The Asian Thyroid Working Group, from 2017 to 2023.

The Asian Thyroid Working Group was founded in 2017 at the 12th Asia Oceania Thyroid Association (AOTA) Congress in Busan, Korea. This group activity aims to characterize Asian thyroid nodule practice and establish strict diagnostic criteria for thyroid carcinomas, a reporting system for thyroid fine needle aspiration cytology without the aid of gene panel tests, and new clinical guidelines appropriate to conservative Asian thyroid nodule practice based on scientific evidence obtained from Asian patient cohorts. Asian thyroid nodule practice is usually designed for patient-centered clinical practice, which is based on the Hippocratic Oath, "First do not harm patients," and an oriental filial piety "Do not harm one's own body because it is a precious gift from parents," which is remote from defensive medical practice in the West where physicians, including pathologists, suffer from severe malpractice climate. Furthermore, Asian practice emphasizes the importance of resource management in navigating the overdiagnosis of low-risk thyroid carcinomas. This article summarizes the Asian Thyroid Working Group activities in the past 7 years, from 2017 to 2023, highlighting the diversity of thyroid nodule practice between Asia and the West and the background reasons why Asian clinicians and pathologists modified Western systems significantly.

Tonsil tissue control is ideal for monitoring estrogen receptor immunohistochemical staining.

BACKGROUND: Estrogen receptor (ER) testing performed using immunohistochemistry (IHC) is a critical predictive tool for breast cancer treatment. This study aimed to investigate the use of tonsil control for monitoring ER staining and hypothesize that optimal staining would reduce interlaboratory variations. METHODS: A proficiency test for ER IHC was conducted using 21 tissue cores. The staining quality was centrally reviewed based on tonsil ER staining. RESULTS: We found that 64.9% of participant samples demonstrated optimal or good staining quality. Poor staining quality was significantly associated with the use of Ventana autostainers and concentrated antibodies. Although the concordance rate did not show significant differences across staining quality levels, interparticipant agreement declined as staining quality deteriorated. Among the 19 discordant responses, 63.2% could be attributed to staining problems, whereas 36.8% could be due to misinterpretation. Poor staining quality due to inadequate staining was the primary reason for undercalls, which can lead to false-negative results. Misinterpretations of nonspecific faint staining that was weaker than the staining of the tonsil control were the cause of most overcalls. CONCLUSION: Tonsil tissue is an ideal control for monitoring ER staining and can serve as a reference for determining the lower bound for ER positivity. Optimal ER staining and appropriate references for ER positivity can further improve ER IHC quality.

The diagnostic utility of trichorhinophalangeal syndrome type 1 immunohistochemistry for metastatic breast carcinoma in effusion cytology specimens.

BACKGROUND: Trichorhinophalangeal syndrome type 1 (TRPS1) is a novel immunohistochemical marker with excellent performance in distinguishing breast carcinoma from other cancers in surgical specimens. The aim of this study was to evaluate the diagnostic utility of TRPS1 compared with GATA3 for metastatic breast carcinoma in effusion cytology specimens. METHODS: In total, 91 cell blocks of malignant effusion specimens, including 47 metastatic breast carcinomas (nine triple-negative breast carcinomas [TNBCs] and 38 non-TNBCs) and 44 nonmammary malignancies, were selected for TRPS1 and GATA3 immunohistochemistry. Modified H scores ≥ 200 were considered positive staining. RESULTS: The positive rate of TRPS1 was similar between TNBC and non-TNBC (77.8% vs 73.3%, p = .802), whereas the positive rate of GATA3 was lower in TNBC than in non-TNBC (66.7% vs 89.5%, p = .087). The positive rate of TRPS1 was significantly higher in breast carcinoma than in urothelial carcinoma (74.5% vs 0%, p < .001), whereas the positive rate of GATA3 showed no difference between these two (85.1% vs 85.7%, p = .956). Notably, diffuse and strong aberrant expression of TRPS1 was observed in one lung adenocarcinoma and one serous adenocarcinoma in this series. The overall sensitivity, specificity, positive predictive value, and negative predictive value of TRPS1 immunohistochemistry for breast carcinoma were 74.5%, 95.5%, 94.6%, and 77.8%, respectively. CONCLUSION: TRPS1 is a sensitive and specific marker for metastatic breast cancer in serous effusion cell-block specimens. It shows superior sensitivity and specificity compared with GATA3, especially in the TNBC setting and for excluding urothelial carcinoma.

