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Adrenal gland & paraganglia

Pheochromocytoma / paraganglioma

Paraganglioma


Editorial Board Member: Bonnie Choy, M.D.
Deputy Editor-in-Chief: Maria Tretiakova, M.D., Ph.D.
Luvy Delfin, M.D.
Sylvia L. Asa, M.D., Ph.D.

Last author update: 18 January 2022
Last staff update: 20 January 2022

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PubMed Search: Paraganglioma[TI] adrenal gland "last 5 years"[DP] review[PT]

Luvy Delfin, M.D.
Sylvia L. Asa, M.D., Ph.D.
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Table of Contents
Definition / general | Essential features | Familial pheochromocytoma and paraganglioma syndromes | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | ICCR guidelines for pheochromocytoma and paraganglioma | AJCC staging | Risk stratification (controversial) | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Delfin L, Asa SL. Paraganglioma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/adrenalparaganglioma.html. Accessed December 9th, 2022.
Definition / general
  • Nonepithelial, neural crest derived neuroendocrine neoplasms arising from the adrenal medulla (pheochromocytoma) and extra-adrenal paraganglia
  • Composed of paraneuronal peptide hormone secreting neuroendocrine cells
  • Histologically similar, regardless of location
  • 2 categories:
    • Parasympathetic: arises predominately in the head and neck
    • Sympathetic: arises in the retroperitoneum, thorax and pelvis
Essential features
  • Nonepithelial neuroendocrine tumors producing dopamine, epinephrine, norepinephrine and other peptide hormones
  • Occuring at almost any location, except within the brain and bones
  • All tumors have metastatic potential; they are referred to as metastatic or nonmetastatic instead of benign or malignant
  • Because of frequency of multifocal primary tumors, metastatic deposits should only routinely be considered as such at sites where normal chromaffin tissue is not present, including bone, brain and lymph node; however, metastatic disease can involve any organ
  • Regrowth or recurrence in the surgical bed should not be identified as metastatic pheochromocytoma / paraganglioma
  • At least 20% are multiple (bilateral or multicentric)
  • Tumor with highest degree of heritability among all human neoplasms
Familial pheochromocytoma and paraganglioma syndromes
  • Associated with various syndromes and familial conditions, known as familial pheochromocytoma and paraganglioma syndromes, including:
    • SDHx related syndromes (SDHB, SDHD, SDHA, SDHC and SDHAF2)
    • Von Hippel-Lindau (VHL)
    • Neurofibromatosis type 1 (NF1)
    • Multiple endocrine neoplasia type 2 (MEN2)
    • Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or FH tumor predisposition syndrome
    • TMEM mutations
    • MAX mutations
    • EPAS1 mutations (Pazak-Zhuang syndrome)
    • EGLN1/2 mutations
    • MDH2 mutations
    • KIF1B mutations
    • Multiple endocrine neoplasia type 1 (MEN1)
    • Carney triad (gastrointestinal stromal tumor, paraganglioma and pulmonary chondroma): nonhereditary genetic disorder potentially associated with currently unknown somatic mosaicism or SDH genetic defects, including DNA hypermethylation of SDHC or rarely SBHx pathogenic variant
  • Genetic testing and counseling should be offered to all patients with paraganglioma regardless of patient and family characteristics (J Intern Med 2019;285:187)
  • Genetic status represents a key element for accurate diagnosis, follow up and prognosis


