new 45 glomus tumors 01

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.