Testicular Cancer in Singapore

From 1968 to 1992, there were 264 cases of testicular cancers registered with the Singapore Cancer Registry representing about 1% of all cancers in Singapore. Although small in number compared to other urological cancers, it has seen the most dramatic improvements in cure rates in a cancer that impacts significantly on the economically important young males of society. The application of data from clinical trials in a logical manner to maximize efficacy and minimize toxicity also provides a model for the treatment of other malignancies.

Guideline development and target group

This present guideline is an outcome of comprehensive literature review of major reports and extensive discussion amongst the testes cancer workgroup. The recommendations were presented in the Second Uro-oncology Consensus Conference held in 1-2 April 2000 National Cancer Centre, Singapore. This guideline was derived from the consensus drawn from the above named meeting. Extragonadal germ cell tumors, non-germ cell testicular tumors and specific issues of fertility were not discussed in detail at this meeting due to the pressures of time and will be dealt with at the next concensus meeting.

The guideline will serve as an updated reference of the practical management of patients suffering from testicular cancer for family physicians, as well as specialists interested in the practice of uro-oncology.

A. Screening and Risk factors

Testicular cancer accounts for about 1% of all malignancies in men. Ninety five percent of these are of germ cell origin with lymphomas being the commonest of the non germ cell types.

There is a rising incidence in the West with a younger peak incidence age.

There is no role at present for general population screening of testicular cancer but in view of the fact that testicular cancers is prevalent in those males between 20-40 years of age, a strong case was made for testicular self examination to be taught to all males in this age group. Individuals with risk factors should also be screened and followed up. A registry of cryptoorchidism was also proposed.

Risk factors include cryptoorchidism(about 7 times), contralateral testes of patients with testicular germ cell tumors (intratubular germ cell neoplasia occurs in 5% of these with half progressing to invasive germ cell tumor), infertility( about 2 times risk), family history of testicular tumors (2 times increased risk in fathers and 12 times risk in brothers) and testicular microlithiasis (2% on routine ultrasound with 36% reported to have testicular malignancy). Other factors that may have an increased risk include ambiguous genitalia, occupational exposure to plastic works, repellents, radar and radio operators.

B. Histological Classification

The consensus meeting agreed to adopt the modified WHO classification (See Appendix A) which is a histogenetically accurate classification with good correlation to specific serum markers and biologic behaviour. It is also widely used in USA and other parts of the world where most of the advances of treatment for testes cancer have originated. The term "carcinoma in situ" should be avoided as it is not histogenetically accurate and should be replaced with the term intratubular germ cell neoplasia instead.

C. Diagnosis

The classical presentation of testicular tumors is as a painless testicular mass. It rarely occurs with pain or swelling unless there is a concomitant epididymitis or bleeding within the tumor. It can present with gynaecomastia, galactorrhea or both abeit rarely.

Ninety to ninety-five per cent of patients with testicular tumors have an obvious primary lesion. For those with disseminated disease, 25% present with symptoms of metastatic spread namely: severe back pain, chest pain, shortness of breath and hemoptysis.

Palpation of the testes is the method of choice in diagnosis. Ultrasound may be used in large hydroceles and chronic epididymitis where full palpation of the testes is difficult. It is also useful in detecting microlithiasis and an impalpable lesion of the testes in the high risk groups. It however is not specific enough to distinguish tumor from benign diseases.

Useful serum markers of germ cell tumors of the testes include alpha fetoprotein(AFP), human chorionic gonadotrophin(HCG) and Lactate dehydrogenase (LDH). Although they aid diagnosis, they lack specificity and are more useful for staging and measuring response to treatment.

Diagnosis is confirmed histologically with a radical inguinal orchidectomy and high ligation of the spermatic cord. Scrotal violation does not impart a worse prognosis and no further treatment is necessary.

D. Staging

Clinical staging of testicular tumors is necessary to enable appropriate strategy for treatment, prognostication and comparison of data.

Primary extent is best assessed on histological evaluation of the primary tumor. Retroperitoneal nodal spread is best assessed using CT scanning based on size criteria. Using a criteria of >4mm on the short axis, a sensitivity of 93% and a specificity of 58% can be achieved. CXR is a good option to exclude lung metastasis in place of CT scanning of the thorax. MRI and lymphography do not have an established role in the management of testicular cancers when compared to CT.

In addition to assessing the primary tumor extent, nodal involvement and distant metastasis, staging in testicular tumor also involves the presence or absence of tumor markers, notably AFP, beta HCG and LDH. (See Appendix B) Staging errors can be reduced from 50% to 15% in stage I and II tumors using tumor markers.

E. Management of germ cell tumors GCT of the testes

Management of GCT is multimodal involving surgery, radiotherapy and chemotherapy. It can be divided into management of seminomatous GCT and non-seminomatous GCT.

Radiotherapy is the gold standard of treatment for stage one seminoma after an inguinal orchidectomy. It treats about 20% of patients with occult metastasis that would be missed on surveillance and is relatively well tolerated in a disease with no tumor markers for follow-up. In the absence of risk factors for pelvic spread i.e. previous inguinoscrotal or retroperitoneal surgery or tumor invading through the tunica vaginalis, irradiation of the retroperitoneal lymph nodes using 2500 to 3000cGy is sufficient with less leukopenia and diarrhoea compared to the traditional dog-leg irradiation. Seminoma patients with a higher risk of pelvic spread would still require the traditional dog-leg irradiation.

