SentinelLymphNodeIdentificationinPenileCancers CancersoftheMaleGenitalia29

Sentinel Lymph Node Identification in Penile Cancers

In the tumor types specific to the male, correlations between sentinel node labeling and biopsy and their significance must be discussed as part of a strategy concept in the treatment of penile cancer. The rates recorded for this tumor type in the western world are not extremely high, but neither are they very low. Ex- perience with large numbers has been reported from India, where penile cancer has a high frequency.

The clinical features taken into consideration in the assessment of regional lymph node involve- ment are confusing. The following facts document the inadequacy of physical examination and radio- imaging for confirmation or exclusion of regional lymph node involvement (Mukamel 1987; Abi Aad and de Kernion 1992).

The early change from the temporary use of lymphangiography to sentinel node evaluation for investigating the lymphatic spread of this tumor types was reported by Cabanas (1977). He treated penile cancer patients without the dissection of in- guinal, femoral, and iliacal lymph nodes when the sentinel node was tumor free. The 5-year survival rate of his patients was 90%.

Cabanas (1992) repeated and modified his re- commendations without far-reaching changes. His principles were: Primarily, bilateral sentinel lymph node (SLN) biopsy should be performed. In cases with positive nodes inguino-femoral dissection should be carried out. In node-negative cases no further surgical treatment is indicated, but the pa- tient needs to be observed closely, with examina- tions monthly for 1 year and then every 2 months for 3 years. He repeated this scheme again in 2000.

Ravi et al. reported as long ago as in 1991 on 52 patients with invasive penile cancers who were treated by ªpickingº of inguinal lymph nodes. In 5 patients (9.6%) the nodes were positive. (ªPickingº is similar to berry-picking in the case of thyroid

cancer, meaning here revision of all lymph nodes that are enlarged, including the SLN.)

However, in 7 of 47 cases with negative results the patients developed inguinal recurrences, 3 of which were distant metastases.

The 5-year survival rates of patients with ingu- inal nodes that were positive and negative on pick- ing were 100% and 82%, respectively. In conclu- sion: the ªinguinal pickº technique is helpful in node-positive cases, but does not guarantee the ab- sence of regional metastases.

Similarly, Akduman et al. (2001) investigated 5 cases with microscopic involvement of a single lymph node only (confirmed by full-groin dissec- tion), and gamma probe identification was 100%

accurate. None of the patients with negative senti- nel nodes had a recurrence.

Recently Senthil-Kumar et al. (1998) developed an acceptable program for lymph node staging. They stated that clinical node examination alone is inade- quate in selecting cases for bloc dissection. Fine- needle biopsy seems to be accurate and specific in cases with palpable nodes. In cases with impalpable nodes a preliminary medial inguinal node (MIN) biopsy followed by sentinel node biopsy in MIN biopsy-negative cases will allow accurate selection of all patients with metastases in the inguinal nodes.

If intraoperative staging is possible bloc dissection can be carried out at the same time.

Pizzocaro et al. (1997) also recommended fine- needle aspiration cytology (FNAC) combined with imaging investigations to obtain a better overview for surgical intervention.

Recently Valdes et al. (2001), working in Am- sterdam, published their data, which are derived from a larger number of investigated cases than any other grouphas examined (Table 1). In their groupof 74 patients there were only 2 with false- negative SLNs. These data seem to offer helpfor further developments.

In rare cases malignant melanoma may develop in the penile skin or mucosa of the glans or in the

Cancers of the Male Genitalia 29

male urethra (Begun et al. 1984). In these melano- ma cases the diagnostic and treatment strategies discussed for malignant melanomas in general, and in some cases, those discussed specifically for penile cancers, must be carefully considered to find the best method of individual treatment.

Nonetheless, there are also a few publications that express negative opinions of inguinal node evaluation. Perinetti et al. (1980) reported a case in which 6 months after inguinal lymph node ex- amination with a negative result an unresectable node recurrence was found to have developed.

In additional investigations by Pettaway (1999), among 20 patients with negative SLN, 5 had devel- oped metastases after 3±21 months. On the basis of these depressing results the authors suggest that routine node dissection can no longer be recom- mended.

The last two publications discussed are depress- ing. However, on the basis of the facts presented, it seems to be impossible to come to a definitive as- sessment of the value of nodal staging on the basis of evaluation of these statements alone.

The positive results recorded by the other inves- tigators cited are much more persuasive according to the data presented in detail.

