The impact of intraoperative neural monitoring during papillary thyroid cancer surgery on completeness of thyroidectomy and thyroglobulin response: a propensity-score matched study.

BACKGROUND: Intraoperative neural monitoring (IONM) has been utilized for a variety of thyroid pathologies, including papillary thyroid carcinoma (PTC). Remnant thyroid tissue following total thyroidectomy (TT) in patients with PTC is associated with increased recurrence. The aim of this study is to investigate whether the use of IONM in PTC surgery has an impact on the completeness of thyroidectomy. METHODS: Retrospectively, patients with preoperative diagnosis of PTC, who underwent TT in a tertiary center were reviewed. They were grouped based on the IONM usage, and 1:1 propensity-score match was performed. Primary outcome was the completeness of thyroidectomy, determined by measuring postoperative stimulated thyroglobulin levels (sTg). RESULTS: Among 274 clinically node-negative PTC patients who underwent TT and ipsilateral prophylactic central lymph-node dissection, a total of 170 patients (85:85) were matched. Postoperative sTg levels were significantly lower in the IONM group (1 ng/dL vs. 0.4 ng/dL; p < 0.01) with higher percentage of the patients with sTg levels <1 ng/ml (50.6% vs. 69.4%; p = 0.01). More patients in the no-IONM group received RAI ablation with significantly higher doses (mean mci: 120 vs. 102; p = 0.02). CONCLUSION: The use of IONM during thyroidectomy provides improvement in the completeness of thyroidectomy and reduction in postoperative sTg levels which can be used as a guide by clinicians to avoid RAI ablation in selected PTC patients and to adjust low ablative doses in patients who are scheduled for remnant ablation.

Evaluation of immune density, PD-L1, and CXCR4 expressions in metaplastic breast carcinoma to predict potential immunotherapy benefit.

Metaplastic breast carcinoma (MBC) -rare but fatal subtype of invasive breast carcinomas- provides limited benefit from conventional triple-negative breast carcinoma chemotherapy. We aimed to determine the immune density of this tumor and to evaluate of programmed death-ligand 1 (PD-L1) and chemokine receptor type 4 (CXCR4) expressions to determine whether it would benefit from immunotherapy. Clinicopathological characteristics of 85 patients diagnosed as MBC between 1997 and 2017 were retrospectively assessed. We evaluated the immunohistochemical expression of PD-L1 and CXCR4, and the extent of tumour infiltrating lymphocytes (TILs), with survival data. TILs groups were statistically significantly associated with lymph node status, histological subtype, squamous component, local recurrence and/or systemic metastasis, and disease-related deaths (p < 0.05). PD-L1 positivity in immune cells (ICs) has a statistically significant relationship with the presence of squamous component (p = 0.011) and HER2 positivity (p = 0.031). PD-L1 positivity in tumor cells (TCs) was found to be significantly more frequent in high-TILs density (p = 0.003). PD-L1 combined positive score was significantly associated with the tumors containing high-TILs density (p = 0.012) and squamous component (p = 0.035). Disease-free and disease-specific survival rates were found to be longer for the cases displaying PD-L1 positivity in ICs; and also PD-L1 positivity in ICs was found to be an independent prognostic factor. When the expression of CXCR4 was compared with clinicopathological and survival parameters, no statistically significant association was found (p > 0.05). Based on the results of this retrospective study, PD-L1 and TILs appear to be prognostic. This study provides rationale for further studies to determine whether a subset of patients with metaplastic breast cancer could derive a meaningful benefit from immune-targeting therapies.

The Role of Morphology in Predicting Fumarate Hydratase-deficient Uterine Leiomyomas in Young Women.

