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Detection of Malignancy in Body Fluids: A Comparison of the Hematology and Cytology Laboratories

Body Fluid Malignancy

Journal of Applied Clinical Pathology. 2018;1(1):5
DOI: 10.24983/scitemed.jacp.2018.00077
Article Type: Original Article

Abstract

Objective: An increasing burden is loaded on clinical laboratories for daily testing of body fluids, including pleural fluid, peritoneal fluid (ascites), pericardial fluid, and cerebrospinal fluid. The request for detection of cellular components in the body fluid samples is usually delivered simultaneously to the hospital’s hematology laboratory and cytology laboratory. The medical technologists of hematology laboratory provide the screening result for suspicious malignant cells; meanwhile, the pathologists of cytology laboratory provide the presence of cancer cells at a diagnostic level. However, unfortunately, neither of these results reaches 100% sensitivity or specificity. To assess the clinical practice values, the present study performed a comparison of the hematology and cytology laboratories on the detection of malignancy in body fluids.
Methods: The body fluid specimens were collected either in the absence or in the presence of an anticoagulant agent, such as heparin. The finding of body fluid malignancy was remarked along with the differential count of blood cells in the report. Cytology laboratory, the body fluid specimens were subjected to cytospin centrifugation, followed by Papanicolaou stain, and then the morphological results were graded as negative, atypical, suspicious or positive for malignancy. The agreement of body fluid malignancy between the hematology laboratory and cytology laboratory was assessed by Kappa statistics and the differences between the groups were evaluated by chi-square test.
Results: A total of 248 body fluid samples, including 191 (77.0%) pleural fluids, 50 (20.1%) ascites, 4 (1.6%) pericardial fluids, and 3 (1.2%) cerebrospinal fluids were retrospectively surveyed in the National Cheng Kung University Hospital. The comparisons resulted in 105 (42.3%) positive and 106 (42.7%) negative reports of malignancy matched between hematology and cytology laboratories (Kappa agreement = 0.70). At a follow-up for 6 months, 141 fluid samples were confirmed with malignancy and 107 were without malignancy. It comprised 19 cancer types and the yielding of sensitivity, specificity, positive prediction value, and negative prediction value were 89.4%, 100.0%, 100.0% and 87.7% respectively for the hematology laboratory, and 85.8%, 99.1%, 99.2% and 84.1% respectively for the cytology laboratory. Furthermore, the hematology laboratory reported 15 false negative cases but no false positive, while the cytology laboratory reported 20 false negative cases and 1 false positive.
Conclusion: The hematology laboratory equipped with well-trained laboratory technical staff could provide early reporting service on body fluid malignancy, which might hold a potential reaching comparable competency similar to the cytology laboratory.

Keywords

  • Body fluid; cytology laboratory; hematology laboratory; malignancy

Introduction

Body fluids, including pleural, peritoneal (ascites), pericardial, and cerebrospinal effusions, consist of testing parameters which provide diagnostic values by examining the biochemical analytes and cellular components, such as infiltrating benign and malignancy cells [1,2]. The evaluation of the cellular compositions in these specimens is performed in either the hematology laboratory or the cytology laboratory or both, on the samples which were concomitantly collected but independently processed. The hematology expertise of medical technologists provides primarily reports based on absolute and differential hematological cell counts in the paired specimen of body fluid and peripheral blood, and screens for any suspicious malignant cells of other tumor types along with hematological lineage of differential precursors. Meanwhile, the cytology expertise of pathologists centrally checks for the presence of malignancy at a diagnostic-level rather than at a screening-level, yielding various sensitivities as reported; for example, an average of around 70% in detecting malignant cells in pleural fluid [3] and 40-65% in peritoneal fluid [4]. The diagnostic yields for malignancy by cytology might vary due to personnel skills and likewise depend on tumor and effusion types [5,6]; for example, a high sensitivity of > 95% in carcinoma in peritoneal fluids [4], but low sensitivities of < 50% in lymphomas, and < 25% in sarcomas and mesotheliomas in pleural fluids [3].

