The Prostate 76:776–780 (2016)
See the Unseen: Mesorectal Lymph Node Metastases in Prostate Cancer Sameh Hijazi,1* Birgit Meller,2 Conrad Leitsmann,1 Arne Strauss,1 Christian Ritter,3 Joachim Lotz,3 Johannis Meller,2 Lutz Trojan,1 and Carsten-Oliver Sahlmann2 1
Department of Urology, University Medical Center G€ottingen, G€ottingen, Germany Department of Nuclear Medicine, University Medical Center G€ottingen, G€ottingen, Germany 3 Institute for Diagnostic and Interventional Radiology, University Medical Center G€ottingen, G€ottingen, Germany 2
BACKGROUND. Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by 68Ga-PSMA-PET/CT. METHODS. We retrospectively analyzed 76 consecutive PCa patients who underwent 68 Ga-PSMA-PET/CT: 61 PCa patients with biochemical recurrence (BCR) after curative treatment and 15 high-risk PCa before primary therapy. We assessed PET-positive MLN, which are indicative for PCa. RESULTS. We detected PET-positive lesions for PCa in 68Ga-PSMA-PET/CT in 66 of 76 (87%) patients. Nodal disease was imaged in 47 of 66 (71%) patients. Indicative mesorectal nodal lesions for PCa were detected in 12 of 76 (15.8%) patients. The median number of PETpositive MLN was one per patient. Seven of twelve patients had recurrent PCa after radical prostatectomy with a median PSA value of 1.84 ng/ml (range 0.31–13). Five of twelve patients had untreated first diagnosed high-risk PCa with median PSA value of 90 ng/ml (range 4.6–93) at PET/CT, respectively. For all PET positive MLN a morphological correlate was found in CT (shortest diameter median 4 mm [range 4–21]; longest diameter median 7.5 mm [range 5–25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLN, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three highrisk PCa patients received hormonal therapy, and two patients were treated with adjuvant hormonal therapy after radical prostatectomy. CONCLUSIONS. Detection and exact location of nodal metastasis for PCa is crucial for the choice of treatment and the patient’s prognosis. 68Ga-PSMA-PET/CT seems to improve the detection of nodal metastasis in PCa, especially concerning mesorectal lymph nodes. Prostate 76:776–780, 2016. # 2016 Wiley Periodicals, Inc. KEY WORDS: prostate cancer; mesorectal lymph nodes; PET/CT; nodal metastases
68
Ga-PSMA-PET/CT; PSMA;
INTRODUCTION Prostate cancer (PCa) is the most common cancer in male patients with increasing incidence. Regional lymph node involvement is one of the most important prognostic factors. A sensitive and reliable detection of nodal disease is prerequisite to determine appropriate and individual therapy in PCa patients because clinically localized PCa can be curatively treated with radical prostatectomy (RP) and radiation therapy. Pelvic lymph node dissection is still the gold standard for assessing the nodal status in PCa [1–3]. The ß 2016 Wiley Periodicals, Inc.
Conflicts of interest: The authors declare that they have no conflict of interest. Correspondence to: Sameh Hijazi, M.D., Department of Urology, University Medical Center Goettingen, Grosse Str. 41, 49477 Ibbenbueren, Germany. E-mail: [email protected] Received 20 October 2015; Accepted 2 February 2016 DOI 10.1002/pros.23168 Published online 16 February 2016 in Wiley Online Library (wileyonlinelibrary.com).
Mesorectal Lymph Node Metastases in Prostate Cancer detection of nodal micrometastases of PCa is a major challenge for imaging methods [4]. The sensitivity and specifity of conventional imaging as well as computed tomography (CT) and magnetic resonance imaging (MRI) to assure the nodal involvement are limited. CT and MRI assess nodal invasion only by the measurement of lymph node diameter and cannot detect lymph node micrometastases. Since their sensitivity is low using a 10 mm threshold [5–9], it remains a substantial risk of preoperative understaging. Prostate specific membrane antigen (PSMA) seems to be an ideal target for detection of PCa metastases because of its high expression by nearly all PCa cells [10,11]. Several studies presented promising findings in the early detection of lymph node metastases in untreated high-risk PCa and in recurrent PCa detected by 68Ga-PSMA-ligand positron emission tomography in combination with computerized tomography (68Ga-PSMA-PET/CT), especially in the case of low PSA values [12–15]. For patients with first diagnosed or recurrent PCa, the exact localization of lymph node metastases is essential for the choice of the appropriate treatment. PCa spreads subsequently to the lower sacral vessel lymph nodes, the proximal external iliac, the obturator, the upper sacral, common iliacs and, ultimately, the paraaortic lymph nodes [16]. PCa rarely may metastasize to mesorectal lymph nodes (MLN) [16]. Assessment of nodal staging for PCa based on obturator lymph node dissection alone is not totally accurate and probably underestimates the real risk by 50% or more [16]. A better understanding of the lymphatic drainage should improve efficacy of lymph node targeted therapy [16]. Nodal oligometastatic high-risk PCa can be primarily treated with RP combined with extended pelvic lymph node dissection and targeted resection of the detected pelvic lymph node metastases by 68Ga-PSMA PET/CT [15]. Our study is the first study that evaluates the incidence of MLN in high-risk and recurrent PCa after primary treatment imaged by 68Ga-PSMA-PET/CT. The detection of MLN metastases especially in nodal oligometastatic PCa, may change the therapeutic strategy in those patients requiring an additional therapy after primary treatment.
