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International Journal of Urology (2014) 21, 905–908
doi: 10.1111/iju.12466
Original Article: Clinical Investigation
Growing teratoma syndrome: Clinical and radiographic characteristics Dennis J Lee,1 Hooman Djaladat,1 Nicholas N Tadros,2 Mehran Movassaghi,1 Tapas Tejura,1 Vinay Duddalwar1 and Siamak Daneshmand1 1 USC Institute of Urology, Keck Medical Center of USC, Los Angeles, California, and 2Department of Urology, Oregon Health & Science University, Portland, Oregon, USA
Abbreviations & Acronyms AFP = α-fetoprotein CT = computed tomography GTS = growing teratoma syndrome HCG = human chorionic gonadotropin IVC = inferior vena cava LDH = lactate dehydrogenase NSGCT = non-seminomatous germ cell tumor PC-RPLND = postchemotherapy retroperitoneal lymph node dissection Correspondence: Siamak Daneshmand M.D., USC Institute of Urology, Keck Medical Center of USC, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90089, USA. Email: [email protected] Received 24 October 2013; accepted 16 March 2014. Online publication 21 April 2014
Objectives: To present an overview of our surgical experience in the management of growing teratoma syndrome. Methods: A retrospective analysis of all patients undergoing post-chemotherapy retroperitoneal lymphadenectomy between November 2005 and February 2012 revealed 15 patients who met the criteria for growing teratoma syndrome. Their clinical data, imaging characteristics, and surgical and oncological outcomes were reviewed. Results: The median age at diagnosis was 23 years. Primary testis tumors included nonseminomatous germ cell tumor in 12 of 15 patients, seminoma in two of 15 patients and hemorrhagic mass in one patient. Mature teratoma was present in just six (40%) of the orchiectomy specimens. All patients received preoperative chemotherapy. On imaging, the median size of the largest retroperitoneal mass was 7 cm (range 3.9–24.5 cm). The median rate of linear growth was 0.5 cm/month (range 0.03–2.9), and the increase in volume was 9.2 cm3/month. All tumors were found to have cystic and necrotic components. Median operative time was 6.2 h (range 4.2–15.2 h). Estimated blood loss was 600 mL (range 100– 7000 mL), and median length of stay was 5 days (range 3–19 days). Four patients required resection of non-retroperitoneal growing teratoma masses after post-chemotherapy retroperitoneal lymphadenectomy to achieve tumor-free status. There were two minor (Clavien I–II) and two major postoperative complications (Clavien ≥III). All patients are alive and disease free with a median duration of follow-up of 8 months (range 1–64 months). Conclusions: Growing teratoma syndrome tumors vary in their growth rate, but they all appear to have cystic features with necrosis elements on radiographic evaluation. Aggressive surgical excision is associated with excellent outcomes.
Key words:
germ cell tumor, lymph node dissection, teratoma, testis cancer.
Introduction Cisplatin-based chemotherapy regimens in combination with current surgical techniques have resulted in overall survival rates greater than 90% for patients with advanced testicular cancer.1,2 Of patients with advanced NSGCT, 26–65% achieve a complete serological and radiographic response to first-line chemotherapy.3–5 However, in a small subset of patients who undergo chemotherapy for metastatic NSGCT, continued tumor growth occurs, despite normalization of tumor markers.6 This finding was first described by Logothetis et al. as the GTS, and was defined by three criteria: (i) normalization of elevated serum tumor markers; (ii) tumor growth during or after systemic chemotherapy given for NSGCT; and (iii) the histological presence of only mature teratoma at tumor resection.7–9 Jeffrey et al. has reported minor elevations in tumor markers with GTS, but diagnosis otherwise follows the aforementioned criteria.6 GTS most commonly presents in the retroperitoneum, and has a prevalence of 1.9–7.6% in patients with NSGCT.6,8,10 GTS has a variable time-course in presentation.2,6 The diagnosis can be made during chemotherapy, after a significant disease-free period or after an initial reduction in size during chemotherapy, followed by regrowth.6 GTS is resistant to chemotherapy and radiotherapy, and should be managed with complete surgical excision. Failure to treat ultimately leads to morbidity and death resulting from compression of adjacent structures or malignant transformation. In the present study, we report our surgical experience in patients with GTS.
Methods We carried out an institutional review board-approved retrospective chart review of all patients who underwent PC-RPLND at the University of Southern California and Oregon Health and © 2014 The Japanese Urological Association
905
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(a)
(b)
Fig. 1 Coronal view showing growth of para-aortic GTS mass from (a) 1.5 to (b) 7.5 cm.
