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Accuracy of frozen section examination of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer
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Gynecologic Oncology 90 (2003) 605– 609
www.elsevier.com/locate/ygyno
Accuracy of frozen section examination of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer Heinz S. Scholz,a,* Sigurd F. Lax,b Christoph Benedicic,a Karl Tamussino,a and Raimund Wintera a
Department of Obstetrics and Gynecology, University of Graz, Graz A-8036, Austria b Department of Pathology, University of Graz, Graz A-8036, Austria Received 18 December 2002
Abstract Objective. We evaluated the accuracy of intraoperative frozen section histology of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer. Methods. A total of 96 patients with cervical cancer FIGO stage IB1 to IIB had surgery including systematic pelvic or pelvic and paraaortic lymphadenectomy and intraoperative frozen section examination of pelvic lymph nodes at our department between January 1997 and October 2001. The results of frozen section were compared with those of final histology. Results. A total of 1044 pelvic lymph nodes underwent intraoperative frozen section examination and node metastases were found in 29 patients (30%). Final histopathology yielded a total of 5042 lymph nodes and identified an additional seven patients with node metastases for a false negative rate of 19%. The specificity and the positive predictive value of frozen section examination were 100%; the negative predictive value was 90% (60/67). Conclusion. The diagnostic accuracy of frozen section analysis of pelvic lymph nodes should be considered when intraoperative decisions are based on its results. © 2003 Elsevier Inc. All rights reserved. Keywords: Frozen section; Pelvic lymph nodes; Cervical cancer; Cervical carcinoma
Introduction The status of the lymph nodes is one of the most important prognostic factors in patients with cervical cancer. Pelvic lymph node involvement occurs with 9% to 30% of FIGO stage IB, 7% to 50% of FIGO stage IIA, and 16% to 57% of FIGO stage IIB tumors [1]. Accordingly, systematic pelvic lymph node dissection is an established component of the surgical treatment of cervical cancer. Because paraaortic lymph node involvement is rare in patients with negative pelvic nodes, frozen section histology of the pelvic nodes is frequently used to identify patients in whom
* Corresponding author. Department of Obstetrics and Gynecology, University of Graz, Auenbruggerplatz 14, A-8036 Graz, Austria. Fax: ⫹43-316-385-3061. E-mail address: [email protected] (H.S. Scholz). 0090-8258/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0090-8258(03)00398-6
paraaortic dissection can be omitted. In the present study we evaluated the accuracy of intraoperative frozen section histology of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer. Materials and methods A total of 96 patients with cervical cancer FIGO stage IB1 to IIB (mean age, 44.6 years; range, 22– 69) had surgery including systematic pelvic or pelvic and paraaortic lymphadenectomy and intraoperative frozen section examination of pelvic lymph nodes at our department between January 1997 and October 2001. Forty-nine women had FIGO stage IB1, 12 had IB2, 12 had IIA, and 23 had IIB tumors. Ninety-four patients underwent radical abdominal hysterectomy, one total abdominal hysterectomy, and one conization. All patients underwent systematic pelvic lymphade-
606
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
Table 1 Number of pelvic lymph nodes examined at frozen section and at final histopathology in 96 patients with cervical cancer FIGO stages IB1 to IIB (T1b1 to T2b) Lymph node region
Right External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral Subaortal Left External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral
No. of patients
Frozen section
Final histopathology
Nodes per patient (Mean (range))
Total no. of lymph nodes examined
Nodes per patient (Mean (range))
Total no. of lymph nodes examined
80 60 33 77 12 39 48 37
1.8 (1–5) 1.5 (1–3) 1.2 (1–3) 1.5 (1–5) 1.3 (1–2) 1.5 (1–4) 1.5 (1–3) 1.4 (1–3)
146 87 39 117 16 57 70 51
5.7 (0–16) 3.8 (1–11) 2.7 (0–10) 5.6 (1–16) 1.5 (0–7) 2.7 (0–15) 3.0 (0–10) 3.6 (0–16)
550 363 260 540 139 265 285 348
82 45 20 63 11 26 42
