Colonic tubular adenoma with clear cell change - case report with whole exome sequencing and updated review of the literature.

INTRODUCTION: Colorectal tubular adenomas displaying clear cell change are rare entities, with unknown clinical relevance, prognosis, immunohistochemical, and molecular features. CASE PRESENTATION: Hereby we report a case of a 43-year-old female patient with a rectosigmoid polyp. Histologically, conventional dysplasia was visible with scattered areas displaying clear cell change. Whole exome sequencing (WES) was carried out and revealed high tumour mutation burden, and 7 pathogenic mutations, including TP53, APC, FGFR4, EHBP1, IL4R, TYR, and ACTN3. CONCLUSION: Clear cell change may only be present in less than 0,1% of adenomas. Aetiology is not well understood, additionally, few authors suggest autolysis or fixation problems. Our WES resulted in newly found pathogenic mutations, and high mutation burden, proving the lesion's neoplastic origin. Hitherto, neither special stainings, nor immunohistochemical markers proved to be useful in the diagnostic process. From a differential diagnostic perspective, enteroblastic differentiation, primary and secondary clear cell adenocarcinoma has to be excluded.

Primary follicular dendritic cell sarcoma of the kidney - a case report of a rare tumor with emphasis on diagnostic pitfalls.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare low-grade tumor of the lymph nodes, but roughly one-third of the cases emerge from extranodal sites, posing diagnostic challenges. CASE PRESENTATION: In this report, we present the case of a 59-year-old lady who complained of renal colic. During investigation, a kidney tumor was discovered. A radical nephrectomy was performed, and histological examination identified the tumor as a sarcomatoid renal cell carcinoma. The case was then referred to a genitourinary pathologist for further evaluation. The tumor cells exhibited positive staining for CD21, CD23, somatostatin receptor 2 A, and MDM2 expression. Additionally, MDM2 gene amplification was confirmed by the FISH study. Ultimately, the tumor was diagnosed as a primary renal FDCS. The patient was placed under active oncological surveillance and did not receive any further therapy. Remarkably, after 91 months of follow-up, she remains tumor-free. CONCLUSION: This case represents a well-documented primary renal FDCS. Our aim in presenting this extremely rare tumor is to enhance awareness and highlight the importance of considering FDCS in the differential diagnosis.

[Myxoinflammatory fibroblastic sarcoma of the lower limb]. / Az alsó végtag myxoinflammatoricus fibroblastos sarcomája.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade, painless tumor of mesenchymal origin. In the current, 5th edition of the World Health Organisation (WHO) 'Classification of tumors: Soft tissue and bone tumors', there is no exact diagnostic genetic alteration defined in MIFS. Hereby we present the case of a 71-year-old female patient, with a medical history of benign essential hypertension, who visited the hospital because of a lesion above her right shin. She perceived the lesion 1.5 years prior to the medical attendance, and she only attended the medical facility because of the development of pain, erosion and papule formation on the skin surface. Microscopically, the lesion had cellular and pleomorphic appearance with nodular structure, and showed honeycomb-like infiltration of the subcutaneous fat tissue. Tumor cell infiltration was visible among the collagen fibers of the dermis. Tumor cells frequently displayed multinuclear morphology with prominent, viral inclusion-like nucleoli and exuberant fibrillary, often vacuolated and ground-glass cytoplasm. With immunohistochemical examination, tumor cells showed multifocal positivity with CD34, CD31, podoplanin (D2-40), cyclin D1, and epithelial membrane antigen (EMA). Furthermore, the tumor cells proved to be diffusely positive with smooth muscle actin (SMA). After meeting all the essential criteria of the current WHO classification, the case was concluded as MIFS, showing high-grade features. According to our experience, an immunohistochemistry panel of podoplanin, ciklin-D1, CD10, EMA, CD34, and CD31 can facilitate the correct conclusion. Our case of MIFS highlights the unusual, focally high-grade features of this complicated, challenging disease. Diffuse SMA positivity is a known, but uncommon feature of these tumors. Orv Hetil. 2023; 164(41): 1637-1641.

[Morphological variants of the invasive urothelial cell carcinoma.] / Az invazív urothelsejtes carcinoma morfológiai variánsai.