Science University, Los Angeles, California, USA. Out of 108 patients who underwent PC-RPLND, 15 patients were identified who met the criteria for a diagnosis of GTS between November 2005 and February 2012. Patient clinical data, imaging characteristics, and surgical and oncological outcomes were retrospectively collected. All received systemic chemotherapy before RPLND. All patients underwent serial abdominal and pelvic CT scanning to evaluate their response to treatment. CT imaging was reviewed by an experienced radiologist to evaluate tumor volume, growth and characteristics (Fig. 1). Precise tumor growth measurements were available in 11 patients using a CT image-rendering program (3D Synapse; Fujifilm Medical Systems, Stamford, CT, USA). Tumor volume was measured in the other four patients using the equation for 4 an ellipsoid ( V = ). Postoperatively, all specimens were 3πabc histologically confirmed to contain only mature teratoma and no viable cancer.
Results Patient characteristics The clinical characteristics of the 15 patients with GTS are summarized in Table 1. The median age at diagnosis was 23 years. The primary testis tumors were NSGCT in 12 (80%) patients, seminoma in two (13%) and a hemorrhagic mass with necrosis in which no malignant cells were identified in one (7%) patient. Mature teratoma was present in six (40%), a yolk sac in six (40%) and both in four (27%) of the orchiectomy specimens. All patients received cisplatin-based preoperative systemic chemotherapy with a median of four cycles (range 3–6 cycles). The median interval from completion of chemotherapy to PC-RPLND was 3 months (range 2–45 months).
GTS characteristics on preoperative imaging On CT imaging, all GTS tumors were found to have cystic components and evidence of necrosis. The median maximal diameter and volume of the largest retroperitoneal mass on imaging were 7 cm and 70.8 cm3, respectively. The median rate of linear growth was 0.5 cm/month, and increase in volume was 9.2 cm3/month (Table 1 and Fig. 2).
Surgical data Five PC-RPLND were carried out through a midline extraperitoneal approach we previously described, and a nervesparing technique was utilized in six cases.11 All other cases 906
Table 1
Patient and tumor characteristics
Median age at diagnosis (range) Median body mass index, kg/m2 (range) Median tumor markers before PC-RPLND (range) AFP (ng/mL) HCG (mlU/mL) LDH (IU/L) Clinical stage at initial presentation, n (%) IIA IIB IIC IIIA IIIB IIIC International Germ Cell Cancer Collaborative Group classification, n (%) Good risk Intermediate risk Poor risk No. testis primary tumor histology (%) Contained mature teratoma Contained yolk sac NSGCT Seminoma† Hemorrhagic mass with necrosis No. primary tumor pathologic stage (%) pT0 pT1 pT2 Unknown No. metastatic testis Ca sites, n (%) Retroperitoneum Lung Mediastinum Neck Median largest retroperitoneal mass (range) Diameter (cm) Volume (cm3) Median rate of growth of GTS per month (range) Diameter (cm) Volume (cm3)
23 (16–39) 28.6 (18.2–44.4) 2.2 (1–17) 1 (0.6-5) 174 (130–268) 2 (13) 4 (27) 2 (13) 1 (7) 3 (20) 3 (20)
10 (67) 3 (20) 2 (13) 6 (40) 6 (40) 12 (80) 2 (13) 1 (7) 1 (7) 10 (67) 3 (20) 1 (7) 15 (100) 2 (13) 1 (7) 3 (20) 7 (3.9–24.5) 70.8 (22–2938) 0.5 (0.03-2.9) 9.2 (-279–344)
†Patients with elevated alpha fetoprotein (AFP) and only seminoma in their primary orchiectomy specimen are considered to have NSGCT.
were carried out through a standard midline intraperitoneal or modified thoracoabdominal approach. The median operative time was 6.2 h (range 4.2–15.2 h), estimated blood loss was 600 mL (range 100–7000 mL) and three patients required greater than 2 units of blood transfusions intraoperatively. The median length of stay was 5 days (range 3–19 days) (Table 2). © 2014 The Japanese Urological Association
Growing teratoma syndrome
(b)
(a) 8
Table 2
6
80 Volume (cm3)
Fig. 2 Tumor growth rate. Each line represents a patient. The dotted line represents the median rate. (a) Linear growth rate represents change in maximal diameter along an axis. (b) Tumor growth rate represents overall volume growth. Two patients are not shown as a result of overall tumor shrinkage, but with growth along an axis. The data points of four patients lie outside the axial limit, but their growth trajectories are shown.
