Journal of Pathology and Translational Medicine

Review

Lymphoproliferative disorder involving body fluid: diagnostic approaches and roles of ancillary studies: Jiwon Koh, Sun Ah Shin, Ji Ae Lee, Yoon Kyung Jeon; J Pathol Transl Med. 2022;56(4):173-186. Published online July 4, 2022; DOI: https://doi.org/10.4132/jptm.2022.05.16

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Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.

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The urgency of Burkitt lymphoma diagnosis in fluid cytology—A tertiary care experience
Soundarya Ravi, Anu K. Devi, Prabhu Manivannan, Debasis Gochhait, Rakhee Kar, Neelaiah Siddaraju
Cytopathology.2024; 35(2): 275. CrossRef
Immunocytochemistry on frozen-embedded cell block for the diagnosis of hematolymphoid cytology specimen: a straightforward alternative to the conventional cell block
Youjeong Seo, Sanzida Alam Prome, Lucia Kim, Jee Young Han, Joon Mee Kim, Suk Jin Choi
Journal of Hematopathology.2024; 17(1): 1. CrossRef
Lymphoma presenting as the first finding in pleural fluid cytology: A rare cytologic presentation
Kafil Akhtar, Gowthami Nagendhran, Anjum Ara, Masheera Akhtar
IP Archives of Cytology and Histopathology Research.2024; 8(4): 250. CrossRef

Original Articles

Utility of Promoter Hypermethylation for Differentiating Malignant and Benign Effusions in Liquid-Based Cytology Specimens.: Ga Eon Kim, Jo Heon Kim, Yeong Hui Kim, Chan Choi, Ji Shin Lee; Korean J Pathol. 2010;44(3):315-321.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.3.315

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Abstract PDF

BACKGROUND
Making the cytologic differentiation between benign and malignant effusions can be difficult. Because promoter hypermethylation of tumor suppressor genes is a frequent epigenetic event in many human cancers, it could serve as a marker for the diagnosis of cancer. The aim of this study was to investigate the feasibility of detecting promoter hypermethylation as a diagnostic tool with using liquid-based cytology samples for differentiating between malignant and benign effusions.
METHODS
A multiplex, nested, methylation-specific polymerase chain reaction analysis was used to examine promoter methylation of 4 genes (retinoic acid receptor-beta, [RAR-beta], adenomatous polyposis coli [APC], Twist and high in normal-1 [HIN-1]) in malignant (n = 85) and benign (n = 31) liquid-based cytology samples.
RESULTS
The frequencies of hypermethylation of RAR-beta, APC, Twist and HIN-1 were significantly higher in the malignant effusions than in the benign effusions (p < 0.001 for each). On the receiver-operating characteristic analysis, the area under the curve (AUC) for APC was the greatest. The AUC for the best two-gene combination (APC/HIN-1) was not statistically different from the AUC for the best individual tumor suppressor gene (APC).
CONCLUSIONS
This study suggests that promoter methylation analysis on residual liquid-based effusion samples may be a feasible approach to detect malignant effusions, and that APC is the best marker for differentiating between malignant and benign effusions.

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A comparative analysis of conventional cytopreparatory and liquid based cytological techniques (Sure Path) in evaluation of serous effusion fluids
Hrishikesh Dadhich, Pampa Ch Toi, Neelaiah Siddaraju, Kalidas Sevvanthi
Diagnostic Cytopathology.2016; 44(11): 874. CrossRef

Malignant Mesothelioma in Body Fluids: with Special Reference to Differential Diagnosis from Metastatic Adenocarcinoma.: Jin Ho Paik, Jin Haeng Chung, Baek Hui Kim, Gheeyoung Choe; Korean J Pathol. 2009;43(5):458-466.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.5.458

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Abstract PDF: BACKGROUND
Malignant mesothelioma (MM) is a rare malignant neoplasm occurring in pleura, pericardium, and peritoneum. The differential diagnosis between MM and metastatic adenocarcinoma (MA) causes diagnostic, staging, and therapeutic dilemmas. Herein, we investigated characteristic cytologic features of MM.
METHODS
Cytologic specimens of MM (n=10), MA (n=25), and reactive mesothelial hyperplasia (n=10) were retrieved and reviewed from archival materials in the Department of Pathology, Seoul National University Bundang Hospital from May 2003 to July 2008.
RESULTS
MM showed tumor cell clusters and singly scattered malignant tumor cells forming single cell populations with sparse reactive benign mesothelial cells. In contrast, MA showed distinct two cell populations of tumor cell clusters and scattered reactive mesothelial cells. Furthermore, MM frequently exhibited a characteristic long chain-like arrangement (hand-in-hand appearance) and intercellular windows, which were rarely evident in MA. Variable nuclear size, relatively consistent nuclear-cytoplasmic ratio, bior multi-nucleation, and lacy cytoplasmic borders were also frequently observed in MM.
CONCLUSIONS
Differential diagnosis of MM from MA in body fluids is possible based on meticulous examination of certain cytologic parameters, which could have significant implications in staging and treatment.