1.9 (1–5) 1.4 (1–5) 1.4 (1–3) 1.4 (1–4) 1.2 (1–2) 1.4 (1–3) 1.7 (1–4)
157 64 27 91 13 37 72
6.4 (2–16) 3.4 (0–11) 2.0 (0–8) 4.9 (1–13) 1.3 (0–6) 2.7 (0–13) 3.2 (0–13)
616 327 189 474 122 255 310
nectomy and 20 patients underwent additional paraaortic lymphadenectomy. Pelvic lymphadenectomy aimed to remove all lymph nodes from the femoral ring to the bifurcation of the aorta. The spaces between and behind the vessels were cleared, as was the obturator fossa to the pelvic floor and the subaortic and internal iliac regions [2]. Eighty-one patients had squamous cell carcinoma, six had adenosquamous carcinoma, eight had adenocarcinoma, and one had small cell carcinoma. All tissue removed from the particular pelvic lymph node regions underwent intraoperative frozen section examination. The examining pathologists palpated and dissected the adipose tissue for lymph nodes. Lymph nodes thicker than 5 mm were bisected and lymph nodes thicker than 1 cm were cut into several pieces and the cut-surfaces were inspected. Lymph nodes for frozen section were selected according to consistency, size, and appearance of the cutsurface. Two to four frozen sections from each lymph node were cut at a distance of about 20 –30 m and stained with hematoxylin and eosin (H&E). The remaining tissue from the frozen section as well as the lymph nodes that did not undergo frozen section were fixed in 4% buffered formalin overnight. For final histology, all lymph nodes and the perinodal adipose tissue were processed and embedded in paraffin, and depending on the size of the lymph nodes, 2– 4 serial sections per block were cut and stained with H&E.
tastases were found in 29 patients (30%), with a mean of 1.7 positive lymph nodes (range 1– 8) per patient. Frozen section analysis showed metastatic disease in one lymph node region in 17 patients, in two regions in eight patients, in three regions in three patients, and in eight regions in one patient. Final histopathologic examination yielded a total of 5042 lymph nodes, with a mean of 52.5 lymph nodes (range 21–109) per patient (Table 2). Lymph node metastases were found in 36 patients (38%) with a mean of 2.4 positive nodes (range 1–13) per patient. Frozen section analysis showed metastatic disease in one node region in 13 patients, in two regions in 14 patients, in three regions in three patients, in four regions in two patients, in five regions in three patients, and in 13 regions in one patient. Seven patients were negative for lymph node metastases at frozen section examination but showed metastases during final histopathology (Table 3). In five of seven cases, the correct lymph node region was selected for frozen section examination but three of five metastases were 2 mm or less in largest diameter. In two cases the lymph node region with the metastasis was not examined intraoperatively. There was no false positive case of lymph node metastasis during frozen section. The sensitivity, specificity, and positive and negative predictive values of frozen section as a diagnostic test for predicting the final node stations are shown in Table 4.
Results A total of 1044 pelvic lymph nodes underwent intraoperative frozen section examination (Table 1). A mean of 10.9 lymph nodes (range 1–24) and 7.0 lymph node regions (range 1–13) were examined per patient. Lymph node me-
Discussion In our series, seven of 36 patients with cervical cancer FIGO stage IB1 to IIB had false negative results of frozen
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
607
Table 2 Number of pelvic lymph node metastases and maximum diameter of metastases as detected by intraoperative frozen section and by final histopathology in 96 patients with cervical cancer FIGO stages IB1 to IIB (T1b1 to T2b) Lymph node region
Frozen section examination Patients with positive nodes (%)
Right External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral Subaortal Left External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral
Final histopathology
No. of pelvic node metastases (Mean (range))
Maximum diameter of pelvic node metastases, mm (Mean (range))
Patients with positive nodes (%)
No. of pelvic node metastases (Mean (range))
8 (8) 2 (2) 1 (1) 9 (9)
1.1 (1–2) 1.5 (1–2) 3 1.2 (1–2)
8 (1–30) 6.5 (5–8) 5 12.4 (5–30)
13 (14) 3 (3) 2 (2) 13 (14)
1.5 (1–4) 2 (1–3) 4.5 (1–8) 1.8 (1–4)
6.9 (1–30) 5.7 (4–8) 3 (1–5) 9.4 (0.5–30)
