Abstract
Background:
The “international system for reporting serous fluid cytopathology”(TIS) consists of five diagnostic categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). The study was conducted to reclassify effusion cytology samples according to the newly proposed TIS to calculate the risk of malignancy (ROM) for each category and to conduct performance analysis.
Materials and Methods:
The study was a retrospective observational study conducted at a tertiary care institution in North India. Clinical data of the cases from June 2013 to July 2021 were retrieved and the cases were reviewed by two cytopathologists. All cases were reclassified according to the proposed TIS system into five categories.
Results:
A total of 2318 patients were included in the study over a time span of 8 years, and 1614 (69.6%) cases of pleural effusion cytology, 612 (26.4%) cases of peritoneal effusion cytology, and 92 (3.9%) cases of pericardial effusion cytology were included. All effusion cytology smears were recategorized as per TIS guidelines into ND, NFM, AUS, SFM, and MAL with 4 (0.17%), 1756 (75.75%), 12 (0.51%), 57 (2.46%), and 489 (21.11%) cases, respectively, and ROM was 25%, 17.9%, 66.7%, 75.4%, and 96.5%, respectively, for the categories.
Conclusion:
Besides being a simple, easy, and user-friendly system, TIS has the benefit of risk stratification and ROM for each category. The TIS system proposed a tiered scheme, which places the effusion cytology into well-defined categories, and therefore has lesser chances of false-positive and false-negative cases.
Keywords: Effusion cytopathology, pericardial effusion, peritoneal effusion, pleural effusion, risk of malignancy
INTRODUCTION
Serous cavity fluids are one of the most common specimen types received in cytopathology laboratory for initial evaluation of the etiology of effusion with a high sensitivity.[1] serous effusions are a common presentation of various diseases including inflammatory, benign, or malignant neoplasm. Malignancy as an etiology for effusion accounts for approximately 10%–60% of total effusion.[2-6] A majority of the malignant effusions are caused by metastasis from adenocarcinoma of the lung, breast, gastrointestinal tract, and genital tract including ovaries. In addition to metastasis, malignant mesothelioma can also present as serous effusion in 10%–53% of cases.[7-11] Many a times, serous effusion is the first or only sign of malignancy in patients.[12,13]
Serous fluid cytology (SFC) is a very cost-effective, simple, minimally invasive, and safe procedure and in addition to routine initial biochemical and microbiological examination, SFC serves as a diagnostic tool to establish the origin of malignancy. It also aids in determining the stage and prognosis of the disease and guides toward the rationale use of ancillary tools. The sensitivity and specificity reported in literature for the diagnosis of malignant pleural effusions range from 40% to 90% and from 90% to 100%, respectively, and for malignant peritoneal effusion, they range from 22% to 81% and from 97% to 100%, respectively.[14]
Despite being a useful sensitive and specific diagnostic tool, there are few factors which affect the diagnostic yield, such as collection and preparation techniques, diversity and heterogenicity of malignant tumors, morphological overlap between different malignant tumors and even between benign and malignant tumors, and last but not the least, the experience of cytopathologists. Because of a lack of uniform diagnostic terminology among cytopathologists, various standardized reporting systems have been developed for reporting of salivary gland, urine, breast, cervical, thyroid, and pancreatico-biliary cytopathology.[15-20] The well-defined diagnostic categories in the tiered system lead to better diagnostic yield, lesser interobserver variability, and well-defined risk of malignancy (ROM) for each category, thus guiding toward better risk stratification and better patient management.
Following the footsteps, to develop a standardized reporting pattern which better guides the clinician toward better patient management, the International Academy of Cytologists in collaboration with the American Society for Cytopathology proposed a similar five-tiered terminology system termed as “the international system for reporting serous fluid cytopathology” (TIS).[21,22] The international system “TIS” consists of five diagnostic categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL) [Table 1].
Table 1.
