Grand Rounds Hypermetabolic Residual Retroperitoneal Mass After Chemotherapy for Primary Seminoma Jamie Sungmin Pak, Edan Shapiro, Elizabeth M. Margolskee, and James M. McKiernan
CASE PRESENTATION
A
21-year-old previously healthy man presented with a 6-month history of “two bumps” in the right testicle detected on self-examination, which had significantly expanded in size over the course of a few weeks. Doppler ultrasound of the scrotum revealed an enlarged right testis largely replaced at the upper aspect by a heterogeneous hypervascular mass, as well as a second mass measuring 2.2 3.2 cm noted to be projecting above the right testis with possible epididymal involvement; the contralateral testis was normal in appearance. Computed tomography (CT) scan of the chest, abdomen, and pelvis was also performed and revealed a 4.5 4.5 cm retroperitoneal (RP) mass located anterior to the proximal inferior vena cava, compatible with metastatic lymphadenopathy; there was no involvement of the chest. Tumor markers resulted in a slightly elevated alpha-fetoprotein (AFP) level of 9.1 ng/mL (0.0-8.5 ng/mL), normal human chorionic gonadotropin of 3 cm, there was a higher incidence of viable tumor or local disease progression.1-3 Herr et al2 discovered viable tumor in 8 of 27 residual masses (30%) >3 cm, consisting of 6 seminomas and 2 teratomas, vs 0 of 28 masses 3 cm were either found to have viable tumor at the time of resection or site relapse after observation; of the 3 resected tumors, there were 2 seminomas and 1 teratoma. There have also been case reports of a schwannoma and leiomyosarcoma mimicking residual RP masses of a primary seminoma, although these are much rarer.4,5
ADDITIONAL MANAGEMENT AND PATHOLOGIC EVALUATION Despite the final pathology revealing a primary seminoma, the patient’s slightly elevated AFP level http://dx.doi.org/10.1016/j.urology.2015.01.016 0090-4295/15
987
Figure 1. Pathology evaluation of the right testicular mass. (A) Diffuse effacement of normal testicular architecture with lobulated cellular mass (4, hematoxylin and eosin [H&E]) and (B) seminoma cells with clear cytoplasm and eccentric nuclei, bounded by thin fibrous septa (20, H&E). Immunohistochemical stains show diffuse positivity for OCT-4 (C) and no expression of CD30 (D). (E) Focal venous invasion is seen (10, H&E). (Color version available online.)
throughout much of the postoperative course, as well as the minimal response of the RP mass to chemotherapy, was suggestive of a nonseminomatous component to the mass. A joint decision by the urologic and medical oncology teams was to perform a fluorine-18 fluorodeoxyglucose (FDG)epositron emission tomography (PET) scan to better characterize this mass. This revealed a mildly hypermetabolic precaval adenopathy measuring 4.0 3.2 cm with a standardized uptake value of 2.2 at the site of the RP disease, located just below the level of the lower pole of the right kidney (Fig. 3). With the findings on FDG-PET, the patient was scheduled to undergo surgical resection of the mass with intraoperative frozen section, and a plan for a full RP lymph node dissection, if there was evidence of nonseminomatous germ cell tumor (NSGCT). The mass was found to be adherent to the vena caval wall with a local desmoplastic reaction but was successfully dissected free. 988
All pericaval and precaval lymph nodes were also removed. After meticulous intraoperative review by a dedicated genitourinary pathologist, the RP mass was a benign myofibroblastic tumor that required further evaluation on permanent sections. There were no viable seminomatous, NSGCT, or teratomatous elements present within the mass. Final pathologic diagnosis was a smooth muscle neoplasm, consistent with vascular leiomyoma (Fig. 4). Histologic review of the RP mass showed a bland spindlecell proliferation without atypia or mitoses. Prominent thick-walled vessels were noted. Immunohistochemical staining was positive for desmin and smooth muscle actin, confirming the diagnosis of vascular leiomyoma. Most significantly for clinical staging, no germ cell neoplasm was identified. This restaged the patient as pT2N0Mx. Since resection of the RP mass, the patient has been followed up for 2 years with regular chest x-rays, magnetic UROLOGY 85 (5), 2015
Figure 2. Postorchiectomy computed tomography of abdomen or pelvis in transverse plane showing retroperitoneal mass.
resonance imaging of the abdomen and pelvis, and serum tumor markers; there is no evidence of disease recurrence.
