High concordance of molecular subtyping between pre-surgical biopsy and surgical resection specimen (matched-pair analysis) in patients with vulvar squamous cell carcinoma using p16- and p53-immunostaining.

OBJECTIVE: Vulvar squamous cell carcinoma (VSCC) can be stratified into three molecular subtypes based on the immunoexpression of p16 and p53: HPV-independent p53-abnormal (p53abn) (most common, biologically aggressive), HPV-associated, with p16-overexpression (second most common, prognostically more favourable) and more recently recognised HPV-independent p53-wildtype (p53wt) (rarest subtype, prognostically intermediate). Our aim was to determine whether molecular subtypes can be reliably identified in pre-operative biopsies and whether these correspond to the subsequent vulvectomy specimen. METHODS: Matched-paired pre-surgical biopsies and subsequent resection specimen of 57 patients with VSCC were analysed for the immunohistochemical expression of p16 and p53 by performing a three-tiered molecular subtyping to test the accuracy rate. RESULTS: Most cases 36/57 (63.2%) belonged to the HPV-independent (p53-abn) molecular subtype, followed by HPV-associated 17/57 (29.8%) and HPV-independent (p53wt) 4/57 (7.0%). The overall accuracy rate on biopsy was 91.2% (52/57): 97.3% for p53-abnormal, 94.1% for p16-overexpression and 50% for p16-neg/p53-wt VSCC. Incorrect interpretation of immunohistochemical p53 staining pattern was the reason for discordant results in molecular subtyping in all five cases. In one case there was an underestimation of p53 pattern (wildtype instead of abnormal/aberrant) and in one case an overestimation of the p53 staining pattern (abnormal/aberrant instead of wildtype). In 3/5 there was a "double positive" staining result (p16 overexpression and abnormal/aberrant p53 staining pattern). In that cases additional molecular workup is required for correct molecular subtyping, resulting in an overall need for molecular examination of 3/57 (3.5%). CONCLUSIONS: Compared to the final resections specimen, the three-tiered molecular classification of VSCC can be determined on pre-surgical biopsies with a high accuracy rate. This enables more precise surgical planning, prediction of the response to (chemo) radiation, selection of targeted therapies and planning of the optimal follow-up strategy for patients in the age of personalised medicine.

Molecular subclassification of vulvar squamous cell carcinoma: reproducibility and prognostic significance of a novel surgical technique.

OBJECTIVES: Vulvar squamous cell carcinoma is subclassified into three prognostically relevant groups: (i) human papillomavirus (HPV) associated, (ii) HPV independent p53 abnormal (mutant pattern), and (iii) HPV independent p53 wild type. Immunohistochemistry for p16 and p53 serve as surrogates for HPV viral integration and TP53 mutational status. We assessed the reproducibility of the subclassification based on p16 and p53 immunohistochemistry and evaluated the prognostic significance of vulvar squamous cell carcinoma molecular subgroups in a patient cohort treated by vulvar field resection surgery. METHODS: In this retrospective cohort study, 68 cases treated by vulvar field resection were identified from the Leipzig School of Radical Pelvic Surgery. Immunohistochemistry for p16 and p53 was performed at three different institutions and evaluated independently by seven pathologists and two trainees. Tumors were classified into one of four groups: HPV associated, HPV independent p53 wild type, HPV independent p53 abnormal, and indeterminate. Selected cases were further interrogated by (HPV RNA in situ hybridization, TP53 sequencing). RESULTS: Final subclassification yielded 22 (32.4%) HPV associated, 41 (60.3%) HPV independent p53 abnormal, and 5 (7.3%) HPV independent p53 wild type tumors. Interobserver agreement (overall Fleiss' kappa statistic) for the four category classification was 0.74. No statistically significant differences in clinical outcomes between HPV associated and HPV independent vulvar squamous cell carcinoma were observed. CONCLUSION: Interobserver reproducibility of vulvar squamous cell carcinoma subclassification based on p16 and p53 immunohistochemistry may support routine use in clinical practice. Vulvar field resection surgery showed no significant difference in clinical outcomes when stratified based on HPV status.

The diagnostic value of core needle biopsy in cervical cancer: A retrospective analysis.