Hereditary leiomyomatosis and renal cell carcinoma is caused by germline mutations in the fumarate hydratase (FH) gene and is associated with an increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma. Pathologic evaluation of uterine leiomyoma can provide an opportunity for early recognition of the syndrome. We reviewed all archived slides of the cases to identify the characteristic morphologic features described for FH-deficient leiomyomas. We performed immunohistochemistry on whole sections of patients with uterine leiomyoma to evaluate for both FH and 2-succinocysteine (2SC) expression. Of the 106 cases, 19 showed the characteristic eosinophilic nucleoli with perinuclear halos, and 24 revealed a characteristic eosinophilic cytoplasmic inclusion consisting of pink globules present within the cytoplasm. Both of these morphologic findings were present together in 15 cases, and hemangiopericytomatous vessels were detected in 23 cases. The loss of FH protein expression was detected in 14 out of 106 cases (13%), and 13 out of 106 cases (12%) were positive for 2SC. We detected 10 cases with both 2SC-positive and FH expression loss. The presence of eosinophilic nucleoli with perinuclear halos and eosinophilic cytoplasmic inclusion was associated with both loss of FH protein expression and 2SC positivity ( P < 0.001). These findings underscore the importance of hematoxylin and eosin-based predictive morphology in FH-deficient uterine leiomyomas. Therefore, morphologic assessment of uterine leiomyomas for features of FH deficiency can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing patients to be divided according to their hereditary risk assessment.

Long-term outcomes and predictors of recurrence in node-negative early stage breast cancer patients.

BACKGROUND: We evaluated the outcomes, and risk factors for recurrence in patients with early stage node-negative breast cancer in this study. METHOD: Retrospective data analysis was done on patient treatment records from 1988 to 2018. The patient's demographic, clinical, pathological, and therapeutic characteristics were noted. To evaluate survival analysis and predictors of recurrence, we employed Kaplan-Meier analysis with the log-rank test. RESULTS: A total of 357 patients in all were enrolled in the research. At the time of diagnosis, the median age was 50 (with a range of 18-81). A total of 85.5% of patients had undergone a lumpectomy, while 14.5% had a mastectomy. 78.7% of patients had sentinel lymph node biopsy, and 21.3% had axillary lymph node dissection. In addition, the patients received adjuvant radiotherapy (88.7%), adjuvant endocrine therapy (82.1%), and adjuvant chemotherapy (48.5%). Recurrence of the tumor occurred in 31 (8.7%) patients (local recurrence 45.2% and metastatic disease 54.8%). Ten- and twenty-year recurrence-free survival rates were 92% and 77%. 19 (5.3%) patients had also developed contralateral breast cancer. Ten-year survival rates were 91.6%, and 20-year survival rates were 76.6%, respectively. Aged over 65 years (p = 0.004), necrosis (p = 0.002), mitosis (p = 0.003), and nuclear pleomorphism (p = 0.049) were found as statistically significant factors for recurrence in univariate analysis. In the ROC analysis, the largest size of the tumor (over 1.45 cm, p = 0.07) remained outside the statistical significance limit in terms of recurrence. CONCLUSIONS: Thirty-year outcomes in individuals with early stage, node-negative breast cancer were shown in this study. We found that the recurrence ratios between 10 and 20 years were more frequent than the first 10 years during the follow-up. Despite the small number of patients who experienced a recurrence, we demonstrated that, in univariate analysis, being older than 65 and having some pathological characteristics (nuclear pleomorphism, mitosis, and necrosis) were statistically significant factors for disease recurrence.

DICER1 Mutations Do Not Always Indicate Dismal Prognosis in Pediatric Poorly Differentiated Thyroid Carcinomas.