DISCUSSION About one-fifth of patients with primary seminoma present with clinical stage II disease, and standard treatment for patients with “bulky disease” (stage IIB or IIC) has involved multiagent cisplatin-based chemotherapy. In this setting, chemotherapy has proven to be a very effective treatment, with 5-year overall survival of 86% and 72% in patients with good or intermediate risk according to International Germ Cell Cancer Collaborative Group criteria, respectively. Even so, up to 80% of patients with initially bulky disease will exhibit a residual mass on follow-up CT scan, as seen in the presented patient.6 Options for management of these masses include surveillance, resection, radiotherapy (RT), or a PET scan. Based on the early surgical series, residual masses 3 cm, optimal management is still controversial. Surgical resection of the mass is commonly used based on data supporting its local control benefit over biopsy or observation, even with radiation and chemotherapy on a salvage basis.2 Resection also has the added benefit of histologic confirmation of the resected mass to inform additional therapy. Unlike with primary NSGCT, surgery for the residual mass in primary seminoma does not involve RP lymph node dissection owing to the technical difficulty of operating after the desmoplastic reaction of these masses after chemotherapy. RT is also used for residual masses, especially for those in which surgical resection is deemed too difficult. However, a large European study demonstrated no significant difference in progression-free survival at 3 years for patients with or without RT. There was also no significant difference in median progression-free survival for UROLOGY 85 (5), 2015
Figure 3. Fluorine-18 fluorodeoxyglucoseepositron emission tomography scan after chemotherapy. (A) Transverse plane and (B) coronal plane. (Color version available online.)
patients who relapsed after radiation vs those who relapsed during observation.7 In addition, RT does not appear to reduce the risk of relapse, and without histologic diagnosis, many patients likely receive RT unnecessarily.8 To fulfill the need for a noninvasive assessment of disease, PET scans have been increasingly used in this setting to guide further management, as was done for our patient. The prospective SEMPET trial demonstrated the superiority of FDG-PET in predicting viable tumor in residual masses vs the CT size criteria of 3 cm. FDG-PET performed especially well with masses >3 cm, demonstrating 100% accuracy in predicting the absence or presence of viable tumor.9 Subsequent studies have demonstrated rates of false-positive FDG-PET findings ranging from 0% to 50%.10-12 These false-positive findings either displayed no progression clinically or on CT, or eventually revealed fibrosis, necrosis, or inflammation with surgery. It is important to note that the time from completion of chemotherapy to FDG-PET in these studies was variable. For example, Hinz et al12 had a median time from completion of chemotherapy to an FDG-PET of 29 days. Of particular importance, Bachner et al demonstrated a significant improvement in the accuracy of FDG-PET with a cut-off level of 6 weeks after the end of the last 989
Figure 4. Pathology of retroperitoneal mass. (A) Low-power view of spindle-cell lesion with areas of degeneration and prominent vessels (2, hematoxylin and eosin), (B) spindle cells arranged in fascicles with ample eosinophilic, fibrillar cytoplasm, compatible with smooth muscle cells (20, hematoxylin and eosin), and (C) positive immunohistochemical staining for desmin confirms smooth muscle lineage (10). (Color version available online.)
chemotherapy cycle. The positive predictive value increased from 25% to 69%, with the overall accuracy improving significantly from 73% to 88% before and after the cut-off, respectively.11 Despite the FDG-PET being performed 7 weeks after our patient’s last chemotherapy cycle, careful review of the pathologic specimen revealed a benign leiomyoma with no evidence of malignancy. Therefore, this case is the first known report of a benign vascular lesion mimicking a hypermetabolic, residual RP mass after chemotherapy of a primary seminoma. Although there are no superior alternatives to FDG-PET scan at this time, the possibility of false-positive findings must be accounted for in the decision to proceed with subsequent treatment in this patient population. References 1. Flechon A, Bompas E, Biron P, et al. Management of postchemotherapy residual masses in advanced seminoma. J Urol. 2002;168:1975-1979. 2. Herr HW, Sheinfeld J, Puc HS, et al. Surgery for a postchemotherapy residual mass in seminoma. J Urol. 1997;157: 860-862. 3. Ravi R, Ong J, Oliver RT, et al. The management of residual masses after chemotherapy in metastatic seminoma. BJU Int. 1999;83: 649-653.
