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1
Department of Radiology, Seoul National University College of Medicine, 28
Yongon-dong, Chongno-gu, Seoul 110-744, Korea.
2
Clinical Research Institute, Seoul National University Hospital, 28
Yongon-dong, Chongno-gu, Seoul 110-744, Korea.
3
Research Laboratories of Schering AG, D 13342, Berlin, Germany.
Received October 28, 1999;
accepted after revision December 20, 1999.
Supported in part by a grant from Schering AG.
Abstract
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MATERIALS AND METHODS. VX2 carcinoma was inoculated into 24 rabbit thighs. T1-weighted contrast-enhanced MR imaging with IV gadopentetate dimeglumine (2-min delay) and gadolinium mesoporphyrin (20-hr delay) was performed 3-4 days (n = 6), 6-7 days (n = 6), 10-11 days (n = 5), and 13-14 days (n = 7) after the implantation of VX2 carcinoma. All tumors were sectioned along the same plane of MR images, and a detailed MR imaging-histopathologic correlation was performed.
RESULTS. Pathologically, areas enhanced with gadolinium mesoporphyrin included necrotic tissue, viable tumor, inflammatory granulation tissue, hemorrhage, and fibrosis. On gadopentetate dimeglumine-enhanced MR images, unenhanced areas of the tumor corresponded with intratumoral necrosis and hemorrhage.
CONCLUSION. Gadolinium mesoporphyrin enhances tumor necrosis on delayed phase MR imaging; however, it is impossible to specifically depict necrosis with gadolinium mesoporphyrin because it also enhances other parts of lesions, including viable tumor.
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IV contrast media for MR imaging can be classified into three types: extracellular, blood-pool, and intracellular contrast agents. Gadopentetate dimeglumine is a representative extracellular agent, which rapidly diffuses out of the vascular compartment into the extracellular interstitial space. To enhance specific organs or diseases, contrast agents bind to or are absorbed by specific cells. Currently, researchers are exploring the use of intracellular or cell-bound contrast agents to depict hepatocytes, the reticuloendothelial system, lymph nodes, specific tumor tissue, or antigens [1]. Today, one area of research includes the use of porphyrin derivatives for the diagnosis and treatment of malignant tumors [2,3,4,5,6]. Also, paramagnetic metalloporphyrins, a variety of porphyrins and analogs chelated with paramagnetic metal ions, are being evaluated as promising intracellular contrast agents for MR imaging. Although the tumor specificity of porphyrins has been widely accepted, this is not true for that of metalloporphyrins. Some researchers report that metalloporphyrins are tumor-specific [7,8,9,10,11,12,13,14,15]; however, scientific evidence to support these claims is lacking. The enhancement of a tumor is not proof of tumor-specific accumulation. Gadopentetate dimeglumine elicits tumor enhancement but it is not tumor specific. Some porphyrins used in photodynamic therapy elicit some tumor-specific accumulation [2,3,4,5,6]. However, recent experimental studies suggest that metalloporphyrins do not reveal any specific accumulation in viable tumor tissue but show delayed and persistent enhancement in nonviable intratumoral components such as necrosis [16, 17]. These researchers also report that metalloporphyrins enhance several types of induced benign necrosis and infarcted myocardium [17,18,19]. Therefore, further studies are required to confirm their results, which were contradictory to prior results, and seek applications of metalloporphyrins using their strong affinity for nonviable tissues.
We determined the enhancement features of experimentally induced malignant tumors on gadolinium mesoporphyrin-enhanced MR imaging. Also, we performed a detailed histopathologic correlation of gadolinium mesoporphyrin-enhanced areas with those of standard contrast material (gadopentetate dimeglumine) on MR images.
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VX2 carcinoma is a rapidly growing anaplastic tumor that was originally developed in the 1930s as a transformation of virus-induced rabbit papilloma [20]. This tumor usually contains necrosis and is moderately firm and lobulated with little capsule formation [21, 22]. VX2 carcinoma was serially implanted in the thighs of carrier New Zealand white rabbits. After 14-21 days, the tumor was surgically removed and placed in calcium- and magnesiumfree Hanks balanced salt solutions (Grand Island Biological, Grand Island, NY). Tumor tissue was diced into approximately 1-mm3 fragments and suspended in 5 ml of Dulbecco's modified eagle medium/F-12 (Life Technologies, Grand Island, NY). VX2 carcinomas were then implanted in the bilateral thighs of each animal using a 16-gauge needle.
To make models with various degrees of tumor necrosis, we injected VX2 carcinoma into four groups of rabbits and then performed MR imaging at different time intervals: group A (n = 8) underwent imaging after 3-4 days, group B (n = 6) after 6-7 days, group C (n = 5) after 10-11 days, and group D (n = 7) after 13-14 days.
