Partial Orchiectomy for Presumed Malignancy in Patients With a Solitary Testis Due to a Prior Germ Cell Tumor: A Large North American Experience

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1 Partial Orchiectomy for Presumed Malignancy in Patients With a Solitary Testis Due to a Prior Germ Cell Tumor: A Large North American Experience Nathan Lawrentschuk,* Alvaro Zuniga, Arthur C. Grabowksi, Ricardo A. Rendon and Michael A. S. Jewett From the Division of Urology, Departments of Surgical Oncology and Surgery, Princess Margaret Hospital and the University Health Network, University of Toronto (NL, AZ, MASJ) and Department of Urology, Rouge Valley Health Center (ACG), Toronto, Ontario and Department of Urology, Dalhousie University and Queen Elizabeth II Health Sciences Centre (RAR), Halifax, Nova Scotia, Canada Abbreviations and Acronyms CIS carcinoma in situ, intratubular germ cell neoplasia or testicular intratubular germ cell neoplasia GCT germ cell tumor PO partial orchiectomy Submitted for publication May 5, Study received institutional ethics board approval. * Correspondence: Division of Urology., University of Toronto, 610 University Ave., 3-124, Toronto, Ontario, Canada M5G 2C4 (telephone: ; FAX: ; lawrentschuk@gmail.com). Financial interest and/or other relationship with Wyeth, Wyeth/Canadian institutes of Health Research, Pfizer, Viventia, Gyrus, ACMI, Argos and Antigenics. Purpose: Partial orchiectomy is becoming more accepted for indications such as a metachronous germ cell tumor due to reported oncological control, and minimal functional, physical and psychological morbidity. Most data originate from Europe. Thus, we reviewed our North American experience with such men who underwent partial orchiectomy for a presumed contralateral testicular malignancy. Materials and Methods: We identified demographic, clinical, pathological and outcome data on men in our institutional database who underwent partial orchiectomy for presumed testicular malignancy from 1994 to 2009 and had a prior germ cell tumor. Patients were followed with examination, markers and imaging. Results: We identified 27 men, of whom 17 (63%) had malignancy, including seminoma in 9, teratoma in 3, embryonal lesion in 1, Leydig cell tumor in 3 and carcinoma in situ in 1, and 10 (37%) had benign lesions. Frozen section was accurate, no positive margins were reported and all tumors were stage 1. Carcinoma in situ was found in 9 patients (53%). No perioperative complications were recorded. Management after partial orchiectomy was observation in 12 of 17 cases. Two patients underwent completion orchiectomy for local recurrence of carcinoma in situ only, including chemotherapy in 1. A patient with seminoma elected radiation and 1 required retroperitoneal lymph node dissection for teratoma. The remaining 5 patients with carcinoma in situ were surveilled. Of the men 31% required testosterone substitution. All patients were disease free at a median 5.7-year followup with no local recurrences. Conclusions: Partial orchiectomy is an option to decrease morbidity in men with a metachronous germ cell tumor. Clearly a definite benefit of partial orchiectomy is that a significant proportion of patients with suspicious testicular lesions did not have malignancy and were definitively treated with an organ sparing approach. However, partial orchiectomy is potentially associated with the need for adjuvant treatment and androgen substitution, which should be discussed with all patients. Key Words: testis; neoplasms, germ cell and embryonal; orchiectomy; androgens; biopsy TESTICULAR GCTs remain uncommon but comprise 2% of all human male malignancies and are the most common solid tumor in men between ages 15 and 35 years. Worldwide the incidence has more than doubled in the last 40 years with an estimated 8,400 new cases of testicular cancer diagnosed in /11/ /0 Vol. 185, , February 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 PARTIAL ORCHIECTOMY FOR PRESUMED MALIGNANCY IN SOLITARY TESTIS 509 the United States in ,2 Men who have had testicular cancer are at increased risk for a contralateral tumor. The incidence of contralateral testis cancer is 1% to 5%. 3 Metachronous tumors are far more common than bilateral synchronous tumors but the interval between the first and second tumor varies. Bilateral orchiectomy is standard treatment, resulting in androgen insufficiency, infertility and psychological stress. 4 Testis sparing surgery has been advocated to decrease the aforementioned morbidities and PO was originally described in 1984 by Richie. 5 Since then there has been a steady interest in PO for considered indications such as a suspected metachronous germ cell tumor or a mass in a solitary testicle. In concert with this PO has also become more commonplace when lesions are suspected of being benign due to the increase in small nonpalpable lesions detected by ultrasound even in men with a normal contralateral testis. 6 However, if we focus on patients with bilateral GCT most data on PO originate from Europe, 7 9 where the practice is supported by current European Association of Urology guidelines 10 with a paucity of data from North America due to differing practice patterns. Particularly data have mostly been published by the German Testicular Cancer Group 7,8 with a handful of isolated of case reports. 