Paragangliomas of the Head
and Neck
-INTRODUCTION
-HISTORY
-THE
PARAGANGLION SYSTEM, ANATOMY AND FUNCTION
-INCIDENCE and
GENETICS
-PATHOLOGY
-MALIGNANCY
-BIOCHEMICAL
ACTIVITY
-CAROTID BODY TUMORS
Signs and Symptoms
Diagnostic Radiology
System of Classification
Treatment
-VAGAL PARAGANGLIOMAS
Clinical presentation
Evaluation
Surgical management
-GLOMUS TYMPANICUM AND GLOMUS
JUGULARE TUMORS
Historical perspective
Tumor Classification
Diagnosis
Management
-RADIATION
THERAPY
-SUMMARY
Paragangliomas of the Head and Neck
aragangliomas are generally benign, slow growing
tumors arising from widely distributed paraganglionic tissue thought to
originate from the neural crest, comprising part of the diffuse neuroendocrine
system. They comprise a unique subset of tumors of the head and neck.
Paraganglia are distributed throughout the head and neck and superior
mediastinum along the course of the major vasculature. Paraganglia are also
found in the orbit, the larynx, and along the course of the vagus nerve.
Various terminologies have been used in the
past to describe these tumors based on their histopathologic and anatomical
presentations. Glenner and Grimley’s classification scheme helped
distinguish the adrenal paragangliomas from the extra-adrenal paragangliomas.
The tumors are thus divided into adrenal paragangliomas or pheochromocytomas and
extra-adrenal paragangliomas. The branchiomeric paragangliomas and intravagal
paragangliomas are found in the head and neck and mediastinum. Terms used in the
past have included: glomus tumors, chemodectomas, carotid body tumors, and
nonchromaffin tumors. Currently, the correct terminology is paraganglioma based
on the anatomical location (e.g. carotid paraganglioma and jugulotympanic
paraganglioma). Because the terms glomus tympanicum and glomus jugulare have
persisted, they will be used to differentiate the jugulotympanic paragangliomas
in this Grand Round.
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Adrenal |
Extra-Adrenal |
|
Pheochromocytoma |
Branchiomeric
Aorticopulmonary
Coronary
Intercarotid
Jugulotympanic
Laryngeal
Nasal
Orbital
Pulmonary
Subclavian
Intravagal
Aorticosympathetic
Visceroautonomic |
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The
carotid body was first described by anatomist Von Haller in 1743. He
described the carotid body; however, the function of this receptor organ
remained unclear for decades.
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Carotid body tumors first were described in
Europe in 1862 by Von Luschka and in 1891 by Marchand. Scudder, in the United
States, reported the removal of a carotid body tumor in 1903.
Tissue similar to the carotid body then was
discovered in various sites in the body.
Histiologic studies of the carotid body
revealed glandular acini so the carotid body was renamed the carotid gland.
The gland was renamed a vascular glomerulus
or glomus. The term glomus today refers to any collection of specialized tissue.
The term paraganglion was first used by histologist Kohn in 1903 to describe the
carotid body. This term was most appropriate as cells of the carotid body
originate from the neural crest and migrate in close association with autonomic
ganglion cells.
Anatomists had described ganglions along the
course of the Jacobson’s nerve as early as 1840, but no association with
paraganglioma was made until 1941.
White discovered paraganglionic tissue in
the vagal perineum in 1935. Stout is credited with the first report of a tumor
of this tissue along the vagus nerve.
Guild first described vascularized tissue in
the dome of the jugular bulb and on the promontory of the middle ear and named
it "glomic tissue" in 1941.
In 1945, Rosenwasser reported a "carotid
body tumor" of the middle ear and mastoid and the correlation between these
tumors was made.
THE PARAGANGLION SYSTEM, ANATOMY AND FUNCTION
The paraganglion system
was the name coined by Mascorro and Yates to denote collection of
neuroectoderm-derived chromaffin cells in extra-adrenal sites. The system is
vital in fetal development until the formation of the adrenal medulla, as a
source of cathecholamines. Most of the cells in the paraganglion system
degenerate after birth, with the exception of those along the autonomic nervous
system and in the walls of certain organs. These cells are located in the
vascular adventicia and intraneuronally.
The function of chromaffin
cells is similar to those in the adrenal medulla.
