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(12) United States Patent (10) Patent No.: US 7,186,522 B2 Lapen Et Al

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(12) United States Patent (10) Patent No.: US 7,186,522 B2 Lapen Et Al US007 186522B2 (12) United States Patent (10) Patent No.: US 7,186,522 B2 Lapen et al. (45) Date of Patent: Mar. 6, 2007 (54) PAPANICOLAU STAINING PROCESS (56) References Cited (75) Inventors: Daniel Lapen, Lancaster, MA (US); U.S. PATENT DOCUMENTS Norman Soule, Brockton, MA (US); 6,143,512 A 11/2000 Markovic et al. Somthouk Lim, Farmingham, MA (US) 2002fOO19001 A1 2/2002 Light OTHER PUBLICATIONS (73) Assignee: CYTYC Corporation, Marlborough, MA (US) PCT International Search Report for PCT/US2004/09437, Appli cant: Cytyc Corporation, Forms PCT/ISA/210 and 220, dated Mar. 24, 2005 (4 pages). (*) Notice: Subject to any disclaimer, the term of this PCT Written Opinion of the International Search Authority for patent is extended or adjusted under 35 PCT/US2004/09437, Applicant: Cytyc Corporation, Form PCT/ U.S.C. 154(b) by 458 days. ISA/237, dated Mar. 24, 2005 (5 pages). (21) Appl. No.: 10/404.879 Primary Examiner Ralph Gitomer Assistant Examiner Kailash C. Srivastava (22) Filed: Mar. 31, 2003 (74) Attorney, Agent, or Firm Vista IP Law Group LLP (65) Prior Publication Data (57) ABSTRACT US 2004/O19 1854 A1 Sep. 30, 2004 A method for treating a biological sample with a Papanico laou staining process is provided. The method comprises (51) Int. C. incorporating a detergent treatment into the staining process GOIN L/30 (2006.01) at any of various steps. The method has been found to GOIN 33/48 (2006.01) advantageously reduce the number of artifacts produced (52) U.S. Cl. ..................................................... 435/405 during Papanicolaou staining. Also provided is a sample (58) Field of Classification Search ............... 435/40.5; stained by Such a process. 51Of 406 See application file for complete search history. 18 Claims, 1 Drawing Sheet U.S. Patent Mar. 6, 2007 US 7,186,522 B2 US 7,186,522 B2 1. 2 PAPANICOLAU STAINING PROCESS and improved ability to detect cellular, nuclear and chroma tin morphology. Additionally, the removal of excess stain TECHNICAL FIELD from the cytoplasm may lead to an increased ability to detect hyperchromasia associated with abnormality. This invention relates to methods, articles and composi The term "Papanicolaou staining process,” “pap stain.” tions useful in staining biological samples. “pap test” and the like refer to a modified or unmodified Papanicolaou staining procedure which differentially stains BACKGROUND OF THE INVENTION cell nuclei and cytoplasm in a sample, for example a sample obtained during a gynecological screening examination Such Medical diagnostic testing methods are critical screening 10 as a pap Smear. tools for the early detection of pathological conditions. Early The test relies on the ability to distinguish the staining detection permits the identification of Such conditions at a pattern, staining intensity and the size and shape of the stage when Successful treatment is more likely. Early treat nucleus and cytoplasm of different cell types within the ment also frequently involves less damaging or less invasive sample. The Papanicolaou staining process advantageously treatment methods and decreases the impact on the patient. 15 provides dark stained nuclei and transparent cytoplasms, In addition to routine Screening, diagnostic testing is also which is particularly useful in detecting abnormal cells used in a variety of other applications, including biopsy within multi-layered samples provided by certain sampling analysis and monitoring the results of ongoing medical techniques including pap Smears. treatment. One particularly useful tool in diagnostic testing is the A usable test depends on the ability to read a significant Papanicolaou staining process. This process was first devel percentage of cells in the sample, otherwise test accuracy oped for the staining of gynecological specimens, and has may be comprised and samples may be rendered unusable, led to a dramatic decrease in the fatality rate from cervical leading to additional rescreening costs and increased patient cancer. Papanicolaou staining is now used in diagnosing a anxiety. variety of pathological conditions from many different tis 25 Consequently, staining artifacts which reduce the ability Sues and organs. to discern the true staining pattern of cells in a sample can However, Papanicolaou staining is subject to artifacts that dramatically impair the usefulness of a pap test. Artifacts can can adversely affect the ability of a technologist or machine reduce the ability to differentiate between the staining pat to Successfully read a processed sample. These artifacts tern of the nucleus and the cytoplasm, can increase the include spurious non-specific cytoplasmic staining, artifacts 30 percentage of cells or sample area which are unreadable, and Such as cytoplasmic cracking, cornflaking, Smudged nuclear can increase cytoplasmic staining thereby diminishing the detail, hypochromatic staining and hyperchromatic staining. transparency that is one of the primary advantages of the pap Such artifacts, at a