Neuroendocrine Tumors Guidelines

For evaluation of duodenal, jejunal, ileal, and colonic neuroendocrine tumors (NETs), the National Comprehensive Cancer Network (NCCN) recommends abdominal/pelvic multiphasic CT or MRI and any of the following as appropriate ^[1] :

• Somatostatin receptor scintigraphy
• Colonoscopy
• Small-bowel imaging (CT enterography or capsule endoscopy)
• Chest CT
• Biochemical evaluation if clinically indicated by symptoms of hormone secretion

For evaluation of T1 rectal NETs, the NCCN recommends endorectal MRI or endoscopic ultrasound (EUS); for T2-T4 rectal NETs, recommended studies are as follows:

• Colonoscopy
• Abdominal/pelvic multi-phasic CT or MRI
• Endorectal MRI or EUS

In addition, the following are recommended to be done, as appropriate:

• Somatostatin receptor scintigraphy
• Chest CT
• Biochemical evaluation if clinically indicated

For evaluation of gastric NETs, NCCN recommendations are as follows:

• Esophagogastroduodenoscopy (EGD)
• Gastric biopsy
• Serum gastrin level
• Consider gastric pH, as appropriate

For evaluation of bronchopulmonary NETs, the NCCN recommends chest CT and abdominal multiphasic CT or MRI, with the following as appropriate:

• Somatostatin receptor scintigraphy
• Bronchoscopy
• Biochemical workup for Cushing syndrome, if clinically indicated
• Other biochemical evaluation, as clinically indicated

For evaluation of thymus NETs, the NCCN recommends chest/mediastinal multiphasic CT and abdominal multiphasic CT or MRI, the following as appropriate:

• Somatostatin receptor scintigraphy
• Bronchoscopy
• Biochemical workup for Cushing syndrome, if clinically indicated
• Other biochemical evaluation, as clinically indicated

European Neuroendocrine Tumor Society (ENETS) consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors, issued in 2016, include the following minimal consensus recommendations on diagnosis ^[2] :

• Clinical signs and symptoms should guide the appropriate diagnostic procedures
• Chromogranin A and neuron-specific enolase (NSE) testing is not mandatory, but may be useful if levels are elevated at diagnosis; other hormone tests are not routinely recommended
• A minimal diagnostic workup should include site-specific endoscopic assessment with tumor biopsy, and whole-body CT scan (and/or MRI) for tumor staging
• In patients with metastatic disease, an ultrasound-guided percutaneous biopsy may be performed if feasible
• Somatostatin receptor scintigraphy is not routinely indicated but may be considered in tumors with proliferative indexes in the low range of G3 (Ki-67 < 55%)
• Bone scans or brain imaging (CT or MRI) should not be performed in the absence of site-specific symptoms
• Fluorodeoxyglucose positron emission tomography (FDG-PET) may be considered in patients in whom radical surgery is being pursued or if clarification of equivocal findings on conventional imaging may change the therapeutic approach; FDG-PET may be useful in resectable cases for whole-body assessment

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS)  both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs). ^{[3, 4, 5]}

Tumors fall into one of the following three grades:

• G1: Well differentiated, low grade
• G2: Well differentiated, intermediate grade
• G3: Poorly differentiated, high grade

However, for NETs of the lungs and thymus, the WHO includes only mitotic count and assessment of necrosis. ^[6] In its 2015 consensus statement on best practices for pulmonary neuroendocrine tumors, the ENETS noted that tumor grading based on a combination of KI-67, mitotic rate, and necrosis may be of clinical importance but lacks validation. ^[7]

Under the WHO grading scheme, pulmonary and thymic tumors fall into one of the following three grades ^[6] :

• Low-grade tumors: < 2 mitoses/10 high power field (HPF) and no necrosis
• Intermediate tumors: 2-10 mitoses/HPF and/or foci of necrosis
• High grade tumors: >10 mitoses/10 HPF

The European Society for Medical Oncology (ESMO) uses only mitotic count for bronchial and thymic tumors for determining tumor grade, as follows ^[8] :

• Low-grade tumors:  < 10 mitoses/10 HPF
• Intermediate tumors:  10-20 mitoses/10 HPF
• High-grade tumors:  > 20 mitoses/10 HPF

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results. ^[1]

