General Remarks

General Remarks

Prostate cancer accounts for 21% of all neoplasms in the male population in Germany (Schçssler et al. 1993) and has similar rates of incidence in most countries in the Western world.

This cancer type has long been mentally con- nected with ªold men's diseases,º and the level of commitment to research aimed at the development of new diagnostic and therapeutic approaches to it has therefore been relatively low. Now, however, with increasing survival rates even in older age groups, interest in improving its diagnosis and treatment is growing. With new trends in N-stag- ing (see Wawroschek et al. 1999, 2000) in mind, it will be much more difficult to developconvincing strategies for detection of sentinel lymph node(s) (SLN), and it is also more difficult to dissect them, whether in isolation or together with secondary nodes within the pelvis, in the course of prostate cancer treatment than in the procedures used in breast cancer or malignant melanoma treatment.

The difficulties are connected mainly with prob- lems in administering contrast agents for sentinel node detection and orientation in the local topog- raphy of the lymphatic network structures of the pelvis.

In addition, the problem is rendered more diffi- cult because not only the lymph nodes must be dissected, but also the network of lymphatics in continuity with the prostate gland, which can con- tain cancer cells or cancer cell clusters.

Invasive and noninvasive imaging techniques have been flawed by unacceptably high false-posi- tive and false-negative rates in most approaches (Loening et al. 1977; Wilson et al. 1977; McCarthy and Pollak 1991; Schçssler et al. 1993).

In view to this fact and since we have no uniform and highly developed concept for detection of senti- nel node(s) that is actually practiced by the majority of our urologists at present, systematic iliac and ob-

turator lymph node dissection is currently generally referred to as the ªgold standardº when positive nodes are suspected, followed by prostatectomy in the case of confirmed prostate cancer.

As a rule of thumb, it is generally accepted and well documented that cancer-positive aortic nodes are connected with positive pelvic nodes and that at least in these cases it must be accepted that the condition is incurable.

As much as 20 years ago three different options for prostate cancer treatment in stage D

were tested (radical prostatectomy, extended radiotherapy, and hormone therapy). The median survival in all groups was 39.5 months. None of the three treat- ment strategies was superior in prolonging life (Kra- mer et al. 1981), and there was no convincing break- through improving on this situation up to the 1990s.

New approaches to antiandrogen- and radioche- motherapy see Chapter 33.

Serum Values of Prostate-specific Antigen and Prostate Acid Phosphatase

as Indicators for Cancer, Metastatic Spread and Cancer Recurrence

Bluestein et al. (1994) follow from their investiga- tions on 1632 patients that prostate-specific anti- gen (PSA) is the best predictor of pelvic lymph node metastases (P<0.0001).

Definition of the Degrees of Malignancy in Gleason's Grading (Scoring) System

This section starts with a detailed analysis of the grading strategy (characteristic features of the sub- groups).

The predictive power is enhanced by consider- ing the Gleason grading (scoring) (P<0.001) and Chapter 30

Prostate Cancer: an Overview 30

Is Sentinel Node Detection Helpful

in the Curative Treatment of Prostate Cancer?

the local clinical stage of the primary together (P<0.001). The basic patterns leading to the Glea- son scores are described in Table 1.

The main criteria for delineation of the sub- grades are comprehensively summarized in Fig. 1 according to the original publications about Glea- son's scoring system. The subentities are still more precisely characterized by own drawings (Fig. 2).

Recently the WHO published the fascicle ªTumors of the Urinary System and Male Genital Organsº.

The criteria of Gleason patterns and scoring of prostate cancers are summarized in the following overview. The criteria of the main patterns are compatible with the original description, presented in Table 1.

Table 1. Gleason grading system for prostatic adenocarcinoma: histologic patterns Pattern Peripheral

borders Stromal

invasion Appearance of

glands Size of glands Architecture

of glands Cytoplasm

1* Circumscribed

expansive growth

Minimal Simple, round, monotonously replicated

Medium,

regular Closely packed Similar to that in benign epithelium

2* Less circum-

scribed; early infiltration

Mild, with def- inite separa- tion of glands by stroma

Simple, round, some variabil- ity in shape

Medium, less

regular Loosely packed rounded masses

Similar to that in benign epithelium

3A Infiltration Marked Angular, with

variation in shape

Medium to

large Variable

packed irregu- lar masses

More basophil- ic than in pat- terns 1 and 2

3B Infiltration Marked Angular, with

variation in shape

Small Variable

packed irregu- lar masses

More basophil- ic than in pat- terns 1 and 2

3C Smooth,

rounded Marked Papillary and

cribriform Irregular Round to elon-

gated masses More basophil- ic than in pat- terns 1 and 2

4A Ragged

infiltration Marked Microacinar, papillary, and cribriform

Irregular Fused, with chains and cords

Dark

4B Ragged

infiltration Marked Microacinar, papillary, and cribriform

Irregular Fused, with chains and cords

Clear (hyper- nephroid)

5A Smooth,

rounded Marked Comedocarci-

noma Irregular Round to elon-

gated masses Variable

5B Ragged

infiltration Marked Difficulty in identifying glands' lumens

Irregular Fused sheets

and masses Variable

* In foci suspicious for cancer (pattern 1 and 2) positive reaction using the antibody P5O4S immunostaining helps to certify cancer diagnosis

WHO-Classification 2004 Gleason pattern 1

1+1 =2 =Gleason score Well circumscribed nodule of closely packed glands, no infiltration (local in situ condition).

Gleason pattern 2

2+2 =4 =Gleason score Round or oval glands, loosely arranged, not as uniform as in pattern 1.

Facultative minimal invasion, glands of intermediate size, with less vari-

ation than in Gleason pattern 3.

In order to give an impression of the histo- pathological differences of high, moderate, and low differentiation cancers, Figs. 3±7 show the characteristic histopathological features of each.

Correlations with Molecular Biological and Clinical Parameters

Investigations carried out by Conrad et al. (1998) in 345 cases showed that the amount and distribution of undifferentiated Gleason grades (pattern 4 and 5) cancer in the biopsies were the best predictors of the lymphatic spread, followed by serum PSA.

In classification and regression analyses, nearly 80% of the patients who had Gleason score 4 or 5 disease in 3 or fewer biopsies and did not have a predominance of high-grade cancer in any biopsy can be classified as low-risk patients. Positive nodes were found in this groupin only 2.2% (95%

confidence interval, 0.8±4.7%). The authors con- clude that the sextant biopsy principle enhances the predictive accuracy of algorithms, which define the probability of lymphatic spread.

However, use of PSA and prostate acid phospha- tase (PAP) values does have some limitations:

· Oesterling et al. (1988) concluded from their studies that preoperative levels of PSA are not sufficiently reliable for the prediction of the pathological stage in patients with early cancer.

But they confirmed the findings of other labora- tories, demonstrating that PSA is a sensitive tu- mor marker for the detection of residual disease after radical prostatectomy and subsequent re- currence of the cancer in long-term follow-up studies.

Correlations with Molecular Biological and Clinical Parameters 451

Gleason pattern 3

3+3 =6=Gleason score Most common pattern: Higher degree of infiltration distance of glands more variable, more often malignant glands between preexis- tent. Often angular and small glands besides large ones. Cribriform pattern is rare and difficult to distinguish from cribriform high grade PIN.

