Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

NOTCH1 and PIK3CA mutation are related to HPV-associated vulvar squamous cell carcinoma.

NOTCH1 and PIK3CA are members of important cell signalling pathways that are deregulated in squamous cell carcinomas of various organs. Vulvar squamous cell carcinomas (vulvSCC) are classically divided into two pathways, HPV-associated or HPV-independent, but the effect of NOTCH1 and PIK3CA mutations in both groups is unclear. We analysed two different cohorts of vulvSCC using Hybrid Capture-based Comprehensive Genomic Profiling and identified NOTCH1 and PIK3CA mutations in 35% and 31% of 48 primary vulvSCC. In this first cohort, PIK3CA and NOTCH1 mutations were significantly correlated with HPV infection (p < 0.01). Furthermore, mutations in both genes were associated with an advanced tumor stage and poorly differentiated status (p < 0.05). PIK3CA and NOTCH1 mutations were also associated with shorter patient survival which did not reach significance. In the second cohort of 735 advanced vulvSCC from metastatic site biopsies or from sites of unresectable loco-regional disease, NOTCH1 and PIK3CA mutations were reported in 14% and 20.3%, respectively. 4 of 48 (8%) and 22 of 735 vulvSCC (3.0%) featured genomic alterations (short variants and/or copy number changes and/or rearrangements) in both NOTCH1 and PIK3CA. NOTCH1 mutations were mostly located in the extracellular EGF-like domains, were inactivating and indicated that NOTCH1 functions predominantly as a tumor suppressor gene in vulvSCC. In contrast, PIK3CA mutations favored hotspot codons 1624 and 1633 of the gene, indicating that PIK3CA acts as an oncogene in vulvar carcinogenesis. In conclusion, NOTCH1 and PIK3CA mutations are detectable in a substantial proportion of vulvSCC and are related to HPV infection and more aggressive tumor behaviour.

Improving the turnaround time of molecular profiling for advanced non-small cell lung cancer: Outcome of a new algorithm integrating multiple approaches.

BACKGROUND: Molecular tumor profiling to identify oncogenic drivers and actionable mutations has a profound impact on how lung cancer is treated. Especially in the subgroup of non-small cell lung cancer (NSCLC), molecular testing for certain mutations is crucial in daily clinical practice and is recommended by international guidelines. To date, a standardized approach to identify druggable genetic alterations are lacking. We have developed and implemented a new diagnostic algorithm to harmonize the molecular testing of NSCLC. PATIENTS AND METHODS: In this retrospective analysis, we reviewed 119 patients diagnosed with NSCLC at the University Hospital Zurich. Tumor samples were analyzed using our standardized diagnostic algorithm: After the histological diagnosis was made, tissue samples were further analyzed by immunohistochemical stainings as well as the real-time PCR test Idylla™. Extracted DNA was further utilized for comprehensive genomic profiling (FoundationOne®CDx, F1CDx). RESULTS: Out of the 119 patients were included in this study, 100 patients were diagnosed with non-squamous NSCLC (nsqNSCLC) and 19 with squamous NSCLC (sqNSCLC). The samples from the nsqNSCLC patients underwent testing by Idylla™ and were evaluated by immunohistochemistry (IHC). F1CDx analysis was run on 67 samples and 46 potentially actionable genomic alterations were detected. Ten patients received the indicated targeted treatment. The median time to test results was 4 days for the Idylla test, 5 days for IHC and 13 days for the F1CDx. CONCLUSION: In patients with NSCLC, the implementation of a standardized molecular testing algorithm provided information on predictive markers for NSCLC within a few working days. The implementation of broader genomic profiling led to the identification of actionable targets, which would otherwise not have been discovered.

WHO 2022 classification of penile and scrotal cancers: updates and evolution.

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as "subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.

[Oncocytic tumours of the kidney-new differential diagnoses]. / Onkozytäre Tumoren der Niere ­ neue Differenzialdiagnosen.

