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Background: Single hormone receptor-positive breast cancers (BCs) display two distinct phenotypes: ER+/PgR– and ER–/PgR+ further stratified by their HER2 status. Their molecular features are not well defined. Our study aimed to identify differentially expressed genes in ER–/PgR+ BCs compared to other phenotypes. Methods: Our cohort comprised 15 ER+/PgR–/HER2–, 11 ER+/PgR–/HER2+, 17 ER–/PgR+/HER2–, 9 ER–/PgR+/HER2+, 5 ER+/PgR+/HER2–, and 5 ER–/PgR–/HER2– invasive BCs collected from 9 Polish and 2 Hungarian centers. The cases were selected from a larger cohort after being matched according to grade, HER2 status, lymph nodes, and distant metastasis status. ER–/PgR+ group was thoroughly validated via immunohistochemistry [Kunc et al. 2022]. The expression of 776 genes was profiled with nCounter® Breast Cancer 360™ Panel in archival formalin-fixed paraffin-embedded tissue samples. A gene was defined as differentially expressed between groups if it met the following criteria: the log2 fold-change in the expression of >1 or ←1 and the p-value < 0.05 (Mann-Whitney U test). Additionally, weighted correlation network analysis (WGCNA) was performed to identify modules of at least 15 highly correlated genes. Subsequently, the association between gene modules and PgR status in ER– subgroup was performed. Identified mRNAs were subjected to functional annotation analysis to determine the top enriched pathways. Results: ER–/PgR+ BCs were characterized by significantly lower expression of ESR1 compared to double-positive (p< 0.001) and ER+/PgR– tumors (p< 0.001), whereas PGR expression was higher compared to ER+/PgR– (p< 0.001), and no significantly different from ER+/PgR+ BCs (p=0.14). Triple-negative BCs had no detectable PGR mRNA. Four genes (MIA, ID4, FOXC1, CDC20) were consistently up-regulated and six genes (FAM214A, MLPH, NFKBIZ, FOS, SLC44A4, SPDEF) were down-regulated in ER–/PgR+/HER2– tumors compared to other HER2– subgroups. Compared to ER+/HER2– BCs, ER–/PgR+/HER2– cases showed up-regulation of 15 genes associated with response to vitamin D, response to ketone, and regulation of transcription, and downregulation of 33 genes involved in response to estrogen, negative regulation of cell population proliferation, regulation of epithelial-mesenchymal transition, and controlled by ESR1 and SUZ12. In WGCNA analysis of the ER– subgroup, PgR status was negatively correlated with 4 gene modules and positively correlated with 1 gene module. In line with differential gene expression analysis, genes negatively correlated with ER–/PgR+ status are regulated by ESR1 and SUZ12 and are involved in the regulation of cell proliferation, extracellular matrix organization, and NOTCH1 signaling. Genes positively correlated with ER–/PgR+ status are regulated by E2F4, FOXM1, SIN3A, NFYB, E2F1, FOS, IRF1, ZMIZ1, and UBTF and participate in cell cycle, regulation of mitosis, and microtubule cytoskeleton regulation. Conclusions: ER–/PgR+ BCs display a distinct mRNA expression profile characterized by the down-regulation of genes controlled by ESR1 and SUZ12. The latter as a part of Polycomb Repressive Complex 2 contributes to chromatin silencing, and some previous studies suggested its role in the regulation of steroid hormone receptors expression. Additionally, ER–/PgR+ BCs overexpress FOXC1 which is linked to more aggressive, high-grade, and treatment-resistant breast cancers. Our data indicate the need to unravel the mechanism of epigenetic regulation of PGR expression, especially its methylation status, in ER–/PgR+ breast cancer. Citation Format: Michał Kunc, Marta Popęda, Michał Bieńkowski, Marcin Braun, Aleksandra Łacko, Barbara Radecka, Joanna Pikiel, Maria Litwiniuk, Katarzyna Pogoda, Magdalena Niemira, Anna Szałkowska, Ewa Iżycka-Świeszewska, Gabor Cserni, Wojciech Biernat, Elżbieta Senkus. Estrogen receptor-negative progesterone receptor-positive breast cancer is a molecularly distinct group characterized by the down-regulation of genes controlled by ESR1 and SUZ12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-06.

Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.

