- Email: [email protected]
Sentinel lymph node biopsy in gynaecological cancers: The importance of micrometastases in cervical cancer
Surgical Oncology (2008) 17, 227e235
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/suronc
REVIEW
Sentinel lymph node biopsy in gynaecological cancers: The importance of micrometastases in cervical cancer Emile Daraı¨ *, Roman Rouzier, Marcos Ballester, Emmanuel Barranger, Charles Coutant Department of Gynaecology and Obstetrics, Hoˆpital Tenon, Assistance Publique des Hoˆpitaux de Paris, CancerEst, Universite´ Pierre et Marie Curie, Paris 6, France
KEYWORDS Sentinel lymph node; Cervical cancer; Lymph node metastasis; Micrometastases; Prognosis; Serial sectioning; Immunohistochemistry; Molecular biology
Abstract Lymph node metastases is a recognized prognostic factor in women with cervical cancer. However, there is a need for consensual histological definition of micrometastases in this indication which could give rise to a classification system similar to that used in breast cancer. We thus conducted a MEDLINE and EMBASE database analysis to evaluate the concept of micrometastases in cervical cancer. Retrospective studies place the incidence of micrometastasis between 1.5 and 15% depending on the technique used to evaluate lymph node status. Sentinel lymph node biopsy with serial sectioning and immunohistochemical analysis appears to be the most accurate micrometastases detection technique. The value of RT-PCR in micrometastases detection remains to be clarified by further studies. From a clinical view point, few data are available to support the prognostic relevance of micrometastases. However, case control and longitudinal studies have underlined the risk of recurrence in women with micrometastases, raising the issue of a revision of adjuvant therapy indications in this specific population. ª 2008 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Analysis of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
* Corresponding author. Service de Gyne ´cologie-Obste ´trique, Ho ˆpital Tenon, 4 rue de la Chine, 75020 Paris, France. Tel.: þ33 1 56 01 73 18; fax: þ33 1 56 01 73 17. E-mail address: [email protected] (E. Daraı¨). 0960-7404/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2008.04.002
228
E. Daraı¨ et al. Concept of the sentinel lymph node procedure in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Definition of micrometastases in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Incidence and impact of micrometastases in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Introduction Cervical cancer remains the third most frequent female malignancy worldwide despite a gradual decrease in incidence in industrialized countries following the introduction of screening programs [1]. Nearly 471 000 new cases are detected worldwide each year causing 233 000 deaths [1]. Human papillomavirus (HPV), and especially types 16 and 18, is an established cause [2,3]. Several prognostic factors have been identified in women with cervical cancer. Some of these factors can be directly assessed on the primary tumour: lesion size, depth of stromal invasion, presence of lymphatic space involvement, histological type, and invasion of surgical margins [4]. Lymph node status is also a major prognostic factor and a decision criterion for adjuvant therapy. Using routine histology, previous studies have demonstrated that pelvic lymph node metastases are detected in 0e4.8% and 0e17% of patients with stage IA and IB cervical cancer, respectively. Even in patients with stage IIA and IIB disease, lymph node involvement is observed in only 12e27% and 25e39%, respectively [5,6]. The sentinel lymph node (SLN) concept has been accepted as an alternative to lymphadenectomy in many malignancies, including melanoma [7] and, more recently, breast cancer [8,9]. In gynaecological malignancies, the SLN procedure is well established in vulvar cancer [10] but is still under evaluation for cervical cancer. Despite the lack of apparent lymph node involvement, some patients have recurrences and shorter survival [11,12]. Holmgren et al. suggested that histologically undetectable, ‘‘dormant’’ or ‘‘occult’’ metastases in the lymphatic system could explain some recurrences [13]. In contrast to several carcinomas as melanoma or breast cancer, the concept and the clinical significance of the so-called lymph node micrometastases in women with cervical cancer is rarely debated. The aims of the present literature review, therefore, were to define the concept of micrometastases in women with cervical cancer and to evaluate its potential impact on therapeutic management and prognosis.
Analysis of the literature To evaluate the concept and the prognostic significance of micrometastases in cervical cancer, we performed a comprehensive computer literature search to identify relevant articles on lymph node metastasis and micrometastases in women with cervical carcinoma. MEDLINE and EMBASE databases up to January 2008 were searched for the following terms: ‘‘cervix neoplasm, uterine cervical carcinoma, lymph node metastases, sentinel node, and micrometastases’’ as medical subject
headings (MeSH). The list of articles was supplemented by extensive crosschecking of the reference lists of the identified articles. A hundred and forty-four articles were initially selected including review articles, letters, comments, conference proceedings, unpublished data, case reports, and non-English language studies. Our second selection phase excluded 37 non-English language studies, 26 review articles and 17 letters or short comments leaving us with 64 research articles from 43 medical teams. We finally included studies meeting the following inclusion criteria: (1) a minimum sample size of 10 patients and, (2) assessment of the histopathology analysis of lymph node involvement. The exclusion criterion was an overlap in patient data (duplicate publication), in which case the more recent article with most patients and an adequate description of the study population was retained. Finally, 29 studies fulfilled all criteria (Table 1). From this review, it is important to note that only three studies included at least 100 patients.
Concept of the sentinel lymph node procedure in cervical cancer The sentinel lymph node (SLN) technique was introduced for patients with cervical cancer in 1999 by Echt [14]. The sentinel concept postulates that the SLN is the first node draining a defined anatomic region and that its histological evaluation is thus representative for all lymph nodes draining this region [11,15e25]. However, there is no consensus whether SLN corresponds to the drainage of an organ or a tumour. The uterine cervix is a sagittal organ with several uniand bilateral drainage routes. The exact and reproducible location of pelvic lymph nodes is difficult since no consensual classification has been established for lymph nodes draining the cervix and corpus of the uterus. Reiffenstuhl identified eight lymphatic areas: aortic, promontoric, common iliac, external iliac, superior gluteal, inferior gluteal, interiliac and sacral [26]. Plentl described six pathways: three are lateral groups draining into the interiliac, external iliac and gluteal areas, and two posterior common iliac and subaortic areas. In addition, there is one anterior group draining to interiliac area [27]. Benedetti-Panici defined seven aortic areas of drainage namely paracaval, precaval, retrocaval, intercavoaortic, preoartic, para-aortic, retroaortic areas and eight pelvic areas namely deep and superficial common iliac, external iliac, presacral, deep and superficial obturator, internal iliac and parametric areas [28]. The latter author suggested that early-stage cervical cancer spreads more frequently to the superficial obturator, external iliac and superficial common iliac lymph nodes, whereas advanced tumours more frequently involve the deep common iliac lymph nodes [28]. Levenback
Sentinel lymph node biopsy in gynaecological cancers Table 1
229
Results of the sentinel lymph node (SLN) biopsy in studies of cervical cancer according to the detection technique
Studies
Year
No. of patients
FIGO stage
No. of patients with SLN (SLN detection rate per patient) (%)
Bilaterality (%)
Blue dye alone O’Boyle [33] Malur [41] Plante [11] Di Stefano. [48] Rob [34] Yuan [63] Seong [64] Total
2000 2001 2003 2005 2005 2007 2007
20 9 41 50 100 81 89 390
IBeIIA IeIV IAeIIA IA2eIIA IA2eIB2 IB1eIIA IA2eIIB
12 5 34 45 80 67 51 294
(60) (55.5) (83) (90) (80) (82.7) (57.3) (75.4)
41.6 ni 51.2 60 62 78 ni
0 50 0 10 4.8 23 9
(0/3) (1/2) (0/e) (1/10) (1/21) (3/13) (1/11)
Radiocolloid alone Malur [41] Lantzsch [22] Chung [19] Li [65] Silva [37] Angioli [35] Kamprath [66] Lin [36] Wang [6] Total
2001 2001 2002 2004 2005 2005 2005 2005 2006
21 14 26 28 56 37 18 30 46 276
IeIV IB1 IeIIA IBeIIA IA2eIIA IB1 ni IA2eIIA Early
16 14 26 27 52 26 16 30 46 253
(76.2)
ni 38.5 19.2 70.4 37.5 30.8 ni ni ni
0 0 16.7 0 18 0 0 0 0
(0/0) (0/1) (1/6) (0/6) (3/17) (0/6) (0/1) (0/7) (0/11)
ni 91 72.4 ni 64.9 94.1 83.3 64 90.4 53.6 60 42.6 66 40.7 ni 71.8 76
0 (0/4) 33 (1/3) 0 (0/e) 0 (0/19) 0 (0/5) 8 (1/12) 0 (0/2) 0 (0/4) 0 (0/15) ni 0 (0/9) 0 (0/21) 13.6 (3/22) 11.8 (2/17) 9 (1/11) 33 (1/3) 0 (0/2)
Combined detection (blue dye and radiocolloid) Malur [41] 2001 20 Lambaudie [40] 2003 12 Plante [11] 2003 29 Dargent and Enria [20] 2003 70 Hubalewska [49] 2003 37 Pijpers [43] 2004 34 Niikura [42] 2004 20 Martinez-Palones [5] 2004 23 Rob [34] 2005 83 Marnitz [15] 2006 151 Frumovitz [46] 2006 50 Kraft [67] 2006 54 Wydra [45] 2006 100 Coutant [56] 2007 59 Lee. [68] 2007 57 Hauspy [69] 2007 39 Bats [70] 2007 25 Total
IeIV IA2eIB1 IAeIIA IA1eIIB IeIIA Early IB1eIIA IA2eIIA IA2eIB2 IA2eIVA IA2eIB1 IB1eIII IB1eIIA IAeII IBeIIA IA1eIIA IA2eIB1
863
18 11 27 63 37 33 20 25 80 111 48 50 84 59 57 38 22
(96.4) (92.8) (70) (89)
FN rate (%)
(91.7) (90) (91.7) (93) (90) (97)
(96.4) (73.5) (96) (92.6) (84)
(39) (88)
783 (90.7)
SLN, sentinel lymph node; No, number; ni, not investigated; FN, false negative.