Loss of Major Histocompatibility Complex Class I, CD8 + Tumor-infiltrating Lymphocytes, and PD-L1 Expression in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC), a chemoresistant ovarian cancer, shows a modest response to anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) therapies. The effects of anti-PD-1/PD-L1 therapies rely on cytotoxic T-cell response, which is triggered by antigen presentation mediated by major histocompatibility complex (MHC) class I. The loss of MHC class I with simultaneous PD-L1 expression has been noted in several cancer types; however, these findings and their prognostic value have rarely been evaluated in OCCC. We collected data from 76 patients with OCCC for clinicopathologic analysis. Loss of MHC class I expression was seen in 44.7% of the cases including 39.3% to 47.4% of the PD-L1 + cases and was associated with fewer CD8 + tumor-infiltrating lymphocytes (TILs). PD-L1 positivity was associated with a higher number of CD8 + TILs. Cox proportional hazard models showed that high (≥50/mm 2 ) CD8 + TILs was associated with shorter disease-specific survival (hazard ratio [HR]=3.447, 95% confidence interval [CI]: 1.222-9.720, P =0.019) and overall survival (HR=3.053, 95% CI: 1.105-8.43, P =0.031). PD-L1 positivity using Combined Positive Score was associated with shorter progression-free survival (HR=3.246, 95% CI: 1.435-7.339, P =0.005), disease-specific survival (HR=4.124, 95% CI: 1.403-12.116, P =0.010), and overall survival (HR=4.489, 95% CI: 1.553-12.972, P =0.006). Loss of MHC class I may contribute to immune evasion and resistance to anti-PD-1/PD-L1 therapies in OCCC, and CD8 + TILs and PD-L1 positivity using Combined Positive Score may have a negative prognostic value.

Primary poorly differentiated carcinoma of the vagina with focal neuroendocrine differentiation: a tumour with aggressive behaviour.

Primary vaginal neuroendocrine tumours are extremely rare but aggressive. We report a case of primary poorly differentiated vaginal carcinoma with focal neuroendocrine differentiation. The clinical stage was cT3N1M0, FIGO stage III. The patient received six cycles of cisplatin-based concurrent chemoradiation therapy (CCRT) followed by six cycles of adjuvant chemotherapy (IEP protocol: ifosfomide, epirubicin and cisplatin). Pelvic MRI scans obtained after treatment completion revealed no residual tumour in the vagina. However, the patient experienced severe dyspnoea 2 months later. Chest X-ray revealed a reticulonodular interstitial pattern over bilateral lungs with suspicion of lymphangitic carcinomatosis. Further chest, abdominal and pelvic CT scans showed bilateral lung metastases with multiple mediastinal, left lower neck and left axilla, intra-abdominal and pelvic lymphadenopathies. For this rare tumour, cisplatin-based CCRT followed by IEP protocol adjuvant chemotherapy may have a limited treatment effect. Further studies are necessary to provide more information on clinical management.

NTRK-rearranged papillary thyroid carcinoma demonstrates frequent subtle nuclear features and indeterminate cytologic diagnoses.

