Extrapelvic sentinel lymph nodes in cervical cancer: a review

ObjectiveTo determine the frequency of extrapelvic sentinel lymph node in patients with cervical cancer.Materials and methodsWe performed systematic searches (Medline, Pubmed; up to April 2010) to determine the route of lymphatic spread in cervical cancer and to review results on extrapelvic sentinel lymph nodes.ResultsAccording to our search, 2.51% of detected sentinel lymph nodes in patients with cervical cancer were extrapelvic: 2% in the inguinal chain and 98% in the lower paraaortic area.Discussion and conclusionThe unusual localizations of sentinel lymph nodes impose to the gynaecologic surgeons to be hardened in performing lymph node dissection in all the territories potentially affected.     

Topographic distribution of sentinel lymph nodes in patients with cervical cancer

BACKGROUND: Since the introduction of the sentinel concept in cervical cancer in 1999, various studies have been demonstrated the feasibility, detection rate and sensitivity and rate of false-negative sentinel lymph nodes (SLN). There are only limited data regarding the mapping of the removed SLN. A correlation between the localization of SLN and the tumor stage, histology or marker substance has never been investigated. METHODS: Between 2/2000 and 6/2005, the SLN distribution of 151 patients with histologically confirmed cervical cancer (FIGO stages IA n = 21, IB n = 95, IIA n = 14, IIB n = 18, IIIB n = 2, IVA n = 1), who participated in the ongoing "Uterus 3" sentinel study of the German Association of Gynecologic Oncologists (AGO), was retrospectively analyzed with respect to the histology, tumor stage and detection substance. The tumors comprised mostly of squamous cell carcinomas (75.5%) with a smaller fraction of adenocarcinomas (24.5%). RESULTS: Altogether, 406 SLN, an average of 2.7 (1-7) SLN per patient, were removed. More than one SLN was detected in 111 patients (73.5%). SLN were found unilaterally in 70 patients (46.4%) und bilaterally in 81 patients (53.6%). SLN sites were paraaortic in 4%, common iliac in 5%, external iliac in 5%, internal iliac in 8%, interiliac in 71% and parametric in 7%. Irrespective of the detection drug applied, most SLN were interiliac (blue 70%, TC 67%, TC and blue 71%). Combined application of technetium and blue dye revealed significantly more SLN in the paraaotic region (P = 0.006). Adenocarcinomas and squamous carcinomas did not differ in the distribution of SLN (P = 0.205). The majority of SLN are interiliac in all tumor stages (FIGO IA 76%, IB 68%, IIA 61%, IIB 83%, III and IV 88%). CONCLUSIONS: Removal of SLN in the external iliac, interiliac and obturator area enables evaluation of more than 80% of all SLN. The pattern of SLN is independent from histology and tumor stage. Combined use of technetium and blue dye detects sentinels more frequently in the paraaortic region than a single marker.     

子宫颈癌的前哨淋巴结问题

恶性肿瘤威胁生命,且目前对其发展规律认识不够。在手术治疗中,曾长期以广泛、整块切除为原则,即将肿瘤的原发灶及其周围组织连同区域性淋巴组织完整切除。子宫颈癌治疗中的子宫广泛切除 盆腔淋巴清扫术即子宫颈癌根治术是这一原则的典型体现。     

Value of intraoperative imprint cytology of sentinel nodes in patients with cervical cancer

OBJECTIVE: The purpose of this study was to evaluate intraoperative imprint cytology (IC) for the detection of sentinel node (SN) involvement in patients with cervical cancer. METHODS: Thirty-six consecutive patients with cervical cancer underwent a laparoscopic SN procedure with intraoperative IC, followed by complete laparoscopic pelvic lymphadenectomy, with or without laparoscopic para-aortic lymphadenectomy. The SN was bisected and both cut surfaces were applied to the surface of glass slides. Permanent sections were stained with H&E and immunohistochemical methods. The IC results were compared with the final histological results. RESULTS: At least one SN (mean: 2 SN per patient, range: 1-5) was detected in 34 of the 36 patients. Eight patients (22.2%) had a total of 12 metastatic SNs (four macrometastatic, five micrometastatic, and three with isolated tumor cells). No false-negative results of SN biopsy were obtained. Only one metastasis was identified by IC. No false-positive findings were obtained with IC. The overall sensitivity, specificity, accuracy, and positive and negative predictive values of IC were 8.3%, 100%, 85.7%, 100%, and 85.5%, respectively. CONCLUSION: These results suggest that intraoperative imprint cytology of sentinel nodes is unreliable in patients with cervical cancer.     