pointed to a direct lymphatic drainage to the common iliac and para-aortic areas [23]. Finally, Marnitz proposed a new classification of lymph node drainage based on SLN procedure comprising 11 areas: para-aortic, common iliac bilateral, external iliac bilateral, internal iliac bilateral including presacral, interiliac bilateral and parametric bilateral [15]. However, recent studies [29,30] have completely modified the anatomic knowledge of parametrium putting both the anatomical drainage of the cervix and the surgical classification of radical hysterectomy into question Table 2. SLNs were initially detected with blue dye [14,24,31e 34], then with radiocolloid [22,35e38] or a combined
technique [5,11,17e21,23,39e45]. For radiocolloid and combined techniques, a preoperative lymphoscintigraphy is recommended to identify and to localize the SLN and detect aberrant anatomical lymphatic drainage. Frumovitz et al. have recently underlined a discrepancy between day-before lymphoscintigraphy and surgical mapping of SLNs, raising the issue of its usefulness and cost-effectiveness in routine practice [46]. Marnitz addressed the issue of whether detection of multiple SLNs in one patient indicates an overflow of the labelling substance to the second echelon lymph nodes or results from multiple independent lymphatic pathways [15,33,35]. In fact, the time between lymphoscintigraphy and surgery
230
Table 2
Rate of macrometastases and micrometastases in studies using sentinel lymph node (SLN) biopsy in cervical cancer
Studies
Year No. of Method of patients detection
FIGO stage No. of patients Method of with SLN (SLN histopathologic detection rate analysis of SLN per patient) (%)
No. of patients with Definition of No. of patients with macrometastases micrometastatic micrometastatic in SLN (%) SLN (%)
O’Boyle [33] Malur [41] Lantzsch [22] Chung [19] Lambaudie [40] Plante [11] Dargent and Enria [20] Hubalewska [49] Pijpers [43] Niikura [42] Martinez-Palones [5] Li [65] Silva [37] Rob [34] Angioli [35] Di Stefano [48] Lin [36] Kamprath [66] Marnitz [15] Frumovitz [46] Kraft [67] Wang [6] Wydra [45] Yuan [63] Coutant [56] Seong [64] Lee [68] Hauspy [69] Bats et al. [70]
2000 20 2001 50 2001 14 2002 26 2003 12 2003 70 2003 70 2003 37 2004 34 2004 20 2004 23 2004 28 2005 56 2005 183 2005 37 2005 50 2005 30 2005 18 2006 151 2006 50 2006 54 2006 46 2006 100 2007 81 2007 59 2007 89 2007 57 2007 39 2007 25
IBeIIA IeIV IB1 IeIIA IA2eIB1 IAeIIA IA1eIIB IeIIA early IB1eIIA IA2eIIA IBeIIA IA2eIIA IA2eIB2 IB1 IA2eIIA IA2eIIA
3 6 1 5 2 8 19 5 12 2 3 6 17 35 6 9 7 1 34 9 21 18 ni 17 15 11 11 2 3
B B þ R þ CT R R CT B þ CT CT CT CT CT CT R R B þ CT R B R R CT CT CT R B CT B CT CT CT
IA2eIVA IA2eIB1 IB1eIII early IB1eIIA IB1eIIA IAeII IA2eIIB IBeIIA IA1eIIA IA2eIB1
12 39 14 26 11 61 63 37 33 20 25 27 52 160 26 45 30 16 111 48 50 46 84 67 59 51 57 38 25
(60) (78)
(91.7) (87.1) (90) (97)
(96.4) (92.8) (87.4) (70) (90) (89) (73.5) (96) (92.6) (84) (82.7) (57.3) (39)
HES HES HES þ SS þ IHC HES HES þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ IHC HES þ IHC ni HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC ni ni HES HES þ SS þ IHC HES þ IHC HES þ SS þ IHC þ CK19PCR ni HES þ SS þ IHC HES þ SS þ IHC þ HPV DNA HES HES þ HPV DNA detection HES þ SS þ IHC HES þ SS þ IHC
(25) (15.4) (7.1) (19) (18.2) (13.1) (30.2) (13.5) (36.3) (10) (13) (22.2) (32.7) (21.9) (23) (20) (22.3) (6.3) (30.6) (18.8) (42) (39)
(25.4) (21.6) (19.3) (5.2) (12)
No No No No No No No No No No No No No No No No No No No No No No No No Yesa No No No No
3 (100) ni 0 ni 0 3 (37.5) 9 (47.4) ni 4 (33) 0 0 ni 3 (17.6) ni 0 2 (22.2) ni ni ni ni ni 7 (38.9)b ni 4 (23.5) 3 (20) ni ni ni 1 (33)
E. Daraı¨ et al.
No, number; SLN, sentinel lymph node; CT, combined detection; R, radiocolloid alone; B, blue dye alone; ni, not investigated; H&E, standard H&E; SS, serial sectioning; IHC, immunohistochemistry. a Macrometastases as a single focus of metastatic disease per node measuring more than 2 mm, micrometastases as a focus of metastatic disease ranging from 0.2 mm to no more than 2 mm and submicrometastases as metastases measuring no more than 0.2 mm (including the presence of single non cohesive tumour cells). b More than 8 patients with CK19 RT PCR.
Sentinel lymph node biopsy in gynaecological cancers is probably the most determinant factor: the longer one waits before surgical mapping, the more radiocolloid migrates and contributes to detect second- or third-tier lymph nodes [43]. Numerous studies have evaluated the feasibility, sensitivity and detection rate of SLN techniques and specifically the false-negative SLN rate [11,14,17e20,22,23,32,34e 38,40,41,44]. However, analysis is difficult due to differences in the volume and quantity of labelling substance, the site of injection (pericervical, peritumoural or intratumoural), the number of injection sites, the volume of the tumour [47], and the interval between injection and detection from one study to another [20,31,33e35,37e 40,42,45]. In our literature review, the SLN detection rates for blue dye alone, radiocolloid alone, and combined technique were: 75.4, 91.7, and 90.7%, respectively (Table 1). These results are partly in keeping with those of Di Stefano et al. [48]. In their study, the detection rate by side for blue dye alone, radiocolloid alone and combined technique ranged from 7.7 to 89.9%, 45.9 to 82.1% and 59.6 to 97.1%, respectively. Combining technetium and blue dye appeared more effective in terms of SLN detection per patient than blue dye alone or technetium alone. In the literature, bilateral distribution of SLN is reported in 0 to 94.9% of patients depending on the SLN technique [15,24,34,43,49]. The occurrence of unilateral or bilateral SLN can be related to anatomical variation in lymphatic drainage, tumour size, technique of injection and the number of injection sites, raising the issue of the necessity of performing systematic lymphadenectomy on the pelvic side if no SLNs are detected [11]. The false-negative rate of the SLN biopsy in our literature review ranges from 0 to 50% with a negative predictive value from 75 to 100% [48]. As for the SLN procedure, no consensus exists on an ‘‘acceptable’’ falsenegative rate. In accordance with other malignancies for which SLN biopsy is recognised to be an alternative to systematic lymphadenectomy, a false-negative rate of 5% seems acceptable [16].
Definition of micrometastases in cervical cancer Overall, there is an absence of universal agreement on the definition of lymph node metastases in cervical cancer. In accordance with the Philadelphia Consensus Conference on sentinel nodes in breast cancer [9], we propose that the following definitions be applied: macrometastases as a single focus of metastatic disease per node measuring more than 2 mm, micrometastases as a focus of metastatic disease ranging from 0.2 mm to no more than 2 mm and, in accordance with Marchiole, submicrometastases as metastases measuring no more than 0.2 mm (including the presence of single non-cohesive tumour cell) [24,50]. This lack of consensual definition of micrometastases in cervical cancer could explain why its concept is controversial. Indeed, the presence of micrometastases differs according to the technique used for their identification: haematoxylin and eosin (H&E) staining on a few slides, serial sectioning H&E and immunohistochemistry (IHC) with an anti-cytokeratin antibody cocktail, reverse-transcriptase
231 PCR (RT-PCR) detection of cytokeratin 19 (CK 19) mRNA, or HPV-16 and -18 DNA detection by PCR. Using routine histopathological examination, it has been estimated that the chances of identifying a tumour cell cluster of less than three cell diameters was only 1% [51]. In breast cancer, Cote et al. noted that serial sectioning alone was able to detect 7% of ‘‘occult’’ metastases in negative lymph nodes and that a 20% detection was reached when using cytokeratine immunochemistry [52]. In cervical cancer, using both serial sectioning and IHC on 976 pelvic lymph nodes from 49 patients, Juretzka et al. identified four patients with lymph node micrometastases not initially identified on routine H&E examination [4]. However, this combined technique on all nodes is time consuming and expensive thus limiting its routine use and justifying the concept of the SLN biopsy. As previously mentioned, SLN is defined as the first node in the lymphatic system draining a tumour. This concept, histologically validated by serial sectioning and IHC, suggests that when the SLN is not metastatic then all other nodes should also be disease-free [16]. However, Marchiole ´ et al. noted that even when serial sectioning is used, very small clusters of tumour cells can escape IHC staining raising the question of their prognostic significance [24,50]. Since the first report by Smith, although several molecular markers for micrometastases and various PCR protocols have been described, none have been introduced in standard clinical practice [53e55]. Using RT-PCR for CK 19, Van Trappen noted that 44% of histologically uninvolved lymph nodes in 32 patients exhibited CK 19 transcription [55]. Sixteen of them had positive RT-PCR lymph nodes. Ha ¨fner found that HPV 16 E6 mRNA was more specific and more sensitive for detecting tumour cells in SLNs than CK19 mRNA [51]. Coutant reported that HPV DNA was detected in 10 (50%) of 20 positive sentinel node (seven of 15 patients) and in five (5.6%) of 90 negative sentinel node (five of 44 patients) (p < 0.0001). Moreover, in this study, no relation was found between clinical or histological prognostic parameters and the presence of HPV DNA in the SLN or the primary cervical tumour [56]. The frequency of SLN HPV positivity does not differ according to the existence of macrometastases, micrometastases, or isolated tumour cells [56]. Van Trappen underlined that specific tumour DNA found in histologically normal lymph nodes may originate from dead cell material or macrophages and that viral DNA can be found in various cell types thus limiting its usefulness as a molecular marker for micrometastases [55]. Moreover, Marchiole ´ noted that even RTPCR had a better sensitivity than IHC, though this is counterbalanced by a lack of specificity [24]. Indeed, it is not possible to differentiate macrometastases from benign glandular inclusion using only RT-PCR. Moreover, even if a correlation has been established between the number of copy cells and the size of metastases, RT-PCR lacks accuracy in differentiating true macrometastases from multiple micrometastases or submicrometastases. Finally, for clinical practice, the combination of the SLN procedure with serial sectioning and IHC seems to be not only the easiest technique to apply in routine practice but also the most efficient and cost-effective way of detecting micrometastases. Van der Velde-Zimmermann suggested another possible strategy for analysing SLNs by use of
