Cancer Cytopathology

Our medical research library holds 28 studies published in Cancer Cytopathology (2013–2023). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 25 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 1 study PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: Wiley-Blackwell
• Published: 2010 to the present, United States
• Language: English
• ISSN: 1934-662X (print), 1934-6638 (electronic)
• Its record in the NLM Catalog

2020s

• Reliability of assessing morphologic features with prognostic significance in cytology specimens of epithelioid diffuse pleural mesothelioma and implications for cytopathology reporting. Y. Li, A.M. Salama, M.K. Baine, et al. 2023;131(8):495-506. PubMed · Publisher · Free full text

  Abstract

  Background: The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology.

  Methods: Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement.

  Results: Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ = 1.000; p < .001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ = 0.842; p < .001) and 85.7% (κ = 0.481; p = .001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ = 0.127; p = .037). In cytology cases (n = 23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ = 1.000; p < .001, each), the presence of necrosis showed moderate agreement (κ = 0.465; p = .008), and assessment of architectural patterns showed slight agreement (κ = 0.162; p = .15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens.

  Conclusions: Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology.

  © 2023 American Cancer Society.

• Analysis of early pleural fluid samples in patients with mesothelioma: A case series exploration of morphology, BAP1, and CDKN2A status with implications for the concept of mesothelioma in situ in cytology. A. Louw, C. van Vliet, J. Peverall, et al. 2022;130(5):352-362. PubMed · Publisher

  Abstract

  Background: The concept of mesothelioma in situ has been revisited and is a new World Health Organization diagnostic entity. The definition centers on ancillary techniques used in pleural mesothelioma (PM) assessment. At the authors' institution, most PM diagnoses are made on cytologic specimens. Effusion samples obtained before definitive PM diagnosis were interrogated using BRCA1-associated protein 1 gene (BAP1), cyclin-dependent kinase inhibitor 2A gene (CDKN2A) and cytologic evaluation to assess whether early or possible in situ disease could be characterized.

  Methods: All cases of PM diagnosed between January 2008 and December 2019 were identified at a tertiary referral center. Patients who had a pleural fluid sample collected 24 months before the diagnosis were selected, numbering 8 in total. The cytomorphology of each sample was reviewed; and, retrospectively, BAP1 immunohistochemistry (IHC) and CDKN2A fluorescence in situ hybridization (FISH) were performed on initial and diagnostic samples.

  Results: The initial samples were deemed benign in 5 cases and atypical mesothelial proliferations in 3 cases. A spectrum of apparently normal to atypical cytomorphologic changes was identified. BAP1 loss was present in 6 of 8 initial cases, whereas CDKN2A homozygous deletion was identified in 1 of 7 initial cases. Either abnormality was identified in 7 of 8 initial samples.

  Conclusions: Detectable abnormalities of BAP1 IHC and CDKN2A FISH were present in pleural fluid specimens before the development of cytomorphologic features diagnostic of PM. This is the largest series to date describing cytology samples early in the course of PM development, thereby highlighting a possible cytological equivalent for mesothelioma in situ.

  © 2022 American Cancer Society.

• Diagnostic mesothelioma biomarkers in effusion cytology. A. Eccher, I. Girolami, E. Lucenteforte, et al. 2021;129(7):506-516. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.

  © 2021 American Cancer Society.

• Fluorescence in situ hybridization detection of chromosome 22 monosomy in pleural effusion cytology for the diagnosis of mesothelioma. Y. Kinoshita, M. Hamasaki, S. Matsumoto, et al. 2021;129(7):526-536. PubMed · Publisher

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is characterized by mutations in several genes, including cyclin-dependent kinase-inhibitor 2A/p16 in the 9p21 locus, BRCA1-associated protein 1 (BAP1), and neurofibromatosis type 2 (NF2) in the 22q12 locus. Recent studies indicate that fluorescence in situ hybridization (FISH) detects hemizygous loss of NF2 in tissue specimens of MPM. The authors investigated whether NF2 FISH, either alone or in combination with other diagnostic assays (9p21 FISH, methylthioadenosine phosphorylase [MTAP] immunohistochemistry [IHC], and BAP1 IHC), effectively distinguishes MPM cells from reactive mesothelial cells (RMCs) in cell blocks prepared from pleural effusions.

  Methods: FISH assays were used to examine the deletion status of NF2 and 9p21, and IHC was used to determine the expression of MTAP and BAP1 in cell blocks from 54 cases with MPM and 18 cases with RMCs.

  Results: Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) showed 51.9% sensitivity (48.1% for chromosome 22 monosomy and 3.7% for hemizygous deletion) and 100% specificity in differentiating MPM cells from RMCs. Combinations of NF2 FISH, 9p21 FISH, and BAP1 IHC assays yielded greater sensitivity (98.1%) than any assay alone (9p21 FISH, 61.1%; MTAP IHC, 52.8%; or BAP1 IHC, 60.4%). The level of hemizygous NF2 loss in cell blocks positively correlated with that in corresponding tissues. Furthermore, to overcome cytologic specimen-specific challenges, FISH combined with cytokeratin AE1/AE3 immunofluorescence was necessary in 25.9% of MPM cases for FISH assessment of predominantly scattered MPM cells.

  Conclusions: NF2 FISH alone or in combination with other diagnostic assays effectively differentiates MPM cells from RMCs in cell blocks prepared from pleural effusions.

  © 2021 American Cancer Society.