Surveillance is another alternative treatment for stage I SGCT. However recurrences of 15-20% at 5 years and an intensive follow-up programme requiring monthly tumor markers and bimonthly CT scans limits its use to patients who are compliant and able to afford it financially. It is best indicated in patients with horseshoe kidney, inflammatory bowel disease, previous radiotherapy and those medically or mentally unable to tolerate treatment.

At present, there is no established role for chemotherapy for stage II seminoma and chemotherapy can only be considered in patients where radiotherapy is contraindicated. Two cycles of carboplatin is an acceptable alternative.

For stage I NSGCT, radical inguinal orchidectomy followed by retroperitoneal lymph node dissection (RPLND) gives good results if the expertise for RPLND is present. Twenty seven per cent of these would be upstaged to stage two disease with RPLND. Recurrence is about 15% with pulmonary metastasis being the commonest. This is half of that treated with surveillance. Follow-up is easier and cheaper and the psychological burden of carrying the tumor is reduced. However 60-70% of patients will not have required an RPLND and complication rates abeit low are present. About 10% of patients have anejaculation despite using the modified template for RPLND. Other complications include pleural effusion, ileus, femoral neuropraxia, small bowel obstruction, pancreatitis and infection. The presence of lymphangio-vascular invasion predicts relapse. Chemotherapy is started on first evidence of relapse.

Radical inguinal orchidectomy without RPLND followed by surveillance is another option. Relapse rates of 24-30% are reported rising to 50-60% if there is lymphangio-vascular invasion. It however requires monthly serum markers and CXRs; 2 monthly abdominal CT in the first year and long follow up since relapses can occur more than 5 years after orchidectomy without RPLND. It should be considered only if CT and serum markers are negative and if patient and physician are able to comply with the strict follow-up regime.

Adjuvant chemotherapy after orchidectomy using 2 cycles of BEP is the management of choice for high risk patients with stage 1 NSGCT based on lymphatic and vascular invasion and histological type as there is a 50% chance of relapse in this group. Relapse rates after treatment are only about 2%. As it also allows for a less stringent surveillance, has minimal toxicity, avoids surgical morbidity and allows greater peace of mind, its use in all stage 1 NSGCT is acceptable although questions of over-treatment as in RPLND may persist. Individual choice in consultation with his physician is probably the best option giving the risk and benefits of each modality.

Adjuvant chemotherapy using two cycles of PVB gives a relapse rate of <5% versus 49% on observation but relapsed NSGCT can still be given chemotherapy with equivalent survival and no risk of overtreatment. Both options are acceptable.

For large retroperitoneal masses diagnosed on clinical examination or abdominal CT scans, radical inguinal orchidectomy followed by chemotherapy with delayed surgery is a good option. The chemotherapeutic protocol is as for stage III NSGCT disease.

For patients with small volume retroperitoneal disease, primary chemotherapy appears to have similar benefits to RPLND although no large scale randomised studies are available at present.

Chemotherapy is the mainstay of treatment in advanced GCT. BEP is preferable with less neuromuscular side effects , equivalent myelosuppression and pulmonary toxicity and greater effectiveness when compared to the traditional PVB in advanced disease. Disease free survival of 92% are obtained with this regimen.

BEP x 3 or EP x 4 are alternative regimes that can give equivalent results in "good risk patients" as defined by the International Germ Cell Cancer Collaborative Group.(see Appendix C)

In summary, the consensus conference recommended the following for the management of NSGCT.

Clinical stage I

high risk: adjuvant chemotherapy

not high risk: adjuvant chemotherapy or RPLND (if expertise available)

Clinical stage II (non bulky)

Primary chemotherapy or RPLND (if expertise available) + adjuvant chemotherapy

Clinical stage II (bulky)

Chemotherapy +/- salvage RPLND

Clinical stage III

Chemotherapy

F. Follow-up of patients with testicular GCT

There is little written up to justify any particular follow up regime. Most are empirical, based on information gleaned from recurrence patterns from various surveillance protocols, sensitivity and cost of imaging and diagnostic modalities and impact on patient survival.

For stage I NSGCT treated by surveillance only, disease progression is seen in about 30% of patients of which almost all relapse in the first 2 years. This mandates close monitoring in the first 2 years. The commonest site of recurrence is the retroperitoneum detected by CT Abdomen, followed by recurrences seen in CXR. Isolated tumor marker elevation occur in only 1.2% of patients.

Ten to twenty per cent of Stage I seminomas progress. These occur over a longer time frame with a median time to relapse of 16 months. Twenty percent relapse after 4 years. The majority of relapses occur in the retroperitoneum. We suggest monthly tumor markers and CXRⳠand two or three monthly CT abdomen for the first year with decreasing intensity through the years. (See Appendix D for suggested protocols)

For the follow up of patients treated by primary RPLND after orchiectomy, there is a 7-11% risk of relapse for stage 1 NSGCT, all of which are extraperitoneal. Relapses after adjuvant chemotherapy following RPLND for pStage II NSGCT are rare. Almost all occur in the first year and are mainly extraabdominal. Although RPLND should eliminate the retroperitoneal lymph nodes as a relapse site, a small but definite risk (2.7%) of retroperitoneal recurrence exists. In view of the above, we recommend a high intensity follow-up for 5 years followed by a low intensity follow-up of an additional 5 years. (See Appendix D for suggested protocol)

For patients with bulky tumors treated with primary chemotherapy, about 60-70% respond to treatment. However 25-50% require post chemotherapy RPLND. Of these, 10% will relapse from 2-96 months. Half of the relapses occur in the paraaortic nodes. A 5 yr high intensity follow-up is recommended.