Diameter (cm)
100
4 2
0
0 1 2 3 4 5 6 7 810 20 30 40 50 Time (months)
Table 3 6.2 (4.2–15.2) 600 (100–7000) 5 (3–19) 8.0 (0.5–64) 1 1 1 2 1 1 1 1 1
Three patients required adjuvant procedures during the PC-RPLND. A left nephrectomy, an IVC tumor thrombectomy, a right renal artery anastomosis and a resection of a right common iliac vein were required because of tumor involvement. Four patients required additional procedures in order to achieve clearance of all teratomas. In these patients, two modified radical neck dissections and a bilateral resection of lung masses were carried out. One patient required a second operation to resect mediastinal, retrocrural and mesenteric masses as a result of large tumor volume.
Complications Three patients required transfusion of more than 2 units of packed red blood cells intraoperatively. There were four postoperative complications (Table 3): (i) a brachial plexus stretch injury causing mild right upper extremity weakness, which resolved without intervention; (ii) a partial small bowel obstruction, which resolved with supportive care without the need for nasogastric tube decompression; (iii) a right arytenoid dislocation from intubation, requiring reduction in the operating room; and (iv) bilateral renal artery ischemia, requiring renal artery stenting and temporary hemodialysis. Intraoperatively, the patient was found to have narrowing of the right renal artery as a result of extensive dissection. A primary anastomosis of the right renal artery was carried out and Doppler ultrasound was used to confirm bilateral blood flow to the © 2014 The Japanese Urological Association
40 20
Surgical/perioperative outcomes
Median (range) Operative time (h) Estimated blood loss (mL) Length of hospital stay (days) Length of follow-up (months) Non-retroperitoneal procedures (n) Mediastinal mass resection Mesenteric lymphadenectomy Bilateral resection of lung masses Radical neck dissection Adjuvant procedures (n) Nephrectomy Renal artery anastomosis Renal artery embolectomy IVC tumor thrombectomy Resection of common iliac vein
60
0
0
5
10 15 Time (months)
20
Complications
I. Pulmonary, n: Right arytenoid dislocation from intubation requiring reduction in OR II. Neurological: Right brachial plexus stretch injury – eventually resolved III. Renal, n: Bilateral renal artery obstruction requiring stenting and hemodialysis IV. Gastrointestinal, n: Partial small bowel obstruction
1 (clavien IIIb)
1 (clavien I) 1 (clavien IVa)
1 (clavien II)
kidneys at the end of the procedure. Unfortunately, the patient developed anuria and was found to have bilateral renal ischemia. A balloon angioplasty of the left renal artery and placement of bilateral renal artery stents was carried out. The patient required temporary hemodialysis, and ultimately partially recovered his renal function with an estimated glomerular filtration rate of 25.6 mL/min.
Outcome Pathological evaluation confirmed the presence of only mature teratoma in all resected specimens. All patients in the present study are alive and disease free with a mean follow up of 13.7 months.
Discussion GTS was first described by Logothetis as a growing mass with normalized tumor markers after chemotherapy for metastatic GCT more than 30 years ago. However, the condition still remains relatively poorly characterized. Large series from Memorial Sloan-Kettering Cancer Center and Indiana University have shown teratoma to be present in retroperitoneal masses in 67–85% of men with teratoma in primary testicular pathology and 28–48% of men without.1,12 Other studies have cited a yolk sac in the primary tumor to be a significant predictor of teratoma in the retroperitoneum.1 In the present series, six (40%) patients had mature teratoma in the primary tumor, six (40%) had a yolk sac and four (27%) contained both. Because of the small number of cases, it is difficult to draw a statistically significant association between the primary pathology and likelihood of GTS in the retroperitoneum. Tumor growth appears to be the only consistent indicator of GTS. Prior studies have 907
