Abstract
Background and aims
Previous guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime.
Methods
A PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting.
Results
Overall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided.
Conclusion
Effective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.
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Introduction
The aim of the present guideline was to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors. The full-text version in German language is available online (awmf.org/leitlinien/detail/ll/088-008.html) [1]. Six medical societies and organizations as well as a patient support group collectively actualized previous recommendations (04/2000) and subsumed a joint S2k guideline [2].
This guideline refers to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. The guideline extends to interested patients with the aim to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors.
The aim of the guideline is to provide preferably the most effective medical options for the surgical treatment of adrenal lesions. Positive and negative effects balance medical effectiveness while aspects of efficiency and economics are secondarily considered. Moreover, organizational and legal aspects are observed.
The guideline specifically addresses the following questions:
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What are the indications for surgery in adrenal tumors?
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What diagnostic measures are required preoperatively?
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Do effective alternative therapy options to surgery exist?
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What kind of procedures of adrenal resection should be performed?
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What measures are required in the postoperative care?
Methods
This guideline represents an update of the S1 guideline passed 4/2000 “surgical therapy of adrenal diseases” (CAEK; Mitteilungen der Deutschen Gesellschaft für Chirurgie, G92) [1]. In accordance with the requirements of S2 guidelines of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) classification and regulations (http://www.awmf-leitlinien.de) as well as the German instrument for methodical guideline assessment of the AWMF and ÄZQ (DELBI, http://www.delbi.de), the previous recommendations underwent thorough survey and revision on base of a systematic literature review.
Following the mandation process by the members of the German Association of Endocrine Surgeons, leading coordinators convened multidiciplinary experts, legal guidance, and patient support groups. The project was registered online on November 14, 2017 at the AWMF (www.awmf-leitlinien.de, AWMF-Registernummer 088-008) and publicly announced to enable participation or comments. Representativeness of the mandated members was reviewed and confirmed by the 11 working groups who composed a manuscript that underwent written Delphi voting on January 1, 2018. Comments were incorporated by the coordinators (KL, DKB) and underwent written Delphi voting, which was followed by a consensus conference on June 6, 2018 in Frankfurt/Main for final live voting process, moderated by an AWMF representative. A list of the entire constituting members, represented medical societies, and organizations of the guideline group is presented in Appendix.
Phrasing of the recommendations and consensus process
Based on the previous S1 guideline surgical therapy of adrenal diseases published 2000 (Mitteilungen der Deutschen Gesellschaft für Chirurgie, G92) [2], a literature review was performed, and the actualised S2k guidelines generated [1]. A PubMed research using the key words “guidelines” AND “adrenal tumor” AND “surgery”; “adrenal tumor” AND “surgery”; “Conn adenoma” AND “surgery”; “pheochromocytoma” AND “surgery”; “adrenal incidentaloma” AND “surgery”; “adrenocortical carcinoma” AND “surgery”; “adrenal myelolipoma” AND “surgery”; “adrenalectomy” AND “perioperative management” for the interval January 2000–June 2016 was performed, and identified publications were analyzed in the assigned working groups. Of these, only few studies represent evidence-based data, and the majority are retrospective analyses (evidence level III), randomized prospective trials are exceptional (evidence level I and II). Currently, only the American Association of Clinical Endocrinologists (AACE) and the European Network for the Study of Adrenal Tumors (ENSAT) present valid recommendations for incidental adrenal tumors based on systematic literature review with evaluation of evidence levels. The new S2k guideline was generated in accordance with recommendations from the Study of Adrenal Tumors (ENSAT), the European Society of Endocrine Surgeons (ESES), the American Association of Clinical Endocrinologists (AACE), the Associazione Medici Endocrinologi, the European Society of Endocrinology (ESE), and the British Endocrine Association, data from published meta-reviews, and original published data. All studies that were consulted for generation of this guideline are gathered in the reference list.
In presentation of the substance, it was distinguished between core statements/key recommendations and the generation from and presentation in the primary literature (evidence level). Recommendations discriminate quality levels of strength by wording (e.g., “has to”/“must”; “should”; “can”). Recommendations against an intervention are phrased accordingly. In general, the level of recommendation is determined by the quality of evidence (evidence power); thus, a recommendation of average evidence level corresponds to an average recommendation grade. Consensus level was graded with high consensus (> 95% approval, +++), consensus (> 75–95% approval, ++), or majority consensus (50–75% approval, +) in accordance with classification in the AWMF regulations. All recommendations were passed with high consenus or consensus.
Consensus procedure
Eleven working groups were initiated to actualise and overwork the areas of general recommendations, non-functional adrenal tumors, primary hypercortisolism, androgene-/estrogene-producing tumors, primary hyperaldosteronism, pheochromocytoma and paraganglioma, neuroblastoma, ganglioneuroblastoma, ganglioneuroma, adrenal carcinoma, adrenal metastases, peri-, and postoperative management and care. The primary version was circulated to all members. Comments and alternative votes for all statements and recommendations of all members were collected by the coordinators, and consensus phrasing was perfomed in alignement. Preelection of these was done in a written Delphi process, after which all members of the guideline group and all medical societies were invited to comment and provide alternative proprosals. In a concluding consensus conference, involving all members of the guideline group, the representatives of the medical societies reviewed each statement. Moderated by a neutral AWMF representative, each statement and recommendation was seperately discussed and voted, allowing for questions, recording, and collection of modifications of all reasonable changes, and finalizing voting of the modified phrasing by the moderator (nominal group process). Open voting for each single recommendation during the live consensus conference was performed following final editing of statement and recommendation phrasing. Voting rates for approval and disapproval were registered for each recommendation separately. Objections and proposal for modifications were registered and finally addressed in a novel voting process. All recommendations were approved with strong consensus (approval of > 95% of members) or in consensus (approval of > 75% of members). Afterwards, a final editing of the consented commentaries to each recommendation was performed by the working groups and summarized by the coordinators (KL, DKB). The manuscript was then circulated for final approval to all medical societies involved and presented to the board committee of the DGAV (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie) with option to comment and provide alternative proposals. The consented recommendations were thereby left unchanged.
