WO2001069519A1

WO2001069519A1 - Cervical disease management system and method

Info

Publication number: WO2001069519A1
Application number: PCT/US2001/007512
Authority: WO
Inventors: David F. Jadwin
Original assignee: Jadwin David F
Priority date: 2000-03-10
Filing date: 2001-03-09
Publication date: 2001-09-20
Also published as: AU2001240124A1

Abstract

The present invention is directed to a method for determining the adequacy of a Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient for squamous metaplastic endocervical cells, determining whether the number of squamous metaplastic endocervical cells in said sample exceed a critical number, and accepting the validity of the test if said critical number of said metaplastic endocervical cells is exceeded (Fig.5B).

Description

CERVICAL DISEASE MANAGEMENT SYSTEM AND METHOD

FIELD OF THE INVENTION The present invention is specifically directed to a system and method for managing the screening of cervical neoplasia and atypical cells of undetermined significance (ACUS). In particular, the present invention is directed to a method for evaluating the adequacy of a pap test and for quantifying pap test adequacy.

BACKGROUND OF THE INVENTION

Cervical carcinoma is the leading cause of cancer-related mortality in women worldwide. In the United States, however, cervical carcinoma is the seventh leading cause of cancer-related mortality in women. The improved mortality rate for cervical carcinoma in the United States is due to the effectiveness of the Papanicolaou (pap) test, which was introduced in the 1940's. The pap test remained essentially unchanged until the 1990's, when new preparatory techniques such as the Cytyc ThinPrep and autocyte detection techniques including the Papnet and Autopap were FDA approved.

In the conventional pap test, cells from the uterine cervix are scraped or brushed onto a glass slide and fixed. The slide is then stained and examined by a cytotechnologist and/or pathologist. The examination of pap tests are regulated by the Clinical Laboratory Improvement Act of 1988 (CLIA of 1988). The accreditation of laboratories performing the tests is administered primarily by the College of American Pathologists (CAP). National standards for adequacy and reporting were established by the National Institutes of Health conferences held in Bethesda, Maryland. These two conferences (hereinafter Bethesda I and Bethesda II) established minimal criteria for reporting and assessing the adequacy of the pap test, and established uniform categories for pap smear diagnosis and reporting.

Exceptforthe established minimal criteria for specimen adequacy, no complex method to measure the adequacy of endocervical cells in the pap test has yet been established. It is widely held that minimal criteria for adequacy are sufficient for the interpretation of pap test data. Yet, in spite of the reduced mortality associated with cervical carcinoma as a result of the pap test, the pap test has a significant 25% error rate associated with its reporting. These errors frequently result from the evaluation of a single pap test result.

At present, there is no system for the cumulative analysis of multiple sequential pap tests. Yet, as many as 25% (and possibly more) of true positive test results are reported to be negative, i.e., so-called "false negative" tests. Approximately half of all false negative test results are attributed to screening or identification errors. The remaining half are attributable to sampling errors, caused by a failure to transfer a sufficient number of cells especially from the transformation zone of the uterine cervix to the glass slide. Sampling errors may be anticipated whenever only minimal criteria for specimen adequacy are applied.

The pap test process is a highly complex laboratory testing event which is influenced by numerous otherfactors. The complexity of the pap test process makes uniform test assessment and evaluation difficult. Recent technological advances have been introduced to facilitate sample preparation and abnormal cell identification. There are a number of issued U.S. patents which are directed to detecting malignancy-associated changes in cells and the incorporation of technologies to assist in this regard. U.S. Pat. No. 5,889,881 , for example, discloses a method for detecting malignancy-associated cell changes. In this system, a sample of cells is obtained and stained to identify the nuclear DNA material. The sample is imaged with a digital microscope. Objects of interest are then identified in the sample of cells based on the intensity of the pixels that comprise the object versus the average intensity of all pixels in the slide image. An exact image is located for each object and variations in the illumination intensity of the microscope are adjusted. The computer system calculates feature values for each object based on the value of the features. A determination is then made whether the cell exhibits malignancy- associated changes or not.