232 RT-PCR as an initial diagnostic tool to preselect nodes for serial sectioning and IHC [57].
Incidence and impact of micrometastases in cervical cancer As mentioned in the introduction, the aim of this review is not to discuss the prognostic relevance of lymph node metastases in cervical cancer as this has been extensively studied and proven [58]. In 2001, Van Trappen assessed the value of mRNA RTPCR to detect micrometastases in a series of 32 patients with stage IA2 to IB2 cervical cancer [55]. Recurrence developed in one of the three patients with metastases detected by both histology and RT-PCR; in two of the 13 patients with negative histology but positive RT-PCR; and in none of the 16 patients with both negative histology and RT-PCR. [55]. This gave rise to two concepts: first the clinical significance of inframorphological metastases corresponding to micrometastases; and second, the prognostic significance of a complete lymphadenectomy. In 2003, Dargent and Enria evoked the concept of micrometastases without clear histological definition in cervical cancer. They reported that the use of serial sectioning and IHC gave a possible tenfold increase in the detection rate of micrometastases [20]. Moreover, as micrometastases were found when the technique was retrospectively applied to SLNs from women with recurrence, the relevance of both serial sectioning and IHC and its prognostic value were validated. The concept of ultramicroscopic staging was born. However, in 2003, Plante reported the results of SLN biopsy in 70 women with cervical cancer [11]. Serial sectioning (three sections per node or every 40 mm perpendicular to the long axis of the node) and IHC were applied to negative SLNs to detect micrometastases, though no clear histological definition of micrometastases was given. In this series, ultrastaging detected micrometastases which had been missed by routine histology in one patient only. Moreover, it was underlined that this patient had several other histological risk factors for which adjuvant radiotherapy was recommended regardless of the presence of the micrometastases. The clinical relevance of histological ultrastaging was thus put into question. In 2004, Lentz evaluated the incidence of micrometastases in 132 patients with cervical cancer [59]. IHC analysis was used according to recommendations by the International Breast Cancer Study Group [52] and defined as occult metastases lymph nodes exhibiting single or small groups of malignant cells (2e3 cells) [59]. Micrometastases were detected in 1% of the 3 106 nodes examined corresponding to 15% of the patients. Using the CochraneArmitage trend test categorizing the number of lymph nodes resected into four groups (group 1 , 1e13 ; group 2 , 14e20 ; group 3 , 21e30; and group 4 , >30 nodes), the odds ratios to have micrometastases were 0.05 (CI 0.003e0.94), 0.12 (CI 0.01e1.07) and 1.78 (CI 0.59e5.34) compared with the group with more than 30 nodes. These results reinforced the concept of the prognostic significance of complete lymphadenectomy by removal of micrometastases [59]. The same year, Barranger histologically validated the concept of SLN biopsy
E. Daraı¨ et al. in cervical cancer and reported that out of eight positive SLNs (18.2%) from five patients (27.8%) found to be metastatic at the final histological assessment, two were macrometastatic, three micrometastatic and three contained isolated tumour cells (submicrometastases) [16]. In 2007, Coutant from the same team, confirmed the high incidence of micrometastases in cervical cancer but failed to demonstrate the relation between the presence of micrometastases or submicrometastases and the development of recurrence. This was probably due to the small sample size and the low incidence of recurrence [56]. Although in 2005 Silva et al. did not clearly define micrometastases histologically, using H&E, serial sectioning and IHC they found that 5.1% of micrometastases had not been detected by standard histology [37]. In 2006, Wang confirmed the results of previous studies on the value of RT-PCR assay for CK19 to detect micrometastases [6]. Although no definition of micrometastases was given, the representative examples provided by the authors in their paper are in accordance with the definition that we put forward. Seventeen of the 35 patients negative for metastases by conventional histology had micrometastases in SLNs: five were positive by both IHC and RT-PCR, 10 by RT-PCR alone, and two by IHC alone. Numerous papers focus on the potential relevance of SLN biopsy to avoid systematic lymphadenectomy in order to decrease the incidence of postoperative complications. This goal is difficult to reach because of the relative low accuracy of both frozen section and imprint cytology to evaluate intraoperative lymph node status. Moreover, in women with a unilateral SLN, systematic lymphadenectomy on the pelvic side without detectable SLN remains questionable. In fact, the objective of SLN biopsy is not to identify macroscopically involved nodes that are easily detected but rather to identify those involved by subclinical metastases. RT-PCR, due its high sensitivity and in spite of its lower specificity, could possibly be a useful first diagnostic step to select women for lymphadenectomy and subsequently for serial sectioning and IHC on SLN [57]. It is clear that the data available in the literature are insufficient to evaluate the prognostic impact of the presence of micrometastases in women with cervical cancer. From the clinical view point, it is impossible to conclude whether the detection of micrometastases should be included in therapeutic protocols. The potential matching of the incidence of micrometastases observed in previous studies and the well known incidence of recurrence in apparent lymph node negative patients might argue in favour. But this assertion requires validation that appears difficult to confirm due to the low incidence of micrometastases and the absence of reliable data on the recurrence rate in this specific population. Indirectly, a degree of validation could be obtained by analysing similar gynaecological malignancies. Indeed, accumulated data have demonstrated the relation between micrometastases and the risk of recurrence in other gynaecological tumours [60,61]. Narayansingh reported the risk of recurrence was almost 20-fold higher in vulvar cancer patients with micrometastases compared to those without [61]. Therefore, some authors have concluded that the presence of micrometastases in SLNs from patients with vulvar cancer should be an indication for adjuvant therapy
Sentinel lymph node biopsy in gynaecological cancers [62]. In cervical cancer, Pijpers et al. recommended adjuvant therapy for their three patients with IHC-detected micrometastases and observed no recurrence [43]. In 2005, Marchiole ` et al. reassessed the prognostic value of micrometastases in a retrospective caseecontrol study including 52 patients (26 with and 26 without recurrence) [50]. Using a clear definition of micrometastases, they demonstrated a relation between lympho-vascular space involvement and the occurrence of micrometastases in SLNs. Moreover, they found that the relative risk of recurrence in the presence of true micrometastases (focus of metastatic disease ranging from 0.2 mm to no more than 2 mm) was 2.30 (CI 1.65e3.20, p < 0.01) and 2.22 (CI 1.30e3.80, p Z 0.09) in the presence of submicrometastases (focus of metastatic disease no more than 0.2 mm including the presence of single non-cohesive tumour cells). Using bivariate analysis, micrometastases were the only independent risk factor of recurrence [50]. These major data raise the issue of the relevance of adjuvant therapy in women with micrometastases in cervical cancer. In conclusion, there is a lack of data on the prognostic value of micrometastases in cervical cancer. However, accumulated data argue in favour of its prognostic relevance raising the issue of modifying indications for adjuvant therapy. This review is a plea for the use of consensual definition of micrometastases and we reiterate our recommendation of a histological classification using the same criteria as those applied in breast cancer. The value of RTPCR to detect micrometastases in routine practice requires further studies.
233
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
All authors disclose no financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
[18]
References [19] [1] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics. CA Cancer J Clin 2001;2001(51):15e36. [2] Bosch FX, de Sanjose S. Chapter 1: Human papillomavirus and cervical cancer e burden and assessment of causality. J Natl Cancer Inst Monogr 2003:3e13. [3] Fuchs PG, Girardi F, Pfister H. Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases? Int J Cancer 1989;43:41e4. [4] Juretzka MM, Jensen KC, Longacre TA, Teng NM, Husain A. Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis. Gynecol Oncol 2004;93:107e11. [5] Martinez-Palones JM, Gil-Moreno A, Perez-Benavente MA, Roca I, Xercavins J. Intraoperative sentinel node identification in early stage cervical cancer using a combination of radiolabeled albumin injection and isosulfan blue dye injection. Gynecol Oncol 2004;92:845e50. [6] Wang HY, Sun JM, Lu HF, Shi DR, Ou ZL, Ren YL, et al. Micrometastases detected by cytokeratin 19 expression in sentinel lymph nodes of patients with early-stage cervical cancer. Int J Gynecol Cancer 2006;16:643e8. [7] Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative
[20]
[21]
[22]
[23]
[24]
lymphatic mapping and sentinel lymphadenectomy for earlystage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999;230:453e63 [discussion 463e55]. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391e8 [discussion 398e401]. Schwartz GF, Giuliano AE, Veronesi U. Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast April 19 to 22, 2001. Philadelphia, Pennsylvania. Hum Pathol 2002;33:579e89. de Hullu JA, Doting E, Piers DA, Hollema H, Aalders JG, Koops HS, et al. Sentinel lymph node identification with technetium-99m-labeled nanocolloid in squamous cell cancer of the vulva. J Nucl Med 1998;39:1381e5. Plante M, Renaud MC, Tetu B, Harel F, Roy M. Laparoscopic sentinel node mapping in early-stage cervical cancer. Gynecol Oncol 2003;91:494e503. Stehman FB, Bundy BN, DiSaia PJ, Keys HM, Larson JE, Fowler WC. Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 1991;67:2776e85. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149e53. Echt ML, Finan MA, Hoffman MS, Kline RC, Roberts WS, Fiorica JV. Detection of sentinel lymph nodes with lymphazurin in cervical, uterine, and vulvar malignancies. South Med J 1999;92:204e8. Marnitz S, Kohler C, Bongardt S, Braig U, Hertel H, Schneider A, et al. Topographic distribution of sentinel lymph nodes in patients with cervical cancer. Gynecol Oncol 2006; 103:35e44. Barranger E, Cortez A, Commo F, Marpeau O, Uzan S, Darai E, et al. Histopathological validation of the sentinel node concept in cervical cancer. Ann Oncol 2004;15:870e4. Barranger E, Cortez A, Uzan S, Marpeau O, Uzan S, Darai E. Value of intraoperative imprint cytology of sentinel nodes in patients with cervical cancer. Gynecol Oncol 2004;94:175e80. Buist MR, Pijpers RJ, van Lingen A, van Diest PJ, Dijkstra J, Kenemans P, et al. Laparoscopic detection of sentinel lymph nodes followed by lymph node dissection in patients with early stage cervical cancer. Gynecol Oncol 2003;90:290e6. Chung YA, Kim SH, Sohn HS, Chung SK, Rhim CC, Namkoong SE. Usefulness of lymphoscintigraphy and intraoperative gamma probe detection in the identification of sentinel nodes in cervical cancer. Eur J Nucl Med Mol Imaging 2003;30:1014e7. Dargent D, Enria R. Laparoscopic assessment of the sentinel lymph nodes in early cervical cancer. Technique e preliminary results and future developments. Crit Rev Oncol Hematol 2003;48:305e10. Gil-Moreno A, Diaz-Feijoo B, Roca I, Puig O, Pe ´rez-Benavente MA, Aguilar I, et al. Total laparoscopic radical hysterectomy with intraoperative sentinel node identification in patients with early invasive cervical cancer. Gynecol Oncol 2005;96:187e93. Lantzsch T, Wolters M, Grimm J, Mende T, Buchmann J, Sliutz G, et al. Sentinel node procedure in Ib cervical cancer: a preliminary series. Br J Cancer 2001;85:791e4. Levenback C, Coleman RL, Burke TW, Lin WM, Erdman W, Deavers M, et al. Lymphatic mapping and sentinel node identification in patients with cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy. J Clin Oncol 2002;20:688e93. Marchiole P, Buenerd A, Scoazec JY, Dargent D, Mathevet P. Sentinel lymph node biopsy is not accurate in predicting lymph node status for patients with cervical carcinoma. Cancer 2004;100:2154e9.
