Magnetic Resonance Imagmg, Vol. 8, pp. 771-777, Printed in the USA. All rights reserved.
0730-725x/90 $3.00 + .oo Copyright 0 1990 Pergamon Press plc
1990
@ Original Contribution
CHANGES IN MR SIGNAL INTENSITY AND CONTRAST ENHANCEMENT OF THERAPEUTICALLY IRRADIATED SOFT TISSUE BARRY D. FLETCHER, SOHEIL L. HANNA, AND LARRY E. KUN* Departments of Diagnostic Imaging and *Radiation Oncology, St. Jude Children’s Research Hospital; and Department
of Radiology, University of Tennessee, Memphis, Tennessee 38101, USA
Increased MR signal intensity was observed on T,-weighted, STIR, and Gadolinium-DTPA-enhanced T,-weighted images of subcutaneous and muscular soft tissue in 9 of 10 children treated with combination chemotheraphy and radiation therapy (RT) for malignancy in the pelvis or an extremity. Total radiation doses ranged from 59.5 to 65 Gy. Eight of the patients with these changes received hyperfractionated RT (seven for Ewing sarcoma and one for perineal rhabdomyosarcoma); one was treated for pelvic hemangiopericytoma with once-daily fractions. Evidence of soft tissue damage became apparent as early as the sixth week of RT and was seen for up to 69 wk postRT. There was no clear MR evidence of RT-induced soft tissue damage in one patient, who underwent hyperfractionated RT for pelvic rhabdomyosarcoma. Other MR findings in this group included evidence of bladder wall thickening in three of the seven patients given pelvic RT and increased T,-weighted signal of irradiated marrow in nine patients. All patients had clinical evidence of skin, soft tissue, or epithelial radiation effects. Increased MR signal intensity secondary to RT-induced damage can be differentiated from widespread tumor by geometric borders that conform to the margins of the radiation field. Keywords: Magnetic resonance, contrast enhancement; Magnetic resonance, tissue characterization; Radiation injury/effects; Therapeutic radiology, in infants and children.
INTRODUCTION
diation therapy for malignancies of the pelvis or an extremity, we observed abnormally intense signal, corresponding to the radiation ports, on T2-weighted and short tau inversion recovery (STIR) images, as well as increased signal intensity on T,-weighted images enhanced with Gadolinium-DTPA. Here we describe the clinical, MR imaging, and computed tomography (CT) findings in these patients.
Magnetic resonance (MR) images are exquisitely sensitive to changes in tissue hydration, which alter relaxation times and signal intensity and contrast. ‘*’ Injuries, 3,4 rhabdomyolysis, 5 intraarterial chemotherapy6 and even exercise’ can cause extensive and prolonged MR signal alterations in skeletal muscle. Radiation therapy is known to cause MR signal intensity changes in primary tumors’ and bone marrow.9”o Other tissues in the irradiated field may also be affected. Radiologists should be alert to the possibility of such iatrogenic changes so that misinterpretation of radiation-induced alterations in signal intensity which could lead to overestimates of tumor extent can be avoided. During follow-up MR imaging of children given ra-
METHODS MR imaging was performed as part of routine follow-up in 10 consecutively treated children who received chemotherapy and radiation therapy (RT) for unresectable malignancy in the pelvis or an extremity. The 6 male and 4 female patients ranged in age from
RECEIVED4/2/90; ACCEPTED6/20/90. Acknowledgment-Supported in part by the National Cancer Institute, Cancer Center Support (CORE) grant P30CA21765 and by the American Lebanese Syrian Associated Charities. Presented at the Society for Magnetic Resonance Imaging, 8th Annual Meeting, February 1990, Washington, DC.
Address correspondence to Barry D. Fletcher, M.D., Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, TN 38101, USA.
771
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Magnetic Resonance Imaging 0 Volume 8, Number 6, 1990
5 to 18 yr. Diagnoses included Ewing sarcoma (7 patients), rhabdomyosarcoma (2), and hemangiopericytoma (1). All treatment and MR studies were approved by the institution’s Clinical Trials Committee and informed consent was obtained.
(Mesna) was given with cyclophosphamide and ifosfamide. Nine patients received hyperfractionated and one had conventionally fractionated RT. The seven patients with Ewing sarcoma received total radiation doses of 59.5-60 Gy delivered in twice daily fractions of 1lo-120 cGy over 4-6 wk. Two patients with rhabdomyosarcoma in the bladder and perineum, respectively, were treated with 110 cGy twice daily to 60.5 Gy over a 7-wk period. The final patient, who had pelvic hemangiopericytoma, received conventionally fractionated irradiation, 150-180 cGy once daily to a total dose of 65 Gy over 7 wk. Details of RT are given in Table 1.
