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No literature is available on the benign versus malignant breast lesion ratio in trans women (male sex assigned at birth, female gender identity). As hormone treatment in trans women results in breast tissue histologically comparable with cis (non-trans) women, breast pathology may be expected. Previously, an increased breast cancer risk compared with cis men have been observed. We aimed to investigate the frequency and outcomes of breast biopsies in trans women. Therefore, we retrospectively examined the medical files of 2616 trans women. To gain data on breast lesions, we linked our cohort to a national pathology database. In this study we found that 126 people (5%) had one or more breast biopsies (n = 139). Of these, 21 trans women had a breast biopsy before the start of hormone treatment, and 53 after the start of hormone treatment. Breast biopsies were performed predominantly because of abnormalities during physical examination (37%, n = 51/139 biopsies), or because of capsular formation or contraction (28%, n = 16/57 biopsies) in trans women with breast implants. The most common breast lesions after the start of hormone treatment were fibroadenomas (n = 20), breast cancer (n = 6), fibrosis (n = 5), cysts (n = 4), and infections (n = 4). The benign versus malignant breast biopsy ratio was 88:12, which is comparable to the ratio in cis women (90:10). This study shows breast lesions in a limited number of trans women. Since the indications and outcomes of biopsies in trans women were similar to those in cis women, it seems reasonable to follow breast care guidelines as developed for cis women.

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.

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.

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.

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.

We present the case of a 63-year-old Caucasian male who complained of persistent rhinitis and sinusitis accompanied by a total left-sided nasal blockage. The diagnosis nasal T/NK cell lymphoma was established by histopathological investigation. This case was diagnosed as stage IE lymphoma as no other sites were involved. The patient was treated with CHOP (cyclophosfamide, doxorubicin, vincristin and prednisone) chemotherapy and involved-field radiotherapy. The nasal T/NK cell lymphoma is a rare malignancy, which is known to have an extremely aggressive and destructive course. The mainstay of treatment is locoregional radiotherapy combined with chemotherapy, depending on disease stage. A high index of clinical suspicion is imperative to ensure early diagnosis and ultimately improve disease outcome.

Summary The thrombolytic and antithrombotic effects of tissue-type plasminogen activator (t-PA) depend on its concentration in the blood. The mannose receptor is one of the receptors that mediate the rapid clearance of t-PA from the blood by the liver (Noorman and Rijken, Fibrinolysis & Proteolysis 1997; 11: 173–186). We hypothesized that by blocking the binding of t-PA to this receptor it might be possible to decrease the clearance of t-PA and thereby increase the plasma concentration of endogenous t-PA and exogenous t-PA. Inhibitors of the t-PA-mannose receptor interaction may thus be useful drugs in thrombolytic and antithrombotic therapy. We developed monoclonal antibodies against the human mannose receptor. These antibodies are able to inhibit binding of t-PA to the mannose receptor. By use of the antibodies it was shown that the mannose receptor is expressed by few human cell types. The expression of the mannose receptor on macrophages is highly regulated and depends on the type of macrophage activation. The expression of the mannose receptor in the liver is limited to endothelial cells and Kupffer cells. We developed high affinity ligands of the mannose receptor that are able to inhibit the plasma clearance of therapeutic t-PA doses by maximally 60% in the rat. Therapeutical concentrations of the low affinity mannose receptor ligand and antithrombotic agent dextran partially inhibit t-PA plasma clearance (33%) and thereby increase endogenous t-PA plasma concentrations by 20–60% in the rat. Thus mannose receptor inhibitors can be considered as a new tool to increase the t-PA concentration in blood and thereby increase its thrombolytic and antithrombotic effects.