Prognostic significance of high-risk HPV status in advanced cervical cancers and pelvic lymph nodes

OBJECTIVE: In this study, we investigated the presence of high-risk (HR) HPV types most prevalent in the Hungarian population in surgically removed cervical cancers and pelvic lymph nodes. The aim of our work was to determine the prognostic significance of HPV status in the lymph nodes draining the tumor. METHODS: Primary tumor specimens from 150 patients and 900 lymph node samples (six per case) were studied. Fifty-six/150 were early (FIGO IA-IB) stage, while 94/150 were advanced (FIGO IIA-IIIB) stage cancers. Beside histopathological evaluation, DNA extracted from the tissue samples was subjected to nested PCR to detect characteristic type-specific sequences of HPVs 16, 18 and 33. Moreover, clinicopathological data were collected for an average 48-month postoperative follow-up period for the purposes of statistical analysis. RESULTS: The presence of HR-HPV types in the lymph nodes shows no correlation with disease-free survival, whereas the presence of lymph node metastases significantly decreases life expectancy (P = 0.002). Lymph nodes with metastases more frequently carry HR-HPV than nodes with no evidence of tumorous infiltration (65% versus 36%, P < 0.001); however, a high number of metastases surrounding HR-HPV-positive tumors were found negative for the viruses (42/120). CONCLUSIONS: HR-HPV status of pelvic lymph nodes draining cervical cancers has no noticeable influence on the life expectancy of the patients. HR-HPV-positive tumor cells do not necessarily have a selective advantage in forming metastases. Presumably, a number of alterations in cellular genes rather than the presence of papillomavirus DNA may have a decisive role in the progression of cervical cancers.     

Laparoscopic sentinel lymph nodes identification followed by trachelectomy in early stage cervical cancer

The status of regional lymph nodes is the main prognostic factor in diagnosis and treatment of early stage of the cervical cancer. If the first node that drains a tumor site (sentinel node) is not metastatic, other lymph nodes should also be free of the disease. Detection using blue dye and laparoscopic removal of the sentinel lymph nodes let to avoid radical hysterectomy with pelvic limphadenectomy and it is especially useful in young women who want to preserve fertility. We describe a case of a 33- year old woman with invasive cervical cancer who underwent laparoscopic sentinel lymph nodes detection followed by trachelectomy. Thus histopatological examination confirmed no metastasis in removed sentinel lymph nodes, trachelectomy as a minimally invasive procedure was performed.     

Hepatoma-derived growth factor expression as a prognostic marker in cervical cancer

AIM: To examine the association of hepatoma-derived growth factor(HDGF) expression with the prognosis of patients with cervical cancer of the uterus(CC). METHODS: HDGF is a unique nuclear growth factor, and it may play an important role in the development and progression of carcinoma. HDGF expression in 88 CC patients aged 23 to 76 years(median, 54 years) was analyzed by immunohistochemistry. A rabbit polyclonal antibody against the C-terminal amino acids(aa 231-240) of the human HDGF sequence was used as primary antibody at a dilution of 1:5000. This specific anti-HDGF antibody was purified using C-terminal peptide-conjugated Sepharose columns. Staining of endothelial cells in the noncancerous areas of each specimen was used as an internal positive control. Samples with more than 80% of tumor cells showing positive immunoreactivity in both the nucleus and cytoplasm were regarded as HDGF index level 2, more than 80% positive immunoreactivity in either the nucleus or cytoplasm as level 1, and less than 80% in both the nucleus and cytoplasm as level 0. The chisquare test and Fisher's exact probability test were used to examine the relationship between HDGF expression and clinicopathologic parameters, and statistical significance was examined by the log-rank test. Multivariate analysis of factors related to survival was performed using Cox's proportional hazards regression model. Statistical significance was set at P 0.05. RESULTS: The five-year overall survival rate was 82.9%. Fourteen patients died due to tumors, nine of whom had tumor recurrence at 2-21 mo(median, 10 mo) after surgery. Tumor recurrence in five patients was determined at the time of the patients' deaths. Nineteen cases were regarded as HDGF index level 0, 11 as level 1, and 58 as level 2. Patients with level 2 expression showed higher rates of histological classification of keratinized squamous cell carcinomaand adenosquamous carcinoma(44.8% of level 2 patients and 13.3% in levels 0 and 1), deep invasion(p T2-4 in 65.5% of level 2 patients, and 30.0% in levels 0 and 1), the presence of lymphatic invasion(50.0% in level 2, and 20.0% in levels 0 and 1), and the presence of lymph node metastasis(37.9% in level 2, and 6.7% in levels 0 and 1). Patients with an HDGF index of level 2 CC showed poorer 5-year overall survival rates than those with level 0 or 1 CC(74.0% and 100%, respectively, P = 0.0036). Univariate analysis revealed that histological classification(P = 0.04), depth of tumor invasion(P = 0.0001), vascular invasion(P = 0.004), and lymph node metastasis(P = 0.0001) were significant factors affecting overall survival in addition to HDGF expression. Multivariate analysis revealed HDGF expression level and lymph node metastasis as independent prognostic factors for overall survival(P = 0.0148 and P = 0.0197, respectively). The prognostic significance of HDGF was further analyzed in p T1 and p T2-4 patient groups, respectively. Among patients with p T1 CC, one the 39 analyzed patients died during the study, and no difference was observed among patients with HDGF index level 0, 1, or 2 CC. However, prognostic significance of the HDGF index was observed in the p T2-4 patient group, in which the mortality rates of patients with HDGF index level 2 CC and those with level 0 or 1 CC significantly differed(P = 0.0463). CONCLUSION: The HDGF expression level is of prognostic significance in CC.     