Gleason pattern 4

4+4 =8=Gleason score Glands fused, cribriform, may be poorly defined, partly not separated by stroma, edges of fused glands scalopped, thin strands of connec- tive tissue, loss of lumina in cribriform parts.

Hypernephromatoid pattern, a rare variant.

Gleason pattern 5

5+5 =10=Gleason score Almost complete loss of glandular lumina, growth in solid sheets and strands or as single cells. Comedonecroses may be present.

If the tumor has only one pattern, Gleason score is obtained by doubling the pattern number (see scheme).

If there exist two different pattern, the two pattern numbers are summed up, e.g. 3 plus 4=7=Gleason score.

If there is found a tertiary pattern, prognosis worsens additionally.

Fig. 1. Prostate cancer scoring according to Gleason. See Ta-

ble 1 for details of the patterns

· Primarily in high-grade cases, or in the course of dedifferentiation, the PSA values can be low or decrease in spite of persisting or recurrent cancer (Partin et al. 1990).

Conversely, unpredictable contributions from pros- tate parts with benign prostate hyperplasia compo- nents or foci with inflammation leading to in- creased release of PSA can moderate the PSA level, causing increased serum values.

These facts must be given due consideration by urologists, both during primary treatment and also in the follow-upof their patients, but with a view to the SLN concept and the performance of the necessary clinical studies the results are of spe- cial interest.

It was found that PSA and PAP correspond to histopathologically detected metastatic lymph node involvement.

Fig. 2a,b. Analysis of the Gleason pat- terns and cytology of prostate cancer based on growth pattern and cytological criteria derived from the top-view draw- ing presented in original publications 1

Less circumscribed, early invasive

Glands medium to large, partly angular

Small, partly angular and ramified glands

Papillary and cribriform pattern, irregular, round to elongated cancer cell formations, cytoplasm more basophil than in patterns 1 and 2

a

In the course of our daily routine work the P-val- ues of correlations of PSA and PAP in uni- and mul- tivariate analysis are of special interest (Table 2).

In multivariate analysis the serum PSA level was the most powerful independent prognosticator fol- lowed by the Tcategory, tissue PAP and tissue PSA.

But there are limitations to the detection of early cancer development, as already mentioned above.

Correlations with Molecular Biological and Clinical Parameters 453 Fig. 2b

Microacinar, papillary, cribriform patterns, irregular with chains and cords, cytoplasm dark

Microacinar, papillary, cribriform patterns, fused with chains, cytoplasm clear, hypernephroid

Comedocarcinoma, round to elongated cancer cell formations, cytoplasm variable

Soliud fused sheets, difficulty to identify glands

b

Table 2. Relationship of levels of prostate-specific antigen (PSA) and prostate acid phosphatase (PAP) in cancer tissue values to histopathological grade, DNA ploidy and T-catego- ry. The following values were found

N category to serum PSA level P<0.001 to histological grade P<0.001

to tissue PSA P<0.001

to tissue PAP P<0.004

to Tcategory P<0.005

to DNA ploidy P<0.002

Figs. 3±7. Degrees of malignancy of pros- tate cancer: main types

Fig. 3. Highly differentiated prostate can- cer corresponding to Gleason pattern 2, corresponding to Gleason score 2+2=4.

Note the fairly isomorphic glandular structures

Fig. 4. Well-differentiated prostate cancer with fairly isomorphic cancer cell nu- clei, corresponding to Gleason score 3+3=6 low rate of mitoses, only focal branching of the glands

Fig. 5. Moderately differentiated prostate

cancer with more pronounced variation

of the glands. Gleason pattern 4, corre-

sponding to Gleason score 4+4=8

Importance of Tumor Volume to Clinical Significance

in Treatment of Prostate Cancer Minimal Lesions

Stamey et al. (1993) tried to calculate the probabil- ity of having a diagnosis of prostate cancer within a man's life. The prostates of 139 consecutive blad- der cancer patients who had undergone cystopros- tatectomy were examined. Prostate cancer was found in 55 patients (40%), larger cancers being detected only in 8%. The cancers ranged in volume from 0.5 to 6.1 ml. These results allowed the con- clusion that prostate cancers smaller than 0.5 ml

are probably unlikely to reach clinical significance because the doubling time of this cancer is too long.

Relation Between Dysplasia and Cancer

In addition, McNeal (1993), also from Stanford University, investigated prostates with dysplastic changes of glands in the biopsy material. In 48%

of these he found foci fulfilling the criteria for prostate cancer, and in 3 of the 107 cases investi- gated grade 4 cancer (low degree of differentiation) was found. Among patients in whom microcarci- nomas were diagnosed, dysplasia was found in other parts in 81%.

Relation Between Dysplasia and Cancer 455

Fig. 6. Anaplastic prostate cancer with high grade of polymorphism and high rates of mitosis. Gleason score 10

Fig. 7. Anaplastic prostate cancer with

high grade of tumor cell dissociation

and nerve sheath invasion. Gleason

score 10

Gleason Score (Grading) in Ultrasound-guided Biopsies Related to Results in Prostatectomy Specimens

In their comparative studies of ultrasound-guided biopsies and prostatectomy specimens conducted in 289 cases, Gregori et al. (2001) obtained the fol- lowing results summarized in Tables 3 and 4.

It is very interesting that with whole-prostate evaluation (specimen investigations) as reference, upstaging is necessary in about 40%, that among cases with unilateral positive biopsies bilateral can- cer infiltration is found in about 65%, and that among cases with bilateral positive biopsies intra- capsular cancer infiltration is found in about 66%.

These data may also help in decision making when a catalogue of the indications for sentinel node evaluation is developed.

Carlson et al. (1998) also examined the correla- tions between Gleason scores in biopsy specimens and the diagnoses made in prostatectomy speci- mens. They investigated 106 cases and obtained the results summarized in Table 5. The positive predictive values of the different Gleason scores are displayed in Table 6.

Division of Grade II (WHO) Cancers into Favorable and Unfavorable Subgroups Supported by Gleason Grading Lilleby et al. (2001) tried to differentiate more pre- cisely between favorable and unfavorable subtypes of grade II cancers graded by means of the WHO criteria compared with the Gleason-graded sub- groups.

The review of specimens from 178 patients yielded the numbers of cases in the different groups shown in Table 7.

Separating patients with a Gleason score of 7 (score 3+4 vs 4+3) led to a two-tiered Gleason grouping (88 patients in the favorable group and 90 in the unfavorable group).

The authors concluded that equal allocation of patients to subgroups based on the Gleason system helps the clinician to overcome the dilemma of overrepresentation of grade II patients, which does occur with the WHO grading.

Subgrouping grade II cancers by means of the Gleason grading system appears to make separa- tion more of a possibility, for instance with a view to an additional sentinel node search and referral to radiotherapy.

Altay et al. (2001) found that high Gleason scores together with elevated PSA levels (>10 ng/

ml) involved a high risk of extraprostatic cancer extension, in some cases with seminal vesicle in- volvement (P<0.05).

