Glomus Tumors
Anatomy
Glomus
bodies are found in the jugular bulb and along the tympanic (Jacobson) and
auricular (Arnold) branch of the tenth nerve in the middle ear or in other
anatomic sites (Fig. 45.1). Depending on the location, glomus tumors (chemodectoma
or paraganglioma) can be classified as tympanic (middle ear), jugulare, or
carotid vagal, or designated as originating from other locations, such as the
larynx, adventitia of thoracic aorta, abdominal aorta, or surface of the lungs
(56,152) (Fig. 45.2). These tissues are responsive to changes in oxygen and
carbon dioxide tensions and pH.
Figure
45.1. Anatomy of the region of the glomus jugulare.
Figure
45.2. Distribution of paragangliomas of the head and neck region.Laterality was
not specified in three patients with carotid body paragangliomas. The diagram
does not include one left carotid body paraganglioma that was found
incidentally at autopsy and a left vagal body paraganglioma that presented in a
patient who had two other paragangliomas.
Glomus
tumors consist of large epithelioid (smooth muscle) cells with fine granular
cytoplasm embedded in a rich capillary network and fibrous stroma with
reticulin fibers, which derive from embryonic neural crest cells. Although
histologically benign, they may extend along the lumen of the vein to regional
lymph nodes, but rarely to distant sites.
Epidemiology
The mean
age at diagnosis has been reported to be 44.7 years for carotid body tumors
(196) and 52 years for glomus tympanicum (157). These tumors occur three or
four times more frequently in women than in men, suggesting a possible estrogen
influence (145,157,181). Glomus tumors may be familial; they also occur in
multiple sites in 10% to 20% of patients (167,194).
Bilateral
carotid glomus tumors were reported in six of 16 patients (38%) with a positive
family history for these lesions but in only 17/206 patients (8%) without such
a history (196). Multiple paragangliomas of the head and neck are rare
(incidence of 10% of the total patients, but in familial cases it increases up
to 35% to 50%) (167). In the head and neck region, the most common association
is bilateral carotid body tumors or carotid body tumor associated with
tympanic-jugular glomus.
Clinical
Presentation
Glomus
tumors may arise along the nerve roots. Glomus tumors of the middle ear may
initially cause earache or discomfort. As they expand, eventually they produce
pulsatile tinnitus, hearing loss, and, in later stages, cranial nerve paralysis
resulting from invasion of the base of the skull in 10% to 15% of patients.
Some patients endure ear symptoms for 3 to 5 years before seeking medical
attention.
If the
tumor invades the middle cranial fossa, symptoms may include temporoparietal
headache, retro-orbital pain, proptosis, and paresis of cranial nerves V and
VI. If the posterior fossa is involved, symptoms may include occipital
headache, ataxia, and paresis of cranial nerves V to VII, IX, and XII; invasion
of the jugular foramen causes paralysis of nerves IX to XI. Gaut et al. (95)
described a case of a large intranasal glomus tumor that, at presentation, had
eroded through the ethmoid roof to involve the floor of the anterior cranial
fossa. The patient was treated with primary external-beam radiotherapy. To our
knowledge, this is the first report of an invasive glomus tumor of the head and
neck.
Chemodectoma
of the carotid body usually presents as a painless, slowly growing mass in the
upper neck. Occasionally the mass may be pulsatile and may have an associated
thrill or bruit. As it enlarges, the mass may extend into the parapharyngeal
space and be visible on examination of the oropharynx. Very rarely these tumors
may be malignant (171).
Metastases
occur in 2% to 5% of cases (145,220).
Diagnostic
Work-Up
Diagnostic
evaluation for glomus tumors of the ear and base of skull is outlined in Table
45.1. In the majority of glomus tympanicum tumors, physical examination
demonstrates a red, vascular middle ear mass, although occasionally it may be
bluish or white (the latter resembling a cholesteatoma) (157). Audiography may
demonstrate conductive hearing loss in the ear involved by tumor as noted in
33/49 patients evaluated by Larson et al. (157); four of 33 patients with
conductive deficits also exhibited tympanic pulsations. Examination of the neck
may occasionally demonstrate a mass in the neck that may be pulsatile or have a
bruit or regional lymph node metastases.
Table 45.1.
Diagnostic Work-Up for Glomus Tumors of the Ear and Base of Skull,
Hemangiopericytoma, Esthesioneuroblastoma, Extramedullary Plasmacytoma, and
Sarcoma of the Head and Neck
Radiographic
studies are invaluable in the diagnosis of these tumors. Plain mastoid
radiographs never show the soft-tissue mass in the middle ear, although they
frequently demonstrate clouding of the mastoid air cells, suggesting
mastoiditis (157). High-resolution computed tomography (CT) with contrast has
the highest degree of sensitivity and specificity to diagnose this tumor when
located in the middle ear or jugular bulb; masses as small as 3 mm have been
demonstrated in the middle ear. Tumor enhancement is similar to that of the
temporalis muscle (157) (Fig. 45.3). In 46 patients with glomus tympanicum
chemodectomas, there were no instances of local bony erosion; instead, the
tumors engulfed the ossicular chain, bulged or protruded through the tympanic
membrane, filled the middle ear, or extended into the eustachian tube orifice
or aditus ad antrum. This pattern is in contrast to cholesteatomas, which
typically destroy adjacent bony landmarks including the ossicles and
progressively erode the petrous bones as they enlarge (157).
Figure
45.3.A: Late-phase arteriogram illustrating large glomus jugulare tumor with
extension into the neck. B: CT scan with contrast enhancement showing
intracranial component of lesion.
Magnification
angiography is a sensitive and specific means of detecting glomus tympanicum
tumors. This procedure should be performed after high-resolution thin-section
CT scan (with contrast material), only when there is a question regarding the
nature of the lesion or the location of the carotid canal. Findings include a
hypervascular middle ear mass that first appears in the middle to late arterial
phase, persists through the capillary phase, and quickly disappears in the
venous phase without demonstrably early draining veins (162). Biopsy of an
aberrant internal carotid artery can result in major neurologic sequelae or
death.
Vogl et al.
(275) reported on 40 patients with glomus tumors of the skull; diagnostic
interpretations were correlated with histologic examination, digital
subtraction angiography, CT, and clinical follow-up. Sixteen of 18 proven
tumors were detected with spin-echo images alone. Although four high-flying
jugular bulbs were misinterpreted as tumor because of similar signal intensity,
combined evaluation allowed differentiation between tumor and sinusal blood
flow in all cases.
Drape et
al. (68) described magnetic resonance imaging (MRI) findings in 31 patients
with a clinical suspicion of glomus tumor; gadoterate meglumine was injected in
19 patients. Twenty-seven of 28 pathologically confirmed glomus tumors were
detected with MRI; a peripheral capsule was present in most tumors. The
investigators were able to differentiate three subtypes of glomus tumors
(vascular, solid, and myxoid) on the basis of relaxation times and enhancement
characteristics.
Laird et
al. (153) reported on 30 patients with neck masses; a bolus injection of 99mTc
gluconate (20 mCi injected into the basilic vein) immediately followed by rapid
injection of saline and scanning of the head and neck demonstrated glomus
jugulare or carotid body tumors in seven patients, including two with
clinically unsuspected tumors. The procedure was particularly useful in
differentiating chemodectomas from other head and neck lesions such as thyroid
tumors, parathyroid tumors, cystic hygromas, bronchogenic cysts, neural tumors,
sarcomas, and lymph nodes.
Cytochemical
techniques demonstrate increased levels of serotonin, epinephrine, and
norepinephrine in normal glomus tissue of the carotid body. Histologic staining
techniques, including chromaffin and argentaffin reactions, identify patients
with hormonally active tumors. This is important because the glomus tumor may
coexist with a pheochromocytoma, which requires special preoperative
preparation of the patient.
Biopsy of
glomus tumors may result in severe hemorrhage.
Staging
The
prognosis of these tumors is closely related to the anatomic location and the
volume of the lesion, which is reflected in the Glasscock-Jackson
classification shown in Table 45.2. An alternative classification proposed by
McCabe and Fletcher (176) is presented in Table 45.3.
Table 45.2.
Glasscock-Jackson Classification of Glomus Tumors
Table 45.3.