BACKGROUND: The studies on the cytomorphologic features of NTRK-rearranged papillary thyroid carcinoma (PTC) are limited and some reported characteristics, such as frequent indeterminate diagnoses and presence of fibrotic fragments, are inconsistent in literature. METHODS: NTRK gene rearrangements were detected in thyroidectomy specimens of PTC by either fluorescence in situ hybridization or next-generation sequencing. All the cytologic slides of NTRK-rearranged PTC were reviewed to evaluate the cytomorphologic features. The preoperative cytologic diagnoses of NTRK-rearranged PTC were compared with those of NTRK/BRAF wild-type and BRAFV600E -positive PTC. RESULTS: Fourteen PTC cases were identified to harbor NTRK gene rearrangements. Most of them showed a mixed architectural pattern of cell fragments (n = 13, 92.9%) and microfollicles (n = 9, 64.3%) with relatively rare papillary structures (n = 4, 28.6%). Nuclear grooving was frequently present (n = 11, 78.6%) but was mostly subtle and limited. Seven cases (50.0%) showed rounded nuclei without discernible nuclear elongation, and only 3 (21.4%) cases presented with nuclear pseudoinclusions. Among these cases, 7 (50.0%) were diagnosed as The Bethesda System for Reporting Thyroid Cytopathology (TBS) category III, 2 (14.3%) were diagnosed as TBS IV, and 5 (35.7%) were diagnosed as TBS V. The rate of TBS III-IV diagnoses for NTRK-rearranged PTCs was significantly higher (64.3%) than that for the 25 consecutive NTRK/BRAF wild-type PTCs (20.0%, P = .013) and the 70 consecutive BRAFV600E -positive PTCs (7.1%, P < .001) as selected. CONCLUSIONS: NTRK-rearranged PTC demonstrated intermediate nuclear features, such as subtle nuclear grooving, infrequent nuclear elongation, and rare pseudoinclusions, resulting in a significantly higher rate of TBS III-IV diagnoses compared to PTC with other molecular alterations.

Constitutive Cytomorphologic Features of Medullary Thyroid Carcinoma Using Different Staining Methods.

(1) Background: Accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to a spectrum of cytomorphologic features. However, there is a scarcity of studies describing the cytomorphologic features as seen on fine-needle aspiration (FNA) smears prepared using different staining methods. (2) Methods: We performed a retrospective study on MTC cases with available FNA slides from 13 hospitals distributed across 8 Asia-Pacific countries. The differences in the constitutive cytomorphologic features of MTC with each cytopreparatory method were recorded. A comparative analysis of cytologic characteristics was carried out with appropriate statistical tests. (3) Results: Of a total of 167 MTC samples retrospectively recruited, 148 (88.6%) were interpreted as MTC/suspicious for MTC (S-MTC). The staining methods used were Papanicolaou, hematoxylin-eosin, and Romanowsky stains. Seven out of the eleven cytologic criteria can be readily recognized by all three cytopreparatory methods: high cellularity, cellular pleomorphism, plasmacytoid cells, round cells, dyshesive cells, salt-and-pepper chromatin, and binucleation or multinucleation. An accurate diagnosis was achieved in 125 (84.5%) of the 148 samples whose FNAs exhibited five or more atypical features. Conclusions: The present work is the first study on MTC to compare the morphological differences among the cytologic staining techniques. We investigated the constitutive features and the reliability of diagnostic parameters. A feasible scoring system based upon cytomorphologic data alone is proposed to achieve a high degree of diagnostic accuracy.

Development of a Multi-Institutional Prediction Model for Three-Year Survival Status in Patients with Uterine Leiomyosarcoma (AGOG11-022/QCGC1302 Study).

BACKGROUND: The existing staging systems of uterine leiomyosarcoma (uLMS) cannot classify the patients into four non-overlapping prognostic groups. This study aimed to develop a prediction model to predict the three-year survival status of uLMS. METHODS: In total, 201 patients with uLMS who had been treated between June 1993 and January 2014, were analyzed. Potential prognostic indicators were identified by univariate models followed by multivariate analyses. Prediction models were constructed by binomial regression with 3-year survival status as a binary outcome, and the final model was validated by internal cross-validation. RESULTS: Nine potential parameters, including age, log tumor diameter, log mitotic count, cervical involvement, parametrial involvement, lymph node metastasis, distant metastasis, tumor circumscription and lymphovascular space invasion were identified. 110 patients had complete data to build the prediction models. Age, log tumor diameter, log mitotic count, distant metastasis, and circumscription were significantly correlated with the 3-year survival status. The final model with the lowest Akaike's Information Criterion (117.56) was chosen and the cross validation estimated prediction accuracy was 0.745. CONCLUSION: We developed a prediction model for uLMS based on five readily available clinicopathologic parameters. This might provide a personalized prediction of the 3-year survival status and guide the use of adjuvant therapy, a cancer surveillance program, and future studies.

