Renal cell carcinomas with tubulopapillary architecture and oncocytic cells: Molecular analysis of 39 difficult tumors to classify.

So-called oncocytic papillary renal cell carcinoma (OPRCC) is a poorly defined variant of papillary renal cell carcinoma. Since its first description, several studies were published with conflicting results, and thus precise definition is lacking. A cohort of 39 PRCCs composed of oncocytic cells were analyzed. Cases were divided into 3 groups based on copy number variation (CNV) pattern. The first group consisted of 23 cases with CNV equal to renal oncocytoma. The second group consisted of 7 cases with polysomy of chromosomes 7 and 17 and the last group of 9 cases included those with variable CNV. Epidemiologic, morphologic and immunohistochemical features varied among the groups. There were not any particular histomorphologic features correlating with any of the genetic subgroups. Further, a combination of morphologic, immunohistochemical, and molecular-genetic features did not allow to precisely predict biologic behavior. Owing to variable CNV pattern in OPRCC, strict adherence to morphology and immunohistochemical profile is recommended, particularly in limited samples (i.e., core biopsy). Applying CNV pattern as a part of a diagnostic algorithm can be potentially misleading. OPRCC is a highly variable group of tumors, which might be misdiagnosed as renal oncocytoma. Using the term OPRCC as a distinct diagnostic entity is, thanks to its high heterogeneity, questionable.

Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions.

Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter (MLH1ph), and/or the presence of microsatellite instability, and BRAF/KRAS wild-type status (BRAFwt/KRASwt). In this study, we used targeted next generation sequencing (NGS) to explore the occurence of potentially therapeutically targetable gene fusions in an unselected series of BRAFwt/KRASwt CRC cases that displayed MLH1d/MLH1ph. From the initially identified group of 173 MLH1d CRC cases, 141 cases (81.5%) displayed MLH1ph. BRAFwt/RASwt genotype was confirmed in 23 of 141 (~16%) of MLH1d/MLH1ph cases. Targeted NGS of these 23 cases identified oncogenic gene fusions in nine patients (39.1%; CI95: 20.5%-61.2%). Detected fusions involved NTRK (four cases), ALK (two cases), and BRAF genes (three cases). As a secondary outcome of NGS testing, we identified PIK3K-AKT-mTOR pathway alterations in two CRC cases, which displayed PIK3CA mutation. Altogether, 11 of 23 (~48%) MLH1d/MLH1ph/BRAFwt/RASwt tumors showed genetic alterations that could induce resistance to anti-EGFR therapy. Our study confirms that targeted NGS of MLH1d/MLH1ph and BRAFwt/RASwt CRCs could be a cost-effective strategy in detecting patients with potentially druggable oncogenic kinase fusions.

Secondary pulmonary hypoplasia associated with calcified Meckel´s diverticulum with osseous metaplasia.

In this paper, we report autopsy findings of a 1-day old full-term mature female neonate with pulmonary hypoplasia diagnosed postnatally. Death was attributed to acute respiratory failure due to hyaline membrane disease. We describe pathological features of calcified Meckels diverticulum with osseous metaplasia and inflammatory changes in adjacent peritoneum. As far as we know, this case report documents the youngest patient ever diagnosed with calcified Meckels diverticulum with osseous metaplasia.

A Clinicopathological Study of 29 Spitzoid Melanocytic Lesions With ALK Fusions, Including Novel Fusion Variants, Accompanied by Fluorescence In Situ Hybridization Analysis for Chromosomal Copy Number Changes, and Both TERT Promoter and Next-Generation Sequencing Mutation Analysis.

