Hermann Hertel

Multicenter Validation Study of the Sentinel Lymph Node Concept in Cervical Cancer: AGO Study Group

PURPOSE Single-institution case series have demonstrated the feasibility of the sentinel concept in cervical cancer. However, the diagnostic accuracy remains to be validated. We evaluated detection rate and diagnostic accuracy to predict the histopathologic pelvic nodal status in patients with cervical cancer of all stages. PATIENTS AND METHODS In a hypothesis-based, prospective, multicenter cohort study, patients underwent lymph node detection after labeling with technetium, patent blue, or both. After systematic pelvic and, if indicated, para-aortic node dissection, all lymph nodes were histopathologically examined. Detection rate, sensitivity, and negative predictive value (NPV) were calculated. RESULTS According to the protocol, 590 patients were eligible. Detection rate of pelvic sentinel nodes was 88.6% (95% CI, 85.8% to 91.1%) and was significantly higher for the combination of technetium and patent blue (93.5%; 95% CI, 90.3% to 96.0%). Of 106 patients with pelvic lymph node metastases, 82 had pelvic sentinel node metastases. The overall sensitivity was 77.4% (95% CI, 68.2% to 85.0%), which was lower than 90%, the predefined noninferiority margin (P < .001). Sensitivity in women with tumors <or= 20 mm (90.9%), with bilateral detection (87.2%), or with both substances applied (80.3%) was higher compared with the total population. The overall NPV was 94.3% (95% CI, 91.6% to 96.4%) and was higher in patients with tumors <or= 20 mm (99.1%; 95% CI, 96.6% to 100%) compared with patients with tumors more than 20 mm (88.5%; 95% CI, 82.9% to 92.8%; P < .001). CONCLUSION In our cohort (all stages), sensitivity of the sentinel concept was low. However, patients with tumor diameter <or= 20 mm may profit from this concept.

Fertility outcome after radical vaginal trachelectomy: a prospective study of 212 patients.

Objective For treatment in patients with early-stage cervical cancer, radical vaginal trachelectomy (RVT) as a fertility-preserving surgery can be put on a par with radical hysterectomy as to oncologic safety. Our aim was to investigate the fertility concerns and outcome. Methods Prospective collection of fertility data of patients treated with RVT. The data were collected on personal communication, by telephone, or e-mail correspondence. Descriptive statistical analysis was performed. Results Between March 2005 and April 2010, 212 patients were followed up after RVT. Only 76 patients (35.9%) were seeking parenthood currently. Sixty pregnancies occurred in 50 women. Five patients (8.3%) had first-trimester miscarriage, 3 had second-trimester miscarriage (5.0%), 2 patients decided for pregnancy termination (3.3%), and 1 patient (1.7%) had an ectopic pregnancy. Three women (5.0%) delivered prematurely before 28th weeks of gestation, 15 (25.0%) delivered between 28 and 36 weeks, and 27 women (45.0%) reached full term. Four pregnancies are ongoing. Conclusions Preservation of childbearing function is a great advantage for patients with early-stage cervical cancer. Many patients do not seek parenthood immediately. We see no impairment of fertility and have solid data on pregnancy outcome. Premature labor is the main problem in pregnancy after RVT.

Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: Prospective study of 225 patients with early-stage cervical cancer

Objective: The aim of the study was to prove the surgical and oncological safety of radical vaginal trachelectomy (RVT) and laparoscopic lymphadenectomy for patients with early-stage cervical cancer who are seeking parenthood. Methods: A database of 225 patients with early-stage cervical cancer and intention to treat by RVT after laparoscopic lymphadenectomy was prospectively maintained. A total of 212 patients were treated according to the protocol. The procedure was preformed in a standardized manner, and life table analysis was applied. Results: In the cohort of patients treated according to protocol, 8 recurrences occurred and 4 patients died from recurrence. The median follow-up time was 37 months (range, 0-171 months). The 5-year recurrence-free and overall survival was 94.4% and 97.4%, respectively. Perioperative and short-term postoperative complications were rare (2.8% and 7.5%, respectively). No severe long-term complications occurred. Conclusions: Radical vaginal trachelectomy combined with laparoscopic lymphadenectomy is a safe method for treatment of patients with early-stage cervical cancer who are seeking parenthood.