The potential for late relapses is about 2-5% in NSGCT and up to 20% in seminomas. Two to five percent of metachronous tumors occur in the contralateral testis. Hence follow up is recommended beyond five years and possibly for life for all tumors.

Conclusions

The concensus meeting on testicular germ cell tumors has focused primarily on testicular germ cell tumors and these guidelines are its result. Issues concerning non germ cell tumors of the testes, extragonal germ cell tumors and details into the effects of treatment on fertility, second malignancies and toxicity were not covered in detail or not at all due to the pressures of time. As new and more accurate data with higher levels of evidence become available, these guidelines will need to be constantly processed, updated and refined to remain relevant. The next update will hopefully incorporate the above issues to this end.

The interpretation of all such data by the concensus meeting has enabled these series of guidelines for the management of testicular germ cell tumors to be made. The ability to harness the spirit of these guidelines and to tailor it for each one of our patients with testes cancer is where the art of medicine takes off and where the science of medicine ends.

Appendix A

Modified WHO classification

Appendix B

TNM AJCC staging system

Appendix C

Appendix D

Suggested Protocols for Stage I GCT o n surveillance

MSK (3)

PRINCESS MARGARET HOSPITAL (2)

Protocols for follow up of patients treated by primary RPLND after orchiectomy Indiana University Medical Center

Low Intensity:

High Intensity:

Risk Factors for Testicular Cancer

Cryptoorchidism

This condition has been reported to increase the risk of developing testicular cancer of up to 15 times. However the risk is generally accepted to be closer to 7 times. In a large cohort study of 1075 boys with cryptoorchidism, who had either orchidopexy or hormonal treatment, there were 12 testicular cancers in 11 patients (1) and another report from Pinczowski (2), where 4 testicular cancers were discovered from a group of 2918 patients who had orchidopexy for undescended testes. (III/B)

A) Contralateral Testis of Testicular Germ Cell Tumour

Patients who develop testicular germ cell tumour have an increased risk of a second malignancy in their contralateral testis. Evidence for this comes from the finding of intratubular germ cell neoplasia (CIS) in 5% of the contralateral testis, with 50% of such lesions progressing to invasive germ cell tumours with 5 years (3). A Relative Risk of 27.6 in tumour developing in contralateral testis has been reported (4). (III/B)

B) Infertility

Studies of subfertile men have shown an increased risk of developing testicular cancer. In a population-based case control study, a 2 times relative risk was shown in men who had subfertility (5).(IIa/B)

C) Ambiguous Genitalia

Congenital conditions with ambiguous genitalia, for example, mixed gonadal dysgenesis, are at increased risk of testicular cancer development (6).(III/B)

D) Occupational Exposure

Environmental factors have been long studied as a risk factor. Associations with many occupations and occupational exposure have been made, showing increased risk for a variety of work. For example, in a case-controlled study involving 148 with testicular cancer and 314 controls, Hardell (7) reported an association of plastics work (Odds Ratio 2.9), exposure to repellents (N,N-diethyl-M-toluamide, OR 1.7) and radar and amateur radio operators (OR 2.2).(IIa/B)

E) Genetic

Linkage studies have been done, showing some genetic association. In a Denmark study, looking at testicular cancer patients from 1950 to 1993, fathers of patients had an increased risk of 2 times, opposed to brothers of patients with an 12 times relative risk (8) (III/B).

F .Prenatal factors (9) (III/B)

G. Hormones (10) (III/B)

H. Testicular Microlithiasis (11)

2% incidence of testicular microlithiasis was demonstrated on routine ultrasound of 1100 men, and the finding that 36% had testicular malignancies.(III/B)

Germ Cell tumor of the testes - Do We Screen?

Criteria for screening of a disease has been established and well accepted (12) They describe an ideal setting for which a screening programme would be beneficial. Essential information required in making a rational decision to begin a screening programme include knowing the prevalence of the disease in question, the related morbidity and mortality, the availability of sensitive and specific screening tests that enable early diagnosis, and whether effective treatment regimes exist. These criteria are still relevant today and form the basis for deciding on a screening programme for testicular cancer.

The American Cancer Society reports a 1% rate of testicular cancers of all malignancies (13). In addition, there is epidemiological evidence of an increasing incidence of testicular cancer. This was described for 6 northern European countries on data from 1945 to 1980 (14). A similar trend was reported in the USA (15) where rates have increased from 3.6 per 100000 to 5.4 per 100000. Further review of this phenomenon by Mckiernan (16), who analysed the NCI Surveillance and Epidemiological database showed that there might be a birth cohort effect, with the years 1945 to 1968 particularly affected. Furthermore, there is a trend toward a younger peak age of incidence, which points towards an environmental factor, as a risk factor.

In Singapore, data from the Cancer Registry shows a stable rate of 1% (1968 to 1983).