ALK-fused spitzoid neoplasms represent a distinctive group of melanocytic lesions. To date, few studies addressed genetic and chromosomal alterations in these lesions beyond the ALK rearrangements. Our objective was to study genetic alterations, including ALK gene fusions, telomerase reverse transcriptase promoter (TERT-p) mutations, chromosomal copy number changes, and mutations in other genes. We investigated 29 cases of Spitz lesions (11 Spitz nevi and 18 atypical Spitz tumors), all of which were ALK immunopositive. There were 16 female and 13 male patients, with age ranging from 1 to 43 years (mean, 18.4 years). The most common location was the lower extremity. Microscopically, all neoplasms were polypoid or dome shaped with a plexiform, predominantly dermally located proliferation of fusiform to spindled melanocytes with mild to moderate pleomorphism. The break-apart test for ALK was positive in 17 of 19 studied cases. ALK fusions were detected in 23 of 26 analyzable cases by Archer FusionPlex Solid Tumor Kit. In addition to the previously described rearrangements, 3 novel fusions, namely, KANK1-ALK, MYO5A-ALK, and EEF2-ALK, were found. Fluorescence in situ hybridization for copy number changes yielded one case with the loss of RREB1 among 21 studied cases. TERT-p hotspot mutation was found in 1 of 23 lesions. The mutation analysis of 271 cancer-related genes using Human Comprehensive Cancer Panel was performed in 4 cases and identified in each case mutations in several genes with unknown significance, except for a pathogenic variant in the BLM gene. Our study confirms that most ALK fusion spitzoid neoplasms can be classified as atypical Spitz tumors, which occurs in young patients with acral predilection and extends the spectrum of ALK fusions in spitzoid lesions, including 3 hitherto unreported fusions. TERT-p mutations and chromosomal copy number changes involving 6p25 (RRB1), 11q13 (CCND1), 6p23 (MYB), 9p21 (CDKN2A), and 8q24 (MYC) are rare in these lesions. The significance of mutation in other genes remains unknown.

Arrhythmogenic Ventricular Cardiomyopathy Associated With Fibromuscular Dysplasia of Ostial Right Main Coronary Artery.

In this article, we report the autopsy findings of a 23-year-old woman, who was found unconscious at home by her relatives. During the transportation to the hospital, the woman was handed over to the ambulance personnel, who were the first to provide cardiopulmonary resuscitation. In the hospital, after an hour-lasting asystole, the heart activity was restored. Prolonged cardiac arrest led to hypoxic brain injury, which resulted in a persistent coma. Examinations carried out during hospitalization detected hypokinetic interventricular septum, frequent ventricular extrasystoles and ventricular fibrillation. The patient died within 35 hours of admission to the hospital. Gross findings of the heart included a noticeable increase of the adipose tissue in the right ventricular wall, where histologically focal myocardial atrophy with focal transmural lipomatosis reaching endocardium were detected. Death was attributed to arrhythmogenic ventricular cardiomyopathy. Pathogenic variants in JUP gene and KCNH2 gene confirmed the diagnosis. Other finding of note was fibromuscular dysplasia of ostial right main coronary artery causing a significant luminal narrowing.

Incidental idiopathic focal sclerosing mesenteritis in a 4-month-old child.

Sclerosing mesenteritis is a rare non-cancerous disease affecting the small bowel mesentery, which occurs predominantly in older age. The exact etiology is not known. Clinical symptoms are very variable and they include abdominal pain and distention, nausea, and vomiting. We present a case of a 4-month-old boy, who died suddenly at home. Based on the investigation of the circumstances of death, results of toxicology tests and histological examination the case was concluded as sudden infant death syndrome. During life, the child had repeated abdominal pain with distention. Secondary autopsy finding was a significant thickening of terminal ileum mesentery the length of 2,5 cm, with thickness reaching up to 1,5 cm and affecting almost half the circumference of the small intestine. According to the current literature, the case discussed in this article is the youngest recorded.

Frozen section: history, indications, contraindications and quality assurance.

Frozen section represents one of the most imortant procedures carried out by the pathologist. At the same time, it's one of the most difficult and most stressful tasks in the practice of pathology. The basic rule and the only correct indication for intraoperative consultation is that the result will determine the further conduction of the surgical procedure or will change the immediate patient care after operation. Successful accomplishment of intraoperative consultation requires knowledge of clinical history, familiarity with the surgical procedure technique, a keen knowledge of gross and microscopic pathology and a perfect work of the lab. Regular participation in quality assurance programs is associated with lower discordance rates between frozen section and final section diagnoses and a lower frequency of deferred diagnoses. Both the pathologist and the surgeon should realize the limitations of frozen section technique and, although no formal absolute contraindications to the use of frozen sections exist, there are situations when frozen section should be refused, although only after communication with the surgeon.  Keywords: frozen section - history - indications - contraindications - quality assurance.