U.S. Pat. No. 5,889,880 is directed to an automatic interactive cytology system which provides expedited handling of samples, minimizing false negatives, while not substantially increasing the number of false positives. The computerized system identifies and displays the cells which are of great interest to the cytologist. The system then processes this information on all cells identified to classify the slide as normal, abnormal or questionable based on a statistical analysis of cells meeting given criteria. Before displaying the results of the statistical analysis, cytologists review the cells which the computer has determined to be most significant. It is only then after the cytologist has determined whether the cells are positive, negative or questionable, that the determination is inputted into the automated system. The automated system then compares the cytologist's analysis with its own statistical analysis. Based on the two opinions, the cytologist determines how to advise the doctor regarding the sample.

U.S. Pat. No. 5,487,112 is directed to a method and apparatus for the analysis of magnified video image data to develop quantitative functional and morphological indices for cell-to-cell adhesion. The indices permit distinction between different adhesion modalities and identification of various adhesion pathways of cells.

Although these technologic advances greatly improved pap testing, none of these advances address the limitation of overall sample adequacy in the clinical evaluation of pap test results.

The Bethesda Conference established minimal standards for specimen adequacy, which include: a. "Coverage of more than 10% of the slide surface by well preserved and well visualized squamous (ectocervical) epithelial cells." b. The presence of an adequate endocervical/transformation component which consists of at least two clusters of well- preserved endocervical glandular and/or metaplastic cells each composed of at least five cells.

However, the Bethesda Conference did not attemptto distinguish between the presence of columnar and metaplastic cells on a slide. The distinction between columnar and metaplastic cells is important and the quantification of each of these categories is further important to assess the power of the test to exclude disease.

Other criteria for adequacy include appropriate labeling and identification information, the submission of relevant clinical information, and the presence of partially obscuring blood inflammation, poor fixation, air drying artifact and contamination. In other words, a specimen may be adequate if it is obscured by up to 50% of these processes causing only 50% of the sample on the slide to be available. Further, a sample is only limited (and not unsatisfactory) if it is obscured by up to 75% by these processes.

Yet, as many as 95% or more of pre-neoplastic and neoplastic lesions involving the uterine cervix arise within the transformation zone. The transformation zone is a zone of cells characterized by squamous metaplastic cells, which are intermediate between the deep inner columnar endocervical mucosa and the outer ectocervical squamous mucosa. The presence of columnar endocervical cells on a pap test may serve as a surrogate marker for sampling adequacy. The columnar cells are beyond the transformation zone, and presumably the transformation zone has been sampled if columnar cells are present.

The presence of metaplastic cells on a pap test slide is a direct marker of transformation zone sampling. Therefore, the presence of metaplastic cells on the slide indicates that the transformation zone (the high risk area) for the presence of pre-neoplastic and neoplastic lesions has been directly sampled. However, the Bethesda Conferences never distinguished between columnar and metaplastic cells when defining a minimal criteria for pap test adequacy.

Pap smear categories were defined by the Bethesda Conference as:

A. Within normal limits (WNL);

B. Benign cellular changes (BCC);

C. Atypical squamous cells of undetermined significance (ASCUS);

D. Atypical glandular cells of undetermined significance (AGCUS); E. Low grade squamous intra epithelial lesion (LGSIL);

F. High grade squamous intra epithelial (HGSIL); and

G. Malignant.

WNL and BCC pap smears are considered to be non-epithelial cell abnormalities. The remaining categories represent subcategories of an epithelial cell abnormality (ECA). The "atypical" epithelial cell abnormalities cause a management dilemma for clinicians. These abnormalities are insufficient to warrant classification as a squamous intra epithelial lesion (SIL), but are sufficiently atypical to not warrant diagnosis of WNL or BCC.

In studies, a high portion of atypical pap smears (as much as one in seven) contain a high grade squamous intra epithelial lesion or malignant neoplasm upon colposcopic biopsy. For this reason, clinicians are reluctant to passively monitor patients with atypical pap smears. In other words, they do not have confidence in the pap test to exclude disease. Since as many as 15% or more of patients may have atypical pap smears, a significant number of women will undergo an expensive, invasive procedure.