Whilst agreement is unanimous that testicular-self examination as a form of screening is easy to perform and cost-free for the individual, the prevalence of the disease being so low in the population as a whole would not make screening effective. Lack of education of the general public at this moment in time, would lead to a high number of false positive alarms and unnecessary anxiety. As few men would benefit, the consensus group felt that a case could not be made for population screening of testicular cancer (17;18). Furthermore although cost-free for the individual, there would be a definite cost to the health care system from such false-negative related investigations. (GPP)

However, as seen from the standpoint that testicular cancer is the most prevalent cancer to afflict young men from 20 to 40 years old, and with the knowledge that early testicular cancer once diagnosed is effectively treated with excellent prognosis, a strong case was made to encourage testicular-self examination among this group to reduce delay at presentation. Individuals with other conditions known to increase the risk of developing testicular cancer should also be included.

The Contralateral Testis: Surveillance or Biopsy

Evidence of intratubular germ cell neoplasia in the contralateral testis and the risk of developing invasive germ cell tumour have been discussed. That close surveillence and testicular-self examination of the contralateral testis in patients with primary GCT is essential is supported by reports that show early diagnosis of contralateral testicular tumours (19). Tumours diagnosed were at an early low stage, 83% Stage I and 17% Stage II, with low 25% incidence of vascular invasion. Routine biopsy is not advocated, as it is associated with at least 95% negative biopsy rate, and morbidity to the testis. (20). Therefore, close surveillance of the contralateral testis and patient education on testicular self-examination provide sufficient follow-up for the contralateral testis (21).(III/B)

On the other hand, reports from centres where routine biopsy is done, confirm intratubular germ cell neoplasia rates of 5% (22;23). Intratubular germ cell neoplasia has been shown to be sensitive to both chemotherapy and low-dose radiotherapy. However, there is evidence that there may be development of invasive cancer in spite of chemotherapy and for this reason, radiotherapy is recommended for intratubular germ cell neoplasia (24). Supportors of routine biopsy of the contralateral testis are adamant that early diagnosis of intratubular germ cell neoplasia, which being effectively controlled by low-dose radiotherapy, provides optimal treatment for the patient (25).(III/B)

Another area of discussion was for the use of adjunctive procedures in surveillance which might lead to earlier diagnosis of testicular cancer, or to the better identification of patients with intratubular germ cell neoplasia, so as to reduce the negative biopsy rate. In particular, the usefulness of testicular ultrasound was debated. Lenz (26) reported a predictive value of 22% for intratubular germ cell neoplasia in the contralateral testis on visualising characteristic echogenic features. And a negative predictive value of 97.6% should those features be absent. The finding of testicular microlithiasis and the association with malignant change has been discussed (11). Finally that the use of ultrasound routinely increases the identification of testicular cancer is supported by Pierik (27) where out of 1372 men screened as part of their subfertility work-up, 0.5% had testicular cancer.(III/B)

The consenses group felt that although there was good value in the early diagnosis of intratubular germ cell neoplasia, the 95% negative biopsy rate was a real drawback. Furthermore there would be the problem of sampling error of biopsy, and the false negative biopsy rates are not known. Another important factor would be whether the incidence of intratubular germ cell neoplasia still remains at 5%, after the patient undergoes and completed chemotherapy for his primary germ cell tumour. Ultrasound imaging is seen as very sensitive but not specific for intratubular germ cell neoplasia. In addition, there was concern that there is lack of localising techniques for biopsy should a lesion be identified on ultrasound.

The recommendation for routine biopsy and the use of ultrasound is therefore optional for the above reasons. It is however strongly recommended that the physician discuss the options available, with the patient understanding the caveats of each option, and thus work out a treatment plan together with his patient.(GPP)

Testicular Germ Cell Tumours: Classification & Terminology

The 2 major systems used to classify testicular germ cell tumours are those formulated by the British Testicular Tumour Panel (BTTP) and the World Health Organisation (WHO). The WHO classification is largely based on the work of Friedman and Moore, Dixon and Moore, Melicow and Mostofi and Price.

The modified WHO classification is currently the preferred system (B/III). Its basis is that all germ cell tumours are derived from neoplastic germ cells that differentiate along different pathways. In contrast, the BTTP classifies testicular neoplasms into 2 main categories of seminoma or teratoma, with teratomas further subclassified into undifferentiated, intermediate and trophoblastic; based on the belief that seminomas are of germ cell origin but non-seminomas are derived from displaced, developmentally disorganised embryonic blastomeres. A comparison between the 2 systems is depicted in Table 1.

The histogenetic correctness of the modified WHO classification is supported by the close relationship between intratubular germ cell neoplasia, unclassified (IGCNU, discussed later) and all germ cell tumours (seminoma and non-seminoma) with the exception of spermatocytic seminoma. In addition, there is the advantage of correlation of histology with biologic behaviour and serum tumour markers (28) that is lost when the BTTP system is used, eg. the BTTP classifies tumours with embryonal carcinoma and teratoma, yolk sac tumour and teratoma; both into the subcategory of malignant teratoma intermediate. The presence of yolk sac tumour elements is associated with raised serum alpha-foetoprotein (29), while embryonal carcinoma is regarded as more aggressive (30). There is also the reported negative correlation between the histological finding of yolk sac tumour elements and occult metastases in clinical stage I patients (31).

Finally, for effective comparison between results of therapies and prognoses, a uniform classification system that is widely used has to be adopted. The recommended modified WHO classification is well accepted by urologists and oncologists in the United Sates and many other countries. A detailed description of the modified WHO classification is shown in Table 2.