They secrete and store cathecholamines, and release them on neuronal or chemical signals acting as
endocrine organs.
Carotid bodies are located in the adventitia
of the posteromedial aspect of the bifurcation of the common carotid artery.
They are small pink ovoid structures that have been shown to have a
chemoreceptor role by modulating respiratory and cardiovascular function in
response to fluctuations in arterial pH, oxygen and carbon dioxide tension, and
other chemical alterations. Their blood supply is primarily from the external
carotid artery and sensory innervation is from the glossopharyngeal nerve.
Guild described the paraganglia of the
temporal bone as ovoid, lobulated bodies measuring between 1-1.5mm in diameter.
On the average, there are three such bodies in each ear. These paraganglioma are
usually found accompanying Jacobson’s nerve (from CNIX) or Arnold’s nerve (from
CNX), or in the adventitia of the jugular bulb. Tumors of these paraganglioma
are usually seen involving the mucosa of the promontory (glomus tympanicum) or
the jugular bulb (glomus jugulare). The blood supply to jugulotympanic
paragangliomas is the ascending pharyngeal artery via inferior tympanic and
neuromeningeal branches. Numerous other arteries can contribute especially if
the tumor is large or has intracranial extension.
Vagal paraganglia are small cell groups that
rest within the perineurium of the vagus nerve. Their precise nerve supply has
not been determined.
Paragangliomas are located
in all the major areas of the head and neck. The most common is the carotid
body, followed by jugulotympanic paragangliomas and vagal paragangliomas... Lack
et al estimated that 0.012% of all tumors in humans are head & neck
paragangliomas; this number derived from examining 600,000 surgical neck
specimens. Approximately 1 in 30,000 head and neck tumors is a paraganglioma.
Evidence suggests the
incidence of carotid body paragangliomas is higher in people living above an
altitude of 2000meters.
In the United States, the
male to female ratio for carotid body paragangliomas is 2:1. In Mexico, this
ratio is 1:8.3!
The occurrence of
multiple head and neck paragangliomas is strongly related to hereditary
disease. For familial tumors, the incidence of multiple paragangliomas is 25% to
50%., generally, the incidence of multiple lesions is 10%.The familial basis has
been established firmly with the identification of at least three genetic loci:
PGL1, PGL2 and PGL3. The PGL1 gene at chromosome band 11q23 is the most common
locus.
Tumors that arise from the paraganglion
system are called PARAGANGLIOMAS. Approximately 90% of tumors of this type are
in the adrenal gland (pheochromocytoma), the largest collection of chromaffin
cells. Most of the extra-adrenal paragangliomas arise in the abdomen (85%), with
some in the thorax (12%), and some less commonly in the head & neck area (3%).
Most paragangliomas are solitary. Multiple pheochromocytomas and paragangliomas
are seen in familial syndromes, mainly MEN IIA, IIB. But we should not
underestimate the possibility of multicentricity because the most common
combination of head and neck paragangliomas is a bilateral carotid body tumor!
Their histiologic appearance is similar to
the normal histology of the paraganglia. They consist of clusters of Type I or
chief cells which are members of the amine precursor and uptake decarboxylase (APUD)
family and Type II or sustentacular cells (modified Schwann cells). These two
cell types are arranged into clusters with a core of chief cells surrounded by
the sustentacular cells embedded in a fibrous stroma. The clusters of cells make
up the histologic structure termed Zellballen. Nuclear pleomorphism and cellular
hyperchromatism are common in paragangliomas and should not be considered
evidence of malignancy.
Malignancy has been reported in all
locations of paragangliomas. Cellular criteria for malignancy, however, have not
been established. According to Batsakis, increased mitotic rate, and capsular
invasion should not be considered as determinants of malignancy. Malignancy can
not be determined histologically but is reserved for the presence of local,
regional or distant metastasis.
Malignant paragangliomas have been reported
in 6% of carotid body paragangliomas; in 5% of jugulotympanic paragangliomas; in
10% to 19% of vagal paragangliomas; in 3% of laryngeal paragangliomas, and in
17% of sinonasal paragangliomas.
Data from the National Cancer Data Base
suggest a 60% 5-year survival rate based on 59 reported cases in which regional
metastasis were found. Distant metastases had a worse prognosis.
