Advances in Endocrine Surgery
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Michael S. Lui, MD, Aditya S. Shirali, MD, Bernice L. Huang, MD, Sarah B. Fisher, MD1, Nancy D. Perrier, MD1,*
KEYWORDS
. Papillary thyroid cancer . Thyroid lobectomy . Lymph node dissection
. Hyperparathyroidism . Parathyroid carcinoma . Adrenocortical carcinoma
. Pheochromocytoma · Cushing’s syndrome
KEY POINTS
. Well-selected patients with low-risk papillary thyroid carcinoma can be adequately treated with thyroid lobectomy. Identification of available radiologic, pathologic, and molecular risk factors can help identify those at higher risk of disease recurrence who are better served with total thyroidectomy.
· Prophylactic central lymph node dissection for patients with papillary thyroid carcinoma should not be routinely performed but should be considered for selected patients with large primary tumors considered to be at risk for clinically significant occult nodal disease.
· Advancements in multiple imaging modalities and localization adjuncts have allowed for more directed surgical approaches in the management of primary hyperparathyroidism.
· Management of localized parathyroid carcinoma involves parathyroidectomy with en bloc resection of directly involved tissue, whereas the management of locally advanced or distantly metastatic parathyroid carcinoma requires multidisciplinary care including well-selected surgical resection, antiresorptive therapies, and calcimimetics to control hy- percalcemia, with immunotherapy and/or targeted therapy showing promise as potential therapeutics.
· A minimally invasive approach to adrenalectomy should be considered for benign and/or functional adrenal tumors, whereas an open approach is preferred when there is a concern for potential primary malignancy.
ADVANCES IN THE MANAGEMENT OF PAPILLARY THYROID CARCINOMA Introduction
Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with an estimated incidence of 43,800 people in the United States alone in 2022 (Table 1).1 Survival is favorable, with 5-year survival greater than 98%.2 Thyroid cancer
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
1 Co-senior authorship.
* Corresponding author. Unit 1484, 1515 Holcombe Boulevard, Houston, TX 77030.
E-mail address: Nperrier@mdanderson.org
Surg Oncol Clin N Am 32 (2023) 199-220 https://doi.org/10.1016/j.soc.2022.08.004
| Authors, Year | Randomized Groups | n | Ages | Primary Tumor Size (cm)c | Follow-up (months) | Nodal Disease (n, %) | Recurrence (n) | Endpoint Outcomes | Complications |
|---|---|---|---|---|---|---|---|---|---|
| Lee et al, 44 (2015) | TT TT/pCLND | 104 153 | 51.6 52.3 | 1.6 1.7 | 49.2 55.2 | n/a 35 (22.8%) | 4 5 | No mortality in either group Recurrence Rate (P = . 780) TT: 3.9% | TT/pCLND: 3.3% | TT/pCLND had higher transient hypocalcemia (36.6% vs 20.3%, P = 0.043) |
| No difference in transient/ permanent vocal cord paralysis and postoperative bleeding (P = NS) | |||||||||
| Viola et al,45 (2015) | TT | 88 | 41 | 1.6 | 6 (6.8%) | 7 7 | Persistent/Recurrence (P = 0.9) TT: 8.0% | TT/pCLND: 7.5% | TT/pCLND had higher permanent | |
| TT/pCLND | 93 | 45.5 | 1.6 | 60 (median) | 43 (46.2%) | hypoparathyroidism (19.4% vs 8%, P = 0.02) No difference in recurrent laryngeal nerve palsy (P = NS) | |||
| ªKim et al, 46 (2020) | Lobectomy Lobectomy pCLND | 82 82 | 47.9 48.5 | 0.6 0.68 | 72.6 74.2 | n/a 41 (50%) | 1 3 | Recurrence Rate (P > 0.99) Lobectomy: 1.2% Lobectomy/pCLND:3.6 No difference in recurrence free survival (P = . 929) | No difference in vocal cord paralysis (1.2% vs 0%, P = 0.49) No patients developed hypocalcemia. No reported mortality |
| bSippel et al, 47 (2020) | TT TT/pCLND | 30 30 | 46.1 50.1 | 2.45 1.91 | 12 12 | 10% 27.6% | 1 1 | 1 y Tg < 0.2 (P = 1.00) TT: 88.9%, | TT/pCLND 90.0% 1 y negative-US (P = 0.7) TT: 85.7% | TT/pCLND: 85.1% Indeterminate US/Tg data (P = 0.70) TT: 10.7% | TT/pCLND 14.8% | No difference in |
| hypoparathyroidism or recurrent laryngeal nerve paralysis at 2-wk and 6-mo after surgery (P = NS) No difference in QOL based on the thyroid cancer-specific QOL measures between groups |
| Ahn TT et al, 48 (2022) | 50 | 51.8 | 1.1 | 46.3 | 3 (6%) 1 | No patients developed structural recurrence | No difference in hypoparathyroidism or recurrent laryngeal nerve paralysis after surgery (P = NS). |
|---|---|---|---|---|---|---|---|
| TT/pCLND | 51 | 53.6 | 1.0 | 46.8 | 14 (27.5%) 1 | No difference local recurrence rates (2% vs 2%, P = 0.945) | All postoperative symptoms resolved at 6-mo follow-up |
Abbreviations: ATA, American Thyroid Association; pCLND, prophylactic central lymph node dissection; US, ultrasound; TT, total thyroidectomy; Tg, thyroglobulin, QOL, quality of life
a Kim et al looked at patients with microcarcinomas with an intention to treat protocol.