Treatment Multiagent chemotherapy was administered to all patients before, during, and after RT according to institutional protocols. This included cycIophosphamide, adriamycin and vincristine, with or without dactinomycin or ifosfamide. In the seven patients who received pelvic irradiation, a uroprotective agent
Table 1. Clinical and MRI findings in patients receiving radiation therapy MRI
RADIATION Patient
Dimis/Site
Daily Fractian
cwmse)
1
Euinglfemr
Total &%I)
120 x 2
Dose
ueeks
Wy)
60
Wll)
2
Euing/prbis
120 X 2
60
(M/17)
Ewing/radius
3
110 x 2
59.5
(F/7)
Ewing/ilium
4
120 x 2
60
U4/24)
5
Euingliliun
120 x 2
60
(F/19)
Ewing/tibia
6
120 x 2
60
(M/13) 7
Euing/ischiun
120 x 2
60
Rhabdomyosarccml
110 X 2
60.5
of
Atncumal Tissue
UT
P 16
+
P 30
+
P 51
+
P 17
+
P 28
+
P 41 P 54
+ +
F 16
+
P 39 P 52
+ +
P
6
+
P 15 P 23
+ +
P 37
+
P 52
+
P 69
+
P 25
+
P 44' P 53
+
P 62
+
+
P 17
+
P 40
+
P 20
+
D
2
0
D
4
D
0
7
0
P 3 P 11
0 +
P 22
+
P 56 P68
0 0
P 74
0
P a7
0
(M/12) a
perineum
(F/12)
9
RhabdmyosarcmW bladder
(F/6)
HemngiopericytcmW
10
Abbreviations: Recurrent
la0 X 1
60.5
65
pubis
(M/16)
l
110 x 2
twr
RT = Radiation
therapy;
P = Post RT; D= During
D
6
+
P
3
+
P 12
+
P 25
+
RT.
Soft
Signal
Soft tissue 0 B.D. FLETCHERET AL.
Imaging Studies All patients had baseline MR imaging prior to therapy. A total of 37 fohow-up MR studies were performed (range, l-6 per patient) which were done after completion of RT (3-87 wk) in eight patients and both during and after RT in two. MR imaging was performed on a 1.O T system (Siemens, Iselin, NJ) using T,-weighted (TE: 15 msec; TR: 0.76 set) and 7”-weighted (TE: 90.0 msec; TR: 2.0-2.5 set) and STIR (TE: 22.0 msec; TI: 150.0 msec; TR: 2.5 set) images. T,-weighted images were then repeated within 15 min after intravenous injection of Gadolinium-DTPA (Magnevist, Berlex Laboratories), 0.2 mL/kg (0.1 mmol/kg), in the majority of studies (26136). The MR examinations were reviewed by two of the authors (BDF, SLH) for abnormalities of tissue signal intensity. Regions with visibly abnormal signal intensity were compared with irradiated volumes based on simulator and port films and dosimetric analyses of the target volumes. In six patients, contrast-enhanced CT scans, performed within l-11 days of a corresponding MR study, were also available. RESULTS On MR studies performed before the initiation of radiation therapy, intensity of the soft tissues adjacent to tumor appeared normal in all patients. The timing and results of subsequent MR studies, as well as details of RT, are given in Table 1. Signal intensity of skeletal muscle continued to appear normal during and after RT on Ti-weighted images. However, T2weighted, STIR, and Gadolinium-DTPA enhanced T,weighted images revealed increased signal intensity of adjacent skeletal musculature in nine of the ten patients. These changes were noted in eight of the nine patients who received hyperfractionated RT (7/7 with Ewing sarcoma and l/2 with rhabdomyosarcoma) and in the one patient treated with single daily RT doses for pelvic hemangiopericytoma. In the latter patient, changes were observed on an MR study 6 wk after the initiation of RT. In the patients given hyperfractionated therapy, MR changes were also seen as early as 6 wk and persisted on subsequent MR examinations up to 69 wk after completion of therapy. In all abnormal cases, the region of altered signal corresponded to the radiation volume and was accompanied by linear strands of edema or fibrosis in the irradiated subcutaneous fat (Figs. 1,2). In one case of Ewing sarcoma of the ilium that recurred 44 wk after completion of RT, signal characteristics of the tumor similar to those of irradiated muscle were present on STIR images (Fig. 3), but the tumor was slightly less
113
intense than irradiated muscle on T2-weighted images. Signal intensity of the external pelvic musculature and subcutaneous soft tissues remained normal in one patient, who was treated to 60.5 Gy for rhabdomyosarcoma and studied from 56 to 87 wk after termination of RT. However, there was a mild increase in signal intensity of perivesicular and perirectal connective tissues on 7”-weighted and STIR images, with slight enhancement with Gadolinium-DTPA, as well as bladder wall thickening. In addition to increased signal intensity of the soft tissues, atrophy of the involved muscles was observed on MR studies of six patients. This finding was present as early as six wk post-RT in one patient. Three of the