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TESTICULAR CANCER : CURRENT MANAGEMENTB D Kashyapi*, J N Kulkarni**
*Research Fellow, **Professor and Head, Division of UroOncology, Tata Memorial Hospital, Mumbai.
INTRODUCTION
Testicular cancer is the commonest solid tumour malignancy occurring in young adults, highest frequency being seen in the age group of 20-35 years. The introduction of platinum based chemotherapy has made testicular tumours one of the strong models of cancer cure. Approximately 90% of germ cell cancers of the testis are curable today with advances in knowledge of pathology and natural history, diagnostic tools and surgery, radiotherapy and chemotherapy. Current management strategies in the testicular cancer treatment are outlined in this article.
Epidemiology and Aetiology
The incidence of testicular tumours is approximately 3-4 cases per 1,00,000 males each year. The incidence is believed to be doubling every 30 years for the white males. The incidence is highest in Scandinavia, Switzerland and Germany (5-6 cases per 1,00,000 males annually), intermediate in USA and UK while it is lowest in Asia and Africa (0.8 per 1,00,000 males in Japan annually). [1] At Tata Memorial Hospital about 150-160 cases are seen every year, the commonest age group affected is between 20-35 years. [2]
Testicular cancer is slightly more common on the right than on the left, which parallels the increased incidence of cryptorchidism on the right side. One to 2% of primary testicular tumours are bilateral, and up to half of these tumours have history of unilateral or bilateral cryptorchidism. Tumours may be synchronous or metachronous but they are usually of the same histologic type.
Although the cause of testicular cancer is unknown, both congenital and acquired factors are linked with its development. Cryptorchid tests are at a higher risk for tumour development. Level of descent of the testis appears to be correlated with the risk of tumour development, risk for intra abdominal testis is 1 in 20 and for the inguinal testis 1 in 80. Seminoma is the commonest histologic type. Orchiopexy facilitates the examination of testis but does not alter the risk of tumour development. Current studies have implicated the role of transplacental damage to the foetal gonads by the maternal oestrogen levels. Offsprings of dizygotic twin pregnancies are associated with increased testis cancer risk (odds ratio (OR)1.5) as compared to offsprings from monozygotic twin pregnancies. [3] Similarly, sons born after a pregnancy characterized by severe maternal nausea are associated with increased testis cancer risk. [4] Other acquired factors such as trauma and infection-related testicular atrophy (mumps orchitis) have been found to have weak association with risk of testis cancer development. Recent segregation analysis of Swedish and Norwegian families has suggested a role of a high-frequency recessive gene in familial testis cancer. [5]
Clinico-pathological features
About 95% of testicular tumours are of germ cell origin (GCT), only 5% of tumours are of other histologic types. Current accepted model of testicular tumour development is that totipotential germ cells follow abnormal pathways of differentiation resulting into either seminoma or embryonal carcinoma. Embryonal cells give rise to teratoma by intra-embryonic differentiation while yolk sac tumour or choriocarcinoma are produced by extra-embryonic differentiation. [6,7] Virtually all germ cell tumours of the testis develop from the intratubular germ cell neoplasia (carcinoma in situ, CIS) except spermatocytic seminoma and the rare prepubertal tumours. CIS is usually a diffuse disease, which can be diagnosed with a random testicular biopsy. CIS gives rise to invasive GCT in approximately 50% of cases of cases within 5 years. It is bilateral in 5% of cases and progression to tumour development can be prevented by low dose testicular irradiation (20-25 Gy).
Only 40% of GCT are of one histologic type, while the remaining 60% display mixed histology. Combination of seminoma and one or more non-seminomatous elements is considered as non-seminomatous tumour. Apparently pure seminomas with abnormal AFP (> 10-20 ng/ml) and/or highly elevated hCG (> 200 mIU/ml) are treated as non-semonomatous tumours. Pure seminomas usually spread by lymphatics mainly to paraaortic nodes, sometimes to mediastinal and supraclavicular nodes. Haematigenous spread is extremely rare. Seminoma is extremely sensitive to radiotherapy and to chemotherapy.
Non-seminomatous germ cell tumours (NSGCT) metastasize both to the lymphatics and via the blood stream, especially to the lungs. Embryonal carcinoma is the most undifferentiated tumour and is very responsive to chemotherapy. Teratoma is the tumour that has undergone somatic differentiation. Incomplete differentiation leads to immature teratoma while complete maturation leads to mature teratoma, but mature teratoma is benign only in children. Teratoma is poorly responsive to chemotherapy and to radiotherapy. Yolk sac tumour is the most common tumour in children; it spreads mainly to the lung and can be cured with chemotherapy. Pure choriocarcinoma is extremely rare; it metastasizes diffusely by the blood stream and involves a very poor prognosis. When it is mixed with other histologies, it is potentially curable.
