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Original Research |
1 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
2 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan
University School of Medicine, 50 Ilwon-Dong, Kangnam-Gu, Seoul 135-710,
Korea.
3 Department of Preventive Medicine, School of Medicine, Kyung Hee University,
Seoul, Korea.
Received January 4, 2008;
accepted after revision April 19, 2008.
Address correspondence to S. J. Huh
(sj5201.huh{at}samsung.com).
Abstract
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MATERIALS AND METHODS. Two radiologists retrospectively evaluated pelvic MR images of 510 patients (mean age, 54.7 years) who underwent pelvic irradiation for uterine cervical cancer for the presence and location of insufficiency fractures by consensus. We calculated the cumulative prevalence of pelvic insufficiency fractures on the basis of their results. In addition, we identified other associated bony complications of the female pelvis by reviewing the MR images.
RESULTS. Insufficiency fractures were diagnosed in 100 patients; the 5-year cumulative prevalence was 45.2%. An insufficiency fracture was diagnosed a median of 16.9 months after radiation therapy. The fracture sites were the sacrum body and alae, medial side of the iliac bone, the roof of the acetabulum, superior rami of the pubic bone, femoral heads, and L5 vertebra. Sixty-one patients (61%) developed multiple fractures, and among them, 40 (40%) had bilateral symmetric lesions of the sacral alae. Other complications associated with the radiation therapy, as determined by evaluation of the MR images, were osteolysis and avascular necrosis of the femoral head.
CONCLUSION. Radiation-induced pelvic insufficiency fractures are a frequent complication of radiation therapy for uterine cervical cancer. Osteolysis and avascular necrosis of the femoral head were also diagnosed using MRI after radiation therapy.
Keywords: MRI • oncologic imaging • pelvic insufficiency fracture • radiotherapy complications • uterine cervical cancer • women's imaging
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The findings on conventional radiographs are usually subtle and may be misleading. However, the fractures usually show increased uptake on radionuclide bone scans. A pattern of increased uptake in the body of the sacrum and in one or both sacrum alae [2–4] is indicative of a fracture, but increased uptake may also be present in metastases and sacroiliac joint osteoarthritis [8]. The importance of understanding a pelvic insufficiency fracture lies in the potential for its misdiagnosis as bony metastases.
MRI is highly sensitive for revealing the reactive bone marrow changes associated with insufficiency fractures [5, 9, 10]. In addition to pelvic insufficiency fracture, other complications associated with radiation therapy have been reported including radiation osteitis and osteolysis [11, 12]. The purpose of this study was to assess the prevalence, distribution, and MRI findings of radiation-induced insufficiency fractures and to investigate other complications of the female pelvis associated with radiation therapy using MRI. The number of the enrolled MR studies in this study is the largest reported in the literature to our knowledge, and we included patients with MR studies obtained before radiotherapy to exclude the possibility of pre-treatment insufficiency fractures.
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A retrospective analysis was conducted in the remaining 510 patients who had MR studies before and after radiation therapy. Their ages at the time of radiation therapy ranged from 40 to 84 years, with a mean age of 54.7 years. One hundred ninety-two patients (37.6%) had previous surgery and 193 patients (37.8%) received concurrent chemotherapy. Concurrent chemother apy consist ed of cisplatin (60 mg/m2, x1) and 5-fluorouracil (1,000 mg/m2/d, x5) every 3 weeks; or cisplatin (30 mg/m2) weekly. None of the patients received corticosteroids. MRI was performed after radiation therapy to evaluate and rule out recurrence of the primary cancer and metastases. The median follow-up period was 14 months (range, 1–109 months). Whether patients developed pain was determined by reviewing hospital records.
