Adrenal Neuroendocrine Tumors

Cancers Staged Using This Staging System

Pheochromocytoma and paraganglioma are staged in this section.

Cancers Not Staged Using This Staging System

These histopathologic types of cancer…	Are staged according to the classification for…	and can be found in chapter…
Neuroendocrine tumor of the pancreas	Neuroendocrine tumors of the pancreas	34
Carotid body tumors	Not staged	N/A

Summary of Changes

This is a new chapter for the AJCC Cancer Staging Manual.

ICD-O-3 Topography Codes

Code	Description
C74.1	Adrenal medulla
C75.5	Aortic body and other paraganglioma

WHO Classification of Tumors

This list includes histology codes and preferred terms from the WHO Classification of Tumors and the International Classification of Diseases for Oncology (ICD-O). Most of the terms in this list represent malignant behavior. For cancer reporting purposes, behavior codes /3 (denoting malignant neoplasms), /2 (denoting in situ neoplasms), and in some cases /1 (denoting neoplasms with uncertain and unknown behavior) may be appended to the 4-digit histology codes to create a complete morphology code.

Code	Description
8680	Paraganglioma, malignant
8690	Jugulotympanic paraganglioma
8692	Carotid body paraganglioma
8693	Composite paraganglioma
8693	Laryngeal paraganglioma
8693	Sympathetic paragangliomas
8693	Vagal paraganglioma
8700	Composite pheochromocytoma
8700	Pheochromocytoma

Lloyd RV, Osamura RY, Klöppel G, Rosai J, eds. World Health Organization Classification of Tumours of Endocrine Organs. Lyon: IARC; 2017. Used with permission.

International Agency for Research on Cancer, World Health Organization. International Classification of Diseases for Oncology. ICD-O-3-Online.http://codes.iarc.fr/home. Accessed August 16, 2017. Used with permission.

Introduction ⬆ ⬇

Pheochromocytomas (PHs) and paragangliomas (PGs) are rare neuroendocrine tumors originating in the paraganglia. The paraganglia is a group of neuroendocrine cells that during embryonic life migrate to give origin to the different components of the autonomous nervous system. PHs originate in the adrenal medulla and are sympathetic tumors. PGs may originate either in parasympathetic or sympathetic autonomous nervous system ganglia.

Sympathetic PGs (SPGs) and PHs frequently secrete catecholamines, such as noradrenaline and /or adrenaline, predisposing to cardiovascular disease, gastrointestinal complications, and other endocrine problems. Unlike SPGs, many PHs secrete adrenaline. Approximately 30% of PH/PGs have a hereditary predisposition. At the end of the 20^th century, several hereditary disorders with a relatively obvious phenotype were identified as predisposing diseases for PH/PGs, including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 syndrome (MEN2A and B), and neurofibromatosis type 1 (NF1).¹ At the beginning of the 21^st century, new germline mutations were identified in the genes that code for the different subunits of the mitochondrial enzymatic complex 2 or succinate dehydrogenase enzyme. These mutations predispose to PH/PGs, kidney cancer, and gastrointestinal stromal tumors. These syndromes are called paraganglioma syndromes 1 through 4. Most recently, mutations in the fumarase, malate dehydrogenase, MAX, and TMEM127 genes also were associated with the development of rare hereditary PH/PGs.²-⁴

Malignant PH/PGs account for 14-17% of PH/PGs.⁵ The incidence of malignant PH/PGs is less than 1% per million people per year, and malignant PH/PGs account for less than 1% of all endocrine tumors. Unlike most other tumors, no molecular or histologic markers exist for determining whether a PH/PG is malignant. Vascular invasion, mitotic activity, cellular atypia, and even local recurrence without soft tissue or lymph node tumor involvement cannot be used to definitively identify and differentiate tumors with metastatic potential.⁶

The current TNM means of staging patients with PH/PG is challenging because currently it is impossible to differentiate benign from malignant tumors from a histologic perspective, and because there are no molecular, biochemical, or genetic markers that can absolutely predict risk of distant spread. Nevertheless, TNM staging may help in the follow-up and treatment of patients with PH/PG; therefore, this staging system should be based on the recognition of clinical predictors of metastases and survival in the context of metastatic disease.

Anatomy ⬆ ⬇

Primary Site(s)

The adrenal gland s are in a retroperitoneal position above the kidneys and are surrounded by connective and adipose tissues. These gland s are enclosed within the renal (Gerota's) fascia. Each gland has an outer cortex that is lipid rich and an inner component, known as the adrenal medulla, composed of chromaffin cells. These gland s are very vascular organs; their vascular supply is derived from the aorta and the renal and inferior phrenic arteries. Veins emerge from the hilus of the gland s. The shorter right central vein drains into the inferior vena cava, and the left central vein drains into the renal vein.

The name pheochromocytoma is given to tumors arising from the adrenal medulla. Paragangliomas are tumors arising from the autonomic nervous system ganglia (paraganglia outside the adrenal medulla). PGs may occur in the head, neck, chest, abdomen, or pelvis.

PGs of the head and neck areas are classified as parasympathetic PGs (PPGs); PGs located in the thorax, abdomen, and pelvis usually are SPGs. PPGs almost never secrete catecholamines. These tumors may be locally invasive; however, they rarely develop metastases. SPGs frequently secrete catecholamines, such as dopamine and /or noradrenaline, leading to hormonal syndromes characterized by cardiovascular, gastrointestinal, and constitutional symptoms. They do not secrete adrenaline. Occasionally, these tumors do not secrete catecholamines, and their clinical manifestations are derived from location and tumor burden. Currently, malignancy is defined only by the presence of metastasis.

Regional Lymph Nodes

PG/PHs can metastasize to locoregional lymph nodes. For abdominal and pelvic PGs, the regional lymph nodes are aortic (para-aortic, periaortic) and retroperitoneal. For thoracic PGs, regional lymph nodes are usually located in the posterior mediastinum.