seven patients who received pelvic irradiation developed bladder wall thickening confined to the irradiated volume. Hematuria was present in one of these patients, in whom MR studies also showed a large, hemorrhagic intravesical clot. Nine of the 10 patients had fatty replacement of irradiated marrow as early as 3 wk post-RT, which appeared on unenhanced Tiweighted images as increased intensity of the irradiated bone marrow. In the remaining patient, the marrow exhibited intense Tr -weighted signal on baseline MR studies, with no further increase in brightness on follow-up MR studies during or after therapy. CT scans, which were obtained in six of the patients with Ewing sarcoma demonstrated abnormalities in four consisting of faint, enhanced reticular densities in the subcutaneous fat visible as early as 15 wk post-RT, but no muscle enhancement could be seen, Muscle atrophy was seen equally well on CT and MR images. Clinically, all patients developed acute, subacute, or late skin or soft tissue manifestations, with fibrosis in three cases. Epithelial changes included hematuria in two patients, both of whom had bladder wall thickening on MR. Proctitis developed in one patient and small bowel reaction in one. Only one patient, in whom Ewing sarcoma recurred one yr post-RT, complained of pain in the irradiated volume. DISCUSSION Radiation-induced alterations of MR signal intensity and enhancement characteristics of skeletal muscle and subcutaneous fat were found in 9 of 10 patients treated for primary tumors of the pelvis or an extremity. The importance of recognizing these findings lies in the possibility that they may be mistaken for neoplasm, thus leading to overestimation of tumor extent. Such errors can usuahy be avoided by noting the geometric rather than anatomic configuration of the involved tissues and by comparing the MR images
114
Magnetic Resonance Imaging 0 Volume 8, Number 6, 1990
with simulator and port films or dosimetric displays. However, we encountered some difficulty in distinguishing radiation effects from recurrent tumor on STIR images of one patient with Ewing sarcoma of the ilium. The MR findings of increased signal on T2-
weighted, STIR and Gadolinium-DTPA-enhanced T, -weighted images of irradiated soft tissues may reflect minor, usually subclinical, tissue damage with edema or inflammation. These signal changes are consistent with an increase in total water content” and extracellular fluid volume’* of the affected tissues.
D
Fig. 1. Serial MR studies of a patient (no. 4) treated for Ewing sarcoma of the right ilium. On transverse T2-weighted (2.OW90) image before irradiation (A), the musculature and subcutaneous fat appear normal; the slight decrease in intensity of the soft tissues of right pelvis is attributed to artifact. Six wk after completion of RT (B), a transverse T2-weighted image (2.00/90) shows decreased muscle mass in the right pelvis with slight increase in intensity of the right gluteus maximus muscle. T2-weighted image (2.5/90) 15 wk post-RT (C) shows further muscle atrophy and increased intensity; also note reticular areas of increased signal intensity in the subcutaneous fat of the right pelvis, which are probably due to edema and inflammation. Transverse STIR (150/2.50/22) image 23 wk post-RT (D), shows marked increase in brightness of atrophic muscles of the right pelvis. CT dosimetry (E), indicates high dose volumes that correlate with regions of abnormal signal intensity shown in MR images.
Soft tissue 0 B.D. FLETCHERET AL.
C
Fig. 2. MR studies of a patient (no. 1) treated for Ewing sarcoma of the right femur. Transverse Gadolinium-DTPAenhanced T,-weighted (A), and T,-weighted images (B), 28 wk post-RT show increased intensity of atrophic muscle of the right thigh with well-defined medial border. Coronal STIR image (C), shows geometric pattern of increased brightness corresponding to radiation field shown on port film (D).
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116
A
6, 1990
B
Fig. 3. STIR images of patient (no. 5) treated for right iliac Ewing sarcoma. Transverse STIR image 44 wk post-RT (A), shows diffuse increase in signal intensity of atrophic right pelvic musculature masking a recurrent tumor (arrow) of similar intensity. Follow-up transverse STIR image (B), obtained 18 wk later, shows further atrophy of the right pelvic muscle bulk, while recurrent tumor has increased in size. Note interval appearance of left iliac metastases.