minimum, reduce the fraction of the test, thus making it more difficult to distinguish abnormal sample which can be evaluated, can produce false staining cells within the sample. patterns that interfere with accurate diagnosis, and may 35 Before the present invention is described in further detail, render the sample unreadable. Difficulties in analyzing Such it is to be understood that this invention is not limited to the samples leads to an increase in patient anxiety, rescreening particular methodology, Solutions or apparatuses described, costs, delays in diagnosis and, more importantly, potential as such methods, Solutions or apparatuses can, of course, misdiagnosis. vary. It is also to be understood that the terminology used There is a need in the art for improved procedures for 40 herein is for the purpose of describing particular embodi staining diagnostic specimens, and for compositions and ments only, and is not intended to limit the scope of the articles of manufacture useful in Such methods. present invention. Use of the singular forms “a,” “an,” and “the include SUMMARY OF THE INVENTION plural references unless the context clearly dictates other 45 wise. Thus, for example, reference to “a sample” includes a An improved method for treating a biological sample with plurality of samples, reference to “a detergent” includes a a Papanicolaou staining process is provided. The method plurality of such detergents, reference to “a counterstain comprises incorporating a detergent treatment into the stain includes a plurality of counterstains, and the like. Addition ing process at any of various steps. The method has been ally, use of specific plural references, such as “two,” “three.” found to advantageously reduce the number of artifacts 50 etc., read on larger numbers of the same Subject unless the produced during Papanicolaou staining. Also provided is a context clearly dictates otherwise. sample stained by Such a process. Terms such as “connected,” “attached, and “linked' are used interchangeably herein and encompass direct as well as BRIEF DESCRIPTION OF THE DRAWINGS indirect connection, attachment, linkage or conjugation 55 unless the context clearly dictates otherwise. Where a range FIG. 1 shows a sample stained with a Papanicolaou of values is recited, it is to be understood that each inter staining process. vening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifi DETAILED DESCRIPTION OF THE cally disclosed, along with each Subrange between Such INVENTION 60 values. The upper and lower limits of any range can inde pendently be included in or excluded from the range, and The inventors have advantageously discovered that incor each range where either, neither or both limits are included poration of a detergent treatment into a Papanicolaou stain is also encompassed within the invention. Where a value ing procedure reduces the occurrence of artifacts to which being discussed has inherent limits, for example where a the procedure is susceptible. Use of a detergent has been 65 component can be present at a concentration of from 0 to found to clear excess stain from the cytoplasm of cells 100%, or where the pH of an aqueous solution can range stained by this procedure, allowing for increased contrast from 1 to 14, those inherent limits are specifically disclosed. US 7,186,522 B2 3 4 Where a value is explicitly recited, it is to be understood that color using an agent as known in the art (e.g., Scott's tap values which are about the same quantity or amount as the water Substitute, ammonia water, lithium carbonate). The recited value are also within the scope of the invention, as bluing solution can be incorporated without a differentiation are ranges based thereon. Where a combination is disclosed, step. each subcombination of the elements of that combination is Multiple cytoplasmic counterstains are used in Papanico also specifically disclosed and is within the scope of the laou staining to allow identification of the various cell types invention. Conversely, where different elements or groups of in the sample, their morphology and their frequency. elements are disclosed, combinations thereof are also dis The cytoplasmic stains Orange G and Eosin Y—Light closed. Where any element of an invention is disclosed as Green/Fast Green are prepared in alcohol. Orange G is a having a plurality of alternatives, examples of that invention 10 monochromatic stain that stains cell cytoplasms yellow or in which each alternative is excluded singly or in any orange if keratin is present, allowing for the distinction of combination with the other alternatives are also hereby mature or maturing keratin-producing malignant cells from disclosed; more than one element of an invention can have the less conspicuous benign cells. Orange G can be used in Such exclusions, and all combinations of elements having the form of a solution known in the art of cell staining, for Such exclusions are hereby disclosed. 15 example as OG-6. Unless defined otherwise or the context clearly dictates Traditionally, Eosin Y—Light Green/Fast Green is pre otherwise, all technical and scientific terms used herein have pared as a mixture of three stains, Eosin Y.
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