Metastatic Sites

The most common locations of metastases are the lymph nodes (80%), skeleton (72%), liver (50%), and lungs (50%).⁷ The liver, pancreas, and kidneys may be infiltrated because of adjacent tumor vicinity.⁸ Patients occasionally have presented with metastases in the skin or breasts. Malignant potential appears to be associated with the tumor genotype. Malignant tumors are very rare in patients with MEN2 and PGL3 and have not yet been described in patients with TMEM127 mutations and PGL2.⁹-¹¹ Approximately 5% of patients with PH/PG associated with VHL or NF1 present with metastases.¹ Metastatic PH/PG may occur in 3% of patients with PGL1.¹² Conversely, up to 50% of PH/PG patients with PGL4 may have metastatic disease.¹³

Classification Rules ⬆ ⬇

Clinical Classification

Patients who present with a PH larger than 5 cm, a SPG, and mutations in the succinate dehydrogenase subunit B gene (SDHB) should be suspected of harboring a malignant PH/PG.⁵ From a clinical perspective, the hormonal manifestations are similar to those observed in patients with benign tumors (e.g., hypertension, throbbing headaches, palpitations, diaphoresis). Constipation has been observed more often in patients with malignant disease.¹⁴ Some patients with malignant PH/PGs associated with an excessive secretion of catecholamines have minimal or no symptoms related to the excessive hormonal secretion.

Preoperative biopsy of patients with suspected PH/PGs is not recommended because of the increased risk of a catecholamine crisis, tumor rupture, and seeding.¹⁵

Evaluation of biochemical function is critical if there is clinical suspicion of the disease. In fact, the presence of plasma or urinary fractionated metanephrine concentrations higher than three times the upper limit of normal suggests the diagnosis of these tumors before they are removed.¹⁶ The final diagnosis usually is assigned once the primary tumor has been removed.

The prognostic significance of regional lymph node involvement is unclear. There are no current studies addressing this issue. Until more is known about the prognostic significance of regional lymph node metastases, data pertaining to the extent of lymph node dissection, number of lymph nodes removed, and number of lymph nodes with metastatic disease should be recorded. Malignant tumors may not be associated with locoregional lymph node metastases.⁷

Imaging

Both computed tomography (CT) and magnetic resonance (MR) imaging provide useful information for assessing PH and PG, and either may be an appropriate first imaging test. MR provides T2-weighted imaging information on adrenal and extra-adrenal masses and does not involve the use of iodinated contrast media. Abdominal CT scanning has an accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater but is less accurate for lesions smaller than 1 cm. Differentiating an adenoma from a PH is difficult using CT scanning. Although most PHs have CT attenuation of greater than 10 Hounsfield units (HU), they very rarely contain sufficient intracellular fat to have an attenuation less than 10 HU.¹⁷ Although it has been thought that the use of intravenous contrast poses a risk of inducing hypertensive crisis in patients with PH, a controlled prospective study in patients receiving low-osmolar CT scan contrast¹⁸ and a retrospective review in patients who received nonionic contrast¹⁹ concluded that the use of intravenous contrast is safe, even in patients not receiving α- or β-blockers. When contrast is given, PHs usually are more hypervascular than adenomas on early postcontrast imaging. Approximately one third show washout-like adenomas on delayed-washout analysis.

MR imaging is preferred for detection of PH in children and in pregnant or lactating women. MR imaging has a reported sensitivity of up to 100% in detecting adrenal PHs, does not require contrast, and does not expose the patient to ionizing radiation. MR imaging also is superior to CT scanning for detecting PGs. In approximately 70% of cases, PHs appear hyperintense on T2-weighted images because of their high water content.²⁰ Similar to what is observed with CT, the tumor is hypervascular post contrast, unless it has undergone mass degeneration. Even in such cases, the more peripheral nondegenerated regions of the mass usually continue to enhance.

Imaging with iodine-123 (I)-labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a PH is confirmed biochemically but CT scanning or MR imaging does not demonstrate a tumor. MIBG is a substrate for the norepinephrine transporter and concentrates within adrenal or extra-adrenal PHs. MIBG scanning frequently is used in cases of familial PH syndromes, recurrent PH, or malignant PH. Estimates of the sensitivity and specificity of I-MIBG vary widely; the reported sensitivity ranges from 53-94% and the specificity from 82-92%.²¹-²³

Positron emission tomography (PET) scanning with 18-fluoro-2-deoxyglucose (¹⁸F-FDG) has been demonstrated to detect occult PHs. ¹⁸F-FDG is selectively concentrated as part of the abnormal metabolism of many neoplasms. PHs usually show increased uptake on FDG-PET scanning.²⁴

Usually, CT or MR is the initial imaging modality of choice. MIBG imaging is considered if there is concern regarding metastases/multifocality or if the diagnosis of PH/PG is unclear. MR angiography/MR venography is performed if there is concern regarding vascular invasion.

Until now, there was no stand ard staging system for PH and PG. Patients traditionally were classified into one of three categories: localized (apparently benign) disease, regional disease, and metastatic disease.

The Radiology Society of North America (RSNA) advocates the use of structured reporting templates for describing adrenal masses (http://www.radreport.org). In terms of the primary tumor, the recommendation includes reporting the site and size of the mass, the unenhanced appearance, the unenhanced attenuation, the parenchymal phase attenuation, and the delayed phase attenuation. Absolute washout also should be documented.

CT and MR are useful in assessing for local extent of the tumor, as well as nodal involvement and distant spread. As previously mentioned, MR imaging is superior to CT in assessing for extra-adrenal PH. Dedicated adrenal CT is excellent for adrenal medulla tumors; MIBG imaging may also be of benefit for this indication. ¹⁸F-FDG PET is useful in assessing for nodal involvement and distant spread.

In terms of emerging imaging modalities, there are several promising options. Regarding scintigraphy, impressive results to date have been observed with 6-[¹⁸F]-fluorodopamine (FDOPA) PET scanning.²² Studies suggest that scans performed with this radioisotope are extremely useful in the detection and localization of PHs. Further results from studies with this agent are eagerly awaited.