• Higher concordance of PD-L1 expression between biopsies and effusions in epithelioid than in nonepithelioid pleural mesothelioma. M.S.I. Mansour, T. Seidal, U. Mager, et al. 2021;129(6):468-478. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MM) is a therapy-resistant tumor, often causing an effusion. Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have shown promising results, but assessment of PD-L1 expression to select patients for therapy has mainly been performed on histologic tissue samples. In a previous study, we showed that MM effusions are suitable for PD-L1 assessment with results comparable to those reported in histologic studies, but no studies have compared PD-L1 expression in histologic and cytologic samples.

  Methods: PD-L1 expression was determined immunohistochemically (clone 28-8) in 61 paired samples of effusions and biopsies from patients with pleural MM, obtained at the time of diagnosis. Only cases with >100 tumor cells were included. Membranous staining in tumor cells was considered positive at ≥1%, >5%, >10%, and >50% cutoff levels.

  Results: Of 61 histologic samples, PD-L1 expression was found in 28 and 7 samples at ≥1% and >50% cutoffs, respectively; the corresponding figures for cytology were 21 and 5, respectively. The overall percentage agreement between histology and cytology was 69% and 84%, with a kappa (κ) of 0.36 and 0.08 at ≥1% and >50% cutoffs, respectively. The concordance between cytology and histology tended to be higher for epithelioid MM versus nonepithelioid MM at a ≥1% cutoff. PD-L1 positivity in biopsies, but not in effusions, correlated with the histologic subtype at a ≥1% cutoff.

  Conclusions: A moderate concordance of PD-L1 expression between biopsies and effusions from pleural MM, especially for the epithelioid subtype, indicates biological differences between the 2 types of specimens. Cytology and histology may be complementary.

  © 2021 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.

• Should uncertainty concerning the risk of malignancy be included in diagnostic (nongynecologic) cytopathology reports?. D.N. Poller, F. Schmitt. 2021;129(1):16-21. Review PubMed · Publisher

  Abstract

  In diagnostic cytology, the known site-specific false positive rates at various anatomical sites for the risk malignancy (ROM) when a confirmed malignant diagnosis is made are comparatively well documented. ROM figures for diagnostic cytology specimens may vary according to the anatomical site of the specimen, the exact nature of the specimen received, the staining method(s) used, and the use of additional laboratory techniques including molecular profiling; furthermore, they often differ to some extent from institution to institution, between differing cytologists within the same institution, and over time. A brief literature review for a selected group of routine diagnostic cytology specimens shows a published ROM for a confirmed malignant diagnosis as follows: bile duct brushings, ~99% (range, 97%-100%); breast fine needle aspiration, 98.5% (range, 92%-100%); serous effusion fluid, 98.9% (range, 90%-100% although lower for squamous cell carcinoma, mesothelioma, and lymphoma), pulmonary endobronchial ultrasound cytology, ~99% (range, 86.6%-100%); thyroid FNA, 98% (range, 97%-99% if NIFTP tumors are excluded), salivary gland FNA, ~90%; (range 57%-100%) and lateral neck cyst FNA, ~99% (range, 95.5%-100%). Because most diagnostic cytology specimens have a small but accepted false-positive rate, this information is vitally important for the clinical management of patients and for shared patient decision making. In our view, the known false-positive rate for a given diagnostic cytology specimen could be included within the cytology report to assist in explaining the limitations of the diagnostic cytology interpretation and help facilitate the clinical decision-making process.

  © 2020 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.

• The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas. L. Bernardi, T. Bizzarro, F. Pironi, et al. 2021;129(4):275-282. PubMed · Publisher

  Abstract

  Background: The distinction between mesothelioma with epithelioid features and metastatic carcinoma may be challenging, particularly on cytology. A novel 2-hit Claudin-4 and BRCA-associated protein 1 (BAP1) panel was investigated.

  Methods: The objective of this study was to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the panel on cytology from pleural effusions and matched biopsies, including 49 malignant mesotheliomas on cytology with 43 matched biopsies, 49 normal/reactive mesothelial proliferations, and 49 pleural metastatic carcinomas from different primaries with 21 matched pleural biopsies. The diagnostic role of the 4 categories obtained by crossing the immunostaining results was analyzed.

  Results: Claudin-4 strongly stained all metastatic carcinomas and tested completely negative in normal mesothelium, benign reactive mesothelial hyperplasia, and malignant mesothelioma. All normal and benign mesothelial proliferations and all carcinomas except 1 were immunoreactive for BAP1, whereas BAP1 loss was observed in 88% of malignant mesotheliomas. The expression of Claudin-4 alone excluded all benign and malignant mesothelial growth, consistently characterizing all metastatic carcinomas. Double negativity was evident in all malignant mesotheliomas, and double positivity was observed in all metastatic carcinomas. BAP1-positive/Claudin-4-negative status was observed only in malignant mesotheliomas and benign mesothelial proliferations. A single metastatic anal squamous cell carcinoma had BAP1-negative/Claudin-4-positive staining.

  Conclusions: Claudin-4 expression was completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations. BAP1 staining characterized 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity was observed almost exclusively in mesotheliomas. This 2-hit panel is probably the best compromise for differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.

  © 2020 American Cancer Society.

• Testing for BAP1 loss and CDKN2A/p16 homozygous deletion improves the accurate diagnosis of mesothelial proliferations in effusion cytology. M. Chevrier, S.E. Monaco, J.A. Jerome, et al. 2020;128(12):939-947. PubMed · Publisher

  Abstract

  Background: A number of ancillary tests have been developed that aid in the diagnosis of mesothelioma in cytology specimens. The aim of this retrospective study was to determine whether testing for BAP1 and CDKN2A/p16 status in effusion specimens preceding the tissue diagnosis of mesothelioma would improve diagnostic accuracy and allow an earlier diagnosis of malignancy.