NCCN guidelines recommend staging according to the 8^th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. ^[1] The AJCC uses separate staging systems for carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix, as well as adrenal gland tumors. Bronchopulmonary carcinoids are staged using the same system as for other pulmonary malignancies, and pancreatic NETS are staged the same as for exocrine pancreatic tumors. ^[9]

For staging of GEP-NETs, the ESM0 guidelines, updated in 2020, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2010 WHO grading system. ^[10] For staging of bronchopulmonary and thymus NETs, the ESMO prefers the AJCC system. ^[8] For adrenal carcinoma staging, the 2009 European Network for the Study of Adrenal Tumors (ENSAT) TNM system is recommended over the AJCC system. ^[11]

In 2012, the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) released updated guidelines for the management of GEP-NETs. Recommendations for grading and staging are as follows ^[12] :

• For grading: WHO 2010 grading system

• For staging: 7^th edition of the AJCC Cancer Staging Manual

• Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system

• The TNM classification used should be specified

• Underlying features of the T-stage classification (eg, tumor size, extent of invasion) should be documented to allow for translation between different classification systems

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage. ^[13]

The following organizations have issued clinical guidelines for the treatment of carcinoid tumors:

• National Comprehensive Cancer Network (NCCN)
• North American Neuroendocrine Tumor Society (NANETS)
• European Neuroendocrine Tumor Society (ENETS)
• European Society for Medical Oncology (ESM0)
• UK and Ireland Neuroendocrine Tumour Society (UKI NETS)

Treatment for locoregional disease

NCCN guidelines recommend resection as the primary treatment for most carcinoid tumors of the gastrointestinal (GI) tract, lung, and thymus. Specific recommendations vary by tumor subtype. However, for neuroendocrine tumors at any site, cholecystectomy is recommended during surgical resection if treatment with a somatostatin analog (ie, octreotide, lanreotide) is planned, due to the increased rate of biliary problems associated with long-term use of these agents. ^[1]

Gastric tumors

For gastric tumors, the NCCN recommendations are as follows ^[1] :

• With hypergastrinemia/Type 1: Endoscopic resection of prominent tumors followed by endoscopic surveillance and resection of prominent tumors every 2 to 3 years

• With hypergastrinemia/Type 2: Resect primary gastinoma; for primary gastinoma not resected, consider endoscopic surveillance and resection of prominent tumors or octreotide or lanreotide and high-dose proton pump inhibitors to manage gastric hypersecretion

• With normal gastrin levels: Radical gastric resection and regional lymphadenectomy (preferred); endoscopic or wedge resection can be considered for tumors < 1cm

Gastric carcinoids can be subclassified into the following three distinct groups ^[14] :

• Type I – Those associated with chronic atrophic gastritis/pernicious anemia (70-80%)

• Type II – Those associated with Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (MEN I) (5%)

• Type III – Sporadic NETs of the stomach (15-20%)

In 2013, NANETS released updated guidelines with the following recommendations for treatment of gastric carcinoid tumors ^[15] :

• Type I or II, < 1 cm: Surveillance or endoscopic removal

• Type I, 1 cm to < 2 cm: Surveillance with repeat endoscopy every 3 years or endoscopic resection

• Type II, 1 cm to < 2 cm: Endoscopic resection

• Type I, ≥2 cm (≤6 polyps), or type II ≥2 cm: Endoscopic resection, if possible, or open surgical resection

• Type I, ≥2 cm (>6 polyps): Individualized treatment required; surveillance, endoscopic resection, or surgical resection

• Type III: Partial gastrectomy and lymph node dissection

The 2016 revised ENETS guidelines prefer conservative management strategies over surgery for type I tumors. The guidelines recommend resection of tumors ≥10 mm performed by endoscopists experienced in gastric tumors, using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). ^[16]

For type II tumors, local or limited excision can be recommended, but this should be patient-tailored at multidisciplinary NET centers of excellence. Type III tumors should be treated similarly to gastric adenocarcinoma, with partial or total gastrectomy and lymph node dissection. Systemic therapy is required for inoperable or stage 4 disease. ^[16]

Duodenal tumors

For duodenal tumors, the NCCN recommends the following treatments ^[1] :

• Endoscopic resection with follow-up upper endoscopy
• Transduodenal local excision with or without lymph node sampling
• Pancreatoduodenectomy

