The role of pelvic lymph node dissection in the management of invasive bladder cancer

Urologic Oncology 4 (1998) 168–171

The role of pelvic lymph node dissection in the management of invasive bladder cancer William Bedford Waters, M.D. a,*, Pierfrancesco Bassi, M.D. b, Yoshitada Ohi, M.D. c, Shinichi Ohshima, M.D. d, Hein P.A.M. van Poppel, M.D. e, Joseph A. Smith, Jr., M.D. f, Atsushi Tajima, M.D. g a

Department of Urology, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL, 60153, USA b Instituto di Urolgia, Universita degli Studi, Via Giustiniani 2, Padova, 35128, Italy c Department of Urology, Kagoshima University, 8-35-1, Sakura-ga-oka, Kagoshima, 890, Japan d Department of Urology, Nagoya University School of Medicine, 65 Tsuruma-cho Showa-ku, Nagoya, 4668550, Japan e Department of Urology, UZ St. Pieter, Brusselsestraat 69, 3000 Leuven, Belgium f Vanderbilt University Medical Center, Department of Urology, Medical Center North, Rm. A1302, Nashville, TN, 37232, USA g Department of Urology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113, Japan Manuscript accepted February 5, 1999

Regional pelvic lymph nodes are often the first site of metastatic disease in patients with invasive transitional cell carcinoma of the bladder. The presence of lymph node metastasis has profound adverse prognostic implications but long term survival is seen in a limited number of patients with histologically positive nodes removed at the time of radical cystectomy. Nonetheless, the value of pelvic lymph node dissection as a staging versus a therapeutic maneuver has been a subject of debate. The development of cytotoxic chemotherapeutic agents with proven efficacy against bladder cancer changes some of the rationale supporting various attitudes toward lymph node dissection. Moreover, nonoperative or less invasive methods for assessing or removing pelvic lymph nodes are now available and may also influence patient management. 1. Incidence of lymph node metastasis The frequency with which lymph node metastasis occurs is directly related to several known prognostic parameters associated with the primary tumor including stage, grade, and extent [1]. Of these, tumor stage has been studied most frequently. Lymph node metastasis occurs rarely in patients without a documented history of a muscle invasive primary tumor and lesions of pathologic stage T3b or higher comprise most reported series of patients with positive nodes [2, 3,4,5]. The impact of tumor grade is difficult to assess as an independent factor given the strong association between tu-

* Corresponding author. Tel.:708-216-4076; Fax: 708-216-6585; E-mail: [email protected].

mor grade and depth of invasion. Vieweg et al. [6] found that 94% of patients with histologically positive lymph nodes had a poorly differentiated (grade 3) primary tumor and only 6% had moderately differentiated lesions. None of the patients with lymph node metastasis in their series had a well-differentiated primary tumor. In a series reported by Zincke et al. [7], 98% of patients had what was classified as a poorly differentiated tumor while only one (2%) had a moderately differentiated cancer. The lymphatic drainage of the bladder consists of a series of interconnecting channels which originate in the deep detrusor muscle and perivesical fat. Careful step sectioning shows the apparent presence of lymph nodes in the perivesical fat. Inclusion of patients with lymph node metastasis to perivesical lymph nodes in some series exploring the therapeutic role of surgery and lymph node dissection confounds comparison with others which include only those with metastasis identified in the regional lymph nodes [8]. Regional lymphatic drainage occurs to nodes located along the iliac vessels. Discrimination of particular sites of lymph node metastasis becomes confused partly by semantics. The obturator lymph nodes are often considered the initial site of metastatic disease while this same lymph node chain would be termed internal iliac nodes in other series. Regardless, the initial location of metastatic lymph node metastasis usually is at the origin of the vascular pedicle of the bladder just anterior to the proximal portion of the internal iliac artery and along the obturator nerve posterior to the external iliac vein. Metastasis to nodes more anteriorly along the external iliac artery is usually a secondary phenomena. Spread to nodes cephalad to the bifurcation of the iliac vessels is rare in the absence of identifiable nodes located at a more distal location in the pelvis.

