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BACKGROUND: Renal transplant recipients (RTRs) have a 3- to 5-fold higher risk of developing malignant tumors than the general population, with new malignant tumors after transplantation considered to be the leading cause of death in RTRs. In pathological practice, it is rare for neoplasms with different histology to be located in the same organ. We report the first case of a synchronous papillary renal neoplasm with reverse polarity (PRNRP) and urothelial carcinoma (UC) in the ipsilateral kidney in an RTR. Molecular detection was conducted by next-generation sequencing. CASE PRESENTATION: A 68-year-old female suffered from uremia 19 years ago and underwent renal transplantation (RT) after receiving dialysis for 6 months. Hematuria occurred one month ago and an enhanced CT showed that there were two abnormal density foci in the middle and lower parts of the autologous left kidney. A laparoscopic left nephrectomy and ureterectomy were performed. Gross examination revealed a mass (I) in the left renal parenchyma, 2*1.8*1.5 cm in size, that protruded from the renal capsule, and a cauliflower-like mass (II), 5*2.5*2 cm in size, adjacent to the mass (I). Microscopic findings revealed these lesions were PRNRP and UC, respectively. PCR analysis revealed a KRAS gene mutation (G12D in exon 2) in the PRNRP, while NGS analysis revealed FGFR3 (S249C in exon 7) and KDM6A (Q271Ter in exon 10 and A782Lfs in exon 17) mutations in the UC. CONCLUSIONS: We report here for the first time an extraordinarily rare case of synchronous renal tumors of a PRNRP and UC in the ipsilateral kidney of an RTR. We identified simultaneous KRAS, FGFR3, and KDM6A mutations in two different renal masses in the ipsilateral kidney. Pathologic assessment with comparative molecular analysis of mutational profiles facilitates tumor studies after RT and may be of great value in clinical management strategies.

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Crouzon syndrome with acanthosis nigricans is an autosomal dominant disease, with typical features of classic Crouzon craniosynostosis, verrucous hyperplasia, and hyperpigmentation of the skin. While several mutations in FGFR2 cause classic Crouzon syndrome, Crouzon syndrome with acanthosis nigricans results from a point mutation in the fibroblast growth factor receptor 3 gene (FGFR3). We report the case of an 8-year-old Vietnamese girl diagnosed with Crouzon syndrome with acanthosis nigricans, showing typical clinical features, including a crouzonoid face and dark plaques on the skin. Genetic testing showed a missense variation in FGFR3, associated with Crouzon syndrome with acanthosis nigricans. Following diagnosis, we treated acanthosis nigricans with 10% urea cream. This case study and literature review discuss the cutaneous manifestations and dermatological treatments while demonstrating the importance of clinical examination and evaluation of the patient's medical history during diagnosis. Our findings contribute to the global pool of data, providing practical insights into the manifestations of Crouzon syndrome.

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BACKGROUND: Immunotherapy and FGFR3-targeted therapy play an important role in the management of locally advanced and metastatic bladder cancer (BLCA). Previous studies indicated that FGFR3 mutation (mFGFR3) may be involved in the alterations of immune infiltration, which may affect the priority or combination of these two treatment regimes. However, the specific impact of mFGFR3 on the immunity and how FGFR3 regulates the immune response in BLCA to affect prognosis remain unclear. In this study, we aimed to elucidate the immune landscape associated with mFGFR3 status in BLCA, screen immune-related gene signatures with prognostic value, and construct and validate a prognostic model. METHODS: ESTIMATE and TIMER were used to assess the immune infiltration within tumors in the TCGA BLCA cohort based on transcriptome data. Further, the mFGFR3 status and mRNA expression profiles were analyzed to identify immune-related genes that were differentially expressed between patients with BLCA with wild-type FGFR3 or mFGFR3 in the TCGA training cohort. An FGFR3-related immune prognostic score (FIPS) model was established in the TCGA training cohort. Furthermore, we validated the prognostic value of FIPS with microarray data in the GEO database and tissue microarray from our center. Multiple fluorescence immunohistochemical analysis was performed to confirm the relationship between FIPS and immune infiltration. RESULTS: mFGFR3 resulted in differential immunity in BLCA. In total, 359 immune-related biological processes were enriched in the wild-type FGFR3 group, whereas none were enriched in the mFGFR3 group. FIPS could effectively distinguish high-risk patients with poor prognosis from low-risk patients. The high-risk group was characterized by a higher abundance of neutrophils; macrophages; and follicular helper, CD4, and CD8 T-cells than the low-risk group. In addition, the high-risk group exhibited higher expression of PD-L1, PD-1, CTLA-4, LAG-3, and TIM-3 than the low-risk group, indicating an immune-infiltrated but functionally suppressed immune microenvironment. Furthermore, patients in the high-risk group exhibited a lower mutation rate of FGFR3 than those in the low-risk group. CONCLUSIONS: FIPS effectively predicted survival in BLCA. Patients with different FIPS exhibited diverse immune infiltration and mFGFR3 status. FIPS might be a promising tool for selecting targeted therapy and immunotherapy for patients with BLCA.