  Methods: The study cohort included 99 matched cytology fluid specimens from 74 patients with a surgical specimen diagnosis of malignant mesothelioma (67 epithelioid, 7 biphasic, 55 pleural, and 19 peritoneal). BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) were performed retrospectively.

  Results: BAP1 or p16 FISH testing revealed a loss in 7 of 18 (39%) samples originally categorized as benign/reactive, 20 of 33 (61%) interpretable samples categorized as atypical, and 10 of 14 (71%) cases suspicious for mesothelioma. In some cases, the diagnosis of mesothelioma could have been made up to 9 months before biopsy. Similarly, loss of BAP1 or p16 was found in 28 of 30 (93%) samples categorized as malignant, with some cases diagnosable up to 6 months before biopsy. Overall, loss of BAP1 and/or CDKN2A/p16 homozygous deletion would change the diagnostic interpretation in 37 of 60 (62%) (P = .07) effusion specimens, particularly in pleural effusions (32 of 48 samples) (P = .002). The sensitivity of morphologic interpretation alone was 30.3%; however, adding testing for BAP1 and p16 resulted in an increase in sensitivity to 68.7%. (P < .0001).

  Conclusion: These findings suggest that routine use of BAP1 immunochemistry and p16 FISH as adjunctive tests improves the diagnostic accuracy of cytology specimens and potentially allows an earlier diagnosis of malignant mesothelioma.

  © 2020 American Cancer Society.

• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. K.B. Berg, A.M. Churg, S. Cheung, et al. 2020;128(2):126-132. PubMed · Publisher

  Abstract

  Background: The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult. Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens.

  Methods: A total of 21 effusion cytology cases of malignant mesothelioma were stained for MTAP and BRCA-associated protein 1 (BAP1), with 15 reactive mesothelial cytology cases used as a control. Fourteen cases had a paired surgical specimen for comparison, and 7 cases were run for CDKN2A deletion by fluorescence in situ hybridization.

  Results: Complete loss of MTAP cytoplasmic staining was noted in 7 of 21 effusion samples (33%), and no loss was observed in 11 effusion samples (52%); 11 of these cases had a matching surgical specimen and all 11 specimens demonstrated the same MTAP pattern. Partial loss was observed in 3 effusion specimens (80%, 40%, and 40% intact staining, respectively), but in all 3 the surgical specimen demonstrated 100% staining. None of the 15 reactive mesothelial cytology specimens demonstrated MTAP cytoplasmic loss. CDKN2A FISH demonstrated concordance in 5 of 7 cases (71%). MTAP immunohistochemistry had a sensitivity of 33% and a specificity of 100% for this differential diagnosis.

  Conclusions: MTAP staining demonstrated generally good concordance between the cytologic and surgical specimens and appears to be useful in the diagnosis of mesothelioma on effusion specimens. Complete loss of MTAP is a reliable marker of malignancy, but the significance of partial loss of MTAP staining is unclear.

  © 2019 American Cancer Society.

2010s

• Immunohistochemical validation studies in effusion cytology: A cautionary tale. R. Pillappa, A.O. Kraft. 2019;127(11):680-683. PubMed · Publisher

  Summary

  In this commentary, the authors discussed the need to validate immunohistochemistry (IHC) assays used on cytological specimens from body-cavity effusions. Such testing is increasingly used for diagnosis, prognosis and treatment decisions. They noted that IHC assays are typically validated on formalin-fixed, paraffin-embedded tissue. Effusion cell blocks, by contrast, are prepared by more than 10 methods in the United States, and some of these use alcohol fixation, which has been reported to reduce staining or cause false-negative results. They summarized College of American Pathologists guidance: a minimum of 10 positive and 10 negative specimens for initial validation of nonpredictive assays, at least 20 of each for most predictive assays, and at least 90% overall concordance. They then described several examples. First, TTF1 antibody clones differ in sensitivity and specificity. Second, loss of BAP1 staining, CDKN2A deletion testing by fluorescence in situ hybridization, and MTAP staining can help diagnose malignant mesothelioma in effusions; they cautioned that good internal controls are needed and that negative BAP1 staining in their absence should be regarded as noncontributory. Third, progesterone receptor and HER2 results in breast cancer are unreliable after ethanol fixation. Fourth, PD-L1 scoring has pitfalls, including the need to evaluate at least 100 tumor cells. The authors concluded that analytical validation is needed, particularly for non-formalin-fixed material, and that awareness of preanalytic, analytic and postanalytic variables will lead to better patient care.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• MicroRNA profiling in serous cavity specimens: Diagnostic challenges and new opportunities. L. Nicolè, F. Cappello, R. Cappellesso, et al. 2019;127(8):493-500. Review PubMed · Publisher

  Abstract

  The cytomorphologic evaluation of serous cavity specimens can quickly determine the cause of an effusion as well as the presence or absence of a neoplastic process. Ancillary tests such as immunohistochemistry and fluorescence in situ hybridization are frequently used to help to definitively identify malignant cells, determine a site of origin, and distinguish between malignant and reactive mesothelial proliferations. In recent years, microRNAs (miRNAs) have been increasingly evaluated in cytologic specimens, including those from serous cavities. The examination of miRNA is attractive because of the stability of miRNA in such specimens and data suggesting that miRNA can provide prognostic and therapeutic information in addition to its role in diagnosis. Furthermore, miRNAs exist within extracellular exosomes, and this allows for their analysis in specimens that contain only rare malignant cells, degenerated cells, or obscuring components. This review discusses the technical aspects of specimen processing for miRNA analysis, recent studies of miRNA expression in malignant serous cavity specimens, and the potential importance of miRNA expression analysis for serous cavity specimens in the near future.