All patients were treated using external beam radiation therapy with a median dose of 50.4 Gy (range, 30.6–66.6 Gy) in 1.8-Gy fractions for 5 days each week using 10- or 15-MV x-rays. The external dose was individualized according to tumor size, lymph node involvement, and the patient's performance status. The general whole-pelvis fields prescribed were as follows (Fig. 1A, 1B): The superior border was the L5–S1 vertebral level in patients with negative pelvic nodes and L4–L5 in patients with positive pelvic nodes. The inferior border was at the bottom of the obturator foramen or 2–3 cm below the lowest extent of cervical or vaginal disease. The lateral borders were placed approximately 1.5–2 cm lateral to the inner bony margins of the true pelvis. For the lateral fields, the anterior border included the anterior one third of the symphysis pubis, and the posterior border was usually located at the S2–S3 junction and was modified according to the extent of disease. Intracavitary brachytherapy with a high dose rate (microSelectron-HDR, Nucletron) of 24 Gy in six fractions was conducted twice each week in 315 patients (61.8%). A tandem and two ovoids were used for intracavitary brachytherapy. A parallel opposing anteroposterior–postero anterior field technique was used in 103 patients (20.2%) and a four-field box technique in 407 patients (79.8%).
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We retrospectively reviewed 510 pelvic MR studies (502 studies with 1.5-T units and eight studies with 3-T units) obtained before radiation therapy and 1,113 MR studies (956 studies with 1.5-T units and 157 studies with 3-T units) obtained after radiation therapy in 510 patients. MR image sets obtained before and after radiation therapy were evaluated together by two investigators who were not aware of the patient's clinical symptoms, radiation dose, and other clinical data. The reviewers were aware of the history of radiation therapy. Images obtained with different sequences during one MR examination were reviewed together as a group.
Bone marrow irradiation led to zones of red marrow depletion. The zones appeared on T1-weighted images as areas of high signal intensity [9]. Reactive bone marrow change associated with insufficiency fracture was noted by low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Insufficiency fracture on MR examination was diagnosed if linear low signal intensity on T2-weighted and contrast-enhanced T1-weighted images was accompanied by hypointense reactive bone marrow change on T1-weighted images. The loca tion and characteristics of the areas of abnormal marrow signals and the presence of a low-intensity line were reviewed.
We investigated other bone complications and their prevalence after radiation therapy by reviewing the MR images. Osteolysis of the symphysis pubis or sacroiliac joint and avascular necrosis of the femur head were noted. Osteolysis was defined as a widening with sclerotic changes and joint fluid within the symphysis pubis or sacroiliac joint. Avascular necrosis of the femur head was diagnosed if there was a geographic subchondral lesion with or without the double line sign in the anterosuperior portion of the femoral head.
We investigated the cumulative prevalence of pelvic insufficiency fractures using Kaplan-Meier methods. To account for variability of entry into the study and variability of follow-up, we derived a Kaplan-Meier estimate. The time of onset was defined as the time when a pelvic insufficiency fracture was detected on MR images. A software package (SPSS, version 14, SPSS) was used for statistical calculations.
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Osteolysis (Fig. 7A, 7B) was detected in four patients (0.8%): in the symphysis pubis in three and in the right sacroiliac joint in one. Avascular necrosis of the femoral head (Fig. 6B) was diagnosed in two patients (0.4%). Both had avascular necrosis of the left femoral head and were treated with conservative management. The femoral heads appeared normal on MR images obtained before treatment, and neither patient had risk factors such as trauma or alcoholism. Biopsy to confirm the pelvic insufficiency fracture was not performed in any of the patients in our series because a biopsy would have put the patients at risk for overt fracture.
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Concurrent chemotherapy is used frequently in treating patients with gynecologic cancer for increasing tumor control, but it is known that chemotherapy also increases the toxicity of radiation [17]. The results of our previous study [18], however, showed that the use of concurrent chemotherapy did not affect the development of pelvic insufficiency fracture. In this study, we also found that the prevalence of pelvic insufficiency fracture in patients undergoing concurrent chemotherapy (33/193, 17.1%) was not significantly higher than that of patients not undergoing concurrent chemotherapy (67/317, 21.1%). In the current study, we did not investigate the risk factors of pelvic insufficiency fracture after pelvic radiation therapy.