Closely distinct sample processes of body fluid in the hematology and cytology laboratories are applied with sodium citrate or heparin serving as anticoagulants and the cytospin methodology to concentrate scant cells. The medical technologists in the hematology laboratory examine the cells which are widely stained with Romanowsky dyes (Wright, Giemsa and Liu’s stain) [7,8], whereas the pathologists in the cytology laboratory perform morphological observation upon the cells with Papanicolaou stain [9]. Furthermore, the hematology laboratory runs for 24 hours per day and usually presents the screening reports earlier than the diagnostic reports from the cytology laboratory on the sample duplicates. Since the body fluid malignancy has not yet been fully detectable merely by cytology laboratory service, it is worthy to investigate the possibility of compensation with the results from the hematology laboratory. In this study within a hospital, the performance for finding positive body fluid malignancy in the hematology laboratory was evaluated and compared with that of the cytology laboratory.

Materials and Methods

Study Design
This study was designed retrospectively to assess and compare the performance of detecting body fluid malignancy by the hematology laboratory and the cytology laboratory of National Cheng Kung University Hospital (NCKUH). The cases were recruited from the consecutive body fluid specimen duplicates submitted for testing in the NCKUH hematology and cytology laboratories during 2015 to 2016. The exclusion criteria were the specimens that were inadequate for both examinations, and the cases that were incomplete for follow-up. The types of body fluid and reports of body fluid malignancy were recorded independently. The final diagnosis on the patient’s malignancy was then combined with the reports of further diagnostic services with positron emission tomography, computed tomography, histological examinations of biopsy, and bone marrow aspiration, as requested thereafter within 6 months. The study was approved by the Institutional Review Board of National Cheng Kung University Hospital vide no. B-ER-107-06 for data collection and analysis under waived informed consent from individual patients.  

Morphological Examination and Reporting
The body fluid specimens were collected either in the absence or in the presence of an anticoagulant agent, such as heparin. In NCKUH hematology laboratory, the samples were analyzed with automated complete cell counter (LH750, Beckman Coulter, Brea, CA) to determine the absolute and differential blood cell numbers; meanwhile, also mounted on a slide by cytospin centrifugation (Shandon cytospin 3, Thermo Scientific, Waltham, MA) and then visualized under microscopy with Liu’s stain to determine the hematological lineage of differential stages of blood cells and concomitantly with other solid-cancer originated malignant cells. The finding of body fluid malignancy was remarked along with the differential count of blood cells in the report. In NCKUH cytology laboratory, the body fluid specimens were subjected to cytospin centrifugation, followed by Papanicolaou stain, and then the morphological results were graded as negative, atypical, suspicious or positive for malignancy.

Statistical Analysis
The agreement of body fluid malignancy between the NCKUH hematology laboratory and cytology laboratory was assessed by Kappa statistics and the differences between the groups were evaluated by chi-square test. The statistical analysis was conducted using SPSS software (V.19.0; SPSS, Chicago, IL).

Results

In a total of 248 body fluid samples, the matched reports of malignancy were 105 (42.3%) positive and 106 (42.7%) negative in both hematology and cytology laboratories. Discrepancy was shown in 21 (8.5%) samples which were hematology-positive/cytology-negative and in 16 (2.4%) samples which were hematology-negative/cytology-positive. The results shown in Table 1 suggested that the reports of malignancy from NCKUH hematology laboratory and cytology laboratory might agree substantially (Kappa = 0.70, 95% confidence intervals = 0.61-0.79).

As stratified by sample types, the 248 effusions consisted of 191 (77.0%) pleural fluids, 50 (20.1%) ascites, 4 (1.6%) pericardial fluids, and 3 (1.2%) cerebrospinal fluids. The breakdown findings with malignancy in the 4 sample types by NCKUH hematology laboratory and cytology laboratory were displayed in Table 2, showing no significant differences between the groups of pleural fluid and non-pleural fluids (P = 0.140).