11 However, since the indication is that oncological outcome is rarely compromised, we have performed PO for almost 15 years. Thus, we reviewed our North American institutional experience and outcomes in men who underwent prior radical orchiectomy for GCT, presented with a presumed contralateral testicular malignancy and underwent PO. Figure 1. Key features of partial orchiectomy. A, using inguinal approach with early vascular control with Penrose drain as temporary tourniquet mass is isolated with or without ultrasound. Incision is made in tunica albuginea, allowing around 5 mm normal parenchyma around the mass. B, tumor with margin is excised en bloc. Macroscopic margin (inset) is confirmed before immediate frozen section examination. C, testicle may now be repaired with tunica albuginea carefully sutured with meticulous hemostasis. Testis is returned to scrotum or completion radical orchiectomy is done after frozen section examination result is known. METHODS We have maintained a database of patients with testicular GCT at our institution for 2 decades with institutional ethics board approval. All men specifically consented to PO after being offered radical orchiectomy or PO. We limited our cohort to a retrospective review of men who underwent contralateral testicular surgery after initial orchiectomy for primary GCT between 1994 and Partial orchiectomy was done in standard fashion. The key feature was an inguinal approach with early vascular control using a rubber tourniquet before testicular mobilization into the field to avoid systemic tumor seeding, after which the mass was excised with a core of normal parenchyma around the mass (fig. 1). 12 Frozen section examination was done to determine whether the lesion was malignant and whether a clear margin was obtained. This necessitated 10-minute clamping at our center. Multiple biopsies of the remaining parenchyma, as practiced at other centers, was not done. 7 It is important to avoid violating the tumor capsule in situ since this may increase the risk of local recurrence. Like others, 13,14 in patients with small lesions we have occasionally performed intraoperative ultrasound to locate lesions. Warm or cold ischemia remains controversial 15 but we have not used it. The wound was closed after we received confirmation of clear margins from the pathologist. Patients are discharged home that day unless it is late in the day. Followup consisted of physical examination, tumor markers, imaging according to institutional protocol at varying intervals depending on tumor type and periodic scrotal ultrasound of the remaining testis. All patients were reviewed at our testicular multidisciplinary clinic unless discharged home. Patients were taught regular self-examination of the remaining testis and ultrasound was only initiated if a discrete nodule or change in shape was perceived by the patient or physician. Patients only proceeded to surgery when masses were larger than 1 cm or they showed growth on serial imaging. RESULTS We identified 30 men with metachronous (28) or synchronous (2) testicular masses and a history of

3 510 PARTIAL ORCHIECTOMY FOR PRESUMED MALIGNANCY IN SOLITARY TESTIS GCT. In 3 men metachronous GCT was not amendable to PO due to size in the same period and they underwent radical orchiectomy. In 1 of these men PO had been attempted but it was converted to radical orchiectomy due to tumor size with too small a remnant that would have remained. Thus, 27 men with a median age of 34 years fulfilled the study criteria of contralateral testicular surgery after initial orchiectomy and subsequent PO. The table 1 lists characteristics. Overall 17 men (63%) had malignant lesions, including seminoma in 9, teratoma in 3, embryonal in 1, Leydig cell in 3 and CIS in 1, while 10 (37%) had benign pathological findings (fig. 2). Frozen section detected malignancy accurately but differentiation of GCT from Leydig was difficult in two cases where seminoma was provisionally reported but this did not alter management. CIS was difficult to detect on frozen section. Final histopathology revealed no positive margins and all tumors were stage 1. Testosterone was normal before PO. No perioperative hematomas occurred that required drainage or hospitalization and no infection, or other perioperative or late complication was recorded. Median followup was 5.7 years (range 1.5 to 15.1) in men with malignant lesions. Two patients were followed in other provinces and were censored at last followup, resulting in an overall and diseasefree median followup of 7.1 years in the malignant cohort. In 4 patients ultrasound was done due to perceived irregularity of the remaining testis, including 3 in whom small impalpable lesions were identified that grew but were benign after surgery. Remaining ultrasounds in the series were prompted by self-examination findings of a palpable lump in the testis. CIS was noted in 9 patients (53%), including in 7 with seminoma (see table). Figure 2 shows management after orchiectomy. Four patients who had CIS also received further treatment. Followup revealed local recurrence in 2 patients with seminoma despite clear margins and each underwent completion radical orchiectomy. The first patient had 6 mm pure seminoma that was marker negative and not multifocal, which recurred at 8 