ENETS guidelines provide the following recommendations for treatment of duodenal tumors ^[16] :

• All localized tumors should be removed
• Endoscopic resection for tumors ≤1 cm confined to the submucosal layer, without lymph node or distant metastasis
• Surgical resection with lymphadenectomy for tumors in the periampullary region
• Surgical resection for tumors >2 cm and tumors of any size with lymph node metastases

Bowel tumors

NCCN recommendations are as follows ^[1] :

• Surgical resection with lymphadenectomy

• Careful examination of the entire bowel and assessment of proximity to or involvement of the superior mesenteric artery and superior mesenteric vein

• Prophylactic cholecystectomy if further treatment with octreotide or lanreotide is planned

The NANETS guidelines include the following recommendations ^[15] :

• Tumors of the cecum: Right hemicolectomy with node dissection

• Tumors of the jejunal or ileum: Resection with node dissection; full bowel examination required

• Distal colon and rectum tumors < 1 cm: Endoscopic resection (polypectomy, endoscopic mucosal resection, endoscopic submucosal dissection) for mucosal or submucosal tumors

• Distal colon and rectum tumors 1-2 cm: Transanal excision via rigid or flexible dissection; could also be considered after endoscopic resection with positive margins

• Distal colon and rectum tumors >2 cm: Surgical resection (low anterior resection or abdominoperineal resection) for larger tumors, tumors invading muscularis propria, or those with lymphadenopathy

The ENETS guidelines provide following recommendations ^{[17, 18]} :

Rectal tumors ^[17]

• Endoscopic resection by simple polypectomy, endoscopic mucosal resection (EMR) with modified EMR band ligation, endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEMS).

• For lesions < 10 mm and no involvement of the muscularis propria, EMR is adequate, but EMR band-assisted ligation may improve the number of complete resections 

• If EMR results in an incomplete resection, then ESD or TEMS may be indicated as salvage therapy

Jejunum and ileum tumors ^[18]

• Curative resection of the primary tumor and dissection of the locoregional lymph node metastasis along the superior mesenteric root and around the mesentery
• Lymphatic mapping is not a standardized procedure and is not generally recommended 

Appendix tumors

NCCN recommendations for appendix NETs are as follows ^[1] :

• T1 confined to the appendix: Appendectomy

• T2-T4 or incomplete resection: Staging with abdominal/pelvic CT or MRI; if no distant disease, reexploration with a right hemicolectomy

The NANETS guidelines include the following recommendations ^[15] :

• Excision for tumors ≤2 cm; consider right hemicolectomy with node dissection if high-risk features are present

• Tumors >2 cm: Right hemicolectomy with node dissection

The 2016 ENETS revised guidelines recommendations include the following ^[19] :

• Tumors ≤2 cm: Simple appendicectomy unless incompletely resected
• Tumors >2 cm: Right hemicolectomy with node dissection

In rare cases, right hemicolectomy with node dissection may be indicated for appendiceal tumors measuring 1–2 cm. This exception applies only to tumors with one or more of the following ^[19] :

• Positive or unclear margins or with deep mesoappendiceal invasion (ENETS T2)
• Higher proliferation rate (G2)
• Vascular invasion

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic carcinoid tumors of the GI tract include the following ^[1] :

• Somatostatin scintigraphy to assess sites of metastases and somatostatin receptor status if octreotide or lanreotide is being considered

• Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases

• Unresectable hepatic progressive disease: Radiofrequency ablation or cryoablation or hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization)

• Palliative small bowel resection for patients with abdominal pain from bowel obstruction or ischemia related to the primary tumor

• Octreotide or lanreotide to control tumor growth in patients with clinically significant tumor burden or progressive disease; everolimus can be considered for advanced tumors; for persistent diarrhea, telotristat 250 mg orally, three times daily, can be added; additional therapy may be used for any persistent symptoms (eg, flushing, diarrhea)

• Consider cytotoxic chemotherapy if no other options are feasible (category 3)

• Consider interferon alfa-2b after octreotide or lanreotide failure (category 3)

• Malignant carcinoid syndrome: Octreotide or lanreotide; cardiology consultation, and echocardiogram to assess for heart disease