Oestrogen receptor (ER)-negative (–) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER–/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER–/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER–/PgR+ breast cancer were collected from 11 institutions from the period 2006–2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER–/PgR+ phenotype, including 21 HER2+ and 55 HER2– tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2– cohort, confirmed ER–/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER–/PgR+/HER2– breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3–19.2, p=0.019). We performed one of the largest validation studies so far on ER–/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor.

Chemoresistance constitutes a major challenge in the treatment of triple-negative breast cancer (TNBC). Mixed-Lineage Kinase 4 (MLK4) is frequently amplified or overexpressed in TNBC where it facilitates the aggressive growth and migratory potential of breast cancer cells. However, the functional role of MLK4 in resistance to chemotherapy has not been investigated so far. Here, we demonstrate that MLK4 promotes TNBC chemoresistance by regulating the pro-survival response to DNA-damaging therapies. We observed that MLK4 knock-down or inhibition sensitized TNBC cell lines to chemotherapeutic agents in vitro. Similarly, MLK4-deficient cells displayed enhanced sensitivity towards doxorubicin treatment in vivo. MLK4 silencing induced persistent DNA damage accumulation and apoptosis in TNBC cells upon treatment with chemotherapeutics. Using phosphoproteomic profiling and reporter assays, we demonstrated that loss of MLK4 reduced phosphorylation of key DNA damage response factors, including ATM and CHK2, and compromised DNA repair via non-homologous end-joining pathway. Moreover, our mRNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, which facilitate TNBC cells survival. Lastly, we found that high MLK4 expression is associated with worse overall survival of TNBC patients receiving anthracycline-based neoadjuvant chemotherapy. Collectively, these results identify a novel function of MLK4 in the regulation of DNA damage response signaling and indicate that inhibition of this kinase could be an effective strategy to overcome TNBC chemoresistance.

Purpose Neuropeptide Y (NPY) is a pleiotropic peptide, which is involved in many biological mechanisms important in regulation of cell growth and survival. The aim of this study was a comprehensive analysis of the NPY system in prostate pathology. Methods The study was based on immunohistochemical analysis of NPY and its receptors, Y1R, Y2R and Y5R, in tissue samples from benign prostate (BP), primary prostate cancer (PCa) and PCa bone metastases. Tissue microarray (TMA) technique was employed, with analysis of multiple cores from each specimen. Intensity of the immunoreactivity and expression index (EI), as well as distribution of the immunostaining in neoplastic cells and stromal elements were evaluated. Perineural invasion (PNI) and extraprostatic extension (EPE) were areas of special interests. Moreover, a transwell migration assay on the LNCaP PCa cell line was used to assess the chemotactic properties of NPY. Results Morphological analysis revealed homogeneous membrane and cytoplasmic pattern of NPY staining in cancer cells and its membrane localization with apical accentuation in BP glands. All elements of the NPY system were upregulated in pre-invasive prostate intraepithelial neoplasia, PCa and metastases. EI and staining intensity of NPY receptors were significantly higher in PCa then in BP with correlation between Y2R and Y5R. The strength of expression of the NPY system was further increased in the PNI and EPE areas. In bone metastases, Y1R and Y5R presented high expression scores. Conclusion The results of our study suggest that the NPY system is involved in PCa, starting from early stages of its development to disseminated states of the disease, and participates in the invasion of PCa into the auto and paracrine matter.

Background Laparoscopy for the resection of liver tumors in children has remained undeveloped in comparison to adults. Most of the indications for pediatric laparoscopic hepatic surgery have been limited to diagnostic laparoscopy (biopsy). Over the past ten years, however, laparoscopic liver resections for pediatric hepatic diseases have been performed successfully, and many case reports have been published. Methods The authors report 6 cases of laparoscopic hepatic resection of benign tumors in children. The most important aspects of surgical technique are presented. There were 3 boys and 3 girls, with age between 4 months and 16 years. The lesions were located in the following segments: II and III (4 patients), I (1), V (1). The maximum tumor size was 7 cm. Results One anatomical (left bisegmentectomy) and 5 nonanatomical resections were performed. Conversion to laparotomy was necessary in 1 patient owing to bleeding from the posterior branch of the right hepatic artery. There were no postoperative complications and patients were discharged on postoperative day 4, 5, 5, 5, 7 and 3 accordingly. The postoperative pathology of the specimens confirmed their benign nature: infantile hemangioendothelioma (1), nested stromal epithelial tumor (1), focal nodular hyperplasia (3), mixed benign tumor (hamartoma + vascular malformation) (1). Conclusions This report demonstrates the feasibility of a laparoscopic hepatic resection in children. On the other hand, laparoscopic liver resection is challenging and teamwork and specific training are necessary.

Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa.

Currently available treatment options for patients with refractory metastatic prostate, bladder, or kidney cancers are limited with the prognosis remaining poor. Advances in the pathobiology of tumors has led to the discovery of cancer antigens that may be used as the target for cancer treatment. Antibody-drug conjugates (ADCs) are a relatively new concept in cancer treatment that broaden therapeutic landscape. ADCs are examples of a 'drug delivery into the tumor' system composed of an antigen-directed antibody linked to a cytotoxic drug that may release cytotoxic components after binding to the antigen located on the surface of tumor cells. The clinical properties of drugs are influenced by every component of ADCs. Regarding uro-oncology, enfortumab vedotin (EV) and sacituzumab govitecan (SG) are currently registered for patients with locally advanced or metastatic urothelial cancer following previous treatment with an immune checkpoint inhibitor (iCPI; programmed death receptor-1 [PD-1] or programmed death-ligand 1 [PD-L1]) inhibitor) and platinum-containing chemotherapy. The EV-301 trial showed that EV significantly prolonged the overall survival compared with classic chemotherapy. The TROPHY-U-01 trial conducted to evaluate SG demonstrated promising results as regards the objective response rate and duration of response. The safety and efficacy of ADCs in monotherapy and polytherapy (mainly with iCPIs) for different cancer stages and tumor types are assessed in numerous ongoing clinical trials. The aim of this review is to present new molecular biomarkers, specific mechanisms of action, and ongoing clinical trials of ADCs in genitourinary cancers. In the expert discussion, we assess the place of ADCs in uro-oncology and discuss their clinical value.

Introduction: Many retrospective studies have confirmed that capecitabine combined with temozolomide is effective in neuroendocrine neoplasms. Most of the studies focused on grade 1 and grade 2 neuroendocrine tumours, mainly of pancreatic origin. There are limited data regarding the efficacy capecitabine with temozolomide in grade 3 neuroendocrine tumours. The new World Health Organisation 2017 classification distinguished well-differentiated grade 3 neuroendocrine tumours from poorly differentiated grade 3 neuroendocrine carcinomas. Treatment options for grade 3 neuroendocrine neoplasms are limited, and the overall prognosis is better in the subgroup of patients with grade 3 neuroendocrine tumours. Material and methods: It was a retrospective study in the population of patients with diagnosed grade 3 neuroendocrine neoplasms of different origin treated with capecitabine and temozolomide. Data on clinical and demographic characteristics of the population were collected from four Polish clinical centres. This study aimed to evaluate response and survival parameters and compare outcomes of treatment of neuroendocrine tumours and carcinomas. Results: The study included 32 patients with grade 3 neuroendocrine tumours treated with capecitabine and temozolomide. The disease control rate was twice as high in the group of patient with neuroendocrine tumours in comparison to carcinomas (70 vs. 30%). The progression-free survival for patients with neuroendocrine tumours was 15.3 months (95% CI: 3.9–30.4), and for patients with neuroendocrine carcinomas it was 3.3 months (95% CI: 2.5–7.1). Median overall survival was 22 months (95% CI: 11.8–22.0) and 4.6 months (95% CI: 2.2–5.9) for patients with tumours and carcinomas, respectively. The treatment regimen was generally well tolerated. Conclusions: The combination of capecitabine and temozolomide is an effective treatment for patients with grade 3 neuroendocrine tumours with Ki-67 index ranging between 20 and 54%. The treatment did not overcome the aggressive character of neuroendocrine carcinomas and resulted in low response and survival outcomes in comparison to those achieved in tumour therapy.

Tissue is considered as a highly informative matrix in omics studies. Most commonly used tissues in metabolomics are fresh-frozen specimens. However, an alternative metabolomics matrix, up to now most often applies in immunohistochemistry or histopathology, is formalin-fixed, paraffin-embedded tissue (FFPE). The main advantages of FFPE tissues over fresh-frozen ones are the possibility to be stored at ambient temperature which is a cost-effective method and, consequently, their higher availability in biobanks. The main aim of the study was to develop and optimize the preparation protocol for FFPE samples in metabolomics, using cancer tissue and corresponding control tissue sections. Several conditions were evaluated: type and volume of deparaffinization solvent, number of purification cycles, solvent used in purification step, extraction solvent, and thickness of FFPE samples. Samples were analyzed by gas chromatography coupled with mass spectrometry (GC–MS). As a result, a sample preparation protocol of FFPE tissues for metabolomics was developed. Moreover, applicability of the proposed method was tested with the use of FFPE tissues obtained from prostate cancer patient and non-cancer controls.