234 [25] Torne A, Puig-Tintore LM. The use of sentinel lymph nodes in gynaecological malignancies. Curr Opin Obstet Gynecol 2004; 16:57e64. [26] Reiffenstuhl G. [Contribution on the nomenclature of the pelvic lymph nodes]. Wien Klin Wochenschr 1956;68:247e8. [27] Plentl AA, Friedman EA. Lymphatic system of the female genitalia. The morphologic basis of oncologic diagnosis and therapy. Major Probl Obstet Gynecol 1971;2:1e223. [28] Benedetti-Panici P, Maneschi F, Scambia G, Greggi S, Cutillo G, D’Andrea G, et al. Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. Gynecol Oncol 1996;62:19e24. [29] Hockel M. Do we need a new classification for radical hysterectomy? Insights in surgical anatomy and local tumor spread from human embryology. Gynecol Oncol 2007;107:S106e12. [30] Hockel M, Dornhofer N. Pelvic exenteration for gynaecological tumours: achievements and unanswered questions. Lancet Oncol 2006;7:837e47. [31] Dargent D, Martin X, Mathevet P. Laparoscopic assessment of the sentinel lymph node in early stage cervical cancer. Gynecol Oncol 2000;79:411e5. [32] Medl M, Peters-Engl C, Schutz P, Vesely M, Sevelda P. First report of lymphatic mapping with isosulfan blue dye and sentinel node biopsy in cervical cancer. Anticancer Res 2000;20:1133e4. [33] O’Boyle JD, Coleman RL, Bernstein SG, Lifshitz S, Muller CY, Miller DS. Intraoperative lymphatic mapping in cervix cancer patients undergoing radical hysterectomy: a pilot study. Gynecol Oncol 2000;79:238e43. [34] Rob L, Strnad P, Robova H, Charvat M, Pluta M, Schlegerova D, et al. Study of lymphatic mapping and sentinel node identification in early stage cervical cancer. Gynecol Oncol 2005;98: 281e8. [35] Angioli R, Palaia I, Cipriani C, Muzii L, Calcagno M, Gullotta G, et al. Role of sentinel lymph node biopsy procedure in cervical cancer: a critical point of view. Gynecol Oncol 2005;96:504e9. [36] Lin YS, Tzeng CC, Huang KF, Kang CY, Chia CC, Hsieh JF. Sentinel node detection with radiocolloid lymphatic mapping in early invasive cervical cancer. Int J Gynecol Cancer 2005;15: 273e7. [37] Silva LB, Silva-Filho AL, Traiman P, Triginelli SA, de Lima CF, Siqueira CF, et al. Sentinel node detection in cervical cancer with (99m)Tc-phytate. Gynecol Oncol 2005;97:588e95. [38] van Dam PA, Hauspy J, Vanderheyden T, Sonnemans H, Spaepen A, Eggenstein G, et al. Intraoperative sentinel node identification with Technetium-99m-labeled nanocolloid in patients with cancer of the uterine cervix: a feasibility study. Int J Gynecol Cancer 2003;13:182e6. [39] Barranger E, Grahek D, Cortez A, Talbot JN, Uzan S, Darai E. Laparoscopic sentinel lymph node procedure using a combination of patent blue and radioisotope in women with cervical carcinoma. Cancer 2003;97:3003e9. [40] Lambaudie E, Collinet P, Narducci F, Sonoda Y, Papageorgiou T, Carpentier P, et al. Laparoscopic identification of sentinel lymph nodes in early stage cervical cancer: prospective study using a combination of patent blue dye injection and technetium radiocolloid injection. Gynecol Oncol 2003;89:84e7. [41] Malur S, Krause N, Kohler C, Schneider A. Sentinel lymph node detection in patients with cervical cancer. Gynecol Oncol 2001;80:254e7. [42] Niikura H, Okamura C, Akahira J, Takano T, Ito K, Okamura K, et al. Sentinel lymph node detection in early cervical cancer with combination 99mTc phytate and patent blue. Gynecol Oncol 2004;94:528e32. [43] Pijpers R, Buist MR, van Lingen A, Dijkstra J, van Diest PJ, Teule GJ, et al. The sentinel node in cervical cancer:
E. Daraı¨ et al.
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
scintigraphy and laparoscopic gamma probe-guided biopsy. Eur J Nucl Med Mol Imaging 2004;31:1479e86. Verheijen RH, Pijpers R, van Diest PJ, Burger CW, Buist MR, Kenemans P. Sentinel node detection in cervical cancer. Obstet Gynecol 2000;96:135e8. Wydra D, Lass P, Bandurski T. Usefulness of lymphoscintigraphy and intraoperative gamma probe detection in the identification of sentinel nodes in cervical cancer. Eur J Nucl Med Mol Imaging 2004;31:293. author reply 294. Frumovitz M, Coleman RL, Gayed IW, Ramirez PT, Wolf JK, Gershenson DM, et al. Usefulness of preoperative lymphoscintigraphy in patients who undergo radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Am J Obstet Gynecol 2006;194:1186e93 [discussion 1193e5]. Barranger E, Coutant C, Cortez A, Uzan S, Darai E. Sentinel node biopsy is reliable in early-stage cervical cancer but not in locally advanced disease. Ann Oncol 2005;16:1237e42. Di Stefano AB, Acquaviva G, Garozzo G, Barbic M, Cvjeticanin B, Meglic L, et al. Lymph node mapping and sentinel node detection in patients with cervical carcinoma: a 2-year experience. Gynecol Oncol 2005;99:671e9. Hubalewska A, Sowa-Staszczak A, Huszno B, Markocka A, Pityn ´ski K, Basta A, et al. Use of Tc99m-nanocolloid for sentinel nodes identification in cervical cancer. Nucl Med Rev Cent East Eur 2003;6:127e30. Marchiole P, Buenerd A, Benchaib M, Nezhat K, Dargent D, Mathevet P. Clinical significance of lympho vascular space involvement and lymph node micrometastases in early-stage cervical cancer: a retrospective case-control surgicopathological study. Gynecol Oncol 2005;97:727e32. Hafner N, Gajda M, Altgassen C, Hertel H, Greinke C, Hillemanns P, et al. HPV16-E6 mRNA is superior to cytokeratin 19 mRNA as a molecular marker for the detection of disseminated tumor cells in sentinel lymph nodes of patients with cervical cancer by quantitative reverse-transcription PCR. Int J Cancer 2007;120:1842e6. Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, et al. Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group. Lancet 1999;354:896e900. Raj GV, Moreno JG, Gomella LG. Utilization of polymerase chain reaction technology in the detection of solid tumors. Cancer 1998;82:1419e42. Smith B, Selby P, Southgate J, Pittman K, Bradley C, Blair GE. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet 1991;338:1227e9. Van Trappen PO, Gyselman VG, Lowe DG, Ryan A, Oram DH, Bosze P, et al. Molecular quantification and mapping of lymph-node micrometastases in cervical cancer. Lancet 2001;357:15e20. Coutant C, Barranger E, Cortez A, Dabit D, Uzan S, Bernaudin JF, et al. Frequency and prognostic significance of HPV DNA in sentinel lymph nodes of patients with cervical cancer. Ann Oncol 2007;18:1513e7. van der Velde-Zimmermann D, Schipper ME, de Weger RA, Hennipman A, Borel Rinkes IH. Sentinel node biopsies in melanoma patients: a protocol for accurate, efficient, and cost-effective analysis by preselection for immunohistochemistry on the basis of Tyr-PCR. Ann Surg Oncol 2000;7:51e4. Sartori E, Tisi G, Chiudinelli F, La Face B, Franzini R, Pecorelli S. Early stage cervical cancer: adjuvant treatment in negative lymph node cases. Gynecol Oncol 2007;107:S170e4. Lentz SE, Muderspach LI, Felix JC, Ye W, Groshen S, Amezcua CA. Identification of micrometastases in histologically negative lymph nodes of early-stage cervical cancer patients. Obstet Gynecol 2004;103:1204e10.
