Extra-Adrenal Paragangliomas

Paraganglia, derived from the neural crest, are widely dispersed in the body and are composed of morphologically and cytochemically similar neuroendocrine cells. Paraganglia have varied anatomic distributions. Their characteristic cells perform different functions. For physiologic and pathophysiologic purposes, they may be broadly divided into two groups, existing in close proximity to branches of either the sympathetic or parasympathetic nervous systems. The prototype for sympathetic paraganglia is adrenal medulla, while that of parasympathetic paraganglia is carotid body. Both are functionally different. Sympathetic paraganglia are distributed along the pre- and paravertebral sympathetic chains and follow the sympathetic innervation of the pelvic and retroperitoneal organs. Parasympathetic paraganglia are distributed along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.

The sympathetic paraganglia are referred to as chromaffin cells because of the brown discoloration with addition of chromates, while those of parasympathetic paraganglia, which do not react with chromate salts, are referred to as nonchromaffin. This reaction is now considered to be due to oxidation of stored catecholamines rather than the affinity for chromates.

HISTORY

Kohn at the beginning of the 20th century coined the term paraganglia because they formed ganglion-like bodies, were composed of chromaffin cells, and were connected to the sympathetic nervous system. However, they still were not genuine ganglion cells as they lacked axons and dendrites; hence Kohn referred them as “paraganglia.”

Subsequently, the finding of innervation of carotid body by glossopharyngeal nerve and the discovery of chemo-receptor functions of the carotid and other similar bodies associated with vagus nerve divided the paraganglia into sympathetic and parasympathetic types. A new term “chemodectoma” was introduced for the neoplasms derived from these organs. Another term for the parasympathetic paraganglia is glomus, and the tumors arising from these organs are referred to as “glomus jugulare,” not to be confused with thermoregulatory vascular structures in the skin called as glomus tumor or glomangioma. It was also noted that these paraganglia did not develop reaction with chromate salts, hence the term nonchromaffin.

All paraganglionic cells appear to be derived from the neural crest. The term paraganglia connotes a constellation of morphologic and functional characteristics associated with these cells and are not dependent on a single histochemical reaction. Morphologically the neoplasms arising from both types of paraganglia resemble each other and are often indistinguishable. They also exhibit widely overlapping secretory products and other neuroendocrine markers reflecting the similarities of their normal counterparts.

DISTRIBUTION OF NORMAL PARAGANGLIA

Paraganglia are grouped into four categories, based on location and innervation: branchiometric, intravagal, aorticosympathetic, and visceral autonomic (Fig. 15.1).

Sympathetic paraganglia are found associated with all parts of the peripheral sympathetic nervous system along the sympathetic trunks and in connective tissue in or near the walls of the pelvic organs. They are small, not grossly visible, except for organs of Zuckerkandl. Parasympathetic paraganglia are associated with distribution of cranial and thoracic branches of the glossopharyngeal nerve. Those associated with vagus nerves are located along jugular, superior and inferior laryngeal, subclavial and aortopulmonary, and cardiothoracic branches near the base of the great vessels.

Fig. 15.1: A: Anatomic distribution of sympathoadrenal paraganglia. B: Anatomic distribution of paraganglia in head and neck. (From Lack EE. Tumors of the Adrenal Glands and Extra-Adrenal Paraganglia. AFIP Atlas of Tumor Pathology Series 4, Fascicle 8, Washington, DC: American Registry of Pathology; 2007, pp. 283, Fig. 11.1; pp. 323, Fig. 12.1. Reproduced with permission from American Registry of Pathology.)

STRUCTURE OF PARAGANGLIA

With the exception of the organs of Zuckerkandl and carotid bodies, paraganglia are <1 mm in size and not visible to the naked eye. They contain two types of cells namely neuroendocrine cells and Schwann cell-like glial cells. The former is referred to as chromaffin cells or granule-containing cells when associated with sympathetic paraganglia. Those associated with parasympathetic ganglia are termed as glomus cells, type I cells, or chief cells. The Schwann cell-like glial cells are referred to as sustentacular cells, type II cells, satellite cells, or supporting cells.

The cells of paraganglia are polygonal, have abundant cytoplasm, small, round to ovoid, pale-staining nucleus. The cells can be identified by silver stains, autofluorescence, ultrastructure, or neuroendocrine markers. These cells are completely surrounded by glial cells, which contain less cytoplasm and flattened more deep-staining nuclei containing coarse chromatin, and stain positively with S100 protein.

HISTOCHEMISTRY

The chief cells of the paraganglia are argyrophilic and stain positively with Grimelius.