Frozen section examination of pancreas, gallbladder, extrahepatic biliary tree, liver, and gastrointestinal tract.

The main indications for intraoperative consultation of gastrointestinal tract, liver, and pancreatobiliary system are to evaluate the resection margin and to make a tissue diagnosis of lesions for which preoperative histology is not aviable for various reasons. Special situations include the evaluation of liver donor biopsies for the presence of steatosis and inflamation, or determination that ganglion cells are present in the bowel wall at the level where the anastomosis will be placed in case of Hirschprung's disease. The most worrisome pitfalls include differentiating pancreatic ductal carcinoma from chronic pancreatitis, distinguishing biliary tree and gallbladder carcinoma from reactive changes caused by inflammation, and recognizing the presence of diffuse adenocarcinoma at the resection margin of the esophagus and stomach. Keywords: frozen section - gastrointestinal tract - liver - gallbladder - extrahepatic biliary tree - pancreas.

[Update on the 2016 WHO classification of tumors of the central nervous system - Part 1: Diffusely infiltrating gliomas]. / Novinky vo WHO klasifikácii nádorov centrálneho nervového systému 2016 - 1. cast: Difúzne infiltrujúce gliómy.

Revised WHO 2016 classification of tumors of the central nervous system (CNS) incorporates for the first time genetic information in addition to morphology for classification of many tumor entities. One of the most important changes is restructuring the chapter of diffuse gliomas. Based on shared genetic driver mutations, diffusely infiltrating astrocytomas and oligodendrogliomas are now classified together, separately from "other" glial tumors with a more circumscribed growth pattern, different pathogenesis and clinical outcome. Diffuse gliomas can now be more objectively diagnosed and further prognostically stratified by use of a relatively small number of markers (ATRX and IDH1/2 mutations and del 1p/19q). Another newly genetically-defined and clinically relevant entity is diffuse midline glioma, H3 K27M-mutant. Some glioma entities, variants and growth patterns were deleted and new variants, such as epithelioid glioblastoma and glioblastoma with a primitive neural component were added. In the article, the most important changes of diffuse gliomas classification are summarized and a practical diagnostic approach is illustrated.

Endometrial Endometrioid Carcinoma With Large Cystic Growth Configuration and Deceptive Pattern of Invasion Associated With Abundant Nodular Fasciitis-like Stroma: A Unique Hitherto Unreported Histology in Endometrioid Carcinoma.

We describe a case of an unusual endometrial endometrioid carcinoma occurring in a 67-year-old woman. The tumor involved uterine corpus as well as lower uterine segment and presented as polypoid tumor protruding through the cervical orifice. Microscopically, the tumor was characterized by broad zones of cytologically bland fibromyxoid stroma resembling nodular fasciitis, showing vaguely nodular architecture. Neoplastic glands were characterized by interconnected elongated slit-like and large cystic profiles, mostly lined by flattened epithelium with variable squamous differentiation, whereas typical columnar endometrioid cells were only focally present. Voluminous nodules of the stroma produced phyllodes-like appearance of the tumor. The tumor showed some resemblance to the microcystic, elongated, and fragmented (MELF) glands growth pattern, but in contrast with MELF pattern, where fibromyxoid change occurs focally, in the presented case abundant myofibroblastic proliferation was present throughout the tumor and the neoplastic glands showed anastomosing "large cystic" rather than "small cystic" profiles. Some of the neoplastic glands presented almost complete or complete squamous differentiation, with relatively bland-looking squamous cells and no hint of endometrioid differentiation, which resulted in initial misdiagnosis of Müllerian adenofibroma. We believe that nodular fasciitis-like pattern represents yet undescribed, and diagnostically challenging pattern of invasion in endometrial endometrioid carcinoma.

Lynch syndrome-associated upper tract urothelial carcinoma frequently occurs in patients older than 60 years: an opportunity to revisit urology clinical guidelines.

Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.

Predictive factors of endometriosis progression into ovarian cancer.