The reduced fiber size of grossly atrophic muscles and the consequent expansion of extracellular fluid space13 may contribute to and prolong the MR signal abnormalities. Clinically apparent soft tissue changes during and immediately after irradiation include acute epithelial reactions, often associated with subcutaneous and submucosal edema.14 Subacute effects of irradiation, generally described as beginning two wk to four mo after treatment, are primarily visceral changes related to direct effects on the more slowly regenerated parenchymal cells. Other subacute soft tissue changes, clinically apparent as “cellulitis-like” events, have been described anecdotally’4 and clinical effects of radiation on normal tissues are well documented. I5 Clinical changes related to hemorrhagic cystopathy and uroepithelial alterations have been documented both during and immediately following RT.“j Hemorrhagic cystitis has also been associated with both cyclophosphamide and ifosfamide,” which the majority of our patients received. The volume-related bladder wall thickening apparent in three patients in our series suggests a combined urodisruptive effect of chemotherapy and irradiation. Fatty replacement of radiation-depleted hematopoietic tissue is also well known’8p19 and the MR findings associated with this process in our patients were similar to those previously described.‘*” Fractionation schemes are used in radiation oncology in an effort to reduce the effects of radiation on normal tissues while delivering maximal doses to the tumor.20 Hyperfractionated RT involves the use of
more than one daily fraction, with each considerably smaller than a conventional 180-200 cGy once-daily dose. In early clinical experience, hyperfractionation has been associated with acute epithelial reactions. However, increased subacute effects on normal tissue have not been predicted or well described to date. There are no published data comparing the effects of conventional and hyperfractionated irradiation. The degree of soft tissue changes documented within the target volume after irradiation may reflect enhanced tissue changes due to hyperfractionated RT or accelerated effects of hyperfractionated RT on normal tissue. However, we also observed early, extensive soft tissue changes within the target volume of the single patient in this series who received conventional RT. The absence of abnormal signal intensity in the irradiated external pelvic musculature and subcutaneous tissues on MR images of one patient who received hyperfractionated RT was somewhat surprising. This patient had clinically evident skin and epithelial changes, as well as bladder wall thickening, fatty replacement of hematopoietic marrow, and MR imaging findings attributed to mild edema of internal pelvic connective tissues. The fact that MR images were not obtained until more than one yr after completion of RT might account for the lack of signal abnormalities in the irradiated muscles, although these changes were seen at later assessment times in other patients. This study however, indicates that, in the majority of patients receiving RT for malignant musculoskeletal tumors, changes in MR signal intensity corresponding to the irradiation field are to be expected.
Soft tissue 0 B.D.
FLETCHERET AL.
771
REFERENCES 1. Bottomley, P.A.; Foster, T.H.; Argersinger, R.E.; Pfeifer, L.M. A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from l-100 MHz: Dependence on tissue type, NMR frequency, temperature, species, excision, and age. Med. Phys. 11:425448; 1984. 2. Mitchell, D.G.; Burk, D.L. Jr.; Vinitski, S.; Rifkin, M.D. The biophysical basis of tissue contrast in extracranial MR imaging. AJR 149:831-837; 1987. 3. Fleckenstein, J.L.; Weatherall, P.T.; Parkey, R.W.; Payne, J.A.; Peshock, R.M. Sports-related muscle injuries: evaluation with MR imaging. Radiology 172:793798; 1989. 4. Huber, D.J.; Sumers, E.; Klein, M. Soft tissue pseudotumor following intramuscular injection of “DPT”: A pitfall in magnetic resonance imaging. Skeletal Radiof. 16:469-473; 1987. 5. Zagoria, R.J.; Karstaedt, N.; Koubek, T.D. MR Imaging of Rhabdomyolysis. J. Comput. Assist. Tomogr. 10: 268-270; 1986. 6. Pan, Cr.; Raymond, A.K.; Carrasco, C.H.; Wallace, S.; Kim, E.E.; Shirkhoda, A.; Jaffe, N.; Murray, J.A.; Benjamin, R.S. Osteosarcoma: MR imaging after preoperative chemotherapy. Radiology 174:517-526; 1990. 7. Fleckenstein, J.L.; Canby, R.C.; Parkey, R.W.; Peshock, R.M. Acute effects of exercise on, MR imaging of skeletal muscle in normal volunteers. AJR 151: 231-237; 1988. 8. Vanel, D.; Lacombe, M.-J.; Couanet, D.; Kalifa, C.; Spielmann, M.; Genin, J. Musculoskeletal tumors: Follow-up with MR imaging after treatment with surgery and radiation therapy. Radiology 164:243-245; 1987. 9. Ramsey, R.G.; Zacharias, C.E. MR imaging of the spine after radiation therapy: Easily recognizable effects. AJR 144:1131-1135; 1985.
