- Email: [email protected]
Conservative Surgical Therapy for Leydig Cell Tumor
Conservative Surgical Therapy for Leydig Cell Tumor Luca Carmignani,* Renzo Colombo, Franco Gadda, Giacomo Galasso, Andrea Lania, Juan Palou, Ferran Algaba, Humberto Villavicencio, Giovanni Maria Colpi, Ottavio Decobelli, Roberto Salvioni, Giorgio Pizzocaro, Patrizio Rigatti and Francesco Rocco From the Urology Unit (LC, FG, FR, GG) and Endocrinology Unit (AL), Department of Medicine and Surgery, University of Milan, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Urology Unit, University of Milan, Istituto Europeo di Oncologia (OD), Urology Unit, Fondazione Istituto Nazionale per lo Studio e la Cura dei Tumori (RS, GP), Urology Unit, Università Vita e Salute, Istituto San Raffaele (RC, PR), Andrology Unit, San Paolo Hospital (GMC), Milan, Italy, and Urology Unit (JP, HV) and Pathology Unit (FA), Fundacio Puigvert, Barcelona, Spain
Purpose: We performed a long-term evaluation of conservative surgical treatment of benign Leydig cell tumor. Materials and Methods: A multicenter retrospective clinical study was performed at 6 European centers. Case files of all patients diagnosed with Leydig cell tumor and treated with conservative surgery were examined. Patients underwent physical examination, hormone and tumor marker assays, scrotal and abdominal ultrasound, chest x-ray, and an endocrinological examination. Results: From 1987 to 2006, 22 patients with Leydig cell tumor underwent conservative surgery. Mean patient age was 35 years (range 5 to 61). Mean followup was 47 months (range 1 to 230). No local recurrence or metastasis was observed. Patients presented with a palpable testicular nodule (3 patients, 13.7%) or a nodule diagnosed by ultrasound (15 patients, 68.2%), gynecomastia (2 patients, 9.1%), precocious pseudopuberty (1 patient, 4.5%) or scrotal pain (1 patient, 4.5%). Three patients were monorchid after contralateral orchiectomy for inguinal hernia repair (1 patient, 28 years before surgery) and nonseminomatous germ cell tumor (2 patients, 1 month and 6 years before surgery). Diagnosis after frozen section examination was Leydig cell tumor in 20 of 22 cases (91.0%). Mean histological size of the nodule was 1.11 cm (range 0.5 to 2.5). Preoperative FSH and LH levels were high in 4 patients. Tumor markers were normal before and after surgery. Followup was conducted for all patients every 3 to 6 months with physical examination, tumor markers, scrotal and abdominal ultrasound, chest x-ray. Six patients (27.3%) underwent abdominal computerized tomography. Conclusions: When diagnosed early Leydig cell tumors present a favorable followup. In select cases with motivated patients, conservative surgery proved to be a feasible and safe choice. Key Words: Leydig cell tumor, early diagnosis, prognosis
tromal and paratesticular tumors are rare diseases and account for less than 3% of testicular neoplasia.1 Leydig cell tumors are the most common stromal tumors. The natural history of these forms is poorly known and it is not always easy to distinguish between benign and malignant forms. The literature presents conflicting data, as several mostly benign case reports exist alongside other publications that report the possibility of tumor metastasis.2–5 In particular instances, when patients were highly motivated because they were monorchid or infertile, a conservative therapy was opted for, removing exclusively the tumor nodule, with favorable results. The aim of this study was long-term evaluation of conservative therapy for Leydig cell tumors performed at 6 urology centers.
MATERIALS AND METHODS
S
A retrospective clinical study was performed at 6 European centers: the Ospedale Maggiore Policlinico, San Paolo Hospital, San Raffaele Hospital, Istituto Nazionale per lo Studio e la Cura dei Tumori and Istituto Europeo di Oncologia in Milan, and the Puigvert Foundation in Barcelona. Case files of all patients who were diagnosed with Leydig cell tumor and who underwent conservative therapy were analyzed. Only patients who were first diagnosed at 1 of the 6 participating centers were considered. All patients were recalled by the center coordinating the study and reassessed by medical history, physical examination, tumor marker assays, hormone assays (LH, FSH, PRL, testosterone, estradiol), scrotal and abdominal ultrasound, chest x-ray, an endocrinological examination, and postoperative paternity evaluation. Appendix 1 shows the parameters considered in the study. Fertility status was also taken into account. Following the definition by the WHO, we considered patients to be infertile when they were unable to achieve conception after at least 1 year of unprotected intercourse.6 Differences in the postoperative followup between the various participating centers were also evaluated.
Submitted for publication November 30, 2006. * Correspondence: Department of Medicine and Surgery, Urology Unit, University of Milan, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Via Luigi Sacco 7, 20146 Milano, Italy (telephone: 0039 02-55034502; FAX: 0039 02-50320584; e-mail: [email protected]).
0022-5347/07/1782-0507/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
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Vol. 178, 507-511, August 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.03.108
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CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR
Surgical Strategy Conservative surgery was performed via inguinotomy with preventive clamping of the spermatic cord and exposure of the testicle in a separate operative field. Ultrasound guidance was used, or palpation if lesions were palpable. The lesion was isolated and the material was sent for frozen section examination. Particular care was taken to make sure the entire lesion and the separate margins were sent for examination. Intraoperative examination was performed in all cases. Half of the tumor nodule was examined by a senior pathologist with at least 2 hematoxylin and eosin stained sections. The entire tumor then underwent microscopic examination on permanent sections after formaldehyde fixation, following the macroscopic sampling protocol used for testicular cancer.