Modification of Mccabe and Fletcher Classification of Chemodectomas
General
Management
Surgery
Surgery is
generally selected for treatment of small tumors that can be completely
excised. Glomus tympanicum tumors are particularly well managed with excision,
via tympanotomy or mastoidectomy. Percutaneous embolization of a low-viscosity
silicone polymer has been used, frequently as preoperative preparation of the
tumor embolization of feeding vessels allows meticulous microsurgery with
virtually complete hemostasis (194).
Surgical
treatment of a glomus tumor arising in the jugular bulb, however, often
consists of piece-by-piece removal accompanied by significant bleeding with
damage to adjacent neurovascular structures and requires more complex surgical
approaches involving the base of the skull. Intraoperative bleeding during
surgical removal of head and neck paragangliomas may be a major problem in the
management of these highly vascularized tumors. Preoperative embolization via a
transarterial approach has proved beneficial but is often limited by vascular
anatomy and unfavorable locations. Abud et al. (2) report experience with
preoperative devascularization using direct puncture and an intralesional
injection of cyanoacrylate (acrylic glue) under fluoroscopic guidance in nine
patients with head and neck paragangliomas. Angiograms showed that complete
devascularization was achieved in all cervical glomus tumors, whereas subtotal
devascularization was achieved in jugular paragangliomas, because the injection
of acrylic glue was limited by the potential risk of reflux into normal brain
via feeders from the internal carotid or vertebral artery. The tumors were
surgically removed.
The local
tumor control rate with surgery alone is only about 60%, and there is
significant morbidity, particularly cranial nerve injury and bleeding.
In a
retrospective review of all skull-base surgery cases treated at Baylor
University 175 jugulotympanic glomus tumors and nine malignant cases (5.1%)
were identified (171). The 5-year survival rate was 72%.
Radiation Therapy
Irradiation
is frequently used in the treatment of glomus tumors, particularly for those in
the tympanicum and jugulare bulb locations. Tumors with destruction of the
petrous bone, jugular fossa, or occipital bone or patients with jugular foramen
syndrome are more reliably managed with irradiation
(60,104,157,166,181,217,240). Some surgeons, such as Glasscock et al. (98) and
Spector et al. (247), have questioned the effectiveness of radiation therapy in
the treatment of chemodectomas because on histologic sections, obtained even
many years after irradiation, it is possible to find chromophilic cells
remaining in the tumor. However, there is also evidence of fibrosis and
decreased vascularity (247). Suit and Gallager (256) demonstrated in a murine
mammary carcinoma model that morphologically intact cells may have lost their
reproductive ability after irradiation, which is the ultimate end point of cell
killing. Furthermore, it is extremely unusual to observe clinical regrowth of a
glomus tumor after irradiation, even if they do not regress completely.
Some
reports describe successful combinations of surgery with either preoperative or
postoperative irradiation (93,247), or preoperatively in an attempt to make an
unresectable tumor operable, postoperatively when obvious tumor could not be
resected.
Radiation
Therapy Techniques
Radiation
therapy techniques are determined by the location and extent of the tumor,
which must be defined before treatment (53,185,249). Limited, usually
bilateral, portals should be used for relatively localized glomus tumors,
whether or not the treatment is combined with surgery (Fig. 45.4). Dickens et
al. (63) used a three-field arrangement with a superior-inferior wedged and
lateral open field, with a weighting of 1:1:0.33. Figure 45.5 shows
superior-inferior 60-degree and 45-degree wedged filtered fields. Electrons (15
to 18 MeV) with a lateral portal or combined with cobalt-60 (60Co) or 4- to
6-MV photons (20% to 25% of total tumor dose) render a good dose distribution
(Fig. 45.6). In patients in whom tumor has spread into the posterior fossa, it
may be necessary to use parallel opposed portals with 6- to 18-MV photons.
Treatment is given at the rate of 1.8 to 2 Gy tumor dose per day with five
treatments per week for a total tumor dose of 45 to 55 Gy in 5 weeks.
Three-dimention (3D) conformal radiotherapy (RT) or image-guided radiation
therapy (IMRT) are highly desirable techniques to treat these tumors, with
excellent dose distributions (see Fig. 45.6). Table 45.4 summarizes the doses
of irradiation recommended by several investigators and the probability of
tumor control (185,249,280).
Figure
45.4.A: Portal used for relatively localized glomus tumor. B: Simulation film
of patient with glomus tumor. C: Isodose distribution of a mixed-beam
unilateral portal for a glomus tympanicum lesion (80% 16-MeV electrons, 20%
4-MV photons).
Figure
45.5.Isodose distributions using superior-inferior pairs of 60-degree (A) and
45-degree (B) converging wedge filtered 60Co fields, demonstrating limited
volume of irradiation.
Figure
45.6. Female 59-years-old with an unusual malignant left glomus jugulare, who
had a metastatic left upper cervical lymph node.She was treated definitively
with intensity-modulated radiation therapy (66 Gy in 2-Gy fractions). A: Cross,
(B) coronal, and (C) sagittal sections showing dose distributions at primary
site and left neck, sparing normal structures (D) dose-volume histogram:
Structure Dose Range (Gy) Mean Dose (Gy)
Planning
target volume (including left neck) 38-77 70
Brain 0-59 2
Brainstem 6-35 12
Spinal cord 0-32 13
Table 45.4.
Local Control with Radiation Therapy for Chemodectoma of the Temporal Bone
(glomus tympanicum and Jugulare)
Leber et
al. (158) reported on 13 patients with glomus tumors treated with radiosurgery
because of recurrences after surgical removal in six patients. Histology was
not available in seven patients, diagnosis was made from neuroradiological
features only. Two patients had partial embolization before Gamma Knife
(Elekta, Norcross, GA) treatment. Mean follow-up was 42 months (range, 14 to 72
months). Within the follow-up period there was no tumor progression and no
clinical deterioration in any patient; 64% of the patients had an improvement
of their symptoms, and in 36% the volume of the lesion decreased in size. There
was no radiation-related morbidity.
Results of
Therapy
The
postirradiation change in tumor size is slow, with an increase in proliferative
and perivascular fibrosis and minimal alterations in the chief epithelial cells
(247). Histologic evaluation of tumor cell viability is not reliable (256).
Despite the persistence of tumor both clinically and angiographically (166),
amelioration of symptoms, absence of disease progression, and occasional return
of cranial nerve function have been reported.
Seventeen
patients were treated for glomus tympanicum tumors at Washington University
(145). In five patients initial treatment consisted of irradiation alone, and
all were tumorfree at last follow-up (4.5 years in one patient) or at
death.Seven of eight patients irradiated for surgical recurrence were free of
disease 4.5 to 19 years after irradiation. The remaining four patients were
treated preoperatively or postoperatively; only one had recurrence and was
salvaged surgically and tumorfree 10 years later. Of six patients with glomus
jugulare lesions treated with irradiation, two with extensive lesions died of
their disease, whereas the glomus tumor was controlled in four, including two
patients with intracranial extension. Irradiation doses ranged from 46 to 52
Gy, with 86% to 100% tumor control with doses over 46 Gy and 50% (two of four)
with doses below 46 Gy.
Of 19
patients treated with irradiation at the M.D. Anderson Cancer Center, five had
only a biopsy without any surgical excision and 14 had partial excision (264).
Ten patients had bony destruction; five of these had petrous pyramid and
jugular foramen destruction, with accompanying multiple cranial nerve
paralysis. Seventeen patients were treated with 60Co anteriorposterior or
superior-inferior wedged filtered fields, and two patients received electrons
and photons (3:1) via a single lateral field. Of 18 patients surviving a
minimum of 5 years (13 surviving more than 10 years), all are alive and free of
disease or have died of other causes.
Wang et al.
(280) reported on 32 patients with tympanic chemodectomas; 13 treated with
surgery alone, 15 with irradiation alone, and four with a combination of both
modalities. The initial tumor control rate was 46% with surgery alone;
ultimately 84% of patients were tumor-free after salvage with additional
surgery. Although 78% survived 10 years, 31% developed complications. Of the
patients treated with irradiation, 84% had initial local tumor control; 77%
survived 10 years, and only 11% developed complications. The doses of
irradiation used were slightly higher than those reported by others (mean 58.32
Gy). However, no improvement in tumor control was noted with higher doses.
Complications occurred in two patients receiving 66 Gy.
