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RESEARCH ARTICLE
CytoJournal 2015,  12:14

Survey of cytopathologists and cytotechnologists for the clinical impact of the use of atypia or follicular lesion of undetermined significance


1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA
2 Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA
3 Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
4 Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
5 Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota, USA
6 Division of Endocrinology, Mayo Clinic, Jacksonville, Florida, USA

Date of Submission21-Aug-2014
Date of Acceptance27-Sep-2014
Date of Web Publication23-Jun-2015

Correspondence Address:
Aziza Nassar
Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1742-6413.159246

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 » Abstract 

Background: The cytologic diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) is controversial because of variation in how it is applied in practice, as well as uncertainty about patient management. We aimed to assess the percentage of thyroid fine-needle aspiration biopsies (FNABs) with AUS/FLUS diagnoses in different North American and European practice settings (e.g. community, academic, etc.), assess whether patients were managed according to current guidelines, and determine patient outcomes.
Materials and Methods: A detailed questionnaire survey was posted in secure websites used separately by cytopathologists and cytotechnologists. The questionnaire was posted from August 1 through December 31, 2013.
Results: Endocrinologists and cytopathologists performed 51.7% and 37.1% of thyroid FNABs, respectively. The Bethesda reporting system for thyroid FNAB was used in 90% of practices. The rate of AUS/FLUS varied widely among institutions, with 46.1% of represented institutions reporting AUS/FLUS rates of 3-10%. The median follow-up rate of patients with an initial AUS/FLUS diagnosis was 70% (range, 10-100%). For the majority of represented institutions (86.4%), patients with initial AUS/FLUS diagnosis had follow-up with endocrinologists. Of repeat AUS/FLUS thyroid FNABs, a median of 52% was considered benign, and 18% were suspicious of or positive for malignancy (median, 10% and 7.5%, respectively).
Conclusions: Reporting of the AUS/FLUS category varied widely among different institutions. The median follow-up rate was lower than published guidelines. The most common follow-up diagnosis was benign thyroid nodule. Improved standardization of cytologic criteria should be adopted to reduce such variation.


Keywords: Cytology, fine-needle aspiration, follicular lesion of undetermined significance, questionnaire, thyroid


How to cite this article:
Nassar A, Reynolds JP, Kerr SE, Jenkins SM, Lackore KA, Bernet V. Survey of cytopathologists and cytotechnologists for the clinical impact of the use of atypia or follicular lesion of undetermined significance. CytoJournal 2015;12:14

How to cite this URL:
Nassar A, Reynolds JP, Kerr SE, Jenkins SM, Lackore KA, Bernet V. Survey of cytopathologists and cytotechnologists for the clinical impact of the use of atypia or follicular lesion of undetermined significance. CytoJournal [serial online] 2015 [cited 2017 Jun 23];12:14. Available from: http://www.cytojournal.com/text.asp?2015/12/1/14/159246

Editorial/Peer Review Statement
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double blind model (authors are blinded for reviewers and vice versa) through automatic online system.



 » Introduction Top


Thyroid nodules are prevalent, with palpable nodules occurring in 4-7% and nonpalpable nodules in 20-70% of the US population. [1],[2] Thyroid fine-needle aspiration biopsy (FNAB) is a commonly used procedure worldwide for evaluating thyroid nodules. Epidemiologic studies have shown that the prevalence of palpable thyroid nodules is approximately 5% in women and 1% in men living in iodine-sufficient parts of the world. [2],[3]

Endocrinologists, radiologists, and cytopathologists evaluate thyroid nodules using predominantly ultrasound-guided FNABs. In addition, cytopathologists evaluate these nodules microscopically using different reporting standardized terminology (e.g., nondiagnostic or unsatisfactory, benign, atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), suspicious for neoplasm or malignancy, and malignancy). [4] The AUS/FLUS category is controversial because of variation in how this category is applied in cytopathology practice and uncertainty about how these patients should be managed.