Contrast Agents
Gadolinium mesoporphyrin (Gadophrin-2; Schering, Berlin, Germany) is a new
porphyrinmetal compound with improved proton relaxivity and dedicated
pharmacokinetics. In gadolinium mesoporphyrin, two gadopentetate dimeglumine
moieties are covalently linked to the side chains of mesoporphyrin. Therefore,
the enhancing properties of gadolinium mesoporphyrin and gadopentetate
dimeglumine can differ greatly, even if they are used at the same dose.
Detailed characteristics of gadolinium mesoporphyrin have been described by Ni
et al. [16]. Gadolinium
mesoporphyrin was administered IV at a dose of 0.05 mmol/kg as recommended by
Schering research laboratories. Gadopentetate dimeglumine (Magnevist;
Schering) was used as a nonspecific control.
MR Imaging
The same anesthetic regimen used for tumor implantation was used for MR
imaging. The ear vein of the rabbit was cannulated with a 22-gauge infusion
set connected to a 1-ml tuberculin syringe loaded with contrast material. Then
the rabbits were fixed in the supine position on a board made of rigid
paper.
MR imaging was performed on a 1.0-T system (Magnetom Expert; Siemens, Erlangen, Germany) with a knee coil. All images were obtained in the axial plane. In all sequences, we used an asymmetric field of view of 113 x 150 mm, a section thickness of 7 mm, a matrix size of 113 x 256, and an intersection gap of 20%. T1-weighted MR imaging was performed with a spin-echo technique, a TR/TE of 500/20, and three excitations. T2-weighted MR imaging was performed with a spin-echo technique, a TR/TE of 2000/70, and two excitations. MR imaging was performed over a 2-day period because a long delay time was required for gadolinium mesoporphyrin-enhanced MR imaging.
After unenhanced spin-echo T1- and T2- weighted MR imaging, additional spin-echo T1-weighted MR images were obtained 2 min after the IV injection of gadopentetate dimeglumine (0.15 mmol/kg). After the first day of MR imaging, gadolinium mesoporphyrin (0.05 mmol/kg) was injected IV. Gadolinium mesoporphyrin spinecho T1-weighted delayed MR imaging was performed 20 hr after injection.
Pathologic Examination
Immediately after we performed MR imaging, the rabbits were sacrificed with
an IV injection of thiopental sodium (Pentothal; Choong Wae Pharmacy, Seoul,
Korea) and frozen in the refrigerator at a temperature of -70°C. After
several days, we cross-sectioned frozen rabbit thighs using an electrical saw.
We cut 5- to 7-mm slices along the same plane of MR imaging. In each tumor, we
selected a representative section, which included the largest part of the
tumor and was well matched with corresponding MR images. After the tissue
sections were photographed, they were fixed with 10% formalin and processed
with H and E staining on large microscopic slides (5 x 7.5 cm or 7.5
x 10 cm). Histopathologic findings of the tumor were correlated with MR
imaging findings by the consensus opinion of two radiologists and a
pathologist, with particular emphasis on the enhanced area of the images.
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The cut surface of the tumors revealed a whitish-gray firm tumor containing a variable degree of brownish or whitish yellow suggestive of necrosis in the central portion of the tumor. On microscopic examination, tumor cells of VX2 carcinomas were undifferentiated, with a high degree of pleomorphism. Cancer cells were arranged in broad sheets, cords, or small acinar-like structures. In the early phase of necrosis, mosaic patterns were accompanied by an admixture of small areas of necrosis and viable neoplastic cell nests and a few inflammatory cells infiltrated among the tumor cell arrangements. In the late phase of necrosis, degenerating neoplastic cells were scattered with a marked degree of infiltrated inflammatory cells. Later, necrotic areas filled with degenerated tumor cells appeared as amorphous eosinophilic areas with or without calcifications; these areas were sometimes lost during slide preparation. Fibrous capsules surrounding the tumors were found in all tumors in groups C and D and four tumors in group B. Fibrous septa within the tumor were visible in six tumors in group D, four in group C, and one in group B.
MR Imaging Findings
All 24 tumors appeared slightly hyperintense on T1-weighted MR images and
strongly hyperintense on T2-weighted MR images. The enhancement pattern of
gadolinium mesoporphyrin and gadopentetate dimeglumine was variable, as
summarized in Table 1.
