Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

BACKGROUND: The effect of gender-affirming testosterone therapy (TT) on breast cancer risk is unclear. This study investigated the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). METHODS: Of the 444 TMIs who underwent chest-contouring surgeries between 2013 and 2019, breast tissue composition was assessed in 425 TMIs by the pathologists (categories of lobular atrophy and stromal composition) and using our automated deep-learning algorithm (% epithelium, % fibrous stroma, and % fat). Forty-two out of 444 TMIs had mammography prior to surgery and their breast tissue density was read by a radiologist. Mammography digital files, available for 25/42 TMIs, were analyzed using the LIBRA software to obtain percent density, absolute dense area, and absolute non-dense area. Linear regression was used to describe the associations between duration of TT use and breast tissue composition or breast tissue density measures, while adjusting for potential confounders. Analyses stratified by body mass index were also conducted. RESULTS: Longer duration of TT use was associated with increasing degrees of lobular atrophy (p < 0.001) but not fibrous content (p = 0.82). Every 6 months of TT was associated with decreasing amounts of epithelium (exp(ß) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(ß) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(ß) = 1.01, 95%CI 0.98,1.05, adj p = 0.39). The effect of TT on breast epithelium was attenuated in overweight/obese TMIs (exp(ß) = 0.98, 95% CI 0.95,1.01, adj p = 0.14). When comparing TT users versus non-users, TT users had 28% less epithelium (exp(ß) = 0.72, 95% CI 0.58,0.90, adj p = 0.003). There was no association between TT and radiologist's breast density assessment (p = 0.58) or LIBRA measurements (p > 0.05). CONCLUSIONS: TT decreases breast epithelium, but this effect is attenuated in overweight/obese TMIs. TT has the potential to affect the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.

Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer.

BACKGROUND: Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status. METHODS: Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative. RESULTS: In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like). DISCUSSION: The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.

Response to neoadjuvant chemotherapy and the 21-gene Breast Recurrence Score test in young women with estrogen receptor-positive early breast cancer.

PURPOSE: The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT). METHODS: We identified patients with stage I-III ER+/HER2- BC treated with NCT from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling. RESULTS: 76 women received NCT for ER+/HER2- BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24-40). Scores ranged between 5 and 77 with 50% >25 and 5% <11. Median Recurrence Score result was significantly higher among tumors achieving pCR vs. non-pCR response (61.5 vs. 23, pwilcoxon = 0.0005). pCR rate in patients with scores >25 was 21% (8/38) vs. 5% in patients with scores <25 (2/38) (p = 0.09), with both pCRs in the <25 group in patients with scores between 21 and 25. In multivariable analysis, only Recurrence Score result was significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01). CONCLUSIONS: In young women with ER+/HER2- BC who received NCT, higher pretreatment Recurrence Score result was associated with an increased likelihood of pCR. Gene expression profile assays may have a role in decision making in young women in need of neoadjuvant therapy.

Testosterone therapy and breast histopathological features in transgender individuals.

Testosterone therapy (TT) is administered to enhance masculinization in transgender individuals. The long-term effect of exogenous testosterone on breast tissues remains unclear. Our study evaluated the modulation of breast morphology by TT in transgender individuals with special attention to duration of TT. We reviewed 447 breast surgical specimens from gender affirming chest-contouring surgery, and compared histopathological findings including degree of lobular atrophy, and atypical and non-atypical proliferations between subjects who did (n = 367) and did not (n = 79) receive TT. TT for one patient was unknown. TT for >12 months was associated with seven histopathological features. Longer duration of TT was significantly associated with higher degrees of lobular atrophy (p < 0.001). This relationship remained significant after accounting for age at surgery, ethnicity, body mass index, and presurgical oophorectomy (adjusted p < 0.001). Four types of lesions were more likely to be absent in breast tissues exposed to longer durations of TT: cysts (median = 16.2 months; p < 0.01; adjusted p = 0.01), fibroadenoma (median = 14.8 months; p = 0.02; adjusted p = 0.07), pseudoangiomatous stromal hyperplasia (median = 17.0 months; p < 0.001; adjusted p < 0.001), and papillomas (median = 14.7 months; p = 0.04; adjusted p = 0.20). Columnar cell change and mild inflammation were also less likely to occur in subjects receiving TT (p < 0.05), but were not linked to the duration of TT. Atypia and ductal carcinoma in situ were detected in 11 subjects (2.5%) all of whom received TT ranging from 10.1 to 64.1 months. The incidental findings of high-risk lesions and carcinoma as well as the risk of cancer in residual breast tissue after chest-contouring surgery warrant the consideration of culturally sensitive routine breast cancer screening protocols for transgender men and masculine-centered gender nonconforming individuals. Long-term follow-up studies and molecular investigations are needed to understand the breast cancer risk of transgender individuals who receive TT.

