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Background: The third edition of The Bethesda System (TBS) subclassifies the atypia of undetermined significance (AUS) category on the basis of the presence of nuclear atypia (AUS‐Nuclear). This approach is supported by studies showing significant differences in the risk of malignancy (ROM) between AUS‐Nuclear and those without (AUS‐Other). Although aspirates of follicular neoplasms (FNs) are characterized by marked architectural atypia, TBS recognizes the infrequent occurrence of FNs with mild nuclear atypia (FN‐Nuclear). Furthermore, limited studies have shown significant differences in ROM between FN‐Nuclear and those without (FN‐Other). This study explored potential differences in ROM, molecular‐derived risk of malignancy (MDROM), and molecular alterations between FN‐Nuclear and FN‐Other. Methods: A retrospective database search identified 93 FN aspirates. Cytology slides, molecular reports, and histologic follow‐ups were reviewed. Both groups' benign call rate (BCR), positive call rate (PCR), MDROM, and ROM were computed and compared. Results: Eighty‐six percent of aspirates (80 of 93) comprised FN‐Other, whereas 14% (13 of 93) were FN‐Nuclear. The BCR and PCR for FN‐Other were 51% and 49%, respectively. In contrast, they were 23% and 77% for FN‐Nuclear, respectively. The MDROM significantly differed between FN‐Other (30%) and FN‐Nuclear (56%) (p <.05). HRAS mutation was the most common molecular alteration in FN‐Nuclear, whereas mutations in NRAS/KRAS and copy number alterations were more common in FN‐Other. The ROM1/ROM2 in FN‐Other and FN‐Nuclear were 16%/31% and 54%/88%, respectively. Conclusions: These results reveal that FN‐Nuclear exhibits significantly higher MDROM and ROM than FN‐Other, which provides support for a subclassification scheme for FNs based on the presence of nuclear atypia. Follicular neoplasm with nuclear atypia exhibits significantly higher risk of malignancy and molecular‐derived risk of malignancy than follicular neoplasm without nuclear atypia, which supports a subclassification scheme based on the presence of nuclear atypia, similar to the approach recommended for the atypia of undetermined significance category. [ABSTRACT FROM AUTHOR]

Background and Objectives: Urine serves as a vital diagnostic fluid, and urine cytology analysis plays a crucial role in identifying urinary system illnesses such as bladder cancer and kidney stones. The Paris System for Reporting Urinary Cytology establishes a uniform method for diagnosing urinary tract cancer. This study aimed to provide valuable insights that can inform diagnostic strategies related to kidney stones and ultimately improve patient outcomes via the early detection of the cellular changes associated with kidney stones and their relation to kidney function tests. Materials and Methods: A comparative study was conducted and comprised two groups: group 1, consisting of 50 patients diagnosed with kidney stones, and group 2, comprising 50 patients diagnosed with other kidney diseases. Renal function tests and urinalysis (via the PAP staining of urine cellular deposits to detect nuclear changes) were performed, and the results were analyzed. Results: There was a statistically significant increase in urinary red blood cells, white blood cells, and nuclear reactive atypical changes in urinary sediments of kidney stone patients compared to the patients without stones, while there was a decrease in the estimated glomerular filtration rate (eGFR). eGFR showed a 96.7% specificity in detecting cases with nuclear reactive atypia. Conclusions: eGFR emerges as a reliable diagnostic marker for the comprehensive assessment of kidney stones, particularly when associated with nuclear atypia. The significant correlation between the indicators of chronic kidney disease, such as decreased eGFR, and the presence of kidney stones emphasizes the urgent need for efficient diagnostic practices. [ABSTRACT FROM AUTHOR]

