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.

Challenging lesions in cervical cytology: The elusive HSIL.

Cervical cytology has been an integral part of cervical cancer screening since the mid-20th century with the implementation of screening protocols utilising Pap testing. During that time, cervical cancer has gone from the leading cause of cancer deaths in women to not even appearing in the top 10 causes of US cancer deaths. However, despite its long and widespread use, cervical cytology remains a diagnostically challenging area in the practice of cytopathology. Of particular importance for diagnosticians is the accurate diagnosis of high-grade squamous intraepithelial lesions (HSILs), given the significant risk of progression to invasive cervical cancer and the importance to patient management. Therefore, this review is presented in order to highlight the diagnostic features of HSIL, its various appearances, and important benign and neoplastic differential considerations with an emphasis on morphological clues that can aid in distinguishing between these different processes.

Criteria for placental examination for obstetrical and neonatal providers.

Pathologic examination of the placenta can provide insight into likely (and unlikely) causes of antepartum and intrapartum events, diagnoses with urgent clinical relevance, prognostic information for mother and infant, support for practice evaluation and improvement, and insight into advancing the sciences of obstetrics and neonatology. Although it is true that not all placentas require pathologic examination (although alternative opinions have been expressed), prioritization of placentas for pathologic examination should be based on vetted indications such as maternal comorbidities or pregnancy complications in which placental pathology is thought to be useful for maternal or infant care, understanding pathophysiology, or practice modifications. Herein we provide placental triage criteria for the obstetrical and neonatal provider based on publications and expert opinion of 16 placental pathologists and a pathologists' assistant, formulated using a modified Delphi approach. These criteria include indications in which placental pathology has clinical relevance, such as pregnancy loss, maternal infection, suspected abruption, fetal growth restriction, preterm birth, nonreassuring fetal heart testing requiring urgent delivery, preeclampsia with severe features, or neonates with early evidence of multiorgan system failure including neurologic compromise. We encourage a focused gross examination by the provider or an attendant at delivery for all placentas and provide guidance for this examination. We recommend that any placenta that is abnormal on gross examination undergo a complete pathology examination. In addition, we suggest practice criteria for placental pathology services, including a list of critical values to be used by the relevant provider. We hope that these sets of triage indications, criteria, and practice suggestions will facilitate appropriate submission of placentas for pathologic examination and improve its relevance to clinical care.

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.

Histopathologic findings in breast surgical specimens from patients undergoing female-to-male gender reassignment surgery.

Breast reduction surgery or mastectomy following administration of androgen therapy is part of the female-to-male gender reassignment process. Details regarding the histopathologic findings in breast tissue from patients undergoing female-to-male gender reassignment surgery are limited. We reviewed hematoxylin and eosin-stained sections of breast tissue from 148 patients who underwent breast reduction surgery or mastectomy as part of the female-to-male gender reassignment process at our institution between January 2014 and May 2017. The spectrum of histologic features in each case was catalogued. The median patient age was 27 years (range 18-60 years). Lobular atrophy was seen to some degree in 73% of cases and was prominent in 42%. A predominantly fibrotic stroma was seen in 45% of cases and areas resembling the fibrous stage of gynecomastia were seen in 41%. Other features included variably ectatic ducts in 96% of cases, cysts in 42%, apocrine metaplasia in 32%, fibroadenomatous change in 27%, usual ductal hyperplasia in 26%, and pseudoangiomatous stromal hyperplasia in 19%. Five cases (3%) demonstrated atypical hyperplasia (atypical ductal hyperplasia in 2; atypical lobular hyperplasia in 2; both atypical ductal hyperplasia and atypical lobular hyperplasia in 1). One case demonstrated high grade ductal carcinoma in situ. No invasive carcinomas were identified. In conclusion, the majority of breast specimens from patients undergoing female-to-male gender reassignment demonstrate at least some degree of lobular atrophy as well as ectatic ducts, fibrous stroma, and areas resembling the fibrous stage of gynecomastia. Only rare cases showed atypical lesions; the clinical significance of these lesions in this setting is uncertain.