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shown the likelihood of finding teratoma in 94% of patients with enlarging retroperitoneal disease after chemotherapy.1,12 In the present cohort, the median linear growth rate was 0.5 cm/ month and volume increase was 9.2 cm3/month. In two patients, overall tumor shrinkage was observed, but continued growth was seen along an axis. There was significant variability in growth patterns, and we were unable to classify GTS based solely on growth rate. This is consistent with the data from Spiess et al.9 Radiographically, all masses showed evidence of necrosis and cystic components. GTS is unresponsive to chemotherapy and radiation therapy, and requires surgical excision to avoid morbidity from malignant transformation and compression.3,8,13 Expeditious surgery is important, as noncompliance and delay in treatment has been associated with increased morbidity and death.14 We do not recommend truncating the chemotherapy regimen if GTS is found unless the surgeon anticipates further tumor growth will render the tumor unresectable or significantly compromise the outcomes of the operation. In men who do not undergo RPLND after systemic chemotherapy, there is a 3–6% risk of malignant transformation of teratoma into non-germ cell elements, such as sarcoma or carcinoma.1 However, the most common complications from GTS result from compression as a result of tumor volume. Reported complications include mesenteric compression with bowel necrosis, obstructive renal failure, bowel obstruction and bile duct obstruction.6,8,10 Giant GTS resulting in high-volume retroperitoneal disease, defined as >10 cm, presents a technical challenge, but should not be considered a contraindication to surgery. Circumferential involvement of major vascular structures is often seen in high-volume disease, and is associated with a 7.1% vena cava resection rate and a 31.3% nephrectomy rate.15,16 Four patients in the present series had high-volume retroperitoneal disease and three of those required adjuvant procedures as a result of vascular involvement: one patient required a left nephrectomy, one patient required re-anastomosis of the right renal artery after narrowing of the artery was seen following removal of circumferential tumor, and one patient required an IVC tumor thrombectomy and resection of the right common iliac vein. In large-volume disease, occlusion of the IVC might be seen due to extrinsic compression from the desmoplastic reaction resulting from chemotherapy and/or tumor volume.17 In most cases, it is safe to resect the IVC because of the development of collateral vasculature.16 However, if there are clinical indications of inadequate collateral circulation, such as lower extremity edema, an IVC reconstruction with a graft might be considered. In patients with inoperable disease, tumor stabilization with medical management could become an option in the future. There are case reports citing the use of interferon,18,19 bevacizumab20 and cyclin-dependent kinase inhibitors to stabilize tumors in inoperable GTS.21 Further research validating the benefits of medical management in these patients is warranted. However, surgical excision remains the current gold standard treatment for GTS, and a complete resection can result in a cure in most patients. PC-RPLND for GTS is a technically demanding procedure, and should be carried out at centers of excellence with vascular expertise to optimize outcomes, because recurrence rates of up to 83% are associated in patients with partial resections.9 908
GTS tumors vary significantly in their rate and pattern of growth, but they all appear to have cystic features with elements of necrosis on radiographic evaluation. Surgery should be carried out as soon as practicably possible to minimize morbidity. Aggressive surgical excision with concomitant adjuvant surgery, if necessary, is associated with excellent outcomes.
Conflict of interest None declared.
References 1 Carver BS, Bianco JFJ, Shayegan B et al. Predicting teratoma in the retroperitoneum in men undergoing post-chemotherapy retroperitoneal lymph node dissection. J. Urol. 2006; 176: 100–4. 2 Risk MC, Foster RS. Postchemotherapy retroperitoneal lymph node dissection for testis cancer. Expert Rev. Anticancer Ther. 2010; 11: 95–106. 3 Daneshmand S, Albers P, Fosså SD et al. Contemporary management of postchemotherapy testis cancer. Eur. Urol. 2012; 62: 867–76. 4 Ehrlich Y, Brames MJ, Beck SDW, Foster RS, Einhorn LH. Long-term follow-up of cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission? J. Clin. Oncol. 2010; 28: 531–6. 5 Kollmannsberger C, Daneshmand S, So A et al. Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery. J. Clin. Oncol. 2010; 28: 537–42. 6 Jeffery G, Theaker J, Lee A, Blaquiere R, Smart C, Mead G. The growing teratoma syndrome. Br. J. Urol. 1991; 67: 195–202. 7 Logothetis C, Samuels M, Trindade A, Johnson D. The growing teratoma syndrome. Cancer 1982; 50: 1629–35. 8 André F, Fizazi K, Culine S et al. The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients. Eur. J. Cancer 2000; 36: 1389–94. 9 Spiess PE, Kassouf W, Brown GA et al. Surgical management of growing teratoma syndrome: the M. D. Anderson Cancer Center Experience. J. Urol. 2007; 177: 1330–4. 