BACKGROUND: Recent developments in differential diagnosis have led to new knowledge about oncocytic renal neoplasms. OBJECTIVES: Overview of differential diagnosis of oncocytic tumours. MATERIALS AND METHODS: We performed a literature search on oncocytic renal tumours and mapped known tumour types. Possible differential diagnoses are discussed. RESULTS: Besides the tumour types already acknowledged by the 2016 WHO classification, there is new evidence regarding the group of hard-to-classify oncocytic neoplasms. Findings point to immunohistochemical and molecular characteristics that may lead to the establishment of new entities in the future. In addition, important differential diagnosis can now be identified, facilitating specific therapies for oncocytic renal tumours. CONCLUSION: A correct diagnosis of oncocytic renal tumours not only improves prognostic assessment (and, if necessary, specific therapies) but is also clinically relevant regarding a possible association with hereditary tumour syndromes.

[FH-deficient renal cell carcinoma expands the spectrum of renal papillary tumors]. / Das FH-defiziente Nierenzellkarzinom erweitert das Spektrum der papillären Tumoren in der Niere.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a distinct entity, which shows a biallelic inactivation of the FH gene that consequently leads to FH protein expression and function loss, respectively. This alteration leads to an accumulation of the oncometabolite fumarate in the citrate cycle and various disorders of the cell balance and DNA processing. FH-deficient RCC often shows a morphologically overlapping spectrum with papillary renal cell carcinoma (type 2), whereby a typical mixture of growth patterns including tubulo-cystic, cribriform, and/or solid differentiation can be observed. A characteristic but non-specific morphological feature is prominent eosinophilic, virus-inclusion body-like nucleoli with perinucleolar halos. Tumoral immunohistochemical loss of FH expression supports the diagnosis but may be preserved in rare cases. Most FH-deficient RCCs show very aggressive biological behavior and are often metastasized at the time of diagnosis. The initial description encompassed RCC in association with the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, which also includes cutaneous and uterine leiomyomas. However, current data also show an increasing proportion of sporadic cases, so that a distinction (hereditary vs. sporadic) seems appropriate. So far, few but promising data on effective systemic therapeutic options have been reported. In summary, precise diagnosis is of great importance due to the frequent aggressive biological behavior, potential need to deviate from the therapeutic standard, and the possible indicator of a hereditary disease.

[Histological subtypes of renal cell carcinoma : Overview and new developments]. / Histologische Subtypen des Nierenzellkarzinoms : Übersicht und neue Entwicklungen.

BACKGROUND: The classification of renal cell carcinoma (RCC) has changed remarkably in recent years. OBJECTIVES: This is a short overview of the classification of RCC, focusing on new developments. MATERIALS AND METHODS: A literature search was performed resulting in an overview of the classification of RCC. Emerging entities were discussed in detail. RESULTS: Apart from the RCC subtypes in the WHO classification of 2016, several emerging entities came up over the last few years that are characterized by typical morphology, immunophenotype, and especially specific genetic alterations. CONCLUSION: Precise classification of RCC is the key to better prognostic assessment with potential tumor-specific therapy and plays an important role in the recognition of possible association with hereditary tumor syndromes.

[Characterization of different renal cell carcinoma entities]. / Charakterisierung der unterschiedlichen Entitäten beim Nierenzellkarzinom.

BACKGROUND: In recent years, the characterization of different renal cell carcinoma entities has significantly improved, in particular due to molecular typing. OBJECTIVES: Classical, accepted and emerging renal cell carcinoma entities are described. MATERIALS AND METHODS: A literature search was performed, followed by evaluation and description of the literature focusing on different renal cell carcinoma entities. RESULTS: Classical renal cell carcinoma entities such as clear cell carcinoma, papillary renal cell carcinoma and chromophobe renal cell carcinoma have been expanded in particular by molecular techniques to include, for example, translocation carcinoma or carcinoma with mutations in genes of the mitochondrial energy metabolism. Some rare entities have been accepted by the World Health Organization (WHO) classification, while some are considered as emerging entities. CONCLUSIONS: A range of newly accepted and emerging renal cell carcinoma entities have been introduced in the 2016 WHO classification. A precise and correct diagnosis is of major importance regarding the prognostic assessment, potential new therapeutic strategies and possible hereditary associations.

