[Pathology of the nipple-areola complex : I. Paget's disease of the nipple, variants, and differential diagnoses]. / Pathologie der Mamillenregion : I. Morbus Paget der Mamille, Varianten und Differenzialdiagnosen.

The classical Paget's disease of the nipple is histologically characterized by tumor cell infiltration originating in intraductal or invasive breast carcinoma, immunohistologically by a frequent overexpression of HER2 and clinically by eczema-like changes of the nipple and areola. Variants with different histological, immunohistological, and clinical features are observed in nonclassical forms of Paget's disease, such as isolated Paget's disease of the nipple, anaplastic Paget's disease, Paget's disease with invasion, and pigmented Paget's disease of the nipple. In the differential diagnosis of Paget's disease, benign changes have to be considered, including Toker cell hyperplasia, nipple eczema, and rare dermatoses.

[Pathology of the nipple-areola complex : Part II. Tumors, tumor-like lesions, and supernumerary breast lesions]. / Pathologie der Mamillenregion : Teil II: Tumoren, tumorartige Läsionen und Überschussbildungen.

The nipple-areola complex is the origin of various morphologically distinct tumors and tumor-like lesions, which can be delineated from the special structures of the nipple, in particular the intramammary ducts, skin-appendages, and the intramammary stroma. Benign tumors are most frequent and this includes epithelial tumors such as mammary adenoma and syringomatous tumor of the nipple. Less commonly observed are benign mesenchymal tumors such as leiomyoma of the nipple, or tumor-like lesions like pseudo-lymphoma. With excess formations of the nipple, the different forms of polythelia and polymastia have to be considered.

IgG4-related sclerosing mastitis in a 49-year-old patient with multiple, tumor-like nodules-Diagnostic accuracy of core needle biopsy.

Recently, it has been reported that IgG4-related disease may occur in the breast manifesting as nodular sclerosing interstitial mastitis. Here we report a case with multiple tumor-like nodules in one breast. The histologic diagnosis was established on core needle biopsies, and treatment was initiated without open biopsy. Diagnosis of IgG4-related sclerosing mastitis should be suspected in cases of tumor-like lesions on imaging with an interstitial plasma cell-rich sclerosing inflammation on histology.