A Rare Case of a Pilar Cyst With Ductal Differentiation.

Pilar cysts are common squamous-lined cysts that typically occur on the scalp. They are believed to arise from the isthmus of anagen hairs or from the sac surrounding catagen and telogen hairs. The authors describe a rare case of a pilar cyst with prominent ductal differentiation, presumably of eccrine derivation. Sweat duct differentiation has been described in a myriad of cutaneous neoplasms and rarely within epidermoid cysts. The authors could only find one other case in the literature describing a pilar cyst with sebaceous and apocrine differentiation. The clinicopathologic findings are described here.

Cytopathology fellowship match: Pros and cons.

A cytopathology fellowship match would create an enforced and structured recruitment timeline for the benefit of applicants and programs. Major benefits would include delaying fellowship applications to allow residents to explore different subspecialty areas, a standardized application process for administrative ease, and optimization of matches between applicants and programs based on ranked preferences rather than use of time-limited "exploding offers." The overall gains in efficiency and achieving the primary goals of supporting trainees and recruiting in an equitable and inclusive manner outweigh any downsides to instituting a cytopathology fellowship match. We aim to review the major discussions around this ongoing debate, arriving at the same conclusion as others in the literature that a pan-pathology fellowship match is ideal and that leadership from the Association of Pathology Chairs will be essential in unifying the fractured fellowship recruitment process.

Evaluation of abdominal fat pad aspiration highlighting challenges to interpretation.

INTRODUCTION: Fine-needle aspiration (FNA) of abdominal fibroadipose tissue is a commonly utilized method for the detection of amyloidosis. While generally regarded as an accurate and specific detection method, the sensitivity is variable. The objective of this study was to investigate the performance of fat pad FNAs in detecting amyloidosis relative to other tissue biopsies. MATERIALS AND METHODS: Fat pad FNA results from January 1, 2014, to December 31, 2022, were catalogued. Clinical data including FNA indication were ascertained for each case. The results of any subsequent tissue biopsy/biopsies evaluated for amyloidosis by Congo red staining were also assessed. Challenges to diagnostic interpretation were explored. RESULTS: A total of 334 fat pad FNAs were identified. The most common indications were peripheral neuropathy (29.3%), cardiomyopathy/heart failure (28.1%), monoclonal gammopathy (27.8%), and multiple myeloma/lymphoplasmacytic lymphoma (21.0%). Cytologic interpretations were: 7 (2.1%) nondiagnostic, 284 (85.0%) negative, 18 (5.4%) indeterminate, 16 (4.8%) suspicious, and 9 (2.7%) positive for amyloid deposition. In our sample, 103 (30.8%) patients had Congo red testing performed on a subsequent surgical specimen(s) including: 3 of 7 of nondiagnostic cases, none which were positive on the subsequent surgical; 70 of 284 negative cases, 27 which were positive on the subsequent surgical; 11 of 18 indeterminate cases, 7 which were positive on the subsequent surgical; 13 of 16 suspicious cases, 2 which were positive on the subsequent surgical; and 6 of 9 positive cases, 3 which were positive on the subsequent surgical. Challenges to FNA interpretation included scant cellularity, focal staining/birefringence, and overstaining. CONCLUSIONS: It is best to view fat pad aspiration versus other tissue biopsy results as complimentary diagnostic tests that should be interpreted in the context of the clinical setting and overall clinical suspicion for amyloidosis.

A case of lung FNA with atypical squamous cells.

Fine-needle aspiration (FNA) is a commonly employed method for initial diagnosis and work-up of pulmonary nodules. Utilization of rapid on-site evaluation (ROSE) has the added benefit of allowing for triaging of material as appropriate for ancillary studies including microbiology testing. While many pulmonary lesions are easily categorized by cytologic evaluation, more difficult cases exist. In particular, pulmonary lesions demonstrating atypical squamoid cells can cause diagnostic challenge given the morphologic overlap between benign and malignant pulmonary lesions showing atypical squamoid cells. We herein review these common and uncommon squamoid lesions, which may enter within the differential when encountering atypical squamoid cells in pulmonary FNA specimens with emphasis on morphologic pitfalls and approaches to appropriate categorization.