Table 1

Comparison of the Modified WHO with the British Testicular Tumour Panel (BTTP) Classification

Table 2

Modified WHO Classification

Tumours of One Histologic Type

Seminoma

• Variant: with syncytiotrophoblastic cells

Spermatocytic Seminoma

• Variant: with sarcomatous component

Embryonal Carcinoma

Yolk Sac Tumour (endodermal sinus tumour)

Trophoblastic tumours

• Choriocarcinoma
• Placental site trophoblastic tumour
• Unclassified

Teratoma

• Mature teratoma
• Variant: dermoid cyst

Immature teratoma

With a sarcomatous or carcinomatous component

Monodermal teratoma

• Carcinoid
• Primitive neuroectodermal tumour
• Others

Mixed Germ Cell Tumours

• Embryonal carcinoma and mature and/or immature teratoma
• Yolk sac tumour and mature and/or immature teratoma
• Seminoma and teratoma
• Seminoma and embryonal carcinoma
• Choriocarcinoma and embryonal carcinoma
• Choriocarcinoma and teratoma
• Choriocarcinoma and seminoma
• Polyembryoma
• Diffuse embryoma

Regressed ("burnt out") Germ Cell Tumours

• Scar only
• Scar with intratubular germ cell neoplasia
• Scar with minor residual germ cell tumour (teratoma, seminoma,other)

Note:

Spermatocytic seminoma is a distinct entity, thought to have a different pathogenesis from other germ cell tumours. There is no strong association with cryptorchidism (32;33) and it does not occur with IGCNU (34) or other germ cell tumours. It has an excellent prognosis, such that patients with this tumour are treated by orchiectomy without adjuvant therapy (32). However, if there is sarcomatous dedifferentiation within the tumour, the prognosis is poor (35;36) .

Intratubular Germ Cell Neoplasia

Intratubular germ cell neoplasia, unclassified, (IGCNU) is believed to be the precursor lesion of most germ cell tumours. The synonymous term of carcinoma in situ (CIS) was used by Skakkebaek to describe this lesion (37;38). CIS, however, is not an accurate term histogenetically as the intratubular malignant germ cells do not disclose epithelial characteristics, nor do they express cytokeratin (39) or demonstrate epithelial junctions on electron microscopy (40). The invasive neoplasm that intratubular germ cells resemble, ie seminoma, is not a carcinoma.

The alternative term "seminoma in-situ" is also not appropriate as the lesion may be associated, synchronously or metachronously, with all other invasive germ cell tumours (except spermatocytic seminoma).

The preferred classification of IGCN is shown in table 3 (B/III).

Table 3

Classification of Intratubular Germ Cell Neoplasia

• Intratubular germ cell neoplasia, unclassified
• Intratubular germ cell neoplasia, unclassified, with extratubular extension (early seminoma)
• Intratubular seminoma
• Intratubular embryonal carcinoma
• Intratubular yolk sac tumour
• Intratubular germ cell neoplasia, others

Diagnosis of Germ Cell Carcinoma of Testis

Clinical Presentation

The classical presentation of testicular tumour is a painless testicular mass (41). The patients occasionally present with testicular pain and swelling when associated with epididymitis or bleeding within the tumour and less commonly with gynaecomastia, galactorrhoea or both (42;43). About 90% to 95% of the patients with a testicular primary tumour have an obvious primary lesion. Symptoms of metastatic disease such as severe back pain, shortness of breath, chest pain or haemoptysis in about 25% of patients with disseminated disease (44).

Investigation

Ultrasonography may be used as a complementary test to clinical examination and its use is optional, to improve accuracy of clinical diagnosis of testicular tumours. Ultrasound examination is also useful in cases of large hydrocoele and chronic epididymitis where full palpation of the testis is difficult. Testicular ultrasound can be used to differentiate accurately palpable scrotal masses and to distinguish between intratesticular and extratesticular abnormalities. However, ultrasound of testis is not specific enough to differentiate a tumour from benign diseases involving testicular parenchyma. (45-47) Ultrasound scan has also been able to identify impalpable testicular tumours in the evaluation of patients with extragonadal GCT or retroperitoneal metastasis and palpably normal testis. (48-50)

The most useful tumour markers for diagnosis in GCT are Alpha fetoprotein (AFP) and Human Chorionic Gonadotrophin (HCG). These tumour markers may aid in establishing diagnosis of testicular cancer but should not replace tissue diagnosis as they lack specificity and sensitivity. Measurement of serum AFP, HCG and Lactate dehydrogenase(LDH) are taken preoperatively to aid diagnosis as well as a comparative baseline for staging purposes following orchidectomy. Upper reference limit of AFP and HCG are approximately 15mcg/L (10kU/L) and 5U/L respectively.