All paragangliomas contain neurosecretory
granules, but few reach levels of clinical significance. One to 3% of
paragangliomas are considered functional.
Patients with headache, excessive sweating,
and palpitations should be evaluated for a possible functional tumor. 24hrs
urine collection for norepinephrine and its metabolites (VMA, metanephrine…)
should be performed preoperatively, to allow adequate time for pharmacologic
alpha and beta blockades. The extra-adrenal paragangliomas rarely produce
epinephrine because they lack phenylethanolamine-N-methyltransferase, which is
necessary to degrade norepinephrine to epinephrine.
CAROTID BODY
TUMORS
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Riegner performed the first
excision of a carotid body tumor in 1886. The patient did not survive. In
1888, Maydl removed a carotid body tumor; his patient survived with
hemiplegia and aphasia. In 1889, Albert was the first to excise a carotid
body tumor successfully without ligating the carotid vessels.
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Signs and Symptoms
A characteristic feature
of carotid body tumors is slow growth rate, which is reflected clinically by the
delay between the first symptoms and the diagnosis, which averages between 4 and
7 years. A history spanning over 25 years is common. The median tumor doubling
times (Td) is 7.13 years.
A carotid body tumor
usually presents as a lateral cervical neck mass, which is often less mobile in
the craniocaudal direction because of its adherence to the carotid arteries. Is
located lateral to the hyoid, whereas the vagal body tumors are found more
cranially behind the ascending part of the mandible and sometimes project into
the oropharynx? Many carotid body tumors are pulsatile by transmission from the
carotid vessels or less commonly expand themselves, reflecting their extreme
intrinsic vascularity. Sometimes a bruit may be heard by auscultation, but can
disappear with carotid compression. The consistency of the tumor varies from
soft and elastic to firm. Classically, it is not painful. 75% of patients are
expected to develop cranial nerve palsy, predominantly of the vagal and
hypoglossal nerves. Recurrent laryngeal nerve involvement occurs in 8% of cases.
Carotid sinus syndrome
syncope is defined as loss of consciousness accompanied by a reflex bradycardia
and hypertension, and occasionally may be associated with carotid body tumors.
The episodes may occur spontaneously on movement of the head or after pressure
is applied to the tumor.
Diagnostic Radiology
Today, the diagnosis can
be made with MR imaging in axial and coronal planes. The settings
should include gadolinium-enhanced three-dimensional time-of-flight sequences,
which demonstrate the extension of the tumor in relation to the carotid arteries
and the involvement of the base of skull. Additionally, MR imaging provides a
perfect screening tool for multifocal (i.e., occult) head and neck
paragangliomas, differential diagnosis can also be made.
Angiography
remains valuable for preoperative evaluation, and the possibility of
preoperative embolization. Angiography can confirm the diagnosis and can provide
information about the vascular supply of the paraganglioma, the status of the
carotid arteries and the patency of the circle of Willis.
To evaluate the collateral
cerebral circulation, external compression of the common carotid artery with EEG
is frequently used, or a transcranial duplex examination or a balloon occlusion
test is performed.
Preoperative Transarterial
embolization of a carotid body tumor first reported by Schick in 1980,
·
Would reduce the bleeding intraop.
·
Has increase risk of cerebral
complications,
·
The surgical plane of cleavage can be
obscured,
·
If attempted should be performed
immediately before surgery.
·
Several authors showed that embolization
did not improve the outcome of surgery, the amount of blood loss, the operative
time and the perioperative morbidity.
Ultrasound-guided fine-needle
aspiration biopsy can be helpful when the radiologic diagnosis is unclear, in
rare cases.
System
of Classification
The three-stage classification by
Shamblin et al in 1971 was used to grade difficulty of resection in carotid body
tumors. Type I tumors were defined as localized and easily resected. Type II
covered tumors adherent to or partially surroundings the vessels. Type III
carotid body tumors completely encased the carotids.
Most carotid body tumors (70% in
the Mayo Clinic series) are designed as types II and III.
Treatment
The preferred treatment for
carotid body tumors is surgery.
During resection of a small
carotid body tumor, proximal and distal control of the carotid artery must be
established as the first step in resection.