Radiation has a direct effect on bone and an indirect effect associated with vascular changes [19]. A reduction in the number of osteoblast cells after irradiation is associated with decreased collagen production and alkaline phosphatase activity. Because both collagen and alkaline phosphatase play a role in mineralization, researchers have proposed that this is a pathway to osteopenia [20]. One of the main factors responsible for the late effects of irradiated bone is an injury to the microvasculature of mature bone. Microcirculation occlusion ultimately results in an increased susceptibility for insufficiency fractures. Mature bone tolerates doses in the 65- to 70-Gy range (tolerance dose 5% complication in 5 years to tolerance dose for 50% complication in 5 years). Conventional pelvic irradiation with megavoltage equipment uses radiation doses to the pelvic bone that do not exceed the tolerated dose [21]. Because megavoltage equipment with a reduced absorbed dose in the bone is used, radiation-induced pelvic insufficiency fracture is expected to be a rare complication compared with radiation-related injuries to the rectum or bladder [22]. However, bone complications remain an important late sequela of radiation treatment.
Although postirradiation fractures of the pelvis have been reported frequently in the past, the prevalence of pelvic insufficiency fracture after radiation therapy is not certain [2, 3, 23]. The time to develop a pelvic insufficiency fracture from radiation therapy is between 1 and 190 months and is unpredictable [24, 25]. Several groups of researchers report the prevalence of symptomatic pelvic fractures to be 3–6% [24, 25]. Abe et al. [4] retrospectively reviewed bone scintigraphy results in 80 patients with uterine cervical cancer who underwent radiation therapy; pelvic insufficiency fractures were identified in 27 patients (34%). However, Blomlie et al. [5] reported the prevalence of radiation-induced pelvic insufficiency fracture as 16 (89%) of 18 patients who had radiation therapy of the pelvis, prospectively based on MRI.
Pelvic insufficiency fractures are considered to be increasing in number as our population ages. Insufficiency fractures occur when the elastic resistance of bone is inadequate to withstand the stress of weight bearing. The sacrum, sacroiliac joints, and medial parts of the iliac bones are the major weight-bearing structures of the body. Bone displacement at the fracture sites may occur in neglected cases. A pelvic insufficiency fracture may occur first in the sacrum, which is the site of direct transfer of weight-bearing forces in the spinal column [26]. Sacral insufficiency fractures are often bilateral and may course vertically or slightly obliquely in the alae just lateral to the margins of the lumbar spine. This distribution suggests that the weight of the body transmitted through the spine may be at least partially responsible for the fractures [3]. With continued stress, a transverse sacral fracture may develop. Visualization of additional fractures in the roof of the acetabulum, the superior pubic rami, and the lumbar spine is expected. The results of our study also showed one insufficiency fracture after radiation therapy at the right ischium and three fractures at the femoral heads.
Many pelvic insufficiency fractures are multiple, and coexistence of fractures at different sites is in accordance with the findings from previous studies of radiation-induced alterations of the bony pelvis [2–4]. Identification of one type of insufficiency fracture on MRI in the pelvis should alert the radiologist to look for other fractures. The significance of pelvic insufficiency fractures is that they can be misdiagnosed as bone metastases, and consequently, patients may undergo inappropriate treatment. Clinical suspicion is necessary for accurate diagnosis and patients who have undergone pelvic irradiation due to pelvic cancer must be carefully assessed when pain arises.
A pelvic insufficiency fracture on conventional radiography is usually subtle and radiographic findings may be misleading. Bone scans show increased radionuclide uptake at one or more foci at the sacroiliac joint or the sacrum in most cases of pelvic insufficiency fracture. The foci are sometimes distributed bilaterally and symmetrically at both sacroiliac joints, with a characteristic H or butterfly appearance [8]. A bone scan is very sensitive for the detection of an area of increased radionuclide uptake, but it is less specific. CT is also an appropriate method for the differential diagnosis of bone metastases; it shows fracture lines in many cases of pelvic insufficiency fractures [2]. Pelvic insufficiency fractures are not associated with osteolytic lesions or soft-tissue growth, which are common in metastatic disease [3].
