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Introduction Extramammary Paget disease (EMPD) is an uncommon malignant cutaneous neoplasm that are divided into primary and secondary forms. In this multicenter study, histologically proven cases of primary and secondary EMPD were reviewed for clinical outcomes with subgroup analysis for secondary EMPD. Methodology Cases of EMPD were identified from pathology report of the involved institutions over a period of over two decades. Cases of secondary EMPD were identified review of case notes, radiology, and pathology reports. Clinicopathological and outcome data were retrieved for statistical analysis. Results A total of 109 cases were retrieved, including 19 cases of secondary EMPD, most commonly associated with colorectal (n=6), anal (n=5) and prostatic carcinomas (n=3). A difference was observed between older age and secondary (versus primary) EMPD (p=0.016), but no differences were seen in other clinico-demographical parameters. Male sex (p=0.018), age over 60 years old (p=0.004) and involvement of margins (resectable) (p=0.018) were associated with shorter OS. For DSS, involvement of margins (p=0.009) was an adverse predictor. Secondary EMPD had a shorter DSS than primary EMPD (p=0.005). Multivariable analysis confirmed all above associations (p<0.05). In subgroup analysis for secondary EMPD, margin involvement remained associated with shorter OS (p = 0.007) and DSS (p = 0.003). Conclusions Secondary EMPD is associated with poorer outcomes. Margin involvement is strong and independent indicator of shorter OS and DSS, including secondary EMPD. Resectability is a strong predictor of favorable outcome and excision with clear margins should be attempted when surgically feasible., (The Author(s). Published by S. Karger AG, Basel.)

Introduction: Compared to urothelial carcinomas (UCs), the cytomorphology of renal cell carcinomas (RCCs) is underdescribed. This study aims to investigate whether UCs and RCCS of the upper urinary tract can be differentiated cytologically, and to identify distinguishing cytomorphological features., Methodology: Consecutive urine cytology specimens with atypical/C3, suspicious/C4 or malignant/C5 diagnoses matched with a nephrectomy or ureterectomy specimen with UC or RCC over a 15-year period were reviewed for cellularity, architecture, background composition and cytomorphologic features., Results: Totally 132 specimens were retrieved, comprising 24 RCCs and 108 UCs. Clear cell RCC (CCRCC) (n = 18) was the most common RCC. Urine cytology specimens from UC showed a trend of higher cellularity (p = 0.071) against RCC and was significant in subgroup analysis with CCRCC (p < .001). Epithelial structures in sheets, tubules, and papillae were exclusive in specimens of UC (p < .05). For background features, squamous cells were more common for RCC (p = .006) including CCRCC (p = .003), whereas polymorphs (p = .011) and necrotic material (p = .010) were associated with UC. Average nuclear size was larger and nuclear size variation (p < .001) and nuclear-cytoplasmic ratio (p = .001) were greater in UC (p = .001) than RCC. Comparing RCC to high-grade UCs only, nuclear-cytoplasmic ratio maintained statistical significance (p = .006) while average nuclear size showed a trend (p = .063)., Conclusion: A clean background free of tumor necrosis and polymorphs, and the lack of complex tumor fragments favors RCC. UCs also display larger nuclear size, higher nuclear size variation and nuclear-cytoplasmic ratio. These cytomorphological features with corroboration of clinical/radiological findings, can aid in raising a diagnosis of RCC., (© 2024 The Author(s). Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Aims: The international system for reporting serous fluid cytopathology (ISRSFC) set forth a five-tiered reporting system with comprehensive validation on pleural and peritoneal fluid cytology. An algorithmic approach for cytomorphological assessment and immunocytochemistry was also described in ISRSFC. Limited data on pericardial fluid are supportive but would benefit from further investigation., Methods: Consecutive pericardial fluid cytology over a 4-year period was reviewed by multiple board-certified pathologists according to the ISRSFC. Cytomorphology and immunocytochemistry were assessed sequentially, with respective diagnostic performances computed and compared. Literature review was performed., Results: In total 358 specimens, including 53 with immunocytochemistry available, were reviewed. There were 137 benign and 221 malignant (MAL) cases. The risks of malignancy were 23.5% non-diagnostic (ND), 29.2% negative for malignancy (NFM), 56.0% atypia of undetermined significance (AUS), 82.6% suspicious for malignancy (SFM) and 99.2% (MAL) for cytomorphological assessment, improving to 23.5% (ND), 29.1% (NFM), 56.8% (AUS), 78.9% (SFM) and 99.3% (MAL) incorporating immunocytochemistry. Ten cases (2.8%) received a change in diagnosis after review of immunocytochemistry. All revisions of diagnostic category were appropriate upgrades/downgrades referenced against clinical information. Cytomorphological typing was accurate for adenocarcinoma (n=81/83, 97.6%), while other carcinomas and lymphomas required immunocytochemistry. Certain subcategories within AUS and SFM pertaining to bland indeterminate epithelial cells or mucinous material were not seen for pericardial fluid., Conclusions: The ISRSFC shows robust diagnostic performance for pericardial fluid cytology. For pericardial effusion, disease composition and applicable cytological subcategories differ from its peritoneal and pleural counterparts. Incorporating immunocytochemistry by an algorithmic approach improves diagnostic accuracy. Cytomorphology is accurate for identifying adenocarcinomas, but further typing necessitates immunocytochemistry is necessary., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Urine cytology is robust for the diagnosis of urothelial lesions, but data on the detection rates of prostatic adenocarcinoma in urine cytology is limited. In this study, a multicenter review was performed to define the clinical role of urine cytology in diagnosis of prostatic adenocarcinoma., Methods: Cytologic diagnoses of lower tract urine cytology specimens with histology-proven prostatic adenocarcinoma from three institutions, from a period of over two decades, were reviewed. Clinicopathological parameters-tumor grade, stage, histologic features, and preanalytical factors-prostate-specific antigen (PSA) level and lesion size, were retrieved and compared with cytologic diagnoses., Results: In total, 2115 urine cytology specimens from 1119 patients were retrieved. The atypia (or above/C3+) and suspicious (or above/C4+) rates were 19.48% and 3.36%. Bilobar and extracapsular involvement, lymphovascular invasion, Gleason score, and International Society of Urological Pathology grade were associated with a positive urine diagnosis (p < 0.05). The atypia (C3+) and suspicious (C4+) rates of urine cytology in patients with a PSA level of ≤4.0 ng/mL was paradoxically higher (p < 0.01), but PSA levels correlated positively with urine diagnosis at higher cutoffs (>10, >20, >50, >100 ng/mL). All these factors remained significant on multivariate analysis (p < 0.05), including a negative correlation with low-PSA (≤4.0 ng/mL, p = 0.001) and positive correlation with high-PSA (>20 ng/mL, p = 0.020). Lesion size and multifocality were not associated with urine cytology diagnosis (p > 0.05)., Conclusion: Urine cytology showed low sensitivity in detection of prostatic adenocarcinoma. Detection rates were largely positively correlated with PSA levels but not for lesion size nor multifocality, limiting its clinical utility., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Background: Metastatic breast cancers are frequently encountered in cytology and require immunocytochemistry (ICC). In this study, traditional and multiplex ICC (mICC) for GATA-binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP15), and mammaglobin (MMG) were performed with the aim of validating mICC in cell blocks, with further single-cell expression pattern analysis to identify the single markers and combinations of markers most sensitive in subtypes of breast cancer., Methods: GATA3, GCDFP15, and MMG were paired with OptiView 3,3'-diaminobenzidine and Ventana DISCOVERY Purple and Blue, respectively, with cyclical and serial staining. Bright-field imaging was performed with the Mantra 2 system and analyzed with the inForm Tissue Finder (Akoya Biosciences). Cell detection and phenotyping were further confirmed by two pathologists., Results: In the 36 cases studied, traditional ICC and mICC demonstrated good concordance (kappa coefficient, >0.5; p < .01) at three cutoffs (1%, 5%, and 50%), except for GATA3 at the 1% cutoff. Single-marker positivity outnumbered double-marker positivity and the exceedingly rare triple-marker positivity (<3%). GATA3 was the leading single marker-positive phenotype in all breast cancer subtypes, except for MMG in estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancers. Limited to two markers, GATA3/MMG included the greatest number of tumor cells for luminal breast cancers (ER+/PR+/HER2+, 60.6%; ER+/PR+/HER2+, 31.4%), whereas HER2-overexpressed breast cancers (27.4%) and triple-negative breast cancers (26.4%) favored the combination of GATA3/GCDFP15., Conclusions: For a single marker, GATA3 displayed the highest sensitivity. The addition of MMG for hormone receptor-positive breast cancers and GCDFP15 for hormone receptor-negative breast cancers further increased sensitivity. The low proportion of multimarker-positive cells suggested that the coexpression observed with traditional ICC is attributable to intratumoral heterogeneity, not genuine coexpression., (© 2024 The Author(s). Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Neuroendocrine tumors of the lung display characteristic cytomorphologic features allowing direct diagnosis. The specificity of these features in distinguishing subtypes of neuroendocrine tumors, and their differences among types of cytologic specimen poses as interpretative potential pitfalls. This study reviewed and compared bronchial, effusion fluid and fine-needle aspiration cytology specimens of neuroendocrine tumors of the lung to address these issues. Histology-proven cytology specimens of neuroendocrine tumors were reviewed for cytomorphological parameters focusing on reported specific neuroendocrine nuclear and background features. Totally, 46 cases (26 bronchial, 11 effusion and 9 aspirate specimens), corresponding to 37 small cell carcinomas, 7 neuroendocrine carcinomas and 2 carcinoids were reviewed. Nuclear moulding (n = 35/37, 95 %), naked nuclei (n = 33/37, 89 %) and marked nuclear irregularity (n = 32/37, 86 %) were the three most common features of small cell carcinoma. The only specific feature for small cell carcinoma was the lack of prominent nucleoli (p = 0.004). For pulmonary carcinoids, in addition to the above features, other features associated with neuroendocrine carcinoma reviewed including crush artifact and necrotic material were absent. Compared to bronchial and aspiration cytology, crush artifact (p < 0.001) and necrotic material (p = 0.014) were absent on effusion fluid specimens and naked nuclei were less frequently seen (p = 0.022), while prominent nucleoli were more often observed (p = 0.005). Nuclear moulding, irregularity and naked nuclei are common but not unique features to small cell carcinomas. Effusion fluid specimens have "cleaner" backgrounds while displaying greater nuclear atypia. The type of cytologic preparation/specimen is an important factor which must be considered during diagnostic interpretation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Claudin-4 has been described as a highly sensitive immunocytochemical marker for detection of metastatic carcinoma cells in effusion cytology specimens. This study aims to challenge the performance of claudin-4 in different types of malignancies and low cellularity specimens, by comparison with other markers in a large cohort of carcinomatous effusion specimens., Methodology: Cell block preparations from peritoneal and pleural fluid specimens were retrieved, with malignant (carcinoma) diagnoses confirmed by review of hospital diagnosis code and pathology reports. Claudin-4, BerEP4, CEA, and MOC31 immunocytochemistry were performed and scored by expression proportion and intensity. Tumor cellularity was assessed for subgroup analysis of low cellularity specimens., Results: Totally 147 specimens (70 pleural, 77 peritoneal) of 68 lung, 62 breast, 9 gynecological, and 7 gastrointestinal carcinomas were retrieved. The average proportion expression of claudin-4 was highest (89.6%, vs. CEA 40.5%, BerEp4 18.6%, MOC31 16.8%) and the percentage of strong expression was highest for claudin-4 (72.1%). Expression levels of claudin-4 were consistently higher than other markers in subgroups of all primary sites. The difference was more significant for low cellularity specimens. High (≥50%) proportion expression was seen for 96.61% of cases for claudin-4 (vs. BerEp4 8.77%, CEA 46.55%, MOC31 8.77%, p < 0.001). These factors contributed to a low concordance between claudin-4 and BerEp4, CEA and MOC31 (K = 0.010-0.043)., Conclusion: Claudin-4 is more sensitive than CEA, BerEp4 and MOC31, suitable for low cellularity specimens of most types of metastatic carcinoma and is a robust immunocytochemical marker for carcinoma that can be used solitarily., (© 2024 The Author(s). Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2 mm 2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Competing interests: None declared.