[Eulogy to Prof. Dr. Med. Michael J. Mihatsch : Presentation of the Rudolf Virchow Medal 2019 of the German Society of Pathology]. / Laudatio auf Prof. Dr. med. Michael J. Mihatsch : Verleihung der Rudolf-Virchow-Medaille 2019 der Deutschen Gesellschaft für Pathologie.

Michael Mihatsch, born in 1943 in Gleiwitz, studied medicine in Bonn and Freiburg, and then went to Basel to begin studying pathology. In 1978, he became Assistant Professor at the University of Basel, and led the Institute there from 1988 until 2007. Mihatsch made Basel a center for prospective renal pathologists.His most significant achievement is the description of the connection between phenacetin administration and nephropathy with renal atrophy and the concomitant occurrence of urothelial carcinoma. His campaign against phenacetin finally contributed to a ban on the medication.His textbook Renal Pathology in Biopsy is a classic of medical literature.As a leading nephropathologist worldwide, Prof. Dr. Med. Michael J. Mihatsch received the Rudolf Virchow Medal of the German Society of Pathologists in 2019.

Erratum to "Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma".

[This corrects the article DOI: 10.1155/2015/432479.].

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study.

Background: The vascular endothelial growth factor antibody bevacizumab (Avastin®), received approval for the treatment of recurrent glioblastoma in many countries including the USA and Switzerland, but not the European Union, in 2009. Here, we explored the hypothesis that the approval of bevacizumab improved outcome with glioblastoma on a population level. Patients and methods: The prognostic significance of epidemiological, molecular genetic, and clinical data including treatment for glioblastoma patients diagnosed from 2010 to 2014 in the Canton of Zurich, Switzerland, was retrospectively analyzed using log-rank test and Cox proportional hazards models. Data were compared with data for the years 2005-2009. Results: In total, 310 glioblastoma patients were identified in the years 2010-2014. Median overall survival was 13.5 months for patients with known isocitrate dehydrogenase (IDH) wild-type (wt) (IDH1R132H-non-mutant) tumors (N = 248), compared with 11.3 months for IDH wt patients (P = 0.761) before (2005-2009). In the IDH wt cohort, bevacizumab use at any time increased from 19% in 2005-2009 to 49% in 2010-2014. Multivariate analysis did not identify bevacizumab exposure at any time to be associated with survival. Yet, upon the second-line treatment, baseline doses of corticosteroids were reduced by more than half in 83% of patients on bevacizumab compared with 48% of the patients treated with bevacizumab-free regimens (P = 0.007). Conclusion: This epidemiological study of a small, but clinically well-annotated patient cohort fails to support the assumption that the strong increase of bevacizumab use since 2010 improved survival in glioblastoma although clinical benefit associated with decreased steroid use may have been achieved.

PD-L1 is a positive prognostic factor in squamous cell carcinoma of the nasal vestibule.

BACKGROUND: Aim was to analyse the role of PD-L1 in squamous cell carcinomas of the nasal vestibule. Advanced squamous cell carcinoma of the nasal vestibule is a highly aggressive tumour. The role of PD-L1 expression is unclear in this tumour type. METHODOLOGY: Forty-six patients diagnosed between 1995 and 2014 were analyzed. Baseline characteristics and outcome were correlated to immunohistochemical staining of PD-L1. PD-L1 positivity of tumour cells and tumour infiltrating immune cells (TIIC) was defined by any staining of more than 1% of the tumour cells. RESULTS: PD-L1 expression was interpretable in 31 of 46 patients (67.4%). PD-L1 positivity was present in 14 (45.2%) patients tumour cells and 17 (54.8%) patients TIIC. PD-L1 positivity of tumour cells was associated with a favourable disease free survival (p=0.019). CONCLUSIONS: Positivity for PD-L1 in tumour cells is a prognostic factor in squamous cell carcinoma of the nasal vestibule and might enable a patient-tailored treatment.