1 (1)
2
2 (2)
1.5 (1–2)
3.5 (3–4)
1 (1) 3 (3) 1 (1)
2 1 (1–1) 1
14 7.7 (3–16) 18
2 (2) 5 (5) 7 (7)
2.5 (1–4) 1.2 (1–2) 1.6 (1–3)
9.5 (5–14) 5 (1–16) 7.3 (1–18)
1.2 (1–2) 1 1 (1–1) 1.4 (1–3)
6.9 (1–25) 3 2.5 (2–3) 13.9 (1–26)
17 (18) 2 (2) 4 (4) 13 (14)
1.6 (1–7) 1 (1–1) 1 (1–1) 1.5 (1–3)
6.1 (1–25) 5 (3–7) 2 (1–3) 11.1 (1–26)
0
—
—
1
1
12
0 0
— —
— —
1 1
2 5
15 17
13 (14) 1 (1) 2 (2) 8 (8)
3
section examination of the pelvic lymph nodes, for a false negative rate of 19%. The specificity and the positive predictive value of frozen section examination were 100%, the negative predictive value, i.e., the probability that a person with a negative result at frozen section will have negative nodes at final histology, was 90% (60/67). Various factors were associated with failure of intraoperative frozen section examination. The most important seems to be the size of the metastasis. All seven lymph node metastases that were missed were smaller than 8 mm in largest diameter and six were smaller than 5 mm. In two
Maximum diameter of pelvic node metastases, mm (Mean (range))
patients (Nos. 3 and 7, Table 3), the involved lymph node region was not examined during frozen section. In two patients (Nos. 1 and 5, Table 3), the involved lymph node region but not the involved lymph node was examined and in three cases (Nos. 2, 4, and 6, Table 3), the involved lymph nodes were examined but the metastasis was missed at frozen section (Table 3). The 8-mm metastasis that was missed resided in a large lymph node more than 3 cm in diameter. Our results are consistent with those of other studies of accuracy of frozen section examination of the pelvic lymph
Table 3 Details of the seven patients with positive pelvic lymph nodes missed at frozen section FIGO Patient
Stage
1 2 3 4 5 6
IB1 IIA IIB IIB IIB IB1
Adenosquamous Squamous Squamous Squamous Squamous Squamous
7
IIA
Squamous
Node region with metastases
Total no. of pelvic lymph nodes examined at frozen section
Frozen section examination performed station/ node
No. of positive and total lymph nodes in final histology
Diameter of lymph node metastasis in final histology (in mm)
Left external iliac Right external iliac Left external iliac Right external lateral iliac Left internal iliac Left external iliac Right external iliac Right obturator (below nerve) Left obturator (above nerve)
8 9 10 18 12 16
Yes/no Yes/yes/ (wrong level) No Yes/yes/ (wrong level) Yes/no Yes/yes/ (wrong level) No No No
1/6 1/11 1/6 1/3 1/12 1/8 1/12 1/3 2/8
2 1 3 5 1 8 1 4 3
Histology
9
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H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
Table 4 Sensitivity, specificity, and positive and negative predictive values of frozen section as a diagnostic test for predicting the final node stations Sensitivity Specificity Positive predictive value Negative predictive value
81% 100% 100% 90%
nodes in patients with cervical cancer, which have reported false negative rates of 8% to 32% [3–5]. Benedetti-Panici et al. evaluated 28 patients with cervical cancer FIGO stage IA1 to IB1. Seven of eight patients with positive lymph nodes were detected by frozen section (sensitivity 86%) [3]. In a series of 80 patients, Morice et al. found a sensitivity of 92% for frozen section examination of pelvic nodes in patients with cervical cancer FIGO stage IB or II (1 of 13 false negative) [4]. In contrast, Bjornsson et al. reported a false negative rate of 32% (6/19) in a series of 127 patients [5]. A decrease in sensitivity has been found in series with larger numbers of patients with positive lymph nodes [3–5]. The accuracy of frozen section analysis of lymph nodes has been investigated in prostate cancer (pelvic lymph nodes), breast carcinoma, and malignant melanoma (sentinel lymph node biopsies). Frozen section analysis of pelvic lymph nodes during staging operations for prostate cancer showed a 5%–30% false negative rate [6 –9], which is similar to the findings for cervical cancer. Frozen section analysis of sentinel lymph nodes for breast carcinoma was false-negative in 4.6%– 42% [10 –13], depending on the intraoperative frozen section procedure, the protocol for permanent histology, and size of the metastatic deposits. The detection rate of micrometastasis was poor with a false-negative rate of 72%– 83%, whereas it was less than 