Bone marrow macrophages are found in intimate contact with erythroblasts. Exact mechanisms and functions of this interaction are unclear. New insights into erythroblast binding were obtained using a newly developed bone marrow frozen section assay. This modified Woodruff and Stamper assay has some important advantages compared to other adhesion assays. Erythroblasts specifically adhered to bone marrow macrophages forming clusters, as appear in vivo. Selective depletion of bone marrow macrophages by intravenous injection of dichloromethyl-enediphosphonate resulted in a release of immature erythroid cells to the peripheral blood. Furthermore no erythroblasts adhered to bone marrow sections without macrophages. Evaluating the binding of erythroblasts to bone marrow macrophages we found that this binding is temperature and cation dependent. The receptor for erythroblasts present on macrophages recognizes a sialyated protein as ligand on erythroblasts, since neuraminidase treatment of erythroblasts resulted in a decrease in binding. A possible candidate for the erythroblast receptor on macrophages is the ED2 antigen. ED2 is a differentiation antigen present on resident macrophages that has some biochemical features characteristic of an adhesion molecule. Erythroblast binding to bone marrow was inhibited using a monoclonal antibody directed against ED2.

The haematopoietic microenvironment is believed to play an important role in controlling the haematopoietic process. Ultrastructural studies have shown that the haematopoietic stroma is composed of cellular as well as extracellular components. Relatively little is known about the distribution of the different stromal components in the bone marrow. The knowledge on the bone marrow microenvironment is mainly based on studies in which in vitro long-term bone marrow cultures have been used. Although this culture system offers a unique possibility to study haematopoietic in vitro, it does not fully represent the complexity of intact bone marrow. In the present study we describe the immunohistochemical distribution of different cellular and extracellular stromal components in frozen sections of rat bone marrow as well as in long-term bone marrow cultures, in order to compare the haematopoietic microenvironment used in in vitro studies in the in situ situation. We found that in situ a specific compartmentalization of stromal components exists in the bone marrow. Under culture conditions however, most stromal components are indeed present but the architecture present in the in situ situation had almost completely disappeared. The interaction between the different stromal elements was studied in the long-term bone marrow cultures. It appeared that under the chosen conditions, nodules were formed with a core of reticular cells and extracellular matrix. In close contact with this core immature macrophages appeared to proliferate and differentiate into mature, non-dividing macrophages.

Background Breast-conserving surgery currently focuses on improving margin clearance and excision volume, the main pathology report parameters for oncological and cosmetic outcomes. Aim To quantitatively evaluate discrepancies in surgical and pathological estimates of breast specimen sizes, including the influence of formalin fixation. Methods This prospective multicentre study included 68 breast specimens of consecutive patients undergoing breast-conserving surgery for breast cancer in three affiliated hospitals between November 2010 to May 2011. Specimens were weighed immediately after excision. Specimen volumes were calculated from the length, width and height. Actual specimen volumes were measured using volume displacement. Specimens were weighed once again after arrival at the pathology department, and volumes recalculated. The smallest pre- and post-fixation distances to the tumour-free margin were compared. Results The mean surgical specimen weight was 47.7 g and was approximately similar to the actual specimen volume of 49.8 cm 3 . The weights of specimens immediately following surgery and on pathological appraisal were equal (p=0.94). The calculated volumes differed significantly from the actual specimen volumes (p>0.05). The mean distance to the closest tumour-free margin, 0.35 cm, was not altered by formalin fixation (p=0.1). Conclusions No evidence was found to suggest that surgical breast specimens shrink in the period between the surgical procedure and pathological examination, or following formalin fixation. The pathological appraisal of specimen margins and volumes is not affected by changes in specimen size. As calculations of specimen volumes are unreliable, the use of water displacement or the more readily available specimen weight is recommended for accurate volume measurement. Pathologists should be encouraged to always measure and record specimen weight.

