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Objective: To assess the incidence of testicular cancer in trans women (male sex assigned at birth, female gender identity) using gender-affirming hormonal treatment. Materials and methods: Data of trans women starting hormonal treatment at our gender identity clinic between 1972 and 2017 were linked to the national pathology database to obtain testicular cancer diagnoses. The standardized incidence ratio (SIR) was calculated using the number of observed testicular cancer cases in our cohort and the number of expected cases based on age-specific Dutch incidence rates. Subgroup analyses were performed in testicular tissues send for histopathological analysis at time of bilateral orchiectomy, and when follow-up time exceeded 5 years. Results: The cohort consisted of 3,026 trans women with a median follow-up time of 2.3 years (interquartile range 1.6-3.7). Two testicular cancer cases were identified whilst 2.4 cases were expected (SIR 0.8, 95% CI 0.1-2.8). In addition, one testicular cancer case was encountered in an orchiectomy specimen (0.1%). In the 523 trans women with a follow-up time exceeding 5 years (median 8.9 years, interquartile range 6.4-13.9), no testicular cancer was observed. Conclusion: Testicular cancer risk in trans women is similar to the risk in cis men. The testicular cancer cases occurred within the first 5 years after commencing hormonal treatment, and the percentage of cases encountered at time of bilateral orchiectomy was low. Since no testicular cancer was observed in trans women with a long follow-up time, long-term hormonal treatment does not seem to increase testicular cancer risk. Keywords: carcinogenesis; estrogen; gender dysphoria; gender-affirming hormonal treatment; testicular cancer; transgender.

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.

Immunoglobulin light chain (AL) amyloidosis is characterized by the deposition of amyloid fibers derived from pathologic immunoglobulin light chains. Although systemic plasma cell neoplasms are the most common cause of AL amyloidosis, a subset of cases is caused by B-cell lymphoproliferative disorders such as lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Recently, SOX11-negative IGH hypermutated mantle cell lymphoma (MCL) is recognized to show frequent plasmacytic differentiation and indolent clinical course. Here we report three cases of peritumoral AL amyloidosis associated with SOX11-negative MCL. All three cases showed Cyclin D1 expression by immunohistochemistry and CCND1 translocation as detected by fluorescence in situ hybridization analysis. Peritumoral AL amyloidosis was observed at the biopsy sites in the GI tract, a supraclavicular lymph node, and a cervical lymph node, and all presented with marked plasmacytic differentiation of lymphoma cells. None of the cases showed evidence of bone marrow involvement by morphology and immunophenotyping. None of the patients had distant organ involvement with systemic amyloidosis. All three patients had an indolent clinical course and are alive with disease at the time of last follow up (range 48–74 months). Our findings show that MCL with plasmacytic differentiation can cause amyloid deposition and CCND1 abnormalities should be performed in all cases of extramedullary AL amyloidosis. Recognition of indolent MCL as a cause of peritumoral AL amyloidosis may have important clinical management implications.

Summary: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy. Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course. Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41–78). Median disease course (time from onset of symptoms to death) was 22 days (range 5–44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5–44]; ten patients with neutrophilic plugs, 21 days [5–44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.. Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. Funding: Amsterdam UMC Corona Research Fund.

Purpose For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. Methods Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff’s alpha (KA) and Gwet’s AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. Results Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05–6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35–5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34–10.23) were independently associated with a higher iIBC risk. Conclusions Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

Context Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. Objective To assess the incidence of prostate cancer in trans women using hormone treatment. Design In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. Setting Gender identity clinic. Participants Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. Main Outcome Measures Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. Results The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). Conclusions Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.

The role of cytopathology in malignant lymphoma is largely restricted to primary screening in patients with lymphadenopathy of unknown causes and evaluation of relapse and transformation during follow-up of patients with known and fully classified malignant lymphoma. Few lymphoma diagnoses fully rely on cytology, although breast-implant associated anaplastic large cell lymphoma is currently the centre of clinical attention. Due to the major attention both in the medical and lay media for the recently substantiated high lymphoma risk in women with breast implants, cytopathology departments now frequently receive seroma fluid aspirates with this specific differential diagnostic consideration. In this review, we discuss clinico-pathological aspects of breast-implant associated anaplastic large cell lymphoma from a cytological point of view and provide guidelines for the processing of aspirates in daily practice and strategies for diagnostic work-up of seroma fluids.