Two probable reasons for the failure to detect more significant epithelial cell lesions in an atypical pap smear may be due to difficulty in identification of small cells as well as the failure to have a sufficient sample from the transformation zone present on the slide. When insufficient sampling of the transformation zone is present in a pap test, the pap test may contain only a few atypical cells not reflective of a more serious squamous intra epithelial lesion. Contrary to the Bethesda standards, which specify only minimal criteria for adequacy, it would follow that the more cellular the sample from the transformation zone contained on the pap test, the more likely the pap test will exclude the presence of abnormal cells (i.e., the more likely the pap test will contain abnormal cells).

No system disclosed in the prior art is directed to a system which characterizes or grades the adequacy of a Papanicolaou (pap) test. Further, no system disclosed in the prior art is directed to or discloses a system which determines when to initiate a colposcopy. No system disclosed in the prior art is directed to characterizing validity of a pap test based upon a sampling of cells from the transformation zone of both columnar and metaplastic cells. It is the object of the present invention to provide a method for evaluating the adequacy of a pap test, and to provide a comprehensive guide to the patient's well being.

These and other objects of the present invention and features of the present invention will become apparent from the detailed description and from the following summary detailed description and claims.

SUMMARY OF THE INVENTION In accordance with the present invention, a method for determining the adequacy of a Papanicolaou test is disclosed. The invention comprises the following steps: taking sample cells from the uterine cervix of a patient pursuant to a Papanicolaou test; determining the number of metaplastic endocervical cells taken from the transformation zone of the uterine cervix; determining whether the number of squamous metaplastic endocervical cells in said sample exceed a critical number, and accepting the validity of the test if said number of said metaplastic endocervical cells is exceeded. In a further embodiment, the invention is a method for determining the adequacy of a negative Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient for squamous metaplastic endocervical cells, determining whether the number of squamous metaplastic endocervical cells in said sample exceed a critical number, accepting the validity of the test if said critical number of said squamous metaplastic endocervical cells is exceeded and none of said cells exceed the atypical squamous cells of undetermined significance (ASCUS) category.

In yet a further embodiment, the invention is a method for determining the adequacy of a Papanicolaou test comprising the following steps: sampling a group of squamous metaplastic endocervical cells from the transformation zone of the uterine cervix of a patient to be examined and placing said sample on a slide for analysis, determining whether a pre-determined critical number of said squamous metaplastic endocervical cells appear on the slide, accepting the test as valid if said number of metaplastic cells exceeds a critical number of metaplastic cells and rejecting said test as invalid if said number of cells is less than said critical number of metaplastic cells.

In still a further embodiment, the present invention comprises a method for characterizing the adequacy of a Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient to be tested and placing said sample on a slide, determining the number of metaplastic or columnar cells of the patient which appear from the sample, characterizing the test as having first adequacy level of sensitivity if more metaplastic or columnar cells appear on the slide, characterizing the test as having a second adequacy level of sensitivity if between about 25 cells and 300 metaplastic or columnar cells appear on the slide, characterizing the test as having third adequacy level of sensitivity if between 1 and about 24 metaplastic or columnar cells appear on the slide, and characterizing the test as achieving fourth adequacy level of sensitivity if no metaplastic cells appear on the slide.

In yet a further embodiment, the invention is a method for determining the adequacy of a Papanicolaou test and for determining whether to initiate a colposcopic biopsy comprising the following steps: sampling a group of squamous metaplastic endocervical cells from the transformation zone of the uterine cervix of a patient and placing said sample on a slide for analysis, determining whether a predetermined number of metaplastic cells appear on the slide, accepting the test as valid if said number of metaplastic cells exceeds a pre-determined number of metaplastic cells and rejecting said test as invalid if said number of cells is less than said pre-determined number of metaplastic cells, and determining if valid, whether any of said cells exceed the atypical squamous cells.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A illustrates a secure login window for enabling a health care provider with proper permissions to interact with a computer software interface for facilitating the storage and control of pap smear data in accordance with the present invention. FIG. 1 B illustrates a main menu which can be utilized to create a plurality of reports which track the prior health results of a patient.

