Selected Summary

VOLUME 16 NUMBER 6 November/December 2003

Detecting lymph node metastases in prostatic cancer: [PDF]

Harsinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, de la Rosette J, Weissleder R. (Massachusetts General Hospital and Harvard Medical School, Boston and University Medical Center, Nijmegen, the Netherlands.) Noninvasive detection of clinically occult lymph node metastases in prostate cancer. N Engl J Med 2003;348:2491–9.

The natural history and aggressiveness of prostate cancer varies widely, and the means to identify men with clinically occult lymph node metastases is lacking. The authors investigated whether lymphotropic superparamagnetic nanoparticles can be used in conjunction with magnetic resonance imaging (MRI) to detect metastatic tumour in local and distant lymph nodes in humans, as they have been used in mouse models. The authors were particularly interested in cases in which metastases had not caused an increase in the size of the lymph node (clinically occult disease). They prospectively determined the accuracy of the method in 334 lymph nodes in 80 patients with biopsy-proven prostate cancer who subsequently underwent resection of the tumour or pelvic lymph nodes (or both) or a targeted lymph node biopsy.

Eighty patients with resectable prostate cancer as determined by conventional imaging methods, digital rectal examination, ultrasound-guided sextant core biopsy, and measurement of serum prostate-specific antigen (PSA) levels were enrolled in the study. All patients had stage Tl, T2 or T3 prostate cancer before surgical intervention. The lymphotropic superparamagnetic nanoparticle used in this study was a monocrystalline iron oxide. The lyophilized iron oxide was reconstituted in normal saline and injected at a dose of 2.6 mg of iron per kg body weight over a period of 15–30 minutes. Five patients reported low back pain during the infusion, which disappeared after the infusion was temporarily stopped; the pain did not recur when the infusion was resumed. All patients received the full dose and completed the entire study. MR images of the pelvis, extending from the pubic symphysis to the level of the aortic bifurcation, were obtained before and 24 hours after the intravenous administration of lymphotropic superparamagnetic nanoparticles. On conventional MRI, lymph nodes were classified as malignant if the short-axis diameter was elongated and exceeded 10 mm, or was rounded and exceeded 8 mm, according to standard criteria. On MRI with lymphotropic superparamagnetic nanoparticles, nodes were considered malignant when one of the following three criteria were present: a decrease in signal intensity of less than 30% on T2-weighted, fast spin-echo or gradient-echo sequences after the administration of lymphotropic superparamagnetic nanoparticles; a heterogeneous signal (giving the entire node a mottled appearance), discrete focal defects (isolated islands of high signal intensity), or both; and nodes with a central area of hyperintensity (excluding a fatty hilum) but a peripheral decrease in signal intensity. The diagnostic standard was histopathological evaluation of each lymph node. Three-dimensional reconstructions of the pelvic anatomy were also obtained in a subgroup of 40 patients to aid in the approach to surgery and radiotherapy.

Open resections were performed in 60 patients, and 15 underwent a laparoscopic resection. In 5 patients, the presence or absence of nodal metastases in specific lymph nodes was ascertained by computed tomography (CT)-guided biopsy and no surgery was performed. Open and laparoscopic dissection of the pelvic lymph nodes consisted of a generally accepted resection of the left and right obturator lymph nodes and included more extensive exploration in 9 patients because of suggestive findings on imaging. To ensure optimal correlation, the surgeon was given a schematic drawing or a three-dimensional rendering identifying all the lymph nodes in relation to the iliac vessels. Resected nodes were placed on a grid identifying their location and orientation and then sent for histopathological analysis. Multiple sections of all of the resected lymph nodes were stained with haematoxylin and eosin, and the slides were reviewed by at least 2 pathologists who had no knowledge of the MRI findings.

Of the 334 lymph nodes, 271 were benign (81.1%) and 63 (18.9%)—from 33 patients (41%)—contained microscopically detectable metastases. Of these 63 nodes, 17 measured <5 mm, 28 were 5–10 mm, and 18 were >10 mm. Overall, 71.4% of the malignant nodes did not fulfil the traditional imaging criteria for malignancy (>10 mm if elongated or >8 mm if rounded). In normal lymph nodes, the signal intensity decreased homogeneously after the administration of lymphotropic superparamagnetic nanoparticles, indicating normal delivery of the nanoparticles to the lymph nodes and normal uptake of the particles by nodal macrophages. In lymph nodes containing metastases, there was either a limited decrease in signal intensity or discrete focal defects within the node owing to replacement of the nodal architecture by tumour deposits.