In a
compilation of several studies, Kim et al. (139) noted a 25% local failure rate
in 83 patients treated with <40 Gy and 1.4% local failure in 142 patients
receiving more than 40 Gy. Arthur (6) reported no recurrences in 24 patients
treated with doses of 45 to 50 Gy; only one failure was observed in a patient
receiving 30 Gy in 15 fractions in 21 days. If the tolerances of the brain and
brainstem to irradiation are considered, doses of 50 Gy (1.8- to 2-Gy
fractions) are considered optimal for treatment of these lesions.
Powell et
al. (216) reported on 84 patients with chemodectoma of the head and neck, 46 of
which were in the glomus jugulare and tympanicum, treated with irradiation
alone (45 to 50 Gy in 25 fractions). Local control of the lesion was 73% at 5
years. Thirty patients were treated with surgery after irradiation with no
recurrences (median follow-up of 9 years). Four patients, treated with surgery
alone, developed recurrences by 7 years. Four carotid body and glomus vagal
tumors treated with irradiation were locally controlled at 1, 2, 8, and 11
years, respectively. In 13 patients treated with surgery alone, the 15-year
local control rate was 54%.
Mendenhall
et al. (181) treated six chemodectomas of the carotid body and ganglion nodosum
in four patients with doses of 40.8 to 48.5 Gy using 60Co, 8-MV x-rays, or a
combination of 8- and 17-MV x-rays. Lesions have remained stable in four
patients 2 to 4.5 years after irradiation. Treatment results in a few patients
with this type of tumor are summarized in Table 45.5.
Table 45.5.
Chemodectomas of the Carotid Body and Ganglion Nodosum
Hinerman et
al. (119) reported on 71 patients with 80 chemodectomas of the temporal bone,
carotid bone, or glomus vagal treated with radiation therapy alone in 71
patients or subtotal resection and radiation therapy (eight tumors). Fourteen
patients had undergone a previous treatment (surgery 11, irradiation one, or
both two). Fifty-three patients had temporal bone chemodectomas, 46 of which
were classified as glomus jugulare and nine as glomus tympanicum. Pathologic
confirmation of chemodectomas was obtained in 21 patients and the diagnosis was
made on physical or radiographic findings in the remaining 32 patients. Fifty
patients were treated with radiation therapy alone and five with subtotal
resection followed by postoperative radiation therapy for gross residual tumor.
Median dose was 45 Gy with daily fractions of 1.5 to 2 Gy delivered with 60Co,
6-MV, or 8-MV x-rays, or a combination of different beam energies. Twenty-eight
patients were treated with ipsilateral wedge pair field arrangement, 18 with
parallel-opposed fields; one patient was treated with stereotactic irradiation,
and two were treated with three-dimensional conformal radiation therapy
(3DCRT). Local control was obtained in 43 previously untreated lesions (93%)
and in 11/12 (92%) previously chemodectomas. The results of treatment for
temporal bone chemodectoma are summarized in Table 45.6.
Table 45.6.
Temporal Bone Chemodectomas: Local Control After Radiation Therapy Alone or
Radiation Therapy and Surgery
Eighteen
patients had 25 chemodectomas of carotid body and/or glomus vagal; 15 tumors
originated in the carotid body and 10 in the glomus vagal. Pathologic
confirmation of chemodectoma was obtained in 10 patients, and diagnosis was
based on physical and radiographic findings in the remaining eight. Twenty-two
lesions were treated with radiation therapy alone, and two received
postoperative radiation therapy after surgical resection for gross residual
tumor with malignant changes and lymph node involvement. Patients with benign
glomus tumors received 45 Gy in 25 fractions, in most instances, whereas
patients with malignant carotid body tumors received 64.8 Gy to 70 Gy in 1.8 Gy
fractions. Local tumor control was obtained in 14/15 carotid body and 10/10
glomus vagal (overall 96% tumor control) (274). The results of treatment for
carotid body/glomus vagal are summarized in Table 45.7.
Table 45.7.
Chemodectomas of Carotid Body/Glomus Vagale: Radiation Therapy Alone or
Radiation Therapy After Surgery
Complications
were rare in patients treated with chemodectoma of the head and neck.
Hemangiopericytoma
Hemangiopericytomas
are rare soft-tissue neoplasms that account for 3% to 5% of all soft-tissue
sarcomas and 1% of all vascular tumors. Some 15% to 30% of all
hemangiopericytomas occur in the head and neck; of these, approximately 5%
occur in the sinonasal area.
These
tumors are believed to originate from the pericytes of Zimmerman extravascular
cells morphologically resembling smooth muscle, found around the capillaries or
from primitive mesenchymal cells. The function of the pericyte is uncertain but
is believed to provide mechanical support for the capillaries having
contractile function (254).
Epidemiology
Hemangiopericytomas
is an unusual tumor; it represents approximately 1% of all vascular neoplasms;
it occurs in both genders with equal frequency and is found primarily in
adults. Only 45 cases of primary hemangiopericytomas of bone were described in
the world literature in 1988.
In the head
and neck, the most common sites are the nasal cavity and the paranasal sinuses,
and usually, the orbital region, the parotid gland, and the neck (77,201,253).
Pathology
Hemangiopericytomas
are composed of a proliferation of tightly packed pericytes around thin-walled
endothelial-lined vascular channels ranging from capillary-sized vessels to
large, gaping sinusoidal spaces (77). The tumor has a tendency to grow slowly
and invade locally into adjacent structures. Although they are always well
circumscribed and partially or completely surrounded by a pseudocapsule, benign
tumors may be difficult to differentiate from malignant ones. However,
prominent mitoses (greater than four per high-power field), foci of necrosis,
and increased cellularity are suggestive of malignancy (77); the definitive
sign is local recurrence or development of metastases. In general, tumors of
the central nervous system, lower extremity, and mediastinum tend to be more
malignant, with local recurrence occurring in up to 50% of cases (77). The
final diagnosis of hemangiopericytomas is based on the histopathology and
immunochemistry, and whether the tumor is benign or malignant is defined on the
basis of the clinical history. Hemangiopericytomas located in the sinonasal
area is generally benign.
Kowalski
and Paulino (148) reviewed 12 cases of hemangiopericytomas. Proliferation index
was assessed using an immunoperoxidase stain for MIB-1 (Ki-67). The mitotic
index per 10 high power fields varied from 0 or 1 to 15. Proliferation indices
using MIB-1 ranged from 2.6% to 52.5%. Clinical follow-up revealed three cases
with recurrence all possessing proliferation indices of approximately 10%,
indicating amore aggressive subset of hemangiopericytomas. Vuorinen et al.
(278) found the proliferation index to be a poor predictor of prognosis.
Meningeal
hemangiopericytomas almost always recur, despite seemingly complete removal due
to infiltrative properties of hemangiopericytoma cells and not just higher proliferation
potential. They often metastasize.
Clinical
Presentation
Soft-tissue
hemangiopericytoma is a firm, painless, slowly expanding mass that is often
nodular and well localized. The skin overlying the mass does not have any
discoloration or redness to indicate its vascular origin because the
capillaries are emptied of the blood by compression of massive numbers of
pericytes surrounding them (55,77).
In the head
and neck, the tumor may constitute a polypoid, soft gray or red mass that grows
slowly and may cause nasal obstruction. Epistaxis and nasal obstruction are
common symptoms. The hemangiopericytomalike tumors of the nasal passages and
paranasal sinuses differ slightly from those occurring elsewhere and probably
represent a related but separate entity because they have little tendency
toward recurrence or metastases regardless of the type of therapy.
Orbital
hemangiopericytomas account for 3% of orbital malignancies and most frequently
occur with painless proptosis (236). Hemangiopericytoma rarely originates in
the lacrimal sac; it occurs in a younger age group than that of
hemangiopericytoma of other locations. Charles et al. (42) reported on seven
cases previously described and added one case.
Hemangiopericytoma
may occur intracranially. When it arises in the brain, it is a solid mass
attached to the meninges that grossly resembles a meningioma (128). These
intracranial hemangiopericytomas carry a high risk of local failure (80%), as
well as higher potential for dissemination. The mean time for local recurrence
is 75 months (128).
The
incidence of metastasis, which depends on the site of origin, can be 50% to
80%. Late metastases occurring 10 years after diagnosis are not uncommon.