Background: The 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) divides AUS diagnoses into two major subcategories: atypia of undetermined significance (AUS) nuclear atypia (AUS‐N) and other (AUS‐O). This study aims to compare the histological outcome and malignant rate of pediatric AUS thyroid nodules classified into AUS‐N and AUS‐O subcategories. Design: A search of our institutional electronic pathology database for the period from January 2012 to July 2023 was conducted to identify pediatric (<21 years old) thyroid nodules that were interpreted as AUS and subsequently had surgery. Cases were further divided into AUS‐N and AUS‐O subcategories. Results of follow‐up surgical resections were collected. The malignant rate was calculated and compared between AUS‐N and AUS‐O groups. Results: The study identified 62 thyroid nodules from 58 pediatric patients. Among these nodules, 29 and 33 were subcategorized as AUS‐N and AUS‐O, respectively. Both groups exhibited a female predominance and displayed a similar nodule size distribution. Histological analysis revealed 15 carcinomas in AUS‐N nodules, including 11 cases of classic papillary thyroid carcinoma (PTC) and four cases of follicular type of PTC. In contrast, in the AUS‐O group, a total of five carcinomas were documented, including two PTCs and three oncocytic thyroid carcinomas. Notably, the malignant rate of AUS‐N nodules (52%) is significantly higher than that of AUS‐O nodules (15%) (p =.002). Conclusion: In pediatric AUS thyroid nodules, the malignant risk in AUS‐N is significantly higher than that in AUS‐O. These findings may guide more appropriate clinical triage and/or improve management of pediatric patients with AUS thyroid nodules. This study aims to compare the histological outcome and malignant rate of pediatric atypia of undetermined significance (AUS) thyroid nodules classified into nuclear atypia (AUS‐N) and other (AUS‐O) subcategories. In pediatric AUS thyroid nodules, the malignant risk in AUS‐N is significantly higher than that in AUS‐O. These findings may guide more appropriate clinical triage and/or improve management of pediatric patients with AUS thyroid nodules. [ABSTRACT FROM AUTHOR]

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required. [ABSTRACT FROM AUTHOR]

Significant interobserver variabilities exist for Bethesda category III: atypia of undetermined significance (AUS) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Thus, subcategorization of AUS including AUS "nuclear" and AUS "other" is proposed in the recent 3rd edition of TBSRTC. This study investigated the impact of the nuclear features/architectural features/nuclear score (NS) (3-tiered)/subcategories and subgroups on risk of malignancy (ROM) in thyroid fine-needle aspirations (FNA). 6940 FNAs were evaluated. 1224 (17.6%) cases diagnosed as AUS were reviewed, and 240 patients (initial FNAs of 260 nodules and 240 thyroidectomies) were included. Subcategories and subgroups were defined according to TBSRTC 2nd and 3rd editions. Histological diagnostic groups included nonneoplastic disease, benign neoplasm, low-risk neoplasm, and malignant neoplasm. Overall, ROM was 30.7%. ROM was significantly higher in FNAs with nuclear overlapping (35.5%), nuclear molding (56.9%), irregular contours (42.1%), nuclear grooves (74.1%), chromatin clearing (49.4%), and chromatin margination (57.7%), and these features were independent significant predictors for malignancy. FNAs with NS3 had significantly higher ROM (64.2%). Three-dimensional groups were significantly more frequent in malignant neoplasms (35.7%). ROM was significantly higher in AUS-nuclear subcategory (48.2%) and in AUS-nuclear and architectural subcategory (38.3%). The highest ROM was detected in AUS-nuclear1 subgroup (65.2%). ROM was significantly higher in the group including AUS-nuclear and AUS-nuclear and architectural subcategories, namely "high-risk group" than the group including other subcategories, namely "low-risk group" (42.0%vs 13.9%). In conclusion, subcategorization may not be the end point, and nuclear scoring and evaluation of architectural patterns according to strict criteria may provide data for remodeling of TBSRTC categories. [ABSTRACT FROM AUTHOR]

Background and Objectives: Urine serves as a vital diagnostic fluid, and urine cytology analysis plays a crucial role in identifying urinary system illnesses such as bladder cancer and kidney stones. The Paris System for Reporting Urinary Cytology establishes a uniform method for diagnosing urinary tract cancer. This study aimed to provide valuable insights that can inform diagnostic strategies related to kidney stones and ultimately improve patient outcomes via the early detection of the cellular changes associated with kidney stones and their relation to kidney function tests. Materials and Methods: A comparative study was conducted and comprised two groups: group 1, consisting of 50 patients diagnosed with kidney stones, and group 2, comprising 50 patients diagnosed with other kidney diseases. Renal function tests and urinalysis (via the PAP staining of urine cellular deposits to detect nuclear changes) were performed, and the results were analyzed. Results: There was a statistically significant increase in urinary red blood cells, white blood cells, and nuclear reactive atypical changes in urinary sediments of kidney stone patients compared to the patients without stones, while there was a decrease in the estimated glomerular filtration rate (eGFR). eGFR showed a 96.7% specificity in detecting cases with nuclear reactive atypia. Conclusions: eGFR emerges as a reliable diagnostic marker for the comprehensive assessment of kidney stones, particularly when associated with nuclear atypia. The significant correlation between the indicators of chronic kidney disease, such as decreased eGFR, and the presence of kidney stones emphasizes the urgent need for efficient diagnostic practices.