The 2008 National Cancer Institute (NCI) state of the science conference for thyroid FNAB recommended using the FLUS category for thyroid aspirates with cytomorphologic findings that are neither convincingly benign nor sufficient for interpretation of neoplasia or malignancy. [4] According to the Bethesda System for thyroid cytopathology reporting, the rate of AUS/FLUS should be < 7% of all reported thyroid FNABs within the laboratory, but practices vary in rates of AUS/FLUS (from 1% to > 25%). [5] The recommendation for this atypical category is follow-up with ultrasound imaging and another biopsy within 6 months. [3] The AUS/FLUS category has a 5-10% estimated risk of malignancy, which is intermediate between the risk of a benign aspirate and an aspirate suspicious for neoplasm. [4]

The aim of the current study was to assess the percentage of biopsy samples being categorized as AUS/FLUS in different North American and European practice settings (e.g., community, academic), assess whether the clinicians are managing these patients according to current guidelines, and determine patient outcomes of those patients who received follow-up FNAB. We collected survey data because no data sources with this information were available from the different institutions.


 » Materials and methods Top


The study was approved by the institutional review board. Patient consent for this study was waived because the study did not confer any risk.

Sampling frame

We sought to survey cytopathologists, cytotechnologists, and endocrinologists who were current members of the American Society of Cytopathology (ASC) or the American Society for Cytotechnology (ASCT). Members are in North America, Europe, and other continents and practice in various settings (e.g., community hospitals, academic centers, specialized referral centers). Of the 2847 current members of ASC, approximately 1000 participate in the E-mail discussion list. Of the 560 members of the ASCT, approximately 200 participate in the E-mail discussion list.

The survey was posted in two secure web sites used separately by cytopathologists and cytotechnologists; an E-mail with information about the survey was sent to members. The survey was a 21-item questionnaire [Appendix] and was created using Survey Tracker (Training Technologies, Inc.) in collaboration with the Survey Research Center in Mayo Clinic's Department of Health Sciences Research. The survey questionnaire was pretested by 10 practicing cytopathologists (colleagues in different practice settings) through E-mail correspondence.

Sample size

We had a target of 100 respondents, with the goal of a 10% margin of error. Three E-mail reminders were sent to a different mailing list for survey participation.

Statistical methods

All analyses were descriptive. Survey data were summarized with frequencies and percentages for categorical items and with medians and ranges (or means and standard deviations) for continuous items.


 » Results Top


The survey questionnaire was accessible from August 1 through December 31, 2013, and promoted through the ASC and ASCT E-mail lists. The survey had 90 respondents (cytopathologists, n = 43; cytotechnologists, n = 39; general pathologists, n = 6; endocrinologists, n = 2). The majority of respondents were from community hospitals (n = 41 [45.6%]) and academic centers (n = 33 [36.7%]). Most (n = 67 [74.4%]) were from the United States, Europe (n = 8 [8.9%]), and Canada (n = 4 [4.4%]). Survey results are detailed in [Table 1].
Table 1: Questionnaire survey results (n=90)a

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Specimen acquisition and preparation

Endocrinologists and cytopathologists performed 51.7% and 37.1% of thyroid FNABs, respectively. The majority of thyroid FNABs (64.0%) was performed using ultrasound guidance. Most institutions represented in the survey (65.2%) indicated that an on-site adequacy assessment for thyroid FNABs was performed. Thirty-four represented institutions (40%) indicated performing an average of 21-60 thyroid FNABs annually.

Specimen reporting and follow-up

Eighty represented institutions (90%) reported using the Bethesda system for thyroid cytopathology reporting. The estimated AUS/FLUS rate ranged from 3% to 10% for 41 represented institutions (46.1%). Fifty-nine represented institutions (67.0%) recommended a repeat FNAB for the AUS/FLUS category. Of represented institutions, 45.8% of those surveyed thought that the optimal interval for a repeat thyroid FNAB was 6 months, whereas 33.9% thought that 3 months were the optimal interval. In 41.6% of represented institutions, surgeons requested an intraoperative consultation after a thyroid lobectomy for a previous cytologic diagnosis of AUS/FLUS. Of represented institutions, 29.2% had a ≤10% rate of repeat FNAB after an initial cytologic diagnosis of AUS/FLUS. Of represented institutions, 31.5% had an approximate rate of surgery of ≤10% after an initial AUS/FLUS diagnosis. For the majority of represented institutions (86.4%), endocrinologists managed patients after an initial AUS/FLUS diagnosis. The median follow-up FNA evaluation rate for patients with an AUS/FLUS diagnosis was 70% among different institutions (mean [SD], 63.1% [30.6%]). The median rate of benign thyroid nodule diagnoses after an initial AUS/FLUS diagnosis was 52.0% (mean [SD], 56.2% [27.3%]) following either repeat cytologic aspiration or surgery. For 44.2% of respondents, the most common cause of an AUS/FLUS diagnosis was believed to be the type of thyroid nodule aspirated (solid vs. cystic vs. mixed). Only 10% of represented institutions routinely used the Afirma gene expression classifier (Veracyte, Inc.), a molecular test, for an AUS/FLUS diagnosis.