10. Remedios, P.A.; Colletti, P.M.; Raval, J.K.; Benson, R.C.; Chak, L.Y.; Boswell, W.D. Jr.; Halls, J.M. Magnetic resonance imaging of bone after radiation. Magn. Reson. Imaging 6:301-304; 1988. 11. Herfkens, R.J.; Sievers, R.; Kaufman, L.; Sheldon, P.E.; Ortendahl, D.A.; Lipton, M.J.; Crooks, L.E.; Higgins, C.B. Nuclear magnetic resonance imaging of the infarcted muscle: A rat model. Radiology 147:761764; 1983. 12. Polak, J.F.; Jolesz, EA.; Adams, D.F. NMR of skeletal muscle differences in relaxation parameters related to extracellular/intracellular fluid spaces. Invest. Radio/. 23:107-l 12; 1988. 13. Polak, J.F.; Jolesz, EA.; Adams, D.F. Magnetic resonance imaging of skeletal muscle prolongation of T, and T, subsequent to denervation. Invest. Radiol. 23: 365-369; 1988. 14. Moss, W.T.; Cox, J.D. Radiation Oncology: Rationale, Technique, Results. St. Louis: C.V. Mosby Co.; 1989: pp. 88-90. 15. Bloomer, W.D.; Hellman, S. Normal tissue responses to radiation therapy. N. Engl. J. Med. 29:80-83; 1975. 16. Aron, B.S.; Schlesinger, A. Complications of radiation therapy: The genitourinary tract. Semin. Roentgenol. 9: 65-74; 1974. 17. Javadpour, N.; Barakat, H.A. Bladder toxicity due to cyclophosphamide. Experimental induction treatment. Urology 2:634-636; 1973. 18. Sykes, M.P.; Chu, F.C.H.; Wilkerson, W.G. Local bone-marrow changes secondary to therapeutic irradiation. RadioIogy 75:919-929; 1960. 19. Rubin, P.; Scarantino, C.W. The bone marrow organ: The critical structure in radiation-drug interaction. Znt. J. Radiat. Oncol. Biol. Phys. 413-23; 1978. 20. Withers, H.R. Biologic basis for altered fractionation schemes. Cancer 55:2086-2095; 1985.
0730-725x/90 $3.00 + .oo Copyright 0 1990 Pergamon Press plc
1990
@ Original Contribution
CHANGES IN MR SIGNAL INTENSITY AND CONTRAST ENHANCEMENT OF THERAPEUTICALLY IRRADIATED SOFT TISSUE BARRY D. FLETCHER, SOHEIL L. HANNA, AND LARRY E. KUN* Departments of Diagnostic Imaging and *Radiation Oncology, St. Jude Children’s Research Hospital; and Department
of Radiology, University of Tennessee, Memphis, Tennessee 38101, USA
Increased MR signal intensity was observed on T,-weighted, STIR, and Gadolinium-DTPA-enhanced T,-weighted images of subcutaneous and muscular soft tissue in 9 of 10 children treated with combination chemotheraphy and radiation therapy (RT) for malignancy in the pelvis or an extremity. Total radiation doses ranged from 59.5 to 65 Gy. Eight of the patients with these changes received hyperfractionated RT (seven for Ewing sarcoma and one for perineal rhabdomyosarcoma); one was treated for pelvic hemangiopericytoma with once-daily fractions. Evidence of soft tissue damage became apparent as early as the sixth week of RT and was seen for up to 69 wk postRT. There was no clear MR evidence of RT-induced soft tissue damage in one patient, who underwent hyperfractionated RT for pelvic rhabdomyosarcoma. Other MR findings in this group included evidence of bladder wall thickening in three of the seven patients given pelvic RT and increased T,-weighted signal of irradiated marrow in nine patients. All patients had clinical evidence of skin, soft tissue, or epithelial radiation effects. Increased MR signal intensity secondary to RT-induced damage can be differentiated from widespread tumor by geometric borders that conform to the margins of the radiation field. Keywords: Magnetic resonance, contrast enhancement; Magnetic resonance, tissue characterization; Radiation injury/effects; Therapeutic radiology, in infants and children.
INTRODUCTION
diation therapy for malignancies of the pelvis or an extremity, we observed abnormally intense signal, corresponding to the radiation ports, on T2-weighted and short tau inversion recovery (STIR) images, as well as increased signal intensity on T,-weighted images enhanced with Gadolinium-DTPA. Here we describe the clinical, MR imaging, and computed tomography (CT) findings in these patients.