Urothelial cell carcinoma is the most common malignant tumor of the urinary tract, which develops in the renal pelvis, ureter, and bladder, and rarely it develops in the ureter. Histologically, urothelial cell carcinoma is categorized into non-invasive and invasive forms. Non-invasive urothelial cell carcinoma has papillary growth, it is usually well differentiated, and has a favorable outcome, while invasive urothelial cell carcinoma infiltratively spreads the organs of origin, it is typically poorly differentiated, and often associated with a poor prognosis. In the case of invasive urothelial cell carcinoma, the clinical course is primarily determined by the depth of invasion, but according to recent data, morphological variants of urothelial cell carcinoma respond differently to oncological treatments, and their biological behavior is also distinct. These subtypes and variants are significantly underdiagnosed in Hungary and internationally because the criteria for histological diagnosis are not clear for many subsets. The latest 2022 WHO classification of urinary tract tumors significantly clarified the definitions of various subtypes and variants. In this paper, utilizing the current classification, we review and explain these subtypes' morphological, immunohistochemical, differential diagnostic, prognostic, and predictive characteristics intending to make them appear as much as possible in everyday diagnostic practice. Also, the work aims to present the individual urothelial cell carcinoma subtypes and variants to the Hungarian community of pathologists, oncologists, and urologists, so that the previously high level of urological oncology care can become even more personalized. Orv Hetil. 2023; 164(40): 1567-1582.

Penile melanoma: a pathological report of two cases.

BACKGROUND: Penile melanoma (PM) is a rare tumor, accounting for less than 2% of all penile cancers. PM can occur on the surface of the glans, foreskin, and opening of the urethra. Furthermore, PM primarily affects older individuals and is not associated with sun exposure. Currently, there is no specific staging system for genitourinary tract melanomas, so these tumors are typically staged using the criteria for cutaneous melanoma. Limited data in the literature suggests that PM generally has a poor clinical prognosis. CASE PRESENTATION: Here, we describe two cases of PM. The first case affected a 62-year-old male who presented with hematuria and a painful tumor in the distal urethra, leading to a suspicion of penile cancer. The second case involved a 68-year-old male who noticed a rapidly evolving dark spot on his foreskin. Histological analysis confirmed the presence of melanoma in both patients. The tumors showed a diffuse and strong PRAME-positivity and lacked BRAF mutation in both cases. Additionally, the second tumor harbored an activating CKIT mutation. An enhanced PD-L1 expression was observed in both tumors. CONCLUSIONS: We presented two rare forms of mucosal melanoma and highlighted the entities in the differential diagnosis. Based on our experience PRAME is a helpful marker for making the diagnosis of PM, and PD-L1 can predict the success of the immunotherapy. We also emphasize the need for an organ-specific staging system for PMs.

Alterations of miRNA Expression in Diffuse Hyperplastic Perilobar Nephroblastomatosis: Mapping the Way to Understanding Wilms' Tumor Development and Differential Diagnosis.

Wilms' tumor (WT) is the most common renal malignancy in children. In diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), nephrogenic rests result in a bulky enlargement of the kidney, a condition considered as a premalignant state before WT. Despite relevant clinical differences between WT and DHPLN, they are often challenging to distinguish based on histology. Molecular markers would improve differential diagnosis, but none are available at present. In our study, we investigated the potential of microRNAs (miRNAs) as such biomarkers, also aiming to shed light on the chronological order of expression changes. Formalin-fixed, paraffin-embedded (FFPE) samples from four DHPLN cases and adjacent healthy tissues were tested using a PCR array containing primers for 84 miRNAs implicated in genitourinary cancer. Expression in DHPLN was compared to WT data available in dbDEMC. Let-7, miR-135, miR-146a-5p, miR-182-5p, miR-183-5p, miR-20b-3p, miR-29b-3p, miR-195-5p and miR-17-5p showed potential to be used as biomarkers to distinguish WT and DHPLN in cases when traditional differential diagnosis is inconclusive. Our study also revealed miRNAs which may play a role in the initial steps of the pathogenesis (at a precancerous stage) and ones which become deregulated later in WT. More experiments are needed to confirm our observations and find new candidate markers.

Novel concept of Wilms' tumor development: involvement of pluripotential cells of ureteric bud.