The wide scope of neuropathology is also connected to different systemic pathology findings. Neuroectodermal-type female genital tract lesions are not frequent. This article presents a short review of such entities in gynecological pathology and reports on two rare cases. The first described lesion is an endometrial glial polyp in a young woman. The second is a mature cystic teratoma accompanied by a peritoneal gliomatosis in an adolescent girl. Both presented entities posed diagnostic difficulties from the clinical and pathological perspective. They demanded careful sampling, immunophenotyping, as well as neuropathological consultation.

Simple Summary Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare neoplasm that most commonly develops within maxilla in infants. It usually has a benign clinical course and is treated with only surgery. However, patients with large, inoperable, metastatic or multiply recurring MNTI may require systemic treatment. The role of pre- and post-surgery chemotherapy (CHT) in the management of MNTI is unclear. Here, we have presented the disease courses and outcomes of four infants treated with multidrug CHT due to inoperable/recurrent MNTI. Additionally, a systematic literature review was performed which revealed 38 similar cases in the last 42 years. Most children with primarily inoperable MNTI responded to CHT, which allowed physicians to perform complete, non-mutilating delayed surgery. However, it is still uncertain whether CHT administered after incomplete resection of MNTI prevents recurrence. This study aimed to contribute to the establishment of standards of management in patients with inoperable, metastatic or persistently recurring MNTIs, which are currently lacking. Abstract Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.

This article constitutes a summary of the knowledge on the involvement of the nervous system in COVID-19, concerning its general pathobiology, clinical presentation and neuropathological features as well as the future directions of investigation. Variable definitions, selection bias, mainly retrospective analyses of hospitalized patients and different methodologies are implemented in the research of this new disease. Central nervous system (CNS) pathology presents most frequently features of non-specific neuroinflammation with microglial activation and lymphoid infiltrations, ischemic/hypoxic encephalopathy, acute cerebrovascular disease, and microthrombi. Some brain specimens remain unaffected or show only non-specific changes of the critical status. Interpretations of the neuropathological findings are not always balanced in a clinical context and discrepant in consequence. Designing of longitudinal neuropathological studies, more frequent autopsies, and building of COVID-19 brain banks, together with neuroimaging analyses is essential. Genetic predispositions or immunological factors corresponding to the disease profile as well as cerebrospinal fluid (CSF) or serum biomarkers of COVID-19, the impact of different virus variants and influence of the therapy need to be identified. The mechanisms causing neuroCOVID and cognitive impairment - whether they are infectious, toxic, vascular or metabolic - create other aspects under research. There are also many existential questions about post-COVID and delayed sequelae of the infection. The fight with pandemic is a challenge for the global society, with neuropathologists and neuroscientists as important allies in struggle for understanding and conquering COVID-19.