General recommendations for surgery
R1: Functional adrenal tumors generally represent an indication for surgery irrespective of their size (consensus+++).
R2: In a given indication for surgery, primary adrenal tumors ≤ 6 cm without signs of malignancy should be operated minimally invasively (consensus+++).
R3: Laparoscopic and retroperitoneoscopic approaches are equal. The choice depends on experience and preference of the surgeon (consensus+++).
R4: Non-functional adrenal tumors (exception myelolipoma) with diameter ≥ 6 cm should be operated in open technique due to the risk of malignancy.
In tumors from 4 to 6 cm, indication for surgery is to be decided on individual patient criteria.
Non-functional adrenal tumors < 4 cm without criteria of malignancy should not be operated. Indication for surgery should be decided interdisciplinary (consensus+++).
R5: In open adrenalectomy, transabdominal or thoraco-abdominal approaches are preferred as suspicion of malignancy and large tumor size is the main indication for these approaches (consensus+++).
R6: “Single-port” and “multiple-port” adrenalectomy are equal. Utilization of a robot in minimally invasive adrenalectomy demonstrated as yet no advantage (consensus+++).
R7: Standard procedure for unilateral tumors is adrenalectomy. Adrenal preserving resection may be considered in case all functional tissue can be completely removed (consensus+++).
R8: For bilateral adrenal tumors, preservation of adrenocortical functional reserve is to be pursued. Minimum of one third of adrenal tissue is therefore required; preservation of the adrenal vein is not obligatory (consensus+++).
R9: There is no indication for surgery in asymptomatic myelolipoma and asymptomatic adrenal cyst. Due to their benign nature, tumor diameter is not relevant (consensus+++).
R10: Adrenocortical carcinoma requires open surgery. In tumors < 6 cm without signs of local or lymph node infiltration (ENSAT stage I + II), minimally invasive adrenalectomy can be performed in given expertise (consensus+++).
Adrenocortical carcinoma without evidence of distant metastases requires radical tumor resection without capsular rupture and locoregional lymphadenectomy. Indication for resection of tumors with oligo metastases should be based on individual assessment (consensus+++).
R11: Bilateral adrenalectomy may represent an ultima ratio in ACTH-dependent Cushing’s syndrome when causative therapy fails (consensus+++).
R12: Indication for resection of adrenal metastases should be made on patients’ individual criteria (consensus+++).
Resection of adrenal metastases can be performed minimally invasive. In case of tumor size > 6 cm or signs of infiltration of neighboring structures, surgery should be performed in open technique (consensus++).
Commentary
Exception to R1 is primary hyperaldosteronism due to bilateral hyperplasia without reliable definition of right or left origin.
Limits for a minimally invasive approach are tumor size and imaging criteria of malignancy. Regarding size, a 6-cm rule is accepted, larger tumors may be approached conventionally open; however, in lack of evidence for this rule, in exceptional expertise, larger tumors may be also approached minimally invasively if the patient is informed and a complete excision can safely be performed without capsular rupture [3,4,5].
Tumor size and imaging morphology determine the indication for surgery. There is evidence for a positive correlation of tumor size and risk of malignancy [6, 7]. Prevalent data suggest increasing risk of malignancy in tumors > 4 cm, arguing for the indication for surgery, ideally after interdisciplinary consultation [8]. Imaging criteria for malignancy remain uncertain unless infiltrations of neighboring structures or metastases are prevalent. Additional information with Houndsfield units (HU) > 10 in native CT or MRI with chemical shift imaging may provide further guidance [9, 10].
In due consideration of the risk of malignancy in tumors > 6 cm and imaging criteria for malignancy with general recommendation for open surgery, some clinical data support laparoscopic approach in adrenocortical carcinoma and larger tumors or show equal outcomes regarding recurrence and prognosis. Therefore, providing great experience and dedicated patients’ informed consent, a minimally invasive approach for tumors up to 10 cm may be eligible in individual patients [11, 12].
Adrenalectomy is the standard procedure for all adrenal tumors with indication to surgery; however, preservation of the adrenocortical functional reserve, requiring about a third of the non-tumorous remnant of the adrenal, is increasingly acknowledged and may be indicated especially in Conn syndrome with small tumors, rarely in Cushing adenoma. For this, preservation of the adrenal vein is not obligatory [13,14,15,16].
Ideal indications for adrenal preserving surgery are hereditary disease, namely bilateral pheochromocytoma, and Cushing’s syndrome with bilateral macronodular hyperplasia as typical complications of corticoid substitution therapy may be avoided [14, 17, 18]. This advantage needs to be weighed against the risk of local tumor recurrence in the adrenal remnant. Clinical data indicate a higher incidence of hereditary pheochromocytoma up to 19% as previously estimated. Although risk factors remain unreliable, age < 45 years, extraadrenal tumor localisation, previous cervical paraganglioma, and multiple tumors were identified in multivariate analysis and should be acknowledged [19]. Substitution-free survival is also described in adrenal preserving surgery for Cushing’s syndrome [20].
Decision on the optimal approach in suspicion of adrenocortical cancer (laparoscopic vs. open) should regard the individual risk of tumor capsule rupture and incomplete resection, and demands appropriate surgical expertise. Open adrenalectomy remains the standard therapy for tumors > 6 cm and evidence of infiltration. Incidence of lymph node infiltration in adrenal adrenocortical cancer is about 20%; however, the role of lymphadenectomy remains undefined in regard to outcome and locoregional extension [18,19,20].
Curative trans-sphenoidal tumor resection remains standard therapy for ACTH-dependent Cushing’s syndrome; however, in up to 31% incomplete tumor resection and recurrence demand further neurosurgery or radiation [21]. In failure of these measures or in case of paraneoplastic excess cortisol expression, bilateral adrenalectomy may provide efficient improvement of clinical symptoms with minimum recurrence rate [22].
