To our knowledge, the present study is the first to detail the clinical presentation, management and outcomes of patients with MEN2-related bPHEO in an ethnic Han Chinese cohort. We found bilateral disease in approximately 59% of patients with PHEO, which is similar to that Castinetti et al.[2] previously reported where accounts for 61%. In this series, bilateral disease only associated with RET-C634 mutations, as MEN2A (90%) and RET-M918T, as MEN2B (10%), but absence of other mutations of RET, showing a relatively single mutation genotype [2, 13, 21, 32] (Table 1, 2). Our finding also revealed that bPHEO was exclusively benign, synchronously involving both adrenal glands in about four fifths, in approximately 23% diagnosed at an asymptomatic stage, and the mean tumor size was 3.8 cm, while those observed in patients with PHEO found through mutation-based screening less than symptomatic PHEO (P = 0.003) [10, 32]. Multifocal about 83%, and affected patients were mostly initial operated on before 40 years of age [2, 3, 10, 13]. However, it should still highlight the need for an optimal surgical procedure of choice to manage these patients, in spite of these PHEO-related deaths occur less frequently. In contrast, previously, the majority of studies mainly focusing on a more common cause of death and the outcome of MTC in these patients [2, 3, 10, 13], the use of prophylactic thyroidectomy in genotype-specific age, or extent of thyroidectomy based on genotype and serum calcitonin levels had became routine and formal practice guidelines recommended [1–4,9−13,23–26,33,34].
By contrast, the second major component PHEO of MEN2 could be treated by laparoscopic excision already established conventional procedure, which should be removed prior to surgery for either MTC or hyperparathyroidism [13, 14, 34]. In the last two decades, also, laparoscopic bilateral adrenalectomy for bPHEO showed a sharp reduction of intraoperative haemodynamic instability, providing an equal chance to cure hypertension, and less intraoperative blood loss, lower overall complication rates, while also caused a faster, better postoperative recovery and a better cosmetic result rather than the open approach [11–14, 20, 35, 36]. In this study, the similar results were also revealed that less bleeding volume and shorter hospitalizations, which are possible with LCSA compared with those in OCSA or hybrid surgery (all P < 0.05; Table 1–4, and Fig. 1). As for CSA approach for treatment of PHEO, should only be considered as an alternative procedure or a relatively weak recommendation, but not become established in the routine MEN2 practice guidelines [11–14, 34, 38, 39]. Of these mainly concerns the risk of remnant recurrences, reoperation, metastases, and likelihood of corticosteroid independence after CSA. Nevertheless, CSA as a feasible surgical approach for unilateral/bilateral PHEO in MEN2 patients was still performed by numerous clinicians [1–4,10,12,15–23,26,33,37−40]. A recent multicentre study of 563 MEN2 patients with PHEO, which includes some patients from our cohort, showed that malignant disease was in less than 1%, bPHEO with CSA in one or two operated glands associated with recurrence in 5% out of 114 patients and of whom 57% did not required steroid dependency at a median of 9.5 years (range, 1–28) postoperatively [2]. Another multicentre study of bPHEO (n = 625), of in 505 of 526 tested patients (96%) with germline mutations were detected that the majority of patients had RET mutations rather than VHL or other gene mutations (282 versus 184 versus 39, respectively), showed that CSA is associated with recurrence in 13% and malignant disease in 2% of patients at follow-up of a median of 8 years (IQR 4–17) [1]. In this series, of which 29 patients underwent LCSA or OCSA, trying to preserve most of the uninvolved adrenals using PHEO enucleation or subtotal adrenalectomy (CSA) with as much as possible rim (0.5 to 1.0 cm) of normal adrenal tissue. Postoperatively, in approximately 48% out of these patients still required lifetime steroid replacement, and in 2 of them (6.9%) suffered transient complications of steroid dosage. Meanwhile, about 10% out of these patients experienced tumor recurrence, showing that real recurrences are typically found about 8 years (range, 3–16) or later after CSA, but lacking metastatic or PHEO-related death (0%) (Table 1, 3, 4, and Fig. 1). It is noticeable that, nearly total adrenalectomy is sometimes inevitable when a large tumor (such as P30) is in an unfavorable location or when multifocal tumors (P24) are present or reoperation for recurrent PHEO (P25, P29) by laparoscopic procedure. Interestingly, however, patients (P1), who with 9 small multifocal tumors underwent PHEO enucleation, did not require steroid replacement follow-up 17.5 years postoperatively (Table 1). It seemingly to imply that enucleation may be more beneficial to preserving vascularized adrenal cortical tissue/function than subtotal adrenalectomy — preserving at least 10–15% of one remnant of properly vascularised adrenal cortical tissue appear to offer adrenal stress capacity [22, 31, 36]. However, the long-term follow up for at least 10 years should be still need in all these patients due to a persisting disease, because of the risk of recurrent PHEO is about 20% within 20 years after CSA [10, 11, 13]. Nevertheless, LCSA or OCSA approach did not decrease survival and imply that offers excellent oncologic and functional outcomes, particularly, LCSA (including robotic surgery [37]) as a safe and effective surgical management for the treatment of bilateral and/or multifocal PHEO (even for tumors measuring > 6 cm [36]) in MEN2 should be routine considered to utilize or might be more prone to recommend [1–4,10,15–23,26, 33,35−40].