• Liver transplantation is investigational and not recommended as routine care

Note that the use of ablative techniques for hepatic disease is associated with increased infectious complications. Although the NCCN guidelines cite category 2b evidence for cryoablation and radiofrequency ablation, most centers use radiofrequency or microwave ablation. Cryoablation is generally used only in centers providing ablation for renal cell cancers, and it is associated with a small but definite risk of subsequent acute respiratory distress syndrome. ^[20]

Thoracic carcinoids

For thymic NETs, NCCN recommendations include the following ^[1] :

• Localized disease: Surgical resection
• Locoregional disease: Reresection; if resection is incomplete, follow with radiation therapy and/or chemotherapy

The NANETS guidelines include the following additional recommendations for thymic NETs ^[15] :

• Locoregional disease: Surgical resection including mediastinal lymphadenectomy

• Metastatic or unresectable disease: Options include radiation therapy, everolimus, interferon alpha, or temozolomide

The ESMO guidelines note that a protracted follow-up should always be performed after surgical resection because of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatin-based regimens have been of value and temozolomide-based treatment gives some benefit. ^[8]

Brochopulmonary NETs

NCCN recommendations for bronchopulmonary NETs are as follows ^[1] :

• Stage I-II: Lobectomy or wedge resection and lymph node dissection or sampling or stereotactic body radiation therapy (SBRT), if surgery is contraindicated; thermal ablation, if surgery and SBRT are contraindicated

• Stage IIIA resectable tumors: Lobectomy or wedge resection and lymph node dissection or sampling

• Stage III (A/B/C) low grade (typical) nonresectable tumors: Observation, if asymptomatic; octreotide or lanreotide, if SSR-positive and/or hormonal symptoms are present; other options include everolimus, temozolomide with or without capecitabine or radiation therapy

• Stage III (A/B/C) intermediate grade nonresectable tumors: Observation, if asymptomatic and nonprogressive; octreotide or lanreotide, if SSR-positive and/or hormonal symptoms are present; other options include radiation therapy with or without cisplatin/etoposide or carboplatin/etoposide, cytotoxic chemotherapy, or everolimus

The ESMO guidelines are similar to those of the NCCN, with some minor variances. ^{[15, 8]} The ESMO guidelines include the following additional recommendations ^[8] :

• Bronchoscopic laser excision should be considered a suboptimal treatment and be reserved for inoperable patients or performed as a preoperative disobliterating procedure

• Lobectomy and sleeve resection are preferred for locoregional tumors and systemic nodal dissection should be performed

• Pneumonectomy should be avoided

In 2020, the Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs) and NANETS released join guidelines on the managment of lung neuroendocrine tumors, which included the following recommendations for resectable tumors ^{[21, 22]} :

• Lobectomy or sleeve resection are preferred; sublobar resection is an alternative for peripheral tumors < 2 cm if complete resection is achievable; complete resection and systematic nodal dissection for patients with peripheral tumors. Lung parenchyma–sparing surgery is preferred over pneumonectomy; endobronchial resection for patients at unacceptably high risk for surgical resection or as a possible bridge to surgery.
• Radiation and thermal therapies may be used for locoregional control of primary lung neuroendocrine tumors or for palliation therapy in patients who are not surgical candidates.
• Adjuvant therapy with somatostatin analogs (SSAs), chemotherapy, or radiation is not recommended following complete resection.

For nonresectable tumors, locally advanced or metastatic disease, the key recommendations include the following ^{[21, 22]} :

• Observation, if asymptomatic
• SSAs for first- line treatment of carcinoid syndrome and as antiproliferative treatment of advanced tumors with good prognosis
• For somatostatin receptor–positive tumors, peptide receptor radionuclide therapy 
• External-beam radiation for palliative treatment in advanced and metastatic tumors
• Everolimus should be considered in progressive nonfunctional tumors and may be considered in functional tumors.
• Use of streptozocin-based, oxaliplatin-based, etoposide-based, or temozolomide-based chemotherapy may be considered to treat advanced tumors

Treatment for locoregional disease

National Comprehensive Cancer Network (NCCN) guidelines recommend resection as the primary treatment for most localized pancreatic neuroendocrine tumors (NETs). Exceptions include patients with life-limiting comorbidities or high surgical risk. In addition, observation may be appropriate for incidentally discovered tumors < 1 cm, depending on the site. ^[1]