早期子宫颈癌前哨淋巴结检测的临床意义

目的　评价前哨淋巴结 (SLN)对早期宫颈癌盆腔淋巴结转移状况的预测价值 ,探讨检测SLN在指导早期宫颈癌盆腔淋巴清扫术中的意义。方法　对 2 0 0 2年 11月～ 2 0 0 3年 8月在山东省肿瘤医院手术治疗的 2 3例早期宫颈癌患者行SLN检测 ,分别利用亚甲蓝和99mTc 硫胶体定位并原位切除SLN送快速冰冻病理检查 ,然后行经腹广泛全子宫切除 盆腔淋巴清扫术 ,比较SLN快速冰冻切片、SLN及其他盆腔淋巴结石蜡切片和抗角蛋白免疫组化染色结果。结果　 2 3例患者中 19例成功检测到SLN ,共检出SLN 5 9枚 ,平均每例 3枚 ,SLN检出率为 83% (19/2 3)。SLN活检术灵敏性为 83% ,特异性为 10 0 % ,与病理检查结果符合率为 95 %。结论　SLN检测能较为准确地预测早期宫颈癌盆腔淋巴结的转移状况 ,但以SLN活检术替代传统的手术方式的可行性和安全性还需要更大样本量的前瞻性病例研究来进一步评价     

前哨淋巴结检测对预测早期子宫颈癌淋巴转移的价值

目的 评价早期宫颈癌前哨淋巴结(SLN)检测的临床价值。方法 选择早期宫颈癌(临床分期Ⅰa-Ⅱa期)患者28例,于术前约18h,分别于宫颈10点及2点处黏膜下注射37MBq(0．4ml)的放射性核素——^99mTc标记的右旋糖酐(^99mTc—DX),即刻行淋巴核素显像。次日行广泛性子宫切除及盆腔淋巴清扫术。手术标本随即行γ探测仪体外探测识别SLN,解剖出SLN后单独送检,病理检查结果与非前哨淋巴结(NSLN)进行比较。结果 28例患者中27例(96％)识别出SLN。手术标本共取得814枚淋巴结,其中123枚为SLN。SLN集中分布于盆腔的髂内、外血管周围及闭孔区。6例(21％)发现盆腔淋巴结转移,共11枚转移淋巴结均为SLN,无假阴性情况出现。结论 SLN对宫颈癌盆腔淋巴结转移具有预测性,临床应用价值尚待进一步探讨。     

纳米炭在腹腔镜下早期宫颈癌前哨淋巴结示踪的临床研究

目的:探讨腹腔镜下应用纳米炭混悬液检测前哨淋巴结(SLN)在早期宫颈癌患者中的识别价值。方法:选取2014年1月至2016年1月在广西医科大学附属肿瘤医院行手术治疗的ⅠA2~ⅡA期宫颈癌患者40例。术前从宫颈3、9点注射纳米炭混悬注射液,腹腔镜直视下识别最先黑染淋巴结作为SLN并切取,单独行病理检查及免疫组化检查。切取SLN后,患者均行腹腔镜下盆腔淋巴结切除术+根治性子宫切除(±腹主动脉旁淋巴结取样术)。结果:40例患者中,38例成功检出至少1枚SLN,检出率为95%(38/40),共检出173枚SLN,平均每例每侧3.9枚SLN。8例(20%)患者共检出29枚阳性淋巴结,其中包括6例患者的阳性SLN,共25枚(86.20%)。前哨淋巴结定位于闭孔37.52%,髂外29.52%,髂内13.94%,宫旁5.09%,髂总12.13%。SLN检测的灵敏度为75%(6/8),准确性为100.0%(38/38),阴性预测值为100.0%(29/29)。结论:早期宫颈癌SLN的转移状态同盆腔淋巴结真实转移状态一致性较高,闭孔淋巴结为SLN检出频次最高的淋巴结,腹腔镜下纳米炭示踪早期宫颈癌SLN具有可行性。     