  © 2019 American Cancer Society.

• A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma. Y. Kinoshita, T. Hida, M. Hamasaki, et al. 2018;126(1):54-63. PubMed · Publisher

  Abstract

  Background: Homozygous deletion of 9p21 detected by fluorescence in situ hybridization (FISH) and loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC) are useful for the differentiation between malignant pleural mesothelioma (MPM) and reactive mesothelial hyperplasia. The authors previously described that IHC expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, was correlated with the deletion status of 9p21 FISH in MPM tissues. In the current study, the authors investigated whether a combination of MTAP and BAP1 IHC could distinguish MPM from reactive mesothelial cells (RMC) in cell blocks obtained from pleural effusions.

  Methods: The authors examined IHC expression of MTAP and BAP1 in cell blocks obtained from pleural effusions of 45 cases of MPM and 21 cases of reactive mesothelial hyperplasia. Furthermore, IHC expression of MTAP was compared with the deletion status of 9p21 FISH.

  Results: MTAP and BAP1 IHC differentiated MPM from RMC with 100% specificity for both and sensitivities of 42.2% and 60.0%, respectively. The combination of MTAP and BAP1 IHC yielded a sensitivity of 77.8%, which was higher than that of BAP1 IHC alone or 9p21 FISH alone (62.2%). Moreover, a high degree of concordance was observed between the results of MTAP IHC and 9p21 FISH in cell blocks.

  Conclusions: A combination of MTAP and BAP1 IHC in cell blocks from pleural effusions appears to be a reliable and useful method for differentiating MPM cells from RMC and can be used in the routine diagnosis of MPM. Cancer Cytopathol 2018;126:54-63. © 2017 American Cancer Society.

  © 2017 American Cancer Society.

• Ancillary studies in pleural, pericardial, and peritoneal effusion cytology. K.E. Sundling, E.S. Cibas. 2018;126 Suppl 8:590-598. Review PubMed · Publisher

  Abstract

  Pleural, pericardial, and peritoneal effusion specimens present diagnostic challenges and clinical opportunities for cytology. For the patient, these specimens may be the first diagnosis of malignancy or the first sign of disease recurrence. This review aims to provide useful approaches with which to resolve key difficulties in cytologic diagnosis through the use of ancillary studies, focusing on immunohistochemistry. These approaches are suggested in concert with clinical, radiographic, and morphologic findings. The differentiation of reactive mesothelial cells from malignant mesothelioma and adenocarcinoma is a recurring theme, and Wilms tumor 1 (WT1)/AE1/AE3, claudin 4, and BRCA1-associated protein 1 (BAP1) immunostains are useful new tools in the armamentarium. A targeted workup is suggested for patients with no known primary site or with multiple prior malignancies. Molecular and other biomarker testing can be performed on even modestly cellular fluid specimens and may allow patients to benefit from targeted therapy without the need for additional tissue biopsies. Cancer Cytopathol 2018;000:000-000. © 2018 American Cancer Society.

  © 2018 American Cancer Society.

• Insulinoma-associated protein 1 is a sensitive and specific marker of neuroendocrine lung neoplasms in cytology specimens. E.E. Doxtader, S. Mukhopadhyay. 2018;126(4):243-252. PubMed · Publisher

  Abstract

  Background: Recent studies suggest that insulinoma-associated protein 1 (INSM1) is a sensitive and specific marker of neuroendocrine neoplasms. The aims of this study were to determine whether INSM1 can be reliably used in cytology (Cellient) cell blocks, to ascertain whether staining correlates with paired surgical pathology specimens, and to compare its sensitivity and specificity with those of synaptophysin (SYN), chromogranin (CHR), and CD56 for neuroendocrine lung tumors.

  Methods: Seventy-four primary lung neoplasms diagnosed on cytology were stained with INSM1, SYN, CHR, and CD56: 41 small cell lung carcinomas (SCLCs), 1 large cell neuroendocrine carcinoma (LCNEC), 10 carcinoid tumors, 11 adenocarcinomas, 9 squamous cell carcinomas, 1 mesothelioma and 1 poorly differentiated non-small cell lung carcinoma, not otherwise specified. In 20 cases, a paired surgical pathology specimen was also stained with INSM1.

  Results: INSM1 was positive in 48 of 52 primary lung neuroendocrine neoplasms (92%), including 38 of 41 SCLCs (93%), the only LCNEC (100%), and 9 of 10 carcinoid tumors (90%), and it was negative in all 22 non-neuroendocrine primary lung tumors. For SCLC, the sensitivity of INSM1 (93%) was lower than the sensitivity of CD56 (100%), equal to the sensitivity of SYN (93%), and higher than the sensitivity of CHR (35%). For carcinoid tumors, the sensitivity of INSM1 (90%) was lower than the sensitivity of all other markers (100% each). The specificity of INSM1 for neuroendocrine neoplasms as a group was 100%. INSM1 staining was concordant with surgical pathology specimens in all 20 paired cases.

  Conclusions: INSM1 can be used in cytopathology cell blocks, and it is sensitive and highly specific for neuroendocrine lung tumors. INSM1 staining in cytology cell blocks correlates well with surgical pathology specimens. Cancer Cytopathol 2018;126:243-52. © 2018 American Cancer Society.

  © 2018 American Cancer Society.