Treatment Strategies in Premalignant and Occult Malignant Lesions

Besides the mostly benign warty lesions, such pre- malignant lesions as giant condylomas, bowenoid papulosis, and erythroplasia of Queyrat and Bowen's disease have a role (Horenblas 2001a, b;

Horenblas et al. 2000 a,b; von Krogh and Horen- blas 2000a, b).

These premalignant lesions can be excised by laser surgery (van Bezooijen et al. 2001). It is nec- essary that these lesions be histopathologically in- vestigated in serial sections to exclude early stro- mal invasion. In the collective of Bezooijen et al.

(2001), in 3 of 19 patients (19%) recurrences occurred. During the 25-month follow-up period, 5 patients had true carcinomata in situ (26%) and 1 developed invasive cancer. It is clear that when- ever stromal invasion is detected the search for the regional sentinel nodes must be started.

Labeling the SLNs in Penile Cancers by Application of

Tc-Nanocolloid

In Germany the Augsburg group led by Prof. Dr. P.

Heidenreich and his coworkers (H. Vogt, J. Kopp, and H. Wengenmair in the Department of Nuclear Medicine, Prof. Dr. R. Harzmann and Dr. F. Waw- roschek in the Department of Urology, and Dr. T.

Wagner in the Department of Pathology) is highly experienced in SLN-labeling strategies, using dif- ferent subtypes of gamma probes and the investi- gation of removed nodes by serial sectioning and the use of immunohistochemistry for single-cancer cell detection.

The characteristic pictures discussed at this point were kindly put at our disposal by Dr. F.

Wawroschek, Augsburg, Germany and illustrate the performance levels of the various labeling proce- dures in cases with penile cancer.

In Fig. 1, the injection technique used in a case of penile cancer at the glans is demonstrated. The labeled nanocolloid solution is injected strictly peritumorally, using a small tuberculin syringe Chapter 29 Cancers of the Male Genitalia

440

Table 1. Sentinel lymph node (SLN) visualization in penile cancer patients, bilaterality of SLN, synchronous and asynchro- nous drainage

No. of patients (n)

Labeling SLN

visualiza- tion rate

Bilaterality Left groin

only Right

groin Synchro- nous drainage

Asynchro- nous drainage

Positive nodes

74

Tc-nano-

colloid 64.8 MBq 0.3±0.4 ml

72/74

97% 58/72

81% 9/72

13% 6% 22/58

38% 62% 16

22%

a

Additional results: 161 sentinel nodes removed in total

b

Pitfalls: in 4 patients false-positive results were obtained because of skin contamination; at follow-up, 2 patients with neg-

ative SLNs were found to have recurrences

with a suitably fine needle. For a safe injection technique, the penis is fixed in place by hand with the peripenile soft tissue gathered up.

Figures 2 and 3 illustrate unilateral labeling of a lymph node in the groin in a case with penile can- cer. The scintigraphic results 13 min and 2 h after injection are demonstrated. This picture is of basic importance for the surgical preparation along the lymphatic flow to the labeled node(s). Figure 3 shows that the secondary pelvic nodes are also al- ready slightly labeled approximately 30 min after injection. This might be explained as a result of

spillover, in accordance with the small particle di- ameter used for the investigations.

Corresponding to these figures showing exact imaging of the SLN(s), Fig. 4 shows identification of the SLN(s) in the inguinal region using the gamma probe, before its removal for histopatho- logical and immunohistochemical examination.

SLN detection can be difficult in tissues with a dense structure:

a) When the primary is too close to the regional lymph nodes.

b) When the basin is too extensive and vascular and nerve structures pass through it.

c) When the gamma probe used is not fine enough to reach the labeled lymph node(s).

a) This situation is unimportant, because the la- beled area around the primary can be drawn aside.

b) When this applies there are problems. The putative SLN must be carefully loosened from the surrounding areas to make elevation from the base possible. Measurement by the gamma probe is im- proved by this.

c) This is not too serious, because it is possible to use more slender probes.

The surgical preparation of an inguinal node with gentle elevation of the node covered by soft tissue is demonstrated in Fig. 4, and a blue-dye-la- beled node can be seen in Fig. 5.

Fig. 1. One of the injection sites that can be used to admin- ister the labeling solution into the peritumoral subepithelial soft tissue parts. Note how the penis is held firmly in the left hand to ensure a stable position while the injection is given

Fig. 2a,b. Unilateral labeling of a soli- tary enlarged lymph node in the groin.

a Note the labeling at the corpus of the penis and along the course of the ingu- inal ligament, reaching one intensively labeled and enlarged inguinal lymph node within 13 min. b Only one lymph node in the inguinal region is labeled.