Lipoblastic nerve sheath tumors of soft tissue are characterized as schwannoma tumors that exhibit adipose tissue and lipoblast-like cells with signet-ring morphology. They have been documented to arise in various anatomic locations, including the thigh, groin, shoulder, and retroperitoneum. However, to our knowledge, this tumor has not been previously reported as a lymph node primary. We present herein the first case of a benign primary lipoblastic nerve sheath tumor arising in an inguinal lymph node in a 69-year-old man. Microscopic examination revealed a multinodular tumor comprising fascicles of spindle cells, as well as adipocytic and lipoblast-like signet-ring cell component in the context of schwannoma. Despite the presence of some bizarre cells with nuclear atypia, no obvious mitotic activity or necrosis was observed. Immunohistochemical analysis showed strong and diffuse expression of S-100, SOX10, CD56, and NSE in the spindle cells as well as in the signet-ring lipoblast-like cells and the mature adipocytes. Sequencing analysis of the neoplasm identified six non-synonymous single nucleotide variant genes, specifically NF1, BRAF, ECE1, AMPD3, CRYAB, and NPHS1, as well as four nonsense mutation genes including MRE11A, CEP290, OTOA, and ALOXE3. The patient remained alive and well with no evidence of recurrence over a period of ten-year follow-up. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E‐DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology. Methods: Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E‐DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re‐reviewed to determine the reasons for disagreement. Results: Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ = 1.000; p <.001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ = 0.842; p <.001) and 85.7% (κ = 0.481; p =.001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ = 0.127; p =.037). In cytology cases (n = 23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ = 1.000; p <.001, each), the presence of necrosis showed moderate agreement (κ = 0.465; p =.008), and assessment of architectural patterns showed slight agreement (κ = 0.162; p =.15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens. Conclusions: Although complete nuclear grading of E‐DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology. Assessment of morphologic features that are prognostically significant in epithelioid pleural mesothelioma, including nuclear atypia and the presence of necrosis and pleomorphic cytologic features, can be reliably performed in cytology. Reporting these features in cytology reports could provide prognostic information for patients unable to undergo tissue biopsies. [ABSTRACT FROM AUTHOR]

Myxoid liposarcoma (MLS) accounts for 20%‐30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization/International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software‐based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high–nuclear‐grade group according to the modified Fuhrman grading system exhibited a significantly poor disease‐free survival (hazard ratio: 4.43; 95% confidence interval: 0.9‐22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high‐grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density) but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high‐grade group significantly expressed the cell cycle–related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study cytologically compared hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) using image analyzing software. The results indicated that the major/minor axis ratio of ICC was significantly larger than in HCC in Papanicolaou staining. This difference was consistently observed in clinical samples of cytology such as fine-needle aspiration, brushing and ascites. This study indicated a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding is considered to be useful for differential cytodiagnosis of HCC and ICC. To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of HCC and 16 of ICC. The results indicated that the major/minor axis ratio of ICC is significantly larger than that of HCC (1.67 ± 0.27 vs. 1.32 ± 0.11, p < 0.0001) in Papanicolaou staining. This result means that the nucleus of HCC is close to round and the nucleus of ICC is close to an oval. This significant difference in the major/minor axis ratio between ICC and HCC was consistently observed by the same analyses using clinical samples of cytology (4 cases of HCC and 13 cases of ICC) such a fine-needle aspiration, brushing and ascites (ICC: 1.45 ± 0.13 vs. HCC: 1.18 ± 0.056, p = 0.004). We also confirmed that nuclear position center-positioned nucleus (p < 0.0001) and granular cytoplasm (p < 0.0001) are typical features of HCC tumor cells compared to ICC tumor cells. The research study found a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding will be very useful for the differential cytodiagnosis of HCC and ICC. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most widely recognized cancer in women worldwide. By 2018, 627,000 women had died of breast cancer (World Health Organization Report 2018). To diagnose BC, the evaluation of tumours is achieved by analysis of histological specimens. At present, the Nottingham Bloom Richardson framework is the least expensive approach used to grade BC aggressiveness. Pathologists contemplate three elements, 1. mitotic count, 2. gland formation, and 3. nuclear atypia, which is a laborious process that witness's variations in expert's opinions. Recently, some algorithms have been proposed for the detection of mitotic cells, but nuclear atypia in breast cancer histopathology has not received much consideration. Nuclear atypia analysis is performed not only to grade BC but also to provide critical information in the discrimination of normal breast, non-invasive breast (usual ductal hyperplasia, atypical ductal hyperplasia) and pre-invasive breast (ductal carcinoma in situ) and invasive breast lesions. We proposed a deep-stacked multi-layer autoencoder ensemble with a softmax layer for the feature extraction and classification process. The classification results show the value of the multi-layer autoencoder model in the evaluation of nuclear polymorphisms. The proposed method has indicated promising results, making them more fit in breast cancer grading. [ABSTRACT FROM AUTHOR]