• Determination of PD-L1 expression in effusions from mesothelioma by immuno-cytochemical staining. M.S.I. Mansour, T. Seidal, U. Mager, et al. 2017;125(12):908-917. PubMed · Publisher

  Abstract

  Background: Malignant mesothelioma (MM) is an aggressive, fatal tumor. Current therapeutic options only marginally improve survival. Programmed cell death ligand 1 (PD-L1) is a dominant mediator of immunosuppression, binding to programmed cell death 1 (PD-1). PD-L1 is up-regulated in cancer cells, and the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion, thus providing a target for antitumor therapy. Further, a correlation between PD-L1 expression and prognosis has been reported. Studies performed on histological material have revealed expression of PD-L1 in MM, but no study has been performed on MM effusions thus far.

  Methods: PD-L1 expression was determined by a commercially available antibody (clone 28-8) in 74 formalin-fixed, paraffin-embedded cell blocks from body effusions obtained at diagnosis from patients with MM. The presence of MM cells was confirmed with CK5/6, calretinin, and EMA and the admixture of macrophages was assessed with CD68. Only cases containing more than 100 tumor cells were assessed. Membranous staining in tumor cells was considered positive. Survival time was calculated from the appearance of the first malignant effusion until death.

  Results: Reactivity was observed in 23 of 61 (38%) of cases and was classified as ≥1%-5% (n = 9 cases), >5%-10% (n = 4 cases), >10%-50% (n = 4 cases), and >50% (n = 6 cases) positive cells. Survival times did not differ significantly between patients with PD-L1-positive and PD-L1-negative tumors.

  Conclusion: MM effusions are suitable for immune-cytochemical assessment of PD-L1 expression in malignant cells and the results are similar to those reported for histological specimens. Cancer Cytopathol 2017;125:908-17. © 2017 American Cancer Society.

  © 2017 American Cancer Society.

• External quality assurance in nongynecologic cytology: The Australasian experience. P.W. Shield, F. Frost, J.L. Finnimore, et al. 2017;125(5):349-361. PubMed · Publisher

  Abstract

  Background: The Royal College of Pathologists of Australasia Cytopathology Quality Assurance Program has operated an external quality assurance program in nongynecologic cytopathology since 1993. Glass slide preparations of a wide range of nongynecologic cases were circulated to approximately 200 cytopathology laboratories in 16 countries.

  Methods: General nongynecologic cytology cases were manufactured from residual specimens after routine diagnosis. Fine-needle aspiration (FNA) cases were made by sampling fresh tissue and making direct specimens. The majority of cases consisted of both air-dried and fixed preparations. Results returned to laboratories included illustrated case discussions highlighting diagnostic features, key differential diagnoses, and useful adjunctive tests.

  Results: The current study reviewed >22,000 results for 123 nongynecologic cases. Cases found to cause the most diagnostic difficulties included serous effusion cases with metastatic carcinoma in a dispersed pattern, well-differentiated carcinoma, and cellular reactive cases; urine specimens with sparse malignant cells; reactive pneumocytes in a bronchoalveolar lavage; breast FNA cases with papillary lesions; gestational specimens; and fibroadenoma. FNA specimens from the lung and thyroid, particularly papillary thyroid carcinoma, generally were well reported.

  Conclusions: The use of multiple preparations of the same specimen has allowed interlaboratory comparison, and the quality assurance program has played an educational role as well as informing the laboratory accreditation process. Cancer Cytopathol 2017;125:349-361. © 2017 American Cancer Society.

  © 2017 American Cancer Society.

• miR-130A as a diagnostic marker to differentiate malignant mesothelioma from lung adenocarcinoma in pleural effusion cytology. R. Cappellesso, M. Galasso, L. Nicolè, et al. 2017;125(8):635-643. PubMed · Publisher

  Abstract

  Background: Malignant pleural mesothelioma is a rare tumor with a dismal prognosis, usually presenting with recurrent effusions. However, the majority of malignant pleural effusions are due to lung adenocarcinoma (AdC). The distinction between these tumors has considerable therapeutic and medicolegal implications and can be very challenging both histologically and cytologically. Appropriate immunohistochemistry (IHC) is required to support the diagnosis. MicroRNA (miRNA) expression analysis could be a viable diagnostic tool for distinguishing between these tumors. The purpose of the current study was to assess the reliability of miRNAs as diagnostic markers to differentiate epithelioid malignant mesothelioma (MM) from lung AdC.

  Methods: Bioinformatic analysis of publicly searchable data sets regarding miRNA expression profiling was performed to select the most significant differentially expressed miRNAs. These were analyzed by quantitative polymerase chain reaction on histologic (41 MM cases and 40 lung AdC cases) and cytological (26 MM cases and 27 lung AdC cases) specimens and the diagnostic performances were assessed.

  Results: miR-130a, miR-193a, miR-675, miR-141, miR-205, and miR-375 were found to be the best distinguishing markers. Of these, only miR-130a was significantly overexpressed in MM compared with lung AdC (P =.029 in histologic and P =.014 in cytological samples). miR-130a demonstrated a sensitivity of 77%, a specificity of 67%, a positive predictive value of 69%, a negative predictive value of 75%, and an accuracy of 72% in identifying MM.

  Conclusions: The diagnostic performances of miR-130a expression analysis and IHC appear to be similar. miR-130a quantification could be used reliably as second-level diagnostic tool to differentiate MM from lung AdC in pleural effusion cytology, mainly in those cases with ambiguous or negative IHC. Further validation is needed. Cancer Cytopathol 2017;125:635-43. © 2017 American Cancer Society.

  © 2017 American Cancer Society.