ULTRASTRUCTURE

Ultrastructurally, paraganglia cells demonstrate neurosecretory granules.

IMMUNOPROFILE

The chief cells react positively to neuroendocrine markers (neuron-specific enolase, synaptophysin, chromogranin, and CD56) and do not react to cytokeratin. The sustentacular cells in areas, peripheral to the cell nests, react positively to S100 protein.

NEOPLASMS OF THE PARAGANGLIA

Neoplasms of the paraganglia are referred to as paragangliomas. Those arising in adrenal medulla are referred to as “pheochromocytoma” or adrenal paraganglioma. The rest are referred to as extra-adrenal paragangliomas. The cytohistologic features, histochemical properties, ultrastructure, and the immunoprofile of adrenal pheochromocytoma and extraadrenal paragangliomas, whether sympathetic or parasympathetic, are similar. However, pheochromocytomas occurring in adrenal medulla have different clinical presentations than a wide variety of paragangliomas at extraadrenal sites. Pheochromocytomas are frequently associated with multiple endocrine neoplasia syndromes. They are described separately in Chapter 14.

EXTRA-ADRENAL PARAGANGLIOMA

Extra-adrenal paragangliomas occur at any site in the body. The locations described in Table 15.1 cover a long topographic list but by no means an exclusive one. They can also be seen in locations where paraganglia are not usually identified.

EXTRA-ADRENAL SYMPATHETIC PARAGANGLIOMA

Extra-adrenal paragangliomas associated with the sympathetic nervous system can occur anywhere from the upper neck to the pelvic floor. More than 90% occur in the retroperitoneum, and 30% to 50% of these are in the vicinity of organs of Zuckerkandl. The anatomic distribution of sympathetic paragangliomas is intra-abdominal (85%), urinary bladder (10%), intrathoracic (12%), and cervical (3%).

TABLE 15.1. PRIMARY SITES OF EXTRA-ADRENAL PARAGANGLIOMAS^a

Carotid body paraganglioma	Base of the heart, aorticopulmonary sulcus
Jugulotympanic region	Larynx
External ear	Trachea
Superior vagal nerve	Lungs
Sella turcica	Mediastinum
Orbit	Paraaortic region (retroperitoneum)
Nose and paranasal sinuses	Aortic bifurcation
Nasopharynx	Cauda equine
Parapharyngeal space	Gallbladder
Thyroid	Urinary bladder
^aThis is not an exclusive list of sites for paragangliomas.

The superior paraaortic paragangliomas (45%) include those located adjacent to the adrenal glands, in and around the hilum of the kidney and the renal pedicle. Inferior paraaortic (30%) paragangliomas arise below the inferior pole of the kidneys and extend down to the iliac vessels. Paragangliomas in latter location arise from the remnants of organs of Zuckerkandl.

Intra-abdominal paragangliomas occur at any age, but most occur in third to fifth decades of life. Signs and symptoms may be due to excess catecholamine secretions. The symptoms may also be related to the anatomic location. Approximately 25% to 27% of the paragangliomas associated with sympathetic nerves are functional. Nonfunctional tumors may present with symptoms resulting from the effects of a mass lesion or as incidental findings. Extraadrenal sympathetic paragangliomas are more likely to be malignant as compared to their intra-adrenal counterparts (pheochromocytoma), with a likelihood of multicentricity and potential for metastasis. Approximately 30% to 40% of retroperitoneal paragangliomas are reported to metastasize. Despite their general similarities, extra-adrenal paragangliomas in different locations vary somewhat in terms of age distribution and gender predilection.

Urinary bladder paragangliomas have been reported in patients between 11 and 78 years of age with no gender preference. The majority of the patients exhibit a clinical triad consisting of paroxysmal hypertension, gross intermittent hematuria, and micturitional “attacks” of headache, pallor, sweating, anxiety, and other catechol-amine-related symptoms. Urinary bladder paragangliomas may be nonfunctional and present as incidental findings. Visceral paragangliomas also include those associated with the gallbladder.

Intrathoracic paravertebral paragangliomas are usually located in the midthoracic region and may present with catecholamine-related symptoms.

Spinal paragangliomas are more frequently found in the region of the cauda equina and filum terminale. Less common sites include cervical and thoracic regions. They present as extradural or intradural mass without infiltration of the spinal cord, soft tissues, or bone. They may also invade the cranial cavity as local extension from the skull base.

Paragangliomas of the cauda equina are very uncommon and are usually located in the filum terminale. The tumors are mostly intradural, occur slightly more frequently in males, and may be associated with low back pain, neurologic deficiencies, and incontinence. Paragangliomas of the cauda equina region are generally egg shaped or sausage shaped, encapsulated, dark-red tumors, attached to the filum terminale or a nerve root. The size varies from 2 to 4 cm and can be easily shelled out.