MATERIALS AND METHODS
777
high-risk PCa confirmed via biopsy. We evaluated age, PSA at the time of PET/CT, location and number of suspicious lymph nodes in 68Ga-PSMA PET-CT, number and size of positive MLN, and therapy after PET/CT. For all patients, follow-up information was available to the time of manuscript submission. The study was approved by the local Ethics Committee of the University Medical Center Goettingen (approval June 7, 2015). Imaging 68
68
The Ge/ Ga-Generator (iThemba Labs, Cape Town, South Africa) was eluted with 6 ml 1 M HCl to receive median 1,200 (600–2000) MBq 68Ga depending on generator age. Generator eluate was purified by the cationic purification method. For complexation of the isotope, we used PSMA-HBED-CC peptide (6 nmol, ABX, Radeberg, Germany) in 3 ml 1.5 M HEPES buffer. The product was purified as already described. All steps were performed in a GRP Module (Scintomics, Fuerstenfeldbruck, Germany). Radio labeling of 6 nmol PSMA-HBED peptide (ABX, Radeberg, Germany) was performed with median 1,200 (600–2,000) MBq 68GaCl3 (68Ge/68Ga-Generator [iThemba Labs, Cape Town, South Africa]) in a GRP Module (Scintomics, Fuerstenfeldbruck, Germany) using the cationic purification method according to GMP quality standards. Radiochemical purity was determined by TLC and HPLC [11]. A bisphasic PET/ CT was performed (258–315 [median 298.5] MBq 68 Ga-PSMA-HEBD-CC) on a Philips Gemini TF16 PET/CT-scanner (Philips Medical Systems, Cleveland, OH) as described before [15]. Image analysis was performed by an experienced nuclear medicine physician (last author) and an experienced radiologist (both board certified). Each lesion visually considered typical for PCa (within the prostate, lymph node, bone, and distant metastasis) was included. SUVmax at 1 and 3 hr p.i. in PET, as well as shortest and longest diameter in CT was recorded. The location of suspect lymph nodes was noted on an anatomic landmark chart (mesorectal, obturator fossa, internal iliac artery, external iliac vein, common iliac artery, each on both sides). The mesorectum and the posterior pelvic subsite (PPS) were defined according to Roels et al. [17]. There were no side effects in any patient postinjection of the radiotracer recorded.
Patient Population The data of 76 consecutive patients with PCa who underwent 68Ga-PSMA PET/CT between July 2013 and August 2015 in our department were retrospectively analyzed. A total of 61 patients had BCR after primary therapy and 15 patients had a first diagnosed
Statistical Analysis All analyses were performed using the software packages Excel (Microsoft, Redmond, WA) and Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL). All parameters were analyzed with the The Prostate
778
Hijazi et al.
Fisher exact test. The significance level was set at a P-value of less than 0.05.
patients were treated with RP and adjuvant hormonal therapy.
