doi:10.1111/j.1447-0756.2007.00664.x
J. Obstet. Gynaecol. Res. Vol. 33, No. 6: 829–833, December 2007
Asymmetries in pelvic lymph nodes and their metastatic involvement by gynecologic cancer cells Bunyamin Borekci1, Senol Dane2, Cemal Gundogdu3 and Sedat Kadanali1 Departments of 1Obstetrics and Gynecology, 2Physiology and 3Pathology, Medical Faculty, Ataturk University, Erzurum, Turkey
Abstract Aim: The aims of this study were to re-examine left–right asymmetry in pelvic lymph node distribution in patients with gynecologic malignancies, and to investigate if there is a left–right asymmetry in pelvic lymph node metastatic involvement by gynecologic cancer cells. Methods: The oncologic database of our gynecologic department was reviewed to identify patients who had pelvic lymphadenectomy as part of treatment for a variety of gynecologic malignancies. Right and left lymph node counts with and without involvement of cancer cells were retrieved from the pathological reports. Results: Three hundred and thirteen patients were included in the study. The numbers of external iliac, and hypogastric + obturator lymph nodes were higher on the right side than on the left in all gynecologic malignancies. The numbers of involved external iliac, and hypogastric + obturator lymph nodes by metastatic cancer cells were significantly higher on the right side than on the left in all gynecologic malignancies. Conclusion: The results suggest the existence of a left–right asymmetry in pelvic lymph node distribution and pelvic lymph node distribution involved by gynecologic cancer cells. This situation may be due to the asymmetry in the number of pelvic lymph nodes. In addition, stronger cell-mediated immune activity in the left side of humans may be associated with the blocking of metastatic invasion of cancer cells from gynecologic malignancies in the left side of the body. Key words: asymmetry, gynecologic cancer, lymph node involvement, number of lymph nodes, pelvic lymphadenectomy.
Introduction Earlier studies have shown the lateralization of different cancer types. Breast cancer has been noted more frequently on the left side in females.1–3 Right-sided lateralization of squamous cell cancers in the headneck region of right-handed patients and vice versa in left-handed patients, and a higher rate of lefthandedness in patients with squamous cell cancers in the head-neck region have been reported.4
Data from human and animal studies have suggested that lymphoid organs have an anatomical asymmetry along the right–left axis in which the number of rightsided lymph nodes was greater than left-sided lymph nodes.5–7 Left-sided axillary lymph nodes were fewer in number, but larger in size than right-sided ones in women with breast cancer.7 Morphological, biochemical, physiological and pathological asymmetries at different levels of the neuroendocrine system have been reviewed.8 It has been
Received: December 18 2006. Accepted: April 13 2007. Reprint request to: Senol Dane, Department of Physiology, Medical Faculty, Ataturk University, 25240 Erzurum, Turkey. Email:
[email protected]
© 2007 The Authors Journal compilation © 2007 Japan Society of Obstetrics and Gynecology
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reported that there are functional asymmetries of the adrenal glands,9 and in phenotypic and functional characteristics of cells from lymphoid organs.10 It has also been reported that there is asymmetrical function of a bilateral immune organ: the thymus.11 The difference in cell mediated hypersensitivity between the right and left sides of the body has been investigated using the tuberculin test in 22 healthy male and 36 healthy female high school students. Results showed higher cell mediated immune hypersensitivity response in the left side of the body than in the right.12 The same study was replicated in mice using sheep erythrocytes instead of tuberculin.13 The authors reported higher delayed type hypersensitivity (cell mediated immune hypersensitivity) reaction in the left paw of both left- and right-pawed animals. The intensity of delayed type hypersensitivity reaction to sheep red blood cells in the front paws of mice depends not only on whether the antigen is injected into the left or right paw, but also on the motor asymmetry of the hemispheres. A study comparing delayed type hypersensitivity reaction in the back left and right paws of mice showed that in both right- and left-pawed mice, the reaction was much more pronounced in the left paw than in the right. The authors suggested that the intensity of delayed type hypersensitivity reaction in mice may be dependent on the functional asymmetry of regional lymph nodes.14 A more frequent appearance of herpes zoster infection in the left body side of women has been reported.15,16 Cell mediated immune hypersensitivity was smaller on the involved side than in the noninvolved side of the body in patients with herpes zoster infection.16 It has been reported that there is left-sided lateralization of all immune reactions, and diseases are more frequent in left-handed females.17 A report has shown left–right asymmetry in pelvic lymph node distribution in patients with gynecologic malignancies and a right-side prevalence for the number of lymph nodes.18 Pelvic lymphadenectomy is a well-established and widely used procedure for staging and therapeutic decision-making of gynecologic malignancies. To our knowledge, no published gynecologic study has specifically addressed the existence of a left–right asymmetry in pelvic lymph node involvement by metastatic invasion of gynecologic malignancies. In the present study, we aimed to: (i) reexamine left–right asymmetry in pelvic lymph node distribution in patients with gynecologic malignancies; and (ii) investigate if there is left–right asymmetry in
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pelvic lymph node involvement by metastatic invasion of gynecologic malignancies.
