Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.

Independent Validation of the International Grading System for Medullary Thyroid Carcinoma: A Single Institution Experience.

Medullary thyroid carcinoma (MTC), an uncommon C cell thyroid malignancy, accounts for a disproportionate number of thyroid cancer deaths. To predict MTC clinical behavior, the recent international MTC grading system (IMTCGS) was published combining features from the Memorial Sloan Kettering Cancer Center and Royal North Shore Hospital grading systems that incorporates mitotic count, necrosis, and Ki67 proliferative index (Ki67PI). The IMTCGS appears promising, but independent validation data are limited. Here, we applied the IMTCGS to our institutional MTC cohort and assessed its ability to predict clinical outcomes. Our cohort comprised 87 MTCs (30 germline and 57 sporadic). Slides for each case were reviewed by 2 pathologists and histologic features recorded. Ki67 immunostaining was performed on all cases. Each MTC was graded with the IMTCGS based on tumor necrosis, Ki67PI, and mitotic count. Cox regression analysis was performed to assess the impact of various clinical and pathological data on disease outcomes, including overall survival (OS), disease-free survival, disease-specific survival (DSS), and distant metastasis-free survival. In our MTC cohort, 18.4% (n = 16/87) were IMTCGS high grade. IMTCGS grade was strongly prognostic for OS, disease-free survival, DSS, and distant metastasis-free survival on univariate analysis and multivariable analysis in both the entire MTC cohort and in the sporadic subset. Among the individual IMTCGS parameters, while all 3 were associated with poorer survival outcomes on univariate analysis, necrosis had the strongest association with all survival parameters on multivariable analysis, whereas Ki67PI or mitotic count was associated only with OS and DSS. This retrospective study independently demonstrates that the IMTCGS is valid for grading MTCs. Our findings support incorporating IMTCGS into routine pathology practice. IMTCGS grading may help clinicians to better predict the prognosis of MTC. Future studies may shed light on how MTC grading should impact treatment protocols.

Comprehensive Molecular Characterization of Polymorphous Adenocarcinoma, Cribriform Subtype: Identifying Novel Fusions and Fusion Partners.

Polymorphous adenocarcinoma (PAC) is a common, usually low-grade salivary gland carcinoma. While conventional PACs are most associated with PRKD1 p.E710D hotspot mutations, the cribriform subtype is often associated with gene fusions in PRKD1, PRKD2, or PRKD3. These fusions have been primarily identified by fluorescence in situ hybridization (FISH) analysis, with a minority evaluated by next-generation sequencing (NGS). Many of the reported fusions were detected by break-apart FISH probes and therefore have unknown partners or were negative by FISH altogether. In this study, we aimed to further characterize the fusions associated with PAC with NGS. Fifty-four PACs (exclusively cribriform and mixed/intermediate types to enrich the study for fusion-positive cases) were identified and subjected to NGS. Fifty-one cases were successfully sequenced, 28 of which demonstrated gene fusions involving PRKD1, PRKD2, or PRKD3. There were 10 cases with the PRKD1 p.E710D mutation. We identified a diverse group of fusion partners, including 13 novel partners, 3 of which were recurrent. The most common partners for the PRKD genes were ARID1A and ARID1B. The wide variety of involved genes is unlike in other salivary gland malignancies and warrants a broader strategy of sequencing for molecular confirmation for particularly challenging cases, as our NGS study shows.

Ki67 proliferation index in medullary thyroid carcinoma: a comparative study of multiple counting methods and validation of image analysis and deep learning platforms.

AIMS: The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time-consuming task. METHODS AND RESULTS: We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning-based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near-perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease-specific survival and distant metastasis-free survival. CONCLUSIONS: We herein validate a machine learning-based deep-learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3-7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.

The solid variant of papillary thyroid carcinoma: a multi-institutional retrospective study.