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W.B. Waters et al./Urologic Oncology 4 (1998) 168–171

The incidence of lymph node metastasis overall in patients undergoing radical cystectomy is directly proportionate to the stage mix of the series. In general, however, most series have shown an overall incidence ranging between 13 and 24%. Smith and Whitmore [2] found that 89% of patients with involved nodes had a primary tumor of pathologic stage T3 or higher, while Vieweg et al. [6] found that 90% of their patients had pathologic T3a or higher tumors. When analyzed by clinical stage, lymph node metastasis is uncommon without identifiable muscle invasion in precystectomy biopsies. Smith and Whitmore [2] found positive nodes in 0 of 22 patients undergoing cystectomy for CIS alone and in only 2 of 37 (5%) of those with clinical T1 tumors. The incidence of lymph node metastasis was 13% with T2 disease, 18% for T3, and 44% of those with clinical T4 tumors. Clinical understaging of the primary tumor accounts for most patients with positive nodes in the CIS, T1, and T2 categories. Several reports have attempted to stratify patients by the extent of nodal involvement. Smith and Whitmore [2] found that 22% of patients in their series had only a single microscopically involved lymph node, while Grossman and Konnak [9] found a single positive node in 48% of their small series. Fourteen percent of the patients reported by Roehrborn and associates [10] had metastasis to a single lymph node. Wishnow and associates [11] found only one or two involved nodes in 94% of their patients. The number and extent of lymph node metastases is related to the case mix and extent of the primary tumor. In addition, though, differences in pathologic technique and the thoroughness with which analysis is performed clearly may serve as sources of variability in the diagnosis of lymph node metastasis [5]. 2. Assessment of lymph node metastasis Based on the known prognostic implications of lymph node metastasis, determination of lymph node status is important in therapy decisions. Methods other than surgical lymphadenectomy have been used in an attempt to assess the status of the pelvic lymph nodes non-operatively. In addition, recent efforts at minimally invasive surgery have influenced patient management decisions to some extent. Historically, bipedal lymphography has been used to assess pelvic and para-aortic lymph nodes [12]. The disadvantages of lymphography are well described. In addition to the invasiveness of the procedure, hypogastric and obturator lymph nodes are not reliably imaged. Interpretation of internal architectural changes has yielded a high false positive rate with lymphography. Accordingly, the technique is rarely used in contemporary medicine. Computerized tomography (CT) scanning can identify enlargement of pelvic lymph nodes but is not specific with regard to the cause of enlargement. Moreover, lymph node metastasis in patients with bladder cancer often occurs to a single node or is detectable only with microscopy. Therefore, a study such as CT scan, which demonstrates only

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gross nodal enlargement without any internal architectural detail, has a high false negative rate. Magnetic resonance imaging (MRI) is subject to some of the same limitations as CT scan and, in general, does not provide superior imaging capability for pelvic lymph nodes [13,14,15]. Although CT scan and MRI have an inherently high false negative rate, they may be useful in detecting large volume nodal metastasis; 4 mm cuts could help detection of nodes smaller than 1 cm, which would alter the plan of management if identified before surgery [16,17,18]. However, suspected lymph node metastasis should be confirmed histologically by fine needle aspiration. Lymphadenopathy from inflammation or fat infiltration could create false positive scans. The use of whole body positron emission tomography (PET) scan has not evolved and we await broader experience of its use in the pre-operative staging of bladder cancer [19]. Minimally invasive surgery such as laparoscopic lymph node dissection has been used selectively in patients with carcinoma of the bladder [20,21,22,23]. A key issue in deciding upon the value of laparoscopic lymph node dissection is the manner in which information obtained may alter clinical management. Frequently, radical cystectomy with lymph node dissection is recommended even in the face of microscopically positive lymph nodes, thereby diminishing the utility of any information obtained from a laparoscopic lymph node dissection. The anatomic extent of surgical lymph node dissection performed in conjunction with radical cystectomy depends partly upon the surgeon’s belief in the prognostic versus therapeutic value of lymph node removal. Lymph node dissection should include the nodes at greatest risk for tumor involvement, i.e., those along the internal iliac artery and anterior to the obturator nerve. The usual boundaries of node dissection described in most series of patients with bladder cancer is a point 2 cm proximal to the bifurcation of the common iliac artery and to the node of Cloquet distally. The lateral margin is the genito-femoral nerve. The dissection is carried medially to the bladder wall and posteriorly to the obturator nerve. A more extensive dissection incorporating removal of para-aortic lymph nodes has no apparent prognostic or therapeutic value [2].

3. Prognostic value of lymph node dissection There is little debate over the value of pelvic lymph node dissection in providing important prognostic and staging information about bladder cancer. The finding of histologically positive lymph nodes has profound adverse implications for survival. The potential contribution of differences in the size and extent of the primary tumor on prognosis is muted by the overwhelming effect of positive node status. The overall five year survival of patients with histologically positive lymph nodes at the time of cystectomy ranges between 17 and 34.5% [1,2,5,7,10,24,25]. However, a better

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W.B. Waters et al./Urologic Oncology 4 (1998) 168–171

prognosis is seen in patients with a lower primary tumor stage wherein five year survival rates up to 50% have been reported with positive nodes in the face of a T2 primary tumor. In addition to a smaller primary tumor, most of these patients had a limited volume and number of pelvic node metastases. There is a correlation between the extent of nodal metastasis and prognosis. Virtually all series have shown that prognosis is better for a patient with a single microscopic lymph node compared with those with more extensive or more proximal nodal involvement. Smith and Whitmore reported a 17% five year survival after cystectomy and lymph node dissection in patients with a single positive node compared with 0% for those with any disease detected above the bifurcation of the iliac vessels [2]. Other series have shown survival rates of over 30% in patients with limited node involvement [8]. These series may not be comparable. However, careful step sectioning of lymph nodes may reveal small amounts of histologically identifiable tumor which may be undetected by other means of pathologic interpretation.