RESULTS
DISCUSSION 68
PET-positive lesions for PCa in Ga-PSMA-PET/CT were detected in 66 of 76 (87%) patients. Table I shows the results of the PET/CT. The median number of all positive lymph nodes was 1 (range 1–2). We detected indicative mesorectal nodal lesions for PCa in 12 of 76 (15.8%) patients (Fig. 1). In 12 patients, overall 12 MLN and two PPS metastases were found. Ten out of twelve patients showed solitary MLN metastases, 2/12 patients had two metastases, one patient a MLN and a PPS metastasis, one patient two MLN metastases. One out of twelve patients had a rectal relapse of the PCa with two MLN metastases in 68Ga-PSMA-PET/CT. This patient underwent surgery, the recurrence of PCa including two MLN metastases was histopathologically confirmed with additionally immunohistochemically proven high PSMA expression. All lesions had SUVmax values significantly above the background, with rising uptake over time (SUVmax 1 hr p.i. median 5.5 [range 2–31.1]; SUVmax 3 hr p.i. median 6.6 [range 3.2–32.7]). For all PET positive MLN, a morphological correlate was found in CT (shortest diameter median 4 mm [range 4–21]; longest diameter median 7.5 mm [range 5–25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLNs, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three high-risk PCa patients received hormonal therapy, and two TABLE I. Findings of
Variable
68
Ga-PSMA/PET-CT Overall (n ¼ 76)
300 (140–392) Injected activity of 68Ga-PSMA, MBq (median, range) Suspected lesions in PSMA/PET-CT n (%) Patients with PET-positive lesions 66 (87%) (overall) Nodal 47 (62%) Bone 9 (12%) Visceral (pulomnary) 5 (7%) Intraprostatic 18 (24%) Localization of suspicious lymph nodes n(%) Mesorectal 12 (15.8%) Obturator fossa 2 (3%) Internal iliac artery 4 (5%) External iliac vein 14 (18%) Common iliac artery 9 (12%) Another localization 11 (15%)
The Prostate
The investigation of lymph node metastases in patients with PCa is often based on assessment of lymph nodes in the obturator fossa and along the iliac vessels via standard imaging modalities such as CT and MRI. Dissection of pelvic lymph nodes is the diagnostic standard for the detection of nodal metastasis of PCa in obturatorial and iliac lymph nodes which provides important information regarding tumor stage and prognosis. Indeed, the obturator and iliac lymph nodes are clearly one of the possible regions of spread of PCa, but their sole assessment is not adequate to precisely describe the routes of lymph node invasion or the absolute incidence of nodal metastasis [16]. There are several other lymph node regions at risk, from the periprostatic area to the mesorectal lymph nodes [16]. This is important for risk assessment of lymphatic drainage of PCa. The new diagnostic method of 68Ga-PSMA-PET/CT seems to be clinically useful for detection of nodal metastases in PCa patients as could be demonstrated lately with promising results and higher detection rates in high-risk and recurrent PCa patients [14,15]. In our recent study, 68Ga-PSMA-PET/CT had a high diagnostic accuracy in the detection of pelvic lymph node metastases of PCa [15]. This is one the first studies evaluating the incidence of MLN metastases in PCa patients before the beginning of primary therapy or with BCR after curative treatment detected by 68Ga-PSMA-PET/CT. In the current literature, there are only limited studies describing MLN metastases of PCa either as incidental findings during anterior rectal resection of rectal cancer or as findings in context of sentinel lymph node scintigraphy in patients with PCa [18–20]. Murray et al. identified metastatic PCa within MLNs in 5 of 112 patients (4.5%) undergoing abdominoperineal resection for rectal adenocarcinoma [18]. Mourra et al. found 10 MLNs metastases of PCa in 106 lymph nodes histologically examined in patients with rectal cancer who underwent anterior rectal resection with total mesorectal excision [19]. Ganswindt et al. found MLN metastases in 6.2% (20 of 324 lymph nodes) of removed lymph nodes in 61 patients with high-risk PCa detected by preoperative sentinel lymph node scintigraphy using single photon emission computed tomography imaging (SPECT) with good correlation of MLN metastases found by intraoperative gamma probe detection [20]. Recently published data comparing 68Ga-PSMA-PET/CT with 68Ga-PSMA-PET/MR found MLN in 6.3% in a limited number of 26
Mesorectal Lymph Node Metastases in Prostate Cancer
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Fig. 1. 68Ga-PSMA-PET/CT (Philips Gemini TF16); 3 min/bed position; 60 min. p.i.; 303 MBq 68Ga-PSMA; (A) fused axial PET/CT; (B) axial low-dose CT image for attenuation correction; (C) axial full-dose CT image, contrast-enhanced; (A–C) arrows and circles mark a mesorectal lymph node metastasis.
