Paraganglioma ie both 1) Adrenal- Pheochromocytoma 2) Extra-adrenal paragangliomas.

1. PARAGANGLIOMA
By:
Dr. Nishit Gupta
Moderator:
Dr. Anil K. Suri
1

2. INTRODUCTION
• It is also known as glomus tumor,
chemodectoma, perithelioma, fibroangioma,
and sympathetic nevi.
• Paragangliomas are categorised as
neuroendocrine tumors in the WHO
classification.
• Paragangliomas originate from paraganglia in
chromaffin-negative glomus cells derived from
the embryonic neural crest.
• Paragangliomas are closely related
to pheochromocytomas, which however are
chromaffin-positive.
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3. 3

4. PARAGANGLION SYSTEM
• Paraganglia are the collections of
neuroepithelial (Chief) cells scattered
throughout the body, associated with
sympathetic and parasympathetic nervous
system.
• Adrenal medullary chief cells along with
extra-adrenal paraganglia constitute the
paraganglion system.
4

5. 5

6. EXTRA-ADRENAL PARAGANGLIA
RELATED TO
PARASYMPATHETIC
SYSTEM
Majority
Non chromaffin
RELATED TO
ORTHOSYMPATHETIC
SYSTEM
Few. (Extra Adrenal
Pheochromocytomas)
Chromaffin
Located in head and neck, Located in retroperitoneal,
mediastinum
thoracolumbar, para-aortic
region
Secrete little or no
catecholamines.
Secrete catecholamines,
principally norepinephrine.
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7. 7

8. • Microscopically, all paraganglia have a similar
morphology characterized by chief cells
(chromaffin) arranged in well defined nests
(Zellballen-”Cell Balls“ in German) encircled
by a thin layer of supporting sustentacular
cells.
8

9. • Chief cells of adrenal medulla are also called
as Chromaffin Cells (Pheochromocytes)
• The word 'Chromaffin' comes from chromium
and affinity because they can be visualized
by staining with chromium salts which oxidize
and polymerize catecholamines to form a
brown colour.
• Microscopically, cells have finely granular
abundant basophilic-amphophilic-eosinophilic
cytoplasm. Nuclei are round to oval with
stippled(salt and pepper) chromatin and
prominent nucleoli.
9

10. • Ultrastructurally, consist of “dense core”
neurosecretory granules that store
catecholamines.
10

11. PHEOCHROMOCYTOMA
• “ Paraganglioma of the adrenal medulla”
• Greek “Phaios- dark, Chroma- color,
Cytos- cell, Oma- tumor")
• Composed of chromaffin cells.
• Surgically correctable cause of
hypertension.
• Age group 40-60 years.
• Usually sporadic.
11

12. “10% Tumor”
1.
2.
3.
4.
5.
10% extra-adrenal
10% sporadic, bilateral
10% malignant
10% not associated with hypertension
10% (25%) familial
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13. Clinical features
•
•
•
•
•
Usually paragangliomas are asymptomatic. Those
that secrete catecholamines behave as
pheochromocytomas:
Symptom triad of palpitations, headache sweating.
Hypertension paroxysmal or sustained.
(Precipated by emotional stress, exercise,
palpation of tumor)
Orthostatic hypotension ( Fall SBP>20mmHg,
DBP>10mmHg on standing.
Associated nausea, vomiting, abdominal pain
Catacholamine cardiomyopathy, ventricular
arrhythmia.
13

14. HISTOPATHOLOGY
GROSS:
• Few grams upto 2000grams.
• Encapsulated, soft, on section yellowish
brown to reddish brown, with areas of
necrosis, hemorrhage, cyst formation.
• Remnants of the adrenal gland attached to
one pole.
• Incubation of fresh tissue in potassium
dichromate solution turns the tumor to a dark
brown color due to oxidation of stored
catecholamines.
14

15. MICROSCOPY:
• Tumor cells (Chief cells) clustered with
sustentacular cells in well defined nests or
alveoli (ZELLBALLEN) bound by a delicate
fibrovascular stroma.
• Histological patterns :1. An anastomosing cell cord or trabecular
pattern
2. Alveolar pattern and
3. A diffuse or solid arrangement of cells
• Intracytoplasmic hyaline globules.
15