Criteria in favor for adrenalectomy as a treatment option of adrenal metastases are control of extraadrenal tumor manifestation and patients’ general health performance status in regard of planned adrenal surgery. Biopsy confirmation is unnecessary when imaging and patients’ history are confirmative [23]. While some tumor entities demonstrate advantages of adrenalectomy in metastasis, a poorer prognosis is associated with a period of < 2 years of primary malignant diagnosis and evidence of adrenal metastasis, further distant metastases, or incomplete adrenal tumor resection [24]. Adrenalectomy may also be offered in palliative intention, e.g., for control of otherwise refractory pain. Minimally invasive surgery shows equal results to open surgery and may be offered in given expertise [25]; however, open surgery remains the standard approach when multivisceral resection is required. In case adrenalectomy is judged unfavorable, radiofrequency ablation (RFA) may be considered [26].
Primary hyperaldosteronism
R13: The primary hyperaldosteronism (PHA) has to be established preoperatively, e.g., by determination of the aldosterone-renin-quotient (ARQ) (consensus+++).
R14: A lateralization of the disease has to be preoperatively established by imaging and regional localization procedures since the results influence the indication for the operation and the operative strategy (consensus+++).
A cross-sectional imaging has to be performed preoperatively with contrast enhanced computer tomography or MRI imaging. In addition, an endosonography can be performed (consensus+++).
In case of unclear lateralization by imaging, an adrenal venous sampling (AVS) should be performed preoperatively for the functional lateralization of the PHA. In case of clear lateralization by cross-section imaging, the AVS can be omitted if the patient was informed in detail about the risk of a resection of a hormonally inactive lesion. An AVS should not be performed in patients < 40 years with established PHA, a clear unilateral tumor, and a normal contralateral adrenal on imaging (consensus+++).
R15: An adrenal scintigraphy can be performed in case of inconclusive lateralization by AVS (consensus+++).
R16: In the unilateral form of PHA, an operation has to be indicated (consensus+++).
R17: In patients with PHA and bilateral adrenal lesions, an operation can be considered if the AVS shows a functional lateralization (consensus+++).
R18: In patients with PHA and hyperplasia of the adrenal cortex without clear lateralization in the AVS, an operation should not be indicated (consensus+++).
R19: The adrenalectomy should be performed minimally invasive (consensus+++).
R20: In case of a solitary aldosterone producing adenoma (APA), a partial resection of the affected adrenal gland can be performed (consensus+++).
Commentary
The primary hyperaldosteronism (PHA) is caused by an autonomous aldosterone secretion. The determination of the aldosterone–renin quotient (ARQ) allows the identification of patients even with a mild form PHA [27, 28]. The ARQ test is an excellent screening test in the diagnosis of PHA. Patients with an abnormal ARQ should undergo a confirmatory test. The most frequently used confirmatory test is the intravenous NaCl-stress test [29]. Cross-sectional imaging and functional lateralization of the increased aldosterone production is essential for the indication for surgery and for the operative strategy, since only patients with a clearly localized PHA to one adrenal should undergo surgery. CT is the standard cross-sectional imaging method for the imaging of a PHA. However, the identification of a small adenoma can be difficult, since most aldosterone-producing adenomas (APA) are less than 2 cm in size, and the functionality of any detected lesion cannot be established. MRI imaging can be used alternatively to CT imaging. The endoscopic ultrasound of the adrenals can be very useful for the morphological detection of a small adrenal adenoma [30,31,32]. The adrenal venous sampling (AVS) allows the functional lateralization of the PHA [33]. However, the result of the AVS is highly dependent on the experience of the examiner; especially, the cannulation of the right adrenal vein is difficult and has a success rate of at most 75% [34, 35]. Thus, the principal use of the AVS is discussed controversially. In case of a clear lateralization of the APA, especially in younger patients < 40 years, the primary surgery is justified without AVS, if the patient agrees after detailed information about the risk of an inadequate operation. In case of an unclear lateralization by imaging, the AVS is recommended to avoid the risk of an unnecessary or inadequate adrenalectomy [36,37,38]. The adrenal scintigraphy with iodine 131-norcholesterol (NP-59) in association with dexamethasone suppression test is also an opportunity for functional lateralization. However, in adenomas < 1.5 cm in size, the uptake of the tracer is too low in most cases to functionally characterize small adrenal lesions detected by CT [39].
Patients with a PHA clearly associated with one adrenal (unilateral form of PHA) benefit from adrenalectomy [40,41,42]. One important aspect is that surgery reduces not only the pathophysiologically negative effect of the increased aldosterone production on hypertension but also with regard to the fibrosis of the myocard and endothelia [43, 44]. With regard to these aspects, surgery is much more effective than medical treatment with, e.g., spironolactone [43, 45]. In contrast, no surgery should be indicated in patients with PHA and hyperplasia of the adrenal cortex without unequivocal lateralization in the AVS. In case of bilateral adrenal hyperplasia, patients do not benefit from an operation, since unilateral adrenalectomy only marginally influences the increased aldosterone production. Bilateral adrenalectomy is not justified, because of the consecutive need of daily glucocorticoid substitution. In bilateral adrenal hyperplasia of the adrenal cortex, surgery can be indicated, if the AVS clearly shows lateralization to one adrenal gland. Furthermore, in case of asymmetric hyperplasia of the adrenal cortex, the patient might benefit from resection of the dominant adrenal [46]. The minimally invasive adrenalectomy is nowadays the procedure of choice in PHA, which can be performed by either a transperitoneal or retroperitoneal approach [47, 48]. A conventional approach should be restricted to exceptional situations that have to be explained.
The data regarding the question, whether a partial adrenal resection including the adenoma is sufficient, is controversial. Some studies reported comparable results after adrenalectomy or partial resection, but others reported higher recurrence rates after parenchymal sparing resection [15, 48,49,50]. The only prospective randomized study with 212 patients showed no differences regarding the postoperative functional result after partial or total adrenalectomy [51]. If a partial adrenal resection is considered, intraoperative ultrasound should be used to ensure that the adenoma carrying adrenal part will be resected.
Cushing’s syndrome
R21: It has to be differentiated preoperatively between ACTH-dependent (Morbus Cushing, paraneoplastic ectopic ACTH-secretion) and ACTH-independent adrenal hypercortisolism by biochemical functional tests and imaging (consensus+++).