patients [21]. These observations highlight the connection that can exist between mesorectal lymph nodes, and extra mesorectal (pelvic) lymph nodes. To date, there is no systematic data available about the incidence of MLNs metastases in PCa considering different tumor stages, especially high-risk patients. One reason could be the limited value of conventional diagnostic procedures, such as MRT or CT by using the size as criterion for malignancy. In contrast, the 68 Ga-PSMA-PET/CT detects metastases of PCa by measurement of expression of PSMA on the tumor cell surface. In the present study, we could show that most of the metastases found by PET/CT are small, with the longest diameter below 10 mm, and such usually would be assigned as benign in conventional diagnostics [9]. Since the surgical standard treatment of PCa patients—dissection of pelvic lymph nodes—does not include the mesorectum region or the PPS, and since the value of conventional diagnostic procedures in these regions are limited, the findings of the present study demonstrate a possible blind spot within the workup of PCa. 68Ga-PSMA-PET/CT could be a new method to overcome these limitations and provide more accurate staging information. This is most important, because the detection and exact location of lymph node metastases before primary treatment of PCa, as well as in recurrent PCa, affects the choice of the appropriate treatment strategy and may possibly improve patients prognosis. PCa may extend to the MLNs basin and, therefore, influence the lymphatic staging, lymph node dissection, and the treatment of PCa. In the case of limited oligometastatic MLNs metastases of recurrent PCa, the use of a metastases-directed therapy via salvage external radiation is potentially justified. High-risk PCa patients with oligometastatic MLNs metastases can be additionally treated with lesion-directed external radiation after primary treatment. This treatment is a promising approach, however, yet without high level of evidence, but nevertheless, the mesorectal region or the PPS below S3 would usually not be included in the
irradiation region, unless a lymph node involvement is known [22]. Recently published data of 57 patients with BCR of prostate cancer showed a significant impact of a 68Ga-PSMA-HBED-CC(68Ga-PSMA-11)PET/CT on the planning of radiotherapy. However, in 50.8% of the patients, the target volume of radiotherapy had to be changed to incorporate the previously unknown locations of metastases [23]. There are a few limitations to our study. The number of patients in this retrospective evaluation with MLNs metastasis is limited (n ¼ 12). Our study is further limited by the lack of the histological examination of detected MLN, except in one patient presenting a rectal recurrence of a PCa including MLN metastases, but previous data of our group indicate an extremely high specificity with a negligible number of false positive results [15]. CONCLUSIONS For the first time, our study determined the incidence of PCa metastasizing to the mesorectal lymph nodes detected by 68Ga-PSMA PET/CT. We believe that the assesment of the exact extent of nodal metastases may improve the appropriate treatment and prognosis of patients and could increase the curative options for the patients. Overall, we believe that 68 Ga-PSMA-PET/CT may improve the early detection of nodal metastases in prostate cancer, especially in to date rather untypical locations. Large prospective and controlled studies are required to evaluate the value of 68 Ga-PSMA-PET/CT and the incidence of mesorectal lymph node metastases of PCa. REFERENCES 1. Malmstr€ om PU. Lymph node staging in prostatic carcinoma revisited. Acta Oncol 2005;44:593–598. 2. Jensen TK, Holt P, Gerke O, Riehmann M, Svolgaard B, Marcussen N, Bouchelouche K. Preoperative lymph-node staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/computed axial tomography and The Prostate
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magnetic resonance imaging: Correlation with histopathology. Scan J Urol Nephrol 2011;45:122–128. 3. H€acker A, Jeschke S, Leeb K, Prammer K, Ziegerhofer J, Sega W, Langsteger W, Janetschek G. Detection of pelvic lymph node metastases in patients with clinically localized prostate cancer: Comparison of [18F] fluorocholine positron emission tomography-computerized tomography and laparoscopic radioisotope guided sentinel lymph node dissection. J Urol 2006;176:2104–2108. 4. Kosuri S, Akhtar NH, Smith M, Osborne JR, Tagawa ST. Review of salvage therapy for biochemically recurrent prostate cancer: The role of imaging and rationale for systemic salvage targeted anti-prostate-specific membrane antigen radioimmunotherapy. Adv Urol 2012;2012:921674. 5. Flanigan RC, McKay TC, Olson M, Shankey TV, Pyle J, Waters WB. Limited efficacy of preoperative computed tomographic scanning for the evaluation of lymph node metastasis in patients before radical prostatectomy. Urology 1996;48:428–432. 6. Borley N, Fabrin K, Sriprasad S, Mondaini N, Thompson P, Muir G, Poulsen J. Laparoscopic pelvic lymph node dissection allows significantly more accurate staging in “high-risk” prostate cancer compared to MRI or CT. Scand J Urol Nephrol 2003;37:382–386. 7. Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, de la Rosette J, Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491–2499. 8. Abuzallouf S, Dayes I, Lukka H. Baseline staging of newly diagnosed prostate cancer: A summary of the literature. J Urol 2004;171:2122–2127. 9. Hovels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL, Sevrens JL, Barentsz JO. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: A meta-analysis. Clin Radiol 2008;63:387–395. 10. Bouchelouche K, Choyke PL, Capala J. Prostate specific membrane antigen a target for imaging and therapy with radionuclides. Discov Med 2010;9:55–61. 11. Eder M, Neels O, M€ uller M, Bauder-W€ ust U, Remde Y, Sch€ afer M, Hennrich U, Eisenhut M, Afshar-Oromieh A, Haberkorn U, Kopka K. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: A new PET tracer for imaging of prostate cancer. Pharmaceuticals 2014;7:779–796. 12. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, Holland-Letz T, Hadaschik BA, Giesel FL, Debus J, Haberkorn U. Comparison of PET imaging with a (68)Ga- labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2014;41:11–20. 13. Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, Joyal J, Kopka K, Debus J, Babich JW,