Introduction: The Preferentially Expressed Antigen in Melanoma (PRAME) immunostain has seen significant diagnostic use in confirming malignancy for melanocytic lesions. However, the expression of PRAME in genital melanocytic lesions have not been reported. In this study, PRAME staining was performed on a cohort of genital melanocytic lesions, aiming to investigate the diagnostic role of PRAME in genital melanocytic lesions and its expression in atypical genital nevi., Methodology: A cohort including genital invasive melanoma, melanoma-in-situ, atypical genital nevus (AGN), compound nevus, intradermal nevus, blue nevus, lentigo and melanosis was retrieved with histology reviewed and PRAME immunostaining performed., Results: A total of 66 cases were reviewed. The average proportion expression of PRAME were 56.75 % and 57.43 % for invasive melanoma and melanoma-in-situ, with average H-scores of 153.5/300 and 163.14/300 respectively, which were greater than AGN (3.25 %, 7.75/300, p<0.001), compound/intradermal nevi, lentigo/melanosis, and background junctional melanocytes (<1 %, <1/300, p<0.001). The different cutoffs of PRAME expression, the sensitivity and specificity were 65.22 % and 100 % (>100/300); 69.57 % and 95.83 % (>10/300); and 82.61 % and 93.75 % (≥1/300) respectively. Low level PRAME expression was seen in half of the cases of AGN (n=2/4, 50 %), and at low cutoffs (>10/300 and ≥1/300) unable to differentiate invasive melanoma from AGN (p>0.05)., Conclusions: For genital melanocytic lesions, PRAME immunostain shows high specificity at strong and diffuse staining. AGN not uncommonly display low level expression. Focal and/or weak PRAME expression should not be considered as an absolute indication of malignancy, and comprehensive histological assessment remains the key to accurate diagnosis of melanocytic lesions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Introduction : Cytological diagnosis of sarcomas requires detailed cytomorphological assessment and integration of immunocytochemistry and/or molecular testing. The role of exfoliative cytology, as compared to aspiration cytology, is less understood. This case series describes well-differentiated/dedifferentiated liposarcomas in effusions, with cytomorphological features, ancillary test results and clinical outcomes detailed. Methods : A computerized search of the department pathology archives was performed for sarcomatous effusions with histological diagnosis or clinical history of well-differentiated/dedifferentiated liposarcoma. Clinical progress, cytology slides, immunocytochemistry and molecular test results were reviewed. Results : Six patients were identified. In 5 patients with clinical follow up, 4 (80%) were deceased within 5 months of malignant effusion. One patient was alive with 12 years disease-free survival after radical resection with adjuvant radiotherapy. Three patients showed dedifferentiation on histology, and high-grade (dedifferentiated) tumor cells were present in effusion cytology of 2 patients. Two showed well-differentiated components only on biopsy, but high-grade (dedifferentiated) tumor cells were identified in cytology. The high-grade tumor cells displayed marked nuclear irregularity, enlargement, size variation, with macronucleoli and multinucleation. Well-differentiated lipomatous components were demonstrated in 4 patients (66.7%), comprising of multivacuolated lipoblasts and atypical lipocytes. CDK4 and MDM2 immunoreactivity in all 3 cases with cell blocks, and CDK4 and MDM2 amplification in one were successfully demonstrated. Conclusion : Lipomatous and dedifferentiated components can be sampled and cytomorphologically identified on effusion fluids of liposarcomas, with sufficient cellularity for immunocytochemistry and molecular testing. Although generally associated with poor prognosis, long disease-free survival with sarcomatous effusion is possible with radical surgery and adjuvant treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background. Neuroendocrine lesions arising from mediastinal teratomas are rare tumors with only small number of patients reported in literature. The behavior of these lesions appears to be different from traditional neuroendocrine neoplasms. A comprehensive review will be valuable for histologic assessment and treatment planning for similar cases. Case presentation. We present an example of a 57-year-old man who presented with cough. Subsequent work-up revealed an anterior mediastinal mass of 2.1 cm on computed tomography. The patient underwent robot-assisted thoracoscopic thymectomy. Histological examination revealed a mature cystic teratoma with a neuroendocrine component consisting of clusters of tumor cells with round to oval nuclei and a "salt-and-pepper" chromatin pattern. The tumor cells were immunoreactive to cytokeratin, synaptophysin, chromogranin, and INSM1, with a Ki-67 proliferative index of 4%. A histological diagnosis was mature teratoma with well-differentiated low-grade neuroendocrine tumor (carcinoid) was made. The patient was well and without disease after complete surgical excision at 10 months. Literature review. Literature reviewed yielded 13 examples of neuroendocrine lesions arising from mediastinal teratomas. No disease-related mortality was reported, even in lesions with high-grade neuroendocrine, carcinomatous, or immature teratomatous components. Conclusions. Surgical removal is the mainstay of treatment of these lesions, and the presence of a neuroendocrine component does not appear to negatively affect prognosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Bronchial exfoliative cytology is classified as non-abrasive (washing, aspiration and bronchoalveolar lavage) and abrasive (brushing). Brush abrasion dislodges epithelial cells but can induce bleeding and cytomorphologic artifacts. In this study, the largest cohort to date of bronchial cytology specimens were referenced against bronchial biopsy as the reference standard. Findings in the study will be useful for selecting biopsy modality and reducing necessary procedural risks. All consecutive bronchial cytology and bronchial biopsy from 1995 to 2022 were retrieved. The diagnoses were reviewed and categorized into five-tiered diagnostic categories to compare diagnostic agreement and concordance. Review of 14,148 specimens yielded 3963 non-abrasive, 2378 abrasive cytology specimens matched to biopsy, with 4355 matches between non-abrasive and abrasive cytology specimens. Agreement between non-abrasive and abrasive cytology was moderate (κ = 0.580), and similar when referenced against biopsy (κ = 0.456 (non-abrasive), κ = 0.498 (abrasive)). Abrasive bronchial cytology showed a higher percentage of malignant diagnosis (20.95 % vs. 12.63 %, p < 0.001) and over-diagnosis rate (36.40 % vs. 29.79 %, p < 0.001), but higher sensitivity (0.747 vs. 0.572, p = 0.002). For subgroup analysis of transbronchial biopsies, matched abrasive cytology showed higher discordant rates (p < 0.05) and lower accuracy (0.907 vs. 0.873, p = 0.020). With the added bleeding risk associated with brushing, abrasive techniques may only be preferable in cases with clinical or bronchoscopic suspicion of malignancy, in particular endobronchial mucosal lesions. For routine bronchoscopy, non-abrasive bronchial cytology appears to be adequate., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier Inc.)