FIGS. 2A and 2B comprise a patient demography input screens for enabling a health care provider to input clinical history information regarding the patient. FIGS. 3A and 3B comprise worksheet charts of the clinical history of the client and illustrate the historical adequacy of a plurality of tests.

FIG. 4 illustrates a listing of historic tests over a five year period in conformity with the present invention.

FIGS. 5A, 5B and 6 illustrate a series of outputs which provide gynecological pap cytology records and reports whereby patients are cataloged according to their history.

FIGS. 7A, 7B, 8A and 8B illustrate a system by which the present invention provides for a global categorization of pap smear data.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention is directed to a method and system for evaluating the efficacy of a Papanicolaou (pap) test, for evaluating multiple pap tests, and for determining when to authorize or recommend a colposcopy based upon the results of one or multiple pap tests. The present invention is specifically directed to a semi- quantitative model of sampling adequacy which scores both columnar and metaplastic endocervical cells separately and which can facilitate an assessment of the adequacy of the pap test to exclude disease.

In particular, the present invention discloses a model for providing a semi- quantitative measure of columnar and metaplastic cells using a four level sensitivity. The method of the present invention is now described. The method of the invention comprises the steps of taking sample cells from the uterine cervix of a patient pursuant to a pap test. Next, a determination is then made as to the number of metaplastic cells taken from the transformation zone. The transformation zone is the area of cells characterized by squamous metaplastic cells which are intermediate between the deep columnar endocervical mucosa and the outer ecto-cervical squamous mucosa. FIG. 1 illustrates the transformation zone, columnar cells and metaplastic cells of the human cervix.

The sensitivity level of the test is then assessed. The sample is deemed to be "abundant" if there are more than 300 metaplastic cells, "adequate" if there are between 25 to 300 cells, "limited" if there are between 1 and 24 cells, and rejected if there are "none. The sampling from the transformation zone is critical to the present invention because the transformation zone is the high risk area. The above sensitivity levels provides a stratification of pap smears that is up to 18 times more likely (or less likely if the cells are not present) to contain a high grade squamous intra epithelial lesion (HGSIL).

If a pap smear taken from an abundant or adequate sample contains no cells that are above the ASCUS category, as defined by the Bethesda Conference, the test is deemed to be low risk. In addition, the test is further ratified by the number of columnar cells within the sample. The existence of columnar cells is a surrogate marker of transformation sampling and is used in conjunction with metaplastic cell sampling as discussed above. The above disclosed sensitivity parameters (i.e. abundant, adequate, limited, none) are used in characterizing the quantity of columnar cells.

Example and Analysis

The selection system of the present invention has been validated by correlation with subsequent colposcopic biopsies. In a large correlative study, a fraction of pap smears in any category, not correlating with the subsequent colposcopic biopsy has been determined. Although the disparity on individual cases may be attributed to random error, in a large pool of sample, the error associated with the test has been shown to be systematic. The determination of this discordant fraction permits laboratories and clinicians who utilize the present method to assess the validity of the individual pap test in an appropriate manner. The discordant fraction may be used to help the clinician gain confidence that the pap smear has reasonably excluded disease if the fraction is low.

If the fraction is high, then the clinician will have less confidence that the pap test has excluded disease when atypical cells are present. Utilizing the sensitivity parameters of the present invention, only 2% of atypical pap smears that undergo colposcopic biopsy have a high grade squamous intra epithelial lesion (HGSIL) or cancer. The likelihood of three successive pap smears (all adequately sampled and all not greater than ASCUS in category) will miss a high grade squamous intra epithelial lesion or cancer is 1 : 125,000. The probability that five similar pap smears will miss an HGSIL lesion or cancer is 1 :312,000,000. For comparison, if 15% of atypical pap smears have a high grade squamous intra epithelial lesion or cancer on colposcopic biopsy, a FIG. in accordance with conventional sampling methods, then 34 patients out of 10,000 patients will be missed after evaluating three pap smears. Hence, the sensitivity selection method of the present invention significantly improves over prior detection methods.