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With subplatysmal flap
elevation, wide exposure of the carotid system can be obtained with a
cosmetic skin crease incision as outlined. The preauricular extension of the
incision is only needed for infratemporal extension of the tumors, or when a
vagal paraganglioma is also present. |
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With the limited selective
neck finished, the hypoglossal nerve can be identified in the fascia on the
lateral surface of the tumor. With division of the ansa cervicalis, cranial
nerve XII can be retracted superiorly away from the tumor dissection. The
fibrous union of the vagus nerve with the hypoglossal nerve is not dissected
to prevent paresis of the vagus |
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The vascular envelope is
divided in all directions to expose the branches of the external carotid.
The use of bipolar cautery along the dissection of the carotid-tumor
interface allows for better visualization with much less blood in the
operative field. Adjacent nerves receive less trauma with this technique
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With the vagus and the
hypoglossal nerves isolated, the tumor is dissected away from the surface of
the internal carotid in a subadventitial plane if the adventitia is involved
with the tumor. |
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Few large carotid body tumors
extend toward the jugular foramen at the skull base, which harbors important
neurovascular structures.
Although the greatest advance in
surgery, the most disturbing problem remains cranial nerve dysfunction.
Even today, surgeons can make the
same observation as Matthews in 1915:”…this rare tumor presents unusual
difficulties to the surgeon, and should he encounters it without having
suspected the diagnosis, the experience will not soon be forgotten…”
VAGAL
PARAGANGLIOMAS
Vagal paragangliomas account for
less then 5% of all head and neck paragangliomas, and only 200 cases have been
reported in the medical literature.
Clinical
presentation
Vagal paragangliomas usually
originate from the first 2cm of the extracranial course of the vagus nerve, and
most commonly are associated with the inferior vagal or nodose ganglion, tend to
remain limited to the cervical region, whereas tumors from the middle ganglion
are cone-shaped and attached to the skull base.
A neck mass is the most common
presenting sign, followed closely by pulsatile tinnitus, pharyngeal mass, and
hoarseness. Cranial nerve paralysis is common at presentation, Hypoglossal
(17%), spinal accessory (11%), glossopharyngeal (11%), and facial (6%), Horner
syndrome (less).
Evaluation
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MR imaging has merged as the
most informative and valuable preoperative imaging modality, 95% accuracy
rate compared to 84% for CT scan |
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MR angiography or
angiography is essential in the preoperative evaluation of all vagal
paragangliomas and show a classic blush appearance along with the carotid
artery displacement. These lesions may masquerade as carotid body tumors by
splaying apart the internal and external carotids |
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The role of embolization before
extirpation of vagal paragangliomas has not been established definitively.
Decreasing the intraoperative bleeding should be weighted against the risks of
embolization: stroke, facial nerve paralysis, and visual loss. Usually tumors
less than 3cm can be managed without embolization.
Surgical
management
Surgery necessitates a team
consisting of head and neck surgeon, neurotologist, neurosurgeon,
neuroradiologist and speech pathologist.
A lateral approach allows for a
single, continuous progression of exposure for vagal paragangliomas of any size.
The size and extent of the tumor
dictate how much of the potential incision must be made. After subplatysmal
flaps are raised, a selective neck dissection removing the nodal contents of
level II and III is performed to improve access and to rule out nodal
metastasis. The internal jugular vein, carotid artery, and cranial nerves IX, X,
XI and XII carefully are identified and are dissected away from the tumor, if
possible.
It also may be necessary to
divide the digastric muscle to improve access.
To excise a vagal paraganglioma
fully, sacrifice of the vagus nerve almost always is required. A careful
preoperative plan for management of the cranial nerve X deficit must be
formulated.
GLOMUS
TYMPANICUM
AND
GLOMUS
JUGULARE TUMORS
GLOMUS
TYMPANICUM AND GLOMUS JUGULARE TUMORS
Historical perspective
In 1945, Rosenwasser
resected a middle ear lesion that he associated with Guild’s original
description of glomus tympanicum. In 1949, Lundgren attempted jugular bulb
resection. As late as 1950, however, operations were limited to exploration of
these tumors because of the extraordinary morbidity and mortality rate
associated with the resection. In the 1970s sporadic reports of complete
successful tumor resection began to appear. Gardner et al advocated surgery
combined with radiotherapy. Fisch, in 1977, proposed the infratemporal fossa
exposure for disease that extended beyond temporal bone confines.
Tumor Classification
Accurate tumor classification is
essential for tumor surgery planning and reporting standards.