The NCCN recommends that before surgery, symptoms of hormonal excess should be treated with octreotide or lanreotide; however, such treatment is contraindicated in patients with insulinoma because of the potential for fatal complications. Cholecystectomy is recommended during surgical resection if treatment with octreotide or lanreotide is planned, due to the increased rate of biliary problems associated with long-term use of these agents. ^[1]

Nonfunctioning pancreatic tumors

For nonfunctioning pancreatic NETs, treatment recommendations are as follows:

• Tumors ≤2 cm: Enucleation of the tumors with strong consideration of lymph node resection or pancreatectomy (Whipple type or proximal) with or without regional node resection, or distal pancreatectomy with or without regional node resection/splenectomy

• Tumors >2 cm located at the head: Whipple-type or proximal pancreatectomy with regional node resection

• Tumors >2 cm located distally: Distal pancreatectomy with regional node resection and splenectomy

The North American Neuroendocrine Tumor Society (NANETS) guidelines and the European Society for Medical Oncology (ESMO) guidelines for treatment of neuroendocrine pancreatic tumors are similar to those of the NCCN, with some minor variances. ^[23] The ESMO guidelines recommend yearly surveillance with high-quality imaging for tumors ≤2 cm. ^[10]

Gastrinoma

Recommendations for gastrinoma treatment include the following:

• Manage gastric hypersecretion with proton pump inhibitors; consider octreotide or lanreotide

• Occult tumors: Observation or exploratory surgery, including duodenotomy and intraoperative ultrasound with enucleation; local resection if tumors identified, and removal of periduodenal nodes

• Duodenum tumors: Duodenotomy and intraoperative ultrasound with local resection or enucleation and periduodenal node dissection

• Tumors at head of pancreas: Exophytic or peripheral tumors require enucleation and periduodenal node dissection; deeper or invasive tumors or those with proximity to the main pancreatic duct require pancreatoduodenectomy

• Distal tumors: Distal pancreatectomy with or without splenectomy.

Insulinoma

Recommendations for insulinoma treatment include the following:

• Stabilize glucose levels with diet and/or diazoxide; everolimus may be considered

• Primary treatment is enucleation; consider laparoscopic resection for solitary tumors

• Deeper or invasive tumors or those close to the main pancreatic duct require pancreatoduodenectomy if located in the head and laparoscopic distal pancreatectomy if in a distal location, with preservation of the spleen for smaller tumors

Glucagonoma

Recommendations for glucagonoma treatment include the following:

• Stabilize glucose levels with IV fluids; treat hyperglycemia and diabetes

• Tumors located in the head of the pancreas: Pancreatectomy with resection of peripancreatic lymph nodes

• Distal tumors: Distal pancreatectomy with splenectomy and resection of peripancreatic lymph nodes

• Consider perioperative anticoagulation due to increased risk of pulmonary emboli

VIPoma

Recommendations for treatment of NETs that secrete vasoactive intestinal peptide (VIPomas) include the following:

• Stabilize with IV fluids; correct electrolyte imbalance

• Tumors located in the head of the pancreas: Pancreatectomy with resection of peripancreatic lymph nodes

• Distal tumors: Distal pancreatectomy with splenectomy and resection of peripancreatic lymph nodes.

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic pancreatic tumors include the following ^[1] :

• Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases

• Asymptomatic unresectable disease: For select patients with low tumor burden and stable disease, consider observation with marker assessment and imaging every 3-12 months until significant disease progression occurs; lanreotide or octreotide can be considered

• Symptomatic unresectable disease: Octreotide or lanreotide; everolimus or sunitinib; or cytotoxic chemotherapy

• Hepatic-directed therapies include cytoreductive surgery or ablative therapy; bland hepatic arterial embolization, radioembolization, and chemoembolization are additional options but the optimal embolization technique has not been determined

• Liver transplantation is investigational and not recommended as routine care

The European Neuroendocrine Tumor Society (ENETS) consensus guidelines are generally similar to those of the NCCN, and include the following recommendations ^[24] :

• Surgery with curative intent, and/or loco‐regional or ablative therapies, should be considered at initial diagnosis and in the course of the disease as an alternative to systemic therapies

• In patients with a functioning NET, all liver-directed therapies require prior initiation of somatostatin analog therapy (or other specific meaures for controlling symptoms)

• Debulking surgery is indicated to improve symptom control in selected patients with functioning NET with predominant liver disease, even if the liver tumor burden can be reduced by less than 90%

• Liver transplantation is an option in very highly selected patients, preferably young patients with functional syndromes who experience early resistance to medical therapy.