Photodynamic therapy of cervical intraepithelial neoplasia with hexaminolevulinate

CIN is a disease of women in their reproductive years, and treatment includes excisional techniques with increased risk of preterm deliveries. Photodynamic therapy (PDT) using topical precursor of photoactive porphyrins may be a non‐invasive alternative with minimal side effects. This study assessed the feasibility and response rate of PDT with hexaminolevulinate (HAL) in cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV) infection.

Pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate in patients with cervical intraepithelial neoplasia

OBJECTIVE Photodynamic therapy has the potential of a minimal invasive outpatient procedure for CIN patients at reproductive ages. The purpose of this study was to examine the pharmacokinetics and selectivity of porphyrin synthesis after topical application of hexaminolevulinate (HAL) in patients with cervical intraepithelial neoplasia (CIN). STUDY DESIGN Twenty-four women with CIN 1-3 received 4 mmol/L or 10 mmol/L HAL dissolved in thermolabile pluronic F 127 gel topically 5-720 minutes before surgical conization. The microscopic fluorescence pattern was quantified by ex vivo fluorescence spectroscopy at a wavelength of 635 nm and semiquantitatively by digital image analysis from cryosections. RESULTS With 4 and 10 mmol/L HAL, porphyrin fluorescence intensity increased over time, reaching a peak after 180-540 minutes application intervals in CIN and normal epithelium. However, the peak was much more pronounced in CIN than in normal tissues. The fluorescence intensity with 10 mmol/L was significantly higher than that with 4 mmol/L in CIN tissues (P < .05). Maximum intensity could generally be detected in the lower layer of the epithelium. CONCLUSION HAL seems to be a promising molecule for fluorescence diagnosis. For further treatment studies, we recommend application of 10 mmol/L HAL 300-540 minutes before photodynamic therapy in CIN.

Value and advantages of preoperative sentinel lymph node imaging with SPECT/CT in cervical cancer.

Objective Precise detection of sentinel lymph nodes (SLNs) seems to be a crucial factor for optimized treatment of cervical cancer. We assess the use of single photon emission computed tomography combined with computed tomography (SPECT/CT) as an alternative to lymphoscintigraphy (LSG) for preoperative identification of SLN. Methods This study was performed in a prospective, unicentric setting. Patients with cervical carcinoma were scheduled for surgery and additional SLN labeling by peritumoral injection of 10 MBq technetium-99m-nanocolloid and patent blue. Thirty minutes after injection, LSG and SPECT/CT were carried out. We evaluated the number of SLNs detected intraoperatively in LSG and SPECT/CT and the histologic findings of SLN and non-SLN. Subsequently, we determined the impact of these results on the therapeutic approach. Results This represents the largest study about SPECT/CT for SLN detection in cervical cancer so far. Between August 2008 and March 2013, 59 cervical cancer patients underwent intraoperative SLN detection. In addition, 51 of these patients underwent preoperative LSG and SPECT/CT. Imaging with SPECT/CT detected singular SLN at significantly higher rate (47/51, 92.2%) than that with planar LSG (43/51, 84.3%, P = 0.044). Furthermore, SPECT/CT performed better than LSG regarding the total number of detected SLN (SPECT/CT median, 3 [0–18]; LSG median, 2 [0–15]) and detection rates per pelvic side (SPECT/CT 76.9%, LSG 69.2%, P < 0.01). Whenever SLN detection succeeded, histologic evaluation of SLN correctly predicted the lymph node status per patient’s side. Using this type of diagnostic approach for lymph node staging, we reached sensitivity of 100% and negative predictive value of 100% at a rate of false-negative results of 0% even in tumors larger than 4 cm. Conclusions Single photon emission computed tomography combined with computed tomography imaging leads to improved rates of SLN detection and better anatomic correlation compared with planar LSG. Thus, intraoperative detection of SLN can be improved by preoperative SPECT/CT imaging. This enhances the clinical value of SLN technique and improves the oncologic safety of SLN concept.