10 Tongaonkar H, Deshmane V, Dalal A, Kulkami J, Kamat M. Growing teratoma syndrome. J. Surg. Oncol. 1994; 55: 56–60. 11 Kim P, Syan-Bhanvadia S, Djaladat H et al. Midline extraperitoneal approach for retroperitoneal lymph node dissection for testicular germ cell tumor. Urology 2012; 80: 941–5. 12 Beck SDW, Foster RS, Bihrle R et al. Teratoma in the orchiectomy specimen and volume of metastasis are predictors of retroperitoneal teratoma in post-chemotherapy nonseminomatous testis cancer. J. Urol. 2002; 168 (4, Part 1): 1402–4. 13 Aide N, Comoz F, Sevin E. Enlarging residual mass after treatment of a nonseminomatous germ cell tumor: growing teratoma syndrome or cancer recurrence? J. Clin. Oncol. 2007; 25: 4494–6. 14 Karam JA, Raj GV. Growing teratoma syndrome. Urology 2009; 74: 783–4. 15 Beck SDW, Foster RS, Bihrle R, Einhorn LH, Donohue JP. Long-term outcome for patients with high volume retroperitoneal teratoma undergoing post-chemotherapy surgery. J. Urol. 2009; 181: 2526–32. 16 Stella M, Gandini A, Meeus P et al. Retroperitoneal vascular surgery for the treatment of giant growing teratoma syndrome. Urology 2012; 79: 365–70. 17 Spitz A, Wilson TG, Kawachi MH, Ahlering TE, Skinner DG. Vena caval resection for bulky metastatic germ cell tumors: an 18-year experience. J. Urol. 1997; 158: 1813–8. 18 Van der Gaast A, Kok T, Splinter T. Growing teratoma syndrome successfully treated with lymphoblastoid interferon. Eur. Urol. 1991; 19: 257–8. 19 Rustin G, Kaye S, Williams C, Newlands E, Bagshawe KD, Toy J. Response of differentiated but not anaplastic teratoma to interferon. Br. J. Cancer 1982; 50: 611–6. 20 Mego M, Recková M, Sycˇova-Mila Z et al. Bevacizumab in a growing teratoma syndrome. Case report. Ann. Oncol. 2007; 18: 962–3. 21 Vaughn DJ, Flaherty K, Lal P et al. Treatment of growing teratoma syndrome. N. Engl. J. Med. 2009; 360: 423–4. © 2014 The Japanese Urological Association
International Journal of Urology (2014) 21, 905–908
doi: 10.1111/iju.12466
Original Article: Clinical Investigation
Growing teratoma syndrome: Clinical and radiographic characteristics Dennis J Lee,1 Hooman Djaladat,1 Nicholas N Tadros,2 Mehran Movassaghi,1 Tapas Tejura,1 Vinay Duddalwar1 and Siamak Daneshmand1 1 USC Institute of Urology, Keck Medical Center of USC, Los Angeles, California, and 2Department of Urology, Oregon Health & Science University, Portland, Oregon, USA
Abbreviations & Acronyms AFP = α-fetoprotein CT = computed tomography GTS = growing teratoma syndrome HCG = human chorionic gonadotropin IVC = inferior vena cava LDH = lactate dehydrogenase NSGCT = non-seminomatous germ cell tumor PC-RPLND = postchemotherapy retroperitoneal lymph node dissection Correspondence: Siamak Daneshmand M.D., USC Institute of Urology, Keck Medical Center of USC, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90089, USA. Email: [email protected] Received 24 October 2013; accepted 16 March 2014. Online publication 21 April 2014
Objectives: To present an overview of our surgical experience in the management of growing teratoma syndrome. Methods: A retrospective analysis of all patients undergoing post-chemotherapy retroperitoneal lymphadenectomy between November 2005 and February 2012 revealed 15 patients who met the criteria for growing teratoma syndrome. Their clinical data, imaging characteristics, and surgical and oncological outcomes were reviewed. Results: The median age at diagnosis was 23 years. Primary testis tumors included nonseminomatous germ cell tumor in 12 of 15 patients, seminoma in two of 15 patients and hemorrhagic mass in one patient. Mature teratoma was present in just six (40%) of the orchiectomy specimens. All patients received preoperative chemotherapy. On imaging, the median size of the largest retroperitoneal mass was 7 cm (range 3.9–24.5 cm). The median rate of linear growth was 0.5 cm/month (range 0.03–2.9), and the increase in volume was 9.2 cm3/month. All tumors were found to have cystic and necrotic components. Median operative time was 6.2 h (range 4.2–15.2 h). Estimated blood loss was 600 mL (range 100– 7000 mL), and median length of stay was 5 days (range 3–19 days). Four patients required resection of non-retroperitoneal growing teratoma masses after post-chemotherapy retroperitoneal lymphadenectomy to achieve tumor-free status. There were two minor (Clavien I–II) and two major postoperative complications (Clavien ≥III). All patients are alive and disease free with a median duration of follow-up of 8 months (range 1–64 months). Conclusions: Growing teratoma syndrome tumors vary in their growth rate, but they all appear to have cystic features with necrosis elements on radiographic evaluation. Aggressive surgical excision is associated with excellent outcomes.