It is acknowledged that nephron develops after bilateral induction of the metanephric mesenchyma and branching ureteric bud (UB), and that nephrogenic rest and Wilms' tumor (nephroblastoma) arises from impaired differentiation of metanephric blastema. The aim of this study was to obtain more information on the involvement of UB derivatives in nephrogenic rest and Wilms' tumor. We applied immunohistochemistry to analyze nephrogenic rests and Wilms' tumors with mixed histology, including regressive and blastemal types. We used antibodies recognizing UB tip cells (ROBO1, SLIT2, RET), principal cells (AQP2), α- and ß-intercalated cells (SLC26A4, SLC4A1, ATP6V1B1, ATP6V0D2), and their precursors (CA2). Tubules surrounded by tumorous blastemal cells resembling UB tip were positive for RET, ROBO1, and SLIT2 in Wilms' tumor. Moreover, CA2-positive tubular structures and ATP6V1B1- and ATP6V0D2-positive immature non-α- and non-ß-intercalated cells were detected in nephrogenic rest and Wilms' tumor. We suggest that Wilms' tumor is more than nephroblastoma and propose a definition that Wilms tumor is a malignant embryonal neoplasm derived from pluripotential cells of nephrogenic blastema and of ureteric bud tip.

TRPS1 expression in cytokeratin 5 expressing triple negative breast cancers, its value as a marker of breast origin.

The lack of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 expression in breast cancer (BC) is the basis for the categorization of the tumour as triple negative breast carcinoma (TNBC). The majority of TNBCs are aggressive tumours with common metastases and decreased expression of markers that could help in identifying the metastatic lesion as of mammary origin. Breast markers, such as gross cystic disease fluid protein-15 (GCDPF-15), GATA binding protein 3 (GATA3), mammaglobin (MGB) and SOX10, are not uniquely specific to BC. Our aim was to evaluate trichorhinophalangeal syndrome type 1 (TRPS1) protein as a breast marker in a series of cytokeratin-5-expressing TNBC, mostly corresponding to basal-like TNBCs, previously characterized for the expression of other breast markers. One hundred seventeen TNBCs in tissue microarrays were immunostained for TRPS1. The cut-off for positivity was ≥ 10%. The reproducibility of this classification was also assessed. TRPS1 positivity was detected in 92/117 (79%) cases, and this exceeded the expression of previously tested markers like SOX10 82 (70%), GATA3 11 (9%), MGB 10 (9%) and GCDFP-15 7 (6%). Of the 25 TRPS1-negative cases, 11 were positive with SOX10, whereas 5 to 6 dual negatives displayed positivity for the other makers. The evaluation showed substantial agreement. Of the five markers compared, TRPS1 seems the most sensitive marker for the mammary origin of CK5-expressing TNBCs. Cases that are negative are most often labelled with SOX10, and the remainder may still demonstrate positivity for any of the 3 other markers. TRPS1 has a place in breast marker panels.

[Pathological characteristics and genetic background of renal cell carcinoma]. / A vesesejtes karcinómák patológiai jellemzoi és genetikai háttere.

Renal cell carcinoma (RCC) is the most common malignant kidney tumor. It is not a single entity but an umbrella term for several distinct tumor types. The most prevalent and clinically significant subtype of RCC is clear cell carcinoma, which consists of cells with empty cytoplasm. These tumor cells harbor biallelic loss of the VHL gene, resulting in a pseudohypoxic state that promotes angiogenesis and cellular proliferation. Papillary RCC and chromophobe carcinoma are also common subtypes, with the former displaying a papillary appearance and cMET mutation. The latter is characterized by eosinophilic tumor cells and multiple chromosomal losses. These subtypes are responsible for 90-95% of all kidney cancers in adults. Additionally, rare tumor subtypes with unique immunohistochemical features, genetic abnormalities, or a specific clinical course may be identified. Currently, the RCC subtype only holds prognostic significance, and no treatment is associated with any subtype. However, therapies associated with histological subtypes may emerge in the future, and thus, the diagnosis of RCCs should be made following current recommendations.

[Hereditary renal tumor syndromes.] / Örökletes vesetumor-szindrómák.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

Renal Cell Carcinoma in End-Stage Renal Disease: A Retrospective Study in Patients from Hungary.

