Search

Aims: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear., Methods: We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data., Results: TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases., Conclusion: TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours., (© 2022 John Wiley & Sons Ltd.)

Aims: Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphological criteria, and has not been updated since 1988. The objective of this study was to explore the prognostic potential of the Ki67 proliferation index (PI) and tumour-infiltrating lymphocytes (TILs) in ONB., Methods and Results: A retrospective study was conducted on a bicentric series of 45 cases. The Ki67 PI was determined by counting at least 1000 nuclei on whole slides. TILs were evaluated with CD20, CD4 and CD8 immunohistochemical markers on whole slides. In this series, Hyams grades I, II, III and IV accounted for 13.4%, 44.4%, 20% and 22.2% of all cases, respectively. The Ki67 PI ranged from 1 to 93; the Ki67 PI was significantly higher in Hyams grade III-IV ONBs than in Hyams grade I-II ONBs (P < 0.0001). A Ki67 PI of ≥25 was associated with poorer survival (P = 0.02). TILs were present in both stromal and intratumoral compartments, but were located predominantly in the stromal component of the tumour. The numbers of intratumoral CD8+ cells/mm 2 and CD4+ cells/mm 2 were greater in high-grade ONBs than in low-grade ONBs (P = 0.0015 and P = 0.043, respectively). The numbers of T cells/mm 2 and B cells/mm 2 were not associated with survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.04)., Conclusion: Our findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade., (© 2019 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Aims: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC., Methods and Results: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes)., Conclusions: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal., (© 2017 John Wiley & Sons Ltd.)

Aims: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney tumour characterized by translocations involving the transcription factor TFE3 or TFEB. tRCC was introduced into the World Health Organization classification in 2004, but much is still unknown about the natural history, clinicopathological features and outcomes of the disease. The aim of this study was to describe the landscape of fusion transcript in a large single-institution series of fluorescence in-situ hybridization (FISH)-confirmed tRCCs and then to compare it to morphological and clinical data., Methods and Results: Paired-end RNA sequencing was performed within a prospective database of the Department of Pathology, Centre Hospitalier Régional Universitaire (Lille, France). The diagnosis of tRCC was confirmed by FISH. Among a total of 1130 identified renal cell carcinomas, 21 cases (1.9%) showed rearrangement of the TFE3 (n = 20) or (TFEB) (n = 1) gene. Median patient age was 31 years (range = 15-47), and the female-to-male ratio was 6:1. Five different TFE3 fusion transcripts were identified; the most frequent TFE3 partners were PRCC (n = 4) and SFPQ (n = 4). The other partners involved were ASPCR1 (n = 1) and MED15 (n = 1) genes as well as a novel TFE3 partner, GRIPAP1., Conclusions: We identified a new fusion partner, GRIPAP1. The prognostic role of transcript type could not be determined because our number of cases was too small. Four patients (19%) died of the disease, all of which presented with a lymph node involvement at diagnosis. We confirm that tRCC can be an aggressive tumour, especially those of advanced clinical stage., (© 2017 John Wiley & Sons Ltd.)

Aims: Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression., Methods and Results: The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal, with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10-72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases., Conclusion: CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour., (© 2013 John Wiley & Sons Ltd.)

Aims: SALL4 is a marker of germ cell tumours. The aim of this study was to investigate SALL4 expression in blastemal tumours, particularly in hepatoblastoma., Methods and Results: The study included 12 hepatoblastomas. Eight hepatoblastomas were pure epithelial tumours, and four were mixed epithelial and mesenchymal tumours. The patients were nine males and three females with a mean age of 14.6 months. Immunohistochemistry was performed with an antibody against SALL4, using an automated immunostainer. Seven of 12 hepatoblastomas showed nuclear staining only in the embryonal component. Fetal and mesenchymal components were negative., Conclusions: SALL4 is expressed in blastemal tumours, particularly in the embryonal subtype of hepatoblastoma. Pathologists need to be aware of such expression so that misdiagnosis can be avoided., (© 2013 John Wiley & Sons Ltd.)

Aims: This study tests the hypothesis that histopathological fingerprinting of galectins, which are emerging multifunctional effectors in cell sociology, could refine the differential diagnosis of salivary tumours., Methods and Results: We applied non-crossreactive polyclonal antibodies against galectin-1 (Gal-1), galectin-3 (Gal-3), galectin-7 (Gal-7) and galectin-8 (Gal-8) for immunohistochemical analysis of salivary gland tumours (72 cases with benign disease and 39 cases with malignancy) and 29 control specimens. The principal positivity of cases, the site of signal presence and the quantitative parameters concerning percentage of positive cells and labelling intensity were determined. Acinic cell and adenoid cystic carcinomas (specifically tubular and cribriform types) shared the expression signature of Gal-1, Gal-3 and Gal-8 presence combined with Gal-7 absence. Mucoepidermoid carcinomas presented a unique profile based on cytoplasmic Gal-1, Gal-3, Gal-7 and Gal-8 localization in the intermediate cells. Adenomas were separable from malignancy by a consistent decrease in the labelling index (LI) for Gal-7 and Gal-8 (LI Gal-7, P<10(-6) ; LI Gal-8, P=0.001). When present, staining for the tumour suppressor p16(INK4a) coincided with Gal-1 presence., Conclusions: Expression profiling of the four tested galectins in salivary gland tumours revealed non-uniform staining patterns with discriminatory potential based on intracellular localization and quantitative aspects., (© 2011 Blackwell Publishing Limited.)