Table 1: susceptibility genes in hereditary pheochromocytoma and paraganglioma
Gene Secreting phenotype Location Other associated disorders
NF1 Noradrenaline + adrenaline Adrenal medulla Multiple neurofibromas, malignant peripheral nerve sheath tumor, brain stem glioma, optic glioma, pilocytic astrocytoma, duodenal neuroendocrine tumors (somatostatinomas), gastrointestinal stromal tumor, café au lait spots, freckling (axilla and groin), Lisch nodules, bone dysplasia
VHL Noradrenaline Adrenal medulla / abdominal Retinal and CNS hemangioblastomas, clear cell renal cell carcinoma, renal cysts, pancreatic serous cystadenomas, pancreatic and small bowel neuroendocrine tumors, endolymphatic sac tumor, epididymal papillary cystadenoma, cystadenoma of the broad ligament and mesosalpinx
RET Noradrenaline + adrenaline Adrenal medulla Medullary thyroid carcinoma, thyroid C cell hyperplasia, Hirschsprung disease, hyperparathyroidism (multiglandular adenomas), cutaneous lichen amyloidosis, neuromas: lips, tongue, conjunctiva, intestinal ganglioneuromatosis, Marfanoid habitus
EPAS1 Noradrenaline, EPO Adrenal medulla / thoracic / abdominal Congenital polycythemia, pancreatic or duodenal somatostatinoma
EGLN1 / 2 Noradrenaline Adrenal / abdominal / thoracic Congenital polycythemia
SDHA Noradrenaline, dopamine, nonsecreting Head and neck / abdominal Gastrointestinal stromal tumor, renal cell carcinoma, pituitary neuroendocrine tumors
SDHB Noradrenaline, dopamine, nonsecreting Abdominal / head and neck Gastrointestinal stromal tumor, renal cell carcinoma, pituitary neuroendocrine tumors
SDHC Noradrenaline, dopamine, nonsecreting Head and neck Gastrointestinal stromal tumor, renal cell carcinoma, pulmonary chordoma*
SDHD Noradrenaline, dopamine, nonsecreting Adrenal, abdominal, head and neck Gastrointestinal stromal tumor, renal cell carcinoma, pituitary neuroendocrine tumors
SDHAF2 Nonsecreting Head and neck ?
FH Noradrenaline, dopamine, nonsecreting Abdominal Cutaneous and uterine leiomyomas, renal cell carcinoma
TMEM127 Noradrenaline + adrenaline Adrenal medulla and abdominal Renal cell carcinoma
MAX Noradrenaline Adrenal medulla and abdominal Parathyroid, pituitary neuroendocrine tumors, pancreatic neuroendocrine tumors, renal cell carcinoma, squamous cell carcinoma, breast, lung and endometrial cancer
MDH2 Noradrenaline, nonsecreting Head and neck / abdominal
GOT2 Noradrenaline Abdominal
SLC25A11 Noradrenaline, nonsecreting Abdominal
DLST Noradrenaline Thoracic
H3F3A N/A Abdominal / head and neck Giant cell tumor of bone (Clin Cancer Res 2016;22:2301)
DNMT3A Noradrenaline Head and neck Papillary thyroid carcinoma, intellectual disability (Cancers (Basel) 2020;12:3304)
MET N/A Adrenal medulla Medullary thyroid carcinoma
MERTK N/A Abdominal Medullary thyroid carcinoma
KIF1B N/A Adrenal medulla Ganglioneuroma / neuroblastoma, leiomyosarcoma, lung adenocarcinoma
Terminology
  • Parasympathetic paraganglioma
    • Most commonly arises in the head, neck and upper thorax (along glossopharyngeal and vagus nerve)
    • Named according the anatomical sites of origin:
      • Carotid body paraganglioma
      • Jugulotympanic paraganglioma (previously called glomus jugulare or glomus tympanicum)
      • Vagal paraganglioma
      • Laryngeal paraganglioma
      • Cardiac and pulmonary paraganglioma
    • Chemodectoma refers to carotid and aortic body paraganglioma because of their chemoreceptor function but is no longer used
    • Often reported to be both biochemically and clinically silent but if measured, frequently produces dopamine
  • Sympathetic extra-adrenal paraganglia
    • Approximately 85% arise below the diaphragm
      • Distributed along prevertebral and paravertebral sympathetic chain and sympathetic nerve fibers innervating retroperitoneum, thorax and pelvis
      • Largest paraganglia: adrenal medulla (bilateral) and organ of Zuckerkandl
      • Can also arise from cervical sympathetic chain, superior cervical ganglion, ciliary ganglion (orbital paraganglioma)
  • Composite paraganglioma:
    • Rare
    • Combined with ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumor
    • Most common locations: adrenal, urinary bladder and retroperitoneum
  • Misnomers:
    • 2 tumors have been called paragangliomas but are not composed of paraganglial chief cells
