgical centers to collaborate to carry out multicentric prospective surgical studies. For example, the medical community in France was able to do so based on the COMETE network (http://sfendocrino. Org/article/599/recommendations) or ENSAT.
Long-term follow-up While there is no study validating a particular follow-up surveillance protocol, a number of recommendations exist [5]:
Disclosure of interest The authors declare that they have no competing interest.
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9 [54] Kim Y, Margonis GA, Prescott JD, et al. Curative surgical resection of adrenocortical carcinoma: determining long-term outcome based on conditional disease-free probability. Ann Surg 2017;265:197—204. [55] Tran TB, Maithel SK, Pawlik TM, et al. Clinical score predicting long-term survival after repeat resection for recurrent adrenocortical carcinoma. J Am Coll Surg 2016;223: 794—803. [56] Bellantone R, Ferrante A, Boscherini M, et al. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for adrenal cortical carcinoma. Surgery 1997;122:1212—8. [57] Kwauk S, Burt M. Pulmonary metastases from adrenal cortical carcinoma: results of resection. J Surg Oncol 1993;53: 243—6. [58] Mayo-Smith WW, Dupuy DE. Adrenal neoplasms: CT-guided radiofrequency ablation-preliminary results. Radiology 2004;231(1):225—30. [59] Bednarski BK, Habra MA, Phan A, et al. Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy. World J Surg 2014;38:1318—27. [60] Baudin E, Pellegriti G, Bonnay M, et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 2001;92:1385—92. [61] Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027—37. [62] Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372—80. [63] Kendrick ML, Lloyd R, Erickson L, et al. Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 2011;136:543—9. [64] Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202—6.
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Available online at
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REVIEW
Surgical treatment of adrenal carcinoma S. Gaujoux a,b,c,d,∗, M. Weinandt a,b, S. Bonnet a, V. Reslinger a, J. Bertherat b,c,d,e, B. Dousset a,b,c,d a
Service de chirurgie digestive, hépato-biliaire et endocrinienne, hôpital Cochin, AP — HP, 75014 Paris, France b Université Paris-Descartes, 75014 Paris, France c Inserm U567, CNRS UMR8104, institut Cochin, département d’endocrinologie, métabolisme et cancer, 75014 Paris, France d Centre expert national cancer de la surrénale, 75014 Paris, France e Service d’endocrinologie, AP — HP, hôpital Cochin, 75014 Paris, France
KEYWORDS Adrenocortical carcinoma; Adrenal incidentaloma; Adrenal gland; Adrenalectomy
Summary Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The presence of a mass syndrome or signs of hormonal hypersecretion often lead to its discovery, but more and more frequently, adrenocortical malignancy is fortuitously discovered as an incidentaloma. Cross-sectional imaging (CT and MRI) often points to the malignant character of the adrenal mass. Needle biopsy is contraindicated. Laboratory testing showing combined hypersecretion of cortisol, androgens or inactive corticosteroid precursors is highly suggestive of ACC. An 18F-fluoro-deoxyglucose Positron Emission Tomography (PET scan) should be performed to evaluate the malignancy of an adrenal mass and to detect regional or distant metastases. Although the majority of ACC are diagnosed at a locally advanced or metastatic stage, radical resection offers the only hope of cure. The peri-operative management of patients with ACC is not yet standardized. The aim of this review is to summarize the actual knowledge of the surgical management of ACC. © 2017 Elsevier Masson SAS. All rights reserved.