On plain
radiographs, hemangiopericytoma appears as a soft-tissue mass in the nasal
cavity or other portions of the head and neck. A defect caused by pressure
erosion of the surrounding bones may occur, and calcifications are rare. On
arteriography, according to Yaghmai (293), hemangiopericytoma is the only
vascular tumor that has some characteristic angiographic features that include
radially arranged or spiderlike branching vessels around and inside the tumor
and a long-standing, welldemarcated tumor stain. Intracranial tumors typically
have arterial blood supply from both meningeal and cerebral connections, with
one to three main feeders supplying many small corkscrewlike vessels (128). The
most distinctive and constant feature of this tumor is its hypervascularity;
this tissue characteristic also may be demonstrated with contrast-enhanced CT
(201). Intracranially, the diffusely enhancing tumor may closely resemble a
meningioma on CT. However, some CT signs may suggest hemangiopericytoma rather
than meningioma: lack of calcification, scarce surrounding edema, and ringlike
enhancement (198). Both CT and MRI scans are of special value in the
delineation of the full extent of the tumor.
General
Management
Complete
surgical resection, if possible, combined with preoperative embolization of the
tumor, is the treatment of choice. More extensive surgery is required in tumors
that show features of malignancy. Many patients undergo surgical treatment
after embolization of the feeding artery(ies).
For
incompletely resected tumors, postoperative radiation therapy is used (184).
The role of chemotherapy in this tumor is not well determined; a few reports
have described partial tumor regression in some lesions treated with cytotoxic
agents. Doxorubicin, alone or in combination-drug regimens, is the most
effective agent for metastatic hemangiopericytoma, producing complete and
partial remissions in 50% of cases (290). Other drugs prescribed when
metastasis occurs are cyclophosphamide, dacarbazine, vincristine, and
actinomycin-D (113).
Radiation
Therapy Techniques
The role of
radiation therapy alone in the management of hemangiopericytoma is
controversial. The main role of irradiation is as an adjuvant after complete
excision of the lesion or postoperatively for minimal residual disease
(79,131,172,248). The tumor has been considered relatively radioresistant.
Tumor doses of 60 to 65 Gy in 6 to 7 weeks are required to produce local tumor
control in postoperative cases (128). Orbital hemangiopericytoma has been cured
by surgery and postoperative irradiation to 65 Gy (236).
There appears
to be a definite role for postoperative irradiation to the brain for primary
hemangiopericytoma when radical surgery is performed because these tumors tend
to recur after seemingly complete removal. Jha et al. (131) reported local
tumor control in all patients treated with adjuvant externalbeam irradiation
postoperatively. Radiation therapy also has been used as a salvage procedure
after local recurrence following initial surgery and/or chemotherapy.
The fields
of irradiation should be wide, to encompass the tumor bed with a margin of at
least 5 cmto safely avoid marginal recurrence. Portal arrangement and beam
selection are similar to those used in treatment of malignant brain tumors or
softtissue sarcomas.
Results of
Therapy
Billings et
al. (26) reported on 10 patients with hemangiopericytoma of the head and neck;
seven tumors arose from softtissue sites and three from the mucosa. All
patients underwent wide excision of the primary lesion with a local recurrence
rate of 40%. Three patients developed metastatic lung disease 0 to 8 years
after initial diagnosis. Each patient who developed metastatic disease had
abundant mitoses on pathological review compared with rare or absent mitoses in
the lesions that took a more benign course.
Patrice et
al. (208) reported on 18 primary hemangioblastoma tumors (16 had no prior
surgical resection and two were subtotally resected lesions) and 20 lesions
treated after surgical failure with stereotactic irradiation (radiosurgery).
Minimum tumor doses ranged from 12 to 20 Gy (median 15.5 Gy). With a median
follow-up of 24.5 months (range 6 to 77 months), the 2-year actuarial survival
was 88%, and the 3-year freedom from progression was 86%. Four of 22 patients
died. Thirty-one of 36 evaluable tumors (86%) were controlled locally. None of
the 18 primary tumors treated with definitive stereotactic irradiation failed.
Of the 18 recurrent tumors, 13 (72%) were controlled. The median tumor volume
of lesions that failed to be controlled was 7.85 cm3 compared with 0.67 cm3 for
controlled lesions (p = 0.0023). There were no significant permanent
complications attributable to the stereotactic irradiation.
Spitz et
al. (248) published a report on 36 patients (older than 16 years) with
hemangiopericytoma treated at the University of Texas M.D. Anderson Cancer
Center. The median follow-up was 57 months. Twenty-eight patients (78%)
underwent complete and potentially curative resection. Of the nine patients
(32%) who had local recurrences, four (44%) had epidural tumors and three (33%)
had retroperitoneal tumors, but none had extremity tumors. Ten patients had
recurrences at distant sites. Of the 13 patients who experienced any form of
disease recurrence, four had recurrences after a diseasefree interval of more
than 5 years. The 5-year actuarial survival rate for the entire group of 36
patients was 71%.
Carew et
al. (36) reviewed the records of 12 patients with hemangiopericytomas of the
head and neck. Five patients had lesions characterized as high or intermediate
grade histologically, and seven had low-grade lesions. Nine patients were
treated with curative intent; three presented either with pulmonary metastasis
(two patients) or unresectable primary tumor (one patient) and were treated
with radiation therapy and/or palliative doxorubicin-based chemotherapy.
Patients treated with curative intent underwent a variety of surgical
resections dictated by tumor location and size. Four patients received
postoperative radiation therapy to a median dose of 60 Gy, for positive
surgical margins (two patients), high-grade histology (one patient), or a
recurrent lesion (one patient). The 5-year overall survival rate for patients
treated surgically was 87.5%. A single mortality occurred in a patient with a
recurrent high-grade lesion who failed at local, regional, and distant sites.
Payne et
al. (209) described their experience in 12 patients with 15 intracranial
hemangiopericytomas treated using gamma surgery. Clinical and radiographic
follow-up of 3 to 56 months was available for 10 patients with 12 tumors. There
was one tumor present at the time of initial gamma surgery in each patient. Two
new tumors occurred in patients previously treated. Nine of the tumors
decreased in volume and three remained stable. Four of the nine tumors that
shrank later progressed at an average of 22 months after treatment. There were
no complications and the quality of life following the procedure was maintained
or improved in every case.
Chordomas
Anatomy
Chordomas
are rare neoplasms of the axial skeleton that arise from the remnant of the
primitive notochord (chorda dorsalis). About 50% arise in the sacrococcygeal
area; 35% arise intracranially, where they typically involve the clivus, and
the remaining 15% occur in the midline along the path of the notochord, primarily
involving the cervical vertebrae (259).
Epidemiology
Chordomas
are more common in patients in their 50s and 60s but can occur in all age
groups. In children and young adults the prognosis and long-term survival
appear to be better than in older patients (289). No risk factors have been
identified. Male predominance is reported at a 2:1 to 3:1 ratio.
Natural
History
Although
slowly growing, chordomas are locally invasive, destroying bone and
infiltrating soft tissues. Basisphenoidal chordomas tend to cause symptoms
earlier and may be difficult to differentiate histologically from chondromas
and chondrosarcomas and radiographically from craniopharyngiomas, pineal
tumors, and hypophyseal and pontine gliomas. The lethality of these tumors
rests on their critical location, aggressive local behavior, and extremely high
local recurrence rate. The incidence of metastasis, which has been reported to
be as high as 25%, is higher than previously believed and may be related to the
long clinical history. The most common site of distant metastasis is the lungs,
followed by liver and bone. Lymphatic spread is uncommon.
Pathology
Chordoma is
a soft, lobulated tumor that may have areas of hemorrhage, cystic changes, or
calcification. It is frequently encapsulated but may be nonencapsulated or
pseudoencapsulated. Histologically, it is composed of cords or masses of large
cells (physaliferous cells) with typical vacuoles and granules of glycogen in
the cytoplasm and abundant intercellular mucoid material. Usually there are few
mitotic cells. Heffelfinger et al. (114) postulated that a chondroid variant of
chordoma may exist, being prevalent in the spheno-occipital area. Patients with
this type of histologic variant have improved survival.
Aside from
the previously mentioned histologic features, the prognostic factors that most
influence the choice of treatment are location and local extent of tumor.