Comparison of Cytologic Evaluation between Conventional Method and CellprepPlus(R) Liquid-Based Cytology in Body Fluid.: Ji Hae Koo, Ho Chang Lee, Hyung Geun Song, Hye Suk Han, Ki Hyeong Lee, Kang Hyeon Choe, Ki Man Lee, Ok Jun Lee; Korean J Pathol. 2009;43(5):448-452.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.5.448

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Abstract PDF

BACKGROUND
Assessment of body fluid cytology is a useful means of evaluating a metastatic tumor. Liquid-based cytology (LBC) has been developed as a replacement for the conventional Papanicolaou (CP) test. This study was performed to compare CellprepPlus(R) LBC with CP in cytologic diagnosis. METHODS: Body fluid samples (n=188, including 72 peritoneal fluid and 116 pleural fluid samples) were divided equally and analyzed by both CellprepPlus(R) and CP.
RESULTS
CellprepPlus(R) revealed distributed thin layers of non-overlapping cells. All CellprepPlus(R) preparations were adequate, while 18 (9.57%) CP preparations were inadequate. The respective diagnostic rates of CellprepPlus(R) and CP were 75.0% and 76.1% negative, 10.6% and 6.38% atypical, 5.85% and 2.66% suspicious, and 8.51% and 5.32% malignant. Of the 58 confirmed cases, the sensitivity of CellprepPlus(R) and CP was 94.4% and 73.3%, respectively, and the negative predictive value was 97.2% and 87.9%, respectively.
CONCLUSIONS
CellprepPlus(R) LBC has better sensitivity and negative predictive value, and produces higher quality slide preparations than than CP, making it suitable as in screening of body fluid as a cytologic diagnostic tool.

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A COMPARATIVE STUDY OF CYTOLOGIC EVALUATION BETWEEN CONVENTIONAL METHOD & LIQUID BASED CYTOLOGY IN PLEURAL, PERICARDIAL & PERITONEAL FLUIDS
R. P. Siddiqui, Mohd. Jafar Memon, Shraddha Sahu
INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH.2020; : 1. CrossRef
Comparison of liquid-based cytology (CellPrepPlus) and conventional smears in pancreaticobiliary disease
Myeong Ho Yeon, Hee Seok Jeong, Hee Seung Lee, Jong Soon Jang, Seungho Lee, Soon Man Yoon, Hee Bok Chae, Seon Mee Park, Sei Jin Youn, Joung-Ho Han, Hye-Suk Han, Ho Chang Lee
The Korean Journal of Internal Medicine.2018; 33(5): 883. CrossRef
Comparison of diagnostic accuracy between CellprepPlus® and ThinPrep® liquid‐based preparations in effusion cytology
Yong‐Moon Lee, Ji‐Yong Hwang, Seung‐Myoung Son, Song‐Yi Choi, Ho‐Chang Lee, Eun‐Joong Kim, Hye‐Suk Han, Jin young An, Joung‐Ho Han, Ok‐Jun Lee
Diagnostic Cytopathology.2014; 42(5): 384. CrossRef
Evaluation of Urine Cytology in Urothelial Carcinoma Patients: A Comparison of CellprepPlus® Liquid-Based Cytology and Conventional Smear
Seung-Myoung Son, Ji Hae Koo, Song-Yi Choi, Ho-Chang Lee, Yong-Moon Lee, Hyung Geun Song, Hae-Kyung Hwang, Hye-Suk Han, Seok-Joong Yun, Wun-Jae Kim, Eun-Joong Kim, Ok-Jun Lee
Korean Journal of Pathology.2012; 46(1): 68. CrossRef
CellprepPlus® Liquid-based Smear in Sono-guided Thyroid Fine Needle Aspiration: A Comparison of Conventional Method and CellprepPlus® Liquid-based Cytology
Ji Hae Koo, Seung Young Lee, Ho-chang Lee, Jin-Woo Park, Sung Soo Koong, Tae Keun Oh, Hyun Jeong Jeon, Eun-Joong Kim, Ok-Jun Lee
The Korean Journal of Pathology.2011; 45(2): 182. CrossRef

Case Report

The Cytologic Features of Chronic Myelogenous Leukemia and Its Lymphoid Blast Phase in Body Fluid: A Case Report.: Soyoung Im, Changyoung Yoo, Youn Soo Lee, Chang Suk Kang, Sang In Sim, Kyo Young Lee; Korean J Pathol. 2009;43(2):189-194.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.2.189