Progress in the field of pediatric thyroid pathology has linked DICER1 mutations to benign follicular cell-derived thyroid tumors (e.g., follicular adenoma with papillary architecture, follicular nodular disease), low-risk follicular cell-derived differentiated thyroid carcinomas and PDTCs enriched in fatal or recurrent/progressive disease. The dismal outcome of DICER1-harboring pediatric PDTCs stems from a limited number of reported patients' data given the rarity of pediatric PDTCs. In light of the former observations, the current study assessed clinicopathological variables of a series of 5 pediatric (≤ 18 years old) PDTCs using the Turin criteria (WHO 2022) and also examined the status of DICER1 and TERT promoter mutations. Five PDTCs (3 males, 2 females) were included in the study. The mean age at the time of diagnosis was 15.4 years. No patients had a history of DICER1 syndrome-related tumors or other clinicopathological diagnostic features of DICER1 syndrome. The mean tumor size was 3.9 cm. All tumors were completely submitted for microscopic examination. There was increased mitotic activity ranging from 3 to 10 mitoses per 2 mm2. Tumor necrosis was present in two cases. No PDTC harbored TERT promoter mutation. DICER1 hot spot mutation was identified in one (20%) tumor. The DICER1-mutant tumor had neither associated differentiated thyroid carcinoma component nor other pathological findings in the adjacent thyroid parenchyma. The DICER1-mutant PDTC showed widely invasive growth confined to the thyroid parenchyma. Despite the widely invasive growth, the tumor lacked vascular invasion. Two DICER1 wild-type PDTCs had lymphocytic thyroiditis and another one had underlying follicular nodular disease and/or follicular adenomas. Three DICER1 wild-type PDTCs also had an associated differentiated thyroid carcinoma component with no high-grade features. No abnormal p53 expression (overexpression or global loss) was recorded in all tested tumors. Four patients had follow-up data with a mean follow-up time of 60.25 months (range: 18-86 months). One patient with no evidence of disease recurrence died of an unrelated cause after 18 months of the initial surgery, all remaining patients were alive with no distant metastasis at their last visit. Of the 4 patients with lymph node (LN) dissection, one DICER1 wild-type PDTC had recurrent nodal disease. During the follow-up period (72 months), no local recurrence or distant metastases was detected in the DICER1-mutant PDTC. Taken together all reported findings from earlier series, DICER1 mutations alone may not necessarily indicate dismal outcome in a subset of pediatric PDTCs. The occurrence of additional genomic alterations as discussed in some earlier reports may be contributing to tumor progression or aggressivity of pediatric PDTCs. The lack of vascular invasion in the current DICER1-mutant pediatric PDTC may also explain an indolent biologic outcome. The risk escalation of DICER1 mutations should integrate the status of additional genetic events and well-established pathologic variables in order to ensure predictive dynamic risk stratification in DICER1-mutant pediatric PDTCs. Additional studies are needed to corroborate the findings of this study and advance our knowledge in pediatric thyroid neoplasia.

Diverging prognostic effects of CD155 and CD73 expressions in locally advanced triple-negative breast cancer.

Background: Immune checkpoint inhibition, combined with novel biomarkers, may provide alternative pathways for treating chemotherapy-resistant triple-negative breast cancer (TNBC). This study investigates the expression of new immune checkpoint receptors, including CD155 and CD73, which play a role in T and natural killer (NK) cell activities, in patients with residual TNBC after neoadjuvant chemotherapy (NAC). Methods: The expression of biomarkers was immunohistochemically examined by staining archival tissue from surgical specimens (n = 53) using specific monoclonal antibodies for PD-L1, CD155, and CD73. Results: Of those, 59.2% (29/49) were found to be positive (>1%) for PD-L1 on the tumour and tumour-infiltrating lymphocytes (TILs), while CD155 (30/53, 56.6%) and CD73 (24/53, 45.3%) were detected on tumours. Tumour expressions of CD155 and CD73 significantly correlated with PD-L1 expression on the tumour (p = 0.004 for CD155, p = 0.001 for CD73). Patients with CD155 positivity ≥10% were more likely to have a poor chemotherapy response, as evidenced by higher MDACC Residual Cancer Burden Index scores and Class II/III than those without CD155 expression (100% vs 82.6%, p = 0.03). At a median follow-up time of 80 months (range, 24-239), patients with high CD73 expression showed improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) rates compared to those with low CD73 expression. In contrast, patients with CD155 (≥10%) expression exhibited a decreasing trend in 10-year DFS and DSS compared to cases with lower expression, although statistical significance was not reached. However, patients with coexpression of CD155 (≥10%) and low CD73 were significantly more likely to have decreased 10-year DFS and DSS rates compared to others (p = 0.005). Conclusion: These results demonstrate high expression of CD73 and CD155 in patients with residual tumours following NAC. CD155 expression was associated with a poor response to NAC and poor prognosis in this chemotherapy-resistant TNBC cohort, supporting the use of additional immune checkpoint receptor inhibitor therapy. Interestingly, the interaction between CD155 and CD73 at lower levels resulted in a worse outcome than either marker alone, which calls for further investigation in future studies.