Key words:
germ cell tumor, lymph node dissection, teratoma, testis cancer.
Introduction Cisplatin-based chemotherapy regimens in combination with current surgical techniques have resulted in overall survival rates greater than 90% for patients with advanced testicular cancer.1,2 Of patients with advanced NSGCT, 26–65% achieve a complete serological and radiographic response to first-line chemotherapy.3–5 However, in a small subset of patients who undergo chemotherapy for metastatic NSGCT, continued tumor growth occurs, despite normalization of tumor markers.6 This finding was first described by Logothetis et al. as the GTS, and was defined by three criteria: (i) normalization of elevated serum tumor markers; (ii) tumor growth during or after systemic chemotherapy given for NSGCT; and (iii) the histological presence of only mature teratoma at tumor resection.7–9 Jeffrey et al. has reported minor elevations in tumor markers with GTS, but diagnosis otherwise follows the aforementioned criteria.6 GTS most commonly presents in the retroperitoneum, and has a prevalence of 1.9–7.6% in patients with NSGCT.6,8,10 GTS has a variable time-course in presentation.2,6 The diagnosis can be made during chemotherapy, after a significant disease-free period or after an initial reduction in size during chemotherapy, followed by regrowth.6 GTS is resistant to chemotherapy and radiotherapy, and should be managed with complete surgical excision. Failure to treat ultimately leads to morbidity and death resulting from compression of adjacent structures or malignant transformation. In the present study, we report our surgical experience in patients with GTS.
Methods We carried out an institutional review board-approved retrospective chart review of all patients who underwent PC-RPLND at the University of Southern California and Oregon Health and © 2014 The Japanese Urological Association
905
DJ LEE ET AL.
(a)
(b)
Fig. 1 Coronal view showing growth of para-aortic GTS mass from (a) 1.5 to (b) 7.5 cm.
Science University, Los Angeles, California, USA. Out of 108 patients who underwent PC-RPLND, 15 patients were identified who met the criteria for a diagnosis of GTS between November 2005 and February 2012. Patient clinical data, imaging characteristics, and surgical and oncological outcomes were retrospectively collected. All received systemic chemotherapy before RPLND. All patients underwent serial abdominal and pelvic CT scanning to evaluate their response to treatment. CT imaging was reviewed by an experienced radiologist to evaluate tumor volume, growth and characteristics (Fig. 1). Precise tumor growth measurements were available in 11 patients using a CT image-rendering program (3D Synapse; Fujifilm Medical Systems, Stamford, CT, USA). Tumor volume was measured in the other four patients using the equation for 4 an ellipsoid ( V = ). Postoperatively, all specimens were 3πabc histologically confirmed to contain only mature teratoma and no viable cancer.
Results Patient characteristics The clinical characteristics of the 15 patients with GTS are summarized in Table 1. The median age at diagnosis was 23 years. The primary testis tumors were NSGCT in 12 (80%) patients, seminoma in two (13%) and a hemorrhagic mass with necrosis in which no malignant cells were identified in one (7%) patient. Mature teratoma was present in six (40%), a yolk sac in six (40%) and both in four (27%) of the orchiectomy specimens. All patients received cisplatin-based preoperative systemic chemotherapy with a median of four cycles (range 3–6 cycles). The median interval from completion of chemotherapy to PC-RPLND was 3 months (range 2–45 months).
GTS characteristics on preoperative imaging On CT imaging, all GTS tumors were found to have cystic components and evidence of necrosis. The median maximal diameter and volume of the largest retroperitoneal mass on imaging were 7 cm and 70.8 cm3, respectively. The median rate of linear growth was 0.5 cm/month, and increase in volume was 9.2 cm3/month (Table 1 and Fig. 2).
