ABSTRACT
The landscape of uterine sarcomas is becoming increasingly complex with the description of new entities associated with recurrent molecular alterations. Uterine sarcomas, as well as soft tissue sarcomas, can be distinguished into complex genomic sarcomas and simple genomic sarcomas. Leiomyosarcoma and pleomorphic type undifferentiated uterine sarcoma belong to the first group. Low-grade and high-grade endometrial stromal sarcomas, NTRK, COL1A1::PDGFB, ALK, RET, ROS1 associated sarcomas, and SMARCA4 deficient uterine sarcoma belong to the second group. Leiomyosarcoma is the most common uterine sarcoma followed by endometrial stromal sarcomas. Three different histologic subtypes of leiomyosarcomas are recognized with distinct diagnostic criteria and different clinical outcomes, the myxoid and epithelioid leiomyosarcomas being even more aggressive than the fusiform type. The distinction between low-grade and high-grade endometrial stromal sarcoma is based first on morphology and immunohistochemistry. The detection of fusion transcripts helps in the diagnosis. Definitely recognized as a separate entity, uterine PEComa is a rare tumor whose diagnostic criteria are being recently defined. Uterine PEComa has a specific algorithm stratifying the tumors into uncertain malignant potential and malignant tumors. Embryonal rhabdomyosarcomas of the uterine cervix are not restricted to children but can also be observed in adult women and are almost always DICER1 mutated, unlike embryonal rhabdomyosarcoma of the vagina which are DICER1wild-type, and adenosarcoma which can be DICER1 mutated but with less frequency. As sarcomas associated with fusion transcripts involving the NTRK, ALK, COL1A1::PDGFB genes can benefit from targeted therapy, systematic detection are now relevant especially for patients with high risk of relapse or in recurrent setting. The integration of molecular data with dedicated expert pathology review for histology and clinical data allows better identification of uterine sarcomas in order to better treat them.
Subject(s)
Endometrial Neoplasms , Genital Neoplasms, Female , Leiomyosarcoma , Pelvic Neoplasms , Perivascular Epithelioid Cell Neoplasms , Rhabdomyosarcoma, Embryonal , Sarcoma, Endometrial Stromal , Uterine Neoplasms , Adult , Child , Female , Humans , Leiomyosarcoma/diagnosis , Leiomyosarcoma/genetics , Leiomyosarcoma/pathology , Sarcoma, Endometrial Stromal/diagnosis , Sarcoma, Endometrial Stromal/genetics , Sarcoma, Endometrial Stromal/pathology , Protein-Tyrosine Kinases , Proto-Oncogene Proteins , Neoplasm Recurrence, Local , Uterine Neoplasms/diagnosis , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Receptor Protein-Tyrosine Kinases , DNA Helicases , Nuclear ProteinsABSTRACT
The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.
Subject(s)
DEAD-box RNA Helicases , Endometrial Neoplasms , Genital Neoplasms, Female , Leiomyosarcoma , Rhabdomyosarcoma, Embryonal , Ribonuclease III , Sarcoma, Endometrial Stromal , Soft Tissue Neoplasms , Uterine Cervical Neoplasms , Uterine Neoplasms , Adult , Child , Female , Humans , Leiomyosarcoma/diagnosis , Leiomyosarcoma/genetics , Leiomyosarcoma/therapy , Rhabdomyosarcoma, Embryonal/diagnosis , Rhabdomyosarcoma, Embryonal/genetics , Rhabdomyosarcoma, Embryonal/therapy , Sarcoma, Endometrial Stromal/diagnosis , Sarcoma, Endometrial Stromal/genetics , Sarcoma, Endometrial Stromal/therapy , Protein-Tyrosine Kinases , Proto-Oncogene Proteins , Uterine Neoplasms/diagnosis , Uterine Neoplasms/genetics , Uterine Neoplasms/therapy , Receptor Protein-Tyrosine Kinases , DNA Helicases , Nuclear Proteins , Transcription FactorsABSTRACT
A 17-year-old man was referred with a 6-month history of painless left inferior eyelid edema. Ophthalmic examination was normal except for the presence of a reddish conjunctiva in the left eye medial canthus. MRI demonstrated a 20-mm well-defined extraconical mass between the medial and inferior rectus muscle without destruction of the medial orbital wall. A low-grade myxofibrosarcoma was diagnosed on orbital biopsy. The tumor was locally excised, but the patient categorically refused left exenteration or conformal radiotherapy. He accepted to have annual clinical and radiologic checkup. To date, 2 years later, he has been followed up with no evidence of tumor recurrence. Orbital localization of myxofibrosarcoma is extremely rare, with only 2 cases reported in the literature. The differential diagnosis could be difficult: here, a fibromyxoid sarcoma and a myxoid variant of dedifferentiated liposarcoma have been especially discussed in terms of their histopathologic features. Risk of metastasis is related to the tumor grade. Management of these tumors associates surgery with orbital exenteration or globe-sparing approaches and postsurgical adjuvant radiation therapy.