Isthmocervical labelling and SPECT/CT for optimized sentinel detection in endometrial cancer: technique, experience and results.

OBJECTIVE We evaluated the clinical feasibility of a new injection technique for sentinel detection in endometrial carcinoma (EC), transcervical subepithelial injection into the isthmocervical region of the myometrium. We compared detection of sentinel lymph nodes (SLN) by single photon emission computed tomography with CT (SPECT/CT) with planar lymphoscintigraphy. METHODS This is a unicentric prospective study. In all patients, transcervical injection of 10 MBq Technetium-99m-nanocolloid was performed into the isthmocervical myometrium without anaesthesia. After 40 (30-60) min, lymphoscintigraphy and SPECT/CT were performed. Patent blue was administered before surgery. The number and localisation of SLN detected in SPECT/CT and lymphoscintigraphy were recorded and compared to the SLN and non-SLN dissected intra-operatively. RESULTS Between August 2008 and March 2012, 31 patients with EC were enrolled. The new transcervical injection of labelling substances led to high intra-operative (90.3%) detection rates, pelvic bilateral (57%), para-aortic (25%). SPECT/CT significantly identified more SLN than lymphoscintigraphy (mean 2.2 (1-8) to 1.3 (1-7)) in more patients (29/31 (93.5%) to 21/31 (68%), p<0.01). If SLN were identified in one hemi-pelvis, the histological evaluation of the SLN correctly predicted lymph node (LN) metastases for this basin which led to sensitivity 100%, negative predictive value (NPV) 100%, and false negative results 0%. CONCLUSION Transcervical SLN marking in combination with SPECT/CT is easily applicable and leads to high physiologic detection rates in pelvic and para-aortic lymphatic drainage areas. Non-affected SLN truly predicted a non-affected LN basin. Combining both methods SLN dissection may be a safe and feasible staging technique for clinical routine in EC.

Patent blue sentinel node mapping in cervical cancer patients may lead to decreased pulse oximeter readings and positive methaemoglobin results

Background and objective Patent blue (4‐[(4‐diethylaminophenyl)‐(4‐diethylazaniumylidencyclohexa‐2,5‐dienyliden) methyl]‐6‐hydroxy‐3‐sulfo‐benzolsulfonate, sodium salt) is a contrast dye used for the intraoperative detection of the primary lymphatic nodes draining the area of tumour infiltration. The dye is known to interact with pulse oximeter readings. However, the degree of alteration seems to be moderate and predictable when patent blue is injected into the perimammilar region during breast surgery. Methods Here we report severe interference with the anaesthetic monitoring when patent blue was injected into the cervix prior to laparoscopy‐assisted radical vaginal hysterectomy for cervical cancer. Results Injection of patent blue into the cervix induced a rapid (within 14 ± 9 min after the injection) and severe (from ⩾98% to 89 ± 2%) decrease in pulse oximeter readings, accompanied by positive methaemoglobin values of 7.3 ± 2.5% (arterial co‐oximetry, Bayer Rapidlab 865 blood gas analyser; Bayer, Fernwald, Germany). Control of these values by a different device (Radiometer ABL co‐oximeter blood gas analyser; Radiometer, Willich, Germany) yielded negative methaemoglobin results (<1.7%, mean 0.9 ± 0.6%). The arterial PO2 was normal in all patients throughout the procedure. Conclusion Injection of patent blue into the cervix uteri interferes dramatically with pulse oximeter readings. This situation is further complicated by device‐dependent arterial co‐oximetry methaemoglobin results. For the time being it is recommendable to monitor adequate oxygenation of the patient in the presence of patent blue by regular control of the arterial PO2. Clearly, the unresolved issue of reliable methaemoglobin determination in the presence of patent blue remains a matter of clinical concern for anaesthetists.