b Sippel et al categorized oncologic outcomes at 1 year based on 2016 ATA definition for Response to Initial Therapy.20
Tumor sizes recorded as mean unless otherwise labeled.
management focuses on 3 strategies: (1) surgical resection, (2) radioactive iodine ablation (RAI), and (3) thyroid-stimulating hormone suppression. Total thyroidectomy (TT) was traditionally the recommended surgical approach for all patients with DTC greater than 1 cm as it removes disease, facilitates adjuvant therapy with RAI, and al- lows for thyroglobulin monitoring for long-term surveillance. More recently, this para- digm has shifted as studies have shown similar survival and recurrence rates for patients with low-risk cancers undergoing lobectomy alone. Thyroid lobectomy, when oncologically appropriate, preserves native thyroid hormone function and further reduces already low risks of complications.3 The following sections will discuss the studies that have shaped current guidelines in the surgical management of papil- lary thyroid cancer (PTC).
Extent of Surgical Intervention for Papillary Thyroid Cancer
Survival and recurrence data stratified by operative extent
Staging for DTC is unique in that while it incorporates the traditional tumor-node- metastasis classification, it also incorporates age, with all patients aged younger than 55 years classified as stage I unless distant metastases are present (and then classified as stage II).4 Although recent modifications to the eighth edition bet- ter risk stratify patients than previous editions,5 additional meaningful prognostic factors described in prognostic scoring systems (ie, MACIS: metastasis, age, completeness of resection, invasion, size) may better predict cancer-specific sur- vival,6,7 and allow stratification into “low-risk” and “high-risk” categories.8-10 Early studies using risk-stratification scoring systems suggested that in patients with low-risk disease, TT did not improve disease-specific survival (DSS) over lobec- tomy.11,12 In 2007, Bilimoria and colleagues13 published a large retrospective study using the National Cancer Database (NCDB), which showed that patients who un- derwent TT for tumors greater than 1 cm had higher 10-year overall survival (OS), and lower recurrence rates than those that had lobectomy. This robust study was the cornerstone of the 2009 American Thyroid Association (ATA) recommenda- tion for TT for tumors greater than 1 cm.14 However, others point out that other important prognostic factors such as extrathyroidal extension (ETE), patient comor- bidities, and multifocality were not included into the analysis. Follow-up studies us- ing the Surveillance, Epidemiology, and End Results (SEER) database stratified patients by tumor size (in 1 cm increments) and found, after controlling for con- founding variables, no difference in OS or DSS when comparing TT to lobec- tomy.15,16 This was further confirmed by the now largest study combining both NCDB and SEER data which showed no significant difference in OS between TT and lobectomy when adjusting for patient-specific and tumor-specific factors, high- lighting the importance of appropriate patient selection.17-19 In light of these find- ings, the current ATA guidelines now recognize that lobectomy is sufficient for well-selected patients with cancers less than 4 cm in size without clinical evidence of nodal metastasis or adverse histopathologic factors (multifocality, ETE, tall cell/ columnar/hobnail variants, BRAF p.V600 E mutation), provided they have no family history of thyroid cancer or personal history of excess exposure to radiation.20 It is important to note that while molecular testing on fine needle aspiration specimens can sometimes preoperatively identify mutations (ie, BRAF and TERT), the role of mutational status in guiding extent of surgical therapy remains unclear (see “Role of Molecular Testing” section). The decision between lobectomy and TT should incorporate all available objective data as well as patient values and preferences to allow for individualized management.
Role of Molecular Testing
The BRAF p. V600 E mutation is identified in up to 70% of PTC21 and is associated with more aggressive disease biology with increased rates of ETE,21 lymph node metas- tasis,21,22 distant metastasis,22 and recurrence.21,23 However, establishing a direct relationship between BRAF-mutation status and survival remains challenging because it requires prohibitively long prospective studies because OS in these patients remains high compared with other malignancies.20,22,24 It is likely that BRAF-mutation status, in combination with other clinicopathologic factors informs risk stratification, and further research is necessary to evaluate the optimal combination of risk factors that should guide decisions regarding the extent of surgery.