    • They are instead composed of epithelial neuroendocrine cells that are positive for keratins and lack GATA3 expression, often associated with neurons in a gangliocytoma / ganglioneuroma component
    • These tumors are not associated with the genetic alterations found in paragangliomas:
      • Cauda equina / filum terminale paraganglioma: spinal intradural and extramedullary tumors (3 - 4% of spinal tumors)
      • Gangliocytic paraganglioma changing to composite ganglioneuroma neuroendocrine tumor (CoGNET); arises in the duodenal periampular region and has triphasic differentiation: epithelial neuroendocrine cells, spindle shaped Schwannian / sustentacular cells and neuronal ganglion cells (proportion of each cell type varies)
Epidemiology
  • Annual incidence of is about 5 cases per million, with 500 to 1,600 cases reported per year in the United States (Eur J Intern Med 2018;51:68)
  • Prevalence varies from 0.2% to 0.6% in hypertensive patients to less than 0.05% in the general population (J Hypertens 2020;38:1443)
  • Mean age of presentation is 51, plus or minus 16 years
  • Distribution by gender is almost equal
  • Pediatric paragangliomas are almost always hereditary
  • Familial paragangliomas are often multifocal or bilateral
Sites
  • Parasympathetic: head and neck, along parasympathetic nerves near carotid body, jugulotympanicum, vagus nerve and larynx
    • Carotid body is the most common site
  • Sympathetic: 42% adrenal / periadrenal / perirenal, 28% organ of Zuckerkandl / near abdominal aorta, 10% bladder, 12% thorax, 2% cardiac
  • Unusual locations: pituitary, paranasal sinuses, orbit, thyroid, parathyroid glands, trachea, heart and lung, posterior mediastinum, gallbladder, liver, gut, pancreas, mesentery and rarely in testes and ovary (J Clin Med 2018;7:280, Am J Surg Pathol 2006;30:600)
Pathophysiology
  • Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors with strong genetic susceptibility, with approximately 40% harboring germline mutation
  • Almost 30% of the remaining sporadic cases carry a somatic mutation in a predisposition gene
  • Predisposition genes are implicated in mitochondrial metabolism, DNA methylation, chromatin remodeling and mitogen activated protein kinase (MAPK) pathway signaling (see Molecular / cytogenetics description) (Front Mol Neurosci 2019;12:6)
  • Co-occurrence of somatic and germline mutations might have a synergistic effect on driver mutations and cosegregation playing a role in tumor progression (Endocr Rev 2017;38:489)
Etiology
  • Neural crest derived neoplasm
  • Novel experimental evidence suggest that peripheral nerves may represent a stem cell niche for neuroendocrine differentiation in the adrenal medulla and paraganglia
    • Peripheral glial stem cells, also called nerve associated Schwann cell precursors (SCPs), have been shown to generate chromaffin cells via an intermediate progenitor (Science 2017;357:eaal3753)
    • Role of Schwann cell precursors seems to be less significant in the sympathetic paraganglia around the dorsal aorta (Front Mol Neurosci 2019;12:6)
  • Differences in origin of chromaffin cell lineage might explain the variability in biological behavior and genetic landscape related to pheochromocytoma, paraganglioma and neuroblastoma
Clinical features
  • Depends on tumor location, size and secretory phenotype (functional versus nonfunctional, sympathetic versus parasympathetic) (see Table 1) (Endocr Rev 2021 Jun 19 [Epub ahead of print])
    • Asymptomatic: incidentally detected on imaging studies
    • Symptomatic: vary with location and tumor type
  • Sympathetic parangliomas: epinephrine, norepinephrine and dopamine
    • Adrenal pheochromocytomas and most infradiaphragmatic lesions
      • Paroxysmal tachycardia, hypertension, pallor, headache and anxiety
      • Micturition induced paroxysms and hematuria caused by urinary bladder paragangliomas
      • Mass effect with local compression
  • Parasympathetic paraganglioma: dopamine or methoxytyramine
    • Carotid body:
      • Present at the angle of mandible, beneath the anterior edge of the sternocleidomastoid muscle, lateral to the tip of the hyoid bone (bifurcation of common carotid artery)
      • Usually slow growing, painless mass; often pulsatile
      • More frequent in patients living at high altitudes and with history of chronic hypoxia