Analytical validation of human epidermal growth factor receptor 2 immunohistochemistry by the use of the A0485 antibody versus the 4B5 antibody and breast versus gastric scoring guidelines in ovarian clear cell carcinoma.

AIMS: The aim of this study was to evaluate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in ovarian clear cell carcinoma (OCCC) by using two antibodies and two scoring guidelines in correlation with HER2 amplification and clinicopathological features. METHODS AND RESULTS: A tissue microarray was constructed by use of a total of 71 OCCC cases for IHC (the A0485 antibody and the 4B5 antibody) and dual-colour silver in-situ hybridisation (DISH). Two pathologists independently scored the IHC according to the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) breast cancer guidelines (breast guidelines) and the 2016 ASCO/CAP gastro-oesophageal adenocarcinoma guidelines (gastric guidelines). IHC concordances between A0485 and 4B5 were 87.3-93.0%. Three to 16 (4.2-22.5%) cases had an IHC score of 2+/3+ with frequent basolateral/lateral membranous staining. The 4B5 antibody yielded fewer IHC 2+ cases than the A0485 antibody (n = 2-6 versus n = 5-12). Five (7.0%) cases had HER2 amplification as determined with DISH. Cases with papillary-predominant growth patterns were significantly more likely to have HER2 amplification (P = 0.0051). In predicting DISH results, IHC scored according to the gastric guidelines yielded 100%/100% sensitivity and 83.3-95.5%/98.2-100% specificity, and IHC scored according to the breast guidelines yielded 60-80%/33.3-66.7% sensitivity and 95.5-100%/100% specificity (including/excluding IHC 2+ cases). One case had intratumoral heterogeneity, with discordant results between primary and metastatic tumour specimens. CONCLUSION: We demonstrated HER2 amplification in 7% of OCCC cases, and the molecular change is significantly associated with papillary-predominant growth patterns. In predicting HER2 amplification, a combination of 4B5 IHC and gastric guidelines provides the best sensitivity and fewer equivocal (IHC 2+) cases. Given the intratumoral heterogeneity, assessment of HER2 status on whole tissue sections and on both primary and metastatic tumour specimens is recommended.

Molecular Correlates and Nuclear Features of Encapsulated Follicular-Patterned Thyroid Neoplasms.

BACKGROUND: Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAFV600E mutation. METHODS: Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing. RESULTS: Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAFV600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAFV600E than for those with RAS-like mutations (P<0.001). CONCLUSION: Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAFV600E mutation from benign or borderline follicular tumors with RAS-like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAFV600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.

Cytologic diagnosis of medullary thyroid carcinoma in the Asia-Pacific region.

BACKGROUND: The accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to the rarity of tumor and variable cytologic appearance. The Asian experience with diagnosing MTC by fine-needle aspiration (FNA) was scarcely reported. METHODS: Cases of MTC with available FNA slides were enrolled from 13 hospitals representing 8 Asia-Pacific countries. Clinicopathological information, including sample preparation technique, staining method, original cytologic diagnosis and review diagnosis were collected. RESULTS: Of a total of 145 MTC cases retrospectively recruited, 99 (68.3%) were initially interpreted as MTC/suspicious for MTC (S-MTC). The distribution of original FNA diagnostic categories was not associated with the staining method or sample preparation technique. The staining methods used were Papanicolaou, hematoxylin-eosin and Romanowsky stains. Liquid-based cytology (LBC) was used only in three countries. After reviewing all cases, the diagnostic rate of MTC/S-MTC increased to 91.7% (133/145). Cases with initially unrecognized MTC had either marked pleomorphism or cytology mimicking papillary carcinoma or follicular neoplasm. Although LBC provided certain benefits, there was no significant difference in diagnostic accuracy between conventional smear and LBC. Immunocytochemistry was available in 38 cases (26.2%), all of which were correctly recognized as MTC. CONCLUSION: Our report summarizes how MTC is handled in contemporary Asian thyroid FNA practice. Although the detection rate of MTC by cytology alone is less satisfactory, integration with ancillary tests could achieve an excellent performance. The recognition of constitutive cytomorphologic features is needed for each cytopreparatory method, which may result in a lower threshold to initiate further workup for MTC.