Recently, the TERT promoter mutation has been identified as a marker in predicting clinically aggressive behavior in PTC and has been associated with worse disease- free survival (odds ratio 4.68, 95% confidence interval 1.54-14.27).25 Xing and col- leagues26 showed that individuals with a TERT mutation in conjunction with a BRAF-mutation had higher recurrence rates (68.6% vs 8.7%, P < . 001) compared with those that had neither mutation. The ATA has incorporated BRAF-mutation and TERT-mutation status into their risk stratification system with either conferring a higher risk for recurrence.20
Molecular testing is designed to identify mutations in cytologically indeterminate thyroid nodules, with the goal of selecting those nodules at higher risk of malignancy and thus decreasing the number diagnostic lobectomies for ultimately benign patho- logic condition. Two common tests, an RNA-based gene analyzer27 and a DNA-based and RNA-based next generation sequencing28 were found to have sensitivities of 92% and 70% to 96%, and specificities of 52% and 77% to 92%, respectively.29 A recent randomized control trial (RCT) comparing these tests found no statistical difference between the modalities with both having 97% to 100% sensitivities and 80% to 85% specificities.29 Although molecular testing may be helpful in risk stratifying pa- tients with indeterminate cytology, the role of molecular testing in deciding the extent of surgery for known malignancy continues to be an area of research. Routine testing of patients with early stage/resectable thyroid cancers remains controversial and is not universally adopted or recommended in the setting of a clear indication for thyroid- ectomy.20 Future studies evaluating the impact of molecular profiling of thyroid cancer on surgical decision-making are needed.
Active Surveillance
Active surveillance (AS) as a management strategy for papillary thyroid microcarcinoma (typically tumor size <1 cm) was first proposed by Ito and colleagues30 in 2003 in which patients without unfavorable features (tumors adjacent to the trachea, tumors poten- tially invading the recurrent laryngeal nerve, lymph node suggestive of metastasis) were surveilled regularly for signs of progression rather than treated surgically. At 5- year and 10-year follow-up, 6.4% and 15.9% of patients demonstrated tumor enlarge- ment, respectively, defined as growth of at least 3 mm, whereas 1.4% and 3.4% of patients developed nodal metastases, respectively.31 In addition, there were no cases of recurrence or mortality in patients that were later selected for surgery, suggesting the ability to salvage patients who progressed without an impact on DSS. Brito and Ito and colleagues32 developed a risk-stratification system incorporating patient, tumor, and medical team factors to best identify the ideal candidate for AS. Although the 2015 ATA guidelines acknowledge that AS may have a role in low-risk, well-selected patients with PTC, this management strategy requires appropriate counseling, patient motivation and compliance, and an experienced multidisciplinary team.20
Impact of Patient Preferences
Survivorship for patients with well DTC is excellent, yet many report an impaired qual- ity of life similar to that of other cancer survivors. 33,34 The decision between lobectomy and TT, when such a choice is oncologically appropriate, should incorporate individual patient preference and relative value placed on preserving native thyroid hormone function versus concern for recurrence. For example, one recent study examined psy- chological factors influencing patient decision-making regarding surveillance or completion thyroidectomy after lobectomy for low-risk DTC. Fear of taking lifelong thyroid hormone supplementation most frequently swayed patients to choose surveil- lance, whereas fear of disease progression was associated with preference for completion surgery.35 Thyroid hormone supplementation may still be required after lo- bectomy, and this possibility should be clearly communicated preoperatively and factored in to decision-making to avoid a negative impact on the physician-patient relationship. Pairing patient preferences and priorities with appropriate therapy when oncologically reasonable is essential for developing a personalized manage- ment plan.
Lymph Node Dissection for Papillary Thyroid Cancer
Therapeutic compartmental lymph node dissection is appropriate for patients with clin- ically evident lymph node metastases (LNM). The management of clinically negative regional lymph nodes within the central neck is more controversial, with rates of occult LNM ranging from 20% to 90% depending on the extent of dissection performed.20,36,37 Current ATA recommendations support consideration of a prophylactic central LN dissection (pCLND) in patients with advanced primary tumors (T3/T4) or in patients with clinically involved lateral neck lymph nodes.2º Proponents of pCLND cite better dis- ease clearance, lower postoperative thyroglobulin levels,38 potential decrease of local recurrence rates, 39 and no increased risk of permanent morbidity in expert hands.40 In contrast, the identification of occult micro-LNM found during pCLND no longer up- stages patients in the eighth edition American Joint Committee on Cancer guidelines, 41 and others argue that there is no conclusive evidence that pCLND improves long-term outcomes, 42 with several studies demonstrating higher morbidity.39,43
To date, there are 5 RCTs published studying the impact of pCLND on locoregional recurrence (LRR) and complication rates in patients with low-risk PTC.44-48 Four of these studies included patients who had low-risk PTCs originally scheduled for TT, 44,45,47,48 whereas Kim and colleagues46 focused on patients with papillary thyroid microcarcinoma undergoing lobectomy. Most of these studies had extended median follow-up of 5 years with average primary tumor sizes less than 2 cm. Sippel and col- leagues47 reported a follow-up time of 12 months as their study was specifically pow- ered to look at short-term predictors of recurrence. The incidence of occult LNM ranged from 23% to 43%. No study found differences in LRR rates although there was heterogeneity in indications for and application of adjuvant RAI. No study identi- fied any difference in recurrent laryngeal nerve palsy rates. Two of the studies found that patients who had pCLND had higher transient (36.6% vs 20.3%)44 and permanent hypoparathyroidism (19.4% vs 8.0%).45 A recent meta-analysis of these 5 RCTs calculated that the number of patients needed to treat with pCLND was 500, whereas the number of patients needed to harm was 33.49 In patients undergoing lobectomy, concomitant pCLND may place the recurrent laryngeal nerve at risk of injury while do- ing little to prevent recurrence as structural recurrence is frequently seen on the contralateral lobe.50 The decision for pCLND with concomitant TT should be a shared decision after balancing clinical risk factors and patients’ preferences.