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Haberkorn U. Radiation dosimetry and first therapy results with a (124)I/(131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging 2014;41:1280–1292. 14. Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, Eisenhut M, Boxler S, Hadaschik BA, Kratochwil C, Weichert W, Kopka K, Debus J, Haberkorn U. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Mol Imaging 2015;42:197–209. 15. Hijazi S, Meller B, Leitsmann C, Strauss A, Meller J, Ritter CO, Lotz J, Schildhaus HU, Trojan L, Sahlmann CO. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/ computerized tomography. Prostate 2015;75:1934–1940. 16. Swanson GP, Hubbard JK. A better understanding of lymphatic drainage of the prostate with modern imaging and surgical techniques. Clin Genitourin Cancer 2013;11:431–440. 17. Roels S, Duthoy W, Haustermans K, Penninckx F, Vandecaveye V, Boterberg T, De Neve W. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys 2006;65:1129–1142. 18. Murray SK, Breau RH, Guha AK, Gupta R. Spread of prostate carcinoma to the perirectal lymph node basin: Analysis of 112 rectal resections over a 10-year span for primary rectal adenocarcinoma. Am J Surg Pathol 2004;28:1154–1162. 19. Mourra N, Parc Y, McNamara D, Tiret E, Fiejou JF, Parc R. Lymph node metastases of prostatic adenocarcinoma in the mesorectum in patients with adenocarcinoma or villous tumor of the rectum with collision phenomenon in a single lymph node: Report of five cases. Dis Colon Rectum 2005;48:384–389. 20. Ganswindt U, Schilling D, M€ uller AC, Bares R, Bartenstein P, Belka C. Distribution of prostate sentinel nodes: A SPECTderived anatomic atlas. Int J Radiat Oncol Biol Phys 2011;79: 1364–1372. 21. Freitag MT, Radtke JP, Hadaschik BA, Kopp-Schneider A, Eder M, Kopka K, Haberkorn U, Roethke M, Schlemmer HP, AfsharOromieh A. Comparison of hybrid (68)Ga-PSMA PET/MRI and (68)Ga-PSMA PET/CT in the evaluation of lymph node and bone metastases of prostate cancer. Eur J Nucl Med Mol Imaging 2016;43:70–83. 22. Lawton CA, Michalski J, El-Naqa I, Buyyounouski MK, Lee WR, Menard C, O’Meara E, Rosenthal SA, Ritter M, Seider M. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009;74:383–387. 23. Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K, Afshar-Oromieh A, Debus J, Haberkorn U, Giesel FL. (68)Ga-PSMA-11 PET/CT: A new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 2016;43:34–41.
See the Unseen: Mesorectal Lymph Node Metastases in Prostate Cancer Sameh Hijazi,1* Birgit Meller,2 Conrad Leitsmann,1 Arne Strauss,1 Christian Ritter,3 Joachim Lotz,3 Johannis Meller,2 Lutz Trojan,1 and Carsten-Oliver Sahlmann2 1
Department of Urology, University Medical Center G€ottingen, G€ottingen, Germany Department of Nuclear Medicine, University Medical Center G€ottingen, G€ottingen, Germany 3 Institute for Diagnostic and Interventional Radiology, University Medical Center G€ottingen, G€ottingen, Germany 2
BACKGROUND. Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by 68Ga-PSMA-PET/CT. METHODS. We retrospectively analyzed 76 consecutive PCa patients who underwent 68 Ga-PSMA-PET/CT: 61 PCa patients with biochemical recurrence (BCR) after curative treatment and 15 high-risk PCa before primary therapy. We assessed PET-positive MLN, which are indicative for PCa. RESULTS. We detected PET-positive lesions for PCa in 68Ga-PSMA-PET/CT in 66 of 76 (87%) patients. Nodal disease was imaged in 47 of 66 (71%) patients. Indicative mesorectal nodal lesions for PCa were detected in 12 of 76 (15.8%) patients. The median number of PETpositive MLN was one per patient. Seven of twelve patients had recurrent PCa after radical prostatectomy with a median PSA value of 1.84 ng/ml (range 0.31–13). Five of twelve patients had untreated first diagnosed high-risk PCa with median PSA value of 90 ng/ml (range 4.6–93) at PET/CT, respectively. For all PET positive MLN a morphological correlate was found in CT (shortest diameter median 4 mm [range 4–21]; longest diameter median 7.5 mm [range 5–25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLN, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three highrisk PCa patients received hormonal therapy, and two patients were treated with adjuvant hormonal therapy after radical prostatectomy. CONCLUSIONS. Detection and exact location of nodal metastasis for PCa is crucial for the choice of treatment and the patient’s prognosis. 68Ga-PSMA-PET/CT seems to improve the detection of nodal metastasis in PCa, especially concerning mesorectal lymph nodes. Prostate 76:776–780, 2016. # 2016 Wiley Periodicals, Inc. KEY WORDS: prostate cancer; mesorectal lymph nodes; PET/CT; nodal metastases
68
Ga-PSMA-PET/CT; PSMA;
INTRODUCTION Prostate cancer (PCa) is the most common cancer in male patients with increasing incidence. Regional lymph node involvement is one of the most important prognostic factors. A sensitive and reliable detection of nodal disease is prerequisite to determine appropriate and individual therapy in PCa patients because clinically localized PCa can be curatively treated with radical prostatectomy (RP) and radiation therapy. Pelvic lymph node dissection is still the gold standard for assessing the nodal status in PCa [1–3]. The ß 2016 Wiley Periodicals, Inc.