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: The neutrophil-lymphocyte ratio (NLR) is a systemic reflection of cancer-associated inflammation and a prognostic marker for breast cancer. For the local tumour microenvironment, tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) are also highly correlated with breast cancer survival. This study aimed to explore the relationship between the circulating and local immune microenvironment, and to further delineate the prognostic role of NLR in breast cancer patients receiving neoadjuvant chemotherapy (NAC)., Methods: A cohort of breast cancer patients receiving NAC with subsequent surgery was retrieved. Clinical data were reviewed. Histological slides and CD8 immunohistochemistry from biopsy (pre-chemotherapy) and excision (postchemotherapy) specimens were assessed for TILs and TAMs., Results: A total of 146 patients were included. There was a significant positive correlation between pre- and postsurgery NLR at a cut-off of 2.6 (median pre-chemotherapy NLR) (P < 0.001). NLR pre-chemotherapy was associated positively with necrosis on biopsy (P = 0.027) and excision (P = 0.021) and TAMs on excision (P = 0.049). NLR 1 year postsurgery was associated with high tumour stage (P = 0.050) and low histological grade (P = 0.008). TIL count was lower in NLR-high cases at almost all time-points by histological assessment and CD8 immunostaining (P < 0.050). In multivariate analysis, postsurgery NLR is an independent predictor for overall survival [OS; hazard ratio (HR) = 9.524, P < 0.001], breast cancer-specific survival (BCSS) (HR = 10.059, P = 0.001) and disease-free survival (DFS; HR = 2.824, P = 0.016)., Conclusions: The association between NLR with tumour necrosis, TAMs and TILs illustrates an interaction between the circulating and local immune microenvironment. Late NLR is a strong indicator of outcome and may be useful for prognostication and disease monitoring., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Introduction: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [hereafter, SJS/TEN] are uncommon but severe mucocutaneous reactions. Although they have been described in many populations worldwide, data from Hong Kong are limited. Here, we explored the epidemiology, disease characteristics, aetiology, morbidity, and mortality of SJS/TEN in Hong Kong., Methods: This retrospective cohort study included all hospitalised patients who had been diagnosed with SJS/TEN in Prince of Wales Hospital from 1 January 2004 to 31 December 2020., Results: There were 125 cases of SJS/TEN during the 17-year study period. The annual incidence was 5.07 cases per million. The mean age at onset was 51.4 years. The mean maximal body surface area of epidermal detachment was 23%. Overall, patients in 32% of cases required burns unit or intensive care unit admission. Half of the cases involved concomitant sepsis, and 23.2% of cases resulted in multiorgan failure or disseminated intravascular coagulation. The mean length of stay was 23.9 days. The cause of SJS/TEN was attributed to a drug in 91.9% of cases, including 84.2% that involved anticonvulsants, allopurinol, antibiotics, or analgesics. In most cases, patients received treatment comprising either best supportive care alone (35.2%) or combined with intravenous immunoglobulin (43.2%). The in-hospital mortality rate was 21.6%. Major causes of death were multiorgan failure and/or fulminant sepsis (81.5%)., Conclusion: This study showed that SJS/TEN are uncommon in Hong Kong but can cause substantial morbidity and mortality. Early recognition, prompt withdrawal of offending agents, and multidisciplinary supportive management are essential for improving clinical outcomes., Competing Interests: All authors have disclosed no conflicts of interest.

Introduction: Compared with urothelial lesions of the upper urinary tract, the diagnostic performance of urine cytology in detection of renal cell carcinomas is underreported. This study aims to establish the role of urine cytology in the assessment of renal carcinomas by a multi-institute review of urine cytology from nephrectomy confirmed renal cell carcinomas, referenced against renal urothelial and squamous cell carcinomas., Methods: Records of nephrectomy performed from the 1990s to 2020s at three hospitals were retrieved and matched to urine cytology specimens collected within 1 year prior. Patient demographics, specimen descriptors, and histology and staging parameters were reviewed and compared against cytologic diagnoses., Results: There were 1147 cases of urine cytology matched with renal cell carcinomas, with 666 renal urothelial/squamous carcinomas for comparison. The detection rate for urothelial/squamous (atypia or above [C3+]: 63.1%; suspicious or above [C4+]: 24.0%) were higher than renal cell carcinoma (C3+: 13.1%; C4+: 1.5%) (p < 0.001). The positive rate for upper tract urine exceeded other collection methods at 45.0% (C3+) and 10.0% (C4+) (p < .01). Other factors associated with increased positive rates were male sex, collecting duct carcinoma histology, nuclear grade, and renal/sinus involvement (p < .05). Multivariate analysis revealed additional positive correlations with presence of sarcomatoid tumor cells, lymphovascular invasion, and perinephric fat involvement (p < .05). Larger lesion size and higher urine volume did not improve detection rates (p < .05)., Conclusions: The detection rate of renal cell carcinomas is suboptimal compared with urothelial carcinomas, although urine samples collected from cystoscopy or percutaneous nephrostomy significantly outperformed voided urine specimens., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Fine-needle aspiration cytology (FNAC) is a versatile diagnostic procedure uniquely suited for tissue biopsy of breast carcinomas and axillary metastases and/or recurrences. With the expanding treatment options and accompanying theragnostic tests, it is crucial to recognize the developments on ancillary testing and digital cytopathology techniques related to aspiration cytology of metastatic breast carcinoma. In this review, we aim to summarize and update the evidence of immunocytochemistry, for the detection of carcinoma cells (epithelial markers), confirmation of breast primary (breast-specific markers), assessment of surrogate immunostains (hormone receptors, ki-67 proliferative index and HER2) and theragnostic biomarkers, with discussion on potential diagnostic pitfalls, followed by the application of molecular tests, and digital cytopathologic techniques for assessing metastatic breast carcinoma in cytology., (© 2023 John Wiley & Sons Ltd.)