Grading Errors in Gleason Grading Evaluations Compared with a Database

King and Long (2000) investigated the question of grading errors. A pooled database from ten series (n=2687) served as a baseline for comparison aimed at checking the accuracy of Gleason score Table 3. Predictive value of Gleason score, up- and down-

grading (according to Gregori et al. 2001) Recorded

no. of patients Identical Gleason score in the biopsies

Up-grading vs down-grading related to histo- logically investi- gated specimens

289 126 (43%) 118 (40.8%) vs

43 (14.8%)

Table 4. Specimen-related histopathological results in cases with uni- and bilateral positive biopsies (according to Gre- gori et al. 2001)

Unilateral positive biopsy vs cancer on one side

Bilateral

disease Organ

confined Capsule penetration

193 (66.7%) 127

(65.8%) 142

(73.5%) 41

(26.4%) (33.1) 46

Bilateral positive biopsy (n)

Intra- capsular cancer vs speci- men confined

Overall positive margins

Postero- lateral capsular penetra- tion

Apical capsular penetra- tion

96 64

(66.6%) 14% 52/83

(61.4%) 28/83

(33.7%)

32 (33.3%)

grading. With the biopsy technique used an exact Gleason score match was achieved in 57% of the cases, a mean of 42% (P=0.055) compared with the pooled database (PD). Table 8 shows the P-val- ues for deviation from the database. King and Long's conclusion was that: ªSampling effects may contribute significantly to grading errors in pros- tate needle biopsies.º

Koksal et al. (2000) found that Gleason grading error compared with the grading of prostatectomy specimen grading was highest in highly differen- tiated cancers. This can be easily understood on the basis of primary multifocality clonal selections.

Allsbrook et al. (2001) evaluated the interob- server reproducibility of the Gleason grading: con- stant undergrading was observed in the Gleason scores, at the following rates:

· Scores of 5 and 6 in 47%

· Score of 7 in 47%

· Scores of 8±10 in 25%

Underestimation of the growth pattern was also observed:

· Pattern 2 in 32%

· Pattern 3 in 39%

· Pattern 5 in 30%

The authors recommend training programs and courses to improve the quality in grading-practice and to reduce interobserver differences.

Simultaneous Lymphogenous

and Hematogenous Metastatic Spread?

The fact that autopsy studies both in the United States and in Japan show identical rates for meta- static involvement of lymph nodes and of bone marrow (see Fig. 11) can be interpreted as showing that regional lymphatic spread and hematogenous retrograde transport to the column and other bone regions are closely connected.

The additional finding of lung metastases in two-thirds of cases with lymph node and bone marrow involvement can be explained by the com- munication of the venous periprostatic and prever- tebral venous plexus with the azygos veins, which Simultaneous Lymphogenous and Hematogenous Metastatic Spread? 457

Table 5. Accuracy of Gleason biopsy grading No. of

patients Correlation of biopsy with radical

prostatectomy

Correlation

within one grade All patients correlated within 2grades

Under-grading Over grading

106 72 (68%) 103 (97%) 106 (100%) 26 (25%) 8 (8%)

Table 6. Predictive values

Percentage of positive predictive values Well

differentiated Moderately

differentiated Moderately to poorly differentiated

Poorly differentiated

Gleason 5

66% 6

67% 7

71% 2±4 5±6

70% 7 8±10

Table 7. Distribution of prostate cancer cases (n=178) within the Gleason grading scheme and rate of grade 2 cancers in this collective (WHO grading)

Total no. of cases Gleason <7 (n) Gleason 7 (n) Gleason 8±10 (n) Grade II WHO (n)

178 44 58 76 130

Table 8. Deviations of grading prostate cancer cases using the Gleason scale from the database

Within 1 point in 93% P=0.029

Compared with database in 78% P=0.029

Upgrading of biopsies in 35% P=0.19

Compared with database in 43% P=0.19

Gleason 7 exact match in 78% P=0.07

Gleason 7 database in 20% P=0.07

are directly connected with the vena cava inferior.

It follows from this that it is only in the very early stages of local lymphatic spread that there can be any hope of local curative lymphatic operative tu- mor clearance.

These reflections are important because they can influence the development of a catalog of indi- cations for sentinel and pelvic lymph node extirpa- tion and investigation projects. That means that it is very important to perform bone and lung-inves- tigations before surgical procedures are started.

Significance of Degree of Malignancy and Number of Biopsies Taken for N-staging and the Sentinel Lymph Node Concept

According to the experience of pathologists, foci of high-grade prostate cancer can be found in a set of the typical six-point biopsy series. This leads to the conclusion that high-grade cancers develop as subclones in the course of cancer extension.

McNeal (1993) investigated this problem again and demonstrated the derivation of high-grade cancers as more or less extended subclones in low- grade cancers within the prostate gland.

Usually the majority of nonextended microcar- cinomas develop from preexistent dysplasia. Inves- tigations of nonextended early cancer of the pros- tate show areas with high-grade cancer in only 3%

of cases.

Knowledge of these proportions seems to be im- portant for the development of a sentinel lymph node concept that is suitable for application in the treatment of prostate cancer, especially with the aim of finding the limits for N-staging in early cancer cases with a low grade of malignancy.

Smith et al.'s (1983) investigations already make it clear that locoregional metastatic spread de- pends heavily on how malignant the primary is (Tables 9, 10). These data help in preoperative cal- culation of the risk of locoregional cancer progres- sion.

In addition, the following data published by Walsh et al. (1994) can be used to obtain a pro- spective assessment of 10-year survival, depending on Gleason grade and capsule infiltration or per- foration by the cancer (Fig. 8).

These data allow easier formulation of indica- tions for a differentiated sentinel lymph node (SLN) search based, for instance, on the new re- sults and developments published by the Augsburg research group (Wawroschek et al. 1999, 2000).

Danella et al. (1993) reported that in their group of patients with clinically localized prostatic can- cer, 5.7% had nodal metastases. The predictive val- ue in patients with prostate-specific antigen levels elevated to >40 ng was 53%. The authors empha- size that laparoscopic lymph node dissection should be the method of choice in view of the low rate of nodal metastases.

In the context of these important facts, in addi- tion to local regional operative pelvic cancer clear- ance, if the near future were to see improvements in prostate cancer grading including the emer- gence of important prognostic factors indicative of likely proliferation and blood vessel invasion with a high predictive value these would be greatly ap- preciated.

Table 9. Distribution of tumor grade by stage

Stage Well differentiated Moderately differentiated Poorly differentiated Total no. of patients

A1 28 (68) 12 (29) 1 (3) 41

A2 7 (21) 19 (58) 7 (21) 33

B1 53 (34) 94 (60) 9 (6) 156

B2 27 (18) 106 (69) 21 (13) 154

C 10 (15) 44 (64) 14 (21) 68

125 (28) 275 (61) 52 (11) 452

n (%) n (%) n (%)

Is the Primary Cancer Detection Rate Higher with Twelve Biopsies than with Six?

Prospective randomized studies carried out in 244 men by Naughton et al. (2000) and comparing the impact of the number (6 versus 12) prostate biopsies on cancer detection did not show higher detection rates when 12 core biopsy specimens were taken and investigated in a screening program (P=0.9).

At around the same time a report of a study conducted by Ravery et al. (2000) to evaluate 303 consecutive cases showed an overall detection rate for prostate cancer of 38.9% in their patient popu- lation, the rate being higher by 6.6% when more biopsy investigations were done (6.5% in men with PSA 10 ng/ml or less and 7% in men with PSA

>10 ng/ml). (For more information on increases in detection rates see also: Eskew et al. 1996; Beurton et al. 1997; Ravery et al. 1999.)

Basic Research for Complete Pelvic Lymph Node (N-) Staging

Metastatic Involvement of the Main Node Groups and Statistical Evaluations of Side Differences

Weingårtner et al. (1996) tried to find mean values in an attempt to answer the question of how many lymph nodes need to be investigated to give the complete metastatic profile in the pelvis. They per- formed investigations both on cadavers and in liv- ing cancer patients. The means found were 22.7 for the cadavers (Ô10.2, range 8±56) and 20.5 for the prostate cancer patients (Ô6.6, range 10±37).

