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Intraoperative frozen section analysis for the diagnosis of early stage ovarian cancer in suspicious pelvic masses

  • Review
  • Diagnostic

Authors


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.

Objectives

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).

Search methods

We searched MEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015) and relevant Cochrane registers.

Selection criteria

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.

Data collection and analysis

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.

Main 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.

Authors' 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.

Plain language summary

Is a 'quick diagnosis' test on an ovarian mass during surgery accurate?

The issue

When women go to their doctor with a mass that could be ovarian cancer, they are normally referred for surgery, since the mass may need to be removed and examined microscopically in a laboratory in a procedure known as paraffin section histopathology. A third of women with ovarian cancer present with a cyst or mass without any visible evidence of spread elsewhere. However, in these apparently early-stage cancers (confined to the ovary) surgical staging is required to decide if chemotherapy is required. This staging consists of sampling tissues within the abdomen, including lymph nodes.

Different staging strategies exist. One is to perform surgical staging for all women who might have a cancer, to get information about spread. This may result in complications due to additional surgical procedures that may turn out to be unnecessary in approximately two thirds of women.

A second strategy is to perform an operation to remove just the suspicious mass and await the paraffin section diagnosis. This may result in needing a further operation in one third of women if cancer is confirmed, putting them at increased risks from another operation.

A third strategy is to send the mass to the laboratory during the operation for a quick diagnosis, known as 'frozen section'. This helps the surgeon decide if further surgical treatment is required during a single operation.

Why is this review important?

Frozen section is not as accurate as the traditional slower paraffin section examination, and it entails a risk of incorrect diagnosis, meaning that some women may not have all the samples taken at the initial surgery and may need to undergo a second operation; and others may undergo unnecessary surgical sampling.

How was this review conducted?

We searched all available studies reporting use of frozen section in women with suspicious ovarian masses. We excluded studies without an English translation and studies without enough information to allow us to analyse the data.

What are the findings?

We included 38 studies (11,181 women), reporting three types of diagnoses from the frozen section test.

1. Cancer, which occurred in an average of 29% of women.

2. Borderline tumour, which occurred in 8% of women.

3. Benign mass.

In a hypothetical group of 1000 patients where 290 have cancer and 80 have a borderline tumour, 261 women would receive a correct diagnosis of a cancer and 706 women would be correctly diagnosed without a cancer based on a frozen section result. However, 4 women would be incorrectly diagnosed as having a cancer where none existed (false positive), and 29 women with cancer would be missed and potentially need further treatment (false negative).

If surgeons used a frozen section result of either a cancer or a borderline tumour to diagnose cancer, 280 women would be correctly diagnosed with a cancer and 635 women would be correctly diagnosed without a cancer. However, 75 women would be incorrectly diagnosed as having a cancer, and 10 women with cancer would be missed on the initial test and found to have a cancer after surgery.

If the frozen section result reported the mass as benign or malignant, the final diagnosis would remain the same in, on average, 94% and 99% of the cases, respectively.

In cases where the frozen section diagnosis was a borderline tumour, there is a chance that the final diagnosis would turn out to be a cancer in, on average, 21% of women.

What does this mean?

Where the frozen section diagnosis is a borderline tumour, the diagnosis is less accurate than for benign or malignant tumours. Surgeons may choose to perform additional surgery in this group of women at the time of their initial surgery in order to reduce the need for a second operation if the final diagnosis turns out to be a cancer, as it would on average in one out of five of these women.

Laički sažetak

Je li brzi dijagnostički test za procjenu mogućeg karcinoma jajnika tijekom kirurškog zahvata točan?

Problem

Žene za koje se utvrdi da imaju sumnjive mase tkiva u zdjelici koje bi mogle biti karcinom jajnika obično se upućuju na kriruški zahvat jer to tkivo treba ukloniti i ispitati pod mikroskopom u laboratoriju postupkom koji se naziva histopatologija parafinskih rezova. Trećina žena koje imaju karcinom jajnika javlja se kad imaju cistu ili tumor bez vidljivih dokaza o širenju tumora na druga mjesta. Međutim, u tim karcinomima koji su naizgled ranog stadija (ograničeni na jajnik) nužno je napraviti tzv. kirurško stupnjevanje (određivanje stadija proširenosti) kako bi se odlučilo je li nužna kemoterapija (liječenje lijekovima protiv karcinoma). To stupnjevanje uključuje uzimanje uzorka sumnjivog tkiva u trbuhu, uključujući i limfne čvorove.