Distribution of total cases into different categories and ROM for each category
| Category | ND (no. and percentage) | NFM (no. and percentage) | AUS (no. and percentage) | SFM (no. and percentage) | MAL (no. and percentage) | Total (no. and percentage) |
|---|---|---|---|---|---|---|
| No. of cases | 4 (0.17%) | 1756 (75.75%) | 12 (0.51%) | 57 (2.46%) | 489 (21.11%) | 2318 |
| Nonmalignant cases | 3 (75%) | 1441 (82.1%) | 4 (33.3%) | 14 (24.6%) | 17 (3.5%) | 1479 (63.8%) |
| Total no. of malignant cases after final diagnosis | 1 (25%) | 315 (17.9%) | 8 (66.7%) | 43 (75.4%) | 472 (96.5%) | 839 (36.2%) |
| ROM | 25% | 17.9% | 66.7% | 75.4% | 96.5% | 36.2% |
AUS=atypia of undetermined significance, MAL=malignant, ND=nondiagnostic, NFM=negative for malignancy, ROM=risk of malignancy, SFM=suspicious for malignancy
The present study was conducted in the Department of Pathology, GSVM Medical College Kanpur, Uttar Pradesh, India, with a purpose to review and reclassify the effusion cytology samples in the period from December 2013 to December 2021. The samples were reclassified according to newly proposed TIS to calculate ROM for each category and to conduct performance analysis.
MATERIALS AND METHODS
The study was a retrospective observational study conducted at the Department of Pathology, GSVM Medical College, Kanpur. Clinical data of the cases were retrieved from the database of pathology department and/or medical record section of the hospital from June 2013 to July 2021. The data regarding demographic features, clinical features, radiological investigation, cytology, histology reports, cell block cytology, and immunohistochemistry (IHC) were collected, wherever they were available. The effusion cytology slides were retrieved from the record section, and the cases were reviewed by two different cytopathologists, one at a time, posted in the cytopathology lab.
The received samples were processed within 2 h of receipt. The specimens were centrifuged at 1500 rpm for 10 min; the supernatant was decanted and smears were prepared from the sediment pellet and fixed in alcohol. In a subset of cases where sample quantity was sufficient, two cytospin slides and cell blocks were also prepared. Cell blocks were prepared by formalin cell block technique by fixing the cell pellet with 10% formalin. The cell pellet was wrapped in a filter paper and was processed and further embedded in paraffin wax. Sections of thickness 5 μm were cut and stained with hematoxylin and eosin. IHC was outsourced from a different pathology lab and was performed on the cell block specimen in selected cases. A panel of selected immunohistochemical markers CK7/20, calretenin, estrogen receptor, progesterone receptor, and Ki67 were analyzed as per the need of the case. Information regarding possible primary site was obtained based on history, physical examination, radiological findings, and immunohistochemical findings.
All cases were reclassified according to proposed TIS system into five categories as follows [Figure 1]:
Figure 1.
(a) Category 2 (NFM) shows predominantly reactive mesothelial cells and occasional lymphocytes. (b) Category 2 (NFM) shows predominantly reactive lymphoid cell population with occasional mesothelial cells. (c) Category 3 (AUS) shows cell cluster having overlapping and mild pleomorphism. (d) Category 4 (SFM) shows atypical vacuolated cells, giving a signet ring cell appearance. (e) Category 5 (MAL) shows cell ball and nest showing pleomorphism, hyperchromatic nucleus, high nuclear cytoplasmic ratio, and prominent nucleoli. (f) Cell block preparation from category 5 (MAL) shows malignant cells forming acini and balls. AUS = atypia of undetermined significance, MAL = malignant, NFM = negative for malignancy, ROM = risk of malignancy, SFM = suspicious for malignancy
ND: Hemorrhagic smears and smears with scant cellularity (<10 cells) or no cells. The cells included scattered mesothelial cells, macrophages, lymphocytes, or polymorphs.
NFM: The morphology of the cells, including mesothelial cells, macrophages, lymphocytes, and polymorphs, was benign, irrespective of the clinical history and imaging studies. The cells showed no evidence of primary or secondary malignancies.
AUS: This category incorporated the specimens where few cells, but not many, showed atypia in either smears, but were not distinct enough to be placed in the neoplastic category. This also included cases where the clinical suspicion was benign, but occasional cells exhibited atypia.
SFM: These smears were characterized by presence of cells with atypia not enough for a diagnosis of malignancy, but such diagnosis strongly indicates malignancy. The atypia was demonstrated by mesothelial cells, epithelial cells, lymphocytes, or any other malignancy like melanoma.
MAL: This category demonstrated high cellularity with malignant cells in clusters and scattered singly on the cytosmears.
Statistical analysis was conducted using Microsoft Office Excel 2016. The cases in each category were reviewed for the presence of malignancy. To calculate ROM, malignancy was confirmed by cytology, cell block or tissue histology, immunohistochemistry, or radiology. ROM was calculated for each category and is presented as the proportion of cases with confirmatory tests. Performance analysis was done by calculating sensitivity, specificity, positive predictive value, negative predictive value, and accuracy.