Interobserver agreement and diagnostic challenges of Congo red staining for amyloid detection on fat pad aspiration biopsies.

INTRODUCTION: Congo red staining of fat pad fine needle aspiration specimens is a method utilized for evaluation of amyloid deposition. However, these specimens can pose diagnostic challenges for cytopathologists. As part of ongoing internal quality improvement measures, the objective of this study was to evaluate the intradepartmental interobserver agreement of these specimens and to identify factors that affect the variability of the interpretations. MATERIALS AND METHODS: There were 7 participants, which included 3 trainees, 3 cytopathologists, and 1 cytotechnologist. Each participant reviewed 50 Congo red stained fat pad fine needle aspiration slides. The interpretations were categorized into 3 groups: negative, indeterminate/suspicious, and positive. The participants also noted any interpretation challenges they encountered for each case. RESULTS: There was only slight interobserver agreement among all participants (κ = 0.133). Stratified by participant group, the interobserver agreement among the trainees was slight bordering on poor (κ = 0.028) and among cytopathologists was fair (κ = 0.249). The highest agreement between 2 observers was between 2 cytopathologists and the level of agreement was moderate bordering on fair (κ = 0.426). There were only 3 cases (6.0%) with full agreement among observers, while in 25 cases (50.0%), there were 2 category differences in interpretations. The primary diagnostic challenge reported by participants was when weak or focal birefringence was encountered as well as cases complicated by poor stain quality and overstaining. CONCLUSIONS: We found only slight interobserver agreement among all study participants. A major area of challenge was cases with weak birefringence resulting in high variance of interpretation among participants.

Cytologic features of differentiated high-grade thyroid carcinoma: A multi-institutional study of 40 cases.

BACKGROUND: Differentiated high-grade thyroid carcinoma (DHGTC) is recently recognized by the World Health Organization (WHO) as a subgroup of thyroid carcinomas with high-grade features while retaining the architectural and/or cytologic features of well-differentiated follicular-cell-derived tumors. The cytomorphology of DHGTC is not well documented despite potential implications for patient triage and management. METHODS: The pathology archives of six institutions were searched for cases diagnosed on resection as "high-grade thyroid carcinoma" using WHO criteria. The fine-needle aspiration (FNA) cohort represents a 10-year period (2013-2023); all were reviewed to confirm DHGTC classification. The corresponding FNAs were assessed for 32 cytomorphologic features. RESULTS: Forty cases of DHGTC with prior FNA were identified. The mean patient age was 64.2 years. The average lesion size was 4.9 cm, and the majority demonstrated a TI-RADS score of 4 or 5 (95.2%). Three main high-grade subsets of DHGTC based on corresponding histology included papillary thyroid carcinoma (65%), follicular carcinoma (22.5%), and oncocytic carcinoma (12.5%). Over 97% of FNA cases were classified as Bethesda category IV or above. Approximately 25% of DHGTC showed cytologic features that included marked cytologic atypia, increased anisonucleosis, large oval nuclei, mitotic activity, or necrosis (p < .05); 68% of DHGTC cases were associated with high-risk molecular alterations. TERT mutations occurred in 41%, of which 89% of these were associated with a second mutation, usually RAS or BRAF p.V600E. CONCLUSIONS: Cytology has a low sensitivity for DHGTC, although a subset of DHGTCs have cytologic features raising the possibility of a high-grade thyroid carcinoma. Other findings include high-risk molecular changes and clinicopathologic features such as older patient age and larger lesion size.

Cervicovaginal Papanicolaou tests in transgender men: Cytomorphologic alterations, interpretation considerations, and clinical implications.