Cervical carcinoma is a major cause of morbidity and mortality among women worldwide. Histological subtype, lymphovascular space invasion and tumor grade could have a prognostic and predictive value for patients' outcome and the knowledge of these histologic characteristics may influence clinical decision making. However, studies evaluating the diagnostic value of various biopsy techniques regarding these parameters of cervical cancer are scarce. We reviewed 318 cases of cervical carcinoma with available pathology reports from preoperative core needle biopsy (CNB) assessment and from final postoperative evaluation of the hysterectomy specimen. Setting the postoperative comprehensive pathological evaluation as reference, we analysed CNB assessment of histological tumor characteristics. In addition, we performed multivariable logistic regression to identify factors influencing the accuracy in identifying LVSI and tumor grade. CNB was highly accurate in discriminating histological subtype. Sensitivity and specificity were 98.8% and 89% for squamous cell carcinoma, 92.9% and 96.6% for adenocarcinoma, 33.3% and 100% in adenosquamous carcinoma respectively. Neuroendocrine carcinoma was always recognized correctly. The accuracy of the prediction of LVSI was 61.9% and was positively influenced by tumor size in preoperative magnetic resonance imaging and negatively influenced by strong peritumoral inflammation. High tumor grade (G3) was diagnosed accurately in 73.9% of cases and was influenced by histological tumor type. In conclusion, CNB is an accurate sampling technique for histological classification of cervical cancer and represents a reasonable alternative to other biopsy techniques.

Epithelial-mesenchymal transition (EMT) in vulvar cancer with and without inguinal lymph node involvement.

PURPOSE: Epithelial-mesenchymal transition (EMT) is associated with increased metastatic spread and poor prognosis. Data on vulvar carcinoma are limited. METHODS: Thirty-two cases of squamous cell carcinoma of the vulva (16 with and 16 without inguinal lymph node metastases) and their lymph node deposits were evaluated for immunohistochemical expression of EMT markers (vimentin, cyclin D1, e-cadherin), p16, p53 and Ki-67. Results of EMT-immunostainings were compared to lymph node involvement and expression of p53 and p16. The micro-anatomical staining pattern for EMT markers comparing the tumor center with the front of invasion was analysed in each tumor. RESULTS: There was no difference in the expression of EMT markers between node negative and node positive tumors. Staining for vimentin and cyclin D1 was seen within tumor cells at the front of invasion in 100 and 84.4% of the tumors, respectively. The majority of cases (68.7%) showed negative or reduced staining for e-cadherin in this micro-anatomical localization. Tumor cells within the lymph node metastases showed positive staining for e-cadherin in 75% and for cyclin D1 in 49% of the cells but were negative for vimentin in 13 out of 16 cases (81.3%). Tumors with aberrant p53 staining represented a non-significant higher vimentin but significantly higher cyclin D1 expression at the front of invasion than those with p53 wild-type pattern. CONCLUSION: The present study shows no differences in the expression of EMT markers between node positive and node negative vulvar cancers. The evaluation of immunostaining within the micro-anatomical context indicates that an EMT-phenotype is restricted to the tumor cells at the front of invasion. Paired analyses of vulvar carcinomas and their lymph node deposits suggest mesenchymal-epithelial transition (MET) in the metastatic deposits. Immunohistochemical staining results may suggest that EMT is more prevalent in vulvar cancer with aberrant p53 staining.

The Importance of Clinical Examination under General Anesthesia: Improving Parametrial Assessment in Cervical Cancer Patients.

BACKGROUND: Parametrial tumor involvement is an important prognostic factor in cervical cancer and is used to guide management. Here, we investigate the diagnostic value of clinical examination under general anesthesia (EUA) and magnetic resonance imaging (MRI) in determining parametrial tumor spread. METHODS: Post-operative pathological findings of 400 patients with primary cervical cancer were compared to the respective MRI data and the results from EUA. The gynecological oncologist had access to the MR images during clinical assessment (augmented EUA, aEUA). RESULTS: Pathologically proven parametrial tumor invasion was present in 165 (41%) patients. aEUA exhibited a higher accuracy than MRI alone (83% vs. 76%; McNemar's odds ratio [OR] = 2.0, 95%CI 1.25-3.27, p = 0.003). Although accuracy was not affected by tumor size in aEUA, MRI was associated with a lower accuracy in tumors ≥2.5 cm (OR for a correct diagnosis compared to smaller tumors 0.22, p < 0.001). There was also a decrease in specificity when evaluating parametrial invasion by MRI in tumors ≥2.5 cm in diameter (p < 0.0001) compared to smaller tumors (< 2.5 cm). Body mass index had no influence on performance of either method. CONCLUSIONS: aEUA has the potential to increase the diagnostic accuracy of MRI in determining parametrial tumor involvement in cervical cancer patients.