Histological Evaluation The definitive histological evaluation was made on the entire tumor, each hematoxylin and eosin stained section was examined and (starting in 1998) immunohistochemical analysis was performed to assess the proliferation rate with antibody Mib-1 (Zymed Laboratories, San Francisco, California). More recently, immunoreaction procedures used the antibody inhibin (Dako, Carpinteria, California) which diffusely and intensely colors the Leydig cell cytoplasm. All diagnoses of benign LCT were based on the criteria originally proposed by Kim et al,7 which include size (maximum diameter of the neoplasm), infiltrating margins and extratesticular extension, atypias, necrosis and angioinvasion, and a high mitotic index. These criteria were further defined and completed by Cheville et al with the inclusion of parameters such as ploidy and proliferation rate during definitive histological analysis.8
ule and hormone tests were normal. After removal of the neoplasm (histology of the frozen section examination sample suggestive of Leydig cell tumor) the patient underwent LH-RH analog therapy for 2 years. The patient is currently 12 years old and is healthy, with no evidence of neoplasia and with normal hormone levels. Two patients presented with gynecomastia at diagnosis. Preoperative and postoperative FSH levels were high in 4 patients (3 patients with azoospermia, 1 of whom was monorchid, 1 patient with monorchidism who underwent chemotherapy). Preoperative LH levels were high in the same 4 patients. Two patients showed normal LH values postoperatively. Testosterone and estrogen levels were normal. Two patients showed hyperprolactinemia. Of the 2 patients with gynecomastia 1 showed persistence of gynecomastia at postoperative endocrinological examination, with persistence of hyperprolactinemia (PRL 27.3 ng/ml). Of 22 patients 8 (36.4%) were infertile at the time of diagnosis (4 with azoospermia, 18.2%). No paternities were observed in the followup and 1 patient reported 3 unsuccessful intracytoplasmic sperm injection attempts. Followup was conducted for all patients every 3 to 6 months, and included physical examination, tumor marker testing, scrotal ultrasound, chest x-ray and complete abdominal ultrasound. Six patients (27.3%) underwent contrast enhanced abdominopelvic CT during followup. The participating infertility center also performed hormone assays at regular intervals (LH, FSH, prolactin, estradiol, testosterone). Average preoperative testosterone levels were 7.20 ng/ml and at followup they were 5.13 ng/ml. All patients were reevaluated at least once by the coordinating center. Appendix 2 shows the differences in postoperative tests at the participating centers.
DISCUSSION RESULTS From September 1987 to June 2006, 22 patients with LCT underwent conservative therapy at our centers. No local recurrence or distant metastasis was observed in the average followup of 47 months (range 3 to 230). All patients were free from disease at followup. Patients presented with a palpable testicular nodule or a nodule incidentally diagnosed by ultrasound during assessments related to infertility, gynecomastia, precocious pseudopuberty, scrotal pain or hydrocele. Mean ultrasound size of the testicular nodule was 1.14 cm (range 0.5 to 3.1) and mean histological size was 1.14 cm (range 0.5 to 2.5). Diagnosis after frozen section examination was LCT in 20 of 22 cases (91.0%), nonmalignant stromal tumor in 1 case (4.5%) and large B cell lymphoma in 1 case (4.5%). Tumor markers were normal before and after surgery. The table outlines the clinical profiles of the 22 patients. Three patients were monorchid, having undergone either right radical orchiectomy for nonseminomatous germ cell tumor (2 patients, 1 month and 6 years before surgery) or inguinal hernia repair (1 patient, 28 years before surgery). The 2 patients with NSCGT underwent retroperitoneal lymph node dissection and 1 of them underwent adjuvant chemotherapy for pulmonary metastasis. In a 5-year-old patient who presented with signs of precocious puberty, ultrasound showed a 6 mm testicular nod-
The results of this study confirm the favorable data on the benign course of Leydig cell tumors treated with orchiectomy.9,10 Previous descriptions of conservative therapy are sporadic, due to the rarity of this disease and to the fact that conservative therapy is not standardized.10 To the best of our knowledge, this is the largest case series of conservative therapy for Leydig cell tumors. The patients we examined had a low average age (34 years) and were frequently infertile (36.4%) and therefore motivated to preserve the testicles. Furthermore, late onset hypogonadism was reported in patients undergoing radical orchiectomy.11 All our patients had small tumors (average diameter 1.2 cm). Frozen section examination was reliable in 91% of cases. This percentage increased to approximately 95% if the diagnosis of benign stromal tumor was also considered. A single mistake in interpretation was made in which diagnosis based on frozen section examination was of large B cell lymphoma. Conservative therapy was chosen even in this case and the patient was meant to undergo adjuvant therapy. Tumor markers (␣-fetoprotein, -human chorionic gonadotropin, lactate dehydrogenase) were always negative. In 3 patients some clear endocrine anomalies were observed (precocious pseudopuberty and gynecomastia). A favorable oncological followup was observed even in these cases.