EXTRA-ADRENAL PARASYMPATHETIC PARAGANGLIOMAS

Jugular and tympanic paraganglia are the most common sites of origin of parasympathetic paragangliomas in most published series (57% to 81% of tumors), followed by carotid body (8% to 36%), vagal (4% to 13%), and aortic (4% to 10%). In contrast to adrenal and extra-adrenal sympathetic paragangliomas, which cause catecholamine-related symptoms in majority of the cases, only about 1% of parasympathetic paragangliomas are clinically functional.

Irrespective of the site, origin, or location, cytohistologic features of all paragangliomas are the same. However, their incidence, variations in clinical presentation, radiologic findings, and differential diagnosis may differ, which are site specific. Although paragangliomas as a whole are relatively uncommon tumors, some are more frequently encountered than the others are. These are carotid body paragangliomas, jugulotympanic paragangliomas, intraabdominal (retroperitoneal) paragangliomas, and spinal paragangliomas involving the cauda equina. Table 15.2 lists their clinicopathologic features. Those involving rare sites will not be further discussed as they share the same histologic features as the rest of paragangliomas. Cytologic documentation of the paragangliomas at the rare sites is very sparse and reported as anecdotal cases. Readers are requested to refer to the literature for more information on the extremely rare cases.

GROSS AND MICROSCOPIC FEATURES

The paragangliomas are usually solitary but may be multiple. The gross appearance (Fig. 15.2A) is similar to that of pheochromocytomas. They are well-defined tumors ranging from 2 to 10 cm and can attain a large size. Paragangliomas are vascular tumors and may show hemorrhage, degeneration, and cystic changes.

Histologically, paragangliomas present features identical to that of pheochromocytomas (Fig. 15.2B-G). The characteristic alveolar or nesting pattern, popularly referred to as “Zellballen,” consists of rounded masses of neoplastic cells that can be delineated by reticulin stain. The other frequent pattern is a trabecular one with slender to broad anastomosing trabeculae. The third pattern is solid or diffuse growth pattern. Sinusoidal vessels are often noted separating the tumor cells. A given paraganglioma may be monomorphic or present combination of patterns. The paraganglioma cells vary in size and shape. They can be large polygonal or small round to cuboidal and plasmacytoid. Spindle, racket-shaped, and strap cells are seen in pleomorphic paragangliomas. The cell borders are well to poorly defined. Their cytoplasm is variable, and cytoplasmic processes are frequently noted. The nuclei are round, oval to oblong with typical salt-pepper chromatin. Intranuclear inclusions are often seen. Large, pyknotic, deep-staining nuclei with and without multilobulation are occasionally encountered. Mitoses are unusual. Areas of degeneration, hemorrhage, and necrosis may be present. Excessive, sclerotic stroma is sometimes seen in paragangliomas, especially the jugulotympanic paragangliomas, resulting in lack of typical nesting or alveolar pattern (see Figs. 15.7G and 15.8E).

CYTOPATHOLOGIC FEATURES

The specimens for cytologic diagnosis are predominantly fine needle aspiration (FNA) biopsies. In cases originating in central nervous system, the specimens are small forceps biopsies for intraoperative consultation and are processed by crush preparations. Exfoliative cytology is used on extreme occasions. With lung involvement, bronchoscopically obtained specimens may be processed (see Fig. 14.14).