Binary subclassification scheme (AUS-Nuclear versus AUS-Other) adequately risk-stratifies thyroid fine needle aspiration specimens classified as Atypia of Undetermined Significance.

INTRODUCTION: The Bethesda System for Reporting Thyroid Cytopathology previously described 4 subclasses of atypia within the Atypia of Undetermined Significance (AUS) category: nuclear (AUS-Nuc), architectural (AUS-A), oncocytic (AUS-Onc), and atypia not otherwise specified (AUS-NOS). Accumulating evidence supports a binary AUS subclassification scheme based primarily on the presence of nuclear atypia only. The purpose of this study is to compare the risk stratification of binary versus 4-tier AUS subclassification systems among AUS nodules with molecular and/or histologic follow-up. MATERIALS AND METHODS: Thyroid aspirates classified as AUS and tested using Afirma (Veracyte, Inc.) between 6/2013 and 7/2021 were included. For resected nodules, histological classification was considered as the final outcome. For unresected nodules, benign Afirma results were considered low-risk outcomes, similar to histologically benign nodules. Suspicious or nondiagnostic Afirma results were considered indeterminate outcomes. The prevalence of outcomes warranting surgery (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] or cancer) was calculated for each AUS subclass. RESULTS: A total of 559 AUS nodules with Afirma testing were identified. Excluding nodules with indeterminate molecular outcomes, NIFTP/cancer prevalence for AUS-Nuc was 21% (57/266), which was higher than that for AUS-A (6%, 11/188), AUS-Onc (8%, 4/53), and AUS-NOS (0%, 0/9). A binary AUS subclassification scheme based on nuclear atypia showed a significant difference in NIFTP/cancer prevalence (21% versus 6%, P < 0.0001). CONCLUSIONS: Binary reporting of AUS subclasses based on nuclear atypia distinguishes cases with a higher risk of NIFTP/cancer. There is a low but non-negligible prevalence of NIFTP/cancer in cases without nuclear atypia.

Pragmatic guide to the macroscopic evaluation of breast specimens.

The pathological assessment of a breast surgical specimen starts with macroscopic evaluation, arguably one of the most critical steps, as only a small percentage of the tissue is examined microscopically. To properly evaluate and select tissue sections from breast specimens, it is essential to correlate radiological findings, prior biopsies, procedures and treatment with the gross findings. Owing to its fatty nature, breast tissue requires special attention for proper fixation to ensure appropriate microscopic evaluation and performance of ancillary studies. In addition, knowledge of the information necessary for patient management will ensure that these data are collected during the macroscopic evaluation, and appropriate sections are taken to obtain the information needed from the microscopic evaluation. Herein, we present a review of the macroscopic evaluation of different breast specimen types, including processing requirements, challenges and recommendations.

Gastrointestinal stromal tumors in fine-needle aspiration biopsies.

Gastrointestinal stromal tumors (GISTs), although rare, are the most common mesenchymal neoplasms of the gastrointestinal tract. Their potential for malignancy underscores the significance of identifying them through cytomorphologic findings and pertinent immunohistochemical markers. GISTs can emerge anywhere along the gastrointestinal tract with a predilection for the stomach. The clinical manifestations vary from nonspecific abdominal symptoms to incidental discovery during diagnostic interventions for unrelated signs and symptoms. Cytologically, GIST aspirates contain spindle or epithelioid cells with immunoreactivity for CD117/c-KIT, DOG-1, and CD34. Molecularly, KIT or PDGFRA mutations are prevalent, guiding targeted therapy with tyrosine kinase inhibitors. Distinct subtypes like succinate dehydrogenase-deficient GISTs pose challenges, often affecting younger individuals and displaying unique features. Histologically, GISTs are graded by mitotic rates, aiding prognostication. Distinguishing GISTs from similar entities is pivotal, necessitating attention to their immunostaining patterns for making an accurate diagnosis and molecular alterations for effectively planning treatment. Common differential diagnoses include leiomyoma, schwannoma, and solitary fibrous tumor. This article presents a classic GIST case and showcases relatively simple diagnostic clues for identifying similar lesions that may occur in diverse locations.

Rapid Examination of Nonprocessed Renal Cell Carcinoma Using Nonlinear Microscopy.