Quality of life and associated factors after surgical treatment of vulvar cancer by vulvar field resection (VFR).

PURPOSE: To investigate patient-reported quality of life (QoL) and associated factors in vulvar cancer patients treated surgically by vulvar field resection (VFR) without adjuvant radiation. METHODS: We retrospectively evaluated patient-reported QoL as part of the prospective monocentric VFR trial using the 30-item European Organization for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ-C30) supplemented by a question assessing sexual activity. All patients had been treated by VFR and no participant had received adjuvant radiotherapy. The gynecologic cancer lymphedema questionnaire (GCLQ) was used to determine the presence of lymphedema. Structured telephone interviews were conducted to assess postoperative sequelae and long-term complications. RESULTS: Forty-three VFR patients (median age 63 years) were available for QoL assessment. Thirty-eight (88%) had received inguinal lymph-node dissection in addition to VFR. Mean global QoL (global health status) rating among all patients was 66.1 (± 25.5) on a scale from 0 to 100 with higher scores indicating better QoL. Higher GCLQ scores were significantly associated with lower global QoL scores (Spearman's rank correlation ρ =- 0.7, p < 0.0001). The presence of preoperative co-morbidities and postoperative wound-healing complications were also linked to reduced QoL (p < 0.01 for both). In a multivariable regression model, there was a significant interaction between preoperative co-morbidities and wound-healing complications with regard to global QoL (p < 0.05). CONCLUSION: Overall, VFR patients exhibit good quality of life postoperatively. The presence of lymphedema, wound-healing complications, and preoperative morbidities were associated with reduced QoL. Prospective longitudinal studies have to confirm our findings in the future.

ECCO Essential Requirements for Quality Cancer Care: Prostate cancer.

BACKGROUND: ECCO Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give oncology teams, patients, policymakers and managers an overview of essential care throughout the patient journey. PROSTATE CANCER: Prostate cancer is the second most common male cancer and has a wide variation in outcomes in Europe. It has complex diagnosis and treatment challenges, and is a major healthcare burden. Care must only be a carried out in prostate/urology cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

Roadmap to Local Tumour Growth: Insights from Cervical Cancer.

Wide tumour excision is currently the standard approach to surgical treatment of solid cancers including carcinomas of the lower genital tract. This strategy is based on the premise that tumours exhibit isotropic growth potential. We reviewed and analysed local tumour spreading patterns in 518 patients with cancer of the uterine cervix who underwent surgical tumour resection. Based on data obtained from pathological examination of the surgical specimen, we applied computational modelling techniques to simulate local tumour spread in order to identify parameters influencing preferred infiltration patterns and used area-proportional Euler diagrams to detect and confirm ordered patterns of tumour spread. Some anatomical structures, e.g. tissues of the urinary bladder, were significantly more likely to be infiltrated than other structures, e.g. the ureter and the rectum. Computational models assuming isotropic growth could not explain these infiltration patterns. Introducing ontogenetic distance of a tissue relative to the uterine cervix as a parameter led to accurate predictions of the clinically observed infiltration likelihoods. The clinical data indicates that successive infiltration likelihoods of ontogenetically distant tissues are nearly perfect subsets of ontogenetically closer tissues. The prevailing assumption of isotropic tumour extension has significant shortcomings in the case of cervical cancer. Rather, cervical cancer spread seems to follow ontogenetically defined trajectories.

Surgical resection based on ontogenetic cancer field theory for cervical cancer: mature results from a single-centre, prospective, observational, cohort study.