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Patient clinical profiles Notes (No. pts) Mos followup: Min Max Mean Pt age: Min Max Mean No. presented due to (%): Incidental ultrasound diagnosis Palpable nodule Scrotal pain Gynecomastia Precocious pseudopuberty No. incidental ultrasound diagnosis (15 pts): Hydrocele Infertility Varicocele Not specified No. infertile (%) No. physical examination (%): Nonpalpable Palpable No. nodule site: Rt Lt Ultrasound diameter (cm): Min Max Mean Histological diameter (cm): Min Max Mean No. frozen section (%): Leydig cell tumor Benign stromal neoplasia Large B-cell lymphoma No. paraneoplastic syndromes (%): Gynecomastia Precocious pseudopuberty No. nodule echogenicity (12/22 pts): Hypoechoic Hyperechoic % High FSH (4/22 pts) % High preop LH (4/22 pts) % Hyperprolactinemia (2/22 pts)
1 230 47 5 61 35 15 3 1 2 1
(68.2) (13.7) (4.5) (9.1) (4.5)
2 5 1 7 8
(36.4)
14 8
(63.7) (36.3)
Monorchid (2), gynecomastia (2)
14 8 0.5 3.1 1.14 0.5 2.5 1.11 20 1 1
(91.0) (4.5) (4.5)
2 1
(9.1) (4.5)
11 1 18.2 18.2 9.1
Monorchid ⫹ azoospermia (1), azoospermia (2), monorchid ⫹ chemotherapy (1) Monorchid ⫹ azoospermia (1), azoospermia (2), monorchid ⫹ chemotherapy (1), postop LH normalization (2) Gynecomastia (1)
The parameters of Kim et al in establishing benignity or malignancy of Leydig cell tumors have up to now proven effective and easy to interpret for pathologists.7 However, all patients had been informed about the risk of a possible error in the frozen section examination and had been told that conservative therapy would be performed if the disease appeared to be benign. To optimize the preoperative evaluation we consider it useful to perform staging with complete abdominal CT and preoperative testosterone assay, since radical orchiectomy should be performed without a preliminary frozen section examination if retroperitoneal disease is present. A high level of testosterone may be suggestive of the presence of a Leydig cell tumor. The retrospective multicentric study design inevitably exposes it to potential bias. However, it is extremely difficult to perform prospective randomized studies for such rare diseases. All the centers participating in the study performed similar preoperative and postoperative evaluations, on the basis of the European guidelines for malignant testicular tumors that represent our common cultural reference.12 There were only a few differences in preoperative and postoperative assessments, especially con-
cerning laboratory tests (Appendix 2). These variations were due to the different focus of the centers where patients underwent surgery and subsequent followup. Since tumor markers were constantly negative and postoperative complete abdominal CT was normal in all cases, we believe it is legitimate to exclude CT from the followup procedures. This would considerably reduce followup costs. Appendix 2 lists recommended tests based on author experience. Late onset cases of metastasis are described in the literature up to 8 years after orchiectomy.13 Survival with metastasis is unpredictable and varies from 2 months to 17 years with a median survival of 2 years.14 This is the reason why we recommend to extend followup to 10 to 15 years after surgery. Unfortunately it is difficult to establish a priori the benign status of testicular masses or nodules diagnosed with ultrasound since there are no ultrasound features that make it possible to determine with certainty the presence of a Leydig cell tumor and differentiate among Leydig cell tumors the benign forms and the malignant ones.15 In our case series lesions were described as hyperechoic in some cases
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CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR
and hypoechoic in others. The only aid in diagnosis is provided by the presence of gynecomastia in adult patients or precocious pseudopuberty in Leydig cell tumor in childhood.16,17 These clinical signs can be strongly suggestive of stromal testicular neoplasia.7 Other clinical parameters that are an indication of a negative prognosis are the advanced age of the patient, size of tumor, presence of vascular infiltration and margin section infiltration. Therefore, frozen section examination during surgery is essential, and the role of the pathologist as a guide in surgical strategy is of the utmost importance. Awareness of the favorable natural history of Leydig cell tumors justifies conservative therapy in selected patients. Avoiding a mutilating orchiectomy makes it possible not to alter the way patients see themselves.
Abbreviations and Acronyms CS CT FSH LCT LH LH-RH PRL
1.
3.
Leydig cell tumors are a rare disease and it is therefore extremely difficult to perform prospective randomized studies. Despite this limitation in the last few years early diagnosed forms have been shown to present a favorable followup. In selected cases with motivated patients it is possible to opt for a conservative therapy, which has proved to be safe. Furthermore, it is possible to establish a standardized followup.
4.
5.
6.
APPENDIX 1 Parameters Considered in the Retrospective Analysis
7. Parameter Reason for presentation Case history Physical examination Ultrasound characteristics Ultrasound size of the nodule Tumor markers Fertility status Standard chest x-ray Frozen section examination Histological size of the nodule Followup Postoperative paternity
Notes
8. Maximum diameter ␣-Fetoprotein, -human chorionic gonadotropin, lactate dehydrogenase
Maximum diameter
Normal male hormonal ranges: PRL 2.5–17 ng/ml LH 0.8 –7.6 mUI/ml FSH 0.7–11.1 mUI/ml Testosterone up to 49 years old 2.7–15 ng/ml, older than 50 years 2.1–7.5 ng/ml Estradiol less than 56 pg/ml
9.
10.
11.
12.
13.