Oldring & Fisch
A, B, C, D classifications:
|
Type A |
Tumors limited to the middle
ear cleft |
|
Type B |
Tumors limited to the
tympanomastoid area |
|
Type C |
Tumors involving the
infralabyrinthine |
|
Type D1 |
Tumors with an intracranial
extension less than 2cm in diameter |
|
Type D2 |
Tumors with an intracranial
extension larger than 2cm in diameter |
The Glasscock-Jackson
system retained the basic tympanicum-jugular dichotomy.
The classification for glomus
tympanicum is as follows:
|
Type I |
Small mass limited to the
promontory |
|
Type II |
Tumor completely filling the
middle ear space |
|
Type III |
Tumor filling the middle ear
and extending into mastoid process |
|
Type IV |
Tumor filling middle ear,
extending into mastoid or through tympanic membrane to fill external
auditory canal; may extend anterior to internal carotid artery |
The following is the
classification for glomus jugulare
|
Type I |
Small tumor involving jugular
bulb, middle ear, and mastoid process |
|
Type II |
Tumor extending under
internal auditory canal; may have intracranial extension |
|
Type III |
Tumor extending into petrous
apex; may have intracranial extension |
|
Type IV |
Tumor extending beyond
petrous apex into clivus or infratemporal fossa; may have intracranial
extension |
Diagnosis
Clinical:
The most common physical
sign is a vascular middle ear mass.
The most common presenting
symptom is pulsatile tinnitus (80%) followed by hearing loss (60%). Otoscopy can
be misleading. The mesotympanic mass, the margins of which are visible at
360degree, can be identified as glomus tympanicum tumor. The same mass, the
margins of which cannot be identified, must be assumed to be a glomus jugulare
tumor until proved otherwise. (Differential diagnosis: high jugular bulb).
Myringotomy and biopsy are to be
avoided.
Tests
and Imaging:
The CT scan with
thin-section temporal bone detail is the best test to differentiate glomus
tympanicum tumors from glomus jugulare tumors and to assess the extent of the
tumor relative to the vital anatomy of the temporal bone. CT scanning is
performed in axial and coronal planes. An intact jugular bulb defines a glomus
tympanicum tumor.
If a jugular paraganglioma
is present, intracranial extension and the relation of the tumor to the regional
neurovascular anatomy are assessed best by MR imaging (and to assess
multicentricity).
Bilateral Carotid
angiography is performed to evaluate the relationship of the tumor to the
internal carotid artery, and is done immediately preoperatively so that
embolization can be accomplished simultaneously. The value of angiography also
is used to determine tumor blood supply. The value of embolization has been well
documented, and embolization should precede surgery by no longer than 72hours
(preferably 24hours).
Management:
Treatment for
paraganglioma is palliative or curative.
Observation and radiation therapy
are palliative.
Surgery is curative.
Observation is selected when, in
the natural course of the patient’s projected lifespan, the paraganglioma is not
expected to cause excessive morbidity or mortality.
Surgery:
Paraganglioma growth is
multidirectional and occurs as the tumor spreads from its point of origin along
tracts of least resistance, predominantly the air cell system of the temporal
bone. Vascular lamina, neurovascular foramina, and Eustachian tube provide
routes of extratemporal extension intracranially, into the infratemporal fossa
or along the skull base. Bone erosion is by ischemic necrosis.
The approach must provide:
- Access to all tumor margins
- Access to intracranial extension
- Exposure for control of major
vessels and cranial nerves.
The facial nerve and internal
carotid artery are critical landmarks in the successful execution of
paraganglioma surgery.
Glomus tympanicum tumors:
All type I GT tumors, the
margins of which can be seen circumferentially, can be exposed and removed by
transcanal tympanotomy strategies.
When any margin is
indistinct on otoscopy (type II-IV), a postauricular, transmastoid approach,
using the extended facial recess or the infratympanic extended facial recess
approaches should be used.
Usually, pedicled on the
tympanic branch of the ascending pharyngeal artery, once cauterized, blood loss
is minimal and the tumor can be removed.
Glomus Jugulare Tumor Types I and II
For tumors confined to the
infralabyrinthine chamber, involving only the tympanic segment of the internal
carotid artery, a hearing conservation approach can be used (i.e., the external
auditory canal and the middle ear structures are conserved).