Recent studies demonstrated high diagnostic accuracy with gallium-68 DOTA,1-Nal(3)-octreotide (Ga-DOTANOC) PET/CT in patients in whom PH is suspected.²⁶,²⁷ A study of 62 patients found that Ga-DOTANOC PET/CT was superior to I-MIBG imaging for this purpose. The best results of Ga-DOTANOC PET/CT were seen in patients with MEN2-associated and malignant PH.²⁶

Initial studies suggest that MR spectroscopy may be used to distinguish PHs from other adrenal masses.²⁸,²⁹ Specifically, a resonance signature of 6.8 ppm appears to be unique to PHs; the signature apparently is attributable to the catecholamines and catecholamine metabolites present in PHs.²⁹

Pathological Classification

Pathological classification of PH and extra-adrenal PG requires total tumor removal. If adjacent tissue is involved, extirpation should be complete. Tumors may vary in color from gray-white to pink-tan, with foci of congestion.³⁰ Larger tumors may contain areas of fibrosis or may show focal cystic degeneration. Familial PHs are usually bilateral and multicentric, and the adjacent medulla may appear hyperplastic. Tumors are composed of medium-sized to large polygonal cells, which may be arranged in various trabecular or solid patterns. The nuclei are usually round to ovoid. Large tumors may show hemorrhage and necrosis, and the stroma may show myxoid change. In some cases, amyloid may be present in the stroma. Foci of capsular and vascular invasion may be observed, but these features do not correlate with malignant behavior.

Immunohistochemical stains are usually positive for chromogranin A and synaptophysin. S-100 protein usually stains the sustentacular cells, although these cells may be decreased or lost in malignant tumors. The diagnosis of malignant PH or PG is confirmed in the presence of metastatic disease. Recent studies used morphologic and biochemical features to assist in the diagnosis.³¹,³² These systems include the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS)³¹ and the Grading System for Adrenal Pheochromocytomas and Paragangliomas (GAPP system) from Japan,³² which incorporates Ki-67 labeling index and epinephrine and norepinephrine secretion into the factors needed to make a diagnosis. However, these systems are difficult to reproduce by different pathologists who study the same tumor sample. Therefore, they cannot be used to confirm the diagnosis of malignancy.

Prognostic Factors ⬆ ⬇

Prognostic Factors Required for Stage Grouping

Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping.

Additional Factors Recommended for Clinical Care

Clinical Predictors of Malignancy and Overall Survival

Many patients with malignant PH/SPGs present with apparently benign tumors (no evidence of metastasis at the time of diagnosis); however, some of these patients will later develop metastatic disease (metachronous metastasis).⁵ Historically speaking, most of these patients have not had adequate follow-up; consequently, by the time malignancy is recognized most have extensive, unresectable disease. It is then important to recognize clinical predictors of metastasis to determine which patients need long-term follow-up so that metastatic recurrence could be identified early and treated, preventing further spread and /or complications. Age, gender, and histologic or biochemical characteristics do not predict the risk of metastases in patients with PH/PGS.⁵ Currently, there are only three well-recognized clinical predictors of metastasis: 1) primary tumor size, 2) primary tumor location (adrenal vs. extra-adrenal), and 3) germline mutations of SDHB.⁵,¹³

Primary Tumor Size

The size of the primary tumor is defined as the measurement of the longest axis of the primary tumor in millimeters. Retrospective studies evaluated size as a prognostic factor. A PH larger than 5 cm is associated with an increased risk of metastasis and shorter overall survival (OS). Metastatic disease in PHs smaller than 5 cm, although possible, is uncommon (<5% of cases).⁵,³³

AJCC Level of Evidence: II

Primary Tumor Location

A PG located in the abdominal (e.g., Zuckerkand l organ, para-aortic, and perirenal), pelvic (bladder), and thoracic cavities are frequently malignant, and metastatic disease may be observed in 40-70% of cases. Although in most metastatic SPGs, the primary tumor is larger than 5 cm, in up to 20% of cases, the primary tumor is smaller than 5 cm, and distant metastases have been described in patients with tumors as small as 1 cm. An extra-adrenal location is associated with twice the risk of death from disease compared with a primary tumor larger than 5 cm, making an extra-adrenal location a stronger predictor of aggressiveness, metastasis, and decreased survival than primary tumor size. Nevertheless, metastatic PHs and SPGs have similar OS, suggesting that their oncopathogenesis overlaps.⁵ (Figure 75.1).

AJCC Level of Evidence: II

SDHB Mutations

Metastatic disease and decreased OS are also observed in approximately 50% of patients with PH/SPG associated with SDHB mutations.¹³ Although most SDHB tumors are SPGs, several metastatic SPGs are not associated with SDHB mutations. Therefore, the higher prevalence of malignancy in SPG cannot be explained in every case by an association between the genetic background and tumor site alone.⁸

A retrospective study with a limited population of patients compared the OS of patients with metastatic SDHB PH/PGs with that of patients with sporadic metastic tumors. The study suggested that SDHB carriers may have a lower OS³⁴ (Figure 75.2).

AJCC Level of Evidence: III

Prognostic Factors at the Time of Diagnosis of Metastases

The natural history of metastatic PH/SPG has not been described yet. As for most well-differentiated neuroendocrine tumors, the prognosis of metastatic tumors is characterized by their heterogeneity. The consequences of excess catecholamine on blood pressure increase, cardiovascular function, and other organ physiology (e.g., gastrointestinal tract) as well as the tumor extent should be actively characterized. Indeed, reported causes of death in these patients include hypertensive crisis, cardiac dysfunction, colonic obstruction, and /or tumor burden and progression. Only four studies looked for prognostic parameters in patients with metastatic disease.

Tumor Burden versus Catecholamine Secretion

Timmers et al.³⁵ evaluated the impact of excessive catecholamine secretion and the tumor extent on clinical outcome in patients with PH/SPG. Although the excessive secretion of catecholamines was associated with substantial morbidity, the tumor burden was the main determinant of survival. This study, however, did not clearly define tumor burden.

AJCC Level of Evidence: III

Extent of Invasion of Primary Tumor

No studies have addressed whether the extent of invasion of the primary tumor affects overall prognosis.