16. CYTOLOGY OF
PHEOCHROMOCYTOMA
• Many dispersed and loosely clustered neoplastic
cells.
• Prominent anisokaryosis, uniformly bland nuclear
chromatin.
• Abundant fragile cytoplasm ; indistinct cell
borders.
• Fine red cytoplasmic granulation in a proportion of
cells.
• Distinct nucleoli
• Contraindicated in view of the risk of precipitating
a hypertensive crisis.
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17. 17

18. Important points
• Cellular and nuclear pleomorphism, giant cells,
mitotic figures and even capsular and vascular
invasion are not an expression of malignancy.
• The definitive diagnosis of malignancy is based
exclusively on the presence of metastases.
• Metastasize to skeletal system (ribs & spine),
regional lymph nodes, lungs.
• Malignant tumors are usually larger, have more
necrosis and are composed of smaller cells than
their benign counterparts.
18

19. EM & IHC
CG
 Ultrastructurally, the hallmark of pheochromocytoma
is the presence of dense-core neurosecretory granules
and abundant large mitochondria.
 IHC –
• Chief cells reactive for catecholamines,
S-100
catecholamine-synthesizing enzymes, NSE,
chromogranin, synaptophysin, galanin, neurofilaments,
serotonin and synaptophysin and opioid peptides.
Keratin negative (differentiating with other
neuroendocrine carcinomas)
• Sustentacular cells are strongly positive for S-100.
19

20. Extra-adrenal Paragangliomas
1. CAROTID BODY TUMOR
• Located at the bifurcation of common
carotid artery.
• Chemodectoma- because it has
chemoreceptor function.
• 10 times more frequent in the people
living at higher altitudes.
• Larger lesions cause cranial nerve palsy
(X & XII)
20

21. 2. JUGULOTYMPANIC
PARAGANGLIOMAS
• Also called GLOMUS TUMOR.
• Female preponderance.
A. Glomus juglare: arise from the dome of
juglar bulb.
B. Glomus Tympanicum: arise from the
promontary of the middle ear.
• Spread to inner ear, juglar foramen
causing cranial nerve palsy, eustachian
tube, nasopharynx and intracranial.
21

22. • Present as a middle ear mass resulting
in tinnitus (in 80%) and hearing loss (in 60%).
• On otoscopy, through intact tympanic
membrane “Rising sun” appearance, when it
originates from floor of middle ear.
• Pulsation sign (Brown’s Sign) is positive
when ear canal pressure is raised with
Siegle’s speculum, tumor pulsates vigorously
and then blanches.
22

23. 3. VAGAL PARAGANGLIOMA
• Least common of paragangliomas.
• Located in the anterolateral portion of the
neck
• Presents as painless neck mass or with
dysphagia and hoarsness of voice.
• Can also occur along the peripheral
distribution of the vagus nerve.
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24. 4. MEDIASTINAL
PARAGAGLIOMA
• Originate in supra-aortic/aorticopulmonary
bodies (Chemodactomas)
• Found in the anteriosuperior portion of the
mediastinum, in the area of aortic arch.
• Higher incidence of aggressive tumor
growth.
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25. 5. RETROPERITONEAL
PARAGANGLIOMA
• Anywhere along paravertebral chain.
25