Clinical
Presentation
Chordomas
tend to originate from the clivus and chondrosarcomas from the temporal bone
(141). Clinical symptoms vary with the location and extent of the tumor. In the
head, extension may be intracranial or extracranial, into the sphenoid sinus,
nasopharynx, clivus, and sellar and parasellar areas, with a resultant mass
effect. In chordomas of the spheno-occipital region, the most common presenting
symptom is headache. Other presentations include symptoms of pituitary
insufficiency, nasal stuffiness, bitemporal hemianopsia, diplopia, and other
cranial nerve deficits. Fuller and Bloom (88) reported on 13 patients with
clivus chordoma, all of whom had multiple cranial nerve palsies. Facial pain
was present in 11/13 patients.
Volpe et
al. (277) reviewed the clinical features of 48 patients with chordoma and 49
patients with low-grade chondrosarcoma of the skull base. Twenty-five patients
(52%) with chordoma and 24 patients (49%) with chondrosarcoma had ocular
symptoms (diplopia or visual impairment) as the initial manifestation of the
disease. Of the 59 patients (both groups) with diplopia, the diplopia was initially
intermittent in 25 (42%). Headache and diplopia from abducens nerve palsy
occurred in 22 patients (46%) with chordoma and 23 (47%) with chondrosarcoma.
Diagnostic
Work-Up
The
diagnostic work-up varies with the primary location of disease. Most patients
have significant bony destruction, and some may have calcifications in the
tumor; hence, plain films and, specifically, CT scans or MRI are very useful
(67) (Table 45.8). In most cases, the soft-tissue component is much more
extensive than initially appreciated, and a CT scan with contrast enhancement
is required (Fig. 45.7A). CT and MRI are equivalent for demonstration of the
presence and site of these tumors. MRI is inferior to CT in its ability to
demonstrate bony destruction and intratumoral calcification (Fig. 45.7B)
(197,258). MRI is superior to CT regarding the delineation of the exact extent
of the tumor, which allows for better treatment planning (67). Because of
availability and lower cost, CT appears to be the technique of choice for
routine follow-up of previously treated patients (197).
Table 45.8.
Diagnostic Work-Up for Chordoma
Figure
45.7.A: Contrast material-enhanced axial computed tomography scan demonstrates
a large chordoma with extension into the posterior fossa and left parasellar
region. B: Computed tomography scan photographed at bone windows shows the bony
destruction and intratumoral calcifications. C: Treatment planning field
arrangement for illustrated clivus chordoma using standard irradiation
techniques with wedges on lateral points.
Reliable
signs of chordoma of the skull base are posterior extension to the pontine
cistern; a lobulated, “honeycomb” appearance after gadolinium; the swollen
appearance of the bone in the early stages; bone erosion on CT; and frequent
extension to critical structures such as the circle of Willis, cavernous
sinuses, and brainstem (67).
General
Management
Because of
their surgical inaccessibility and relative resistance to radiation therapy,
clivus chordomas represent a formidable therapeutic challenge. The general
management of the patient is dictated by the anatomic location of the tumor and
the direction and extent of spread. A surgical approach is recommended (when
feasible), but complete surgical extirpation alone is unusual (230). Regression
of preoperative symptoms without additional postoperative morbidity could be
achieved by radical transoral tumor extirpation documented by MRI (234).
Intracranial spread usually requires steroid coverage and therapy directed to
correction of neurologic deficits that may be present. Because of the high
incidence of local recurrence, combined surgical excision and irradiation is
frequently used. No effective chemotherapeutic agent or combination of drugs
has been identified.
Radiation
Therapy Techniques
Irradiation
techniques vary considerably, depending on the location of the tumor along the
craniospinal axis. Basisphenoidal tumors usually are treated by a combination
of parallel opposed lateral fields, anterior wedges, and photon and electron
beam combinations, depending on the extent of the neoplasm. Precision radiation
therapy planning, using CT and MRI, is required because high doses of
external-beam radiation therapy are needed. Three-dimensional CRT or IMRT
provide optimal dose distributions (Fig. 45.8).
Figure
45.8. Chordoma of clivus in 81-year-old man treated with 70 Gy in 2-Gy
fractions.Example of IMRT plan: A: Cross-section in upper portion of planning
target volume (PTV), demonstrating coverage of target volume with sparing of
ocular structures. B: Sagittal plane dose distribution with excellent coverage
of PTV. C: Dose-volume histogram:
Structure Dose Range (cGy) Mean Dose (Gy)
PTV
(including left neck) 60-75 70
Optic
nerves/chasm 25-50 41
Ocular
globe 3-30 12
The tumor
usually surrounds the spinal cord and infiltrates vertebral bones. A combined
technique using protons or electrons to boost the initial photon fields is
generally applied. In the treatment of chordomas surrounding the spinal cord,
IMRT can provide high-dose homogeneity and planning target volume (PTV)
coverage. Frequent digital portal image-based setup control reduces random
positioning errors for head and neck cancer patients immobilized with
conventional thermoplastic masks. Gabriele et al. (90) treated a patient with incomplete
resection of a vertebral chordoma surrounding C2-3 with a total dose of 58 Gy
(International Commission of Radiation Units and Measurements point) in 2-Gy
daily fractions. Beam arrangement consisted of seven 6 MV nonopposed coplanar
IMRT fields using 120-leaf collimator in sliding window mode. To verify the
daily setup, portal images at 0 degrees and 90 degrees were compared with the
simulation images before treatment delivery (manual matching) and after
treatment delivery (automatic anatomy matching). The mean dose to the PTV was
57.6 ± 2.1 Gy covering 95% of the PTV with the 95% isodose. The minimum dose to
the PTV (D99) was 53.6 Gy in the overlapping area between the PTV and the
spinal cord planning organ at risk volume (PRV). The maximum dose to the spinal
cord was 42.2 Gy and to the spinal cord PRV (8 mm margin) 53.7 Gy. The mean
dose to the parotid glands were 37.4 Gy (homolateral gland) and 19.5 Gy
(contralateral gland). Average deviation in setup was -1.1 ± 2.5 mm
(anterior-posterior), 2.4 ± 1.3 mm (laterolateral), 0.7 ± 0.9 mm (craniocaudal)
and –0.43 ± 1 degree (rotation).
Because of
the slow proliferative nature of chordomas, high linear energy transfer may
prove useful in their management, as it will be discussed later. Brachytherapy
can be used for recurrent tumors of the base of skull or adjacent to the spine
when a more aggressive surgical exposure is offered. Three of five chordomas
were rendered stable when treated with iodine-94 (94I) implants by Gutin et al.
(105), performed with CT stereotactic technique. Kumar et al. (150) reported
use of 94I intraoperative interstitial implantation in two patients with
recurrent chordomas. Disease was effectively controlled in both.
Results of
Therapy
Photons
Although
survival in some patients with chordoma may be long term, the salient feature
of this unusual neoplasm is local recurrence with eventual death. The course
may be indolent, with multiple treatments for recurrences, but the overall
5-year diseasefree survival rate is <10% to 20%. At M.D. Anderson Cancer
Center, of 19 patients treated definitively, three were alive and free of
disease with relatively short follow-up of 3, 6, and 7.5 years, respectively.
Fuller and Bloom (88), in 25 patients treated with external-beam irradiation,
found 96% stabilization or reduction of pain; the overall actuarial survival
rates were 44% and 17% at 5 and 10 years, respectively
Catton et
al. (37) analyzed the long-term results of treatment for patients with chordoma
of the sacrum, base of skull, and mobile spine treated predominantly with
postoperative photon irradiation. In 20 base of skull chordomas, most of them
irradiated with conventionally fractionated radiation to a median dose of 50 Gy
in 25 fractions for 5 weeks (range 25 Gy to 50 Gy), median survival was 62
months (range 4 to 240 months) from diagnosis with no difference between clival
and nonclival presentations. There was no survival advantage to patients
receiving radiation doses >50 Gy (median 60 Gy) compared with lower doses
<50 Gy (median 40 Gy). Hyperfractionation regimens did not influence the
degree or duration of symptomatic response or progressionfree survival. Median
survival after retreatment was 18 months.
Forsyth et
al. (86) reported on 51 patients with intracranial chordomas (19 classified as
chondroid) treated surgically (biopsy in 11 patients and subtotal removal or
greater in 40); 39 patients received postoperative irradiation. At the time of
the analysis, 17 patients were alive. The 5- and 10-year survival rates were
51% and 35%, respectively; 5-year survival was 36% for biopsy patients and 55%
for those who had resection. Patients who underwent postoperative irradiation
tended to have longer diseasefree survival times.