      • May cause cranial nerve palsy, dysphagia, hoarseness or carotid sinus syndrome (bradycardia and syncope)
      • Mainly secrete dopamine
      • May adhere to carotid bifurcation and involve vagus nerve (group II and III Shamblin classification)
      • May invade locally or metastasize to lymph nodes or to the lungs (must rule out multicentric synchronous or metachronous tumor)
    • Jugulotympanic:
      • Usually arise lateral in temporal bone or jugular bulb, erode through floor and present as mass of external auditory canal or middle ear; also mass at base of skull, middle ear polyps
      • 40% extend into cranial cavity
      • Usually adults; female preponderance
      • Often misidentified as hemangiomas
      • Bone involvement can be present
    • Vagal / intravagal:
      • Arise from small dispersed collection of paraganglia following the cervical course of the vagus nerve (jugular and nodal ganglia)
      • Symptoms: painless neck mass, hoarseness, dysphagia, weakness of the tongue, vocal cord paralysis and Horner syndrome
      • More frequent on the right side
      • More common in women
      • Mean age: 50 years
    • Laryngeal:
      • Rare
      • Usually arise from superior paraganglia
      • Hoarseness and dysphagia
      • 25% mortality
      • Often tender subcutaneous metastases
    • Aorticopulmonary:
      • May cause hoarseness, dysphagia or chest pain / discomfort
      • Rarely hemoptysis or superior vena cava syndrome
  • Composite paraganglioma:
    • Extremely rare tumors
    • Age at diagnosis: 15 months to 81 years
    • Slight female predominance
    • Most common paraganglioma with ganglioneuroma
    • Most common location: adrenal, urinary bladder and retroperitoneum
    • Clinically silent, associated with catecholamies related signs or rarely associated with watery diarrhea, hypokalaemia and achlorhydria (WDHA syndrome) due to secretion of vasoactive intestinal polypeptide (VIP)
Diagnosis
  • Distinct signs and symptoms on presentation (as described above) (Pancreas 2021;50:469)
  • Increase levels of fractionated metanephrines and catecholamines in plasma and urine (values 3 - 4 times higher than the upper reference limit are almost always considered diagnostic for PPGLs)
  • Anatomical documentation of the tumor by imaging studies
  • Sometimes asymptomatic and discovered incidentally
Laboratory
  • Plasma and urinary metanephrines or catecholamines levels (liquid chromatography tandem mass spectrometry based) (Pancreas 2021;50:469)
    • PPGLs can be classified according to their biochemical profile (N Engl J Med 2019;381:552)
      1. Truly biochemically silent phenotype (usually head and neck region)
      2. Biochemically pseudosilent phenotype: normal or near normal levels of catecholamines and metanephrines
      3. Noradrenergic phenotype: increased levels of norepinephrine NE / NMN (usually extra-adrenal)
      4. Adrenergic phenotype: either purely elevated epinephrine (E) / metanephrine (MN) or in both E / MN and NE / NMN (usually adrenals)
      5. Dopaminergic phenotype: high levels of DA / 3-methoxytyramine (3-MT) with normal or near normal levels of E / MN and NE / NMN (extra-adrenal and mainly in the head and neck region
    • Plasma chromogranin A levels as a complement to metanephrines assays can be used as tumor marker to follow disease progression (Pancreas 2021;50:469)
Radiology description
  • Anatomical imaging studies: Doppler ultrasonography, CT, MRI, MRA, CT angiography (Cancer Imaging 2012;12:153, Insights Imaging 2019;10:29, Eur J Nucl Med Mol Imaging 2019;46:2112)
    • CT is the anatomic imaging modality of choice due to its excellent spatial resolution
    • MRI is recommended for children, pregnant women or patients with hereditary syndromes or metastatic disease
    • Functional imaging studies: there are 3 types of PET / CT radiopharmaceuticals that exert their actions through different receptors: 18F-FDG, 18F-fluorodopa (18F-FDOPA) and 68Galium(68Ga)-tetraazacyclododecanetetraacetic acid (DOTA) analogs (Front Endocrinol (Lausanne) 2018;9:515)
      • Ga 68-DOTATATE PET / CT is the preferred modality, binds to somatostatin receptor (SSTR2) expressed in paragangliomas with a detection rate of 80 - 100%, demonstrating increased uptake in the tumor anatomical location
    • See Radiology images
Radiology images