10% for macrometastasis [10,12]. Veronesi et al., using an extensive and laborious intraoperative work-up of sentinel lymph nodes, were able to detect a fair number of micrometastases and obtain an overall false negative rate of 5% [11]. The detection rate of metastases in sentinel lymph nodes for malignant melanoma was found to be poor, with a false-negative rate of about 50%– 60% [14,15]. Accordingly, frozen section analysis of sentinel lymph nodes is not recommended for melanoma. The results of frozen section examination of pelvic lymph nodes can influence the surgical management of patients with cervical cancer. Positive paraaortic nodes have been found in 26% of patients with FIGO stages IB to IIB disease and positive pelvic lymph nodes [1], but paraaortic lymph node involvement without positive pelvic lymph nodes is rare [1,16,17]. As a consequence, in the absence of gross lymph node metastasis, the indication for paraaortic lymphadenectomy, is often based on the results of intraoperative frozen section examination of the pelvic lymph nodes. The status of the pelvic lymph nodes potentially could be used to guide the surgical management of patients with
FIGO stage IA and IB tumors. Overall, the probability of parametrial spread in these patients is 4% to 16% [1,18]. However, parametrial spread occurs with 50% to 100% of patients with positive pelvic nodes as compared with 13% of those with negative nodes [19 –21]. Also, Sakuragi et al. found a significant correlation between pelvic lymph node metastasis and parametrial invasion [17]. Scambia et al. and Covens et al. have recently discussed less parametrial resection in patients with locally advanced cervical cancer and negative lower pelvic nodes [22] and in patients with FIGO stage IA2 and IB disease [18]. In our series, the sensitivity of frozen section examination would have been only 92% (33 of 36) if each single removed lymph node had been examined without serial sections or 89% if the selected lymph nodes would have been serially sectioned. Thus, our results raise two key problems for intraoperative analysis of lymph nodes which were also present in other investigations for sentinel lymph nodes and pelvic lymph nodes for prostate and cervical cancer: the detection of micrometastasis and the selection of the correct lymph nodes. We conclude that it will be difficult to improve the accuracy of frozen section examination of pelvic lymph nodes; the technique is laborious and timeconsuming, and it is not feasible to process all nodes with serial sections intraoperatively. The diagnostic accuracy of frozen section analysis of pelvic lymph nodes should be considered when intraoperative decisions are based on its results.
References [1] Burghardt E. Distant spread in cervical cancer. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, editors. Surgical gynecologic oncology. Stuttgart: Thieme; 1993, p. 212–5. [2] Winter R. Lymphadenectomy. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, editors. Surgical gynecologic oncology. Stuttgart: Thieme; 1993, p. 281–90. [3] Benedetti-Panici P, Maneschi F, Cutillo G, et al. Tailored surgery in stage IA2-IB1 cervical cancer based on lymphadenectomy of primary pelvic groups. Preliminary results of a pilot study. Ital J Gynaecol Obstet 2000;12:1–5. [4] Morice P, Sabourin JC, Pautier P, et al. Indications and results of frozen section examination of pelvic lymph nodes in the surgical strategy of stage Ib or II cervical cancers. Ann Chir 1999;53:583– 6. [5] Bjornsson BL, Nelson BE, Reale FR, Rose PG. Accuracy of frozen section for lymph node metastasis in patients undergoing radical hysterectomy for carcinoma of the cervix. Gynecol Oncol 1993;51: 50 –3. [6] Kramolowsky EV, Narayana AS, Platz CE, Loening SA. The frozen section in lymphadenectomy for carcinoma of the prostate. J Urol 1984;131:899 –900. [7] Link RE, Morton RA. Indications for pelvic lymphadenectomy in prostate cancer. Urol Clin N Am 2001;28:491– 8. [8] Bangma CH, Hop WC, Schroder FH. Eliminating the need for perioperative frozen section analysis of pelvic lymph nodes during radical prostatectomy. Br J Urol 1995;76:595–9. [9] Fowler JE Jr, Torgerson L, McLeod DG, Stutzman RE. Radical prostatectomy with pelvic lymphadenectomy: observations on the accuracy of staging with lymph node frozen sections. J Urol 1981; 126:618 –9.