Introduction: Fine-needle aspiration biopsy (FNAB) of the breast is an effective and widely adopted diagnostic technique. Histopathologic grading of ductal carcinoma in situ (DCIS) has prognostic significance. In this current study, FNAB of DCIS was reviewed to identify parameters that predict grading, histopathologic architecture, and presence of invasion in DCIS., Methods: Aspirates from histopathology-proven cases of DCIS were retrieved and reviewed for cytomorphologic parameters including cellularity, composition, epithelial fragment architecture cellular/nuclear features., Results: In total 104 aspirates were reviewed. Cytopathologic cellular features - large nuclear size (p = 0.005), prominent nucleoli (p = 0.011), increased nuclear membrane irregularity (p = 0.043), high variation in nuclear size (p = 0.025), and presence of apoptotic figures in epithelial structures (p &lt; 0.001); and background debris (p = 0.033) correlated with a high-grade diagnosis. Cytoplasmic vacuolation (p = 0.034) was seen exclusively in non-high-grade aspirates. Epithelial fragment architecture did not correlate with grading. A predominance (≥50%) of solid aggregates and papillary fragments on FNAB correlated with histopathologically solid (p = 0.039, p = 0.005) and papillary (p = 0.029, &lt; p = 0.001) patterns. No parameter showed correlation with invasion., Conclusion: FNAB is effective in predicting DCIS grading. Epithelial fragment architecture assessment is limited to papillary or solid types, and FNAB cannot predict focal invasion in DCIS., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Specific diagnosis of endometrial carcinomas on cervical cytology is difficult with few useful cytomorphological clues reported. This study reviews a cohort of cervical cytology to investigate the presence of keratinization in atypical glandular cells (AGC), an undescribed cytomorphological clue for identifying endometrial endometrioid carcinomas on cervical cytology., Methods: Cervical cytology slides from patients with a histologic diagnosis of endometrial endometrioid carcinoma were reviewed for the presence of keratinization associated with AGCs. Corresponding histology slides were reviewed for tumour grading and degree of squamous differentiation., Results: In total, 42 cases of cervical cytology specimens from 41 patients were retrieved, including 7 (16.7%) with keratinization associated with AGCs seen and 35 (83.3%) without. Comparison of histologic grading did not demonstrate an association with the presence of keratinization on cytology (p = 0.565). Corresponding histology slides were available for 37 cases. Cytologic and histologic keratinization were associated statistically (p = 0.002). Frank keratinization was seen on histologic slides of five cases, with four also showing cytologic keratinization. Area of squamous differentiation, including squamous morule formation, did not correlate with keratinization on cytologic preparation (p = 0.185)., Conclusion: Histologic and cytologic keratinization are observed in endometrioid endometrial carcinomas. Such is reflected in cervical cytology by the presence of orangeophilic, rigid and acellular fragments within or associated with AGC clusters. Keratinization, when identified with AGCs, should be regarded as a cytologic clue suggestive of an endometroid carcinoma of endometrial origin., (© 2023 The Authors. Cytopathology published by John Wiley & Sons Ltd.)

DEK::AFF2 fusion-associated papillary squamous cell carcinoma is a novel entity characterized by its unique translocation and malignant clinical course. In this study, AFF immunohistochemistry (IHC) was performed in recurrent sinonasal papillomas for reviewing the prevalence of undiagnosed DEK::AFF2 carcinomas and to investigate the performance of AFF IHC in diagnosis of DEK::AFF2 carcinomas. Recurrent sinonasal papillomas after surgical excision in a two-decade period were retrieved. Histologic slides were reviewed for features of DEK::AFF2 carcinoma. AFF IHC was performed, and cases with any (> 1%) nuclear positivity were validated by DEK break apart fluorescence in situ hybridization. Totally 43 cases were included, comprising 28 inverted, 6 exophytic, one oncocytic, and 8 non-specified sinonasal papillomas. Five (11.6%) cases exhibited positivity to AFF IHC. Three cases exhibited patchy weak to moderate staining intensity predominantly in a granular cytoplasmic pattern. Two cases exhibited strong and diffuse (> 90%) nuclear staining. Cases showing weak staining were negative for DEK rearrangement, while those with strong staining were positive. Both cases of DEK::AFF2 carcinoma showed aggressive behavior with extensive local invasion and nodal metastasis. Background stromal plasma cells, when present, consistently showed strong and diffuse staining. AFF IHC was further performed in plasmacytoma samples as control and showed strong and diffuse immunoreactivity. A significant minority of recurrent sinonasal papillomas represent DEK::AFF2 carcinomas. Granular, cytoplasmic, or incomplete AFF staining should be considered as negative. In view of the rarity of DEK::AFF2 carcinomas, plasma cells and plasma cell neoplasms are potential for internal and surrogate external controls., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Bronchoscopy is a useful diagnostic tool capable of performing core biopsy, forceps biopsy, bronchoalveolar lavage, and bronchial brushing. This study compares the cellularity of bronchial cytology including pre- and post-biopsy lavage by digital image analysis, aiming to increase diagnostic and tumor yield by optimizing the sequence and combination of bronchial biopsy and cytology., Methods: Alveolar macrophage, bronchial epithelium, and tumor cell cellularity from liquid-based cytology preparations of bronchial brushing and pre-biopsy and post-biopsy bronchoalveolar lavage were annotated on digitized whole-slide images and compared. Secondary analysis on the relationship of tumor cell and non-lesional cell yield was performed., Results: Overall, 118 cytology specimens from 43 patients were retrieved in total. Bronchial epithelium count was higher in pre-biopsy than post-biopsy lavage (p &lt; 0.01) but not for alveolar macrophages nor tumor cell (p &gt; 0.05). Tumor cell count was higher for bronchial brushing cytology samples than lavage (p = 0.018). The alveolar macrophage count was higher in post-biopsy lavage than bronchial brushing (p = 0.033); otherwise, brushing showed consistently higher bronchial epithelium and tumor cell counts. There were 33 false negative (tumor cell absent) specimens, and the combination of bronchial brushing and pre-biopsy lavage yielded the lowest false negative cases. Correlation between bronchial epithelium and alveolar macrophage counts with tumor cell count was weak (correlation coefficient = -0.168-0.203) except for post-biopsy lavage (correlation coefficient = 0.412-0.479, p &lt; 0.05)., Conclusion: Bronchial brushing yields a greater amount of tumor cell than lavage, and timing lavage before or after core biopsy does not affect tumor cell yield. Combining bronchial brushing and pre-biopsy lavage results in the lowest false negative rate., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Cystic changes, calcification, colloid material, and multinucleated giant cells are frequently associated with primary and metastatic papillary thyroid carcinoma (PTC). These features are sometimes present in negative lymph node fine-needle aspiration cytology (FNAC). This study aims to review nodal aspirates of PTC to elucidate the significance of these cytological features in aspirates without tumor cells., Methods: FNAC specimens from patients with PTC confirmed on thyroidectomy were reviewed for cystic changes, tumor-associated features, and lymphoid components. Histologic follow-up of the lymph nodes were retrieved for correlation., Results: A total of 113 aspirates were retrieved, of which 79 showed tumor cells on the FNAC specimen, and 95 were matched to a positive lymph node histology. At univariable analysis, calcification (n = 18/113, p = .044), colloid material (n = 40/113, p = .001), multinucleated giant cells (n = 29/113, p = .028), tumor cells (n = 79/133, p < .001), foamy histiocytes (n = 36/113, p = .002) and pigmented histiocytes (n = 62/113, p < .001) were associated with a positive histology. Presence of lymphoid fragments (n = 11/113, p < .001) and abundant background lymphocytes correlated with a negative histologic follow-up (n = 45/113, p = .005). In aspirates without tumor cells, multivariable analysis demonstrated colloid material (p < .001) and pigmented histiocytes (p = .003) to be independently predictive of metastatic PTC, whereas lymphoid fragments (p < .001) were independently associated with a negative histologic follow up., Conclusion: Colloid material and pigmented histiocytes, and to lesser degree calcification and multinucleated giant cells, when seen in an aspirate without tumor cells, raises suspicion metastatic disease. On the contrary, the lymphoid fragments can be regarded as supportive evidence of adequate sampling and a true negative result., (© 2023 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Background: The lung is an extensively epithelialized organ, producing ample exfoliated material for sputum and bronchial cytology. In view of the updates in the World Health Organization classification of early (T1/≤ 3 cm) lung cancer with respect to adenocarcinomas with lepidic pattern, this study retrospectively reviews sputum and bronchial cytology paired with resection-confirmed lung cancers., Methods: A computerized search for all lung resection specimens of carcinomas over a 20-year period was performed. Cytologic diagnoses of corresponding sputum and bronchial cytology were classified into five-tiered categories (C1-insufficient/inadequate, C2-benign, C3-atypia, C4-suspicious and C5-malignant). Reports and slides of the resection specimen were reviewed for reclassification of T1 cancers., Results: Totally 472 and 383 sputum and bronchial cytology specimens respectively were included. Sensitivity for T1 lesions on sputum cytology were 10.6 %, 2.1 % and 0.5 % at cutoffs of atypia/C3, suspicious/C4 and malignant/C5 categories, lower than bronchial cytology (35.1 %, 15.5 %, 8.1 %; p < 0.001). T1 lesions correlated with lower detection rates, whereas squamous cell carcinoma histology, larger size and bronchial invasion were associated with increased detection rates in sputum and bronchial cytology (p < 0.050). Detection rates for abrasive bronchial cytology (brushing) were overall higher (p = 0.018- < 0.001), but on subgroup comparison, non-abrasive (aspiration, lavage and washing) cytology demonstrated favorable trends (p = 0.063-0.088) in detecting T1 lesions. Adenocarcinomas with lepidic pattern had lower suspicious/C4 (p = 0.040) or above and malignant/C5 (p = 0.019), but not atypia/C3 or above (p = 0.517) rates., Conclusions: Most adenocarcinomas with lepidic pattern are only diagnosed as atypia/C3 on cytology. With its modest sensitivity, interpretation of negative and indeterminate cytology results mandates caution., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023. Published by Elsevier Inc.)