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Based on a case report, this review explores the genomic landscape for patients with liposarcomas and possible relationships with gene mutations related to craniosynostosis. We describe the case of a 40-year-old man, known for a surgical correction of craniosynostosis before the age of 1 year, who underwent a radical resection of a voluminous retroperitoneal liposarcoma; histopathological analysis revealed a low-grade well-differentiated, mostly sclerosing, liposarcoma. A genetic analysis searching for mutations in blood DNA was performed and did not detect any specific mutation. A literature review was also conducted. Several tumors related to syndromic and non-syndromic craniosynostosis are mentioned in the literature; no specific link with retroperitoneal liposarcoma is established but the FGFR3 mutation is detected in dedifferentiated liposarcomas. To date, no case has been reported in the literature demonstrating a genetic relationship between craniosynostosis and low-grade differentiated retroperitoneal liposarcoma. We conclude that further studies for gene complex mutations should be conducted to show a possible genetic relationship between retroperitoneal liposarcoma and craniosynostosis.

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Primary spinal cord glioblastoma (PSC GBM) is a rare disease with limited treatment options. Here, we describe a case of PSC GBM treated with anlotinib in this report. Molecular characterization confirmed the presence of the MGMT promoter unmethylated, IDH wild type, FGFR3 p.S249C and p53 p.V73fs mutations in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that target VEGFR2/3, FGFR1-4, PDGFRα/ß, and c-kit. After a partial resection of the tumor at the extramedullary invasion site, the patient was administered anlotinib 12 mg p.o. once every day (days 1-14, 21-day cycle) in combination with irinotecan chemotherapy (days 1 and 8, 21-day cycle). The patient exhibited significant symptom remission and partial response and was maintained for more than 10 months of follow-up. This case study showed that FGFR3 S249C may be a new marker for the treatment of PSC GBM with anlotinib. This case is also another strong support for molecular diagnosis and precision medicine.

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FGFR3 mutations are frequently mutually exclusive of TP53 mutations in invasive high grade urothelial carcinoma (HGUC) and p53 immunohistochemistry is often used as a surrogate for TP53 mutations. A 10 % staining cut off has been used in HGUC for designation as p53 positive or negative however, a novel contemporary method we have previously proposed (0% or >50 % - abnormal vs. 1-49 % - wild type) has shown significant correlation with oncologic outcome as well. We aimed to compare how a ≥10 % vs. 0 % and ≥ 50 % cut off p53 assessment method correlates with TP53 and FGFR3 mutation status. Tissue microarrays created from three retrospective cohorts (two cystectomy cohorts (cohort A, n = 206 and cohort B, n = 91; one T1 transurethral resection cohort (cohort C, n = 47)) were stained with p53 and scored by two blinded reviewers using both p53 scoring schemes. 50 cases from cohort A were assessed for TP53 and FGFR3 mutation status using next generation sequencing and FGFR3 mutation status was separately assessed in cohorts B and C using SNaPshot methodology. 202 (58.7 %) and 142 (41.3 %) cases showed abnormal and wild type p53 staining, respectively. Using the 10 % cut off, 254 cases were positive (73.8 %) and 90 cases were negative (26.2 %). 27 (14.4 %) and 15 (30 %) assessed cases demonstrated FGFR3 and TP53 mutations, respectively; 19/27 FGFR3 mutated showed a wild type pattern of p53 expression while 15/15 TP53 mutated tumours showed an abnormal pattern of p53 expression. There was a significant correlation between the contemporary p53 scoring scheme and TP53 and FGFR3 mutations (p < 0.0001 and p = 0.002, respectively). Improved sensitivity, specificity, positive predictive value, and negative predictive value for TP53 mutation was also seen compared to the 10 % cut off; specifically, the sensitivity and negative predictive value were 100 %. These findings might be of clinical relevance in the era of precision medicine.

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Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.