On a patient-by-patient analysis, MRI with lymphotropic superparamagnetic nanoparticles correctly identified all patients with metastases (100% sensitivity). This modality provided the correct diagnosis in 96% of patients free of lymph node metastases. MRI with lymphotropic superparamagnetic nanoparticles was also more accurate than conventional MRI with respect to published and validated nomograms for predicting lymph node metastases. In the low risk group of 12 patients, 1 had nodal metastases (true incidence 8%; estimated risk <4%). In the intermediate risk group, 15 of 48 patients had nodal metastases (true incidence 31%; estimated risk 18%), and in the high risk group, 17 of 20 patients had metastases (true incidence 85%). On a node-by-node basis, the overall sensitivity of MRI with lymphotropic superparamagnetic nanoparticles was 90.5% and was significantly higher (p<0.00l) than that of conventional MRI (sensitivity 35.4%). Similarly, the administration of lymphotropic superparamagnetic nanoparticles improved the diagnostic specificity from 90.4% to 97.8%. For lymph nodes with a short-axis diameter of 5–10 mm, which would be considered normal on conventional MRI, the sensitivity of MRI with lymphotropic superparamagnetic nanoparticles was 96.4%. Metastases were histologically confirmed at distant sites in all 9 patients in whom MRI with lymphotropic superparamagnetic nanoparticles suggested the presence of metastases in the lymph nodes, who were not classically considered candidates for resection and who underwent more extensive exploration. The false-positive nodes were all >10 mm and showed reactive hyperplasia on staining, which most likely resulted in heterogeneous uptake of lymphotropic superparamagnetic nanoparticles. All false-negative nodes had a short-axis diameter <5 mm, which is probably below the current detection threshold of MRI.

The authors found that lymph node metastases can be accurately diagnosed by high-resolution MRI with lymphotropic superpara-magnetic nanoparticles but not by conventional MRI. On a patient-by-patient basis, the addition of lymphotropic superparamagnetic nanoparticles increased the sensitivity of MRI from 45.4% to 100%, with a specificity of 95.7%. The authors also found that the three-dimensional reconstruction techniques used were of particular help in displaying and analysing the massive amount of high-resolution data. With these, it was feasible to show both normal and abnormal lymph nodes and their location with respect to important surgical landmarks such as vessels, the obturator nerves and ureters.

The adverse prognostic implications of lymph node metastases in prostatic cancer have been widely established. MRI provides images with excellent anatomical detail and soft tissue contrast but is relatively insensitive for the detection of lymph node metastases. However, the results of MRI can be improved by using different imaging agents and acquisition techniques. In particular, the use of lymphotropic superparamagnetic nanoparticles holds considerable promise. These nanoparticles have a monocrystalline, inverse spinel, superparamagnetic iron oxide core, contain a dense packing of dextrans to prolong their time in circulation, and are avidly taken up by lymph nodes in animals and humans. The nanoparticles are slowly extravasated from the vascular into the interstitial space, from which they are transported to the lymph nodes by way of the lymphatic vessels. Within the lymph nodes, lymphotropic superparamagnetic nanoparticles are internalized by macrophages, and these intracellular iron-containing particles cause changes in magnetic properties detectable by MRI.

The status of the pelvic lymph nodes provides important information with respect to management because a curative treatment approach has a low probability of success in the setting of lymph node metastasis. An effective means to detect these micro-metastases would enable the appropriate selection of patients and help in the formulation of management guidelines in this clinical situation.
Dissection of the pelvic lymph nodes is the diagnostic standard for detecting metastatic prostate cancer in the iliac lymph nodes and is performed by either an open or a laparoscopic technique in most patients deemed candidates for surgery. This approach, however, has several limitations. First, the area of surgical exploration is limited to groups within the external iliac–obturator nodes, but so-called skip metastases to the internal and common iliac nodes are not uncommon and go undetected if this method is used. Nine examples of this phenomenon were encountered in the 80 patients studied. Second, morbidity and complication rates of 4%–5% with this invasive technique cannot be overlooked. Third, dissection of the pelvic lymph nodes is expensive and requires hospitalization. Fourth, it is typically a one-time procedure performed at the beginning of cancer treatment. Although these aspects of cost and outcome of MRI with lymphotropic superparamagnetic nanoparticles will have to be studied in larger, prospective clinical trials, this approach could provide both clinical and cost benefits.

Surgical removal and histological examination of the pelvic lymph nodes provide the most accurate staging information relative to the pelvic lymph node status. Pelvic lymph node dissection (PLND) has been routinely performed in conjunction with radical prostatectomy. PLND can also be performed laparoscopically, although the indications for this approach are controversial. A relative indication for laparoscopic PLND is a high suspicion of lymph node metastases based on the findings of (i) enlarged pelvic lymph nodes by pelvic imaging, (ii) pre-biopsy serum PSA level >20 ng/ml, (iii) poorly differentiated tumour on needle biopsy of the prostate (Gleason score 8–10), or (iv) a palpable, locally advanced tumour. In an attempt to reduce the extent and duration of surgery, the sentinel lymph node concept has been tried in PLND using preoperative ultrasound-guided injection of 99mTc-labelled nanocolloid particles, with encouraging initial results.1 Some authors, however, believe that PLND at the time of radical prostatectomy is unnecessary for men at low risk of having pelvic lymph node metastases based on the preoperative parameters of T stage, serum PSA and tumour grade.2

On the other hand, in a prospective study of 103 consecutive patients undergoing radical prostatectomy for localized prostate cancer, Heidenreich et al. found that extended pelvic lymphadenectomy was associated with a high rate of lymph node metastasis outside the fields of standard lymphadenectomy.3 They advocated that extended field lymphadenectomy, including the internal iliac lymph nodes, should be performed in all patients with prostate cancer who are at high risk for lymph node involvement, as indicated by a PSA level >10.5 ng/ml and biopsy Gleason score >7.3 In these circumstances, the limits of lymph node dissection may be tailored and modified according to the individual patient in the presence of an accurate modality to detect microscopic lymph node metastases preoperatively.

