Rhabdomyosarcoma of the oral soft tissues

Rhabdomyosarcoma of the oral soft tissues

Rhabdomyosarcoma of the Oral soft tissues J. Bras, D.M.D., Ph.D.,* J.G. Batsakis, M.D., and M.A. Luna, M.D., Houston, Texas UNIVERSITY OF TEXAS SYST...

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Rhabdomyosarcoma of the Oral soft tissues J. Bras, D.M.D., Ph.D.,* J.G. Batsakis, M.D., and M.A. Luna, M.D., Houston, Texas UNIVERSITY

OF TEXAS

SYSTEM

CANCER

CENTER,

M.D. ANDERSON

HOSPITAL

AND TUMOR

INSTITUTE

Between 1944 and 1984 16 patients with rhabdomyosarcoma of the oral soft tissues were treated at the M.D. Anderson Hospital and Tumor Institute. Before 1968 treatment consisted only of surgery. Chemotherapy and radiotherapy were used when surgery was impossible or in an effort to treat recurrent disease. After 1968 treatment design was multidisciplinary and included (excision) biopsy, followed by a combination of high-dose radiotherapy and multidrug chemotherapy. Of the six patients treated before 1968, five (83%) died of disease. In eight of the ten patients treated after 1968, follow-up was 4 years or more. Of these eight patients, seven (87.5%) are free of disease. The clinicopathologic aspects, treatment, complications of treatment, and survival figures are discussed. (ORAL SURC ORAL MED ORAL PATHOL 1987;64585-96)

R

habdomyosarcoma, a tumor of childhood, is one of the most common soft tissue sarcomas and the most common soft tissue sarcoma of the head and neck. In a series of 1215 soft tissue sarcomas, 177 tumors were found in the head and neck; of these 80 tumors (45%) were classified as rhabdomyosarcoma.’ The literature dealing with rhabdomyosarcomas of the oral soft tissues is sparse. Since the reviews of Dito and BatsakiszT3in 1962 and 1963, the only large study found in the English literature is of that O’Day and colleagues4in 1965, which describes 11 rhabdomyosarcomasof the oral soft tissues and is included in the series of 88 head and neck rhabdomyosarcomas reported by Masson and Soule.5 Since these studies, only a few case reports have been added to the literature and, since the advent of the multidisciplinary approach to treatment, most of the reported oral rhabdomyosarcomas have been studied and described as part of large series on all sites, lacking details on oral involvement.“‘3 Although this approach has led to a better understanding and a significant increase in survival, it has obscured the clinicopathologic aspects of oral involvement. This study reports on 16 patients with rhabdomyosarcoma of the oral soft tissues treated between 1944 and 1984 at the M.D. Anderson Hospital and Tumor *Department of Pathology, Academic Medical Center at the University of Amsterdam, The Netherlands. Worked at the Department of Pathology, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, during April, May, and June 1984.

Institute. The findings and relevant literature are discussed. For detailed descriptions of the general and histologic aspects of rhabdomyosarcoma, the reader is referred to recent publications.L4*15 MATERIAL AND METHODS

Patients with sarcoma of the oral soft tissues, including lips, cheek, and tonsillar region, treated between 1944 and 1984 at the M.D. Anderson Hospital and Tumor Institute were identified by a search of the patient data base of the Department of Patient Studies. A review of the slides and medical records yielded 16 patients with rhabdomyosarcoma (Table I). These represent about 12% of all patients with rhabdomyosarcoma of the head and neck treated at the M.D. Anderson Hospital during the same period. The patients were staged according the staging system of the Intergroup Rhabdomyosarcoma Study (IRS) (Table II).6 RESULTS Clinical aspects

Clinical data on the 16 patients with rhabdomyosarcoma of the oral soft tissues are summarized and arranged according to date of initial treatment in Table I. The age at diagnosis ranged from 3 to 30 years, with a median of 9.5 years and an average of 11.8 years. The time between first symptoms and the biopsy was given in 12 patients and ranged from 0 to 26 weeks, with a median of 7 weeks and an average of 7.4 weeks.The most common symptom was a usually progressive enlarging or rapidly growing painless 585

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Oral Surg November 1987

Table I. Rhabdomyosarcoma of oral soft tissues, M.D. Anderson Hospital (1944-1984) Patient No.