Additionally, treating patients with synchronous bPHEO can be challenging, and there is no uniform standard surgical approach whether synchronous or two-stage (metachronous) procedures. Following laparoscopic device innovation, the accumulation of sufficient experience and proficient surgical skill, synchronous surgery including SB-LCSA was increasingly used in clinical practice for treating these bPHEO [10, 15–23, 41]. Walz et al. [16] reported that 15 patients with bPHEO (the tumor size of average 4.6 cm; 2 cases of recurrent PHEO on one side) underwent synchroenous bilateral laparoscopic adrenalectomy, of whom 14 (93.3%) were successfully removed bilateral tumors duration of the same anesthesia. In another case the procedures were split due to cardiac arrhythmias during laparoscopic removal of a 12 cm right-sided PHEO, and the contralateral 3 cm tumor was extirpated 5 weeks later retroperitoneoscopically. Kittah et al. [10] reported 98.7% out of 75 patients with synchronous PHEO (41 MEN2, 13 VHL, 7 NF1 and 14 other PHEO; the median tumor size of 3.0 cm), of who 74 underwent a simultaneous bilateral adrenal surgery, and in 18 (24%) of them, a simultaneous bilateral CSA was successfully performed. Nine (44.4%) of the 18 patients required steroid replacement, 3 (16.7%) had recurrent at a median of 16.2 years (range, 3.6–51.9), and 2 developed metastatic PHEO 20 years postoperatively. Contrary to the present study, 27 patients (87.1%) had initial synchronous PHEO. Of these, 23 were simultaneous successfully removed bPHEO, where the median size of tumors were 3.8 cm, and 10 (43.5%) of them, required steroid replacement at a median follow-up of 10.5 years (range, 1.8–23), whereas none of them had recurrent and metastatic postoperatively (Table 1, 3, 4). Despite, there were 38.9% out of 18 underwent SB-LCSA, or 60% out of 5 underwent SB-OCSA, who respectively required steroid replacement, and the mean tumor size was (3.8 ± 1.7) or (5.1 ± 2.3) cm, yet had no significantly different (P = 0.397; P = 0.060). SB-LCSA can be safely performed and used for synchronous bPHEO surgery, which had advantages of less blood loss and shorter hospitalizations than MB-OCSA (Table 4). Moreover, in other 1 cases (P28) of recurrent PHEO (1.2 cm) on one side and developed contralateral PHEO (5.3 cm) was also subjected to SB-LCSA (Table 1). However, re-operation seems harder than primary operations mainly due to adhesions, but there can also be performed laparoscopically. SB-LCSA or SB-OCSA is technically safe and feasible [10,12,16−19], in particular, SB-LCSA can be considered as preferential choice in the surgical management for synchronous bPHEO in MEN2, even for recurrent PHEO as potential options.
With regard to whether the adrenal central vein should be preserved duration of the CSA. From our data and from descriptions by previous studies, there seems unnecessary to deliberately preserve the central adrenal vein [16, 18, 22]. However, it may be important not to excessive separate the remnant adrenal gland from the adjacent space, since the vascular bed adjacent to the remnant adrenal gland is integral to the preservation of its function. Correspondingly evidence of the presence of successful adrenal auto-transplantation was low [10, 16, 18, 22, 42]. In addition, it is not necessary to beforehand dissociate or ligate the central vein. In general, the surrounding adrenal tissue can be separated at a distance of 0.5–1.0 cm from PHEO by harmonic scalpel. Especially when the preoperative CT/MRI scan showed that the PHEO was large and the splenic/renal vessels were obviously compressed and deformed, it should be preferentially separated from the surrounding tissue vessels along the surface of PHEO capsule, and the central vein could be ligated after the boundary was clear (Fig. 2A, 2B). Meanwhile once the specimen removed, it should need to be carefully examined and preliminary assessment of whether there is an adequate disease-free margin around PHEO.