TABLE 15.2. CLINICOPATHOLOGIC FEATURES OF EXTRA-ADRENAL PARAGANGLIOMAS

	Carotid Body Tumor	Jugulotympanic	Retroperitoneal Intra-abdominal	Cauda Equina/Filum Terminale
Synonyms	Chemodectoma, nonchromaffin paraganglioma	Glomus tumor, glomus jugulare, glomus tympanicum	Extra-adrenal paraganglioma	–
Location	Neck, at the bifurcation of the carotid artery; localized deep to the anterior border of sternocleidomastoid muscle, just below the angle of mandible; may be attached to the arteries or even encase them	Middle ear, external meatus 85%, parapharyngeal space, base of the skull; intracranial extension possible	Along the sympathetic trunk; commonly in retroperitoneum; can arise from organs of Zuckerkandl visceral involving urinary bladder, gall bladder	Intradural, or extradural; attached to filum terminale or a nerve root
Incidence	85% of head and neck paragangliomas	Most common tumor of the middle ear	90% associated with sympathetic nervous system	Very uncommon
Average age	Wide age range but common in fifth decade	Fifth decade	Third to fifth decade	Third to fifth decade
Gender predilection	None; but common in females at higher altitude	Common in females; M:F, 1:5	None	Slight increase in males
Radiologic findings	Homogeneous hypervascular, well-delineated mass lesion at the carotid artery bifurcation by carotid arteriogram	Soft tissue mass; bone erosion	Mass on CT scan	Mass on CT scan, MRI, blockage on myelogram
Association with other paragangliomas and syndromes	May be associated with jugulotympanic paragangliomas, a part of Carney triad (GIST, pulmonary chondroma, and carotid body tumor); may be associated with pheochromocytoma, or MEN syndrome	May be associated with carotid body paraganglioma; can be part of familial multifocal head and neck paragangliomas as an autosomal dominant trait	None	None
Presenting symptoms	Painless, slowly enlarging neck mass, located below the angle of the mandible; deep to the anterior border of sternocleidomastoid muscle; vertically fixed but movable horizontally; may be pulsatile	Tinnitus; aural pulsations; conduction-type hearing loss; ear fullness; pain; otorrhea; vertigo; dizziness; facial palsy; bulging of tympanic membrane; tumor may fill the middleear cavity and extend into external auditory canal or extend into cranial cavity	Back pain; palpable mass; symptoms due to secretion of norepinephrine	Lower back pain, radicular pain or sciatica is common; sensory-motor deficits include paraplegia and sphincter disturbances
Gross pathology	Encapsulated, well circumscribed; ovoid, rubbery to firm; redpink to tan-gray	Polypoid, red fragile mass; bleed profusely to touch	3-20 cm; well-defined mass, solid cut surface; hemorrhage and cystic change frequent; usually solitary	Generally egg shaped or sausage shaped; encapsulated; dark red, attached to filum terminale or a nerve root; size 2-4 cm
Histology	Typical alveolar or nesting pattern (Zellballen); can be trabecular, or solid with diffuse growth pattern; monomorphic to pleomorphic; scant stroma	Typical nesting pattern; may show marked stromal fibrosis, lacking the typical pattern	Typical alveolar or nesting pattern (Zellballen); can be trabecular, or solid with diffuse growth pattern; monomorphic to pleomorphic; scant stroma; prominent vascularity; no attached remnants of adrenal tissue	Typical alveolar or nesting pattern or solid growth pattern; ganglionic differentiation frequent; may express cytokeratin
Differential diagnoses	Medullary thyroid carcinoma Malignant melanoma Alveolar soft-part sarcoma Malignant lymphoma Metastatic carcinoma	Hemangiopericytoma Pituitary adenoma Meningioma, small cell type Malignant lymphoma Plasmacytoma Olfactory neuroblastoma Middle ear adenoma	Adrenocortical carcinoma Renal cell carcinoma Hepatocellular carcinoma Metastatic poorly differentiated carcinoma Malignant melanoma Malignant lymphoma Soft tissue tumors	Hemangiopericytoma Ependymoma Chondrosarcoma Malignant lymphoma Plasmacytoma Meningioma

The cytopathologic features of paragangliomas (Table 15.3; Figs. 15.3,15.4,15.5,15.6,15.7,15.8,15.9,15.10,15.11,15.12,15.13,15.14,15.15 and 15.16) are similar to that of pheochromocytomas (see Figs. 14.3,14.4,14.5,14.6,14.7,14.8,14.9,14.10,14.11,14.12 and 14.13). The cellularity of the aspirated specimens is variable, from poor to overwhelmingly cellular. The presentation can be monomorphic to pleomorphic. The latter is more frequent. In Papanicolaou-stained material, the neoplastic cells are predominantly discrete, loosely cohesive, and occasionally in tissue fragments. They are small, medium to large with occasional giant forms. In fact, the presence of an occasional giant cell in the background is quite common (Figs. 15.3C,D; 15.8B,C; 15.9B; 15.14D). The pleomorphic cells can be round, oval to plasmacytoid, polygonal, caudate, racket, and spindle shaped. Their cell borders are well to poorly defined, and their cytoplasm is variable in amount, appearing pale to dense. Sometimes, the cytoplasm is vacuolated, and prone to disintegrate, resulting in naked nuclei (Fig. 15.9B). The cytoplasm is often drawn into delicate cytoplasmic processes intertwining with neighboring cells. Red granules are noted in the cytoplasm with Romanowsky stain. Their nuclei are eccentric, round, oval, elliptical to elongated, spindle shaped, with coarsely granular chromatin (salt-pepper), and with or without nucleoli. Intranuclear inclusions are often seen. Mitoses are rare.