APPENDIX 2
14.
Recommended Followup Examinations for Benign Leydig Cell Tumor Examination Scrotal ultrasound Abdominal ultrasound Hormone assays (FSH, LH, PRL, testosterone, estradiol) Analysis of fertility medical history
15.
Particularly Recommended in the Presence of
16. Gynecomastia or precocious pseudopuberty No paternity, abnormal hormone values
conservative surgery computerized tomography follicle-stimulating hormone Leydig cell tumor luteinizing hormone luteinizing hormone releasing hormone prolactin
REFERENCES
2.
CONCLUSIONS
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
17.
Masur Y, Steffens J, Ziegler M and Remberger K: Leydig-ZellTumoren des Hodens-Klinische und morphologische Aspekte. Urologe A 1996; 35: 468. Glavind K and Sondergaard G: Leydig cell tumor: diagnosis and treatment. Case report and review. Scand J Urol Nephrol 1988; 22: 343. Mosharafa AA, Foster RS, Bihrle R, Koch MO, Ulbright TM, Einhorn LH et al: Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors? Cancer 2003; 98: 753. Kressel K, Schnell D, Dettmann R, Hartmann M and Butz M: Diagnosis and therapy of non-germ cell testicular tumors. Organ preservation or orchiectomy? Urologe A 1993; 32: 237. Adeagbo BA and Shertz W: Pathologic quiz case: patient with testicular pain. Benign Leydig cell tumor. Arch Pathol Lab Med 2004; 128: 105. Rowe PJ, Comhaire FH, Hargreave TB and Mahmoud AMA: WHO Manual for the Standardized Investigation, Diagnosis and Management of the Infertile Male. Cambridge, United Kingdom: Cambridge University Press 2000. Kim J, Young RH and Scully RE: Leydig cell tumor of the testis: a clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9: 177. Cheville JC, Sebo TJ, Lager DJ, Bostwick DG and Farrow GM: Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors. Am J Surg Pathol 1998; 22: 1361. Carmignani L, Salvioni R, Gadda F, Colecchia M, Gazzano G, Torelli T et al: Long-term followup and clinical characteristics of testicular Leydig cell tumor: experience with 24 cases. J Urol 2006; 176: 2040. Wegner HE, Dieckmann KP, Herbst H, Andresen R and Miller K: Leydig cell tumor– comparison of results of radical and testis-sparing surgery in a single center. Urol Int 1997; 59: 170. Huddart RA, Norman A, Moynihan C, Horwich A, Parker C, Nicholls E et al: Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer 2005; 93: 200. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A et al: Guidelines on testicular cancer. Eur Urol 2005; 48: 885. Bertram KA, Bratloff B, Hodges GF and Davidson H: Treatment of malignant Leydig cell tumor. Cancer 1991; 5: 2324. Grem JL, Robins HI, Wilson KS, Gilchrist K and Trump DL: Metastatic Leydig cell tumor of the testis. Report of three cases and review of the literature. Cancer 1986; 58: 2116. Dogra VS, Gottlieb RH, Rubens DJ and Liao L: Benign intratesticular cystic lesions: US features. Radiographics 2001; 21: S273. O’Donovan JJ, Terry TR and Williams G: Occult Leydig cell testicular tumour presenting with gynaecomastia. J R Soc Med 1989; 82: 49. Davis JM, Woodroof J, Sadasivan R and Stephens R: Case report: congenital adrenal hyperplasia and malignant Leydig cell tumor. Am J Med Sci 1995; 309: 63.
CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR EDITORIAL COMMENT The authors should be congratulated for completing this multi-institutional retrospective analysis of a large series of patients with Leydig cell tumors. LCTs are uncommon tumors without a classic presentation. The patients in this series presented with palpable lesions or incidental lesions discovered during evaluation for infertility or endocrinopathy. Although the authors found that 36.4% of patients with LCTs were infertile, it is important to recognize that this does not mean that Leydig cell tumors are associated with infertility or vice versa. Tal et al reported that 55% of incidental ultrasonography detected tumors in infertile men were malignant germ cell tumors.1 Infertile men are more likely to undergo scrotal ultrasonography and, thus, incidental tumors are more likely to be discovered. The authors do not provide information regarding the number of small tumors that were treated conservatively that were, in fact, germ cell tumors. This information, as well as followup data, would be important in the discussion of the appropriateness of conservative testes sparing management of small testes tumors. That said, this article addresses the management of Leydig cell tumors. In this series all patients were followed every 3 to 6 months with tumor markers, scrotal and abdominal ultrasonography and chest x-ray. Only 27.3% underwent CT studies. The authors comment on the late onset of metastases in LCT and recommend followup for 10 to 15
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years. The real question, which is unanswered, is how do these patients need to be followed? Although the authors recommend abdominal ultrasonography to minimize the cost, it is difficult to subscribe to this approach since this has not been demonstrated to be sensitive or specific for retroperitoneal disease. A recent comprehensive review of imaging of genitourinary malignancies indicates that surveillance of the retroperitoneum is accomplished by CT or positron emission tomography. Ultrasonography is not even discussed as an alternative approach.2 Although conservative management of LCT would seem appropriate, based on the infrequent malignant behavior of LCTs, prolonged followup, as suggested by the authors, is probably warranted. It would seem that surveillance for LCTs should use the modalities established for surveillance of other testes tumors but, perhaps, performed with less frequency. Harris M. Nagler Department of Urology Beth Israel Medical Center New York, New York 1.