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In group A, five of six tumors revealed diffuse enhancement in the entire lesion by both contrast agents (Fig. 1A,1B,1C,1D). In one tumor, diffuse enhancement was visible on gadolinium mesoporphyrin-enhanced MR images, whereas gadopentetate dimeglumine enhanced only the periphery of the lesion. In group B, the most common enhancement pattern was a combination of peripheral rim enhancement by gadopentetate dimeglumine and peripheral rim enhancement with central diffuse mild enhancement by gadolinium mesoporphyrin, which was found in three of six tumors (Fig. 2A,2B,2C,2D). In groups C and D, the most common enhancement pattern was a combination of diffuse enhancement by gadolinium mesoporphyrin and diffuse enhancement with irregular unenhanced defects by gadopentetate dimeglumine, which was found in six of 12 tumors (Fig. 3A,3B,3C). Hyperintense areas on T2-weighted MR imaging corresponded with areas of enhancement by gadolinium mesoporphyrin (Fig. 2A,2B,2C,2D).
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MR Imaging—Histopathologic Correlation
The histopathologic features of enhancement patterns of gadolinium
mesoporphyrin and gadopentetate dimeglumine are summarized in
Table 2. Areas with diffuse
enhancement by both contrast agents (n = 9) were viable tumor cells
with infiltrating growth and variable degrees of inflammation and pathologic
fibrosis. Small necrotic foci were visible in two tumors. Enhanced areas of
both contrast agents included areas of viable tumor cells, inflammation, and
fibrosis (Fig.
1A,1B,1C,1D).
We were unable to differentiate viable tumor from inflammation and fibrosis by
evaluating enhancement patterns on MR imaging.
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For imaging with peripheral rim enhancement by gadopentetate dimeglumine and rim enhancement with central mild diffuse enhancement by gadolinium mesoporphyrin, the peripheral rim corresponded with the capsule composed of fibrosis and inflammatory granulation tissue and the central portion corresponded with pathologic necrosis. Viable tumor cells were present in the capsules of two tumors and manifested as a focal thickening of the peripheral rim (Fig. 2A,2B,2C,2D).
Tumors with diffuse enhancement by gadolinium mesoporphyrin and diffuse enhancement with irregular central defects by gadopentetate dimeglumine corresponded with tumors containing viable tumor cells, fibrous capsules, and variable degrees of necrosis and hemorrhage. Unenhanced areas on gadopentetate dimeglumine-enhanced MR images represented areas of necrosis or hemorrhage (Fig. 3A,3B,3C). Gadolinium mesoporphyrin nonspecifically enhanced necrosis, hemorrhage, viable tumor cells, fibrosis, and inflammation.
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Currently, researchers are evaluating paramagnetic metalloporphyrins as promising tumor-seeking contrast agents for MR imaging. At first, manganese porphyrins were preferred because of greater relaxivities than ferric derivatives and greater complex stability than gadolinium porphyrins [1, 23, 24]. Tumor enhancement with manganese tetra (4-sulfonatophenyl) porphyrin was revealed in human-mouse xenograft models of lymphoma, fibrosarcoma, and carcinoma [7]. Tumor enhancement with manganese tetra (4-sulfonatophenyl) porphyrin also appeared in experimental human tumor xenografts in nude mice [8,9,10] and experimental rat and cat brain tumors [11,12,13]. Later, metalloporphyrins chelated with gadolinium tetra (4-sulfonatophenyl) porphyrin [14, 15] and gadolinium texaphyrin were developed and used for the evaluation of experimental tumors [25, 26]. The contrast agent used in our study, gadolinium mesoporphyrin, is a metalloporphyrin with enhanced proton relaxivity compared with other porphyrins. In gadolinium mesoporphyrin, two gadopentetate dimeglumine moieties are covalently linked to the side chains of the mesoporphyrin; therefore, the proton relaxivity is superior to that of previously used agents.
Many studies have reported the uses of metalloporphyrins. A recent study using rats with hepatic tumors by Ni et al. [16] suggested that metalloporphyrins bind with nonviable intratumoral components such as necrosis, thrombosis, and cystic secretions but not with viable tumor tissue. Additionally, another group of researchers report that metalloporphyrins enhance various types of induced benign necrosis [18]. Moreover, some researchers report the usefulness of metalloporphyrins for the evaluation of myocardial infarction [17, 19, 27]. Finally, one article reported a new application of metalloporphyrins in the evaluation of cerebral infarction [28].
Contrast material is also used in the evaluation of tumor necrosis (e.g., tumor staging and therapy control). MR imaging allows the characterization of tumors on the basis of signal intensity characteristics, morphologic features, or both. Necrosis is one of the morphologic features of tumors. Moreover, necrosis of tumors can be used as a tumor grade predictor or as a prognostic indicator of patients with malignant tumors that develop after various kinds of treatment [21]. Recent developments in techniques such as percutaneous ethanol injection therapy, cryotherapy, and radiofrequency ablation have increased the importance of imaging in depicting necrotic areas of tumors.