Note very weak labeling of two pelvic

lymph nodes after weak spillover of the

labeling fluid, 2 h after injection

Testicular Cancers

This category of cancers is subdivided into semi- nomatous and nonseminomatous subtypes and combined types, meaning seminomatous and non- seminomatous entities together.

Cancers developing in the testes can often be detected early, because with tumor growth the ten- sion on the capsule of the testis is accompanied by pain reactions.

The lymphatic metastatic process involves the retroperitoneal lymph nodes.

Seminomas can also primarily develop in the retroperitoneum along the so-called Keimbahn (ªgerm trailº) or in the mediastinum.

The tumor biology is similar in all primary locations (testis, retroperitoneum, mediastinum) (Osada et al. 1998; Bokemeyer et al. 2001). This applies especially to chemosensitivity. As a rule, testicular tumors show high degrees of chemosen- sitivity. This property is sometimes exploited to achieve down-staging, which gives a better starting position for surgical treatment. However, in the last few decades this high degree of chemosensitiv- ity has led to obvious indifference to the surgical aim of attaining R0 resection. As a result, it has become very rare for strategies designed to im- prove lymph node removal to be developed with the aim of achieving R0 resection as the primary result.

Main Macroscopic and Microscopic Features of Malignant Testicular Tumors

Malignant teratomas have cystic parts in a high proportion of cases. This special feature helps in preoperative evaluations based on ultrasound in- vestigation (Fig. 6).

In contrast, seminomas generally show a homo- geneous medullary structure (Fig. 7). This homo- geneous picture is recognized in the microscopic Chapter 29 Cancers of the Male Genitalia

442

Fig. 3. Labeling of inguinal sentinel lymph node(s) (SLN(s) in a case with penile cancer). The picture clearly demon- strates an inguinal SLN in a patient with penile cancer (black arrow). In addition, the secondary nodes (outlined arrows) are also labeled after 34 min

Fig. 4. A SLN being pulled up above

the level of the epidermis with forceps

for direct measurement with the gam-

ma probe. The probe is coated with a

plastic ªstockingº to keep it clean and

free of infectious material

growth pattern. The cancer cells grow in a pattern reminiscent of a lawn (Fig. 7). They mostly have round nuclei with pale karyoplasm and prominent nucleoli (Fig. 8), and characteristic loosely layered lymphocytes and sarcoidosis-like granulomas can be found in the interstitium.

Such granulomas can sometimes also be de- tected in the organs, where they are obviously in- duced by substances released from the tumor. Sur- geons and pathologists must be careful not to mis- interpret these small foci as metastases.

The international literature does not so far in- clude any publications on labeling with blue dyes

or radionuclides with the aim of detecting sentinel nodes in the presence of such tumors.

In orientation on testicular cancer development partly of multifocal origin within the testis, it would be only possible to administer labeling sub- stances into the region of vascular supply. But there is a real danger of injecting the labeling fluid intravenously into the local vascular plexus.

When all the known facts (high chemosensitiv- ity) and all existing problems are considered to- gether, there seems to be no chance at present of developing proposals for sentinel node labeling procedures that could be useful in daily routine.

Fig. 5. Exposure of an inguinal lymph node double-labeled by blue stain injec- tion and

Tc-nanocolloid injection.

Gamma probe is being approached to it for SLN identification

Figs. 6±8. Malignant testicular tumors Fig. 6. Malignant teratoma of the testis.

Lymphatic spread has a subordinate

role compared with hematogenous

spread into the lungs

Biological Prognostic Factors: Implications for Risk-adjusted Therapy Regimens

Some nonseminomatous germ cell tumors (NSGCT), and to a lesser degree also seminoma- tous germ cell tumors (SGCT), show early metasta- sis to the lungs and from there to the liver. There- fore, besides the scientific interest in locoregional lymphatic spread, research has also been steadily concentrated on collecting new information on tu- mor-associated factors that are important for vas- cular invasion and thus for a potential tendency to systemic spread.

Heidenreich et al. (1999) analyzed cases of clini- cal stage I NSGCT with the intention of finding out about the prospective value of investigating differ- ent markers that are frequently associated with rapid cancer progress. In particular, they evaluated the importance of MIBI (Ki67), mutated p53, bcl2 expression, cathepsin D and E-cadherin, using a semiquantitative scoring system. In addition, they assessed the percentage of embryonal carcinoma parts (% EC) and the presence of vascular invasion (VI). Investigation of 149 clinical stage I NSGCT cases revealed the following:

Chapter 29 Cancers of the Male Genitalia 444

Fig. 7. Seminoma of the testis. Lymphatic spread into iliacal and retroperitoneal paraaortic and paracaval lymph nodes is possible. Therefore, a search for sentinel node(s) and/or metastases into the nodes could be helpful for therapy plan- ning

Fig. 8. Histology of seminoma. Notice

the round nuclei with prominent nu-

cleoli and pale cytoplasm

· % EC (P<0.001) and VI (P <0.0001) were the most independent risk factors associated with pathological stage II disease.