The patients were then checked within 6 months by the other diagnostic services of positron emission tomography, computed tomography, histological examinations of biopsy, and bone marrow aspiration to confirm malignancy. Among the total of 248 patients, malignancy was confirmed in 141 and 107 were without malignancy. The yielding of sensitivity, specificity, positive prediction value and negative prediction value were 89.4%, 100.0%, 100.0% and 87.7% respectively for the hematology laboratory, and 85.8%, 99.1%, 99.2% and 84.1% respectively for the cytology laboratory, as shown in Table 3. The results (Table 3) displayed that the NCKUH hematology laboratory reported 15 false negative cases but no false positive, while the cytology laboratory reported 20 false negative cases and 1 false positive. Taken together, the survey in this study indicated that the NCKUH hematology laboratory could reach a comparable diagnostic competency similar to that of the cytology laboratory.

This study comprised 19 types of malignancy, showing the top two cancers originating from lung and breast. As displayed in Table 4, no significant differences existed between the cancer types among the reports of body fluid malignancy by the NCKUH hematology laboratory and cytology laboratory. Additionally, pleural effusions were dominant in the diagnosis in the order of lung cancer, breast cancer, lymphoma, pancreatic cancer, and esophageal cancer, whereas ascites were dominant in the order of ovarian cancer, gastric cancer, hepatocellular carcinoma and esophageal cancer, as shown in Table 5.

NCKUH, National Cheng Kung University Hospital.

 

NCKUH, National Cheng Kung University Hospital.
a Hema, from hematology laboratory; cyto, from cytology laboratory.
b Non-pleural fluids consist of ascites, pericardial fluid and cerebrospinal fluid.
c Comparison between the groups of pleural fluid versus non-pleural fluids.

 

NCKUH, National Cheng Kung University Hospital; NPV, Negative Predictive Value; PPV, Positive Predictive Value.

 

NCKUH, National Cheng Kung University Hospital.

 

Discussion

Increasing clinical testing requests on body fluids represent diagnostic values, which reflect the differential bio-tracer of the local sampling site. However, the analysis features with a stressful burden because the body fluid compositions and the processing methods largely vary between fluid types [1]. Besides, even the regulatory compliance for complete blood count automation in the hematology laboratory is frequently not optimized for body fluid samples. The microscopic morphological observation of body fluid malignancy by manual methods, therefore, depends on the expertise of well-trained and experienced staffs. A substantial number of body fluid duplicate samples are simultaneously delivered to the hematology and cytology laboratories. The examinations on body fluids in the hematology laboratory include physical parameters, chemical analytes, blood cell count, and lineage differentiation, mainly with a purpose to differentiate transudates versus exudates [10], and concomitantly to screen for morphologically aberrant cells. Meanwhile, the cytology laboratory aims to examine the presence of malignancy at a diagnostic level. The results of hematology body fluid routine are requested in less than 12 hours, but it takes 3 days for cytology laboratory reports, which likely represent the “gold standard”. In this study, the first-line screening of body fluid was re-visited in the hematology laboratory. Nevertheless, the hematology laboratory currently reached comparable sensitivity and specificity as achieved by the cytology laboratory for the detection of body fluid malignancy. The results, therefore, suggested that the hematology laboratory might provide reports which are as valuable as those from the cytology laboratory, not only for screening but also for diagnostic orientation. Since the hematology laboratory is quicker in reporting positive results, it is promising to establish a real-time alarming rule with the cytology laboratory within a hospital.