AIMS: The definition of papillary thyroid carcinoma, solid variant (PTC-SV) varies from >50% to 100% of solid/trabecular/insular growth (STI). We aimed to identify prognostic factors and to establish an appropriate STI cutoff for PTC-SV in this multi-institutional study of 156 PTCs with STI. RESULTS: Nodal metastases were seen in 18% and were associated with a higher percentage of papillary and STI. When substratified by infiltration/encapsulation status, the STI percentage did not impact the risk of nodal metastasis. pN1 stage was seen in 51% of infiltrative tumours and 1% of encapsulated lesions. Overall, PTC with STI had an excellent prognosis. The 10-year disease-free survival (DFS) was 87% in the entire cohort, 94% in encapsulated lesions, and 76% in infiltrative tumours. The STI percentage did not impact DFS. Fifty-four patients had noninvasive encapsulated lesions with 2-100% STI. None developed recurrence. Encapsulated lesions were enriched with RAS mutations (54%), whereas infiltrative lesions lacked RAS mutations (4%). The BRAF V600E mutation was an infrequent event, being seen in 11% of the entire cohort. CONCLUSION: In PTC with STI, the determining factor for nodal metastasis and DFS is the encapsulation/infiltration status rather than the STI percentage. Encapsulated noninvasive tumours with STI follow an indolent course with a very low risk of nodal metastasis and recurrence. Overall, PTC with STI has an excellent prognosis, with a 10-year disease-specific survival (DSS) and DFS of 96% and 87%, respectively. Therefore, the classification of SV-PTC as an aggressive PTC subtype may be reconsidered.

MYB rearrangement and immunohistochemical expression in adenomyoepithelioma of the breast: a comparison with adenoid cystic carcinoma.

AIMS: Adenomyoepithelioma (AME) and adenoid cystic carcinoma (ACC) of the breast have been noted to occur simultaneously, raising the possibility that AME may represent a related or precursor lesion to ACC. ACC frequently harbours genetic rearrangement of the MYB gene. We sought to clarify the relationship between AME and ACC by comparing their rates of MYB expression by IHC and MYB rearrangement by FISH. METHODS AND RESULTS: IHC and FISH for MYB rearrangement were performed on paraffin-embedded sections of 11 breast ACCs, 11 non-breast ACCs and 11 breast-AMEs. Using FISH, five of eight (63%) interpretable breast ACCs demonstrated MYB gene rearrangement. Nine of 11 (81%) breast ACCs demonstrated MYB expression (range = 20-95%). Of the three FISH-negative breast ACCs, two were solid variant and demonstrated strong MYB expression by IHC. Of the 10 interpretable non-breast ACCs, six showed MYB rearrangement, all of which were conventional type. Nine of these 11 (81%) cases showed MYB immunoexpression (range = 10-90%), including three solid-variant cases which were negative by FISH. No MYB rearrangements were detected by FISH in 10 interpretable AMEs. However, three of 11 cases (27%) showed weak to moderate MYB expression by IHC (range = 10-40%). CONCLUSIONS: Our results indicate that AMEs do not harbour MYB gene rearrangement. IHC for MYB may be helpful in diagnosing FISH-negative cases of ACC, particularly the diagnostically more difficult solid variants. However, weak to moderate MYB expression in a subset of AMEs highlights not only a potential diagnostic pitfall, but also shared pathophysiology with ACC worth investigating further at the genomic level.

Delivery room breastfeeding for prevention of hypoglycaemia in infants of diabetic mothers.

OBJECTIVE: To evaluate the effect of duration of early breastfeeding in the delivery room on blood glucose levels among term neonates of diabetic mothers. METHODS: Mothers with gestational diabetes were encouraged to breastfeed their infants immediately after birth in the delivery room. The breastfeeding duration was recorded by the midwife. RESULTS: The longer duration of breastfeeding subgroup (n = 39) demonstrated a lower rate of hypoglycaemia in the first 8 hours of life (< 40 mg/dl) compared to the shorter duration subgroup (n = 40), but this difference did not reach statistical significance (2.6% vs. 17.5% respectively, p = 0.057). Hypoglycaemia was mainly predicted by lower cord glucose for each decrease of 10 mg/dl (OR 2.11 [CI 1.1-4.03] p = 0.024. CONCLUSION: Longer duration of delivery room breastfeeding did not reduce the rate of hypoglycaemia, which was mainly influenced by lower cord blood glucose level.