ADVANCES IN THE MANAGEMENT OF PARATHYROID DISEASE Introduction
The management of parathyroid disease has evolved during the past decade with emerging technologies to guide surgical decision-making and changes in treatment of advanced malignancy. In 2016, the American Association of Endocrine Surgeons published guidelines for the diagnosis, management, and surveillance of primary hy- perparathyroidism (PHPT) based on years of available evidence.51 Since then, ad- vancements in radiographic studies, our understanding of parathyroid biology, and molecular profiling have moved the management of parathyroid disease forward.
Preoperative Localization Strategies
Preoperative radiographic studies for parathyroid localization commonly include ultra- sonography (US), parathyroid scintigraphy using technetium (99Tc) sestamibi-single photon emission computed tomography/computed tomography (sestamibi-SPECT/ CT), and four-dimensional computed tomography (4D-CT; Fig. 1). Minimally invasive parathyroidectomy (MIP) requires localization of a single abnormal gland on at least one imaging modality, with accuracy increasing with multiple concordant studies. 52,53 Sestamibi-SPECT/CT and US individually have a sensitivity of between 72% and 79% with false-positive results frequently related to benign or malignant thyroid pathologic condition or lymphadenopathy.54 Four-dimensional CT is up to 97% accurate for later- alization of single gland disease and up to 87% accurate for quadrant localization.55 When 4D-CT was combined with sestamibi-SPECT/CT, quadrant localization increased to 94% and was superior to sestamibi-SPECT/CT alone.55 Despite accu- racy in localization with 4D-CT, this study has been only slowly adopted by surgeons throughout the United States. In a study of more than 7000 patients at 14 different
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institutions, Kuo and colleagues56 found that 4D-CT was used in only 20.4% of pa- tients with institutional rates of use ranging from 0.1% to 88.7% despite previous studies demonstrating the association of 4D-CT with increased utilization of MIP and decreased length of stay.57 Cost-utility analysis of preoperative localization stra- tegies for PHPT found that while institutional differences in localization sensitivity exist, analyses have pointed to the selective utility of 4D-CT as being the most cost-effective strategy in parathyroidectomy due to decreased rates of bilateral cervical exploration.58,59
Imaging with 11C-labeled and 18F-labeled choline analogs and PET/CT, although limited to a few centers in the United States, has shown promise in parathyroid ade- noma localization with high sensitivity (89%) and specificity (96%),60 with particular utility in the reoperative setting. Latge and colleagues61 showed 95% sensitivity and 88% detection rate for 18F-fluorocholine PET/CT compared with 4D-CT in patients with persistent or recurrent PHPT with no increase in detection after combining the 2 modalities. Although significant advancements in imaging modalities have been made in the detection of parathyroid disease, the most important aspect of preoper- ative imaging is that the surgeon understands the institution-specific strengths and weaknesses of each technique.