Magnetic resonance (MR) images are exquisitely sensitive to changes in tissue hydration, which alter relaxation times and signal intensity and contrast. ‘*’ Injuries, 3,4 rhabdomyolysis, 5 intraarterial chemotherapy6 and even exercise’ can cause extensive and prolonged MR signal alterations in skeletal muscle. Radiation therapy is known to cause MR signal intensity changes in primary tumors’ and bone marrow.9”o Other tissues in the irradiated field may also be affected. Radiologists should be alert to the possibility of such iatrogenic changes so that misinterpretation of radiation-induced alterations in signal intensity which could lead to overestimates of tumor extent can be avoided. During follow-up MR imaging of children given ra-
METHODS MR imaging was performed as part of routine follow-up in 10 consecutively treated children who received chemotherapy and radiation therapy (RT) for unresectable malignancy in the pelvis or an extremity. The 6 male and 4 female patients ranged in age from
RECEIVED4/2/90; ACCEPTED6/20/90. Acknowledgment-Supported in part by the National Cancer Institute, Cancer Center Support (CORE) grant P30CA21765 and by the American Lebanese Syrian Associated Charities. Presented at the Society for Magnetic Resonance Imaging, 8th Annual Meeting, February 1990, Washington, DC.
Address correspondence to Barry D. Fletcher, M.D., Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, TN 38101, USA.
771
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Magnetic Resonance Imaging 0 Volume 8, Number 6, 1990
5 to 18 yr. Diagnoses included Ewing sarcoma (7 patients), rhabdomyosarcoma (2), and hemangiopericytoma (1). All treatment and MR studies were approved by the institution’s Clinical Trials Committee and informed consent was obtained.
(Mesna) was given with cyclophosphamide and ifosfamide. Nine patients received hyperfractionated and one had conventionally fractionated RT. The seven patients with Ewing sarcoma received total radiation doses of 59.5-60 Gy delivered in twice daily fractions of 1lo-120 cGy over 4-6 wk. Two patients with rhabdomyosarcoma in the bladder and perineum, respectively, were treated with 110 cGy twice daily to 60.5 Gy over a 7-wk period. The final patient, who had pelvic hemangiopericytoma, received conventionally fractionated irradiation, 150-180 cGy once daily to a total dose of 65 Gy over 7 wk. Details of RT are given in Table 1.
Treatment Multiagent chemotherapy was administered to all patients before, during, and after RT according to institutional protocols. This included cycIophosphamide, adriamycin and vincristine, with or without dactinomycin or ifosfamide. In the seven patients who received pelvic irradiation, a uroprotective agent
Table 1. Clinical and MRI findings in patients receiving radiation therapy MRI
RADIATION Patient
Dimis/Site
Daily Fractian
cwmse)
1
Euinglfemr
Total &%I)
120 x 2
Dose
ueeks
Wy)
60
Wll)
2
Euing/prbis
120 X 2
60
(M/17)
Ewing/radius
3
110 x 2
59.5
(F/7)
Ewing/ilium
4
120 x 2
60
U4/24)
5
Euingliliun
120 x 2
60
(F/19)
Ewing/tibia
6
120 x 2
60
(M/13) 7
Euing/ischiun
120 x 2
60
Rhabdomyosarccml
110 X 2
60.5
of
Atncumal Tissue
UT
P 16
+
P 30
+
P 51
+
P 17
+
P 28
+
P 41 P 54
+ +
F 16
+
P 39 P 52
+ +
P
6
+
P 15 P 23
+ +
P 37
+
P 52
+
P 69
+
P 25
+
P 44' P 53
+
P 62
+
+
P 17
+
P 40
+
P 20
+
D
2
0
D
4
D
0
7
0
P 3 P 11
0 +
P 22
+
P 56 P68
0 0
P 74
0
P a7
0
(M/12) a
perineum
(F/12)
9
RhabdmyosarcmW bladder
(F/6)
HemngiopericytcmW
10
Abbreviations: Recurrent
la0 X 1
60.5
65
pubis
(M/16)
l
110 x 2
twr
RT = Radiation
therapy;
P = Post RT; D= During
D
6
+
P
3
+
P 12
+
P 25
+
RT.
Soft
Signal
Soft tissue 0 B.D. FLETCHERET AL.