Conflicts of interest: The authors declare that they have no conflict of interest. Correspondence to: Sameh Hijazi, M.D., Department of Urology, University Medical Center Goettingen, Grosse Str. 41, 49477 Ibbenbueren, Germany. E-mail: [email protected] Received 20 October 2015; Accepted 2 February 2016 DOI 10.1002/pros.23168 Published online 16 February 2016 in Wiley Online Library (wileyonlinelibrary.com).
Mesorectal Lymph Node Metastases in Prostate Cancer detection of nodal micrometastases of PCa is a major challenge for imaging methods [4]. The sensitivity and specifity of conventional imaging as well as computed tomography (CT) and magnetic resonance imaging (MRI) to assure the nodal involvement are limited. CT and MRI assess nodal invasion only by the measurement of lymph node diameter and cannot detect lymph node micrometastases. Since their sensitivity is low using a 10 mm threshold [5–9], it remains a substantial risk of preoperative understaging. Prostate specific membrane antigen (PSMA) seems to be an ideal target for detection of PCa metastases because of its high expression by nearly all PCa cells [10,11]. Several studies presented promising findings in the early detection of lymph node metastases in untreated high-risk PCa and in recurrent PCa detected by 68Ga-PSMA-ligand positron emission tomography in combination with computerized tomography (68Ga-PSMA-PET/CT), especially in the case of low PSA values [12–15]. For patients with first diagnosed or recurrent PCa, the exact localization of lymph node metastases is essential for the choice of the appropriate treatment. PCa spreads subsequently to the lower sacral vessel lymph nodes, the proximal external iliac, the obturator, the upper sacral, common iliacs and, ultimately, the paraaortic lymph nodes [16]. PCa rarely may metastasize to mesorectal lymph nodes (MLN) [16]. Assessment of nodal staging for PCa based on obturator lymph node dissection alone is not totally accurate and probably underestimates the real risk by 50% or more [16]. A better understanding of the lymphatic drainage should improve efficacy of lymph node targeted therapy [16]. Nodal oligometastatic high-risk PCa can be primarily treated with RP combined with extended pelvic lymph node dissection and targeted resection of the detected pelvic lymph node metastases by 68Ga-PSMA PET/CT [15]. Our study is the first study that evaluates the incidence of MLN in high-risk and recurrent PCa after primary treatment imaged by 68Ga-PSMA-PET/CT. The detection of MLN metastases especially in nodal oligometastatic PCa, may change the therapeutic strategy in those patients requiring an additional therapy after primary treatment.
MATERIALS AND METHODS
777
high-risk PCa confirmed via biopsy. We evaluated age, PSA at the time of PET/CT, location and number of suspicious lymph nodes in 68Ga-PSMA PET-CT, number and size of positive MLN, and therapy after PET/CT. For all patients, follow-up information was available to the time of manuscript submission. The study was approved by the local Ethics Committee of the University Medical Center Goettingen (approval June 7, 2015). Imaging 68
68
The Ge/ Ga-Generator (iThemba Labs, Cape Town, South Africa) was eluted with 6 ml 1 M HCl to receive median 1,200 (600–2000) MBq 68Ga depending on generator age. Generator eluate was purified by the cationic purification method. For complexation of the isotope, we used PSMA-HBED-CC peptide (6 nmol, ABX, Radeberg, Germany) in 3 ml 1.5 M HEPES buffer. The product was purified as already described. All steps were performed in a GRP Module (Scintomics, Fuerstenfeldbruck, Germany). Radio labeling of 6 nmol PSMA-HBED peptide (ABX, Radeberg, Germany) was performed with median 1,200 (600–2,000) MBq 68GaCl3 (68Ge/68Ga-Generator [iThemba Labs, Cape Town, South Africa]) in a GRP Module (Scintomics, Fuerstenfeldbruck, Germany) using the cationic purification method according to GMP quality standards. Radiochemical purity was determined by TLC and HPLC [11]. A bisphasic PET/ CT was performed (258–315 [median 298.5] MBq 68 Ga-PSMA-HEBD-CC) on a Philips Gemini TF16 PET/CT-scanner (Philips Medical Systems, Cleveland, OH) as described before [15]. Image analysis was performed by an experienced nuclear medicine physician (last author) and an experienced radiologist (both board certified). Each lesion visually considered typical for PCa (within the prostate, lymph node, bone, and distant metastasis) was included. SUVmax at 1 and 3 hr p.i. in PET, as well as shortest and longest diameter in CT was recorded. The location of suspect lymph nodes was noted on an anatomic landmark chart (mesorectal, obturator fossa, internal iliac artery, external iliac vein, common iliac artery, each on both sides). The mesorectum and the posterior pelvic subsite (PPS) were defined according to Roels et al. [17]. There were no side effects in any patient postinjection of the radiotracer recorded.