The diagnostic ability of hematology laboratory in detecting body fluid malignancy has been compared with that of cytology laboratory, yielding less satisfactory sensitivities ranging from 23% to 64.9% in the previous studies [6,11,12], whereas an elevated sensitivity of 89.4% has been achieved in our current evaluation. Sample and cancer types, stain of specimen, and personnel education might contribute to the outcomes of detecting body fluid malignancy. In our study population, the pleural fluid samples outnumbered ascites, but it was vice versa in the other studies [6]. The Romanowsky Liu’s stain was used routinely to visualize hematological cell morphology in the NCKUH hematology laboratory while Wright stain [13] in the other. Nevertheless, the carcinoma types in Taiwan local area might account for the present diagnostic yields, as suggested previously [5,6]. Besides, the highly qualified personnel techniques in the NCKUH hematology laboratory might also be one determinant factor that confers diagnostic competence of body fluid malignancy. In Taiwan local area, the medical technologists receive a 4-year full-term education comprising academic-based and laboratory professional courses and undergo clinical hospital practice at the university level before obtaining the national license for an entry into the real-world services. Furthermore, regular continued education and skilled training resumption in morphological identification are obligated on a per year basis. Concomitantly, the previous results demonstrated that the sensitivity of detecting body fluid malignancy could be elevated from 23.4% to 60% after an implant of the quality assurance plan with educational components [6]. Taken together, the diagnostic values in body fluid malignancy can be increased by improving the abilities of hematology laboratory’s technologists in identifying cell morphology.

Currently, the increasing aged population might give rise to cancer incidence [14]. Colon cancer, hepatocellular carcinoma, and lung cancer are the top leading malignancy for males, whereas breast cancer, colon cancer, and lung cancer for females in Taiwan. The four common types of cancer together account for more than 50% of the overall cancer illness [11]. In this study, most of the body fluid malignancy came from lung cancer and breast cancer cells, which primarily exfoliated in pleural effusions and secondarily in ascites. It was shown that the body fluid analysis could establish the diagnosis of metastatic adenocarcinoma in > 70% of cases, which was much higher than the reported sensitivities for mesothelioma (10%), squamous-cell carcinoma (20%), sarcoma (25%), and lymphoma (25-50%) [4]. Therefore, the predominant malignant types of lung and breast cancers involving the pleural fluid might be attributed to the high sensitivity and comparable detection in the NCKUH hematology and cytology laboratories.

The limitations of the study included that it was conducted with cases with query for testing in both the NCKUH hematology and cytology laboratories; and the numbers of several cancer types were small in the context of the majority pleural fluid specimens.

Conclusion

The hematology laboratory when providing well-trained competences might potentially be comparable to the cytology laboratory for a diagnosis of body fluid malignancy.