Both AFP and HCG are not tumour specific as AFP are raised in NSGCT and hepatocellular carcinoma, but also in gastric, colon, biliary, pancreatic and lung cancers while HCG levels may be increased in pancreatic adenocarcinoma and islet cell tumours, tumours of the small and large bowel, hepatoma, stomach , ovarian, breast and renal cancer. (51-53) HCG is raised <20% of testicular seminomas (stage I and metastatic) indicating in such case the presence of trophoblastic elements. AFP is not elevated in pure seminoma unless the liver is involved, and in other circumstances the histology is mixed germ cell tumour. (54)

Surgical diagnosis

A radical inguinal orchidectomy with high ligation of the spermatic cord at the internal ring is the initial standard approach when testicular tumours are suspected. Non standard surgical approach or scrotal violation ( scrotal orchidectomy, open testicular biopsy and fine needle aspiration ) have historically been condemned as significantly compromising patient prognosis and patients were subjected to a variety of adjuvant therapies, including hemiscrotectomy, inguinal lymph node dissection, local radiotherapy or chemotherapy. (55;56)

However, recent studies demonstrated that scrotal violation does not impart a significantly worser prognosis and Stage I disease patients with scrotal violation should not necessary be disqualified from surveillance protocols or subjected to adjuvant local therapy (57-61) .

Clinical staging of testicular tumours is necessary to enable an appropriate strategy for treatment, prognostication and comparison of data. Based on the current staging systems in use, the staging modalities of testicular tumours would include an assessment of the following:

The extent of the primary tumour or T stage is dependent on histological evaluation of the radical orchiectomy specimen. This is by necessity a pathological staging.

1. alpha-feto protein [AFP]
2. b subunit of human chorionic gonadotropin [b HCG]
3. Lactic Acid Dehydrogenase [LDH]

Staging is now further sub-divided by the presence or absence of markers. These should be obtained prior to initial orchiectomy . (IV). Elevated levels tend to indicate poorer prognoses. When elevated, they are also helpful in monitoring the treatment response and for detection of recurrences (62). Staging errors may be reduced from 50% to less than 15% in stages I and II by AFP and b HCG determination (51).(III/B).

The modes of assessment include radiographic imaging methods and the retroperitoneal lymph node dissection. In radiographic imaging (clinical staging), the following are usually used:

1) CT scan of the abdomen

CT is modality of choice for clinical staging of retroperitoneal nodal status but has limited accuracy in the patient with early stage disease (67 to 70% sensitivity) (63;64). CT assessment is based on size. A smaller size criteria will be more sensitive in detecting metastases but will also result in a larger proportion of false positive (i.e. unnecessary treatment). Using a criteria of > 4mm in the short axis for metastases, a sensitivity of 93% and a specificity of 58% is achieved (Hilton) (63-66).(III/B).

2) Chest radiograph

The initial mode of screening for chest metastases has always been the chest radiograph. Chest Radiography should be performed for staging (67).(III/B).

3) CT scan of the chest

CT thorax is recommended for staging if the abdominal CT is positive for lymphadenopathy. CT Thorax has higher sensitivity for detecting pulmonary metastases and is the recommended staging investigation for non-seminomatous testicular tumors. Out of 283 patients with nonseminomatous testicular tumor, CT is the only positive examination in 20 out of 47 intrathoracic metastases (68-70).(III/B)

4) CT scan of the pelvis

Pelvic CT is indicated at staging. It is indicated for surveillance only if there is abdominal adenopathy. In one study, sixteen out of 167 patients (9.6%) with germ cell testicular tumors had pelvic adenopathy. Thirteen of the 16 patients with pelvic adenopathy had identifiable risk factor (abdominal nodal enlargement). The other 3 out of 16 had unequivocal abdominal nodal metastases (71). (III/B).

5) MRI

MRI does not have an established role in nodal staging. Signal characteristics cannot diagnose tumor presence. MRI cannot offer information on effectiveness of chemotherapy (72-74). (III/B).

6) Lymphography

Lymphography does not have an established role in nodal staging. Compared to CT with tumor markers, lymphography diagnosed additional metastases in 4% but provided misinformation in another 4% and has limited additional role to staging by CT and serum markers (75;76).(III/B)

5. Treatment

Management of Non Seminomatous Germ Cell Tumour of the Testis (NSGCT)

STAGE I NON SEMINOMA

(AJCC: any T, N0, M0)

The traditional approach in Stage I NSGCT is to perform radical inguinal orchidectomy followed by retroperitoneal lymph node dissection (RPLND). However, 27 % of clinical stage I patients are upstaged to pathological stage II after RPLND (77) . The recurrence rate in pathological stage I has been reported to be 15%, with the lungs as the main site of recurrence (77). In pathological stage I, the presence of lymphatic or vascular invasion (LVI) in the primary tumor predicts for a higher relapse risk compared to those without vascular invasion.(19% versus 6%) (78). Chemotherapy is recommended on first evidence of recurrence.

An alternative approach involves radical inguinal orchidectomy without RPLND followed by a stringent surveillance program, which includes monthly physical examination, serum markers and chest X-rays, and 2-monthly abdominal CT scans in the first year. Careful follow up is important since relapses can occur more than 5 years after orchidectomy in patients who did not undergo RPLND. This option is only considered if both patient and physician accept the need for frequent CT scans and agree to diligently follow the strict surveillance program recommended. Relapse rates are about 30 to 35%, but excellent long term disease free survival results (close to 100%) are obtained with chemotherapy on relapse (79;80) . (B/IIb) Relapse rates are higher in those with LVI compared to those without (61% versus 24%) (79).