Contributed by Luvy Delfin, M.D. and Sylvia L. Asa, M.D., Ph.D.
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Ga-DOTATATE PET / CT



Images hosted on other servers:
   

Left carotid body tumor

Prognostic factors
  • Aggressive biologic behavior can be due to metastases or locally aggressive / multicentric inoperable disease (Pancreas 2021;50:469)
  • Poor clinical outcome is also related to high Ki67 labelling index
  • In addition, low tumoral and plasma levels of chromogranin B (CHGB) have recently been suggested as a marker for potential aggressive behavior (Am J Surg Pathol 2019;43:409)
  • Molecular predictive and prognostic markers:
    • Several markers with different levels of evidence have been proposed as genetic and expressional indicators of metastatic disease (Cancers (Basel) 2019;11:225)
    • Presence of constitutional SDHB mutations is the strongest genetic risk factor for the development of metastasis
    • Other significant markers include somatic mutations in ATRX or SETD2
    • High somatic mutational burden and global hypermethylation status
    • TERT gene abberancies
    • Gene fusions involving MAML3
    • 2 mRNA clustering subtypes: the pseudohypoxia (cluster 1) and the Wnt altered (cluster 2)
Case reports
Treatment
  • Complete surgical excision is the primary treatment (North American Neuroendocrine Tumor Society guidelines April 2021) (Pancreas 2021;50:469)
  • Intraoperative risk is kept to the minimum with appropriate preoperative medical treatment:
    • Blockage of catecholamine effect for 10 - 14 before surgery with alpha adrenoreceptor blockade followed by beta adrenoreceptor blockade
    • Preoperative volume expansion with saline infusion and increase water intake to limit volume contraction after surgery
  • Laparoscopic surgery is the first option for adrenal and extra-adrenal tumors
  • Partial cortical sparing adrenalectomies are advocated for bilateral adrenal disease
  • Long term periodic follow up is always recommended
    • Plasma free or fractionated urine metanephrines
    • Recommended at 6 and 12 months following resection (every 3 - 6 months for advanced disease), then annually
    • Duration of follow up not defined
    • Chromogranin A (neuroendocrine marker): consider if tumor does not produce plasma metanephrines
  • Advanced disease management:
    • Palliative surgery
    • Radiofrequency ablation or cryoablation of metastatic lesions
    • High dose versus fractionated 131I MIBG is used in patients with positive 123-I MIBG scintigraphy
    • Chemotherapy provide tumor regression and symptom relief in up to 50% of patients with negative 123-I MIBG scintigraphy
    • External beam irradiation represent and appropriate approach for bone metastasis
Gross description
Gross images

Contributed by Luvy Delfin, M.D., Sylvia L. Asa, M.D., Ph.D. and Debra Zynger, M.D.
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Adrenal pheochromocytoma