References

  1. Block DR, Algeciras-Schimnich A. Body fluid analysis: clinical utility and applicability of published studies to guide interpretation of today’s laboratory testing in serous fluids. Critr Rev Clin Lab Sci 2013;50:107-124. PMID: 24156653; DOI: 10.3109/10408363.2013.844679
  2. McPherson RA, Bidkorpeh EK, Castellani WJ, et al. Analysis of Body Fluids in clinical Chemistry; Approved Guideline. 2nd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2016.
  3. Light RW. Clinical practice. Pleural effusion. N Engl J Med 2002;346:1971-1977. DOI: 10.1056/NEJMcp010731
  4. Runyon BA, Hoefs JC, Morgan TR. Ascitic fluid analysis in malignancy‐related ascites. Hepatology 1988;8:1104-1109. PMID: 3417231
  5. Maskell NA ,Butland RJA. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 2003;58:ii8-17. PMID: 12728146; PMCID: PMC1766019
  6. Jerz JL, Donohue RE, Mody RR, Schwartz MR, Mody DR, Zieske AW. Detection of malignancy in body fluids: a comparison of the hematology and cytology laboratories. Arch Pathol Lab Med 2014;138:651-657. PMID: 24786122; DOI: 10.5858/arpa.2013-0295-OA
  7. Bentley SA, Marshall PN,Trobaugh FJ. Standardization of the Romanowsky staining procedure: an overview. Anal Quant Cytol 1980;2:15-18. PMID: 6155098
  8. Horobin R. How Romanowsky stains work and why they remain valuable—including a proposed universal Romanowsky staining mechanism and a rational troubleshooting scheme. Biotech Histochem 2011;86:36-51. PMID: 21235292; DOI: 10.3109/10520295.2010.515491
  9. Chantziantoniou N, Donnelly AD, Mukherjee M, Boon ME, Austin RM. Inception and development of the Papanicolaou stain method. Acta Cytolo 2017;61:266-280. PMID: 28384641; DOI: 10.1159/000457827
  10. Joseph J, Badrinath P, Basran GS, Sahn SA. Is the pleural fluid transudate or exudate? A revisit of the diagnostic criteria. Thorax 2001;56:867-870. PMID: 11641512; PMCID: PMC1745948
  11. Ben-Ezra J, Stastny JF, Harris AC, Bork L, Frable WJ. Comparison of the clinical microscopy laboratory with the cytopathology laboratory in the detection of malignant cells in body fluids. Am J Clin Pathol 1994;102:439-442. PMID: 7942600
  12. Kendall B, Dunn C, Solanki P. A comparison of the effectiveness of malignancy detection in body fluid examination by the cytopathology and hematology laboratories. Arch Pathol Lab Med 1997;121:976-979. PMID: 9302931
  13. Cornbleet PJ. Wright-Giemsa cytology of body fluids: criteria for identification of malignant cells. Lab Med 1998;29:26-31. DOI: 10.1093/labmed/29.1.26
  14. Chiang CJ, Lo WC, Yang YW, You SL, Chen CJ, Lai MS. Incidence and survival of adult cancer patients in Taiwan, 2002-2012. J Formos Med Assoc 2016;115:1076-1088. PMID: 26786251; DOI: 10.1016/j.jfma.2015.10.011

Editorial Information

Publication History

Received date: April 24, 2018
Accepted date: June 20, 2018
Published date: August 18, 2018

Funding

None

Conflict of Interest

None

Disclosures

The manuscript was presented at a meeting: 9th Asia-Pacific Forum of Medical Laboratory Sciences 2017, Taiwan Association of Medical Technologists (TAMT), Taoyuan, Taiwan, held on April 15-16, 2017.

Acknowledgement

The authors would like to thank Ting-Yu Hou for her assistance in the manuscript preparation.

Copyright

© 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY).

Hematology Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
Hematology Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
  1. Hematology Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
  2. Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  1. Hematology Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
  2. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  1. Hematology Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
  2. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Address: No. 1 University Road, Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
Table 1.JPG
Table 1. Reports of malignancy in body fluid by NCKUH hematology and cytology laboratories (N=248). NCKUH, National Cheng Kung University Hospital.
Table 2.JPG
Table 2. Comparisons of the findings with malignancy in four body fluid sample types by NCKUH hematology and cytology laboratories (N=248). NCKUH, National Cheng Kung University Hospital. a Hema, from hematology laboratory; cyto, from cytology laboratory. b Non-pleural fluids consist of ascites, pericardial fluid and cerebrospinal fluid. c Comparison between the groups of pleural fluid versus non-pleural fluids.
Table 3.JPG
Table 3. Sensitivity, specificity and predictive values for detection of body fluid malignancy by NCKUH hematology and cytology laboratories (N=248). NCKUH, National Cheng Kung University Hospital; NPV, Negative Predictive Value; PPV, Positive Predictive Value.
Table 4.JPG
Table 4. Comparisons of the cancer types regarding report of body fluid malignancy by NCKUH hematology and cytology laboratories. NCKUH, National Cheng Kung University Hospital.
Table 5.JPG
Table 5. The cancer types of confirmed malignancy regarding body fluid sample types.