Ductal Carcinoma In Situ Arising in Sentinel Axillary Lymph Nodes Excised From Patients With Breast Carcinoma - A Potential Diagnostic Pitfall. Report of Two Cases.

We present two cases of ductal carcinoma in situ (DCIS) that arose in axillary lymph nodes excised as the sentinel lymph node from two patients with breast carcinoma. The patient ages were 72 and 36 years and both patients underwent mastectomy and axillary lymph node dissection. In addition to DCIS in the sentinel lymph node, the first patient had a wide DCIS and microinvasion in the ipsilateral breast and a micrometastasis in another sentinel lymph node. The second patient was operated on after neoadjuvant chemotherapy and had DCIS and a small focus of invasion, in addition to invasive and in situ ductal carcinoma in the lymph node having signs of chemotherapy-induced regression. The presence of DCIS was confirmed by use of the immunohistochemical method with antibodies against myoepithelial cells. As a potential source of cellular origin, DCIS was accompanied by benign epithelial cell clusters in the lymph node in both cases. Morphologic and immunohistochemical features were similar in breast and lymph node neoplasms. We conclude that DCIS may rarely develop from benign epithelial inclusions in the axillary lymph node and is a potential diagnostic pitfall in cases having ipsilateral breast carcinoma.

Transglutaminase 2 expression is associated with increased risk of lymph node metastasis and recurrence in papillary thyroid cancer.

PURPOSE: Transglutaminase 2 (TG2) is associated with mobilization, invasion, and chemoresistance of tumor cells. We aimed to determine whether the immunohistochemical staining with TG2 antibody differs between metastatic and non-metastatic papillary thyroid cancer patients. METHODS: We included 76 patients with papillary thyroid cancer (72% female, median age 52 (24-81) years, follow-up time 107 (60-216) months). Thirty of them with no metastasis, 30 of them with only lymph node metastasis and 16 patients with distant ± lymph node metastasis. Immunohistochemical staining of TG2 antibody was evaluated in the primary tumor and extra-tumoral tissue. We also divided subjects into two groups according to their primary tumor TG2 staining score (group A, high risk group: ≥3, n = 43; group B, low risk group: <3, n = 33). RESULTS: Vascular invasion (p < 0.001), thyroid capsule invasion (p < 0.001), extrathyroidal extension (p < 0.001), intrathyroidal dissemination (p = 0.001), lymph node metastasis (p < 0.001), presence of aggressive histology (p < 0.001) were significantly higher in group A. No significant difference was found between the groups in terms of distant metastasis. Based on ATA risk classification 95.5% of patients with low risk were in group B but 86.8% of intermediate risk and 56.3% of high risk were in group A. In regression analysis, lymph node metastasis increased by 1.9 times with each one point increase in TG2 staining score. CONCLUSION: TG2 staining score of the primary tumor may be a predictive factor for lymph node metastasis. High or low TG2 scores may effect the frequency of follow-up and decision of treatment regimens.

Evaluation of Benign Breast Diseases With or Without Atypical Epithelial Hyperplasia Accompanying Radial Scars.

Objective: A radial scar (RS) is a benign breast lesion (BBL) that has an obscure etiology. RS is easily confused with breast carcinoma and therefore correct identification radiologically and pathologically is important. The aim of this study was to determine the incidence of atypical lesions by evaluating RS detected with BBL and to investigate whether atypia and RS are related to their characteristics. Materials and Methods: A total of 1.370 patients with a diagnosis of BBL postoperatively in a single department were analyzed retrospectively. Forty-six confirmed RS/complex sclerosing lesion (CSL) cases were selected. The demographic and clinical characteristics of the patients and the relationship between RS and other BBL were evaluated. In addition, the relationship between RS/CSL and the presence of atypia was interpreted. Results: The mean age was 45.17±8.72 years. Spiculated lesion (34.8%) on mammography and microcalcification (37%) on histopathological examination were the most common features. The most common BBL accompanying RS/CSL was adenosis. Atypical epithelial hyperplasia (AEH) was presented in 15 (32.6%) of those diagnosed with RS. Although all patients were benign, the frequency of AEH accompanying RS was found to be significantly higher. The mean size of RS was 10.8±8.4 mm (2-30 mm). The size of RS/CSL was not significantly associated with atypia. Conclusion: RS/CSLs usually present as suspicious lesions that must be distinguished radiologically from malignancy. However RS, which can be present with malign breast lesions, can be also seen with all BBL. Therefore, core biopsy and/or excisional biopsy continue to be important for definitive histopathological diagnosis.