BACKGROUND: The transgender population faces unique psychosocial and physical obstacles to cervical cancer screening. Additionally, most individuals undergo masculinizing testosterone hormone therapy, and the physiologic changes can cause cytomorphologic alterations that may mimic lesions. Although the literature on cervicovaginal cytology is growing in this patient population, it is still limited. METHODS: The pathology information system was queried for all Papanicolaou (Pap) tests from transgender men from January 2013 to February 2023. The original diagnostic categories were catalogued. Cases were reviewed to evaluate the cytomorphologic alterations. Clinical data were also sought, including whether the sample was self-collected. Two comparison groups were established: one was a postpartum atrophic group and the other was an all-comer group. RESULTS: A total of 51 cases from 43 individuals were identified, with a mean age of 31 years. Approximately a third of cases (18 of 51; 35%) were self-collected. The abnormal rate was low, with 5.9% of cases rendered atypical squamous cells of undetermined significance on original review and no lesions identified. The Pap unsatisfactory rate according to original reports was 3.9%. This increased to 13.7% when the cases were rereviewed, which was significantly higher than the all-comer comparison group. The unsatisfactory rate did not correlate with self-collection. Atrophy was a prevalent cytomorphologic alteration, with the vast majority of cases (92%) showing at least mild atrophy. Small blue cells and transitional cell metaplasia were seen in many cases (53% and 43%, respectively). CONCLUSIONS: There are clinical and morphologic considerations that are distinct to the transgender patient population. Laboratory personnel and diagnosticians need to be aware of these in order to optimize patient care.

Fun with fungi: a comprehensive review of common fungal organisms encountered in cytology.

The ability to detect and diagnose infection is essential in the practice of cytopathology. The identification of suppurative or granulomatous inflammation should prompt careful evaluation for infection. Many of the most commonly encountered fungal organisms demonstrate characteristic microscopic appearances that allow accurate identification even with routine cytology stains, particularly when considered in the context of clinical factors such as geographic location, social history, patient immune status, and symptoms. Given the vital role cytopathologists play in the accurate diagnosis or presumptive identification of infections, this review explores the epidemiology, clinical manifestations, and morphologic features of common fungal pathogens in addition to their differential diagnoses and ancillary testing methods.

Leveraging thoughtful quality metric selection for individual and system improvements: the atypical category and use of dashboards.

Quality management is integral to the practice of cytopathology, especially given the heavily manual workflows and expanding ancillary testing requirements inherent to the cytopathology laboratory. Monitoring quality data like turnaround time, specimen unsatisfactory rates, and diagnostic category utilization rates allows for better understanding of performance with opportunities for targeted improvement if there are variations from that which is expected. However, there are costs to quality monitoring including the time and resources needed, and, in already taxed systems, quality management risks being viewed as just another box to check. While there are mandated quality metrics that must be collected by cytology laboratories, thoughtful selection of key performance indicators can be of tremendous benefit in helping to better understand complex laboratory processes and directing improvement endeavors where needed. The following short communication is a discussion on quality management in the cytopathology laboratory from 3 Cytopathology Quality Management Directors. The discussion focuses on monitoring the atypical reporting category with an emphasis on how trending and visualizing quality metrics can provide laboratories with key data.

Thyroblastoma: A DICER1-associated embryonal neoplasm and fine needle aspiration diagnostic criteria.

Thyroblastoma is a rare, aggressive embryonal thyroid neoplasm associated with DICER1 mutation. It usually presents as a rapidly growing thyroid mass diffusely infiltrating the thyroid lobes and extending into perithyroidal tissue. Most thyroblastomas were initially diagnosed as malignant teratoma or carcinosarcoma. The cytologic features of thyroblastoma have not been well documented. Here, we present the cytological findings of a case of thyroblastoma in a 19-year-old female with a dominant solid left thyroid nodule. A fine needle aspiration biopsy of the mass revealed a highly cellular aspirate composed of crowded, atypical, high nuclear to cytoplasmic ratio epithelial cells, arranged in a variety of architectural patterns including rosette-like microfollicular, solid, and morular. In addition, the background contains a minor population of atypical mesenchymal cells. The cytologic differential diagnosis of thyroblastoma includes primary thyroid neoplasms such as adenomatous nodule, follicular adenoma, follicular carcinoma, and poorly differentiated thyroid carcinoma as well as metastatic carcinoma.