Gay et al.
(96) analyzed the outcome of 46 patients with cranial base chordomas and 14
with chondrosarcomas treated with extensive surgical resection: 50% of them had
been treated previously; 20% received postoperative irradiation. Nine patients
with chordomas and two with chondrosarcomas died during the postoperative
follow-up period. The 5-year recurrencefree survival rate for all patients was
76%. Chondrosarcomas had a better prognosis than chordomas (5-year
recurrencefree survival rates of 90% and 65%, respectively) (p = 0.09).
Patients who had undergone previous surgery had a greater risk of recurrence
than did those who had not undergone previous surgery (5-year recurrencefree
survival rates of 64% and 93%, respectively) (p <0.05). Those with total or
near-total resection had a better 5-year recurrencefree survival rate (84%)
than did patients with partial or subtotal resection (64%) (p <0.05).
Postoperative leakage of cerebrospinal fluid was the most frequent complication
(30% of patients) and was found to increase the risk of permanent disability.
Patients who had undergone previous irradiation had a greater risk of death in
the postoperative period (within 3 months of operation) and during follow-up.
Tai et al.
(259) reviewed the results of irradiation combined with surgery, irradiation
alone, and surgery alone in 159 patients reported in the literature. An
analysis of the optimal biologically equivalent dose was performed using the
linearquadratic formula on 47 patients. With conventional photon irradiation no
dose-response relationship was shown. Survival improved in patients undergoing
surgery followed by irradiation.
Chetty et
al. (45) reported on 18 chordomas, 61% of them occurred in the sphenoid region.
Follow-up for 12 patients ranged from 3 to 170 months. Various combinations of
surgery and radiation therapy were used. Mean survival was 73.4 months, with a
survival rate of 50% (six of 12 patients).
Keisch et
al. (138) reported on 21 patients with chordoma treated at our medical center:
five had clival tumors, two had nasopharyngeal tumors, and one had a lumbar
spine tumor. Nine patients were treated with surgery alone, eight had subtotal
resection and postoperative irradiation, and four received irradiation alone
after biopsy. The 5- and 10-year actuarial survival was significantly better in
patients treated with surgery alone or surgery and irradiation than in those
treated with radiation therapy alone (52%, 32%, and 0%, respectively) (p =
0.02). Diseasefree survival of patients with base of skull tumors was not
significantly different among the treatment groups.
Debus et
al. (59) reported on 45 patients treated for chordoma or chondrosarcoma with
postoperative fractionated 3D stereotactic radiation therapy. Median dose at
isocenter was 66.6 Gy for chordomas and 64.9 Gy for chondrosarcomas. All
chondrosarcomas achieved and maintained local tumor and recurrencefree status
at 5-years follow-up. Local control rate of chordomas at 5 years was 50% and
survival was 82%. Clinically significant late toxicity developed in only one
patient.
Kondziolka
et al. (144) assessed the use of radiosurgery in four patients with chordoma
and two with chondrosarcoma (in five patients as adjuvant therapy for residual
or recurrent tumors after surgical debulking; in one patient with a chordoma as
primary treatment). No patient received fractionated externalbeam irradiation.
All tumors were <30 mm in diameter and were treated with 20 Gy to the tumor
margin. During follow-up (mean 22 months; range 8 to 36 months), they found no
progression of the treated tumor in any patient. Neurologic deficits before
treatment improved in three patients; the other three patients remained in
stable neurologic condition. Serial follow-up imaging studies demonstrated
reduction in tumor size in two patients, and four patients had no tumor growth.
One patient showed tumor progression outside the radiosurgical treatment
volume.
Protons
The best
results in the treatment of chordomas have been obtained with radical surgical
procedures followed by high-dose proton irradiation. Berson et al. (22)
described 45 patients with chordomas or chondrosarcomas at the base of the
skull or cervical spine who were treated by subtotal resection and
postoperative irradiation. Twenty-three patients were treated definitively by
charged particles, 13 patients with photons and particles, and nine were
treated for recurrent disease. Doses ranged from 36 to 80 Gy equivalent. There
appeared to be significant benefit for patients with smaller tumor volumes (80%
vs. 33% actuarial survival rate at 5 years). Patients treated for primary
disease had a 78% actuarial local control rate at 2 years, whereas the rate for
patients with recurrent disease was 33% (21).
Tatsuzaki
and Urie (261) described the use of proton beam therapy at high doses for
chordomas and chondrosarcomas of the base of the skull and cervical spine.
Treatment delivered 74 cobalt gray equivalent (CGE) to the tumor while
maintaining the central brainstem and central spinal cord at 48 CGE or less;
and the surface of the brainstem, spinal cord, and optic structures at 60 CGE
or less. Proton beam plans and 10-MV x-ray beam plans were developed with these
assumptions and dose constraints. In all cases the proton beam plans delivered
more dose to a larger percentage of the tumor volume, and the estimated tumor
control probability was higher than with the x-ray plans. However, without
precise positioning both the proton plans and the x-ray plans deteriorated,
with a 12% to 25% decrease in estimated tumor control probability.
O'Connell
et al. (193) reported on 62 patients with base of skull chordomas treated with
proton beam irradiation (65 to 73.5 Gy equivalent); 29 patients (19 women and
10 men) experienced local failure, and 14 women (48%) and seven men (21%) died
of disease. On histologic analysis, presence of more than 10% necrosis,
prominent nucleoli, and tumor larger than 70 mm were significant predictors of
short-term disease-specific survival. Chondroid chordoma and conventional
chordomas had equivalent outcome.
Proton beam
boosts have been recommended. Rich et al. (223) reported results in 48 patients
with chordomas: 14 patients were treated with surgery and 17 with combination
of partial surgical resection and irradiation, or irradiation alone after
biopsy (15 patients) (Table 45.9). Various techniques were used to deliver
doses of 45 to 80.4 Gy with photons alone or combined with 160-MeV protons,
usually 2 Gy daily.
Table 45.9.
Patient Status Correlated with Treatment and Radiation Dose Level in Chordoma
Fagundes et
al. (80) updated the Massachusetts General Hospital experience with 204
patients treated for chordoma of the base of the skull or cervical spine.
Sixty-three patients (31%) had treatment failures, which were local in 60
patients (29%) and the only site of failure in 49 patients. Two patients had
regional lymph node relapse, and three developed surgical pathway recurrence.
Thirteen patients relapsed in distant sites (especially lungs and bones). The
5-year actuarial survival rate after any relapse was 7%. There was no
significant difference in survival for patients who had a local or distant
failure. Two patients (1.4%) with local tumor control developed distant
metastases in contrast with 10/60 patients (16%) who failed locally and
distantly.
Terahara et
al. (262) reported on 132 patients with skull base chordoma treated with
combined photon and proton irradiation; in 115 patients dose-volume data and
follow-up were available. The prescribed doses ranged from 66.6 CGE to 79.2 CGE
(median of 68.9 CGE). The dose to the optic structures (optic nerves and chiasm),
the brainstem surface, and the brainstem center was limited to 60, 64, and 53
CGE, respectively. Local failure developed in 42/115 patients, with the
actuarial local tumor control rates at 5 and 10 years being 59% and 44%
respectively. In a Cox multivariate analysis, the models equivalent uniform
dose (EUD) suggest that the probability of recurrence of skull-base chordomas
depends on gender, target volume, and target dose inhomogeneity; EUD was shown
to be a useful parameter to evaluate dose distribution for the target volume.
Hug et al.
(123) analyzed treatment efficacy of fractionated proton radiation therapy
administered for skull base 33 chordomas and 25 chondrosarcomas. Following
various surgical procedures, residual tumor was present in 91% of patients; 59%
demonstrated brainstem involvement. Target doses ranged from 64.8 to 79.2 (mean
70.7) CGE. The range of follow-up was 7 to 75 months (mean, 33 months). In 10
patients (17%) the treatment failed locally, resulting in local control rates
of 92% (23/25 patients) for chondrosarcomas and 76% (25/33 patients) for
chordomas. All tumors with volumes of 25 mL or less remained locally controlled
compared with 56% of tumors larger than 25 mL (p = 0.02). Of patients without
brainstem involvement 94% did not experience recurrence; whereas with brainstem
involvement (and dose reduction because of brainstem tolerance constraints) the
tumor control rate was 53% (p = 0.04). Actuarial 5-year survival rates were
100% for patients with chondrosarcoma and 79% for patients with chordoma. Grade
3 and 4 late toxicities were observed in four patients (7%) and were
symptomatic in three (5%).