Adjuvant chemotherapy after orchidectomy has recently been strongly advocated for patients at high risk for relapse. 2 cycles of chemotherapy for high risk patients, defined as those with about 50% risk of relapse based on presence of vascular invasion and/or histological type, has produced excellent results (see table 1). (B/IIb)

Table 1: Results after 2 cycles of adjuvant chemotherapy in high risk stage I NSGCT

* follow up longer than 2 years

STAGE II NON SEMINOMA

(AJCC: any T, N1-3, M0)

Radical inguinal orchidectomy followed by RPLND results in a relapse rate of 20-30% if followed without chemotherapy, and most are cured with standard chemotherapy if they relapse (86). The relapse rate after RPLND is higher in those with LVI (64% versus 24%)[78]. Patients whose markers do not return to normal following RPLND should be given chemotherapy (87;88). A randomised trial found that 2 cycles of adjuvant chemotherapy given after RPLND reduced the relapse risk to less than 5%, compared to about 50% in those observed after RPLND. However, treatment at relapse resulted in equivalent survival for the observation arm (89). (A/Ib)

Recently, primary chemotherapy after orchidectomy has been used in patients with small volume retroperitoneal disease in an effort to avoid RPLND (90;91). In one small series, patients with less than 5 cm lymph nodes received 3 or 4 cycles of chemotherapy (PVB), with 6 out of 19 still requiring RPLND after chemotherapy. The disease free survival with a median follow up of 28 months was 100% (90). Although there are no randomised comparisons, it appears that primary chemotherapy may produce similar survival results in clinical stage II patients when compared to RPLND. (B/IIb)

In stage II patients with unresectable retroperitoneal masses, primary chemotherapy after orchidectomy is the treatment of choice, with delayed surgery for removal of residual masses if present.

The various treatment options for early stage (I and II) testicular NSGCT are summarised in Table 2, each with their advantages and disadvantages.

Table 2: Treatment options for Early Stage testicular NSGCT

chemo: chemotherapy RPLND: retroperitoneal lymph node dissection

The Urology Consensus Meeting this year made the following recommendations on the treatment of early stage Testicular NSGCT, adhering closely to the aim of "cure with least morbidity".

Recommendations for treatment options after orchidectomy

Clinical stage I

high risk: adjuvant chemotherapy

(especially LVI)

not high risk: adjuvant chemotherapy

or

RPLND (if expertise available)

Surveillance (following a strict protocol) was deemed an acceptable option in those not at high risk of relapse.

Clinical stage II (resectable) Primary chemotherapy

or

RPLND (if expertise available)

+ adjuvant chemotherapy

Clinical stage II (unresectable) Primary chemotherapy

STAGE III NON SEMINOMA

(AJCC: any T, any N, M1)

Chemotherapy is the treatment of choice for advanced NSGCT.

In a randomized study BEP (Bleomycin, etoposide, cisplatin) was preferable to PVB (cisplatin, vinblastine , bleomycin) with less neuromuscular side effects, equivalent myelosuppression and pulmonary toxicity, and better survival rates in patients with more advanced disease (p = 0.048 by MD Anderson criteria, p = 0.017 by Indiana University criteria) (92). (A/Ib) 3 cycles of BEP was found to be as effective as 4 cycles of BEP in those with minimal to moderate stage disease (Indiana University criteria), with 92% disease free survival in both arms, and the 3 cycles arm incurring less cost, toxicity and inconvenience (93). (A/Ib) 4 cycles of EP (etoposide and cisplatin) was also found to give good results in good risk patients (Memorial Sloan Kettering criteria), with 87% long term disease free survival (94). (B/IIb) Bleomycin was found to be an essential component of BEP when only 3 courses are administered in minimal to moderate stage disease (Indiana U) (95). (A/Ib) 4 cycles of BEP was found to have equivalent overall survival and time to treatment failure when compared to 4 cycles of VIP in advanced chemo-naïve disease, with worse hematologic side-effects with VIP (96). (A/Ib) In poor risk patients, standard dose cisplatin regimens were equivalent to high dose cisplatin in terms of complete response, cure rate and survival, with the high dose cisplatin giving more toxicity (97).

If serum markers normalise, attempts should be made to resect residual masses. If residual tumor cells are found in the post chemotherapy resected residual mass, further chemotherapy is indicated. In a retrospective series (98), it was found that 2 additional courses of cisplatin based chemotherapy was safe and effective therapy for reducing relapse after complete resection of residual mass after primary chemotherapy. Additional standard dose chemotherapy following complete resection after salvage chemotherapy, however, appeared to offer no benefit. Incomplete resection of viable NSGCT after primary or salvage chemotherapy portended a very poor prognosis. (B/III)

In 1997 the International Germ Cell Cancer Collaborative Group collected clinical data from 10 countries on over 5000 patients with metastatic germ cell tumours treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and independent adverse factors identified. An easily applicable, clincally based prognostic classification was formulated for use in clinical practice and research. See table 3 (99). (B/III)

RPLND For Germ cell tumor of the testes

Role of RPLND in Stage I NSGCT

Seminoma RMH Stage I

(AJCC IA, IB, IS)

RADIATION THERAPY AFTER ORCHIECTOMY

Prophylactic radiotherapy to the draining lymphatics is the standard treatment after inguinal orchiectomy (116;117). (III/B)

Approximately 15 to 20% of these patients have occult metastases that can be cured with radiotherapy.

Adjuvant treatment is recommended because there are no tumour markers to follow-up and surveillance would otherwise require frequent CT examinations which would be costly.

The dose for radiotherapy for seminoma is also relatively low and well tolerated.