Diffuse Intratumoral Stromal Inflammation in Ovarian Clear Cell Carcinoma is Associated With Loss of Mismatch Repair Protein and High PD-L1 Expression.

Ovarian clear cell carcinoma (OCCC) is an aggressive chemotherapy-resistant cancer with limited treatment options, and some OCCCs have mismatch repair (MMR) deficiency (MMRD). Emerging evidence has revealed that various cancers with MMRD are susceptible to anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) immunotherapy, and certain histologic features are associated with MMRD. However, few studies have addressed this in OCCC. We reviewed 76 OCCCs for tumor-associated inflammation (intratumoral stromal inflammation and peritumoral lymphocytes) and performed immunohistochemistry for 4 MMR proteins and PD-L1. MMR-deficient OCCCs were analyzed for microsatellite instability (MSI), and those with MLH1 loss were tested for MLH1 promoter methylation. No patients fulfilled the Amsterdam II criteria for the diagnosis of Lynch syndrome. Four (5.3%) tumors showed diffuse intratumoral stromal inflammation obliterating the tumor-stroma interfaces, and none had peritumoral lymphoid aggregates. MMRD was found in 2 (2.6%) tumors; one had MLH1/PMS2 loss (MSI-high and MLH1 promoter methylation was detected) and the other had MSH2/MSH6 loss (MSI-low). Twenty (26.3%) tumors showed tumoral PD-L1 expression ≥1%. Both MMR-deficient tumors showed diffuse intratumoral stromal inflammation and tumoral PD-L1 expression ≥50%. Three of the 4 (75%) tumors with diffuse intratumoral stromal inflammation also showed tumoral PD-L1 expression ≥50%. None of the tumors without diffuse intratumoral stromal inflammation showed MMRD (P=0.021) or tumoral PD-L1 expression ≥50% (P=0.0001). We identified a strong correlation among diffuse intratumoral stromal inflammation, MMRD, and high tumoral PD-L1 expression in a small but significant subset of OCCCs. Histologic evaluation can facilitate patient selection for subsequent anti-PD-1/PD-L1 immunotherapy.

Thyroid fine-needle aspiration cytology in Taiwan: a nationwide survey and literature update.

In Taiwan, thyroid fine-needle aspiration cytology is easily accessible and reliable for evaluating thyroid nodules. The sonographic pattern plays a major role and is the deciding factor for aspiration. We conducted a nationwide survey in 2017 and it revealed that 31% of laboratories had adopted The Bethesda System for Reporting Thyroid Cytopathology. There was a relatively high unsatisfactory rate (24.04%) and low rates of indeterminate diagnoses, including atypia of undetermined significance/follicular lesions of undetermined significance: 4.87%, and follicular neoplasm/suspicious for a follicular neoplasm: 0.35%. Moreover, the risks of malignancy in benign, atypia of undetermined significance, and suspicious for a follicular neoplasm were relatively high. These may reflect strict diagnostic criteria for indeterminate categories and better patient selection for surgery. Improvements in specimen sampling and continuing education programs are crucial. Newly-developed thyroid cytology technologies, such as immunocytochemistry, molecular testing, and computerized cytomorphometry, may further facilitate cytology diagnoses.

