Liquid-based cervical cytology vs. conventional Pap smears

[Anna Plastic]

For all of you cytologically inclined folks: I came across this doing a lit search for something else (I'm happy to say my days of reviewing cervical cytology are behind me). Interesting to see their results, but I confess I didn't scruitinize the paper. These findings harken back to our discussion on technology and what it adds to pathology practice. Discuss.

BMJ, doi:10.1136/bmj.39196.740995.BE (published 21 May 2007)

Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening randomised controlled trial
Guglielmo Ronco 1*, Jack Cuzick 2, Paola Pierotti 3, Maria Paola Cariaggi 4, Paolo Dalla Palma 5, Carlo Naldoni 6, Bruno Ghiringhello 7, Paolo Giorgi-Rossi 8, Daria Minucci 9, Franca Parisio 7, Ada Pojer 5, Maria Luisa Schiboni 10, Catia Sintoni 11, Manuel Zorzi 12, Nereo Segnan 1, Massimo Confortini 4, and the New Technologies for Cervical Cancer Screening (NTCC) Working Group

Objective To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer.

Design Randomised controlled trial.

Setting Nine screening programmes in Italy.

Participants Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm.

Interventions Conventional cytology compared with liquid based cytology and testing for human papillomavirus.

Main outcome measure Relative sensitivity for cervical intraepithelial neoplasia of grade 2 or more at blindly reviewed histology, with atypical cells of undetermined significance or more severe cytology considered a positive result.

Results In an intention to screen analysis liquid based cytology showed no significant increase in sensitivity for cervical intraepithelial neoplasia of grade 2 or more (relative sensitivity 1.17, 95% confidence interval 0.87 to 1.56) whereas the positive predictive value was reduced (relative positive predictive value v conventional cytology 0.58, 0.44 to 0.77). Liquid based cytology detected more lesions of grade 1 or more (relative sensitivity 1.68, 1.40 to 2.02), with a larger increase among women aged 25-34 (P for heterogeneity 0.0006), but did not detect more lesions of grade 3 or more (relative sensitivity 0.84, 0.56 to 1.25). Results were similar when only low grade intraepithelial lesions or more severe cytology were considered a positive result. No evidence was found of heterogeneity between centres or of improvement with increasing time from start of the study. The relative frequency of women with at least one unsatisfactory result was lower with liquid based cytology (0.62, 0.56 to 0.69).

Conclusion Liquid based cytology showed no statistically significant difference in sensitivity to conventional cytology for detection of cervical intraepithelial neoplasia of grade 2 or more. More positive results were found, however, leading to a lower positive predictive value. A large reduction in unsatisfactory smears was evident.

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[djmd]

I'm a little confused did they compare with an eventual BX diagnosis? or was just compared to the relative frequency of the conventional prep?

Also for a screening test as a general rule of thumb, the more sensitive is better screening test, and the thin prep show significantly less unsats, which is also good for a screening test.

 

[Anna Plastic]

You would make me actually read the paper, wouldn't you djmd? 🙂

OK, this was a randomized trial, where women were randomized to either receiving a conventional Pap smear or liquid cytology. They used the Bethesda 1991 system, except they did not use the subcategories of ASCUS, just ASCUS itself. Women in the ThinPrep arm were referred to colposcopy if they received ASCUS.

Their primary end point was histologically confirmed cervical intraepithelial neoplasia of grade 2 or more detected during the recruitment phase as a result of abnormal cytology.

THe difference in unsatisfactory smear rates was 4.11% for conventional, 2.57% for liquid based. ThinPrep was significantly better at picking up Grade 1 lesions, but no better than conventional cytology in picking up Grade 2 or higher lesions.

There is more to a good screening test that just sensitivity. Cost of testing is a big factor too--and Thin prep adds a few dollars per test as compared to Pap smears. And the decreased +PV in this study was mostly due to the increase dincidence of low grade lesions picked up by ThinPrep.

Hey, I don't know exactly how the dollars/cents/sense of this will fall out. I just think, considering this is the first large scale randomized trial, that ThinPrep may not be superior to conventional in all regards. But it certainly trumps conventional in being able to test for HPV.

Also, just to throw another social medicine aside there: a couple references to discussion of the US health care system as compared to other industrialized countries. Clearly we are spending far more than other countries and getting much less:

US comes last in international comparison of health systems
Janice Hopkins Tanne
BMJ 2007;334:1078, doi:10.1136/bmj.39223.354942.DB

JAMA 2007;297:2131-3

 

[djmd]

You would make me actually read the paper, wouldn't you djmd? 🙂

You aren't studying for boards.. I am. 😱

I agree that sensitivity is not the final word in screening testing, but 'better' doesn't actually mean more cost effective.

It seems that one could sum up their point as "Thin prep is somewhat better, but not markedly so, but the extra cost limits the usefulness."
It is an interesting suggestion/argument.

a couple references to discussion of the US health care system as compared to other industrialized countries. Clearly we are spending far more than other countries and getting much less:

That pretty much sums up the US health care system in its entirety.
Well except from the getting much less. Unless they ment dollar for dollar getting less.