Sentinel lymph node biopsy in gynaecological cancers [60] Knopp S, Holm R, Trope C, Nesland JM. Occult lymph node metastases in early stage vulvar carcinoma patients. Gynecol Oncol 2005;99:383e7. [61] Narayansingh GV, Miller ID, Sharma M, Welch CJ, Sharp L, Parkin DE, et al. The prognostic significance of micrometastases in node-negative squamous cell carcinoma of the vulva. Br J Cancer 2005;92:222e4. [62] Hakim AA, Terada KY. Sentinel node dissection in vulvar cancer. Curr Treat Options Oncol 2006;7:85e91. [63] Yuan SH, Xiong Y, Wei M, Yan XJ, Zhang HZ, Zeng YX, et al. Sentinel lymph node detection using methylene blue in patients with early stage cervical cancer. Gynecol Oncol 2007;106:147e52. [64] Seong SJ, Park H, Yang KM, Kim TJ, Lim KT, Shim JU, et al. Detection of sentinel lymph nodes in patients with early stage cervical cancer. J Korean Med Sci 2007;22:105e9. [65] Li B, Zhang WH, Liu L, Wu LY, Zhang R, Li N. Sentinel lymph node identification in patients with early stage cervical cancer
235
[66]
[67]
[68]
[69]
[70]
undergoing radical hysterectomy and pelvic lymphadenectomy. Chin Med J (Engl) 2004;117:867e70. Kamprath S, Possover M, Schneider A. Laparoscopic sentinel lymph node detection in patients with cervical cancer. Am J Obstet Gynecol 2000;182:1648. Kraft O, Sevcik L, Klat J, Koliba P, Curı´k R, Krı´ozva ´ H. Detection of sentinel lymph nodes in cervical cancer. A comparison of two protocols. Nucl Med Rev Cent East Eur 2006;9:65e8. Lee YS, Rhim CC, Lee HN, Lee KH, Park JS, Namkoong SE. HPV status in sentinel nodes might be a prognostic factor in cervical cancer. Gynecol Oncol 2007;105:351e7. Hauspy J, Beiner M, Harley I, Ehrlich L, Rasty G, Covens A. Sentinel lymph nodes in early stage cervical cancer. Gynecol Oncol 2007;105:285e90. Bats AS, Clement D, Larousserie F, Lefre `re-Belda MA, Faraggi M, Froissart M, et al. Sentinel lymph node biopsy improves staging in early cervical cancer. Gynecol Oncol 2007;105:189e93.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/suronc
REVIEW
Sentinel lymph node biopsy in gynaecological cancers: The importance of micrometastases in cervical cancer Emile Daraı¨ *, Roman Rouzier, Marcos Ballester, Emmanuel Barranger, Charles Coutant Department of Gynaecology and Obstetrics, Hoˆpital Tenon, Assistance Publique des Hoˆpitaux de Paris, CancerEst, Universite´ Pierre et Marie Curie, Paris 6, France
KEYWORDS Sentinel lymph node; Cervical cancer; Lymph node metastasis; Micrometastases; Prognosis; Serial sectioning; Immunohistochemistry; Molecular biology
Abstract Lymph node metastases is a recognized prognostic factor in women with cervical cancer. However, there is a need for consensual histological definition of micrometastases in this indication which could give rise to a classification system similar to that used in breast cancer. We thus conducted a MEDLINE and EMBASE database analysis to evaluate the concept of micrometastases in cervical cancer. Retrospective studies place the incidence of micrometastasis between 1.5 and 15% depending on the technique used to evaluate lymph node status. Sentinel lymph node biopsy with serial sectioning and immunohistochemical analysis appears to be the most accurate micrometastases detection technique. The value of RT-PCR in micrometastases detection remains to be clarified by further studies. From a clinical view point, few data are available to support the prognostic relevance of micrometastases. However, case control and longitudinal studies have underlined the risk of recurrence in women with micrometastases, raising the issue of a revision of adjuvant therapy indications in this specific population. ª 2008 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Analysis of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
* Corresponding author. Service de Gyne ´cologie-Obste ´trique, Ho ˆpital Tenon, 4 rue de la Chine, 75020 Paris, France. Tel.: þ33 1 56 01 73 18; fax: þ33 1 56 01 73 17. E-mail address: [email protected] (E. Daraı¨). 0960-7404/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2008.04.002
228
E. Daraı¨ et al. Concept of the sentinel lymph node procedure in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Definition of micrometastases in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Incidence and impact of micrometastases in cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Introduction Cervical cancer remains the third most frequent female malignancy worldwide despite a gradual decrease in incidence in industrialized countries following the introduction of screening programs [1]. Nearly 471 000 new cases are detected worldwide each year causing 233 000 deaths [1]. Human papillomavirus (HPV), and especially types 16 and 18, is an established cause [2,3]. Several prognostic factors have been identified in women with cervical cancer. Some of these factors can be directly assessed on the primary tumour: lesion size, depth of stromal invasion, presence of lymphatic space involvement, histological type, and invasion of surgical margins [4]. Lymph node status is also a major prognostic factor and a decision criterion for adjuvant therapy. Using routine histology, previous studies have demonstrated that pelvic lymph node metastases are detected in 0e4.8% and 0e17% of patients with stage IA and IB cervical cancer, respectively. Even in patients with stage IIA and IIB disease, lymph node involvement is observed in only 12e27% and 25e39%, respectively [5,6]. The sentinel lymph node (SLN) concept has been accepted as an alternative to lymphadenectomy in many malignancies, including melanoma [7] and, more recently, breast cancer [8,9]. In gynaecological malignancies, the SLN procedure is well established in vulvar cancer [10] but is still under evaluation for cervical cancer. Despite the lack of apparent lymph node involvement, some patients have recurrences and shorter survival [11,12]. Holmgren et al. suggested that histologically undetectable, ‘‘dormant’’ or ‘‘occult’’ metastases in the lymphatic system could explain some recurrences [13]. In contrast to several carcinomas as melanoma or breast cancer, the concept and the clinical significance of the so-called lymph node micrometastases in women with cervical cancer is rarely debated. The aims of the present literature review, therefore, were to define the concept of micrometastases in women with cervical cancer and to evaluate its potential impact on therapeutic management and prognosis.
Analysis of the literature To evaluate the concept and the prognostic significance of micrometastases in cervical cancer, we performed a comprehensive computer literature search to identify relevant articles on lymph node metastasis and micrometastases in women with cervical carcinoma. MEDLINE and EMBASE databases up to January 2008 were searched for the following terms: ‘‘cervix neoplasm, uterine cervical carcinoma, lymph node metastases, sentinel node, and micrometastases’’ as medical subject
headings (MeSH). The list of articles was supplemented by extensive crosschecking of the reference lists of the identified articles. A hundred and forty-four articles were initially selected including review articles, letters, comments, conference proceedings, unpublished data, case reports, and non-English language studies. Our second selection phase excluded 37 non-English language studies, 26 review articles and 17 letters or short comments leaving us with 64 research articles from 43 medical teams. We finally included studies meeting the following inclusion criteria: (1) a minimum sample size of 10 patients and, (2) assessment of the histopathology analysis of lymph node involvement. The exclusion criterion was an overlap in patient data (duplicate publication), in which case the more recent article with most patients and an adequate description of the study population was retained. Finally, 29 studies fulfilled all criteria (Table 1). From this review, it is important to note that only three studies included at least 100 patients.
Concept of the sentinel lymph node procedure in cervical cancer The sentinel lymph node (SLN) technique was introduced for patients with cervical cancer in 1999 by Echt [14]. The sentinel concept postulates that the SLN is the first node draining a defined anatomic region and that its histological evaluation is thus representative for all lymph nodes draining this region [11,15e25]. However, there is no consensus whether SLN corresponds to the drainage of an organ or a tumour. The uterine cervix is a sagittal organ with several uniand bilateral drainage routes. The exact and reproducible location of pelvic lymph nodes is difficult since no consensual classification has been established for lymph nodes draining the cervix and corpus of the uterus. Reiffenstuhl identified eight lymphatic areas: aortic, promontoric, common iliac, external iliac, superior gluteal, inferior gluteal, interiliac and sacral [26]. Plentl described six pathways: three are lateral groups draining into the interiliac, external iliac and gluteal areas, and two posterior common iliac and subaortic areas. In addition, there is one anterior group draining to interiliac area [27]. Benedetti-Panici defined seven aortic areas of drainage namely paracaval, precaval, retrocaval, intercavoaortic, preoartic, para-aortic, retroaortic areas and eight pelvic areas namely deep and superficial common iliac, external iliac, presacral, deep and superficial obturator, internal iliac and parametric areas [28]. The latter author suggested that early-stage cervical cancer spreads more frequently to the superficial obturator, external iliac and superficial common iliac lymph nodes, whereas advanced tumours more frequently involve the deep common iliac lymph nodes [28]. Levenback
Sentinel lymph node biopsy in gynaecological cancers Table 1
229
Results of the sentinel lymph node (SLN) biopsy in studies of cervical cancer according to the detection technique
Studies
Year
No. of patients
FIGO stage
No. of patients with SLN (SLN detection rate per patient) (%)
Bilaterality (%)
Blue dye alone O’Boyle [33] Malur [41] Plante [11] Di Stefano. [48] Rob [34] Yuan [63] Seong [64] Total
2000 2001 2003 2005 2005 2007 2007
20 9 41 50 100 81 89 390
IBeIIA IeIV IAeIIA IA2eIIA IA2eIB2 IB1eIIA IA2eIIB
12 5 34 45 80 67 51 294
(60) (55.5) (83) (90) (80) (82.7) (57.3) (75.4)
41.6 ni 51.2 60 62 78 ni
0 50 0 10 4.8 23 9
(0/3) (1/2) (0/e) (1/10) (1/21) (3/13) (1/11)
Radiocolloid alone Malur [41] Lantzsch [22] Chung [19] Li [65] Silva [37] Angioli [35] Kamprath [66] Lin [36] Wang [6] Total
2001 2001 2002 2004 2005 2005 2005 2005 2006
21 14 26 28 56 37 18 30 46 276
IeIV IB1 IeIIA IBeIIA IA2eIIA IB1 ni IA2eIIA Early
16 14 26 27 52 26 16 30 46 253
(76.2)
ni 38.5 19.2 70.4 37.5 30.8 ni ni ni
0 0 16.7 0 18 0 0 0 0
(0/0) (0/1) (1/6) (0/6) (3/17) (0/6) (0/1) (0/7) (0/11)
ni 91 72.4 ni 64.9 94.1 83.3 64 90.4 53.6 60 42.6 66 40.7 ni 71.8 76
0 (0/4) 33 (1/3) 0 (0/e) 0 (0/19) 0 (0/5) 8 (1/12) 0 (0/2) 0 (0/4) 0 (0/15) ni 0 (0/9) 0 (0/21) 13.6 (3/22) 11.8 (2/17) 9 (1/11) 33 (1/3) 0 (0/2)
Combined detection (blue dye and radiocolloid) Malur [41] 2001 20 Lambaudie [40] 2003 12 Plante [11] 2003 29 Dargent and Enria [20] 2003 70 Hubalewska [49] 2003 37 Pijpers [43] 2004 34 Niikura [42] 2004 20 Martinez-Palones [5] 2004 23 Rob [34] 2005 83 Marnitz [15] 2006 151 Frumovitz [46] 2006 50 Kraft [67] 2006 54 Wydra [45] 2006 100 Coutant [56] 2007 59 Lee. [68] 2007 57 Hauspy [69] 2007 39 Bats [70] 2007 25 Total
IeIV IA2eIB1 IAeIIA IA1eIIB IeIIA Early IB1eIIA IA2eIIA IA2eIB2 IA2eIVA IA2eIB1 IB1eIII IB1eIIA IAeII IBeIIA IA1eIIA IA2eIB1
863
18 11 27 63 37 33 20 25 80 111 48 50 84 59 57 38 22
(96.4) (92.8) (70) (89)
FN rate (%)
(91.7) (90) (91.7) (93) (90) (97)
(96.4) (73.5) (96) (92.6) (84)
(39) (88)
783 (90.7)
SLN, sentinel lymph node; No, number; ni, not investigated; FN, false negative.