DEK::AFF2 fusion-associated papillary squamous cell carcinoma is a recently characterized sinonasal malignancy defined by its unique translocation. DEK::AFF2 carcinomas may be deceptively monotonous and lack keratinization, resembling transitional epithelium. The lack of traditional cytological atypia presents diagnostic challenges. Our case describes the first report of fine-needle aspiration cytology of a lymph node involved by DEK::AFF2 carcinoma in a patient with previously resected sinonasal inverted papilloma with carcinomatous transformation six years prior to presentation. This aspirate consisted of a lymphoid-rich background admixed with a moderate amount of epithelial cells arranged in cohesive structures of variable size, including large sheets. The tumor cells resembled those of the corresponding biopsy, featuring mildly hyperchromatic nuclei with fine to vesicular chromatin. Lesional cells lacked keratinization, mitoses, or hyperchromasia. Our finding suggests that in nodal aspirates of patients with a history of sinonasal-type papillomas, especially those with prior malignant transformation or atypia, there should be consideration for the possibility of DEK::AFF2-related primary. When in doubt, DEK FISH of AFF2 immunohistochemistry should be performed for confirmation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis is characterized by serological detection of anti-MDA5 antibody and rapidly progressive interstitial lung disease. In this study, the largest cohort of skin biopsies to date of anti-MDA5 dermatomyositis was reviewed and compared with cases of dermatomyositis with negative serology. Findings contribute to the histological diagnosis and evaluation of the severity of cutaneous inflammation in anti-MDA5 dermatomyositis. Skin biopsies collected over a 7-year period from individuals with clinically and histologically confirmed dermatomyositis with anti-MDA5 serology were reviewed. A total of 46 cases with 17 anti-MDA5 positive cases were retrieved. Patients with positive antibody were younger (53.7 vs. 60.6 years, p = .013). No differences in epidermal changes (p > .05) were observed. Pertaining to interface changes, anti-MDA5 dermatomyositis showed a higher degree of pigmentary incontinence (p = .014), suggesting increased and sustained cutaneous inflammation. Periodic acid-Schiff (PAS) stain demonstrated a greater degree of basement membrane thickening (p = .045). Other parameters, including dermal inflammation, dermal mucin deposition and vasculitic/vasculopathic features did not show statistical difference between anti-MDA5 positive and negative dermatomyositis (p > .05). Findings suggest increased cutaneous inflammation for anti-MDA5 dermatomyositis. In skin biopsies, marked pigmentary incontinence or basement membrane thickening should raise suspicion of anti-MDA5 dermatomyositis., (© 2023 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Endometrial lesions are morphologically diverse and uncommon on cervical smears, with its detection rate and associated diagnostic categories uncharacterized. In this study, cervical smears matched to histologically proven endometrial hyperplasias and carcinomas were reviewed and compared with cervical in-situ-carcinomas/carcinomas, aiming to detail the diagnostic performance of cervical smears for upper tract and glandular lesions., Methods: Pathology reports of cervical smears, hysterectomies, endometrial and cervical biopsies from 1995 to 2021 were retrieved. Diagnoses of cervical smears were matched to endometrial hyperplasias and carcinomas, or cervical carcinomas and reviewed., Results: Totally 832 cervical smears (272 cervical carcinomas, 312 endometrial carcinomas, and 248 hyperplasias) were included. Considering all cytologic glandular diagnosis as positive, the detection rate of cervical adenocarcinoma-in-situ was the highest (64.3%), followed by cervical adenocarcinoma (63.8%), endometrial carcinoma (31.7%), and hyperplasia (with atypia-8.5%; without atypia-2.3%) (p < 0.001). Endometrial hyperplasia was most often diagnosed as atypical squamous cells of undetermined significance (ASCUS) (5.0%) or atypical glandular cells, not otherwise specified (3.6%) without indication of endometrial origin. For endometrial carcinomas, higher FIGO grading and endocervical involvement were associated with higher detection rates across all diagnostic categories (p = 0.002-0.028). High FIGO grade was associated with suspicious/favor neoplastic (C4) (31.1%vs10.3%, p < 0.001) and carcinoma (C5) (17.8% vs. 5.6%, p = 0.005) categories, but not for all glandular diagnoses combined (33.3% vs. 31.0%, p = 0.761)., Conclusion: Detection rates for endometrial lesions are lower than cervical lesions but not insignificant. Endometrial hyperplasia should be recognized as a differential of human papilloma virus-negative ASCUS and prompt consideration of investigation of the upper genital tract., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pulmonary adenoid cystic carcinoma (AdCC) is a central and superficial primary lung neoplasm, well-suited for sampling by bronchial cytology. This study aims to review the cytologic features of pulmonary AdCC on bronchial cytology, and to report an experience of applying immunocytochemistry on this rare entity., Methods: A multi-institute review of bronchial cytology specimens from histologically proven pulmonary AdCCs was performed. Published cases of bronchial cytology of pulmonary AdCC were reviewed. The cytologic features and immunocytochemical profile for pulmonary AdCC was summarized and compared with pertinent differentials., Results: A total of 16 specimens from eight patients were retrieved. The initial cytologic diagnoses were negative (n = 7), atypia (n = 6), suspicious (n = 2) and AdCC (n = 1). Retrospective review showed eight bronchial cytology specimens (including five cases of atypia) with tumor cells present. The tumor cells displayed small basaloid nuclei with occasional small nucleoli, mild nuclear atypia, and scanty cytoplasm. Architectural patterns observed included clusters, tubules, solid sheets, three-dimensional balls, papillary-like fronds, and complex cribriform structures. Basement-membrane-like material, free or associated with tumor cells, were seen in all cases. Immunocytochemistry was performed in one specimen. MYB was positive. TTF-1, synaptophysin and chromogranin were negative. Epithelial and basal markers demonstrated a dual cell population. Literature review yielded 28 cases. Cytologic features described were similar except for cytoplasmic vacuolation in one case., Conclusion: Basement membrane-like material is specific for AdCC. MYB positivity, TTF-1 and neuroendocrine marker negativity, support a diagnosis of AdCC. Other immunocytochemistry and cytologic features overlap significantly with adenocarcinoma and small cell carcinoma of lung., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