Initial treatment

Stage m.7

Sex

Age (Y4

1

M

3

I

Soft palate

1951

Surgery (myxosarcoma)

2

M

15

I

Right cheek

June 1960

Surgery

3

F

3

III

Right floor of the mouth, alveolar ridge and cheek, extension into right zygoma, antrum, and orbit

Aug. 1964

Chemotherapy (dactinomycin, radiotherapy (5000 rad)

4

F

5

III

March 1966

5

M

4

III

Left lower gingiva, extension into mandible, submandibular node Right side of mandible, cheek

Chemotherapy (PAM, dactinomycin, vincristine), surgery Chemotherapy (dactinomycin, cyclophosphamide), radiotherapy

6

F

19

II

Site

Date

Dec. 1967

May 1968

Upper lip

Type

Surgery, radiotherapy (6000 rad)

NED = No evidenceof diseasesincelast treatment. DOD = Died of disease.time sinceinitial treatment.

mass, accompanied by a sore throat in two patients with involvement of the soft palate and tonsillar region and loosening of teeth in one p.atient with involvement of the gingiva and tumor extension into the mandible. Before biopsy, anti-inflammatory treatment was employed in five patients. Intra oral examination usually revealed a firm, large, nonulcerated, definite or irregular, sometimes multilobular or exophytic mass (Figs. 1 and Z), with multiple satellite lesions in one patient. At the time of diagnosis, enlarged regional lymph nodes suggestive of metastatic disease were found in 19% (3/ 16) of the patients. During the course of the disease, another three patients (19%), had clinical evidence of lymph node metastases Patient 5, when referred to

the M.D. Anderson Hospital, had a mass involving the right side of the cheek, extending into the nose, maxilla, mandible, and temporal and suboccipital areas, with cervical and axillary lymphadenopathy (Fig. 3). At the time of initial treatment, bone destruction was present in five patients. HiItologic

aspkds

Of the 16 tumors studied, 9 were classified as embryonal rhabdomyosarcoma, 3 as embryonal rhabdomyosarcoma with pleomorphic differentiation, and 4 as alveolar rhabdomyosarcoma (Table III). The embryonal subtypes varied from myxoid (Figs. 4 and 5) to cellular (Figs. 6 to 9) with the cells varying from smali round cells with little cytoplasm

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Recurrences (local, metastatic) and treatment

Apr. 1958-Local -Surgery (granuloma?) Aug. 1959-Local -Surgery (rhabdomyoma?) Feb. 1960-Local --Surgery (rhabdomyoma?) Sept. 1960-Left neck, admitted to MDAH -Surgery, chemotherapy (dactinomycin), radiotherapy (3800 rad) Nov. 1960-Local, surgery June 1962-Pterygoid fossa base of skull, mandibular ramus, maxilla -Surgery, radiotherapy (5000 rad) Sept. 1964 to May 1965 -Chemotherapy (vincristine, cyclophosphamide, methotrexate), radiotherapy (5225 and 3500 rads) cranial extension Dec. 1966Loca1, surgery June 1970-Local, surgery Jan. 1971-Local -Surgery, chemotherapy (vincristine, mitomycin), radiotherapy-no response Nov. 1973-Admitted to MDAH, large tumor mass, multiple nodes -Chemotherapy (vincristine, Adriamycin, DIC, cyclophosphamide, dactinomycin, cis-platinum) Apr. 1969-Lymph node submandibular surgery Dec. 1969-Lymph node preauricular, surgery Jan. 1972-Floor of mouth -Radiotherapy (5600 rad), chemotherapy (VAC)