Hydronephrosis as a prognostic factor for patients of figo IIIB cervical cancer

OBJECTIVE: The aim of this study was to assess whether hydronephrosis is a prognostic factor for patients of FIGO stage III B cervical cancer. MATERIAL AND METHODS: A retrospective review of 145 stage III B cervical cancer patients treated with radiotherapy between 1989-1993 at Maria Sk?odowska-Curie Memorial Cancer Center in Warsaw was performed. Radiotherapy consisted of External Beam Irradiation (EBI) and Brachytherapy (BT) or EBI alone. RESULTS: Multivariate analysis revealed that hydronephrosis and Brachytherapy following EBI as the second part of the treatment were statistically significant factors in survival of FIGO stage III B cervical cancer patients. The five-year survival rate was 36% for patients without hydronephrosis treated with EBI and BT, compared to the group with hydronephrosis treated with EBI alone (no regression or too slow regression of the tumor to use BT), in which the survival rate was only 17 months. CONCLUSION: FIGO III b cervical cancer patients with hydronephrosis are treated only with palliative intent.     

Chlamydia trachomatis infection: implications for HPV status and cervical cancer

Genital Chlamydia trachomatis (CT) infections have been identified as a major health problem concern. CT is associated with adverse effect on women reproduction and also associated with cervical hypertrophy and induction of squamous metaplasia, providing a possible relationship with human papillomavirus (HPV) infection. Infection by high-risk HPV types is crucial to the pathogenesis of invasive cervical cancer (ICC), but other co-variants/cofactors must be present for the development of malignancy. CT biological effect may damage the mucosal barrier, improving HPV infection, or may interfere in immune response and viral clearance supporting the persistence of HPV infection. Moreover, CT-related chronic cervical inflammation, decrease of lower genital tract antigen-presenting cells, inhibition of cell-mediated immunity, and anti-apoptotic capacity may influence the natural history of HPV infection, namely persistence progression or resolution. Although several epidemiological studies have stated a positive association involving CT and HPV-related cervical neoplastic lesions and/or cervical cancer (CC), the specific role of this bacterium in the pathogenesis of cervical neoplasia has not been completely clarified. The present review summarizes several studies on CT role in cervical cancer and suggests future research directions on HPV and CT interaction.     

Young age as a prognostic factor in cervical cancer: Results of a population-based study

Objective: Our goal was to use population-based data to determine the difference in 5-year survival in women diagnosed with cervical cancer between those aged 18-34 years and those aged 40-60 years. Study Design: The SEER (Surveillance, Epidemiology, and End Results) public-use database, 1973-1994, was used for this investigation. Only subjects with cervical carcinoma diagnosed between 1988 and 1990 were included. Subjects were stratified on age at diagnosis (<35 years or 40-60 years), clinical stage, histologic type, race-ethnicity, and grade. Results: Two thousand cases of invasive cervical cancer were identified. The younger subgroup of patients was diagnosed with earlier-stage disease more frequently than the older group (P = .0001). When adjustments were made for non–cervical cancer causes of death, there was no difference in 5-year survival between the 2 cohorts. African American women had a poorer 5-year survival (P = .02) Conclusion: There was no overall difference in survival between the 2 cohorts when appropriate adjustments were made for cause of death and for stage, histologic type, and grade of disease. (Am J Obstet Gynecol 1999;180:1464-7.)     

HPV-18 is a poor prognostic factor, unlike the HPV viral load, in patients with stage IB-IIA cervical cancer undergoing radical hysterectomy

Objectives

This study was conducted to determine the prognostic significance of the human papillomavirus (HPV) genotype using the HPV DNA chip (HDC) test and the HPV viral load by the hybrid capture II assay (HC2) in FIGO stage IB-IIA cervical cancer undergoing radical hysterectomy.

Methods

Between January 2001 and December 2005, 204 consecutive patients who underwent radical hysterectomy with pelvic lymphadenectomy for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA cervical cancer were retrospectively reviewed. The Cox proportional hazard models adjusted for covariates were used for analyses and a receiver operating characteristic (ROC) curve was used to determine the HPV viral load in predicting disease progression.