2.
Tal R, Holland R, Belenky A, Konichezky M and Baniel J: Incidental testicular tumors in infertile men. Fertil Steril 2004; 82: 469. Bradford TJ, Montie JE and Hafez KS: The role of imaging in the surveillance of urologic malignancies. Urol Clin North Am 2006; 33: 377.
Purpose: We performed a long-term evaluation of conservative surgical treatment of benign Leydig cell tumor. Materials and Methods: A multicenter retrospective clinical study was performed at 6 European centers. Case files of all patients diagnosed with Leydig cell tumor and treated with conservative surgery were examined. Patients underwent physical examination, hormone and tumor marker assays, scrotal and abdominal ultrasound, chest x-ray, and an endocrinological examination. Results: From 1987 to 2006, 22 patients with Leydig cell tumor underwent conservative surgery. Mean patient age was 35 years (range 5 to 61). Mean followup was 47 months (range 1 to 230). No local recurrence or metastasis was observed. Patients presented with a palpable testicular nodule (3 patients, 13.7%) or a nodule diagnosed by ultrasound (15 patients, 68.2%), gynecomastia (2 patients, 9.1%), precocious pseudopuberty (1 patient, 4.5%) or scrotal pain (1 patient, 4.5%). Three patients were monorchid after contralateral orchiectomy for inguinal hernia repair (1 patient, 28 years before surgery) and nonseminomatous germ cell tumor (2 patients, 1 month and 6 years before surgery). Diagnosis after frozen section examination was Leydig cell tumor in 20 of 22 cases (91.0%). Mean histological size of the nodule was 1.11 cm (range 0.5 to 2.5). Preoperative FSH and LH levels were high in 4 patients. Tumor markers were normal before and after surgery. Followup was conducted for all patients every 3 to 6 months with physical examination, tumor markers, scrotal and abdominal ultrasound, chest x-ray. Six patients (27.3%) underwent abdominal computerized tomography. Conclusions: When diagnosed early Leydig cell tumors present a favorable followup. In select cases with motivated patients, conservative surgery proved to be a feasible and safe choice. Key Words: Leydig cell tumor, early diagnosis, prognosis
tromal and paratesticular tumors are rare diseases and account for less than 3% of testicular neoplasia.1 Leydig cell tumors are the most common stromal tumors. The natural history of these forms is poorly known and it is not always easy to distinguish between benign and malignant forms. The literature presents conflicting data, as several mostly benign case reports exist alongside other publications that report the possibility of tumor metastasis.2–5 In particular instances, when patients were highly motivated because they were monorchid or infertile, a conservative therapy was opted for, removing exclusively the tumor nodule, with favorable results. The aim of this study was long-term evaluation of conservative therapy for Leydig cell tumors performed at 6 urology centers.
MATERIALS AND METHODS
S
A retrospective clinical study was performed at 6 European centers: the Ospedale Maggiore Policlinico, San Paolo Hospital, San Raffaele Hospital, Istituto Nazionale per lo Studio e la Cura dei Tumori and Istituto Europeo di Oncologia in Milan, and the Puigvert Foundation in Barcelona. Case files of all patients who were diagnosed with Leydig cell tumor and who underwent conservative therapy were analyzed. Only patients who were first diagnosed at 1 of the 6 participating centers were considered. All patients were recalled by the center coordinating the study and reassessed by medical history, physical examination, tumor marker assays, hormone assays (LH, FSH, PRL, testosterone, estradiol), scrotal and abdominal ultrasound, chest x-ray, an endocrinological examination, and postoperative paternity evaluation. Appendix 1 shows the parameters considered in the study. Fertility status was also taken into account. Following the definition by the WHO, we considered patients to be infertile when they were unable to achieve conception after at least 1 year of unprotected intercourse.6 Differences in the postoperative followup between the various participating centers were also evaluated.
Submitted for publication November 30, 2006. * Correspondence: Department of Medicine and Surgery, Urology Unit, University of Milan, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Via Luigi Sacco 7, 20146 Milano, Italy (telephone: 0039 02-55034502; FAX: 0039 02-50320584; e-mail: [email protected]).
0022-5347/07/1782-0507/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
507
Vol. 178, 507-511, August 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.03.108
508
CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR
Surgical Strategy Conservative surgery was performed via inguinotomy with preventive clamping of the spermatic cord and exposure of the testicle in a separate operative field. Ultrasound guidance was used, or palpation if lesions were palpable. The lesion was isolated and the material was sent for frozen section examination. Particular care was taken to make sure the entire lesion and the separate margins were sent for examination. Intraoperative examination was performed in all cases. Half of the tumor nodule was examined by a senior pathologist with at least 2 hematoxylin and eosin stained sections. The entire tumor then underwent microscopic examination on permanent sections after formaldehyde fixation, following the macroscopic sampling protocol used for testicular cancer.