RESULTS
A total of 2318 patients were included in the study over a time span of 8 years from June 2013 to July 2021. In the present study, only those cases were included in whom the follow-up was either histological, cell block cytology, immunohistological, or radiological. Out of 2318 cases, 1325 (57.2%) were male and 993 (42.8%) were female, with a male to female ratio of 1.3:1. The age of patients ranged from 3 to 92 years. Overall, highest number of effusion cases were observed in the age group 21–40 years (30.1%), followed by 41–60 years (30.2%) and 61–80 years (25.3%).
The study included 1614 (69.6%) cases of pleural effusion cytology, 612 (26.4%) cases of peritoneal effusion cytology, and 92 (3.9%) cases of pericardial effusion cytology. All effusion cytology smears were recategorized as per TIS guidelines into ND, NFM, AUS, SFM, and MAL, with 4 (0.17%), 1756 (75.75%), 12 (0.51%), 57 (2.46%), and 489 (21.11%) cases in each category, respectively [Table 1]. The cytological characterization of each effusion fluid was as follows.
Cytological diagnosis of pleural effusion and ROM according to TIS categories
A total of 1614 cases of pleural effusion cytology were evaluated, out of which 921 were male and 693 cases were female. The distribution of cases in ND, AFM, AUS, SFM, and MAL categories was 3 (0.1%), 1280 (79.3%), 7 (0.4%), 29 (1.8%), and 295 (18.3%), respectively. Overall ROM for pleural effusion was 35.37% [Table 2]. The category-wise distribution of cases was as follows:
Table 2.
Distribution of cases in pleural, pericardial, and peritoneal fluid and ROM in each category
| Type of fluid and follow-up diagnosis | ND | NFM | AUS | SFM | MAL | Total | |
|---|---|---|---|---|---|---|---|
| Pleural | Total | 3 | 1280 | 7 | 29 | 295 | 1614 |
| Benign | 2 | 1029 | 1 | 7 | 4 | 1043 | |
| Malignant | 1 | 251 | 6 | 22 | 291 | 571 | |
| ROM | 33.3% | 19.6% | 85.7% | 75.86% | 98.64% | 35.37% | |
| Peritoneal | Total | 1 | 418 | 4 | 26 | 163 | 612 |
| Benign | 1 | 354 | 3 | 6 | 11 | 375 | |
| Malignant | - | 64 | 1 | 20 | 152 | 237 | |
| ROM | - | 15.3% | 25% | 76.92% | 93.25% | 38.72% | |
| Pericardial | Total | - | 58 | 1 | 2 | 31 | 92 |
| Benign | - | 58 | - | 1 | 2 | 61 | |
| Malignant | - | - | 1 | 1 | 29 | 31 | |
| ROM | - | - | 100% | 50% | 93.54% | 33.69% | |
| Total | 4 | 1756 | 12 | 57 | 489 | 2318 | |
AUS=atypia of undetermined significance, MAL=malignant, ND=nondiagnostic, NFM=negative for malignancy, ROM=risk of malignancy, SFM=suspicious for malignancy
ND: Out of three cases, one case turned out to be malignant (metastasis from adenocarcinoma lung) and ROM for this category was 33.3%.
NFM: Out of 1280 cases, on follow-up, 251 patients with a negative pleural fluid proved to have malignant neoplasm and ROM for this category was 19.6%. After follow up, in male 90 cases had metastasis from lung adenocarcinoma followed by 12 cases from metastasis from adenocarcinoma of gastrointestinal tract. Among females, 50 cases had metastasis from carcinoma breast, followed by 25 cases with metastasis from adenocarcinoma lung.
AUS: Out of seven cases, on follow-up, six patients with a negative pleural fluid proved to have malignant neoplasm and ROM for this category was 85.7%. After follow-up, among males, two cases were found to have metastasis from lung adenocarcinoma, followed by one case each with metastasis from adenocarcinoma gastrointestinal tract and testis. Among females, there were two cases with metastasis from carcinoma breast.
SFM: After follow-up of 29 cases in this category, 22 patients with a negative pleural fluid proved to have malignant neoplasm; hence, ROM for this category was 75.9%. Among males, four cases had metastasis from adenocarcinoma lung and in females, two cases had breast carcinoma metastasis.