 » Discussion Top


The reporting of AUS/FLUS was highly variable among institutions. The majority of thyroid nodule biopsies were performed by endocrinologists using ultrasound guidance. Two-thirds of represented institutions performed on-site adequacy assessment for thyroid aspirates. The Bethesda system for reporting thyroid FNABs was widely used. Most institutions performed a repeat FNAB within 3-6 months after an initial AUS/FLUS diagnosis. The median follow-up FNA evaluation rate for an initial AUS/FLUS diagnosis was 70%. The most common follow-up diagnosis following an AUS/FLUS diagnosis was benign thyroid nodule. Most respondents thought that the 2 most common causes for AUS/FLUS diagnosis were nodule type and poor aspiration technique (65.1%).

The definition of the FLUS subgroup by the Bethesda system for reporting FNAB results [4] states that it is "a heterogeneous category that includes cases in which the cytologic findings are not convincingly benign, yet the degree of cellular or architectural atypia is not sufficient for an interpretation of "follicular neoplasm" or "suspicious for malignancy." This category was introduced as optional, and when utilized, would ideally represent <7.0% of all thyroid FNAB interpretations at an institution. [4] However, reporting rates vary widely among different laboratories, ranging from 3% to 27.2%. [6],[7] For patients with indeterminate biopsy findings, factors such as sex, age, nodule size, and thyroid ultrasound characteristics can be considered to identify those with an elevated risk of malignancy. Indications for hemithyroidectomy in the setting of an FLUS diagnosis should include clinical and radiologic examination findings and patient preference. [8],[9],[10]

The AUS/FLUS category is a diagnosis of exclusion, resulting from several factors such as borderline cellularity, preparation artifacts, or equivocal cytologic or architectural features. [6] The AUS: Malignancy ratio, which varies from 0.5% to 4.9%, has been described as a measure for assessing the AUS category use. [11] In most laboratories, the AUS: Malignancy ratio should be between 1.0 and 3.0; ratios exceeding 3.0 are most likely indicative of overcalling AUS/FLUS or undercalling the malignant category. [11]

The reported sensitivity and specificity of thyroid FNAB are 86% and 62%, respectively. [10] The diagnostic accuracy of a thyroid FNAB approaches 95%; nevertheless, thyroid FNAB can be nondiagnostic in up to 20% of cases. [1] In a questionnaire survey of endocrinologists and surgeons, respondents believed that the nodule characteristics most commonly caused a nondiagnostic FNAB (48%), followed by poor biopsy technique (29%). [1]

The percent of biopsies in the indeterminate category (including FLUS and suspicious for follicular or Hürthle cell neoplasm) ranges from 6% to 55% among different institutions, [12] with marked variation in the rate at which the indeterminate category was used among pathologists (2.5-28.6%) and institutions (3.3-14.9%). [13] In approximately 20-28% of AUS/FLUS cases, a repeat thyroid FNAB is still given an AUS/FLUS diagnosis. [7] Nodule size was found to be an independent predictor of malignancy in FLUS [8] and the "suspicious for neoplasm" category. [9] Most respondents in the current study (44.2%) believed that nodule type (cystic, solid, mixed) accounts for the majority of FLUS diagnosis in their respective institutions. The most significant cytologic features predictive of neoplasia in the FLUS category include the presence of syncytial tissue fragments, isolated microfollicles, follicles with scalloped borders, scant cytoplasm, irregular nuclear membranes, nuclear overlapping, coarse chromatin, and increased cellularity. [13]