WT1 immunostain is expressed in various benign and malignant neoplasms, as well as normal myoepithelial cells. WT1 shows differential expression in non-neoplastic, benign, and malignant neoplastic myoepithelial cells of the salivary gland. In this study, WT1 immunostain and other myoepithelial markers were compared to investigate the value of WT1 as a myoepithelial marker, and to delineate the expression profile of WT1 in nonsalivary gland myoepithelial cells. WT1, p63, and calponin immunostains were performed on normal and lesional tissues from the breast (adenosis, sclerosing adenosis, lactating adenoma, nipple adenoma, tubular adenoma, adenomyoepithelioma, and adenoid cystic carcinoma [ACC]), skin (cutaneous mixed tumor, hidradenoma, spiradenoma, and ACC), and salivary gland (pleomorphic adenoma and ACC). The stained slides were digitized and orientated with H&E images and assessed simultaneously using QuPath. A total of 129, 58, and 56 breast, cutaneous, and salivary gland lesions, respectively, were included. There was poor agreement between WT1-p63 and WT1-calponin (κ < 0.1) in all organs, with absence of WT1 expression in normal salivary gland myoepithelium and most ACCs. There were no significant differences in WT1 expression in myoepithelial cells in normal breast tissue and benign breast neoplasms. Compared to pleomorphic adenomas, cutaneous mixed tumors showed lower WT1 expression (P < .001). WT1 is a less sensitive myoepithelial marker than calponin and p63. However, its unique pattern of expression in salivary gland primary for pleomorphic adenomas/cutaneous mixed tumor can favor a diagnosis of benign salivary gland tumors, particularly in small biopsy specimens., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The relocation and reconstruction of health care resources and systems during the coronavirus disease 2019 (COVID-19) pandemic may have affected cancer care. An umbrella review was undertaken to summarize the findings from systematic reviews on impact of the COVID-19 pandemic on cancer treatment modification, delays, and cancellations; delays or cancellations in screening and diagnosis; psychosocial well-being, financial distress, and use of telemedicine as well as on other aspects of cancer care. Bibliographic databases were searched for relevant systematic reviews with or without meta-analysis published before November 29th, 2022. Abstract, full- text screening, and data extraction were performed by two independent reviewers. AMSTAR-2 was used for critical appraisal of included systematic reviews. Fifty-one systematic reviews were included in our analysis. Most reviews were based on observational studies judged to be at medium and high risk of bias. Only two reviews had high or moderate scores based on AMSTAR-2. Findings suggest treatment modifications in cancer care during the pandemic versus the pre-pandemic period were based on low level of evidence. Different degrees of delays and cancellations in cancer treatment, screening, and diagnosis were observed, with low- and- middle- income countries and countries that implemented lockdowns being disproportionally affected. A shift from in-person appointments to telemedicine use was observed, but utility of telemedicine, challenges in implementation and cost-effectiveness in cancer care were little explored. Evidence was consistent in suggesting psychosocial well-being of patients with cancer deteriorated, and cancer patients experienced financial distress, albeit results were in general not compared to pre-pandemic levels. Impact of cancer care disruption during the pandemic on cancer prognosis was little explored. In conclusion, substantial but heterogenous impact of COVID-19 pandemic on cancer care has been observed., Competing Interests: TM, JL, SF, JI No competing interests declared, (© 2023, Muka et al.)

Idiopathic granulomatous mastitis (IGM) is a benign mimic of breast carcinomas. It is defined histologically by the presence of granulomas and inflammation. The closely related cystic neutrophilic granulomatous mastitis (CNGM) shows lipogranulomas, with a reported association with corynebacteria. A large cohort of IGM was reviewed to compare clinical, microbiological and histological features between non-CNGM IGM and CNGM. Cases of IGM were reviewed for histological parameters including the presence of lipogranulomas and composition of inflammatory cells. Clinical data were obtained through hospital records. The cohort included 79 cases, including 51 non-CNGM IGM and 28 CNGM. Comparing non-CNGM IGM and CNGM, there were no differences in clinical or demographical data, other than a younger age of presentation (36.2 vs 41.5 years, p=0.012) for CNGM. Most IGM resolved within the follow-up period (n=57/64, 89.1%), with similar outcomes regardless of treatment (p>0.05). In CNGM, there were more infiltrates of neutrophils (p=0.001), histiocytes (p=0.047), and multinucleated giant cells (p=0.006), but less lymphocytes (p=0.008). Corynebacteria was cultured in two (25%) cases of CNGM, and one non-CNGM IGM (14.3%). Gram-positive bacilli were identified in two cases of CNGM. 'Early' lipogranulomas were observed closely associated to inflamed ducts in three cases of CNGM. Apart from age, there was no distinct clinical or microbiological feature for CNGM. These findings do not support CNGM as a distinct entity. Rather, CNGM-pattern may represent a continuum of IGM, possibly age-related and attributable to ductal inflammation and cystic changes in the breast parenchyma., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Introduction: Worldwide, >130 babies have been born from ovarian tissue cryopreservation (OTC) and ovarian tissue transplantation (OTT). Ovarian tissue cryopreservation can improve quality of life among young female cancer survivors. Here, we assessed the feasibility of OTC and subsequent OTT in Hong Kong via xenografts in nude mice., Methods: This pilot study was conducted in a university-affiliated tertiary hospital. Fifty-two ovarian tissues were collected from 12 patients aged 29 to 41 years during ovarian surgery, then engrafted into 34 nude mice. The efficacies of slow freezing and vitrification were directly compared. In Phase I, non-ovariectomised nude mice underwent ovarian tissue engraftment. In Phase II, ovariectomised nude mice underwent ovarian tissue engraftment, followed by gonadotrophin administration to promote folliculogenesis. Ovarian tissue viability was assessed by gross anatomical, histological, and immunohistochemical examinations before and after OTC. Follicular density and morphological integrity were also assessed., Results: After OTC and OTT, grafted ovarian tissues remained viable in nude mice. Primordial follicles were observed in thawed and grafted ovarian tissues, indicating that the cryopreservation and transplantation protocols were both effective. The results were unaffected by gonadotrophin stimulation., Conclusion: This study demonstrated the feasibility of OTC in Hong Kong as well as primordial follicle viability after OTC and OTT in nude mice. Ovarian tissue cryopreservation is ideal for patients who cannot undergo the ovarian stimulation necessary for oocyte or embryo freezing as well as prepubertal girls (all ineligible for oocyte freezing). Our findings support the clinical implementation of OTC and subsequent OTT in Hong Kong., Competing Interests: As an editor of the journal, JPW Chung was not involved in the peer review process of the article. All other authors have no conflicts of interest to disclose.