Aims: In kidney cancer, new anti-angiogenic therapies have emerged requiring parameters of effectiveness. The aim was to analyse the expression of endocan or endothelial cell-specific molecule-1, which is a proteoglycan up-regulated in presence of pro-angiogenic factors., Method and Results: We investigated 44 renal clear cell carcinomas (RCC) and 25 papillary carcinomas (PC). Circulating endocan was detected by enzyme-linked immunosorbent assays (ELISA) in 14 patients with RCC, in eight with PC and in 15 healthy volunteers. Endocan was detected by immunohistochemistry in endothelial cells in almost all the cases of RCC without immunoreactivity in tumour cells. In PC, only 5/25 tumours exhibited weak immunoreactivity. Reverse transcriptase-polymerase chain reaction study confirmed that endocan levels were strongly increased in RCC. Endocan was also detected by ELISA at levels from 3- to 10-fold higher in the sera of patients with RCC. In vitro, addition of sunitinib prevented the release of endocan in human umbilical vascular endothelial cells when induced by vascular endothelial growth factor., Conclusions: Our results showed that endocan is overexpressed in patients with RCC. Endocan could therefore appear as a marker of interest in the follow-up and may be a potential parameter to monitor the tumour response to anti-angiogenic therapeutics.

Aims: To examine the immunohistochemical expression of helicase-like transcription factor (HLTF) in relation to the prognosis of hypopharyngeal (HSCCs) and laryngeal (LSCCs) squamous cell carcinomas, and to characterize the HLTF protein variants expressed in biopsy specimens of head and neck squamous cell carcinoma (HNSCC) as well as the HeLa cell line., Methods and Results: HLTF expression was determined by immunohistochemistry on a series of 100 hypopharyngeal (stage IV) and 56 laryngeal SCCs (stages I, II and IV). The HLTF variants were defined using reverse transcriptase-polymerase chain reaction and Western blots in 13 fresh HNSCC biopsies and in HeLa cells. High levels of HLTF expression were associated with rapid recurrence rates in a subgroup of 81 stage IV hypopharyngeal SCCs (with complete follow-up). A 95-kDa HLTF variant truncated at the carboxyl-terminal domain was detected in addition to the 115-kDa full-size protein in HNSCC biopsies, while six variants were observed in HeLa cells., Conclusions: Our results demonstrate, for the first time, that hypopharyngeal SCCs presenting high levels of HLTF have a worse prognosis. The quantitative determination of HLTF in hypopharyngeal SCCs was an independent prognostic marker alongside tumour node metastasis staging. HNSCCs expressed the truncated HLTF variant lacking the domains involved in DNA repair.

Aims: To examine the level of expression of the pleiotropic regulators galectins-1 and -7 in relation to neoplastic progression of hypopharyngeal (HSCCs) and laryngeal (LSCCs) squamous cell carcinomas., Methods and Results: The presence of galectins-1 and -7 was investigated using quantitative immunohistochemistry in (i) a series of 78 HSCCs by comparison with 17 normal epithelia (N&#95;E), 26 low-grade dysplasia (low&#95;D) and 27 high-grade dysplasia (high&#95;D) and (ii) a series of 56 LSCCs by comparison with 50 N&#95;E, 23 low&#95;D and 29 high&#95;D. Galectin-1 positivity expressed as a percentage of cells was significantly higher in carcinomas (HSCCs and LSCCs) than in N&#95;E, low&#95;D or high&#95;D (P < 10(-6)). Galectin-7 expression was elevated in low&#95;D (P = 0.0004) compared with N&#95;E and in carcinomas (HSCC) compared with high&#95;D (P = 0.0002). Tumour progression from high&#95;D to carcinomas was associated with a shift of galectin-1 localization from the nucleus towards the cytoplasm. Increased expression of galectin-7 in dysplasias was accompanied by a shift from the cytoplasmic compartment (N&#95;E) to the nucleus (low&#95;D and high&#95;D)., Conclusions: Our data reveal an association between the level of presence of galectins-1 and -7 and neoplastic progression of HSCCs and LSCCs. Moreover, inverse shifts between nuclear and cytoplasmic positivity intimating functional divergence were detected.

Aims: Human mucins are large O-glycoproteins expressed by epithelial cells. Mucins are thought to be implicated in cell protection, cell adhesion and signalling. The aim of this study was to investigate the expression of the human mucin genes (MUC1-4, 5AC, 5B, 6-7) in normal kidney and renal cell carcinoma., Methods and Results: We analysed by in-situ hybridization, immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of these genes in normal adult kidney (n=14) and renal cell carcinomas (n=29). MUC1, MUC3 and MUC6 were expressed both in normal kidney and in renal carcinomas. In normal kidney, MUC1 was expressed in the distal convoluted tubules and in collecting ducts, whereas MUC3 was restricted to the proximal tubules. MUC4 was strongly expressed in epithelial urothelial cells of pyelocalyceal cavities. MUC6 was only detected by RT-PCR. In renal carcinoma, we showed a heterogeneous expression of MUC1 and MUC3 with an over-expression of MUC3 in renal clear cell carcinoma. The level of MUC3 expression by in-situ hybridization was associated with the nuclear grade in clear cell carcinoma., Conclusions: This study is the first large series investigating human mucin gene expression in the kidney. MUC1, MUC3 and MUC6 are expressed in normal and tumour kidney. The over-expression of MUC3 in renal cell carcinomas favours its implication in renal tumorigenesis.