In the patient group, involvement of pelvic lymph nodes was significantly more frequent on the left side (see Fig. 9). Lymph nodes were more frequently enlarged in cancer patients than in con- trols, regardless of whether they were cancer infil- Basic Research for Complete Pelvic Lymph Node (N-) Staging 459

Table 10. Incidence of pelvic node metastasis by histological grade and clinical stage [from Smith et al. (1983)]

Stage Well differentiated Moderately differentiated Poorly differentiated Total no. of patients

A1 0/28 0/12 0/1 0/41

A2 0/7 5/19 (26) 3/7 (43) 8/33 (24)

B1 2/53 (4) 13/94 (14) 3/9 (33) 18/156 (12)

B2 5/27 (18) 29/106 (27) 9/21 (43) 43/154 (28)

C 5/10 (50) 18/44 (41) 13/14 (93) 36/68 (53)

125 (28) 275 (61) 52 (11) 452 (23)

No. (%) No. (%) No. (%) No. (%)

Fig. 8. Actuarial probability of freedom

from recurrence of elevated PSA in rela-

tion to stage and Gleason grade. These

data are based on follow-up studies of

955 men treated at Johns Hopkins Hos-

pital by Walsh et al. (1994)

trated or tumor free. Therefore, enlarged lymph nodes cannot be used for diagnostic purposes as they are in breast or lung cancer, e.g. in imaging investigations. These results indicate that it is im- possible to use CT or MRI to diagnose metastatic cancer involvement of the pelvic nodes.

The rates of metastatic lymph node involvement from prostate cancer in the different pelvic posi- tions (iliac and obturator) are shown in Fig. 9.

In Gervasi et al.'s (1989) series of 511 prostate cancer patients, N0 and N+ patients were com- pared for metastatic lymph node involvement over a median follow-upof 8.6 years; the P-value was less than <0.00005 (Table 11).

The hematogenous metastatic rates determined for N+ patients were:

N1 80%

N2 84%

N3 88%

Survival Rate Versus Lymph Node Metastasis

In a comment on Gervasi's results (see Table 11), Paulson (1989) suggested that hematogenous met- astatic spread develops more or less in parallel at the same time. This suggestion seems to hold true for many cancer cases progressing by the hematog- enous route, but we cannot at present relate this assumption to particular cancer cases on the basis of specific clinical and molecular biological fea- tures (Fig. 10).

However, in spite of these tentative conclusions, locoregional pelvic cancer clearance (tumor-free margins of the primary, complete node dissection) should be consistently developed in an indepen- dent way.

Before a sentinel node search is conducted dis- tant metastases should be excluded. The frequen- cies and sites of hematogenous metastases are listed in Fig. 11.

It is worth emphasizing that in the prostate the lymphatics follow the larger lymph channels leav- ing the prostate posteriorly and then spread pri- marily to the perivesical, hypogastric, obturator, presacral and presciatic and obturator lymph nodes as the first stations (McLaughlin et al.

1976). These results are already quite old and are not fully included in the current routine principles of lymph node clearance.

This posterior extracapsular region could be one of the points where the contrast solution for SLN la- beling could be injected. Systemic iron oxide (Siner- em) injection should also be discussed again as a possibility for labeling the first (sentinel) stations.

In Schçssler's investigations (1993) in cases with palpable disease (stages B1, B2, C), 36% had lymph node involvement. This value corresponds to many other series investigated in different clinics (Flocks et al. 1959; McCullough et al. 1974, 1977; McLaugh- lin et al. 1976; Bruce et al. 1977; Wilson et al. 1977;

Freiha et al. 1979; Brendler et al. 1980; Grossman et al. 1980; Fowler and Whitmore 1981; Catalona and Stein 1982; Donohue et al. 1982).

Widely different frequencies have been recorded for metastases to the external iliac lymph nodes:

Nicholson and Richie (1997) 17%

McLaughlin et al. (1976) 10%

Arduino and Glucksman (1962) 57%

Bruce et al. (1977) 54%

Schçssler et al. (1993) 30%

Fig. 9. Main pelvic lymph node groups that can be involved

in metastatic spread. Note that the left-sided lymph nodes

are more frequently involved

Basic Research for Complete Pelvic Lymph Node (N-) Staging 461

Table 11. Actuarial all-cause and cancer-specific survival rates at 5, 10 and 15 years by extent of nodal metastases (percentÔ2 SE) (from Gervasi et al. 1989)

All-cause survival rate Cancer-specific survival rate

N0 90Ô3 62Ô6 36Ô14 98Ô2 83Ô6 70Ô13

N+ 65Ô8 32Ô9 6Ô10 75Ô7 43Ô11 21Ô17

N1 68Ô15 40Ô19 ± 82Ô13 60Ô19 ±

N2 63Ô11 22Ô11 ± 72Ô10 34Ô15 ±

N3 69Ô17 35Ô22 ± 75Ô17 42Ô24 ±

5 Years % 10 Years % 15 Years % 5 Years % 10 Years % 15 Years %

Fig. 10. Distant metastases (actuarial rate) by presence and extent of nodal metastases. Vertical bars indicate 95% confi- dence intervals (meanÔSE). Although distant metastases appeared less rapidly in the N1 subgroup, the rate of devel-

opment of distant metastases was parallel in each of the three subgroups of N+ cancer patients (see Gervasi et al.

1989, Table 11)

Fig. 11. Sites and frequencies of metasta-

ses from prostate cancer and most com-

mon sites of prostate cancer metastases

found at autopsy in the United States

and Japan [from Bostwick and Eble

(1993) with permission]

These wide differences (10% to nearly 60%) in the rates of external iliac lymph node metastases are disturbing when we are trying to collect clear- cut information for use as a basis for the develop- ment of a SLN concept.

The percentages of cases upstaged to D1 from the different lower stages according to Schçssler (1993) evaluations of lymph node involvement are as follows:

A2 27%

B1 15%

B2 52%

C 50%

The percentages for stages B2 and C are very high. Better information on prognostic factors is thus long overdue.

When all aspects are considered together, two principles seem to be the most important indica- tors of regional lymph node involvement and thus to constitute indications for a search for sentinel nodes and in addition, when the sentinels are pos- itive, for pelvic lymphadenectomy. These two most important principles are:

1. Evaluation of grade of malignancy with rating of nuclear grade plus, if possible, evaluation of the percentages of cancer cells in DNA synthesis and in the proliferative compartment, using the antibody MiBI and the CASS 2000 machine for the determination of percentages.

2. Proof of cancer infiltration and perforation of the prostate capsule; when these pathohistologi- cal, biologically based parameters allow the con- clusion that a high-grade or high-risk cancer is present SLN staging should be performed.

· In addition to the standard dissection involving the nodes along the common iliac artery, the external iliac artery, genitofemoral nerve, hypo- gastric vessels and obturator fossa also need in- vestigation (Flocks et al. 1959; Arduino and Glucksman 1962; Barzell et al. 1977; Bruce et al.

1977; Freiha and Salzman 1977; Nicholson and Richie 1977; Grossman et al. 1980; Fowler and Whitmore 1981; Donohue et al. 1982).