Background: Pleural effusion can be caused by a wide range of benign and malignant conditions. Pleural biopsy and effusion cytology represent two key methods of pathological diagnosis. To compare the performance these two methods, a large cohort of matched pleural biopsy and effusion cytology with clinical follow-up was reviewed., Methods: Pleural biopsies and effusion cytology specimens over a period of 18 years were retrieved. Cytology specimens collected within 7 days of pleural biopsy were matched. Reports were reviewed, and the cause for pleural effusion was determined by hospital disease coding and clinical data., Results: Totally, 3026 cases were included. The leading cause of benign effusion was tuberculosis (n = 650). Malignant pleural effusion (MPE) was more common in older females (p < 0.001) and mostly due to lung cancer (n = 959), breast cancer (n = 64), and mesothelioma (n = 48). The inadequate/insufficient (B1/C1) rate of biopsy was higher than cytology (15.6% vs. 0.3%) but the rates for other diagnostic categories were similar. Biopsy and cytology showed a correlation coefficient of 0.315, improving to 0.449 when inadequate/insufficient (B1/C1) cases were excluded. The ROM for benign cytology (C2) was lower than biopsy (B2) (p < 0.001). Compared with biopsy, the diagnostic accuracy was higher in cytology overall and for metastatic carcinomas (p < 0.001) but lower for hematolymphoid malignancies (p = 0.014) and mesotheliomas (p = 0.002)., Conclusions: These results suggest that effusion cytology may be better for confirming benignity and diagnosing carcinomatous MPE. In these cases, pleural biopsy may be withheld to reduce procedural risks. However, for suspected hematolymphoid malignancies and mesothelioma, biopsy should be considered., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Evaluation of oestrogen receptor (ER) expression by immunostaining is essential in the pathological assessment of breast cancer. Its expression is intercorrelated with clinicopathological features, molecular typing, and treatment selection. The development of novel therapeutic agents related to ER status, the recent ASCO introduction of an ER-low positive category of breast cancers, and the ever-increasing plethora of diagnostic and theragnostic markers call for a timely update. In this article we aim to review the clinicopathological features of ER-positive breast cancers, with an emphasis on ER-low positive breast cancers, and a focus on updating the (i) assessment, reporting and interpretation of ER immunohistochemical (IHC) staining, (ii) correlations of ER status with other diagnostic and theragnostic markers, and (iii) implications for treatment selection and response. In the face of the developments in IHC and molecular techniques and targeted therapy, ER immunostaining is still expected to remain as the core component of prognostic and theragnostic assessment of breast cancers., (© 2022 John Wiley & Sons Ltd.)

Introduction: Volume recommendations of 80-200 mL have been proposed for peritoneal fluid cytology. While cutoffs are impractical when volume is limited by the amount present and disease factors, collections, however, can be repeated. This study addresses adequacy and number needed to diagnose by comparing diagnostic agreement to volumes in single specimens, total volumes collected daily, and within admissions. The diagnostic yield of repeating collection within a single day, admission, and throughout admissions of a patient's lifetime was also investigated., Methods: Peritoneal fluid cytology specimens over a 27-year period were retrieved and matched by collection date, admission number, and patient number. Case notes were reviewed to establish all cases of malignant ascites., Results: In total, 19,392 specimens from 14,327 admissions and 11,089 patients were retrieved, with 1,531 patients confirmed with malignant ascites. Agreements between cytologic diagnoses within the same day and admission were high (κ &gt; 0.8). Fluid volume increased with grade of cytologic diagnosis (p &lt; 0.001), and greater volume was associated with higher discordance (p &lt; 0.05). Specimens of 60-100 mL showed the best diagnostic concordance. To achieve a 99.5% diagnostic rate, three sequential aliquots, collections from two different days in an admission, or three admissions within a lifetime are required. The diagnostic yield of one aliquot within batches from the same day was only 88.9%. Gastrointestinal (p = 0.040), gynecologic (p = 0.005), and lung (p &lt; 0.001) malignancies required the least repeats for diagnosis., Conclusions: Omission of any fluid from laboratory submission is strongly discouraged. As a simple rule, three repeats are necessary for excluding malignant ascites., (© 2023 S. Karger AG, Basel.)

Introduction: Increasing molecular evidence indicates that tubular adenoma of the breast is distinct from fibroepithelial lesions, leading to its reclassification as an epithelial tumor in the 5th World Health Organization classification of tumors of the breast. However, tubular adenoma remains poorly characterized on fine-needle aspiration cytology (FNAC) and often not distinguished from fibroadenomas. In this study, the largest cohort, to date, of histologically confirmed aspirates of tubular adenomas were reviewed and compared with aspirates of fibroadenomas. Findings from this study further define the cytological features of tubular adenoma and allow differentiation from fibroadenoma., Methodology: Aspirates of histologically confirmed tubular adenomas were reviewed for features of the background, myoepithelial, epithelial, and stromal components and then compared to a cohort of aspirates of fibroadenomas., Results: Totally, 43 (tubular adenoma) and 94 (fibroadenoma) aspirates were included. Tubular adenomas displayed moderate epithelial cellularity with high cohesiveness, with stromal fragments containing epithelium. Tubules are more common in tubular adenomas (p = 0.009) and "tubular fragments" (tissue fragments containing multiple tubular structures with/without stroma) is a pathognomonic feature of tubular adenoma (p < 0.001). Calcification and fibrocystic changes were variably seen (4.65-13.5%) but without difference to fibroadenomas (p > 0.05). Cytomorphologically malignant features and mitoses were absent in all aspirates of tubular adenoma. Presence of tubules and stromal fragments were independent factors associated with tubular adenomas, whereas a predominance of large epithelial fragments and naked stromal fragments were associated with fibroadenomas., Conclusion: Tubular adenomas are not only histologically and molecularly separate from fibroepithelial lesions but also a distinct entity on FNAC., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Papillary thyroid carcinoma (PTC) is the most common primary malignant thyroid neoplasm and malignant diagnosis in thyroid aspirates. Metastatic adenocarcinoma of the lung is an under-recognised mimicker which overlaps cytomorphologically and immunocytochemically with PTC. This case series reviews thyroid aspirates of metastatic lung carcinomas, aiming to address the similarities and methods of differentiating this entity from PTC., Methods: Thyroid aspirates of metastatic lung carcinomas were obtained by a computerised search. Clinico-cytological features and ancillary test results were reviewed. A literature review was performed for published cases of metastatic lung carcinomas in thyroid aspirates., Results: A total of 14 cases were found, including nine adenocarcinomas, three TTF1-positive non-small cell lung carcinomas (NSCLCs), one small cell carcinoma and one squamous cell carcinoma. The adenocarcinomas and TTF1-positive NSCLCs displayed PTC-like features including papillae/papillary-like fronds (n = 6/12, 50%), nuclear grooves (n = 5/12, 41.7%) and inclusions (n = 1/12, 8.3%), chromatin clearing (n = 3/12, 25%), calcifications (n = 3/12, 25%) and multinucleated giant cells (n = 2/12, 16.7%). Useful distinguishing features observed were prominent nucleoli, coarse chromatin, mitosis, and necrosis. TTF-1 immunocytochemistry was positive in most cases (n = 5/6, 83.3%), while PAX8 and thyroglobulin were consistently negative. EGFR exon 19 deletion was detected on cell block preparation in a single case, corresponding to its lung primary. The literature search yielded 84 cases of metastatic malignancies, with lung carcinomas comprising of 3.6%-33.3% in case series of metastatic malignancies., Conclusion: Metastatic adenocarcinoma of lung and PTC share significant cytomorphological and immunocytochemical similarities. A high degree of caution, meticulous clinico-cytological assessment and prudent use of ancillary techniques is necessary to avoid potential misdiagnosis., (© 2022 John Wiley & Sons Ltd.)