pointed to a direct lymphatic drainage to the common iliac and para-aortic areas [23]. Finally, Marnitz proposed a new classification of lymph node drainage based on SLN procedure comprising 11 areas: para-aortic, common iliac bilateral, external iliac bilateral, internal iliac bilateral including presacral, interiliac bilateral and parametric bilateral [15]. However, recent studies [29,30] have completely modified the anatomic knowledge of parametrium putting both the anatomical drainage of the cervix and the surgical classification of radical hysterectomy into question Table 2. SLNs were initially detected with blue dye [14,24,31e 34], then with radiocolloid [22,35e38] or a combined
technique [5,11,17e21,23,39e45]. For radiocolloid and combined techniques, a preoperative lymphoscintigraphy is recommended to identify and to localize the SLN and detect aberrant anatomical lymphatic drainage. Frumovitz et al. have recently underlined a discrepancy between day-before lymphoscintigraphy and surgical mapping of SLNs, raising the issue of its usefulness and cost-effectiveness in routine practice [46]. Marnitz addressed the issue of whether detection of multiple SLNs in one patient indicates an overflow of the labelling substance to the second echelon lymph nodes or results from multiple independent lymphatic pathways [15,33,35]. In fact, the time between lymphoscintigraphy and surgery
230
Table 2
Rate of macrometastases and micrometastases in studies using sentinel lymph node (SLN) biopsy in cervical cancer
Studies
Year No. of Method of patients detection
FIGO stage No. of patients Method of with SLN (SLN histopathologic detection rate analysis of SLN per patient) (%)
No. of patients with Definition of No. of patients with macrometastases micrometastatic micrometastatic in SLN (%) SLN (%)
O’Boyle [33] Malur [41] Lantzsch [22] Chung [19] Lambaudie [40] Plante [11] Dargent and Enria [20] Hubalewska [49] Pijpers [43] Niikura [42] Martinez-Palones [5] Li [65] Silva [37] Rob [34] Angioli [35] Di Stefano [48] Lin [36] Kamprath [66] Marnitz [15] Frumovitz [46] Kraft [67] Wang [6] Wydra [45] Yuan [63] Coutant [56] Seong [64] Lee [68] Hauspy [69] Bats et al. [70]
2000 20 2001 50 2001 14 2002 26 2003 12 2003 70 2003 70 2003 37 2004 34 2004 20 2004 23 2004 28 2005 56 2005 183 2005 37 2005 50 2005 30 2005 18 2006 151 2006 50 2006 54 2006 46 2006 100 2007 81 2007 59 2007 89 2007 57 2007 39 2007 25
IBeIIA IeIV IB1 IeIIA IA2eIB1 IAeIIA IA1eIIB IeIIA early IB1eIIA IA2eIIA IBeIIA IA2eIIA IA2eIB2 IB1 IA2eIIA IA2eIIA
3 6 1 5 2 8 19 5 12 2 3 6 17 35 6 9 7 1 34 9 21 18 ni 17 15 11 11 2 3
B B þ R þ CT R R CT B þ CT CT CT CT CT CT R R B þ CT R B R R CT CT CT R B CT B CT CT CT
IA2eIVA IA2eIB1 IB1eIII early IB1eIIA IB1eIIA IAeII IA2eIIB IBeIIA IA1eIIA IA2eIB1
12 39 14 26 11 61 63 37 33 20 25 27 52 160 26 45 30 16 111 48 50 46 84 67 59 51 57 38 25
(60) (78)
(91.7) (87.1) (90) (97)
(96.4) (92.8) (87.4) (70) (90) (89) (73.5) (96) (92.6) (84) (82.7) (57.3) (39)
HES HES HES þ SS þ IHC HES HES þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ IHC HES þ IHC ni HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC HES þ SS þ IHC ni ni HES HES þ SS þ IHC HES þ IHC HES þ SS þ IHC þ CK19PCR ni HES þ SS þ IHC HES þ SS þ IHC þ HPV DNA HES HES þ HPV DNA detection HES þ SS þ IHC HES þ SS þ IHC
(25) (15.4) (7.1) (19) (18.2) (13.1) (30.2) (13.5) (36.3) (10) (13) (22.2) (32.7) (21.9) (23) (20) (22.3) (6.3) (30.6) (18.8) (42) (39)
(25.4) (21.6) (19.3) (5.2) (12)
No No No No No No No No No No No No No No No No No No No No No No No No Yesa No No No No
3 (100) ni 0 ni 0 3 (37.5) 9 (47.4) ni 4 (33) 0 0 ni 3 (17.6) ni 0 2 (22.2) ni ni ni ni ni 7 (38.9)b ni 4 (23.5) 3 (20) ni ni ni 1 (33)
E. Daraı¨ et al.
No, number; SLN, sentinel lymph node; CT, combined detection; R, radiocolloid alone; B, blue dye alone; ni, not investigated; H&E, standard H&E; SS, serial sectioning; IHC, immunohistochemistry. a Macrometastases as a single focus of metastatic disease per node measuring more than 2 mm, micrometastases as a focus of metastatic disease ranging from 0.2 mm to no more than 2 mm and submicrometastases as metastases measuring no more than 0.2 mm (including the presence of single non cohesive tumour cells). b More than 8 patients with CK19 RT PCR.
Sentinel lymph node biopsy in gynaecological cancers is probably the most determinant factor: the longer one waits before surgical mapping, the more radiocolloid migrates and contributes to detect second- or third-tier lymph nodes [43]. Numerous studies have evaluated the feasibility, sensitivity and detection rate of SLN techniques and specifically the false-negative SLN rate [11,14,17e20,22,23,32,34e 38,40,41,44]. However, analysis is difficult due to differences in the volume and quantity of labelling substance, the site of injection (pericervical, peritumoural or intratumoural), the number of injection sites, the volume of the tumour [47], and the interval between injection and detection from one study to another [20,31,33e35,37e 40,42,45]. In our literature review, the SLN detection rates for blue dye alone, radiocolloid alone, and combined technique were: 75.4, 91.7, and 90.7%, respectively (Table 1). These results are partly in keeping with those of Di Stefano et al. [48]. In their study, the detection rate by side for blue dye alone, radiocolloid alone and combined technique ranged from 7.7 to 89.9%, 45.9 to 82.1% and 59.6 to 97.1%, respectively. Combining technetium and blue dye appeared more effective in terms of SLN detection per patient than blue dye alone or technetium alone. In the literature, bilateral distribution of SLN is reported in 0 to 94.9% of patients depending on the SLN technique [15,24,34,43,49]. The occurrence of unilateral or bilateral SLN can be related to anatomical variation in lymphatic drainage, tumour size, technique of injection and the number of injection sites, raising the issue of the necessity of performing systematic lymphadenectomy on the pelvic side if no SLNs are detected [11]. The false-negative rate of the SLN biopsy in our literature review ranges from 0 to 50% with a negative predictive value from 75 to 100% [48]. As for the SLN procedure, no consensus exists on an ‘‘acceptable’’ falsenegative rate. In accordance with other malignancies for which SLN biopsy is recognised to be an alternative to systematic lymphadenectomy, a false-negative rate of 5% seems acceptable [16].
Definition of micrometastases in cervical cancer Overall, there is an absence of universal agreement on the definition of lymph node metastases in cervical cancer. In accordance with the Philadelphia Consensus Conference on sentinel nodes in breast cancer [9], we propose that the following definitions be applied: macrometastases as a single focus of metastatic disease per node measuring more than 2 mm, micrometastases as a focus of metastatic disease ranging from 0.2 mm to no more than 2 mm and, in accordance with Marchiole, submicrometastases as metastases measuring no more than 0.2 mm (including the presence of single non-cohesive tumour cell) [24,50]. This lack of consensual definition of micrometastases in cervical cancer could explain why its concept is controversial. Indeed, the presence of micrometastases differs according to the technique used for their identification: haematoxylin and eosin (H&E) staining on a few slides, serial sectioning H&E and immunohistochemistry (IHC) with an anti-cytokeratin antibody cocktail, reverse-transcriptase
231 PCR (RT-PCR) detection of cytokeratin 19 (CK 19) mRNA, or HPV-16 and -18 DNA detection by PCR. Using routine histopathological examination, it has been estimated that the chances of identifying a tumour cell cluster of less than three cell diameters was only 1% [51]. In breast cancer, Cote et al. noted that serial sectioning alone was able to detect 7% of ‘‘occult’’ metastases in negative lymph nodes and that a 20% detection was reached when using cytokeratine immunochemistry [52]. In cervical cancer, using both serial sectioning and IHC on 976 pelvic lymph nodes from 49 patients, Juretzka et al. identified four patients with lymph node micrometastases not initially identified on routine H&E examination [4]. However, this combined technique on all nodes is time consuming and expensive thus limiting its routine use and justifying the concept of the SLN biopsy. As previously mentioned, SLN is defined as the first node in the lymphatic system draining a tumour. This concept, histologically validated by serial sectioning and IHC, suggests that when the SLN is not metastatic then all other nodes should also be disease-free [16]. However, Marchiole ´ et al. noted that even when serial sectioning is used, very small clusters of tumour cells can escape IHC staining raising the question of their prognostic significance [24,50]. Since the first report by Smith, although several molecular markers for micrometastases and various PCR protocols have been described, none have been introduced in standard clinical practice [53e55]. Using RT-PCR for CK 19, Van Trappen noted that 44% of histologically uninvolved lymph nodes in 32 patients exhibited CK 19 transcription [55]. Sixteen of them had positive RT-PCR lymph nodes. Ha ¨fner found that HPV 16 E6 mRNA was more specific and more sensitive for detecting tumour cells in SLNs than CK19 mRNA [51]. Coutant reported that HPV DNA was detected in 10 (50%) of 20 positive sentinel node (seven of 15 patients) and in five (5.6%) of 90 negative sentinel node (five of 44 patients) (p < 0.0001). Moreover, in this study, no relation was found between clinical or histological prognostic parameters and the presence of HPV DNA in the SLN or the primary cervical tumour [56]. The frequency of SLN HPV positivity does not differ according to the existence of macrometastases, micrometastases, or isolated tumour cells [56]. Van Trappen underlined that specific tumour DNA found in histologically normal lymph nodes may originate from dead cell material or macrophages and that viral DNA can be found in various cell types thus limiting its usefulness as a molecular marker for micrometastases [55]. Moreover, Marchiole ´ noted that even RTPCR had a better sensitivity than IHC, though this is counterbalanced by a lack of specificity [24]. Indeed, it is not possible to differentiate macrometastases from benign glandular inclusion using only RT-PCR. Moreover, even if a correlation has been established between the number of copy cells and the size of metastases, RT-PCR lacks accuracy in differentiating true macrometastases from multiple micrometastases or submicrometastases. Finally, for clinical practice, the combination of the SLN procedure with serial sectioning and IHC seems to be not only the easiest technique to apply in routine practice but also the most efficient and cost-effective way of detecting micrometastases. Van der Velde-Zimmermann suggested another possible strategy for analysing SLNs by use of