· An extended dissection also includes the nodes in the presacral and lateral sacral areas (see also Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer in this chapter). It is note- worthy that some investigations have indicated

Fig. 12. Inverted-V peritoneotomy ac-

cording to See et al. (1993). The perito-

neal flapis dissected superficially and

folded back along the dotted lines

shown in the schematic

that in approximately 13±15% of cases these locations are the only ones involved in the met- astatic process.

· The limited dissection procedure is derived from the standard method. The lateral border is limited by the lateral margin of the lateromedial aspect of the external iliac artery instead of the genitofemoral nerve (Brendler et al. 1980; Paul- son 1980; Lieskovsky and Skinner 1983; Gervasi et al. 1989; McDowell et al. 1990). The common iliac artery is left undissected, which is easily understood in view of the difficulty of imple- menting lymph node and lymph vessel clearing principles in the pelvic region.

· A fourth possibility is obturator fossa node dis- section (Kozlowski and Grayhack 1987; Winfield and Kavoussi 1991; Winfield et al. 1991), which is a simpler procedure with low morbidity rates.

· In comparison with linear peritoneotomy, an in- verted-V peritoneotomy, which is designed to allow wider exposure of the target tissue, im- proves the nodal yield of laparoscopic lympha- denectomy (Fig. 12).

It may be that inverted-V peritoneotomy will be one of the keys to complete lymphadenectomy in the further development of a sentinel node concept for treatment of prostate cancer. It is clear that high complication rates of standard pelvic lymph node dissection with complication rates nearly equal to those of laparoscopic lymphadenectomy (30±32% for both methods) complicate the devel- opment of sophisticated methods for SLN dissec- tion programs. The complications are: hemor- rhage, bowel laceration, ureteral injury, and devel- opment of lymphocele.

Is Laparoscopic Lymph Node Staging Equivalent to Open Pelvic Lymph Node Dissection?

Compatibility with a Pelvic SLN Concept

Parra et al. (1992) state that laparoscopic node ex- cision gives node detection rates identical with those obtained with open operative dissection. No more nodes were found after laparoscopic node dissection from the surgical margins by open re- operation in patients who had undergone second-

ary prostatectomy. Nonetheless, the application of this method has limitations.

· Trocars (three 11 mm and two 5 mm in diame- ter) need to be inserted at five locations , dis- tributed over the lower parts of the abdomen.

· This method has a similar complication rate to open biopsy.

· The fundamental problem of cancer progression after nodectomy in cancer-positive cases is not improved.

Therefore, improved local clearance in the sense of the SLN concept has not yet been reached.

Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer Intraoperative lymph node staging in frozen sec- tions needs close cooperation between pathologists and their technicians, because sometimes microfo- ci of cancer infiltration are visible even at the sec- tion surface. Double investigations of frozen sec- tions from each lymph node slice and of imprint cytology of each slice of the nodes can increase ef- ficiency and lower the false-negative rate.

However, we should always keepin mind that the quantity of tissue lost is much greater in frozen sec- tions than in paraffin embedding and paraffin sec- tioning. Therefore, when two-stepsurgery is planned (node evaluation and prostatectomy) basing a decision for prostatectomy exclusively on frozen sections of the lymph nodes is of restricted value.

This question becomes even more difficult when attempts at development of a SLN concept are afoot, because sentinel nodes, as the key nodes in metastasis, must be investigated in serial sections, a technical procedure that is more reliable and eas- ier to perform when the paraffin technique is used.

In recent times, results of some screening- and comparative studies have been published to allow evaluation of the efficiency of different methods.

Epstein et al. (1986) presented their N-staging data based on a series of 299 cases. They empha- sized that the detection of metastases by the frozen section technique is quite precise. The average ex- tension of the metastases was 2.5 mm, and the false-negative rate was 3.5%.

In a frozen section lymph node analysis carried

out by Davies (1995) a 90% diagnostic efficiency

could be reached, which is similar to that of MRI

analysis (88%). However, the aggregated sensitivity

Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer 463

of MRI was less than 67% that obtained with fro- zen section analysis.

In our opinion, the histopathological efficiency can still be increased by intraoperative serial sec- tion analysis using an immunohistochemical tech- nique newly developed by Hæfler and Nåhrig, in which the staining procedure takes only 12±20 min (see also Chapter 17).

As in staging procedures used for other cancers [see Chapter on Melanoma (Chapter 25)], Okegawa et al. (2000) also performed RT-PCR studies of the dissected lymph nodes for staging prostate cancer by preliminary investigations, to detect early lymph node metastases, and to define the indica- tions for prostatectomy more precisely. Positive re- sults were obtained in 11% of stage pT2a and in 25% of stage pT2b cases.

Invasion of prostate cancer into seminal vesicles did not significantly alter the frequency of involved nodes (61% versus 70%), as published by Barzell et al. (1977).

Is Whitmore's Staging Scheme Established in 1984 Still Compatible

with Our Current Knowledge?

The establishment of indications for a search for SLNs is at least partly hampered by the fact that the clinical staging devised by Whitmore in 1984 is incompatible with tumor biology in important points. To help readers understand the critical points, first of all the topographically oriented scheme of Whitmore should be described:

A2: Any quantity of cancer within the prostate, without discrimination between the different degrees of malignancy, meaning by implication high-grade cancer types.

B1: Cancer nodule involving less than half of a lobe.

B2: Cancer nodule involving more than half of a lobe or bilateral cancer nodes.

C: Local extension of any cancer beyond the pros- tate gland.

D1: Prostate cancer with positive pelvic nodes.

D2: Prostate cancer with distant metastasis.

It is clear that inclusion of all high-grade cancers in stage A2 must give worse results in terms of tu-

mor progression than B1 cancers with involvement of less than half of a lobe of the prostate.

The reason why the Whitmore scaling cannot be used as a basis of decision about in which cases lymph node staging will be helpful for further de- cision-making (sentinel node labeling, prostate adenectomy, etc.) lies in values given (for example) by Schçssler et al. (1993) (Table 12).

A decision in favor of lymph node dissection is made possible by the fact that lymph node in- volvement is more frequent (according to collective evaluations) in A2 than in B1 stages (26% vs 16%). However, the background to this marked discrepancy is that all extensions and all grading groups are included under A2! This seems a poor basis for preoperative selection of the cases in which lymph node involvement must be assumed.

The percentages of different rates of lymph node involvement published by different working groups on the basis of the Whitmore staging (A2±

C), are listed in Table 13. Some investigations give the impression that lymph node involvement is found almost exclusively in cases in which the can- cer has broken out through the prostate capsule.

However, a systematic search for nodal microme- tastases by means of modern immunohistochem- ical techniques reveals micrometastases in 16% of pT3N0 cases and also in lower pT stages (Gomella et al. 1993; Moul et al. 1994).

In the context of these findings we must see that many case series are incorrectly staged. This knowledge has a marked influence on our new approaches to developing a sentinel node concept.

Table 12. Rates of lymph node involvement in different stages of prostate cancer in the collective published by Schçssler et al. (1993)

Stage No. of

cases Cases with positive nodes

Ul

28 0 0

A2 11 3 27

B1 21 3 15

B2 21 11 52

C 6 3 50

a

Adenocarcinoma of prostate detected by ultrasound only and in addition with view to the literature [see also Ta- ble 13, also from Schçssler et al. (1993)]

No. %

The metastatic rates in a series of 521 patients investigated by Petros and Catalona (1992) were as follows:

A1 0%

A2 3.3%

B1 5.3%

B2 9.7%

In a series of 452 cases investigated by Smith et al.