BACKGROUND: Previous findings from our centre suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. We aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumour control without the need for adjuvant radiotherapy. METHODS: We did the final clinical and histopathological evaluation of data from, the single-centre, observational, cohort study, the Leipzig School Mesometrial Resection Study. Patients of any age with stage IB1, IB2, IIA1, IIA2, or IIB cervical cancer (according to 2009 International Federation of Gynecology and Obstetrics [FIGO]) had total mesometrial resection or extended mesometrial resection and therapeutic lymph node dissection, done on the basis of ontogenetic cancer fields. We defined sentinel node, first-line, second-line, and third-line lymph node regions as progressive regional cancer fields. Primary outcomes were disease-specific survival and recurrence-free survival, and treatment-related morbidity (assessed with the Franco-Italian glossary). Applying Cox proportional hazard models, ontogenetic local (T) and regional (N) tumour staging was compared with pathological T and N staging. This trial is registered with the German Clinical Trials Register, number DRKS00015171. FINDINGS: Between Oct 16, 1999, and June 27, 2017, 523 patients were treated per protocol and followed up for a median of 61·8 months (IQR 49·3-94·8). In 495 patients with cervical cancer treated with cancer field surgery, 5-year disease-specific survival was 89·4% (95% CI 86·5-92·4) and recurrence-free survival was 83·1% (79·7-86·6). In the per-protocol population of 523 patients, treatment-related morbidity comprised 112 (21%) grade 2 and 15 (3%) grade 3 complications. The most common moderate and severe treatment-related complications and sequelae were wound dehiscence (17 [3%]), hydronephrosis (17 [3%]), bowel obstruction (26 [5%]), and lymph oedema (33 [6%]). One patient (<1%), who received total mesometrial resection, died from postoperative brain infarction. INTERPRETATION: Total or extended mesometrial resection with therapeutic lymph node dissection based on ontogenetic cancer fields results in good survival outcomes of patients with cervical cancer in our institution, but needs to be investigated further in multicentre trials. FUNDING: Leipzig School of Radical Pelvic Surgery, University of Leipzig Medical School, and the Gynecologic Oncology Research Foundation.

The Order of Cancer: A Theory of Malignant Progression by Inverse Morphogenesis.

Local spread patterns of malignant tumors follow permissive tissue territories, i.e., cancer fields, as shown for cervical and vulvar carcinoma. The cancer fields are associated in reverse order to the mature derivatives of the morphogenetic fields instrumental in the stepwise development of the tissue from which the tumor arose. This suggests that cancer progression may be linked to morphogenesis by inversion of the cellular bauplan sequence. Successive attractor transitions caused by proliferation-associated constraints of topobiological information processing are proposed for both morphogenesis and cancer. In morphogenesis these transitions sequentially activate bauplans with increasing complexity at decreasing plasticity restricting the permissive territories of the progenitor cell populations. Somatic mutations leading to cell proliferation in domains normally reserved for differentiation trigger the inverse cascade of bauplan changes that increase topobiological plasticity at decreased complexity and stepwise enlarge the permissive territory of neoplastic cells consistent with the clinical manifestations of cancer. The order provided by the sequence of attractor transitions and the defined topography of the permissive territories can be exploited for more accurate tumor staging and for locoregional tumor treatment either by surgery or radiotherapy with higher curative potential.

Vulvar field resection based on ontogenetic cancer field theory for surgical treatment of vulvar carcinoma: a single-centre, single-group, prospective trial.