Grading medullary thyroid carcinoma on fine-needle aspiration cytology specimens with the International Medullary Thyroid Carcinoma Grading System: A cytologic-histologic correlation.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare cancer of parafollicular C-cell origin. The International MTC Grading System (IMTCGS) incorporates mitotic activity, the presence of necrosis, and the Ki67 proliferation rate (PR) to classify MTCs as low or high grade. The ability to predict IMTCGS grade in cytology was assessed. METHODS: MTCs with cytology and subsequent surgical follow-up were reviewed. Cytology slides were reviewed for mitotic figures, apoptoses, and necrosis, and a Ki67 PR was calculated when possible. Findings were correlated with final IMTCGS grade. RESULTS: Twenty-five MTC fine-needle aspirations (FNAs) were identified, with nine identified as high grade (36%). By using a PR cutoff of 5%, Ki67 on FNA material (Ki67FNA) showed 92% concordance (n = 22 of 24) with surgical Ki67 and a correlation coefficient (R2) of 0.72. Sensitivity and specificity of Ki67FNA for predicting high-grade MTC were 38% and 100%, respectively. Multiple mitotic figures were present in a single slide of 43% (n = 3 of 7) of evaluable high-grade MTCs, whereas only one of 16 low-grade MTCs showed a single mitotic figure. Definitive apoptoses were present in five of seven high-grade MTC FNAs but were absent in 16 low-grade MTCs. The sensitivity and specificity of apoptoses/necrosis on cytology for high-grade MTCs were 71% and 88%, respectively. CONCLUSIONS: Ki67FNA ≥5% shows low sensitivity but high specificity for predicting high-grade MTC. The presence of multiple mitotic figures in a single slide or definitive apoptotic bodies are both highly suggestive of high-grade MTC, and should warrant a close examination for necrosis and a careful Ki67 PR count.

Clearing the Air: Acute Invasive Fungal Rhinosinusitis in Hematologic Cancer Patients.

OBJECTIVES: Air quality has been shown to impact the rates of fungal infection of the airway, causing diseases such as acute invasive fungal rhinosinusitis (AIFRS), particularly in immunocompromised patients. We theorize that patients with hematologic malignancies in units with aging air handling units (AHUs) have a higher attack rate of AIFRS. METHODS: Retrospective chart review identified patients with hematologic malignancy and AIFRS in two distinct and equal time periods between 2013 and 2022, representing the presence of aging AHUs and new AHUs, respectively. Cubic feet per minute (CFM) air flows, AIFRS attack rates, and clinical data were compared between the two groups and statistical analyses performed. RESULTS: The older AHUs produce air flow of 27,610 CFM and the newer AHUs produce air flow of 80,000 CFM. There were 18 patients with air supplied by older AHUs and 7 patients with air supplied by new AHUs who developed AIFRS. There was a significantly higher AIFRS attack rate for patients supplied by the older AHUs compared with patients supplied by newer AHUs (p = 0.033). The patients supplied by the older AHUs tended to be younger. The white blood cell counts, absolute neutrophil counts, and the mean time to diagnosis did not differ between the two groups. CONCLUSIONS: To our knowledge, this is the first study to examine AIFRS in immunocompromised patients' inpatient environment. Further research should explore whether higher CFM AHUs can decrease this disease among our most vulnerable patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Monkeypox virus cytologic findings: An institutional experience with an emerging threat.

OBJECTIVES: Mpox is a viral disease caused by monkeypox, a highly contagious orthopoxvirus that resulted in a global outbreak beginning in spring 2022. Diagnosis is confirmed via polymerase chain reaction (PCR) testing of swabs from mucocutaneous lesions. Rare reports have documented the histologic changes of mpox lesions, but the cytologic features have not been described. We present the cytology findings of samples taken from swabs of mucocutaneous mpox lesions in 3 different patients. METHODS: The patients were all male, aged 55, 43, and 37 years, all with mpox confirmed by PCR testing. Swabs from chest (cases 1 and 2) and tongue (case 3) lesions were directly sampled and submitted in Aptima (case 1) or PreservCyt solution (cases 2 and 3). Liquid-based preps were prepared and stained using the Papanicolaou method. Specimens were assessed for viral cytopathic changes. RESULTS: All cases showed nuclear cytopathic changes (enlarged nuclei with open chromatin and prominent red nucleoli), 2 cases demonstrated multinucleated keratinocytes, and 1 case showed potential Guarnieri bodies. The chromatin margination and nuclear molding typical of herpesviruses was not appreciated. CONCLUSIONS: The cytopathic changes of monkeypox are not specific, but their recognition could prompt appropriate PCR testing. Monkeypox shows distinct cytologic changes compared with herpesviruses.