The dose of radiation is required is 2500 to 3000 cGy (116;118). (III/B)

In the absence of risk factors for pelvic spread, the volume to be treated by irradiation may be limited to the retroperitoneal lymph nodes alone (116). (lb/A)

In patients with previous inguino-scrotal surgery, previous retroperitoneal surgery, or tumour invading through the tunica vaginalis, the para-aortic as well as the ipsilateral pelvic lymph nodes should be irradiated (116). (Ib/A)

The results of patients treated with irradiation to the para-aortic strip alone compared very well with those receiving "dog-leg" irradiation (116).

3-yr relapse free survival 96% vs 96.6%.

Overall survival 99.3% vs 100%.

Pelvic relapse-free survival 98.2% vs 100%. (95% CI for the difference = 0 - 3.7%)

Statistically significantly less leukopenia and diarrhoea.

(Ib/A)

SURVEILLANCE AFTER ORCHIECTOMY

Surveillance as an alternative to radiation therapy for stage I seminoma is not generally recommended (except in patients at higher risk for morbidity from radiation therapy). Between 15% and 20% will relapse during surveillance. The median time to relapse is approximately 12 months, but relapses do occur more than 5 years following orchiectomy (117). (III/B)

(For the procedures involved in surveillance, please see section on "surveillance in NSGCT".)

With surveillance, the overall tumour recurrence rate at 5 years is 15 to 20%. However, nearly all of these may be salvaged by radiotherapy or chemotherapy giving an overall cure rate similar to those receiving adjuvant radiotherapy following orchidectomy (117;119). (III/B)

Prolonged surveillance is required as 20% of relapses occur 4 or more years after diagnosis (119). (III/B)

Certain patients may be considered for followed-up with surveillance following orchidectomy. These include patients with horseshoe kidney, Inflammatory bowel disease, previous abdominal radiotherapy, and those medically or mentally unable to tolerate treatment. (IV/C)

Alternatively, these patients may be given 2 courses of carboplatin chemotherapy (120). (III/B)

RMH STAGE IIA & IIB

(AJCC Tany, N1-2 M0)

After orchidectomy, radiation is given to the para-aortic and ipsilateral pelvic lymph nodes, 25 - 30 Gy + boost to bring total dose to enlarged nodes to 35 ?Gy. This achieves a cure rate of more than 90% (118). (III/B)

SCROTAL VIOLATION

Adjuvant radiotherapy to the scrotum is not necessary for scrotal violation. In a meta-analysis (non-randomised series) of 1182 cases of testicular cancer, which included 206 cases with scrotal violation, no statistical difference in metastases, and survival rates were found between those who underwent inguinal orchidectomy and those who had scrotal violation.

Among those with scrotal violation, there was no statistical difference in local or distant recurrence rate between those who did and those who did not receive prophylactic scrotal irradiation. Only 1/44 of those who did not receive adjuvant treatment to the scrotum relapsed locally (58). (III/C)

LATE SIDE-EFFECTS OF RADIOTHERAPY

The possible late side-effects of para-aortic and ipsilateral irradiation include peptic ulceration (6%), persistent increase in bowel frequency, chronic pancreatitis (rare), transient fall in sperm counts, and second malignancy with increase in incidence more than 15 years following RT. (TCC urinary tract, rectum, connective tissues, melanoma, NHL, acute leukaemias) (121-126)

TABLE 3

Based on the available data, the Urology Consensus Conference this year made the following recommendations on the use of chemotherapy in advanced Testicular Germ Cell Tumours:

Recommended chemotherapy (non-adjuvant setting):

Including Stage II & III non-seminoma and

Stage IIC & III seminoma

Indications and Outcomes of surgery in postchemotherapy residual masses

Treatment of residual retroperitoneal mass after chemotherapy in locally advanced non-seminomatous germ cell tumour remains controversial. Histology of the residual masses may be necrosis, mature teratoma or carcinoma. In a review series by Steyerberg et al (127), the proportion of histology is 45%, 42% and 13% (III) respectively in more than 1000 cases on residual retroperitoneal masses where salvage RPLND was done as a routine.

If all cases of residual masses were subjected to salvage RPLND, a large proportion of cases will be exposed to a surgery with a high morbidity rate (127-129) for a potentially benign condition. Hence, several authors have tried to develop several models to predict the histology of the residual mass. It had been suggested that masses of small size (<10 or 20mm), non-teratoma in the histology of the primary tumour, normal prechemotherapy tumour markers and reduction of transversal diameter more than 70% of the primary mass are factors that help predict a benign nature of the mass, hence eliminating the need for salvage RPLND for such cases (127-129). However, these guidelines are all drawn from retrospective reviews. No randomised trials have been attempted. Due to the potential of leaving malignant tissues in the mass, the concensus group recommends that salvage RPLND be done for postchemotherapy residual masses whenever feasible. (III/B)

Extent of RPLND is the second controversial issue in this topic. Donohue et al (130) proposes bilateral retroperitoneal resection in all patients as they have found that on tissue analysis of the retroperitoneal masses a considerable proportion of positive histology arises from the apparently normal appearing part of the retroperitoneum. However, due to the high percentage of serious morbidity and improved accuracy of frozen sections, other authors have recommended that if frozen sections of the masses revealed necrosis only; only modified RPLND is required. Otherwise, bilateral RPLND is indicated for the patient (131-134). (III/B)

Follow up Protocols

Introduction