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609 [10] Weiser MR, Montgomery LL, Susnik B, et al. Is routine intraoperative frozen section examination of sentinel nodes in breast cancer worthwhile? nn Surg Oncol 2000;7:651–5. [11] Veronesi U, Zurrida S, Mazzarol G, Viale G. Extensive frozen section examination of axillary sentinel nodes to determine selective axillary dissection. World J Surg 2001;25:806 – 8. [12] Chao C, Wong SL, Ackermann D, et al. Utility of intraoperative frozen section analysis of sentinel lymoph nodes in breast cancer. Am J Surg 2001;182:609 –15. [13] Turner RR, Hansen NM, Stern SL, Giuliano AE. Intraoperative examination of the sentinel lymph node for breast carcinoma staging. Am J Clin Pathol 1999;112:627–34. [14] Tanis PJ, Boom RP, Koops HS, et al. Frozen section investigation of the sentinel node in malignant melanoma and breast cancer. Ann Surg Oncol 2001;8:222– 6. [15] Koopal SA, Tiebosch AT, Albertus Piers D, et al. Frozen section analysis of sentinel lymph nodes in melanoma patients. Cancer 2000; 89:1720 –5. [16] Deppe G, Lubicz S, Galloway BT Jr, et al. Aortic node metastases with negative pelvic nodes in cervical cancer. Cancer 1984;53:173–5.
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[17] Sakuragi N, Satoh C, Takeda N, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with stages IB, IIA and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85:1547–54. [18] Covens A, Rosen B, Murphy J, et al. How important is removal of the parametrium at surgery for carcinoma of the cervix? Gynecol Oncol 2002;84:145–9. [19] Burghardt E. Criteria of spread in cervical cancer. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, editors. Surgical gynecologic oncology. Stuttgart: Thieme; 1993, p. 316 –20. [20] Benedetti-Panici P, Maneschi F, D’Andrea G, et al. Early cervical carcinoma. The natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer 2000;88:2267–74. [21] Winter R, Haas J, Reich O, et al. Parametrial spread of cervical cancer in patients with negative pelvic lymph nodes. Gynecol Oncol 2002; 84:252–7. [22] Scambia G, Ferrandina G, Distefano M, et al. Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients? Gynecol Oncol 2001;83:319 –24.
Gynecologic Oncology 90 (2003) 605– 609
www.elsevier.com/locate/ygyno
Accuracy of frozen section examination of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer Heinz S. Scholz,a,* Sigurd F. Lax,b Christoph Benedicic,a Karl Tamussino,a and Raimund Wintera a
Department of Obstetrics and Gynecology, University of Graz, Graz A-8036, Austria b Department of Pathology, University of Graz, Graz A-8036, Austria Received 18 December 2002
Abstract Objective. We evaluated the accuracy of intraoperative frozen section histology of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer. Methods. A total of 96 patients with cervical cancer FIGO stage IB1 to IIB had surgery including systematic pelvic or pelvic and paraaortic lymphadenectomy and intraoperative frozen section examination of pelvic lymph nodes at our department between January 1997 and October 2001. The results of frozen section were compared with those of final histology. Results. A total of 1044 pelvic lymph nodes underwent intraoperative frozen section examination and node metastases were found in 29 patients (30%). Final histopathology yielded a total of 5042 lymph nodes and identified an additional seven patients with node metastases for a false negative rate of 19%. The specificity and the positive predictive value of frozen section examination were 100%; the negative predictive value was 90% (60/67). Conclusion. The diagnostic accuracy of frozen section analysis of pelvic lymph nodes should be considered when intraoperative decisions are based on its results. © 2003 Elsevier Inc. All rights reserved. Keywords: Frozen section; Pelvic lymph nodes; Cervical cancer; Cervical carcinoma
Introduction The status of the lymph nodes is one of the most important prognostic factors in patients with cervical cancer. Pelvic lymph node involvement occurs with 9% to 30% of FIGO stage IB, 7% to 50% of FIGO stage IIA, and 16% to 57% of FIGO stage IIB tumors [1]. Accordingly, systematic pelvic lymph node dissection is an established component of the surgical treatment of cervical cancer. Because paraaortic lymph node involvement is rare in patients with negative pelvic nodes, frozen section histology of the pelvic nodes is frequently used to identify patients in whom
* Corresponding author. Department of Obstetrics and Gynecology, University of Graz, Auenbruggerplatz 14, A-8036 Graz, Austria. Fax: ⫹43-316-385-3061. E-mail address: [email protected] (H.S. Scholz). 0090-8258/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0090-8258(03)00398-6