Histological Evaluation The definitive histological evaluation was made on the entire tumor, each hematoxylin and eosin stained section was examined and (starting in 1998) immunohistochemical analysis was performed to assess the proliferation rate with antibody Mib-1 (Zymed Laboratories, San Francisco, California). More recently, immunoreaction procedures used the antibody inhibin (Dako, Carpinteria, California) which diffusely and intensely colors the Leydig cell cytoplasm. All diagnoses of benign LCT were based on the criteria originally proposed by Kim et al,7 which include size (maximum diameter of the neoplasm), infiltrating margins and extratesticular extension, atypias, necrosis and angioinvasion, and a high mitotic index. These criteria were further defined and completed by Cheville et al with the inclusion of parameters such as ploidy and proliferation rate during definitive histological analysis.8
ule and hormone tests were normal. After removal of the neoplasm (histology of the frozen section examination sample suggestive of Leydig cell tumor) the patient underwent LH-RH analog therapy for 2 years. The patient is currently 12 years old and is healthy, with no evidence of neoplasia and with normal hormone levels. Two patients presented with gynecomastia at diagnosis. Preoperative and postoperative FSH levels were high in 4 patients (3 patients with azoospermia, 1 of whom was monorchid, 1 patient with monorchidism who underwent chemotherapy). Preoperative LH levels were high in the same 4 patients. Two patients showed normal LH values postoperatively. Testosterone and estrogen levels were normal. Two patients showed hyperprolactinemia. Of the 2 patients with gynecomastia 1 showed persistence of gynecomastia at postoperative endocrinological examination, with persistence of hyperprolactinemia (PRL 27.3 ng/ml). Of 22 patients 8 (36.4%) were infertile at the time of diagnosis (4 with azoospermia, 18.2%). No paternities were observed in the followup and 1 patient reported 3 unsuccessful intracytoplasmic sperm injection attempts. Followup was conducted for all patients every 3 to 6 months, and included physical examination, tumor marker testing, scrotal ultrasound, chest x-ray and complete abdominal ultrasound. Six patients (27.3%) underwent contrast enhanced abdominopelvic CT during followup. The participating infertility center also performed hormone assays at regular intervals (LH, FSH, prolactin, estradiol, testosterone). Average preoperative testosterone levels were 7.20 ng/ml and at followup they were 5.13 ng/ml. All patients were reevaluated at least once by the coordinating center. Appendix 2 shows the differences in postoperative tests at the participating centers.
DISCUSSION RESULTS From September 1987 to June 2006, 22 patients with LCT underwent conservative therapy at our centers. No local recurrence or distant metastasis was observed in the average followup of 47 months (range 3 to 230). All patients were free from disease at followup. Patients presented with a palpable testicular nodule or a nodule incidentally diagnosed by ultrasound during assessments related to infertility, gynecomastia, precocious pseudopuberty, scrotal pain or hydrocele. Mean ultrasound size of the testicular nodule was 1.14 cm (range 0.5 to 3.1) and mean histological size was 1.14 cm (range 0.5 to 2.5). Diagnosis after frozen section examination was LCT in 20 of 22 cases (91.0%), nonmalignant stromal tumor in 1 case (4.5%) and large B cell lymphoma in 1 case (4.5%). Tumor markers were normal before and after surgery. The table outlines the clinical profiles of the 22 patients. Three patients were monorchid, having undergone either right radical orchiectomy for nonseminomatous germ cell tumor (2 patients, 1 month and 6 years before surgery) or inguinal hernia repair (1 patient, 28 years before surgery). The 2 patients with NSCGT underwent retroperitoneal lymph node dissection and 1 of them underwent adjuvant chemotherapy for pulmonary metastasis. In a 5-year-old patient who presented with signs of precocious puberty, ultrasound showed a 6 mm testicular nod-
The results of this study confirm the favorable data on the benign course of Leydig cell tumors treated with orchiectomy.9,10 Previous descriptions of conservative therapy are sporadic, due to the rarity of this disease and to the fact that conservative therapy is not standardized.10 To the best of our knowledge, this is the largest case series of conservative therapy for Leydig cell tumors. The patients we examined had a low average age (34 years) and were frequently infertile (36.4%) and therefore motivated to preserve the testicles. Furthermore, late onset hypogonadism was reported in patients undergoing radical orchiectomy.11 All our patients had small tumors (average diameter 1.2 cm). Frozen section examination was reliable in 91% of cases. This percentage increased to approximately 95% if the diagnosis of benign stromal tumor was also considered. A single mistake in interpretation was made in which diagnosis based on frozen section examination was of large B cell lymphoma. Conservative therapy was chosen even in this case and the patient was meant to undergo adjuvant therapy. Tumor markers (␣-fetoprotein, -human chorionic gonadotropin, lactate dehydrogenase) were always negative. In 3 patients some clear endocrine anomalies were observed (precocious pseudopuberty and gynecomastia). A favorable oncological followup was observed even in these cases.