Subject(s)
Fibrosarcoma/diagnosis , Orbital Neoplasms/diagnosis , Adolescent , Diagnosis, Differential , Humans , MaleABSTRACT
Ewing sarcoma (ES) is a highly malignant round cell sarcoma, characterized by gene fusion involving FET (FUS, EWSR1, TAF15) and ETS family genes, respectively. The involvement of the EWSR1 gene has been reported in approximately 90% of cases of ES, with the EWSR1::FLI1 fusion being the most frequent. We report the case of a newborn with a localized soft tissue paravertebral neoplasm diagnosed prenatally. Histopathology and immunophenotype were consistent with a CD99 + , NKX2.2 + undifferentiated round cell sarcoma (URSC); whole-exome RNA-sequencing demonstrated an undescribed in-frame TAF15::ETV4 fusion transcript, while consensus clustering analysis showed high transcriptomic proximity to the ES group. Given clinical context, high tumor chemosensitivity to ES conventional drugs, morphological characteristics, nature of the fusion partners involved, and high transcriptomic proximity to bona fide ESs, this case may represent a new genetic variant of ES.
Subject(s)
Sarcoma, Ewing , Sarcoma , Soft Tissue Neoplasms , TATA-Binding Protein Associated Factors , Gene Fusion , Humans , Infant, Newborn , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins c-ets/genetics , RNA , RNA-Binding Protein EWS/genetics , Sarcoma/genetics , Sarcoma, Ewing/diagnosis , Sarcoma, Ewing/genetics , Sarcoma, Ewing/pathology , Soft Tissue Neoplasms/pathology , TATA-Binding Protein Associated Factors/genetics , Translocation, GeneticABSTRACT
OBJECTIVE: To assess transforming growth factor ß-receptor II (TGFBRII) protein expression in benign prostatic hyperplasia (BPH) using immunohistochemistry analysis, and to compare the analysis with phenotypic properties. METHODS: TGFBRII protein expression was profiled using three clinical outcome tissue microarrays (TMAs), sampled from 231 patients who underwent surgery for BPH. Using these TMAs, five inflammatory cell markers were also assessed, including CD3, CD4, CD8, CD20, and CD163. The surgical procedure was open prostatectomy in 95 patients and transurethral resection of the prostate in 136 patients. RESULTS: TGFBRII protein expression was found in BPH epithelium cells for both basal and secretory cells, as well as in fibromuscular stromal cells. TGFBRII staining was also strong in most of the lymphocytes infiltrating the prostate. TGFBRII stromal staining was found to be significantly associated with prostate volume (P = 0.04), whereas TGFBRII epithelial staining was found to be significantly associated with 5-α-reductase-inhibitor medical therapy received by patients before surgery (P = 0.004). Both stromal and epithelial TGFBRII staining were found to be associated with CD4 T-lymphocyte infiltrate, independently of prostate volume (P < 0.001 and P = 0.002). CONCLUSIONS: TGFBRII protein expression in BPH is associated with prostate gland volume and with CD4 T-lymphocyte prostatitis. TGFBRII might be a promising therapeutic target to prevent prostate enlargement or even to decrease prostate volume.