Imaging Studies All patients had baseline MR imaging prior to therapy. A total of 37 fohow-up MR studies were performed (range, l-6 per patient) which were done after completion of RT (3-87 wk) in eight patients and both during and after RT in two. MR imaging was performed on a 1.O T system (Siemens, Iselin, NJ) using T,-weighted (TE: 15 msec; TR: 0.76 set) and 7”-weighted (TE: 90.0 msec; TR: 2.0-2.5 set) and STIR (TE: 22.0 msec; TI: 150.0 msec; TR: 2.5 set) images. T,-weighted images were then repeated within 15 min after intravenous injection of Gadolinium-DTPA (Magnevist, Berlex Laboratories), 0.2 mL/kg (0.1 mmol/kg), in the majority of studies (26136). The MR examinations were reviewed by two of the authors (BDF, SLH) for abnormalities of tissue signal intensity. Regions with visibly abnormal signal intensity were compared with irradiated volumes based on simulator and port films and dosimetric analyses of the target volumes. In six patients, contrast-enhanced CT scans, performed within l-11 days of a corresponding MR study, were also available. RESULTS On MR studies performed before the initiation of radiation therapy, intensity of the soft tissues adjacent to tumor appeared normal in all patients. The timing and results of subsequent MR studies, as well as details of RT, are given in Table 1. Signal intensity of skeletal muscle continued to appear normal during and after RT on Ti-weighted images. However, T2weighted, STIR, and Gadolinium-DTPA enhanced T,weighted images revealed increased signal intensity of adjacent skeletal musculature in nine of the ten patients. These changes were noted in eight of the nine patients who received hyperfractionated RT (7/7 with Ewing sarcoma and l/2 with rhabdomyosarcoma) and in the one patient treated with single daily RT doses for pelvic hemangiopericytoma. In the latter patient, changes were observed on an MR study 6 wk after the initiation of RT. In the patients given hyperfractionated therapy, MR changes were also seen as early as 6 wk and persisted on subsequent MR examinations up to 69 wk after completion of therapy. In all abnormal cases, the region of altered signal corresponded to the radiation volume and was accompanied by linear strands of edema or fibrosis in the irradiated subcutaneous fat (Figs. 1,2). In one case of Ewing sarcoma of the ilium that recurred 44 wk after completion of RT, signal characteristics of the tumor similar to those of irradiated muscle were present on STIR images (Fig. 3), but the tumor was slightly less
113
intense than irradiated muscle on T2-weighted images. Signal intensity of the external pelvic musculature and subcutaneous soft tissues remained normal in one patient, who was treated to 60.5 Gy for rhabdomyosarcoma and studied from 56 to 87 wk after termination of RT. However, there was a mild increase in signal intensity of perivesicular and perirectal connective tissues on 7”-weighted and STIR images, with slight enhancement with Gadolinium-DTPA, as well as bladder wall thickening. In addition to increased signal intensity of the soft tissues, atrophy of the involved muscles was observed on MR studies of six patients. This finding was present as early as six wk post-RT in one patient. Three of the seven patients who received pelvic irradiation developed bladder wall thickening confined to the irradiated volume. Hematuria was present in one of these patients, in whom MR studies also showed a large, hemorrhagic intravesical clot. Nine of the 10 patients had fatty replacement of irradiated marrow as early as 3 wk post-RT, which appeared on unenhanced Tiweighted images as increased intensity of the irradiated bone marrow. In the remaining patient, the marrow exhibited intense Tr -weighted signal on baseline MR studies, with no further increase in brightness on follow-up MR studies during or after therapy. CT scans, which were obtained in six of the patients with Ewing sarcoma demonstrated abnormalities in four consisting of faint, enhanced reticular densities in the subcutaneous fat visible as early as 15 wk post-RT, but no muscle enhancement could be seen, Muscle atrophy was seen equally well on CT and MR images. Clinically, all patients developed acute, subacute, or late skin or soft tissue manifestations, with fibrosis in three cases. Epithelial changes included hematuria in two patients, both of whom had bladder wall thickening on MR. Proctitis developed in one patient and small bowel reaction in one. Only one patient, in whom Ewing sarcoma recurred one yr post-RT, complained of pain in the irradiated volume. DISCUSSION Radiation-induced alterations of MR signal intensity and enhancement characteristics of skeletal muscle and subcutaneous fat were found in 9 of 10 patients treated for primary tumors of the pelvis or an extremity. The importance of recognizing these findings lies in the possibility that they may be mistaken for neoplasm, thus leading to overestimation of tumor extent. Such errors can usuahy be avoided by noting the geometric rather than anatomic configuration of the involved tissues and by comparing the MR images
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with simulator and port films or dosimetric displays. However, we encountered some difficulty in distinguishing radiation effects from recurrent tumor on STIR images of one patient with Ewing sarcoma of the ilium. The MR findings of increased signal on T2-
weighted, STIR and Gadolinium-DTPA-enhanced T, -weighted images of irradiated soft tissues may reflect minor, usually subclinical, tissue damage with edema or inflammation. These signal changes are consistent with an increase in total water content” and extracellular fluid volume’* of the affected tissues.