MAL: Of 295 cases in this category, after follow-up, 291 patients with a negative pleural fluid proved to have malignant neoplasm, and hence, ROM was 98.6%. After follow-up in males, 120 cases were found to have adenocarcinoma lung metastasis and 14 had testis malignancy. In females, 36 cases were found to have metastasis from carcinoma breast, followed by 24 cases with adenocarcinoma lung metastasis.
Cytological diagnosis of peritoneal effusion and ROM according to TIS categories
The distribution of cases in peritoneal fluid cytology was 1 (0.2%), 418 (68.3%), 4 (0.7%), 26 (4.2%), and 163 (26.6%) cases for ND, NFM, AUS, SFM, and MAL, respectively. Overall ROM for peritoneal fluid was 38.72% [Table 2]. The category-wise distribution of cases was as follows:
ND: One case of the ND category was found to be negative for malignancy on follow-up.
NFM: Out of 418 cases, after follow-up, 64 of the patients with a negative peritoneal fluid proved to have malignant neoplasm and ROM for this category was 15.3%. In males, metastasis from renal carcinoma was the most common diagnosis followed by metastasis from gastrointestinal tract. In females, metastasis from female genital tract (including uterus and ovaries) was the most common diagnosis followed by metastasis from gastrointestinal tract.
AUS: Of total four cases, only one patient with a negative peritoneal fluid proved to have malignant neoplasm and it was metastasizing from renal cell carcinoma in a male patient. ROM for this category was 25%.
SFM: Out of 26 cases , after follow up , 20 patients with a negative peritoneal fluid proved to have malignant neoplasm and the ROM was 76.92% for this category. Highest number of cases were found to have metastasis from Gastro intestinal tract (GIT) and female genital tract among males and females, respectively.
MAL: Of 163 cases, after follow-up, 152 patients with a negative peritoneal fluid proved to have malignant neoplasm. In males, metastasis from gastrointestinal tract was the most common, while in females, metastasis from female genital tract was the most common. ROM for this category was 93.25%.
Cytological diagnosis of pericardial effusion and ROM according to TIS categories
No case was reported in the ND category.
NFM: In the NMF category, all the 58 cases turned out to be benign after follow-up.
AUS: One case of the AUS category proved to have malignancy, and it was metastasis from carcinoma lung. ROM for this category was 100%.
SFM: Two cases were followed up, and one case with a negative pericardial fluid proved to have malignant neoplasm and it was a metastasis from carcinoma breast.
MAL: In this category, out of 31 cases, 29 patients with a negative pericardial fluid proved to have malignant neoplasm after follow-up. ROM was 92.54%. In males and females, the largest number of cases were from lung and breast metastasis, respectively.
Overall sensitivity of TIS system was 56.26%, with a specificity of 98.85%, positive predictive value of 96.52%, negative predictive value of 79.93% and diagnostic accuracy of 83.43%.
DISCUSSION
TIS was proposed by the International Academy of Cytology and the American Society of Cytopathology. Following the diagnostic criteria of TIS, in the present study, we reclassified the effusion cytology and recategorized the cases as ND (four cases, 0.17%), NFM (1756 cases, 75.8%), AUS (12 cases, 0.5%), SFM (57 cases, 2.5%) and MAL (489 cases, 21.1%). ROM for each category was 25%, 17.9%, 66.7%, 75.4%, and 96.5%, respectively, and these results were similar to those reported in other studies.[23-26] Overall, the most common site of malignancy was metastasis from lung, followed by gastrointestinal tract and breast [Table 3], which is similar to that reported in previous studies.[22,27]
Table 3.
