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We here describe the development of an evidence-based cancer dataset by an International Collaboration on Cancer Reporting expert panel for the reporting of primary testicular neoplasia, and present the 'required' and 'recommended' elements to be included in the pathology report, as well as a commentary. This dataset encompasses the updated 2016 World Health Organisation classification of urological tumours, the results of an International Society of Urological Pathology consultation, and also staging with our preferred method: the American Joint Committee on Cancer version 8. Implementation of this dataset will facilitate consistent and accurate data collection between different cohorts, facilitate research, and hopefully result in improved patient management.

AIMS Testicular seminomas require accurate staging for effective management. Twenty per cent are metastatic at presentation, while 80% are clinical stage I, requiring only orchiectomy and surveillance. Tumour size, rete testis invasion, hilar soft tissue invasion and lymphovascular invasion have been shown to incur a higher risk of metastasis and recurrence in clinical stage I seminomas, with little congruence between studies. METHODS AND RESULTS We reviewed 211 cases of testicular seminomas and recorded patient age, tumour size, lymphovascular invasion and rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea and tunica vaginalis involvement. A univariate and multivariate analysis was performed comparing clinical stage I to advanced clinical stage patients (stages II and III) in reference to these factors. We found that tumour size (P = 0.02), vascular invasion (P = 0.02) and invasion of rete testis stroma (P = 0.01), epididymis (P = 0.02), spermatic cord (P = 0.047) and hilar soft tissue (P = 0.04) were predictors of higher clinical stage at the univariate level. However, multivariate analysis showed that only tumour size and vascular invasion remained significant (P = 0.008 and 0.032, respectively). A tumour size of 4 cm was the cut-off size found to be significant. CONCLUSIONS Tumour size and vascular invasion are the strongest predictors of higher clinical stage in testicular seminomas. Our univariate data suggest that rete testis and hilar soft tissue invasion relate to higher clinical stage. However, neither of these factors were found to be independent risk factors at multivariate analysis. Therefore, this study supports tumour upstaging based only upon size and vascular invasion.

Aims Accurate histological diagnosis and classification of germ cell tumours (GCTs) is key to informing successful therapeutic and surveillance strategy. The modern therapeutic approach for yolk sac tumour (YST) is highly curative. Because YST takes on a large morphological spectrum, it can be confused for other GCT subtypes as well as somatic carcinomas, particularly when YST presents in an extragonadal or a metastatic setting. Currently available immunohistochemical markers are limited by suboptimal sensitivity and specificity. We reported recently that ZBTB16 is a sensitive and specific marker for testicular YST. ZBTB16 is absent in other GCTs and in most common somatic carcinomas, including those of gastrointestinal, pancreatobillary, respiratory, genitourinary and gynaecological tracts. The purpose of this study is to investigate the diagnostic utility of ZBTB16 in the settings of metastatic and extragonadal YST. Methods and results We studied 32 archived metastatic and four extragonadal primary YSTs as well as 51 somatic malignancies for their immunohistochemical expression of ZBTB16. For comparison, α-fetoprotein (AFP) and glypican-3 were also studied in parallel. Our results demonstrated an overall sensitivity of 91.6% for ZBTB16 in detecting metastatic and extragonadal YSTs. The non-YST elements (teratoma and embryonal carcinoma) in 15 YST-containing metastatic mixed GCTs were non-reactive. With the exception of occasional myoepithelial cells of salivary gland carcinoma, all the 51 somatic malignancies were negative for ZBTB16. Conclusions ZBTB16 is a sensitive and specific marker for YST and is diagnostically superior to AFP and glypican-3 in metastatic and extragonadal settings.

Advances in modern chemotherapy and targeted treatments have resulted in lengthened survival in a variety of tumour types in the last decade. Increasingly in the 21st century, postchemotherapy resections are considered as a possible mode of treatment. Due to their exquisite chemosensitivity, resection of postchemotherapy masses has long been part of the armamentarium of treatment in testicular germ cell neoplasia, which has resulted in a variety of new morphological variants being described after treatment. Here we discuss the possible reasons for germ cell tumour chemosensitivity and hypotheses on the biological pathways leading to resistance to treatment, as well as an outline of the diverse morphology of those tumours which prove recalcitrant to standard treatment methods. The large range of morphologies and their diagnostic challenges may throw light upon the future problems to be encountered in non-germ cell solid tumour pathology, as the resection of postchemotherapy masses becomes increasingly important in patient management.