Benk et al.
(18) described results in 18 children 4 to 18 years of age with base of skull
or cervical spine chordomas who received fractionated high-dose postoperative
irradiation using mixed-photon and 160-MeV proton beams. Median tumor dose was
69 CGE with a 1.8-CGE daily fraction. With a median followup of 72 months, the
5-year survival was 68%, and the 5-year diseasefree survival rate was 63%.
Patients with cervical spine chordomas had a worse survival rate than did those
with base of skull lesions (p = 0.008). The incidence of treatment-related
morbidity was acceptable: two cases of growth hormone deficit corrected by
hormone replacement, one temporal lobe necrosis, and one fibrosis of the
temporalis muscle, improved by surgery.
A report on
proton therapy for base of skull chordoma was published by the Royal College of
Radiologists (228). They concluded that outcome after proton irradiation is
superior to that reported for conventional photon irradiation. Radiation
therapy schedules involving a mixed schedule of protons and photons have
achieved an approximately 60% local tumor control rate at 5 years.
Sequelae of
Treatment
In patients
treated with high irradiation doses, as well as with charged particles, there
is an increasing probability of sequelae, including brain damage, spinal cord
injury, bone or soft-tissue necrosis, and xerostomia. In a report by Berson et
al. (22), three patients experienced unilateral visual loss, and four patients
had radiation injury to the brainstem.
Santoni et
al. (231) reported on the temporal lobe damage rate in 96 patients (75 primary
and 21 recurrent tumors) treated with postoperative high-dose proton and photon
irradiation for chordomas and chondrosarcomas of the base of the skull. All the
patients were randomized to receive 66.6 or 72 CGE with conventional
fractionation (1.8 CGE per day, five fractions a week) using opposed lateral
fields for the photon component and a noncoplanar isocentric technique for the
proton component. Of the 96 patients, 10 developed temporal lobe damage,
(lateral in two and unilateral in eight). The cumulative temporal lobe damage
incidence at 2 and 5 years was 7.6% and 13.2%, respectively. CT and MRI scans
were evaluated for white matter changes; the MRI areas suggestive of temporal
lobe damage in 10 patients were always separate from the tumor bed.
In patients
receiving high-dose proton therapy for clivus tumors, Slater et al. (242)
observed a 26% incidence of endocrine abnormalities at 3 years and 37% at 5
years, with hypothyroidism being the most frequent sequela. The dose to the
pituitary in patients with abnormalities ranged from 63.1 to 67.7 Gy
equivalent.
Lethal Midline Granuloma
Natural
History and Pathology
Lethal
midline granuloma (LMG) or midline malignant polymorphic reticulosis is a
clinical entity characterized by progressive, unrelenting ulceration and
necrosis of the midline facial tissues. LMG is associated with Epstein-Barr
virus, which has at least two subtypes with different biologic properties that
can be identified by their genomic configuration. The occurrence of the rare
subtype 2 in LMG may relate to a covert immune defect (28). Considerable controversy
exists regarding various disorders characterized by a necrotizing and
granulomatous inflammation of the tissues of the upper respiratory tract and
oral cavity. It is now clear that if infections and other known agents such as
cocaine use, sarcoidosis, environmental toxins, and various neoplasms can be
excluded, three clinicopathologic entities remain: Wegener's granulomatosis,
LMG, and polymorphic reticulosis (PMR) (12). A review of the literature
suggests that cases described as idiopathic midline destructive disease and PMR
are a large evolutionary spectrum from almost benign to fatal malignant
lymphoma (21).
Wegener's
granulomatosis is an epithelioid necrotizing granulomatosis with vasculitis of
small vessels. Systemic involvement of the kidneys and lungs is common.
PMR is an
unusual disorder with distinctive clinical and pathologic features (177).
Histologically, PMR is characterized by an atypical mixed lymphoid infiltration
of the submucosa with extensive areas of necrosis, sometimes extending to bone
or cartilage. The lesion consists of variable zones of small lymphocytes with
scattered immunoblastic forms, abundant plasma cells with occasional
eosinophilia, and histiocytosis (243). PMR has been considered a
lymphoproliferative disorder; most, if not all, cases are peripheral T-cell
lymphomas (163,283). Several authorities believe that PMR and systemic
lymphomatoid granulomatosis are the same disease with the latter predominantly
involving the lungs (94,163).
Idiopathic
LMG describes a localized disorder not characterized by visceral lesions but by
destruction of the midfacial area, which, if left untreated, is uniformly
fatal. The histopathologic findings are nonspecific, with a relatively
nondescript inflammatory reaction with acute and chronic inflammation and
necrosis. Despite specific clinicopathologic features, the distinction between
LMG and PMR is often difficult; although controversial, they may represent two
phases of the same disease, with LMG remaining histologically benign or evolving
into PMR. LMG occurs more frequently in men (94). Ages range from 21 to 64
years; almost half of the patients are in their 50s at presentation. Most
patients have involvement of the nasal cavity (including destruction of the
septum) and the paranasal sinuses (particularly maxillary antrum). The primary
lesion may extend into the orbits, the oral cavity (palate, gingiva), and even
the pharynx.
Characteristics
of the three different diseases are outlined in Table 45.10.
Table
45.10. Differential Features of Three Clinicopathologic Entities
Clinical
Features and Diagnostic Work-Up
Clinical
manifestations include progressive nasal discharge, obstruction, foul odor
emanating from the nose, and, in later stages, pain in the nasal cavity,
paranasal areas, and even in the orbits.
Examination
discloses ulceration and necrosis in the nasal cavity, perforation or
destruction of nasal septum and turbinates, and even ulceration of the nose.
Edema of the face and eyelids may be noted, and the bridge of the nose may be
sunken. Radiographic studies initially show soft-tissue swelling, mucosal
thickening, and findings consistent with chronic sinusitis.
CT is
invaluable in demonstrating the full extent of the tumor, including bone or
cartilage destruction. In 13 patients presenting with LMG, CT proved essential
for determining the extent of the disease, guiding biopsy, and planning
radiation therapy (173). MRI was also helpful for the latter because it could
distinguish fluid retained within the paranasal sinuses from solid masses and
tumor from granulation tissue; it was of little value for detecting bone lysis.
Eight patients proved to have T-cell lymphoma, two had Crohn's disease, in one
the lesion was factitious, and two had granulomas without diagnostic histologic
features.
General
Management and Radiation Therapy Techniques
When
treatment of these patients is planned, it is extremely important to exclude
the diagnosis of Wegener's granulomatosis, a benign process that is commonly
treated with antimicrobial agents, steroids, and systemic chemotherapy
(94,190). Bona fide LMG does not respond to steroids; the treatment of choice
is radiation therapy (64,89,237).
Target
volume should encompass all areas of involvement, including adjacent areas at
risk (i.e., for a lesion of the maxillary antrum it will include the antrum as
well as all of the paranasal sinuses) with a 2- to 3-cm margin (106). Because
marginal failures are a significant problem, wide margins are necessary for
treatment of these patients (243).
Irradiation
techniques are similar to those described for tumors of the paranasal sinuses,
nasal cavity, or nasopharynx. Several investigators have described complete
responses with doses of 30 to 50 Gy; most patients are treated with 35 to 45 Gy
in 3 to 4.5 weeks (64,83,84,237). We recommend 45 to 50 Gy in 4.5 to 5.5 weeks
in 1.8- to 2-Gy daily fractions.
Results of
Therapy
Because of
the rarity of this tumor, experience is limited. Fauci et al. (84) reported on
10 patients with extensive midline granuloma treated with irradiation. Three
received 10 Gy, and all failed within 2 years (retreated with 40 to 46 Gy). The
remaining seven patients received 40 to 50 Gy. Local control of disease was
77%; two patients had local recurrences, one outside the initially irradiated
volume.
The Mayo
Clinic reports the most extensive experience in treatment of PMR or LMG with
irradiation doses of 40 to 42 Gy (177). Of 20 patients irradiated for localized
upper airway PMR, 13 were alive and well for an average of 9.5 years; two were
alive and well with <1 year of follow-up; four were dead of other disease,
and one was lost to follow-up.