In this study, we induced VX2 carcinoma in four groups of rabbits. Each group developed a different degree of necrosis because of different inoculation times. Because VX2 carcinoma revealed necrosis in early-stage tumors, it could be used to study the progression of necrosis in tumors. Because we made cross sections of frozen rabbit thigh at the same plane as that of MR imaging, we correlated gadolinium mesoporphyrin-enhanced areas within those of gadopentetate dimeglumine.
Although we noted that necrotic areas in the tumor were enhanced with gadolinium mesoporphyrin on 20-hr delayed images, gadolinium mesoporphyrin did not specifically bind to necrosis. Gadolinium mesoporphyrin also enhanced viable tumor tissue, inflammatory cell opacities, hemorrhage, and fibrotic capsules or septa. Therefore, it was impossible to specifically detect necrotic areas.
The results of our study are inconsistent with those of the study by Ni et al. [16], who reported that, in a rat model, gadolinium mesoporphyrin and a manganese tetra (4-sulfonatophenyl) porphyrin derivative enhanced nonviable tumor tissue but not viable tumor tissue. The cause of this difference is unclear, but we think that the delayed enhancement pattern of gadolinium mesoporphyrin might be different in animal and tumor models. Because prior studies reporting tumor enhancement of metalloporphyrins [7,8,9,10,11,12,13,14,15] are consistent with our study, we assume that induced hepatocellular carcinomas and implanted Novikoff hepatomas in rats, which were used in the study of Ni et al. [16], probably have different enhancement patterns than those of VX2 carcinoma.
Robinson et al. [29] performed a similar experimental study using VX2 carcinoma in rabbit livers. These researchers found that the tumor was mildly enhanced, whereas the liver parenchyma was strongly enhanced on 60- to 90-min delayed manganese mesoporphyrin-enhanced MR images. We think that the differences result from differences in delay time after contrast injection, implanted organs, and contrast agents. Additionally, because manganese tetra (4-sulfonatophenyl) porphyrin is more hydrophobic than gadolinium mesoporphyrin and is mostly excreted through the liver, the enhancement pattern can be different.
On the basis of our results, gadolinium mesoporphyrin could be used as a nonspecific contrast agent to enhance tumor-related tissue. However, it may be necessary to compare the usefulness of gadolinium mesoporphyrin with that of gadopentetate dimeglumine in the evaluation of tumors in other animal models. Gadolinium mesoporphyrin has several advantages over gadopentetate dimeglumine. First, the tumor enhancement of gadolinium mesoporphyrin persists longer than that of gadopentetate dimeglumine. Therefore, images in different planes can be obtained without additional contrast material, and MR imaging can be performed without time limitations. Second, gadolinium mesoporphyrin can potentially improve the detection of small necrotic tumors because the enhanced area of the tumor with gadolinium mesoporphyrin is larger than that with gadopentetate dimeglumine. Conversely, gadolinium mesoporphyrin may have disadvantages compared with gadopentetate dimeglumine. First, examination time is lengthy because of required delayed imaging. Second, because considerable delayed enhancement occurs in the kidney [16], tumors in this organ could be obscured by decreased contrast material.
One limitation of our study was the use of two contrast agents at different times with a 20-hr interval. Because VX2 carcinoma is a rapidly growing tumor with necrosis forming in the early stage, changes of enhancement patterns during the 20-hr interval may have occurred. However, we think that this time difference did not change the results of our study. Additionally, we could not evaluate the enhancement pattern of gadolinium mesoporphyrin during the early phase because sufficient delay was required to eliminate the enhancement of gadopentetate dimeglumine. According to the results of Ni et al. [16], gadolinium mesoporphyrin enhanced in the primary and implanted hepatomas of rats during the early phase of imaging, similar to gadopentetate dimeglumine. Early-phase images obtained after the injection of gadolinium mesoporphyrin might reveal tumor enhancement similar to that of gadopentetate dimeglumine, although they were not obtained in our study. However, additional studies are required to assess the enhancement patterns of early-phase tumors. Another limitation of our study design is the possibility of considerable residual enhancement of the tumor by gadopentetate dimeglumine at the 20-hr delay. Although gadopentetate dimeglumine excretes rapidly through the kidney with greater than 90% recovery in 24 hr [16, 30], the enhancement of necrotic tissue can persist 20 hr after the infusion of gadopentetate dimeglumine.
In conclusion, gadolinium mesoporphyrin strongly enhances tumor necrosis on delayed phase MR imaging; however, it is impossible to specifically depict necrosis with gadolinium mesoporphyrin because it also enhances other parts of lesions, including viable tumor. Because gadolinium mesoporphyrin has several advantages over gadopentetate dimeglumine, gadolinium mesoporphyrin will probably be used in the evaluation of tumors when clinical applications are approved in the future.
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