NED

DOD

Disease-free period

11 yr

9 yr

19 yr

8 mo

15 mo

7 yr

6.5 yr

9 mo

2 yr

continued

in the less differentiated forms to rounded cells with an eccentrically placed nucleus and a deep eosinophilic cytoplasm and strap-shaped and spindled cells in the more differentiated forms (Figs. 8 and 9). The alveolar subtype manifested aggregates of small round cells, adhering fibrous trabeculae and showing central cell loss, creating alveolar spaces. In more solid areas, the fibrous trabeculae were delicate or absent (Figs. 10 and 11). Treatment

and follow-up

As Table I shows, until the middle of 1968 (patients 1 to 6) initial treatment merely consisted of surgery. Other treatment modalities were used when surgery was impossible or in an effort to stop recurrent disease.In patient 5 the initial chemotherapy and radiotherapy were based on the diagnosis of

neuroblastoma, which was changed to rhabdomyosarcoma in 1970 after recurrent tumors were examined. Of these six patients, five (83%) died 8 months to 11 years after diagnosis. Since the middle of 1968, all patients except patient 12 were treated after biopsy by a combination of radiotherapy and chemotherapy. No chemotherapy was administered to patient 12. Patients 7 to 9 were treated with high-dose radiotherapy and VAC chemotherapy (vincristine, D-actinomycin, cyclophosphamide) as described by Donaldson and colleagues.I6 Patients 10 and 11 were included in the IRS-I group III and were respectively randomized for the F regimen (high-dose radiotherapy, VAC pulse, and Adriamycin chemotherapy) and E regimen (high-dose radiotherapy, VAC pulse chemotherapy).6 Patient 16 is included in the IRS-II group

588

Bras, Batsakis, and Luna

Table

I. Cont’d

Patient No.

Sex

Age (Yr)

Stage IRS

7

M

6

III

8

F

7

III

9

F

12

10

F

11

Oral Surg November 1987

Initial treatment Site

Date

Type

Nov. 1968

Radiotherapy (6075 rad P, 4000 rad N) chemotherapy VAC) Radiotherapy (6500 rad), chemotherapy (VAC)

III

Left tonsil, soft palate, extension into mandible, subdigastric nodes Right trigonum retromolare, cheek, destruction of maxillary sinus, posterior mandible, inferior orbit, possible extension into cranial fossa Soft palate

Sept. 1971

1

III

Soft palate

May 1973

M

12

III

Soft palate

Nov. 1975

12

F

30

I

13

M

23

III

Soft palate

Dec. 1976

14

M

18

III

Soft palate

Sept. 1978

15

F

24

III

Soft palate, subdigastric node

Oct. 1981.

16

F

7

III

Tongue

Aug. 1983

Nov. 1969

Oct. 1976

III regimen 2S8 and is at this writing halfway through her therapy. The nonpediatric patients 13, 14, and 15 received high-dose radiation therapy and Cy-CA-DIC (cyclophosphamide, vincristine, adriamycin, dacarbazine) .“*‘* One patient received adjuvant immunotherapy. In eight of the ten patients treated since the middle of 1968, the follow-up is 4 years or more. During the follow-up recurrent disease developed in one patient. The remaining seven patients (87%) are free of disease. Oral compttcations

Irradiation and the additive effect of dactinomycin usually caused a severe and confluent mucositis, which necessitated nasogastric feeding in some patients. One patient, probably becauseof his excellent oral hygiene, manifested only a mild oral mucosal erythema. A severe postirradiation trismus was found in five patients. In one patient an ankylosis of

Radiotherapy (6500 rad) chemotherapy (VAC) Radiotherapy (6000 rad) chemotherapy (VAC push, Adr.) Radiotherapy (6500 rad) chemotherapy (VAC push) (Excision) biopsy, radiotherapy (6000 rad P, 5000 rad N) Radiotherapy (6500 rads), chemotherapy (Cy-VA-DIC) immunotherapy (BCG, sarcoma lysate) Radiotherapy (6000 rad P, 5000 rad N) chemotherapy (Cy-VA-DIC) Radiotherapy (6072 rad) chemotherapy (Cy-VA-DIC) ‘Excision’ biopsy radiotherapy, chemotherapy WAC)

the right temporomandibular joint developed. Trismus usually afflicted the level of oral hygiene, leading in one patient to severe dental disease. Osteoradionecrosis developed in two patients. Dental decay was described in two patients. DtSCltSStON