Introduction Although the incidental discovery of adrenal masses by cross-sectional imaging now occurs frequently, adrenocortical carcinoma (ACC) remains a rare tumor, with an estimated annual incidence in Europe and North America of 0.5 to 2 cases per one million inhabitants [1]; ACC accounts for 0.04—0.2% of cancer deaths. ACC is one of the most dangerous malignant endocrine tumors with metastatic disease found in 20—40% of patients at the time of diagnosis, mostly involving liver, lung or bone [2]. Radical resection offers the
∗ Corresponding author at: service de chirurgie digestive, hépatobiliaire et endocrinienne, hôpital Cochin, 27, rue du Faubourg-SaintJacques, 75679 Paris cedex 14, France. E-mail address: [email protected] (S. Gaujoux).
only hope of cure, but overall survival at five years varies between 30 and 40% [3] and depends mainly on tumor stage. Stage is now evaluated according to the European Network for the Study of Adrenal Tumors classification (ENSAT) [4]. Despite recent recommendations from the European Society of Endocrine Surgeons (ESES) and ENSAT [5], several questions concerning the surgical management of ACC remain unanswered including: • the need for lymph node dissection and its extent; • the place of the laparoscopic approach; • the indications for resection of loco-regional recurrences and resectable metastases; • the place of adjuvant mitotane treatment. This review is devoted to the surgical management of sporadic ACC in adults, which is generally associated with a worse prognosis than ACC occurring in children [6].
http://dx.doi.org/10.1016/j.jviscsurg.2017.06.010 1878-7886/© 2017 Elsevier Masson SAS. All rights reserved.
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Key points • Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis; metastatic disease (hepatic, pulmonary or bone) is present in 20—40% at diagnosis. • Clinical or subclinical hormonal hypersecretion is present in 75% of cases, which makes it possible to orient the diagnosis. • Approximately 10% of ACC are discovered fortuitously (incidentaloma). • The only indication for adrenal biopsy (pheochromocytoma must first be ruled out) is to eliminate the diagnosis of secondary adrenal metastasis, if necessary. • The surgical treatment of ACC is wide en-bloc resection. Nephrectomy is not necessary in all cases. • Lymphadenectomy must include peri-adrenal and peri-renal fat nodes of the renal hilum (although this approach is disputed). • The laparoscopic approach is conceivable only for lesions smaller than 6 cm, stage I or II, and performed by highly experienced teams.
Epidemiology and clinical presentation There are two frequency peaks, the first in childhood, the second between the fourth and fifth decades; there is a slight female predominance (sex ratio 1.5) [2,7]. There are no proven environmental risk factors. Although tobacco and oral contraceptive medications have been suggested as risk factors, their roles appear to be negligible. ACC’s are sporadic in more than 95% of cases, although some hereditary diseases such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome and Lynch syndrome [8] are associated with an increased risk of ACC development. Cases have also been reported in patients with Multiple Endocrine Neoplasia Type I or familial adenomatous polyposis [9], but no certain causation can be imputed. Three main clinical pictures may be seen at presentation: • nearly half of ACC’s are associated with clinical signs of hormonal hypersecretion, which entails, by decreasing frequency, a mixed hypersecretion of cortisol and androgens, an isolated hypersecretion of cortisol, virilization due to androgenic hypersecretion, or other varied associations of steroidal hypersecretion [2]. ACC’s that secrete aldosterone, estradiol or corticosteroid precursors alone are more rare. Overall, complete testing for adrenal hormones is likely to reveal clinical or subclinical hypersecretion in 75% of the cases, which makes it possible to orient the diagnosis [2]; • presentation with a palpable mass is frequent in nonsecreting ACC. Palpable ACC’s have an average weight of > 500 grams and a diameter of 12—15 cm on pathological exam [2,10]. Symptoms may include abdominal or lumbar pain, palpable mass, weight loss, tumor fever, or signs of inferior vena cava (IVC) compression. It should be noted that ACC patients maintain a good general clinical condition for a long time, explaining the frequency of late diagnosis of these tumors; • more rarely, the diagnosis of ACC is made during the investigation of an incidentaloma, that is to say, following the fortuitous discovery of an adrenal tumor on an imaging study carried out for another indication. Currently, about 10% of ACC’s are discovered incidentally, and these are
most often in early stages [2]. It is important to note that the probability of malignancy increases with the size of the adrenal mass [11]: malignancy is extremely rare for lesions < 4 cm and about 15—20% for lesions > 6 cm. The frequency of incidental diagnosis seems to be increasing [3], although this observation is not always confirmed, particularly in the United States [12]. The discovery of malignant lesions at an early stage is a major challenge in the management of incidentalomas. Finally, it is not uncommon for ACC to be discovered in the context of the assessment of its metastatic lesions.