Subject(s)
Prostate/pathology , Prostatic Hyperplasia/metabolism , Protein Serine-Threonine Kinases/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Aged , Aged, 80 and over , Antigens, CD/metabolism , Antigens, CD20/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , CD3 Complex/metabolism , CD4 Antigens/metabolism , CD8 Antigens/metabolism , Epithelial Cells/chemistry , Humans , Lymphocytes/chemistry , Male , Middle Aged , Phenotype , Prostate/chemistry , Prostatectomy , Prostatic Hyperplasia/pathology , Receptor, Transforming Growth Factor-beta Type II , Receptors, Cell Surface/metabolism , Stromal Cells/chemistry , Transurethral Resection of ProstateABSTRACT
A novel histomolecular tumor of the central nervous system, the "intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive" has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient's death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology "IMT, FET-CREB fusion-positive", and that further series of cases are needed to better characterize them.
Subject(s)
Brain Neoplasms/genetics , Cyclic AMP Response Element Modulator/genetics , Neoplasms, Second Primary/genetics , Oncogene Proteins, Fusion/genetics , Transcription Factors/genetics , Adult , Fatal Outcome , Humans , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Neoplasms, Second Primary/pathologyABSTRACT
BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
Subject(s)
Sarcoma/epidemiology , Sarcoma/pathology , Adolescent , Adult , Aged , Female , France/epidemiology , Humans , Incidence , Male , Middle Aged , Neoplasm Grading , Prospective Studies , Sarcoma/classification , Sarcoma/diagnosis , World Health Organization , Young AdultABSTRACT
In glial tumors, the loss of heterozygosity of the 1p and 19q chromosomal arms is thought to be a marker of good prognosis in oligodendroglial tumors. However, 1p and 19q loss of heterozygosity may be telomeric, interstitial, centromeric or affect the whole arm of the chromosome and the associations between these different patterns and tumor type, other molecular markers and patient prognosis remain unclear. We analyzed microsatellite markers in a region spanning the chromosome from the telomere to the centromere, to characterize the pattern of 1p and 19q loss of heterozygosity in 39 infiltrative gliomas, including astrocytomas, glioblastomas, oligoastrocytomas and oligodendrogliomas. We then studied the association between loss of heterozygosity and the expression of p53 protein and Olig2, as analyzed using immunohistochemistry, and epidermal growth factor receptor (EGFR) gene amplification, as investigated using fluorescence in situ hybridization (FISH). Finally, we assessed the influence of molecular markers on the overall survival of patients. We identified five different 1p19q loss of heterozygosity patterns among the tumors studied and found that loss of heterozygosity over the whole 1p arm was associated with loss of heterozygosity over the whole 19q arm in 90% of cases. 1p19q whole loss was present in all the classical oligodendrogliomas, whereas other 1p19q loss patterns predominated in oligoastrocytomas. 1p19q whole loss was also significantly associated with Olig2 overexpression, but was never observed in tumors overexpressing p53 protein. We also found that, among patients with contrast-enhancing tumors, those with 1p19q whole loss tended to survive for longer. In combination with classical histological and immunohistochemical data, 1p19q status determination provides pertinent information useful for (1) discriminating between histological types of gliomas and (2) identifying a subgroup of tumors that are associated with a better prognosis.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Glioma/genetics , Nerve Tissue Proteins/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/genetics , ErbB Receptors/genetics , Female , Gene Amplification , Glioma/mortality , Glioma/pathology , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Kaplan-Meier Estimate , Loss of Heterozygosity , Male , Microsatellite Repeats , Middle Aged , Oligodendrocyte Transcription Factor 2 , Polymerase Chain Reaction , PrognosisABSTRACT