The use of cross-sectional imaging modalities such as CT and MRI are fraught with problems such as low sensitivity and accuracy. These modalities are not suitable for use in all cases of localized carcinoma prostate. Pelvic imaging may be warranted in men at higher risk for metastases suspected by locally advanced disease on direct rectal examination, marked elevation of PSA (>20 ng/ml) or the presence of poorly differentiated cancer on needle biopsy. In an attempt to improve the sensitivity and accuracy of cross-sectional imaging for the detection of positive pelvic lymph nodes, Wolf et al. combined the use of MRI/CT with fine needle aspiration cytology preoperatively in patients planned for radical prostatectomy but could achieve a sensitivity of only 25%.4

Magnetic resonance lymphography with superparamagnetic iron oxide as a contrast agent was developed in an animal model with tumour-bearing lymph nodes. In a study on rats by Weissleder et al., experimental results indicated that MR lymphography might potentially increase the sensitivity of MRI in the detection of lymphatic malignancy.5 Subsequently, the application of this technology has been tested in various malignancies including primary lung carcinoma6 and vulval carcinoma7 with encouraging results.

In the present study, the authors report the use of this technique for improving the sensitivity of MRI in the detection of pelvic lymph node metastases by using iron oxide-laden lymphotropic superparamagnetic nanoparticles. Most importantly, the ability to detect metastases in normal-sized lymph nodes (which would otherwise have been considered non-malignant by the size criterion alone) is the major advantage of this technique. Pending further study and training requirements for this technique, it is possible that this modality may replace the use of pelvic lymph node dissection in patients with carcinoma prostate in the future and help in better staging and management of the disease in individual patients.

Monoclonal antibody radioimmunoscintigraphy (radiolabelled monoclonal antibody scan) is another promising approach for the identification of microscopic cancer deposits at regional and distant sites. The monoclonal antibody to PSMA (7E11), an antigen that is expressed to a greater degree in prostate cancer cells than in normal prostate tissue, has been chelated to 111In for immunoscintigraphic use and is known as 111In-capromab pendetide or ProstaScint. An early study designed to detect pelvic lymph node involvement with the ProstaScint scan demonstrated a positive predictive value of 50%.8 A recent study of men who underwent pelvic lymphadenectomy and who had a high risk of nodal disease by virtue of PSA level, Gleason score and advanced clinical stage reported a positive predictive value of 62%.9 The reported sensitivity and specificity for nodal disease of 62% and 72%, respectively, can be compared with a sensitivity of <20% and a specificity of 100% for cross-sectional imaging in the same study. The use of ProstaScint, together with estimation of the PSA level, histological grade and clinical stage, appears to provide additional predictive information.
Positron emission tomography (PET) has also been evaluated in the preoperative non-invasive staging of pelvic lymph nodes in prostate cancer. In a prospective study, de Jong et al. examined 67 consecutive patients with histologically proven prostate cancer with 11C-choline PET and calculated a sensitivity of 80%, a specificity of 96%, and an accuracy of 93%. The authors concluded that 11C-choline PET is sensitive and accurate in the preoperative staging of pelvic lymph nodes in prostate cancer.10

Hence, while the search for an ideal non-invasive replacement to pelvic lymphadenectomy in patients of carcinoma prostate continues, these three modalities hold promise for the future.

  1. Rudoni M, Sacchetti GM, Leva L, Inglese E, Monesi G, Minocci D, et al. Recent applications of the sentinel lymph node concept: Preliminary experience in prostate cancer. Tumori 2002;88:S16–S17.
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  7. Hawnaur JM, Reynolds K, Wilson G, Hillier V, Kitchener HC. Identification of inguinal lymph node metastases from vulval carcinoma by magnetic resonance imaging: An initial report. Clin Radiol 2002;57:995–1000.
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  9. Manyak MJ, Hinkle GH, Olsen JO, Chiaccherini RP, Partin AW, Piantadosi S, et al. Immunoscintigraphy with indium-111–capromab pendetide: Evaluation before definitive therapy in patients with prostate cancer. Urology 1999;54:1058–63.
  10. de Jong IJ, Pruim J, Elsinga PH, Vaalburg W, Mensink HJ. Preoperative staging of pelvic lymph nodes in prostate cancer by 11C-choline PET. J Nucl Med 2003;44:331–5.
Gagan Gautam
Monish Aron
Department of Urology
All India Institute of Medical Sciences
New Delhi


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