Sable M, Panda M, Acharya P
… +6 more, Mishra P, Purkait S, Sethy M, Ayyanar P, Adhya AK, Patra S
Cancer Cytopathol
· 2025 Feb · PMID 39902551
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BACKGROUND: Fine-needle aspiration cytology (FNAC) has been used as the first line approach to lymphadenopathy, which is a common presentation in pediatric age group. The Sydney system for reporting of lymph node (LN) cy...BACKGROUND: Fine-needle aspiration cytology (FNAC) has been used as the first line approach to lymphadenopathy, which is a common presentation in pediatric age group. The Sydney system for reporting of lymph node (LN) cytology has been proposed to assess the reliability, performance, and accuracy of the aspiration procedure. This study intends to assess the role of FNAC in the pediatric population according to the Sydney system. METHODS: This was a retrospective observational study from a tertiary care center in Eastern India. All the patients in the age group of 0-18 years evaluated during years 2016-2024 were reclassified according to the Sydney system. Based on the cytology and histology diagnoses, the cases were categorized into true-negative, true-positive, false-negative, and false-positive. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and risk of malignancy (ROM) was calculated for each category. RESULTS: Of 803 cases of pediatric LN-FNACs, 35 (4.35%) cases were reported as inadequate (L1), 689 (85.8%) cases as benign (L2), four (0.49%) cases as atypical cells of undetermined significance (L3), 22 cases as suspicious for malignancy (L4), and 53 (6.6%) cases as malignant (L5). The sensitivity, specificity, PPV, NPV, and accuracy was 72.34%, 98.48%, 97.14%, 83.33%, and 87.61%, respectively. The ROM was 16.67% for L2 and 100% for both L4 and L5 categories. CONCLUSIONS: FNAC is a highly accurate and specific test for LN pathology, especially in the pediatric population. The incorporation of the Sydney system helps to achieve uniformity and reproducibility in LN cytology diagnosis.
Cancer Cytopathol
· 2025 Feb · PMID 39865498
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BACKGROUND: Major mutations (e.g., KRAS, GNAS, TP53, SMAD4) in pancreatic cyst fluid (PCF) are useful for classifying and risk stratifying certain cyst types, particularly in cases with nondiagnostic cytology. However, t...BACKGROUND: Major mutations (e.g., KRAS, GNAS, TP53, SMAD4) in pancreatic cyst fluid (PCF) are useful for classifying and risk stratifying certain cyst types, particularly in cases with nondiagnostic cytology. However, the significance of uncommon minor mutations in PCF has yet to be reported. METHODS: In total, 127 PCF specimens (2014-2021) from 121 patients that underwent molecular analysis were identified, and detailed clinicopathologic data were recorded. Molecular testing was performed using a laboratory-developed next-generation sequencing panel. RESULTS: Forty-five variants other than KRAS, GNAS, RNF43, TP53, CDKN2A, and SMAD4 were detected. Variants that were detected in five or more cases included ARID1A (n = 28), VHL (n = 17), BRAF (n = 12), ATM (n = 8), APC (n = 8), MEN1 (n = 5), serine threonine kinase 11 (STK11; n = 5), PIK3CA (n = 5), and CDH1 (n = 5). Thirty-eight of 121 patients (31%) had histologic confirmation on follow-up resection. Twenty-seven of 28 cysts (96%) with ARID1A mutations had concurrent KRAS/GNAS mutations; 17 (61%) were diagnosed as neoplastic mucinous cysts on cytology, and 10 (36%) were diagnosed as intraductal papillary mucinous neoplasm (IPMN) on histology (80% low grade). No patients developed disease recurrence or died of disease. Cysts with STK11 mutations had RAS co-mutations (KRAS, n = 5; NRAS, n = 1), and four of those five cysts (80%) were mucinous neoplasms with high-grade atypia on cytology. All three resection specimens were IPMNs with high-grade dysplasia or invasive carcinoma, and two of those patients died of disease. CONCLUSIONS: In PCFs, ARID1A mutations were consistently associated with IPMNs (predominantly low grade) with no recurrences or deaths from disease. STK11 mutations appeared to be associated with high-risk mucinous cysts. The detection of minor variants may provide useful preoperative information and add value beyond single-gene genotyping of major mutations.