Pericytic tumors encompass several entities sharing morphologic and immunohistochemical features. A subset of perivascular myoid tumors associated with the SRF-RELA fusion gene was previously described. Herein, we report a series of 13 tumors belonging to this group, in which we have identified new fusion genes by RNA-sequencing, thus expanding the molecular spectrum of this entity. All patients except 1 were children and infants. The tumors, frequently located in the head (n=8), had a mean size of 38 mm (range 10 to 150 mm) and were mostly (n=9) well-circumscribed. Exploration of the follow-up data (ranging from 3 to 68 mo) confirmed the benign behavior of these tumors. These neoplasms presented a spectrum of morphologies, ranging from perivascular patterns to myoid appearance. Tumor cells presented mitotic figures but without marked atypia. Some of these tumors could mimic sarcoma. The immunohistochemical profiles confirmed a pericytic differentiation with the expression of the smooth muscle actin and the h-caldesmon, as well as the frequent positivity for pan-cytokeratin. The molecular analysis identified the expected SRF-RELA fusion gene, in addition to other genetic alterations, all involving SRF fused to CITED1, CITED2, NFKBIE, or NCOA2. The detection of SRF-NCOA2 fusions in spindle cell rhabdomyosarcoma of the infant has previously been described, representing a risk of misdiagnosis, although the cases reported herein did not express MyoD1. Finally, clustering analyses confirmed that this group of SRF-fused perivascular myoid tumors forms a distinct entity, different from other perivascular tumors, spindle cell rhabdomyosarcomas of the infant, and smooth muscle tumors.
Subject(s)
Biomarkers, Tumor/genetics , Gene Fusion , Neoplasms, Connective and Soft Tissue/genetics , Serum Response Factor/genetics , Transcription Factor RelA/genetics , Adolescent , Aged , Apoptosis Regulatory Proteins/genetics , Child , Child, Preschool , England , Female , France , Humans , I-kappa B Proteins/genetics , Male , Neoplasms, Connective and Soft Tissue/pathology , Nuclear Receptor Coactivator 2/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Trans-Activators/geneticsABSTRACT
In view of the important oncogenic action of phospholipase A(2)(PLA(2)) we investigated PLA(2) transcripts in human meningiomas. Real-time PCR was used to investigate PLA(2) transcripts in 26 human meningioma tumors. Results indicated that three Ca(2+)-dependent high molecular weight PLA(2) (PLA(2)-IVA, PLA(2)-IVB, PLA(2)-IVC), one Ca(2+)-independent high molecular weight PLA(2) (PLA(2)-VI) and five low molecular weight secreted forms of PLA(2) (PLA(2)-IB, PLA(2)-IIA, PLA(2)-III, PLA(2)-V, and PLA(2)-XII) are expressed with PLA(2)-IVA, PLA(2)-IVB, PLA(2)-VI, and PLA(2)-XIIA as the major expressed forms. PLA(2)-IIE, PLA(2)-IIF, PLA(2)-IVD, and PLA(2)-XIIB are not detected. Plasma (PLA(2)-VIIA) and intracellular (PLA(2)-VIIB) platelet-activating factor acetylhydrolase transcripts are expressed in human meningiomas. However no difference was found for PLA(2) transcript amounts in relation to the tumor grade, the subtype of meningiomas, the presence of inflammatory infiltrated cells, of an associated edema, mitosis, brain invasion, vascularisation or necrosis. In conclusion numerous genes encoding multiples forms of PLA(2) are expressed in meningiomas where they might act on the phospholipid remodeling and on the local eicosanoid and/or cytokine networks.