(1983), especially in the B

group the rate of me-

tastases was hardly more than half of Schçssler's rate.

With a view to tumor malignancy grade, in to- tal metastases were detected in only 10% of low- grade cancers, in 24% of moderately differentiated cancers, and in 54% of high-grade tumors (poorly differentiated).

The fact that the rate of metastases from well- differentiated cancers (A1=0%, B1=4%) is very low led to the conclusion that lymphadenectomy should not be performed in these cases even at the Is Whitmore's Staging Scheme Established in 1984 Still Compatible with Our Current Knowledge? 465

Table 13. Laparoscopic standard of pelvic node dissection for prostate cancer. Incidence of positive nodes according to clin- ical stage: review of the literature according to Schçssler et al. (1993)

Reference Clinical stage

Donohue et al.

(1982) 59 13 (22) 179 26 (15) 99 46 (46) ± ±

Freiha et al.

(1977) 2 0 (0) 13 2 (15) 44 10 (22) 41 24 (58)

Bruce et al. (1977) 3 0 (0) 6 0 (0) 13 5 (38) 8 6 (75)

Nicholson and

Richie (1977) ± ± 26 2 (8) 14 2 (14) 6 2 (33)

McLaughlin et al.

(1976) ± ± 19 4 (21) 17 5 (29) 24 12 (50)

Brendler et al.

(1980) 22 3 (14) 58 11 (19) 27 14 (52) 17 10 (58)

Catalona and

Stein (1982) 9 3 (33) 49 14 (28) 28 9 (32) ± ±

Grossman et al.

(1980) 47 25 (53) 18 3 (17) 14 4 (28) 9 5 (55)

Fowler and Whit-

more (1981) ± ± 75 5 (7) 129 56 (43) 96 58 (60)

Gervasi et al.

(1989) 130 29 (22) 165 35 (21) 100 37 (37) 116 51 (44)

Wilson et al.

(1977) 8 0 (0) 36 5 (14) 29 9 (31) 19 10 (52)

McCullough et al.

(1977) ± ± ± ± ± ± 27 19 (70)

Flocks et al.

(1959) ± ± ± ± ± ± 382 144 (37)

Totals 280 73 (26) 644 107 (16) 514 197 (38) 745 341 (46)

A2B1 B2 C

Total Patients no. of with patients positive

nodes n (%)

Total Patients no. of with patients positive

nodes n (%)

Total Patients no. of with patients positive

nodes n (%)

Total Patients no. of with patients positive

nodes

n (%)

beginning of the 1980s. Conversely, in poorly dif- ferentiated cases in stage C, metastatic behavior can be assumed in more than 90% (93% according to Smith et al. 1983).

In conclusion, on the basis of their own results and those in the literature, Petros and Catalona (1992) reflect on genuine changes in our estimates of the stage at which prostate cancer is currently diagnosed. The authors emphasize that the main factors in the lower metastatic rates seem to be:

· Higher index of suspicion

· Earlier detection

· More aggressive intervention to establish the di- agnosis

· Ultrasound-guided prostate biopsies

· More widespread screening for prostate cancer.

Development of a SLN Concept in Relation to Tumor Stages Evaluation of Preconditions

Recently Huland (1998) tried to discuss the value of radical prostatectomy in node-positive cases. In a first statement he declared that in the course of last 10 years, in stages T1 and T2 lymph node in- volvement has decreased from 20 to less than 7%.

In a second statement he deals with the relapse rates recorded by Abbas and Scardina (1993), Catalona and Smith (1994), and Walsh et al.

(1994): nearly 100% in stages N1. He goes on to say that according to these studies that have ema- nated from Johns Hopkins, Houston and St. Louis Hospitals and to other studies it seems doubtful whether ever a patient with positive node(s) could be cured by radical prostatectomy and lymphade- nectomy (Abbas and Scardino 1993; Catalona and Smith 1994; Walsh et al. 1994).

Huland cites the Gæteborg studies and empha- sizes that among 514 patients 319 died from pro- gression of their prostate cancer; 131 of these 319 cases (41%) needed a ªtransurethralº operation, and 98 needed palliative radiation therapy to the urinary bladder.

In 53 cases (17%) urine had to be diverted into the cranial part of the urinary bladder. In approxi- mately 20% of cases a prostatectomy could help to avoid later severe complications that could other- wise be caused by growth of the cancer, but we have no method of identifying the groups ahead of

time. Therefore, a wait-and-see strategy is mostly adopted with the background intention of per- forming palliative radiation therapy if necessary.

In these conditions there is only one choice, as has long been the case in many clinics:

· Investigation of the six routinely taken biopsies, with the possibility of dividing the cases into two main groups

± Low-risk groupwith regional lymph node in- volvement in a maximum of 2% of cases: low grade (I) with limited intraprostatic exten- sion, no capsule perforation

± High-risk groupwith regional lymph node involvement in upto approximately 30%.

· Giving the patient information, with the aim of making him feel able to give informed consent to further treatments.

This means regional lymph node investigations on frozen sections during the operation and prosta- tectomy in patients with negative nodes.

This is the most frequently practiced concept, and it does not fit in directly with the concept of sentinel node labeling. Changes are needed to bring about better quality of the investigations and of decision-making process.

The sentinel lymph node concept is already practiced in many different ways and could be adapted to the prostate cancer problem as follows:

· To obtain the most clear-cut information possi- ble about the localization, especially when the positions of the sentinel nodes are atypical, it is necessary, especially in cases in the high risk group, to wait for the results obtained in paraf- fin sections of the nodes (principally investi- gated in the same way as in breast cancer or melanoma cases).

· Decisions about prostatectomy can then be made with informed consent from the patient and the possibility of later adjuvant radiation therapy can also be discussed with him.

It has long been unclear whether the survival rate of

N-positive cases can be increased by more discrim-

inating and continuous surgical removal of regional

lymph nodes. This is partly because no results of

systematic comparative studies of groups treated

with and without node resection, each subdivided

into low- and high-grade groups, are available. How-

ever, it is easy to understand why this is so, because

it must be seen that it would be unethical not to dis-

sect the regional lymph nodes, i.e., the iliac and ob-

turator lymph nodes on both sides, in the case of larger tumors, especially when the prostatic capsule is shown by histological investigation to be tumor infiltrated, something that can already be detected in the biopsies in special cases.

This dilemma is further complicated by the fact that some authors see laparoscopic and open surgi- cal procedures for lymph node extirpation as com- peting methods. With this rather confused situation, the approach to looking for sentinel node(s) has been founded on a very unclear basis. Many points are still open and urgently need to be cleared up.

The following questions arise in this context of the approach that is striven for:

1. Can laparoscopic and open surgical pelvic lym- phadenectomy be recognized as methods of equal value?

2. Is it possible to label the cancer within the prostate gland with the aim of secondary senti- nel lymph node labeling using the methods de- scribed by Harzmann and his group, for exam- ple (see Wawroschek et al. 1999, 2000)?

3. Can labeling of sentinel nodes with atypical lo- cations be helpful in revealing micrometastases?

Ad 1: Minimally invasive surgical methods allow excision of the iliac and obturator lymph nodes on both sides for pathohistological investigation of al- most the same quality as is possible with an open operative procedure.