R22: In ACTH-independent adrenal hypercortisolism caused by a unilateral adenoma or a resectable adrenocortical carcinoma, adrenalectomy should be performed (consensus+++).
R23: Bilateral adrenalectomy can be performed after treatment of a persistent Morbus Cushing or a non-resectable ectopic ACTH-producing tumor, if medical treatment is exhausted (consensus+++).
R24: Minimally invasive surgery is to be performed in tumors less than 6 cm in size without suspicion of malignancy (consensus+++).
Commentary
The differential diagnosis of ACTH-dependent vs. ACTH-independent hypercortisolism should be made by determination of the basal ACTH (plasma) and basal cortisol concentration in combination with a dexamethasone suppression test or CRF stimulation test [52,53,54]. In general, every Cushing’s syndrome should be treated. An indication for adrenalectomy is always given in case of a unilateral adenoma or resectable adrenocortical carcinoma. In case of a primary hyperplasia of the adrenal cortex, persistent Morbus Cushing after treatment of the pituitary gland or non-resectable ectopic ACTH-producing tumor, bilateral adrenalectomy can be indicated to remove the target organs. The indication for bilateral adrenalectomy should always be weighted very carefully despite its effective treatment of hypercortisolism, since this operation results in a life-long necessity for medical substitution of the adrenal cortex and has a high risk for the development of an ACTH-producing tumor of the pituitary [55,56,57] (Nelson tumor). In cases of an adrenal tumor < 6 cm in size without suspicion of malignancy as well as in adrenal hyperplasia, minimally invasive adrenalectomy is to be performed.
Adrenal tumors with androgene/estrogene overproduction
R25: Any androgene- or estrogene-producing adrenal tumor should be operated (consensus+++).
In all androgene- or estrogene-producing adrenal tumors adrenal carcinoma must be considered because adenomas are rare (consensus+++).
Depending on the tumor size (up to 6 cm), and in absence of infiltration or lymph node involvement, minimally invasive adrenalectomy can be performed (consensus++).
In suspicion of underlying adrenocortical cancer (ACC), locoregional lymphadenectomy should be performed (consensus++).
Commentary
Adrenal disease with overproduction of androgene or estrogene clinically presents in congenital enzymatic defect of the adrenal steroid biosynthesis, called adrenocortical syndrome (AGS) or in adrenal tumor with increased production of adrenal sex hormones (carcinoma, rarely adenoma). Only adrenal tumors are indication for surgery that is mostly carcinoma; AGS without adrenal tumor is treated medically [58]. All adrenal tumors with sex hormone production represent an indication for surgery irrespective of tumor size due to the risk of malignancy [8, 59,60,61].
Pheochromocytoma and paraganglioma
R26: In suspicion of pheochromocytoma or paraganglioma by clinical or imaging criteria, the assessment of metanephrines (metanephrine, normetanephrine) in plasma-free serum represents the method of choice (consensus+++).
R27: Patients with 2–3-fold elevation of metanephrines should undergo repeat assessment after horizontal rest and repeat after another 6 months. In case ambiguous results persist, clonidine test can be considered (consensus+++).
R28: Whenever metanephrines exceed 3-fold normal range, imaging diagnostics (CT/MRI) should beinitiated (consensus+++).
R29: Primary choice for imaging is abdominal CT. In pregnancy, children, and patients with contrast media intolerance or previous relevant radiation exposure, MRI should alternatively be used (consensus+++).
In extraadrenal tumors, recurrence, or metastases, MRI is favored over CT due to the higher sensitivity (consensus+++).
In case of dubious findings or in clarification of metastases, additional functional imaging with 123iodine-metaiodobenzyleguanidine (MIBG)-scintigraphy, 18F-fluorodeoxyglucose (FDG) PET/CT, or 18F-fluorodihydroxyphenylalanine (DOPA)-PET/CT should be performed due to the higher specificity (consensus+++).
R30: In proven pheochromocytoma and/or extracervical paraganglioma, surgery should be performed (consensus+++).
Patients with symptomatic pheochromocytoma or paraganglioma should undergo preoperative alpha-blockade. In asymptomatic patients without hypertension (mainly VHL and paranglioma), it may be considered to dispense with preoperative alpha-blockade (consensus+++).
In unilateral pheochromocytoma < 6 cm, minimally invasive adrenalectomy should be performed. For tumors > 6 cm and/or in presence of metastases, open surgery should be performed (consensus++).
In bilateral hereditary pheochromocytoma, adrenal resection with preservation of at least one third of a unilateral adrenal parenchyma should be performed in order to preclude postoperative adrenal insufficiency (consensus+++).
In accordance with tumor localization and surgeon’s experience, abdominal paraganglioma may be operated minimally invasively or via an open approach (consensus+++).
In accordance with tumor localization and surgeon’s experience, thoracic and mediastinal paraganglioma may be operated minimally invasively by thoracic or open approach (consensus+++).
Commentary
Assessments of metanephrines in plasma-free serum or 24-h urine are the superior tests when pheochromocytoma (PCC) or paranglioma (PGL) is suspected [62, 63], ideally performed in liquid-chromatographic method (LC-ECD or LC-MS/MS) that may even be assessed in saliva probes [64]. Clonidine suppression test may discriminate false from correct positive result in patients with 2–3-fold elevated metanephrines after repeat assessment in horizontal position and resting [65,66,67].
First imaging choice is CT with a sensitivity of 88–100% revealing typical PCC/PGL features of regressive alterations like necrosis, calcification, and cysts with density > 10 HU without contrast media [68, 69]. CT sensitivity is lower (57%) for extraadrenal tumors, recurrence, and metastases; therefore, MRI is preferable [70] and is alternatively performed whenever CT is unfavorable. Functional confirmation of PCC/PGL with superior specificity may be achieved with 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 18F-fluorodeoxyglucose (FDG) PET/CT, or 18F-fluorodihydroxyphenylalanine (DOPA)-PET/CT [71, 72]. Unequivocal biochemical evidence with typical adrenal imaging does not require functional imaging. This is, however, recommended in young patients, suspicion of metastases, large or multifocal tumors, extraadrenal manifestation, and syndromatic disease (MEN 2 A/B, VHL, NF1, SDH-mutation) for which MIBG scintigraphy is first choice, if negative 18F-FDG-PET or 18F-DOPA-PET should be performed, also preparing basis for tumor follow-up imaging [73,74,75].