ThyroSeq overview on indeterminate thyroid nodules: An institutional experience.

BACKGROUND: Molecular triage of indeterminate thyroid aspirates offers the opportunity to stratify the risk of malignancy (ROM) more accurately. Here we examine our experience with ThyroSeq v3 testing. METHODS: We analyzed 276 of 658 (42%) fine needle aspiration samples classified as indeterminate thyroid nodules using ThyroSeq v3 (Sept 2017-Dec 2019). The test provides a ROM and detects specific mutations. Surgical diagnoses were reviewed. RESULTS: Of 276 ThyroSeq-tested cases, 42% (n = 116) harbored genetic alterations, whereas 64% (n = 74) had surgical follow-up. Notably, 79% cases within intermediate to higher risk mutations were highly associated with surgical intervention, resulting in a 77.5% ROM when including both cancer and noninvasive follicular thyroid neoplasia with papillary-like features (cancer+NIFTP) and 68% malignant diagnosis when excluding NIFTP. RAS-like alterations were most common (66%), exhibiting a 73.4% ROM and a 59% malignant diagnosis. Interestingly, this group included 24 encapsulated follicular variant papillary thyroid carcinomas (EFVPTCs), 1 infiltrative FVPTC, 9 follicular carcinomas, and 7 NIFTP. Additionally, three high-risk mutations and eight BRAF/V600E mutations had a 100% ROM, all diagnosed as classic-type papillary thyroid carcinoma (cPTC). Combined analysis of thyroid nodules from Bethesda III and IV categories revealed a 78.2% positive predictive value (PPV) and a 75.9% negative predictive value (NPV). CONCLUSION: ThyroSeq v3 effectively stratifies the ROM in indeterminate thyroid nodules based on specific genetic alterations, guiding appropriate surgical management. Notably, the BRAFV600E/high-risk group and RAS-like groups exhibited ROM of 100% and 77.5%, respectively, with promising predictive accuracy (PPV of 78.2% and NPV of 75.9%).

Comprehensive evaluation of cytomorphologic, histologic, and molecular features of DICER1-altered thyroid lesions on FNA: A multipractice experience.

BACKGROUND: DICER1 mutations, though infrequent, are encountered on preoperative molecular testing of indeterminate adult and pediatric thyroid fine-needle aspiration (FNA) specimens. Yet, published cytomorphologic features of DICER1-altered thyroid lesions are limited. Cytomorphological features of DICER1-altered thyroid lesions were examined in a multipractice FNA cohort with clinical, radiological, and histologic data. METHODS: The cohort comprised 18 DICER1-altered thyroid FNAs, with 14 having slides available and eight having corresponding surgical resections. Smears, ThinPrep, and formalin-fixed cell block slides were reviewed and correlated with histology, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: Most DICER1-altered FNAs were classified as atypia of undetermined significance (94.4%). DICER1 mutations occurred in codons 1709 (50%), 1810 (27.8%), and 1813 (22.2%). One patient had an additional DICER1 p.D1822N variant in both of their FNAs. Lesions were often hypoechoic (35.3%) and solid (47.1%) on ultrasound. Notable cytomorphologic features include mixed but prominent microfollicular or crowded component, variable colloid, and insignificant nuclear atypia. On resection (n = 10), histologic diagnoses ranged from benign follicular adenoma and low-risk follicular thyroid carcinoma to high-grade follicular-derived nonanaplastic thyroid carcinoma. Subcapsular infarct-type change was the most common histologic change. There was no evidence of recurrence or metastasis in eight patients on limited follow-up. CONCLUSION: DICER1-altered thyroid lesions occurred frequently in young females and FNAs show RAS-like cytomorphology including crowded, mixed macro-/microfollicular pattern, and bland nuclear features. On resection, DICER1-altered thyroid lesions include benign (50%), low-risk lesions (30%), or high-risk malignancies (20%).