If this statement were absolutely correct, the approach could be to perform histopathological examination of the laparoscopically dissected nodes, followed in node-negative cases by transur- ethral or perineal prostatectomy. However, this therapeutic approach does not allow labeling of prostate gland with

Tc and a search for the sen- tinel regional lymph node(s) by means of the gam- ma probe, because SLNs in atypical locations can- not be dissected by laparoscopic methods. This procedure would only be possible with open op- erative methods. In addition, there is real doubt among urologists about the comparability of mini- mally invasive and open lymphadenectomy.

Ad 2: As is generally well known, it is already diffi- cult to obtain significant prostate gland material from the six different areas of the gland, because the procedure for obtaining core biopsies of the pros- tate gland is very painful for the patient. On this ba- sis, we can be sure that the injection of 2 ml colloidal solution, for instance, into the prostate gland is tol-

erated by most patients, but is not ideal in terms of lymphatic flow from the tumor region to the SLN(s).

In addition, because it is often not possible to distinguish the outline of the cancer within the gland, the injection would be given directly into cancer tissue, which seems to be dangerous, espe- cially in view of the increased pressure that must follow the injection of 2 ml of the labeling-solu- tion, which can cause blood and lymphatic vessels to open (see also discussion of this problem in Chapter 7, which is focused on breast cancer label- ing procedures).

On the other hand periprostatic injection of the contrast solution also seems to be problematic, be- cause venous blood vessels of the plexus prostati- cus can be opened, followed by bleeding and thrombosis (see Fig. 13).

Ad 3: The influence of lymphogenic micrometastases on tumor progression cannot be judged precisely at present, because the data available are in a highly de- gree divergent and based on different preconcep- tions. Therefore, the following options must be thought through before we can find better solutions:

· Is it possible to localize small cancers very accu- rately by ultrasound and inject labeling solution into the interstitial non-cancer-infiltrated part of the prostate gland body?

· Is it possible to localize smaller foci of cancer, for instance in cases with multifocality, and in- ject labeling solution into the interstitial pros- tate gland body?

· Is it possible to inject the contrast solution into the vicinity of the primary outside the gland body but in highly reduced volumes of maximally 0.2±

0.5 ml in order to reduce the interstitial pressure to a high degree so as to avoid opening of blood vessels, which is otherwise induced by high pres- sure and leads to interruption of the continuity of vascular wall structures?

Current Survival Rates as a Measure of Improvements in Lymph Node Staging and Clearance by the Sentinel Node Concept When surgical lymph node clearance, especially in cases with occult or micrometastases, needs to be extended, as already proposed by Wawroschek, Vogt, and Harzmann, the procedure should be ori- ented on the current survival rates.

Current Survival Rates as a Measure of Improvements in Lymph Node Staging and Clearance 467

Cheng et al. (1993) published the overall surviv- al rates achieved with different therapeutic princi- ples (see Table 14).

In other series, e.g. that published by Hanks (1993), the results obtained with adjuvant radia- tion therapy have also been limited (see Table 15).

The data presented in Tables 14 and 15 confirm that operative procedures obviously have some benefit but that this is limited compared with irra- diation therapy, and suggest that orchidectomy prolongs survival.

In these circumstances, and in view of the fact that by 10 years after the primary diagnosis most patients have reached the mean general survival age, it seems that sentinel node detection with curative intent is limited, when all stages are taken together; therefore, sentinel node detection must be focused on the early stages of cancer develop- ment with histologically occult metastases and mi- crometastases, such as those detectable only by immunohistochemical serial sectioning, to improve locoregional clearance. Such efforts may improve the statistically evaluated success rate, but must be seen mainly under the aspect of individual thera- py.

Whereas in locoregional tumor clearance in breast cancer irradiation therapy (homogeneous ir- radiation after wide excision of the primary) is very successful in preventing local recurrence and in gen- eral in improving healing rates, the same level of success obviously cannot be reached in radiotherapy for prostate cancer (see Tables 14 and 15).

Fig. 13. Venous pelvic bloodstream: Note the intensively developed venous plexus prostaticus (PP) and plexus presacralis.

The PP is closely connected to the pre- vertebral and vertebral plexuses. These connections are relevant after veins have been opened and venous blood pressure has risen in connection with prostate and pelvic lymphadenectomy, as they al- low so-called retrograde transport of cancer cells into the vertebral bone mar- row. After Leibovitch et al. (1995)

Table 14. Five years respectively ten years survival rates in D

-prostate cancer patients (non-randomized study) at 631 cases by Cheng et al. (1993) (IO intraoperative, PO post- operative)

Therapy regimen Survival

Prostatectomy and orchi-

dectomy (PO, n=251) 91% 78%

Prostatectomy alone

(PO, n=78) 91% 75%

Irradiation and orchidec-

tomy (IO, n=97) 84% 54%

Orchidectomy alone

(PO, n=60) 84% 45%

5 Years 10 Years

Because radiotherapy has limited success even in low-grade cases and in early lymphogenous me- tastatic spread, it seems that even in many patients in the early N1 (D1) stages, systemic hematoge- nous spread has already occurred. This has already been underlined by the results published by Ger- vasi et al. (1989).

The risk of distant metastases and of death from prostate cancer has been found to be much higher in cases with positive nodes than in node-negative cases (P<0.00005).

Does Radical Prostatectomy Improve the Results in Lymph Node-Positive Cases (D1)?

The discussion of this question has given rise to some controversy. Opinions on this point vary quite widely and are frequently related to individu- al patients' preconceptions.

However, more recent investigations by Frazier et al. (1994) give a significant answer to this prob- lem · With reference to D1 cases and survival

· With reference to complication rates in cases with and without prostatectomy (see Table 16).

The survival advantage of patients who have un- dergone a radical prostatectomy was independent of any adjuvant therapeutic support. Radical retro- pubic prostatectomy had no perioperative compli- cations in 72% of the cases.

Complication rates were significantly associated with anesthesiological problems and comorbidity rather than age (ASA class P=0.006; operative blood loss P = 0.015) (Dillioglugil et al. 1997).

Parra et al. (1996) recommend perineal prosta- tectomy in low-risk cases (PSA <10 ng/ml, Glea- son score <7). In his 75 low-risk cases he found no nodal metastases. In contrast, among 81 cases with worse parameters metastases were detected in 5 (=6.1%).

In Conclusion

· In prostate cancer regional lymph node involve- ment depends heavily on:

± Degree of malignancy

± Stage: whereas in grade I pT1N involvement is nearly zero; in pT2±3 (B2, C) lymph node involvement is very much more frequent.

Does Radical Prostatectomy Improve the Results in Lymph Node-Positive Cases (D1)? 469

Table 15. Outcome of radiation therapy oncology. Groups of patients with node positive and negative disease treated with radiation

No. Survival Free of any failure

T1B, T2

Node negative 104 87% 63% 85% 67%

Node positive 43 60% 24% 38% 20%

T3, T4

Node negative 47 82% 58% 69% 49%

Node positive 59 65% 26% 32% 10%

5 years 10 years 5 years 10 years

Table 16. Comparison of survival rates in cases with and without radical prostatectomy Stages A and B with pelvic lymph

node metastasis D1 Patients with radical prostatectomy Group 1

Patients without radical prostatectomy

Group 2

P-value

Control without positive nodes 11.2 years 5.8 years 0.005

1±2 positive nodes 20.2 years 5.9 years 0.015

Complication rates 9.5% 24.6%

· When lymph nodes are involved the healing rates are low, in some statistics near zero.