Early diagnosis of breast cancer, the most common disease among women around the world, increases the chance of treatment and is highly important. Nuclear atypia grading in histopathological images plays an important role in the final diagnosis and grading of breast cancer. Grading images by pathologists is a time consuming and subjective task. Therefore, the existence of a computer‐aided system for nuclear atypia grading is very useful and necessary. In this study, two automatic systems for grading nuclear atypia in breast cancer histopathological images based on deep learning methods are proposed. A patch‐based approach is introduced due to the large size of the histopathological images and restriction of the training data. In the proposed system I, the most important patches in the image are detected first and then a three‐hidden‐layer convolutional neural network (CNN) is designed and trained for feature extraction and to classify the patches individually. The proposed system II is based on a combination of the CNN for feature extraction and a two‐layer Long short‐term memory (LSTM) network for classification. The LSTM network is utilised to consider all patches of an image simultaneously for image grading. The simulation results show the efficiency of the proposed systems for automatic nuclear atypia grading and outperform the current related studies in the literature. [ABSTRACT FROM AUTHOR]

Background: It has been known that the “atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)” category is the most problematic category in Bethesda system due to its highly heterogeneous morphological features. Recently, it has been reported that aspirates including nuclear atypia in the AUS/FLUS category have a higher risk of malignancy. Aims: This study aimed to assess each nuclear property in aspirates with cytological atypia and also to determine the relationship with the risk of malignancy. Material and Methods: We reviewed 980 AUS/FLUS fine-needle aspirations (FNAs) performed between '2012 and 2019' at a single institution. We classified these aspirates into four groups: AUS-N (nuclear atypia), AUS-A (architectural atypia), AUS-H (Hurthle cell change), and AUS-O (other). Nuclear features were detailed sub-classified; size and shape (enlargement, elongation, and overlapping), membrane irregularities (irregular contours, grooves, pseudoinclusion), and chromatin characteristics (pale chromatin). The estimated risk of malignancy (ROM) was calculated for each subgroup. Results: Of 980 AUS/FLUS cases, follow-up histological outcome data were available for 209 cases. Among these cases, the estimated ROM was 27.8%. The ROM were 26.4%, 15.4%, and 22.5% for AUS-N, A, and H, respectively. The most common nuclear findings associated with ROM were nuclear groove (67.9%); irregular contours (76.9%) suspected pseudoinclusion (100%) and overlapping (56%) (P < 0,001). But nuclear findings such as nuclear enlargement, mild pleomorphism, or pale chromatin have a similar ROM as architectural atypia. Conclusion: Although it is known that the presence of cytological atypia in an AUS/FLUS nodule increases the estimated risk of malignancy, all nuclear properties are not equally effective in predicting malignancy risk. Emphasizing nuclear atypia details in reports of AUS case may be a more sensitive way to identify nodules with a high risk of malignancy.