Testicular lymphatics travel along the spermatic cord to the paracaval, paraaortoc and pericaval group nodes. Therefore any suspected testicular tumour should be removed by the inguinal route (high orchidectomy) as scrotal violation leads to altered lymphatic patterns along with some increased risk of local recurrence. Previous orchiopexy also alters lymphatic pathways. These factors need to be considered when planning radiotherapy fields. Testicular tumours (especially NSGCT) have rapid doubling times, hence follow up requires frequent close observation at 2-6 monthly intervals in least first 3 years of follow up.
Clinical Presentation (Symptomatology)
Painless gradual enlargement of the testis is the commonest presentation. Testicular lump may be more or less hard and more or less irregular in contour. Delays in patient seeking definitive treatment after recognition of the initial lesion are frequent (3-6 months) and it correlates with development of metastases. [8] Trauma to the testis (e.g. cricket ball injury) can sometimes lead to confusion in diagnosis. The testicular lump discovered after trivial trauma is erroneously attributed to haematoma with serious consequences. Sometimes even physicians contribute to this delay in definitive diagnosis. Every testicular lump should be assumed to be malignant unless proved otherwise. Availability of scrotal ultrasonography and tumour markers should avoid these diagnostic pitfalls. At least one third of testicular tumour patients seen at Tata Hospital had initial scrotal surgery elsewhere with the diagnosis of either hydrocoele, hematocoele or rarely pyocoele. High index of suspicion and patient education regarding self examination is important. About 10% of testicular tumours present with acute pain which is due to intra-tumoral haemorrhage. Undescended testicular tumours present with suprapubic lump, urinary complaints or bowel complaints. Development of torsion in an undescended testicle can sometimes be the warning sign of testicular tumour. Rarely testiculartumours may present with symptoms of abdominal lump, chronic cough or as a "neck node with unknown primary". Testicular nodule may be preceded by a variably long period of testicular hypersensitivity and hypotrophy. These two signs are characteristic of testicular CIS.
Scrotal ultrasound is an important non-invasive diagnostic tool. GCT of the testis appears as an intratesticular hypo-echoic lesion, irregular in shape and heterogeneous in density. "Burnt out" tumours appear as few microcalcifications in a sclerotic area. Intratesticular microlithiasis represents testicular CIS. FNAC of testicular tumours is generally not recommended as it is useful only if it is positive, exact typing (seminoma versus NSGCT) is not reliable on FNAC and due to the theoretical risk of needle tract recurrence. FNAC is valuable in metastatic sites like retroperitoneum or neck nodes. Any suspected testicular tumour should be explored by inguinal route and if necessary frozen section confirmation or otherwise should be obtained (Chevassue’s manoeuvre).
Tumour Markers
Serum beta human chorionic gonadotrophin (bhCG), alpha foeto protein (AFP) and lactate dehydrogenase (LDH) are the most important testicular tumour markers. Elevated bhCG level are seen in 30% of pure seminomas before orchiectomy, while in nonseminoma AFP and/or bhCG are raised in approximately 90% of cases. Following orchiectomy, bhCG is normal in clinical stage I. In comparison, markers remain elevated in 5-10% of clinical stage I NSGCT (occult disease) and only in 40% of patients with histologically documented metastases. In advanced disease (both seminoma and NSGCT), markers remain positive even after orchiectomy. Negative markers do not exclude the diagnosis of germ cell tumour of the testis.
Half-lives of these markers (AFP-5 to 7 days, bhCG-1 to 3 days) are useful in staging as well as prognosis and follow up of these patients. LDH is not a specific marker but is useful in prognostication. AFP and bhCG are measured by radio-immuno assays or monoclonal antibody techniques while LDH is determined by enzymatic assay. Normal values are 10 to 15 ng/ml for AFP and upto 5 mIU/ml for bhCG. Approximately, 1 ng of AFP corresponds to 1 mIU, and 1 ng/ml of bhCG corresponds to 5 mIU/ml. LDH titres are related to upper limit of the normal value (N) of each individual laboratory.