The overall risk of malignancy in all patients with a thyroid nodule is from 5% to 7%. [14] The malignancy rate for an AUS/FLUS diagnosis varies (6-27%) among different institutions. [7],[13],[14],[15],[16],[17] The malignancy rate for the indeterminate category is higher for those with nuclear atypia (56%) than for those with architectural atypia (7.0%). [17] The reported malignancy rate of AUS/FLUS after a repeat FNAB is much greater (19-27%) than the malignancy rate of an AUS/FLUS diagnosis with the initial FNAB (2.7-12%). [18] The most common malignancy for a patient with an AUS/FLUS diagnosis is papillary thyroid carcinoma (PTC; 44%), followed by follicular variant of PTC (38%). [14] Seventy percent of malignant diagnoses in the indeterminate group with architectural atypia were follicular variants of PTC. [7],[17] In one institution, the overall incidence of incidental PTC was 21.3%. [10]

Repeat FNAB of the AUS/FLUS category is more cost effective, with better-quality-adjusted life years than lobectomy. [18] Despite the NCI state of the science conference on thyroid FNAB, only 19-35% of patients have a repeat FNAB and 30-60% of patients go directly to surgery after an initial AUS/FLUS diagnosis. [18] However, thyroid surgery is not without inherent risks and complications, including hematoma, recurrent laryngeal nerve palsy, hypoparathyroidism, and hypothyroidism requiring life-long thyroid hormone replacement therapy. [19] The rate of hypothyroidism requiring thyroid hormone replacement therapy is 35% after hemithyroidectomy [18] and 47% after lobectomy for an indeterminate FNAB (FLUS and suspicious for follicular or Hürthle cell neoplasm). [19]

Molecular testing may be performed on AUS/FLUS lesions to further characterize the nature of the lesion. AUS/FLUS lesions with a V600E BRAF mutation likely represent classical or tall-cell variants of PTC. [20] The Afirma gene expression classifier can be used to test indeterminate thyroid nodules, including those characterized as AUS/FLUS, suspicious for follicular neoplasm, suspicious for Hürthle cell neoplasm, and suspicious for malignancy; it has high negative predictive value for discerning benign nodules. [21],[22] Sending indeterminate thyroid samples for molecular testing may increase the positive predictive value (BRAF testing) or negative predictive value (Afirma testing). In this study, 10% of respondents routinely sent samples for molecular testing.

The current study has several limitations. Only a select group of cytopathologists and cytotechnologists was surveyed. (Some members forwarded the survey link to endocrinologists in their respective institutions, but only two Endocrinologists responded to the survey.) Our findings have limited generalizability because of selection bias. Furthermore, despite sending 3 reminders, the overall response rate was low.


 » Conclusion Top


This study confirms that the reporting of the AUS/FLUS category varied widely among different institutions. Furthermore, the median follow-up rate of the AUS/FLUS category was only 70%, despite the American Thyroid Association management guidelines. [3] . The most common follow-up diagnosis after an initial AUS/FLUS diagnosis and repeat FNAB was benign thyroid nodule. Strict cytologic criteria should be adopted to minimize the variable AUS/FLUS diagnosis rates. Adherence to American Thyroid Association management recommendations and guidelines should be encouraged.


 » Competing interest statement by all author Top


The authors declare that they have no competing interests.


 » Authorship Statement by All Author Top


All authors of this article declare that we qualify for authorship as defined by ICMJE. Each author has participated sufficiently in the work and take public responsibility for appropriate portions of the content of this article. AN: Design and conception of the study, data interpretation, writing of initial and final draft; JPR: Data interpretation and review of final draft; SEK: Design of study survey and review of final draft; SMJ: Statistical analysis and data interpretation and review of final draft; KAL: Statistical analysis and data interpretation and review of final draft. All authors read and approved the final manuscript. Each author acknowledges that this final version was read and approved.


 » Ethics statement by all author Top


The study was approved by our institutional review board. Patient consent for this study was waived because the study did not confer any risk.