Background: The risk of malignancy (RoM) of indeterminate thyroid nodules (ITNs) shows a high variability in interinstitutional cohorts. The RoM is partially associated with the cytological degree of atypia and the ultrasound (US) pattern. This study evaluated the cancer risk of ITNs by jointly considering the cytological subcategory and the American Thyroid Association (ATA)-based US risk classification. Methods: This study features a retrospective cohort from two Brazilian centers comprising 238 ITNs with confirmed outcomes. US classification, according to ATA-based guidelines, and cytological subcategorization were determined. The cytological subgroups were as follows: (1) nuclear atypia (NA) related to papillary thyroid carcinoma (PTC) but insufficient to categorize the cytology as suspicious for malignancy; (2) architectural atypia without NA (AA); (3) both architectural and nuclear atypia (ANA); (4) oncocytic pattern (OP) without NA; and (5) NA not related to PTC (NANP). NA was divided into three subgroups: nuclear size and shape, nuclear membrane appearance, and/or chromatin aspects. Results: The overall frequency of malignancy was 39.5%. Among the cytological subcategories, the highest RoM was related to the NA (43.9%) and to the ANA (43.5%), followed by AA (29.4%), and OP (9.4%). NA was positively and independently associated with cancer (odds ratio [OR]: 4.5; confidence interval [CI: 1.2–16.6]) as was the occurrence of ANA (OR 6.6 [CI 1.5–29.5]). AA and OP were not independently associated with cancer. Both ATA-based high- and intermediate-risk categories showed an independent association with cancer (OR 6.8 [CI 2.9–15.5] and OR: 2.6 [CI 1.1–5.8], respectively). ITNs with cytological findings of NA or ANA when combined with intermediate US patterns had RoM values of 47.5% and 56.7%, respectively. Both cytological subcategories, when combined with the ATA high-suspicion class reached an RoM >70%. The type of NA with the highest odds for cancer was related to the nuclear membrane (OR 11.5). Conclusions: The RoM of ITNs can reach almost 80% when both NA and ATA-based high-risk US features are present. The presence of such cytological features also increased the RoM in the ATA-based intermediate-risk US category. In addition, AA and OP were not independently related to higher cancer risk. These results strengthen the recommendations for combing cytological subcategorization and US risk classification in the workup for ITNs before the decision of a molecular testing, clinical observation, or diagnostic surgery. [ABSTRACT FROM AUTHOR]