990
4. Zhang SQ, Wu S, Yao K, et al. Retroperitoneal schwannoma mimicking metastatic seminoma: case report and literature review. Chin J Cancer. 2013;32:149-152. 5. Stein ME, Leviov M, Drumea K, et al. Radiation-induced sarcoma following curative radiotherapy for testicular seminoma: case report and brief review of the literature. Tumori. 1997;83:721-723. 6. Alexander EJ, White IM, Horwich A. Update on management of seminoma. Indian J Urol. 2010;26:82-91. 7. Duchesne GM, Stenning SP, Aass N, et al. Radiotherapy after chemotherapy for metastatic seminoma—a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer. 1997;33:829-835. 8. Horwich A, Paluchoswka B, Norman A, et al. Residual mass following chemotherapy of seminoma. Ann Oncol. 1997;8:37-40. 9. De Santis M, Becherer A, Bokemeyer C, et al. 2-18fluoro-deoxy-Dglucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol. 2004;22:10341039. 10. Lewis DA, Tann M, Kesler K, et al. Positron emission tomography scans in postchemotherapy seminoma patients with residual masses: a retrospective review from Indiana University Hospital. J Clin Oncol. 2006;24:e54-55. 11. Bachner M, Loriot Y, Gross-Goupil M, et al. 2-18fluoro-deoxy-Dglucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial. Ann Oncol. 2012;23:59-64. 12. Hinz S, Schrader M, Kempkensteffen C, et al. The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol. 2008;179: 936-940.
UROLOGY 85 (5), 2015
CASE PRESENTATION
A
21-year-old previously healthy man presented with a 6-month history of “two bumps” in the right testicle detected on self-examination, which had significantly expanded in size over the course of a few weeks. Doppler ultrasound of the scrotum revealed an enlarged right testis largely replaced at the upper aspect by a heterogeneous hypervascular mass, as well as a second mass measuring 2.2 3.2 cm noted to be projecting above the right testis with possible epididymal involvement; the contralateral testis was normal in appearance. Computed tomography (CT) scan of the chest, abdomen, and pelvis was also performed and revealed a 4.5 4.5 cm retroperitoneal (RP) mass located anterior to the proximal inferior vena cava, compatible with metastatic lymphadenopathy; there was no involvement of the chest. Tumor markers resulted in a slightly elevated alpha-fetoprotein (AFP) level of 9.1 ng/mL (0.0-8.5 ng/mL), normal human chorionic gonadotropin of 3 cm, there was a higher incidence of viable tumor or local disease progression.1-3 Herr et al2 discovered viable tumor in 8 of 27 residual masses (30%) >3 cm, consisting of 6 seminomas and 2 teratomas, vs 0 of 28 masses 3 cm were either found to have viable tumor at the time of resection or site relapse after observation; of the 3 resected tumors, there were 2 seminomas and 1 teratoma. There have also been case reports of a schwannoma and leiomyosarcoma mimicking residual RP masses of a primary seminoma, although these are much rarer.4,5
ADDITIONAL MANAGEMENT AND PATHOLOGIC EVALUATION Despite the final pathology revealing a primary seminoma, the patient’s slightly elevated AFP level http://dx.doi.org/10.1016/j.urology.2015.01.016 0090-4295/15
987
Figure 1. Pathology evaluation of the right testicular mass. (A) Diffuse effacement of normal testicular architecture with lobulated cellular mass (4, hematoxylin and eosin [H&E]) and (B) seminoma cells with clear cytoplasm and eccentric nuclei, bounded by thin fibrous septa (20, H&E). Immunohistochemical stains show diffuse positivity for OCT-4 (C) and no expression of CD30 (D). (E) Focal venous invasion is seen (10, H&E). (Color version available online.)