Surgery for phyllodes tumour of the breast. What should be surgical margins?

BACKGROUNDS: Optimal and tailored surgical treatment of phyllodes tumour(PT) of the breast is controversial. This study aims to determine the appropriate surgical margin in the treatment of PT. METHODOLOGY: The data of 132 patients who underwent breast surgery with the diagnosis of PT at the Breast Unit of Istanbul Faculty of Medicine from 2000 to 2022 were retrospectively reviewed. RESULTS: Median age was 38 and patients with benign PT were younger than others(median age was 34, 44, and 43 for benign, borderline, and malignant, respectively) (P = 0.001). Local recurrence was observed in 7 (5.3%) patients, systemic recurrence was observed in 3 (2.3%) patients, and disease-related death was observed in 2 (1.5%) patients. Local recurrence occurred in 1.4% (n = 1) of benign tumours, 8.3% (n = 2) of borderline tumours, and 10.3% (n = 4) of malignant tumours. All of the systemic recurrences and deaths were seen in the malignant group. The local recurrence rate was found to be higher in borderline and malignant tumours with surgical margins less than 10 mm (44.4% versus 3.7%, P = 0.003), and tumours larger than 5 cm (11.8% versus 1.3%, P = 0.015). In comparison, there was no correlation between the surgical margin proximity, tumour diameter, and local recurrence rates in benign PT (P > 0.05). CONCLUSION: According to our findings, negative surgical margins seem to be sufficient in the treatment of benign phyllodes tumours. Furthermore at least 1 cm negative surgical margins must be achieved for malignant and borderline phyllodes tumours to avoid local recurrence.

Investigation of mRNA Expression Levels of Tip60 and Related DNA Repair Genes in Molecular Subtypes of Breast Cancer.

INTRODUCTION: Studies in breast cancer (BC) have been shown that many tumor cells carry mutations that disrupt the DNA damage response mechanism. In eukaryotic cells, the overexpression or deprivation of DSBs repair genes is linked closely to a higher risk of cancer. PATIENTS AND METHODS: In this study, mRNA expression levels of some genes, such as Tip60, ATM, p53, CHK2, BRCA1, H2AX, which are associated with DNA damage repair, were measured using RT-PCR method in tumor and matched-normal tissues of 58 patients with BC. RESULTS: According to the study results, 55% in Tip60, 59% in ATM, 57% in BRCA1, 48% in H2AX, 66% in CHK2, and 43% in p53 decreased in tumor tissue of patients compared to the matched normal tissue. When evaluated according to molecular subtypes, expression of all genes in the pathway was found significantly higher in normal tissues than in tumor tissues especially in Luminal B and Luminal B+HER2 groups. One of the most important results of the study is that CHK2 mRNA expressions in normal tissues were higher than tumor tissue in 90% of patients in Luminal B and Luminal B-HER2 + groups. This is the first study showing DNA repair genes' expressions in molecular subtypes of breast cancer. In general, the decrease in the expression of DNA damage repair genes in tumor tissue indicates that these genes may have a role in the development of BC. Our study results also suggest that CHK2 may be a candidate marker in the molecular classification of breast cancer.

The impact of intraoperative cavity shaving on re-excision rates in breast-conserving surgery.