Giant molluscum contagiosum (MC) is a peculiar variant of the disease with the presence of multiple or single lesions larger than 5 mm. In contrast to typical molluscum contagiosum, dermoscopic features of giant lesions have been poorly described, and none of the reports included multiple giant lesions in an immunocompromised patient. We present a patient with acquired immunodeficiency syndrome diagnosed with multiple giant molluscum contagiosum along with the dermoscopic features of this entity. We examined a 40-year-old patient who had been diagnosed with acquired immunodeficiency syndrome (AIDS) two months earlier. The disease defining AIDS was cerebral toxoplasmosis (initially presenting as a brain tumor several months earlier). Laboratory investigation showed a decreased CD4 cell count of 11 cells/mm3 and HIV viral load of 252 472 copies/mL. The patient was referred to the Department of Dermatology due to multiple flesh-colored, asymptomatic nodules with superficial telangiectasia that had been observed on the face for several weeks (Figure 1, a). Dermoscopy of larger (5 mm) skin lesions showed yellowish globules of different size and random distribution, separated by smaller, oval-shape white globules and polymorphic vessels (Figure 1, b-d). Dermoscopy of smaller skin lesions showed the presence of a central yellow globule and white structureless area with irregular linear vessels of radial arrangement at the periphery (Figure 1, e). Histopathological examination confirmed the diagnosis of molluscum contagiosum (MC); special staining showed the details of the lesion (Figure 2, a-c). Antiretroviral therapy with Triumeq® (dolutegravir + abacavir + lamivudine) was initiated. After discussing MC treatment options with the patient, we decided to delay the treatment and wait for the effect of antiretroviral therapy. Partial regression of MC lesions was observed after 5 months; laboratory investigations showed a CD4 cell count of 99 cells/mm3 and a HIV viral load of 56 copies/mL. Along with continuation of antiretroviral therapy, the patient received treatment with topical imiquimod (Aldara®) for 12 weeks. Subsequently, a few lesions resistant to previous treatment were treated with cryosurgery and the patient was instructed to apply imiquimod only to new-onset/regrowing lesions. Clinical evaluation after 2 months revealed a good clinical and aesthetic effect (Figure 3). MC is a viral disease caused by a DNA virus of the Poxviridae family (MCV-1 or MCV-2). The infection most commonly affects children and sexually active adults, and may be diagnosed based on physical examination in the majority of cases. Typical clinical presentation includes single to multiple, 2-5 mm, flesh-colored, asymptomatic nodules with central umbilication. Dermoscopy is a non-invasive diagnostic method that allows skin examination with magnification, therefore improving the accuracy of dermatological diagnosis. It was primarily developed to detect melanoma, but in recent years the role of this method in general dermatology has been constantly increasing. There have been several published reports that demonstrated the utility of dermoscopy in the diagnosis of MC. Most commonly observed structures include a central orifice and blood vessels arranged in punctiform, radial or mixed flower pattern (1). Giant molluscum contagiosum is an atypical variant of the disease, with the presence of multiple or single lesions larger than 5 mm (2). The diagnosis of giant MC usually indicates immunodeficiency and has been mainly described in HIV-positive patients, but also in coexistence with leukemia, sarcoidosis, Wiskott-Aldrich syndrome, selective immunoglobulin M deficiency, atopic dermatitis, and after splenectomy, bone marrow transplantation, and during immunosuppressive therapy (3). Giant MC may mimic other benign or malignant dermatoses, and the final diagnosis is usually based on histopathological examination. The list of differential diagnoses is long and includes basal cell carcinoma, keratoacanthoma, viral wart, varicella, intradermal nevi, pyogenic granuloma, lichen planus, atypical mycobacterial infection, pneumocystosis, cutaneous cryptococcosis, and histoplasmosis (3). In contrast to typical MC, dermoscopic features of giant MC have been poorly described, and none of the reports included multiple lesions in immunocompromised patient. Mun et al. described a pattern of multiple shiny white clods in giant MC observed in a 2-year-old girl in the perianal area (4). A different dermoscopic image - with prominent arborizing vessels and polylobular white structureless areas - was reported by Uzuncakmak et al., who described giant MC on the eyelid in a 25-year-old woman (2). Similar dermoscopic features of atypical MC (5 mm in size) were described by Zaballos et. al. (5). The course and treatment of MC differ in immunocompetent and in immunocompromised individuals. While the infection is usually mild and self-limiting in the former group, in the latter it may be extensive, symptomatic, and resistant to therapy. Treatment methods commonly applied in immunocompetent patients such as cryotherapy, curettage, and electrocautery are not generally recommended in patients with severe immunodeficiency as they pose a risk of secondary infection or autoinoculation (6). Additionally, such treatment of multiple lesions is connected with pain and higher risk of postinflammatory changes/scarring (7). According to the literature, treatment with local immunomodulators - including imiquimod cream, interferon-a (IFN-a) injections and cidofovir - appears to be effective (6). Topical 5% imiquimod was most commonly used, and although not licensed for this indication it was shown to be effective in HIV-positive individuals, including treatment of giant MC lesions (7). Regardless of the topical treatment, previous reports documented a correlation between immunity status and the extension of MC lesions. Therefore, effective antiretroviral therapy may itself lead to resolution of MC [8]. To sum up, the presented report introduced additional observations into the dermoscopic spectrum of giant MC. The observed dermoscopically large yellowish globules seem to correspond with the crypts and the surrounding white structures with the areas of lobulated, endophytic epidermal hyperplasia. The presence of vascular structures in dermoscopy corresponds with the blood vessels tightly surrounding inverted hyperplastic epidermal lobules (Figure 2, b). Dermoscopic features od giant MC are different than those observed in small lesions. Interestingly, the dermoscopic appearance of smaller lesions observed in our patient seemed to be similar to MC eruptions described in immunocompetent patients (1). In case of clinical suspicion giant MC coexisting with smaller lesions, dermoscopic assessment of the latter may serve as a clue to diagnosis.