paraaortic dissection can be omitted. In the present study we evaluated the accuracy of intraoperative frozen section histology of pelvic lymph nodes in patients with FIGO stage IB1 to IIB cervical cancer. Materials and methods A total of 96 patients with cervical cancer FIGO stage IB1 to IIB (mean age, 44.6 years; range, 22– 69) had surgery including systematic pelvic or pelvic and paraaortic lymphadenectomy and intraoperative frozen section examination of pelvic lymph nodes at our department between January 1997 and October 2001. Forty-nine women had FIGO stage IB1, 12 had IB2, 12 had IIA, and 23 had IIB tumors. Ninety-four patients underwent radical abdominal hysterectomy, one total abdominal hysterectomy, and one conization. All patients underwent systematic pelvic lymphade-
606
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
Table 1 Number of pelvic lymph nodes examined at frozen section and at final histopathology in 96 patients with cervical cancer FIGO stages IB1 to IIB (T1b1 to T2b) Lymph node region
Right External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral Subaortal Left External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral
No. of patients
Frozen section
Final histopathology
Nodes per patient (Mean (range))
Total no. of lymph nodes examined
Nodes per patient (Mean (range))
Total no. of lymph nodes examined
80 60 33 77 12 39 48 37
1.8 (1–5) 1.5 (1–3) 1.2 (1–3) 1.5 (1–5) 1.3 (1–2) 1.5 (1–4) 1.5 (1–3) 1.4 (1–3)
146 87 39 117 16 57 70 51
5.7 (0–16) 3.8 (1–11) 2.7 (0–10) 5.6 (1–16) 1.5 (0–7) 2.7 (0–15) 3.0 (0–10) 3.6 (0–16)
550 363 260 540 139 265 285 348
82 45 20 63 11 26 42
1.9 (1–5) 1.4 (1–5) 1.4 (1–3) 1.4 (1–4) 1.2 (1–2) 1.4 (1–3) 1.7 (1–4)
157 64 27 91 13 37 72
6.4 (2–16) 3.4 (0–11) 2.0 (0–8) 4.9 (1–13) 1.3 (0–6) 2.7 (0–13) 3.2 (0–13)
616 327 189 474 122 255 310
nectomy and 20 patients underwent additional paraaortic lymphadenectomy. Pelvic lymphadenectomy aimed to remove all lymph nodes from the femoral ring to the bifurcation of the aorta. The spaces between and behind the vessels were cleared, as was the obturator fossa to the pelvic floor and the subaortic and internal iliac regions [2]. Eighty-one patients had squamous cell carcinoma, six had adenosquamous carcinoma, eight had adenocarcinoma, and one had small cell carcinoma. All tissue removed from the particular pelvic lymph node regions underwent intraoperative frozen section examination. The examining pathologists palpated and dissected the adipose tissue for lymph nodes. Lymph nodes thicker than 5 mm were bisected and lymph nodes thicker than 1 cm were cut into several pieces and the cut-surfaces were inspected. Lymph nodes for frozen section were selected according to consistency, size, and appearance of the cutsurface. Two to four frozen sections from each lymph node were cut at a distance of about 20 –30 m and stained with hematoxylin and eosin (H&E). The remaining tissue from the frozen section as well as the lymph nodes that did not undergo frozen section were fixed in 4% buffered formalin overnight. For final histology, all lymph nodes and the perinodal adipose tissue were processed and embedded in paraffin, and depending on the size of the lymph nodes, 2– 4 serial sections per block were cut and stained with H&E.
tastases were found in 29 patients (30%), with a mean of 1.7 positive lymph nodes (range 1– 8) per patient. Frozen section analysis showed metastatic disease in one lymph node region in 17 patients, in two regions in eight patients, in three regions in three patients, and in eight regions in one patient. Final histopathologic examination yielded a total of 5042 lymph nodes, with a mean of 52.5 lymph nodes (range 21–109) per patient (Table 2). Lymph node metastases were found in 36 patients (38%) with a mean of 2.4 positive nodes (range 1–13) per patient. Frozen section analysis showed metastatic disease in one node region in 13 patients, in two regions in 14 patients, in three regions in three patients, in four regions in two patients, in five regions in three patients, and in 13 regions in one patient. Seven patients were negative for lymph node metastases at frozen section examination but showed metastases during final histopathology (Table 3). In five of seven cases, the correct lymph node region was selected for frozen section examination but three of five metastases were 2 mm or less in largest diameter. In two cases the lymph node region with the metastasis was not examined intraoperatively. There was no false positive case of lymph node metastasis during frozen section. The sensitivity, specificity, and positive and negative predictive values of frozen section as a diagnostic test for predicting the final node stations are shown in Table 4.