Confirmation of malignancy when faced with an adrenal mass suspicious for ACC Above all, every adrenal mass must be subjected to specific clinical, laboratory and radiological assessment, the details of which are beyond the scope of this review.
Clinical and laboratory criteria Presentation with a voluminous palpable adrenal mass causing pain and signs of caval compression, while not specifically diagnostic, is highly suspicious of malignancy. Laboratory findings of a combined hypersecretion of cortisol and androgens, the presence of androgens with virilization, or estrogens with feminization, or the hypersecretion of inactive steroid precursors (17-hydroxy-progesterone, Deoxy cortisone, compound S) are very suggestive of the diagnosis of ACC [2].
Radiological criteria On CT, the typical aspect of ACC is that of a large adrenal mass, > 6 cm in diameter, with poorly-defined borders, containing areas of intra-lesional necrosis, with heterogeneous contrast uptake after injection, and possibly containing calcifications due to intra-tumoral hemorrhages. The presence of aorto-caval or para-aortic lymphadenopathy, invasion of adjacent organs, thrombus within the IVC or left renal vein, or hepatic and/or pulmonary metastases strongly suggest the diagnosis of ACC. For intermediate-sized lesions between 3 and 6 cm, well-established radiological CT criteria suggest malignancy. For this purpose, millimeter-thin slice CT should be performed, with measurement of the non-injected density and the density at one minute and 10 minutes after contrast injection. The density ratio allows calculation of the wash-out percentage. Several concordant studies have established that the vast majority of malignant lesions have a spontaneous density greater than 20 Hounsfield units (HU) with relative or absolute washout less than 40% or 60% at 10 minutes [13], respectively. CT can exclude the diagnosis of benign adenoma with a sensitivity and specificity greater than 90% [14]. On MRI, ACC appears as a hypo- or iso-intense tumor on the T1 sequences with heterogeneous contrast enhancement after gadolinium injection [13], and an iso- or hyper-intense signal on T2 sequences. Morphologic findings on MRI that favor the diagnosis of malignancy are similar to those observed on CT scan [15]. Benign adrenal adenomas, unlike ACC’s, have high lipid content. With in-phase sequences and out-of-phase sequences (fat subtraction), MRI can differentiate adenomas from suspected malignant lesions with excellent sensitivity (85—100%) and specificity (92—100%) according to reported series [13,14]. For adenomas, there
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Scintigraphic criteria Studies have reported that 18-fluoro-desoxyglucose PET scan has a high sensitivity (95—100%) and specificity (91—94%) to differentiate benign adrenal cortical tumors from ACC [16,17]. A multicenter prospective study of 77 adrenal tumors found the sensitivity and specificity for distinguishing adenoma from ACC were 100% and 88%, respectively, using a relative adrenal/liver SUV ratio (standard uptake value) of 1.45 [18]. Several studies [19,20] have since confirmed the value of PET scan in the management of ACC, although using different criteria or cut-offs [19,21].
3 since wide resection may entail the need for nephrectomy, although in practice it is rarely necessary. The hormonal assessment must be complete in order not to underestimate a subclinical hypersecretion; this is particularly important as a tumor marker for longterm follow-up and for immediate post-operative hormone replacement. This includes 8 am cortisol level, the urine free cortisol, the cyclical level of serum or salivary cortisol (the midnight time being the most informative), ACTH assay, 1 mg dexamethasone suppression test, aldosterone and plasma renin activity, testosterone, Dehydroepiandrosterone, delta-4 androstenedione, estradiol, intermediate derivatives (17-hydroxyprogesterone, Deoxycorticosterone, compound S), and urinary methoxylated derivatives.