Intraoperative Adjuncts
During parathyroidectomy most surgeons use intraoperative adjuncts to localize a suspicious hyperfunctioning gland, confirm the histology of a resected parathyroid specimen, and/or confirm operative completion. The most commonly used adjunct is the use of intraoperative parathyroid hormone assay (ioPTH), which relies on the rapid rate of decay of PTH to quantitatively detect a decline following excision of a sus- pected hyperfunctioning parathyroid gland. The most common ioPTH protocols antic- ipate a greater than 50% PTH drop at 10 minutes from either the highest preincision or preexcision (before the parathyroid vascular pedicle is ligated) ioPTH level in a periph- eral blood sample to conclude parathyroidectomy; and some also require the final PTH to decrease to the normal range. Both criteria have a positive predictive value of 97% for postoperative eucalcemia and cure rates of 97% to 99%.62 Yet the ioPTH process requires laboratory expertise and equipment and may add variable operative time. Recently, some groups have advocated for MIP without ioPTH guidance, partic- ularly in well-selected cases with suspected single gland disease with at least 2, but especially 3, concordant imaging studies. The combination of a functional isotope study (sestamibi) combined with anatomic cross-sectional study with perfusion (4D- CT) and sonographic evaluation of surrounding structures (US) is particularly sensitive. A recent single-institution study of more than 2400 parathyroidectomies performed without ioPTH compared bilateral cervical exploration with MIP, indicated for sus- pected single-gland disease with concordant imaging, and found similar combined persistence and recurrence rates of 2.2% on intention-to-treat analysis.63 Although few studies exist comparing MIP with and without ioPTH, it is clear that successful MIP hinges on a combination of high-quality preoperative localization studies, intrao- perative findings, and surgeon experience.
Due to variability in the location and appearance of parathyroid glands, adjuncts may be used to confirm in vivo localization and ex vivo tissue confirmation apart from intraoperative frozen section or parathyroid aspiration. The discovery of parathy- roid glands exhibiting strong autofluorescence under near-infrared light has led to the use of near-infrared autofluorescence (NIRAF) for intraoperative identification of para- thyroid glands using 2 Food and Drug Administration-approved products: PTeye (probe-based; AiBiomed, Santa Barbara, CA) and Fluobeam-800 (image-based;
Fluoptics, France). 64 These fluorescence-based products were found to be accurate in detecting parathyroid tissue, with abnormal parathyroid glands showing different autofluorescence intensity compared with normal parathyroid tissue.65,66 An early prospective feasibility trial of 59 patients undergoing parathyroidectomy by 2 experi- enced endocrine surgeons showed that NIRAF utilization led to an increase in surgeon confidence of adequate resection compared with visual inspection of the specimen with a 20% improvement in in vivo localization.67 For surgeons with less experience identifying parathyroid tissue, NIRAF may be a useful tool to aid with localization of suspected parathyroid glands during both thyroid and parathyroid surgery. This tech- nology may be particularly helpful in identifying and preserving parathyroid tissue in the setting of bulky lymphadenopathy while performing a central neck dissection for thyroid cancer, which has a risk of transient hypoparathyroidism of 15% to 30%.39,68 Although further research is needed to examine its utility in identifying para- thyroid disease, NIRAF may have the ability to replace intraoperative frozen section analysis or gland aspiration for PTH, which may help decrease operative time.
Treatment of Parathyroid Carcinoma
Surgical management of parathyroid carcinoma (PC) is the principal initial treatment strategy for patients with localized disease. The extent of surgery depends on the level of local invasion and includes parathyroidectomy and en bloc resection of directly involved tissue.69 The presence of nodal metastases is rare (3%)70 and performance of prophylactic central neck dissection is not correlated with DSS.71,72 Patients with locally advanced or distantly metastatic PC often require multiple surgical resections and a combination of antiresorptive therapies and calcimimetics to control hypercal- cemia, which is the primary factor impacting survival in this disease. Although multi- modality therapy in the form of chemotherapy and/or external beam radiation with calcimemetics has been shown to improve control of hypercalcemia in select patients, no definitive impact on OS or DSS has been observed.73 Tyrosine kinase inhibitors have shown efficacy in suppressing the proliferative and bone resorptive properties of PC as demonstrated by several case studies from various institutions with the use of cabozantinib, sorafenib, lenvatinib, and everolimus.74,75 The use of next gener- ation sequencing and germline testing in PC has paved the way for therapies targeted against patient-specific mutation pathways.74 Recent studies examining the PC tumor microenvironment and mutational burden have identified increased programmed death ligand I and tumor-infiltrating expression in surrounding microenvironment of some tumors as well as high mutational tumor burdens with microsatellite instability and DNA mismatch repair, suggesting a potential role for immunotherapy in some pa- tients with PC.75,76 Two reports describe the use of pembrolizumab to achieve biochemical and radiographic regression in patients with metastatic PC.77,78 Due to the rarity of the disease, clinical trials are lacking for both treatment approaches and prognostication of patients with advanced parathyroid PC. As the pendulum swings toward the use of liquid biopsy to guide treatment and prognostication of solid tumors, multi-institutional collaborations and consolidation of databases and tumor banks are of utmost importance.
ADVANCES IN THE MANAGEMENT OF ADRENAL DISEASE Introduction
Adrenalectomy is indicated for patients with symptomatic large benign tumors, func- tional tumors, primary malignancy (when technically feasible and oncologically appro- priate), metastatic disease (in conjunction with multidisciplinary management for
well-selected patients), and in certain palliative situations to control secondary hor- monal excess.