Results A total of 1044 pelvic lymph nodes underwent intraoperative frozen section examination (Table 1). A mean of 10.9 lymph nodes (range 1–24) and 7.0 lymph node regions (range 1–13) were examined per patient. Lymph node me-
Discussion In our series, seven of 36 patients with cervical cancer FIGO stage IB1 to IIB had false negative results of frozen
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
607
Table 2 Number of pelvic lymph node metastases and maximum diameter of metastases as detected by intraoperative frozen section and by final histopathology in 96 patients with cervical cancer FIGO stages IB1 to IIB (T1b1 to T2b) Lymph node region
Frozen section examination Patients with positive nodes (%)
Right External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral Subaortal Left External iliac Common iliac Internal iliac Obturator (above nerve) Obturator (below nerve) External iliac lateral Common iliac lateral
Final histopathology
No. of pelvic node metastases (Mean (range))
Maximum diameter of pelvic node metastases, mm (Mean (range))
Patients with positive nodes (%)
No. of pelvic node metastases (Mean (range))
8 (8) 2 (2) 1 (1) 9 (9)
1.1 (1–2) 1.5 (1–2) 3 1.2 (1–2)
8 (1–30) 6.5 (5–8) 5 12.4 (5–30)
13 (14) 3 (3) 2 (2) 13 (14)
1.5 (1–4) 2 (1–3) 4.5 (1–8) 1.8 (1–4)
6.9 (1–30) 5.7 (4–8) 3 (1–5) 9.4 (0.5–30)
1 (1)
2
2 (2)
1.5 (1–2)
3.5 (3–4)
1 (1) 3 (3) 1 (1)
2 1 (1–1) 1
14 7.7 (3–16) 18
2 (2) 5 (5) 7 (7)
2.5 (1–4) 1.2 (1–2) 1.6 (1–3)
9.5 (5–14) 5 (1–16) 7.3 (1–18)
1.2 (1–2) 1 1 (1–1) 1.4 (1–3)
6.9 (1–25) 3 2.5 (2–3) 13.9 (1–26)
17 (18) 2 (2) 4 (4) 13 (14)
1.6 (1–7) 1 (1–1) 1 (1–1) 1.5 (1–3)
6.1 (1–25) 5 (3–7) 2 (1–3) 11.1 (1–26)
0
—
—
1
1
12
0 0
— —
— —
1 1
2 5
15 17
13 (14) 1 (1) 2 (2) 8 (8)
3
section examination of the pelvic lymph nodes, for a false negative rate of 19%. The specificity and the positive predictive value of frozen section examination were 100%, the negative predictive value, i.e., the probability that a person with a negative result at frozen section will have negative nodes at final histology, was 90% (60/67). Various factors were associated with failure of intraoperative frozen section examination. The most important seems to be the size of the metastasis. All seven lymph node metastases that were missed were smaller than 8 mm in largest diameter and six were smaller than 5 mm. In two
Maximum diameter of pelvic node metastases, mm (Mean (range))
patients (Nos. 3 and 7, Table 3), the involved lymph node region was not examined during frozen section. In two patients (Nos. 1 and 5, Table 3), the involved lymph node region but not the involved lymph node was examined and in three cases (Nos. 2, 4, and 6, Table 3), the involved lymph nodes were examined but the metastasis was missed at frozen section (Table 3). The 8-mm metastasis that was missed resided in a large lymph node more than 3 cm in diameter. Our results are consistent with those of other studies of accuracy of frozen section examination of the pelvic lymph
Table 3 Details of the seven patients with positive pelvic lymph nodes missed at frozen section FIGO Patient
Stage
1 2 3 4 5 6
IB1 IIA IIB IIB IIB IB1
Adenosquamous Squamous Squamous Squamous Squamous Squamous
7
IIA
Squamous
Node region with metastases
Total no. of pelvic lymph nodes examined at frozen section
Frozen section examination performed station/ node
No. of positive and total lymph nodes in final histology
Diameter of lymph node metastasis in final histology (in mm)
Left external iliac Right external iliac Left external iliac Right external lateral iliac Left internal iliac Left external iliac Right external iliac Right obturator (below nerve) Left obturator (above nerve)
8 9 10 18 12 16
Yes/no Yes/yes/ (wrong level) No Yes/yes/ (wrong level) Yes/no Yes/yes/ (wrong level) No No No
1/6 1/11 1/6 1/3 1/12 1/8 1/12 1/3 2/8
2 1 3 5 1 8 1 4 3
Histology
9
608
H.S. Scholz et al. / Gynecologic Oncology 90 (2003) 605– 609
Table 4 Sensitivity, specificity, and positive and negative predictive values of frozen section as a diagnostic test for predicting the final node stations Sensitivity Specificity Positive predictive value Negative predictive value
81% 100% 100% 90%