The incision should allow
access to the temporal bone and neck. The carotid arteries; internal jugular
vein; and cranial nerves IX, X, XI, and XII are isolated and controlled.
The extratemporal facial
nerve is identified. The internal carotid artery is exposed and se- cured with
vascular loops. The internal jugular vein is ligated, and the lateral venous
sinus is occluded.
Complete mastoidectomy is
performed with removal of the mastoid tip. An extended facial recess exposure is
made through removal of the inferior temporal bone and skeletonization of the
inferior-anterior external auditory canal, which is preserved. This step allows
access to the mesotympanum and exposure of the tympanic internal carotid artery
to the level of the eustachian tube.
The facial nerve undergoes
short mobilization. Proximal control of the lateral venous sinus is achieved by
intraluminal packing with oxidized cellulose absorbable hemostat (e.g.,
Surgicel). The tumor is dissected from the internal carotid artery and is
mobilized from the infralabyrinthine space. Opening the jugular bulb to remove
the intraluminal tumor causes bleeding from the inferior petrosal sinus. This
bleeding is controlled by packing. Delicate dissection of the glomus jugulare
tumor from the contents of the pars nervosa and hypoglossal canal is critical to
preserve the lower cranial nerves.
Glomus Jugulare Tumor Types
/II and IV
When the tumor extends
beyond the temporal bone into the infratemporal fossa or when control of the
petrous internal carotid artery is needed, a modified or extended infratemporal
fossa approach is necessary. These approaches provide access to the deep
recesses of the temporal bone, infratemporal fossa, clivus, nasopharynx, and
cavernous sinus. The posterior, middle, and anterior cranial fossae can be
accessed expediently if intracranial extension exists. Complete conductive
hearing loss is conceded.
The same incision used for
types I and II glomus jugulare tumors is executed, but the external auditory
canal is transected and oversewn. The external auditory canal, TM, and middle
ear contents lateral to the stapes are resected. Access to the petrous internal
carotid artery and infratemporal fossa necessitates anterior and inferior
dislocation of the mandible by dividing its anteromedial ligaments.
The facial nerve undergoes
long mobilization. Current technical modifications preserve the periosteal
tissue of the stylomastoid foramen and soft tissue surrounding the facial nerve
during translocation.
Mandibular retraction or
segmental resection may be necessary to gain wider exposure. Access may be
extended farther when the anterosuperior extension of the tumor is extreme. When
the zygoma and the temporo- mandibular joints are resected together, the
temporalis muscle is reflected inferiorly, the mandible is dislocated
anteroinferiorly, and the infratemporal fossa can be accessed widely. The
eustachian tube is resected, and the contents of the foramen spinosum are
sacrificed as the internal carotid artery is exposed and mobilized from the
pterygoid region to its precavernous segment. Access to the middle cranial
fossa, nasopharynx, foramen rotundum, clivus, posterior cranial fossa, and
cavernous sinus is possible. Tumor resection proceeds as previously described.
The best primary treatment
for paragangliomas is debated among surgeons and radiation therapists. Cummings
et al articulated the position on radiotherapy:”…the relief of symptoms and the
failure of the tumor to grow during the remainder of the patient’s lifetime is a
practical measure of successful treatment.”
Jackson et al reviewed 157
studies that addressed radiation therapy for paraganglioma. Although growth was
arrested in several patients, a high incidence of hearing loss, CNS damage,
osteoradionecrosis, and radiation-induced malignancy occurred. They concluded
that the real risks of radiation therapy are long-term, ongoing and
undetermined. Stereotactic radiation therapy preliminarily has been proposed for
the treatment of primary or recurrent paragangliomas.
Surgery speaks to disease
cure; radiation therapy to disease control; and coexistence with a biologically
altered tumor. In most cases, surgical outcome is predictable and finite.
Paragangliomas are tumors
arising from the extra-adrenal collection of chromaffin cells. They may be
catecholamine-secreting or inactive. Some cases, especially the multiple ones,
may be associated with syndromes. Overall, their behavior is benign, but they
can recur. Surgical resection of neck and neurotologic skull base tumors using
modern techniques is effective, safe, and predictable. The quality of
postsurgical survival is extraordinary considering the acute magnitude of the
process and its local impact on the patient as a whole.