Patient Population The data of 76 consecutive patients with PCa who underwent 68Ga-PSMA PET/CT between July 2013 and August 2015 in our department were retrospectively analyzed. A total of 61 patients had BCR after primary therapy and 15 patients had a first diagnosed
Statistical Analysis All analyses were performed using the software packages Excel (Microsoft, Redmond, WA) and Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL). All parameters were analyzed with the The Prostate
778
Hijazi et al.
Fisher exact test. The significance level was set at a P-value of less than 0.05.
patients were treated with RP and adjuvant hormonal therapy.
RESULTS
DISCUSSION 68
PET-positive lesions for PCa in Ga-PSMA-PET/CT were detected in 66 of 76 (87%) patients. Table I shows the results of the PET/CT. The median number of all positive lymph nodes was 1 (range 1–2). We detected indicative mesorectal nodal lesions for PCa in 12 of 76 (15.8%) patients (Fig. 1). In 12 patients, overall 12 MLN and two PPS metastases were found. Ten out of twelve patients showed solitary MLN metastases, 2/12 patients had two metastases, one patient a MLN and a PPS metastasis, one patient two MLN metastases. One out of twelve patients had a rectal relapse of the PCa with two MLN metastases in 68Ga-PSMA-PET/CT. This patient underwent surgery, the recurrence of PCa including two MLN metastases was histopathologically confirmed with additionally immunohistochemically proven high PSMA expression. All lesions had SUVmax values significantly above the background, with rising uptake over time (SUVmax 1 hr p.i. median 5.5 [range 2–31.1]; SUVmax 3 hr p.i. median 6.6 [range 3.2–32.7]). For all PET positive MLN, a morphological correlate was found in CT (shortest diameter median 4 mm [range 4–21]; longest diameter median 7.5 mm [range 5–25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLNs, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three high-risk PCa patients received hormonal therapy, and two TABLE I. Findings of
Variable
68
Ga-PSMA/PET-CT Overall (n ¼ 76)
300 (140–392) Injected activity of 68Ga-PSMA, MBq (median, range) Suspected lesions in PSMA/PET-CT n (%) Patients with PET-positive lesions 66 (87%) (overall) Nodal 47 (62%) Bone 9 (12%) Visceral (pulomnary) 5 (7%) Intraprostatic 18 (24%) Localization of suspicious lymph nodes n(%) Mesorectal 12 (15.8%) Obturator fossa 2 (3%) Internal iliac artery 4 (5%) External iliac vein 14 (18%) Common iliac artery 9 (12%) Another localization 11 (15%)
The Prostate
The investigation of lymph node metastases in patients with PCa is often based on assessment of lymph nodes in the obturator fossa and along the iliac vessels via standard imaging modalities such as CT and MRI. Dissection of pelvic lymph nodes is the diagnostic standard for the detection of nodal metastasis of PCa in obturatorial and iliac lymph nodes which provides important information regarding tumor stage and prognosis. Indeed, the obturator and iliac lymph nodes are clearly one of the possible regions of spread of PCa, but their sole assessment is not adequate to precisely describe the routes of lymph node invasion or the absolute incidence of nodal metastasis [16]. There are several other lymph node regions at risk, from the periprostatic area to the mesorectal lymph nodes [16]. This is important for risk assessment of lymphatic drainage of PCa. The new diagnostic method of 68Ga-PSMA-PET/CT seems to be clinically useful for detection of nodal metastases in PCa patients as could be demonstrated lately with promising results and higher detection rates in high-risk and recurrent PCa patients [14,15]. In our recent study, 68Ga-PSMA-PET/CT had a high diagnostic accuracy in the detection of pelvic lymph node metastases of PCa [15]. This is one the first studies evaluating the incidence of MLN metastases in PCa patients before the beginning of primary therapy or with BCR after curative treatment detected by 68Ga-PSMA-PET/CT. In the current literature, there are only limited studies describing MLN metastases of PCa either as incidental findings during anterior rectal resection of rectal cancer or as findings in context of sentinel lymph node scintigraphy in patients with PCa [18–20]. Murray et al. identified metastatic PCa within MLNs in 5 of 112 patients (4.5%) undergoing abdominoperineal resection for rectal adenocarcinoma [18]. Mourra et al. found 10 MLNs metastases of PCa in 106 lymph nodes histologically examined in patients with rectal cancer who underwent anterior rectal resection with total mesorectal excision [19]. Ganswindt et al. found MLN metastases in 6.2% (20 of 324 lymph nodes) of removed lymph nodes in 61 patients with high-risk PCa detected by preoperative sentinel lymph node scintigraphy using single photon emission computed tomography imaging (SPECT) with good correlation of MLN metastases found by intraoperative gamma probe detection [20]. Recently published data comparing 68Ga-PSMA-PET/CT with 68Ga-PSMA-PET/MR found MLN in 6.3% in a limited number of 26
Mesorectal Lymph Node Metastases in Prostate Cancer
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Fig. 1. 68Ga-PSMA-PET/CT (Philips Gemini TF16); 3 min/bed position; 60 min. p.i.; 303 MBq 68Ga-PSMA; (A) fused axial PET/CT; (B) axial low-dose CT image for attenuation correction; (C) axial full-dose CT image, contrast-enhanced; (A–C) arrows and circles mark a mesorectal lymph node metastasis.