Surgical Approach
Minimally Invasive Surgery
For small benign and/or functional adrenal tumors a minimally invasive approach is appropriate79 and is associated with decreased operative time, length-of-stay, and lower 30-day morbidity rates when compared with open adrenalectomy. 80-82
Generally, the choice between laparoscopic transabdominal and retroperitoneal ap- proaches is based on surgeon preference and experience, although certain patient and tumor characteristics may favor a particular approach. A retroperitoneoscopic approach is preferential for bilateral disease and may be preferred in a patient with multiple prior abdominal surgeries, whereas operative times for the retroperitoneo- scopic approach may be longer in patients with greater posterior adiposity.83 Several RCTs have attempted to compare both minimally invasive approaches. Chai and col- leagues84 found similar mean operative times, blood loss, postoperative pain, and overall complication rates in a study of 83 patients, whereas Barczynski and col- leagues85 noted shorter surgery duration, less operative blood loss, and lower postop- erative pain, and Kozlowski and colleagues86 also noted less postoperative pain and shorter length-of-stay with the retroperitoneal approach despite similar safety and efficacy.
Robotic adrenalectomy has also been increasingly performed. Ma and colleagues87 conducted an RCT with 140 patients with pheochromocytoma, which compared robotic-assisted laparoscopic adrenalectomy with laparoscopic adrenalectomy and concluded, although both approaches were similarly safe and effective, select pa- tients with higher catecholamine excess may benefit from the reduced blood loss and shorter operative time with the robotic approach although it was associated with higher overall cost. The benefits of the chosen operative approach will depend on surgeon choice, determination of time spent versus benefits, familiarity, and expertise.
Surgical Approach for Malignancy
Open adrenalectomy is generally reserved for larger tumors or if there is concern for malignancy. The oncologic success of all treatment is largely based on complete sur- gical resection because there are no proven systemic therapies for recurrence of met- astatic disease, which portends such a poor prognosis. Patient outcomes in adrenocortical carcinoma (ACC), including recurrence rates and OS, are highly depen- dent on a complete margin negative resection without tumor spillage.88 This can be challenging to achieve from a minimally invasive surgery (MIS) approach, particularly in large or locally invasive tumors, with retrospective studies demonstrating decreased OS with the laparoscopic approach due to higher incidence of incomplete resection and need for conversion to open procedure; en bloc resection remains the standard of care.89-91 Although a few experienced adrenal surgeons use MIS approaches for highly selected patients with small ACCs,92 the preference for surgical approach re- mains open resection with complete clearance using palpation and manual dexterity as key technical indicators.
In contrast to ACC, MIS approaches to adrenalectomy for patients with metastatic disease are technically feasible and oncologically appropriate for highly selected pa- tients. Retrospective series of patients with adrenal metastases from lung, melanoma, renal, and other primary malignancies demonstrated prolonged survival as compared with medical therapy alone, which is most likely a function of multimodality therapy
and patient selection rather than surgery alone.82,93-96 Factors associated with decreased survival after metastectomy include larger metastasis size, synchronous presentation, and incomplete resection of adrenal disease, with primary tumor histol- ogy also likely impacting prognosis. Interestingly, the presence of extra-adrenal oligo- metastatic disease in well-selected patients may not affect prognosis.97 Biopsy confirmation of a suspected metastatic adrenal lesion is not required but may be considered if the results would affect the treatment plan and only after appropriate hormonal workup has been completed. The utilization of radiation therapy and other ablative technologies should not be performed without multidisciplinary discussion with surgical inclusion due to the complexity of adrenalectomy after tumor progression following these techniques.
Clinical Trials in the Surgical Management of Functional Tumors
Localization in Primary Aldosteronism
Primary aldosteronism (PA) occurs in 5% to 10% of all hypertensive patients98 and up to 14% to 21% of patients with medically resistant hypertension.99 Laparoscopic adrenalectomy is the treatment-of-choice for PA due to a unilateral aldosterone- producing adenoma or unilateral adrenal hyperplasia. There is generally no role for surgery in PA due to bilateral adrenal hyperplasia, which is managed medically with mineralocorticoid antagonists.