BACKGROUND: The incidence of vulvar cancer is increasing, but surgical treatment-the current standard of care-often leads to unsatisfactory outcomes, especially in patients with node-positive disease. Preliminary results at our centre showed that locoregional spread of vulvar carcinoma occurs within tissue domains defined by stepwise embryonic and fetal development (ontogenetic cancer fields and associated lymph node regions). We propose that clinical translation of these insights into practice could improve outcomes of surgical treatment of vulvar cancer. METHODS: We did a single-centre prospective trial at the University of Leipzig's Cancer Center. Eligible patients were aged 18 years or older, had ontogenetic stage 1-3b histologically proven primary carcinoma of the vulva, and had not undergone previous surgical or radiotherapy treatment for vulvar cancer or any other major perineal or pelvic disease. In view of staged morphogenesis of the vulva from the cloacal membrane endoderm at Carnegie stage 11 to adulthood, we defined the tissue domains of tumour spread according to the theory of ontogenetic cancer fields. On the basis of ontogenetic staging, patients were treated locally with partial, total, or extended vulvar field resection; regionally with therapeutic inguinopelvic lymph node dissection; and anatomical reconstruction without adjuvant radiotherapy. The primary endpoints were recurrence-free survival, disease-specific survival, and early postoperative complications. Analysis of tumour spread and early postoperative surgical complications was done by intention to treat (ie, all patients were included), whereas outcome analyses were done per protocol. This ongoing trial is registered with the German Clinical Trials Register, number DRKS00013358. FINDINGS: Between March 1, 2009, and June 8, 2017, 97 consecutive patients were included in the study, of whom 94 were treated per protocol with vulvar field resection, therapeutic inguinopelvic lymph node dissection, and anatomical reconstruction without adjuvant radiotherapy. 46 patients had moderate or severe postoperative complications, especially infectious perineal and inguinal wound dehiscence. 3-year recurrence-free survival in all patients was 85·1% (95% CI 76·9-93·3), and 3-year disease-specific survival was 86·0% (78·2-93·8). INTERPRETATION: Our results support the theory of ontogenetic cancer fields for vulvar carcinoma, accord with our previous findings in cervical cancer, and suggest the general applicability of the theory. Application of the concept of cancer field resection could improve outcomes in patients with vulvar carcinoma, but needs to be investigated further in multicentre randomised controlled trials. FUNDING: Leipzig School of Radical Pelvic Surgery and Gynecologic Oncology Research Foundation.

Extended mesometrial resection (EMMR): Surgical approach to the treatment of locally advanced cervical cancer based on the theory of ontogenetic cancer fields.

BACKGROUND: Based on ontogenetic-anatomic considerations, we have introduced total mesometrial resection (TMMR) and laterally extended endopelvic resection (LEER) as surgical treatments for patients with cancer of the uterine cervix FIGO stages I B1 - IV A. For a subset of patients with locally advanced disease we have sought to develop an operative strategy characterized by the resection of additional tissue at risk for tumor infiltration as compared to TMMR, but less than in LEER, preserving the urinary bladder function. METHODS: We conducted a prospective single center study to evaluate the feasibility of extended mesometrial resection (EMMR) and therapeutic lymph node dissection as a surgical treatment approach for patients with cervical cancer fixed to the urinary bladder and/or its mesenteries as determined by intraoperative evaluation. None of the patients received postoperative adjuvant radiotherapy. RESULTS: 48 consecutive patients were accrued into the trial. Median tumor size was 5cm, and 85% of all patients were found to have lymph node metastases. Complete tumor resection (R0) was achieved in all cases. Recurrence free survival at 5years was 54.1% (95% CI 38.3-69.9). The overall survival rate was 62.6% (95% CI 45.6-79.6) at 5years. Perioperative morbidity represented by grade II and III complications (determined by the Franco-Italian glossary) occurred in 25% and 15% of patients, respectively. CONCLUSION: We demonstrate in this study the feasibility of EMMR as a surgical treatment approach for patients with locally advanced cervical cancer and regional lymph node invasion without the necessity for postoperative adjuvant radiation.

Anogenital lichen sclerosus: Change of tissue position as pathogenetic factor.

•Lichen sclerosus in females primarily involves the hairless anogenital skin.•Skin tissue outside this area is constitutionally not at risk for lichen sclerosus.•Transplantation into the vulvar field may turn skin susceptible to lichen sclerosus.•Tissue inherent positional information might affect lichen sclerosus susceptibility.

Surgical treatment and histopathological assessment of advanced cervicovaginal carcinoma: A prospective study and retrospective analysis.