Surgical data Five PC-RPLND were carried out through a midline extraperitoneal approach we previously described, and a nervesparing technique was utilized in six cases.11 All other cases 906
Table 1
Patient and tumor characteristics
Median age at diagnosis (range) Median body mass index, kg/m2 (range) Median tumor markers before PC-RPLND (range) AFP (ng/mL) HCG (mlU/mL) LDH (IU/L) Clinical stage at initial presentation, n (%) IIA IIB IIC IIIA IIIB IIIC International Germ Cell Cancer Collaborative Group classification, n (%) Good risk Intermediate risk Poor risk No. testis primary tumor histology (%) Contained mature teratoma Contained yolk sac NSGCT Seminoma† Hemorrhagic mass with necrosis No. primary tumor pathologic stage (%) pT0 pT1 pT2 Unknown No. metastatic testis Ca sites, n (%) Retroperitoneum Lung Mediastinum Neck Median largest retroperitoneal mass (range) Diameter (cm) Volume (cm3) Median rate of growth of GTS per month (range) Diameter (cm) Volume (cm3)
23 (16–39) 28.6 (18.2–44.4) 2.2 (1–17) 1 (0.6-5) 174 (130–268) 2 (13) 4 (27) 2 (13) 1 (7) 3 (20) 3 (20)
10 (67) 3 (20) 2 (13) 6 (40) 6 (40) 12 (80) 2 (13) 1 (7) 1 (7) 10 (67) 3 (20) 1 (7) 15 (100) 2 (13) 1 (7) 3 (20) 7 (3.9–24.5) 70.8 (22–2938) 0.5 (0.03-2.9) 9.2 (-279–344)
†Patients with elevated alpha fetoprotein (AFP) and only seminoma in their primary orchiectomy specimen are considered to have NSGCT.
were carried out through a standard midline intraperitoneal or modified thoracoabdominal approach. The median operative time was 6.2 h (range 4.2–15.2 h), estimated blood loss was 600 mL (range 100–7000 mL) and three patients required greater than 2 units of blood transfusions intraoperatively. The median length of stay was 5 days (range 3–19 days) (Table 2). © 2014 The Japanese Urological Association
Growing teratoma syndrome
(b)
(a) 8
Table 2
6
80 Volume (cm3)
Fig. 2 Tumor growth rate. Each line represents a patient. The dotted line represents the median rate. (a) Linear growth rate represents change in maximal diameter along an axis. (b) Tumor growth rate represents overall volume growth. Two patients are not shown as a result of overall tumor shrinkage, but with growth along an axis. The data points of four patients lie outside the axial limit, but their growth trajectories are shown.
Diameter (cm)
100
4 2
0
0 1 2 3 4 5 6 7 810 20 30 40 50 Time (months)
Table 3 6.2 (4.2–15.2) 600 (100–7000) 5 (3–19) 8.0 (0.5–64) 1 1 1 2 1 1 1 1 1
Three patients required adjuvant procedures during the PC-RPLND. A left nephrectomy, an IVC tumor thrombectomy, a right renal artery anastomosis and a resection of a right common iliac vein were required because of tumor involvement. Four patients required additional procedures in order to achieve clearance of all teratomas. In these patients, two modified radical neck dissections and a bilateral resection of lung masses were carried out. One patient required a second operation to resect mediastinal, retrocrural and mesenteric masses as a result of large tumor volume.
Complications Three patients required transfusion of more than 2 units of packed red blood cells intraoperatively. There were four postoperative complications (Table 3): (i) a brachial plexus stretch injury causing mild right upper extremity weakness, which resolved without intervention; (ii) a partial small bowel obstruction, which resolved with supportive care without the need for nasogastric tube decompression; (iii) a right arytenoid dislocation from intubation, requiring reduction in the operating room; and (iv) bilateral renal artery ischemia, requiring renal artery stenting and temporary hemodialysis. Intraoperatively, the patient was found to have narrowing of the right renal artery as a result of extensive dissection. A primary anastomosis of the right renal artery was carried out and Doppler ultrasound was used to confirm bilateral blood flow to the © 2014 The Japanese Urological Association
40 20
Surgical/perioperative outcomes
Median (range) Operative time (h) Estimated blood loss (mL) Length of hospital stay (days) Length of follow-up (months) Non-retroperitoneal procedures (n) Mediastinal mass resection Mesenteric lymphadenectomy Bilateral resection of lung masses Radical neck dissection Adjuvant procedures (n) Nephrectomy Renal artery anastomosis Renal artery embolectomy IVC tumor thrombectomy Resection of common iliac vein
60
0
0
5
10 15 Time (months)
20
Complications
I. Pulmonary, n: Right arytenoid dislocation from intubation requiring reduction in OR II. Neurological: Right brachial plexus stretch injury – eventually resolved III. Renal, n: Bilateral renal artery obstruction requiring stenting and hemodialysis IV. Gastrointestinal, n: Partial small bowel obstruction
1 (clavien IIIb)
1 (clavien I) 1 (clavien IVa)
1 (clavien II)
kidneys at the end of the procedure. Unfortunately, the patient developed anuria and was found to have bilateral renal ischemia. A balloon angioplasty of the left renal artery and placement of bilateral renal artery stents was carried out. The patient required temporary hemodialysis, and ultimately partially recovered his renal function with an estimated glomerular filtration rate of 25.6 mL/min.