throughout much of the postoperative course, as well as the minimal response of the RP mass to chemotherapy, was suggestive of a nonseminomatous component to the mass. A joint decision by the urologic and medical oncology teams was to perform a fluorine-18 fluorodeoxyglucose (FDG)epositron emission tomography (PET) scan to better characterize this mass. This revealed a mildly hypermetabolic precaval adenopathy measuring 4.0 3.2 cm with a standardized uptake value of 2.2 at the site of the RP disease, located just below the level of the lower pole of the right kidney (Fig. 3). With the findings on FDG-PET, the patient was scheduled to undergo surgical resection of the mass with intraoperative frozen section, and a plan for a full RP lymph node dissection, if there was evidence of nonseminomatous germ cell tumor (NSGCT). The mass was found to be adherent to the vena caval wall with a local desmoplastic reaction but was successfully dissected free. 988
All pericaval and precaval lymph nodes were also removed. After meticulous intraoperative review by a dedicated genitourinary pathologist, the RP mass was a benign myofibroblastic tumor that required further evaluation on permanent sections. There were no viable seminomatous, NSGCT, or teratomatous elements present within the mass. Final pathologic diagnosis was a smooth muscle neoplasm, consistent with vascular leiomyoma (Fig. 4). Histologic review of the RP mass showed a bland spindlecell proliferation without atypia or mitoses. Prominent thick-walled vessels were noted. Immunohistochemical staining was positive for desmin and smooth muscle actin, confirming the diagnosis of vascular leiomyoma. Most significantly for clinical staging, no germ cell neoplasm was identified. This restaged the patient as pT2N0Mx. Since resection of the RP mass, the patient has been followed up for 2 years with regular chest x-rays, magnetic UROLOGY 85 (5), 2015
Figure 2. Postorchiectomy computed tomography of abdomen or pelvis in transverse plane showing retroperitoneal mass.
resonance imaging of the abdomen and pelvis, and serum tumor markers; there is no evidence of disease recurrence.
DISCUSSION About one-fifth of patients with primary seminoma present with clinical stage II disease, and standard treatment for patients with “bulky disease” (stage IIB or IIC) has involved multiagent cisplatin-based chemotherapy. In this setting, chemotherapy has proven to be a very effective treatment, with 5-year overall survival of 86% and 72% in patients with good or intermediate risk according to International Germ Cell Cancer Collaborative Group criteria, respectively. Even so, up to 80% of patients with initially bulky disease will exhibit a residual mass on follow-up CT scan, as seen in the presented patient.6 Options for management of these masses include surveillance, resection, radiotherapy (RT), or a PET scan. Based on the early surgical series, residual masses 3 cm, optimal management is still controversial. Surgical resection of the mass is commonly used based on data supporting its local control benefit over biopsy or observation, even with radiation and chemotherapy on a salvage basis.2 Resection also has the added benefit of histologic confirmation of the resected mass to inform additional therapy. Unlike with primary NSGCT, surgery for the residual mass in primary seminoma does not involve RP lymph node dissection owing to the technical difficulty of operating after the desmoplastic reaction of these masses after chemotherapy. RT is also used for residual masses, especially for those in which surgical resection is deemed too difficult. However, a large European study demonstrated no significant difference in progression-free survival at 3 years for patients with or without RT. There was also no significant difference in median progression-free survival for UROLOGY 85 (5), 2015
Figure 3. Fluorine-18 fluorodeoxyglucoseepositron emission tomography scan after chemotherapy. (A) Transverse plane and (B) coronal plane. (Color version available online.)