months. Resultant orchiectomy showed a small 4 mm recurrence. The second patient presented with synchronous GCT. The 26 mm primary or right radical orchiectomy specimen was mixed (80% embryonal and 20% seminoma) and the 15 mm left PO specimen was pure seminoma and not multifocal. He was monitored but tumor markers did not normalize. Completion orchiectomy again revealed pure seminoma. However, given the original pathological findings of embryonal carcinoma and no evidence of disease on imaging, he was treated with chemotherapy (3 cycles of bleomycin, etoposide and cisplatin) for micrometastatic dis- Outcome in men with PO who underwent prior orchiectomy for GCT Histopathology Median Yrs Followup After PO (range) No. Multifocal/ No. CIS Frozen Section (No. pts) Median mm Size (range) Median mm Ultrasound Size (range) Site (upper/ mid/lower pole) Median Yrs Primary Contralat Mass (range) Primary Tumor (No. pts) Testicular Mass at PO No. Pts 3/4/3 10 (5 28) 7.5 (3 15) 0/0 Correct (10) Not applicable Benign (0 9.4) Seminoma (8), nonseminomatous GCT (2) 5.7 (0 14.1) 6/5/6 11 (6 27) 14 (3 27) 5/9 Correct (17), correct for type (15) Malignant (0 15.1*) Seminoma (11), nonseminomatous GCT (3), mixed (1), teratoma (2) 7.1 (0 14.1) Seminoma 9 3 (0 13.4*) Seminoma (8), mixed (1) 3/3/3 11 (6 27) 15 (11 27) 3/7 Seminoma (8), seminoma CIS (1) 9.2 ( ) 2/1/0 12 (6 15) 9 (3 15) 1/1 Teratoma (1), GCT (1), GCT CIS (1) Teratoma 3 1 ( ) Teratoma (1), nonseminomatous GCT (3) Embryonal Teratoma embryonal 1/ / 11 No CIS Embryonal 7.7 CIS Seminoma / /1 9 CIS MF CIS 12.5 Leydig tumor ( ) Seminoma (2), /1/2 8 (7 11) 11 (9 14) 0/0 Seminoma (2), Leydig (1) 3.9 ( ) nonseminomatouscgt (1) * Primary surgery date not available on 1 patient. Including 2 patients discharged to another province for care.

4 PARTIAL ORCHIECTOMY FOR PRESUMED MALIGNANCY IN SOLITARY TESTIS 511 Figure 2. Management in cohort presenting with metachronous testicular mass in solitary testis. RPLND, retroperitoneal lymphadenectomy. ease 4 months after the original PO. He responded and it is now 2 years later. One patient with seminoma with CIS and the patient with only CIS elected local radiation 4 months after PO. Each had normal testosterone. The remaining 5 patients with CIS underwent surveillance without evidence of disease recurrence for a median of 8.6 years (range 3.1 to 10.4). Testosterone substitution was observed in 31% of the malignant cohort and in only 1 patient in the benign cohort. In the malignant cohort all except 1 of these men received further local radiation or systemic treatment. Otherwise, there was no relationship between tumor size, multifocality or CIS. Another patient without CIS in whom the primary contralateral tumor was teratoma had distant recurrence after PO for a 10 mm embryonal carcinoma that was not multifocal with a 2 cm retroperitoneal node and negative serum markers at 4-month followup. This necessitated retroperitoneal lymphadenectomy with embryonal cancer in the solitary node. The residual testis was left and remained disease-free. All patients were disease-free. One patient with a Leydig cell tumor had a stable 2 mm lesion on ultrasound that has not progressed in 2 years. DISCUSSION PO represents another branch of minimally invasive oncology management. In this case morbidity, functionality, cosmesis and psychological results are decreased. Many small testicular masses discovered today are benign and radical treatment usually represents overtreatment, contributing to the uptake of PO. However, concerns remain regarding the risk of compromising disease specific survival and the success of organ sparing to avoid the side effects that prompted the initial effort to preserve apparently normal testicular tissue. The most common approach to organ preserving surgery has been PO but high intensity focused ultrasound, radiation therapy and chemotherapy have been reported. 16,17 Current European Germ Cell Cancer Consensus group guidelines state the situations in which an organ sparing approach should be considered, including synchronous bilateral testis tumors and a metachronous contralateral (second) testis tumor in a solitary testis. 18 There should be sufficient endocrine function and PO should be done only at experienced centers. Our series shows that PO is feasible and safe, and provides acceptable cancer control. A significant number of benign lesions thought to be malignant were removed, sparing unnecessary morbidity in these patients. However, 2 patients required completion orchiectomy for local recurrence. This is certainly more than we would have anticipated and serves as caution when offering PO. One patient had few consequences and was disease free after completion orchiectomy. However, in the other patient with synchronous disease persistent markers developed, requiring chemotherapy for stage CS disease soon after completion orchiectomy. The PO side was pure seminoma and the other side was other mainly embryonal. One may speculate that disease from the other primary lesion rather than from the PO side explained this systematic disease. CIS is defined as malignant, preinvasive testicular GCT 7 with 50% to 70% cumulative probability of a testicular tumor after 5 to 7 years. 19,20 As a result, CIS in the affected testis at PO or after testicular sparing surgery remains a challenge. The gold standard remains completion orchiectomy but radiother-