Imaging studies Summary For any adrenal tumor suspected of being an ACC, thoracoabdomino-pelvic CT, MRI and 18F-fluoro-desoxyglucose PET scan should be systematically performed. If there is invasion of the IVC, these examinations must include delayed vascular sequences to properly visualize the relationship of the lesion with the IVC. Performance of pre-operative biopsy is generally contraindicated because of its low sensitivity and specificity for the diagnosis of ACC and the theoretical risk of capsular rupture and seeding on the needle track. The only indication for pre-operative adrenal biopsy is to obtain histological evidence of a secondary adrenal metastasis from a known primary or adrenal lymphoma, if doubt persists after all the above-mentioned investigations. Before needle biopsy, the diagnosis of pheochromocytoma must be excluded [22].
Pre-operative evaluation The pre-operative evaluation includes clinical, laboratory and hormonal evaluation, and imaging studies to specify the stage, the secretory profile, the resectability of the tumor, and the surgical risk.
Clinical evaluation Clinical evaluation includes assessment for a palpable mass, peripheral signs of hormonal hypersecretion (Cushingoid syndrome, virilization, gynecomastia), signs of IVC compression (which increases the risk of peri-operative thrombophlebitis especially in the case of excessive hormone secretion), and lower extremity edema for right-sided ACC, or segmental portal hypertension for left-sided ACC. The clinical examination should also assess nutritional status, WHO status and co-morbidities prior to major surgery.
Biochemical and hormonal evaluation Pre-operative blood chemistries are important to detect: hyperglycemia (hypercorticism), hypokalemia (excess mineralocorticoid secretions or severe hypercorticism), hypoalbuminemia and disorders of hemostasis (malnutrition), anemia (inflammatory response, portal hypertension), thrombocytopenia (hypersplenism due to segmental portal hypertension), or renal insufficiency. In patients with renal impairment, measurement of creatinine clearance and fractional clearance by MAG3 scintigraphy are important
The imaging assessment includes thoraco-abdominal angioCT with contrast injection, abdominal MRI, and PET scan. These examinations allow for definitive diagnosis, evaluation of loco-regional or metastatic extension, and assessment of resectability (vascular anatomy, venous extension). In the case of a large IVC extension, transesophageal cardiac ultrasound is essential to determine the upper level of a tumor thrombus [23]. A lower limb venous echo-Doppler can be performed pre-operatively to rule out lower extremity thrombophlebitis, whose risk is increased with large tumors, IVC compression, hypercorticism or hyperestrogenism.
Surgical treatment Indications for surgery The dogma remains that surgical excision is indicated for any potentially resectable ACC [24,25]. Based on the now widely used ENSAT classification, (Table 1), adrenalectomy encompassing the cellular and nodal surroundings is the rule for stage I and II tumors. Resection is also indicated in ENSAT stage III ACC’s with evidence of loco-regional invasion, including nodal extension to neighboring organs or the vena cava or in case of loco-regional recurrences. In most cases, the resection of ACC is a complex open surgery that may require an extended excision to access neighboring organs that may be invaded. However, ACC surgery can be performed by laparoscopy for lesions less than 6 cm at expert centers. The value of resection for stage IV metastatic ACC is much more debatable since recidivism is the general rule [26]. Synchronous metastases, usually to the liver or lung, are present in 17—42% [3,7,10,27]. Palliative chemotherapy for stage IV ACC has very limited efficacy. A prospective randomized international study (FIRM-ACT) determined that the gold-standard first-line treatment is combination chemotherapy with etoposide, doxorubicin, cisplatin and mitotane [28]. In an Italian phase II trial, 10 of the 72 patients (13%) with non-resectable metastatic ACC could be operated secondarily following an objective response to mitotane-associated chemotherapy [29] (Table 1).
Operative strategy In view of the rarity of ACC, these lesions should be managed in expert centers. However, there is no consensus on what constitutes an expert center. Different thresholds of
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ENSAT classification.