 » List of abbreviations Top


FNAB = Fine-Needle Aspiration Biopsy

AUS = Atypia of Undetermined Significance

FLUS = Follicular Lesion of Undetermined Significance

NCI = National Cancer Institute

ASC = American Society of Cytopathology

ASCT = American Society for Cytotechnology

 
 » References Top

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American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214.  Back to cited text no. 3
    
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Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: A synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425-37.  Back to cited text no. 4
    
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Jo VY, Stelow EB, Dustin SM, Hanley KZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2010;134:450-6.  Back to cited text no. 5
    
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Raparia K, Min SK, Mody DR, Anton R, Amrikachi M. Clinical outcomes for "suspicious" category in thyroid fine-needle aspiration biopsy: Patient′s sex and nodule size are possible predictors of malignancy. Arch Pathol Lab Med 2009;133:787-90.  Back to cited text no. 8
    
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Mehta RS, Carty SE, Ohori NP, Hodak SP, Coyne C, LeBeau SO, et al. Nodule size is an independent predictor of malignancy in mutation-negative nodules with follicular lesion of undetermined significance cytology. Surgery 2013;154:730-6.  Back to cited text no. 9
    
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Teixeira GV, Chikota H, Teixeira T, Manfro G, Pai SI, Tufano RP. Incidence of malignancy in thyroid nodules determined to be follicular lesions of undetermined significance on fine-needle aspiration. World J Surg 2012;36:69-74.  Back to cited text no. 10
    
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Krane JF, Vanderlaan PA, Faquin WC, Renshaw AA. The atypia of undetermined significance/follicular lesion of undetermined significance: Malignant ratio: A proposed performance measure for reporting in The Bethesda System for thyroid cytopathology. Cancer Cytopathol 2012;120:111-6.  Back to cited text no. 11
    
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Seningen JL, Nassar A, Henry MR. Correlation of thyroid nodule fine-needle aspiration cytology with corresponding histology at Mayo Clinic, 2001-2007: An institutional experience of 1,945 cases. Diagn Cytopathol 2012;40 Suppl 1:E27-32.  Back to cited text no. 12
    
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Jing X, Roh MH, Knoepp SM, Zhao L, Michael CW. Minimizing the diagnosis of "follicular lesion of undetermined significance" and identifying predictive features for neoplasia. Diagn Cytopathol 2011;39:737-42.  Back to cited text no. 13
    
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Broome JT, Solorzano CC. The impact of atypia/follicular lesion of undetermined significance on the rate of malignancy in thyroid fine-needle aspiration: Evaluation of the Bethesda System for reporting thyroid cytopathology. Surgery 2011;150:1234-41.  Back to cited text no. 14
    
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Chen JC, Pace SC, Chen BA, Khiyami A, McHenry CR. Yield of repeat fine-needle aspiration biopsy and rate of malignancy in patients with atypia or follicular lesion of undetermined significance: The impact of the Bethesda System for reporting thyroid cytopathology. Surgery 2012;152:1037-44.  Back to cited text no. 15
    
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Faquin WC, Baloch ZW. Fine-needle aspiration of follicular patterned lesions of the thyroid: Diagnosis, management, and follow-up according to National Cancer Institute (NCI) recommendations. Diagn Cytopathol 2010;38:731-9.  Back to cited text no. 16
    
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Horne MJ, Chhieng DC, Theoharis C, Schofield K, Kowalski D, Prasad ML, et al. Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification. Diagn Cytopathol 2012;40:410-5.  Back to cited text no. 17
    
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19.
Balentine CJ, Domingo RP, Patel R, Laucirica R, Suliburk JW. Thyroid lobectomy for indeterminate FNA: Not without consequences. J Surg Res 2013;184:189-92.  Back to cited text no. 19
    
20.
Ohori NP, Singhal R, Nikiforova MN, Yip L, Schoedel KE, Coyne C, et al. BRAF mutation detection in indeterminate thyroid cytology specimens: Underlying cytologic, molecular, and pathologic characteristics of papillary thyroid carcinoma. Cancer Cytopathol 2013;121:197-205.  Back to cited text no. 20
    
21.
Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 2012;367:705-15.  Back to cited text no. 21
    
22.
Ali SZ, Fish SA, Lanman R, Randolph GW, Sosa JA. Use of the afirma® gene expression classifier for preoperative identification of benign thyroid nodules with indeterminate fine needle aspiration cytopathology. PLoS Curr 2013:5.  Back to cited text no. 22
    



 
 
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