The following illustrates actual colposcopic correlations as determined in accordance with the method of the present invention. As shown, actual test results determined that there was and is tight correlation between the sensitivity levels of the present invention and the error rates in determining high grade or malignant lesions. COLPOSCOPIC CORRELATION

CIN 2 or Higher

ASCUS (1995) 6% (13.8% Published) ASCUS (1997) 4.6% (14.3%) ASCUS (96-8) 2.7% (15.0%) 0.02 x 0.02 x 0.02 = 1 :125,000 (12 months)

X 0.02 x 0.02 = 1 :312,000,000 (36 months)

As shown, there is a 2% probability of missing a malignancy on a single test by utilizing the sampling techniques of the present invention. The odds of missing malignancy during three successive pap tests is 1 in 125,000 and 1 in 312 million in 5 tests. This compares with the 15% error rate nationally.

COLPOSCOPIC CORRELATION

LGSIL 2%

ASCUS (1994-5) 6% (13.8% Published)

CAP Q-Probe Study: 22,400 Biopsies in 348 Laboratories (1995)

The importance of the sampling of the transformation zone is a key to assessing the power of the pap test to exclude disease and the method of the present invention. The cervical disease management and selectivity system of the present invention is designed to assess this fraction, analyze single and cumulative pap smear results and provide comprehensive longitudinal monitoring of patients to ensure appropriate care. The ability of the sampling model to evaluate the adequacy of the pap smear is the importance in determining the power of the pap test to exclude disease. The following tables illustrate the correlation between the sensitivity of a sampling and the percentage of cells. As shown, in an "abundant" metaplastic sampling, there is approximately 18 times more HGSIL cells than in a "none" and 4.27 LGSIL cells than in a "none" sampling.

DETECTION VS. ADEQUACY Metaplastics - Normalized Across Categories

Metaplastic WNL/BCC ASCUS/LG HGSIL/Ca Low Grade High Grade

(%) (%) (%) (X) (X)

Abundant 85.4 12.8 1.8 4.27 18

Adequate 90.4 9 0.6 3 6

Limited 94.3 5.2 0.4 1.73 4

None 96.9 3 0.1 1 1

~ 4.3x more LGSIL if >300 metaplastics than if none. 18x more HGSIL if >300 metaplastics than if none.

Similarly, as shown below, there are respective 4.0 and 2.6 more HGSIL and LGSIL cells at the abundant columnar sampling level as compared to the "none" sampling level.

DETECTION VS. ADEQUACY

Columnars - Normalized Across Categories

Columnar WNL/BCC ASCUS/LG HGSIL/Ca Low Grade High Grade

(%) (%) (%) (X) (X)

Abundant 87 11.8 1.2 2.62 4

Adequate 90.7 8.8 0.5 1.96 1.67

Limited 94.9 4.7 0.4 1.04 1.33

None 95.2 4.5 0.3 1 1

~ 2.6x more LGSIL if >300 columnars than if none. 4x more HGSIL if >300 columnars than if none.

The following illustrates the respective numbers of cells at both the "abundant" and "none" levels for both metaplastic and columnar cells.

SAMPLING VS. CATEGORY Quantity of Endocervical Cells Normalized within Category

0% Unsat WNL BCC ACUS LGSIL HGSIL Ca

Columnar

Abundant 0 20 19 28.3 29.6 42.6 36.8

None 8.5 7.4

Metaplastic

Abundant 0 9 11.1 14.2 17.4 31.5 21

None 1.9 1.8 Columnars: Step Function (Surrogate Marker)

Metaplastics: Linear Function (Direct Marker)

~ 8% of LGSIL & HGSIL have no columnars .-. if no columnars, ...

- 2% of LGSIL & HGSIL have no metaplastics .-. if no metaplastics, ...

The above tables illustrate the critical importance of abundant transformation grading zone sampling. The present invention has been described with reference to the above detailed description. The true nature and scope of the present invention are determined with reference to the claims appended hereto.

The present invention has been specifically adapted to a computer software interface for facilitating the storage and control of pap smear data in accordance with the present invention. As shown, FIG. 1A illustrates a secure login window for enabling a health care provider with proper permissions to interact with the interface. FIG. 1 B illustrates a main menu which can be utilized to create a plurality of reports which track the prior health results of a patient. FIGS. 2A and 2B comprise a patient demography input screens. These screens enable a health care provider to input information regarding the patient, such as birth date and social security number.