patients who relapsed after radiation vs those who relapsed during observation.7 In addition, RT does not appear to reduce the risk of relapse, and without histologic diagnosis, many patients likely receive RT unnecessarily.8 To fulfill the need for a noninvasive assessment of disease, PET scans have been increasingly used in this setting to guide further management, as was done for our patient. The prospective SEMPET trial demonstrated the superiority of FDG-PET in predicting viable tumor in residual masses vs the CT size criteria of 3 cm. FDG-PET performed especially well with masses >3 cm, demonstrating 100% accuracy in predicting the absence or presence of viable tumor.9 Subsequent studies have demonstrated rates of false-positive FDG-PET findings ranging from 0% to 50%.10-12 These false-positive findings either displayed no progression clinically or on CT, or eventually revealed fibrosis, necrosis, or inflammation with surgery. It is important to note that the time from completion of chemotherapy to FDG-PET in these studies was variable. For example, Hinz et al12 had a median time from completion of chemotherapy to an FDG-PET of 29 days. Of particular importance, Bachner et al demonstrated a significant improvement in the accuracy of FDG-PET with a cut-off level of 6 weeks after the end of the last 989
Figure 4. Pathology of retroperitoneal mass. (A) Low-power view of spindle-cell lesion with areas of degeneration and prominent vessels (2, hematoxylin and eosin), (B) spindle cells arranged in fascicles with ample eosinophilic, fibrillar cytoplasm, compatible with smooth muscle cells (20, hematoxylin and eosin), and (C) positive immunohistochemical staining for desmin confirms smooth muscle lineage (10). (Color version available online.)
chemotherapy cycle. The positive predictive value increased from 25% to 69%, with the overall accuracy improving significantly from 73% to 88% before and after the cut-off, respectively.11 Despite the FDG-PET being performed 7 weeks after our patient’s last chemotherapy cycle, careful review of the pathologic specimen revealed a benign leiomyoma with no evidence of malignancy. Therefore, this case is the first known report of a benign vascular lesion mimicking a hypermetabolic, residual RP mass after chemotherapy of a primary seminoma. Although there are no superior alternatives to FDG-PET scan at this time, the possibility of false-positive findings must be accounted for in the decision to proceed with subsequent treatment in this patient population. References 1. Flechon A, Bompas E, Biron P, et al. Management of postchemotherapy residual masses in advanced seminoma. J Urol. 2002;168:1975-1979. 2. Herr HW, Sheinfeld J, Puc HS, et al. Surgery for a postchemotherapy residual mass in seminoma. J Urol. 1997;157: 860-862. 3. Ravi R, Ong J, Oliver RT, et al. The management of residual masses after chemotherapy in metastatic seminoma. BJU Int. 1999;83: 649-653.
990
4. Zhang SQ, Wu S, Yao K, et al. Retroperitoneal schwannoma mimicking metastatic seminoma: case report and literature review. Chin J Cancer. 2013;32:149-152. 5. Stein ME, Leviov M, Drumea K, et al. Radiation-induced sarcoma following curative radiotherapy for testicular seminoma: case report and brief review of the literature. Tumori. 1997;83:721-723. 6. Alexander EJ, White IM, Horwich A. Update on management of seminoma. Indian J Urol. 2010;26:82-91. 7. Duchesne GM, Stenning SP, Aass N, et al. Radiotherapy after chemotherapy for metastatic seminoma—a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer. 1997;33:829-835. 8. Horwich A, Paluchoswka B, Norman A, et al. Residual mass following chemotherapy of seminoma. Ann Oncol. 1997;8:37-40. 9. De Santis M, Becherer A, Bokemeyer C, et al. 2-18fluoro-deoxy-Dglucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol. 2004;22:10341039. 10. Lewis DA, Tann M, Kesler K, et al. Positron emission tomography scans in postchemotherapy seminoma patients with residual masses: a retrospective review from Indiana University Hospital. J Clin Oncol. 2006;24:e54-55. 11. Bachner M, Loriot Y, Gross-Goupil M, et al. 2-18fluoro-deoxy-Dglucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial. Ann Oncol. 2012;23:59-64. 12. Hinz S, Schrader M, Kempkensteffen C, et al. The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol. 2008;179: 936-940.
UROLOGY 85 (5), 2015