Surgical Treatment (High Orchiectomy/Radical Orchiectomy)
Lymphatic drainage of testis dictates the high "inguinal" route of orchiectomy. The spermatic cord is isolated and divided at the internal inguinal ring. In doubtful cases, a soft non-crushing clamp is applied to the cord, tunica layers of testis are opened after proper isolation of the field, frozen section examination of suspicious areas is done followed by either orchiectomy (if positive for GCT) or else closure and reposition of testis into the scrotum (Chevassue’s manoeuvre). The specimen is sent for histological examination. T category is determined by this pathological examination of specimen.
Staging
Clinical and subsequent pathological staging follows high orchiectomy and histopathological confirmation of the diagnosis. Tumours are classified into pure seminomas or NSGCT. Grading is not applied to testicular tumours.
The TNM system (1997) is currently used.9 The procedures needed to define T,N,M and S categories are:
T category : pathologically only
N category : clinical examination and imaging findings
M category : clinical examination, imaging findings and serum tumour markers
TNM Classification of Testicular tumours9 primary tumour
(defined pathologically only)pTx Radical orchiectomy not performed. pTO Histological scar or no evidence of primary tumour. pT is Intratubular germ-cell neoplasia. pT1 Tumour limited to testis, including epididymis and albuginea. pT2 Tumour limited to testis with evidence of vascular (Haematic or lymphatic) invasion; or tunica vaginalis involved by tumour. pT3 Tumour involving spermatic cord with or without vascular invasion. pT4 Tumour involving scrotum, with or without vascular invasion. S category : serum tumour markers.
Regional lymph nodes are the bilateral peri-aortocaval nodes, the ipsilateral common iliac nodes and nodes accompanying the spermatic vessels. Pelvic and inguinal nodes are considered regional only following previous inguino-scrotal surgery.
Clinical
Pathological
Nx Regional nodes cannot be assessed. Regional nodes cannot be assessed NO No regional-node metastasis. No regional-nodemetastases N1 Single or multiple none > 2 cm in thegreatest diameter metastases to 1-5 nodes.metastases, al
l < 2 cm in greatest diameter.N2 single or multiple extension of the disease.in greatest diameter Idem, or extranodalmetastases 2-5 cm N3 Lymph-node > 5 cm. Lymph-node metastasismetastasis > 5 cm
Mx
Presence of distant metastasis cannot be assessed
M0 No distant metastasis M1 Distant metastasis
M1a Metastasis to extra-regional lymph-nodes or to the lung.
M2b Distant metastasis in other sites.
Sx Serum tumour markers not available. S0 Normal serum tumour markers AFP (ng/ml) hCG (mlU/ml) hCG (mlU/ml) S1 < 1,000 < 5,000 < 1.5 S2 1,000-10,000 5,000-50,000 1.5-10 S3 > 10,000 > 50,000 > 10 Various clinical staging systems are used like Royal Marsden, MSKCC, MD Anderson and Boden/Gibb systems. MSKCC staging system is shown below:
Stage I - Lesion confined to the testis Stage II -Spread to the regional nodes (bilateral periaortocaval, ipsilateral common iliac nodes and nodes along spermatic vessels. Pelvic and inguinal nodes considered regional only following previous inguino-scrotal surgery.) II A - Less than 5 cm nodal mass II B - 5-10 cm nodal mass II C - More than 10 cm nodal mass Stage III - Spread beyond retroperitoneum. Correct clinical staging is necessary for proper treatment of testicular tumours. Physical examination of neck (supraclavicular nodes), breasts )for hCG related gynaecomastia), abdomen (palpable nodal mass) and scrotum (for testicular lump, secondary hydrocoele etc) is carried out. Radiographic imaging with chest X-rays, computed tomography (CT) scan of the abdomen and pelvis is done. USG alone for the retroperitoneum is not sensitive enough. Ultrasound is machine and operator dependent and it can approach utility up to CT scan or MRI in good hands, with a good machine and non-fat patients. A CT scan of chest is normally not done in presence of normal chest X-ray findings except when massive retroperitoneal lymphadenopathy is present. Brain CT or MRI are usually performed in symptomatic patients only. Positron emission tomography (PET) has shown some promise in detection of post chemotherapy residual masses but is costly and not available at many places. Lymphangiography is no longer performed in the work up of patients.