• Young investigator challenge: MicroRNA-21/MicroRNA-126 profiling as a novel tool for the diagnosis of malignant mesothelioma in pleural effusion cytology. R. Cappellesso, L. Nicolè, B. Caroccia, et al. 2016;124(1):28-37. PubMed · Publisher

  Abstract

  Background: In pleural effusion cytology, the distinction of malignant mesothelioma (MM) from reactive mesothelial cells (RMCs) may be challenging, even with the aid of immunocytochemistry or fluorescence in situ hybridization. It has been demonstrated that several microRNAs (miRNAs) are useful for this purpose in cell lines and histologic samples. In the current study, the authors evaluated the utility of an miRNA-based classifier as a complement to cytology.

  Methods: Quantitative reverse transcriptase-polymerase chain reaction analysis of 15 miRNAs was performed in mesothelial (MET-5A) and MM (H28 and H2052) cell lines. Significant miRNAs were validated in 51 MM and 40 nonneoplastic pleural histologic samples and then were tested in 29 MM and 24 RMC cytologic specimens. The performance of individual and combined miRNAs was assessed for their ability to differentiate between MM and RMCs.

  Results: MiRNA-19a (MiR-19a), miR-19b, miR-21, miR-25, and miR-126 were differentially expressed in cell lines and histologic samples. MiR-126 was down-regulated in MM surgical specimens compared with nonneoplastic specimens, whereas all of the other miRNAs were overexpressed. In cytologic specimens, all miRNAs except miR-25 were confirmed, exhibiting a sensitivity or a specificity higher than the threshold of 0.80, as recommended by the International Mesothelioma Interest Group. The best classifier resulted from the combination of miR-21 and miR-126, which achieved 0.86 sensitivity and 0.87 specificity.

  Conclusions: Subject to validation of the current results in further larger studies, miR-21 and miR-126 profiling could be an effective and reliable tool for the diagnosis of MM in pleural effusions complementary to cytology evaluation.

  © 2016 American Cancer Society.

• Comments on the recently published "Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma". A. Hjerpe, K. Dobra. 2015;123(8):449-53. Comment PubMed · Publisher

• The role of liquid-based cytology and ancillary techniques in pleural and pericardic effusions: an institutional experience. E.D. Rossi, T. Bizzarro, F. Schmitt, et al. 2015;123(4):258-66. PubMed · Publisher

  Abstract

  Background: Fine-needle aspiration cytology (FNAC) of serous membrane effusions may fulfil a challenging role in the diagnostic analysis of both primary and metastatic disease. From this perspective, liquid-based cytology (LBC) represents a feasible and reliable method for empowering the performance of ancillary techniques (ie, immunocytochemistry and molecular testing) with high diagnostic accuracy.

  Methods: In total, 3171 LBC pleural and pericardic effusions were appraised between January 2000 and December 2013. They were classified as negative for malignancy (NM), suspicious for malignancy (SM), or positive for malignancy (PM).

  Results: The cytologic diagnoses included 2721 NM effusions (2505 pleural and 216 pericardic), 104 SM effusions (93 pleural and 11 pericardic), and 346 PM effusions (321 pleural and 25 pericardic). The malignant pleural series included 76 unknown malignancies (36 SM and 40 PM effusions), 174 metastatic lesions (85 SM and 89 PM effusions), 14 lymphomas (3 SM and 11 PM effusions), 16 mesotheliomas (5 SM and 11 SM effusions), and 3 myelomas (all SM effusions). The malignant pericardic category included 20 unknown malignancies (5 SM and 15 PM effusions), 15 metastatic lesions (1 SM and 14 PM effusions), and 1 lymphoma (1 PM effusion). There were 411 conclusive immunocytochemical analyses and 47 molecular analyses, and the authors documented 88% sensitivity, 100% specificity, 98% diagnostic accuracy, 98% negative predictive value, and 100% positive predictive value for FNAC.

  Conclusions: FNAC represents a primary diagnostic tool for effusions and a reliable approach with which to determine the correct follow-up. Furthermore, LBC is useful for ancillary techniques, such as immunocytochemistry and molecular analysis, with feasible diagnostic and predictive utility.

  © 2015 American Cancer Society.

• Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology. V.Y. Jo, E.S. Cibas, G.S. Pinkus. 2014;122(4):299-306. PubMed · Publisher

  Abstract

  Background: Adenocarcinoma can be challenging to distinguish from malignant mesothelioma in effusions, and this distinction often requires ancillary studies and clinical correlation. Immunohistochemistry for claudin-4, a tight-junction-associated protein, has recently been shown to distinguish adenocarcinoma from malignant mesothelioma, mostly in surgical specimens. Our aim was to validate and assess the immunoreactivity profile of claudin-4 in a large series of malignant effusions.

  Methods: We evaluated 159 malignant effusions (84 adenocarcinomas and 75 malignant mesotheliomas). Claudin-4 immunohistochemistry was performed on cell-block paraffin sections and scored for staining intensity, staining pattern (cytoplasmic versus membranous), and percentage of positive tumor cells. Appropriate positive and negative controls were used throughout.

  Results: All cases of mesothelioma were negative for claudin-4 (0 of 64). Eighty-three of 84 cases of adenocarcinoma were positive (99%); 1 case of serous carcinoma was negative. Most adenocarcinomas showed strong and diffuse membranous staining (71 of 84; 84%); 12 cases (14%) showed membranous staining of moderate intensity. The overall sensitivity for adenocarcinoma was 99% (83 of 84).

  Conclusions: Claudin-4 immunohistochemistry effectively distinguishes adenocarcinoma from malignant mesothelioma with high sensitivity and specificity in the evaluation of malignant effusions.

  © 2014 American Cancer Society.