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study.

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

Duration of vancomycin treatment for coagulase-negative Staphylococcus sepsis in very low birth weight infants.

AIM: Vancomycin is widely used to treat late onset coagulase-negative Staphylococcus (CoNS) sepsis in very low birth weight (VLBW) infants. Although vancomycin is associated with a risk of toxicity and bacterial resistance, the appropriate duration of use has not been established. This study sought to investigate the association between the duration of vancomycin therapy and clinical outcome in VLBW infants with CoNS sepsis. METHODS: The files of all VLBW infants treated for CoNS sepsis at a tertiary paediatric medical centre from 1995-2003 were reviewed for clinical data, laboratory variables and outcome. Only patients with two positive diagnostic blood cultures were included. The findings were analyzed by duration of vancomycin treatment after the last positive blood culture. RESULTS: The study cohort included 126 infants, 48 treated for 5 days, 32 for 6-7 days, 31 for 8-10 days and 15 for >10 days. There were no differences among the groups in perinatal characteristics, central catheter dwell time, laboratory data including haematologic, renal and liver function tests, or rate of complications of prematurity. Five infants were diagnosed with infective endocarditis or aortic thrombi and were treated for >10 days. CoNS sepsis recurred in two infants (1.6%). No toxicity of vancomycin treatment was observed. CONCLUSIONS: In VLBW infants with uncomplicated CoNS sepsis, treatment with vancomycin for 5 days after the last positive blood culture appears to be associated with a satisfactory outcome and no adverse effects. A well-controlled prospective multicentre study is needed to confirm these findings.

Significance of oncocytic features in poorly differentiated thyroid carcinoma - a bi-institutional experience.

Poorly differentiated thyroid carcinoma (PDTC), defined by Turin criteria, comprises a subset of high-grade follicular-derived thyroid carcinomas with intermediate prognosis. While differentiated oncocytic thyroid carcinomas demonstrate clinicopathologic and genetic differences compared to their non-oncocytic counterparts, similar data is limited in oncocytic (Hurthle) PDTCs (OPDTCs). Here, we assessed the impact of various oncocytic cut-offs in PDTCs on clinical, histologic and survival parameters.Our bi-institutional cohort comprised 210 primary PDTCs with available slides reviewed by at least one pathologist. Histologic features, including oncocytic fraction, were recorded. Clinicopathologic data were obtained, including overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), locoregional recurrence free survival (LRRFS), and distant metastasis-free survival (DMFS). Radioactive iodine avidity data was available for 125 PDTCs based on postoperative whole-body scanning.Within our cohort, 39.0% PDTCs had any oncocytic component with 24.8% meeting the 75% World Health Organization (WHO) oncocytic definition. Any oncocytic component and > 25% oncocytic cut-off correlated with decreased DSS and LRRFS, respectively, compared to non-oncocytic PDTCs (NOPDTCs) on univariate and multivariate analysis. The 100% oncocytic cut-off was significant for DSS on univariate analysis but a non-significant trend on multivariate analysis. Any oncocytic cut-off (100%, > 75%, > 50%, > 25%, or > 0%) conferred higher radioactive iodine (RAI)-refractoriness to OPDTCs compared to NOPDTCs. NF1 and PTEN alterations were enriched in OPDTCs (40% vs. 0%, and 60% vs 8%, respectively), whereas NRAS mutations were frequent in NOPDTCs (47% vs. 7%).Among PDTCs, the presence of oncocytes led to downward trend in all outcome parameters, especially for DSS and LRRFS. OPDTCs were enriched in NF1 and PTEN mutations. Consistently, all oncocytic cut-offs were associated with RAI-refractoriness. Accordingly, additional studies are needed to reassess the current 75% cut-off used to define oncocytic thyroid lesions.

Exploration of Digital Image Analysis for Ki67 Quantification in the Grading of Medullary Thyroid Carcinoma: A Pilot Study with 85 Cases.