Cancer Cytopathol
· 2025 Feb · PMID 39804329
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BACKGROUND: Fumarate hydratase-deficient renal cell carcinoma (FHRCC) is an aggressive carcinoma that typically presents as advanced-stage disease. Prompt recognition of FHRCC is critical for appropriate clinical care an...BACKGROUND: Fumarate hydratase-deficient renal cell carcinoma (FHRCC) is an aggressive carcinoma that typically presents as advanced-stage disease. Prompt recognition of FHRCC is critical for appropriate clinical care and genetic counseling for patients and family members. However, diagnosing FHRCC from cytology specimens is challenging, with limited characterization and no reports describing prospectively identified cases. METHODS: Cytology fine-needle aspiration (FNA) cases diagnosed as FHRCC were reviewed, including two prospectively identified cases. RESULTS: Five cases of FHRCC diagnosed by FNA cytology were identified in five unique patients. The cytologic samples included four FNAs with core biopsy and one FNA with cell block. Biopsy sites included kidney (n = 1), chest wall (n = 1), omentum (n = 1), lung (n = 1), and cervical lymph node (n = 1). All cases demonstrated cytologically malignant epithelial cells characterized by enlarged, round nuclei with variable pleomorphism, irregular nuclear membranes, prominent nucleoli, and moderate-to-abundant amounts of cytoplasm. Perinucleolar halos characterized by chromatin margination and pallor around macronucleoli were seen in all cases. Cytologic features not previously described included cytoplasmic macrovacuoles and eosinophilic globules, cytophagocytosis, and floral groups. Papillary architecture was rarely present on aspirate smears. Cell block sections showed variable architectural patterns. By immunohistochemistry, FH was definitively lost in three of five cases (60%), and 2-succinocysteine was positive in all 5 cases (100%). CONCLUSIONS: Cytologic specimens of FHRCC demonstrate salient cytomorphologic features that can support their initial diagnosis. Confirmatory immunohistochemical testing using a dual panel of fumarate hydratase and 2-succinocysteine is recommended for the diagnosis in limited biopsy samples.
Iorgulescu JB, Yang RK, Roy-Chowdhuri S
… +1 more, Sura GH
Cancer Cytopathol
· 2025 Jan · PMID 39746874
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INTRODUCTION: This study aimed to assess the feasibility of implementing the Idylla system, an ultra-rapid, cartridge-based assay, as an extension of rapid on-site evaluation (ROSE) in cytology. The authors conducted a p...INTRODUCTION: This study aimed to assess the feasibility of implementing the Idylla system, an ultra-rapid, cartridge-based assay, as an extension of rapid on-site evaluation (ROSE) in cytology. The authors conducted a pilot validation study on specimens from non-small cell lung carcinoma, thyroid carcinoma, and melanoma, evaluating four assays designed to detect alterations in KRAS, EGFR, BRAF, gene fusions, and expression imbalances in ALK, ROS1, RET, NTRK1/2/3, and MET exon 14 skipping transcripts. They investigated the feasibility of providing accurate biomarker molecular testing results in a cytopathology laboratory within hours of specimen collection. METHODS: The authors evaluated the performance characteristics and turn-around-time of the Idylla system by testing a total of 144 cartridge assays across various specimen types, including fine-needle aspirate smears, formalin-fixed paraffin-embedded (FFPE) cell blocks, small tissue biopsy FFPE blocks, and control cell line FFPE scrolls. RESULTS: The average time from specimen input to results output was 2-3 hours. Accuracy across the four cartridge types was: KRAS assay: 100%, EGFR assay: 94%, BRAF assay: 100%, and GeneFusion assay: 94%. Analytical sensitivity ranged from 1% to 5% variant allele frequency for all assays. Inter-assay precision and analytical specificity were both 100%. CONCLUSION: Using the Idylla system, actionable genetic alterations can be reliably detected within 2-3 hours from cytology and small biopsy samples with minimal input requirements. The findings of this study demonstrate the feasibility of incorporating same-day molecular testing as part of ROSE procedures in the cytopathology laboratory, ultimately shortening the time from procedure to personalized treatment for cancer patients.