[Establishment of a living biobank : Improved guidance of precision cancer care with in vitro and in vivo cancer models]. / Etablierung einer Living Biobank : Bessere Steuerung der Präzisionsonkologie durch In-vitro- und In-vivo-Krebsmodelle.

BACKGROUND: Precision oncology is a clinical approach aimed towards tailoring treatment strategies for patients based on the genetic profile of each patient's cancer. The integration of a living biobank, consisting of patient-derived tumor organoids and PDXs, with next generation sequencing approaches and high-throughput drug screening help to guide clinical decision-making and clinical trial development. METHODS: Tumor organoids derived from fresh tumor samples were used for in vitro and in vivo high-throughput drug testing. RESULTS: Over a period of two years we established 56 in vitro tumor organoids and 19 in vivo xenografts from 18 different solid tumor types. Tumor morphology and molecular profiles show good concordance between the in vitro and in vivo models compared to their native tumor. High-throughput drug screening (up to 160 drugs) has been tested on eight tumor organoid lines. Seven of them underwent an additional combination drug screen. We nominated several targeted small molecules and novel combinations that have been validated in corresponding xenograft models. CONCLUSION: This precision medicine approach outlines the integration of genomic data with drug screening from personalized preclinical cancer models to guide precision cancer care. It also fuels next generation research and has been implemented for clinical trial development.

[Clinical autopsies in Switzerland : A status report]. / Klinische Obduktionen in der Schweiz : Ein Statusbericht.

BACKGROUND: The number of autopsies has been steadily declining worldwide over the past decades. The reasons for this are diverse. Legislation regarding opposition and consent rules does not appear to have had a significant impact on the autopsy rates. Above all, structural causes and the attitude of the medical profession are the reasons for this decline. The main argument for a high autopsy rate is the identification of diagnostic errors; however, diagnostic discrepancies are relatively independent of the rate of autopsies performed. At the University Hospital (UniversitätsSpital) Zurich it could be shown in a study that from 1972-2002 the frequency of relevant diagnostic discrepancies (classes I and II) decreased from 30% to 7%. OBJECTIVE: The aim of this article is to present the necessity of a stable autopsy rate and to examine the situation of the autopsy in Switzerland. MATERIAL AND METHODS: For this purpose, the importance of autopsies in the fields of quality assurance of medical diagnostics, cancer statistics, medical research as well as further education of doctors in Switzerland is shown. Efforts are being made by the pathologists to counteract the declining autopsy rates. RESULTS AND DISCUSSION: Declining autopsy numbers have a significant influence on cancer statistics. The rate of newly discovered tumors in autopsies in Switzerland decreased from 42% in 1980 to 17% in 2010. Pediatric autopsies are an important tool for quality assurance of medical diagnostics in neonatology and pediatrics in Switzerland, but the rate of autopsies carried out is also declining. Postmortem magnetic resonance imaging (MRI) examinations (virtopsy) could increase the acceptance of the parents for an autopsy in the future. Autopsies make an important contribution in research and in documentation of therapy-associated side effects and they are an important component of further education of the upcoming medical generations.

[The WHO/ISUP grading system for renal carcinoma]. / WHO-ISUP-Graduierungssystem für Nierenkarzinome.