AimsThe handling and reporting of testicular tumours is difficult due to their rarity. Methods and resultsA survey developed by the European Network of Uro-Pathology (ENUP) and sent to its members and experts to assess the evaluation of testicular germ cell tumours. Twenty-five experts and 225 ENUP members replied. Areas of disagreement included immaturity in teratomas, reported by 32% of experts but 68% of ENUP. Although the presence of rete testis invasion was reported widely, the distinction between pagetoid and stromal invasion was made by 96% of experts but only 63% of ENUP. Immunohistochemistry was used in more than 50% of cases by 68% of ENUP and 12% of experts. Staging revealed the greatest areas of disagreement. Invasion of the tunica vaginalis without vascular invasion was interpreted as T1 by 52% of experts and 67% of ENUP, but T2 by the remainder. Tumour invading the hilar adipose tissue adjacent to the epididymis without vascular invasion was interpreted as T1: 40% of experts, 43% of ENUP; T2: 36% of experts, 30% of ENUP; and T3: 24% of experts, 27% of ENUP. ConclusionsThere is remarkable consensus in many areas of testicular pathology. Significant areas of disagreement included staging and reporting of histological types, both of which have the potential to impact on therapy.

Aims We examined gene rearrangement and the expression of anaplastic lymphoma kinase (ALK) in urinary bladder inflammatory myofibroblastic tumour (IMT) using fluorescence in-situ hybridization (FISH) and two immunohistochemical antibodies to ALK. We also investigated whether IMT represents an immunoglobulin (Ig)G4-related disease. Methods and results The performance of the Dako FLEX ALK monoclonal antibody (CD246) and the Cell Signaling Technology ALK (D5F3) XP monoclonal antibody were compared. Overall, 11 of 16 tumours showed ALK expression by immunohistochemistry (69%). Ten demonstrated ALK expression with both stains and one was positive with D5F3 but not CD246 (91% correlation). The D5F3 antibody yielded a stronger staining intensity and a higher sensitivity. Nine tumours demonstrated ALK rearrangements (56%) by FISH. Three were ALK+ by immunohistochemistry but negative for rearrangement by FISH, whereas one showed rearrangement by FISH but was negative by immunohistochemistry. In total, 12 tumours were positive for ALK abnormalities (75%). Using current criteria, no cases were classified as an IgG4-related disease. Conclusions The ALK D5F3 immunohistochemical stain showed superior staining characteristics compared with ALK CD246. Discrepancies in the results between FISH and immunohistochemistry for ALK abnormalities may have causes that are multifactorial. By current criteria, IMT does not represent an IgG4-related disease.

Aims Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumours that are unable to be diagnosed as other well-defined entities. We aim to describe the morphological findings of tumours within this category and to determine the most frequent morphological features leading to classification difficulty. Methods and results One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n = 66), followed by 2 (n = 42) and 4 (n = 28). Tumour size ranged from 0.6 to 24.9 cm. The American Joint Committee on Cancer (AJCC) pathological T categories included pT1a (n = 50), pT1b (n = 14), pT2a (n = 7), pT2b (n = 4), pT3a (n = 50) and pT4 (n = 9). Forty-four cases included lymph node(s), 41% of which (n = 18) had metastases. Tumours were assessed for a variety of histological features and assigned to the following morphological groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like and pure sarcomatoid phenotypes were mainly high stage (pT3 or pT4). Conclusions Renal cell carcinoma, unclassified is a term that encompasses tumours with a variety of morphological features and a wide biological spectrum. The most common source of diagnostic difficulty was tumours composed of predominantly eosinophilic cells.