Approximately 40% of all rhabdomyosarcomas are found in the head and neck.9*Is Because of significant prognostic differences according to primary site of involvement in the head and neck, the rhabdomyosarcomas have been subdivided into orbital and nonorbital types. The latter, in turn, can be further segregated into parameningeal (middle ear, mastoid, ear canal, sinonasal, nasopharynx, and infratemporal fossa) and other (nonorbital, nonparameningeal) types (Table IV). These divisions acknowledge the poor prognosis usually associated with parameningeal rhabdomyosarcomas and the

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Recurrences {local, metastafic) and treatment

DOD

NED

589

Disease-free period

July 1974-Pulmonary metastasis -Chemotherapy (Adriamycin, DIG) 14 yr

Oct. 1974-Radiotherapy (3000 rad) -Chemotherapy (VAC)

4v

12 yr 10 yr

6 yr 7 yr

4 yr

1.5 yr

1 yr

better prognosis attributed to rhabdomyosarcomas arising within the orbit.‘9e2’ In the IRS series, 11% of all head and neck rhabdomyosarcomas and 39% of the nonorbital, nonparameningeal rhabdomyosarcomas arise in the oral and oropharyngeal soft tissues and the parotid region, with a nearly equal distribution between these sites.21*22 In our series and others in which definite anatomic distributions have been given,5*23.24 oral rhabdomyosarcomas account for about 5% of all rhabdomyosarcomas and about 12% of all head and neck rhabdomyosarcomas. In the oral region, the most common site of involvement is the soft palate. Rhabdomyosarcoma is usually a fast-growing, often infiltrative tumor. In fewer than 10% of all rhabdomyosarcomas, when arising just beneath the mu-1 lining, a fairly well-circumscribed multinodular or distinctly polypoid or grapelike mass can be

found (botryoid rhabdomyosarcoma).6*I5325-27The symptoms may be vague and may mimic other conditions. Suspectedinfection is an important cause of delay in diagnosis.28On the basis of this study and two other series,5*23 rhabdomyosarcoma of the oral soft tissues usually appears as an enlarging and painless mass. In the advanced stagesof the disease, becauseof infiltrative growth and depending on site, pain, paresthesia, loosening of teeth, and trismus occur. The histopathologic spectrum manifested by rhabdomyosarcoma has permitted subclassification of the neoplasms into embryonal, alveolar, and pleomorphic types.29-33 Embryonal rhabdomyosarcoma is the most common type diagnosed. Pleomorphic rhabdomyosarcoma, before 1950 the preponderant type diagnosed, is now a debatable entity. Weiss and Enzinger indicate that most of the so-called pleomorphic rhabdomyosarcomas in adult patients actu-

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Fig. 1. Patient 13, Table I. Embryonal rhabdomyosarcoma of the left soft palate, manifesting as a relatively small swelling.

Fig. 2. Patient 10, Table I. Embryonal rhabdomyosarcoma of the soft palate, a multilobular exophytic soft tissue mass.

II. Intergroup Rhahdomyosarcoma Study (IRS) staging system for childhood rhabdoyosarcoma6

Table III.

Table

Group I. Localized disease, completely resected, regional nodes not involved -Confined to muscle or organ of origin -Contiguous involvement, infiltration outside the muscle or organ of origin, as through the facial planes Group II. Grossly resected tumor with miscroscopic residual disease (nodes negative) Regional disease, completely resected (nodes positive or negative) Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual disease Group III. Incomplete resection or biopsy with gross residual disease Group IV. Distant metastatic disease present at onset

ally are examples of malignant fibrous histiocytoma. According to Enzinger and Weiss,ls in some casesit is difficult to draw a sharp line between embryonal and pleomorphic rhabdomyosarcoma, which was also found in three of our patients. In the IRS subgroup of oral, oropharyngeal, and parotid area rhabdomyosarcomas, multivariate analysis did not show prognostic differences between the embryonal and alveolar types.22 The significant progress in the management of patients with rhabdomyosarcomas is reflected in our series. Treatment has evolved from an almost purely surgical approach to multidisciplinary protocols, including surgery, radiotherapy, and chemotheraPY.