232 RT-PCR as an initial diagnostic tool to preselect nodes for serial sectioning and IHC [57].
Incidence and impact of micrometastases in cervical cancer As mentioned in the introduction, the aim of this review is not to discuss the prognostic relevance of lymph node metastases in cervical cancer as this has been extensively studied and proven [58]. In 2001, Van Trappen assessed the value of mRNA RTPCR to detect micrometastases in a series of 32 patients with stage IA2 to IB2 cervical cancer [55]. Recurrence developed in one of the three patients with metastases detected by both histology and RT-PCR; in two of the 13 patients with negative histology but positive RT-PCR; and in none of the 16 patients with both negative histology and RT-PCR. [55]. This gave rise to two concepts: first the clinical significance of inframorphological metastases corresponding to micrometastases; and second, the prognostic significance of a complete lymphadenectomy. In 2003, Dargent and Enria evoked the concept of micrometastases without clear histological definition in cervical cancer. They reported that the use of serial sectioning and IHC gave a possible tenfold increase in the detection rate of micrometastases [20]. Moreover, as micrometastases were found when the technique was retrospectively applied to SLNs from women with recurrence, the relevance of both serial sectioning and IHC and its prognostic value were validated. The concept of ultramicroscopic staging was born. However, in 2003, Plante reported the results of SLN biopsy in 70 women with cervical cancer [11]. Serial sectioning (three sections per node or every 40 mm perpendicular to the long axis of the node) and IHC were applied to negative SLNs to detect micrometastases, though no clear histological definition of micrometastases was given. In this series, ultrastaging detected micrometastases which had been missed by routine histology in one patient only. Moreover, it was underlined that this patient had several other histological risk factors for which adjuvant radiotherapy was recommended regardless of the presence of the micrometastases. The clinical relevance of histological ultrastaging was thus put into question. In 2004, Lentz evaluated the incidence of micrometastases in 132 patients with cervical cancer [59]. IHC analysis was used according to recommendations by the International Breast Cancer Study Group [52] and defined as occult metastases lymph nodes exhibiting single or small groups of malignant cells (2e3 cells) [59]. Micrometastases were detected in 1% of the 3 106 nodes examined corresponding to 15% of the patients. Using the CochraneArmitage trend test categorizing the number of lymph nodes resected into four groups (group 1 , 1e13 ; group 2 , 14e20 ; group 3 , 21e30; and group 4 , >30 nodes), the odds ratios to have micrometastases were 0.05 (CI 0.003e0.94), 0.12 (CI 0.01e1.07) and 1.78 (CI 0.59e5.34) compared with the group with more than 30 nodes. These results reinforced the concept of the prognostic significance of complete lymphadenectomy by removal of micrometastases [59]. The same year, Barranger histologically validated the concept of SLN biopsy
E. Daraı¨ et al. in cervical cancer and reported that out of eight positive SLNs (18.2%) from five patients (27.8%) found to be metastatic at the final histological assessment, two were macrometastatic, three micrometastatic and three contained isolated tumour cells (submicrometastases) [16]. In 2007, Coutant from the same team, confirmed the high incidence of micrometastases in cervical cancer but failed to demonstrate the relation between the presence of micrometastases or submicrometastases and the development of recurrence. This was probably due to the small sample size and the low incidence of recurrence [56]. Although in 2005 Silva et al. did not clearly define micrometastases histologically, using H&E, serial sectioning and IHC they found that 5.1% of micrometastases had not been detected by standard histology [37]. In 2006, Wang confirmed the results of previous studies on the value of RT-PCR assay for CK19 to detect micrometastases [6]. Although no definition of micrometastases was given, the representative examples provided by the authors in their paper are in accordance with the definition that we put forward. Seventeen of the 35 patients negative for metastases by conventional histology had micrometastases in SLNs: five were positive by both IHC and RT-PCR, 10 by RT-PCR alone, and two by IHC alone. Numerous papers focus on the potential relevance of SLN biopsy to avoid systematic lymphadenectomy in order to decrease the incidence of postoperative complications. This goal is difficult to reach because of the relative low accuracy of both frozen section and imprint cytology to evaluate intraoperative lymph node status. Moreover, in women with a unilateral SLN, systematic lymphadenectomy on the pelvic side without detectable SLN remains questionable. In fact, the objective of SLN biopsy is not to identify macroscopically involved nodes that are easily detected but rather to identify those involved by subclinical metastases. RT-PCR, due its high sensitivity and in spite of its lower specificity, could possibly be a useful first diagnostic step to select women for lymphadenectomy and subsequently for serial sectioning and IHC on SLN [57]. It is clear that the data available in the literature are insufficient to evaluate the prognostic impact of the presence of micrometastases in women with cervical cancer. From the clinical view point, it is impossible to conclude whether the detection of micrometastases should be included in therapeutic protocols. The potential matching of the incidence of micrometastases observed in previous studies and the well known incidence of recurrence in apparent lymph node negative patients might argue in favour. But this assertion requires validation that appears difficult to confirm due to the low incidence of micrometastases and the absence of reliable data on the recurrence rate in this specific population. Indirectly, a degree of validation could be obtained by analysing similar gynaecological malignancies. Indeed, accumulated data have demonstrated the relation between micrometastases and the risk of recurrence in other gynaecological tumours [60,61]. Narayansingh reported the risk of recurrence was almost 20-fold higher in vulvar cancer patients with micrometastases compared to those without [61]. Therefore, some authors have concluded that the presence of micrometastases in SLNs from patients with vulvar cancer should be an indication for adjuvant therapy
Sentinel lymph node biopsy in gynaecological cancers [62]. In cervical cancer, Pijpers et al. recommended adjuvant therapy for their three patients with IHC-detected micrometastases and observed no recurrence [43]. In 2005, Marchiole ` et al. reassessed the prognostic value of micrometastases in a retrospective caseecontrol study including 52 patients (26 with and 26 without recurrence) [50]. Using a clear definition of micrometastases, they demonstrated a relation between lympho-vascular space involvement and the occurrence of micrometastases in SLNs. Moreover, they found that the relative risk of recurrence in the presence of true micrometastases (focus of metastatic disease ranging from 0.2 mm to no more than 2 mm) was 2.30 (CI 1.65e3.20, p < 0.01) and 2.22 (CI 1.30e3.80, p Z 0.09) in the presence of submicrometastases (focus of metastatic disease no more than 0.2 mm including the presence of single non-cohesive tumour cells). Using bivariate analysis, micrometastases were the only independent risk factor of recurrence [50]. These major data raise the issue of the relevance of adjuvant therapy in women with micrometastases in cervical cancer. In conclusion, there is a lack of data on the prognostic value of micrometastases in cervical cancer. However, accumulated data argue in favour of its prognostic relevance raising the issue of modifying indications for adjuvant therapy. This review is a plea for the use of consensual definition of micrometastases and we reiterate our recommendation of a histological classification using the same criteria as those applied in breast cancer. The value of RTPCR to detect micrometastases in routine practice requires further studies.
233
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
All authors disclose no financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
[18]
References [19] [1] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics. CA Cancer J Clin 2001;2001(51):15e36. [2] Bosch FX, de Sanjose S. Chapter 1: Human papillomavirus and cervical cancer e burden and assessment of causality. J Natl Cancer Inst Monogr 2003:3e13. [3] Fuchs PG, Girardi F, Pfister H. Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases? Int J Cancer 1989;43:41e4. [4] Juretzka MM, Jensen KC, Longacre TA, Teng NM, Husain A. Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis. Gynecol Oncol 2004;93:107e11. [5] Martinez-Palones JM, Gil-Moreno A, Perez-Benavente MA, Roca I, Xercavins J. Intraoperative sentinel node identification in early stage cervical cancer using a combination of radiolabeled albumin injection and isosulfan blue dye injection. Gynecol Oncol 2004;92:845e50. [6] Wang HY, Sun JM, Lu HF, Shi DR, Ou ZL, Ren YL, et al. Micrometastases detected by cytokeratin 19 expression in sentinel lymph nodes of patients with early-stage cervical cancer. Int J Gynecol Cancer 2006;16:643e8. [7] Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative
[20]
[21]
[22]
[23]
[24]
lymphatic mapping and sentinel lymphadenectomy for earlystage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999;230:453e63 [discussion 463e55]. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391e8 [discussion 398e401]. Schwartz GF, Giuliano AE, Veronesi U. Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast April 19 to 22, 2001. Philadelphia, Pennsylvania. Hum Pathol 2002;33:579e89. de Hullu JA, Doting E, Piers DA, Hollema H, Aalders JG, Koops HS, et al. Sentinel lymph node identification with technetium-99m-labeled nanocolloid in squamous cell cancer of the vulva. J Nucl Med 1998;39:1381e5. Plante M, Renaud MC, Tetu B, Harel F, Roy M. Laparoscopic sentinel node mapping in early-stage cervical cancer. Gynecol Oncol 2003;91:494e503. Stehman FB, Bundy BN, DiSaia PJ, Keys HM, Larson JE, Fowler WC. Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 1991;67:2776e85. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149e53. Echt ML, Finan MA, Hoffman MS, Kline RC, Roberts WS, Fiorica JV. Detection of sentinel lymph nodes with lymphazurin in cervical, uterine, and vulvar malignancies. South Med J 1999;92:204e8. Marnitz S, Kohler C, Bongardt S, Braig U, Hertel H, Schneider A, et al. Topographic distribution of sentinel lymph nodes in patients with cervical cancer. Gynecol Oncol 2006; 103:35e44. Barranger E, Cortez A, Commo F, Marpeau O, Uzan S, Darai E, et al. Histopathological validation of the sentinel node concept in cervical cancer. Ann Oncol 2004;15:870e4. Barranger E, Cortez A, Uzan S, Marpeau O, Uzan S, Darai E. Value of intraoperative imprint cytology of sentinel nodes in patients with cervical cancer. Gynecol Oncol 2004;94:175e80. Buist MR, Pijpers RJ, van Lingen A, van Diest PJ, Dijkstra J, Kenemans P, et al. Laparoscopic detection of sentinel lymph nodes followed by lymph node dissection in patients with early stage cervical cancer. Gynecol Oncol 2003;90:290e6. Chung YA, Kim SH, Sohn HS, Chung SK, Rhim CC, Namkoong SE. Usefulness of lymphoscintigraphy and intraoperative gamma probe detection in the identification of sentinel nodes in cervical cancer. Eur J Nucl Med Mol Imaging 2003;30:1014e7. Dargent D, Enria R. Laparoscopic assessment of the sentinel lymph nodes in early cervical cancer. Technique e preliminary results and future developments. Crit Rev Oncol Hematol 2003;48:305e10. Gil-Moreno A, Diaz-Feijoo B, Roca I, Puig O, Pe ´rez-Benavente MA, Aguilar I, et al. Total laparoscopic radical hysterectomy with intraoperative sentinel node identification in patients with early invasive cervical cancer. Gynecol Oncol 2005;96:187e93. Lantzsch T, Wolters M, Grimm J, Mende T, Buchmann J, Sliutz G, et al. Sentinel node procedure in Ib cervical cancer: a preliminary series. Br J Cancer 2001;85:791e4. Levenback C, Coleman RL, Burke TW, Lin WM, Erdman W, Deavers M, et al. Lymphatic mapping and sentinel node identification in patients with cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy. J Clin Oncol 2002;20:688e93. Marchiole P, Buenerd A, Scoazec JY, Dargent D, Mathevet P. Sentinel lymph node biopsy is not accurate in predicting lymph node status for patients with cervical carcinoma. Cancer 2004;100:2154e9.