The false negative rates for retroperitoneal nodes are about 30% for both CT and MRI. False positive rates for retroperitoneal nodes up to 2 cm in size with positive markers is almost 0% but in marker negative patients it is as high as 50%. [10]
Differential Diagnosis
Any scrotal pathology needs to be separated
Nonseminoma Seminoma Testis or retroperitoneal primary and No nonpulmonary Any primary site and No nonpulmonary visceral metastases
andvisceral metastases and Normal Good markers (all of the following) AFP, anyhCG, any LDH AFP < 100 ng/ml hCG < 5000 IU/L (1000 ng/ml) LDH < 1.5 x upper limit of normal. 56% of nonseminomas 90% of seminomas 5-year, PFS, 89% 5-year PFS, 82% 5-year survival, 92% 5-year survival, 86% Nonseminoma Seminoma Testis or retroperitoneal primary and No nonpulmonary Any primary site and No nonpulmonary visceral metastases and visceral metastases and Normal Intermediate markers AFP, anyhCG, any LDH (any of the following) AFP " 1000 and ƒ 10,000 ng/ml
orhCG " 5000 IU/L and ƒ 50,000 IU/L
orLDH " 1.5 x N and ƒ 10 X N 28% of nonseminomas 10% of seminomas 5-year PFS, 75% 5-year PFS, 67% 5-year survival, 80% 5-year survival, 72% Nonseminoma Seminoma Mediastinal primary
orNonpulmonary visceral metastases.
orPoor markers (any of the following) No patients classified as poor prognosis AFP > 10,000 ng/ml
orhCG > 50,000 IU/L
orLDH > 10x upper limit of normal 16% of nonseminomas 5-year PFS, 41% 5-year survival, 48% into testicular or extra-testicular pathologies. Hydrocoele, haematocoele, pyocoele or chronic granulomatous diseases of the testis like tuberculosis need to be differentiated from testicular tumours. This can be accomplished with help of physical examination, scrotal USG, tumour markers and, in doubtful cases by biopsy (frozen section examination with application of non crushing clamps to the cord at the internal inguinal ring).
Management
Histological report and clinical staging guide the further management of testicular tumours. International Germ Cell Cancer Collaborative Group has defined better prognostication based on the pooled analysis of nearly six thousand germ cellcancers and it has also been validated on independent data set. [11]
Seminoma
Low stage (I, IIA) : Seminoma is highly radiosensitive. Radical orchiectomy followed by retroperitoneal irradiation (usually 2500 rads) cures 95 to 98% of clinical stage I seminomas. There are minimal, if any, gastrointestinal side effects. Low volume retroperitoneal disease can also be treated with retroperitoneal irradiation with an average 5-year survival rate approaching 90%. Prophylactic mediastinal irradiation is given up because of significant myelosuppression. Post irradiation relapses are treated with chemotherapy.
High Stage Seminoma (II-B, II-C, III) : Patients with bulky seminomas should be treated with good-risk platinum based chemotherapy regimen like BEP (bleomycin, etoposide and cisplatinum) or EP (etoposide and cisplatinum). Ninety per cent of Stage III patients will achieve complete response with chemotherapy. Extensive desmoplastic reaction in the retroperitoneum is evoked. Residual masses usually contain fibrosis only, only discrete residual nodal masses more than 3 cm in diameter are excised. The excision is often made difficult and bloody by the desmoplastic reaction. About 35% of residual masses will harbour active disease; such patients are given salvage chemotherapy (VIP-vincristine, ifosphamide and cisplatinum). 5-year survival rates approach 65-70%.
Low Stage NSGCT (I,II-A) : Radical orchiectomy is followed by either by close surveillance or retroperitoneal lymph node dissection (RPLND). Patients who are clinically stage I are likely to be pathologically stage II-A in about 25-30% of cases. This is due to lack of sensitivity of imaging modalities.
Surveillance : Patients need to come for clinical visits and marker studies every 2 monthly and for abdominal CT scans (or sometimes USG) every 4 monthly for at least first 2 years of follow up. This is necessary in view of rapid tumour doubling times and poor prognosis of advanced tumours. This entails a significant burden, financial as well as psychological, on these patients who are in their twenties. Moreover, they are likely to miss one or two follow ups because they feel alright. It will also cause frequent disruptions in their routine work. Therefore patients who are to be put on surveillance should:
- Have understood the full implications of the rigid follow up schedule.
- Should live sufficiently close to the treating hospital.
- Should be able to afford the cost of investigations.
- Should be intelligent enough and motivated.
Thus, surveillance is not "masterly inactivity" but "close observation". Involvement of another responsible family member helps in improved compliance. Advantages of this approach are that surgery and its morbidity are avoided in about 75% of patients and relapses if they occur can still be very well treated with chemotherapy.