In proven evidence of pheochromocytoma and/or paraganglioma, indication to surgery is generally given due to the cardiovascular morbidity and mortality of uncontrolled catecholamine secretion as well as for local tumor growth and malignant potential [72]. In metastasized PCC/PGL, surgery aims to prevent local complication, reduce hormone production, and improve successive therapeutic measures [73, 76, 77]. Surgery of a catecholamine producing tumor should only be undertaken after sufficient alpha-blockade. In selective cases without arterial hypertension, this may be dispensed with. In coexistent tachycardia and arrhythmia, additional beta-blockade following sufficient alpha-blockade should be provided [72, 78, 79]. Open surgery should be performed in suspicion of malignant disease or whenever capsular rupture is anticipated. Adrenal preserving resection is considered for bilateral hereditary adrenal PCC, ideally in benign eccentric localized tumors to prevent postoperative adrenal insufficiency at the risk of a higher recurrence rate [72, 80, 81].
Nonfunctioning adrenocortical adenomas
R31: All patients with adrenal tumors should preoperatively undergo clinical, biochemical, and radiological evaluation to confirm or exclude hormonal activity and/or malignancy (consensus+++).
R32: Non-functioning adrenal tumors ≥ 6 cm should be operated because of the increased risk for malignancy. For tumors between 4 and 6 cm in size no clear recommendation can be made, the decision has to be done individually (consensus+++).
R33: The indication for surgery of non-functioning adrenal tumors less than 4 cm in size has to be specifically explained (consensus+++).
R34: Non-functioning adrenal tumors without suspicion of malignancy < 6 cm in size shall be operated via a minimally invasive approach (consensus+++).
Commentary
Non-functioning adrenal adenomas are often detected incidentally by cross-sectional imaging which is primarly not performed to diagnose adrenal disease or for tumor staging [82]. The prevalence of these adrenal incidentalomas > 1 cm ranges between 1.4 and 8.7% depending on age [83,83,85]. The workup of adrenal incidentaloma has to answer the following questions:
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Is the tumor hormonally active?
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Does the tumor exhibit radiological characteristics that indicate malignancy?
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Does the patient have a personal or familial history of cancer?
According to the European Guideline “incidentaloma,” the hormonal activity of each adrenal incidentaloma > 1 cm has to be evaluated by an endocrinological biochemical workup. This has to include a dexamethasone suppression test to exclude an adrenal Cushing’s syndrome, determination of free metanephrines in plasma to exclude a pheochromocytoma, and in hypertensive patients, the determination of the aldosterone–renin quotient to exclude a Conn syndrome. If the imaging gives any suspicion for adrenocortical carcinoma, DHEAS, 17-OH-progesteron, and estradiol should be determined in serum [86]. If the presence of a metastasis cannot be excluded by imaging, a fine needle aspiration of the adrenal tumor can be considered [86, 87]. Before any adrenal puncture, pheochromocytoma has to be biochemically excluded.
Surgery has to be indicated in all non-functioning adrenal tumors ≥ 6 cm, since the risk of malignancy is about 25% [88]. Based on the available data, no definitive recommendation can be given for adrenal tumors between 4 and 6 cm without radiological suspicion of malignancy [86]. An individual approach, either surveillance or minimally invasive adrenalectomy, has to be discussed with the patient. Since there is very low risk of malignancy in non-functioning adrenal tumors < 4 cm (< 2%), there is in general no indication for resection of these tumors. Non-functioning adrenal tumors without suspicion of malignancy should be operated minimally invasively up to a size of 6 cm, since several large retrospective case series have shown that the minimally invasive approach (laparoscopically, retroperitoneoscopically) has advantages with regard to pain, convalescence, hospital stay, and development of incisional hernias [89, 90]. Larger tumors up to 10 cm without suspicion of malignancy may also be operated via a minimally invasive approach, provided the expertise of the surgeon is given [91].
Adrenocortical carcinoma
R35: The initial preoperative biochemical diagnostic workup should be performed in parallel to the imaging and has to include at least a 1-mg dexamethasone-suppression test, determination of plasma or urine metanephrines, sexual hormone, and steroid precursors. In hypertensive and/or hypocalemic patients, the aldosterone/renin-quotient should also be determined (consensus+++).
R36: Preoperatively, an intravenous contrast-enhanced CT or MRI of the abdomen and a CT of the thorax should be performed to determine tumor extension. In suspicion of bone metastasis a bone scintigraphy should be performed. An FDG-PET-CT can be considered (consensus+++).
R37: Surgery has to be indicated, if no distant metastases are present (consensus+++).
R38: ACC should only be operated in centers with more than ten adrenalectomies per year and a high expertise in surgical visceral oncology (consensus+++).
R39: Standard treatment is open en bloc resection of the tumor with its surrounding fatty tissue, using an abdominal or thoraco-abdominal incision. Rupture of the tumor capsule has to be avoided. Thus, parenchymal-sparing resections are contraindicated (consensus+++).
R40: ACC in stage 1 or stage 2 up to 10 cm can be operated via a minimally invasive approach, if the expertise to fulfill all oncological principals is given and if the patient is informed about the potential risks (consensus+++).
R41: In suspicion of infiltration of neighboring organs, en bloc resection has to be performed (consensus+++).
R41: In case of enlarged lymph nodes, a locoregional lymphadenectomy has to be performed (consensus+++).
R44: The resection of primarily unresectable infiltrative or metastasized ACC can be considered, if the tumor shows an objective regression after neoadjuvant chemotherapy, and a radical resection appears possible (consensus+++).
R45: Local recurrences should be operated, if they occur after more than 12 months latency and if they appear resectable (consensus+++).
R46: A cytoreductive resection (R2 resection) can be considered in case of a severe endocrine syndrome caused by hormonal excess that cannot be controlled by medical treatment and survival of more than 6 months can be expected (consensus+++).