nodes in patients with cervical cancer, which have reported false negative rates of 8% to 32% [3–5]. Benedetti-Panici et al. evaluated 28 patients with cervical cancer FIGO stage IA1 to IB1. Seven of eight patients with positive lymph nodes were detected by frozen section (sensitivity 86%) [3]. In a series of 80 patients, Morice et al. found a sensitivity of 92% for frozen section examination of pelvic nodes in patients with cervical cancer FIGO stage IB or II (1 of 13 false negative) [4]. In contrast, Bjornsson et al. reported a false negative rate of 32% (6/19) in a series of 127 patients [5]. A decrease in sensitivity has been found in series with larger numbers of patients with positive lymph nodes [3–5]. The accuracy of frozen section analysis of lymph nodes has been investigated in prostate cancer (pelvic lymph nodes), breast carcinoma, and malignant melanoma (sentinel lymph node biopsies). Frozen section analysis of pelvic lymph nodes during staging operations for prostate cancer showed a 5%–30% false negative rate [6 –9], which is similar to the findings for cervical cancer. Frozen section analysis of sentinel lymph nodes for breast carcinoma was false-negative in 4.6%– 42% [10 –13], depending on the intraoperative frozen section procedure, the protocol for permanent histology, and size of the metastatic deposits. The detection rate of micrometastasis was poor with a false-negative rate of 72%– 83%, whereas it was less than 10% for macrometastasis [10,12]. Veronesi et al., using an extensive and laborious intraoperative work-up of sentinel lymph nodes, were able to detect a fair number of micrometastases and obtain an overall false negative rate of 5% [11]. The detection rate of metastases in sentinel lymph nodes for malignant melanoma was found to be poor, with a false-negative rate of about 50%– 60% [14,15]. Accordingly, frozen section analysis of sentinel lymph nodes is not recommended for melanoma. The results of frozen section examination of pelvic lymph nodes can influence the surgical management of patients with cervical cancer. Positive paraaortic nodes have been found in 26% of patients with FIGO stages IB to IIB disease and positive pelvic lymph nodes [1], but paraaortic lymph node involvement without positive pelvic lymph nodes is rare [1,16,17]. As a consequence, in the absence of gross lymph node metastasis, the indication for paraaortic lymphadenectomy, is often based on the results of intraoperative frozen section examination of the pelvic lymph nodes. The status of the pelvic lymph nodes potentially could be used to guide the surgical management of patients with
FIGO stage IA and IB tumors. Overall, the probability of parametrial spread in these patients is 4% to 16% [1,18]. However, parametrial spread occurs with 50% to 100% of patients with positive pelvic nodes as compared with 13% of those with negative nodes [19 –21]. Also, Sakuragi et al. found a significant correlation between pelvic lymph node metastasis and parametrial invasion [17]. Scambia et al. and Covens et al. have recently discussed less parametrial resection in patients with locally advanced cervical cancer and negative lower pelvic nodes [22] and in patients with FIGO stage IA2 and IB disease [18]. In our series, the sensitivity of frozen section examination would have been only 92% (33 of 36) if each single removed lymph node had been examined without serial sections or 89% if the selected lymph nodes would have been serially sectioned. Thus, our results raise two key problems for intraoperative analysis of lymph nodes which were also present in other investigations for sentinel lymph nodes and pelvic lymph nodes for prostate and cervical cancer: the detection of micrometastasis and the selection of the correct lymph nodes. We conclude that it will be difficult to improve the accuracy of frozen section examination of pelvic lymph nodes; the technique is laborious and timeconsuming, and it is not feasible to process all nodes with serial sections intraoperatively. The diagnostic accuracy of frozen section analysis of pelvic lymph nodes should be considered when intraoperative decisions are based on its results.
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