· % EC and VI combined allowed correct predic- tion of the final pathological stage in 88% of the patients.

· Less than 45% EC and absence of VI identified pathological stage I disease correctly in 91.5%.

· In contrast, more than 80% EC and presence of VI predicted pathological stage II correctly in 88% of the patients.

We can conclude from Heidenreich's results that the percentage of EC and the presence or absence of VI seem to be reliable indicators making it pos- sible to distinguish between patients at high and at low risk for occult retroperitoneal disease.

In stage I patients, p53, bcl2, MIBI, cathepsin D and E-cadherin did not appear to have any prog- nostic value in clinical stage I NSGCT patients.

Fujikawa et al. (2000) evaluated the mean nucle- ar volume (MNV) in 57 seminoma patients. Multi- variate logistic regression analysis revealed that in their series, compared with the analysis of beta HCG, AFP, ALP, and LDH, MNV was the only vari- able predicting lymph node metastasis (P=0.0315).

In stage I patients the estimated MNV was the only variable that was significantly correlated with pro- gression-free survival (P=0.0118).

Initial, Meanwhile Obviously Abandoned, Approach to Retroperitoneal (Sentinel) Node Labeling in Testicular Cancer

Systematic labeling with consecutive radioimaging of inguinal and retroperitoneal lymph nodes has been carried out only very rarely in patients with testicular tumors.

Mechev and Sakalo (1994) have investigated the largest number of cases. They recruited 181 pa- tients with germ-cell tumors of the testis, 80 pa- tients with no evidence of retroperitoneal lymph node metastases, and 101 patients with metastasis in the regional lymph nodes.

Eighty patients underwent transperitoneal lym- phadenectomy. It was therefore possible to com- pare the results of histological and of lymphoscin- tigraphic investigation. In the lymphoscintigraphic investigations the following results were obtained:

sensitivity 83%, specificity 90.9%, significance 86.2%.

The authors conclude from their results that lymphoscintigraphy helps to confirm sites, exten- sion, and topographical distribution of lymph node metastases, which makes it a valuable tool that is helpful in decision-making about adjuvant therapeutic regimens (radiotherapy, chemotherapy, etc.).

Can Radiotherapy or Chemotherapy be at Least Partly Replaced by More Accurate Stage-related Surgical Treatment?

Seminomas account for approximately 50% of germ cell tumors, the other 50% being nonsemino- matous tumors, which also include cancers with trophoblastic parts.

Because seminomas, in contrast to NSGCTs, spread preferentially by the lymphogenic route, this category would presumably be most suitable for primary lymphatic control. At the moment it seems that there is no need to establish a sentinel node concept, because radio- and chemotherapy programs seem to be optimal. The treatment pro- tocols applied are roughly as follows:

Stage I surveillance or retroperitoneal radio- therapy (28 Gy).

Stage IIa disease with limited retroperitoneal lymph node metastasis: treatment by retroperitoneal radiotherapy, or alternatively systemic chemotherapy with carboplatin.

Stage II b, III disease with bulky retroperitoneal lymph node involvement or distant metastases: systemic chemotherapy including cisplatin and etoposide as the standard approach.

After exclusively paraaortic radiation, even with

follow-upperiods in excess of 5 years, the inci-

dence of pelvic lymph node relapses remained be-

low 4% (Sedelmayer et al. 1999). However, radio-

therapy, especially with the late vascular changes it

causes through ªcreepingº endothelial proliferation,

and the systemic toxicity caused by the drugs used

in chemotherapy are not without effect on long-

term results. Therefore, more precise lymph node

evaluations of the retroperitoneum resulting from

improvements to radioimaging and radio- and radioimmunolabeling or Sinerem, etc. must be re- flected in the aspects of new methodical strategies in advanced stages of development. New positive results could then helpmake it possible to modify or avoid unnecessary treatments and to restrict radio- and/or chemotherapy to more strictly se- lected collectives.

The discouraging features discussed above must be contrasted with the demonstration of positive regional lymph nodes by FDG-PET and/or CT.