We spend way more than most (all?) other 1st world countries countries. Health care spending is like say red cell saturation curve (boards boards boards). And we spend lots money to move from 80% pO2 to 90% pO2. Other countries stop spending money somewhere between 50-85%. The last part of the curve takes a lot of O2 (err money) but doesn't actually get much more out of it.
I'm not saying it is right or makes sense, but it is what the American pubic wants, and is even somewhat willing to pay for...


Total aside if are 1st world and poor countries are 3rd (and 4th?) world? Who are the current 2nd world countries? sorry silly unimportant aside/hijack...

 

[deschutes]

The last part of the curve takes a lot of O2 (err money) but doesn't actually get much more out of it.
I'm not saying it is right or makes sense, but it is what the American pubic wants, and is even somewhat willing to pay for...

That depends on what you define as "American public". It seems that when the term "American public is used", it most often refers to social groups in the middle-class and higher. Which I think is skewed.

Total aside if are 1st world and poor countries are 3rd (and 4th?) world? Who are the current 2nd world countries? sorry silly unimportant aside/hijack...

I've often wondered that myself, ever since I came across the term as a kid 🙂

 

[djmd]

That depends on what you define as "American public". It seems that when the term "American public is used", it most often refers to social groups in the middle-class and higher. Which I think is skewed.

I've often wondered that myself, ever since I came across the term as a kid 🙂

I did specifically say that the American public WANTED the best health care in the world. Not all of them can pay for it, but they all want it.

The response to the FDA is a prefect example. They want the FDA to approve the latest drugs faster, but they also want no significant side effects.


And to answer my own aside...
The terms are confusing and do not have clear meanings.
The term third world was originally coined to describe things outside of the US/NATO vs WARSAW/PRC spheres. A great meany of the those countries are poor/underdeveloped nations. Additionally, US/NATO started refering to itself at as 1st world. (making USSR and friends, 2nd world)

Then 3rd world was split into 3rd and 4th world to separate developing countries from developed non-aligned. (Swiss, India... )
And now there is no clear 1st vs 2nd world any more.
So we are left with 1st, 3rd/4th world?

 

[Anna Plastic]

We spend way more than most (all?) other 1st world countries countries. Health care spending is like say red cell saturation curve (boards boards boards). And we spend lots money to move from 80% pO2 to 90% pO2. Other countries stop spending money somewhere between 50-85%. The last part of the curve takes a lot of O2 (err money) but doesn't actually get much more out of it.
I'm not saying it is right or makes sense, but it is what the American pubic wants, and is even somewhat willing to pay for...

Well, you know I'm a sucker for hemoglobin saturation references, so I wish I could agree with you here. But I think this is inaccurate. We are doing poorly compared to other industrialized countries in measures of adult life expectancy, infant mortality, child immunizations, etc--countries that spend half of what we do per capita, too. Hell, Jordan does better than the U.S. in terms of adult life expectancy. So no, I don't think we are spending money to get from 80-90%. We are spending disproportionate amounts of money just to try to get to 50-60%, if that.

We have to get over the idea that we have the best health care system in the world, and that our health care expenses are accounted for by that luxury. THe U.S. doesn't disproportionately have citizens who are brilliant physicians and scientists--we recruit the cream of the world's crop, or at least we had before restrictive visas status post 9/11 started choking off this flow. And now the funding to our academic centers is bottoming out. Guys, if we can't turn this around, U.S. physicians may become the "IMGs", losing out competitively to other countries.

 

[djmd]

But I think this is inaccurate. We are doing poorly compared to other industrialized countries in measures of adult life expectancy, infant mortality, child immunizations, etc--countries that spend half of what we do per capita, too. Hell, Jordan does better than the U.S. in terms of adult life expectancy. So no, I don't think we are spending money to get from 80-90%. We are spending disproportionate amounts of money just to try to get to 50-60%, if that.

I don't have the time to devote to more detailed searching, but:
Infant mortality is a poor metric because japan, most of Europe, and other countries exclude and child that does not breath after birth. (and I have no idea how they deal with premature infants.) Many countries shift their infant mortality to Perinatal mortality (and without a fixed cut off can also push that down by raising neonatal mortality). Partly due to neonatal care, and partly due to right to life politics I am fairly certain that the US includes more perinatals as infants.
Secondly, the life expectancy can, and is altered by the rate of violent and accidental deaths in this country. We have a higher rate of MVA deaths and GWS and crime related deaths.
From the CDC data http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_14.pdf

Number of survivors by age, out of 100,000 born alive
age 0 is 100,000 (by definition) age 1: 99,313 a decrease of ~700. The next 5 year decrease that matches that is 35-40 ~800.
So between our inclusive infant mortality statistics and violent crime/accidental death rate (80 age 10-15; 300 age 15-20 ;470 age 20-25; 460 age 25-30).
That spike that starts at 15 and runs through 25 is not bad quality health care.

Like Mark Twain said, lies, damn lies and statistics.