In our series, only one of the 6 patients treated before the middle of 1968 has survived ( 16.6%). This

Rhabdomyosarcoma oral soft tissues, histologic subtypes of patients in Table I Subtype

Embryonal Embryonal-pleomorphic Alveolar

I

Patieni

3, 7, 8, 10, 11 13, 14, 15, 16 4, 9, 12 1, 2, 5, 6

is comparable with the findings in a series of head and neck rhabdomyosarcomas collected from the literature before 1962, in which the estimated 5-year survival was 8.2% for all head and neck rhabdomyosarcomas and 12.2% for those involving the oral cavity and pharynx. 2*3 In a Mayo Clinic study covering the time period from 1920 to 1964, 8.3% of all patients and 36.6% of the patients with oral rhabdomyosarcomas were free of disease for periods ranging from 1.8 to 20 years.4*5 Since the advent of multimodal therapy, oral rhabdomyosarcomas have almost always been included as a part of larger series. In the IRS data on head and neck rhabdomyosarcoms, a 75% overall 3-year disease-free survival was noted for patients with stage I to III nonorbital, nonparameningeal rhabdomyosarcomas. No differences were found between the three stages (Table III). A survival rate for patients with stage IV nonorbital, nonparameningeal rhabdomyosarcomas has not been given.21The overall actuarial 5-year disease-freesurvival rate for patients with stage I to III nonorbital, nonparameningeal head and neck rhabdomyosarcomas is 78%. In this group of patients the survival rate for patients with involvement of the neck was significantly lower

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Rhabdomyosarcoma of oral soft tissues 591

3. Patient 5, Table I. Alveolar rhabdomyosarcoma of the right cheek, initially (7 years before death) diagnosed as neuroblastoma and treated by chemotherapy and radiotherapy, followed by surgery and surgery combined with chemotherapy. A and B, at time of admission to hospital (12 months before death) with massinvolving the right side of the cheek and extending into the mandible, maxilla, nose,temporal, and suboccipital areas and involvement of neck and axillary lymph nodes. C and D, Patient 3 months before death. Fig.

than for patients with oral, oropharyngeal, and laryngeal involvement. However, exact data are not given.** These data suggest an even better prognosis for patients with stage I to III oral rhabdomyosarcoma& and this is evidenced by our findings in which 88% (7/8) of the patients treated since the middle of 1968 were free of disease for 4 years or more. Of these eight patients, seven would be classified as stkge Iii, one as stage I. Treatment is multidisciplinary and includes (depending on site and size of the tumor) surgery, radiotherapy, and chemotherapy. The role of multidrug, multicycle chemotherapy is now well exhib-

ited.3s The role of surgery is limited by site and extent of the tumor. When a tumor has been completely resected (IRS stage I), radiotherapy adds no benefit? I1 whereas in cases of microscopic residual disease (IRS stage II) the tumor dose can be lowered. Treatment of oral rhabdomyosarcomas does not diverge from the aforementioned. If the tumor is easily accessible and if a stage I can be achieved without creating major defects, radical surgery followed by postoperative chemotherapy is the treatment of choice, since this approach prevents the severe oral complications of radiotherapy. Elective

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Fig. 4. Patient 14, Botryoid type of embryonal rhabdomyosarcoma. Polypoid and myxoid appearance with a subepithelial zone of increased cellularity (cambium layer). (Hematoxylin and eosin stain. Original magnification, X5.)

Fig. 5. Botryoid type of embryonal rhabdomyosarcoma. Higher magnification of specimen in Fig. 4 showing a mucomyxoid stroma with haphazardly arranged primitive mesenchymal cells. (Hematoxylin and eosin stain. Original magnification, X200.)

neck dissection is rarely indicated since in the IRS series in 3% of all patients with nonorbital head and neck rhabdomyosarcoma and in 6% of those patients with stage II diseasemetastatic diseasewas found.7*36 Also, if oral and pharyngeal tumors are irradiated, the high nodes generally are included in the primary treatment field.16However, it must be stressed that in the small series of Donaldson and coworkerP and in material presented here, regional lymph nodes clinically suspected of representing metastatic dis-

easewere found in, respectively, 26% and 19% of the patients at the time of initial treatment. Therapeutic node dissection is appropriate when nodes are palpable or are found to be involved.6 The side effects of the aggressivemultidisciplinary treatment of rhabdomyosarcoma are considerable. Direct complications of chemotherapy include alopecia, neurotoxicity, paresthesias, and/or pain in the jaws and teeth with use of vincristine. Dactinomycin (actinomycin-D) produces myelosuppression, ulcer-

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593

Fig. 6. Patient 6. Embryonal rhabdomyosarcoma, consisting chiefly of poorly differentiated round cells and a few scattered rhabdomyoblasts, (Hematoxylin and eosin stain. Original magnification, x200.)