Histopathologic Assessment of Capsular Invasion in Follicular Thyroid Neoplasms-an Observer Variation Study.

The assessment of capsular invasion is an essential but challenging step in the diagnosis of encapsulated follicular thyroid neoplasms. Therefore, interobserver agreement in the assessment of capsular invasion in these tumors was investigated among 11 thyroid pathologists by using virtual slides of 20 cases in which the original diagnosis considered the differential diagnosis of definite capsular invasion versus questionable capsular invasion. The assessment of capsular invasion was divided into three categories: (1) non-invasive, (2) questionable invasive, and (3) clear-cut invasive. The interobserver agreements for clear-cut invasive and non-invasive categories were fair (Kappa value = 0.578 and 0.404, respectively), whereas agreement for the questionable invasion was poor (Kappa value = 0.186). Disagreements in the assessment of invasion resulted in variable final pathological diagnoses. For example, the agreement for a diagnosis of malignancy was only fair (Kappa value = 0.545). Moreover, pathologists did not have a uniform approach for rendering a final diagnosis in cases with questionable capsular invasion, though nine of 11 pathologists did use the follicular tumor of uncertain malignant potential diagnosis as proposed by the World Health Organization classification of endocrine organs published in 2017. In conclusion, this study revealed considerable interobserver variation in the evaluation of capsular invasion, especially in follicular neoplasms with questionable invasion.

Anal human papillomavirus and its associations with abnormal anal cytology among men who have sex with men.

Human papillomavirus (HPV) infection contributes to most anal cancers and premalignant intraepithelial lesions. This study investigated anal HPV infections and cytological abnormalities among men who have sex with men (MSM). Sociodemographic characteristics and sexual behaviors were collected by using a structured questionnaire. Anal cytological results were examined, and HPV genotyping was performed by the Linear Array HPV Genotyping test. Logistic regression was used to estimate risk factors and their associations with high-risk HPV infection and cytological abnormalities. Among 163 MSM, 101 were seropositive for human immunodeficiency virus (HIV) and 62 were seronegative for HIV. The overall prevalence of HPV was 66.2%. A total of 61.9% and 48.2% of participants had never acquired any of either the quadrivalent or nonavalent vaccine HPV types, respectively. Cytological findings showed 15.3% atypical squamous cells of undetermined significance, 16.6% low-grade squamous intraepithelial lesion, 4.9% atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion and 17% high-grade squamous intraepithelial lesion. The number of high-risk HPV types was the predominant risk factor for abnormal anal cytology (OR 2.02, 95% CI 1.27-3.24). Infection with high-risk HPV was a significant predictor for cytological abnormality. MSM should be encouraged to obtain the HPV vaccine.

Diagnostic Agreement for High-Grade Urothelial Cell Carcinoma in Atypical Urine Cytology: A Nationwide Survey Reveals a Tendency for Overestimation in Specimens with an N/C Ratio Approaching 0.5.

In the Paris System (TPS), standardized cytomorphological criteria and diagnostic categories were proposed for reporting urine cytology. To evaluate the diagnostic agreement and interobserver concordance for assessing TPS criteria, the Taiwan Society of Clinical Cytology organized an online survey with 10 atypical urine cytology cases. A total of 137 participants completed the survey. The mean agreement of diagnosis was 51.2%, ranging from 34.3% to 83.2% for each case. For 60% (6/10) of cases, the agreement was <50%. The interobserver concordance of diagnosis and cytological criteria assessment showed poor agreement. The nuclear-to-cytoplasmic (N/C) ratio had the highest kappa value of 0.386, indicating a significantly higher interobserver concordance and reproducibility than the other three TPS criteria. The correct rate of assessing the N/C ratio increased as the N/C ratio increased (correlation coefficient: 0.891, p < 0.01). Three cases with an N/C ratio near 0.5 were overestimated. Poor interobserver concordance of diagnosis and TPS criteria was revealed. Compared with other cytological features, the N/C ratio assessment was quantitative and more reproducible, but a tendency to overestimate cells was noted when the N/C ratio was approximately 0.5. Continuing education programs should emphasize the accurate assessment of N/C ratio to improve the application of TPS.