Commentary
The working group adrenocortical cancer of the European Network for the Study of Adrenal Tumors (ENSAT) and the European Society of Endocrine Surgeons (ESES) recommended standards for the biochemical workup of suspected ACC [8]. Goal is the structured evaluation of any hormonal dysfunction. The workup includes a dexamethasone suppression test, free cortisol in 24 h urine, basal cortisol level and basal ACTH level in plasma and serum, sexual hormones, and their precursors (e.g., DHEAS) in serum, mineralocorticoids, the aldosterone-renin quotient in case of hypertension and hypokalemia, and an excess of catecholamines (normetanephrine and methoxytyramine in plasma) [92]. For the clarification of the dignity of the adrenal tumor, cross-sectional imaging should be performed. The most important imaging modality is contrast-enhanced CT. Density levels > 10 Hounsfield units in native phase and a washout rate of < 50% after 15 min. indicate a malignant process and need further clarification [93, 94]. Equally effective is modern MRI imaging with dynamic gadolinium enhancement and chemical shift technique [95]. For functional imaging, the 18FDG-PET is currently most valued. It allows whole body staging with regard to metastasis. The preoperative staging to clarify the presence of metastatic disease should include CT of the abdomen and thorax [8, 96]. In proposed stages 1 and 2, adrenalectomy is the treatment of choice. The complete resection of the tumor with the surrounding paraadrenal and perirenal fat tissue should be performed. An incomplete resection, rupture of the tumor capsule or an R2 resection should be avoided in all circumstances, since these are associated with higher recurrence rate and with inferior survival [8, 97, 98]. Several groups suggest that ACC should be only operated in institutions that either perform more than 4 ACC operations per year or more than 15 adrenalectomies for different indications per year [8, 12, 99]. Since there is always the possibility of necessary multivisceral resection, this expertise has to be provided in centers that operate on ACC. In case of a tumor thrombosis that reaches the inferior vena cava or the right atrium, this might require the use of the heart–lung machine or the replacement of the vena cava. The standard incision should be a median laparotomy or in big tumors a thoraco-abdominal incision. In ACC stages 1 and 2 up to 10 cm, a laparoscopic approach can be considered, if there is a high laparoscopic expertise and the oncological criteria will be respected. The data with regard to this topic based on retrospective case series are, however, not conclusive. In one retrospective study with 165 patients, including 64 laparoscopically operated patients, a higher local recurrence rate and an inferior overall survival was shown after laparoscopic procedures [100]. A meta-analysis of 673 patients, however, concluded that no definitive conclusion can be drawn due to the highly heterogeneous retrospective data, so that the gold standard should be the open adrenalectomy [97]. In case of invasion of the ipsilateral kidney or another surrounding organ (mostly liver, pancreas tail or spleen), simultaneous en bloc resection of these organs should be performed to avoid rupture of the tumor capsule. Routine nephrectomy is not recommended, since the influence on overall survival is not proven [101]. Even in cases of infiltration of the renal vein, vena cava or a tumor thrombus which extends into the vena cava or sometimes into the right atrium a R0 resection should be achieved, since the 5-year survival rates are up to 29% [102, 103]. The incidence of lymph node metastasis varies between 10 and 70% [104,105,106,107]. In large cohorts from the USA and France, the rate of lymphadenectomy during the primary resection was only 30% [108, 109]. The German ACC registry showed that the resection of more than five lymph nodes reduces the risk of a local recurrence and the overall mortality [97]. Lymph node metastases are most frequently found in the perirenal, paraaortal, and paracaval lymph nodes [109]. As yet, there are no clear recommendations which lymph node stations and how many lymph nodes should be removed. The ENSAT/ESES guidelines recommend a lymph node dissection in the ipsilateral kidney hilus at the origin of the kidney vessels as well as ipsilateral paraaortal and paracaval region [8]. Lymphadenectomy should especially remove lymph nodes that are enlarged on preoperative imaging. A neoadjuvant therapy can be considered in so-called borderline resectable ACC [110, 111]. In one small retrospective study, 13 of 15 ACC could be resected after neoadjuvant treatment and the median disease-free survival was 28 months [111]. A local recurrence occurs in 20–60% of patients [112, 113]. The decision for reoperation should only be made, if an R0 resection appears possible and the anticipated morbidity is low. Patients with a local recurrence within 6 months after primary resection have a poor prognosis, so that the indication for reoperation should be very restrictive. A resection of metastasis should be only performed in patients with a low Ki-67 index and development of their metastasis at least 12 months after the primary resection, since these patients might have a survival benefit compared to medical treatment only [8, 114,115,116,117]. It is evident that patients who underwent only R2 resection have a similar poor prognosis like patients who had no surgery [118]. In case of otherwise untreatable hormonal excess, however, a debulking of at least 80% of the tumor burden can be considered to achieve symptom control [119].
Ganglioneuroma, neuroblastoma and myelolipoma
R51: For adrenal neuroblastoma therapy must follow risk adaption (resection only or in combination with chemo-, radiation-, or MIBG-therapy (consensus+++).
R52: In symptomatic ganglioneuroma, resection is indicated (consensus+++).
R53: Symptomatic myelolipoma should be resected (consensus+++).
Commentary
Neuroblastomas are malignant tumors of infancy that most frequently manifest in the adrenal. Prognosis and therapy are linked to MYCN mutation, and patients should be registered in a study for risk-adapted therapy (NB2004) involving resection, chemotherapy, external radiation, and MIBG-therapy or a combination of these [120].
Ganglioneuroma are rare, mostly benign, sometimes hormone producing tumors of the autonomous nerve system, evolving during childhood. Primary therapy is resection in symptomatic tumors [121].
Adrenal myelolipoma are rare functional inactive and mostly asymptomatic benign tumors containing mature adipose and hematopoetic tissue evolving in the fifth to seventh decade. Large tumors, necrosis, or bleeding may cause pain, thus representing indication to resection [122].
Adrenal metastases
R54: Patients with a history of malignant disease should be evaluated for adrenal metasasis when an adrenal lesion does not meet adenoma characteristics on imaging (consensus+++).