patients [21]. These observations highlight the connection that can exist between mesorectal lymph nodes, and extra mesorectal (pelvic) lymph nodes. To date, there is no systematic data available about the incidence of MLNs metastases in PCa considering different tumor stages, especially high-risk patients. One reason could be the limited value of conventional diagnostic procedures, such as MRT or CT by using the size as criterion for malignancy. In contrast, the 68 Ga-PSMA-PET/CT detects metastases of PCa by measurement of expression of PSMA on the tumor cell surface. In the present study, we could show that most of the metastases found by PET/CT are small, with the longest diameter below 10 mm, and such usually would be assigned as benign in conventional diagnostics [9]. Since the surgical standard treatment of PCa patients—dissection of pelvic lymph nodes—does not include the mesorectum region or the PPS, and since the value of conventional diagnostic procedures in these regions are limited, the findings of the present study demonstrate a possible blind spot within the workup of PCa. 68Ga-PSMA-PET/CT could be a new method to overcome these limitations and provide more accurate staging information. This is most important, because the detection and exact location of lymph node metastases before primary treatment of PCa, as well as in recurrent PCa, affects the choice of the appropriate treatment strategy and may possibly improve patients prognosis. PCa may extend to the MLNs basin and, therefore, influence the lymphatic staging, lymph node dissection, and the treatment of PCa. In the case of limited oligometastatic MLNs metastases of recurrent PCa, the use of a metastases-directed therapy via salvage external radiation is potentially justified. High-risk PCa patients with oligometastatic MLNs metastases can be additionally treated with lesion-directed external radiation after primary treatment. This treatment is a promising approach, however, yet without high level of evidence, but nevertheless, the mesorectal region or the PPS below S3 would usually not be included in the
irradiation region, unless a lymph node involvement is known [22]. Recently published data of 57 patients with BCR of prostate cancer showed a significant impact of a 68Ga-PSMA-HBED-CC(68Ga-PSMA-11)PET/CT on the planning of radiotherapy. However, in 50.8% of the patients, the target volume of radiotherapy had to be changed to incorporate the previously unknown locations of metastases [23]. There are a few limitations to our study. The number of patients in this retrospective evaluation with MLNs metastasis is limited (n ¼ 12). Our study is further limited by the lack of the histological examination of detected MLN, except in one patient presenting a rectal recurrence of a PCa including MLN metastases, but previous data of our group indicate an extremely high specificity with a negligible number of false positive results [15]. CONCLUSIONS For the first time, our study determined the incidence of PCa metastasizing to the mesorectal lymph nodes detected by 68Ga-PSMA PET/CT. We believe that the assesment of the exact extent of nodal metastases may improve the appropriate treatment and prognosis of patients and could increase the curative options for the patients. Overall, we believe that 68 Ga-PSMA-PET/CT may improve the early detection of nodal metastases in prostate cancer, especially in to date rather untypical locations. Large prospective and controlled studies are required to evaluate the value of 68 Ga-PSMA-PET/CT and the incidence of mesorectal lymph node metastases of PCa. REFERENCES 1. Malmstr€ om PU. Lymph node staging in prostatic carcinoma revisited. Acta Oncol 2005;44:593–598. 2. Jensen TK, Holt P, Gerke O, Riehmann M, Svolgaard B, Marcussen N, Bouchelouche K. Preoperative lymph-node staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/computed axial tomography and The Prostate
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