Introduction: Due to the widespread use of magnetic resonance imaging (MRI) in neurological diagnostics, the number of patients detected as having cerebral microbleeds (CMBs) continues to increase. However, their clinical impact still remains controversial, especially the question of whether CMBs significantly increase the risk of life-threatening intracerebral haemorrhage (ICH) in patients undergoing intravenous thrombolysis (IVT) or endovascular thrombectomy (EVT), or in patients on anticoagulant therapy or statins. State of the art: The term ‘CMB’ is a radiological concept that aims to illustrate microscopic pathology of perivascular hemosiderin deposits corresponding most probably to small foci of past bleeding. MRI images in sequence T2*-GRE and susceptibility-weighted imaging (SWI) are used for a diagnosis of a CMB. This review summarises the current knowledge regarding the definition, prevalence, genetics, risk factors, radiological diagnosis and differential diagnosis of a CMB. We discuss its role as an indicator of future ischaemic or haemorrhagic events in high risk patients or those on antiplatelet or anticoagulant therapy, and its prognostic value for reperfusion strategies and for the development of dementia. Future direction: The place of CMBs in current guidelines is explored herein. It must be emphasised that the recommendations relating to CMBs are expert opinions. Therefore, at the end of this review, we pose a number of questions that future clinical trials should answer.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

Introduction: Neuropathological brain and spinal cord post mortem examination is a distinct procedure that still plays an important role in modern medicine. In front of increasing amounts of clinical and genetic data, together with important developments in the field of neuroimaging, the Polish Association of Neuropathologists have updated their recommendations regarding central nervous system (CNS) examination. These guidelines are aimed at neuropathologists, pathologists and clinicians.Aim of the study: Presentation of the outlined recommendations as their goal is to improve the quality, informativity, and cost effectiveness of CNS post mortem examinations. A comprehensive study of the literature was conducted to provide a clinical background of neuropathological autopsy. There are numerous open questions in neuroscience, and new strategies are required to foster research in CNS diseases. These include the challenge of organizing brain banks tasked with managing and protecting detailed multidisciplinary information about their resources. Complex neuropathological analyses of post mortem series are also important to assess the effectiveness of diagnostics and therapy, identify environmental impact on the development of neurological disorders, and improve public health policy. The recommendations outline the need for collaboration between multiple specialists to establish the proper diagnosis and to broaden knowledge of neurological disorders.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

Giant molluscum contagiosum (MC) is a peculiar variant of the disease with the presence of multiple or single lesions larger than 5 mm. In contrast to typical molluscum contagiosum, dermoscopic features of giant lesions have been poorly described, and none of the reports included multiple giant lesions in an immunocompromised patient. We present a patient with acquired immunodeficiency syndrome diagnosed with multiple giant molluscum contagiosum along with the dermoscopic features of this entity.

The second part of the comprehensive work concerning pathology museums and collections presents their history since the 19th century. The evolution and specialisation of museums, depending on the attitude of their creators and geographic localization, have been analysed. The changing aspects of obtaining the exhibits and how they were preserved, presented, and stored are also a part of this work. The methods of human organ fixation reached excellence in the 19th century, but the rarity of some pathologies urged the scientists to recreate them artificially in models for didactic purposes. In the 19th and 20th centuries one could observe the flourishing development with a plateau and then decline from the second part of the 20th century to the reorientation of the museums that took place in Europe and North America. The history of anatomopathological museums is connected with ethical problems related to acquisition of exhibits in previous centuries and especially during World War II. The changing purpose of the collections, as well as their unclear future and the impact on the visitors, are evident. For the last 50 years, many museums have been closing completely, but some collections have been digitalised and are still in permanent use. The uniqueness of old specimens with certain diseases, often long gone and not observed anymore, makes them important in many aspects nowadays. Pathology museums are themselves relics of the past, being at the same time tangible proof of ways of development in medicine, but also a way of preservation of human knowledge in a special type of relation with the human body.