AJCC Level of Evidence: IV

Lymph Node Metastasis

No studies have evaluated whether the presence of lymph node metastases might predict outcome.

AJCC Level of Evidence: IV

Distant Metastases

Distant metastasis is defined as evidence of disease in organs in which chromaffin cells are not supposed to exist, including the liver, lungs, and bones. Several studies demonstrated that the presence of distant metastases portends worse survival. In fact, only 60% of patients with distant metastases are alive 5 years after initial diagnosis.⁸

AJCC Level of Evidence: I

Timing of Metastases: Synchronous versus Metachronous

Ayala-Ramirez et al.⁵ found that approximately 50% of patients with malignant PH/SPG present with metastasis >=6 months after the initial time of diagnosis and /or resection of the primary tumor (metachronous metastasis). As expected, timing of metastasis is an important determinant of prognosis, as patients with metachronous metastasis exhibit better OS than those with synchronous metastasis (diagnosis of metastases at the time of or <6 months after diagnosis of the primary tumor).

AJCC Level of Evidence: I

Location of Distant Metastases

In another study by Ayala-Ramirez et al.,⁷ patients who manifested malignancy exclusively with skeletal metastasis (20%) exhibited a significantly longer OS that those with or without skeletal metastasis but with metastasis to other organs, such as the liver and lungs (12 years vs. 5 years vs. 7.5 years, respectively; log-rank test p value = 0.005; Figure 75.3).

AJCC Level of Evidence: II

The authors have not noted any emerging factors for clinical care.

Risk Assessment ⬆ ⬇

Risk Assesment Models

The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use.³⁶ Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

TNM Definitions ⬆ ⬇

Clinical T (cT)

cT Category	cT Criteria
cTX	Primary tumor cannot be assessed
cT1	PH less than 5 cm in greatest dimension, no extra-adrenal invasion
cT2	PH greater than or equal to 5 cm or PG-sympathetic of any size, no extra-adrenal invasion
cT3	Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys)

PH: within adrenal gland

PG-sympathetic: functional

PG Parasympathetic: nonfunctional, usually in the head and neck region. Parasympathetic paraganglioma are not staged because they are largely benign.

Pathological T (pT)

pT Category	pT Criteria
pTX	Primary tumor cannot be assessed
pT1	PH less than 5 cm in greatest dimension, no extra-adrenal invasion
pT2	PH greater than or equal to 5 cm or PG-sympathetic of any size, no extra-adrenal invasion
pT3	Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys)
cTX	Primary tumor cannot be assessed
cT1	PH less than 5 cm in greatest dimension, no extra-adrenal invasion
cT2	PH greater than or equal to 5 cm or PG-sympathetic of any size, no extra-adrenal invasion
cT3	Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys)

PH: within adrenal gland

PG-sympathetic: functional

PG Parasympathetic: nonfunctional, usually in the head and neck region. Parasympathetic Paraganglioma are not staged because they are largely benign.

Neoadjuvant Clinical T (yT)

ycT Category	ycT Criteria
ycTX	Primary tumor cannot be assessed
ycT1	PH less than 5 cm in greatest dimension, no extra-adrenal invasion
ycT2	PH greater than or equal to 5 cm or PG-sympathetic of any size, no extra-adrenal invasion
ycT3	Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys)

PH: within adrenal gland

PG-sympathetic: functional

PG Parasympathetic: nonfunctional, usually in the head and neck region. Parasympathetic Paraganglioma are not staged because they are largely benign.

Neoadjuvant Pathological T (yT)

ypT Category	ypT Criteria
ypTX	Primary tumor cannot be assessed
ypT1	PH less than 5 cm in greatest dimension, no extra-adrenal invasion
ypT2	PH greater than or equal to 5 cm or PG-sympathetic of any size, no extra-adrenal invasion
ypT3	Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys)

PH: within adrenal gland

PG-sympathetic: functional

PG Parasympathetic: nonfunctional, usually in the head and neck region. Parasympathetic Paraganglioma are not staged because they are largely benign.

Definition of Regional Lymph Node (N)

Clinical N (cN)

cN Category	cN Criteria
cNX	Regional lymph nodes cannot be assessed
cN0	No lymph node metastasis
cN1	Regional lymph node metastasis

Pathological N (pN)

pN Category	pN Criteria
pNX	Regional lymph nodes cannot be assessed
pN0	No lymph node metastasis
pN1	Regional lymph node metastasis
cNX	Regional lymph nodes cannot be assessed
cN0	No lymph node metastasis
cN1	Regional lymph node metastasis

Neoadjuvant Clinical N (pY)

ycN Category	ycN Criteria
ycNX	Regional lymph nodes cannot be assessed
ycN0	No lymph node metastasis
ycN1	Regional lymph node metastasis

Neoadjuvant Pathological N (pY)

ypN Category	ypN Criteria
ypNX	Regional lymph nodes cannot be assessed
ypN0	No lymph node metastasis
ypN1	Regional lymph node metastasis

Definition of Distant Metastasis (M)- Clinical M (cN)

cM Category	cM Criteria
cM0	No distant metastasis
cM1	Distant metastasis
cM1a	Distant metastasis to only bone
cM1b	Distant metastasis to only distant lymph nodes/liver or lung
cM1c	Distant metastasis to bone plus multiple other sites
pM1	Microscopic evidence of distant metastasis
pM1a	Microscopic evidence of distant metastasis to only bone
pM1b	Microscopic evidence of distant metastasis to only distant lymph nodes/liver or lung
pM1c	Microscopic evidence of distant metastasis to bone plus multiple other sites

Definition of Distant Metastasis (M)- Pathological M (pN)

pM Category	pM Criteria
cM0	No distant metastasis
cM1	Distant metastasis
cM1a	Distant metastasis to only bone
cM1b	Distant metastasis to only distant lymph nodes/liver or lung
cM1c	Distant metastasis to bone plus multiple other sites
pM1	Microscopic evidence of distant metastasis
pM1a	Microscopic evidence of distant metastasis to only bone
pM1b	Microscopic evidence of distant metastasis to only distant lymph nodes/liver or lung
pM1c	Microscopic evidence of distant metastasis to bone plus multiple other sites