BACKGROUND: Although uncommon, medullary thyroid carcinoma (MTC) accounts for a significant proportion of thyroid cancer deaths. Recent studies have validated the two-tier International Medullary Thyroid Carcinoma Grading System (IMTCGS) to predict clinical outcomes. A 5% Ki67 proliferative index (Ki67PI) cut-off separates low-grade from high-grade MTC. In this study, we compared digital image analysis (DIA) to manual counting (MC) for determining the Ki67PI in a MTC cohort, and explored the challenges encountered. METHODS: Available slides from 85 MTCs were reviewed by two pathologists. The Ki67PI was documented by immunohistochemistry for each case, scanned with the Aperio® slide scanner at 40× magnification, and quantified using the QuPath® DIA platform. The same hotspots were screenshot, printed in color, and blindly counted. For each case, over 500 MTC cells were counted. Each MTC was graded using IMTCGS criteria. RESULTS: In our MTC cohort (n = 85), 84.7 and 15.3% were low- and high-grade with the IMTCGS. In the entire cohort, QuPath® DIA performed well (R2 = 0.9891) but appeared to undercall compared to MC. QuPath® performed better in high-grade cases (R2 = 0.99) compared to low-grade cases (R2 = 0.7071). Overall, Ki67PI determined with either MC or DIA did not affect IMTCGS grade. Encountered DIA challenges include optimizing cell detection, overlapping nuclei, and tissue artifacts. Encountered MC challenges include background staining, morphologic overlap with normal elements, and counting time. CONCLUSION: Our study highlights the utility of DIA in quantifying Ki67PI for MTC and can serve as an adjunct for grading in conjunction with the other criteria of mitotic activity and necrosis.

Does Milan affect management? A retrospective analysis of resection rate and time to surgery among Milan categories.

INTRODUCTION: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is an established system with reproducible risk of malignancies (ROM) for salivary gland fine needle aspiration (SGFNA). No studies have reviewed the relationship between Milan categories and the resection rate (RR) and time to resection (TTR). METHODS: We searched our database (January 1, 2011 to January 4, 2021) for non-lymphoma SGFNAs and assigned appropriate MSRSGC categories. RR and TTR were calculated and compared for each category. A literature search was performed; RRs and TTRs were compared. RESULTS: Seven hundred and eighty SGFNAs were identified, 333 with follow-up. RR was highest in suspicious for malignancy (SUS, V; 70.6%, n = 12/17), followed by the salivary gland neoplasm of uncertain malignant potential (SUMP, IVb; 69.6%, n = 80/115) and malignant (M, VI; 55.6%, n = 75/135). Among M, primary tumors had a higher RR (65.1%, n = 41/63) than metastases (47.2%, n = 34/72, p = .36). In literature review, SUS had the highest RR (69.3%, n = 233/336) followed by M (61.6%, n = 821/1332) and SUMP (60.2%, n = 632/1050). TTR was shorter in SUS (mean = 32.3 days, median = 25 days). Within the benign neoplasms (BN, IVa), Pleomorphic adenomas (PAs) had a higher RR than Warthin tumors (WTs) (66.3% vs. 37.2%, p < .00001), and a shorter TTR (median = 63 days vs. 90 days). CONCLUSIONS: Tumors classified as SUS had higher RR and at shorter intervals than those classified as SUMP. PAs have higher RRs and more expedient surgery than WTs. Cases classified as M are less likely to undergo follow-up than SUS, perhaps due to a lower RR for metastases.

Microcribriform Adenocarcinoma of Salivary Glands: A Unique Tumor Entity Characterized by an SS18::ZBTB7A Fusion.