Stage
ENSAT
Definition
I II III
T1 T2 T1 T3
IV
M1
T1: tumor ≤ 5 cm, localized T2: tumor >5 cm, localized T3: tumor infiltrating adjacent adipose tissue T4: tumor infiltrating adjacent organs, or thrombus within the renal vein or IVC Metastases
(≤ 5 cm), N0, M0 (> 5 cm), N0, M0 or T2, N1, M0 or T4, N0/1, M0
activity have been proposed in the literature, varying from 4 to 10 adrenalectomies for ACC or from 10 to 20 laparoscopic adrenalectomies [30—32]. Beyond the obvious necessity of technical expertise, multidisciplinary management of these patients is also necessary, including surgeons, endocrinologists, oncologists, radiologists, pathologists, biologists and nuclear medicine specialists. The role of laparoscopy for stage I and small stage II ACC remains a subject of debate [33,34]. While there is consensual agreement among experts that the laparoscopic approach has become the reference technique for the removal of benign adrenal tumors [35], this is also increasingly discussed for ACC. Reported series are limited and heterogeneous [33,34,36] but some teams feel that laparoscopy has been associated with an increased risk of capsular rupture [34], loco-regional recurrence or peritoneal carcinomatosis. The grave implications of capsular rupture and the overall poor prognosis of ACC should lead the surgeon to favor quality of excision over the choice of the approach. However, for stage I and small stage II ACC, laparoscopic resection of ACC can be considered, provided that a confirmed diagnosis of malignancy is made pre-operatively and the operative team has a wide experience with laparoscopic adrenal surgery and a rigorous technique (removal of the entire peri-adrenal cellulo-fatty envelope without tumor spillage, skeletonization of the renal vessels, extraction of the specimen in a bag), and that this approach is only used for small lesions < 6 cm [5]. If there is any doubt pre-operatively or intra-operatively, initial open surgery or conversion should be the rule. Most ACC’s present as locally advanced stage II, III or IV tumors depending on the presence of loco-regional or metastatic spread, and with a weight and size that contraindicate the laparoscopic approach. The main objective of the surgical procedure for ACC is to obtain a complete R0 excision without tumor rupture, including at least a nodal dissection of the renal pedicle, in order to minimize the risk of loco-regional recurrence. The risk of tumor invasion should not be underestimated. It increases with the size of the ACC, its deeply placed anatomical situation, the existence of a fragile capsule, the presence of hypervascular adhesions to the adjacent parenchymatous organs, and increased tissue fragility in the case of cortisol hypersecretion; these factors require a choice of surgical approach that allows good exposure and atraumatic tumor manipulation [37,38]. The opening of invaded anatomical planes between the ACC and neighboring organs (kidney, diaphragm, right liver, spleen, left pancreas) appears to be an important factor in loco-regional recurrence, due to capsular invasion, hemorrhage, or insufficient margins [39—41]. This invasion is often difficult to determine pre- or intra-operatively. In 30% of cases, tumors that were initially classified as stage II are reclassified stage III after pathological examination has revealed the invasion of the adjacent tissues [42]. The excision of locally advanced adrenal tumors may
therefore require en bloc surgery that includes not only the tumor, but also the kidney, adjacent invaded organs, and the entire continuity of peri-adrenal and perirenal fat. There are only scant data from the literature showing a benefit of extensive lymph node dissection. However, one study showed that ACC was associated with a 73% lymph node invasion rate, and a recent study suggests that ACC resection with clearing of at least 5 lymph nodes was associated with a reduction in the risk of local recurrence and ACC mortality [43]. Lymph node dissection also allows a more accurate staging of the disease, although its influence on survival remains uncertain [44]. Thus, a lymph node dissection should be performed and must include at least peri-adrenal and peri-renal fat including the lymph nodes of the renal hilum. It is less clear and still debated whether there is value to a latero-aortic and inter-aortocaval nodal dissection and such nodal clearing should not be considered as a standard. On the right side, if there is hepatic invasion, resection may require right hepatectomy. On the left side, it may be necessary to divide the pancreatic isthmus to gain access to the spleno-mesenteric venous confluence and the mesenteric arterial take-off from the aorta. In more favorable situations (voluminous stage II), an extended adrenalectomy encompassing the ensemble of the adrenal and peri-renal fat allows a complete locoregional lymph node dissection including the renal hilum and makes it possible to preserve the homolateral kidney (Fig. 1). Nephrectomy is not recommended unless it is necessary to obtain an R0 margin, especially for tumors adjacent to the renal pedicle, regardless of their size. Extension into the IVC occurs in less than 10% of patients; it is usually associated with venous extension of a tumor thrombus most commonly arising in the main adrenal vein, and it occurs more frequently for right-sided ACC (Fig. 2). IVC involvement consists more often of a caval tumor thrombus than direct tumor extension into the venous wall. This is associated with a high risk of hepatic and/or pulmonary metastases [23]. Depending on the upper level of thrombus extension (subhepatic IVC, retrohepatic IVC, suprahepatic IVC), thrombectomy may require supra-renal vena cava clamping under hepatic vascular exclusion with supra-hepatic sub-diaphragmatic or intra-pericardial vena cava clamping, or, in exceptional cases, extracorporeal venous circulation when thrombus extends into the right atrium. [23]. Direct invasion of the IVC wall is often quite limited and accessible to partial caval resection with direct closure or a prosthetic, autologous (peritoneal) or heterologous (bovine pericardium) patch (Fig. 2).
Post-operative management Post-operative morbidity depends directly on the extensiveness of the surgical gesture, but is also strongly
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Figure 1.
Operative view after removal of a stage II ACC and preservation of the kidney. A. Right-sided ACC. B. Left-sided ACC.
Figure 2.
Operative view after removal of a right-sided ACC invading the inferior vena cava.
influenced by cortisol secretion and how well it is controlled pre-operatively [45]. In a North American registry study (SEER) involving more than 2000 patients, post-operative mortality approached 2% [30], confirming the results of another multicenter North American study [46]. In the latter study, the overall morbidity was 37% [46]; morbidity was increased by thoraco-abdomino-pelvic approaches, and in surgery for a secreting tumor. In the immediate post-surgical period, care should be taken to prevent acute adrenal insufficiency, particularly in patients with glucocorticoid secreting tumors. Initial intravenous supplementation (hydrocortisone hemisuccinate) is
followed by oral supplementation of hydrocortisone. One of the risks associated with lymph node dissection at the level of the aortico-caval axis is the occurrence of postoperative lymphorrhea. This can occur late, after the patient has resumed oral alimentation and is manifested by the appearance of an opalescent lymphatic fluid leak, rich in triglycerides, lymphocytes and chylomicrons. If chylous fluid appears in the drain, management includes a strict fatfree diet for a period of six weeks, with supplementation in medium-chain triglycerides, which is absorbed directly by the portal venous network without passing through the lymphatic vessels.
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Pathology and classifications
Place of local treatments
Histological scores
Radiofrequency (RF) ablation has been demonstrated to be feasible and effective in the treatment of primary tumors, hepatic and pulmonary metastases or in the palliative treatment of symptomatic bone metastases. RF therapy may therefore appear to be an alternative to surgical treatment for solitary hepatic or pulmonary metastasis of ACC in patients in whom surgery is contraindicated, although only one very heterogeneous series has been published [58]. In fact, no randomized prospective study has yet proved the equivalence of RF to surgery, particularly in terms of survival.
The histologic definition of whether an adrenal mass is malignant, apart from evident signs of malignancy (metastases, loco-regional invasion, vascular or lymph node involvement), is difficult and is based on different histological scores [47,48]. In clinical practice, the Weiss score is the most widely used (Table 2), while the Bisceglia score is applied to oncocytic tumors [49]. A number of immunohistochemical criteria may also be used as diagnostic tools. Ki-67 is especially important [48—52]; it has major prognostic value either after primary tumor surgery or in the management of metastatic disease. Increasing values of Ki-67 (<10%, 10—19%, and ≥ 20%) are associated with a corresponding decrease in recurrence free and overall survival. Other immuno-histochemical markers include P53, IGF-2, catenin [53] or Cyclin E, but these are not commonly used as histo-prognostic markers.