However, these imaging methods only give positive results when cancer infiltration is sufficiently ex- tensive.

The results and experiences of the last few years are summarized by Avril et al. in the next section.

Is FDG-PET Helpful in N-staging

of Germ Cell Tumors (SGCT and NSGCT)?

N. Avril, W. Weber, M. Schwaiger Does FDG-PET have Advantages in Determining the Extension and Delineating Malignant Parts within Primaries?

As stated above, germ cell tumors are divided into seminomatous (SGCT) and nonseminomatous (NSGCT) subtypes and in addition mixed types in- cluding both these categories. With this in mind, FDG uptake and metabolism in the different com- ponents and comparison with results of CT are of special interest.

Wilson et al. (1995) examined 21 patients with metastasized SGCT or NSGCT by FDG-PET. While metastases of both types of germ cell tumors showed metabolic activity, the FDG uptake in ne- crotic and fibrotic tissue, but also in the mature teratoma, was comparable to that in normal tissue.

Three patients who responded to therapy showed a decline in metabolic activity in their tumors, while 2 nonresponders did not show any change.

Value of FDG-PET and Comparison with Results of CT in Staging Procedures

In a study of 54 patients (27 with SGCT and 27 with NSGCT), Mçller-Mattheis et al. (1998) com- pared PET with abdominal CT, tumor markers, and histopathological findings obtained following

primary or postchemotherapy retroperitoneal lym- phadenectomy. In 21 patients with stage I SGCT, the results of the PET scan were identical with the results of the CT. As the patients had received ra- diation therapy and the results were not histo- pathologically validated, the value of PET in this groupremained unclear. In 2 of the 7 patients with stage I NSGCT, metastases that had not been seen on CT were detected by PET, while in 4 of the 7 patients micrometastases remained undetected by PET. In 3 of the 4 patients who underwent surgery for a pure seminoma in stage IIB or IIC, PET cor- rectly identified tumor-free lymph nodes following chemotherapy. In one case the histological exami- nation of a mass that persisted even after chemo- therapy revealed a ganglioneuroma, even though the PET scan had been negative.

Value of FDG-PET in Detection of Cancer-infiltrated SLNs and in General Retroperitoneal Lymph Node Staging

Hain et al. (2000) proved in their study that when used for primary staging, FDG-PET can detect me- tastases that are missed by conventional diagnostic methods. In another recent study, Albers et al.

(1999) reported correct retroperitoneal staging using PET in 34 out of 37 cases, compared with 29 out of 37 using CT. Seven out of 10 distant metas- tases were detected by PET, while CT identified only 4 metastases. The PET scans did not produce any false-positive results, although neither malig- nant lesions less than 5 mm in size nor mature teratomas (regardless of size) were detected. Cre- merius et al. (1999) examined 50 patients and ob- tained comparable results.

Is PET Helpful in Detection of Residual Tumor after Chemotherapy?

All studies have documented that PET is unsuitable for detecting residual tumor parts, because there is a high degree of overlapwith resorptive inflamma- tory reactions after the completion of chemother- apy regimens. The use of PET after chemotherapy even for tumors in late stages is the subject of some controversy (Cremerius et al. 1998; Ganjoo et al. 1999).

Chapter 29 Cancers of the Male Genitalia

446

Prospective Views

This review shows that SLN detection in operative and conservative treatment is now an international focus of research interest. Several research projects are based on interdisciplinary radiological, nuclear medical, and histopathological and immunohisto- chemical approaches.

Even for some neoplasms, such as breast cancer and malignant melanoma, which have already been the subjects of many studies, there are still open problems and definitive answers to important questions are still lacking. Whereas localization of the sentinel node(s) can be determined in a high proportion of cases, it is still not possible to say definitively on the basis of imaging results whether incipient metastatic involvement is present preop- eratively. Some sophisticated approaches that may be successful in the near future are based on PET, iron oxide nanocolloid application, and the use of labeled monoclonal antibodies or their fragments directed at the surface structures of cancer cells.

Another problem is the delineation of the lymphat- ic stream, especially in head and neck tumors and tumors of different categories draining into the nodes of the inguinal region. These problems arise when the primaries are located in different com- partments and organ structures and the lympha- tics do not follow a linear course but form net- works, some of them intensive. Therefore, we must always think in three dimensions.

Consideration of the progress made as the result of research into breast cancer and malignant mela- noma makes it clear that future developments will point the way for increased R0 resection. This pro- gress and the ongoing investigations worldwide with highly specialized techniques lead us to hope that there will be further successful developments.

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