Utilization of Oil Red O staining for assessing aspiration risk in lung transplant patients: A multidisciplinary prospective study with clinical practice insights.

BACKGROUND: Gastroesophageal reflux disease with microaspiration has been associated with graft dysfunction in lung transplant patients. Identifying patients with aspiration is clinically important because it enables implementation of appropriate interventions like antireflux therapy. Oil Red O (ORO) staining with determination of the lipid-laden macrophage index (LLMI) has been proposed as a noninvasive surrogate marker in the detection of aspiration. The aim of this study was to prospectively evaluate clinical utilization of ORO staining in the assessment of aspiration risk. METHODS: All transbronchial surgical pathology biopsies obtained in lung transplant patients undergoing routine surveillance from August 2020 through November 2021 were included in this study. Clinical team members prospectively ascertained the aspiration risk category (ARC) of each patient both before and after biopsy findings and recorded reasons for change in ARC. RESULTS: A total of 132 transbronchial biopsies with concurrent LLMI were included in the study. LLMI was low in 51 cases (38.6%), including 21 of the 54 cases (38.9%) where aspiration was suggested based on the transbronchial biopsy findings. In total, 19 cases (14.4%) underwent a change in ARC post-biopsy including 10 that were upgraded and nine cases that were downgraded. Transbronchial biopsy findings were noted as the reason for change in ARC in the majority (15/19; 79%) of cases; only a minority (2/19; 10.5%) were due to the LLMI. Notably, 16 cases (12.1%) had a low LLMI with high-risk post-biopsy ARC and nine cases (6.8%) had a high LLMI with low-risk post-biopsy ARC. CONCLUSIONS: This study observed that clinical evaluation for aspiration relied more heavily on transbronchial biopsy findings. Although LLMI may retain clinical utility in some scenarios, reevaluation of the clinical value of ORO testing would be prudent.

Cytopathology fellowship recruitment: historical context, current state, and future considerations.

Fellowship recruitment and retention of a skilled workforce is one of the biggest challenges that not only cytopathology is facing but that the field of pathology in general is being confronted with. There have long been issues with the fellowship recruitment process for both applicants and fellowship directors, including pressure to move the application process earlier and earlier and frustrations stemming from applicants needing to determine different individual timelines and program requirements. The unified timeline for fellowship recruitment was established as an attempt to standardize the recruitment process and to address the key issues of the push for earlier and earlier decision-making, which placed significant anxiety on trainees, as well as the burden on programs of more unexpected openings. While institution of the unified timeline has had many successes, there have been problems as well. Here, we discuss the multifaceted and intertwined factors that affect fellowship recruitment with a review of the historical context and the current setting and with an eye towards future directions. In the end, the issues we are currently facing are complex and there is likely no perfect solution to fixing an inherently broken system. However, the ultimate goal should be in better supporting our trainees' development and promoting a more fair and equitable recruitment process. Only by working together can we optimize the process for both applicants and programs alike.

Cell blocks in cytology: review of preparation methods, advantages, and limitations.

Cell blocks are cytologic preparations that are processed as paraffin embedded blocks in a manner comparable to formalin-fixed paraffin-embedded tissue in surgical pathology. In addition to serving as an adjunct to other cytologic preparations for morphologic diagnosis, cell blocks play an increasingly important role as they yield tissue sections that can be utilized for ancillary testing such as immunohistochemical stains and molecular studies. While essentially universally viewed as playing a pivotal role in cytopathology practice, there are various factors that limit their use in practice and contribute to dissatisfaction with cell block quality. Cell block preparation, as opposed to tissue processing in surgical pathology, is more variable with many different protocols in use today. This review explores the most commonly used cell block preparation techniques currently in use with review of the unique advantages and limitations each method presents. The goal of this work is to serve as a resource that can aid in making more informed decisions about which cell block protocol may work best for individual laboratories.