HISTOCHEMISTRY

Paragangliomas associated with sympathetic nervous system are argentaffin positive while those associated with parasympathetic nerves are argyrophilic.

Gross and Histologic Patterns of Paragangliomas

Fig. 15.2: A: Gross photograph of a carotid body paraganglioma. Note the fleshy surface and areas of hemorrhage and cystic changes. B: Typical alveolar or nesting pattern, also known as “Zellballen,” consisting of large round to polygonal cells arranged in alveoli or nests, separated by a delicate stromal network that can be highlighted with reticulin stain. Note the cells are large with uniform nuclei and moderate amount of cytoplasm (H&E). C: Trabecular pattern formed by elongated cells, aligned perpendicular to the sinusoids. The nuclei are uniform and the cytoplasm is moderate in amount (H&E). D: Diffuse pattern formed by round to cuboidal cells with scant cytoplasm and uniform nuclei (H&E). E: Pleomorphic cell pattern. Note the cells with giant forms (arrows) (H&E). F: The “Zellballen” pattern is formed by spindle-shaped neoplastic cells (H&E).

Fig. 15.2: (continued) G: This paraganglioma of the middle ear shows a dispersed pattern formed by small cuboidal cells, separated by an appreciable stroma (H&E).

IMMUNOPROFILE

The paraganglioma cells react to all neuroendocrine markers: chromogranin, synaptophysin, neuron-specific enolase, and CD56. They do not react to cytokeratin. The sustentacular cells react positively to S100 protein.

ULTRASTRUCTURE

Ultrastructurally, the paraganglioma cells demonstrate neurosecretory granules.

TABLE 15.3. CYTOPATHOLOGIC FEATURES OF EXTRA-ADRENAL PARAGANGLIOMAS^a

Cellularity	Variable; scant to cellular
Presentation	Cells discrete with a dispersed pattern and/or in loosely cohesive groups and in syncytial tissue fragments as nests, trabeculae, occasionally rosettes; naked nuclei +/-
Cells	Size and shapes variable; monomorphic to extremely pleomorphic; small to giant forms; round, oval, plasmacytoid, polygonal to spindle shapes, strap cells; cell borders poorly defined; N/C ratios variable
Nucleus	Variable in size; central to eccentric; bi- to multinucleation; round to oblong; smooth nuclear membranes; occasionally convoluted; granular chromatin; nucleoli prominent in aggressive tumors; intranuclear inclusions +/-; mitoses +/-; large bare nuclei +/-
Cytoplasm	Variable, scant indiscernible to abundant; pale, dense to granular to vacuolated; cytoplasmic processes, generally unipolar, may intertwine with neighboring cells; melanin pigment +/-, lipid +/-
Background	Bare nuclei frequent; bloody; necrosis –
Chromaffin reaction	+ with paragangliomas associated with sympathetic nervous system; negative with those associated with parasympathetic nervous system
Histochemistry	Argyrophilic
Immunoprofile	Positive reactivity to neuroendocrine markers; S100 positivity for sustentacular cells; TTF-1 negative; cytokeratin negative
Ultrastructure	Membrane-bound neurosecretory granules
^aNote: The cytomorphology of extra-adrenal paragangliomas is identical to that of adrenal paraganglioma or pheochromocytoma.

Spectrum of Cytopathologic Features of Paragangliomas (Figs. 15.3,15.4,15.5,15.6,15.7,15.8,15.9,15.10,15.11,15.12,15.13,15.14,15.15 and 15.16)

Figs. 15.3: A-D: FNA of a carotid body paraganglioma. The aspirate is very cellular, consisting of a large population of small- to medium-sized round to cuboidal cells with poorly defined cell borders. The nuclei are uniform with bland chromatin pattern. Also, note frequent giant forms (arrows).

Fig. 15.4: FNA of a carotid body paraganglioma. A, B: This cellular aspirate shows very pleomorphic cells ranging from small round to spindle cells with cytoplasmic processes. The nuclei are round, with coarsely granular to compact chromatin. Note the eccentric location of the nuclei. Their cytoplasm is variable and the cell borders are poorly defined. This pattern can be mistaken for medullary thyroid carcinoma.

Fig. 15.4: (continued) C, D: FNA of a different case of carotid body paraganglioma. C: The neoplastic cells are small, arranged in a syncytial tissue fragment with no architectural pattern. The cytoplasm is scant with high N/C ratios. D: This field shows loosely cohesive spindle cells with delicate cytoplasmic processes. The differential diagnoses should include medullary thyroid carcinoma, paraganglioma, and possibly a soft tissue tumor. Immunostains are necessary for correct diagnosis.

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