BACKGROUND AND OBJECTIVES: This trial aimed to investigate the effects of circumferential shaving on reducing the reoperation rates during breast-conserving surgery (BCS). METHODS: In the study, before 2014, 404 (39.9%) breast cancers (BCs) out of a total of 1012 BCs underwent BCS without intraoperative cavity shaving (ICS) and constituted the no-ICS group. After this date, ICS was added to 608 (60.1%) BCSs (ICS group) and intraoperative margin analysis was not requested from pathologists during these second BCS procedures. RESULTS: The patient and BC characteristics in the no-ICS and ICS groups were similar. Carcinoma detection at the margin and reoperation rates were 13.9% in the no-ICS group and 7.6% in the ICS group (p = 0.001). No significant difference was detected between patients who underwent BCS with intraoperative frozen section analysis (FSA) and patients who underwent BCS with additional ICS (5.6% vs. 7.6%, p = 0.383). CONCLUSIONS: ICS decreased the rates of positive margins and reoperations among patients with BCS to an acceptable level compared with intraoperative FSA. It may be concluded that ICS is feasible to achieve BC margin control.

Pure Mucinous Breast Carcinoma With a Favorable Tumor Biology and Clinical Outcomes.

Objective: A few studies suggest that mucinous breast carcinoma (MBC) is a rare breast carcinoma with good prognostic features. Therefore, the aim of this study was to evaluate biological features and clinicopathological characteristics of pure mucinous breast carcinoma (PMBC) to determine clinical outcome in PMBC. Materials and Methods: The data of 87 patients diagnosed with PMBC between November 2004 and February 2022 were retrospectively analyzed in terms of clinicopathological and demographic characteristics, management, and outcome. Results: The majority of the patients in this study were female, with a median (range) age of 63 (28-90) years. Out of 87 patients, 60 had breast conserving surgery, 27 had a mastectomy, 58 had sentinel lymph node biopsy (SLNB), and 24 had axillary dissection due to a positive SLNB or clinical axilla. Due to age and comorbidities, five patients were not suitable for axillary surgery. The median largest tumor diameter was 23 (5-100) mm. Only 23 patients (26.4%) received adjuvant chemotherapy, whereas almost all patients received hormone therapy. The median duration of follow-up was 53 (6-207) months. There was no local or systemic recurrence in any of the patients. Only 10 patients (11.5%) died from non-cancer causes during the follow-up and treatment period. In this study, tumor diameter was significantly higher in grade II/III tumors (p = 0.039) and in patients under the age of 50 (p = 0.027). Furthermore, lymph node metastasis was statistically significantly more likely in patients under the age of 50 (60% versus 40%, p = 0.013). Patients who had not received chemotherapy or radiotherapy tended to be older than 50 years (p = 0.002). Conclusion: In this study, the majority of patients were in the luminal subgroups with excellent prognosis and low incidences of lymph node metastasis. As a result, PMBC has favorable tumor biology. We believe that minimal axillary surgery would be the most appropriate approach during patient treatment, due to the low rate of lymph node involvement and favorable prognosis in PMBC patients.

DICER1 Mutations Occur in More Than One-Third of Follicular-Patterned Pediatric Papillary Thyroid Carcinomas and Correlate with a Low-Risk Disease and Female Gender Predilection.