The landscape of salivary gland carcinomas is ever-changing, with a growing list of new tumors and newly elucidated variants of well-known tumor entities. The routine use of next-generation sequencing has been instrumental in identifying novel fusions and tumor entities, which has helped bring the classification to a more objective and evidenced-based model. However, morphology remains critical in assessing the validity of these novel molecular findings, and most importantly, in assessing which of these findings will have an impact on the prognosis and treatment decisions for patients. The recognition of microsecretory adenocarcinoma (MSA) as a distinct low-grade malignancy of salivary glands, underpinned by MEF2C::SS18 , and a single possibly related case of SS18::ZBTB7A , recently expanded this growing list of distinctive tumors. It was not until now, however, that the morphology of the latter case was known to be unique and reproducible. The authors have now seen 4 of these distinctive tumors that show a combination of distinctive oncocytic cells forming compact glandular growth as well as amphophilic cells forming tubular growth, and suggest the appellation "microcribriform adenocarcinoma" (MCA). So far, these tumors appear to preferentially occur in nonoral sites (2 parotid, 1 submandibular gland, and 1 bronchial seromucous glands). By immunohistochemistry, they express S100 and SOX-10 with focal outer myoepithelial cells marked by circumferential p63, p40, and smooth muscle actin staining around some of the nests and tubules. The tumors show infiltrative growth within a hyalinized and myxoid stroma. Cytologically, they appear generally low grade, similar to MSA. The morphologic and molecular uniformity of these 4 microcribriform adenocarcinoma cases warrants their recognition, and while related to MSA, they are sufficiently different to be classified as a distinct tumor. So far, in limited follow-up, these tumors appear to be relatively indolent.

Neonatal outcomes in women with preterm premature rupture of membranes at periviable gestational age.

To examine the outcomes of preterm infants born to women with preterm premature rupture of membranes (PPROM) at periviable gestational age. This is an observational retrospective cohort study analyzing data collected on singleton deliveries complicated by prolonged premature rupture of membranes occurring between 17 and 33 weeks of gestation. Neonatal outcomes including birth weight, Apgar score, retinopathy of prematurity, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, hearing impairment and mortality were evaluated. Ninety-four preterm infants who were born after a prolonged premature rupture of membranes of at least 7 days were included in the study. Median gestational week at onset of membrane rupture was 27.1 ± 4.2 weeks (range 17-33) and median latency period in days was 16 ± 21.8 (range 7-105). The cohort was stratified by gestational week (GW) at onset of PPROM (group 1: 17-23, group 2: 24-27, and group 3: 28-33). We found that the survival rate to discharge within neonates born after prolonged rupture of membrane at gestational week less than 24 weeks is 79.2% and 88.9% in group 2. These neonates did not show an increased rate of major morbidities compared to neonates born following membrane rupture at gestational week 24 to 27. We described a high survival rate to discharge without major morbidities following prolonged preterm membrane rupture of at least 7 days of latency before viability.

Cytomorphologic features of thyroid nodules harboring thyroid adenoma-associated fusion: A single institutional review of 11 cases.

BACKGROUND: Thyroid adenoma-associated (THADA) fusions are being identified more frequently with increased preoperative molecular testing on indeterminate thyroid fine-needle aspirates (FNA). However, data on cytomorphologic features of THADA-fusion thyroid lesions are limited. We examined cytomorphologic features of a THADA-fusion thyroid FNA cohort with clinical, radiologic, and histologic data. METHODS: Our THADA fusion FNA cohort included 11 specimens from 11 patients with a mean age and F:M ratio of 56.5 years and 2.7:1, respectively. Ten cases had FNA slides available for review and five cases had histopathology. Air-dried Diff-Quik and alcohol-fixed Papanicolaou smears, and formalin-fixed cell blocks were reviewed and findings were correlated with the matched resection, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: THADA fusion thyroid lesions were hypoechoic or isoechoic (80%), solid (80%) with well-demarcated margins (100%) on ultrasound. Notable cytomorphologic features include crowded or prominent microfollicular groups (100%), scant colloid (91%), and mild nuclear atypia with nuclear grooves (100%), insignificant nuclear pleomorphism (100%), and without intranuclear pseudoinclusions (100%). All cases were classified as either atypia of undetermined significance (91%) or suspicious for follicular neoplasm (9%). Five resected cases were all low-risk lesions (benign and malignant) with no evidence of recurrence in the limited available follow-up. CONCLUSION: THADA-fusion thyroid FNAs show a crowded or prominent microfollicular pattern with mild nuclear atypia and without intranuclear pseudoinclusions, which overlaps with the cytomorphology of other RAS-like thyroid lesions. In our cohort, resected THADA lesions were low risk on histologic analysis.