Peer Review Report: Round 1

Reviewer 1 Comments

  1. Authors may need to specify the criteria used for the inclusion and exclusion of specimens in study. For example, the body fluid specimens that were not adequate for testing or patients who were lost to follow up should be excluded in the study.
     ResponseThanks for the comments and suggestions. The inclusion and exclusion criteria in this study has been clearly described in the revised Material and Method section-Study design, as follows. “The cases were recruited from the consecutive body fluid specimen duplicates submitted for testing in NCKUH hematology and cytology laboratories during 2015 to 2016, while the exclusion criteria were specimens that inadequate for both examinations, and the cases that incomplete for follow up.” Please see page 6 in the manuscript.
     
  2. In Table 2, several values are quite small, such as 0, 1, and I wonder whether the differences between groups should be assessed by Fisher’s Exact test or chi-square test.
    ResponseThanks for the comments on the statistical analysis by chi-square test between the groups with small sample sizes in Table 2, such as ascites, pericardial fluid and cerebrospinal fluid. In the revised Table 2, the cases with ascites, pericardial fluid and cerebrospinal fluid were combined as a single group of non-pleural fluids to compare with those of pleural fluid group by statistics. The results were therefore revised as “The breakdown findings with malignancy in the 4 sample types by NCKUH hematology laboratory and cytology laboratory were displayed in Table 2, showing no significant differences between groups of pleural fluid and non-pleural fluids (P = 0.140).”  Please review the revised Results section (please see page 8 in the manuscript).
     
  3. Research outcomes should be compared with those obtained in previous studies. Possible explanations should be proposed in cases where the current findings are inconsistent with those in the literature.
    ResponseThanks for your valuable suggestions. Comparisons of and possible explanations on research outcomes between ours and those in previous studies have been boosted in the revised Discussion section as follows. “The diagnostic ability of hematology laboratory at detecting body fluid malignancy has been compared with that of cytology laboratory, yielding less satisfactory sensitivities ranged from 23% to 64.9% in the previous studies, whereas an elevated sensitivity of 89.4% was obtained in our current evaluation. Sample and cancer types, stain of specimen and personnel education might contribute to the outcomes of detecting body fluid malignancy. In our study population, pleural fluid samples outnumbered ascites but vice versa in the other studies. The Romanowsky Liu’s stain was used routinely to visualize hematological cell morphology in NCKUH hematology laboratory while Wright stain in the other. Nevertheless, the carcinoma types in Taiwan local area might account for the present diagnostic yields, as suggested previously. Besides, highly qualified personnel techniques in NCKUH hematology laboratory might also be one determinant factor that confers diagnostic competence of body fluid malignancy. In Taiwan local area, the medical technologists having received a 4-year full-term education comprising academic-based and laboratory professional courses, and clinical hospital practice at a university level before obtaining the national license for an entry of real-world services. Furthermore, regular continued education and skill training renew in morphological identification is obligated at a per year basis. Concomitantly, the previous results demonstrated that the sensitivity of detecting body fluids malignance could be elevated from 23.4% to 60% after an implant of the quality assurance plan with educational components. Taken together, the diagnostic values in body fluid malignancy can be increased by improving the abilities of hematology laboratory’s technologists in identifying cell morphology.” The paragraph has been revised in the Discussion section (pages 10-11) and references 11-13 (page 14).
     
  4. Please address and discuss the possibility that bias has been introduced at any stage of the study, including selection bias. Authors should include a comprehensive description of the limitations of the research.
    ResponseThanks for the suggestion, the selection bias and limitation of this study has been added in the Discussion section (please see page 12 in the manuscript).
     
  5. There was an agreement by Kappa statistics (k = 0.7). Is there a statistical significance in terms of P value?
    ResponseKappa statistics might serve as the most commonly reported measure of interobserver agreement in the medical literature. The following Table helps to interpret Kappa Agreement. With a large enough sample size, any kappa above 0 becomes statistically significant. Meanwhile, a P-value does not test the strength of Kappa agreement. (Anthony J. Viera, et al. Fam Med 2005;37(5):360-3).
     