Some pediatric papillary thyroid carcinoma (PPTC) cohorts have suggested a preliminary correlation with respect to DICER1 mutation status and histomorphology in both benign and malignant follicular cell-derived nodules; however, the data regarding correlates of DICER1-related sporadic PPTCs subtyped based on the 2022 WHO classification criteria are largely unavailable. The current study investigated the status of hotspot DICER1 mutations with clinical, histological and outcome features in a series of 56 patients with PPTCs with no clinical or family history of DICER1-related syndromic manifestation. Fifteen (27%) PPTCs harbored BRAF p.V600E. Eight (14%) cases of PPTCs harbored DICER1 mutations with no associated BRAF p.V600E. DICER1 mutations were identified in exons 26 and 27. A novel D1810del (c.5428_5430delGAT) mutation was also detected. We also confirmed the absence of hotspot DICER1 mutations in the matched non-tumor tissue DNA in all 8 DICER1-related PPTCs. The mean age of DICER1-harboring PPTCs was 15.1 (range: 9-18) years whereas the rest of this cohort had a mean age of 14.8 (range 6-18) years. With the exception of one PPTC, all DICER1-related PPTCs were seen in females (female-to-male ratio: 7). The female to male ratio was 3.8 in 48 DICER1-wild type PPTCs. In terms of histological correlates, 5 of 8 (63%) DICER1-mutant PPTCs were invasive encapsulated follicular variant papillary thyroid carcinomas (FVPTCs) including 4 minimally invasive FVPTCs and 1 encapsulated angioinvasive FVPTC, whereas the remaining 3 PPTCs were infiltrative classic papillary thyroid carcinomas (p < 0.05). The incidence of DICER1 mutations was 19.5% in BRAF p.V600E-wild type PPTCs. Sixty-three percent of DICER1 hotspot mutations occurred in invasive encapsulated FVPTCs, and this figure represents 38% of invasive encapsulated FVPTCs. Only one (12%) patient with DICER1-related disease showed a single lymph node with micro-metastasis. Unlike DICER1-wild type patients, no distant metastasis is identified in patients with DICER1-related PPTCs. The current series expands on the surgical epidemiology of somatic DICER1-related PPTCs by correlating the mutation status with the clinicopathological variables. Our findings underscore that female gender predilection and enrichment in low-risk follicular-patterned PTCs are characteristics of DICER1-related PPTCs.

High co-expression of immune checkpoint receptors PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT on tumor-infiltrating lymphocytes in early-stage breast cancer.

High expression of immune checkpoint receptors (ICRs) in the tumor microenvironment regulates the anti-tumor response. In this study, the differential expressions of ICRs on tumor-infiltrating lymphocytes (TILs) in patients with early-stage breast cancer were investigated.The study included 32 patients who underwent surgery with a diagnosis of early-stage breast cancer between September 2018 and March 2020. TIL isolation was performed using a MACS tumor separation device and tumor separation kit. PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT expression of cytotoxic T and natural killer (NK) cells on TILs and peripheral blood lymphocytes (PBLs) were determined by flow cytometry.Patients with a high Ki-67 index, high TIL density, and HER-2 positivity were more likely to have increased CD16+CD56dim NK cells on TILs. Patients with T2 tumors were more likely to have increased expression of PD-1, LAG-3, and TIGIT on tumor-infiltrating CD8+ cytotoxic T cells than those with T1 tumors. PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 expression of CD8+ T and CD16-CD56bright NK cells in TILs showed significant positive correlations with each other. PD1+CD8+, TIGIT+CD16+, and CTLA-4+CD56+ cells in PBLs and TILs were found to be negatively correlated, whereas only TIM-3+ expression of CD8+ T and CD16+CD56dim cells in PBLs and TILs showed positive correlations.Our results suggest that CD16+CD56dim NK cells on TILs may play a major role in the immune response against HER2-positive or highly proliferating breast tumors in patients with early-stage breast cancer. Furthermore, various ICRs were found to be highly co-expressed with each other on TILs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT. These receptors may synergistically suppress the response to the tumor, which may trigger immune escape mechanisms in the early stage of carcinogenesis. However, ICR expressions other than TIM3 on PBLs were not found to accompany their counterparts on TILs.

Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood.

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients. Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male. Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient. Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Abbreviated and Standard Breast MRI in Neoadjuvant Chemotherapy Response Evaluation: A Comparative Study.

OBJECTIVES: This study aims to investigate the efficacy of abbreviated breast magnetic resonance imaging (MRI) in neoadjuvant chemotherapy (NAC) response evaluation. METHODS: MR images of 50 locally advanced breast cancer patients who underwent standard protocol (SP) breast MRI before and after NAC were re-evaluated retrospectively. Abbreviated protocol (AP) was obtained by extracting images from SP and then evaluating them in a separate session. Protocols were compared with the histological findings after surgery as the reference standard. RESULTS: A statistically significant difference was found between the two protocols in response evaluation by the McNemar test (p=0.018). However, the Kappa value was 0.62 (p<0.001), which indicates substantial agreement. No statistically significant differences were found between the two protocols (AP and SP) and pathological results in the McNemar test (p=0.12, p=0.60, respectively). Kappa values were 0.48 (p<0.001) and 0.60 (p<0.001), respectively, which indicates moderate agreement for both protocols with higher values by SP evaluation. The residual maximum median diameters were smaller than the pathology, with both protocols (p<0.001). CONCLUSION: Despite the statistical differences, there was a significant correlation in response evaluation between the two protocols. The pathological results were moderately correlated with both protocols, with SP slightly higher. However, the residual maximum median diameters were smaller than the pathology with both protocols. These results may limit the use of AP in evaluating the local extent of the tumor, especially in patients who will undergo breast-conserving surgery.