Fig. 7. Embryonal rhabdomyosarcoma. Higher magnification of specimen in Fig. 6 showing rhabdomyoblasts with fibrillary material surrounding the nucleus or arranged longitudinally (arrows]. (Hematoxylin and eosin stain. Original magnification, x500.)

ation of the oral mucosa, abdominal pain, nausea, and vomiting. Side effects of cyclophosphamide (Cytoxan) include myelosuppression, alopecia, ulceration of the oral mucosa, nausea and vomiting, hemorrhagic cystitis, and (at high doses) cardiac toxicity. Adriamycin causes myelosuppression, alopecia, ulceration of the oral mucosa, xerostomia, nausea and vomiting, and (at total dosesabove 600 mg/m’) cardiac toxicity. Mucosal ulceration and cardiotoxicity are enhanced when these sites are also

irradiated. Because of the myelosuppression, oral secondary infections are likely to develop.7*‘O-l33 I6 Possiblechemotherapy-related effects on teeth developing at the time of administration are an acquired amelogenesis imperfecta, microdontia, a tendency toward thinning of roots, and enlarged pulp chambers.37Seventeenpercent (23/135) of the patients in the IRS-series died of drug toxicity.38 A late complication of chemotherapy is the induction of secondary tumors. In the series reported by Ghavimi and

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Fig. 8. Patient 4. Embryonal rhabdomyosarcoma with loosely arranged rhabdomyoblasts and pleomorphic rhabdomyosarcoma-like areas with bizarre cells arranged in bundles. (Hematoxylin and eosin stain. Original magnification, X50.)

Fig. 9. Embryonal rhabdomyosarcoma. Higher magnification of pleomorphic area in Fig. 8 showing bizarre cells with usually an abundant eosinophilic cytoplasm and pleomorphic nuclei with a distinct nucleolus. (Hematoxylin and eosin stain. Original magnification, X200.)

coworkers” one patient developed an acute monocytic leukemia and died. For treatment of the oral complications of chemotherapy, the reader is referred to the work of Lockhart.39 Reported complications of radiotherapy to the oral and oropharyngeal regions are severe mucositis, growth disturbances of hard and soft tissues, dental decay and abnormal occlusion, trismus, osteoradio-

necrosis, and secondary infections.*0-*3~ I6337 In the series of Jaffe and colleagues,40a postirradiation sarcoma of the mandible developed in one patient 10 years after initial treatment. This patient has been reported separately.41 Although multidisciplinary treatment has led to a significant increase in survival, further studies are needed to reduce the considerable side effects of radiotherapy and chemotherapy.

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Fig. 10. Patient 6. Alveolar rhabdomyosarcoma. Aggregates of small cells adhering to delicate fibrous trabeculae and showing central loss, creating alveolar spaces. (Hematoxylin and eosin stain. Original magnification, X200.)

Fig. 11. Alveolar rhabdomyosarcoma. Higher magnification of specimen in Fig. 10 showing poorly differentiated round and racket-shapedcells adhering to delicate fibrous trabeculae. (Hematoxylin and eosin stain. Original magnification, X500.) Tab deIV.

andI siite* - -

Rhabdomyosarcoma of head and neck; 3-year relapse free survival rates related to stage (IR -

s tage

Ail sites (%;II

I II

87 69

III IV

51

18

Head and neck (H and N) All H and N 83% 79% 59% 18%

( 516 ) (22/28) (41169) ( 2/11)

*Based on reports by Stow et aLzl and Maurer and Ragab”

Orbit 100% ( l/l ) 89% ( 8/9 ) 92% (12/13

-

Parameningeal

Other H&

100% ( l/l ) 75% ( 314 ) 41% (16/39)

75% ( 3/4 ) 73% (11/15) 76% (13/17)

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36. 37.

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