    Kappa

    Agreement

    0.01–0.20

    Slight Agreement

    0.21– 0.40

    Fair Agreement

    0.41–0.60

    Moderate Agreement

    0.61–0.80

    Substantial Agreement

    0.81–0.99

    Almost Perfect Agreement


    The Kappa of 0.70 in our results might indicate “substantial agreement”. The 95% confidence intervals for Kappa were 0.61-0.79, which further added informative and strengthened interpretation in the revised Table 1. The following sentences have been revised in the Result section (page 8) as follows. “The results in Table 1 suggested that reports of malignancy from NCKUH hematology laboratory and cytology laboratory might agree substantially (Kappa=0.70, 95% confidence intervals=0.61-0.79).

Reviewer 2 Comments

  1. In the study, the morphological results were graded as negative, atypical, suspicious or positive for malignancy. The authors should clarify how they finally categorized these results into positive or negative outcomes for malignancy.
    ResponseThe classification of cell morphology was based on “Color Atlas of Body Fluids, College of American Pathologists” as negative, atypical, suspicious or positive for malignancy. However, the cases in this study showed the reading results of either negative or positive for malignancy.
     
  2. There are some typo errors, e.g., “Among the total 248 patients, malignancy WAS confirmed in 141 and 107 were without…”, “…at a university level before OBTAINING the national license for an entry of real-world services.”, and “…99.1%, 99.2% and 84.1% for the cytology laboratory, RESPECTIVELY as shown in Table 3.”
    ResponseThanks for the critique on the typo errors, which have been corrected in the revised version of manuscript (pages 9, 11).
     
  3. The authors stated that the most body fluid malignancy came from lung cancer and breast cancer cells which primarily exfoliated in pleural effusions and secondarily in ascites. The predominant malignant types of lung and breast in body fluids might be attributed to the comparable detection in the NCKUH hematology and cytology laboratories. This point needs to be further clarified and be well explained.
    ResponseThanks for the suggestion. We have clarifyied the point as follows. “In this study, the most body fluid malignancy came from lung cancer and breast cancer cells which primarily exfoliated in pleural effusions and secondarily in ascites. It has been shown that body fluid analysis could establish the diagnosis of metastatic adenocarcinoma in > 70% of cases, which was much higher than the reported sensitivities for mesothelioma (10%), squamous-cell carcinoma (20%), sarcoma (25%) and lymphoma (25-50%). Therefore, the predominant malignant types of lung and breast cancers involving the pleural fluid might be attributed to the high sensitivity and comparable detection in the NCKUH hematology and cytology laboratories.” The paragraph has been revised in the Discussion section (page 12).
     
  4. The value of Kappa between 0.6 and 0.79 indicates “moderate” level of agreement. I would suggest the conclusion should be made in a conservative way in health care or in clinical research, especially when results of studies may change clinical practice.
    ResponseThanks for the suggestion to make the conclusion in a more conservative way. The sentences have been revised as follows. “In conclusion, the hematology laboratory prepared by well-trained laboratory technical staffs could provide early reporting service on body fluid malignancy which might hold a potential reaching comparable competency as similar to the cytology laboratory.” In the revised Abstract section (pages 3-4), and “The hematology laboratory when providing well-trained competences might potentially be comparable to the cytology laboratory for a diagnosis of body fluid malignancy.” In the revised Conclusion section (page 12).

    We would like to thank the Academic editor/reviewers of Journal of Applied Clinical Pathology for their time and valuable criticism on our manuscript. We also appreciate the opportunity of revision. The comments from reviewers have helped us greatly to improve data presentation, analysis and interpretation of this study. The revised manuscript attempts to incorporate all the referees’ salient points and is now re-submitted accordingly. The responses to individual reviewer are listed point-by-point and the changes made in resubmitted manuscript. Both tracking and clear versions of revised manuscript are uploaded for review.
     

Peer Review Report: Round 2

Reviewer 1 Comments

After reviewing the revised manuscript, I am satisfied with the authors' responses and the corrections in the manuscript.

Reviewer 2 Comments

I accept the revised manuscript for publication.