Immunohistochemical FAP Expression Reflects 68Ga-FAPI PET Imaging Properties of Low- and High-Grade Intraductal Papillary Mucinous Neoplasms and Pancreatic Ductal Adenocarcinoma.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are grossly visible (typically > 5 mm) intraductal epithelial neoplasms of mucin-producing cells, arising in the main pancreatic duct or its branches. According to the current 2-tiered grading scheme, these lesions are categorized as having either low-grade (LG) dysplasia, which has a benign prognosis, or high-grade (HG) dysplasia, which formally represents a carcinoma in situ and thus can transform to pancreatic ductal adenocarcinoma (PDAC). Because both entities require different treatments according to their risk of becoming malignant, a precise pretherapeutic diagnostic differentiation is inevitable for adequate patient management. Recently, our group has demonstrated that 68Ga-fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT shows great potential for the differentiation of LG IPMNs, HG IPMNs, and PDAC according to marked differences in signal intensity and tracer dynamics. The purpose of this study was to biologically validate FAP as a target for PET imaging by analyzing immunohistochemical FAP expression in LG IPMNs, HG IPMNs, and PDAC and comparing with SUV and time to peak (TTP) measured in our prior study. Methods: To evaluate the correlation of the expression level of FAP and α-smooth muscle actin (αSMA) in neoplasm-associated stroma depending on the degree of dysplasia in IPMNs, 98 patients with a diagnosis of LG IPMN, HG IPMN, PDAC with associated HG IPMN, or PDAC who underwent pancreatic surgery at the University Hospital Heidelberg between 2017 and 2023 were identified using the database of the Institute of Pathology, University Hospital Heidelberg. In a reevaluation of hematoxylin- and eosin-stained tissue sections of formalin-fixed and paraffin-embedded resection material from the archive, which was originally generated for histopathologic routine diagnostics, a regrading of IPMNs was performed by a pathologist according to the current 2-tiered grading scheme, consequently eliminating the former diagnosis of "IPMN with intermediate-grade dysplasia." For each case, semithin tissue sections of 3 paraffin blocks containing neoplasm were immunohistologically stained with antibodies directed against FAP and αSMA. In a masked approach, a semiquantitative analysis of the immunohistochemically stained slides was finally performed by a pathologist by adapting the immunoreactive score (IRS) and human epidermal growth factor receptor 2 (Her2)/neu score to determine the intensity and percentage of FAP- and αSMA-positive cells. Afterward, the IRS of 14 patients who underwent 68Ga-FAPI-74 PET/CT in our previous study was compared with their SUVmax, SUVmean, and TTP for result validation. Results: From 98 patients, 294 specimens (3 replicates per patient) were immunohistochemically stained for FAP and αSMA. Twenty-three patients had LG IPMNs, 11 had HG IPMNs, 10 had HG IPMNs plus PDAC, and 54 had PDAC. The tumor stroma was in all cases variably positive for FAP. The staining intensity, percentage of FAP-positive stroma, IRS, and Her2/neu score increased with higher malignancy. αSMA expression could be shown in normal pancreatic stroma as well as within peri- and intraneoplastic desmoplastic reaction. No homogeneous increase in intensity, percentage, IRS, and Her2/neu score with higher malignancy was observed for αSMA. The comparison of the mean IRS of FAP with the mean SUVmax, SUVmean, and TTP of 68Ga-GAPI-74 PET/CT showed a matching value increasing with higher malignancy in 68Ga-FAPI-74 PET imaging and immunohistochemical FAP expression. Conclusion: The immunohistochemical staining of IPMNs and PDAC validates FAP as a biology-based stromal target for in vivo imaging. Increasing expression of FAP in lesions with a higher degree of malignancy matches the expectation of a stronger FAP expression in PDAC and HG IPMNs than in LG IPMNs and corroborates our previous findings of higher SUVs and a longer TTP in PDAC and HG IPMNs than in LG IPMNs.

Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions.

PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.

Non-Response of Epstein-Barr Virus-Associated Breast Cancer after Primary Chemotherapy: Report of Two Cases.

Based on epidemiological evidence and molecular findings, a possible association of Epstein-Barr virus (EBV) with the carcinogenesis of breast cancer has been described. However, the frequency of EBV in breast cancer and the role of EBV regarding tumor progression or therapeutic results is largely unexplored. Here, we report on two cases of advanced, lymph node-positive invasive breast cancer of no special type (NST), histologically showing no clinical or histological evidence of tumor regression as an equivalent of a lack of response to primary systemic therapy. Both tumors were considered to be EBV-associated due to their positivity in EBV-encoded RNA (EBER) in situ hybridization (ISH) and their immunoreactivity against EBV Epstein-Barr nuclear antigen 1 (EBNA1). We hypothesize that the unusual non-response to chemotherapy in these cases of breast cancer classified as triple-negative and HER2-positive may be linked to the EBV co-infection of tumor cells. Therefore, EBV tumor testing should be considered in patients with breast cancer presenting with resistance to chemotherapy. This hypothesis may provide a new aspect in the context of EBV-associated mechanisms of tumor progression.

A Systematic Review and Illustrative Case Presentation of Low-Grade Myofibroblastic Sarcoma (LGMS) of the Extremities.