Introduction: Accurate staging of patients with locally advanced breast cancer or locoregional recurrent (LRR) breast cancer is essential for providing a tailored treatment. According to current guidelines, staging is preferably done with positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), combined with diagnostic computed tomography (CT). Previous studies suggest that [18F]FDG PET might underperform in patients with grade 1-2, estrogen receptor positive (ER+) breast cancer as these tumors are often metabolically less active than other subtypes of breast cancer. Thus, there is a need to improve current diagnostics for this population. 16α-[18F]-fluoro-17β-estradiol ([18F]FES), radioactive labeled estradiol, has emerged as a powerful imaging tool for in vivo visualization of ER+ lesions. The aim of this study was to investigate whether [18F]FES PET/CT improves staging of patients with clinical stage II/III or LRR ER+ breast cancer, compared to [18F]FDG PET/CT. Methods: Patients with clinical stage II/III or LRR 1-2, ER+ breast cancer were included in this prospective multicenter clinical trial (NCT03726931). All patients underwent a [18F]FES PET/CT and a [18F]FDG PET/CT scan. Both PET scans were visually assessed, independently of each other. Visually suspect lesions for malignancy were verified pathologically (by biopsy or fine needle aspiration) or by conventional imaging (mammography, ultrasound, magnetic resonance imaging, CT). The stage of the disease was determined twice in a multidisciplinary team, based on conventional diagnostics (conventional imaging and pathology) and [18F]FDG PET/CT or [18F]FES PET/CT, respectively. Semi-quantitative PET parameters, standardized uptake values (SUVs) and tumor-to-blood ratios (TBRs), were obtained by defining volumes of interest in the aorta ascendens and in suspect tumor lesions. These PET parameters were correlated with various pathological features, such as histological subtype, grade and ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression. Results: A total of 40 patients were included. On patient level, the sensitivity of [18F]FES PET/CT and [18F]FDG PET/CT to detect ER+ disease was 87.5% and 82.5%, respectively. [18F]FES PET/CT correctly determined the stage in 34/40 patients (85.0%) whereas [18F]FDG PET/CT correctly determined the stage in 29/40 patients (72.5%). [18F]FES PET/CT correctly changed the stage in 8/40 patients (20.0%) with upstaging in 6 patients and downstaging in 2 patients, compared to [18F]FDG PET/CT. On lesion level, a total of 140 suspect lesions were analyzed: 82 lesions were pathologically verified whereas 58 were radiographically verified. The sensitivity for lesion detection on [18F]FES PET/CT and [18F]FDG PET/CT was 90.6% and 77.3%, respectively. [18F]FES PET/CT identified more lesions correctly: 120/140 (85.7%) lesions vs 103/140 (73.6%) on [18F]FES PET/CT vs [18F]FDG PET/CT, respectively. [18F]FES PET/CT also missed less lesions (12/140, 8.6%) compared to [18F]FDG PET/CT (29/140, 20.7%). [18F]FES SUVmax, SUVmean, SUVpeak and TBR correlated with ductal subtype and percentage of PR expression (p Citation Format: Ramsha Iqbal, Emma C Bonjer, Annette van Zweeden, Lemonitsa H Mammatas, Jaap JM Teunissen, Jan Booij, Gwen MP Diepenhorst, Laura Schijf, Susanne van der Velde, Katya Duvivier, Ellis Barbé, Daniela E Oprea-Lager, Catharina W Menke-van der Houven van Oordt. Towards a new standard for staging: A comparative study of [18F]FES PET/CT vs [18F]FDG PET/CT in patients with clinical stage II/III and locoregional recurrent estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-11.

Background Neoadjuvant chemotherapy (NACT) is increasingly used in patients with operable disease due to the potential of converting patients requiring mastectomy to breast conserving surgery (BCS) or lowering resection volumes to improve cosmetic outcome. This nationwide retrospective study aims to determine margin status and specimen volume in patients with invasive breast cancer who underwent BCS after NACT. Methods All patients who underwent BCS in 2012–2013 for invasive breast cancer were selected from a nationwide network and registry of histology and cytopathology in the Netherlands (PALGA). Results Of the 9901 patients, 626 (6.3%) received NACT. After primary surgery 949 (10.2%) patients had tumour-involved margins compared to 152 (24.3%) after NACT. Close margins (≤1 mm) were seen in another 111 (17.7%) patients after NACT. The adjusted odds ratio for involved margins after NACT was 2.94, meaning a three times higher risk of involved margins compared with primary surgery. In patients with lobular carcinoma (54.9%) and no response to NACT (42.1%) higher tumour-involved margins were seen. High resection volumes >60 cc were observed in 224 (36%) patients after NACT of which 37 (16.5%) had tumour involved margins and 32 (14.3%) close margins ≤1 mm. Conclusion The primary goal of the surgeon performing BCS after NACT, to reach tumour-free margins, is not accomplished in one out of four patients. Patients especially at risk are patients with ILC and no pathological tumour response. Excessive resection volumes after NACT do not guarantee tumour-free margins. Further research is necessary to analyze whether we are counterproductive when NACT is given in order to lower resection volumes.

Real‐time assessment of excised tissue may help to improve surgical results in breast tumor surgeries. Here, as a step towards this purpose, the potential of second and third harmonic generation (SHG, THG) microscopy is explored. SHG and THG are nonlinear optical microscopic techniques that do not require labeling of tissue to generate 3D images with intrinsic depth‐sectioning at sub‐cellular resolution. Until now, this technique had been applied on fixated breast tissue or to visualize the stroma only, whereas most tumors start in the lobules and ducts. Here, SHG/THG images of freshly excised unprocessed healthy human tissue are shown to reveal key breast components—lobules, ducts, fat tissue, connective tissue and blood vessels, in good agreement with hematoxylin and eosin histology. DNA staining of fresh unprocessed mouse breast tissue was performed to aid in the identification of cell nuclei in label‐free THG images. Furthermore, 2‐ and 3‐photon excited auto‐fluorescence images of mouse and human tissue are collected for comparison. The SHG/THG imaging modalities generate high quality images of freshly excised tissue in less than a minute with an information content comparable to that of the gold standard, histopathology. Therefore, SHG/THG microscopy is a promising tool for real‐time assessment of excised tissue during surgery., Most breast cancers are carcinomas, a type of cancer that is derived from epithelial cells, aligning ducts and lobules. This study shows that second and third harmonic generation (SHG/THG) microscopy reveals the morphology of those key structures in freshly excised, unprocessed human breast tissue, including their cells and cell nuclei. The SHG/THG images have an information content comparable to that of the gold standard, (H&E histology) but are generated much faster, in less than a minute.

ObjectiveTo investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.DesignRetrospective, nationwide cohort study.SettingSpecialised tertiary gender clinic in Amsterdam, the Netherlands.Participants2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.Main outcome measuresIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.ResultsThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).ConclusionsThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.