Staging Various staging systems have been used, but the one proposed by ENSAT is currently the most commonly used [4].
Place of neo-adjuvant and adjuvant therapy Neo-adjuvant chemotherapy There is only one study on the role of neo-adjuvant chemotherapy in the treatment of primary or metastatic ACC, the results of which remain difficult to interpret [59]. Surgery first is the general rule for all primary or metastatic ACC whenever they are resectable.
Mitotane (O, p’DDD)
Re-operation After resection of the primary tumor, 60—85% of the patients will develop loco-regional or metastatic recurrence despite initial surgery that is a priori complete [39—41,54,55]. These recurrences usually occur within two years and are usually not amenable to surgical salvage. The risk of recurrence is influenced by the ENSAT stage and thus the size of the tumor, its Ki-67 status, the association with cortisol secretion, but also the quality of the initial surgical management (in particular, the absence of tumor capsular violation) [39—41,54,55]. However, these recurrences may nevertheless be amenable to curative resection if an R0 resection is still feasible. This must be discussed in the context of a multidisciplinary expert consultation meeting.
Used for the first time in 1959, o,p’DDD or mitotane, ® (Lysodren , HRA-Pharma, France), is the most commonly used adjuvant treatment and the one on which the literature is most abundant. Several series have reported the efficacy of mitotane [7], albeit with response rates less than 25% [60,61]. Mitotane is associated with many side effects and, for maximum efficacy and tolerance, measurement of plasma levels must be performed, which should fall within a narrow therapeutic range of 14—20 mg/L [60]. While the effectiveness of adjuvant mitotane therapy remains limited, the current standard of care is to offer adjuvant mitotane chemotherapy, with serial measurement of plasma levels for all patients [62]. A prospective randomized international trial (ADIUVO) is currently underway comparing mitotane vs. surveillance in ACC patients with low or intermediate recurrence risk, defined as stage I to III tumors with complete excision and Ki-67 <10% (http://www.ensat.org).
Loco-regional recurrences
Chemotherapy
For recurrence in the tumor bed, re-operation is justified if an R0 resection is possible, because up to 40% of the patients are alive five years after R0 excision for this type of recurrence, with a significant improvement in symptoms [56], thus justifying this aggressive attitude [3]. These loco-regional recurrences often invade the right liver, the mesocolon, the diaphragm, or the tail of the pancreas. They may therefore require extensive surgery, especially if this has not been done during the initial procedure.
For a long time, systemic treatment of ACC has been limited to mitotane (o.p’DDD), whose response rates are low; effects on overall survival have not been demonstrated. However, a randomized, multicenter prospective study on chemotherapy of non-resectable ACC stages III and IV (FIRMACT) compared EDP chemotherapy (etoposide, doxorubicin and cisplatin) + mitotane to streptozotocin + mitotane. The final results of this trial showed better response rates and progression-free survival with the EDP + mitotane regimen with equivalent toxicity but no significant effect on overall survival [61].
Metachronous metastasis Metachronous hepatic or pulmonary metastases can be resected [57], when an R0 excision is feasible. Although such metastases are rarely isolated, their resection is more likely to lead to complete surgical extirpation than re-intervention for local recurrences. However, 5-year recurrence-free survival is extremely rare.
Prognosis and prognostic factors Clinical ACC stage at the time of diagnosis and completeness of initial surgery (R0) appear to be the main prognostic factors
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Weiss histo-prognostic score (0—9). A score ≥ 3 is indicative of malignancy.