Postoje različite strategije određivanja stadija karcinoma. Jedan je postupak provedba kirurškog stupnjevanja u svih žena koje bi mogle imati karcinom, kako bi se dobile informacije o mogućem širenju. To može dovesti do komplikacija jer su potrebni dodatni kirurški zahvati koji se mogu pokazati nepotrebnima u gotovo dvije trećine žena.

Druga je mogućnost tijekom operacije izvaditi samo sumnjivu masu tkiva i pričekati da se napravi dijagnoza na parafinskim rezovima tkiva. To može dovesti do potrebe za još jednom operacijom u trećine žena ako se potvrdi karcinom, što ih izlaže još jednom kirurškom zahvatu.

Treća je mogućnost poslati uzorak tkiva u laboratorij tijekom operacije za brzu dijagnozu pomoću tzv. smrznutih rezova tkiva. Na taj način kirurg brzo dobije informaciju da li se radi o karcinomu i je li potrebno dodatno uklanjanje tkiva tijekom jedne operacije.

Zašto je ovaj sustavni pregled važan?

Smrznuti rezovi nisu jednako točni kao analiza tradicionalnih parafinskih rezova, čija je priprema sporija. Stoga analiza smrznutih rezova nosi mogućnost netočne dijagnoze, što znači da će nekim ženama možda trebati ponovna operacija, a druge žene će nepotrebno proći kroz postupak kirurškog uzimanja uzorka tkiva.

Kako je proveden ovaj sustavni pregled literature?

Pretražena je literatura kako bi se našle sve studije koje su ispitale uporabu smrznutih rezova u žena sa sumnjivim tkivom na jajniku. Isključene su studije koje nisu bile objavljene na engleskom jeziku i studije koje nisu sadržavale dovoljno informacija pa za njih nije bilo moguće provesti analizu podataka.

Rezultati

U ovaj Cochrane sustavni pregled uključeno je 38 studija (11.181 žena) koje su opisale tri vrste dijagnoza temeljem smrznutih rezova.

1. Karcinom, koji je dijagnosticiran u prosječno 29% žena.

2. Granični tumor, koji je utvrđen u 8% žena.

3. Benigna (dobroćudna) masa tkiva.

U zamišljenoj skupini od 1000 žena, gdje ih 290 ima karcinom jajnika i 80 ima granični tumor, 261 žena bi dobila točnu dijagnozu karcinoma i 706 žena bi dobile točnu dijagnozu da nemaju karcinom, temeljem analize smrznutih rezova tkiva tijekom operacije. Međutim, u 4 žene bi se postavila netočna dijagnoza da imaju karcinom koji zapravo ne postoji (lažno pozitivna dijagnoza), a u 29 žena se karcinom koji zaista postoji ne bi prepoznao i te žene ne bi dobile daljnje liječenje (lažno negativni rezultat).

Ako kirurzi koriste smrznute rezove za dijagnosticiranje karcinoma ili graničnog tumora, 280 žena bi dobilo točnu dijagnozu karcinoma, a 635 žena bi dobilo točnu dijagnozu da nemaju karcinom. Međutim, u 75 žena bi se netočno postavila dijagnoza karcinoma, a 10 žena s karcinomom ne bi se prepoznalo.

Ako se rezultat na smrznutim rezovima tkiva opisuje samo kao dobroćudan ili zloćudan, konačna dijagnoza bila bi ista u prosječno 94%, odnosno 99% slučajeva.

u slučajevima kad se temeljem smrznutih rezova postavi dijagnoza graničnog tumora, postoji vjerojatnost da će u 21% žena konačna dijagnoza ipak biti karcinom.

Što ti rezultati znače?

Ako se analizom smrznutih rezova postavi dijagnoza graničnog tumora, dijagnoza je manje točna nego za beninge ili maligne tumore. Kirurzi mogu odlučiti napraviti dodatni kirurški zahvat u toj skupini žena u vrijeme početnog kirurškog zahvata kako bi smanjili potrebu za dodatnom operacijom u slučaju da konačna dijagnoza ipak bude karcinom, što se utvrdi u jedne od pet takvih žena.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Является ли точным тест "быстрой диагностики" образования яичника во время операции?