Definition of Distant Metastasis (M)- Neoadjuvant Clinical M (pY)

ycM Category	ycM Criteria
cM0	No distant metastasis
cM1	Distant metastasis
cM1a	Distant metastasis to only bone
cM1b	Distant metastasis to only distant lymph nodes/liver or lung
cM1c	Distant metastasis to bone plus multiple other sites
pM1	Microscopic evidence of distant metastasis
pM1a	Microscopic evidence of distant metastasis to only bone
pM1b	Microscopic evidence of distant metastasis to only distant lymph nodes/liver or lung
pM1c	Microscopic evidence of distant metastasis to bone plus multiple other sites

Definition of Distant Metastasis (M)- Neoadjuvant Pathological M (pY)

ypM Category	ypM Criteria
cM0	No distant metastasis
cM1	Distant metastasis
cM1a	Distant metastasis to only bone
cM1b	Distant metastasis to only distant lymph nodes/liver or lung
cM1c	Distant metastasis to bone plus multiple other sites
pM1	Microscopic evidence of distant metastasis
pM1a	Microscopic evidence of distant metastasis to only bone
pM1b	Microscopic evidence of distant metastasis to only distant lymph nodes/liver or lung
pM1c	Microscopic evidence of distant metastasis to bone plus multiple other sites

Stage Prognostic ⬆ ⬇

Clinical

When T is…	and N is…	and M is…	Then the Clinical Prognostic Stage Group is…
cT1	cN0	cM0	I
cT2	cN0	cM0	II
cT1	cN1	cM0	III
cT2	cN1	cM0	III
cT3	cNX	cM0	III
cT3	cN0	cM0	III
cT3	cN1	cM0	III
cTX	cNX	cM1	IV
cTX	cNX	cM1a	IV
cTX	cNX	cM1b	IV
cTX	cNX	cM1c	IV
cTX	cN0	cM1	IV
cTX	cN0	cM1a	IV
cTX	cN0	cM1b	IV
cTX	cN0	cM1c	IV
cTX	cN1	cM1	IV
cTX	cN1	cM1a	IV
cTX	cN1	cM1b	IV
cTX	cN1	cM1c	IV
cT1	cNX	cM1	IV
cT1	cNX	cM1a	IV
cT1	cNX	cM1b	IV
cT1	cNX	cM1c	IV
cT1	cN0	cM1	IV
cT1	cN0	cM1a	IV
cT1	cN0	cM1b	IV
cT1	cN0	cM1c	IV
cT1	cN1	cM1	IV
cT1	cN1	cM1a	IV
cT1	cN1	cM1b	IV
cT1	cN1	cM1c	IV
cT2	cNX	cM1	IV
cT2	cNX	cM1a	IV
cT2	cNX	cM1b	IV
cT2	cNX	cM1c	IV
cT2	cN0	cM1	IV
cT2	cN0	cM1a	IV
cT2	cN0	cM1b	IV
cT2	cN0	cM1c	IV
cT2	cN1	cM1	IV
cT2	cN1	cM1a	IV
cT2	cN1	cM1b	IV
cT2	cN1	cM1c	IV
cT3	cNX	cM1	IV
cT3	cNX	cM1a	IV
cT3	cNX	cM1b	IV
cT3	cNX	cM1c	IV
cT3	cN0	cM1	IV
cT3	cN0	cM1a	IV
cT3	cN0	cM1b	IV
cT3	cN0	cM1c	IV
cT3	cN1	cM1	IV
cT3	cN1	cM1a	IV
cT3	cN1	cM1b	IV
cT3	cN1	cM1c	IV
cTX	cNX	pM1	IV
cTX	cNX	pM1a	IV
cTX	cNX	pM1b	IV
cTX	cNX	pM1c	IV
cTX	cN0	pM1	IV
cTX	cN0	pM1a	IV
cTX	cN0	pM1b	IV
cTX	cN0	pM1c	IV
cTX	cN1	pM1	IV
cTX	cN1	pM1a	IV
cTX	cN1	pM1b	IV
cTX	cN1	pM1c	IV
cT1	cNX	pM1	IV
cT1	cNX	pM1a	IV
cT1	cNX	pM1b	IV
cT1	cNX	pM1c	IV
cT1	cN0	pM1	IV
cT1	cN0	pM1a	IV
cT1	cN0	pM1b	IV
cT1	cN0	pM1c	IV
cT1	cN1	pM1	IV
cT1	cN1	pM1a	IV
cT1	cN1	pM1b	IV
cT1	cN1	pM1c	IV
cT2	cNX	pM1	IV
cT2	cNX	pM1a	IV
cT2	cNX	pM1b	IV
cT2	cNX	pM1c	IV
cT2	cN0	pM1	IV
cT2	cN0	pM1a	IV
cT2	cN0	pM1b	IV
cT2	cN0	pM1c	IV
cT2	cN1	pM1	IV
cT2	cN1	pM1a	IV
cT2	cN1	pM1b	IV
cT2	cN1	pM1c	IV
cT3	cNX	pM1	IV
cT3	cNX	pM1a	IV
cT3	cNX	pM1b	IV
cT3	cNX	pM1c	IV
cT3	cN0	pM1	IV
cT3	cN0	pM1a	IV
cT3	cN0	pM1b	IV
cT3	cN0	pM1c	IV
cT3	cN1	pM1	IV
cT3	cN1	pM1a	IV
cT3	cN1	pM1b	IV
cT3	cN1	pM1c	IV

Staging applies to Pheochromocytoma/Sympathetic Paraganglioma.

