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A Diagnostic and Therapeutic Approach to Paragangliomas of the Larynx
Kenneth W. Sanders, MD;
Fleurette Abreo, MD;
Edwin Rivera, MD;
Fred J. Stucker, MD;
Cherie-Ann O. Nathan, MD
Arch Otolaryngol Head Neck Surg. 2001;127:565-569.
ABSTRACT
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Background Differentiating paragangliomas from moderately differentiated neuroendocrine
carcinoma in the larynx is a difficult management problem. As the biological
behavior of these 2 entities is different, we developed an algorithm for the
preoperative diagnosis and treatment of this disease.
Design The sample case from which the algorithm was developed consisted of
a 69-year-old man who was transferred to us after tracheostomy and an attempt
at biopsy for airway obstruction secondary to a vascular mass. Biopsy resulted
in substantial bleeding. Flexible laryngoscopy showed a vascular mass of the
supraglottis. A computed tomographic scan showed 2 vascular masses at the
carotid bifurcation and in the larynx. An arteriogram confirmed synchronous
vascular tumors.
Results The arteriogram showed the superior thyroid artery to be the major feeder
vessel to this mass, a situation commonly seen in paragangliomas but not other
neuroendocrine tumors. The presence of synchronous lesions and a vascular
mass based on the superior thyroid artery helped differentiate paraganglioma
from the other neuroendocrine tumors. As the biological behavior of paragangliomas
is relatively benign, we performed a conservative supraglottic laryngectomy
and excision of the carotid body tumor. Histologic diagnosis and immunohistochemical
analysis confirmed the diagnosis of paraganglioma.
Conclusions The vascular nature of neuroendocrine tumors prevents preoperative pathological
diagnosis. Radiologic features demonstrating a vascular mass with a dominant
feeder vessel by the superior or inferior thyroid artery may help in the clinical
diagnosis of paragangliomas of the larynx. Since paragangliomas are rarely
malignant, a conservative surgical procedure should suffice.
INTRODUCTION
NEUROENDOCRINE tumors of the larynx are the subject of much controversy
in the recent literature. The major dispute centers on the pathological classification
of these tumors. This is not a trivial debate because both treatment and prognosis
are very different for the various types of lesions. Neuroendocrine neoplasms
of the larynx are classified in several ways; however, the most accepted method
starts by dividing them into epithelial vs neural origin.1
Paragangliomas are of neural origin. The epithelial group is subdivided into
well-differentiated neuroendocrine carcinoma, moderately differentiated neuroendocrine
carcinoma (MDNEC), and poorly differentiated neuroendocrine carcinoma. Well-differentiated
neuroendocrine carcinoma is very rare, with only 12 cases reported in the
larynx.2 Poorly differentiated neuroendocrine
carcinoma of the larynx is somewhat more common, with about 150 cases in the
literature.
Our discussion will be limited to the difficulty in distinguishing a
paraganglioma from an MDNEC clinicopathologically, because this is where the
controversy lies.3 Since these 2 neoplasms
have different biological behavior with regard to malignancy, the diagnosis
would best be known preoperatively. The usual method of diagnosis, biopsy,
has proved difficult because of the extreme vascularity that many of these
tumors exhibit. We hypothesized that a preoperative evaluation exclusive of
biopsy can help differentiate these lesions into 2 groups, those that should
be managed conservatively and those in which an aggressive intervention is
more appropriate. A representative case is described below.
REPORT OF A CASE
HISTORY AND PHYSICAL FINDINGS
A 69-year-old man with a history of pneumonia and subsequent ventilator
dependence thought to be secondary to poor pulmonary function required a tracheotomy.
His recovery was complicated by several episodes of bright-red hemoptysis
both orally and via the tracheotomy tube. The blood was noted to come from
the tracheostomy site only when the cuff was deflated.
After decannulation of the tracheostomy failed, direct and microscopic
laryngoscopy was performed, which showed a vascular-appearing mass in the
supraglottic larynx on the left side (Figure
1). Attempts at biopsy and laser phototherapy caused brisk bleeding
and were aborted. The patient was transferred to our institution for definitive
workup of this lesion. Flexible laryngoscopy confirmed the referring otolaryngologist's
findings.
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Figure 1. Endoscopic view of obstructing
laryngeal mass.
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RADIOLOGIC FINDINGS
Computed tomography of the neck with contrast medium demonstrated a
large enhancing mass of approximately 4 cm that displaced the left carotid
artery posterolaterally, as well as a supraglottic vascular mass that was
not continuous with the neck lesion (Figure
2A). Magnetic resonance imaging with gadolinium contrast gave similar
findings (Figure 2B). A presumptive
diagnosis of carotid body and laryngeal paraganglioma was made. A 4-vessel
arteriogram was performed (Figure 2C).