Methods The oncologic database of the Obstetrics and Gynecology Department of Ataturk University, Turkey was examined to identify all patients who underwent systematic pelvic laparotomic lymphadenectomy between January 2000 and September 2006. Three hundred and thirteen of 406 women who underwent pelvic lymphadenectomy during the study period were included in the study. The others were excluded because they had removed lymph nodes less than 20 in number. The database includes details on demographics, stages, surgical procedures, pathological examinations, such as lymph node count and involved lymph node count by metastatic cancer cells, intra- and postoperative complications, and hospital stays. In all cases, pelvic lymph dissection was part of the treatment of various gynecologic cancers. All procedures were performed by two surgeons with a comparable background of expertise in gynecologic oncology. During laparotomic procedures, nodal packets of right and left hemi-pelvises were removed and sent for pathological examination as individual specimens (external iliac, and hypogastric + obturator). All gynecologic malignancies were staged according to the surgical staging method. In all endometrial cancer cases, total abdominal hysterectomy and bilateral salpingo-oophorectomy and pelvic lymphadenectomy were performed. Paraaortic lymphadenectomy was also performed in some patients. Other endometrial cancers, except for adenocarcinomas, were not included in the study. In all ovarian cancers, cytoreductive surgery was performed. Surgery involved total abdominal hysterectomy and bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy along with complete omentectomy and resection of any metastatic lesion. Optimal debulking was performed in all ovarian cancers and no macroscopic residual disease was present. Non-epithelial ovarian cancer cases were not included in the study. In all cervical cancers, radical hysterectomy (type III), and pelvic and para-aortic lymphadenectomy were performed. Non-squamous cervical cell cancers were not included in the study. All specimens were analyzed by the same pathologist from the Pathology Department of our university. Pathological examination was performed on formalin
© 2007 The Authors Journal compilation © 2007 Japan Society of Obstetrics and Gynecology
Asymmetry in gynecologic cancer
fixed specimens: lymph nodes were identified by hand and isolated from fat tissue, then counted and macroscopically examined. Lymph nodes were embedded in paraffin and from each block 5-mm thick sections were obtained, which were subsequently stained with hematoxylin and eosin. For statistical evaluation, one-sample difference test, one-way anova and non-parametric Wilcoxon test in SPSS 11.0 for Windows, and hypothesis test for two proportions from one group in the Microsta program were applied.
Results The numbers of external iliac lymph nodes were significantly higher on the right side than on the left side in all gynecologic malignancies (Table 1). In 313 patients, a total of 2933 external iliac lymph nodes were removed: 1594 (54.35%) from the right side and 1339 from the left. Of the 313 patients, 199 (63.57%) had a prevalence of right-sided nodes and 75 (23.96%) had a prevalence of left-sided, while in 39 (12.47%) patients external iliac lymph nodes were equally distributed on the two sides (Z = 8.27, P < 0.001). The numbers of hypogastric + obturator lymph nodes were higher on the right side than on the left in all gynecologic malignancies (Table 1), but this difference was not significant in endometrial cancer. In 313 patients, a total of 3937 hypogastric + obturator lymph nodes were removed: 2075 (52.71%) from the right side and 1862 from the left. One hundred and fortythree (45.69%) patients had a prevalence of right-sided and 85 (27.16%) patients had a prevalence of leftsided lymph nodes, while in 85 (27.16%) patient,s
hypogastric + obturator lymph nodes were equally distributed on the two sides (Z = 3.94, P < 0.001). In endometrial cancer, the number of patients in stages II, II and III were 38, 6 and 47, respectively. There were no differences in the number of right (F = 2.85) and left (F = 0.26) external iliac, and right (F = 0.61) and left (F = 1.39) hypogastric + obturator lymph nodes among stages 1, 2 and 3. The numbers of patients with stages IIIa, IIIb and IIIc ovarian cancer were 40, 62 and 71, respectively. As stages increased, the number of right external (F = 7.13, P < 0.001) and right (F = 11.39, P < 0.001) and left (F = 4.62, P < 0.01) hypogastric + obturator lymph nodes increased, but this relation was not significant for left external iliac lymph nodes (F = 1.77). The numbers of patients with stages 1B and 2A cervical cancer were 24 and 25, respectively. There were no differences in the numbers of right (F = 0.19) and left (F = 0.07) external iliac, and right (F = 1.64) and left (F = 0.07) hypogastric + obturator lymph nodes among stages 1, 2 and 3. The numbers of involved external iliac lymph nodes by metastatic cancer cells were significantly higher on the right side than the left in all gynecologic malignancies (endometrial cancer: Z = 3.25, P < 0.001; ovarian cancer: Z = 2.33, P < 0.05), but this difference was not significant in cervical cancer (Z = 1.41, P > 0.05). Of 1594 right external iliac nodes, 35 were involved and of 1339 left external iliac nodes, 11 were involved. The difference in percentages of the right (76.09%) and left (23.91) sides was statistically significant (Z = 9.48, P < 0.001). Of 313 patients, 36 had involved external iliac lymph nodes. The difference between the percentages of the right (n = 25, 69.44%) and left (n = 5, 13.89%)
Table 1 Numbers of external iliac and hypogastic + obturator lymph nodes (mean ⫾ SD) on the right and left sides of the body n Endometrial cancer External iliac Hypogastric + obturator Ovarian cancer External iliac Hypogastric + obturator Cervical cancer External iliac Hypogastric + obturator Total External iliac Hypogastric + obturator
91
173
49
313
T
P
Right-sided LN
Left-sided LN
5.55 ⫾ 1.87 7.03 ⫾ 1.74
4.51 ⫾ 1.33 6.47 ⫾ 2.62
5.11 1.45
0.05
4.69 ⫾ 0.77 6.26 ⫾ 1.12
3.95 ⫾ 0.68 5.59 ⫾ 1.07
11.21 6.33