234 [25] Torne A, Puig-Tintore LM. The use of sentinel lymph nodes in gynaecological malignancies. Curr Opin Obstet Gynecol 2004; 16:57e64. [26] Reiffenstuhl G. [Contribution on the nomenclature of the pelvic lymph nodes]. Wien Klin Wochenschr 1956;68:247e8. [27] Plentl AA, Friedman EA. Lymphatic system of the female genitalia. The morphologic basis of oncologic diagnosis and therapy. Major Probl Obstet Gynecol 1971;2:1e223. [28] Benedetti-Panici P, Maneschi F, Scambia G, Greggi S, Cutillo G, D’Andrea G, et al. Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. Gynecol Oncol 1996;62:19e24. [29] Hockel M. Do we need a new classification for radical hysterectomy? Insights in surgical anatomy and local tumor spread from human embryology. Gynecol Oncol 2007;107:S106e12. [30] Hockel M, Dornhofer N. Pelvic exenteration for gynaecological tumours: achievements and unanswered questions. Lancet Oncol 2006;7:837e47. [31] Dargent D, Martin X, Mathevet P. Laparoscopic assessment of the sentinel lymph node in early stage cervical cancer. Gynecol Oncol 2000;79:411e5. [32] Medl M, Peters-Engl C, Schutz P, Vesely M, Sevelda P. First report of lymphatic mapping with isosulfan blue dye and sentinel node biopsy in cervical cancer. Anticancer Res 2000;20:1133e4. [33] O’Boyle JD, Coleman RL, Bernstein SG, Lifshitz S, Muller CY, Miller DS. Intraoperative lymphatic mapping in cervix cancer patients undergoing radical hysterectomy: a pilot study. Gynecol Oncol 2000;79:238e43. [34] Rob L, Strnad P, Robova H, Charvat M, Pluta M, Schlegerova D, et al. Study of lymphatic mapping and sentinel node identification in early stage cervical cancer. Gynecol Oncol 2005;98: 281e8. [35] Angioli R, Palaia I, Cipriani C, Muzii L, Calcagno M, Gullotta G, et al. Role of sentinel lymph node biopsy procedure in cervical cancer: a critical point of view. Gynecol Oncol 2005;96:504e9. [36] Lin YS, Tzeng CC, Huang KF, Kang CY, Chia CC, Hsieh JF. Sentinel node detection with radiocolloid lymphatic mapping in early invasive cervical cancer. Int J Gynecol Cancer 2005;15: 273e7. [37] Silva LB, Silva-Filho AL, Traiman P, Triginelli SA, de Lima CF, Siqueira CF, et al. Sentinel node detection in cervical cancer with (99m)Tc-phytate. Gynecol Oncol 2005;97:588e95. [38] van Dam PA, Hauspy J, Vanderheyden T, Sonnemans H, Spaepen A, Eggenstein G, et al. Intraoperative sentinel node identification with Technetium-99m-labeled nanocolloid in patients with cancer of the uterine cervix: a feasibility study. Int J Gynecol Cancer 2003;13:182e6. [39] Barranger E, Grahek D, Cortez A, Talbot JN, Uzan S, Darai E. Laparoscopic sentinel lymph node procedure using a combination of patent blue and radioisotope in women with cervical carcinoma. Cancer 2003;97:3003e9. [40] Lambaudie E, Collinet P, Narducci F, Sonoda Y, Papageorgiou T, Carpentier P, et al. Laparoscopic identification of sentinel lymph nodes in early stage cervical cancer: prospective study using a combination of patent blue dye injection and technetium radiocolloid injection. Gynecol Oncol 2003;89:84e7. [41] Malur S, Krause N, Kohler C, Schneider A. Sentinel lymph node detection in patients with cervical cancer. Gynecol Oncol 2001;80:254e7. [42] Niikura H, Okamura C, Akahira J, Takano T, Ito K, Okamura K, et al. Sentinel lymph node detection in early cervical cancer with combination 99mTc phytate and patent blue. Gynecol Oncol 2004;94:528e32. [43] Pijpers R, Buist MR, van Lingen A, Dijkstra J, van Diest PJ, Teule GJ, et al. The sentinel node in cervical cancer:
E. Daraı¨ et al.
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
scintigraphy and laparoscopic gamma probe-guided biopsy. Eur J Nucl Med Mol Imaging 2004;31:1479e86. Verheijen RH, Pijpers R, van Diest PJ, Burger CW, Buist MR, Kenemans P. Sentinel node detection in cervical cancer. Obstet Gynecol 2000;96:135e8. Wydra D, Lass P, Bandurski T. Usefulness of lymphoscintigraphy and intraoperative gamma probe detection in the identification of sentinel nodes in cervical cancer. Eur J Nucl Med Mol Imaging 2004;31:293. author reply 294. Frumovitz M, Coleman RL, Gayed IW, Ramirez PT, Wolf JK, Gershenson DM, et al. Usefulness of preoperative lymphoscintigraphy in patients who undergo radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Am J Obstet Gynecol 2006;194:1186e93 [discussion 1193e5]. Barranger E, Coutant C, Cortez A, Uzan S, Darai E. Sentinel node biopsy is reliable in early-stage cervical cancer but not in locally advanced disease. Ann Oncol 2005;16:1237e42. Di Stefano AB, Acquaviva G, Garozzo G, Barbic M, Cvjeticanin B, Meglic L, et al. Lymph node mapping and sentinel node detection in patients with cervical carcinoma: a 2-year experience. Gynecol Oncol 2005;99:671e9. Hubalewska A, Sowa-Staszczak A, Huszno B, Markocka A, Pityn ´ski K, Basta A, et al. Use of Tc99m-nanocolloid for sentinel nodes identification in cervical cancer. Nucl Med Rev Cent East Eur 2003;6:127e30. Marchiole P, Buenerd A, Benchaib M, Nezhat K, Dargent D, Mathevet P. Clinical significance of lympho vascular space involvement and lymph node micrometastases in early-stage cervical cancer: a retrospective case-control surgicopathological study. Gynecol Oncol 2005;97:727e32. Hafner N, Gajda M, Altgassen C, Hertel H, Greinke C, Hillemanns P, et al. HPV16-E6 mRNA is superior to cytokeratin 19 mRNA as a molecular marker for the detection of disseminated tumor cells in sentinel lymph nodes of patients with cervical cancer by quantitative reverse-transcription PCR. Int J Cancer 2007;120:1842e6. Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, et al. Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group. Lancet 1999;354:896e900. Raj GV, Moreno JG, Gomella LG. Utilization of polymerase chain reaction technology in the detection of solid tumors. Cancer 1998;82:1419e42. Smith B, Selby P, Southgate J, Pittman K, Bradley C, Blair GE. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet 1991;338:1227e9. Van Trappen PO, Gyselman VG, Lowe DG, Ryan A, Oram DH, Bosze P, et al. Molecular quantification and mapping of lymph-node micrometastases in cervical cancer. Lancet 2001;357:15e20. Coutant C, Barranger E, Cortez A, Dabit D, Uzan S, Bernaudin JF, et al. Frequency and prognostic significance of HPV DNA in sentinel lymph nodes of patients with cervical cancer. Ann Oncol 2007;18:1513e7. van der Velde-Zimmermann D, Schipper ME, de Weger RA, Hennipman A, Borel Rinkes IH. Sentinel node biopsies in melanoma patients: a protocol for accurate, efficient, and cost-effective analysis by preselection for immunohistochemistry on the basis of Tyr-PCR. Ann Surg Oncol 2000;7:51e4. Sartori E, Tisi G, Chiudinelli F, La Face B, Franzini R, Pecorelli S. Early stage cervical cancer: adjuvant treatment in negative lymph node cases. Gynecol Oncol 2007;107:S170e4. Lentz SE, Muderspach LI, Felix JC, Ye W, Groshen S, Amezcua CA. Identification of micrometastases in histologically negative lymph nodes of early-stage cervical cancer patients. Obstet Gynecol 2004;103:1204e10.
Sentinel lymph node biopsy in gynaecological cancers [60] Knopp S, Holm R, Trope C, Nesland JM. Occult lymph node metastases in early stage vulvar carcinoma patients. Gynecol Oncol 2005;99:383e7. [61] Narayansingh GV, Miller ID, Sharma M, Welch CJ, Sharp L, Parkin DE, et al. The prognostic significance of micrometastases in node-negative squamous cell carcinoma of the vulva. Br J Cancer 2005;92:222e4. [62] Hakim AA, Terada KY. Sentinel node dissection in vulvar cancer. Curr Treat Options Oncol 2006;7:85e91. [63] Yuan SH, Xiong Y, Wei M, Yan XJ, Zhang HZ, Zeng YX, et al. Sentinel lymph node detection using methylene blue in patients with early stage cervical cancer. Gynecol Oncol 2007;106:147e52. [64] Seong SJ, Park H, Yang KM, Kim TJ, Lim KT, Shim JU, et al. Detection of sentinel lymph nodes in patients with early stage cervical cancer. J Korean Med Sci 2007;22:105e9. [65] Li B, Zhang WH, Liu L, Wu LY, Zhang R, Li N. Sentinel lymph node identification in patients with early stage cervical cancer
235
[66]
[67]
[68]
[69]
[70]
undergoing radical hysterectomy and pelvic lymphadenectomy. Chin Med J (Engl) 2004;117:867e70. Kamprath S, Possover M, Schneider A. Laparoscopic sentinel lymph node detection in patients with cervical cancer. Am J Obstet Gynecol 2000;182:1648. Kraft O, Sevcik L, Klat J, Koliba P, Curı´k R, Krı´ozva ´ H. Detection of sentinel lymph nodes in cervical cancer. A comparison of two protocols. Nucl Med Rev Cent East Eur 2006;9:65e8. Lee YS, Rhim CC, Lee HN, Lee KH, Park JS, Namkoong SE. HPV status in sentinel nodes might be a prognostic factor in cervical cancer. Gynecol Oncol 2007;105:351e7. Hauspy J, Beiner M, Harley I, Ehrlich L, Rasty G, Covens A. Sentinel lymph nodes in early stage cervical cancer. Gynecol Oncol 2007;105:285e90. Bats AS, Clement D, Larousserie F, Lefre `re-Belda MA, Faraggi M, Froissart M, et al. Sentinel lymph node biopsy improves staging in early cervical cancer. Gynecol Oncol 2007;105:189e93.