Introduction Alpha-fetoprotein (AFP) is a glycoprotein which can be elevated in some non-oncological conditions, and in few types of cancers being a diagnostic and monitoring biomarker. Kidney cancer can produce several substances, which have biological activity and even cause paraneoplastic syndromes. AFP elevation in course of renal cancer is extremely rarely encountered. Aim To present diagnostic difficulties in a case of a 43-year-old man with a kidney tumor. Case study Clinical and pathological case description. Results and discussion The patient initially presented with features of urogenital infection and lumbar pain. Performed diagnostics revealed at first epididymitis, then serum elevation of AFP, and finally renal tumor. Based on wide immunophenotyping, the tumor was histopathologically recognized as high grade clear cell renal cell carcinoma with AFP expression. Clinically the patient presented unexpected rapid cancer progression with parallel increase of above biomarker level, causing repeated exclusion assessment of germ cell tumor. Conclusions The diagnostics of kidney mass in our patient was interfered and complicated by concomitant genital infection and AFP serum elevation. Clinically found increased level of AFP requires extensive evaluation, including diagnostics of different tumors.

Aim: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. Patients & methods: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. Results: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. Conclusion: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.

Aim of the study : Examination of copy number changes in a group of intracranial germ cell tumors (GCTs) with particular focus on putative aberrations of the main genes coding SHh pathway proteins. Material and methods : The study was performed on DNA isolated from fresh-frozen tumor tissue samples from eight GCTs, including six intracranial GCTs. The intracranial group consisted of three germinomas, two mature teratomas and one mixed germ cell tumor. Comparative genomic profiling analysis was carried out using microarray-CGH method (Cytosure ISCA UPD 4×180k, OGT). The results were analyzed with Feature Extraction (Agilent Technologies) and Nexus Copy Number (BioDiscovery) softwares. Results and conclusions : Chromosomal aberrations were found in two intracranial germinomas. These tumors were characterized by complex genomic profiles encompassing chromosomes 7, 8, 9, 10, 11, 12, 16, 17 and 19. Common findings were gain at 12p13.33p11.1 of 35 Mbp and gain at 17q11.1q25.3 of 55 Mbp. In one tumor, also SHh (7q36.3), SMO (7q32.1) and GLI3 (7p14.1) copy gains occurred together with 9q21.11q34.3 loss, including PTCH1 , all being elements of SHh signaling pathway. Moreover, both tumors showed various copy gain of genes being ligands, regulators, receptors or target genes of SHh ( MTSS1; PRKACA and FKBP8 ) as well as gain of genes of SHh coopting WNT pathway ( WNT3 , WNT5B , WNT9B in both tumors; WNT16 , WNT2 in pineal lesion). Further studies on larger group are needed to characterize SHh-related gene alterations in intracranial GCTs and for searching genotype-phenotype relations.

We present an analysis of two first historically documented limb body wall complex (LBWC) cases and our own contemporary perinatal autopsy series of this rare complex. So far it was supposed that the first case of this complex was reported in 1685 by Paul Portal. Studying the Joachim Oelhaf’s autopsy report from 1613 with attached engraving showing the neonate with multiple birth defects led our research team to a conclusion that it was genuinely the first description of LBWC in the medical literature so far. We compared the Oelhaf’s case from 1613 and the Portal’s autopsy report from 1685 with our series of LBWC cases dissected in the Medical University of Gdansk between 1999 and 2011. Reviewing 1100 autopsy reports performed we encountered 9 cases of this unique complex. The analysis was supported by the literature review.

The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous specialized cells interacting with cancer cells by paracrine and autocrine mechanisms. Tumor axonogenesis and neoneurogenesis constitute a developing area of investigation. Prostate cancer (PC) is one of the most common malignancies in men worldwide. During the past years, more and more studies have shown that mechanisms leading to the development of PC are not confined only to the epithelial cancer cell, but also involve the tumor stroma. Different nerve types and neurotransmitters present within the TME are thought to be important factors in PC biology. Moreover, perineural invasion, which is a common way of PC spreading, in parallel creates the neural niche for malignant cells. Cancer neurobiology seems to have become a new discipline to explore the contribution of neoplastic cell interactions with the nervous system and the neural TME component, also to search for potential therapeutic targets in malignant tumors such as PC.