Проблема

Когда женщины идут к своему врачу с образованием, которое может быть раком яичника, они обычно направляются на хирургическую операцию, так как образование, возможно, должно быть удалено и проверено микроскопически в лаборатории с помощью процедуры, известной как гистопатология парафиновых срезов. Треть женщин с раком яичника имеют кисту или образование без каких-либо видимых доказательств распространения куда-либо. Однако, при этих, казалось бы, ранних стадиях рака (относительно яичника), требуется хирургическое определение стадии для решения, требуется ли химиотерапия. Стадирование состоит из взятия проб тканей внутри брюшной полости, включая лимфатические узлы.

Существуют различные стратегии стадирования. Одним из них является проведение хирургического стадирования для всех женщин, которые могут иметь рак, чтобы получить информацию о распространении. Это может привести к осложнениям вследствие дополнительных хирургических процедур, которые могут оказаться ненужными примерно для двух третей женщин.

Вторая стратегия состоит в том, чтобы выполнить операцию, чтобы удалить только подозрительную массу и ждать диагноза парафинового среза. Это может привести к необходимости дальнейшей операции у одной трети женщин, если рак подтвержден, что подвергает их повышенному риску от другой операции.

Третьей стратегией является отправить образование в лабораторию во время операции для быстрой диагностики, известной как "замороженный срез". Это помогает хирургу решить, требуется ли дальнейшее хирургическое лечение во время операции.

Почему этот обзор важен?

Замороженные срезы не такие точные, как традиционное более медленно приготовленные парафиновые срезы. Использование замороженных срезов влечет за собой риск неправильного диагноза, что означает, что некоторым женщинам возьмут не все образцы во время первичной операции и им может потребоваться перенести вторую операцию; а другие могут подвергнуться ненужному хирургическому забору материала.

Как был проведен этот обзор?

Мы провели поиск всех доступных исследований, сообщающих об использовании замороженных срезов у женщин с подозрительными образованиям яичников. Мы исключили исследования без английского перевода и исследования без достаточной информации, позволяющей нам проанализировать информацию.

Каковы результаты?

Мы включили 38 исследований (11,181 женщин), сообщающих три типа диагнозов по тесту замороженного среза.

1. Рак, который наблюдался в среднем у 29% женщин.

2. Пограничная опухоль, которая наблюдалась у 8% женщин.

3. Доброкачественное образование.

В гипотетической группе из 1000 пациентов, где 290 имеют рак и 80 имеют пограничную опухоль, 261 женщина получит правильный диагноз рака и 706 женщинам будет правильно поставлен диагноз отсутствия рака, на основании результатов замороженных срезов. Однако, 4 женщинам будет поставлен неправильный диагноз - рак, где его не было (ложно-положительный), и 29 женщин с раком пропустят и они потенциально будут нуждаться в дальнейшем лечении (ложно-отрицательный).

Если бы хирурги использовали результаты замороженных срезов рака или доброкачественной опухоли для диагностики рака, 280 женщин с раком получили бы правильный диагноз и 635 женщин без рака получили бы правильный диагноз. Однако, 75 женщин получат неправильный диагноз - рак, а 10 женщин с раком пропустят при первичном тесте и рак будет обнаружен после операции.

Если результаты замороженных срезов сообщают, что образование доброкачественное или злокачественное, окончательный диагноз останется таким же в среднем в 94% и 99% случаев соответственно.

В случаях, когда диагнозом замороженного среза был пограничная опухоль, был шанс, что окончательный диагноз окажется раком, в среднем, у 21% женщин.

Что это значит?

Когда диагнозом замороженного среза является пограничная опухоль, диагноз менее точен, чем для доброкачественных или злокачественных опухолей. Хирурги могут выбрать выполнение дополнительной операции в этой группе женщин во время их первичной операции, чтобы уменьшить необходимость во второй операции, если окончательный диагноз окажется раком, так как это будет в среднем одна из пяти этих женщин.

Заметки по переводу

Перевод: Нурхаметова Диляра Фархадовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com