BACKGROUND: Standard treatment of advanced cervicovaginal cancer [international federation of gynecology and obstetrics (FIGO) stages II(B), III(A, B), IVA] is (chemo-)radiation excluding the possibility of systematic histopathological assessment of locoregional tumour spread. Laterally extended endopelvic resection (LEER) and therapeutic lymph node dissection (tLND) are novel surgical treatment options for advanced cervicovaginal cancer. METHODS: The therapeutic efficacy of LEER for locally advanced primary and recurrent cervicovaginal cancer was reassessed by an update of the prospective observational trial at the University of Leipzig. LEER specimens were histopathologically analysed for patterns of locoregional tumour spread with particular consideration of morphogenetic cancer fields. Histopathological features associated with malignant ureteral obstruction were evaluated. Clinical (FIGO), pathological (pT) and ontogenetic (oT) tumour staging were compared. RESULTS: Eighty-eight patients with locally advanced primary and recurrent cervicovaginal cancer were treated with LEER and tLND. LEER removed all but one tumour with microscopically clear margins (R0). After median follow-up of 40 months (7-191) five-year overall survival rate was 50% (95% confidence interval [CI]: 40-62) for the whole cohort and 46% (95% CI: 34-62) for 51 patients without a curative option from current treatment. The tissue domains of cervicovaginal cancer spread mirrored the derivatives of the morphogenetic fields instrumental for the formation of the lower genital ducts. Periureteral fibrosis accompanying mesometrial invasion, tumour infiltration of the mesureter and infiltration of the ureter itself were identified as histopathological correlates of ureteral obstruction associated with an increasingly worse prognosis. Ontogenetic tumour staging based on morphogenetic cancer fields predicted outcome better than pT and FIGO staging. INTERPRETATION: LEER and tLND expand the curative treatment options for advanced cervicovaginal cancer. Histopathological assessment of advanced disease supports the concept of tumour spread within morphogenetic cancer fields, provides insights into the pathomechanism of ureteral obstruction and allows precise tumour staging.

Value of diffusion-weighted MRI in diagnosis of uterine cervical cancer: a prospective study evaluating the benefits of DWI compared to conventional MR sequences in a 3T environment.

BACKGROUND: Imaging of cervical carcinoma remains challenging as local infiltration of surrounding tissues cannot always be discriminated safely. New imaging techniques, like diffusion-weighted imaging (DWI) have emerged, which could lead to a more sensitive tumor detection. PURPOSE: To evaluate the benefits of DWI for determination of size, local infiltration, and tumor grading, in patients with primary and recurrent cervical cancer. MATERIAL AND METHODS: In this prospective, study we enrolled 50 patients with primary (n = 35) and recurrent (n = 15) tumors. All patients underwent 3T magnetic resonance imaging (MRI) including conventional (e.g. T1/T2 ± fs ± contrast) sequences and DWI (b-values of 0, 50, 400, 800 s/mm(2)). All images were analyzed by three readers with different experience levels (1, 3, 6 years), who compared image quality, tumor delineation, dimensions, local infiltration, lymph node involvement, and quantified ADC values compared to the histopathological grading. RESULTS: Additional use of DWI resulted in significantly better (P < 0.001) tumor delineation for the least experienced reader, but not for experienced readers. Tumor dimensions were assessed almost equally (P > 0.05) in conventional sequences and DWI. Use of DWI led to an increase in sensitivity of infiltrated adjacent tissue (from 86% to 90%) and detection of lymph node metastases (from 47% to 67%). Quantitative assessment of carcinomas showed lower ADC values (P < 0.001) with significant inverse correlations between different grading levels. CONCLUSION: Our study demonstrates the overall benefits using DWI in 3T MRI resulting in a higher reader confidence, sensitivity of tissue infiltration, and tumor-grading for cervical cancer.

Morphogenetic fields of embryonic development in locoregional cancer spread.

The ontogenetic theory of locoregional cancer spread regards cancer as a clinical manifestation of the pathological reactivation and maintenance of the sequential developmental programmes that previously controlled the stepwise embryological morphogenesis of the tissue from which the cancer originated. In the state of morphostasis that characterises adult organisms, these programmes are silenced. During malignant progression, these programmes run in retrograde sequence, which leads to cancer infiltration of ever larger tissue areas. However, because the reactivated morphogenetic programmes need topologically defined tissue domains--morphogenetic fields--to provide positional information for their interpretation, local tumour propagation is confined to permissive compartments (topographically defined tissue domains where malignant cells can survive, migrate, and proliferate), which are determined by the state of malignant progression. The tissue at risk of local tumour spread, the cancer field, is the mature tissue derived from the corresponding morphogenetic field in the embryo, which is labelled with the respective positional information. The theory can be tested morphologically and clinically for all tumours. Verification of this theory would offer substantial potential to improve prognostic assessment and surgical treatment. Identification of the complementary positional information for tumour cells in different ontogenetic stages, and their associated cancer fields, could be a molecular research strategy to further test the theory.