RPLND : RPLND includes removal of all nodal tissues between the ureters from below the renal hila to the common iliac bifurcation, either by thoracoabdominal or midline abdominal route. This procedure has a morbidity of failure or ejaculation/emission and since majority of patients are young adults, this issue is important. Detailed anatomical studies by Donohue and coworkers have described the locations of lymphatic spread to specific areas in the retroperitoneum. Based on these studies, modified RPLND and nerve sparing RPLND have been developed. [12] In expert hands, nerve sparing RPLND is able to preserve ejaculation in more than 95% of patients. Patients who have had RPLND have only 1% chance of relapse in the retroperitoneum. Therefore costly CT scans can be avoided in their follow up. Tumour markers and chest X-rays are adequate in follow up. Patients who are found to have positive nodes on RPLND are likely to relapse outside the retroperitoneum in about 25% of cases. They are therefore kept on close follow up or are given adjuvant chemotherapy (usually 2 cycles of BEP regimen). With this approach, the cure rates are 90-100%.
High Stage NSGCT (II-B, II-C, III) : Following orchiectomy, patients with bulky retroperitoneal disease (palpable abdominal mass) or metastases outside the retroperitoneum receive primary cisplatinum based chemotherapy (3/4 cycles of BEP). The response to chemotherapy guides further treatment. If there is complete response (normalization of markers, no residual mass in the retroperitoneum on CT scan, disappearance of lung lesions), these patients are kept under close follow up. For the first year 3 monthly, for the second year 4-6 monthly and from 3rd year onwards a 6 monthly follow up with markers, chest X-rays and CT scan (or later on with good USG) is done. If the response to induction chemotherapy is partial (normal markers but residual masses more than 3 cm on CT scan), these masses should be excised (full bilateral RPLND/excision of lung nodules). About a third would have residual carcinoma, a third will have mature teratoma and the remaining third will have fibrosis. Patients with residual carcinoma are given 2 more cycles of adjuvant chemotherapy. Patients with teratoma and fibrosis are followed up closely. Those who have residual disease with raised tumour markers are given salvage chemotherapy (VIP regimen).
Occasionally, patients are diagnosed to have advanced NSGCT based on biopsy of metastatic site without primary orchiectomy. These are given primary chemotherapy but delayed orchiectomy should be performed as viable cancer is often demonstrated in the testis.
Although the above outlined approach can cure upto 45-60% of high volume disease patients, there still remains a subgroup of patients who fare badly. Better prognostication systems like Indiana University System or MSKCC system have been developed in which patients with poor risk are given primarily VIP (vinblastine, ifosphamide and cisplatinum) or VAB-6 regimen with sometimes even high dose chemotherapy with autologous bone marrow transplantation being employed. The chemotherapy employed (good risk BEP or high risk VIP) has significant morbidity including sepsis, neuropathy, renal toxicity, infertility and sometimes even death.
Chemotherapy Regimens
Various chemotherapy regimens were studied in testicular cancer patients.
Commonly used and most effective regimens are BEP and VIP.
BEP : Bleomycin-30 mg/week
...........Etoposide - 100 mg/m2/d x 5 days
...........Cisplatinum - 20 mg/m2/d x 5 days Q3 weeks.3 cycles are given in nonbulky disease and 4 cycles are given for bulky, advanced disease. The cure rate is more than 90%.
VIP : Vinblastine - 0.11 mg/kg/day, days 1-2I
...........fosfamide - 1.2 g/m2/d for 5 days
...........Cisplatinum - 20 mg/m2/d for 5 daysQ3 weeks.The complete remission rate in relapsing patients is 60%.
Acute toxicity : With standard platinum based combination chemotherapy, acute toxicity is related to myelosuppression, gastrointestinal dysfunction, with nausea and vomiting, and hair loss. These side effects are more easily managed with the supportive means available such as new antiemetics and colony stimulating factors.
Chronic toxicity : includes the following :
Renal toxicity - cisplatin containing regimes affect the GFR. The decrease is approximately 10-15%. They also have an increased risk of developing hypertension in later life. Pulmonary toxicity is related to the use of bleomycin. With proper and close monitoring of doses and lung function tests (including carbon monoxide diffusion capacities), the problem can be lessened.