INTRODUCTION: End-stage renal disease (ESRD) and acquired cystic kidney disease (ACKD) are known risk factors for renal cell carcinoma (RCC). Hereby, the clinicopathological features of RCCs developed in ESRD were investigated. METHODS: A database consisting of 34 tumors from 31 patients with ESRD among 2,566 nephrectomy samples of RCC was built. The demographic, clinical, and follow-up data along with pathological parameters were analyzed. The RCCs were diagnosed according to the current WHO Classification of Urinary and Male Genital Tumors. RESULTS: Twenty-two tumors developed in men and 12 in women, with a median age of 56 years (range: 27-75 years). The causes of ESRD were glomerulonephritis (n = 7), hypertensive kidney disease (n = 6), autosomal dominant polycystic kidney disease (n = 6), chronic pyelonephritis (n = 4), diabetic nephropathy (n = 3), chemotherapy-induced nephropathy (n = 1), and undetermined (n = 4). ACKD complicated ESRD in 12 patients. The following histological subtypes were identified: clear cell RCC (n = 19), papillary RCC (n = 5), clear cell papillary tumor (n = 5), ACKD RCC (n = 3), and eosinophilic solid and cystic RCC (n = 2). The median tumor size was 31 mm (range: 10-80 mm), and 32 tumors were confined to the kidney (pT1-pT2). There was no tumor-specific death during the period of this study. Progression was registered in 1 patient. CONCLUSION: In our cohort, the most common RCC subtype was clear cell RCC (55%), with a frequency that exceeded international data appreciably (14-25%). The incidence of clear cell papillary tumor and ACKD RCC (14.7% and 8.5%) was lower than data reported in the literature (30% and 40%). Our results indicate a favorable prognosis of RCC in ESRD.

Detection of SARS-CoV-2 proteins by immunohistochemistry in human tissues Pathology collaborative analysis / SARS-CoV-2-fehérjék kimutatása immunhisztokémiai módszerrel emberi szövetekben

Introduction: The COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is associated with high mortality rates worldwide. Polymerase chain reaction (PCR) is extensively used for virus detection in both infected patients and deceased persons. PCR, however, gives no information about the localization of the virus in cells and tissues. Detection of spike and nucleocapsid proteins and viral ribonucleic acid (RNA) of the SARS-CoV-2 in situ might provide more information and aid in the discovery of the pathomechanism of cellular damage. There are several commercially available anti-spike and anti-nucleocapsid antibodies used to detect immunohistochemical reactions, though each gives different results. Objective: The goal of the present study was to compare the intensity and specificity of several anti-spike and antinucleocapsid antibodies in different dilutions in four Hungarian university departments. Method: Immunohistochemical reactions were performed on coded slides taken from infected lungs of 3 deceased and placenta samples with appropriate negative controls of formalin-fixed paraffin-embedded tissues, scanned, evaluated unanimously and analysed statistically by the assessors. Results: By comparing the intensity, dilution, background and reproducibility of the different primary antibodies, it was possible to select the antibodies with the best results. Conclusion: The antibodies selected with established dilutions can be used in further studies to detect SARS-CoV-2 proteins in surgical materials and in samples obtained during autopsy.

Novel Diagnostic Value of Driver Gene Transcription Signatures to Characterise Clear Cell Renal Cell Carcinoma, ccRCC.

Routine molecular tumour diagnostics are augmented by DNA-based qualitative and quantitative molecular techniques detecting mutations of DNA. However, in the past decade, it has been unravelled that the phenotype of cancer, as it's an extremely complex disease, cannot be fully described and explained by single or multiple genetic variants affecting only the coding regions of the genes. Moreover, studying the manifestation of these somatic mutations and the altered transcription programming-driven by genomic rearrangements, dysregulation of DNA methylation and epigenetic landscape-standing behind the tumorigenesis and detecting these changes could provide a more detailed characterisation of the tumour phenotype. Consequently, novel comparative cancer diagnostic pipelines, including DNA- and RNA-based approaches, are needed for a global assessment of cancer patients. Here we report, that by monitoring the expression patterns of key tumour driver genes by qPCR, the normal and the tumorous samples can be separated into distinct categories. Furthermore, we also prove that by examining the transcription signatures of frequently affected genes at 3p25, 3p21 and 9p21.3 genomic regions, the ccRCC (clear cell renal cell carcinoma) and non-tumorous kidney tissues can be distinguished based on the mRNA level of the selected genes. Our results open new diagnostics possibilities where the mRNA signatures of tumour drivers can supplement the DNA-based approaches providing a more precise diagnostics opportunity leading to determine more precise therapeutic protocols.