Histological tumor grading is an accepted prognostic parameter of renal cell carcinoma (RCC). In 2012, the International Society of Urologic Pathologists (ISUP) proposed a novel grading system for RCC, mainly based on the evaluation of nucleoli: grade 1 tumors have nucleoli that are inconspicuous and basophilic at ×400 magnification; grade 2 tumors have nucleoli that are clearly visible at ×400 magnification and eosinophilic; grade 3 tumors have clearly visible nucleoli at ×100 magnification; and grade 4 tumors have extreme pleomorphism or rhabdoid and/or sarcomatoid morphology. This grading system was validated for clear cell renal cell carcinoma and papillary renal cell carcinoma. At the same time, the ISUP proposed not grading chromophobe renal cell carcinomas according to this system. At a consensus conference in Zurich the World Health Organization (WHO) recommended the ISUP grading system; thus, the WHO/ISUP grading system is now going to be implemented internationally. The ISUP/WHO grading system has not been validated as a prognostic parameter for other tumor subtypes, but can be used for descriptive purposes.

Homozygous G/G variant of SNP309 in the human MDM2 gene is associated with earlier tumor onset in Caucasian female renal cell carcinoma patients.

Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild-type T/T genotype.

[WHO classification 2016 and first S3 guidelines on renal cell cancer: What is important for the practice?]. / WHO-Klassifikation von 2016 und erste S3-Leitlinie zum Nierenzellkarzinom: Was ist wichtig für die Praxis?

The first S3 guidelines on renal cell cancer cover the practical aspects of imaging, diagnostics and therapy as well as the clinical relevance of pathology reporting. This review summarizes the changes in renal tumor classification and the new recommendations for reporting renal cell tumors. The S3 guidelines recommend the 2016 World Health Organization (WHO) classification of renal cell tumors. Novel renal cell tumor entities and provisional or emerging renal cell tumor entities of the 2016 WHO classification of renal tumors are discussed. The S3 guidelines for renal cell cancer also recommend the use of the WHO/International Society of Urologic Pathology (ISUP) grading system for clear cell and for papillary renal cell carcinomas, which replaces the previously used Fuhrman grading system.

[Nephroblastomas: Almost exclusively in clinical trials!]. / Nephroblastome: Praktisch immer in Studien!

Nephroblastomas are the most commonly occurring renal neoplasms in childhood and are treated almost exclusively in clinical trials. An important factor for further therapeutic management is the pathological evaluation of the nephrectomy specimen. Tumor stage and risk group classification are the most crucial parameters. An independent assessment of the tumor by a reference pathology center is an essential standard procedure. Although many molecular genetic discoveries have been made in nephroblastomas over recent years, molecular parameters do not (yet) play a role in treatment stratification.

[The translocation carcinoma: A pediatric renal tumor also in adults]. / Das Translokationskarzinom: Ein kindlicher Nierentumor auch bei Erwachsenen.

The MiT family of translocation-associated renal cell carcinomas comprise approximately 40 % of renal cell carcinomas in young patients but only up to 4 % of renal cell carcinomas in adult patients. The Xp11.2 translocation-associated tumors are the most frequent and were included in the 2004 World Health Organization (WHO) classification. They contain a fusion of the TFE3 gene with ASPSCR1, PRCC, NONO, SPFQ or CLTC resulting in an immunohistochemically detectable nuclear overexpression of TFE3. The Xp11.2 translocation-associated renal cell carcinomas are characterized by ample clear cytoplasm, papillary architecture and abundant psammoma bodies. The TFEB translocation-associated renal cell carcinomas are much rarer and show a biphasic architecture. Fluorescence in situ hybridization permits the detection of a translocation by means of a break apart probe for the TFE3 and TFEB genes and is recommended for the diagnosis of renal cell carcinomas in patients under 30 years of age. The TFE3 and TFEB translocation-associated tumors are classified as MiT family translocation carcinomas in the new WHO classification.The rare renal cell carcinomas harboring an ALK rearrangement with fusion to VCL in young patients with sickle cell trait show a characteristic morphology and are listed in the new WHO classification as a provisional entity.