D
Fig. 1. Serial MR studies of a patient (no. 4) treated for Ewing sarcoma of the right ilium. On transverse T2-weighted (2.OW90) image before irradiation (A), the musculature and subcutaneous fat appear normal; the slight decrease in intensity of the soft tissues of right pelvis is attributed to artifact. Six wk after completion of RT (B), a transverse T2-weighted image (2.00/90) shows decreased muscle mass in the right pelvis with slight increase in intensity of the right gluteus maximus muscle. T2-weighted image (2.5/90) 15 wk post-RT (C) shows further muscle atrophy and increased intensity; also note reticular areas of increased signal intensity in the subcutaneous fat of the right pelvis, which are probably due to edema and inflammation. Transverse STIR (150/2.50/22) image 23 wk post-RT (D), shows marked increase in brightness of atrophic muscles of the right pelvis. CT dosimetry (E), indicates high dose volumes that correlate with regions of abnormal signal intensity shown in MR images.
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C
Fig. 2. MR studies of a patient (no. 1) treated for Ewing sarcoma of the right femur. Transverse Gadolinium-DTPAenhanced T,-weighted (A), and T,-weighted images (B), 28 wk post-RT show increased intensity of atrophic muscle of the right thigh with well-defined medial border. Coronal STIR image (C), shows geometric pattern of increased brightness corresponding to radiation field shown on port film (D).
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B
Fig. 3. STIR images of patient (no. 5) treated for right iliac Ewing sarcoma. Transverse STIR image 44 wk post-RT (A), shows diffuse increase in signal intensity of atrophic right pelvic musculature masking a recurrent tumor (arrow) of similar intensity. Follow-up transverse STIR image (B), obtained 18 wk later, shows further atrophy of the right pelvic muscle bulk, while recurrent tumor has increased in size. Note interval appearance of left iliac metastases.
The reduced fiber size of grossly atrophic muscles and the consequent expansion of extracellular fluid space13 may contribute to and prolong the MR signal abnormalities. Clinically apparent soft tissue changes during and immediately after irradiation include acute epithelial reactions, often associated with subcutaneous and submucosal edema.14 Subacute effects of irradiation, generally described as beginning two wk to four mo after treatment, are primarily visceral changes related to direct effects on the more slowly regenerated parenchymal cells. Other subacute soft tissue changes, clinically apparent as “cellulitis-like” events, have been described anecdotally’4 and clinical effects of radiation on normal tissues are well documented. I5 Clinical changes related to hemorrhagic cystopathy and uroepithelial alterations have been documented both during and immediately following RT.“j Hemorrhagic cystitis has also been associated with both cyclophosphamide and ifosfamide,” which the majority of our patients received. The volume-related bladder wall thickening apparent in three patients in our series suggests a combined urodisruptive effect of chemotherapy and irradiation. Fatty replacement of radiation-depleted hematopoietic tissue is also well known’8p19 and the MR findings associated with this process in our patients were similar to those previously described.‘*” Fractionation schemes are used in radiation oncology in an effort to reduce the effects of radiation on normal tissues while delivering maximal doses to the tumor.20 Hyperfractionated RT involves the use of
more than one daily fraction, with each considerably smaller than a conventional 180-200 cGy once-daily dose. In early clinical experience, hyperfractionation has been associated with acute epithelial reactions. However, increased subacute effects on normal tissue have not been predicted or well described to date. There are no published data comparing the effects of conventional and hyperfractionated irradiation. The degree of soft tissue changes documented within the target volume after irradiation may reflect enhanced tissue changes due to hyperfractionated RT or accelerated effects of hyperfractionated RT on normal tissue. However, we also observed early, extensive soft tissue changes within the target volume of the single patient in this series who received conventional RT. The absence of abnormal signal intensity in the irradiated external pelvic musculature and subcutaneous tissues on MR images of one patient who received hyperfractionated RT was somewhat surprising. This patient had clinically evident skin and epithelial changes, as well as bladder wall thickening, fatty replacement of hematopoietic marrow, and MR imaging findings attributed to mild edema of internal pelvic connective tissues. The fact that MR images were not obtained until more than one yr after completion of RT might account for the lack of signal abnormalities in the irradiated muscles, although these changes were seen at later assessment times in other patients. This study however, indicates that, in the majority of patients receiving RT for malignant musculoskeletal tumors, changes in MR signal intensity corresponding to the irradiation field are to be expected.
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