R55: Standard evaluation for defining the nature of the adrenal lesion should be abdominal CT or MRI. In suspicion of adrenal metastasis, FDG-PET/CT should be added (consensus+++).
R56: In case imaging remains ambiguous, CT- or ultrasonsography-guided biopsy of the adrenal lesion may be considered after pheochromocytoma is ruled out (consensus+++).
R57: For isolated adrenal metastasis, adrenalectomy can be indicated (consensus+++).
Indication for adrenalectomy for adrenal metastases should be established in interdisciplinary tumor board (consensus+++).
R58: Resection of adrenal metastases should be performed minimally invasively, whenever complete safe resection without spillage can be facilitated. Open surgery should be restricted to rare cases with signs of local infiltration or lesion size > 6 cm (consensus+++).
R59: In inoperable patients, radio-frequency ablation (RFA) as alternative to surgery may be considered (consensus+++).
Commentary
Secondary to benign non-functional adenomas adrenal metastases are the most frequent adrenal tumors [23, 123]. However, even in previous malignancy, 48% of adrenal lesions are benign “incidentalomas” [124]. Origins of adrenal metastases are mainly non-small cell bronchial carcinoma (NSCLC) and breast cancer, but malignant melanoma, hepatic cell carcinoma, and renal cell cancer are also found [23, 125]. In bilateral adrenal lesions, evaluation of adrenal insufficiency is reasonable [97]. Fat content in CT and MRI is critical in differentiation of adrenal adenoma vs. metastasis (low); similarly, high metabolic activity in FDG-PET/CT is found in metastasis rather than in adenoma [126,123,124,129]. Oncologic benefit of adrenalectomy in adrenal metastases remains unclear for most cases; therefore, interdisciplinary tumor board counseling is recommended. Some data show adrenalectomy to be a good prognostic marker for all-over survival in certain primary tumors [130,127,132].
Perioperative management
Primary hypoaldosteronism
R61: Hypokalemia should preoperatively be compensated (consensus+++).
In PHA administration of aldosterone antagonists should be stopped preoperatively for at least 2 weeks in order to compensate hypokalemia (consensus+++).
In patients with unilateral aldosterone producing adenoma (APA), potassium substitution and aldosterone antagonist can be stopped directly with surgery (consensus+++).
In patients with persistent hyperaldosteronism requiring continuation of aldosterone antagonist therapy, slowly increased titration with spironolactone should be first choice (consensus+++).
In very young patients with PHA or in families with several affected individuals, and in case of cerebrovascular infarction at ≤ 40 years, genetic testing (FH-I, FH-III) should be initiated (consensus+++).
Commentary
Preoperative low potassium concentration is frequent in PHA, pronouncedly in APA and is associated with elevated perioperative risk. Compensation can be achieved with potassium substitution and/or administration of aldosterone antagonists [30, 133]. Spironolactone offers good correction of hypertension as well as correcting low potassium; therefore, preoperative treatment, namely in unilateral APA, is efficient [134]. Early postoperative controls of aldosterone and renin level are advised [133]. Postoperative adaption of potassium, antihypertensive medication, and specific diets need to be individually addressed [133, 135,132,133,134,135,140].
Cortisol-producing adrenal tumors (Cushing’s syndrome)
R62: Preoperative treatment to regulate hypertension, compensate electrolytes, and correct diabetes should be initiated (consensus+++).
Susceptibility for infectious disease must be addressed with “single-shot” antibiotic prophylaxis perioperatively, whereas other forms of adrenelactomy do not require antibiotic prophylaxis (consensus++).
Inhibition of steroid synthesis (e.g., ketoconazole) should be avoided due to potential intraoperative side-effects (consensus+++).
Following resection of a cortisol-producing adrenal tumor, consistent postoperative glucocorticoid substitution is obligatory, if necessary adapted to stress (e.g., infection, surgery) and completed with mineralocorticoids. It is compulsory to inform and instruct the patient specifically in these regards. The patient must be supervised by an endocrinologist (consensus+++).
Following bilateral adrenalectomy permanent substitution of glucocorticoids at basal levels, and stress-adapted elevation of dose alongside mineralcorticoid substitution must be provided. The patient must be equipped with an emergency certificate. The patient must be supervised by an endocrinologist and requires specific education (consensus+++).
Commentary
Up to 70% of patients with adrenal tumors undergoing surgery reveal hypertension, 19% diabetes, and patients with adrenal Cushing’s disease are predominantly affected. Correction of hypertension, hyperglycemia, hypokalemia, and alkalosis before surgery are recommended for all patients undergoing adrenal surgery [86, 141,138,143]. Postoperative management of cortisol-producing adrenal tumors, irrespective of unilateral or bilateral surgery, requires glucocorticoid substitution until recovery of the hypothalamic-pituitary axis is evident or permanent following bilateral adrenalectomy [144]. Possible abdication or lower dose and abbreviated duration of glucocorticoid substitution may be managed in accordance with ACTH-(synacthene test (tetracosactid)) stimulation test results [16, 145, 146].
Pheochromocytoma and paraganglioma
R63: Patients with symptomatic pheochromocytoma (PCC) and paraganglioma (PGL) should receive preoperative non-selective or selective α-1-receptor blockade. In asymptomatic patients without hypertension (particularly VHL and PGL), it may be considered to abstain from preoperative blockage (consensus+++).
During surgery for PCC, invasive monitoring with arterial blood pressure assessment, central line, and venous catheter must be performed. Emergency medication to treat hypertensive crisis (e.g., nitroprusside) or hypotension (e.g., arterenole) must be immediately accessible (consensus+++).
Following complete resection of localized benign PCC, perioperative α-blockage should be immediately stopped (consensus+++).
All patients with PCC and PGL should be informed and offered genetic testing in order to clarify heredity. The presenting phenotype may assist orientation in decision algorithm (consensus+++).
Postoperative surveillance and follow-up with laboratory controls should be ascertained or delegated to endocrinology for all patients following surgery for PCC and PGL (consensus+++).