Good staining quality ensuring the reproducibility of Ki67 assessment.

AIMS: Although Ki67 labelling index (LI) is a prognostic and predictive marker in breast cancer, its accuracy and reproducibility must be validated before its clinical application. We aimed to evaluate the agreement of Ki67 LI in clinical practice in Taiwan. METHODS: We conducted a Ki67 immunohistochemistry (IHC) proficiency test. The participants performed the Ki67 IHC test and measured the Ki67 LI of 10 cases of breast cancer tissue on a microarray slide. The staining quality was centrally reviewed based on the Ki67 staining of the tonsil surface epithelium. RESULTS: Ki67 staining and counting methods are diverse in Taiwan. The reproducibility of Ki67 LI was poor to good (intraclass correlation coefficient: 0.581, 95% CI 0.354 to 0.802). The reproducibility and agreement in the high staining quality group were significantly higher than those in the low staining quality group. The majority of the Ki67 LIs derived from the low staining quality group were underestimated. Different counting methods did not reveal significant differences when determining Ki67 LI with microarray sections. CONCLUSIONS: We suggest using the surface epithelium of the tonsil as external control and achieving optimal staining results that consist of a high positive parabasal layer, a low positive intermediate layer and a negative superficial layer. Good Ki67 staining quality can minimise the staining variations among different laboratories, and it is essential for the reproducibility of Ki67 LI.

Risk of malignancy in "atypia of undetermined significance" category of salivary gland fine-needle aspiration: A bi-institutional experience.

BACKGROUND: Many prior institutional and multi-institutional studies have applied the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) retrospectively to their specimens to determine the risk of malignancy (ROM) of each category. Most of these studies focused on general assessment of the system and risk classification. However, there seems to be less focus on the category of atypia of undetermined significance (AUS) that could be attributed to the low number of cases that could fit into this category. Herein, we present a bi-institutional experience with this category. METHODS: A computerized search of the databases was performed to identify all salivary gland fine-needle aspiration (FNA) in two institutions over a period of 12 years. The final diagnosis of each case was reclassified based on MSRSGC, and histology follow-up was retrieved. RESULTS: Sixty AUS cases (out of 1560 salivary gland FNA) were identified with a rate of 3.8%. Forty cases (66%) had a subsequent tissue material. Correlation with histology revealed that the estimated ROM is 37.5% (15/40) and the overall ROM is 25% (15/60). Fifty percent of the cases had a prominent lymphoid component and most commonly represented lymphomas, reactive lymph node or sialadenitis. CONCLUSION: The AUS category is a heterogeneous group of lesions with predominant lymphoid-rich entities. Some variability exists between institutions with most having higher ROM than the suggested 20% by the MSRSGC atlas.

Application of the Milan System for Reporting Salivary Gland Cytopathology: A Retrospective 12-Year Bi-institutional Study.

OBJECTIVES: Multi-institutional studies are required for the validation of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). METHODS: A total of 1,560 fine-needle aspirations of the salivary glands were retrieved from two institutions for a 12-year period. The diagnoses were reclassified based on the MSRSGC. Risk of malignancy (ROM) for each category was calculated based on 694 histologic follow-up cases. RESULTS: The ROM for each category was: 18.3% for nondiagnostic, 8.9% for nonneoplastic, 37.5% for atypia of undetermined significance (AUS), 2.9% for benign neoplasm, 40.7% for salivary gland neoplasm of uncertain malignant potential (SUMP), 100% for suspicious for malignancy, and 98.3% for malignant. The sensitivity, specificity, positive predictive rate, and negative predictive rates were 89%, 99%, 98%, and 96%, respectively. CONCLUSIONS: The results of the current study are in keeping with the MSRSGC. The indeterminate categories of AUS and SUMP showed intermediate ROMs at 37.5% and 40.7%, respectively.