Distribution of malignant cases in different types of fluids and the diagnostic categorization
| Diagnosis (metastasis from) | Pleural fluid | Peritoneal fluid | Pericardial fluid | Total cases |
|---|---|---|---|---|
| Lung ca. | 266 | 6 | 8 | 280 |
| Breast ca. | 91 | 5 | 5 | 101 |
| Renal ca. | 21 | 28 | 3 | 53 |
| Gastrointestinal Ca. | 40 | 72 | 4 | 116 |
| Head and neck ca. | 26 | - | 2 | 28 |
| Lymphoma/leukemia | 8 | 21 | 4 | 33 |
| Mesothelioma | 8 | - | 1 | 9 |
| Testicular ca. | 24 | 7 | 1 | 32 |
| Gall bladder ca. | 10 | 11 | - | 21 |
| Liver malignancy | 2 | 3 | - | 5 |
| Prostate ca. | 11 | 12 | 1 | 24 |
| Soft tissue tumor | 2 | 2 | - | 4 |
| Ovarian ca. | 10 | 28 | - | 38 |
| Uterine ca. | 7 | 15 | - | 22 |
| Esophageal ca. | 4 | - | - | 4 |
| Melanoma | - | 2 | - | 2 |
| Unknown | 41 | 25 | 2 | 68 |
| Total | 571 | 237 | 31 | 839 |
The category ND refers to specimen with inadequate cellular material. Adequacy criterion is not clearly defined in TIS as well as in the previous literature. In the literature, it is recommended to set adequacy criteria according to institutional requirement.[28] In the present study, we had received volume ranging from 1 ml to 1 l with satisfactory morphology in majority of cases, except in four cases where the smears were pauci-cellular and had only scant lymphocytes or degenerated cells and hence were categorized as inadequate. One case of the ND category was recategorized as malignant on follow-up, which was a metastasis from adenocarcinoma lung; on cytology, this case revealed only degenerated cells. ROM for this category was 25%, while in previous studies, ROM ranged from 0% to 100%.[1,23] The wide range of ROM in this category also raises a need to establish minimum adequacy criteria, be it cell count or adequate volume for evaluation.
The NFM category consists of highest number (1756 cases, 75.8%) of cases, including 1280 pleural, 418 peritoneal, and 58 pericardial effusion. Overall ROM for this category was 17.9%, which is similar to that reported in studies conducted by other researchers.[25,27] The morphological findings include presence of lymphocytes, mesothelial cells, macrophages, neutrophils, and red blood cells (RBCs) in cases of hemorrhagic effusions. In majority of cases, on cytology, partially degenerated cells or mesothelial cells were misinterpreted as reactive mesothelial cells or vice versa.
TIS described two intermediate categories, AUS and SFM, which have features that cannot be categorized as negative or malignant category. The AUS category corresponds to cytopathological findings that are not sufficiently clearcut to permit a more specific diagnosis.[29] The SFM category is characterized by cells with greater degree of atypia but cells are limited in number. The AUS category constituted 12 cases (0.5%), and ROM for this category was 66.7%. The SFM category constituted 57 cases (2.5%), and ROM was 75.4%, which corresponds to other studies.[1,23] Majority of the cases belonging to AUS and SFM categories, cytological findings include cells of mesothelial origin, macrophages, cells from cytologically bland malignant tumors or hematolymphoid malignancies.[29] Lymphocyte-rich effusion as seen in chronic lymphocytic leukemia may mimic benign or reactive lymphocytes or vice versa, and in such cases, immunocytochemical staining and/or flow cytometry is essential to differentiate between the two.[30]
Similarly, morphology of reactive mesothelial cells may sometimes mimic adenocarcinoma or mesothelioma as observed in our study, where false-positive cases were seen in SFM and MAL categories. The reactive mesothelial cells can be seen in various infections like tubercular and parasitic effusion or effusions secondary to renal, hepatic, or cardiac disease or various reactive processes and neoplastic or preneoplastic changes. In such cases, a detailed clinical history and radiological findings must be evaluated to exclude MAL or NMF category. IHC of the cell block or flow cytometry can serve as a diagnostic tool in such a situation with dilemma.[30] Due to lack of standardization and due to the overlapping features in cytomorphology, many studies have suggested clearcut guidelines for reporting NMF, and even AUS and SFM categories need to be revised and have yet to be standardized.[22-24,26]
The MAL category includes cases with definitive finding and/or supportive studies indicating primary or secondary malignancies. In our study, the MAL category included 489 cases (21.1%) and ROM was 96.5, which is similar to previous studies.[1] The distinction between SFM and MAL categories was based on morphology and ancillary investigations. The application of IHC of cell block or flow cytometry not only helps to diagnose the malignancy, but also helps to determine the primary site of malignancy in cases without previous history of malignancy or cases with unknown primary.[1,29,30]
CONCLUSION
The TIS system proposed a tiered scheme which places the effusion cytology into well-defined categories, and therefore has lesser chances of false-positive and false-negative cases. Despite there being heterogenicity and morphological overlap between different categories, TIS caters to the need of cytopathologists because beside being a simple, easy, and user-friendly system, it has the benefit of risk stratification and ROM for each category and it provides a standardized terminology for better communication among pathologists and clinicians.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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