In 2014, The Endocrine Society (TES), the American Association for Clinical Chemistry (AACC), and the European Society of Endocrinology (ESE) released joint clinical practice guidelines for the management of pheochromocytoma and paraganglioma (referred to together as PPGL). The guidelines include recommendations (based on strong evidence) and suggestions (based on weaker evidence). ^[25]

In patients suspected of having PPGL, biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines is recommended. The use of liquid chromatography with mass spectrometry or electrochemical-detection methods is suggested over other laboratory methods. Patients with a known germline mutation that predisposes to PPGL should undergo periodic biochemical testing. ^[25]

The 2010 guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend biochemical testing for pheochromocytoma that includes measurements of fractionated metanephrines in plasma, urine, or both, as available, in the following cases ^[26] :

• Symptomatic patients
• Patients with an adrenal incidentaloma
• Patients who have a hereditary risk for developing a pheochromocytoma or paraganglioma (extra-adrenal pheochromocytoma)

The 2021 NANETS guidelines on metastatic and/or unresectable PPGL also recommend at least annual testing of plasma free or 24-hour urine fractionated metanephrines to help detect recurrence or metastatic disease, in patients who had primary PPGL that were secreting. ^[27]

For imaging studies, the joint TES/AACC/ESE guidelines recommend computed tomography (CT) as first line, rather than magnetic resonance imaging (MRI). However, MRI is an option in certain patients, such as those with metastatic PPGL; those allergic to CT contrast media; and those for whom radiation exposure should be limited, such as pregnant women. ^[25]

For preoperative management, TES/AACC/ESE recommendations include the following:

• Blockade of hormonally functional PPGL to prevent cardiovascular complications
• Medical treatment to normalize blood pressure and heart rate
• A high-sodium diet with supplemental fluid intake to prevent severe hypotension after removal of the tumor

The TES/AACC/ESE guidelines recommend minimally invasive (eg, laparoscopic) adrenalectomy for most adrenal pheochromocytomas, with open resection reserved for very large or invasive pheochromocytomas. Open resection is suggested for paragangliomas, although laparoscopic resection is an option for smaller tumors. Partial adrenalectomy is also a possibility for certain types of patients.

In the immediate postoperative period, the TES/AACC/ESE guidelines recommend monitoring of blood pressure, heart rate, and glucose levels. Postoperative measurement of plasma or urine metanephrine levels and lifelong annual biochemical testing are suggested.

For genetic testing, TES/AACC/ESE recommendations are as follows:

• Patients with PPGLs should be engaged in shared decision-making for genetic testing.
• Patients with paraganglioma should undergo testing of SDH mutations.
• Patients with metastatic disease should undergo testing for SDHB mutations.
• Genetic testing should include pre- and posttest genetic counseling.

The 2010 NANETS recommendations for treatment of advanced disease include the following ^[26] :

• Surgical debulking to release tumor pressure on surrounding tissues or to decrease tumor mass
• In select patients, radiofrequency ablation or cryoablation are options
• Chemotherapy is preferred in patients with negative metaiodobenzylguanidine (MIBG) scintigraphy and in those with rapidly progressing tumors
• External-beam irradiation of bone metastases or radiofrequency and cryoablation in selected cases only

European Society for Medical Oncology 2020 guidelines include the following recommendations for treatment of PPGLs ^[11] :

• Most PPGLs can be safely removed laparoscopically by an experienced surgeon.
• Preoperatively, patients should be treated for 10-14 days with an alpha blocker (eg, phenoxybenzamine).
• Meticulous perioperative management of hormonal, glucose, electrolytes, cardiac, and fluid/blood pressure abnormalities is a critical component of patient care.
• Patients with resected PPGL should be followed at regular intervals for at least 10 years (lifelong for patients with a germline mutation). Most authors recommend only annual measurement of metanephrines in most patients, but some authors also carry out regular imaging.