· When

Tc is used for sentinel node detection (Wawroschek et al. 1999, 2000), it is possible for atypically localized sentinel nodes to be de- tected which would not be detected on open or laparoscopic lymphadenectomy.

· Laparoscopic lymphadenectomy is roughly com- parable in value to an open operative procedure, but does not allow removal of atypically local- ized SLNs.

· The chances of achieving more efficient locore- gional tumor clearance by an operative proce- dure are low, because of the dense networks of lymph and blood vessels (plexus prostaticus, presacral plexus) in the pelvis, which are limit- ing factors.

· Immunohistochemical methods (use of cytoke- ratin, PSA antibodies) are helpful in the detec- tion of micrometastases.

· The following improvements could be helpful to increase tumor-free survival:

± Development of strongly improved sentinel node detection systems

± Intraoperative fast immunohistochemical stainings (Nåhrig, Hæfler) for detection of micrometastases (in sentinel nodes) and ex- tended lymphadenectomy depending on the result.

· Meticulous care to avoid opening venous blood vessels in tumor-infiltrated areas to prevent ret- rograde transport via the venous plexus sys- tems.

· Improvements of locoregional radiation therapy, to make it better adapted to the cell cycle of the cancer.

Wawroschek's, Vogt's and Harzmann's

First Approach to Detection of Sentinel Nodes in Prostate Cancer

Following on from these open questions, Harz- mann and his group performed a pilot project with injection of 2 ml of

Tc containing contrast solution transrectally into the body of the prostate gland. They then faded out the central prostatic re- gion and looked for the localization of the SLNs by scintigraphic investigations. With this method they were able to detect the positions of SLNs out- side of the iliac and obturator regions, which are

not normally excised during routine lymphade- nectomy.

Even though this approach has made it possible to detect atypically localized SLNs, these investiga- tions must be seen in a critical light, especially with reference to the points discussed above. Such atypically localized SLNs can be localized in the promontory or presacral region (see Fig. 16).

This has some similarities to the situation in the treatment of rectal cancer. As is well known, in this cancer the healing rates could be significantly increased by operative excision of the presacral re- gion, thus excluding local recurrence.

New approaches are necessary to clarify whether it would be possible to inject minimal amounts of contrast solutions into the capsule re- gion, that is to say into regions where the invasive prostatic cancer is nearest to the capsule or infil- trating the capsule, and to look for the regional lymph nodes that might be involved in a metas- tatic process. It seems to be essential for the vol- ume of contrast solutions injected to be absolutely necessary so as to avoid vascular defects in the in- jection region and with these also hematogenous metastatic processes in the sense of so-called retro- grade transport via plexus prostaticus prevertebral plexus into bone marrow of the lumbar column or into the ossa ilei (see Fig. 13).

In conclusion,

· Sentinel node labeling in prostatic cancer cases is still in a developmental stage.

· The absolutely preliminary results presented by the Harzmann group

± Indicate new ways for operative principles

± Give an answer on possible atypical met- astatic processes in presacral or other node groups.

· According to these reflections and results new approaches seem to be possible.

· But, the knowledge currently available to us is not adequate to allow recommendations on how to proceed rotuinously in the future.

New approaches are necessary for more differen- tiated schemes concerning

· Site of injection for contrast media.

· Reduction of the amount of fluid injected.

We understand from Wawroschek and his collea-

gues (personal communication) that animal ex-

periments in dogs are in progress to elucidate the

facts on the most efficient injection sites, determi-

nation of the most appropriate volume of solution to be injected and how the total volume injected might be reduced.

As things are, it is not possible to be absolutely sure that propagation of lymphatic and hematogenous spread is avoided. It is astonishing that the points above are not seriously discussed in all new efforts to developnew techniques. We think a new discus- sion should not be started on iatrogenic induction of hematogenous spread, as this was under discus- sion as much as 25 years ago, but reflection on the problems touched upon does seem to be relevant.

Dynamic lymphoscintigraphic investigations were carried out by Harzmann et al. (2000) preop- eratively on the basis of an informed consent.

The gamma probe examinations were per- formed intraoperatively before pelvic staging lym- phadenectomy.

Harzmann's group followed the principle of per- forming total-body bone and CT scans, investigat- ing the acid phosphatase and prostate-specific antigen levels, and also performing transrectal ultrasonography, all preoperatively. After these,

99m

Tc nanocolloid (Nanocoll, Sorin, Italy) was injected into the prostate, one or two injections being given into each prostate lobe. When this procedure was followed the total activity reached 100 MBq with a volume of 2 ml.

Harzmann's grouporiented their applications to experiences obtained in breast cancer cases.

Scintigraphic investigations in the anteroposte- rior and dorsal projections were carried out 12 min and 2±4 h after injection (Sopha camera, DSX, LEAP collimator, 100000 counts/picture).

Radioactivity of the SLNs was measured using a gamma probe optimized for the measurement of

99m

technetium (C-trak: Car-wise Medical Products Co. Morgan Hill, Calif., USA) (see also chap- ter 12).

As usual in other regimens of sentinel node de- tection the prostate gland was shielded by a tung- sten plate, placed between the prostate and the lymph nodes intraoperatively to inhibit radiation coming from the prostate gland, which could en- hance inadequate measurements of activity over the lymph node(s).

In their description, the Harzmann group explains that a first operative step is the removal of the nodes detected by preoperative dynamic scintigraphy and intraoperative application of the gamma probe. However, the group emphasizes that

only the area of node localization can be deter- mined, because there exists no means of imaging the course of the blood vessels at the same time.

Nonetheless, in accordance with the sentinel node concept only those lymph nodes with measurable radiation were recognized as sentinels and re- moved intraoperatively.

Subordinate lymph nodes of the particular lym- phatics were excluded from the operative proce- dure. In normal conditions, precise allocation of subordinate lymph nodes is only successful in the case of nodes along the external and common ilia- cal arteries.

As in many histopathology laboratories the nodes were cut in 2-mm-thick slices before paraf- fin embedding.

Besides H and E staining, immunohistochemical studies using antibodies directed to cytokeratin were also used for detection, especially of single cancer cells or very small cancer cell clusters.

Preliminary results obtained by Harzmann's groupshowed that in a series of patients with stage 2A disease (26 cases with grades II and III), 4 of 11 cases had 1±2 micrometastases and in 3 of 4 cases metastases were found exclusively in the SLNs. It is remarkable that the largest positive node measured only 6 mm. The mean number of lymph nodes in pelvic lymphadenectomy was 17.4 (range 12±20).

Vogt et al. (2002) have recently summarized the Augsburg results again. They are collected in Ta- ble 17, which gives an overview of labeled versus positive SLN, total positive nodes versus positive SLN, and atypical localizations of positive SLN.

The authors emphasize clearly:

· Since conspicuous nodes in the presacral and in the anteromedial area of the internal iliac artery are not included in the conventional pelvic lym- phadenectomy program, in two of the four pa- tients seen by the Harzmann team the microme- tastases would not have been discovered or ex- cised. Had tumor progression developed from these nodes an unfavorable outcome would have been inevitable, but, the authors clearly point out that the more precise surgical procedure de- mands an operating time of nearly 5 h.

· Laparoscopic techniques can hardly be used in view of this increased duration and of economic calculations.

All in all, the Harzmann concept must be

viewed critically because of the large volume of

the contrast solution injected, but on the other

Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer 471