INTRODUCTION: Low-grade myofibroblastic sarcoma (LGMS) is a rare tumor entity which occurs in the subcutaneous and deep soft tissues; it is less common in the bone with a predilection for the extremities and the head and neck region. As confirming the diagnosis is difficult and treatment strategies are not standardized, we aimed to identify patient and tumor characteristics, and to summarize treatment strategies and their clinical outcomes to guide surgeons. METHODS: Included were full articles reporting patients with histology of LGMS in the extremities, excluding tumors of the trunk. All patients underwent surgery but with different extend, from marginal to wide resection. Included studies should inform about local recurrence, metastasis, or evidence of disease, depending on the surgical treatment. We conducted a structured search using MEDLINE (via PubMed), Web of Science, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) to identify studies on low-grade myofibroblastic sarcoma of the extremities. Study designs like randomized controlled trials, systematic reviews, prospective trials, retrospective studies, and case reports were included. Prospective studies and comparative studies were not available at all. Therefore, meta-analysis was not possible and statistical analysis was purely descriptive. RESULTS: Of the 789 studies identified from our initial search, 17 studies including 59 cases reported LGMS of the extremities with the surgical treatment and clinical outcome and were therefore analyzed. In addition, we present the rare case and surgical management of a 28-year-old male patient with residual LGMS of the thumb after an initial incomplete resection. The current literature suggests that a wide excision with R0 margins should be considered the standard treatment for LGMS. In cases where surgery leads to significant functional impairment, individual options like free tissue transfer from a donor site have to be considered. Therefore, we also present an illustrative case. For all selected case series and case reports, a high risk of confounding, selection bias, information bias, and reporting bias must be anticipated. Nevertheless, this systematic review provides a comprehensive overview on surgical treatment and clinical outcomes in LGMS surgery of the extremities.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

Comparison of early and late 68Ga-FAPI-46-PET in 33 patients with possible recurrence of pancreatic ductal adenocarcinomas.

Positron emission tomography with 68Gallium (68Ga) labeled inhibitors of fibroblast activation protein (68Ga-FAPI-PET) is a promising imaging technique for patients with recurrent pancreatic ductal adenocarcinomas (PDAC). To date, it is not clear if different acquisition timepoints for 68Ga-FAPI-PET may result in comparable imaging information and if repetitive 68Ga-FAPI-PET imaging may add diagnostic value to single timepoint acquisition for recurrent PDAC. Here we analyzed retrospectively early (20 min p.i.) and late (60 min p.i.) 68Ga-FAPI-PET imaging using FAPI-46 of 33 patients with possible recurrence of PDAC concerning detection rates and uptake over time of local recurrences, metastases, inflammatory lesions of the pancreas, cholestatic lesions of the liver and reactive tissue. 33 patients with histologically confirmed PDAC after complete or partial resection of the pancreas and possible recurrence were examined by 68Ga-FAPI-46-PET acquired 20- and 60-min post injection (p.i.) of the radiotracer. FAPI-positive lesions were classified as local recurrences, metastases, inflammatory lesions of the pancreas (ILP), cholestatic lesions of the liver and reactive tissue based on histology, PET- and CT-morphology and clinical information. Lesions were contoured, and standardized uptake values (SUVmax and SUVmean) and target-to-background ratios (TBR) were analyzed for both acquisition timepoints. In total, 152 FAPI-positive lesions (22 local relapses, 47 metastases, 26 inflammatory lesions of the pancreas, 28 reactive tissues, and 29 cholestatic lesions) were detected. Detection rates for the early and late acquisition of 68Ga-FAPI-46-PET were almost identical except cholestatic lesions, which showed a higher detection rate at early imaging. SUV parameters and TBRs of ILP significantly decreased over time. Cholestatic lesions showed a tendency towards decreasing uptake. All other types of lesions showed relatively stable uptake over time. Early and late acquisition of 68Ga-FAPI-PET results in comparable imaging information in patients with possible recurrence of PDAC. Two timepoint imaging offers additional diagnostic potential concerning differential diagnoses.

Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs.

Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.

FAP-Specific Signalling Is an Independent Diagnostic Approach in ACC and Not a Surrogate Marker of MRI Sequences.