FIGS. 3A and 3B comprise charts of the clinical history of the client and illustrate the historical adequacy of a plurality of tests. They indicate with respect to each test as to whether or not the columnar and metaplastic cells were adequately tested. This is important in evaluating the test history of the patient. FIG.4 illustrates a listing of historic tests over a period of time in conformity with the present invention.

The present invention further provides a series of outputs which provide gynecological pap cytology records and reports. Patients, as shown in FIGS. 5A, 5B and 6, are cataloged according to their history. The present invention further provides for follow-up notification. Finally, as shown in FIGS. 7A, 7B, 8A and 8B the present invention provides for a global categorization of the pap smears. As shown, a plurality of patient pap smears can be gathered and categorized over a period of time. This system affords the acquisition of valuable patient data and the creation of a database which can be utilized to categorize the adequacy of pap tests across a broad spectrum of patients.

The present invention has been described with reference to the above detailed description. It is to be noted that the true spirit and scope of the present invention is to be determined with response to the claims appended hereto.

Claims

1. A method for determining the adequacy of a Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient for squamous metaplastic endocervical cells; determining whether the number of squamous metaplastic endocervical cells in said sample exceed a critical number; and accepting the validity of the test if said critical number of said metaplastic endocervical cells is exceeded.

2. The method of claim 1 , wherein said critical number of squamous metaplastic cells is about 300 cells.

3. The method of claim 1 , wherein said critical number of squamous metaplastic cells is about 25 cells.

4. A method for determining the adequacy of a negative Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient for squamous metaplastic endocervical cells; determining whether the number of squamous metaplastic endocervical cells in said sample exceed a critical number; accepting the validity of the test if said critical number of said squamous metaplastic endocervical cells is exceeded and none of said cells exceed the atypical squamous cells of undetermined significance (ASCUS) category.

5. A method for determining the adequacy of a Papanicolaou test comprising the following steps: sampling a group of squamous metaplastic endocervical cells from the transformation zone of the uterine cervix of a patient to be examined and placing said sample on a slide for analysis; determining whether a pre-determined critical number of said squamous metaplastic endocervical cells appear on the slide; accepting the test as valid if said number of metaplastic cells exceeds a critical number of metaplastic cells and rejecting said test as invalid if said number of cells is less than said critical number of metaplastic cells.

6. A method for characterizing the adequacy of a Papanicolaou test comprising the following steps: sampling the transformation zone of the uterine cervix of a patient to be tested and placing said sample on a slide; determining the number of metaplastic or columnar cells of the patient which appear from the sample; characterizing the test as having first adequacy level of sensitivity if more than about 300 metaplastic or columnar cells appear on the slide; characterizing the test as having a second adequacy level of sensitivity if between about 25 cells and 300 metaplastic or columnar cells appear on the slide; characterizing the test as having third adequacy level of sensitivity if between 1 and about 24 metaplastic or columnar cells appear on the slide; and characterizing the test as achieving fourth adequacy level of sensitivity if no metaplastic cells appear on the slide.

7. The method of claim 6, wherein the test is accepted if it achieves either a first or second level of sensitivity and rejected if it achieves a third or fourth level of sensitivity.

8. The method of claim 7, comprising the steps of repeating steps (a) through (d) of claim 6.

9. A method for determining the adequacy of a Papanicolaou test and for determining whether to initiate a repeat pap comprising the following steps: sampling a group of squamous metaplastic endocervical cells from the transformation zone of the uterine cervix of a patient and placing said sample on a slide for analysis; determining whether an adequate number of metaplastic cells appear on the slide; accepting the test as valid if said number of metaplastic cells exceeds a pre-determined number of metaplastic cells and rejecting said test as invalid if said number of cells is less than said pre-determined number of metaplastic cells; and determining if valid, whether any of said cells exceed the atypical squamous cells of undetermined significance (ASCUS) category and ordering a colposcopic biopsy if said category is exceeded by any of the cells.