Prostate cancer (PCa) is one of the leading types of cancer in men. Although the diagnosis of this disease is currently quite effective, there is still a need to search for noninvasive diagnostic and monitoring methods. Consequently, identifying the mechanisms underlying the development and progression of PCa is crucial. It has been confirmed that the hallmarks of PCa include changes in metabolism, particularly that of fatty acids. Therefore, the application of lipidomics with an accurate histopathological assessment can provide the necessary information and reveal the metabolites that are characteristic of the disease. The use of formalin-fixed, paraffin-embedded (FFPE) tissue samples as an alternative matrix in retrospective research makes this approach highly innovative. The main goal of this study was to perform an untargeted lipidomic analysis of FFPE PCa tissue samples (n = 52) using gas chromatography coupled with mass spectrometry (GC-MS), in comparison to controls (n = 50). To our knowledge, this study is the first to simultaneously conduct a metabolic analysis and histopathological assessment. In the latter, the samples were evaluated based on Gleason grading score and pTNM stage. The obtained results were evaluated by univariate (Student's t-test or Mann-Whitney U-test) as well as multivariate statistical analysis (principal component analysis, partial least squares-discriminant analysis, variable importance into projection, and selectivity ratio) in order to select the metabolites with the most discriminative power. Additionally, the correlation between the level of metabolites and pathological characteristics was determined. The results of the analyses confirmed the changes in the lipid metabolism pathway in PCa. It can be assumed that PCa is linked with elevated de novo biosynthesis of steroid hormone-related fatty acids and beta-oxidation of fatty acids. An increased level of three fatty acids, namely 9-octadecanoic acid, 9,12-octadecadienoic acid, and 5, 8, 1,14-eicosatetraenoic acid, was observed in the PCa samples. These fatty acids were assigned as metabolites with the best discriminative power for the two tested groups. In practice, these compounds could be considered as specific biochemical factors that may be implemented in the diagnosis of PCa, but their significance should be validated on a more extensive set of samples. Undoubtedly, these results are valuable as they provide important information on prostate cancerogenesis in the context of a metabolic switch.

Currently, many new possible biomarkers and mechanisms are being searched and tested to analyse pathobiology of pediatric tumours for the development of new treatments. One such candidate molecular factor is BARD1 (BRCA1 Associated RING Domain 1)—a tumour-suppressing gene involved in cell cycle control and genome stability, engaged in several types of adult-type tumours. The data on BARD1 significance in childhood cancer is limited. This study determines the expression level of BARD1 and its isoform beta (β) in three different histogenetic groups of pediatric cancer – neuroblastic tumours, and for the first time in chosen germ cell tumours (GCT), and rhabdomyosarcoma (RMS), using the qPCR method. We found higher expression of beta isoform in tumour compared to healthy tissue with no such changes concerning BARD1 full-length. Additionally, differences in expression of BARD1 β between histological types of neuroblastic tumours were observed, with higher levels in ganglioneuroblastoma and ganglioneuroma. Furthermore, a higher expression of BARD1 β characterized yolk sac tumours (GCT type) and RMS when comparing with non-neoplastic tissue. These tumours also showed a high expression of the TERT (Telomerase Reverse Transcriptase) gene. In two RMS cases we found deep decrease of BARD1 β in post-chemotherapy samples. This work supports the oncogenicity of the beta isoform in pediatric tumours, as well as demonstrates the differences in its expression depending on the histological type of neoplasm, and the level of maturation in neuroblastic tumours.

We present a short history of anatomopathological museums in Europe. In the first part we provide an insight into the beginnings from the Renaissance until the middle of the 19th century. We assess forms of acquisition and exhibition of the specimens concerning the steps of medicine and pathology development. The prototypes were "curiosities of nature" collections starting in the 15th century. The next milestone collections focusing on the human body were those of Frederik Ruysch in the Netherlands (17th century). In the 18th century teachers in surgical and anatomical schools realized the educational power of such collections. Anatomopathology as a separate medical discipline was developing in parallel. At that time museums such as the one established by Honore Fragonard in Paris, the Hunterian in Glasgow and Narrenturm in Vienna were created. At Polish universities in Cracow and Vilnius, such museums were beginning to emerge at the beginning of the 19th century. Anatomopathological collections became more popular, gathering specimens: osteological, dry and mummified, as well as wet - embedded in alcohol, formalin, and mysterious mixtures. They provide a wealth of important data for scientific, medical, historical and even ethical areas, as well as methods and concepts of conservation and even recreation of human body parts.