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509
Patient clinical profiles Notes (No. pts) Mos followup: Min Max Mean Pt age: Min Max Mean No. presented due to (%): Incidental ultrasound diagnosis Palpable nodule Scrotal pain Gynecomastia Precocious pseudopuberty No. incidental ultrasound diagnosis (15 pts): Hydrocele Infertility Varicocele Not specified No. infertile (%) No. physical examination (%): Nonpalpable Palpable No. nodule site: Rt Lt Ultrasound diameter (cm): Min Max Mean Histological diameter (cm): Min Max Mean No. frozen section (%): Leydig cell tumor Benign stromal neoplasia Large B-cell lymphoma No. paraneoplastic syndromes (%): Gynecomastia Precocious pseudopuberty No. nodule echogenicity (12/22 pts): Hypoechoic Hyperechoic % High FSH (4/22 pts) % High preop LH (4/22 pts) % Hyperprolactinemia (2/22 pts)
1 230 47 5 61 35 15 3 1 2 1
(68.2) (13.7) (4.5) (9.1) (4.5)
2 5 1 7 8
(36.4)
14 8
(63.7) (36.3)
Monorchid (2), gynecomastia (2)
14 8 0.5 3.1 1.14 0.5 2.5 1.11 20 1 1
(91.0) (4.5) (4.5)
2 1
(9.1) (4.5)
11 1 18.2 18.2 9.1
Monorchid ⫹ azoospermia (1), azoospermia (2), monorchid ⫹ chemotherapy (1) Monorchid ⫹ azoospermia (1), azoospermia (2), monorchid ⫹ chemotherapy (1), postop LH normalization (2) Gynecomastia (1)
The parameters of Kim et al in establishing benignity or malignancy of Leydig cell tumors have up to now proven effective and easy to interpret for pathologists.7 However, all patients had been informed about the risk of a possible error in the frozen section examination and had been told that conservative therapy would be performed if the disease appeared to be benign. To optimize the preoperative evaluation we consider it useful to perform staging with complete abdominal CT and preoperative testosterone assay, since radical orchiectomy should be performed without a preliminary frozen section examination if retroperitoneal disease is present. A high level of testosterone may be suggestive of the presence of a Leydig cell tumor. The retrospective multicentric study design inevitably exposes it to potential bias. However, it is extremely difficult to perform prospective randomized studies for such rare diseases. All the centers participating in the study performed similar preoperative and postoperative evaluations, on the basis of the European guidelines for malignant testicular tumors that represent our common cultural reference.12 There were only a few differences in preoperative and postoperative assessments, especially con-
cerning laboratory tests (Appendix 2). These variations were due to the different focus of the centers where patients underwent surgery and subsequent followup. Since tumor markers were constantly negative and postoperative complete abdominal CT was normal in all cases, we believe it is legitimate to exclude CT from the followup procedures. This would considerably reduce followup costs. Appendix 2 lists recommended tests based on author experience. Late onset cases of metastasis are described in the literature up to 8 years after orchiectomy.13 Survival with metastasis is unpredictable and varies from 2 months to 17 years with a median survival of 2 years.14 This is the reason why we recommend to extend followup to 10 to 15 years after surgery. Unfortunately it is difficult to establish a priori the benign status of testicular masses or nodules diagnosed with ultrasound since there are no ultrasound features that make it possible to determine with certainty the presence of a Leydig cell tumor and differentiate among Leydig cell tumors the benign forms and the malignant ones.15 In our case series lesions were described as hyperechoic in some cases
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CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR
and hypoechoic in others. The only aid in diagnosis is provided by the presence of gynecomastia in adult patients or precocious pseudopuberty in Leydig cell tumor in childhood.16,17 These clinical signs can be strongly suggestive of stromal testicular neoplasia.7 Other clinical parameters that are an indication of a negative prognosis are the advanced age of the patient, size of tumor, presence of vascular infiltration and margin section infiltration. Therefore, frozen section examination during surgery is essential, and the role of the pathologist as a guide in surgical strategy is of the utmost importance. Awareness of the favorable natural history of Leydig cell tumors justifies conservative therapy in selected patients. Avoiding a mutilating orchiectomy makes it possible not to alter the way patients see themselves.
Abbreviations and Acronyms CS CT FSH LCT LH LH-RH PRL
1.
3.
Leydig cell tumors are a rare disease and it is therefore extremely difficult to perform prospective randomized studies. Despite this limitation in the last few years early diagnosed forms have been shown to present a favorable followup. In selected cases with motivated patients it is possible to opt for a conservative therapy, which has proved to be safe. Furthermore, it is possible to establish a standardized followup.
4.
5.
6.
APPENDIX 1 Parameters Considered in the Retrospective Analysis
7. Parameter Reason for presentation Case history Physical examination Ultrasound characteristics Ultrasound size of the nodule Tumor markers Fertility status Standard chest x-ray Frozen section examination Histological size of the nodule Followup Postoperative paternity
Notes
8. Maximum diameter ␣-Fetoprotein, -human chorionic gonadotropin, lactate dehydrogenase
Maximum diameter
Normal male hormonal ranges: PRL 2.5–17 ng/ml LH 0.8 –7.6 mUI/ml FSH 0.7–11.1 mUI/ml Testosterone up to 49 years old 2.7–15 ng/ml, older than 50 years 2.1–7.5 ng/ml Estradiol less than 56 pg/ml
9.
10.
11.
12.
13.
APPENDIX 2
14.
Recommended Followup Examinations for Benign Leydig Cell Tumor Examination Scrotal ultrasound Abdominal ultrasound Hormone assays (FSH, LH, PRL, testosterone, estradiol) Analysis of fertility medical history
15.
Particularly Recommended in the Presence of
16. Gynecomastia or precocious pseudopuberty No paternity, abnormal hormone values
conservative surgery computerized tomography follicle-stimulating hormone Leydig cell tumor luteinizing hormone luteinizing hormone releasing hormone prolactin
REFERENCES
2.
CONCLUSIONS
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
17.