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OBJECTIVE: The purpose of our research was to determine the usefulness of different methods for detecting Y373C mutation of gene FGFR3. PATIENTS AND METHODS TOTAL: 138 primary bladder cancer patients (71cases G1 and 67 cases G2-G3) were included in the study. Tumor tissue and urine samples were collected and kept frozen until the isolation of DNA. Sanger sequencing was applied for detecting mutation in cancer and ddPCR was utilized for urine assessment. RESULTS: ddPCR appears to be more effective and it identified FGFR3 mutation (Y373C) in urinary sediment in 20.3% of cases whereas Sanger sequencing did in 15.5%. Only in 8/39 (20.5%) cases the mutation was observed both in urine and tissue. In 12/39 (30.8%) cases (5G1 and 7 G2-G3) we did not detect any FGFR3 mutation in urine although it was confirmed by sequencing. We only found mutation in urine in 20/39 cases (15 G1, 5 G2-G3) (51.3%). The correlation between the presence of FGFR3 mutations and better survival was confirmed. The Log-Rank test indicates a significant difference in the likelihood of survival for patients with the FGFR3 mutation but without recurrence (Cox's F-test P = 0.17006; Log-Rank Test P = 0.00059). CONCLUSION: ddPCR appeared to be more sensitive method for detection FGFR3 gene mutation particularly for detecting low levels of tumor DNA amongst a large excess of nontumor DNA. It is significant as the implementation of such markers into routine practice could be beneficial. The prospective study in larger cohort is needed.

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FGFR3 is one of the most frequently mutated genes in bladder cancer and a driver of an oncogenic dependency. Here we report that only the most common recurrent FGFR3 mutation, S249C (TCC→TGC), represents an APOBEC-type motif and is probably caused by the APOBEC-mediated mutagenic process, accounting for its over-representation. We observed significant enrichment of the APOBEC mutational signature and overexpression of AID/APOBEC gene family members in bladder tumors with S249C compared to tumors with other recurrent FGFR3 mutations. Analysis of replication fork directionality suggests that the coding strand of FGFR3 is predominantly replicated as a lagging strand template that could favor the formation of hairpin structures, facilitating mutagenic activity of APOBEC enzymes. In vitro APOBEC deamination assays confirmed S249 as an APOBEC target. We also found that the FGFR3 S249C mutation was common in three other cancer types with an APOBEC mutational signature, but rare in urothelial tumors without APOBEC mutagenesis and in two diseases probably related to aging. PATIENT SUMMARY: We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3 S249C, one of the most common mutations in bladder cancer. Knowledge about the etiology of this mutation will improve our understanding of the molecular mechanisms of bladder cancer.

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Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.

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PURPOSE: To report a case of juvenile xanthogranuloma involving the iris and skin that clincally was diagnosed with an obvious cutaneous lesion. OBSERVATIONS: A four month-old girl with hyphema and increased intraocular pressure of the left eye persisting for 2 weeks. A suspicious yellow-brown mass with nodular surface and traversed by irregular vascularization was noted on the inferior iris surface. Ultrasound biomicroscopy (UBM; 35 MHz) of the mass revealed multiple nodular irregular hyperreflective lesions in the peripheral iris. Using a biopsy of an obvious cutaneous abdominal skin lesion a diagnosis was made based on histopathological analyses. The biopsy showed dense dermal infiltrate consisting of foamy histiocytes. Additional stains revealed CD68 positivity and CD1a and S100 negativity. This mass revealed histopathologic features identical to juvenile xanthogranuloma and was concurrent with the iris lesion. Next-generation sequencing using Ion AmpliSeqTM Cancer Hotspot Panel revealed a missense mutation of FGFR3 (p.F386L). CONCLUSION AND IMPORTANCE: The diagnosis of a xanthogranuloma of the iris with hyphema can be made easier in patients with obvious cutaneous lesions as described in our case. The significance of FGFR3 mutation in association with JXG is unknown and should be further investigated.