Adrenal vein sampling (AVS) is used to identify patients with unilateral PA through cannulation of bilateral adrenal veins and comparison of serum aldosterone levels sampled from each side while using cortisol levels as a control. Although the addition of AVS to cross-sectional imaging is thought to improve accuracy in lateralization of PA and is generally low-risk when performed by experienced hands, it is still an inva- sive and resource intensive procedure. Part of the challenge of studying AVS and a po- tential reason for the many discordant findings is the variations in techniques and interpretation of results. Previously, most guidelines recommended the routine use of AVS in addition to CT or MRI in all patients undergoing adrenalectomy because aldosterone-producing adenomas tend to be small in size and may not be seen on cross-sectional imaging. In 2016, the SPARTACUS trial showed similar clinical out- comes 1 year after surgery between patients who underwent surgery based on CT findings alone as compared with universal application of CT and AVS together, although concerns have been raised about the study design including selection bias toward patients with florid PA, primary endpoint of intensity of antihypertensive drug treatment instead of cure of PA, and the confounding impact of use of mineralocorti- coid receptor antagonists in the study.100 Several small retrospective studies have demonstrated greater than 90% concordance between CT and AVS findings in young patients (age <35 years) with clear unilateral adenoma greater than 1 cm with normal contralateral adrenal gland on CT imaging.101-103 Recent guidelines state that AVS may be deferred in this particular population based on the risk-benefit ratio of cannu- lating the contralateral gland and causing negative sequalae.98
Preoperative Blockade in Pheochromocytoma
Preoperative alpha (with or without beta) blockade is recommended to minimize the risk of perioperative hemodynamic instability for patients with pheochromocytoma or functional paragangliomas (PPGL). Historically, phenoxybenzamine, a nonselective a-adrenergic blocker, was the medication of choice. Patient tolerance of phenoxy- benzamine is limited by its associated reflex tachycardia and orthostatic hypotension and drug availability. Selective a1-receptor antagonists such as doxazosin, prazosin, and terazosin and calcium channel blockers have been used increasingly in place of
phenoxybenzamine, with overall similar rates of intraoperative hemodynamic stability and no significant difference in postoperative outcomes such as length of stay, need for vasopressor support or rate of postoperative complications. 104-1
Calcium channel blockers can be used in conjunction with a-blockers for preoper- ative blockade in PPGL patients, with a few small-scale studies directly comparing their use alone.107,108 One retrospective review of 155 patients demonstrated similar rates of intraoperative hemodynamic instability between patients blocked with phe- noxybenzamine versus nicardipine (39% vs 35%, P = . 609), with a greater number and duration of severe hypertensive and hypotensive episodes and increased use of intraoperative vasoactive agents in patients on phenoxybenzamine, although this may be influenced by selection bias toward phenoxybenzamine for more active PPGLs. 108
Given overall similar clinical outcomes among the different options, the choice of preoperative blockade still depends on surgeon preference, drug availability, and patient-specific factors. Select studies performed in predominantly normotensive pa- tients at high-volume adrenal centers have demonstrated safe outcomes without pre- operative blockade.109 While preoperative blockage protocols will vary between institutions and providers, the most important part of managing these patients is hav- ing constant communication between the surgeon and anesthesiologist throughout the pre-, peri- and postoperative course to prevent, identify and treat signs of hemo- dynamic instability.
Management of Metastatic Pheochromocytoma or Functional Paragangliomas
Surgical resection or debulking of primary tumor, although rarely curative even when combined with complete resection of metastases, is appropriate in select patients with metastatic PPGL and may prevent local complications and improving quality of life from compression and, lowering rates of hormonal morbidity and potentially improving survival.110,111 There is no clear consensus on the use of adjuvant or neo- adjuvant therapy in metastatic PPGL.
Targeted radionuclide therapies (TRT), immunotherapy, and tyrosine kinase inhibi- tors, either alone or in combination play a role in multimodality therapy. The North American Neuroendocrine Tumor Society (NANETs) 2021 guidelines111 recommend cytotoxic therapy as first-line for patients with symptomatic, bulky, or rapidly progres- sive disease with limited data, suggesting potential partial radiographic and partial biochemical response in 37% and 40% of patients, respectively.112 Tyrosine kinase inhibitors were also described as potential treatment, particularly for meta- iodobezylguanidine (MIBG) nonavid tumors or rapid progression. TRT with high spe- cific activity (HSA) I-131 MIBG has been shown in a single-arm phase II trial to improve symptom control with 25% of patients achieving the primary endpoint of reduction in antihypertensive medication and 69% of patients demonstrating stable disease at 12 months. 113 NANETs guidelines recommend consideration of HSA I-131 MIBG in patients with MIBG avid tumors who require systemic therapy. Additionally, peptide receptor radionuclide therapy Lu-177 DOTATATE, which targets somatostatin recep- tor, has been approved for use in treatment of gastroenteropancreatic neuroendocrine tumors. It has been shown to result in longer median OS in metastatic PPGL when compared with an alternative somatostatin receptor targeted radionuclide therapy Y-90 DOTATOC,114 although it has not been compared with HSA I-131 MIBG. NANETs guidelines suggest consideration of Lu-177 DOTATATE therapy through clin- ical trials for patients with MIBG nonavid and somatostatin receptor PET-avid disease. Although a recent phase II trial of pembrolizumab for metastatic PPGL demonstrated a nonprogression rate of 40% and an objective response rate of 9%,115 NANETs