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Para-aortic paraganglioma

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Carotid body paraganglioma

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Parapharyngeal paraganglioma

Frozen section description
  • Intraoperative consultation is rarely requested and generally discouraged
  • Correct frozen diagnosis can be extremely challenging if low clinical suspicion and unusual location (Int J Surg Pathol 2018;26:213)
  • Tumors are often misdiagnosed due to their dissimilar architectural patterns and cytologic features worsened by freezing artifact
Microscopic (histologic) description
  • Prevailing histologic pattern: epithelioid chief cells arranged in distinctive clusters / nests (zellballen pattern), separated by prominent fibrovascular stroma (J Clin Med 2018;7:280)
  • Trabecular pattern: ribbons or cords of epithelioid cells divided by fibrous bands
  • Other patterns: pseudorosette, angioma-like, spindled and sclerosing
  • Chief cells: round, oval to polygonal cells with abundant granular basophilic, eosinophilic or amphophilic cytoplasm (Surg Pathol Clin 2019;12:951)
  • Intracytoplasmic hyaline globules may be present in sympathoadrenal paragangliomas
  • Giant multinucleated cells and bizarre cells can be present (Srp Arh Celok Lek 2002;130:7)
  • Rarely, elongated and spindle shaped cells with a sarcomatoid appearance may be found
  • Scattered ganglion cells can be seen
  • May have nuclear atypia
  • May have dysmorphic vessels, melanin-like pigment (neuromelanin) (pigmented paraganglioma), amyloid, abundant stroma and osseous metaplasia (Diagn Pathol 2012;7:77, Hum Pathol 1992;23:33)
  • No or rare mitotic figures except in highly aggressive rapidly proliferating lesions
  • May have focal chronic inflammatory infiltrate
  • Necrosis is unusual except in patients who have undergone preoperative tumor embolization
  • Special histopathologic features usually related to genetic syndromes:
Microscopic (histologic) images

Contributed by Luvy Delfin, M.D. and Sylvia L. Asa, M.D., Ph.D.
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Adrenal pheochromocytoma

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Duodenum

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Pheochromocytoma

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Organ of Zuckerkandl


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Pheochromocytoma in VHL

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Pheochromocytoma with metastatic behavior


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Metastatic pheochromocytoma in lymph node

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Metastatic paraganglioma in bone

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Composite pheochromo-
cytoma with ganglioneuroma

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Middle ear: jugulotympanic paraganglioma

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Cardiac paraganglioma


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Para-aortic paraganglioma

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Carotid body paraganglioma

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S100

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Chromogranin

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GATA3


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Tyrosine hydroxylase

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S100 protein

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SOX10

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Ki67

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SDHB intact

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SDHB deficient


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CAIX

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Inhibin

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S100 staining in metastatic pheochromocytoma

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Ki67 in metastatic pheochromocytoma

Cytology description
  • Irregular clusters of tumor cells with eosinophilic finely granular cytoplasm and occasional intracytoplasmic pigment (Acta Cytol 2005;49:421)
  • Mild to severe nuclear pleomorphism with sporadic binucleation and intranuclear pseudoinclusions (Acta Cytol 2006;50:372)
  • Fine needle aspiration not recommended for paragangliomas due to the wide variety of morphologic patterns and high probability of catecholamine crisis and hemorrhage; if required, patients should undergo alpha blocade (Acta Cytol 2003;47:1082)
Positive stains


Contributed by Luvy Delfin, M.D. and Sylvia L. Asa, M.D., Ph.D.
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Pathway of catecholamine biosynthesis

Negative stains
Electron microscopy description
  • Chief cells are polygonal with well developed rough endoplasmic reticulum, prominent Golgi complex and abundant cytoplasmic neurosecretory granules (Arch Pathol Lab Med 1980;104:46)
  • May have giant mitochondria with paracrystalline inclusions
  • Sustentacular cells wrap around chief cells and lack neurosecretory granules
  • No desmosomes
Electron microscopy images