26. 6. ZUCKERKANDL BODY
PARAGANGLIOMA
• Found close to angle formed by the
anterior wall of aorta and the origin of the
inferior mesenteric artery
• Orthosympathetic, chromaffin,
catacholamine secreting.
• May secondarily involve inferior vena
cava.
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27. 7. Other sites
•
•
•
•
•
•
•
•
•
Cavernous sinus
Orbit
Nose
Paranasal cavities
Larynx
Trachea
Thyroid
Heart
Salivary glands
•
•
•
•
Gall bladder
Urinary bladder
Uterus
Spinal chord (Lumbar
region, cauda equina,
exceptionally keratin
positive)
• Lung
• Pineal gland
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28. Familial Pheochromocytoma/
Paraganglioma
• Younger age at presentation
• More often bilateral
• Associations:
1. MEN-2A, MEN-2B (RET gene)
2. Neurofibromatosis (NF1 gene)
3. Von Hippel Lindau (VHL gene)
4. Familial paragangliomas (SDH gene
related.)
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29. SDH gene
• Four distinct syndromes – PGL 1 to 4 are
related to mutations in the succinate
dehydrogenase gene – mitochondrial complex
involved in electron transfer and Krebs cycle.
• Although different SDH mutations occur in
single multi-unit enzyme, they express
significant phenotype heterogeneity. Their
prevalence is estimated to lie between 10–
30% of PGLs.
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30. SDH A
SDH B
SDH C
SDH D
SDH 5
PGL
Syndrome
Leigh
PGL 4
PGL 3
PGL 1
PGL2
Inheritance
AR
AD
AD
Maternal
AD
high
Low
Low
Low
Malignancy None
risk
Multifocal
Disease
Frequent
Frequent
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32. Diagnosis
1. Clinical presentation
2. Histopathological, IHC, EM,
histochemical techniques.
3. For chatecholamine secreting tumors
• Biochemical testing
• Localization of tumor by imaging
32

33. Biochemical testing
• Elevated plasma & urine levels of
catecholamines and methylated metabolites,
(metanephrines and vinyl mandelic acid)
• Can be measured using HPLC, ELISA, other
immunoassays.
• A value more than two-three times the upper
limit of normal, pheochromocytoma highly
likely.
• Plasma tests are more sensitive and
convenient compared to urine tests (with 24
hour urine sample) but latter are more
commonly done.
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34. • Pattern of catecholamines is helpful in
localizing tumor as epinephrine is never
increased in extra-adrenal pheochromocytoma.
• CLONIDINE SUPPRESSION TEST: Diagnostic
test used in the past for a pheochromocytoma.
Administer clonidine, a centrally-acting alpha-2
agonist used to treat high blood pressure.
Clonidine mimics catecholamines in the brain,
causing it to reduce the activity of the
sympathetic nerves controlling the adrenal
medulla. A healthy adrenal medulla will respond
to the by reducing catecholamine production;
the lack of a response is evidence of
pheochromocytoma.
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35. Diagnostic imaging
• CECT scan and MRI with gadolinium
enhancement have equal sensitivity.
• I-123 metiodobenzylguanidine (MIBG) and Fdopa PET scan help localize, as these agents
exhibit selective uptake in paragangliomas
Right (1) and left (2) glomus jugulare tumors; a left glomus
vagale tumor (3); and left (4) and right (5) carotid body
tumors.
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36. Treatment
• The main treatment modalities are surgery
(laparotomy or laparoscopy), tumor
embolization and radiotherapy.
• Pre-surgical alpha receptor antagonist
(Phenoxybenzamine) either alone or
combined with a beta blocker administered to
overcome the severe hypertension caused to
massive release of catecholamines during
manipulation of tumor.
36

37. PHEOCHROMOCYTOMA
PARAGANGLIOMAS.
Originate from Adrenal
medullary sympathetic
ganglia.
Chromaffin-positive.
Originate usually from
parasympathetic ganglia.
Majority symptomatic.
Majority asymptomatic. All
have neurosecretory
granules, but only 1-3%
secrete catecholamines.
10% malignant.
3% malignant.
Chromaffin- negative.
37

38. CASE- 3012/13
(Reported by Dr. M.S. Bal)
• 53/ M, swelling right infra-auricular region- 8
years, painless, no other aural complaints, no
hoarseness of voice, no loss of weight, no loss
of appetite.
• Grossly, a circumscribed, grayish white are
identified in the grayish brown STP measuring
6 X2.5 X1.5
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40. CASE – 1616/13
(Reported by Dr. Anil K. Suri)
• 50 year old female with complaints of pain
abdomen since one month.
• On surgical exploration, a well
circumscribed mass, found attached to the
root of mesocolon, just above the superior
mesenteric vessels.
• Grossly, a circumscribed globular STP
measuring 9 cm.
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43. References
• Rosai & Ackerman’s- Surgical Pathology (10Th
ed.)
• Robbins and cotran- Pathological basis of
disease. (8th ed.)
• P.L Dhingra ENT textbook.
• Pubmed central (NCBI)
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44. ACKNOWLEDGEMENT
Dr. Manjit Singh Bal
Dr. Anil Suri
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