Histologic criteria
Semi-quantitative evaluation
Score calculation
Mitotic index Atypical mitoses High nuclear grade Low percentage of clear cells Confluent foci of necrosis Diffuse architectural structure Venous invasion Sinusoidal invasion Capsular invasion
> 5/50 high-powered fields Presence or absence Presence or absence < 25% of tumor cells Presence or absence > 33% of the tumor Presence or absence Presence or absence Presence or absence
0 0 0 0 0 0 0 0 0
for survival, but the prognosis remains bleak. Indeed, life expectancy at five years in all stages is generally between 16 and 60% [3,7,63]. In an French multicenter study involving 156 patients published in 1992, Icard et al. reported survival rates 58 to 66% for Stages I and II and 0 to 24% for Stages III and IV [3]. These figures are included in the series of patients followed in our center [2]. However, in a recent multicenter study [62] that included 177 patients enrolled over 20 years in more than 50 centers, the stage at diagnosis surprisingly did not appear as a prognostic factor in univariate or multivariate analysis, suggesting the importance of other factors such as the quality and completeness of initial resection. Similarly, 5-year survival after complete R0 resection was between 11 and 62%, versus less than one year of survival after R1 and R2 resections [10]. Examination of the evolution of survival over the last several decades shows contradictory results, and it is impossible to determine whether there has been a real improvement [10,12]. For metastatic ACC, it has recently been shown that the number of organs when the first metastasis is detected and the mitotic index influence survival [2]. Finally, depending on the various studies, tumor size, age > 40 years [7], and secretion of cortisol or cortisol and androgens [29] have been suggested as other factors of poor prognosis, although this has not been found in all studies.
or or or or or or or or or
1 1 1 1 1 1 1 1 1
Immediate post-operative period For secreting tumors, hormonal measurement must be performed following surgery as an indication of whether the resection was complete.
Late follow-up Laboratory testing For all ACC, a complete hormonal assessment must be performed every three months, including cortisol (free urinary cortisol, dexamethasone suppression test), androgens (S-DHEA, androstenedione, testosterone), and precursors. Elevated levels of any these markers indicate tumor recurrence, and are generally noted concomitant with the appearance of abnormal radiological images.
Imaging A thoraco-abdomino-pelvic CT without and with intravenous contrast should be performed every 3 months for 2 years, then every 3—6 months for 3 years, then annually to detect loco-regional recurrence or distant metastasis. CT scan is combined with an 18F-fluoro-desoxyglucose PET-scan every 3 months. If indicated by symptoms, a cerebral MRI or bone scintigraphy should be performed.
Molecular biology Other prognostic factors have been described including Ki-67 [64], overexpression of cyclin E, and mitotic index. A recent study has shown that Ki-67 is an independent predictive factor of recurrence after R0 resection [51]. Intra-tumoral hemorrhage and tumor necrosis are also considered to be factors of poorer prognosis but not consensually. The Weiss score or loss of heterozygosity at 17p13 have been described as independent factors of recurrence-free survival after complete R0 resection, but they had no influence on overall survival. Finally, in the future, molecular biology tools should not only make it possible to better differentiate malignant and benign tumors but also to more precisely determine the prognosis of malignant tumors.
Conclusion ACC is a rare cancer whose prognosis remains grim. The only potentially curative treatment is surgical resection, and the quality of the initial excision is one of the major prognostic factors. However, the quality criteria for this surgery are still poorly defined, and good-quality surgical studies are rare because of the very low incidence of the disease, which makes performance of these studies difficult. There is a need for surgical centers to collaborate to carry out multicentric prospective surgical studies. For example, the medical community in France was able to do so based on the COMETE network (http://sfendocrino. Org/article/599/recommendations) or ENSAT.
Long-term follow-up While there is no study validating a particular follow-up surveillance protocol, a number of recommendations exist [5]:
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Gaujoux S, et al. Surgical treatment of adrenal carcinoma. Journal of Visceral Surgery (2017), http://dx.doi.org/10.1016/j.jviscsurg.2017.06.010