Groin Recurrences in Node Negative Vulvar Cancer Patients After Sole Sentinel Lymph Node Dissection.

Objective This study aimed to evaluate the recurrence rates after sole sentinel dissection in vulvar cancer and describe characteristics of groin recurrences. Methods All vulvar cancer cases between 2008 and 2014 were reviewed. Inclusion criteria were restricted to lymph node–negative patients, sole sentinel lymph node dissection (SLND), and tumor diameter less than 4 cm. In all patients, Tc-99m nanocolloid was used for preoperative SLN imaging. Regularly, planar lymphoscintigraphy and single-photon emission computed tomography with computed tomography were performed. Ultrastaging was routinely conducted on all negative lymph nodes. Results Of 140 vulvar cancer cases, 30 node-negative patients underwent sole SLND and met inclusion criteria. Keratinizing squamous cell carcinoma was determined in final histology in 20/30 (66.7%) patients and the mainly diagnosed tumor stage was pT1b (21/30, 70%). Three perioperative complications occurred. On average, 4.6 (1–9) SLNs were dissected per patient and 2.5 (1–6) per each groin, respectively. During a median follow-up of 43.5 (4–75) months, 5/30 (16.7%; 95% confidence interval, 7.3%–33.6%) local recurrences occurred. In addition, 2/30 (6.6%; 95% confidence interval, 1.9%–21.3%) groin recurrences were identified within a period of 12 months after the primary surgery. Both patients had large (>2 cm) midline tumors. Despite surgical as well as adjuvant treatment of the recurrent disease, both patients with groin recurrences died. Conclusions Sentinel lymph node dissection is a safe and feasible alternative in early vulvar cancer. But false-negative sentinel carry a high risk of mostly fatal groin recurrences. Especially, midline tumors larger than 2 cm have to be treated with caution, because they are mostly found in cases with groin recurrences after sole SLND.

SPECT/CT for SLN dissection in vulvar cancer: Improved SLN detection and dissection by preoperative three-dimensional anatomical localisation

OBJECTIVE In this study, we assessed the feasibility and clinical advantages of single photon emission computed tomography with CT (SPECT/CT) for sentinel lymph node (SLN) detection in vulvar cancer. METHODS This is a unicentric prospective trial. Vulvar cancer patients underwent preoperative SLN marking (10MBq Technetium (TC)-99m-nanocolloid) and subsequent planar lymphoscintigraphy (LSG) and SPECT/CT for SLN visualization. Directly before surgery, a patent blue dye was injected. We assessed detection rates of SPECT/CT and those of planar LSG and intraoperative detection. We analyzed the sensitivity, negative predictive value and false negative rate. RESULTS At Hannover Medical School, 40 vulvar cancer patients underwent SLN dissection after preoperative LSG and SPECT/CT. The mean diameter of all tumors in final histology was 2.23 (0.1-10.5) cm with a mean tissue infiltration of 3.93 (0.25-11) mm. In preoperative imaging, SPECT/CT identified significantly more SLNs (mean 8.7 (1-35) LNs per patient) compared to LSG (mean 5.9 (0-22) LNs, p<0.01). In addition, SPECT/CT led to a high spatial resolution and anatomical localization of SLNs. Thus, SPECT/CT identified aberrant lymphatic drainage in 7/40 (17.5%) patients. There were no significant differences, but significant correlation was found between SPECT/CT and intraoperative SLN identification. Regarding inguino-femoral LNs, for all patients who underwent complete groin dissection, sensitivity was 100%, NPV was 100% and false negative rate was 0%. CONCLUSION SPECT/CT leads to higher SLN identification compared to LSG in vulvar cancer. Due to its higher spatial resolution and three-dimensional anatomical localisation of SLNs, SPECT/CT provides the surgeon with important additional information, facilitates intraoperative SLN detection and predicts aberrant lymphatic drainage.