BACKGROUND: In recent years, the endometriosis has overcome a noteworthy renaissance in the recognition of its potential. In certain patients, a demonstrable malignant progression of ectopic foci leading to development of ovarian cancer is seen. The knowledge of endometriosis overthrow background into endometriosis associated ovarian cancer is of paramount importance for selection of patients at risk. The goal of the presented study was to review a malignant potential of the endometriosis and to specify predictive factors of endometriosis progression into ovarian cancer. Altogether 189 patients were included in the study. Conventional cytogenetics as well as measurement of transcriptional activity of CTNNB1 (ß-catenin) and HIF1A (HIF1-α) genes were prospectively studied in 60 endometriosis patients and 50 control group patients. The retrospective histopathological analysis was performed in 19 endometriosis associated ovarian cancer patients and 60 patients with histologically confirmed endometriosis. RESULTS: Five endometriosis patients showed a deviation from normal cytogenetics finding without affecting of their phenotype. In 6 cases of endometriosis associated ovarian cancer ectopic endometrium was not confirmed. The remaining 13 cases demonstrated either benign or atypical endometriosis or even structures of borderline carcinoma. Atypical endometriosis was histologically confirmed in 20% of 60 endometriosis patients. Determination of gene expression (CTNNB1, HIF1A) formed two subgroups. Transcriptionally incipient endometriosis subgroup with insignificant genes expression compared to control group. In transcriptionally evident endometriosis subgroup were genes expressions significantly higher compared to control group (p < 0.01) as well as transcriptionally incipient endometriosis subgroup (p < 0.05). CONCLUSIONS: Significant structural abnormalities of chromosomes are not included in genetic rigging of endometriosis patients. Atypical endometriosis represents a histopathologically detectable intermediate of endometriosis progression. Determination of genes expression CTNNB1 and HIF1A helps to allocate risk patients with endometriosis where more precise management is needed.

CHEK2p.I157T Mutation Is Associated with Increased Risk of Adult-Type Ovarian Granulosa Cell Tumors.

Pathogenic germline mutations c.1100delC and p.I157T in the CHEK2 gene have been associated with increased risk of breast, colon, kidney, prostate, and thyroid cancers; however, no associations have yet been identified between these two most common European founder mutations of the CHEK2 gene and ovarian cancers of any type. Our review of 78 female heterozygous carriers of these mutations (age > 18 years) found strikingly higher proportion of adult-type granulosa cell tumors of the ovary (AGCTs) among ovarian cancers that developed in these women (~36%) compared to women from the general population (1.3%). Based on this finding, we performed a cross-sectional study that included 93 cases previously diagnosed with granulosa cell tumors, refined and validated their AGCT diagnosis through an IHC study, determined their status for the two CHEK2 mutations, and compared the prevalence of these mutations in the AGCT cases and reference populations. The prevalence ratios for the p.I157T mutation in the AGCT group relative to the global (PR = 26.52; CI95: 12.55−56.03) and European non-Finnish populations (PR = 24.55; CI95: 11.60−51.97) support an association between the CHEK2p.I157T mutation and AGCTs. These rare gynecologic tumors have not been previously associated with known risk factors and genetic predispositions. Furthermore, our results support the importance of the determination of the FOXL2p.C134W somatic mutation for accurate diagnosis of AGCTs and suggest a combination of IHC markers that can serve as a surrogate diagnostic marker to infer the mutational status of this FOXL2 allele.

Lethal hemorrhagic necrotizing pancreatitis in a child with congenital immunodeficiency and COVID-19.