Alhamar M, Rudomina D, Wang L
… +4 more, Feratovic R, Oen H, Lin O, Wei XJ
Cancer Cytopathol
· 2025 Jan · PMID 39745134
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BACKGROUND: Telecytology-assisted rapid on-site evaluation (ROSE) offers a cost-effective method to enhance minimally invasive biopsies like fine needle aspiration and core biopsies with touch preparation. By reducing no...BACKGROUND: Telecytology-assisted rapid on-site evaluation (ROSE) offers a cost-effective method to enhance minimally invasive biopsies like fine needle aspiration and core biopsies with touch preparation. By reducing nondiagnostic sampling and the need for repeat procedures, ROSE via telecytology facilitates prompt triage for ancillary tests, improving patient management. This study examines cases initially deemed adequate for diagnosis during telecytology-assisted ROSE but later categorized as nondiagnostic at final evaluation (NDIS). DESIGN: We performed a retrospective analysis of telecytology-assisted ROSE cases over 7 years at a major cancer center, focusing on fine needle aspiration and touch preparation of core biopsies. Each case was thoroughly reviewed, correlating with clinical data and concurrent core biopsies or subsequent excisions. The study identified leading factors contributing to NDIS. RESULTS: The average NDIS rate was 0.06% (42/70,612). Misinterpretation of benign or reactive cells as neoplastic was the leading cause (76.2%) of discrepancies between original ROSE and final diagnosis. Kidney biopsies had the highest NDIS rate (0.90%), primarily because of misinterpreting nonneoplastic cells. Thyroid biopsies were linked to quantitative threshold issues (0.10%). NDIS events were most associated with misinterpretation in kidney, pancreas, gastrointestinal tract, and lung biopsies. CONCLUSION: In conclusion, the NDIS rate in telecytology-assisted ROSE is low, but quality assurance identified areas for improvement. Recognizing site-specific pitfalls during telecytology-assisted ROSE can enhance diagnostic accuracy and optimize patient care.
Maher MH, Duose DY, Wistuba II
… +3 more, Luthra R, Arjuna S, Roy-Chowdhuri S
Cancer Cytopathol
· 2025 Jan · PMID 39704279
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BACKGROUND: Genomic profiling is essential in the management of non-small cell lung cancer. However, this may often be challenging because of limited cytological tissue and extended turnaround time (TAT) for next-generat...BACKGROUND: Genomic profiling is essential in the management of non-small cell lung cancer. However, this may often be challenging because of limited cytological tissue and extended turnaround time (TAT) for next-generation sequencing (NGS). This study aims to describe a rapid TAT workflow for molecular profiling using fine-needle aspiration (FNA) supernatants. METHODS: A fully automated total nucleic acid extraction using the Genexus Integrated System was compared to a manual extraction using FNA supernatants from 50 patients with non-small cell lung cancer. Molecular profiling using the 50 gene Oncomine Precision Assay GX panel was performed and NGS results were compared with those of paired tissue samples. RESULTS: The FNA samples processed using the automated Genexus purification system (n = 42) and the manual extraction method (n = 8) showed comparable quality control metrics with a median total nucleic acid yield of 1230 ng (18-17720 ng) and 1068 ng (777-1740 ng), respectively. The Genexus purification system reduced the hands-on time from 120 to 30 minutes, enhancing workflow efficiency and decreasing the overall TAT. Of the 50 samples extracted, NGS was performed on 26 samples: seven via manual extraction and 19 using automated extraction. NGS quality control metrics were also comparable between both extraction methods. The overall TAT of the automated NGS workflow from specimen received to test result was 24 hours, providing rapid and reliable molecular results for timely clinical decision-making and improved patient outcomes.
Cancer Cytopathol
· 2025 Jan · PMID 39655621
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BACKGROUND: Nuclear protrusions such as micronuclei (MNs) and nuclear budding (NB) are morphological findings of chromosomal instability and indicators of genotoxic damage. They are increased in malignancies, and their h...BACKGROUND: Nuclear protrusions such as micronuclei (MNs) and nuclear budding (NB) are morphological findings of chromosomal instability and indicators of genotoxic damage. They are increased in malignancies, and their high frequency may be used in the diagnosis of cancers and the follow-up of patients. Urothelial carcinomas are common tumors that cause morbidity and mortality, and cytology is a commonly used method for the monitoring and screening of urothelial carcinoma. Although the cytological evaluation of urinary samples is mainly based on nuclear features, there is limited research focusing on MN frequency in urinary cytology. This study aimed to investigate MN and NB counts in various diagnostic categories of urinary samples. METHODS: This study included 117 urinary cytology samples categorized according to The Paris System for Reporting of Urinary Cytology. Two observers, blinded to the diagnosis, counted the frequency of MNs and NB per 1000 cells on May-Grünwald-Giemsa- and Papanicolaou-stained slides. RESULTS: MN and NB counts significantly differed among the groups (p < .001 for each) with a large effect (Ɛ = 0.509). MN and NB counts were significantly higher in cases with high-grade urothelial carcinoma (HGUC) than in control cases and in cases that were negative for HGUC or with atypical urothelial cells (p < .001 for each). Any MN count greater than 2.5 per 1000 cells indicated HGUC with a 55% sensitivity and 92.4% specificity. CONCLUSIONS: Because increased MN and NB frequencies are closely associated with an increased risk of malignancy, these could be integrated into The Paris System for Reporting of Urinary Cytology.