Context Recently, we identified 2 patients with anaplastic large T-cell lymphoma (ALCL) negative for tyrosine kinase anaplastic lymphoma kinase (ALK-negative) in the fibrous capsule of silicone breast prostheses, placed for cosmetic reasons. Similar cases have been reported in the literature. Although an increased risk of ALCL in patients with breast prostheses has been speculated, no studies have been conducted so far. Objective To determine whether ALCL risk is associated with breast prostheses. Design A search for all patients with lymphoma in the breast diagnosed in the Netherlands between 1990 and 2006 was performed through the population-based nationwide pathology database. Subsequently, we performed an individually matched case-control study. Conditional logistic regression analysis was performed to estimate the relative risk of ALCL associated with breast prostheses. Setting and Patients Eleven patients with breast ALCL were identified in the registry. For each case patient with ALCL in the breast, we selected 1 to 5 controls with other lymphomas in the breast, matched on age and year of diagnosis. For all cases and controls (n = 35), pathological and clinical information was obtained with special emphasis on the presence of a breast prosthesis. Main Outcome Measure Association between breast implants and ALCL of the breast. Results The 11 patients with ALCL of the breast were diagnosed between 1994 and 2006 at a median age of 40 years (range, 24-68 years). In 5 of these patients, bilateral silicone breast prostheses had been placed 1 to 23 years before diagnosis. All received prostheses for cosmetic reasons. Lymphoma classes of 35 eligible control patients were 12 diffuse large B-cell lymphomas, including 1 T-cell rich B-cell lymphoma; 5 Burkitt lymphomas; 10 mucosa-associated lymphoid tissue–type lymphoma; 3 follicular lymphomas; 3 peripheral T-cell lymphomas; and 2 indolent B-cell lymphomas, unclassified. One of 35 control patients had a breast implant placed before diagnosis of lymphoma. The odds ratio for ALCL associated with breast prostheses was 18.2 (95% confidence interval, 2.1-156.8). Conclusions These preliminary findings suggest an association between silicone breast prostheses and ALCL, although the absolute risk is exceedingly low due to the rare occurrence of ALCL of the breast (11 cases in the Netherlands in 17 years). These findings require confirmation in other studies.

Because of the absence of a specific marker for labeling resident macrophages in the rat, there is almost no information available regarding the properties of individual resident macrophages in different organs. The recently described and in our laboratory developed mAb ED2, has been shown to exclusively recognize resident macrophages. The present study examines expression, function and structure of the ED2 antigen to obtain more information about the marker and therefore, more information about resident macrophages. In earlier studies, the expression of ED2 could not be induced by a range of macrophage stimulating factors under non-adherent culture conditions. We show a highly inducible expression of the ED2 antigen under adhering, non proliferating conditions as well as in long-term bone marrow cultures. ED2 appears to recognize a surface protein on resident macrophages consisting of three protein chains of 175, 160, and 95 kDa.

Recently we developed mouse monocloual antibodies (mAb) against the isolated human 175-kDa mannose receptor. In the present study we tested whether these mAb are suitable for the detection of the mannose receptor on cultured macrophages using flow cytometry and on cells in human tissues using immunohistochemistry. Human monocytes did not react with the mAb in flow cytometry. Mannose receptor expression became detectable on monocytes cultured for 3 days (macrophages), and was maximal from 4 days onward. The mannose receptor was up-regulated on dexamethasone-treated (immunosuppressed) macrophages, and down-regulated on lipopolysaccharide-treated (activated) macrophages. Immunohistochemically the staining pattern of our mAb was compared with the marker of monocytes/macrophages KP1. In a bone marrow smear, only macrophages were stained with our mAb, whereas all myeloid cells were stained with KP1. In the thymus and lymph node, mannose receptor-positive branched cells (macrophages and dendritic cells) were detected in connective tissue, thymus cortex (not medulla), and in the T cell area (not the B cell area) of lymph nodes, whereas KP1 stained branched cells in all areas. It was concluded that the mAb are useful tools in flow cytometry and immunohistochemistry for the specific detection of cells expressing mannose receptor. Chemicals/CAS: Antibodies, Monoclonal; Biological Markers; Dexamethasone, 50-02-2; Glucocorticoids; Lectins, C-Type; Lipopolysaccharides; mannose receptor; Mannose-Binding Lectins; Receptors, Cell Surface

Lymphoid tissues are strictly organized in separated compartments populated by different immune-competent cells. Between these compartments differences exist in the composition of stromal components (Van den Berg et al. 1989). In general, stromal components in lymphoid tissue can be devided into cellular- and extra- cellular components.