• Hepatocyte nuclear factor-1β is not a specific marker of clear cell carcinoma in serous effusions. B. Davidson. 2014;122(2):153-8. PubMed · Publisher

  Abstract

  Background: The transcription factor hepatocyte nuclear factor-1β (HNF1β) has been reported to be a specific clear cell carcinoma marker, but its role in the diagnosis of serous effusions is largely unexplored. The objective of this study was to assess the diagnostic role of 2 commercial antibodies against HNF1β in effusion specimens.

  Methods: Effusions (n = 101), consisting of 43 ovarian adenocarcinomas (26 serous, 14 clear cell, 3 endometrioid), 37 nonovarian adenocarcinomas, 10 malignant mesotheliomas, 2 nonepithelial cancers, and 9 reactive specimens, were immunostained using antibodies from Santa Cruz Biotechnology Inc (Santa Cruz, Calif) and Atlas Antibodies AB (Stockholm, Sweden).

  Results: Use of the Santa Cruz antibody was associated with cytoplasmic or background staining in some specimens, whereas distinct staining with minimal background was observed using the Atlas antibody. The Santa Cruz antibody performed better in differentiating clear cell carcinoma from serous ovarian carcinoma and breast carcinoma, whereas staining was consistently negative in benign and malignant mesotheliomas using both antibodies. Distinct nuclear expression of HNF1β was observed in lung and gastrointestinal carcinomas, most often using the Atlas antibody.

  Conclusions: The HNF1β antibody from Atlas performed better than its counterpart from Santa Cruz in terms of staining quality, but was less specific for clear cell carcinoma. Although HNF1β may be of diagnostic value in differentiating clear cell from serous carcinoma in cases with proven genital origin, the role of this marker is questionable in the differential diagnosis between the former tumors and adenocarcinomas of other origin, particularly in the setting of metastasis from an unknown primary tumor.

  © 2013 American Cancer Society.

• Is the cytodiagnosis of mesothelioma any easier these days?. M. Nishino. 2014;122(12):857-8. Review PubMed · Publisher

• Small orangiophilic squamous-like cells: an underrecognized and useful morphological feature for the diagnosis of malignant mesothelioma in pleural effusion cytology. L. Chen, S.G. Caldero, S. Gmitro, et al. 2014;122(1):70-5. PubMed · Publisher

  Abstract

  Background: The cytological diagnosis of malignant mesothelioma (MM) on serous effusion is challenging due to significant morphologic overlap with reactive mesothelial cells and adenocarcinoma. One of the morphologic features of MM in effusion cytology, small orangiophilic squamous-like cells (SOSLC), has received little attention. To the best of the authors' knowledge, the current study is the first to assess the sensitivity and specificity of SOSLC in serous effusion specimens from histology-proven MM cases along with those of reactive mesothelial and adenocarcinoma cases.

  Methods: A total of 130 cases of pleural (86 cases) and peritoneal (44 cases) effusion cytology cases (30 with histology-proven MM, 41 with adenocarcinoma, and 59 with reactive mesothelial cells) were studied. The presence or absence of SOSLC was recorded in each case.

  Results: The cytological diagnoses of the 30 histology-proven MM cases included 1) atypical mesothelial cells, favor reactive (4 cases); 2) atypical mesothelial cells, suspicious for or cannot exclude mesothelioma (18 cases); and 3) positive for MM (8 cases). SOSLC were found in 10 of the 30 MM effusion cases (33.3%), 1 of the 41 adenocarcinoma cases (2.4%), and 5 of the 59 reactive mesothelial cell cases (8.5%). SOSLC were more likely to be present in MM effusions compared with either adenocarcinoma (P<.0001) or reactive mesothelial cell (P<.02) effusions. All 10 cases of MM with SOSLC were from pleural fluids. One case of peritoneal serous adenocarcinoma had SOSLC and 5 cases of reactive mesothelial cells in peritoneal fluid were found to have SOSLC.

  Conclusions: Although not sensitive, the presence of SOSLC is quite specific for MM in pleural fluid cytology specimens. Finding this morphological feature in pleural fluid should alert the pathologist to a possible diagnosis of MM.

  © 2013 American Cancer Society.

• Wilms tumor 1/cytokeratin dual-color immunostaining reveals distinctive staining patterns in metastatic melanoma, metastatic carcinoma, and mesothelial cells in pleural fluids: an effective first-line test for the workup of malignant effusions. J.R. Conner, E.S. Cibas, J.L. Hornick, et al. 2014;122(8):586-95. PubMed · Publisher

  Abstract

  Background: The workup of a malignant effusion usually requires immunostaining with a panel of markers. Although nuclear Wilms tumor 1 (WT1) expression is widely used to detect tumors of ovarian and mesothelial origin, it is less well known that WT1 is also expressed in the cytoplasm of melanomas and mesenchymal tumors. Because to the authors' knowledge the diagnostic utility of cytoplasmic WT1 expression has not been explored to date, the usefulness of a WT1/AE1/AE3 dual-color immunostain in the workup of malignant effusions was evaluated.

  Methods: A total of 86 pleural effusions, including 17 metastatic melanomas, 31 metastatic adenocarcinomas, 10 malignant mesotheliomas, 10 lymphoproliferative disorders, 5 metastatic sarcomas, and 13 benign specimens, were immunostained using a peroxidase-based brown chromogen for WT1 and an alkaline phosphatase-based red chromogen for AE1/AE3 on cell block sections.