Results

Of the 204 cases, the HDC was positive in 195 (95.6%) and the HC2 was positive in 192 (94.1%). The 5-year progression-free survival (PFS) was 78.4%. On multivariate analysis, HPV-18 positivity was an independent prognostic factor predictive for disease progression. The risk of recurrence was higher for HPV-18 positivity (hazard ratio = 2.664; 95% confidence interval [CI], 1.437-4.938; P = 0.003). The 5-year PFS rate for patients who were HPV-18-negative was 83.8%, which was higher than the 5-year PFS for patients who were HPV-18-positive (54.1%; P < 0.001). The area under the ROC curve for the HPV viral load was 0.550 (P = 0.314; 95% CI, 0.455-0.644).

Conclusions

The HPV-18 genotype is a reliable prognostic factor of early-stage cervical cancer; however, the HPV viral load may not be helpful in predicting disease prognosis.     

Lymphatic mapping of sentinel nodes in early vulvar cancer

Objective. The aim of the study was to determine the diagnostic accuracy and feasibility of sentinel lymph node (SLN) detection using a gamma probe in patients suffering from vulvar cancer.Methods. From May 1998 to November 2000, 26 patients with early vulvar cancer, planned for local wide excision or vulvectomy including groin dissection, were eligible for the study. Two to 3 h before the planned procedure we injected technetium⁹⁹ m-labeled microcolloid intradermally at four locations around the tumor. Dynamic and static images were recorded using a gamma camera. SLN locations were marked on the overlying skin. In the operating theater SLNs were identified at the beginning of the procedure using a handheld gamma-detection probe. After resection of suspected SLNs a standard unilateral or bilateral groin dissection was performed, subsequently followed by local wide excision or, if indicated, radical vulvectomy. Sentinel node detection using technetium⁹⁹ m-labeled microcolloid was compared with final histopathological and immunohistochemical results.Results. Scintigraphy showed focal uptake in all 26 patients. Intraoperatively we detected all sentinel nodes by handheld gamma probe. In 20 patients, one sentinel node was identified unilaterally, while in 6 patients two or more nodes were identified bilaterally. Histologically positive SLNs were found in 9 patients. In our preliminary series we did not find any false-negative SLN.Conclusion. Identification of sentinel nodes in vulvar cancer is feasible with preoperatively administered technetium⁹⁹m-labeled microcolloid. We confirm the results of previous studies and improve the evidence that the SLN procedure could be implemented in future therapy concepts.     

Verification of HPV16 as a good prognostic factor for cervical adeno-adenosquamous carcinoma via an international collaborative study

ObjectiveThis study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC).Materials and methodsPatients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993–2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis.ResultsA total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1–15.8; HR5.8, 95% CI 1.6–20.5), lymph node metastasis (HR4.6, 95% CI 2.7–7.9; HR7.3, 95% CI 3.8–14.0), and HPV16-positivity (HR0.3, 95% CI 0.1–0.6; HR0.3, 95% CI 0.1–0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups.ConclusionThis study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.     

Depth of cervical stromal invasion as a prognostic factor after radical surgery for early stage cervical cancer

INTRODUCTION: In the United Kingdom, the Royal College of Pathologists have issued guidelines detailing how the depth of stromal invasion (DOI) in cervical cancer should be measured as a percentage of the overall cervical radius in millimeters. Several studies have found the assessment of the depth of stromal invasion by cancer of the cervix to be of prognostic value. These studies did not take into account patients whose diagnostic procedures required removal of much tumor (large loop excision of the transformation zone [LLETZ] and knife cone biopsies). Furthermore, the Royal College of Pathologists guidelines do not address this issue. MATERIALS AND METHODS: Over the period of 6 years, 228 women had radical hysterectomy (RH) for stage Ib/IIa cervical cancer. The percentage of the depth of stromal invasion was measured according to the Royal College of Pathologist's guidelines in the UK. Patients who had large loop excision of the transformation zone and knife cone biopsies were excluded (91 patients). RESULTS: A Cox regression analysis showed that when nodal involvement, depth of stromal invasion, endothelial lined space invasion (ELSI), and tumor type were fitted simultaneously, only nodal involvement remained as a marker of adverse outcome. CONCLUSIONS: We recommend that when the DOI is measured, account should be taken of the LLETZ/knife cone biopsy size. A randomized controlled trial, which concludes that DOI is an independent prognostic factor, is needed. Until this is properly evaluated, we feel that including DOI as an essential part of the standard pathological report is not warranted.