Pathological

When T is…	and N is…	and M is…	Then the Pathological Prognostic Stage Group is…
pT1	pN0	cM0	I
pT2	pN0	cM0	II
pT1	pN1	cM0	III
pT2	pN1	cM0	III
pT3	pNX	cM0	III
pT3	pN0	cM0	III
pT3	pN1	cM0	III
pTX	pNX	cM1	IV
pTX	pNX	cM1a	IV
pTX	pNX	cM1b	IV
pTX	pNX	cM1c	IV
pTX	pN0	cM1	IV
pTX	pN0	cM1a	IV
pTX	pN0	cM1b	IV
pTX	pN0	cM1c	IV
pTX	pN1	cM1	IV
pTX	pN1	cM1a	IV
pTX	pN1	cM1b	IV
pTX	pN1	cM1c	IV
pT1	pNX	cM1	IV
pT1	pNX	cM1a	IV
pT1	pNX	cM1b	IV
pT1	pNX	cM1c	IV
pT1	pN0	cM1	IV
pT1	pN0	cM1a	IV
pT1	pN0	cM1b	IV
pT1	pN0	cM1c	IV
pT1	pN1	cM1	IV
pT1	pN1	cM1a	IV
pT1	pN1	cM1b	IV
pT1	pN1	cM1c	IV
pT2	pNX	cM1	IV
pT2	pNX	cM1a	IV
pT2	pNX	cM1b	IV
pT2	pNX	cM1c	IV
pT2	pN0	cM1	IV
pT2	pN0	cM1a	IV
pT2	pN0	cM1b	IV
pT2	pN0	cM1c	IV
pT2	pN1	cM1	IV
pT2	pN1	cM1a	IV
pT2	pN1	cM1b	IV
pT2	pN1	cM1c	IV
pT3	pNX	cM1	IV
pT3	pNX	cM1a	IV
pT3	pNX	cM1b	IV
pT3	pNX	cM1c	IV
pT3	pN0	cM1	IV
pT3	pN0	cM1a	IV
pT3	pN0	cM1b	IV
pT3	pN0	cM1c	IV
pT3	pN1	cM1	IV
pT3	pN1	cM1a	IV
pT3	pN1	cM1b	IV
pT3	pN1	cM1c	IV
pTX	pNX	pM1	IV
pTX	pNX	pM1a	IV
pTX	pNX	pM1b	IV
pTX	pNX	pM1c	IV
pTX	pN0	pM1	IV
pTX	pN0	pM1a	IV
pTX	pN0	pM1b	IV
pTX	pN0	pM1c	IV
pTX	pN1	pM1	IV
pTX	pN1	pM1a	IV
pTX	pN1	pM1b	IV
pTX	pN1	pM1c	IV
pT1	pNX	pM1	IV
pT1	pNX	pM1a	IV
pT1	pNX	pM1b	IV
pT1	pNX	pM1c	IV
pT1	pN0	pM1	IV
pT1	pN0	pM1a	IV
pT1	pN0	pM1b	IV
pT1	pN0	pM1c	IV
pT1	pN1	pM1	IV
pT1	pN1	pM1a	IV
pT1	pN1	pM1b	IV
pT1	pN1	pM1c	IV
pT2	pNX	pM1	IV
pT2	pNX	pM1a	IV
pT2	pNX	pM1b	IV
pT2	pNX	pM1c	IV
pT2	pN0	pM1	IV
pT2	pN0	pM1a	IV
pT2	pN0	pM1b	IV
pT2	pN0	pM1c	IV
pT2	pN1	pM1	IV
pT2	pN1	pM1a	IV
pT2	pN1	pM1b	IV
pT2	pN1	pM1c	IV
pT3	pNX	pM1	IV
pT3	pNX	pM1a	IV
pT3	pNX	pM1b	IV
pT3	pNX	pM1c	IV
pT3	pN0	pM1	IV
pT3	pN0	pM1a	IV
pT3	pN0	pM1b	IV
pT3	pN0	pM1c	IV
pT3	pN1	pM1	IV
pT3	pN1	pM1a	IV
pT3	pN1	pM1b	IV
pT3	pN1	pM1c	IV
cTX	cNX	pM1	IV
cTX	cNX	pM1a	IV
cTX	cNX	pM1b	IV
cTX	cNX	pM1c	IV
cTX	cN0	pM1	IV
cTX	cN0	pM1a	IV
cTX	cN0	pM1b	IV
cTX	cN0	pM1c	IV
cTX	cN1	pM1	IV
cTX	cN1	pM1a	IV
cTX	cN1	pM1b	IV
cTX	cN1	pM1c	IV
cT1	cNX	pM1	IV
cT1	cNX	pM1a	IV
cT1	cNX	pM1b	IV
cT1	cNX	pM1c	IV
cT1	cN0	pM1	IV
cT1	cN0	pM1a	IV
cT1	cN0	pM1b	IV
cT1	cN0	pM1c	IV
cT1	cN1	pM1	IV
cT1	cN1	pM1a	IV
cT1	cN1	pM1b	IV
cT1	cN1	pM1c	IV
cT2	cNX	pM1	IV
cT2	cNX	pM1a	IV
cT2	cNX	pM1b	IV
cT2	cNX	pM1c	IV
cT2	cN0	pM1	IV
cT2	cN0	pM1a	IV
cT2	cN0	pM1b	IV
cT2	cN0	pM1c	IV
cT2	cN1	pM1	IV
cT2	cN1	pM1a	IV
cT2	cN1	pM1b	IV
cT2	cN1	pM1c	IV
cT3	cNX	pM1	IV
cT3	cNX	pM1a	IV
cT3	cNX	pM1b	IV
cT3	cNX	pM1c	IV
cT3	cN0	pM1	IV
cT3	cN0	pM1a	IV
cT3	cN0	pM1b	IV
cT3	cN0	pM1c	IV
cT3	cN1	pM1	IV
cT3	cN1	pM1a	IV
cT3	cN1	pM1b	IV
cT3	cN1	pM1c	IV

Staging applies to Pheochromocytoma/Sympathetic Paraganglioma.

Neoadjuvant Clinical

There is no Postneoadjuvant Clinical Therapy (ycTNM) stage group available at this time.