  Results: The majority of malignant effusions stained in 1 of 4 distinctive patterns: 1) all lung and breast adenocarcinomas demonstrated cytoplasmic AE1/AE3 expression without nuclear or cytoplasmic WT1 expression; 2) serous carcinomas of Müllerian origin, mesotheliomas, and benign mesothelial cells were positive for cytoplasmic AE1/AE3 as well as nuclear WT1; 3) melanomas, sarcomas, and a subset of plasma cell neoplasms were positive for cytoplasmic expression of WT1 but negative for AE1/AE3; and 4) large B-cell lymphomas and a subset of plasma cell neoplasms were negative for both markers.

  Conclusions: A WT1/AE1/AE3 dual-color immunostain can reliably identify malignancy in pleural effusions and group malignant cells into discrete subsets, thereby narrowing the differential diagnosis. This simple double stain can be a cost-effective, first-line test in the workup of patients with malignant effusions.

  © 2014 American Cancer Society.

• Morphology of 9p21 homozygous deletion-positive pleural mesothelioma cells analyzed using fluorescence in situ hybridization and virtual microscope system in effusion cytology. S. Matsumoto, K. Nabeshima, T. Kamei, et al. 2013;121(8):415-22. PubMed · Publisher

  Abstract

  Background: In malignant pleural mesothelioma (MPM), most patients first present with pleural effusion; thus, cytologic analysis is the primary diagnostic approach. However, the cytologic distinction between MPM and reactive mesothelial cells (RMCs) in effusions can be extremely difficult due to the lack of both well-established immunocytochemical markers and definite cytological criteria for MPM. Moreover, the existence of both MPM cells and RMCs in effusions from the same patient makes the differentiation even more challenging. Homozygous deletion of the 9p21 locus, the site of the cyclin-dependent kinase inhibitor 2A/p16 (CDKN2A/p16) gene, frequently occurs in MPM but has never been reported in RMCs. The aim of this study was to define the cytomorphological characteristics of MPM cells, identified by the presence of 9p21 homozygous deletion by fluorescence in situ hybridization (FISH).

  Methods: For this purpose, cells on smear preparations were recorded using a virtual microscope system and were subjected to FISH analysis. Thereafter, 9p21 homozygous deletion-positive cells were identified in the recorded virtual slides, followed by analysis of their morphological characteristics.

  Results: Mesothelioma cells positive for the 9p21 homozygous deletion exhibited significantly more frequent cell-in-cell engulfment, multinucleation (more than 2 nuclei), and larger multicellular clusters composed of more than 10 cells than did 9p21 deletion-negative RMCs. Possible cutoff values are also proposed for these morphological markers to differentiate MPM cells from RMCs.

  Conclusions: These morphological differences and cutoff values are useful for cytological differentiation of mesothelioma cells from RMCs. In addition, the novel technique of a combination of virtual microscopy and FISH is introduced for tumor morphological analysis.

  Copyright © 2013 American Cancer Society.

• The diagnosis of malignant mesothelioma in effusion cytology: a reappraisal and results of a multi-institution survey. A. Paintal, K. Raparia, M.F. Zakowski, et al. 2013;121(12):703-7. PubMed · Publisher

  Abstract

  Background: The diagnosis of malignant mesothelioma (MM) in effusion specimens is controversial. At the study institution (Northwestern University), a primary diagnosis of MM is made on fluid cytology specimens. In an effort to estimate the practice at other institutions, a survey was disseminated regarding cytologic diagnosis of MM. The authors also evaluated their own institution's experience with primary cytologic diagnosis of MM.

  Methods: Patients with MM at the study institution were identified from 1992 through 2011. Fluid cytology specimens preceding histologic diagnoses were reviewed. A survey was sent to a number of cytology laboratories to assess practice patterns regarding the diagnosis of MM.

  Results: At the study institution, 20 cases of MM had effusion specimens preceding the diagnostic histologic material. In 6 cases (30%), a definitive diagnosis of MM was rendered via cytology alone. There were no false-positive diagnoses of MM. Of 55 laboratories that responded to the survey, 36 reported making a definitive diagnosis of MM after cytologic analysis. Almost all laboratories (35) willing to diagnose MM in effusions reported performing immunohistochemistry to distinguish adenocarcinoma from MM. A smaller proportion (18) of these laboratories reported doing additional immunohistochemistry or fluorescence in situ hybridization for p16 to help distinguish benign from malignant mesothelial proliferations. Those who do not definitively diagnose MM in fluid specimens state inability to identify invasion and overlap with reactive mesothelial proliferation as factors supporting their practice. Most respondents (32) felt that the clinicians at their institution would manage a patient based on a cytologic diagnosis of MM.

  Conclusions: The majority of respondents reported making a definitive diagnosis of MM in effusion cytology specimens. The diagnosis of MM in effusions, although not sensitive, is extremely specific.

  © 2013 American Cancer Society.

• The marriage of cytology and cytogenetics. P. Dal Cin, X. Qian, E.S. Cibas. 2013;121(6):279-90. PubMed · Publisher

  Abstract

  The past 20 years have witnessed extraordinary advances in the field of cytogenetics, with the discovery that a multitude of neoplasms is characterized by identifiable chromosomal changes. The ability of Cytogenetics to aid in the identification and precise classification of a variety of neoplasms has not gone unnoticed by Cytology. In particular, Cytology has recognized Cytogenetics as a welcome companion in the evaluation of soft tissue tumors, lymphomas, renal and urothelial tumors, and mesothelioma. This relationship requires a good understanding of the proper handling of specimens for optimal evaluation by Cytogenetics. The marriage of Cytology and Cytogenetics will likely grow stronger as more solid tumors (eg, salivary gland neoplasms) are discovered that harbor characteristic chromosomal abnormalities.

  Copyright © 2013 American Cancer Society.

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