The results of this study showed a relatively higher prevalence of pelvic insufficiency fractures compared with previously reported data [3, 7, 21, 23, 27], in which researchers used CT and bone scanning to diagnose insufficiency fractures. Our study was performed using MR images; MRI is highly sensitive for the detection of pelvic insufficiency fractures. In addition, we included asymptomatic patients as well as patients with pelvic pain. The results of our previous study [18] showed that the 5-year cumulative prevalence of pelvic insufficiency fractures was 19.7%. However, that study included patients who had 6 months or more of follow-up and had undergone MRI, CT, or bone scanning.
MRI is sensitive for depicting early medullary change and frequently shows a fracture line in a typical location associated with insufficiency fractures [5, 9, 10, 16, 28]. When a fracture is present, there is also diffuse reactive bone marrow change. In 89% of these cases, there are abnormalities on the MR images, with low signal intensity on T1-weighted images and high signal intensity on STIR images [5]. These abnormalities are typical of metastatic disease too, but the presence of fracture lines—linear low signal intensity on T1-weighted and STIR images and no focal or discrete mass lesion—helps establish the diagnosis. MRI is useful for evaluating the soft-tissue component of bone marrow after irradiation.
When benign and malignant changes cannot be differentiated on CT and bone scans, MRI may be helpful. Except an initial reactive bone marrow change, which may be present during the first 2 weeks after the start of therapy [29], marrow changes in the irradiated bone reflect replacement of cellular bone components with fat [30], which is seen as high signal intensity on T1-weighted images. Signal intensity is reversed in patients with insufficiency fractures after irradiation: It is low on T1-weighted images and high on T2-weighted images. This reversal is related to the diffuse reactive bone marrow change resulting from a fracture. Linear areas of abnormal signal intensity are particularly suggestive of a fracture [11].
Because of the reciprocal signal intensities of fat and water, MRI is well suited for the detection and follow-up of radiation-induced insufficiency fractures [9]. We diagnosed the insufficiency fractures in our study using T2-weighted and contrast-enhanced T1-weighted images. However, unenhanced T1-weighted images are helpful for the detection of hypointense reactive bone marrow change associated with insufficiency fracture [5]. We found that it was sometimes difficult to detect the fracture line on unenhanced T1-weighted images because of reactive bone marrow change associated with the fracture, which was also low signal. The use of contrast material helped us see the fracture lines. We noted the fracture lines on T2-weighted and contrast-enhanced T1-weighted images.
An erroneous diagnosis of metastasis to the sacrum could lead to an unnecessary biopsy or to further irradiation or aggressive chemotherapy, which could be harmful to the patient. Biopsy of a lesion is not recommended because of the high probability of fracture and the low diagnostic efficiency [7, 31]. The histologic findings of the lesions biopsied showed hemorrhage, fibrosis, necrotic bone fragments, and trabecular bone and cartilage growth. Consequently, pelvic insufficiency fracture may be misdiagnosed with an inadequate biopsy specimen as osteomyelitis or a tumor such as enchondroma, osteosarcoma, or chondrosarcoma [26]. Pelvic insufficiency fractures and bone metastases can be diagnosed using CT and MRI and can be confirmed by observing the clinical course thereafter. Knowledge of a pelvic insufficiency fracture is essential to rule out bone metastases and to prevent inaccurate treatment [3, 11, 32].
Our patients were imaged on 1.5- or 3-T platforms; 3-T units have been operated in our institution since November 2004, and fewer MR studies were performed using 3-T units than 1.5-T units. Thus, we could not evaluate the difference in detection rates for insufficiency fractures between platforms. It would be interesting to know whether there is any difference in detection rate for insufficiency fracture.