Viti J, Di Stefano C, Giunti S
… +5 more, Pompeo G, Pezzati P, Terreni A, Sani C, Cytology Working Group
Cancer Cytopathol
· 2025 Jan · PMID 39569623
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BACKGROUND: Whole-slide imaging (WSI) has been adopted in many fields of pathology for education, quality assurance, and remote diagnostics. In 2021, the College of American Pathologists (CAP) updated guidelines to suppo...BACKGROUND: Whole-slide imaging (WSI) has been adopted in many fields of pathology for education, quality assurance, and remote diagnostics. In 2021, the College of American Pathologists (CAP) updated guidelines to support pathology laboratories regarding the WSI systems validation process. However, the majority of published literature refers to histopathology rather than cytology. The aim of this study was to compare conventional light microscopy (CLM) and WSI in thin-layer cervical samples evaluation according to CAP guideline. METHODS: A sample set of 64 thin-layer cervical specimens from women 25-64 years old who participated in cervical cancer screening programs in Tuscany was distributed among five cytologists at Institute for Cancer Research, Prevention and Clinical Network (Florence, Italy) for CLM analysis. After 2 weeks, the corresponding 64 digitally scanned slides were available at several magnifications for WSI evaluation. RESULTS: Substantial/near perfect agreement between CLM and WSI evaluation (0.77 ≥ κ ≥1) was observed for the negative for intraepithelial lesion or malignancy (NILM) class with concordance rates from 83.3% to 100%.Variability in concordance was observed among all the cytologists: 50%-85.7% for low-grade squamous intraepithelial lesion (LSIL), 47.1%-100% for high-grade squamous intraepithelial lesion (HSIL), 50%-100% for atypical glandular cells (AGCs) favors adenocarcinoma (ADK) with moderate/near perfect agreement (0.47 ≥ κ ≥1). Concordance and agreement rates were also variable within the "borderline" cytological categories of atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells cannot exclude an HSIL (ASC-H), and AGCs with lower or not computable kappa for some readers. The overall intralaboratory concordance between CLM and WSI was 92.9% with a near perfect agreement (κ = 0.84) for NILM. Substantial agreement (κ ≥0.65) was assessed for LSIL, HSIL/squamous cell carcinoma, AGCs, and ADK categories whereas the agreement was lower (κ ≤0.39) for ASC-US and ASC-H. CONCLUSIONS: This study showed an overall substantial/near perfect agreement between CLM and WSI for all the cytological categories except the "borderline" ASC-US and ASC-H. Further progress in cytology WSI systems are needed before introducing it in routine diagnostics.
Zhou Y, Liu J, Chen S
… +4 more, Xin X, Xiao M, Qiang X, Zhang L
Cancer Cytopathol
· 2025 Jan · PMID 39555989
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BACKGROUND: To reduce unnecessary examinations and treatments, an effective detection method for differentiating human papillomavirus (HPV)-positive patients is urgently needed. This study aimed to explore the difference...BACKGROUND: To reduce unnecessary examinations and treatments, an effective detection method for differentiating human papillomavirus (HPV)-positive patients is urgently needed. This study aimed to explore the differences in HPV viral loads across various cervical lesions and identify the optimal cutoff value for high-grade squamous intraepithelial lesions (HSILs). METHODS: This retrospective study included patients with varying degrees of cervical lesions admitted to a hospital between January 1, 2023, and March 1, 2024. The HPV genotype and viral load were determined using BioPerfectus multiplex real-time assay. The differences in HPV genotype viral loads among cervical lesion classifications were analyzed to identify the most applicable type of viral load. RESULTS: The viral loads of HPV16, HPV31, HPV33, HPV35, and HPV58 were significantly associated with the grade of cervical lesions (p < .05), with the HPV16 group exhibiting the strongest correlation (p < .01). The HPV16 viral load demonstrated good sensitivity (Se) and specificity (Sp) for predicting HSIL (Se = 81.52%, Sp = 64.13%). The three most prevalent HPV genotypes associated with negative, low-grade squamous intraepithelial lesions (LSILs) and HSILs were HPV16, HPV52, and HPV58. HPV33 exhibited the highest prevalence of HSILs, followed by HPV16. CONCLUSIONS: High-risk HPV viral load is associated with cervical lesion classification. HPV16 viral load can effectively differentiate HSIL from LSIL with good Se and Sp.