BACKGROUND: Fibroblast Activation Protein (FAP) is a new target for positron emission tomography and computed tomography (PET/CT) imaging of epithelial tumours embedded in a fibrous stroma. Adenoid cystic carcinomas (ACCs) have shown elevated tracer uptake in 68Gallium (68Ga)-labelled FAPIs in previous studies. The current gold standard for ACC imaging is contrast-enhanced (ce) MRI, where intertumoural heterogeneity leads to variable appearance on T1-weighted (T1w) and T2-weighted (T2w) images. In this retrospective analysis, we correlated 68Ga-FAPI PET signalling at three time points with ceT1w and T2w MRI signals to further characterise the significance of 68Ga-FAPI uptake in ACCs. METHODS: Clinical PET/CT scans of 12 ACC patients were performed at 10, 60 and 180 min post i.v. administration of 68Ga-labelled-FAPI tracer molecules. 68Ga-PET- and corresponding MRI-scans were co-registered, and 3D volumetric segmentations were performed on ceT1w and T2w lesions of co-registered MRI slides. Signal intensity values of 68Ga-FAPI PET signalling and ceT1w/T2w MRI scans were analysed for their pixelwise correlation in each patient. Pooled estimates of the correlation coefficients were calculated using the Fisher z-transformation. RESULTS: 68Ga-FAPI PET signals showed a very weak positive correlation with ceT1w values (pooled correlation 0.114, 0.147 and 0.162 at 10, 60 and 180 min) and a weak negative correlation with T2w values (pooled correlation -0.148, -0.121 and -0.225 at 10, 60 and 180 min). Individual r-values at 60 min ranged from -0.130 to 0.434 in ceT1w and from -0.466 to 0.637 in T2w MRI scans. CONCLUSION: There are only slight correlations between the intensity of 68Ga-FAPI PET signals and tumour appearance in ceT1w or T2w MRI scans, which underlines that 68Ga-FAPI PET signalling is not a surrogate marker of MRI sequences but an independent signal.

uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.

High intratumoral levels of urokinase-type plasminogen activator (uPA)-plasminogen activator inhibitor-1 (PAI-1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI-1 multiplies the potential of the single proteins to attract pro-tumorigenic neutrophils. To this end, tumor-released uPA-PAI-1 utilizes very low-density lipoprotein receptor and mitogen-activated protein kinases to initiate a pro-inflammatory program in perivascular macrophages. This enforces neutrophil trafficking to cancerous lesions and skews these immune cells toward a pro-tumorigenic phenotype, thus supporting tumor growth and metastasis. Blockade of uPA-PAI-1 heteromerization by a novel small-molecule inhibitor interfered with these events and effectively prevented tumor progression. Our findings identify a therapeutically targetable, hitherto unknown interplay between hemostasis and innate immunity that drives breast cancer progression. As a personalized immunotherapeutic strategy, blockade of uPA-PAI-1 heteromerization might be particularly beneficial for patients with highly aggressive uPA-PAI-1high tumors.

Inflammatory reaction patterns of the lung as a response to alveolar hypoxia and their significance for the diagnosis of asphyxiation.

Providing evidence of asphyxia death is a challenging issue in forensic pathology. Besides helpful macroscopical signs (e.g. strangulation mark, lung edema), recent data from literature indicate that the time of protracted asphyxia suffices to trigger an increase of giant cells and a migration of inflammatory cells from the bone marrow to the lung, thus offering a help in diagnosis of asphyxia death. In search of new valid asphyxia markers, the present study examined this hypothesis and investigated the leading role of pre-existing lung tissue cells and their functional state in reaction patterns to asphyxia. In specimens of suffocated human lungs following a short (n = 13) and a long asphyxia terminal episode (n = 15), and controls (sudden cardiovascular (n = 11) and traumatic deaths (n = 7)), the count of alveolar phagocytes, megakaryocytes, giant and mast cells, using H&E and toluidine blue staining, was performed. To show macrophage activation, immunohistochemical stainings for CD68, late (25F9) and early (MRP-8/-14) stage inflammatory markers were used. Measuring concentration of tryptase in femoral blood acted as a parameter for mast cell degranulation and consequently their activation. Results showed the lack of specificity of macroscopical parameters despite an association of suffocation with heavy lung edema. No significant differences in the numbers of inflammatory cells in the lungs of different case groups were detected. The doubling of MRP-8- and a five-fold elevation of MRP-14-positive cells compared to cardiovascular controls, proved an early activation state of pre-exiting monocytes in protracted asphyxia. These activated monocytes induced the degranulation of mast cells, resulting in slightly elevated tryptase levels in suffocation compared to cardiovascular controls. In summary, the duration of asphyxia (max. 20 min in cases investigated) only suffices to cause changes on molecular level, being not detectable in any specific macroscopical or histological form in the lung. Despite a potential utility of this molecular insight in individual cases, these results point to the classic doctrine of the evaluation of a rounded overall picture, accentuating on the proof of the ligature tool and the marks of suffocation process.