Long-term experience with (laterally) extended endopelvic resection (LEER) in relapsed pelvic malignancies.

Gynecologic cancers recurring in the pelvis are generally advanced in malignant progression limiting curative treatment approaches. The cancer field theory links cancer progression to reversed morphogenesis and allows the exact anatomical delineation of the cancer field, i.e., the tissue compartment of potential tumor infiltration related to the tumor's ontogenetic stage. Cancer surgery is redefined with the resection of ontogenetic stage-related cancer fields instead of the mere removal of the malignant tumor with an uninvolved tissue margin. Most gynecologic pelvic malignancies recurring in the pelvis represent ontogenetic stages 3 and 4. (Laterally) extended endopelvic resection ((L)EER) has been designed to resect the cancer fields of gynecologic tumors in these advanced ontogenetic stages. This paper reports long-term experience with (L)EER for relapsed pelvic malignancies strongly supporting the cancer field theory and the principle and practice of cancer field resection.

Association between developmental steps in the organogenesis of the uterine cervix and locoregional progression of cervical cancer: a prospective clinicopathological analysis.

BACKGROUND: Our previous work provided evidence that early cervical cancer is locally confined to the Müllerian compartment that develops in women from the embryonic paramesonephric-mesonephric complex. We aimed to investigate if the concept of tumour permeation within ontogenetic domains is also valid for tumour progression and advanced disease. METHODS: Starting from Carnegie stage 13, four successive steps in the organogenesis of the human uterine cervix were defined and an ontogenetic staging system for cervical cancer based on organ development was described. Histopathological and clinical data of patients with cervical cancer FIGO stages IB-IVA were raised prospectively from Oct 16, 1999, until Dec 20, 2012, and from March 8, 2000, until April 4, 2013, for two surgical trials of ontogenetic compartment resection without adjuvant radiation at the University of Leipzig (total or extended mesometrial resection [TMMR or EMMR]; and [laterally] extended endopelvic resection [LEER]). The primary endpoints of these trials were pathological resection state and locoregional tumour control. Patients who underwent TMMR and EMMR had follow-up assessment every 3-6 months for 5 years, and yearly thereafter. Patients who had (L)EER, every 3-6 months for 10 years, and yearly thereafter. By analysing the presence of disease within the classified tissues and disease outcome in these patients, and by examining relapse patterns, we were able to observe whether surgical excision within developmental compartments was sufficient for disease control. Survival curves were compared using the log-rank test. The effect of ontogenetic tumour stage and pathological tumour stage on overall survival was assessed by Cox proportional hazard models. The trials are registered as an ongoing observational monocentric study at the University of Leipzig Cancer Centre (ULCC012-13-28012013). FINDINGS: 367 patients were included in our analysis. Staged organogenesis of the uterine cervix and progressive local growth of cervical carcinoma occur in the same tissue domains. The neoplasm originating in the uterine cervix, ontogenetic tumour stage 1 (oT1, n=217), permeates successively during its malignant progression the tissues developed from the Müllerian compartment (oT2, n=101), the genital metacompartment (oT3, n=38), and the urogenitorectal metacompartment (oT4, n=11). Ontogenetic staging, when comparing patients with oT1 and oT2 disease to those with oT3 and oT4 disease (hazard ratio 5·9, 95% CI 2·2-15·5; p=0·00036) was a better prognostic indicator for survival than pathological staging when comparing pT1b and pT2a with pT2b and pT4 disease (2·0, 95% CI 0·7-5·5; p=0·170). Resection of the stage-related ontogenetically specified tissue domains and their associated regional lymphoid tissues achieved an R0 resection in 363 (99%) of 367 patients and locoregional tumour control at 5 years was 94% (95% CI 92-97). 13 patients had grade 3 or 4 adverse events, the majority of which were urinary (10, 77%). INTERPRETATION: Cervical cancer infiltrates the adult tissues established during ontogeny, pursuing the developmental steps in retrograde sequence. Clinical translation of these insights into ontogenetic tumour staging and compartment resection holds the potential to improve prognostic assessment and curative treatment. FUNDING: University of Leipzig and Leipzig School of Radical Pelvic Surgery.