Neoadjuvant Pathological

When T is…	and N is…	and M is…	Then the Postneoadjuvant Pathological Stage Group is…
ypT1	ypN0	cM0	I
ypT2	ypN0	cM0	II
ypT1	ypN1	cM0	III
ypT2	ypN1	cM0	III
ypT3	ypNX	cM0	III
ypT3	ypN0	cM0	III
ypT3	ypN1	cM0	III
ypTX	ypNX	cM1	IV
ypTX	ypNX	cM1a	IV
ypTX	ypNX	cM1b	IV
ypTX	ypNX	cM1c	IV
ypTX	ypN0	cM1	IV
ypTX	ypN0	cM1a	IV
ypTX	ypN0	cM1b	IV
ypTX	ypN0	cM1c	IV
ypTX	ypN1	cM1	IV
ypTX	ypN1	cM1a	IV
ypTX	ypN1	cM1b	IV
ypTX	ypN1	cM1c	IV
ypT1	ypNX	cM1	IV
ypT1	ypNX	cM1a	IV
ypT1	ypNX	cM1b	IV
ypT1	ypNX	cM1c	IV
ypT1	ypN0	cM1	IV
ypT1	ypN0	cM1a	IV
ypT1	ypN0	cM1b	IV
ypT1	ypN0	cM1c	IV
ypT1	ypN1	cM1	IV
ypT1	ypN1	cM1a	IV
ypT1	ypN1	cM1b	IV
ypT1	ypN1	cM1c	IV
ypT2	ypNX	cM1	IV
ypT2	ypNX	cM1a	IV
ypT2	ypNX	cM1b	IV
ypT2	ypNX	cM1c	IV
ypT2	ypN0	cM1	IV
ypT2	ypN0	cM1a	IV
ypT2	ypN0	cM1b	IV
ypT2	ypN0	cM1c	IV
ypT2	ypN1	cM1	IV
ypT2	ypN1	cM1a	IV
ypT2	ypN1	cM1b	IV
ypT2	ypN1	cM1c	IV
ypT3	ypNX	cM1	IV
ypT3	ypNX	cM1a	IV
ypT3	ypNX	cM1b	IV
ypT3	ypNX	cM1c	IV
ypT3	ypN0	cM1	IV
ypT3	ypN0	cM1a	IV
ypT3	ypN0	cM1b	IV
ypT3	ypN0	cM1c	IV
ypT3	ypN1	cM1	IV
ypT3	ypN1	cM1a	IV
ypT3	ypN1	cM1b	IV
ypT3	ypN1	cM1c	IV
ypTX	ypNX	pM1	IV
ypTX	ypNX	pM1a	IV
ypTX	ypNX	pM1b	IV
ypTX	ypNX	pM1c	IV
ypTX	ypN0	pM1	IV
ypTX	ypN0	pM1a	IV
ypTX	ypN0	pM1b	IV
ypTX	ypN0	pM1c	IV
ypTX	ypN1	pM1	IV
ypTX	ypN1	pM1a	IV
ypTX	ypN1	pM1b	IV
ypTX	ypN1	pM1c	IV
ypT1	ypNX	pM1	IV
ypT1	ypNX	pM1a	IV
ypT1	ypNX	pM1b	IV
ypT1	ypNX	pM1c	IV
ypT1	ypN0	pM1	IV
ypT1	ypN0	pM1a	IV
ypT1	ypN0	pM1b	IV
ypT1	ypN0	pM1c	IV
ypT1	ypN1	pM1	IV
ypT1	ypN1	pM1a	IV
ypT1	ypN1	pM1b	IV
ypT1	ypN1	pM1c	IV
ypT2	ypNX	pM1	IV
ypT2	ypNX	pM1a	IV
ypT2	ypNX	pM1b	IV
ypT2	ypNX	pM1c	IV
ypT2	ypN0	pM1	IV
ypT2	ypN0	pM1a	IV
ypT2	ypN0	pM1b	IV
ypT2	ypN0	pM1c	IV
ypT2	ypN1	pM1	IV
ypT2	ypN1	pM1a	IV
ypT2	ypN1	pM1b	IV
ypT2	ypN1	pM1c	IV
ypT3	ypNX	pM1	IV
ypT3	ypNX	pM1a	IV
ypT3	ypNX	pM1b	IV
ypT3	ypNX	pM1c	IV
ypT3	ypN0	pM1	IV
ypT3	ypN0	pM1a	IV
ypT3	ypN0	pM1b	IV
ypT3	ypN0	pM1c	IV
ypT3	ypN1	pM1	IV
ypT3	ypN1	pM1a	IV
ypT3	ypN1	pM1b	IV
ypT3	ypN1	pM1c	IV

Staging applies to Pheochromocytoma/Sympathetic Paraganglioma.

Must have primary site surgical resection.

Registry Data ⬆ ⬇

Registry Data Collection Variables

Primary tumor size (measured in centimeters)
Primary tumor location: PH, PG (specific location: e.g., aortic bifurcation, mediastinum)
Regional lymph node metastases
Location of distant metastases
Hormonal function: 24-hour urinary fractionated metanephrines/plasma metanephrines
Chromogranin A
Mitotic count
Germline mutation status
Plasma methoxytyramine

Histologic grade ⬆ ⬇

HISTOLOGIC GRADE (G)

There is no recommended histologic grading system at this time.

Survival ⬆ ⬇

75.1 A, Overall survival in patients with PHs and SPGs. B, Overall survival in patients with metastatic PHs and SPGs. E/N, number of events/total number of patients. From Ayala-Ramirez et. al. 2011 with permission.

75.2 Probability of survival according to mutation status. From Amar et. al. 2007 with permission.

75.3 Median OS in patients with bone metastases (BM) and other metastases, those without BM, and those with only BM. From Ayala-Ramirez et. al. 2013 with permission.