Contributed by Luvy Delfin, M.D. and Sylvia L. Asa, M.D., Ph.D.
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Paraganglioma

Molecular / cytogenetics description
  • Transcriptome based classification of paragangliomas (see Table 2) (Cancer Cell 2017;31:181):
    • Cluster 1: pseudohypoxia pathway / Krebs cycle related: SDH / FH deficient, mutations in MDH2 and mutant IDH state (1A) and pseudohypoxia pathway / VHL / EPAS1 related (1B): VHL, HIF2A, PHD1 / EGLN2, PHD2 / EGLN1 (dopaminergic or noradrenergic secretory profiles) (Cancers (Basel) 2021;13:3312, Cancer Cell 2017;31:181)
    • Cluster 2: kinase signaling (RAS / RAF / ERK, P13 kinase / AKT / mTOR, TMEM127, NF1 and MYC / MAX / MXD1) pathways (adrenergic and noradrenergic secretory profiles)
    • Cluster 3: wnt / B catenin pathway activation: CSDE1 or MAML3 somatic mutations (Mol Cancer Res 2021;19:1476, Cancer Cell 2017;31:181)
  • Somatic mutations are present in 30% of sporadic paragangliomas: ATRX, TP53, KMT2D, SETD2 and TERT (Int J Endocrinol 2015;2015:138573)