Zalles N, Mukhopadhyay S, Satturwar S
… +4 more, Lajara S, Khader S, Pantanowitz L, Elsheikh TM
Cancer Cytopathol
· 2025 Jan · PMID 39555952
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BACKGROUND: Thoracic switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-deficient (SD) malignancies, including SD undifferentiated tumor (SD-...BACKGROUND: Thoracic switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-deficient (SD) malignancies, including SD undifferentiated tumor (SD-UT) and SD non-small cell lung carcinoma (SD-NSCLC), have been recently described. The cytologic features of these neoplasms in fine-needle aspiration (FNA) and effusion specimens have rarely been reported in the literature. This study aimed to describe and compare the spectrum of cytologic, immunohistochemical, and clinical features of these high-grade malignancies recently encountered at the participating institutions. METHODS: This study documented clinical and imaging characteristics of tumors from 27 patients. Sixteen cytomorphologic features and immunohistochemical findings were compared between SD-UT and SD-NSCLC samples. RESULTS: Twenty three FNAs, two bronchial brushings, and two pleural fluids were evaluated, including 17 SD-UT cases (mean patient age, 70 years) and 10 SD-NSCLC cases (mean patient age, 62 years). Both malignancies presented with large thoracic masses and/or hilar/mediastinal lymphadenopathy. All SD-UT cytologic samples had a discohesive or mixed cohesive-discohesive architecture, and most (13 of 17) showed predominant rhabdoid or mixed rhabdoid-epithelioid features. Most SD-NSCLC cytologic samples (nine of 10) were either cohesive or mixed cohesive-discohesive and had a predominantly epithelioid morphology (eight of 10). Keratins and claudin-4 were negative or focally positive in SD-UT samples, whereas they were diffusely positive in SD-NSCLC samples. Both malignancies were negative for TTF-1 and p40/p63 and showed loss of expression of SMARCA4. CONCLUSIONS: Although there is considerable clinical and cytopathologic overlap between SD-UT and SD-NSCLC, some key features allow for their distinction. SD-UT is mostly discohesive with rhabdoid or mixed rhabdoid-epithelioid features, whereas SD-NSCLC often has cohesive epithelioid morphology. The combination of clinical presentation, cytomorphology, and immunohistochemistry is essential for a definitive diagnosis.
Harinath L, Elishaev E, Ye Y
… +6 more, Matsko J, Colaizzi A, Wharton S, Bhargava R, Pantanowitz L, Zhao C
Cancer Cytopathol
· 2025 Jan · PMID 39498535
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BACKGROUND: Artificial intelligence (AI)-based systems are transforming cytopathology practice. The aim of this study was to evaluate the sensitivity of high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap...BACKGROUND: Artificial intelligence (AI)-based systems are transforming cytopathology practice. The aim of this study was to evaluate the sensitivity of high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) diagnosis assisted by the Hologic Genius Digital Diagnostics System (GDDS). METHODS: A validation study was performed with 890 ThinPrep Pap tests with the GDDS independently. From this set, a subset of 183 cases originally interpreted as HSIL confirmed histologically were included in this study. The sensitivity for detecting HSIL by three cytopathologists was calculated. RESULTS: Most HSIL cases were classified as atypical glandular cell/atypical squamous cell-high grade not excluded (AGC/ASC-H) and above by all cytopathologists. Of these cases, 11.5% were classified as low-grade squamous intraepithelial lesion (LSIL) by pathologist A (P-A), 6% by pathologist B (P-B), and 5.5% by pathologist C (P-C); 3.8%, 2.7%, and 1.6% of these cases were classified as atypical squamous cell of unknown significance (ASC-US) by P-A, P-B, and P-C, respectively. The sensitivity for detection of cervical intraepithelial neoplasia 2 and above (CIN2+) lesions was 100% if ASC-US and above (ASC-US+) abnormalities were counted among all three pathologists. The sensitivity for detection of CIN2+ lesions was 84.7%, 91.3%, and 92.9% by P-A, P-B, and P-C, respectively, for ASC-H and above abnormalities. The Kendall W coefficient was 0.722, which indicated strong agreement between all pathologists. CONCLUSIONS: New-generation AI-assisted Pap test screening systems such as the GDDS have the potential to transform cytology practice. In this study, the GDDS aided in interpreting HSIL in ThinPrep Pap tests, with good sensitivity and agreement between the pathologists who interacted with this system.