guidelines also recommends immunotherapy to be limited to clinical trials while further data is obtained. In the metastatic setting, radiotherapy can provide local control and pain relief from symptomatic metastatic lesions while also preventing pathologic fractures. 113
Genetic Testing in Pheochromocytoma or Functional Paragangliomas
All patients with PPGL should undergo genetic testing, as up to 40% of cases are associated with an identifiable hereditary syndrome, including Von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis 1 (NF1), and familial PPGL syndrome that occur secondary to VHL, RET, NF1, and SDHA/B/C/D (SDHx) germline gene mutations, respectively. These genes may also be implicated in sporadic PPGL. Use of molecular profiling has increased understand- ing of the mechanisms driving tumorigenesis in PPGL, although there remains much to learn. SDHB germline mutations have been most strongly associated with metastatic PPGL but may have better response to cytotoxic chemotherapy and sunitinib ther- apy.116-118 Somatic ATRX mutations and MAML3 fusions are additional molecular prognosticators associated with increased risk of aggressive disease. 119
Patients with VHL, MEN 2, or NF1 are at increased risk of bilateral tumors that should prompt consideration of cortical sparing adrenalectomy if technically feasible, particularly in younger patients. Although cortical sparing adrenalectomy is associated with an increased risk of recurrence in remnant adrenal tissue (recurrence rates 9%- 30%), the recurrence is that of a benign tumor and patients at high risk for needing contralateral adrenalectomy may still benefit overall from preservation of endogenous steroid production, reducing dependence on chronic steroid hormone replacement and risk of adrenal crisis. 120,121
Management of Hypercortisolism Related to Benign Adrenal Pathology
Adrenalectomy is appropriate for patients with Cushing’s syndrome (CS) due to adre- nocorticotropic hormone (ACTH) independent cortisol-secreting adrenal tumors. Mild autonomous cortisol secretion (MACS), formerly known as subclinical CS, is also an indication for adrenalectomy. Patients with MACS demonstrate evidence of nonsup- pressed cortisol (>1.8-5 mcg/dL after low-dose dexamethasone suppression test) without the typical physical stigmata of CS (round face, dorsal fat deposition, hirsut- ism, pronounced skin striae, bruising). These patients often display increased rates of obesity, hypertension, dyslipidemia, type 2 diabetes mellitus, and metabolic bone disease, 122-124 with improvement in blood pressure, glycemic control, and body mass index after adrenalectomy. 125-127
Bilateral ACTH-independent CS can be due to micronodular or macronodular hy- perplasia. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is character- ized by bilateral adrenal nodules greater than 1 cm in diameter with variable levels of excess cortisol secretion, and accounts for less than 2% of all endogenous CS. Recent guidelines recommend consideration of unilateral laparoscopic adrenalec- tomy for CS due to PBMAH in order to achieve control of hypercortisolism without causing permanent adrenal insufficiency, as would result from bilateral adrenalec- tomy. Unilateral adrenalectomy of the largest gland may be sufficient for palliation of hypercortisolism and improvement in obesity, diabetes mellitus, and hyperten- sion, 128-130 although recurrence has been observed in up to two-thirds of patients. 131,132
Nearly all patients with CS and approximately 60% of patients with MACS experi- ence adrenal insufficiency related to contralateral suppression following adrenalec- tomy and require exogenous steroid support. The duration of steroid requirement is
shorter for patients with MACS as compared with those with CS.133,134 Cosyntropin stimulation testing on postoperative day one may identify patients at higher risk of ad- renal insufficiency to allow for selective use of glucocorticoid replacement in patients with MACS. 135
SUMMARY
In summary, the past two decades have greatly influenced our understanding and management of thyroid, parathyroid, and adrenal disease. Utilization of large data- base studies has allowed for the de-escalation of thyroid resection for well-selected patients with low-risk thyroid cancers. Similarly, improved localization imaging and intraoperative testing have paved the way for more minimally invasive parathyroidec- tomies for benign parathyroid disease. Improved understanding of molecular patho- genesis has increased the ability to risk stratify patients with thyroid cancer, identified potential therapeutic targets for patients with parathyroid cancer, and modi- fied guidelines for surveillance of patients with familial adrenal disease.
CLINICS CARE POINTS
· The extent of surgery for thyroid cancer should incorporate all available objective data as well as patient values and preferences to allow for personalized management.
. Although molecular testing may provide prognostic information in select circumstances, there is currently no evidence to support its use in guiding extent of surgery for known malignancy.
. There are no reliable tools to help one recognize parathyroid cancer preoperatively. Apart from extreme PTH and calcium levels, surgeons must recognize the presence and extent of malignant parathyroid disease intraoperatively.
. Outcomes in adrenocortical carcinoma are highly dependent on a complete negative resection margin without tumor spillage, which can be challenging to achieve from a minimally invasive approach. The preferred surgical approach for a suspected adrenocortical carcinoma is open resection.
DISCLOSURE
The authors have no disclosures
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