Uterine leiomyosarcoma (LMS) is a rare but deadly disease. Due to poor understanding of the molecular and genetic causes of the disease, the diagnosis of LMS has been based primarily on histology. Nuclear atypia is one of hallmarks in LMS, however, it also occurs in 2 clinically benign variants, including smooth muscle tumors with fumarate hydratase alteration (SMT‐FH) and leiomyoma with bizarre nuclei (LM‐BN). In addition to nuclear atypia, many well recognized biomarkers used for LMS are also frequently overexpressed in LM‐BN, and the histogenesis and molecular natures for LM‐BN and LMS remain largely unknown. To characterize the molecular profiling of LMS, SMT‐FH, and LM‐BN, we performed integrated comprehensive genomic profiling including whole‐genome sequencing (WGS) and RNA sequencing and genomic microarray analyses to assess genome‐wide copy number alterations (CNAs) and immunohistochemistry (IHC) in all 3 tumor types. We found that both LM‐BN and LMS showed genomic instability and harbored extensive CNAs throughout the whole genome. By contrast, the SMT‐FH presented its characteristic 1q43‐44 deletions in all cases tested, with minimal CNAs in the rest of genomic regions. Further analyses revealed that LMS and LM‐BN groups showed similar patterns of CNAs that are tended to cluster together and separated from the SMT‐FH group. The integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM‐BN and LMS. Our study suggests that LM‐BN, despite having similar nuclear atypia to SMT‐FH, showed similar genomic instability but distinct genomic alterations with its malignant counterpart of LMS. The integrated molecular profiling is of clinical importance in characterizing these rare uterine smooth muscle tumors. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to retrospectively investigate and confirm whether atypical nuclear findings in endometrial cytology are useful when assessed by image morphometry in liquid‐based cytology (LBC) and compared with microscopic evaluation. Methods: In total, 53 cases were selected for this study, including 11 presenting proliferative endometrium, 12 with surface papillary syncytial change with endometrial glandular and stromal breakdown (EGBD‐SPSC), 10 endometrioid carcinoma grade 1 (G1‐EEC), 10 EEC grade 3 (G3‐EEC), and 10 endometrial serous carcinomas (ESC). Nuclear image morphometry for nuclear geometric features (area, grey value, aspect ratio, internuclear distance, nucleolar diameter) was performed using ImageJ computer software. For assessing nucleoli, 3861 nuclei were measured, and for nuclear findings, except for nucleoli, 4036 nuclei were measured in total. Results: (a) Compared with G1‐EEC, G3‐EEC and ESC presented a marked increase in all six parameters (nuclear enlargement, anisonucleosis, nuclear shade, nuclear shape, irregularity of nuclear arrangement, and nucleolar size). (b) EGBD‐SPSC presented a marked increase in two parameters (nuclear shade, nuclear shape) when compared with G1/G3‐EEC and ESC. (c) Compared with EGBD‐SPSC, EEC and ESC demonstrated a marked increase in nucleolar size (≥2.0 μm). (d) ESC presented a marked increase in nucleolar size (≥3.0 μm) when compared with G3‐EEC. Conclusions: Here we confirmed that atypical nuclear findings evaluated by image morphometry are as useful as microscopic evaluations in endometrial cytology. We believe that the objective evaluation of nucleolar size could contribute to an accurate diagnosis of endometrial‐LBC samples. This study investigates whether atypical nuclear findings in endometrial cytology are useful when determined by image morphometry in liquid‐based cytology. Image analysis was found to be as useful as microscopical evaluation and was particularly useful for objective evaluation of nucleolar size, contributing to accurate diagnosis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Bethesda category III, AUS/FLUS, comprises a heterogeneous group of thyroid lesions with variable risk of malignancy (ROM). This study evaluates ROM in two subgroups of this category based on nuclear atypia and architectural atypia., Methods: Cases in Bethesda category III were reported based on nuclear atypia (AUS) and architectural atypia (FLUS). ROM was calculated by comparing the cytologic diagnosis to the follow-up histologic diagnosis., Results: Among the 610 Bethesda category III cases in this study, 306 (50.2%) and 304 (49.8%) cases were reported as AUS and FLUS, respectively. One hundred and eighty six of 306 AUS (60.8%) and 193 of 304 FLUS (63.5%) cases underwent surgical intervention. ROM of the cases in Bethesda category III was 12.8% if all cases were counted and 20.6% if only surgical cases were counted. When analyzing separately, ROM of AUS cases was 17.0% and 28.0% with all cases and surgical cases only, respectively. For FLUS cases, ROM was 8.6% and 13.5% with all cases and surgical cases only, respectively., Conclusion: In Bethesda category III, ROM in the cases with nuclear atypia was significantly higher than the cases with architectural atypia. Sub-classifying the Bethesda Category III cases with nuclear atypia and architectural atypia, respectively may better stratify the ROM., (© 2023 Wiley Periodicals LLC.)

Objectives: Since most patients with ductal carcinoma in situ (DCIS) of the breast are treated upon diagnosis, evidence on its natural progression to invasive carcinoma is limited. It is estimated that around half of the screen-detected DCIS lesions would have remained indolent if they had never been detected. Many patients with DCIS are therefore probably overtreated. Four ongoing randomized noninferiority trials explore active surveillance as a treatment option. Eligibility for these trials is mainly based on histopathologic features. Hence, the call for reproducible histopathologic assessment has never sounded louder.Methods: Here, the available classification systems for DCIS are discussed in depth.Results: This comprehensive review illustrates that histopathologic evaluation of DCIS is characterized by significant interobserver variability. Future digitalization of pathology, combined with development of deep learning algorithms or so-called artificial intelligence, may be an innovative solution to tackle this problem. However, implementation of digital pathology is not within reach for each laboratory worldwide. An alternative classification system could reduce the disagreement among histopathologists who use "conventional" light microscopy: the introduction of dichotomous histopathologic assessment is likely to increase interobserver concordance.Conclusions: Reproducible histopathologic assessment is a prerequisite for robust risk stratification and adequate clinical decision-making. Two-tier histopathologic assessment might enhance the quality of care. [ABSTRACT FROM AUTHOR]