The neck mass was noted to be at the left carotid bifurcation, and the feeding
vessels appeared to arise from several branches of the external carotid artery,
especially the ascending pharyngeal artery. The laryngeal tumor had as its
primary blood supply the superior laryngeal artery branching off the superior
thyroid artery. This was embolized partially via the superior thyroid artery
by means of polyvinyl alcohol particles, with satisfactory results.
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Figure 2. A, Axial contrast-enhanced computed
tomographic scan with laryngeal mass (arrow). B, Sagittal gadolinium-enhanced
magnetic resonance image with laryngeal mass (long arrow) and carotid body
mass (short arrow). C, Angiographic image with laryngeal mass (long arrow).
Note blood supply from branches of superior thyroid artery and carotid body
mass (short arrow).
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TREATMENT AND OUTCOME
The decision was made to perform a supraglottic laryngectomy and resection
of the carotid body tumor. The operation was performed without incident, and
the patient did well postoperatively with no further hemoptysis. Light microscopy
showed the tumor to be composed of round to polygonal epithelioid cells arranged
in nests of varying sizes (Zellballen pattern). The
cells had eosinophilic cytoplasm. Blood vessels were interspersed through
the tumor (Figure 3A). Immunohistochemical
stains for neuron-specific enolase and chromogranin showed immunoreactivity
of the tumor cells (Figure 3B-C).
The S100 protein stained the sustentacular cells (Figure 3D). Calcitonin and cytokeratin did not stain the tumor cells
(Figure 3E-F). These findings support
our diagnosis of paraganglioma of the larynx. Two months postoperatively,
the patient shows no evidence of disease.
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Figure 3. A, "Nesting" of cells and blood
vessels (hematoxylin-eosin, original magnification x20). B, Reactivity
of tumor cells (neuron-specific enolase, original magnification x20).
C, Reactivity of tumor cells (chromogranin, original magnification x20).
D, Staining of sustentacular cells (brown, spindle cells at edge of nest)
(S100 protein, original magnification x40). E, Negative immunoreaction
(calcitonin, original magnification x20). F, Negative immunoreaction
(cytokeratin, original magnification x20).
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COMMENT
Paragangliomas are of neural origin, specifically the paraganglion cells
of the parasympathetic nervous system. It is the only neuroendocrine tumor
that is more common in women (3:1), and it has been seen in almost all decades
of life.4, 5 Only 65 adequately
studied laryngeal paragangliomas have been reported, and most of these were
located in the supraglottis.2 They usually
present in the same way as other laryngeal tumors, with voice changes, airway
compromise, and hemoptysis. Only 1 case of a functional laryngeal paraganglioma
has been reported.6
Some investigators believe paragangliomas of the larynx are almost exclusively
benign and should be treated as such, with local conservative resection and
no further regional nodal dissection. Historically, the literature has reported
a 25% malignancy rate; however, it is apparent that this rate included neuroendocrine
carcinomas.7, 8 Ferlito et al3 used immunohistochemical techniques to prove that
most of these neoplasms were actually MDNEC.
One must not rely on the classic histologic finding known as the Zellballen pattern, which is described as chief cells that
are clustered into round nests of cells. This well-known cellular arrangement
can be found in the carcinoid tumors, melanomas, and medullary carcinomas
of the thyroid.9 There is a fibrovascular stroma
surrounding these cell nests, which contain at their periphery the sustentacular
cells that are difficult to see on routine stains but are easily apparent
on special immunostaining.5, 9
Other characteristic microscopic findings include an eosinophilic cytoplasm
and large nuclei.
The angiographic findings consistent with a paraganglioma are "profuse
vascularity, well-defined nutrient vessels, and a dense, nonhomogeneous tumor
blush in the capillary phase."10 The immunohistochemical
findings most indicative of a paraganglioma are positivity with regard to
neuroendocrine markers such as chromogranin, neurofilament, synaptophysin,
and neuron-specific enolase.11, 12
They should be negative for all epithelial markers, such as cytokeratin, epithelial
membrane antigen, and carcinoembryonic antigen (CEA).2
The sustentacular cells should be positive for S100 protein.9
Neither calcitonin nor bombesin is present in paragangliomas.2
However, immunoreactivity to calcitonin can be found in about two thirds of
the MDNECs.