4. Therapeutic value of lymph node dissection Although the staging value of lymph node dissection is widely accepted, its therapeutic goal is not uniformly defined. Certainly, though, the survival data discussed above strongly imply a therapeutic role for lymph node dissection in some patients. It seems improbable that the survival figures of up to 30% in patients with cystectomy and lymph node dissection for limited nodal metastasis would be achieved in the absence of lymph node removal [27,28]. Recurrence is seen seldom after five years, implying that the lymph node removal itself contributes to a favorable outcome. Distant metastasis is the primary cause of treatment failure in patients with transitional cell carcinoma. A substantial number of patients who ultimately recur do so in the apparent absence of lymph node metastasis, implying hematogenous dissemination as the cause of treatment failure. Few patients fail with pelvic recurrence alone. Nonetheless, local recurrence after cystectomy can be a cause of considerable morbidity. Symptomatic local recurrences most often occur because of primary tumor extension, making it difficult to assess the impact of lymph node dissection in preventing local recurrence. Nonetheless, morbidity resulting from enlarging and unresected pelvic lymph nodes is recognizable in some patients, again suggesting a potential therapeutic role for lymph node dissection at the time of cystectomy (Table 1).

5. Summary recommendations The status of the pelvic lymph nodes remains a key factor in directing treatment for patients with transitional cell carcinoma of the bladder. The therapeutic value of neoadju-

Table 1 The therapeutic value of lymph node dissection in patients following radical cystectomy with pathological nodes incidence and survival

Author

Period

No

N1

%

Strata

Survival .5 yrs (%)

Whitmore [18] Laplante [20]

1940–55 1955–63

230 324

55 12

24

Dretler [ 25] Bredael [26] Reid [29] Smith, Whitmore [2]

1955–67 1964–73 1966-74 1966–77

302 174 135 662

54 26 24 134

13

Skinner [8] Zincke [7] Roehrborn [ 10]

1971–79 1960–80 1971–86

153 — 280

36 57 42

24 — 15

Takashi [1] Lerner, et al. [24]

1978–88 1971–89

86 591

19 132

22 22

Vieweg [6]

1980–88

627

140

26

Bretheau, Ponthieu [30] Kuriki [5]

1970–90

248

40

16

1984–92

131

22

17

overall N4 T4N1–3 T3N1–3 overall overall overall N1 N2 N3 N4 overall overall N1 N2, N3 overall ,P3b .P3b ,P3b .P3b N1 N2 overall

4 0 8 13 17 4 26 17 5 5 0 35 10 23 18 25 50 18 55 22 22 8 34.5

18 20

Adapted from Vieweg J, Fair WR. Pelvic Lymph Node Dissection in Carcinoma of the Urinary Bladder [31].

vant or adjuvant chemotherapy remains undefined but lymph node status is an important prognostic parameter which helps stratify patients according to the need for additional intervention. Most often, if lymph node metastasis is detected preoperatively by CT scan or other methods, systemic chemotherapy is the preferred initial treatment approach. There is controversy about the appropriate management of patients found to have nodal metastasis at the time of laparotomy for planned radical cystectomy. Some surgeons recommend termination of the procedure and administration of chemotherapy while others propose completion of the lymph node dissection and cystectomy because of a presumed therapeutic benefit and the potential to decrease local morbidity. Regardless, the available data continue to support the role of lymph node dissection in conjunction with radical cystectomy both for staging and therapeutic reasons. With limited nodal involvement, survival rates of up to 30% can be anticipated with surgery alone. Outcome is much less favorable with more extensive amounts of nodal disease. Although pelvic lymph node dissection is not considered by many to be therapeutic, the controversy that surrounded it may be resolved since routine pelvic lymphadenectomy has minimal complications. Lymphoceles, prolonged lymphatic drainage, obtruator nerve injury, and vascular injury are rarely reported. Therefore, a pelvic lymphadenectomy

W.B. Waters et al./Urologic Oncology 4 (1998) 168–171

that could be beneficial to a few patients (30%), should be performed in every cystectomy with curative intent.

[16]

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