Background: It has been known that the "atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)" category is the most problematic category in Bethesda system due to its highly heterogeneous morphological features. Recently, it has been reported that aspirates including nuclear atypia in the AUS/FLUS category have a higher risk of malignancy. Aims: This study aimed to assess each nuclear property in aspirates with cytological atypia and also to determine the relationship with the risk of malignancy. Material and Methods: We reviewed 980 AUS/FLUS fine-needle aspirations (FNAs) performed between '2012 and 2019' at a single institution. We classified these aspirates into four groups: AUS-N (nuclear atypia), AUS-A (architectural atypia), AUS-H (Hurthle cell change), and AUS-O (other). Nuclear features were detailed sub-classified; size and shape (enlargement, elongation, and overlapping), membrane irregularities (irregular contours, grooves, pseudoinclusion), and chromatin characteristics (pale chromatin). The estimated risk of malignancy (ROM) was calculated for each subgroup. Results: Of 980 AUS/FLUS cases, follow-up histological outcome data were available for 209 cases. Among these cases, the estimated ROM was 27.8%. The ROM were 26.4%, 15.4%, and 22.5% for AUS-N, A, and H, respectively. The most common nuclear findings associated with ROM were nuclear groove (67.9%); irregular contours (76.9%) suspected pseudoinclusion (100%) and overlapping (56%) (P < 0,001). But nuclear findings such as nuclear enlargement, mild pleomorphism, or pale chromatin have a similar ROM as architectural atypia. Conclusion: Although it is known that the presence of cytological atypia in an AUS/FLUS nodule increases the estimated risk of malignancy, all nuclear properties are not equally effective in predicting malignancy risk. Emphasizing nuclear atypia details in reports of AUS case may be a more sensitive way to identify nodules with a high risk of malignancy. [ABSTRACT FROM AUTHOR]

Introduction: Primary ovarian fibrosarcoma is a rare malignant tumor with few case reports. The current opinion in diagnosis preferring mitotic activity was questioned as there is a large amount of heterogeneity in prognosis between cases. We report a case of primary ovarian fibrosarcoma, and a literature review was performed according to the latest diagnostic trends. This is the first study to review the prognostic factors of primary ovarian fibrosarcoma according to the latest trend in diagnosis. Case Presentation: A 50-year-old woman with primary ovarian fibrosarcoma is reported. The patient was admitted to the hospital due to increasing abdominal girth. Physical examination and CT scan showed a giant mass from the suprapubic area to the xiphoid region which filled her entire abdominopelvic cavity. Frozen sections were performed during an operation to resect, and the pathology report indicated a high degree of malignancy. Because of the degree of malignancy, a bilateral salpingo-oophorectomy and omentectomy were performed. Histopathological examination and immunohistochemical staining confirmed the diagnosis of primary ovarian fibrosarcoma. During the operation, the tumor ruptured, which placed the patient in a FIGO stage IC1. After surgery, the patient received 6 courses of combination chemotherapy, consisting of etoposide, bleomycin, and cisplatin. The patient has been free from disease without evidence of recurrence at 5 months after the initial diagnosis. Conclusions: Herein we report a case of primary ovarian fibrosarcoma and reviewed all published cases in English. Following the latest trend of diagnosis, multiple prognostic factors were used to determine survival prognosis. These included nuclear atypia, FIGO stage, mitotic counts, treatment methods, and tumor size. Only nuclear atypia was found to be associated with patient prognosis (p < 0.05). FIGO stage (p = 0.383), mitotic count per 10 hpfs (p = 0.155), treatment methods (p = 0.185), and tumor size (p = 0.972) were not found to be associated with survival prognosis. Nuclear atypia was an important factor in prognosis of patients. Using surgery with adjuvant medical treatment was inconclusive regarding patient survival. [ABSTRACT FROM AUTHOR]

Extranodal marginal zone B-cell type lymphoma of mucosa-associated lymphoid tissue (MALT) in dogs has similar properties to human low-grade B-cell lymphoma. Both are characterised by a relatively low mitotic rate and a slow manifestation of clinical signs. Primary MALT lymphoma of the third eyelid in canines is very rare. In this case report we describe bilateral MALT lymphoma in a 21-month-old miniature poodle. Histological analysis indicated that the masses were mainly composed of lymphoid cells and lymphoepithelial lesions, a typical feature of MALT lymphoma. Immunohistochemical analysis revealed that the neoplastic cells were positive for CD79α, but negative for CD3. We believe that this case report will facilitate the diagnosis, treatment, and prognosis of canine MALT lymphoma of the third eyelid.