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Abstract PDF: Although chronic myelogenous leukemia (CML) may be involved in any part of the body, infiltration of the body fluid has rarely reported in the literature. Here we report on a 35 year-old male patient who was diagnosed chronic myelogenous leukemia ten years previously and he received allogenic hematopoietic stem cell transplantation. He then presented with left knee pain eight years after the initial diagnosis. MRI revealed a soft tissue mass at the distal femur. Cytology of the joint fluid revealed myeloblasts, promyelocytes, eosinophilic myelocytes, band neutrophils, megakaryocytes and orthochromatic erythroblasts, which was all consistent with leukemic infiltration of the knee joint fluid. The immunohistochemistry was positive for CD34, CD117 and myeloperoxidase (MPO). Despite that the patient underwent radiation therapy, MRI revealed growth of the mass, and ten months later, the lymphoid blast phase of CML was confirmed after biopsy. The patient received an above knee amputation. Five months later, multiple masses were revealed on PET-CT at the left iliopsoas muscle, abdominal wall and bones. Bilateral pleural effusion occurred shortly after this. Cytologic evaluation of the pleural fluid also revealed blast-like cells, and histologic evaluation of the abdominal mass confirmed the lymphoid blast phase of CML with positivity for CD3, UCHL-1, CD34 and CD117, but negativity for MPO.

Original Articles

Methylation Abnormality in Body Fluid Cytology: A Supplemental Molecular Marker for the Diagnosis of Malignant Mesothelioma.: Joon Seon Song, Jin Kyung Jung, Ji Hye Kang, Ilseon Hwang, Se Jin Jang; Korean J Cytopathol. 2008;19(2):126-135.; DOI: https://doi.org/10.3338/kjc.2008.19.2.126

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Abstract PDF

Malignant mesothelioma (MM) is a highly lethal neoplasm arising in pleura and the peritoneum and a rapid and accurate diagnosis is crucial for treatment of the disease. However, the sensitivity of cytological analysis using pleural or ascitic fluid is relatively low, yielding an accurate diagnosis in only 32~79% of cases. We tested the diagnostic value of epigenetic alterations in body fluid cytology as a supplement to conventional methods. Paraffin-embedded tissue blocks from 21 MM patients and associated body fluid cytology slides considered no evidence of malignancy were used to test for epigenetic alteration. Using methylation-specific PCR, we detected methylation of RASSF1A and p16 in 47.6% (10/21) of both surgically resected tumor samples, respectively. Body fluid samples of MM also showed abnormal methylation of RASSF1A and p16INK4a genes in 38.1% (8/21) and 33.3% (7/21) of cases. The concordance in the rates of RASSF1A and p16INK4a gene-methylation abnormalities determined from cytology samples and tissue samples were 61.9% (13/21) and 66.7% (14/21), respectively. Combining both genes increases the sensitivity of the test to 57.1% (12 of 21) of cases. Our results suggest that testing for methylation abnormalities in selected individual genes or gene combinations has diagnostic value as an alternative or adjunct method to conventional cytological diagnosis.

Citations

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Utility of Promoter Hypermethylation for Differentiating Malignant and Benign Effusions in Liquid-Based Cytology Specimens
Ga-Eon Kim, Jo-Heon Kim, Yeong-Hui Kim, Chan Choi, Ji Shin Lee
The Korean Journal of Pathology.2010; 44(3): 315. CrossRef

The Significance of AgNOR Count in Body Fluid: Differential between reactive mesothelial cells & malignant cells.: Seung Sam Paik, Eun Kyung Hong, Se Jin Jang, Moon Hyang Park, Jung Dal Lee; Korean J Cytopathol. 1997;8(2):129-134.

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Abstract PDF: To distinguish reactive mesothelial cells from malignant cells in body fluid, we applied silver staining of nucleolar organizer regions(AgNORs) to ethanol fixed cytologic preparations. Fifty aspirated samples of benign(22 cases) and malignant(26 cases) body fluids were studied using the one step silver staining method. Two cytologically atypical samples were also included in the study. In malignant cases the mean AgNOR count was 3.56+/-0.81, while in benign cases the mean AgNOR count was 2.02+/-0.33. The difference of AgNOR counts between these two groups were statistically significant(p<0.001). The mean of atypical cases was 2.91. Both were diagnosed as malignant in follow-up cytology. In malignant effusions, there is statistically significant difference in AgNOR counts between cells forming complex papillae or clusters and singly scattered cells(p<0.05), 3.29+/-0.95 and 3.83+/-0.55, respectively. We concluded that AgNOR count appears to be useful as a diagnostic tool especially when the cytologic differentiation is difficult.

p53 Immunoreactivity in the Cytology of Body Cavity Fluid.: Sun Hee Sung, Woon Sup Han; Korean J Cytopathol. 1998;9(1):15-20.