Table 2: molecular clusters of pheochromocytoma and paraganglioma
Molecular cluster Mutated gene Percentage of all PPGLs % Hereditary
Pseudohypoxia TCA cycle related Succinate dehydrogenase complex iron sulfur subunit (SDHB) 10 - 15% 100%
Succinate dehydrogenase complex flavoprotein subunit (SDHA)
Succinate dehydrogenase complex subunit C (SDHC)
Succinate dehydrogenase complex subunit D (SDHD)
Succinate dehydrogenase complex assembly factor 2 (SDHAF2)
Fumarate hydratase (FH)
Pseudohypoxia, VHL / EPAS1 related Von Hippel-Lindau tumor suppressor (VHL) 15 - 20% 25%
Endothelial PAS domain protein 1 (EPAS1)
Wnt signaling Cold shock domain containing E1 (CSDE1) 5 - 10% 0%
Mastermind-like transcriptional coactivator 3 (MAML3)
Kinase signaling Ret proto-oncogene (RET) 50 - 60% 20%
Neurofibromin 1 (NF1)
MYC associated factor X (MAX)
Transmembrane protein 127 (TMEM127)
HRAS proto-oncogene, GTPase (HRAS)
ICCR guidelines for pheochromocytoma and paraganglioma
AJCC staging
Risk stratification (controversial)
  • Risk stratification scoring systems proposed when these lesions were classified as benign and malignant:
  • Validation studies have confirmed that both PASS and GAPP have variable predictive value (J Clin Endocrinol Metab 2020;105:e4661, Cancers (Basel) 2019;11:225)
  • Both systems may overestimate risk and have high interobserver variability (Langenbecks Arch Surg 2018;403:785)
  • Histological parameters are best interpreted in conjunction with clinical and molecular data (Hum Pathol 2021;110:8)
  • Prognosis depends on complete tumor resection
    • Considered histological parameters: histologic pattern, cellularity, comedo type necrosis and capsular / vascular invasion
    • Immunohistochemical assessment: Ki67 labeling index
    • Biochemical data: catecholamine type
  • Clinical characteristics of potentially aggressive pheochromocytoma and paraganglioma, North American Neuroendocrine Tumor Society guidelines 2021 (Pancreas 2021;50:469)
    • Presurgical:
      • Tumor size > 5 cm if located in adrenal medulla and > 4 cm if extra-adrenal
      • Gross vessel invasion
      • Germline SDHB pathogenic variant
    • Postsurgical:
      • Tumor with adjacent lymph node involvement
      • Persistently elevated metanephrine levels
      • High mitotic index or Ki67 labeling index
Sample pathology report
  • Adrenal (right), adrenalectomy:
    • Pheochromocytoma, 6 cm (see synoptic report)
    • Synoptic report: pheochromocytoma and extra-adrenal paraganglioma
    • Procedure: adrenalectomy - right
    • Biochemical features: biochemically functioning
      • Metanephrine or adrenaline
      • Normetanephrine or noradrenaline
      • Dopamine
    • Tumor location and size (by imaging)
      • Anatomic location: right adrenal
      • Greatest dimension: 4 cm
      • Additional dimensions: 3.8 cm
    • Specimen description
      • Received: in formalin
      • Specimen integrity: intact
      • Specimen size : 6 x 6 x 3.5 cm
      • Specimen weight: 56.2 grams
    • Tumor focality: unifocal
    • Tumor size: 6 x 4 x 3.5 cm
    • Tumor type: pheochromocytoma
    • Histologic features:
      • Growth pattern: nested (alveolar, zellballen) pattern
      • Composite tumor elements: absent
      • Cytologic variants: epithelioid
      • Necrosis: not identified
      • Mitotic rate: < 2 mitoses (per 10 high power fields or mm2)
      • Additional features: none
      • Encapsulation: no capsule
    • Invasive growth
      • Tumor capsule invasion: not applicable
      • Adrenal capsule invasion: not identified
      • Surrounding tissues: not identified
      • Vascular invasion: not identified
      • Lymphatic invasion: not identified
      • Surgical margins: uninvolved
    • Metastases
      • Lymph nodes: not identified
      • Distant: not assessed
    • Immunohistochemistry
      • Chromogranin A: positive
      • GATA3: positive
      • Tyrosine hydroxylase: positive
      • S100 protein: positive in tumor cells and strong in sustentacular cells
      • SOX10: positive in sustentacular cells
      • SDHB: intact
      • CAIX: negative
      • Inhibin: negative
      • Ki67 10%
    • Associated lesions
      • Adrenal medullary hyperplasia: none
      • Current or past tumors in other organs (specify): none
    • Gross description example
      • Received in formalin, labeled with the patient's name and hospital number and right adrenal gland, are multiple fragments of fibroadipose tissue with an adrenal gland containing a mass; the fragments measure 6.0 x 6.0 x 3.5 in aggregate and weigh 56.2 g. The surface is inked black. The adherent fat is removed and the adrenal gland with mass weighs 43.5 g. The mass measures 6.0 x 4.0 x 3.5 cm and weighs 36.6 g. The cut surface of the mass reveals a well delineated soft homogenous surface with central hemorrhage. The nontumorous adrenal measures 3.0 x 1.5 x 1.0 cm and has an unremarkable cut surface. In the periadrenal fibroadipose tissue there are no nodules or lymph nodes. A photograph is taken. Representative sections are submitted in 26 cassettes.
      • 1 - 3 mass with portion of adrenal gland, serially sectioned
      • 4 - 8 complete cross section of mass
      • 9 - 20 capsule entirely submitted
      • 21 - 23 mass with portion of adrenal gland, serially sectioned
      • 24 - 26 nontumorous adrenal entirely submitted
Differential diagnosis
Board review style question #1
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The presence of which of the following histologic features in pheochromocytomas can be associated with von Hippel-Lindau syndrome?

  1. Bizarre giant cells
  2. Hyaline droplets / globules
  3. Prominent stromal edema, clear cystoplasm and lipid degeneration
  4. Stromal amyloid
Board review style answer #1
C. Prominent stromal edema, clear cytoplasm and lipid degeneration in the tumor are usually asscociated with von Hippel-Lindau syndrome

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Reference: Paraganglioma
Board review style question #2
The strongest genetic risk factor for the development of metastatic paraganglioma is

  1. NF1
  2. RET oncogene
  3. SDHB mutations
  4. THEM127 and VHL
Board review style answer #2
C. Presence of constitutional SDHB mutation is the strongest genetic risk factor for the development of metastasis

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Reference: Paraganglioma
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