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BACKGROUND: Molecular alteration of FGFR3 gene is the most common genetic event currently known in bladder cancer. Notably, FGFR3 mutation has emerged as a promising molecular biomarker for recurrence, prognosis, and therapeutic target in bladder cancer. AIM: The present study explored the frequency and distribution pattern of FGFR3 mutation in 100 Indian bladder cancer patients. METHODS AND RESULTS: Exons 7, 10, and 15 were subjected to nested PCR followed by bidirectional sequencing of the PCR products. Overall, FGFR3 gene mutations were identified in 19 bladder cancer patients (19%, 19 of 100). Most of the mutations were noted in exon 7 (15%), followed by exon 10 (4%). All mutations detected were missense in nature affecting amino acids at codons 248, 249, and 373. The S249C mutations were the most recurrent mutation seen in exon 7, while Y373C was commonly observed in exon 10. In contrast to exons 7 and 10, no mutations were seen in exon 15 in this study. Females and older age patients tend to show increased frequency of FGFR3 mutations. Furthermore, FGFR3 mutations were more common in low pathological stage (6/20 pTa and 13/71 pT1) and low-grade tumors (13/46). This predominance in low-grade tumors were significantly high in comparison to high-grade tumor (P = .04). Likewise, FGFR3 mutations were significantly higher in well-differentiated tumors (32.6%, 14/43) in comparison to moderately differentiated tumors (11.3%, 5/44), and poorly differentiated tumor (0%, 0/13) (P = .007). No other association of FGFR3 with tumor size, necrosis, and variant histology was noted. CONCLUSIONS: The current study highlights the spectrum of FGFR3 mutation in Indian patients, and the data presented here are similar to those reported from across the globe.

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BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes. PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants. RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed. CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.

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AIMS: The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low-grade, non-muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 (FGFR3) mutations are a hallmark of the low-grade pathway, with subsequent progression to muscle invasion occurring when FGFR3 mutant tumours exhibit a homozygous CDKN2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression. METHODS AND RESULTS: We identified retrospectively 29 non-muscle invasive papillary urothelial carcinomas with grade heterogeneity (<20% high grade). Nineteen had sufficient material for immunohistochemistry, CDKN2A fluorescence in-situ hybridization and FGFR3 mutation analysis. Eight pure low-grade urothelial carcinomas (PLGUC) were also analysed. FGFR3 mutation was seen in 10 of 19 cases. A homozygous CDKN2A deletion was identified in the low-grade areas of eight of nine (88%) technically suitable FGFR3 mutant cases (including five pTa cancers), in five of nine FGFR3 wild-type carcinomas and in none of the PLGUC. Increased MIB-1 expression was seen in low-grade areas of 12 of 19, in high-grade areas of 17 of 19 cases with grade heterogeneity and in none of the PLGUC. p53 staining was increased in one of 19 low-grade and seven of 19 high-grade areas. CONCLUSION: Our findings show that grade heterogeneity in urothelial carcinoma is characterized by increased MIB-1 labelling, and particularly in the FGFR3 mutant pathway, with homozygous deletions of CDKN2A in low- and high-grade areas. This would suggest that CDKN2A deletion occurs prior to grade progression and supports the current convention to assign the highest grade to urothelial carcinomas with grade heterogeneity.

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Urothelial cell carcinoma (UCC) includes urothelial bladder carcinoma (UBC), renal pelvic carcinoma (RPC) and ureter carcinoma (UC), and its incidence varies dependent on geographical areas and tumor locations, which indicates different oncogenic mechanisms and/or different genetic susceptibility/environment exposure. The activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene and telomerase reverse transcriptase (TERT) promoter are the most frequent genetic events in UCCs. These mutations have clinical utilities in UCC initial diagnostics, prognosis, recurrence monitoring and management. However, the vast majority of the results are obtained from studies of UCC patients in Western countries, and little has been known about these in Han Chinese patients. In the present study, we screened the FGFR3 gene and TERT promoter for mutations in 116 UBC, 91 RPC and 115 UC tumors from Han Chinese patients by using Sanger Sequencing. TERT promoter mutations occurred at a high frequency in these UCC patients, comparable with that seen in Western patients, however, the FGFR3 mutation was surprisingly lower, only 9.4% for UBCs, 8.8% for RPCs and 2.6% for UCs, respectively. Taken together, the FGFR3 gene is an infrequent target in the pathogenesis of Han Chinese UCCs, and its mutation detection and targeted therapy have limited clinical utility in these patients. Our results underscore the need for extensive characterization of cancer genomes from diverse patient populations, thereby contributing to precision medicine for cancer treatment and prevention.

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Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities due to the above-mentioned entities. All patients manifested significant varus deformity of the lower limbs. Detailed phenotypic characterization, radiologic and genetic testing was carried out as baseline diagnostic tool. We described the re-alignment procedures, which have been applied accordingly. Therefore, bilateral multi-level procedures, multi-apical planning and limb lengthening have been successfully applied. While recognition of the underlying syndromic association in patients who are manifesting angular deformities is the baseline for proper orthopaedic management, this paper demonstrates how to evaluate and treat these complex patients.