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Abstract PDF: Mutant form of the p53 gene product is abnormally accumulated in the nuclei of the tumor cells due to prolonged half life, and readily detected by immunohisto- chemical methods. To determine the positivity rate of p53 in body cavity fluid according the primary site and histological types of tumors and the utility of p53 immunostaining as an adjunct in the diagnosis of malignancy, we reviewed 69 effusions, including pleural effusion, ascitic fluid, and pericardial fluid, that were diagnosed as overt malignancy and 21 effusions of suspicious malignancy. Immuno- histochemistry was performed on paraffin-embedded cell blocks using a monoclonal antibody to p53 supressor gene product(Clone DO7) and a standard avidin-biotin complex technique with a citrate buffer antigen retrieval solution. The results were as follows; of the 46 pleural effusions with overt malignancy, 22 were immunopositive for p53 protein; of the 21 ascitic fluids with overt malignancy, 5 were positive for p53. Positivity rates according to the primary sites of tumors were 18 of 34(52.9%), 8 of 21(38.1%), 1 of 9(11.1%) cases of the tumors of the lung, GI tract, and ovary, respectively. According to the histologic types of lung cancer, 11 cases(61.6%) were positive out of 18 adenocarcinomas, 2 of 5 large cell undifferentiated carcinomas, and 1 of 2 small cell undifferentiated carcinomas. Of 21 cases of suspicious malignancy, 6 were positive for p53 and all of them(6/6) were confirmed as adeno- carcinoma of the lung or GI tract. These findings indicate that p53 immunostaining using paraffin embedded cell block is useful diagnostic and prognostic marker in body fluid cytology although negative immunostaining does not exclude malignancy.

Availability of Toluidine Blue Stain in Body Fluid.: Hye Kyung Lee, Myung Jin Joo, Kwang Min Lee, Eun Hee Lee, Sang In Sim; Korean J Cytopathol. 1999;10(1):7-11.

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Abstract PDF: We evaluated the availability of toluidine blue stain in body fluids, such as peritoneal and pleural fluid and urine. Nine hundreds specimens, i.e., 400 pleural and 400 peritoneal fluids and 100 urine samples, respectively, from Jan. 1995 to May 1996 were included. We obtained the result of high sensitivity and high specificity in toluidine blue stained body fluid in comparison with Papanicolaou stained result. Additionally, we found the diagnostically important crystals in chylothorax and some urine samples, which can not be seen in routine Papanicolaou stain. We thought the toluidine blue stain in body fluid is one of very useful diagnostic methods.

Usefulness of E-Cadherin Expression in Malignant Effusion .: Sung Jig Lim, Gou Young Kim, Youn Wha Kim, Yong Koo Park, Juhie Lee, Moon Ho Yang, Nam Hee Won; Korean J Cytopathol. 1999;10(2):121-126.

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Abstract PDF: The usefulness of E-cadherin immunostaining as a marker of malignancy in the body fluids was investigated in the present study. Thirty-three histologically proven cases of cell blocks from the pleural, peritoneal, and pericardial fluids were studied by immunocytochemistry for E-cadherin antibody using LSAB method. These cases were cytologically diagnosed as adenocarcinoma (25 cases) and atypical cells (8 cases). Tumor cells showed strong positive membranous staining for E-cadherin antibody in 21 out of 25 cases (84%) of adenocarcinoma. E-cadherin staining was not found in 6 of 8 cases of suspicious maligancy. The sensitivity and specificity were 84% and 75%, respectively. Reactive mesothelial cells and inflammatory cells scattered were all negative. In conclusion, E-cadherin is an useful adjunctive marker to distinguish reactive mesothelial cells from the carcinoma cells in the body fluids.

Cytologic Features and Distribution of Primary site of Malignant Cells in Body Fluids.: Kyoung Ho Kim, Kwang Gil Lee; Korean J Pathol. 1990;24(4):456-464.

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Abstract PDF: Many articles concerning the accuracy of diagnosis of malignant tumor cells in body fluids have appeared in the literature, but few authors have attempted to describe the characteristics of these cells to determine the site of the primary tumor as they relate to tumors of specific primary sites. This paper presents the results of a retrospective study on malignant body cavity effusions of which the primary site was established on the basis of either biopsy or surgical resection of the primary neoplasm during the period of 6 years beginning from January 1983 to December 1988. The results obtained are summarized as follows: 1) The 143 fluid specimens from 129 patients were composed of 51 cases of pleural, 69 of peritoneal, and 9 of pericardial origin. 2) Adenocarcinoma was the most frequent type of malignant effusions (78.3%). The most common primary site was the lung (50%) in pleural fluid and stomach (55.2%) in ascites. 3) The results of this study show that the primary site of tumor cells can be identified in the body fluid of accurate cytomorphologic criteria are used. Identification of the primary site of an effusion would be improved by the consideration of clinical information

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