Aims To investigate the immunohistochemical properties of the sex cord cells of gonadoblastoma and Sertoli cell nodule with intratubular germ cell neoplasia unclassified (IGCNU) as a means of objective distinction and to provide insight into the pathogenesis. Methods and results Immunohistochemical stains for SOX9, FoxL2 and SF-1 were performed on 10 gonadoblastomas (all phenotypical females) and 14 Sertoli cell nodules with IGCNU in normal phenotypical males with coexisting germ cell tumours. The sex cord cells of gonadoblastomas showed strong, diffuse FoxL2 and SF-1 positivity and focal weak to moderate SOX9 reactivity, whereas those of Sertoli cell nodules with IGCNU were uniformly, strongly positive for SOX9 and SF-1, while negative for FoxL2. Conclusions Coexpression of SOX9 and FoxL2 in the sex cord cells of gonadoblastomas provides evidence that these morphologically ambiguous sex cord cells are incompletely differentiated. The strong, diffuse SOX9 and SF-1 positivity and absence of FoxL2 reactivity in the Sertoli cell nodules with IGNCU support full Sertoli cell differentiation of the sex cord cells and distinguish them from gonadoblastomas. Deficient SOX9 expression in gonadoblastoma supports a current model of pathogenesis where immature germ cells, in the absence of well-formed Sertoli cells, retain a fetal phenotype and susceptibility to malignant transformation.

The World Health Organization (WHO) released a new tumour classification for the genitourinary system in early 2016 after consensus by pathologists with expertise in these organs. It utilized the framework of the 2004 classification, and incorporated the most up-to-date information concerning these tumours. In testicular tumours, the majority of the changes occurred in the nomenclature and classification of germ cell tumours; however, several modifications were also made for non-germ cell tumours. Among sex cord-stromal tumours, sclerosing Sertoli cell tumour (SCT) is no longer recognized as a separate entity but as a morphological variant of SCT not otherwise specified (NOS), as CTNNB1 gene mutations have been noted in both neoplasms but not in the other forms of SCT. Similarly, the lipid cell variant is not separately classified, but is considered to be a morphological variant of SCT NOS. Large-cell calcifying SCT is recognized as a distinct entity that occurs either sporadically or in association with Carney complex, with the latter patients having a distinct germline PRKAR1A gene mutation. Intratubular large-cell hyalinizing Sertoli cell neoplasia is also accepted as a separate entity linked with Peutz-Jeghers syndrome. The subcategories of 'mixed' and 'incompletely differentiated' forms of sex cord/gonadal stromal tumours have been replaced by 'mixed and unclassified sex cord-stromal tumours'. New entities introduced in the latest WHO revision include: myoid gonadal stromal tumour and 'undifferentiated gonadal tissue', a putative precursor lesion of gonadoblastoma, whereas juvenile xanthogranuloma and haemangioma are included in the miscellaneous category of tumours.

Jain R K, Mehta R J, Nakshatri H, Idrees M T & Badve S S (2011) Histopathology58, 766–772 High-level expression of forkhead-box protein A1 in metastatic prostate cancer Aims: Expression of forkhead-box protein A1 (FOXA1), a transcription factor important for normal development of the prostate gland, is thought to be controlled by steroid hormones and GATA3. The aim of this study was to investigate the expression and potential role of FOXA1 and GATA3 transcription factors as prognostic factors in prostate cancer. Methods and results: Expression of FOXA1, GATA3 and androgen receptor (AR) was retrospectively analysed by immunohistochemistry in a series of 80 primary tumours and 28 metastatic prostate cancers, including 15 matched paired samples. Nuclear AR expression did not significantly differ between primary and metastatic tumours. High-level nuclear FOXA1 expression was seen in 19% of primary and 89% of metastatic tumours (P

Aims : To analyse the expression patterns of GLUT1, p63 and p53 and the possible correlation between these markers in uterine serous papillary carcinoma (USPC) and endometrial intraepithelial carcinoma (EIC). Methods and results : Fourteen cases of USPC, 12 of which also showed EIC, were examined for GLUT1, p63 and p53 immunoreactivity. Four-micrometre sections from formalin-fixed paraffin-embedded tissue were immunostained using commercially available primary antibodies and Dako Envision Plus reagents for visualization. Membranous GLUT1 immunoreactivity was observed in all cases, including all 14 invasive tumours (100%) and 11 of 12 associated EICs (92%), and was confined to neoplastic cells. In USPC, staining tended to be strongest in superficial antistromal regions. p63 positivity was found in 8/14 (57%) USPCs and 9/12 (75%) associated EICs. In 11 cases p53 was overexpressed in both invasive USPC (11/14; 79%) and EIC (11/12; 92%). p53+ USPCs tended to be positive for p63, whereas p53– USPCs were also negative for p63. Conclusions : GLUT1 is expressed in the vast majority of USPC and EIC, suggesting a biological role during the early steps of carcinogenesis in endometrial serous neoplasms. GLUT1 expression may be induced by hypoxia-related as well as other mechanisms.