The term "radiation osteitis" refers to a radiation-induced inflammatory response in the blood vessels, nerve tissue, and bone cells that may lead to a fracture of trabecular and cortical bone. Radiation osteitis of the pelvic bone has been characterized by mixed areas of dense sclerotic bone together with zones of focal demineralization [33]. The findings of radiation osteitis were previously reported using conventional radiography and CT [23, 24, 33]. To our knowledge, there is only one study on radiation osteitis of the pelvic bone with MR images [12]. The results of that study showed that radiation osteitis was diagnosed on the basis of findings of diffuse low signal intensity without linear low-signal lines suggestive of a fracture on T1-weighted images and very low or mixed signal intensity on T2-weighted images [12]. However, we could not differentiate radiation osteitis from an insufficiency fracture with a callus formation using MR images. The two patients with radiation osteitis in the previous study [12] also had insufficiency fractures.
Osteolysis is uncommon and results from a paraarticular insufficiency fracture associated with osteopenia and radiation therapy. Our study population included only four cases of osteolysis, three in the symphysis pubis and one in the right sacroiliac joint. Osteolysis is characterized by radiographic findings of rapidly progressing destructive changes in the symphysis pubis or sacroiliac joint [34]. The presence of an excessive and ineffectual callus suggests an attempt of the fracture to heal with the appropriate osteoblastic response but with a disproportionate osteoclastic response [34]. The MRI findings of osteolysis are cleft-like with an elongated bright signal area suggesting a "fluid collection" within the fracture gap and the absence of contrast enhancement [35]. Knowledge of this MRI pattern is important to avoid an erroneous diagnosis of bone metastases or osteomyelitis.
Irradiation can kill osteoblasts, osteocytes, and osteoclasts and leaves an acellular matrix [11]. Vascular damage can cause progressive ischemic changes that further weaken bone structure. Radiation-induced avascular necrosis can affect any irradiated bone, probably because of injuries to the microvasculature of the mature bone. This injury results in microcirculation occlusion and, consequently, in injury to the periosteal vasculature [7].
There were some limitations of our study. First, our study was retrospectively performed. The follow-up period was inconsistent (range, 1–109 months) and the number of follow-up MR studies for each patient varied (range, 1–8). This might have led to underestimation of the true prevalence of pelvic insufficiency fracture. In addition, we could not evaluate the presence, prevalence, and severity of osteoporosis in patients before treatment.
Second, our study was performed with only MR images. Many patients with CT or bone scans were excluded. However, if we had included patients with only CT or bone scans in this study, the prevalence of pelvic insufficiency fracture would have been lower than the prevalence reported because of the lower sensitivity of CT and the lower specificity of bone scanning for insufficiency fracture.
Third, we did not obtain STIR images and fat suppression was not routinely used for the contrast-enhanced T1 sequences. STIR imaging is the best pulse sequence to show insufficiency fractures [5, 30], but we did not use this technique because the MR images in our study were obtained for routine follow-up to evaluate and rule out recurrence of the primary cancer and metastases after radiation therapy and was not intended for identification of insufficiency fractures. STIR imaging does not provide good contrast between gynecologic organs and the surrounding tissues. Contrast-enhanced images with fat suppression would have been helpful in increasing the conspicuity of insufficiency fractures, metastases, and pelvic soft-tissue edema. We have used fat suppression for the contrast-enhanced T1-weighted images on the 3-T units since 2005.
Fourth, our study had no control group and the observers who assessed the MR images were aware of the patients' history of radiation therapy. In particular, we did not control for other variables such as osteoporosis in our study.
Fifth, there is no tissue proof that a pelvic insufficiency fracture is indeed just that and not a pathologic fracture within a metastatic or other bone lesion. As we mentioned earlier, however, biopsy of a lesion is not recommended because of the high probability of fracture and low diagnostic efficiency [7, 31].
In conclusion, radiation-induced pelvic insufficiency fractures are a frequent complication of standard radiation therapy for uterine cervical cancer. If patients complain of pelvic pain after whole-pelvis radiation therapy for gynecologic malignancies, a pelvic insufficiency fracture must be considered in the differential diagnosis. Knowledge of the characteristic imaging patterns of insufficiency fractures is essential to rule out bone metastases and thus avoid inappropriate treatment. In addition to a pelvic insufficiency fracture, osteolysis and avascular necrosis of the femoral head can develop after radiation therapy.
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