Long-term Follow-up of a Toddler with Papillary Thyroid Carcinoma: A Case Report with a Literature Review of Patients Under 5 Years of Age

Papillary thyroid cancer (PTC) is extremely rare in children. Herein, we present a case diagnosed with PTC at 15 months of age. We conducted a literature review of the published cases with PTC under five years of age. A 1.25-year-old male patient had initially presented with a complaint of progressively enlarging cervical mass that appeared four months earlier. On physical examination, a mass located in the anterior cervical region with the largest measurements of around 3x3 cm was detected. Cervical and thyroid ultrasonography showed a 50x27 mm solid mass in the right lateral neck. Excisional biopsy revealed a follicular variant of PTC with capsular invasion. Subsequently, he underwent a complementary total thyroidectomy. He was diagnosed with intermediate-risk (T3N0M0) PTC. He developed permanent hypoparathyroidism. In the first year of the operation, he was treated with radioiodine ablation (RAI) since basal and stimulated thyroglobulin (Tg) levels tended to increase. Whole-body scintigraphy was normal in the first year of RAI ablation. On levothyroxine sodium (LT4) treatment, levels of thyroid stimulating hormone (TSH) and Tg were adequately suppressed. He is now 8.5-years-old and disease-free on LT4 replacement therapy for seven years and three months. Pediatric PTC has different biological behavior and an excellent prognosis compared to adults. The optimal treatment strategy for pediatric TC is total thyroidectomy, followed by RAI ablation. Post-operative management should include regular follow-up, TSH suppression by adequate LT4 therapy, serial Tg evaluation, and radioiodine scanning when indicated.

Prognostic Implications of Immune Infiltrates in the Breast Cancer Microenvironment: The Role of Expressions of CTLA-4, PD-1, and LAG-3.

The assessment of immune infiltrate in invasive breast carcinomas (IBCs), most commonly referred to as tumor infiltrating lymphocytes (TILs), is gaining importance in the current quest for optimal biomarker selection and prediction of prognosis. In this study, the impact of intensity of TILs and expressions of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and lymphocyte activation gene 3 (LAG-3) in a group of breast carcinomas with regards to the prognosis and conventional pathologic parameters was scrutinized. For this purpose, 238 patients with IBCs containing different proportions of TILs were included in the study. IBCs with higher proportion of TILs were usually grade III carcinomas and correlated with poor prognostic features like receptor negativity, nonluminal intrinsic subtype (P<0.001). Similarly, PD-1 and LAG-3 positivity in immune cells (IC) were more likely to be positive in grade III IBC cases (P=0.004). In addition, PD-1 positivity in IC was more frequent in estrogen receptor-negative tumors (P=0.011) whereas LAG-3 positivity increased in large sized, estrogen receptor and progesterone receptor-negative tumors (P=0.050, 0.023, 0.04, respectively). CTLA-4 positivity in IC was more frequent in large-sized tumors (P=0.040). These 3 markers were also significantly associated with one another and also with the amount of TILs. In survival analysis, cases with prominent-TILs especially displaying CTLA-4, PD-1, and LAG-3 positivity appeared to have longer disease-free and overall survival (CTLA-4: P=0.027, P=0.024; PD-1: P=0.030, P=0.026; LAG-3: P=0.006, P=0.012, respectively). We conclude that the high proportion of TILs and as well as high expression of CTLA-4, PD-1, and LAG-3 in TILs have positively contributed to the outcome despite their correlation with poor conventional pathologic features. We suggest that these 3 immune markers can be used for the determination of proper treatment as well as prediction of prognosis in IBCs with TILs.