5 512 PARTIAL ORCHIECTOMY FOR PRESUMED MALIGNANCY IN SOLITARY TESTIS apy and observation strategies also provide excellent oncologic control in the long term and all should be discussed with the patient. 18,21 At most centers 20 Gy are recommended when adjuvant local radiation treatment is chosen to treat CIS. 7,18,21 However, this dose may compromise androgen production in up to 25% of men. 22 Thus, to preserve testosterone production a radiation dose of less than 20 Gy was investigated but the potential benefit of this strategy is controversial. 7,18,21,23 Observation is recommended in men at low risk for local recurrence who comply with scheduled examination and ultrasound followup with any suspicions findings acted on. The risks of adjuvant procedures are avoided, hence, not compromising endocrine function of the remaining testicle, 12,15 as in our series. Some urologists also contend that if background testosterone is secreted, even in the event of requiring supplementation, fewer peaks and valleys in serum levels likely result if some testis is preserved. However, data are lacking. Regarding adjuvant local radiation for CIS, in our cohort more men elected observation alone than in a German study 8 (56% vs 21%). A possible explanation is that at our center there is interest in surveillance for testicular cancer, particularly since we have found less progression in our population with CIS than is commonly stated in the literature, which has influenced management decisions. Another pertinent finding is that 31% of our patients required supplementation, in contrast to around 10% in the German series. 8 However, all except 1 of our patients on supplementation received adjuvant treatment that may have impacted testicular function. An organ sparing surgical approach is only recommend at our center in select cases and we believe that it should only be performed at centers where there is experience with managing GCT. Radical orchiectomy remains the gold standard and should be discussed as part of informed consent. It is mandatory to highlight the risks of local recurrence and CIS, and treatment (observation, radiation or completion orchiectomy) as well as the need for androgen supplementation and fertility risks. We routinely measure testosterone preoperatively. In men with a healthy normal testis contralaterally we believe that PO is contraindicated when malignancy is suspected. In these men one should only attempt PO when it is almost certain that the lesion is benign, ie no risk factors for GCT, small lesion size, negative markers, no history of trauma, etc. Presenting lesion size is important since those greater than 2 cm are extremely suspicious for malignancy and preserving sufficient parenchyma becomes difficult. In terms of location, as in our series, all locations were equally represented. However, we do not consider medial tumors adjacent to the mediastinum testis favorable, although they are possible. The study limitations are our retrospective data and the fact that fertility data were not available on the whole cohort. Such data are now being collected and we await more time to gather information but it appears we will obtain results similar to those of the German group. 8 Furthermore, it is difficult to assess the impact of an additional annual ultrasound and more physician visits and yet these patients were already being followed for GCT with each, and so we believe that the impact was minimal. It would be ideal to have longer followup (greater than 10 years) in all patients with malignancy to be certain of the safety of PO regarding local recurrence. Finally, specific psychological and quality of life data are not reported but we have received no requests for completion orchiectomy or prostheses to date. Such information is now being collected. CONCLUSIONS Reconsidering the necessity of radical extirpative surgery continues to gather momentum in urological oncology A relevant example is the reconsideration of radical orchiectomy in infertile men with incidentally discovered, small testicular lesions, in whom surveillance may be a sound recommendation when no growth occurs. 27 Thus, urologists must maintain a focused view on the outcomes, advantages and disadvantages of such an approach. In this context organ sparing surgery remains an option in men with imperative indications to decrease morbidity but it is potentially associated with recurrence, adjuvant treatment and androgen substitution. Clearly a definite benefit of PO is that a significant proportion of our patients with suspicious testicular lesions did not have GCT and were definitively treated with an organ sparing approach. Furthermore, endocrine function may be maintained in most men, in addition to the psychological and cosmetic benefits of having the native testicle remain. At this stage we do not pursue PO in men with a normal contralateral testicle unless our index of suspicion for a benign lesion is extremely high, eg using serial observation and imaging of a small lesion in a man with no risk factors for GCT, and until longer term data are available from other centers. ACKNOWLEDGMENTS Janice Yau, Biomedical Communications, University of Toronto provided figure 1.

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