Commentary
Generally, patients undergoing surgery for PPC and PGL require preoperative α-blockage in order to prevent hypertensive crisis perioperatively. Advantages initiated a shift to selective competitive α1-receptor blockage from previously universal use of unselective non-competitive α1- + 2-receptor blockage [2, 72, 147]. In selective cases without hypertension or cardiovascular risk factors, preoperative blockage may be omitted [148,145,150]. Prognostication of intraoperative circulation and blood pressure remains challenging and requires uninterrupted optimal monitoring to enable immediate intervention and close communication between surgeon and anesthesiologist [151]. Postoperative management after complete resection of PCC and PGL is determined by the nature of disease and heredity and oftentimes requires immediate stop of blocking agents [72]. Increasing knowledge of phenotype–genotype correlation in PCC and PGL assists genetic counseling of patients that should generally be offered [152,149,150,151,156]. Biochemical follow-up investigation should be aligned to the nature of disease and the specific differential catecholamine and metabolite profile [72, 156,153,154,155,156,161].
Adrenocortical carcinoma
R64: In ACC, patients with advanced disease, residual tumor or with suspicion of tumor recurrence, diagnostics, and therapy should be aligned to published guidelines (e.g., Berruti et al., 2012) and involve proficient oncologists/endocrinologists with disease specific expertise with the entity. Basic thoracic CT and abdominal CT/MRI are recommended pre- and every 12 weeks postoperatively for 2 years following initial surgical therapy (consensus+++).
Individual steroid profile should be assessed preoperatively in all patients with suspicion of ACC and be reinvestigated every 12 weeks during 2 years after initial surgery.
Commentary
Rapid progression of ACC necessitates brief intervals in follow-up including thoracic and abdominal CT or MRI and plasma or urine steroid concentrations that need to be known previous to primary surgery in order to guide surveillance according to the individual “steroid profile.” After 2 years of follow-up, intervals may be prolonged to 6–12 months and should be maintained for at least 10 years [8, 94].
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Lorenz K: no disclosures
Langer P: no disclosures
Niederle B: no disclosures
Alesina P: no disclosures
Holzer, K: holds Bayer shares
Nies C: no disclosures
Musholt Th: no disclosures
Goretzki P: received consultant’s + speaker’s honorarium from: Sanofi, Ipsen, Novartis GmbH
Rayes N: no disclosures
Quinkler M: received speaker’s honorarium from: Shire plc GmbH, Ipsen GmbH
Waldmann J: no disclosures
Simon D: no disclosures
Trupka A: holds Bayer shares
Ladurner R: no disclosures
Hallfeldt K: no disclosures
Zielke A: no disclosures
Saeger W: received grants from: Ipsen, Novo-Nordisk, Novartis GmbH
Pöppel Th: no disclosures
Kukuk G: no disclosures
Hötker A: no disclosures
Schabram P: no disclosures
Schopf S: holds shares from ISAR-U GmbH
Dotzenrath C: no disclosures
Riss P: no disclosures
Steinmüller Th: no disclosures
Kopp I: no disclosures
Vorländer C: received grants from:Olympus GmbH
Walz M: received speaker’s honorarium from: Karl Storz GmbH, Medtronic Co.
Bartsch DK: received speaker’s honorarium from: Novartis
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Appendix
Appendix
Guideline working group “surgical treatment of adrenal tumors” of the German Society of Endocrine Surgery (CAEK) of the German Society of General and Visceral Surgery (DGAV) (in alphabetical order)
Dr. P. Alesina, Essen
Prof. D.K. Bartsch, Marburg
Prof. C. Dotzenrath, Wuppertal
Prof. P.E. Goretzki, Berlin
Prof. K. Hallfeldt, München
Prof. K. Holzer, Marburg
PD Dr. R. Ladurner, München
Prof. P. Langer, Hanau
Prof. K. Lorenz, Halle
Prof. T.J. Musholt, Mainz
Prof. B. Niederle, Wien
Prof. Chr. Nies, Osnabrück
Prof. N. Rayes, Leipzig
RA P. Schabram, Freiburg
Prof. D. Simon, Duisburg
PD Dr. S. Schopf, Agatharied
Prof. Th. Steinmüller, Berlin
Prof. A.W. Trupka, Starnberg
Dr. C. Vorländer, Frankfurt
Prof. J. Waldmann, Hamburg
Prof. M. Walz, Essen
Prof. A. Zielke, Stuttgart
Delegates from the participating der medical societies and organizations
AWMF, moderator live consnensus conference: Prof. I. Kopp, Marburg
DGAV: represented by the guideline working group of the CAEK
German Society of Endocrinology: Prof. M. Quinkler, Berlin
German Society of Nuclear Medicine: Prof. Dr. Th.Pöppel, Essen
German Society of Pathology: Prof. Saeger, Hamburg
German Society of Radiology: PD R. Guido Kukuk, Bonn, Dr. Andreas Hötker, Zürich
German Society of Medical Oncology: Prof. Heiko Krude, Berlin
Patientent Support Group Network Pituitary and Adrenal Diseases; registered association, Ms. M. Schubert
Participants of the live consensus conference June 6, 2016 in Frankfurt/M
Prof. I. Kopp, AWMF
Dr. P. Alesina, Essen
Prof. D.K. Bartsch, Marburg
Prof. C. Dotzenrath, Wuppertal
Prof. Dr. K. Hallfeldt, München
Prof. K. Holzer, Frankfurt/M.
Prof. P. Langer, Hanau
Prof. K. Lorenz, Halle
Prof. T.J. Musholt, Mainz
Prof. B. Niederle, Wien
Prof. M. Quinkler, Berlin
Prof. N. Rayes, Leipzig
Prof. W. Saeger, Hamburg
RA P. Schabram, Freiburg
Prof. Th. Steinmüller, Berlin
Dr. C. Vorländer, Frankfurt/M.
Prof. J. Waldmann, Hamburg
Prof. M. Walz, Essen
Prof. A. Zielke, Stuttgart
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Lorenz, K., Langer, P., Niederle, B. et al. Surgical therapy of adrenal tumors: guidelines from the German Association of Endocrine Surgeons (CAEK). Langenbecks Arch Surg 404, 385–401 (2019). https://doi.org/10.1007/s00423-019-01768-z
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DOI: https://doi.org/10.1007/s00423-019-01768-z