Feng FX, Birdsong GG, Wei J
… +4 more, Dababneh MN, Reid MD, Hoskins M, Wang Q
Cancer Cytopathol
· 2025 Jan · PMID 39498509
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BACKGROUND: In 2019, the American Society for Colposcopy and Cervical Pathology introduced fundamental shifts toward "risk-based" guidelines, with human papillomavirus (HPV) genotyping as a principal test for investigati...BACKGROUND: In 2019, the American Society for Colposcopy and Cervical Pathology introduced fundamental shifts toward "risk-based" guidelines, with human papillomavirus (HPV) genotyping as a principal test for investigating squamous intraepithelial lesions. This study aims to provide practice-based evidence and supplement the updated guidelines by investigating HPV demographic distribution and uncovering the pathological features of high-grade squamous intraepithelial lesions (HSILs) caused by high-risk HPV (hrHPV) subtypes. METHODS: Patients who underwent Papanicolaou screening and HPV testing in two hospital systems over the course of 4 years were recruited. The cytology results were categorized on the basis of the 2014 Bethesda classification. DNA sequences of 14 types of hrHPV were detected by Aptima test. The histological features of HSILs caused by different subtypes were compared between biopsies and excisions. RESULTS: A total of 63,709 cases were included. The HPV prevalence was 14.70%, predominantly in the 30 to 39-year-old age group, with slightly higher rates observed in African Americans. There was no significant racial distribution difference between HPV 16/18/45 and other types. HPV 16/18/45 infection was directly correlated with the severity of abnormal cytology, although the other subtypes were the major causes of cytological abnormalities. The trend for HPV prevalence was consistent across calendar years, and was associated with 8.77% negative for intraepithelial lesion or malignancy, 30.46% atypical squamous cell of undetermined significance, 64.62% low-grade squamous intraepithelial lesion, 66.75% atypical squamous cell-cannot exclude a high-grade squamous intraepithelial lesion, and 91.80% HSIL. Furthermore, 29.09% of HSILs associated with other subtypes were not detectable on subsequent resections. CONCLUSIONS: Given the HPV demographic distribution and the histological features of HSILs caused by different subtypes, cotesting with reflex HPV genotyping in specific populations, or expanding the subtypes in the primary HPV screening test, should be considered.
Tanaka K, Kayraklioglu N, Chan E
… +2 more, Ding CC, Vohra P
Cancer Cytopathol
· 2025 Jan · PMID 39403894
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BACKGROUND: Human papillomavirus (HPV)-positive urinary tract carcinomas (UTCas) have distinct morphology and molecular features with potential treatment implications. Cytomorphologic analysis of these tumors on urine cy...BACKGROUND: Human papillomavirus (HPV)-positive urinary tract carcinomas (UTCas) have distinct morphology and molecular features with potential treatment implications. Cytomorphologic analysis of these tumors on urine cytology specimens has not yet been reported. The authors evaluated the cytomorphologic findings of HPV-positive UTCa on urine cytology using The Paris System for Reporting Urinary Cytology (TPS) criteria. METHODS: HPV-positive cases were identified by a retrospective review of surgical specimens that had UTCa confirmed by HPV in situ hybridization. Cases that had concurrent urine cytology were reviewed using TPS. Cytomorphologic features of high-grade urothelial carcinoma (HGUC) were evaluated as well as the presence of atypical squamous cells (ASCs) and basaloid features. RESULTS: Sixteen cytology specimens from eight patients with HPV-positive UTCa were included. On original diagnosis, none of the cytology specimens were suggested to be HPV-associated. TPS diagnostic criteria identified eight cases with at least atypical findings, including five HGUC cases, one case that was suspicious for HGUC, and two atypical urothelial cases. Common cytomorphologic features included basaloid clusters (six of eight cases; 75%) and ASCs (four of eight cases; 50%) that matched the corresponding surgical specimens. Most cases exhibited urothelial cell hyperchromasia (seven of eight cases; 88%), and hypochromasia was a frequently observed variant (four of eight cases; 50%), either alone or in addition to hyperchromasia. CONCLUSIONS: HPV-positive UTCa can be identified reliably as HGUC by using TPS criteria; however, these cases may not be recognized as HPV-associated. The presence of basaloid cells or ASCs can help suggest screening for HPV in urine specimens. Larger scale studies are warranted to validate cytomorphologic differences and determine the impact of HPV infection on clinical outcomes for patients with UTCa.