The MDNEC tumors of the larynx are uncommon, with only about 300 cases
reported to date. It is, however, the most common neuroendocrine tumor of
the larynx.2, 13 It has a male-female
ratio of 3:1 and an age range of about 30 to 80 years.14
They are also most commonly seen in the supraglottis. In addition to the symptoms
one would expect with a supraglottic mass, neuropathic pain of glossopharyngeal
origin may occur and can be noted for years before diagnosis.5
Rarely are these tumors metabolically active, resulting in the carcinoid syndrome.15 This tumor, unlike the paraganglioma, has a high
likelihood for metastasis and behaves in an aggressive manner, as shown by
the low (48%) 5-year survival.13 A particularly
distressing feature of these tumors is the 22% incidence of metastasis to
skin, which can occur as the presenting sign without lymph node involvement.16
Microscopically, these tumors can mimic paraganglioma with a Zellballen
pattern.17 The cells have an eosinophilic cytoplasm
with hyperchromatic nuclei that contain large nucleoli. Frequent mitotic figures
are seen. Invasion is a feature that aids in distinguishing paragangliomas
from neuroendocrine carcinomas. The diagnosis should be confirmed by immunohistochemical
and electron microscopic studies. These tumors should also be positive for
the neuroendocrine and, more important, the epithelial markers as listed previously.5 They can stain positive for calcitonin and bombesin.18, 19 Only about 20% of MDNECs are S100
protein positive.2
There have been no reports, to our knowledge, of angiographic studies
of carcinoids of the head and neck. However, angiographic studies of small-intestine
carcinoids have shown "poor to moderate accumulation of contrast medium in
the tumor and no filling of the veins."20
This controversy may be provoking but does nothing to help the otolaryngologist
diagnose these lesions preoperatively, when it would benefit the patient most.
In addition, frozen-section diagnosis is not helpful, as immunohistochemical
stains are required to differentiate these 2 entities. With the potential
dangers of performing a biopsy on such a vascular tumor, a safe and predictable
management decision tree is needed.
We propose an algorithm (Figure 4)
that begins with computed tomography with contrast enhancement to better define
a vascular-appearing, submucosal tumor of the larynx. When no enhancement
is noted, one may plan on endoscopy with biopsy as with any aerodigestive
tract neoplasm. If the mass does indeed enhance, we recommend proceeding to
4-vessel angiography. This would identify whether any major feeding arteries
to the tumor are present, as well as screen for synchronous lesions. These
findings would be more consistent with a paraganglioma. An arteriogram is
also important preoperatively to determine the status of the circle of Willis
and prepare the surgeon for the unlikely event of carotid resection. When
a named feeding vessel is identified, such as the inferior or superior thyroid
artery, we prepare the patient for a conservative resection, since this leads
us to believe the mass is indeed a paraganglioma. In our case, we opted for
a supraglottic laryngectomy. Also, at this point we consider embolization
of the mass, which has been shown to decrease operative time and overall blood
loss.21
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Figure 4. Algorithm for differentiation
of laryngeal paraganglioma and moderately differentiated neuroendocrine carcinoma
(MDNEC). CT indicates computed tomography; MR, magnetic resonance; and Dx,
diagnosis.
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Other factors that favor the neoplasm being a paraganglioma are synchronous
lesions in the head and neck and the profuse tumor blush mentioned above.
Neuroendocrine carcinomas usually do not produce such massive filling with
contrast medium. This suggests that a relatively small volume of blood is
delivered to carcinoids via unnamed vasculature. If no major vessel is identified
or if there is any evidence of metastasis, the lesion is thought to be an
MDNEC and a more radical procedure is suggested, such as a total laryngectomy.
Elective neck dissection in a clinically negative neck (ie, one with no obvious
clinical evidence of nodal metastasis) would be in order, with further dissection
for any positive lymph nodes. The MDNEC is not radiosensitive, although radiotherapy
has been used for palliation after a biopsy was performed.22
CONCLUSIONS
Laryngeal paragangliomas have been difficult to distinguish from MDNECs
of the same site. The inability to examine these vascular tumors by biopsy
has hindered preoperative diagnosis in the past. We believe that one can obtain
a presumptive diagnosis before tissue retrieval, as outlined in Figure 4. This, along with precise pathological studies including
light microscopy and immunohistochemical methods, should help otolaryngologists
reach the correct diagnosis and offer intervention that is appropriate. Further
investigation into this matter is warranted, with prospective studies involving
special attention to arteriography of laryngeal neuroendocrine carcinomas.
AUTHOR INFORMATION
Accepted for publication September 22, 2000.
Presented at the Triological Society Western Section Meeting, San Francisco,
Calif, January 8, 2000.
From the Departments of Otolaryngology/Head and Neck Surgery (Drs Sanders,
Stucker, and Nathan), Pathology (Dr Abreo), and Radiology (Dr Rivera), Louisiana
State University Health Science Center and Veterans Administration Medical
Center Shreveport, Shreveport.
Corresponding author: Cherie-Ann O. Nathan, MD, Department of Otolaryngology/Head
and Neck Surgery, LSU Health Science Center, 1501 Kings Hwy, PO Box 33932,
Shreveport, LA 71130 (e-mail: cnatha{at}lsuhsc.edu).
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