Subject(s)
Meningeal Neoplasms/genetics , Meningeal Neoplasms/metabolism , Meningioma/genetics , Meningioma/metabolism , Phospholipases A2/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Female , Humans , Inflammation Mediators/metabolism , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Phospholipases A2/classification , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND: Lipomatous meningioma is a rare but, most of the time, benign tumor. Its pathogenesis is still debated: it is usually considered to be part of the metaplastic meningioma, but several authors recently suggested that fat accumulation inside the tumor was related to metabolic disorders of the meningothelial cells. CASES DESCRIPTION: We report 2 cases of lipomatous meningioma. Both patients were women older than 60 years. One patient suffered from headache and seizures, the other one presented with behavioral disturbance. Radiological features depended on the amount of fat accumulation within the tumor. Surgical treatment allowed complete resection in both cases without any complications. Both meningiomas were of transitional-type and were apparently composed of 2 populations of cells: meningothelial cells and lipid-laden cells resembling mature adipocytes. Immunohistochemical study showed that lipid-laden cells expressed EMA, CD99, and progesteron receptor, favoring a meningothelial differentiation rather than an adipocytic lineage. CONCLUSION: Our study strongly suggests that lipomatous meningioma results from an accumulation of lipid inside meningothelial cells rather than a true metaplasia.
Subject(s)
Meningeal Neoplasms/pathology , Meningioma/pathology , Female , Humans , Lipids , Meningeal Neoplasms/surgery , Meningioma/surgery , Middle AgedABSTRACT
In France, determination of the mutation status of RAS genes for predictive response to anti-EGFR targeted treatments is carried out by public platforms of molecular biology of cancer created by the French National Cancer Institute. This study aims to demonstrate the feasibility of these analyses by a private pathology laboratory (MEDIPATH) as per the requirements of accreditation. We retrospectively studied the mutation status of KRAS and NRAS genes in 163 cases of colorectal metastatic cancer using the Cobas® technique. We compared our results to those prospectively obtained through pyrosequencing and allelic discrimination by the genetic laboratory of solid tumors at the Nice University Hospital (PACA-EST regional platform). The results of both series were identical: 98.7% positive correlation; negative correlation of 93.1%; overall correlation of 95.7% (Kappa=0.92). This study demonstrates the feasibility of molecular analysis in a private pathology laboratory. As this practice requires a high level of guarantee, its accreditation, according to the NF-EN-ISO15189 quality compliance French standard, is essential. Conducting molecular analysis in this context avoids the steps of routing the sample and the result between the pathology laboratory and the platform, which reduces the overall time of rendering the result. In conclusion, the transfer of some analysis from these platforms to private pathology laboratories would allow the platforms to be discharged from a part of routine testing and therefore concentrate their efforts to the development of new analyses constantly required to access personalized medicine.
Subject(s)
Accreditation , Colorectal Neoplasms/genetics , DNA Mutational Analysis/methods , Genes, ras , Laboratories, Hospital/standards , Mutation , Colorectal Neoplasms/pathology , DNA Mutational Analysis/economics , DNA Mutational Analysis/standards , ErbB Receptors/antagonists & inhibitors , Exons , Feasibility Studies , France , Humans , Laboratories, Hospital/economics , Prospective Studies , Reproducibility of Results , Retrospective StudiesABSTRACT
IMPORTANCE: Cetuximab was recently proposed for advanced cutaneous squamous cell carcinomas (cSCC); however, its efficacy is inconsistent and identification of predictive biomarkers for response is necessary. OBJECTIVE: To search for somatic mutations of the HRAS, KRAS, NRAS, BRAF, and EGFR genes in patients with advanced cSCC treated with cetuximab; and to investigate the efficacy and tolerance of cetuximab according to these mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicentric and retrospective study of 31 patients (22 men, 9 women) with histologically confirmed advanced cSCC carried out in 1 department of dermatology and 2 departments of medical oncology in France between January 2008 and December 2014. The median age of participants was 86 years (range, 48-96 years). INTERVENTIONS: Mutational status was determined by pyrosequencing method, allelic discrimination, or Sanger sequencing. Patients were treated by single-agent cetuximab. MAIN OUTCOMES AND MEASURES: The primary end point was the incidence of somatic mutations of the RAS, BRAF, and EGFR genes and association of cetuximab efficacy with these mutations was investigated by using Fisher test. Secondary end points were the disease control rate (DCR) at week 6, the progression free-survival (PFS), overall survival (OS), and safety profile of cetuximab. RESULTS: Thirty-one samples of cSCC from 31 patients were analyzed. Only 2 RAS mutated samples (6.5%) were identified. The first harbored a NRAS point mutation (c.35G>A) in codon 12, resulting in a p.G12D substitution. The second sample presented a HRAS point mutation (c.38G>T) in codon 13, resulting in a p.G13V substitution. No mutation of KRAS, BRAF, and EGFR genes at the investigated loci was found. Two patients with NRAS and HRAS mutations showed a partial and complete response to cetuximab, respectively. The mean duration of follow-up was 19 months. At week 6, the disease control rate was 67.8%. The median OS was 13 months and the median PFS was 9 months. All patients could continue cetuximab treatment without dose reduction. CONCLUSIONS AND RELEVANCE: Even in elderly patients with advanced cSCC, cetuximab was efficacious and well-tolerated. This suggests that cetuximab is certainly warranted in the treatment of advanced cSCC. However, it is also important to identify tumor specific mutations that may determine response to treatment and prognosis for the disease. We have identified here that the incidence of RAS, BRAF, and EGFR mutations is low in cSCC.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Cetuximab/administration & dosage , Skin Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cetuximab/adverse effects , Disease-Free Survival , ErbB Receptors/genetics , Female , Follow-Up Studies , France , Genes, ras/genetics , Humans , Male , Middle Aged , Mutation , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Survival Rate , Treatment OutcomeABSTRACT
The scientific usefulness of the molecular data obtained from tissue analysis is related directly to the quality of the tissue specimen. The most ideal tissue specimen is the one that carries a complete and unaltered representation of the tissue in vivo. The aim of this review is to provide an overview of the effects of fixation and tissue processing on the content and integrity of nucleic acid and proteins.
Subject(s)
DNA/analysis , Fixatives , Pathology/methods , Proteins/analysis , RNA/analysis , Cryopreservation , Freeze Drying , Humans , Lymph Nodes/pathology , Molecular Biology/methodsABSTRACT
Severe leptospirosis usually associates shock, jaundice, renal failure, and thrombocytopenia. Massive hemoptysis due to diffuse alveolar haemorrhage may rarely occur leading to an acute respiratory failure and multiple organ failure. We present the case of an acute respiratory distress syndrome caused by a severe leptospirosis. The severity of the respiratory failure contrasted with the absence of significant liver or renal dysfunction. Bedside open lung biopsy was only consistent with a postinfectious BOOP. The diagnosis was retrospective when the niece of the patient presented with similar inaugural symptoms ten days later after being scratched by a wild rat which was considered by our patient as a pet.
ABSTRACT
BACKGROUND: Gliomas are tumors of the central nervous system derived from glial cells. They show cellular heterogeneity and lack specific diagnostic markers. Although a possible role for the eicosanoid cascade has been suggested in glioma tumorigenesis, the relationship between enzymes and receptors implicated in arachidonic acid metabolism, with histological tumor type has not yet been determined. DESIGN AND METHODS: Quantitative real-time reverse transcription-polymerase chain reaction was performed to measure and compare transcript levels of enzymes and receptors implicated in both lipoxygenase and cyclooxygenase pathways between oligodendrogliomas, astrocytomas, glioblastomas and mixed oligoastrocytomas. RESULTS: Arachidonic acid metabolism-related enzymes and receptor transcripts (i) were underexpressed in classical oligodendrogliomas compared to astrocytomas and/or glioblastomas, (ii) differed between astrocytomas and glioblastomas and (iii) had an intermediate expression in mixed oligoastrocytomas. CONCLUSIONS: mRNA levels of enzymes and receptors implicated both in lipoxygenase and cyclooxygenase pathways differed significantly in gliomas according to the histological type.