CONTEXT.­: Histology, the traditional method of examining surgical tissue under a microscope, is a time-consuming process involving the fixation of tissue in formalin, dehydration, embedding in paraffin, and cutting into thin sections for hematoxylin-eosin (H&E) staining. Frozen section analysis is a faster alternative used in surgery to quickly evaluate tissue, but it has limitations, such as the size of the specimens that can be analyzed and difficulties with fatty and bony tissues. OBJECTIVE.­: To rapidly examine nonprocessed kidney tumors using nonlinear microscopy (NLM), a fluorescence microscopy technique that can rapidly visualize fresh or fixed, rapidly stained, nonprocessed tissue resembling H&E histology. This technology eliminates the need for fixation, embedding, microtome sectioning, or slide preparation. DESIGN.­: In this study, a total of 190 tissue specimens were collected from 46 patients who underwent partial or radical nephrectomy. RESULTS.­: Two genitourinary pathologists confirmed that diagnostically important features present in the H&E images could also be identified in the NLM images. CONCLUSIONS.­: The results of this study demonstrated that NLM had a high degree of correspondence with H&E staining for the classical variants of renal cell carcinoma. NLM offers several clinical benefits, such as facilitating rapid renal cell carcinoma diagnosis, assessment of targeted kidney biopsies for both tumor and medical kidney diseases, and collection of fresh renal cell carcinoma tissue for molecular studies.

Macroscopic examination of pathology specimens: a critical reappraisal.

Meticulous macroscopic examination of specimens and tissue sampling are crucial for accurate histopathology reporting. However, macroscopy has generally received less attention than microscopy and may be delegated to relatively inexperienced practitioners with limited guidance and supervision. This introductory paper in the minisymposium, Macroscopy Under the Microscope, focuses on issues regarding macroscopic examination and tissue sampling that have been insufficiently addressed in the published literature. It highlights the importance of specimen examination and sampling, discusses some general principles, outlines challenges and suggests potential solutions. It is critical to get macroscopy right the first time as it may not be possible to rectify errors even with expert histological assessment or to retrospectively collect missing data after the specimen retention period. Dissectors must, therefore, receive adequate guidance and supervision until they are proficient in macroscopic specimen examination. We emphasise the importance of the clinical context, optimal specimen fixation, succinct and clinically relevant macroscopic descriptions, macrophotography and judicious tissue sampling. We note that current recommendations based on the number of blocks to be submitted per maximum tumour dimension are ambiguous as the amount of tissue submitted in a cassette is not standardised and it is unclear whether 'block' refers to a tissue block or a paraffin block. Concerns around potential oversampling of 'therapeutic' specimens that could result in overdiagnosis due to detection of incidentalomas are also discussed. We hope that the issues discussed in this paper will engender debate on this clinically critical aspect of pathology practice.

Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

Objective: Determine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). Design: This is a cross-sectional study. Setting: TMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center. Participants: Of the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA. Main Outcomes and Measures: The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area). Results: Length of TT was associated with increasing degrees of lobular atrophy ( p <0.001) but not fibrous content ( p =0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(ß)=0.97, 95% CI 0.95-0.98, adj p =0.005) and stroma (exp(ß)=0.99, 95% CI 0.98-1.00, adj p =0.051), but not fat (exp(ß)=1.01, 95%CI 0.98-1.05, p =0.394) in fully adjusted models. There was no association between TT and radiologist's breast density assessment ( p =0.575) or LIBRA measurements ( p >0.05). Conclusions: TT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk. Summary Box: Very little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.

Multi-institutional 10-year retrospective review of amoeba diagnosed on cytologic evaluation of anal pap tests: what is the significance?

INTRODUCTION: Intestinal amoebae are usually transmitted via ingestion of amoebic cysts in fecally contaminated water or food. However, other modes of transmission include sexual contact through anal-oral sex. While the primary role of anal cytology is the detection of anal cancer and precursor lesions, organisms can also be identified. Despite this, assessment of the clinical significance of cytologic identification of amoebae is lacking in the literature. MATERIALS AND METHODS: A 10-year retrospective review of the pathology archives of 2 institutions in Boston, Massachusetts was conducted. Anal Pap tests that identified amoeba were reviewed and correlated with the medical records for investigation into clinical parameters and patient management. RESULTS: A total of 46 cases were identified between the 2 sites. The majority of patients were male (95.7%) and endorsed having sex with men (84.8%). Only a minority endorsed recent travel (6.5%). Most of the patients were also HIV (human immunodeficiency virus)-positive (71.1%) with all of these patients being well-controlled on antiretroviral therapy. Most patients were asymptomatic (87.0%). On review of the anal Pap tests, the average organism number per case was 35.4. In the majority of cases, follow-up microbiology testing for confirmation and/or speciation was not performed (89.1%) and were not treated (93.5%). CONCLUSIONS: While identification of amoeba is possible on anal cytology, the clinical significance remains unclear as most patients were asymptomatic and not treated in this series. Ultimately, the clinical setting likely plays an important role in determination of management.