In a study
of 34 patients with PMR treated with primary radiation therapy except for one
patient, Smalley et al. (243) found that a minimum dose of 42 Gy or a time-dose
factor of 70 was necessary to achieve long-term local control. The most
frequent failure site was within the original irradiation field. They believe
that this problem should become much less significant with implementation of
proper time-dose-fractionation schemes. Systemic failure occurred in 25% of
their patients initially presenting with limited disease. The salvage of this
subset of patients requires effective systemic chemotherapy. Also, Itami et al.
(127) evaluated nine patients with locally confined nasal non-Hodgkin's
lymphoma (NHL) treated with radiation therapy (all NHLs had T-lineage).
Additionally, unique histological pictures of polymorphism, angiodestruction,
and necrosis were seen in most cases, findings that are the histological
features of PMR, which is the main cause of LMG. Although the disorder was
considered to be locally limited at presentation, only three of the nine
patients with nasal NHL could be induced into long-term remission with involved
field radiotherapy (40 to 60 Gy) and distant extranodal spread was the primary
cause of failure. Multimodality treatment using intensive chemotherapy and
radiation therapy might improve the prognosis of these patients.
Fauci et
al. (83) published a prospective study of 15 patients with systemic
lymphomatoid granulomatosis. Of 13 patients treated with cyclophosphamide and
prednisone, seven sustained complete remission (mean duration of remission, 5.2
± 0.6 years). Two patients receiving only prednisone and six receiving cyclophosphamide
and prednisone died. Six deaths were associated with biopsy-proven lymphoma;
one was caused by a lymphomalike illness unproven by biopsy. The eighth death
was caused by adenocarcinoma in a patient with lymphoma in remission. None of
these patients received radiation therapy.
Chen et al.
(43) reported their experience in 92 cases of LMG or centrofacial malignant
lymphoma treated with radiation therapy. Twenty-five patients received
combination chemotherapy, usually containing doxorubicin, cyclophosphamide,
vincristine, and prednisone (CHOP) or other combinations, including CHOP or
nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) in some
patients. The nose was the most frequently involved site at initial
presentation (85% of patients). Immunophenotyping in 36 patients showed T-cell
lineage in 25 (69%) and B-cell in six (17%). The irradiation technique
consisted of treating all involved and adjacent areas with doses of 30 to 75
Gy. Sixteen patients received neck irradiation (30 to 60 Gy). Daily fractions
were 2 to 3 Gy in five weekly fractions. Actuarial survival rates were 59.5% at
5 years, 56.2% at 10 years, and 40.5% at 20 years. There was no significant
difference in survival in patients receiving more or <50 Gy. A relapse in the
midfacial region was noted in seven patients. Other relapse sites were lung and
skin in three patients, para-aortic or inguinal lymph nodes in two patients,
and brain in one. Survival of patients with recurrences was poor; 73% died
within 8 months.
Hatta et
al. (112) reviewed 18 patients (15 males and three females) with LMG
(polymorphic reticulosis) (about 5.6% of patients with malignant head and neck
tumors). Most of the 18 patients underwent both radiation therapy and
chemotherapy (cyclophosphamide, vincristine, prednisone [COP], CHOP,
methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine,
bleomycin, prednisone [MACOP-B]), but, since their disease had reached an
advanced stage, three underwent radiation therapy only, three chemotherapy only,
and one received no radical therapy. Of the 18 patients, 13 died of the
disease; in six progress was confined to the local lesion. The 5-year
cumulative survival rate was 15.7%. Fourteen autopsy studies revealed that
tumor had invaded the liver (92.8%), lung (92.8%), and spleen (71.4%), and in
all cases it was in leukemic patterns. Five cases were positive for ubiquitin
carboxyl-terminal esterase L1 (ubiquitin thiolesterase) (UCHL-1) (CD45RO) and
10 cases were positive for lysozyme. All cases were positive for Ki-1 (CD30).
Sakata et
al. (229) reported on 107 patients with stage I and II NHL of the head and neck
treated with involved field radiation therapy for orbital, nasal, or paranasal
lymphoma and extended field radiation for Waldeyer's ring or neck lymphoma (39
to 48 Gy). In the latter half of the study, adjuvant chemotherapy was
administered. Of 107 patients, 95 achieved chemoradiation. Of the 12 patients
who did not achieve chemoradiation, nine had nasal T-cell lymphoma (NTL) of the
lethal midline granuloma (LMG-NTL) type. Only one patient who obtained
chemoradiation relapsed in a previously irradiated area. LMG-NTL was the most
significant prognostic factor on multivariate analysis (p <0.001). Older
patients also experienced a higher relative risk than patients of 60 years of
age or less (p = 0.0063). Dose of adriamycin reached borderline significance (p
= 0.0600). Radiotherapy is excellent for obtaining local control of head and
neck NHL and LMG-NTL.
Chloroma
Natural
History
Chloroma
(granulocytic sarcoma, myeloblastoma) is a solid extramedullary tumor composed
of early myeloid precursors usually associated with acute myelocytic leukemia
(41); the most common sites of presentation are in the orbit and other
craniofacial bones. The name chloroma (from the Greek chloros, meaning green)
derives from the green color of affected tissues resulting from the presence of
myeloperoxidase. Because not all deposits exhibit the characteristic green
tint, the term “granulocytic sarcoma” seems more appropriate.
Granulocytic
sarcomas were identified in 3% of 478 patients with acute chronic granulocytic
leukemia; they can be seen with other myeloproliferative disorders, including
polycythemia vera, hypereosinophilia, and myeloid metaplasia (189,190). In the
absence of acute leukemia, granulocytic sarcoma is usually an ominous sign,
suggesting imminent conversion to acute myelocytic leukemia or blast crisis
(190). As survival rates for myelogenous leukemias improve, the number of
patients who relapse with chloromas is increasing (189).
Children
are affected more often than adults. Of 33 patients with orbital chloromas
reported by Zimmerman and Font (294), 75% were in their first decade of life.
Chloromas are found more frequently in children with the M4 and M5 acute
myeloid leukemia subtypes of the French-American-British Cooperative Group
Classification and are also associated with the 8:21 translocation. Chloromas
may appear during bone marrow remission before an increase in blasts is
detected in the bone marrow, so they may herald relapse (189,190).
Clinical
Presentation and Diagnostic Work-Up
Intraorbital
(retrobulbar) chloroma causes progressive exophthalmos or temporal swelling.
Central nervous system involvement causes both local pressure phenomena and
generalized elevation of intracranial pressure with headaches, nausea, and
vomiting (188).
Intracerebral
chloromas may manifest as the rare central nervous system (parenchymal)
involvement of acute nonlymphocytic leukemia. Woo et al. (291) believe that
intracerebral chloromas represent reactivation of sanctuary deposits of
leukemic cells in the central nervous system originated from an initial
hematogenous spread.
All
patients require complete hematologic and neurologic testing as is true for any
patient with suspected leukemia. Open biopsy remains the best diagnostic tool.
Plain radiographic findings consist mainly of localized bone destruction with
predominantly lytic lesions and associated soft-tissue masses in orbital and
periorbital chloromas. Intracranial chloromas may exhibit intermediate or high
attenuation in unenhanced CT scans, with intense, uniform enhancement after
intravenous administration of contrast material. Confusion with meningioma,
hematoma, solitary metastasis, and lymphoma may occur on CT scans (215,244).
Gallium-67
scintigraphy was used to detect unsuspected leukemic infiltrates (165), but is
not used any longer. Currently positron emission tomography (PET) scanning may
be more useful for this purpose and to assess tumor response to therapy.
Radiation
Therapy Techniques
Chloromas
are extremely radiosensitive; however, the optimal dose of irradiation has not
been established. Response rates of leukemic infiltrates have been reported
with doses as low as 4 Gy, yet the need for higher doses up to 30 Gy in certain
locations of extramedullary leukemic infiltrates is well recognized (189,190).
Although the literature is limited regarding the maximum dose needed for
treatment of chloromas, it appears that 30 Gy is the maximum required for local
control. In our limited experience, there appears to be a relationship between
the size of the chloroma and the total dose of irradiation required for
control. The target volume is the tumor mass and an adequate margin (2 to 3
cm). Irradiation techniques depend on the location of the infiltrate. For
superficial lesions, electron beam is recommended. Orbital chloroma may
constitute a radiation therapy emergency because visual loss is possible if the
patient is not treated promptly.