Subject(s)
Arachidonic Acid/metabolism , Central Nervous System Neoplasms/metabolism , Glioma/metabolism , Lipoxygenase/genetics , Prostaglandin-Endoperoxide Synthases/genetics , RNA, Messenger/analysis , Receptors, Prostaglandin/genetics , Adult , Aged , Central Nervous System Neoplasms/diagnosis , Female , Glioma/diagnosis , Humans , Lipoxygenase/metabolism , Male , Middle Aged , Prostaglandin-Endoperoxide Synthases/metabolism , RNA, Messenger/genetics , Receptors, Prostaglandin/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Distinguishing hemangioblastomas from metastatic clear-cell renal cell carcinomas (CCRCCs) in the brain is a diagnostic challenge owing to similar clinical and morphologic presentations. Inhibin-alpha and aquaporin1 were shown as positive markers of hemangioblastoma, but are not totally reliable distinguishing hemangioblastoma from metastatic CCRCC. This study shows that the diagnosis can be achieved using a combination of markers. To identify the panel of markers useful for this differential, 67 hemangioblastomas and 34 metastatic CCRCCs were analyzed using a panel of antibodies including aquaporin1, inhibin-alpha, D2-40, cytokeratin AE1/AE3, epithelial membrane antigen, and CD10. The study confirms the usefulness of aquaporin1 (97% sensitivity, 83% specificity) and inhibin-alpha (88% sensitivity, 79% specificity) as positive markers of hemangioblastoma and shows that aquaporin1 is a superior positive marker versus inhibin-alpha for the differential. Positivity of tumor cells with cytokeratin AE1/AE3 is the signature of a metastatic CCRCC (100% specificity, 88% sensitivity) and CD10 expression as well (100% specificity, 79% sensitivity). The combined use of aquaporin1 and AE1/AE3 yields a high degree of sensitivity and specificity to differentiate between hemangioblastoma and metastatic CCRCC. All tumors but one aquaporin1 positive and cytokeratin AE1/AE3 negative (65/66) correspond to hemangioblastomas (97% sensitivity, 97% specificity, 98.5% diagnostic positive predictive value). Tumors with the opposite profile, aquaporin1 negative, and cytokeratin AE1/AE3 positive, (25/25), correspond to metastatic CCRCC (74% sensitivity, 100% specificity, 100% diagnostic positive predictive value). In summary, aquaporin1 is the most sensitive positive marker of hemangioblastoma. Despite its moderate specificity, when used in combination with epithelial marker AE1/AE3, it allowed to reliably distinguish hemangioblastoma from metastatic CCRCC.
Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/diagnosis , Carcinoma, Renal Cell/diagnosis , Hemangioblastoma/diagnosis , Kidney Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Aquaporin 1/analysis , Brain Neoplasms/chemistry , Brain Neoplasms/secondary , Carcinoma, Renal Cell/chemistry , Carcinoma, Renal Cell/secondary , Child , Diagnosis, Differential , Female , Hemangioblastoma/chemistry , Humans , Keratins/analysis , Male , Middle AgedABSTRACT
OBJECTIVE: Angioleiomyomas are soft tissue tumors with smooth muscle and vascular components. They are extremely rare in intracranial locations and only three cases have been reported in the literature, including one in the cavernous sinus. Furthermore, long-term follow-up after surgery for a tumor at this site has not been described. We report a new case of intracavernous angioleiomyoma with complete surgical removal and no recurrence after 6 years of clinical and radiological follow-up. CLINICAL PRESENTATION: A 50-year-old patient presented with vertical diplopia resulting from left trochlear nerve palsy. Magnetic resonance examination showed a left intracavernous tumor with hypersignal on T2-weighted images, hyposignal on T1-weighted images, and delayed homogeneous enhancement after gadolinium injection. INTERVENTION: Surgical treatment was completed by a left pterional approach. There was a clear plane separating the tumor from the vascular and nervous elements of the cavernous sinus. Complete tumor resection was achieved. Diplopia improved after surgery. Follow-up did not reveal any recurrence. CONCLUSION: Angioleiomyomas are rare benign tumors with an excellent prognosis after total removal that justifies surgical treatment as the first-line treatment.