Bibliography ⬆

Jimenez C, Cote G, Arnold A, Gagel RF. Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? The Journal of Clinical Endocrinology & Metabolism. 2006;91(8):2851-2858.
Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. Feb 2014;14(2):108-119.
Cascón A, Comino-Mendez I, Currás-Freixes M, et al. Whole-Exome Sequencing Identifies MDH2 as a New Familial Paraganglioma Gene. Journal of the National Cancer Institute. 2015;107(5):djv053.
Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nature reviews. Endocrinology. Feb 2015;11(2):101-111.
Ayala-Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. The Journal of clinical endocrinology and metabolism. Mar 2011;96(3):717-725.
Wu D, Tischler AS, Lloyd RV, et al. Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. The American journal of surgical pathology. Apr 2009;33(4):599-608.
Ayala-Ramirez M, Palmer JL, Hofmann MC, et al. Bone metastases and skeletal-related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. The Journal of clinical endocrinology and metabolism. Apr 2013;98(4):1492-1497.
Jimenez C, Rohren E, Habra MA, et al. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep. Aug 2013;15(4):356-371.
Thosani S, Ayala-Ramirez M, Palmer L, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. The Journal of Clinical Endocrinology & Metabolism. 2013;98(11):E1813-E1819.
Rich T, Jackson M, Roman-Gonzalez A, Shah K, Cote GJ, Jimenez C. Metastatic sympathetic paraganglioma in a patient with loss of the SDHC gene. Fam Cancer. Dec 2015;14(4):615-619.
Toledo SP, Lourenco DM, Jr., Sekiya T, et al. Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. The Journal of clinical endocrinology and metabolism. Feb 2015;100(2):E308-318.
Timmers HJ, Pacak K, Bertherat J, et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf). Apr 2008;68(4):561-566.
Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. Dec 1 2005;23(34):8812-8818.
Thosani S, Ayala-Ramirez M, Roman-Gonzalez A, et al. Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma. European journal of endocrinology / European Federation of Endocrine Societies. Sep 2015;173(3):377-387.
Rafat C, Zinzindohoue F, Hernigou A, et al. Peritoneal implantation of pheochromocytoma following tumor capsule rupture during surgery. The Journal of clinical endocrinology and metabolism. Dec 2014;99(12):E2681-2685.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. Aug 20-26 2005;366(9486):665-675.
Szolar DH, Korobkin M, Reittner P, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology. Feb 2005;234(2):479-485.
Baid SK, Lai EW, Wesley RA, et al. Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma. Annals of internal medicine. Jan 6 2009;150(1):27-32.
Bessell-Browne R, O'Malley ME. CT of pheochromocytoma and paraganglioma: risk of adverse events with i.v. administration of nonionic contrast material. AJR. American journal of roentgenology. Apr 2007;188(4):970-974.
Blake MA, Kalra MK, Maher MM, et al. Pheochromocytoma: an imaging chameleon. Radiographics : a review publication of the Radiological Society of North America, Inc. Oct 2004;24 Suppl 1:S87-99.
Wiseman GA, Pacak K, O'Dorisio MS, et al. Usefulness of 123I-MIBG scintigraphy in the evaluation of patients with known or suspected primary or metastatic pheochromocytoma or paraganglioma: results from a prospective multicenter trial. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Sep 2009;50(9):1448-1454.
Fottner C, Helisch A, Anlauf M, et al. 6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression. The Journal of clinical endocrinology and metabolism. Jun 2010;95(6):2800-2810.
Jacobson AF, Deng H, Lombard J, Lessig HJ, Black RR. 123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis. The Journal of clinical endocrinology and metabolism. Jun 2010;95(6):2596-2606.
Taieb D, Sebag F, Barlier A, et al. 18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature? Journal of nuclear medicine : official publication, Society of Nuclear Medicine. May 2009;50(5):711-717.
Yamamoto S, Hellman P, Wassberg C, Sundin A. 11C-hydroxyephedrine positron emission tomography imaging of pheochromocytoma: a single center experience over 11 years. The Journal of clinical endocrinology and metabolism. Jul 2012;97(7):2423-2432.
Sharma P, Dhull VS, Arora S, et al. Diagnostic accuracy of (68)Ga-DOTANOC PET/CT imaging in pheochromocytoma. European journal of nuclear medicine and molecular imaging. Mar 2014;41(3):494-504.
Naswa N, Sharma P, Nazar AH, et al. Prospective evaluation of (6)(8)Ga-DOTA-NOC PET-CT in phaeochromocytoma and paraganglioma: preliminary results from a single centre study. European radiology. Mar 2012;22(3):710-719.
Faria JF, Goldman SM, Szejnfeld J, et al. Adrenal masses: characterization with in vivo proton MR spectroscopy--initial experience. Radiology. Dec 2007;245(3):788-797.
Kim S, Salibi N, Hardie AD, et al. Characterization of adrenal pheochromocytoma using respiratory-triggered proton MR spectroscopy: initial experience. AJR. American journal of roentgenology. Feb 2009;192(2):450-454.
DeLellis RA. Pathology and genetics of tumours of endocrine organs. Vol 8: IARC; 2004.
Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. The American journal of surgical pathology. May 2002;26(5):551-566.
Kimura N, Takayanagi R, Takizawa N, et al. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-related cancer. Jun 2014;21(3):405-414.
Plouin PF, Fitzgerald P, Rich T, et al. Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. May 2012;44(5):390-399.
Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. The Journal of clinical endocrinology and metabolism. Oct 2007;92(10):3822-3828.
Timmers H, Brouwers F, Hermus A, et al. Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma. Endocrine-related cancer. 2008;15(4):1127-1133.
Kattan MW, Hess KR, Amin MB, et al. American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA: a cancer journal for clinicians. Jan 19 2016.

section name header

Disease Prologue ⬇

Summary ⬆ ⬇

Introduction ⬆ ⬇

Anatomy ⬆ ⬇

Classification Rules ⬆ ⬇

Prognostic Factors ⬆ ⬇

Risk Assessment ⬆ ⬇

TNM Definitions ⬆ ⬇

Stage Prognostic ⬆ ⬇

Registry Data ⬆ ⬇

Histologic grade ⬆ ⬇

Survival ⬆ ⬇

75.1 A, Overall survival in patients with PHs and SPGs. B, Overall survival in patients with metastatic PHs and SPGs. E/N, number of events/total number of patients. From Ayala-Ramirez et. al. 2011 with permission.

75.2 Probability of survival according to mutation status. From Amar et. al. 2007 with permission.

75.3 Median OS in patients with bone metastases (BM) and other metastases, those without BM, and those with only BM. From Ayala-Ramirez et. al. 2013 with permission.

Bibliography ⬆