title: Intraoperative frozen section analysis for the diagnosis of early stage ovarian cancer in suspicious pelvic masses.
abstract: BACKGROUND
  Women with suspected early-stage ovarian cancer need surgical staging which involves taking samples from areas within the abdominal cavity and retroperitoneal lymph nodes in order to inform further treatment. One potential strategy is to surgically stage all women with suspicious ovarian masses, without any histological information during surgery. This avoids incomplete staging, but puts more women at risk of potential surgical over-treatment.A second strategy is to perform a two-stage procedure to remove the pelvic mass and subject it to paraffin sectioning, which involves formal tissue fixing with formalin and paraffin embedding, prior to ultrathin sectioning and multiple site sampling of the tumour. Surgeons may then base further surgical staging on this histology, reducing the rate of over-treatment, but conferring additional surgical and anaesthetic morbidity.A third strategy is to perform a rapid histological analysis on the ovarian mass during surgery, known as 'frozen section'. Tissues are snap frozen to allow fine tissue sections to be cut and basic histochemical staining to be performed. Surgeons can perform or avoid the full surgical staging procedure depending on the results. However, this is a relatively crude test compared to paraffin sections, which take many hours to perform. With frozen section there is therefore a risk of misdiagnosing malignancy and understaging women subsequently found to have a presumed early-stage malignancy (false negative), or overstaging women without a malignancy (false positive). Therefore it is important to evaluate the accuracy and usefulness of adding frozen section to the clinical decision-making process.
  
  
  OBJECTIVE
  To assess the diagnostic test accuracy of frozen section (index test) to diagnose histopathological ovarian cancer in women with suspicious pelvic masses as verified by paraffin section (reference standard).
  
  
  METHODS
  We searched MEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015) and relevant Cochrane registers.
  
  
  METHODS
  Studies that used frozen section for intraoperative diagnosis of ovarian masses suspicious of malignancy, provided there was sufficient data to construct 2 x 2 tables. We excluded articles without an available English translation.
  
  
  METHODS
  Authors independently assessed the methodological quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) domains: patient selection, index test, reference standard, flow and timing. Data extraction converted 3 x 3 tables of per patient results presented in articles into 2 x 2 tables, for two index test thresholds.
  
  
  RESULTS
  All studies were retrospective, and the majority reported consecutive sampling of cases. Sensitivity and specificity results were available from 38 studies involving 11,181 participants (3200 with invasive cancer, 1055 with borderline tumours and 6926 with benign tumours, determined by paraffin section as the reference standard). The median prevalence of malignancy was 29% (interquartile range (IQR) 23% to 36%, range 11% to 63%). We assessed test performance using two thresholds for the frozen section test. Firstly, we used a test threshold for frozen sections, defining positive test results as invasive cancer and negative test results as borderline and benign tumours. The average sensitivity was 90.0% (95% confidence interval (CI) 87.6% to 92.0%; with most studies typically reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to 99.7%; range 96% to 100%).Similarly, we analysed sensitivity and specificity using a second threshold for frozen section, where both invasive cancer and borderline tumours were considered test positive and benign cases were classified as negative. Average sensitivity was 96.5% (95% CI 95.5% to 97.3%; typical range 83% to 100%), and average specificity was 89.5% (95% CI 86.6% to 91.9%; typical range 58% to 99%).Results were available from the same 38 studies, including the subset of 3953 participants with a frozen section result of either borderline or invasive cancer, based on final diagnosis of malignancy. Studies with small numbers of disease-negative cases (borderline cases) had more variation in estimates of specificity. Average sensitivity was 94.0% (95% CI 92.0% to 95.5%; range 73% to 100%), and average specificity was 95.8% (95% CI 92.4% to 97.8%; typical range 81% to 100%).Our additional analyses showed that, if the frozen section showed a benign or invasive cancer, the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively.In cases where the frozen section diagnosis was a borderline tumour, on average 21% of the final diagnoses would turn out to be invasive cancer.In three studies, the same pathologist interpreted the index and reference standard tests, potentially causing bias. No studies reported blinding pathologists to index test results when reporting paraffin sections.In heterogeneity analyses, there were no statistically significant differences between studies with pathologists of different levels of expertise.
  
  
  CONCLUSIONS
  In a hypothetical population of 1000 patients (290 with cancer and 80 with a borderline tumour), if a frozen section positive test result for invasive cancer alone was used to diagnose cancer, on average 261 women would have a correct diagnosis of a cancer, and 706 women would be correctly diagnosed without a cancer. However, 4 women would be incorrectly diagnosed with a cancer (false positive), and 29 with a cancer would be missed (false negative).If a frozen section result of either an invasive cancer or a borderline tumour was used as a positive test to diagnose cancer, on average 280 women would be correctly diagnosed with a cancer and 635 would be correctly diagnosed without. However, 75 women would be incorrectly diagnosed with a cancer and 10 women with a cancer would be missed.The largest discordance is within the reporting of frozen section borderline tumours. Investigation into factors leading to discordance within centres and standardisation of criteria for reporting borderline tumours may help improve accuracy. Some centres may choose to perform surgical staging in women with frozen section diagnosis of a borderline ovarian tumour to reduce the number of false positives. In their interpretation of this review, readers should evaluate results from studies most typical of their population of patients.
authors.affiliation: Gynaecological Oncology, Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Sheriff Hill, Gateshead, Tyne and Wear, UK, NE9 6SX.
authors.forename: Nithya D G
authors.initials: ND
authors.lastname: Ratnavelu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Brown
authors.forename: Susan
authors.initials: S
authors.lastname: Mallett
authors.forename: Rob J P M
authors.initials: RJ
authors.lastname: Scholten
authors.forename: Amit
authors.initials: A
authors.lastname: Patel
authors.forename: Christina
authors.initials: C
authors.lastname: Founta
authors.forename: Khadra
authors.initials: K
authors.lastname: Galaal
authors.forename: Paul
authors.initials: P
authors.lastname: Cross
authors.forename: Raj
authors.initials: R
authors.lastname: Naik
mesh_terms: D003951:Diagnostic Errors / Q000706:statistics & numerical data; D005188:False Negative Reactions; D005189:False Positive Reactions; D005260:Female; D005629:Frozen Sections / Q000379:methods*; D006801:Humans; D007432:Intraoperative Period; D009367:Neoplasm Staging / Q000379:methods*; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000601:surgery; D016612:Paraffin Embedding; D010386:Pelvic Neoplasms / Q000473:pathology; D012189:Retrospective Studies; D012680:Sensitivity and Specificity