Purpose: Various manifestations of coronavirus (SARS-CoV-2) have been reported since the pandemic began. Some articles have reported acute pancreatitis in adult patients due to COVID-19 infection. To our knowledge this is the first report of acute hemorrhagic necrotizing pancreatitis in children associated with SARS-CoV-2 infection. Case presentation: A 7-year-old girl with congenital immunodeficiency was referred to the intensive care (ICU) unit with acute respiratory distress syndrome. She required mechanical ventilation (MV) due to pulmonary involvement of COVID-19 (chest CT with lower lung ground-glass opacities). SARS-CoV-2 infection was laboratory confirmed. Following a 49-day stay in the ICU, due to the clinical and radiological signs of acute abdomen and to the rapid deterioration in the clinical status, an indication to proceed an urgent surgerical intervention was made. Intra-operatively an adhesiolysis with blunt dissection of the of gastrocolic ligament was performed, then followed by debridement of the necrotic pancreas (more than 1/2 of the pancreas was damaged). Continuous lavage and drainage were placed. During the post-operative period, patient required aggressive MV and insulin therapy for persistent hyperglycemia. The CT scans reported a necrosis of the pancreas and we observed amylase and lipase elevation in the peritoneal lavage sample. Despite active intensive therapy, the patient's condition did not improve and she died 38 days after laparotomy as a result of multi-organ failure. Conclusion: The mechanism for the development of acute haemorrhagic necrotizing pancreatitis in the COVID-19 positive patients is unclear; perhaps it is due to a direct cytopathic effect from the COVID-19 virus, or due to the ACE2 expression in pancreas.

Fibro-osseous pseudotumor of digits and myositis ossificans show consistent COL1A1-USP6 rearrangement: a clinicopathological and genetic study of 27 cases.

Myositis ossificans (MO) and fibro-osseous pseudotumor of digits (FOPD) are localized, self-limiting bone-producing pseudosarcomatous lesions characterized by nodular fasciitis-like proliferation and osteoid and immature woven bone production, which may eventually develop into more mature lamellar bone. Traditionally, MO and FOPD were thought to be of reactive, non-neoplastic nature. USP6 gene rearrangement was recently reported as a consistent finding in MO and FOPD, thus expanding the spectrum of transient, USP6-rearranged neoplasms. COL1A1 was described as the fusion partner of USP6 in a subset of MO cases, but the fusion partners of USP6-rearranged FOPD have not been uncovered so far. Initially, we carefully reviewed all 27 cases of MO/FOPD from our archives, documenting the remarkable morphological overlap between both lesions. Sixteen cases were seen in consultation, and our review was requested to rule in or rule out tentative diagnoses by referring pathologists. Malignant diagnosis (osteosarcoma) was suggested by the submitting pathologists in 3 cases, whereas 7 cases were sent by the referring pathologists to "rule out sarcoma." In the following step, using next-generation sequencing, we confirmed the COL1A1-USP6 rearrangement in 5/7 cases of MO and found the same abnormality in 4/5 of FOPD. Overall, 9 of the 12 analyzable cases (75%) of MO and FOPD harbored this gene fusion. The presence of COL1A1-USP6 gene rearrangement in MO/FOPD links these lesions to other USP6-driven tumors and represents a very useful supportive marker, which may help to avoid overdiagnosis of MO/FOPD as a sarcoma.

Dysplastic Lipoma: A Distinctive Atypical Lipomatous Neoplasm With Anisocytosis, Focal Nuclear Atypia, p53 Overexpression, and a Lack of MDM2 Gene Amplification by FISH; A Report of 66 Cases Demonstrating Occasional Multifocality and a Rare Association With Retinoblastoma.

In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single-cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor. Similar tumors have been described in small series under the designations "subcutaneous minimally atypical lipomatous tumors" and "anisometric cell lipoma." Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma 1 (RB1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with fluorescence in situ hybridization (FISH) and for TP53 mutations by Sanger sequencing. Next-generation sequencing analysis using a panel of 271 cancer-related genes, including TP53, RB1, and MDM2, was also carried out. Our patient cohort included 57 male patients, 8 female patients, and 1 patient of unstated sex, who ranged in age from 22 to 87 years (mean: 51.2 y). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders, or posterior neck (86.4%). Ten patients had multiple (2 to 5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including 1 patient who had a retinoblastoma diagnosed at age 1. The tumors were generally well circumscribed. At low magnification, there was notable adipocytic size variation with single-cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement, and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2% to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in <1% of the neoplastic cells, but in 4 cases, up to 10% of the cells were positive. Of 32 cases tested, 22 showed a near total loss of RB1 immunoexpression, and the remainder showed partial loss. Three of 13 cases showed RB1 gene deletion in >45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All 5 tested cases showed no TP53 mutation with Sanger sequencing. Because of material quality issues, next-generation sequencing analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1 to 192 mo; mean: 27 mo) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18.9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.