Aims To study clear cell renal cell carcinomas with predominant cystic and sclerotic components, in which a solid epithelial component precluded a diagnosis of multilocular cystic renal cell carcinoma. We designated these tumours ‘cystic partially regressed clear cell renal cell carcinoma.’ Methods and results Twenty-seven tumours were studied, from patients with a median age of 58 years; the stage was most often pT1 (89%). The Fuhrman grade was 2 (48%), 1 (33%), or 3 (19%). The solid epithelial component constituted up to 30% of the tumour volume (median, 10%), whereas the cystic component constituted 15–80% (median, 65%), and the sclerotic component 10–70% (median, 20%). Thin fibrovascular septa lined by cells with clear cytoplasm were almost always present, resembling multilocular cystic renal cell carcinoma. Both zones of sclerosis and fibrovascular septa often contained inconspicuous epithelial cells. Sclerotic areas ranged in appearance from a cellular fibroblastic reaction to scar-like with a residual network of capillaries resembling haemangioma. No patient developed recurrence or metastasis. Conclusions Cystic partially regressed clear cell renal cell carcinoma is an uncommon pattern of clear cell renal cell carcinoma, being composed of cysts with solid epithelial and sclerotic components that differentiate it from multilocular cystic renal cell carcinoma.

Expression of forkhead-box protein A1 (FOXA1), a transcription factor important for normal development of the prostate gland, is thought to be controlled by steroid hormones and GATA3. The aim of this study was to investigate the expression and potential role of FOXA1 and GATA3 transcription factors as prognostic factors in prostate cancer.Expression of FOXA1, GATA3 and androgen receptor (AR) was retrospectively analysed by immunohistochemistry in a series of 80 primary tumours and 28 metastatic prostate cancers, including 15 matched paired samples. Nuclear AR expression did not significantly differ between primary and metastatic tumours. High-level nuclear FOXA1 expression was seen in 19% of primary and 89% of metastatic tumours (P0.0001). FOXA1 expression correlated positively with tumour size, extraprostatic extension, angiolymphatic invasion, AR and lymph node metastases at diagnosis, but did not correlate with age, T stage, Gleason score, presence of prostatic intraepithelial neoplasia or multifocality, seminal vesicle or perineural invasion, or surgical excision margin status. Expression of GATA3 was not seen in either normal epithelium or tumour.Our preliminary analyses suggest that high-level FOXA1 expression is associated with the development of metastatic prostate cancer. If these data are confirmed, FOXA1 expression could be used to classify patients at higher risk for metastases.

To analyse the expression patterns of GLUT1, p63 and p53 and the possible correlation between these markers in uterine serous papillary carcinoma (USPC) and endometrial intraepithelial carcinoma (EIC).Fourteen cases of USPC, 12 of which also showed EIC, were examined for GLUT1, p63 and p53 immunoreactivity. Four-micrometre sections from formalin-fixed paraffin-embedded tissue were immunostained using commercially available primary antibodies and Dako Envision Plus reagents for visualization. Membranous GLUT1 immunoreactivity was observed in all cases, including all 14 invasive tumours (100%) and 11 of 12 associated EICs (92%), and was confined to neoplastic cells. In USPC, staining tended to be strongest in superficial antistromal regions. p63 positivity was found in 8/14 (57%) USPCs and 9/12 (75%) associated EICs. In 11 cases p53 was overexpressed in both invasive USPC (11/14; 79%) and EIC (11/12; 92%). p53+ USPCs tended to be positive for p63, whereas p53- USPCs were also negative for p63.GLUT1 is expressed in the vast majority of USPC and EIC, suggesting a biological role during the early steps of carcinogenesis in endometrial serous neoplasms. GLUT1 expression may be induced by hypoxia-related as well as other mechanisms.