Masur Y, Steffens J, Ziegler M and Remberger K: Leydig-ZellTumoren des Hodens-Klinische und morphologische Aspekte. Urologe A 1996; 35: 468. Glavind K and Sondergaard G: Leydig cell tumor: diagnosis and treatment. Case report and review. Scand J Urol Nephrol 1988; 22: 343. Mosharafa AA, Foster RS, Bihrle R, Koch MO, Ulbright TM, Einhorn LH et al: Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors? Cancer 2003; 98: 753. Kressel K, Schnell D, Dettmann R, Hartmann M and Butz M: Diagnosis and therapy of non-germ cell testicular tumors. Organ preservation or orchiectomy? Urologe A 1993; 32: 237. Adeagbo BA and Shertz W: Pathologic quiz case: patient with testicular pain. Benign Leydig cell tumor. Arch Pathol Lab Med 2004; 128: 105. Rowe PJ, Comhaire FH, Hargreave TB and Mahmoud AMA: WHO Manual for the Standardized Investigation, Diagnosis and Management of the Infertile Male. Cambridge, United Kingdom: Cambridge University Press 2000. Kim J, Young RH and Scully RE: Leydig cell tumor of the testis: a clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9: 177. Cheville JC, Sebo TJ, Lager DJ, Bostwick DG and Farrow GM: Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors. Am J Surg Pathol 1998; 22: 1361. Carmignani L, Salvioni R, Gadda F, Colecchia M, Gazzano G, Torelli T et al: Long-term followup and clinical characteristics of testicular Leydig cell tumor: experience with 24 cases. J Urol 2006; 176: 2040. Wegner HE, Dieckmann KP, Herbst H, Andresen R and Miller K: Leydig cell tumor– comparison of results of radical and testis-sparing surgery in a single center. Urol Int 1997; 59: 170. Huddart RA, Norman A, Moynihan C, Horwich A, Parker C, Nicholls E et al: Fertility, gonadal and sexual function in survivors of testicular cancer. Br J Cancer 2005; 93: 200. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A et al: Guidelines on testicular cancer. Eur Urol 2005; 48: 885. Bertram KA, Bratloff B, Hodges GF and Davidson H: Treatment of malignant Leydig cell tumor. Cancer 1991; 5: 2324. Grem JL, Robins HI, Wilson KS, Gilchrist K and Trump DL: Metastatic Leydig cell tumor of the testis. Report of three cases and review of the literature. Cancer 1986; 58: 2116. Dogra VS, Gottlieb RH, Rubens DJ and Liao L: Benign intratesticular cystic lesions: US features. Radiographics 2001; 21: S273. O’Donovan JJ, Terry TR and Williams G: Occult Leydig cell testicular tumour presenting with gynaecomastia. J R Soc Med 1989; 82: 49. Davis JM, Woodroof J, Sadasivan R and Stephens R: Case report: congenital adrenal hyperplasia and malignant Leydig cell tumor. Am J Med Sci 1995; 309: 63.
CONSERVATIVE SURGICAL THERAPY FOR LEYDIG CELL TUMOR EDITORIAL COMMENT The authors should be congratulated for completing this multi-institutional retrospective analysis of a large series of patients with Leydig cell tumors. LCTs are uncommon tumors without a classic presentation. The patients in this series presented with palpable lesions or incidental lesions discovered during evaluation for infertility or endocrinopathy. Although the authors found that 36.4% of patients with LCTs were infertile, it is important to recognize that this does not mean that Leydig cell tumors are associated with infertility or vice versa. Tal et al reported that 55% of incidental ultrasonography detected tumors in infertile men were malignant germ cell tumors.1 Infertile men are more likely to undergo scrotal ultrasonography and, thus, incidental tumors are more likely to be discovered. The authors do not provide information regarding the number of small tumors that were treated conservatively that were, in fact, germ cell tumors. This information, as well as followup data, would be important in the discussion of the appropriateness of conservative testes sparing management of small testes tumors. That said, this article addresses the management of Leydig cell tumors. In this series all patients were followed every 3 to 6 months with tumor markers, scrotal and abdominal ultrasonography and chest x-ray. Only 27.3% underwent CT studies. The authors comment on the late onset of metastases in LCT and recommend followup for 10 to 15
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years. The real question, which is unanswered, is how do these patients need to be followed? Although the authors recommend abdominal ultrasonography to minimize the cost, it is difficult to subscribe to this approach since this has not been demonstrated to be sensitive or specific for retroperitoneal disease. A recent comprehensive review of imaging of genitourinary malignancies indicates that surveillance of the retroperitoneum is accomplished by CT or positron emission tomography. Ultrasonography is not even discussed as an alternative approach.2 Although conservative management of LCT would seem appropriate, based on the infrequent malignant behavior of LCTs, prolonged followup, as suggested by the authors, is probably warranted. It would seem that surveillance for LCTs should use the modalities established for surveillance of other testes tumors but, perhaps, performed with less frequency. Harris M. Nagler Department of Urology Beth Israel Medical Center New York, New York 1.
2.
Tal R, Holland R, Belenky A, Konichezky M and Baniel J: Incidental testicular tumors in infertile men. Fertil Steril 2004; 82: 469. Bradford TJ, Montie JE and Hafez KS: The role of imaging in the surveillance of urologic malignancies. Urol Clin North Am 2006; 33: 377.