Neurotoxicity - This is the most disturbing long term side effect for majority of patients. Many develop some degree of peripheral sensory neuropathy probably caused by axonal degeneration. Irreversible high frequency hearing loss may be induced in some patients (due to central conduction defects). Raynaud’s phenomenon is seen in nearly half the patients.
Psychosexual problems are usually seen very infrequently.
Fertility in Testicular Cancer Patients
Fertility is an complicated issue in this group of patients. Approximately 40 to 70% of patients are believed to be at least temporarily hypofertile post-orchiectomy prior to any further treatment. Exact cause is not known but various factors like associated cryptorchid state, stress related to the diagnosis or due to high volume of cancer are believed to be important. [13] Radiotherapy also has a depressive effect on spermatogenesis. There is a waiting period of 1-2 years during which the spermatogenesis recovers. About 40 to 70% of patients who desire to have children are able to achieve this end. Bilateral complete RPLND leads to loss of ejaculation in nearly all patients but development of modified templates and nerve sparing RPLND’s preserve ejaculation in 70 to more than 95% of patients. Those who have retrograde ejaculation can be helped by assisted reproduction techniques. Chemotherapy has profound effects on fertility. Almost all patients are azoospermic at 6-months post-chemotherapy but gradual recovery takes place so that about 50% recover spermatogenesis by 2 years post-chemotherapy. Recovery continues to occur beyond 2 years and is seen more in younger patients. Conception may occur despite oligospermia. All these young patients who have not completed their family or who may desire any further children should be counselled regarding the effects of therapies on the fertility as well as the option of cryopreserving their semen. Semen samples are cryo-preserved at -196oC under liquid nitrogen in straws. Such facilities are available in specialized centres in Mumbai.
Undescended testicular tumors
Tumors in undescended testes deserve special mention because by the time they present for therapy, they are usually associated with extensive retroperitoneal adenopathy. The primary tumours are also large in size with frequent infiltration into surrounding bladder and bowel, making their primary resection bloody, difficult and; often, incomplete. Therefore, after a primary diagnosis based on markers and FNAC/Trucut biopsy, an induction of course of chemotherapy is given followed by delayed orchiectomy. Seminoma is the commonest tumour and results are encouraging.
CONCLUSION
Testicular cancers are curable in the majority of patients these days. With the emphasis on cure, the focus of research is now directed towards decreasing the morbidity of treatment modalities. Experience of centres treating large volumes of the disease helps in managing advanced cases.
REFERENCES
- Presti Jr JC ‘Testicular Cancer - an overview’ in Current Genitourinary Cancer Surgery, 2nd edition, edited by E. David Crawford and Sakti Das, Williams and Wilkins publications. 1997; 445.
- Hospital Cancer Registry, Annual report, Tata Memorial Hospital. 1995; 56.
- Swerdlow AJ, De Stavola BL, Swanwick MA, Maconochie NE. Risks of breast and testicular cancers in young adult twins in England and Wales : evidence on prenatal and genetic etiology. Lancet 1997; 350 : 1723-28.
- Petridou E, Roukas KI, Dessypris N, et al. Baldness andother correlates of sex hormones in relation to testicular cancer. Int J Cancer 1997; 71 : 982-85.
- Heimdal K, Olsson H, Tretli S, Fossa SD, Borrensen AL, Bishop DT. A segregation analysis of testicular cancer based on Norwegian and Swedish families. Br J Cancer 1997; 75 : 1084-87.
- Dixon FH, Moore RA. Tumors of the male sex organs. In : Atlas of tumor pathology. Washington, EC : AFIP. 1952.
- Mostofi FK. Testicular tumors : epidemiologic, etiologic and pathologic features. Cancer 1973; 32 : 1186.
- Oliver RT. Factors contributing to the delay in diagnosis of testicular tumors. Br Med J 1985; 290 : 356.
- Union Internationale contre le Cancer : TNM Classification of Malignant Tumors. Sobin LH and Wittekind CH. Eds, Wilry-Liss, New York. 1997.
- Pizzocaro G, Nicolai N, Salvioni R, et al. Comparison between clinical and pathological staging in low stage non-seminomatous germ cell tumors. J Urol 1992; 148 : 76-79.
- International germ Cell Cancer Collaborative Group : International Germ Cell Consensus Classification : a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15 : 594-603.
- Donohue JP, Foster RS, Rowland RG, et al. Nerve sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 1990; 144 : 287.
- Foster RS, Donohue JP. In ‘Fertility in testicular cancer patients’ in AUA Update Series, Lesson 19. 1995; XIV.
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