The use of immunostain for PRAME antigen is well established for cutaneous melanolocytic lesions. However, its staining in other cutaneous structures and lesions is under reported. This study assessed PRAME staining in a large cohort of normal skin tissue, sebaceous lesions, and cutaneous carcinomas to better delineate patterns of PRAME immunoreactivity. PRAME immunostaining was performed on sections of sebaceous lesions and tissue microarrays of basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). Normal cutaneous adnexal structures were assessed on the sections of sebaceous lesions. For sebaceous lesions and non-lesional sebaceous glands, PRAME immunostaining was assessed for mature, germinative and sebocytes independently. A total of 193 sebaceous lesions, 64 BCCs and 35 SCCs were stained for PRAME immunostain. Staining pattern was predominantly cytoplasmic in normal apocrine glands, germinative sebocytes of sebaceous glands, and hair germs (p<0.001). Lesional sebocytes did not show different staining compared to normal sebaceous glands (p>0.05). Rare nuclear staining was observed in the normal epidermis (0.6%) and junctional melanocytes (4.1%). BCC, SCC and sebaceous carcinoma all showed low levels of PRAME immunoreactivity with variable proportions of cases demonstrating nuclear staining (BCC 59.4%, SCC 37.1%, sebaceous carcinoma 5.3%). PRAME immunostaining is positive in germinative sebocytes, various cutaneous structures and carcinomas. Nuclear staining, identical to melanoma, was observed in normal epidermis, junctional melanocytes, BCCs, SCCs, and sebaceous carcinomas. The pattern of PRAME staining in the skin must be recognised to avoid pitfalls in interpretating PRAME immunostain., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

SMARCB1 (INI1)-deficient carcinoma of the sinonasal tract is a rare and distinct entity characterized by the loss of INI1 immunostain expression. These tumors are morphologically diverse, with isolated cases of yolk sac differentiation reported. We report the first case of SMARCB1-deficient sinonasal carcinoma that demonstrated co-loss of SMARCA4 immunostain, and reduced SMARCA2 and ARID1A staining, with the entire tumor showing histological and immunohistochemical evidence of yolk sac differentiation. The clinical, histological, immunohistochemical and molecular features were discussed and compared against SMARCB1-deficient sinonasal carcinomas with yolk sac differentiation and SMARCA4-deficeint sinonasal carcinomas reported in the literature. With a highly aggressive clinical course leading to mortality two months after presentation, the behavior of this tumor appears to be more comparable to that of SMARCA4-deficient sinonasal carcinomas. A comprehensive immunopanel including SMARCB1, SMARCA4, SMARCA2 and ARID1A may be advisable for assessment and prognostication of SWI/SNF-deficient tumors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The prognosis of endometrial cancers has historically been determined by the evaluation of histologic typing, grading, and staging. Recently, molecular classification, pioneered by the 4 prognostic categories from The Cancer Genome Atlas Research Network, has been shown to independently predict the outcome, correlate with biomarker expression, and predict response to adjuvant chemotherapy. In modern-day pathology practice, it has become necessary to integrate the time-honored prognostic pathologic features with molecular classification to optimize patient management. In this review, the significance of the molecular classification of endometrioid carcinomas, the application of practical diagnostic surrogate algorithms, and interpretation of test results will be addressed. Histologic features and theragnostic biomarkers will also be discussed in relation to the molecular subtypes of endometrial cancers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Fine-needle aspiration (FNA) is a robust diagnostic technique often used for tissue diagnosis of metastatic carcinoma. For interpretation of FNA cytology, cell block immunohistochemistry (IHC) and clinicocytologic parameters are indispensable. In this review of a large cohort, the current report: 1) describes clinicocytologic parameters and immunoprofiles of aspirates of metastatic carcinoma, 2) compares the predictivity of immunostains and classical approaches for IHC interpretation, and 3) describes machine learning-based algorithms for IHC interpretation., Methods: Aspirates of metastatic carcinoma that had IHC performed were retrieved. Clinicocytologic parameters, IHC results, the corresponding primary site, and histologic diagnoses were recorded. By using machine learning, decision trees for predicting the primary site were generated, their performance was compared with 2 human-designed algorithms, and the primary site was suggested in the historical diagnosis., Results: In total, 1145 cases were identified. The 6 most populated groups were selected for machine learning and predictive analysis. With IHC input, the decision tree achieved a concordance rate of 94.5% and overall accuracy of 83.6%, which improved to 95.3% and 85.8%, respectively, when clinical data were incorporated and exceeded the human-designed IHC algorithms (P < .001). The historical diagnosis was more accurate unless indeterminate diagnoses were regarded as discordant (P < .001). CDX2 and TTF-1 immunostains had the highest weight in model accuracy, occupied the root of the decision trees, scored higher as features of importance, and outperformed the predictive power of cytokeratins 7 and 20., Conclusions: Cytokeratins 7 and 20 may be superseded in immunostaining panels, including organ-specific immunostains such as CDX2 and TTF-1. Machine learning generates algorithms that surpasses human-designed algorithms but is inferior to expert assessment integrating clinical and cytologic assessment., (© 2022 American Cancer Society.)

Background: Papillary structures are frequently encountered in metastatic carcinomas from various organs and tumours of different histotypes. This study aims to investigate the predictive value of fine needle aspiration cytology (FNAC), immunohistochemistry (IHC) and the clinical parameters which can be examined in the assessment of the primary sites of metastatic carcinomas with papillary architecture., Methods: FNAC samples of metastatic carcinomas with papillary architecture were evaluated for overall cellularity, epithelial cohesion, background features, papillary architecture, cytology and IHC. The corresponding clinical information was also reviewed., Results: A total of 130 cases were included. The most common primary sites were thyroid (38.5%), lung (30.8%) and gynecological organs (22.3%); the others were pancreaticobiliary, urothelial, colorectal, and esophageal. Age (P = 0.039), biopsy site (P < 0.001) and laterality (P = 0.006) correlated with primary site. Papillary structures were confirmed on biopsy/excision of most cases (n = 85/87, 97.7%). Thyroid primaries exhibited broad papillary stalks, thin lining epithelium, fewer epithelial polymorphs, and the presence of background giant cells and histiocytes (P = 0.021- < 0.001). Low-grade cytological features, nuclear grooves and inclusions (P < 0.001) were seen in thyroid primaries. High-grade features (P < 0.001-0.49), multinucleated tumour cells, apoptotic bodies and mitoses (P < 0.001-0.49) were more common in lung/gynecological primaries. Multivariate analysis identified nuclear/cytoplasmic ratio, chromatin character, the presence of nuclear grooves and mitosis as independent features (P = 0.001-0.024). TTF1/TGB/PAX8 panel results showed good agreement with the cytological assessment and site of primary., Conclusion: Papillary structures and cytological features are reproducible in FNAC assessment of metastases and their corresponding primary sites. Cytological features, IHC and clinical information are invaluable in determining the primary site., (© 2022 John Wiley & Sons Ltd.)

Objective: Squamous metaplasia is not uncommonly observed in salivary gland neoplasms, including pleomorphic adenomas (PAs). It poses as a diagnostic pitfall with cytomorphologic features overlapping with low-grade epithelial malignances and carcinoma ex-PA. We report series of aspirates of PAs with squamous metaplasia and review the literature for the clinicopathological and cytologic features of this diagnostically challenging entity., Methods: Three cases including index aspiration cytology, post-aspiration specimen cytology, cell block immunohistochemistry (IHC), histologic correlation, and clinical data were reviewed. Literature search was performed for cases of PAs with squamous metaplasia, yielding 22 case reports including 11 with aspiration cytology performed., Results: Metaplastic squamous components were seen in all index aspirations, but foreign body reaction and cystic changes were observed only after aspiration or in irritated lesions. PLAG1 IHC demonstrated reliable immunoreactivity in cell block preparations. Summarizing cases in this series and in the literature, cytologic features reported were variable and no consistent diagnostic feature was identified. Most reported cases were initially diagnosed as suspicious or malignant, but all ran a benign clinical course. Significant morbidity was reported only in one case due extensive surgery based on a malignant diagnosis., Conclusions: Squamous metaplasia in PAs is not associated with adverse outcomes, but may induce reactive changes upon aspiration/irritation, resulting in worrisome cytologic features. PLAG1 IHC is a useful adjunct when characteristic cytologic features for PAs are absent or obscured. Prudent use of the diagnostic category salivary gland neoplasm of uncertain malignant potential (SUMP) in the Milan system can avoid overtreatment., (© 2021 Wiley Periodicals LLC.)