Outcome Pathological evaluation confirmed the presence of only mature teratoma in all resected specimens. All patients in the present study are alive and disease free with a mean follow up of 13.7 months.
Discussion GTS was first described by Logothetis as a growing mass with normalized tumor markers after chemotherapy for metastatic GCT more than 30 years ago. However, the condition still remains relatively poorly characterized. Large series from Memorial Sloan-Kettering Cancer Center and Indiana University have shown teratoma to be present in retroperitoneal masses in 67–85% of men with teratoma in primary testicular pathology and 28–48% of men without.1,12 Other studies have cited a yolk sac in the primary tumor to be a significant predictor of teratoma in the retroperitoneum.1 In the present series, six (40%) patients had mature teratoma in the primary tumor, six (40%) had a yolk sac and four (27%) contained both. Because of the small number of cases, it is difficult to draw a statistically significant association between the primary pathology and likelihood of GTS in the retroperitoneum. Tumor growth appears to be the only consistent indicator of GTS. Prior studies have 907
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shown the likelihood of finding teratoma in 94% of patients with enlarging retroperitoneal disease after chemotherapy.1,12 In the present cohort, the median linear growth rate was 0.5 cm/ month and volume increase was 9.2 cm3/month. In two patients, overall tumor shrinkage was observed, but continued growth was seen along an axis. There was significant variability in growth patterns, and we were unable to classify GTS based solely on growth rate. This is consistent with the data from Spiess et al.9 Radiographically, all masses showed evidence of necrosis and cystic components. GTS is unresponsive to chemotherapy and radiation therapy, and requires surgical excision to avoid morbidity from malignant transformation and compression.3,8,13 Expeditious surgery is important, as noncompliance and delay in treatment has been associated with increased morbidity and death.14 We do not recommend truncating the chemotherapy regimen if GTS is found unless the surgeon anticipates further tumor growth will render the tumor unresectable or significantly compromise the outcomes of the operation. In men who do not undergo RPLND after systemic chemotherapy, there is a 3–6% risk of malignant transformation of teratoma into non-germ cell elements, such as sarcoma or carcinoma.1 However, the most common complications from GTS result from compression as a result of tumor volume. Reported complications include mesenteric compression with bowel necrosis, obstructive renal failure, bowel obstruction and bile duct obstruction.6,8,10 Giant GTS resulting in high-volume retroperitoneal disease, defined as >10 cm, presents a technical challenge, but should not be considered a contraindication to surgery. Circumferential involvement of major vascular structures is often seen in high-volume disease, and is associated with a 7.1% vena cava resection rate and a 31.3% nephrectomy rate.15,16 Four patients in the present series had high-volume retroperitoneal disease and three of those required adjuvant procedures as a result of vascular involvement: one patient required a left nephrectomy, one patient required re-anastomosis of the right renal artery after narrowing of the artery was seen following removal of circumferential tumor, and one patient required an IVC tumor thrombectomy and resection of the right common iliac vein. In large-volume disease, occlusion of the IVC might be seen due to extrinsic compression from the desmoplastic reaction resulting from chemotherapy and/or tumor volume.17 In most cases, it is safe to resect the IVC because of the development of collateral vasculature.16 However, if there are clinical indications of inadequate collateral circulation, such as lower extremity edema, an IVC reconstruction with a graft might be considered. In patients with inoperable disease, tumor stabilization with medical management could become an option in the future. There are case reports citing the use of interferon,18,19 bevacizumab20 and cyclin-dependent kinase inhibitors to stabilize tumors in inoperable GTS.21 Further research validating the benefits of medical management in these patients is warranted. However, surgical excision remains the current gold standard treatment for GTS, and a complete resection can result in a cure in most patients. PC-RPLND for GTS is a technically demanding procedure, and should be carried out at centers of excellence with vascular expertise to optimize outcomes, because recurrence rates of up to 83% are associated in patients with partial resections.9 908
GTS tumors vary significantly in their rate and pattern of growth, but they all appear to have cystic features with elements of necrosis on radiographic evaluation. Surgery should be carried out as soon as practicably possible to minimize morbidity. Aggressive surgical excision with concomitant adjuvant surgery, if necessary, is associated with excellent outcomes.
Conflict of interest None declared.
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