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.

[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.

[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.

[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.

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.

Prognostic relevance of lactate dehydrogenase and serum S100 levels in stage IV melanoma with known BRAF mutation status.

BACKGROUND: Activating mutations of BRAF provide an important treatment target in patients with melanoma. The prognostic role of several biochemical markers in relation to mutation status is not clear. OBJECTIVES: To analyse the prognostic significance of BRAF mutation in patients with melanoma and correlate it to different markers. METHODS: In total, 162 patients with stage IV melanoma and known BRAF mutation status were included. Clinical, histopathological and laboratory information was collected and compared between patients with BRAF mutant (BRAFm) and wild-type (BRAFwt) melanoma at the time of first distant metastasis. RESULTS: In total, 88 patients (54%) had BRAFm melanoma (V600E/V600K). At the first distant metastasis, S100B levels in BRAFm patients were more frequently elevated (P = 0·01) and significantly higher (P = 0·02). Median overall survival (mOS) was significantly longer in BRAFwt patients with normal compared with patients with elevated S100B levels (P < 0·01). In BRAFm melanoma, elevated S100B levels showed no prognostic influence (P = 0·18). Elevated lactate dehydrogenase (LDH) levels had a significantly negative impact on mOS in both groups. mOS was increased for BRAFm patients treated with a BRAF inhibitor (BRAFi) compared with BRAFm patients not receiving BRAFi (P = 0·01). No difference in mOS between BRAFm patients who did not receive BRAFi treatment and BRAFwt patients was observed. CONCLUSIONS: Better mOS was observed in BRAFm patients treated with BRAFi. BRAFm patients not treated with BRAFi show similar survival curves to BRAFwt patients. Elevated LDH is a BRAF-independent prognostic parameter; S100B has prognostic significance in BRAFwt melanoma only.

[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.

[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.

[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.

[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.

Comprehensive validation of published immunohistochemical prognostic biomarkers of prostate cancer -what has gone wrong? A blueprint for the way forward in biomarker studies.

BACKGROUND: Treatment planning of localised prostate cancer remains challenging. Besides conventional parameters, a wealth of prognostic biomarkers has been proposed so far. None of which, however, have successfully been implemented in a routine setting so far. The aim of our study was to systematically verify a set of published prognostic markers for prostate cancer. METHODS: Following an in-depth PubMed search, 28 markers were selected that have been proposed as multivariate prognostic markers for primary prostate cancer. Their prognostic validity was examined in a radical prostatectomy cohort of 238 patients with a median follow-up of 60 months and biochemical progression as endpoint of the analysis. Immunohistochemical evaluation was performed using previously published cut-off values, but allowing for optimisation if necessary. Univariate and multivariate Cox regression were used to determine the prognostic value of biomarkers included in this study. RESULTS: Despite the application of various cut-offs in the analysis, only four (14%) markers were verified as independently prognostic (AKT1, stromal AR, EZH2, and PSMA) for PSA relapse following radical prostatectomy. CONCLUSIONS: Apparently, many immunohistochemistry-based studies on prognostic markers seem to be over-optimistic. Codes of best practice, such as the REMARK guidelines, may facilitate the performance of conclusive and transparent future studies.

Frequent PD-L1 expression in testicular germ cell tumors.

BACKGROUND: Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies. METHODS: Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue. RESULTS: Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells. CONCLUSIONS: This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

[Neuroendocrine tumors of the kidneys]. / Neuroendokrine Tumoren der Niere.

The 2004 World Health Organization (WHO) classification of renal cancer includes renal carcinoid and neuroendocrine cancer of the kidneys in the group of primary renal neuroendocrine tumors. The histological features of primary renal carcinoids are similar to those of neuroendocrine tumors found in other anatomical locations. Primary carcinoid tumors of the kidneys are frequently misdiagnosed as other kidney cancers, such as papillary renal cell carcinoma, mesonephric tumors, Wilms tumor (WT) and undifferentiated carcinoma. Immunohistochemical staining results are consistent with the diagnosis of a neuroendocrine tumor with immunoreactivity for synaptophysin, chromogranin, CD56, and neuron-specific enolase (NSE). Positive expression of CD99 can also be seen. There is mainly absence of WT1, cytokeratin 7, cytokeratin 20, thyroid transcription factor (TTF1) and LCA, ruling out most other differential diagnoses. Renal carcinoid tumors are regarded as low-grade neuroendocrine tumors; however, many studies have demonstrated metastatic disease in patients with renal carcinoid tumors. The prognostic value of histological parameters is uncertain. Some studies have correlated poor patient prognosis with increased mitotic activity, presence of necrosis and cytological atypia. Cases with higher mitotic rates of > 2 mitoses/10 high power fields (HPF) developed metastases more frequently; therefore, the WHO classification of neuroendocrine tumors used in other organs is recommended for primary renal carcinoid tumors.

Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression.

BACKGROUND: The mechanisms of brain metastasis in renal cell cancer (RCC) patients are poorly understood. Chemokine and chemokine receptor expression may contribute to the predilection of RCC for brain metastasis by recruitment of monocytes/macrophages and by control or induction of vascular permeability of the blood-brain barrier. METHODS: Frequency and patterns of brain metastasis were determined in 246 patients with metastatic RCC at autopsy. Expression of CXCR4, CCL7 (MCP-3), CCR2 and CD68(+) tumour-associated macrophages (TAMs) were analysed in a separate series of 333 primary RCC and in 48 brain metastases using immunohistochemistry. RESULTS: Fifteen percent of 246 patients with metastasising RCC had brain metastasis. High CXCR4 expression levels were found in primary RCC and brain metastases (85.7% and 91.7%, respectively). CCR2 (52.1%) and CCL7 expression (75%) in cancer cells of brain metastases was more frequent compared with primary tumours (15.5% and 16.7%, respectively; P<0.0001 each). The density of CD68(+) TAMs was similar in primary RCC and brain metastases. However, TAMs were more frequently CCR2-positive in brain metastases than in primary RCC (P<0.001). CONCLUSION: Our data demonstrate that the monocyte-specific chemokine CCL7 and its receptor CCR2 are expressed in tumour cells of RCC. We conclude that monocyte recruitment by CCR2 contributes to brain metastasis of RCC.