ESMO guidelines advise that as there are no curative treatment options for metastatic PPGL, the primary aim of treatment is to control excessive catecholamine secretion and tumor burden. Choices include the following:

• A watch-and-wait policy (including alpha blocker to control hypertension)
• Debulking surgery
• Radionuclide therapy ( ¹³¹I-MIBG [iodine-131/meta-iodobenzylguanidine], DOTATOC)
• Systemic chemotherapy (eg, temozolomide/CVD [cyclophosphamide, vincristine, doxorubicin])
• Molecular-targeted therapies (eg, sunitinib)

Guidelines issued by the American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine Surgeons (AAES) in 2009 for the management of adrenal incidentalomas recommend that evaluation of patients with an adrenal incidentaloma include clinical, biochemical, and radiographic testing for the following ^[28] :

• Hypercortisolism
• Aldosteronism (if hypertensive)
• Pheochromocytoma or a malignant tumor

The simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. Salivary cortisol, dexamethasone suppression, and urinary free cortisol testing can be used if clinical suspicion is high (eg, in patients with hypertension, obesity, diabetes mellitus, or osteoporosis).

Primary aldosteronism is confirmed by lack of aldosterone suppression on a 24-hour urine study with salt loading.

To determine the incidentaloma subtype, high-resolution computed tomography scanning should be performed in all patients. In addition, adrenal venous sampling should be performed in most patients older than 40 years.

Treatment recommendations are as follows:

• Surgical resection should be reserved for those with worsening hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis

• In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is preferred over open approaches

• Patients with bilateral idiopathic hyperaldosteronism (IHA) should be managed with selective and nonselective mineralocorticoid receptor blockers

• Open adrenalectomy should be performed if adrenocortical carcinoma is suspected

For patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection, the guidelines recommend radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years. Hormonal evaluation should be performed annually for 5 years.

National Comprehensive Cancer Network (NCCN) guidelines for treatment of adrenal carcinoma include separate recommendations for localized and metastatic disease. ^[1] Recommendations for localized disease are as follows:

• Resection of primary tumor and adjacent lymph nodes
• Open adrenalectomy recommended
• External-beam radiation therapy and adjuvant mitotane may be considered in patients at high risk for recurrence

NCCN treatment recommendations for metastatic disease are as follows:

• Observation for clinically indolent disease with imaging and biomarkers (if functional) every 3 months
• Resection of primary tumor and metastases if >90% removable, particularly if functional
• Systemic therapy, preferably within a clinical trial

The European Society for Medical Oncology (ESMO) guidelines recommend use of the diagnostic workup of the European Network for the Study of Adrenal Tumors (ENSAT) for evaluation of possible adrenocortical carcinomas (ACC), which includes a detailed endocrine assessment and comprehensive hormonal analysis. For treatment of ACC amenable to complete resection, ESMO recommendations are as follows ^[11]

• Open surgery with transperitoneal access for stages I-III; complete en bloc resection necessary, and locoregional lymphadenectomy is suggested.
• Laparoscopic adrenalectomy is reasonable for selected patients who have tumors < 6 cm without evidence of local invasion (eg, incidentalomas), if the surgeon has sufficient experience.
• Margin-free complete resection of locally advanced ACC may require resection of parts of adjacent organs (eg, the wall of the vena cava, liver, spleen, colon, pancreas, stomach)
• In patients at low/intermediate risk (ENSAT stage I-II and Ki-67 expression in ≤10% of neoplastic cells), consider adjuvant mitotane therapy or active surveillance
• In patients at high risk (ENSAT stage III-IV or Ki-67 index > 10%, or recurrence), adjuvant mitotane therapy for 2-5 years
• In some patients, such as those with Ki-67 index >30%, large tumor thrombus in the vena cava, stage IV, or R1 resection, consider additional cytotoxic therapy (eg, four cycles of cisplatin plus etoposide)
• In addition to mitotane, adjuvant radiation therapy (RT) is suggested on an individualized basis in patients with R1 or RX resection or in stage III
• After complete resection, follow up with radiologic imaging every 3 months for 2 years, then every 3-6 months for at least another 3 years
• Re-resection of ACC for recurrence, if margin-free resection is possible and the time to recurrence was > 12 months

For patients with advanced/metastatic disease, first-line therapy is mitotane alone or mitotane plus chemotherapy. Surgery and locoregional therapies should be adopted in addition to systemic therapy in selected patient populations. Locoregional therapies include RT, radiofrequency ablation, cryoablation, microwave ablation, and (chemo-)embolization. ^[11]