The clinical significance of epigenetic and RNAPII variabilities occurring in clear cell renal cell carcinoma as a potential prognostic marker.

Patients diagnosed with clear cell renal cell carcinoma (ccRCC) have poor prognosis for recurrence and approximately 30-40% of them will later develop metastases. For this reason, the appropriate diagnosis and the more detailed molecular characterisation of the primary tumour, including its susceptibility to metastasis, are crucial to select the proper adjuvant therapy by which the most prosperous outcome can be achieved. Nowadays, clinicopathological variables are used for classification of the tumours. Apart from these, molecular biomarkers are also necessary to improve risk classification, which would be the most beneficial amongst modern adjuvant therapies. As a potential molecular biomarker, to follow the transcriptional kinetics in ccRCC patients (n=30), we analysed epigenetic changes (γH2A.X, H3K4me3, and H3K9me3) and the alterations in the level of RNA polymerase II (RNAPII) by immunohistochemical staining on dissected tissue sections. The variabilities between the tumorous and non-tumorous parts of the tissue were detected using quantitative image analysis by monitoring 30 cells from different positions of either the tumorous or the non-tumorous part of the tissue sections. Data obtained from the analyses were used to identify potential prognostic features and to associate them with the progression. These markers might have a value to predict patient outcomes based on their individual cellular background. These results also support that detection of any alteration in the level of H3K4me3, H3K9me3, and γH2A.X can account for valuable information for presuming the progression of ccRCC and the clinical benefits to select the most efficient personalised therapy.

Small cell variant of chromophobe renal cell carcinoma: Clinicopathologic and molecular-genetic analysis of 10 cases.

The morphologic diversity of chromophobe renal cell carcinoma (ChRCC) is well-known. Aside from typical morphology, pigmented adenomatoid, multicystic and papillary patterns have been described. Ten cases of CHRCC composed of small cell population in various percentages were analysed, using morphologic parameters, immunohistochemistry and next-generation sequencing (NGS) testing. Patients were five males and five females, with age ranging from 40 to 78years. The size of tumors ranged from 2.2 cm to 11 cm (mean 5.17 cm). Small cell component comprised 10 to 80% of the tumor volume, while the remaining was formed by cells with classic ChRCC morphology. The immunohistochemical profile of the small cell component was consistent with typical ChRCC immunophenotype, with CD117 and CK7 positivity. Neuroendocrine markers were negative. Mutations of 13 genes were found: DCIER1, FGFR3, JAK3, SUFO, FAM46C, FANCG, MET, PLCG2, APC, POLE, EPICAM, MUTYH and AR. However, only the PLCG2 mutation is considered pathogenic.The small cell variant of ChRCC further highlights and expand upon existing morphologic heterogeneity spectrum. Recognition of small cell variant of CHRCC is not problematic in tumors, where the "classic" CHRCC component is present. However, in limited material (i.e., core biopsy), this may present a diagnostic challenge. Based on the limited follow-up data available, it appears that the small cell tumor component had no impact on prognosis, since there was no aggressive behavior documented.   Awareness of this unusual pattern and applying additional sections to find classic morphology of ChRCC, as well as excluding neuroendocrine nature by immunohistochemistry, may help resolve difficult cases.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

Multifocal Urinary Tract Metastasis of Colorectal Carcinoma.

INTRODUCTION: Secondary urinary tract tumors are uncommon findings and mainly evolve by direct invasion from adjacent organs. Actual metastatic involvement often develops in the urinary bladder, while the upper urinary tract is infrequently affected. In addition, the lungs, breast, and prostate gland are the usual primary sites. Colorectal carcinoma (CRC) may spread to the ureter directly or seeds via vascular or lymphatic channels. It may pose struggles in the differential diagnosis because CRC shares standard pathologic features with the primary adenocarcinoma of the urinary tract. CASE PRESENTATION: We describe the case of an 81-year-old man who was referred to our hospital with a distal ureteral tumor that was treated by a ureteronephrectomy. The histopathological and genetic analysis established the diagnosis of metastatic CRC along with 3 metastases in the renal pelvis. CONCLUSION: This rare case highlights the limitations of conventional histological processing, including immunohistochemistry, and it underlines the role of molecular investigations in certain circumstances.